wikidoc - User contributions [en]

Cardiac allograft vasculopathy laboratory findings

2014-12-28T20:24:29Z

Aarti Narayan:

__NOTOC__
{{Cardiac allograft vasculopathy}}
{{CMG}} {{AE}} {{AN}} {{RT}}

==Overview==
Multiple biomarkers such as [[C-reactive protein]], [[von Willebrand factor]] and [[NT-pro-BNP]] are used to predict all cause mortality in patients with CAV. Elevated levels of each of these biomarkers signify increased risk of developing CAV. Further research is warranted to help identify the role of biomarkers in diagnosing and predicting CAV<ref name="pmid17519779">{{cite journal| author=Arora S, Gullestad L, Wergeland R, Simonsen S, Holm T, Hognestad A et al.| title=Probrain natriuretic peptide and C-reactive protein as markers of acute rejection, allograft vasculopathy, and mortality in heart transplantation. | journal=Transplantation | year= 2007 | volume= 83 | issue= 10 | pages= 1308-15 | pmid=17519779 | doi=10.1097/01.tp.0000263338.39555.21 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17519779 }} </ref>.

==References==
{{reflist|2}}
{{WH}}
{{WS}}

Cardiac allograft vasculopathy laboratory findings

2014-12-28T20:23:13Z

Aarti Narayan: Created page with "__NOTOC__ {{Cardiac allograft vasculopathy}} {{CMG}} {{AE}} {{AN}} {{RT}} ==Overview== Multiple biomarkers like C-reactive protein, von Willebrand factor and NT-pro..."

__NOTOC__
{{Cardiac allograft vasculopathy}}
{{CMG}} {{AE}} {{AN}} {{RT}}

==Overview==
Multiple biomarkers like [[C-reactive protein]], [[von Willebrand factor]] and [[NT-pro-BNP]] are used to predict all cause mortality in patients with CAV. Elevated levels of each of these biomarkers signify increased risk of developing CAV. Further research is warranted to help identify the role of biomarkers in diagnosing and predicting <ref name="pmid17519779">{{cite journal| author=Arora S, Gullestad L, Wergeland R, Simonsen S, Holm T, Hognestad A et al.| title=Probrain natriuretic peptide and C-reactive protein as markers of acute rejection, allograft vasculopathy, and mortality in heart transplantation. | journal=Transplantation | year= 2007 | volume= 83 | issue= 10 | pages= 1308-15 | pmid=17519779 | doi=10.1097/01.tp.0000263338.39555.21 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17519779 }} </ref>.

==References==
{{reflist|2}}
{{WH}}
{{WS}}

Cardiac allograft vasculopathy optical coherence tomography

2014-12-28T20:03:57Z

Aarti Narayan: /* References */

__NOTOC__
{{Cardiac allograft vasculopathy}}
{{CMG}}; {{AE}} {{AN}}; {{RT}}

==Overview==
In 2010, U.S [[FDA]] approved coronary optical cohorence tomography (OCT) as a new catheter based intra-vascular imaging modality with a resolution higher than [[intravascular ultrasound]] ([[IVUS]]). OCT uses near infra-red light and constructs images from the reflected light which is in the same phase (i.e cohorent) with the emitted light. This eliminated the interference from scattered light, thereby producing images with higher resolution.

==Coronary Optical Cohorence Tomography==
===Advantages===
* Allows rapid imaging of coronaries with a higher radial resolution.
* Detects more subtle changes in the intima-media thickness compared to IVUS in patients with early CAV.
* Accurate plaque characterization<ref name="pmid23499356">{{cite journal| author=Khandhar SJ, Yamamoto H, Teuteberg JJ, Shullo MA, Bezerra HG, Costa MA et al.| title=Optical coherence tomography for characterization of cardiac allograft vasculopathy after heart transplantation (OCTCAV study). | journal=J Heart Lung Transplant | year= 2013 | volume= 32 | issue= 6 | pages= 596-602 | pmid=23499356 | doi=10.1016/j.healun.2013.02.005 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23499356 }} </ref>.

===Limitations===
* Complete blood washout from the coronaries is necessary to obtain good quality images.
* Deep tissue penetration is not as good as IVUS<ref name="pmid23499356">{{cite journal| author=Khandhar SJ, Yamamoto H, Teuteberg JJ, Shullo MA, Bezerra HG, Costa MA et al.| title=Optical coherence tomography for characterization of cardiac allograft vasculopathy after heart transplantation (OCTCAV study). | journal=J Heart Lung Transplant | year= 2013 | volume= 32 | issue= 6 | pages= 596-602 | pmid=23499356 | doi=10.1016/j.healun.2013.02.005 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23499356 }} </ref>.

==References==
{{reflist|2}}
{{WH}}
{{WS}}

Cardiac allograft vasculopathy optical coherence tomography

2014-12-28T20:03:32Z

Aarti Narayan: /* Coronary Optical Cohorence Tomography */

Cardiac allograft vasculopathy optical coherence tomography

2014-12-28T19:59:50Z

Aarti Narayan: /* Coronary Optical Cohorence Tomography */

Cardiac allograft vasculopathy optical coherence tomography

2014-12-28T19:56:10Z

Aarti Narayan: /* Coronary Optical Cohorence Tomography */

Cardiac allograft vasculopathy optical coherence tomography

2014-12-28T19:54:05Z

Aarti Narayan:

Cardiac allograft vasculopathy optical coherence tomography

2014-12-28T19:17:22Z

Aarti Narayan: Created page with "__NOTOC__ {{Cardiac allograft vasculopathy}} {{CMG}}; {{AE}} {{AN}}; {{RT}} ==Overview== In 2010, U.S FDA approved coronary optical cohorence tomography (OCT) as a new ca..."

Cardiac allograft vasculopathy history and symptoms

2014-12-20T19:49:19Z

Aarti Narayan: /* History and Symptoms */

__NOTOC__
{{Cardiac allograft vasculopathy}}
{{CMG}}; {{AE}} {{AN}}; {{RT}}

==Overview==
Patients with cardiac allograft vasculopathy (CAV) seldom present with typical angina symptoms due to cardiac denervation at the time of heart transplantation.

==History and Symptoms==
As mentioned above, patients with cardiac transplants do not typically present with [[angina|anginal]] symptoms. About 10-30% of patients regain some renervation to the heart. Hence, they typically present late with the following manifestations.

# Graft failure
# [[Arrhythmia]]s
# Silent [[myocardial infarction]]: Due to denervation at the time of surgery patients with CAV rarely present with typical [[angina]] symptoms, especially in the initial years of [[transplantation]].<ref name="pmid16102462">{{cite journal| author=Di Cori A, Petronio AS, Gemignani C, Zucchelli G, Di Bello V, Mariani M| title=Symptomatic acute myocardial infarction in a cardiac transplant recipient successfully treated with primary coronary angioplasty: evidence of prognostic importance of chest pain after cardiac transplantation. | journal=J Heart Lung Transplant | year= 2005 | volume= 24 | issue= 8 | pages= 1146-9 | pmid=16102462 | doi=10.1016/j.healun.2004.07.003 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16102462 }} </ref> However, studies have demonstrated that re-innervation does occur late after [[heart transplantation]].<ref name="pmid15366426">{{cite journal| author=Gallego-Page JC, Segovia J, Alonso-Pulpón L, Alonso-Rodríguez M, Salas C, Ortíz-Berrocal J| title=Re-innervation after heart transplantation: a multidisciplinary study. | journal=J Heart Lung Transplant | year= 2004 | volume= 23 | issue= 6 | pages= 674-82 | pmid=15366426 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15366426 }} </ref>
# [[Sudden death]]

The current practice is to routinely screen cardiac allograft recipients using [[coronary angiography|conventional angiography]] or [[intravascular ultrasound]] ([[IVUS]]) as discussed in subsequent sections.

==References==
{{reflist|2}}
{{WH}}
{{WS}}

[[Category:Cardiology]]
[[Category:Surgery]]
[[Category:Immunology]]
[[Category:Disease]]

Cardiac allograft vasculopathy history and symptoms

2014-12-20T19:47:37Z

Aarti Narayan:

__NOTOC__
{{Cardiac allograft vasculopathy}}
{{CMG}}; {{AE}} {{AN}}; {{RT}}

==Overview==
Patients with cardiac allograft vasculopathy (CAV) seldom present with typical angina symptoms due to cardiac denervation at the time of heart transplantation.

==History and Symptoms==
As mentioned above, patients with cardiac transplants do not typically present with [[angina|anginal]] symptoms. About 10-30% of patients regain some renervation to the heart. Hence, they typically present late with the following manifestations.

# [[Graft]] failure
# [[Arrhythmia]]s
# Silent [[myocardial infarction]]: Due to denervation at the time of surgery patients with CAV rarely present with typical [[angina]] symptoms, especially in the initial years of [[transplantation]].<ref name="pmid16102462">{{cite journal| author=Di Cori A, Petronio AS, Gemignani C, Zucchelli G, Di Bello V, Mariani M| title=Symptomatic acute myocardial infarction in a cardiac transplant recipient successfully treated with primary coronary angioplasty: evidence of prognostic importance of chest pain after cardiac transplantation. | journal=J Heart Lung Transplant | year= 2005 | volume= 24 | issue= 8 | pages= 1146-9 | pmid=16102462 | doi=10.1016/j.healun.2004.07.003 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16102462 }} </ref> However, studies have demonstrated that re-innervation does occur late after [[heart transplantation]].<ref name="pmid15366426">{{cite journal| author=Gallego-Page JC, Segovia J, Alonso-Pulpón L, Alonso-Rodríguez M, Salas C, Ortíz-Berrocal J| title=Re-innervation after heart transplantation: a multidisciplinary study. | journal=J Heart Lung Transplant | year= 2004 | volume= 23 | issue= 6 | pages= 674-82 | pmid=15366426 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15366426 }} </ref>
# [[Sudden death]]

The current practice is to routinely screen cardiac allograft recipients using [[coronary angiography|conventional angiography]] or [[intravascular ultrasound]] ([[IVUS]]) as discussed in subsequent sections.

==References==
{{reflist|2}}
{{WH}}
{{WS}}

[[Category:Cardiology]]
[[Category:Surgery]]
[[Category:Immunology]]
[[Category:Disease]]

Cardiac allograft vasculopathy history and symptoms

2014-12-20T19:44:01Z

Aarti Narayan:

__NOTOC__
{{Cardiac allograft vasculopathy}}
{{CMG}}; {{AE}} {{AN}}; {{RT}}

==Overview==
Patients with cardiac allograft vasculopathy (CAV) seldom present with typical angina symptoms due to cardiac denervation at the time of heart transplantation.

==History and Symptoms==
As mentioned above, patients with cardiac transplants do not typically present with [[angina|anginal]] symptoms. About 10-30% of patients regain some renervation to the heart. Hence, they typically present late with the following manifestations.

# [[Graft]] failure
# [[Arrhythmia]]s
# Silent [[myocardial infarction]]: Due to denervation at the time of surgery patients with CAV rarely present with typical [[angina]] symptoms, especially in the initial years of [[transplantation]].<ref name="pmid16102462">{{cite journal| author=Di Cori A, Petronio AS, Gemignani C, Zucchelli G, Di Bello V, Mariani M| title=Symptomatic acute myocardial infarction in a cardiac transplant recipient successfully treated with primary coronary angioplasty: evidence of prognostic importance of chest pain after cardiac transplantation. | journal=J Heart Lung Transplant | year= 2005 | volume= 24 | issue= 8 | pages= 1146-9 | pmid=16102462 | doi=10.1016/j.healun.2004.07.003 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16102462 }} </ref> However, studies have demonstrated that re-innervation does occur late after [[heart transplantation]].<ref name="pmid15366426">{{cite journal| author=Gallego-Page JC, Segovia J, Alonso-Pulpón L, Alonso-Rodríguez M, Salas C, Ortíz-Berrocal J| title=Re-innervation after heart transplantation: a multidisciplinary study. | journal=J Heart Lung Transplant | year= 2004 | volume= 23 | issue= 6 | pages= 674-82 | pmid=15366426 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15366426 }} </ref>
# [[Sudden death]]

==References==
{{reflist|2}}
{{WH}}
{{WS}}

[[Category:Cardiology]]
[[Category:Surgery]]
[[Category:Immunology]]
[[Category:Disease]]

Cardiac allograft vasculopathy natural history, complications and prognosis

2014-12-20T19:37:27Z

Aarti Narayan:

__NOTOC__
{{Cardiac allograft vasculopathy}}
{{CMG}}; {{AE}} {{AN}}; {{RT}}

==Overview==
CAV is responsible for approximately 40% of deaths in heart transplant recipients. Survival in these patients has improved significantly over the decades, owing primarily to improved diagnostic techniques, and optimal immunosuppression and risk factor modification. The 2013 adult heart transplant registry noted that 5-year survival in both pediatric and adult heart transplant recipients is 69%.

==Natural History==
* CAV is a slowly progressive disease of the graft vessels. However it may progress rapidly in some post-transplant patients. For example, about 7% of patients from the Cardiac Transplant Research Database had severe disease that progressed rapidly by the end of 5 years.
* In a few years post-transplant, the disease progresses from clean coronary vasculature to diffusely diseased, obstructive pattern.
* A 5 year prospective study by Tsutsui and colleagues using [[intravascular ultrasound]] ([[IVUS]]) revealed that most of the intimal thickening in CAV develops during the first year after heart transplantation <ref name="pmid11489770">{{cite journal| author=Tsutsui H, Ziada KM, Schoenhagen P, Iyisoy A, Magyar WA, Crowe TD et al.| title=Lumen loss in transplant coronary artery disease is a biphasic process involving early intimal thickening and late constrictive remodeling: results from a 5-year serial intravascular ultrasound study. | journal=Circulation | year= 2001 | volume= 104 | issue= 6 | pages= 653-7 | pmid=11489770 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11489770 }} </ref>.
* Late onset of CAV is infrequent. The process of development of CAV is rather slow in those who develop CAV 10 years post-transplant.

==Complications==
Most of the complications of CAV are related to myocardial hypoperfusion. These include:
* Graft failure
* [[Myocardial infarction]]
* [[Sudden death]]
* [[Congestive heart failure]] (sometimes in the form of rapidly developing systolic failure)
* [[Arrhythmia]]s

==Prognosis==
* All-cause mortality data from 1982 up to June 2011 shows 1 year survival of 81% and 5 year survival of 69%, with median survival of 10 years for all and 13 years for those surviving until the end of first year. The most recent cohort of patients show unadjusted 1 year survival of 84%.
* The survival curve demonstrates a steep fall in survival in the first 6 months post-transplant. Thereafter, it steadily decreases by 3.5% per year and continues to do so well beyond 15 years. Presence of CAV is the strongest predictor of mortality in patients who survive beyond 1 year post-transplant.
* The ISHLT Registry showed that CAV together with late graft failure was responsible for about 33% of deaths 5 years post-transplant.
* Also the survival of patients with CAV has in fact improved over the last decade.

==References==
{{reflist|2}}
{{WH}}
{{WS}}

[[Category:Cardiology]]
[[Category:Surgery]]
[[Category:Immunology]]
[[Category:Disease]]

Cardiac allograft vasculopathy medical therapy

2014-12-20T18:49:08Z

Aarti Narayan:

__NOTOC__
{{Cardiac allograft vasculopathy}}
{{CMG}}; {{AE}} {{AN}}; {{RT}}

==Overview==
Once CAV has developed, pharmacologic options to halt progression are limited. Moreover, outcomes resulting from available treatment have been disappointing. Retransplantation is the only definitive treatment of established CAV. Ideal regimen should not affect the lipid profile, blood pressures and renal function, and should have a positive impact on hemodynamics.
==Medical Therapy==
Treatment option for established CAV include:
{|class="wikitable" border="1"
|- align="center"
|'''Pharmacological Management'''
|'''Non-pharmacological Interventions'''
|- align="left"
|
* [[Sirolimus]]
* [[Everolimus]]
|
* Retransplantation
* [[Percutaneous coronary intervention]]s
* [[Coronary artery bypass grafting]] ([[CABG]])
* [[Transmyocardial revascularization]]
* [[LDL apheresis|Heparin induced/mediated extracorporeal LDL plasmapheresis]] (HELP)
|}

===Pharmacologic Management===
====High Dose Immunosuppressive Therapy====
* Lamich and colleagues <ref name="pmid9708469">{{cite journal| author=Lamich R, Ballester M, Martí V, Brossa V, Aymat R, Carrió I et al.| title=Efficacy of augmented immunosuppressive therapy for early vasculopathy in heart transplantation. | journal=J Am Coll Cardiol | year= 1998 | volume= 32 | issue= 2 | pages= 413-9 | pmid=9708469 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9708469 }} </ref> studied the effects of augmented immunosuppressive therapy on progression of established CAV in a prospective trial of 76 cardiac allograft recipients. They concluded that the likelihood of CAV regression is higher when treatment was instituted within one year of transplant (92%) compared to after one year (40%) (P=0.033).
* However, this is not routinely practiced as the risks of high dose immunosuppressive therapy outweighs the benefits.
==References==
{{reflist|2}}
{{WH}}
{{WS}}

Cardiac allograft vasculopathy medical therapy

2014-12-15T16:26:25Z

Aarti Narayan:

Cardiac allograft vasculopathy surgery

2014-12-15T16:25:22Z

Aarti Narayan: Created page with "__NOTOC__ {{Cardiac allograft vasculopathy}} {{CMG}}; {{AE}} {{AN}}; {{RT}} ==Overview== ==Surgery== ===Nonpharmacologic Interventions=== * Retransplantation * Percutaneou..."

__NOTOC__
{{Cardiac allograft vasculopathy}}
{{CMG}}; {{AE}} {{AN}}; {{RT}}

==Overview==

==Surgery==
===Nonpharmacologic Interventions===
* Retransplantation
* [[Percutaneous coronary intervention]]s
* [[Coronary artery bypass grafting]] ([[CABG]])
* [[Transmyocardial revascularization]]
* [[LDL apheresis|Heparin induced/mediated extracorporeal LDL plasmapheresis]] (HELP)

====Retransplantation====
* Retransplantation is the only definitive treatment for CAV. It is associated with satisfactory survival in patients with CAV.
* About 60% of the repeat transplantation procedures performed are due to graft failure secondary to CAV <ref name="pmid16686747">{{cite journal| author=Mehra MR| title=Contemporary concepts in prevention and treatment of cardiac allograft vasculopathy. | journal=Am J Transplant | year= 2006 | volume= 6 | issue= 6 | pages= 1248-56 | pmid=16686747 | doi=10.1111/j.1600-6143.2006.01314.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16686747 }} </ref>. It is a higher risk procedure and raises significant ethical concerns primarily because of scarcity of heart transplant donors <ref name="pmid12909465">{{cite journal| author=Radovancevic B, McGiffin DC, Kobashigawa JA, Cintron GB, Mullen GM, Pitts DE et al.| title=Retransplantation in 7,290 primary transplant patients: a 10-year multi-institutional study. | journal=J Heart Lung Transplant | year= 2003 | volume= 22 | issue= 8 | pages= 862-8 | pmid=12909465 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12909465 }} </ref>.
* Prognosis: One year survival has improved in recent years, but continues to be inferior compared to primary transplants (79% in re-transplant group compared to 85% in primary transplant group) <ref name="pmid10972218">{{cite journal| author=Srivastava R, Keck BM, Bennett LE, Hosenpud JD| title=The results of cardiac retransplantation: an analysis of the Joint International Society for Heart and Lung Transplantation/United Network for Organ Sharing Thoracic Registry. | journal=Transplantation | year= 2000 | volume= 70 | issue= 4 | pages= 606-12 | pmid=10972218 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10972218 }} </ref>.

====Percutaneous Coronary Intervention====
* This procedure is limited only to a selected group of patients with focal disease in a single artery. Moreover, the number of patients who benefit are small.
* Incidence of re-stenosis is high, ranging from 20 to 60% as reported in various studies.
* [[Intracoronary stenting]] appears to have lower rate of re-stenosis as compared to [[coronary angioplasty]] alone.
* Concomitant use of high dose immunosuppressive therapy with [[azathioprine]] and [[mycophenolate]] have shown to significantly reduce the rate of re-stenosis <ref name="pmid15172400">{{cite journal| author=Benza RL, Zoghbi GJ, Tallaj J, Brown R, Kirklin JK, Hubbard M et al.| title=Palliation of allograft vasculopathy with transluminal angioplasty: a decade of experience. | journal=J Am Coll Cardiol | year= 2004 | volume= 43 | issue= 11 | pages= 1973-81 | pmid=15172400 | doi=10.1016/j.jacc.2004.02.045 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15172400 }} </ref>.

====Coronary Artery Bypass Grafting====
* Associated with a high perioperative mortality especially in those with distal disease.
* In a retrospective analysis of 12 patients with CAV who underwent CABG, 4 died perioperatively, while only 7 were alive at the end of 9 months post-surgery <ref name="pmid7797740">{{cite journal| author=Halle AA, DiSciascio G, Massin EK, Wilson RF, Johnson MR, Sullivan HJ et al.| title=Coronary angioplasty, atherectomy and bypass surgery in cardiac transplant recipients. | journal=J Am Coll Cardiol | year= 1995 | volume= 26 | issue= 1 | pages= 120-8 | pmid=7797740 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7797740 }} </ref>.

====Transmyocardial Revascularization====
* Also known as [[Transmyocardial revascularization|transmyocardial laser revascularization]] (TMLR), is a procedure involving creation of transmural channels in the myocardium to enhance blood supply.
* This procedure has been studied in multiple clinical trials in patients with refractory angina and those who are not considered as surgical candidates.
* Mehra and colleagues <ref name="pmid9230169">{{cite journal| author=Malik FS, Mehra MR, Ventura HO, Smart FW, Stapleton DD, Ochsner JL| title=Management of cardiac allograft vasculopathy by transmyocardial laser revascularization. | journal=Am J Cardiol | year= 1997 | volume= 80 | issue= 2 | pages= 224-5 | pmid=9230169 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9230169 }} </ref> first studied the effects of TMLR in patients with diffuse CAV. They reported significant improvement in symptoms and anginal class at 4 and 8 week follow up. However, at 24 month follow up, the procedure showed neither consistent symptomatic improvement nor any change in course of the progression of CAV <ref name="pmid10967275">{{cite journal| author=Mehra MR, Uber PA, Prasad AK, Park MH, Scott RL, McFadden PM et al.| title=Long-term outcome of cardiac allograft vasculopathy treated by transmyocardial laser revascularization: early rewards, late losses. | journal=J Heart Lung Transplant | year= 2000 | volume= 19 | issue= 8 | pages= 801-4 | pmid=10967275 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10967275 }} </ref>.

====Heparin Induced/Mediated Extracorporeal LDL Plasmapheresis====
* Also known as LDL apheresis.
* Leads to significant reductions in [[LDL]], [[lipoprotein(a)]] levels and [[fibrinogen]].
* No effect on [[HDL]] levels.
* In a prospective study by Park et al., patients treated with LDL apheresis had a statistically significant increase in intraluminal diameter between 1 year and 2.5 years of follow up. However, long term trials are required to draw firm conclusions.

==References==
{{reflist|2}}
{{WH}}
{{WS}}

Cardiac allograft vasculopathy medical therapy

2014-12-15T16:23:00Z

Aarti Narayan:

__NOTOC__
{{Cardiac allograft vasculopathy}}
{{CMG}}; {{AE}} {{AN}}; {{RT}}

==Overview==
Once CAV has developed, pharmacologic options to halt progression are limited. Retransplantation is the only definitive treatment of established CAV. Ideal regimen should not affect the lipid profile, blood pressures and renal function, and have a positive impact on hemodynamics.
==Medical Therapy==
Treatment option for established CAV include:
{|class="wikitable" border="1"
|- align="center"
|'''Pharmacological Management'''
|'''Non-pharmacological Interventions'''
|- align="left"
|
* [[Sirolimus]]
* [[Everolimus]]
|
* Retransplantation
* [[Percutaneous coronary intervention]]s
* [[Coronary artery bypass grafting]] ([[CABG]])
* [[Transmyocardial revascularization]]
* [[LDL apheresis|Heparin induced/mediated extracorporeal LDL plasmapheresis]] (HELP)
|}

===Pharmacologic Management===

===Nonpharmacologic Interventions===
* Retransplantation
* [[Percutaneous coronary intervention]]s
* [[Coronary artery bypass grafting]] ([[CABG]])
* [[Transmyocardial revascularization]]
* [[LDL apheresis|Heparin induced/mediated extracorporeal LDL plasmapheresis]] (HELP)

====Retransplantation====
* Retransplantation is the only definitive treatment for CAV. It is associated with satisfactory survival in patients with CAV.
* About 60% of the repeat transplantation procedures performed are due to graft failure secondary to CAV <ref name="pmid16686747">{{cite journal| author=Mehra MR| title=Contemporary concepts in prevention and treatment of cardiac allograft vasculopathy. | journal=Am J Transplant | year= 2006 | volume= 6 | issue= 6 | pages= 1248-56 | pmid=16686747 | doi=10.1111/j.1600-6143.2006.01314.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16686747 }} </ref>. It is a higher risk procedure and raises significant ethical concerns primarily because of scarcity of heart transplant donors <ref name="pmid12909465">{{cite journal| author=Radovancevic B, McGiffin DC, Kobashigawa JA, Cintron GB, Mullen GM, Pitts DE et al.| title=Retransplantation in 7,290 primary transplant patients: a 10-year multi-institutional study. | journal=J Heart Lung Transplant | year= 2003 | volume= 22 | issue= 8 | pages= 862-8 | pmid=12909465 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12909465 }} </ref>.
* Prognosis: One year survival has improved in recent years, but continues to be inferior compared to primary transplants (79% in re-transplant group compared to 85% in primary transplant group) <ref name="pmid10972218">{{cite journal| author=Srivastava R, Keck BM, Bennett LE, Hosenpud JD| title=The results of cardiac retransplantation: an analysis of the Joint International Society for Heart and Lung Transplantation/United Network for Organ Sharing Thoracic Registry. | journal=Transplantation | year= 2000 | volume= 70 | issue= 4 | pages= 606-12 | pmid=10972218 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10972218 }} </ref>.

====Percutaneous Coronary Intervention====
* This procedure is limited only to a selected group of patients with focal disease in a single artery. Moreover, the number of patients who benefit are small.
* Incidence of re-stenosis is high, ranging from 20 to 60% as reported in various studies.
* [[Intracoronary stenting]] appears to have lower rate of re-stenosis as compared to [[coronary angioplasty]] alone.
* Concomitant use of high dose immunosuppressive therapy with [[azathioprine]] and [[mycophenolate]] have shown to significantly reduce the rate of re-stenosis <ref name="pmid15172400">{{cite journal| author=Benza RL, Zoghbi GJ, Tallaj J, Brown R, Kirklin JK, Hubbard M et al.| title=Palliation of allograft vasculopathy with transluminal angioplasty: a decade of experience. | journal=J Am Coll Cardiol | year= 2004 | volume= 43 | issue= 11 | pages= 1973-81 | pmid=15172400 | doi=10.1016/j.jacc.2004.02.045 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15172400 }} </ref>.

====Coronary Artery Bypass Grafting====
* Associated with a high perioperative mortality especially in those with distal disease.
* In a retrospective analysis of 12 patients with CAV who underwent CABG, 4 died perioperatively, while only 7 were alive at the end of 9 months post-surgery <ref name="pmid7797740">{{cite journal| author=Halle AA, DiSciascio G, Massin EK, Wilson RF, Johnson MR, Sullivan HJ et al.| title=Coronary angioplasty, atherectomy and bypass surgery in cardiac transplant recipients. | journal=J Am Coll Cardiol | year= 1995 | volume= 26 | issue= 1 | pages= 120-8 | pmid=7797740 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7797740 }} </ref>.

====Transmyocardial Revascularization====
* Also known as [[Transmyocardial revascularization|transmyocardial laser revascularization]] (TMLR), is a procedure involving creation of transmural channels in the myocardium to enhance blood supply.
* This procedure has been studied in multiple clinical trials in patients with refractory angina and those who are not considered as surgical candidates.
* Mehra and colleagues <ref name="pmid9230169">{{cite journal| author=Malik FS, Mehra MR, Ventura HO, Smart FW, Stapleton DD, Ochsner JL| title=Management of cardiac allograft vasculopathy by transmyocardial laser revascularization. | journal=Am J Cardiol | year= 1997 | volume= 80 | issue= 2 | pages= 224-5 | pmid=9230169 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9230169 }} </ref> first studied the effects of TMLR in patients with diffuse CAV. They reported significant improvement in symptoms and anginal class at 4 and 8 week follow up. However, at 24 month follow up, the procedure showed neither consistent symptomatic improvement nor any change in course of the progression of CAV <ref name="pmid10967275">{{cite journal| author=Mehra MR, Uber PA, Prasad AK, Park MH, Scott RL, McFadden PM et al.| title=Long-term outcome of cardiac allograft vasculopathy treated by transmyocardial laser revascularization: early rewards, late losses. | journal=J Heart Lung Transplant | year= 2000 | volume= 19 | issue= 8 | pages= 801-4 | pmid=10967275 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10967275 }} </ref>.

====Heparin Induced/Mediated Extracorporeal LDL Plasmapheresis====
* Also known as LDL apheresis.
* Leads to significant reductions in [[LDL]], [[lipoprotein(a)]] levels and [[fibrinogen]].
* No effect on [[HDL]] levels.
* In a prospective study by Park et al., patients treated with LDL apheresis had a statistically significant increase in intraluminal diameter between 1 year and 2.5 years of follow up. However, long term trials are required to draw firm conclusions.

==References==
{{reflist|2}}
{{WH}}
{{WS}}

Cardiac allograft vasculopathy medical therapy

2014-12-14T20:36:06Z

Aarti Narayan:

__NOTOC__
{{Cardiac allograft vasculopathy}}
{{CMG}}; {{AE}} {{AN}}; {{RT}}

==Overview==
Once CAV has developed, pharmacologic options to halt progression are limited. Retransplantation is the only definitive treatment of established CAV. Ideal regimen should not affect the lipid profile, blood pressures and renal function, and have a positive impact on hemodynamics.
==Medical Therapy==
===Pharmacologic Management===

===Nonpharmacologic Interventions===
* Retransplantation
* [[Percutaneous coronary intervention]]s
* [[Coronary artery bypass grafting]] ([[CABG]])
* [[Transmyocardial revascularization]]
* [[LDL apheresis|Heparin induced/mediated extracorporeal LDL plasmapheresis]] (HELP)

====Retransplantation====
* Retransplantation is the only definitive treatment for CAV. It is associated with satisfactory survival in patients with CAV.
* About 60% of the repeat transplantation procedures performed are due to graft failure secondary to CAV <ref name="pmid16686747">{{cite journal| author=Mehra MR| title=Contemporary concepts in prevention and treatment of cardiac allograft vasculopathy. | journal=Am J Transplant | year= 2006 | volume= 6 | issue= 6 | pages= 1248-56 | pmid=16686747 | doi=10.1111/j.1600-6143.2006.01314.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16686747 }} </ref>. It is a higher risk procedure and raises significant ethical concerns primarily because of scarcity of heart transplant donors <ref name="pmid12909465">{{cite journal| author=Radovancevic B, McGiffin DC, Kobashigawa JA, Cintron GB, Mullen GM, Pitts DE et al.| title=Retransplantation in 7,290 primary transplant patients: a 10-year multi-institutional study. | journal=J Heart Lung Transplant | year= 2003 | volume= 22 | issue= 8 | pages= 862-8 | pmid=12909465 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12909465 }} </ref>.
* Prognosis: One year survival has improved in recent years, but continues to be inferior compared to primary transplants (79% in re-transplant group compared to 85% in primary transplant group) <ref name="pmid10972218">{{cite journal| author=Srivastava R, Keck BM, Bennett LE, Hosenpud JD| title=The results of cardiac retransplantation: an analysis of the Joint International Society for Heart and Lung Transplantation/United Network for Organ Sharing Thoracic Registry. | journal=Transplantation | year= 2000 | volume= 70 | issue= 4 | pages= 606-12 | pmid=10972218 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10972218 }} </ref>.

====Percutaneous Coronary Intervention====
* This procedure is limited only to a selected group of patients with focal disease in a single artery. Moreover, the number of patients who benefit are small.
* Incidence of re-stenosis is high, ranging from 20 to 60% as reported in various studies.
* [[Intracoronary stenting]] appears to have lower rate of re-stenosis as compared to [[coronary angioplasty]] alone.
* Concomitant use of high dose immunosuppressive therapy with [[azathioprine]] and [[mycophenolate]] have shown to significantly reduce the rate of re-stenosis <ref name="pmid15172400">{{cite journal| author=Benza RL, Zoghbi GJ, Tallaj J, Brown R, Kirklin JK, Hubbard M et al.| title=Palliation of allograft vasculopathy with transluminal angioplasty: a decade of experience. | journal=J Am Coll Cardiol | year= 2004 | volume= 43 | issue= 11 | pages= 1973-81 | pmid=15172400 | doi=10.1016/j.jacc.2004.02.045 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15172400 }} </ref>.

====Coronary Artery Bypass Grafting====
* Associated with a high perioperative mortality especially in those with distal disease.
* In a retrospective analysis of 12 patients with CAV who underwent CABG, 4 died perioperatively, while only 7 were alive at the end of 9 months post-surgery <ref name="pmid7797740">{{cite journal| author=Halle AA, DiSciascio G, Massin EK, Wilson RF, Johnson MR, Sullivan HJ et al.| title=Coronary angioplasty, atherectomy and bypass surgery in cardiac transplant recipients. | journal=J Am Coll Cardiol | year= 1995 | volume= 26 | issue= 1 | pages= 120-8 | pmid=7797740 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7797740 }} </ref>.

====Transmyocardial Revascularization====
* Also known as [[Transmyocardial revascularization|transmyocardial laser revascularization]] (TMLR), is a procedure involving creation of transmural channels in the myocardium to enhance blood supply.
* This procedure has been studied in multiple clinical trials in patients with refractory angina and those who are not considered as surgical candidates.
* Mehra and colleagues <ref name="pmid9230169">{{cite journal| author=Malik FS, Mehra MR, Ventura HO, Smart FW, Stapleton DD, Ochsner JL| title=Management of cardiac allograft vasculopathy by transmyocardial laser revascularization. | journal=Am J Cardiol | year= 1997 | volume= 80 | issue= 2 | pages= 224-5 | pmid=9230169 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9230169 }} </ref> first studied the effects of TMLR in patients with diffuse CAV. They reported significant improvement in symptoms and anginal class at 4 and 8 week follow up. However, at 24 month follow up, the procedure showed neither consistent symptomatic improvement nor any change in course of the progression of CAV <ref name="pmid10967275">{{cite journal| author=Mehra MR, Uber PA, Prasad AK, Park MH, Scott RL, McFadden PM et al.| title=Long-term outcome of cardiac allograft vasculopathy treated by transmyocardial laser revascularization: early rewards, late losses. | journal=J Heart Lung Transplant | year= 2000 | volume= 19 | issue= 8 | pages= 801-4 | pmid=10967275 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10967275 }} </ref>.

====Heparin Induced/Mediated Extracorporeal LDL Plasmapheresis====
* Also known as LDL apheresis.
* Leads to significant reductions in [[LDL]], [[lipoprotein(a)]] levels and [[fibrinogen]].
* No effect on [[HDL]] levels.
* In a prospective study by Park et al., patients treated with LDL apheresis had a statistically significant increase in intraluminal diameter between 1 year and 2.5 years of follow up. However, long term trials are required to draw firm conclusions.

==References==
{{reflist|2}}
{{WH}}
{{WS}}

Cardiac allograft vasculopathy medical therapy

2014-12-13T22:32:32Z

Aarti Narayan:

__NOTOC__
{{Cardiac allograft vasculopathy}}
{{CMG}}; {{AE}} {{AN}}; {{RT}}

==Overview==
==Medical Therapy==
===Pharmacologic Management===

===Nonpharmacologic Interventions===
* Retransplantation
* [[Percutaneous coronary intervention]]s
* [[Coronary artery bypass grafting]] ([[CABG]])
* [[Transmyocardial revascularization]]
* [[LDL apheresis|Heparin induced/mediated extracorporeal LDL plasmapheresis]] (HELP)

====Retransplantation====
* Retransplantation is the only definitive treatment for CAV. It is associated with satisfactory survival in patients with CAV.
* About 60% of the repeat transplantation procedures performed are due to graft failure secondary to CAV <ref name="pmid16686747">{{cite journal| author=Mehra MR| title=Contemporary concepts in prevention and treatment of cardiac allograft vasculopathy. | journal=Am J Transplant | year= 2006 | volume= 6 | issue= 6 | pages= 1248-56 | pmid=16686747 | doi=10.1111/j.1600-6143.2006.01314.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16686747 }} </ref>. It is a higher risk procedure and raises significant ethical concerns primarily because of scarcity of heart transplant donors <ref name="pmid12909465">{{cite journal| author=Radovancevic B, McGiffin DC, Kobashigawa JA, Cintron GB, Mullen GM, Pitts DE et al.| title=Retransplantation in 7,290 primary transplant patients: a 10-year multi-institutional study. | journal=J Heart Lung Transplant | year= 2003 | volume= 22 | issue= 8 | pages= 862-8 | pmid=12909465 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12909465 }} </ref>.
* Prognosis: One year survival has improved in recent years, but continues to be inferior compared to primary transplants (79% in re-transplant group compared to 85% in primary transplant group) <ref name="pmid10972218">{{cite journal| author=Srivastava R, Keck BM, Bennett LE, Hosenpud JD| title=The results of cardiac retransplantation: an analysis of the Joint International Society for Heart and Lung Transplantation/United Network for Organ Sharing Thoracic Registry. | journal=Transplantation | year= 2000 | volume= 70 | issue= 4 | pages= 606-12 | pmid=10972218 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10972218 }} </ref>.

====Percutaneous Coronary Intervention====
* This procedure is limited only to a selected group of patients with focal disease in a single artery. Moreover, the number of patients who benefit are small.
* Incidence of re-stenosis is high, ranging from 20 to 60% as reported in various studies.
* [[Intracoronary stenting]] appears to have lower rate of re-stenosis as compared to [[coronary angioplasty]] alone.
* Concomitant use of high dose immunosuppressive therapy with [[azathioprine]] and [[mycophenolate]] have shown to significantly reduce the rate of re-stenosis <ref name="pmid15172400">{{cite journal| author=Benza RL, Zoghbi GJ, Tallaj J, Brown R, Kirklin JK, Hubbard M et al.| title=Palliation of allograft vasculopathy with transluminal angioplasty: a decade of experience. | journal=J Am Coll Cardiol | year= 2004 | volume= 43 | issue= 11 | pages= 1973-81 | pmid=15172400 | doi=10.1016/j.jacc.2004.02.045 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15172400 }} </ref>.

====Coronary Artery Bypass Grafting====
* Associated with a high perioperative mortality especially in those with distal disease.
* In a retrospective analysis of 12 patients with CAV who underwent CABG, 4 died perioperatively, while only 7 were alive at the end of 9 months post-surgery <ref name="pmid7797740">{{cite journal| author=Halle AA, DiSciascio G, Massin EK, Wilson RF, Johnson MR, Sullivan HJ et al.| title=Coronary angioplasty, atherectomy and bypass surgery in cardiac transplant recipients. | journal=J Am Coll Cardiol | year= 1995 | volume= 26 | issue= 1 | pages= 120-8 | pmid=7797740 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7797740 }} </ref>.

====Transmyocardial Revascularization====
* Also known as [[Transmyocardial revascularization|transmyocardial laser revascularization]] (TMLR), is a procedure involving creation of transmural channels in the myocardium to enhance blood supply.
* This procedure has been studied in multiple clinical trials in patients with refractory angina and those who are not considered as surgical candidates.
* Mehra and colleagues <ref name="pmid9230169">{{cite journal| author=Malik FS, Mehra MR, Ventura HO, Smart FW, Stapleton DD, Ochsner JL| title=Management of cardiac allograft vasculopathy by transmyocardial laser revascularization. | journal=Am J Cardiol | year= 1997 | volume= 80 | issue= 2 | pages= 224-5 | pmid=9230169 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9230169 }} </ref> first studied the effects of TMLR in patients with diffuse CAV. They reported significant improvement in symptoms and anginal class at 4 and 8 week follow up. However, at 24 month follow up, the procedure showed neither consistent symptomatic improvement nor any change in course of the progression of CAV <ref name="pmid10967275">{{cite journal| author=Mehra MR, Uber PA, Prasad AK, Park MH, Scott RL, McFadden PM et al.| title=Long-term outcome of cardiac allograft vasculopathy treated by transmyocardial laser revascularization: early rewards, late losses. | journal=J Heart Lung Transplant | year= 2000 | volume= 19 | issue= 8 | pages= 801-4 | pmid=10967275 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10967275 }} </ref>.

====Heparin Induced/Mediated Extracorporeal LDL Plasmapheresis====
* Also known as LDL apheresis.
* Leads to significant reductions in [[LDL]], [[lipoprotein(a)]] levels and [[fibrinogen]].
* No effect on [[HDL]] levels.
* In a prospective study by Park et al., patients treated with LDL apheresis had a statistically significant increase in intraluminal diameter between 1 year and 2.5 years of follow up. However, long term trials are required to draw firm conclusions.

==References==
{{reflist|2}}
{{WH}}
{{WS}}

Cardiac allograft vasculopathy medical therapy

2014-12-13T22:19:49Z

Aarti Narayan:

__NOTOC__
{{Cardiac allograft vasculopathy}}
{{CMG}}; {{AE}} {{AN}}; {{RT}}

==Overview==
==Medical Therapy==
===Pharmacologic Management===

===Nonpharmacologic Interventions===
* Retransplantation
* [[Percutaneous coronary intervention]]s
* [[Coronary artery bypass grafting]] ([[CABG]])
* [[Transmyocardial revascularization]]
* Heparin induced/mediated extracorporeal LDL plasmapheresis (HELP)

====Retransplantation====
* Retransplantation is the only definitive treatment for CAV. It is associated with satisfactory survival in patients with CAV.
* About 60% of the repeat transplantation procedures performed are due to graft failure secondary to CAV <ref name="pmid16686747">{{cite journal| author=Mehra MR| title=Contemporary concepts in prevention and treatment of cardiac allograft vasculopathy. | journal=Am J Transplant | year= 2006 | volume= 6 | issue= 6 | pages= 1248-56 | pmid=16686747 | doi=10.1111/j.1600-6143.2006.01314.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16686747 }} </ref>. It is a higher risk procedure and raises significant ethical concerns primarily because of scarcity of heart transplant donors <ref name="pmid12909465">{{cite journal| author=Radovancevic B, McGiffin DC, Kobashigawa JA, Cintron GB, Mullen GM, Pitts DE et al.| title=Retransplantation in 7,290 primary transplant patients: a 10-year multi-institutional study. | journal=J Heart Lung Transplant | year= 2003 | volume= 22 | issue= 8 | pages= 862-8 | pmid=12909465 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12909465 }} </ref>.
* Prognosis: One year survival has improved in recent years, but continues to be inferior compared to primary transplants (79% in re-transplant group compared to 85% in primary transplant group) <ref name="pmid10972218">{{cite journal| author=Srivastava R, Keck BM, Bennett LE, Hosenpud JD| title=The results of cardiac retransplantation: an analysis of the Joint International Society for Heart and Lung Transplantation/United Network for Organ Sharing Thoracic Registry. | journal=Transplantation | year= 2000 | volume= 70 | issue= 4 | pages= 606-12 | pmid=10972218 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10972218 }} </ref>.

====Percutaneous Coronary Intervention====
* This procedure is limited only to a selected group of patients with focal disease in a single artery. Moreover, the number of patients who benefit are small.
* Incidence of re-stenosis is high, ranging from 20 to 60% as reported in various studies.
* [[Intracoronary stenting]] appears to have lower rate of re-stenosis as compared to [[coronary angioplasty]] alone.
* Concomitant use of high dose immunosuppressive therapy with [[azathioprine]] and [[mycophenolate]] have shown to significantly reduce the rate of re-stenosis <ref name="pmid15172400">{{cite journal| author=Benza RL, Zoghbi GJ, Tallaj J, Brown R, Kirklin JK, Hubbard M et al.| title=Palliation of allograft vasculopathy with transluminal angioplasty: a decade of experience. | journal=J Am Coll Cardiol | year= 2004 | volume= 43 | issue= 11 | pages= 1973-81 | pmid=15172400 | doi=10.1016/j.jacc.2004.02.045 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15172400 }} </ref>.

====Coronary Artery Bypass Grafting====
* Associated with a high perioperative mortality especially in those with distal disease.
* In a retrospective analysis of 12 patients with CAV who underwent CABG, 4 died perioperatively, while only 7 were alive at the end of 9 months post-surgery <ref name="pmid7797740">{{cite journal| author=Halle AA, DiSciascio G, Massin EK, Wilson RF, Johnson MR, Sullivan HJ et al.| title=Coronary angioplasty, atherectomy and bypass surgery in cardiac transplant recipients. | journal=J Am Coll Cardiol | year= 1995 | volume= 26 | issue= 1 | pages= 120-8 | pmid=7797740 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7797740 }} </ref>.

====Transmyocardial Revascularization====
* Also known as [[Transmyocardial revascularization|transmyocardial laser revascularization]] (TMLR), is a procedure involving creation of transmural channels in the myocardium to enhance blood supply.
* This procedure has been studied in multiple clinical trials in patients with refractory angina and those who are not considered as surgical candidates.
* Mehra and colleagues <ref name="pmid9230169">{{cite journal| author=Malik FS, Mehra MR, Ventura HO, Smart FW, Stapleton DD, Ochsner JL| title=Management of cardiac allograft vasculopathy by transmyocardial laser revascularization. | journal=Am J Cardiol | year= 1997 | volume= 80 | issue= 2 | pages= 224-5 | pmid=9230169 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9230169 }} </ref> first studied the effects of TMLR in patients with diffuse CAV. They reported significant improvement in symptoms and anginal class at 4 and 8 week follow up. However, at 24 month follow up, the procedure showed neither consistent symptomatic improvement nor any change in course of the progression of CAV <ref name="pmid10967275">{{cite journal| author=Mehra MR, Uber PA, Prasad AK, Park MH, Scott RL, McFadden PM et al.| title=Long-term outcome of cardiac allograft vasculopathy treated by transmyocardial laser revascularization: early rewards, late losses. | journal=J Heart Lung Transplant | year= 2000 | volume= 19 | issue= 8 | pages= 801-4 | pmid=10967275 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10967275 }} </ref>.

====Heparin Induced/Mediated Extracorporeal LDL Plasmapheresis====
* Also known as LDL apheresis.
* Leads to significant reductions in [[LDL]], [[lipoprotein(a)]] levels and [[fibrinogen]].
* No effect on [[HDL]] levels.
* In a prospective study by Park et al., patients treated with LDL apheresis had a statistically significant increase in intraluminal diameter between 1 year and 2.5 years of follow up. However, long term trials are required to draw firm conclusions.

==References==
{{reflist|2}}
{{WH}}
{{WS}}

Cardiac allograft vasculopathy medical therapy

2014-12-13T21:06:24Z

Aarti Narayan:

__NOTOC__
{{Cardiac allograft vasculopathy}}
{{CMG}}; {{AE}} {{AN}}; {{RT}}

==Overview==
==Medical Therapy==
===Pharmacologic Management===

===Nonpharmacologic Interventions===
* Retransplantation
* [[Percutaneous coronary intervention]]s
* [[Coronary artery bypass grafting]] ([[CABG]])
* [[Transmyocardial revascularization]]
* Heparin induced/mediated extracorporeal LDL plasmapheresis (HELP)

====Retransplantation====
* Retransplantation is the only definitive treatment for CAV. It is associated with satisfactory survival in patients with CAV.
* About 60% of the repeat transplantation procedures performed are due to graft failure secondary to CAV <ref name="pmid16686747">{{cite journal| author=Mehra MR| title=Contemporary concepts in prevention and treatment of cardiac allograft vasculopathy. | journal=Am J Transplant | year= 2006 | volume= 6 | issue= 6 | pages= 1248-56 | pmid=16686747 | doi=10.1111/j.1600-6143.2006.01314.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16686747 }} </ref>. It is a higher risk procedure and raises significant ethical concerns primarily because of scarcity of heart transplant donors <ref name="pmid12909465">{{cite journal| author=Radovancevic B, McGiffin DC, Kobashigawa JA, Cintron GB, Mullen GM, Pitts DE et al.| title=Retransplantation in 7,290 primary transplant patients: a 10-year multi-institutional study. | journal=J Heart Lung Transplant | year= 2003 | volume= 22 | issue= 8 | pages= 862-8 | pmid=12909465 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12909465 }} </ref>.
* Prognosis: One year survival has improved in recent years, but continues to be inferior compared to primary transplants (79% in re-transplant group compared to 85% in primary transplant group) <ref name="pmid10972218">{{cite journal| author=Srivastava R, Keck BM, Bennett LE, Hosenpud JD| title=The results of cardiac retransplantation: an analysis of the Joint International Society for Heart and Lung Transplantation/United Network for Organ Sharing Thoracic Registry. | journal=Transplantation | year= 2000 | volume= 70 | issue= 4 | pages= 606-12 | pmid=10972218 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10972218 }} </ref>.

====Percutaneous Coronary Intervention====
* This procedure is limited only to a selected group of patients with focal disease in a single artery. Moreover, the number of patients who benefit are small.
* Incidence of re-stenosis is high, ranging from 20 to 60% as reported in various studies.
* [[Intracoronary stenting]] appears to have lower rate of re-stenosis as compared to [[coronary angioplasty]] alone.
* Concomitant use of high dose immunosuppressive therapy with [[azathioprine]] and [[mycophenolate]] have shown to significantly reduce the rate of re-stenosis <ref name="pmid15172400">{{cite journal| author=Benza RL, Zoghbi GJ, Tallaj J, Brown R, Kirklin JK, Hubbard M et al.| title=Palliation of allograft vasculopathy with transluminal angioplasty: a decade of experience. | journal=J Am Coll Cardiol | year= 2004 | volume= 43 | issue= 11 | pages= 1973-81 | pmid=15172400 | doi=10.1016/j.jacc.2004.02.045 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15172400 }} </ref>.

====Coronary Artery Bypass Grafting====
* Associated with a high perioperative mortality especially in those with distal disease.
* In a retrospective analysis of 12 patients with CAV who underwent CABG, 4 died perioperatively, while only 7 were alive at the end of 9 months post-surgery <ref name="pmid7797740">{{cite journal| author=Halle AA, DiSciascio G, Massin EK, Wilson RF, Johnson MR, Sullivan HJ et al.| title=Coronary angioplasty, atherectomy and bypass surgery in cardiac transplant recipients. | journal=J Am Coll Cardiol | year= 1995 | volume= 26 | issue= 1 | pages= 120-8 | pmid=7797740 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7797740 }} </ref>.

====Transmyocardial Revascularization====
* Also known as [[Transmyocardial revascularization|transmyocardial laser revascularization]] (TMLR), is a procedure involving creation of transmural channels in the myocardium to enhance blood supply.
* This procedure has been studied in multiple clinical trials in patients with refractory angina and those who are not considered as surgical candidates.
* Mehra and colleagues <ref name="pmid9230169">{{cite journal| author=Malik FS, Mehra MR, Ventura HO, Smart FW, Stapleton DD, Ochsner JL| title=Management of cardiac allograft vasculopathy by transmyocardial laser revascularization. | journal=Am J Cardiol | year= 1997 | volume= 80 | issue= 2 | pages= 224-5 | pmid=9230169 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9230169 }} </ref> first studied the effects of TMLR in patients with diffuse CAV. They reported significant improvement in symptoms and anginal class at 4 and 8 week follow up. However, at 24 month follow up, the procedure showed neither consistent symptomatic improvement nor any change in course of the progression of CAV <ref name="pmid10967275">{{cite journal| author=Mehra MR, Uber PA, Prasad AK, Park MH, Scott RL, McFadden PM et al.| title=Long-term outcome of cardiac allograft vasculopathy treated by transmyocardial laser revascularization: early rewards, late losses. | journal=J Heart Lung Transplant | year= 2000 | volume= 19 | issue= 8 | pages= 801-4 | pmid=10967275 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10967275 }} </ref>.

==References==
{{reflist|2}}
{{WH}}
{{WS}}

Cardiac allograft vasculopathy medical therapy

2014-12-13T20:31:24Z

Aarti Narayan:

Cardiac allograft vasculopathy medical therapy

2014-12-13T19:58:33Z

Aarti Narayan:

Cardiac allograft vasculopathy medical therapy

2014-12-09T05:02:29Z

Aarti Narayan:

Cardiac allograft vasculopathy medical therapy

2014-12-07T20:14:48Z

Aarti Narayan:

Cardiac allograft vasculopathy prevention

2014-12-07T06:14:04Z

Aarti Narayan: /* Non-Immunosuppressive therapy */

__NOTOC__
{{Cardiac allograft vasculopathy}}
{{CMG}}; {{AE}} {{AN}} {{RT}}

==Overview==

==Prevention==
As the pathogenesis of CAV consists of both immunological and non-immunological insults, it has been suggested that preventative strategies should consist of control of risk factors for CAV and optimal [[immunosuppressive therapy]]. However, the best preventative strategy to delay development of CAV is yet to be determined.

===Optimization of Immunosuppressive Therapy===
The [[rapamycin]] derivatives, [[sirolimus]] and [[everolimus]], have been proven to have significant benefit in the prevention of CAV in addition to [[statins]]. Other options for immunosuppressive therapy include <ref name="pmid16686747">{{cite journal| author=Mehra MR| title=Contemporary concepts in prevention and treatment of cardiac allograft vasculopathy. | journal=Am J Transplant | year= 2006 | volume= 6 | issue= 6 | pages= 1248-56 | pmid=16686747 | doi=10.1111/j.1600-6143.2006.01314.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16686747 }} </ref>:
* [[Corticosteroids]]
* [[Mycophenolate mofetil]]

====Everolimus and Sirolimus====
* Act by inhibiting mTOR (mammalian target), thereby having anti-proliferative effects in response to allo-antigens.
* Everolimus is currently not FDA approved for clinical use in the United States.
* Associated with significantly reduced incidence of [[graft rejection]].
* Serial [[IVUS]] studies to evaluate intimal proliferation demonstrated smaller increase in maximal intimal thickness and intimal index in patients taking [[everolimus]] <ref name="pmid12944570">{{cite journal| author=Eisen HJ, Tuzcu EM, Dorent R, Kobashigawa J, Mancini D, Valantine-von Kaeppler HA et al.| title=Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. | journal=N Engl J Med | year= 2003 | volume= 349 | issue= 9 | pages= 847-58 | pmid=12944570 | doi=10.1056/NEJMoa022171 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12944570 }} </ref>. Similar results were found in trials that studied [[sirolimus]] <ref name="pmid23856215">{{cite journal| author=Matsuo Y, Cassar A, Yoshino S, Flammer AJ, Li J, Gulati R et al.| title=Attenuation of cardiac allograft vasculopathy by sirolimus: Relationship to time interval after heart transplantation. | journal=J Heart Lung Transplant | year= 2013 | volume= 32 | issue= 8 | pages= 784-91 | pmid=23856215 | doi=10.1016/j.healun.2013.05.015 | pmc=PMC3727915 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23856215 }} </ref>.
* Side effect profile:
** Everolimus: increase in [[serum creatinine]] levels, [[hyperlipidemia]], [[anemia]], [[thrombocytopenia]], [[peripheral edema]], [[hypertension]]. However, opportunistic viral infections less often seen.
** Sirolimus: Similar to everolimus, however recent reports of impaired wound healing have been reported in renal transplant patients.

====Mycophenolate mofetil====
* Studies have shown trend towards a lower maximal intimal thickness on [[IVUS]], lower incidence of retransplantation and death with [[mycophenolate]] when compared to [[azathioprine]] <ref name="pmid15896747">{{cite journal| author=Eisen HJ, Kobashigawa J, Keogh A, Bourge R, Renlund D, Mentzer R et al.| title=Three-year results of a randomized, double-blind, controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant recipients. | journal=J Heart Lung Transplant | year= 2005 | volume= 24 | issue= 5 | pages= 517-25 | pmid=15896747 | doi=10.1016/j.healun.2005.02.002 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15896747 }} </ref>.
* Side effect profile: [[chest pain]], [[hypertension]]/[[hypotension]], [[tachycardia]], [[peripheral edema]], [[headache]], [[fever]], [[rash]], [[abdominal pain]], [[nausea]], [[diarrhea]]/[[constipation]], [[leukopenia]], [[anemia]], [[thrombocytopenia]], [[liver function test]] abnormalities, abnormal [[creatinine]] and [[BUN]], increased risk for infections
====Calcineurin inhibitors====
* The use of [[Immunosuppressive drugs#Drugs Acting on Immunophilins|calcineurin inhibitors]] i.e [[cyclosporin]] and [[tacrolimus]] have not been shown to lower the risk of developing CAV.
* This suggests that other immunological pathways may exists that play a role in the pathogenesis of CAV. Moreover, side effects from use of these drugs leads to a high incidence of not only [[chronic renal disease]] but also [[hypertension]] and [[hyperlipidemia]] which in turn may accelerate the process of CAV.

===Non-Immunosuppressive therapy===
Non-immunosuppressive therapy includes:
* Lipid lowering therapy with [[statins]]
* [[Anti-hypertensive]] medications to optimize blood pressure
* Optimal glucose control in [[diabetes|diabetic]] patients
* Anti-cytomegalovirus therapy
* [[Antioxidants]]

====Statins====
* [[Obesity]], elevated levels of [[cyclosporine]], use of [[steroids]] and [[insulin resistance]] all contribute to the development of hyperlipidemia in cardiac transplant patients. Use of statins have proven to reduce mortality in multiple randomized controlled trials.
* Immunomodulatory effects of [[statins]] include:
** Inhibition of [[smooth muscle]] proliferation
*** By inhibiting lipid production, statins halt the intra-cellular signal transduction and consequently protein synthesis
*** By inhibiting expression of genes for [[growth factor]]s essential for proliferation of smooth muscles
** Direct influence on gene expression of endothelin-1, leading to improved endothelial function thereby protecting against [[atherogenesis]].
** Prevents attachment of [[monocytes]] to endothelium, which is the first step in [[atherogenesis]] <ref name="pmid12515749">{{cite journal| author=Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Krobot K et al.| title=Simvastatin initiated early after heart transplantation: 8-year prospective experience. | journal=Circulation | year= 2003 | volume= 107 | issue= 1 | pages= 93-7 | pmid=12515749 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12515749 }} </ref>
** In the presence of immunosuppressants like [[cyclosporin A]], statins reduce [[natural killer cell]] activity, [[T cell]] proliferation and activity in vitro. Moreover, statin induced LDL receptor activation leads to increase in intracellularly available LDL-bound cyclosporin A <ref name="pmid8880225">{{cite journal| author=Kurakata S, Kada M, Shimada Y, Komai T, Nomoto K| title=Effects of different inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, pravastatin sodium and simvastatin, on sterol synthesis and immunological functions in human lymphocytes in vitro. | journal=Immunopharmacology | year= 1996 | volume= 34 | issue= 1 | pages= 51-61 | pmid=8880225 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8880225 }} </ref>.
* Long term effects of [[simvastatin]]: The effects of [[simvastatin]] over a period of 8 years was studied in a randomized controlled trial by Wenke and colleagues <ref name="pmid12515749">{{cite journal| author=Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Krobot K et al.| title=Simvastatin initiated early after heart transplantation: 8-year prospective experience. | journal=Circulation | year= 2003 | volume= 107 | issue= 1 | pages= 93-7 | pmid=12515749 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12515749 }} </ref> in which the study group received simvastatin on the fourth post-operative day, whereas the control group was managed with dietary therapy alone.
** At the end of 8 years, the [[Kaplan-Meier estimator|Kaplan-Meier]] survival rate was 88.6% in the simvastatin group versus 59.5% in the control group (P< 0.006 by log rank, HR 0.24,95% CI, 0.08-0.71). The incidence of angiographically proven CAV was also found to be lower in the simvastatin group compared to the control group.
* Long term effects of [[pravastatin]]: Another randomized controlled trial by Kobashigawa and colleagues studied the effects of [[pravastatin]] at one year <ref name="pmid7637722">{{cite journal| author=Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman L, Wang XM et al.| title=Effect of pravastatin on outcomes after cardiac transplantation. | journal=N Engl J Med | year= 1995 | volume= 333 | issue= 10 | pages= 621-7 | pmid=7637722 | doi=10.1056/NEJM199509073331003 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7637722 }} </ref> and at the end of ten years <ref name="pmid16297773">{{cite journal| author=Kobashigawa JA, Moriguchi JD, Laks H, Wener L, Hage A, Hamilton MA et al.| title=Ten-year follow-up of a randomized trial of pravastatin in heart transplant patients. | journal=J Heart Lung Transplant | year= 2005 | volume= 24 | issue= 11 | pages= 1736-40 | pmid=16297773 | doi=10.1016/j.healun.2005.02.009 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16297773 }} </ref>.
** After 1 year of follow up, the patients in pravastatin group had reduced incidence of severe episodes of transplant rejections causing hemodynamic instability as well as CAV determined by angiography and autopsy. This group also had better survival compared to the non-pravastatin group.
** These significant differences also persisted in a 10 year follow up of the same study cohort which, similar to the above mentioned study, demonstrated survival benefits and reduced incidence of CAV by angiography in an intention to treat analysis.

====Calcium Channel Blockers and ACE inhibitors====
* Mechanisms by which [[calcium channel blockers]] (CCB's) and [[ACE inhibitors]] are thought to prevent CAV are as follows <ref name="pmid12176600">{{cite journal| author=Weis M| title=Cardiac allograft vasculopathy: prevention and treatment options. | journal=Transplant Proc | year= 2002 | volume= 34 | issue= 5 | pages= 1847-9 | pmid=12176600 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12176600 }} </ref>:
** Preservation of endothelial function
** Reduced oxidative stress
** Suppression of [[smooth muscle]] cell migration and proliferation
** Additionally [[nifedipine]] has been shown to cause [[vasodilatation]] in coronary arteries with endothelial dysfunction and inhibition of [[endothelin]] production <ref name="pmid11791002">{{cite journal| author=Weis M, Pehlivanli S, von Scheidt W| title=Vasodilator response to nifedipine in human coronary arteries with endothelial dysfunction. | journal=J Cardiovasc Pharmacol | year= 2002 | volume= 39 | issue= 2 | pages= 172-80 | pmid=11791002 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11791002 }} </ref>.
* In a study by Schroeder and colleagues<ref name="pmid8417382">{{cite journal| author=Schroeder JS, Gao SZ, Alderman EL, Hunt SA, Johnstone I, Boothroyd DB et al.| title=A preliminary study of diltiazem in the prevention of coronary artery disease in heart-transplant recipients. | journal=N Engl J Med | year= 1993 | volume= 328 | issue= 3 | pages= 164-70 | pmid=8417382 | doi=10.1056/NEJM199301213280303 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8417382 }} </ref> involving 57 cardiac transplant patients randomized to either receive [[diltiazem]] or placebo, showed that the coronary artery diameter decreased at a slower rate in patients receiving diltiazem compared to placebo at 1 year follow-up. However the overall survival at the end of 2 years remained unchanged.
* Synergistic effect of CCBs and ACE inhibitors: This was suggested by Erinc et al. when their study involving 82 heart transplant patients showed that combined use of CCB's and ACE inhibitors was associated with improvement in [[IVUS]] indices of CAV. These patients were randomized to receive either calcium channel blockers or ACE inhibitors or both or placebo and followed for one year.
* However, longer term trials are required to prove the effects of CCBs and ACE inhibitors on survival and mortality.

====Anti-cytomegalovirus Therapy====
* [[Cytomegalovirus]] (CMV), the most common infection encountered in cardiac transplant patients, may be subclinical and causes acceleration of CAV development by the following mechanisms:
** Dysregulation of [[nitric oxide]] pathway,
** [[Cytokine]] activation and
** Affects mononuclear adhesion and [[smooth muscle]] migration, causing endothelial dysfunction
* Simialr to CMV, [[adenovirus]], [[parvovirus]] and [[Chlamydiae pneumoniae]] is thought to trigger development of CAV <ref name="pmid14508350">{{cite journal| author=Valantine HA| title=Cardiac allograft vasculopathy: central role of endothelial injury leading to transplant "atheroma". | journal=Transplantation | year= 2003 | volume= 76 | issue= 6 | pages= 891-9 | pmid=14508350 | doi=10.1097/01.TP.0000080981.90718.EB | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14508350 }} </ref>.
* [[Gancicylcovir]] appears to slow the progression of CAV. Also early control of subclinical CMV infections may limit rejection and prevent CAV <ref name="pmid17015794">{{cite journal| author=Tu W, Potena L, Stepick-Biek P, Liu L, Dionis KY, Luikart H et al.| title=T-cell immunity to subclinical cytomegalovirus infection reduces cardiac allograft disease. | journal=Circulation | year= 2006 | volume= 114 | issue= 15 | pages= 1608-15 | pmid=17015794 | doi=10.1161/CIRCULATIONAHA.105.607549 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17015794 }} </ref>.

====Antioxidants====
* Mechanism of antioxidants in prevention of CAV involved:
** Augmenting endothelial nitric oxide (NO) activity
** Inhibiting the deleterious effects of free oxygen radicals on nitric oxide synthesis thereby preventing endothelial dysfunction and development of CAV
* Vitamin C & E, L-arginine and tetrahydrobiopterin supplementation can theoretically be beneficial, however long term trials to establish the effects of these agents in improving survival are lacking <ref name="pmid12176600">{{cite journal| author=Weis M| title=Cardiac allograft vasculopathy: prevention and treatment options. | journal=Transplant Proc | year= 2002 | volume= 34 | issue= 5 | pages= 1847-9 | pmid=12176600 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12176600 }} </ref>.

==References==
{{reflist|2}}
{{WH}}
{{WS}}

Cardiac allograft vasculopathy prevention

2014-12-07T06:13:10Z

Aarti Narayan: /* Anti-cytomegalovirus Therapy */

__NOTOC__
{{Cardiac allograft vasculopathy}}
{{CMG}}; {{AE}} {{AN}} {{RT}}

==Overview==

==Prevention==
As the pathogenesis of CAV consists of both immunological and non-immunological insults, it has been suggested that preventative strategies should consist of control of risk factors for CAV and optimal [[immunosuppressive therapy]]. However, the best preventative strategy to delay development of CAV is yet to be determined.

===Optimization of Immunosuppressive Therapy===
The [[rapamycin]] derivatives, [[sirolimus]] and [[everolimus]], have been proven to have significant benefit in the prevention of CAV in addition to [[statins]]. Other options for immunosuppressive therapy include <ref name="pmid16686747">{{cite journal| author=Mehra MR| title=Contemporary concepts in prevention and treatment of cardiac allograft vasculopathy. | journal=Am J Transplant | year= 2006 | volume= 6 | issue= 6 | pages= 1248-56 | pmid=16686747 | doi=10.1111/j.1600-6143.2006.01314.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16686747 }} </ref>:
* [[Corticosteroids]]
* [[Mycophenolate mofetil]]

====Everolimus and Sirolimus====
* Act by inhibiting mTOR (mammalian target), thereby having anti-proliferative effects in response to allo-antigens.
* Everolimus is currently not FDA approved for clinical use in the United States.
* Associated with significantly reduced incidence of [[graft rejection]].
* Serial [[IVUS]] studies to evaluate intimal proliferation demonstrated smaller increase in maximal intimal thickness and intimal index in patients taking [[everolimus]] <ref name="pmid12944570">{{cite journal| author=Eisen HJ, Tuzcu EM, Dorent R, Kobashigawa J, Mancini D, Valantine-von Kaeppler HA et al.| title=Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. | journal=N Engl J Med | year= 2003 | volume= 349 | issue= 9 | pages= 847-58 | pmid=12944570 | doi=10.1056/NEJMoa022171 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12944570 }} </ref>. Similar results were found in trials that studied [[sirolimus]] <ref name="pmid23856215">{{cite journal| author=Matsuo Y, Cassar A, Yoshino S, Flammer AJ, Li J, Gulati R et al.| title=Attenuation of cardiac allograft vasculopathy by sirolimus: Relationship to time interval after heart transplantation. | journal=J Heart Lung Transplant | year= 2013 | volume= 32 | issue= 8 | pages= 784-91 | pmid=23856215 | doi=10.1016/j.healun.2013.05.015 | pmc=PMC3727915 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23856215 }} </ref>.
* Side effect profile:
** Everolimus: increase in [[serum creatinine]] levels, [[hyperlipidemia]], [[anemia]], [[thrombocytopenia]], [[peripheral edema]], [[hypertension]]. However, opportunistic viral infections less often seen.
** Sirolimus: Similar to everolimus, however recent reports of impaired wound healing have been reported in renal transplant patients.

====Mycophenolate mofetil====
* Studies have shown trend towards a lower maximal intimal thickness on [[IVUS]], lower incidence of retransplantation and death with [[mycophenolate]] when compared to [[azathioprine]] <ref name="pmid15896747">{{cite journal| author=Eisen HJ, Kobashigawa J, Keogh A, Bourge R, Renlund D, Mentzer R et al.| title=Three-year results of a randomized, double-blind, controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant recipients. | journal=J Heart Lung Transplant | year= 2005 | volume= 24 | issue= 5 | pages= 517-25 | pmid=15896747 | doi=10.1016/j.healun.2005.02.002 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15896747 }} </ref>.
* Side effect profile: [[chest pain]], [[hypertension]]/[[hypotension]], [[tachycardia]], [[peripheral edema]], [[headache]], [[fever]], [[rash]], [[abdominal pain]], [[nausea]], [[diarrhea]]/[[constipation]], [[leukopenia]], [[anemia]], [[thrombocytopenia]], [[liver function test]] abnormalities, abnormal [[creatinine]] and [[BUN]], increased risk for infections
====Calcineurin inhibitors====
* The use of [[Immunosuppressive drugs#Drugs Acting on Immunophilins|calcineurin inhibitors]] i.e [[cyclosporin]] and [[tacrolimus]] have not been shown to lower the risk of developing CAV.
* This suggests that other immunological pathways may exists that play a role in the pathogenesis of CAV. Moreover, side effects from use of these drugs leads to a high incidence of not only [[chronic renal disease]] but also [[hypertension]] and [[hyperlipidemia]] which in turn may accelerate the process of CAV.

===Non-Immunosuppressive therapy===
Non-immunosuppressive therapy includes:
* Lipid lowering therapy with [[statins]]
* [[Anti-hypertensive]] medications to optimize blood pressure
* Optimal glucose control in [[diabetes|diabetic]] patients
* Anti-cytomegalovirus therapy
* [[Antioxidants]]

====Statins====
* [[Obesity]], elevated levels of [[cyclosporine]], use of [[steroids]] and [[insulin resistance]] all contribute to the development of hyperlipidemia in cardiac transplant patients. Use of statins have proven to reduce mortality in multiple randomized controlled trials.
* Immunomodulatory effects of [[statins]] include:
** Inhibition of [[smooth muscle]] proliferation
*** By inhibiting lipid production, statins halt the intra-cellular signal transduction and consequently protein synthesis
*** By inhibiting expression of genes for [[growth factor]]s essential for proliferation of smooth muscles
** Direct influence on gene expression of endothelin-1, leading to improved endothelial function thereby protecting against [[atherogenesis]].
** Prevents attachment of [[monocytes]] to endothelium, which is the first step in [[atherogenesis]] <ref name="pmid12515749">{{cite journal| author=Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Krobot K et al.| title=Simvastatin initiated early after heart transplantation: 8-year prospective experience. | journal=Circulation | year= 2003 | volume= 107 | issue= 1 | pages= 93-7 | pmid=12515749 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12515749 }} </ref>
** In the presence of immunosuppressants like [[cyclosporin A]], statins reduce [[natural killer cell]] activity, [[T cell]] proliferation and activity in vitro. Moreover, statin induced LDL receptor activation leads to increase in intracellularly available LDL-bound cyclosporin A <ref name="pmid8880225">{{cite journal| author=Kurakata S, Kada M, Shimada Y, Komai T, Nomoto K| title=Effects of different inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, pravastatin sodium and simvastatin, on sterol synthesis and immunological functions in human lymphocytes in vitro. | journal=Immunopharmacology | year= 1996 | volume= 34 | issue= 1 | pages= 51-61 | pmid=8880225 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8880225 }} </ref>.
* Long term effects of [[simvastatin]]: The effects of [[simvastatin]] over a period of 8 years was studied in a randomized controlled trial by Wenke and colleagues <ref name="pmid12515749">{{cite journal| author=Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Krobot K et al.| title=Simvastatin initiated early after heart transplantation: 8-year prospective experience. | journal=Circulation | year= 2003 | volume= 107 | issue= 1 | pages= 93-7 | pmid=12515749 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12515749 }} </ref> in which the study group received simvastatin on the fourth post-operative day, whereas the control group was managed with dietary therapy alone.
** At the end of 8 years, the [[Kaplan-Meier estimator|Kaplan-Meier]] survival rate was 88.6% in the simvastatin group versus 59.5% in the control group (P< 0.006 by log rank, HR 0.24,95% CI, 0.08-0.71). The incidence of angiographically proven CAV was also found to be lower in the simvastatin group compared to the control group.
* Long term effects of [[pravastatin]]: Another randomized controlled trial by Kobashigawa and colleagues studied the effects of [[pravastatin]] at one year <ref name="pmid7637722">{{cite journal| author=Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman L, Wang XM et al.| title=Effect of pravastatin on outcomes after cardiac transplantation. | journal=N Engl J Med | year= 1995 | volume= 333 | issue= 10 | pages= 621-7 | pmid=7637722 | doi=10.1056/NEJM199509073331003 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7637722 }} </ref> and at the end of ten years <ref name="pmid16297773">{{cite journal| author=Kobashigawa JA, Moriguchi JD, Laks H, Wener L, Hage A, Hamilton MA et al.| title=Ten-year follow-up of a randomized trial of pravastatin in heart transplant patients. | journal=J Heart Lung Transplant | year= 2005 | volume= 24 | issue= 11 | pages= 1736-40 | pmid=16297773 | doi=10.1016/j.healun.2005.02.009 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16297773 }} </ref>.
** After 1 year of follow up, the patients in pravastatin group had reduced incidence of severe episodes of transplant rejections causing hemodynamic instability as well as CAV determined by angiography and autopsy. This group also had better survival compared to the non-pravastatin group.
** These significant differences also persisted in a 10 year follow up of the same study cohort which, similar to the above mentioned study, demonstrated survival benefits and reduced incidence of CAV by angiography in an intention to treat analysis.

====Calcium Channel Blockers and ACE inhibitors====
* Mechanisms by which [[calcium channel blockers]] (CCB's) and [[ACE inhibitors]] are thought to prevent CAV are as follows <ref name="pmid12176600">{{cite journal| author=Weis M| title=Cardiac allograft vasculopathy: prevention and treatment options. | journal=Transplant Proc | year= 2002 | volume= 34 | issue= 5 | pages= 1847-9 | pmid=12176600 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12176600 }} </ref>:
** Preservation of endothelial function
** Reduced oxidative stress
** Suppression of [[smooth muscle]] cell migration and proliferation
** Additionally [[nifedipine]] has been shown to cause [[vasodilatation]] in coronary arteries with endothelial dysfunction and inhibition of [[endothelin]] production <ref name="pmid11791002">{{cite journal| author=Weis M, Pehlivanli S, von Scheidt W| title=Vasodilator response to nifedipine in human coronary arteries with endothelial dysfunction. | journal=J Cardiovasc Pharmacol | year= 2002 | volume= 39 | issue= 2 | pages= 172-80 | pmid=11791002 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11791002 }} </ref>.
* In a study by Schroeder and colleagues<ref name="pmid8417382">{{cite journal| author=Schroeder JS, Gao SZ, Alderman EL, Hunt SA, Johnstone I, Boothroyd DB et al.| title=A preliminary study of diltiazem in the prevention of coronary artery disease in heart-transplant recipients. | journal=N Engl J Med | year= 1993 | volume= 328 | issue= 3 | pages= 164-70 | pmid=8417382 | doi=10.1056/NEJM199301213280303 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8417382 }} </ref> involving 57 cardiac transplant patients randomized to either receive [[diltiazem]] or placebo, showed that the coronary artery diameter decreased at a slower rate in patients receiving diltiazem compared to placebo at 1 year follow-up. However the overall survival at the end of 2 years remained unchanged.
* Synergistic effect of CCBs and ACE inhibitors: This was suggested by Erinc et al. when their study involving 82 heart transplant patients showed that combined use of CCB's and ACE inhibitors was associated with improvement in [[IVUS]] indices of CAV. These patients were randomized to receive either calcium channel blockers or ACE inhibitors or both or placebo and followed for one year.
* However, longer term trials are required to prove the effects of CCBs and ACE inhibitors on survival and mortality.

====Antioxidants====
* Mechanism of antioxidants in prevention of CAV involved:
** Augmenting endothelial nitric oxide (NO) activity
** Inhibiting the deleterious effects of free oxygen radicals on nitric oxide synthesis thereby preventing endothelial dysfunction and development of CAV
* Vitamin C & E, L-arginine and tetrahydrobiopterin supplementation can theoretically be beneficial, however long term trials to establish the effects of these agents in improving survival are lacking <ref name="pmid12176600">{{cite journal| author=Weis M| title=Cardiac allograft vasculopathy: prevention and treatment options. | journal=Transplant Proc | year= 2002 | volume= 34 | issue= 5 | pages= 1847-9 | pmid=12176600 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12176600 }} </ref>.

====Anti-cytomegalovirus Therapy====
* [[Cytomegalovirus]] (CMV), the most common infection encountered in cardiac transplant patients, may be subclinical and causes acceleration of CAV development by the following mechanisms:
** Dysregulation of [[nitric oxide]] pathway,
** [[Cytokine]] activation and
** Affects mononuclear adhesion and [[smooth muscle]] migration, causing endothelial dysfunction
* Simialr to CMV, [[adenovirus]], [[parvovirus]] and [[Chlamydiae pneumoniae]] is thought to trigger development of CAV <ref name="pmid14508350">{{cite journal| author=Valantine HA| title=Cardiac allograft vasculopathy: central role of endothelial injury leading to transplant "atheroma". | journal=Transplantation | year= 2003 | volume= 76 | issue= 6 | pages= 891-9 | pmid=14508350 | doi=10.1097/01.TP.0000080981.90718.EB | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14508350 }} </ref>.
* [[Gancicylcovir]] appears to slow the progression of CAV. Also early control of subclinical CMV infections may limit rejection and prevent CAV <ref name="pmid17015794">{{cite journal| author=Tu W, Potena L, Stepick-Biek P, Liu L, Dionis KY, Luikart H et al.| title=T-cell immunity to subclinical cytomegalovirus infection reduces cardiac allograft disease. | journal=Circulation | year= 2006 | volume= 114 | issue= 15 | pages= 1608-15 | pmid=17015794 | doi=10.1161/CIRCULATIONAHA.105.607549 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17015794 }} </ref>.

==References==
{{reflist|2}}
{{WH}}
{{WS}}

Cardiac allograft vasculopathy prevention

2014-12-07T06:04:50Z

Aarti Narayan: /* Anti-cytomegalovirus Therapy */

__NOTOC__
{{Cardiac allograft vasculopathy}}
{{CMG}}; {{AE}} {{AN}} {{RT}}

==Overview==

==Prevention==
As the pathogenesis of CAV consists of both immunological and non-immunological insults, it has been suggested that preventative strategies should consist of control of risk factors for CAV and optimal [[immunosuppressive therapy]]. However, the best preventative strategy to delay development of CAV is yet to be determined.

===Optimization of Immunosuppressive Therapy===
The [[rapamycin]] derivatives, [[sirolimus]] and [[everolimus]], have been proven to have significant benefit in the prevention of CAV in addition to [[statins]]. Other options for immunosuppressive therapy include <ref name="pmid16686747">{{cite journal| author=Mehra MR| title=Contemporary concepts in prevention and treatment of cardiac allograft vasculopathy. | journal=Am J Transplant | year= 2006 | volume= 6 | issue= 6 | pages= 1248-56 | pmid=16686747 | doi=10.1111/j.1600-6143.2006.01314.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16686747 }} </ref>:
* [[Corticosteroids]]
* [[Mycophenolate mofetil]]

====Everolimus and Sirolimus====
* Act by inhibiting mTOR (mammalian target), thereby having anti-proliferative effects in response to allo-antigens.
* Everolimus is currently not FDA approved for clinical use in the United States.
* Associated with significantly reduced incidence of [[graft rejection]].
* Serial [[IVUS]] studies to evaluate intimal proliferation demonstrated smaller increase in maximal intimal thickness and intimal index in patients taking [[everolimus]] <ref name="pmid12944570">{{cite journal| author=Eisen HJ, Tuzcu EM, Dorent R, Kobashigawa J, Mancini D, Valantine-von Kaeppler HA et al.| title=Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. | journal=N Engl J Med | year= 2003 | volume= 349 | issue= 9 | pages= 847-58 | pmid=12944570 | doi=10.1056/NEJMoa022171 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12944570 }} </ref>. Similar results were found in trials that studied [[sirolimus]] <ref name="pmid23856215">{{cite journal| author=Matsuo Y, Cassar A, Yoshino S, Flammer AJ, Li J, Gulati R et al.| title=Attenuation of cardiac allograft vasculopathy by sirolimus: Relationship to time interval after heart transplantation. | journal=J Heart Lung Transplant | year= 2013 | volume= 32 | issue= 8 | pages= 784-91 | pmid=23856215 | doi=10.1016/j.healun.2013.05.015 | pmc=PMC3727915 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23856215 }} </ref>.
* Side effect profile:
** Everolimus: increase in [[serum creatinine]] levels, [[hyperlipidemia]], [[anemia]], [[thrombocytopenia]], [[peripheral edema]], [[hypertension]]. However, opportunistic viral infections less often seen.
** Sirolimus: Similar to everolimus, however recent reports of impaired wound healing have been reported in renal transplant patients.

====Mycophenolate mofetil====
* Studies have shown trend towards a lower maximal intimal thickness on [[IVUS]], lower incidence of retransplantation and death with [[mycophenolate]] when compared to [[azathioprine]] <ref name="pmid15896747">{{cite journal| author=Eisen HJ, Kobashigawa J, Keogh A, Bourge R, Renlund D, Mentzer R et al.| title=Three-year results of a randomized, double-blind, controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant recipients. | journal=J Heart Lung Transplant | year= 2005 | volume= 24 | issue= 5 | pages= 517-25 | pmid=15896747 | doi=10.1016/j.healun.2005.02.002 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15896747 }} </ref>.
* Side effect profile: [[chest pain]], [[hypertension]]/[[hypotension]], [[tachycardia]], [[peripheral edema]], [[headache]], [[fever]], [[rash]], [[abdominal pain]], [[nausea]], [[diarrhea]]/[[constipation]], [[leukopenia]], [[anemia]], [[thrombocytopenia]], [[liver function test]] abnormalities, abnormal [[creatinine]] and [[BUN]], increased risk for infections
====Calcineurin inhibitors====
* The use of [[Immunosuppressive drugs#Drugs Acting on Immunophilins|calcineurin inhibitors]] i.e [[cyclosporin]] and [[tacrolimus]] have not been shown to lower the risk of developing CAV.
* This suggests that other immunological pathways may exists that play a role in the pathogenesis of CAV. Moreover, side effects from use of these drugs leads to a high incidence of not only [[chronic renal disease]] but also [[hypertension]] and [[hyperlipidemia]] which in turn may accelerate the process of CAV.

===Non-Immunosuppressive therapy===
Non-immunosuppressive therapy includes:
* Lipid lowering therapy with [[statins]]
* [[Anti-hypertensive]] medications to optimize blood pressure
* Optimal glucose control in [[diabetes|diabetic]] patients
* Anti-cytomegalovirus therapy
* [[Antioxidants]]

====Statins====
* [[Obesity]], elevated levels of [[cyclosporine]], use of [[steroids]] and [[insulin resistance]] all contribute to the development of hyperlipidemia in cardiac transplant patients. Use of statins have proven to reduce mortality in multiple randomized controlled trials.
* Immunomodulatory effects of [[statins]] include:
** Inhibition of [[smooth muscle]] proliferation
*** By inhibiting lipid production, statins halt the intra-cellular signal transduction and consequently protein synthesis
*** By inhibiting expression of genes for [[growth factor]]s essential for proliferation of smooth muscles
** Direct influence on gene expression of endothelin-1, leading to improved endothelial function thereby protecting against [[atherogenesis]].
** Prevents attachment of [[monocytes]] to endothelium, which is the first step in [[atherogenesis]] <ref name="pmid12515749">{{cite journal| author=Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Krobot K et al.| title=Simvastatin initiated early after heart transplantation: 8-year prospective experience. | journal=Circulation | year= 2003 | volume= 107 | issue= 1 | pages= 93-7 | pmid=12515749 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12515749 }} </ref>
** In the presence of immunosuppressants like [[cyclosporin A]], statins reduce [[natural killer cell]] activity, [[T cell]] proliferation and activity in vitro. Moreover, statin induced LDL receptor activation leads to increase in intracellularly available LDL-bound cyclosporin A <ref name="pmid8880225">{{cite journal| author=Kurakata S, Kada M, Shimada Y, Komai T, Nomoto K| title=Effects of different inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, pravastatin sodium and simvastatin, on sterol synthesis and immunological functions in human lymphocytes in vitro. | journal=Immunopharmacology | year= 1996 | volume= 34 | issue= 1 | pages= 51-61 | pmid=8880225 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8880225 }} </ref>.
* Long term effects of [[simvastatin]]: The effects of [[simvastatin]] over a period of 8 years was studied in a randomized controlled trial by Wenke and colleagues <ref name="pmid12515749">{{cite journal| author=Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Krobot K et al.| title=Simvastatin initiated early after heart transplantation: 8-year prospective experience. | journal=Circulation | year= 2003 | volume= 107 | issue= 1 | pages= 93-7 | pmid=12515749 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12515749 }} </ref> in which the study group received simvastatin on the fourth post-operative day, whereas the control group was managed with dietary therapy alone.
** At the end of 8 years, the [[Kaplan-Meier estimator|Kaplan-Meier]] survival rate was 88.6% in the simvastatin group versus 59.5% in the control group (P< 0.006 by log rank, HR 0.24,95% CI, 0.08-0.71). The incidence of angiographically proven CAV was also found to be lower in the simvastatin group compared to the control group.
* Long term effects of [[pravastatin]]: Another randomized controlled trial by Kobashigawa and colleagues studied the effects of [[pravastatin]] at one year <ref name="pmid7637722">{{cite journal| author=Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman L, Wang XM et al.| title=Effect of pravastatin on outcomes after cardiac transplantation. | journal=N Engl J Med | year= 1995 | volume= 333 | issue= 10 | pages= 621-7 | pmid=7637722 | doi=10.1056/NEJM199509073331003 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7637722 }} </ref> and at the end of ten years <ref name="pmid16297773">{{cite journal| author=Kobashigawa JA, Moriguchi JD, Laks H, Wener L, Hage A, Hamilton MA et al.| title=Ten-year follow-up of a randomized trial of pravastatin in heart transplant patients. | journal=J Heart Lung Transplant | year= 2005 | volume= 24 | issue= 11 | pages= 1736-40 | pmid=16297773 | doi=10.1016/j.healun.2005.02.009 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16297773 }} </ref>.
** After 1 year of follow up, the patients in pravastatin group had reduced incidence of severe episodes of transplant rejections causing hemodynamic instability as well as CAV determined by angiography and autopsy. This group also had better survival compared to the non-pravastatin group.
** These significant differences also persisted in a 10 year follow up of the same study cohort which, similar to the above mentioned study, demonstrated survival benefits and reduced incidence of CAV by angiography in an intention to treat analysis.

====Calcium Channel Blockers and ACE inhibitors====
* Mechanisms by which [[calcium channel blockers]] (CCB's) and [[ACE inhibitors]] are thought to prevent CAV are as follows <ref name="pmid12176600">{{cite journal| author=Weis M| title=Cardiac allograft vasculopathy: prevention and treatment options. | journal=Transplant Proc | year= 2002 | volume= 34 | issue= 5 | pages= 1847-9 | pmid=12176600 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12176600 }} </ref>:
** Preservation of endothelial function
** Reduced oxidative stress
** Suppression of [[smooth muscle]] cell migration and proliferation
** Additionally [[nifedipine]] has been shown to cause [[vasodilatation]] in coronary arteries with endothelial dysfunction and inhibition of [[endothelin]] production <ref name="pmid11791002">{{cite journal| author=Weis M, Pehlivanli S, von Scheidt W| title=Vasodilator response to nifedipine in human coronary arteries with endothelial dysfunction. | journal=J Cardiovasc Pharmacol | year= 2002 | volume= 39 | issue= 2 | pages= 172-80 | pmid=11791002 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11791002 }} </ref>.
* In a study by Schroeder and colleagues<ref name="pmid8417382">{{cite journal| author=Schroeder JS, Gao SZ, Alderman EL, Hunt SA, Johnstone I, Boothroyd DB et al.| title=A preliminary study of diltiazem in the prevention of coronary artery disease in heart-transplant recipients. | journal=N Engl J Med | year= 1993 | volume= 328 | issue= 3 | pages= 164-70 | pmid=8417382 | doi=10.1056/NEJM199301213280303 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8417382 }} </ref> involving 57 cardiac transplant patients randomized to either receive [[diltiazem]] or placebo, showed that the coronary artery diameter decreased at a slower rate in patients receiving diltiazem compared to placebo at 1 year follow-up. However the overall survival at the end of 2 years remained unchanged.
* Synergistic effect of CCBs and ACE inhibitors: This was suggested by Erinc et al. when their study involving 82 heart transplant patients showed that combined use of CCB's and ACE inhibitors was associated with improvement in [[IVUS]] indices of CAV. These patients were randomized to receive either calcium channel blockers or ACE inhibitors or both or placebo and followed for one year.
* However, longer term trials are required to prove the effects of CCBs and ACE inhibitors on survival and mortality.

====Antioxidants====
* Mechanism of antioxidants in prevention of CAV involved:
** Augmenting endothelial nitric oxide (NO) activity
** Inhibiting the deleterious effects of free oxygen radicals on nitric oxide synthesis thereby preventing endothelial dysfunction and development of CAV
* Vitamin C & E, L-arginine and tetrahydrobiopterin supplementation can theoretically be beneficial, however long term trials to establish the effects of these agents in improving survival are lacking <ref name="pmid12176600">{{cite journal| author=Weis M| title=Cardiac allograft vasculopathy: prevention and treatment options. | journal=Transplant Proc | year= 2002 | volume= 34 | issue= 5 | pages= 1847-9 | pmid=12176600 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12176600 }} </ref>.

====Anti-cytomegalovirus Therapy====
* [[Cytomegalovirus]], the most common infection encountered in cardiac transplant patients, may be subclinical and causes acceleration of CAV development by the following mechanisms:
** Dysregulation of [[nitric oxide]] pathway,
** [[Cytokine]] activation and
** Affects mononuclear adhesion and [[smooth muscle]] migration, causing endothelial dysfunction

==References==
{{reflist|2}}
{{WH}}
{{WS}}

Cardiac allograft vasculopathy prevention

2014-12-07T06:02:57Z

Aarti Narayan: /* Non-Immunosuppressive therapy */

__NOTOC__
{{Cardiac allograft vasculopathy}}
{{CMG}}; {{AE}} {{AN}} {{RT}}

==Overview==

==Prevention==
As the pathogenesis of CAV consists of both immunological and non-immunological insults, it has been suggested that preventative strategies should consist of control of risk factors for CAV and optimal [[immunosuppressive therapy]]. However, the best preventative strategy to delay development of CAV is yet to be determined.

===Optimization of Immunosuppressive Therapy===
The [[rapamycin]] derivatives, [[sirolimus]] and [[everolimus]], have been proven to have significant benefit in the prevention of CAV in addition to [[statins]]. Other options for immunosuppressive therapy include <ref name="pmid16686747">{{cite journal| author=Mehra MR| title=Contemporary concepts in prevention and treatment of cardiac allograft vasculopathy. | journal=Am J Transplant | year= 2006 | volume= 6 | issue= 6 | pages= 1248-56 | pmid=16686747 | doi=10.1111/j.1600-6143.2006.01314.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16686747 }} </ref>:
* [[Corticosteroids]]
* [[Mycophenolate mofetil]]

====Everolimus and Sirolimus====
* Act by inhibiting mTOR (mammalian target), thereby having anti-proliferative effects in response to allo-antigens.
* Everolimus is currently not FDA approved for clinical use in the United States.
* Associated with significantly reduced incidence of [[graft rejection]].
* Serial [[IVUS]] studies to evaluate intimal proliferation demonstrated smaller increase in maximal intimal thickness and intimal index in patients taking [[everolimus]] <ref name="pmid12944570">{{cite journal| author=Eisen HJ, Tuzcu EM, Dorent R, Kobashigawa J, Mancini D, Valantine-von Kaeppler HA et al.| title=Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. | journal=N Engl J Med | year= 2003 | volume= 349 | issue= 9 | pages= 847-58 | pmid=12944570 | doi=10.1056/NEJMoa022171 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12944570 }} </ref>. Similar results were found in trials that studied [[sirolimus]] <ref name="pmid23856215">{{cite journal| author=Matsuo Y, Cassar A, Yoshino S, Flammer AJ, Li J, Gulati R et al.| title=Attenuation of cardiac allograft vasculopathy by sirolimus: Relationship to time interval after heart transplantation. | journal=J Heart Lung Transplant | year= 2013 | volume= 32 | issue= 8 | pages= 784-91 | pmid=23856215 | doi=10.1016/j.healun.2013.05.015 | pmc=PMC3727915 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23856215 }} </ref>.
* Side effect profile:
** Everolimus: increase in [[serum creatinine]] levels, [[hyperlipidemia]], [[anemia]], [[thrombocytopenia]], [[peripheral edema]], [[hypertension]]. However, opportunistic viral infections less often seen.
** Sirolimus: Similar to everolimus, however recent reports of impaired wound healing have been reported in renal transplant patients.

====Mycophenolate mofetil====
* Studies have shown trend towards a lower maximal intimal thickness on [[IVUS]], lower incidence of retransplantation and death with [[mycophenolate]] when compared to [[azathioprine]] <ref name="pmid15896747">{{cite journal| author=Eisen HJ, Kobashigawa J, Keogh A, Bourge R, Renlund D, Mentzer R et al.| title=Three-year results of a randomized, double-blind, controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant recipients. | journal=J Heart Lung Transplant | year= 2005 | volume= 24 | issue= 5 | pages= 517-25 | pmid=15896747 | doi=10.1016/j.healun.2005.02.002 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15896747 }} </ref>.
* Side effect profile: [[chest pain]], [[hypertension]]/[[hypotension]], [[tachycardia]], [[peripheral edema]], [[headache]], [[fever]], [[rash]], [[abdominal pain]], [[nausea]], [[diarrhea]]/[[constipation]], [[leukopenia]], [[anemia]], [[thrombocytopenia]], [[liver function test]] abnormalities, abnormal [[creatinine]] and [[BUN]], increased risk for infections
====Calcineurin inhibitors====
* The use of [[Immunosuppressive drugs#Drugs Acting on Immunophilins|calcineurin inhibitors]] i.e [[cyclosporin]] and [[tacrolimus]] have not been shown to lower the risk of developing CAV.
* This suggests that other immunological pathways may exists that play a role in the pathogenesis of CAV. Moreover, side effects from use of these drugs leads to a high incidence of not only [[chronic renal disease]] but also [[hypertension]] and [[hyperlipidemia]] which in turn may accelerate the process of CAV.

===Non-Immunosuppressive therapy===
Non-immunosuppressive therapy includes:
* Lipid lowering therapy with [[statins]]
* [[Anti-hypertensive]] medications to optimize blood pressure
* Optimal glucose control in [[diabetes|diabetic]] patients
* Anti-cytomegalovirus therapy
* [[Antioxidants]]

====Statins====
* [[Obesity]], elevated levels of [[cyclosporine]], use of [[steroids]] and [[insulin resistance]] all contribute to the development of hyperlipidemia in cardiac transplant patients. Use of statins have proven to reduce mortality in multiple randomized controlled trials.
* Immunomodulatory effects of [[statins]] include:
** Inhibition of [[smooth muscle]] proliferation
*** By inhibiting lipid production, statins halt the intra-cellular signal transduction and consequently protein synthesis
*** By inhibiting expression of genes for [[growth factor]]s essential for proliferation of smooth muscles
** Direct influence on gene expression of endothelin-1, leading to improved endothelial function thereby protecting against [[atherogenesis]].
** Prevents attachment of [[monocytes]] to endothelium, which is the first step in [[atherogenesis]] <ref name="pmid12515749">{{cite journal| author=Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Krobot K et al.| title=Simvastatin initiated early after heart transplantation: 8-year prospective experience. | journal=Circulation | year= 2003 | volume= 107 | issue= 1 | pages= 93-7 | pmid=12515749 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12515749 }} </ref>
** In the presence of immunosuppressants like [[cyclosporin A]], statins reduce [[natural killer cell]] activity, [[T cell]] proliferation and activity in vitro. Moreover, statin induced LDL receptor activation leads to increase in intracellularly available LDL-bound cyclosporin A <ref name="pmid8880225">{{cite journal| author=Kurakata S, Kada M, Shimada Y, Komai T, Nomoto K| title=Effects of different inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, pravastatin sodium and simvastatin, on sterol synthesis and immunological functions in human lymphocytes in vitro. | journal=Immunopharmacology | year= 1996 | volume= 34 | issue= 1 | pages= 51-61 | pmid=8880225 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8880225 }} </ref>.
* Long term effects of [[simvastatin]]: The effects of [[simvastatin]] over a period of 8 years was studied in a randomized controlled trial by Wenke and colleagues <ref name="pmid12515749">{{cite journal| author=Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Krobot K et al.| title=Simvastatin initiated early after heart transplantation: 8-year prospective experience. | journal=Circulation | year= 2003 | volume= 107 | issue= 1 | pages= 93-7 | pmid=12515749 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12515749 }} </ref> in which the study group received simvastatin on the fourth post-operative day, whereas the control group was managed with dietary therapy alone.
** At the end of 8 years, the [[Kaplan-Meier estimator|Kaplan-Meier]] survival rate was 88.6% in the simvastatin group versus 59.5% in the control group (P< 0.006 by log rank, HR 0.24,95% CI, 0.08-0.71). The incidence of angiographically proven CAV was also found to be lower in the simvastatin group compared to the control group.
* Long term effects of [[pravastatin]]: Another randomized controlled trial by Kobashigawa and colleagues studied the effects of [[pravastatin]] at one year <ref name="pmid7637722">{{cite journal| author=Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman L, Wang XM et al.| title=Effect of pravastatin on outcomes after cardiac transplantation. | journal=N Engl J Med | year= 1995 | volume= 333 | issue= 10 | pages= 621-7 | pmid=7637722 | doi=10.1056/NEJM199509073331003 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7637722 }} </ref> and at the end of ten years <ref name="pmid16297773">{{cite journal| author=Kobashigawa JA, Moriguchi JD, Laks H, Wener L, Hage A, Hamilton MA et al.| title=Ten-year follow-up of a randomized trial of pravastatin in heart transplant patients. | journal=J Heart Lung Transplant | year= 2005 | volume= 24 | issue= 11 | pages= 1736-40 | pmid=16297773 | doi=10.1016/j.healun.2005.02.009 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16297773 }} </ref>.
** After 1 year of follow up, the patients in pravastatin group had reduced incidence of severe episodes of transplant rejections causing hemodynamic instability as well as CAV determined by angiography and autopsy. This group also had better survival compared to the non-pravastatin group.
** These significant differences also persisted in a 10 year follow up of the same study cohort which, similar to the above mentioned study, demonstrated survival benefits and reduced incidence of CAV by angiography in an intention to treat analysis.

====Calcium Channel Blockers and ACE inhibitors====
* Mechanisms by which [[calcium channel blockers]] (CCB's) and [[ACE inhibitors]] are thought to prevent CAV are as follows <ref name="pmid12176600">{{cite journal| author=Weis M| title=Cardiac allograft vasculopathy: prevention and treatment options. | journal=Transplant Proc | year= 2002 | volume= 34 | issue= 5 | pages= 1847-9 | pmid=12176600 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12176600 }} </ref>:
** Preservation of endothelial function
** Reduced oxidative stress
** Suppression of [[smooth muscle]] cell migration and proliferation
** Additionally [[nifedipine]] has been shown to cause [[vasodilatation]] in coronary arteries with endothelial dysfunction and inhibition of [[endothelin]] production <ref name="pmid11791002">{{cite journal| author=Weis M, Pehlivanli S, von Scheidt W| title=Vasodilator response to nifedipine in human coronary arteries with endothelial dysfunction. | journal=J Cardiovasc Pharmacol | year= 2002 | volume= 39 | issue= 2 | pages= 172-80 | pmid=11791002 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11791002 }} </ref>.
* In a study by Schroeder and colleagues<ref name="pmid8417382">{{cite journal| author=Schroeder JS, Gao SZ, Alderman EL, Hunt SA, Johnstone I, Boothroyd DB et al.| title=A preliminary study of diltiazem in the prevention of coronary artery disease in heart-transplant recipients. | journal=N Engl J Med | year= 1993 | volume= 328 | issue= 3 | pages= 164-70 | pmid=8417382 | doi=10.1056/NEJM199301213280303 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8417382 }} </ref> involving 57 cardiac transplant patients randomized to either receive [[diltiazem]] or placebo, showed that the coronary artery diameter decreased at a slower rate in patients receiving diltiazem compared to placebo at 1 year follow-up. However the overall survival at the end of 2 years remained unchanged.
* Synergistic effect of CCBs and ACE inhibitors: This was suggested by Erinc et al. when their study involving 82 heart transplant patients showed that combined use of CCB's and ACE inhibitors was associated with improvement in [[IVUS]] indices of CAV. These patients were randomized to receive either calcium channel blockers or ACE inhibitors or both or placebo and followed for one year.
* However, longer term trials are required to prove the effects of CCBs and ACE inhibitors on survival and mortality.

====Antioxidants====
* Mechanism of antioxidants in prevention of CAV involved:
** Augmenting endothelial nitric oxide (NO) activity
** Inhibiting the deleterious effects of free oxygen radicals on nitric oxide synthesis thereby preventing endothelial dysfunction and development of CAV
* Vitamin C & E, L-arginine and tetrahydrobiopterin supplementation can theoretically be beneficial, however long term trials to establish the effects of these agents in improving survival are lacking <ref name="pmid12176600">{{cite journal| author=Weis M| title=Cardiac allograft vasculopathy: prevention and treatment options. | journal=Transplant Proc | year= 2002 | volume= 34 | issue= 5 | pages= 1847-9 | pmid=12176600 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12176600 }} </ref>.

====Anti-cytomegalovirus Therapy====
* [[Cytomegalovirus]], the most common infection encountered in cardiac transplant patients, causes acceleration of CAV development by the following mechanisms:
** Dysregulation of [[nitric oxide]] pathway,
** [[Cytokine]] activation and
** Affects mononuclear adhesion and [[smooth muscle]] migration, causing endothelial dysfunction

==References==
{{reflist|2}}
{{WH}}
{{WS}}

Cardiac allograft vasculopathy prevention

2014-12-07T05:54:46Z

Aarti Narayan: /* Non-Immunosuppressive therapy */

__NOTOC__
{{Cardiac allograft vasculopathy}}
{{CMG}}; {{AE}} {{AN}} {{RT}}

==Overview==

==Prevention==
As the pathogenesis of CAV consists of both immunological and non-immunological insults, it has been suggested that preventative strategies should consist of control of risk factors for CAV and optimal [[immunosuppressive therapy]]. However, the best preventative strategy to delay development of CAV is yet to be determined.

===Optimization of Immunosuppressive Therapy===
The [[rapamycin]] derivatives, [[sirolimus]] and [[everolimus]], have been proven to have significant benefit in the prevention of CAV in addition to [[statins]]. Other options for immunosuppressive therapy include <ref name="pmid16686747">{{cite journal| author=Mehra MR| title=Contemporary concepts in prevention and treatment of cardiac allograft vasculopathy. | journal=Am J Transplant | year= 2006 | volume= 6 | issue= 6 | pages= 1248-56 | pmid=16686747 | doi=10.1111/j.1600-6143.2006.01314.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16686747 }} </ref>:
* [[Corticosteroids]]
* [[Mycophenolate mofetil]]

====Everolimus and Sirolimus====
* Act by inhibiting mTOR (mammalian target), thereby having anti-proliferative effects in response to allo-antigens.
* Everolimus is currently not FDA approved for clinical use in the United States.
* Associated with significantly reduced incidence of [[graft rejection]].
* Serial [[IVUS]] studies to evaluate intimal proliferation demonstrated smaller increase in maximal intimal thickness and intimal index in patients taking [[everolimus]] <ref name="pmid12944570">{{cite journal| author=Eisen HJ, Tuzcu EM, Dorent R, Kobashigawa J, Mancini D, Valantine-von Kaeppler HA et al.| title=Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. | journal=N Engl J Med | year= 2003 | volume= 349 | issue= 9 | pages= 847-58 | pmid=12944570 | doi=10.1056/NEJMoa022171 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12944570 }} </ref>. Similar results were found in trials that studied [[sirolimus]] <ref name="pmid23856215">{{cite journal| author=Matsuo Y, Cassar A, Yoshino S, Flammer AJ, Li J, Gulati R et al.| title=Attenuation of cardiac allograft vasculopathy by sirolimus: Relationship to time interval after heart transplantation. | journal=J Heart Lung Transplant | year= 2013 | volume= 32 | issue= 8 | pages= 784-91 | pmid=23856215 | doi=10.1016/j.healun.2013.05.015 | pmc=PMC3727915 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23856215 }} </ref>.
* Side effect profile:
** Everolimus: increase in [[serum creatinine]] levels, [[hyperlipidemia]], [[anemia]], [[thrombocytopenia]], [[peripheral edema]], [[hypertension]]. However, opportunistic viral infections less often seen.
** Sirolimus: Similar to everolimus, however recent reports of impaired wound healing have been reported in renal transplant patients.

====Mycophenolate mofetil====
* Studies have shown trend towards a lower maximal intimal thickness on [[IVUS]], lower incidence of retransplantation and death with [[mycophenolate]] when compared to [[azathioprine]] <ref name="pmid15896747">{{cite journal| author=Eisen HJ, Kobashigawa J, Keogh A, Bourge R, Renlund D, Mentzer R et al.| title=Three-year results of a randomized, double-blind, controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant recipients. | journal=J Heart Lung Transplant | year= 2005 | volume= 24 | issue= 5 | pages= 517-25 | pmid=15896747 | doi=10.1016/j.healun.2005.02.002 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15896747 }} </ref>.
* Side effect profile: [[chest pain]], [[hypertension]]/[[hypotension]], [[tachycardia]], [[peripheral edema]], [[headache]], [[fever]], [[rash]], [[abdominal pain]], [[nausea]], [[diarrhea]]/[[constipation]], [[leukopenia]], [[anemia]], [[thrombocytopenia]], [[liver function test]] abnormalities, abnormal [[creatinine]] and [[BUN]], increased risk for infections
====Calcineurin inhibitors====
* The use of [[Immunosuppressive drugs#Drugs Acting on Immunophilins|calcineurin inhibitors]] i.e [[cyclosporin]] and [[tacrolimus]] have not been shown to lower the risk of developing CAV.
* This suggests that other immunological pathways may exists that play a role in the pathogenesis of CAV. Moreover, side effects from use of these drugs leads to a high incidence of not only [[chronic renal disease]] but also [[hypertension]] and [[hyperlipidemia]] which in turn may accelerate the process of CAV.

===Non-Immunosuppressive therapy===
Non-immunosuppressive therapy includes:
* Lipid lowering therapy with [[statins]]
* [[Anti-hypertensive]] medications to optimize blood pressure
* Optimal glucose control in [[diabetes|diabetic]] patients
* Anti-cytomegalovirus therapy
* [[Antioxidants]]

====Statins====
* [[Obesity]], elevated levels of [[cyclosporine]], use of [[steroids]] and [[insulin resistance]] all contribute to the development of hyperlipidemia in cardiac transplant patients. Use of statins have proven to reduce mortality in multiple randomized controlled trials.
* Immunomodulatory effects of [[statins]] include:
** Inhibition of [[smooth muscle]] proliferation
*** By inhibiting lipid production, statins halt the intra-cellular signal transduction and consequently protein synthesis
*** By inhibiting expression of genes for [[growth factor]]s essential for proliferation of smooth muscles
** Direct influence on gene expression of endothelin-1, leading to improved endothelial function thereby protecting against [[atherogenesis]].
** Prevents attachment of [[monocytes]] to endothelium, which is the first step in [[atherogenesis]] <ref name="pmid12515749">{{cite journal| author=Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Krobot K et al.| title=Simvastatin initiated early after heart transplantation: 8-year prospective experience. | journal=Circulation | year= 2003 | volume= 107 | issue= 1 | pages= 93-7 | pmid=12515749 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12515749 }} </ref>
** In the presence of immunosuppressants like [[cyclosporin A]], statins reduce [[natural killer cell]] activity, [[T cell]] proliferation and activity in vitro. Moreover, statin induced LDL receptor activation leads to increase in intracellularly available LDL-bound cyclosporin A <ref name="pmid8880225">{{cite journal| author=Kurakata S, Kada M, Shimada Y, Komai T, Nomoto K| title=Effects of different inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, pravastatin sodium and simvastatin, on sterol synthesis and immunological functions in human lymphocytes in vitro. | journal=Immunopharmacology | year= 1996 | volume= 34 | issue= 1 | pages= 51-61 | pmid=8880225 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8880225 }} </ref>.
* Long term effects of [[simvastatin]]: The effects of [[simvastatin]] over a period of 8 years was studied in a randomized controlled trial by Wenke and colleagues <ref name="pmid12515749">{{cite journal| author=Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Krobot K et al.| title=Simvastatin initiated early after heart transplantation: 8-year prospective experience. | journal=Circulation | year= 2003 | volume= 107 | issue= 1 | pages= 93-7 | pmid=12515749 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12515749 }} </ref> in which the study group received simvastatin on the fourth post-operative day, whereas the control group was managed with dietary therapy alone.
** At the end of 8 years, the [[Kaplan-Meier estimator|Kaplan-Meier]] survival rate was 88.6% in the simvastatin group versus 59.5% in the control group (P< 0.006 by log rank, HR 0.24,95% CI, 0.08-0.71). The incidence of angiographically proven CAV was also found to be lower in the simvastatin group compared to the control group.
* Long term effects of [[pravastatin]]: Another randomized controlled trial by Kobashigawa and colleagues studied the effects of [[pravastatin]] at one year <ref name="pmid7637722">{{cite journal| author=Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman L, Wang XM et al.| title=Effect of pravastatin on outcomes after cardiac transplantation. | journal=N Engl J Med | year= 1995 | volume= 333 | issue= 10 | pages= 621-7 | pmid=7637722 | doi=10.1056/NEJM199509073331003 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7637722 }} </ref> and at the end of ten years <ref name="pmid16297773">{{cite journal| author=Kobashigawa JA, Moriguchi JD, Laks H, Wener L, Hage A, Hamilton MA et al.| title=Ten-year follow-up of a randomized trial of pravastatin in heart transplant patients. | journal=J Heart Lung Transplant | year= 2005 | volume= 24 | issue= 11 | pages= 1736-40 | pmid=16297773 | doi=10.1016/j.healun.2005.02.009 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16297773 }} </ref>.
** After 1 year of follow up, the patients in pravastatin group had reduced incidence of severe episodes of transplant rejections causing hemodynamic instability as well as CAV determined by angiography and autopsy. This group also had better survival compared to the non-pravastatin group.
** These significant differences also persisted in a 10 year follow up of the same study cohort which, similar to the above mentioned study, demonstrated survival benefits and reduced incidence of CAV by angiography in an intention to treat analysis.

====Calcium Channel Blockers and ACE inhibitors====
* Mechanisms by which [[calcium channel blockers]] (CCB's) and [[ACE inhibitors]] are thought to prevent CAV are as follows <ref name="pmid12176600">{{cite journal| author=Weis M| title=Cardiac allograft vasculopathy: prevention and treatment options. | journal=Transplant Proc | year= 2002 | volume= 34 | issue= 5 | pages= 1847-9 | pmid=12176600 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12176600 }} </ref>:
** Preservation of endothelial function
** Reduced oxidative stress
** Suppression of [[smooth muscle]] cell migration and proliferation
** Additionally [[nifedipine]] has been shown to cause [[vasodilatation]] in coronary arteries with endothelial dysfunction and inhibition of [[endothelin]] production <ref name="pmid11791002">{{cite journal| author=Weis M, Pehlivanli S, von Scheidt W| title=Vasodilator response to nifedipine in human coronary arteries with endothelial dysfunction. | journal=J Cardiovasc Pharmacol | year= 2002 | volume= 39 | issue= 2 | pages= 172-80 | pmid=11791002 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11791002 }} </ref>.
* In a study by Schroeder and colleagues<ref name="pmid8417382">{{cite journal| author=Schroeder JS, Gao SZ, Alderman EL, Hunt SA, Johnstone I, Boothroyd DB et al.| title=A preliminary study of diltiazem in the prevention of coronary artery disease in heart-transplant recipients. | journal=N Engl J Med | year= 1993 | volume= 328 | issue= 3 | pages= 164-70 | pmid=8417382 | doi=10.1056/NEJM199301213280303 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8417382 }} </ref> involving 57 cardiac transplant patients randomized to either receive [[diltiazem]] or placebo, showed that the coronary artery diameter decreased at a slower rate in patients receiving diltiazem compared to placebo at 1 year follow-up. However the overall survival at the end of 2 years remained unchanged.
* Synergistic effect of CCBs and ACE inhibitors: This was suggested by Erinc et al. when their study involving 82 heart transplant patients showed that combined use of CCB's and ACE inhibitors was associated with improvement in [[IVUS]] indices of CAV. These patients were randomized to receive either calcium channel blockers or ACE inhibitors or both or placebo and followed for one year.
* However, longer term trials are required to prove the effects of CCBs and ACE inhibitors on survival and mortality.

====Antioxidants====
* Mechanism of antioxidants in prevention of CAV involved:
** Augmenting endothelial nitric oxide (NO) activity
** Inhibiting the deleterious effects of free oxygen radicals on nitric oxide synthesis thereby preventing endothelial dysfunction and development of CAV
* Vitamin C & E, L-arginine and tetrahydrobiopterin supplementation can theoretically be beneficial, however long term trials to establish the effects of these agents in improving survival are lacking <ref name="pmid12176600">{{cite journal| author=Weis M| title=Cardiac allograft vasculopathy: prevention and treatment options. | journal=Transplant Proc | year= 2002 | volume= 34 | issue= 5 | pages= 1847-9 | pmid=12176600 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12176600 }} </ref>.

==References==
{{reflist|2}}
{{WH}}
{{WS}}

Cardiac allograft vasculopathy prevention

2014-12-07T05:45:20Z

Aarti Narayan: /* Calcium Channel Blockers and ACE inhibitors */

Cardiac allograft vasculopathy prevention

2014-12-07T05:44:00Z

Aarti Narayan: /* Calcium Channel Blockers and ACE inhibitors */

__NOTOC__
{{Cardiac allograft vasculopathy}}
{{CMG}}; {{AE}} {{AN}} {{RT}}

==Overview==

==Prevention==
As the pathogenesis of CAV consists of both immunological and non-immunological insults, it has been suggested that preventative strategies should consist of control of risk factors for CAV and optimal [[immunosuppressive therapy]]. However, the best preventative strategy to delay development of CAV is yet to be determined.

===Optimization of Immunosuppressive Therapy===
The [[rapamycin]] derivatives, [[sirolimus]] and [[everolimus]], have been proven to have significant benefit in the prevention of CAV in addition to [[statins]]. Other options for immunosuppressive therapy include <ref name="pmid16686747">{{cite journal| author=Mehra MR| title=Contemporary concepts in prevention and treatment of cardiac allograft vasculopathy. | journal=Am J Transplant | year= 2006 | volume= 6 | issue= 6 | pages= 1248-56 | pmid=16686747 | doi=10.1111/j.1600-6143.2006.01314.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16686747 }} </ref>:
* [[Corticosteroids]]
* [[Mycophenolate mofetil]]

====Everolimus and Sirolimus====
* Act by inhibiting mTOR (mammalian target), thereby having anti-proliferative effects in response to allo-antigens.
* Everolimus is currently not FDA approved for clinical use in the United States.
* Associated with significantly reduced incidence of [[graft rejection]].
* Serial [[IVUS]] studies to evaluate intimal proliferation demonstrated smaller increase in maximal intimal thickness and intimal index in patients taking [[everolimus]] <ref name="pmid12944570">{{cite journal| author=Eisen HJ, Tuzcu EM, Dorent R, Kobashigawa J, Mancini D, Valantine-von Kaeppler HA et al.| title=Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. | journal=N Engl J Med | year= 2003 | volume= 349 | issue= 9 | pages= 847-58 | pmid=12944570 | doi=10.1056/NEJMoa022171 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12944570 }} </ref>. Similar results were found in trials that studied [[sirolimus]] <ref name="pmid23856215">{{cite journal| author=Matsuo Y, Cassar A, Yoshino S, Flammer AJ, Li J, Gulati R et al.| title=Attenuation of cardiac allograft vasculopathy by sirolimus: Relationship to time interval after heart transplantation. | journal=J Heart Lung Transplant | year= 2013 | volume= 32 | issue= 8 | pages= 784-91 | pmid=23856215 | doi=10.1016/j.healun.2013.05.015 | pmc=PMC3727915 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23856215 }} </ref>.
* Side effect profile:
** Everolimus: increase in [[serum creatinine]] levels, [[hyperlipidemia]], [[anemia]], [[thrombocytopenia]], [[peripheral edema]], [[hypertension]]. However, opportunistic viral infections less often seen.
** Sirolimus: Similar to everolimus, however recent reports of impaired wound healing have been reported in renal transplant patients.

====Mycophenolate mofetil====
* Studies have shown trend towards a lower maximal intimal thickness on [[IVUS]], lower incidence of retransplantation and death with [[mycophenolate]] when compared to [[azathioprine]] <ref name="pmid15896747">{{cite journal| author=Eisen HJ, Kobashigawa J, Keogh A, Bourge R, Renlund D, Mentzer R et al.| title=Three-year results of a randomized, double-blind, controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant recipients. | journal=J Heart Lung Transplant | year= 2005 | volume= 24 | issue= 5 | pages= 517-25 | pmid=15896747 | doi=10.1016/j.healun.2005.02.002 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15896747 }} </ref>.
* Side effect profile: [[chest pain]], [[hypertension]]/[[hypotension]], [[tachycardia]], [[peripheral edema]], [[headache]], [[fever]], [[rash]], [[abdominal pain]], [[nausea]], [[diarrhea]]/[[constipation]], [[leukopenia]], [[anemia]], [[thrombocytopenia]], [[liver function test]] abnormalities, abnormal [[creatinine]] and [[BUN]], increased risk for infections
====Calcineurin inhibitors====
* The use of [[Immunosuppressive drugs#Drugs Acting on Immunophilins|calcineurin inhibitors]] i.e [[cyclosporin]] and [[tacrolimus]] have not been shown to lower the risk of developing CAV.
* This suggests that other immunological pathways may exists that play a role in the pathogenesis of CAV. Moreover, side effects from use of these drugs leads to a high incidence of not only [[chronic renal disease]] but also [[hypertension]] and [[hyperlipidemia]] which in turn may accelerate the process of CAV.

===Non-Immunosuppressive therapy===
Non-immunosuppressive therapy includes:
* Lipid lowering therapy with [[statins]]
* [[Anti-hypertensive]] medications to optimize blood pressure
* Optimal glucose control in [[diabetes|diabetic]] patients
* Anti-cytomegalovirus therapy
* [[Antioxidants]]

====Statins====
* [[Obesity]], elevated levels of [[cyclosporine]], use of [[steroids]] and [[insulin resistance]] all contribute to the development of hyperlipidemia in cardiac transplant patients. Use of statins have proven to reduce mortality in multiple randomized controlled trials.
* Immunomodulatory effects of [[statins]] include:
** Inhibition of [[smooth muscle]] proliferation
*** By inhibiting lipid production, statins halt the intra-cellular signal transduction and consequently protein synthesis
*** By inhibiting expression of genes for [[growth factor]]s essential for proliferation of smooth muscles
** Direct influence on gene expression of endothelin-1, leading to improved endothelial function thereby protecting against [[atherogenesis]].
** Prevents attachment of [[monocytes]] to endothelium, which is the first step in [[atherogenesis]] <ref name="pmid12515749">{{cite journal| author=Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Krobot K et al.| title=Simvastatin initiated early after heart transplantation: 8-year prospective experience. | journal=Circulation | year= 2003 | volume= 107 | issue= 1 | pages= 93-7 | pmid=12515749 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12515749 }} </ref>
** In the presence of immunosuppressants like [[cyclosporin A]], statins reduce [[natural killer cell]] activity, [[T cell]] proliferation and activity in vitro. Moreover, statin induced LDL receptor activation leads to increase in intracellularly available LDL-bound cyclosporin A <ref name="pmid8880225">{{cite journal| author=Kurakata S, Kada M, Shimada Y, Komai T, Nomoto K| title=Effects of different inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, pravastatin sodium and simvastatin, on sterol synthesis and immunological functions in human lymphocytes in vitro. | journal=Immunopharmacology | year= 1996 | volume= 34 | issue= 1 | pages= 51-61 | pmid=8880225 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8880225 }} </ref>.
* Long term effects of [[simvastatin]]: The effects of [[simvastatin]] over a period of 8 years was studied in a randomized controlled trial by Wenke and colleagues <ref name="pmid12515749">{{cite journal| author=Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Krobot K et al.| title=Simvastatin initiated early after heart transplantation: 8-year prospective experience. | journal=Circulation | year= 2003 | volume= 107 | issue= 1 | pages= 93-7 | pmid=12515749 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12515749 }} </ref> in which the study group received simvastatin on the fourth post-operative day, whereas the control group was managed with dietary therapy alone.
** At the end of 8 years, the [[Kaplan-Meier estimator|Kaplan-Meier]] survival rate was 88.6% in the simvastatin group versus 59.5% in the control group (P< 0.006 by log rank, HR 0.24,95% CI, 0.08-0.71). The incidence of angiographically proven CAV was also found to be lower in the simvastatin group compared to the control group.
* Long term effects of [[pravastatin]]: Another randomized controlled trial by Kobashigawa and colleagues studied the effects of [[pravastatin]] at one year <ref name="pmid7637722">{{cite journal| author=Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman L, Wang XM et al.| title=Effect of pravastatin on outcomes after cardiac transplantation. | journal=N Engl J Med | year= 1995 | volume= 333 | issue= 10 | pages= 621-7 | pmid=7637722 | doi=10.1056/NEJM199509073331003 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7637722 }} </ref> and at the end of ten years <ref name="pmid16297773">{{cite journal| author=Kobashigawa JA, Moriguchi JD, Laks H, Wener L, Hage A, Hamilton MA et al.| title=Ten-year follow-up of a randomized trial of pravastatin in heart transplant patients. | journal=J Heart Lung Transplant | year= 2005 | volume= 24 | issue= 11 | pages= 1736-40 | pmid=16297773 | doi=10.1016/j.healun.2005.02.009 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16297773 }} </ref>.
** After 1 year of follow up, the patients in pravastatin group had reduced incidence of severe episodes of transplant rejections causing hemodynamic instability as well as CAV determined by angiography and autopsy. This group also had better survival compared to the non-pravastatin group.
** These significant differences also persisted in a 10 year follow up of the same study cohort which, similar to the above mentioned study, demonstrated survival benefits and reduced incidence of CAV by angiography in an intention to treat analysis.

====Calcium Channel Blockers and ACE inhibitors====
* Mechanisms by which [[calcium channel blockers]] (CCB's) and [[ACE inhibitors]] are thought to prevent CAV are as follows <ref name="pmid12176600">{{cite journal| author=Weis M| title=Cardiac allograft vasculopathy: prevention and treatment options. | journal=Transplant Proc | year= 2002 | volume= 34 | issue= 5 | pages= 1847-9 | pmid=12176600 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12176600 }} </ref>:
** Preservation of endothelial function
** Reduced oxidative stress
** Suppression of [[smooth muscle]] cell migration and proliferation
** Additionally [[nifedipine]] has been shown to cause [[vasodilatation]] in coronary arteries with endothelial dysfunction and inhibition of [[endothelin]] production <ref name="pmid11791002">{{cite journal| author=Weis M, Pehlivanli S, von Scheidt W| title=Vasodilator response to nifedipine in human coronary arteries with endothelial dysfunction. | journal=J Cardiovasc Pharmacol | year= 2002 | volume= 39 | issue= 2 | pages= 172-80 | pmid=11791002 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11791002 }} </ref>.
* In a study by Schroeder and colleagues<ref name="pmid8417382">{{cite journal| author=Schroeder JS, Gao SZ, Alderman EL, Hunt SA, Johnstone I, Boothroyd DB et al.| title=A preliminary study of diltiazem in the prevention of coronary artery disease in heart-transplant recipients. | journal=N Engl J Med | year= 1993 | volume= 328 | issue= 3 | pages= 164-70 | pmid=8417382 | doi=10.1056/NEJM199301213280303 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8417382 }} </ref> involving 57 cardiac transplant patients randomized to either receive [[diltiazem]] or placebo, showed that the coronary artery diameter decreased at a slower rate in patients receiving diltiazem compared to placebo at 1 year follow-up. However the overall survival at the end of 2 years remained unchanged.
* Synergistic effect of calcium channel blockers and ACE inhibitors: This was suggested by Erinc et al. when their study involving 82 heart transplant patients showed that combined use of CCB's and ACE inhibitors was associated with improvement in [[IVUS]] indices of CAV. These patients were randomized to receive either calcium channel blockers or ACE inhibitors or both or placebo and followed for one year.
* However, longer term trials are required to prove the effects of CCBs and ACE inhibitors on survival and mortality.

==References==
{{reflist|2}}
{{WH}}
{{WS}}

Cardiac allograft vasculopathy prevention

2014-12-07T05:39:15Z

Aarti Narayan: /* Calcium Channel Blockers and ACE inhibitors */

__NOTOC__
{{Cardiac allograft vasculopathy}}
{{CMG}}; {{AE}} {{AN}} {{RT}}

==Overview==

==Prevention==
As the pathogenesis of CAV consists of both immunological and non-immunological insults, it has been suggested that preventative strategies should consist of control of risk factors for CAV and optimal [[immunosuppressive therapy]]. However, the best preventative strategy to delay development of CAV is yet to be determined.

===Optimization of Immunosuppressive Therapy===
The [[rapamycin]] derivatives, [[sirolimus]] and [[everolimus]], have been proven to have significant benefit in the prevention of CAV in addition to [[statins]]. Other options for immunosuppressive therapy include <ref name="pmid16686747">{{cite journal| author=Mehra MR| title=Contemporary concepts in prevention and treatment of cardiac allograft vasculopathy. | journal=Am J Transplant | year= 2006 | volume= 6 | issue= 6 | pages= 1248-56 | pmid=16686747 | doi=10.1111/j.1600-6143.2006.01314.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16686747 }} </ref>:
* [[Corticosteroids]]
* [[Mycophenolate mofetil]]

====Everolimus and Sirolimus====
* Act by inhibiting mTOR (mammalian target), thereby having anti-proliferative effects in response to allo-antigens.
* Everolimus is currently not FDA approved for clinical use in the United States.
* Associated with significantly reduced incidence of [[graft rejection]].
* Serial [[IVUS]] studies to evaluate intimal proliferation demonstrated smaller increase in maximal intimal thickness and intimal index in patients taking [[everolimus]] <ref name="pmid12944570">{{cite journal| author=Eisen HJ, Tuzcu EM, Dorent R, Kobashigawa J, Mancini D, Valantine-von Kaeppler HA et al.| title=Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. | journal=N Engl J Med | year= 2003 | volume= 349 | issue= 9 | pages= 847-58 | pmid=12944570 | doi=10.1056/NEJMoa022171 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12944570 }} </ref>. Similar results were found in trials that studied [[sirolimus]] <ref name="pmid23856215">{{cite journal| author=Matsuo Y, Cassar A, Yoshino S, Flammer AJ, Li J, Gulati R et al.| title=Attenuation of cardiac allograft vasculopathy by sirolimus: Relationship to time interval after heart transplantation. | journal=J Heart Lung Transplant | year= 2013 | volume= 32 | issue= 8 | pages= 784-91 | pmid=23856215 | doi=10.1016/j.healun.2013.05.015 | pmc=PMC3727915 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23856215 }} </ref>.
* Side effect profile:
** Everolimus: increase in [[serum creatinine]] levels, [[hyperlipidemia]], [[anemia]], [[thrombocytopenia]], [[peripheral edema]], [[hypertension]]. However, opportunistic viral infections less often seen.
** Sirolimus: Similar to everolimus, however recent reports of impaired wound healing have been reported in renal transplant patients.

====Mycophenolate mofetil====
* Studies have shown trend towards a lower maximal intimal thickness on [[IVUS]], lower incidence of retransplantation and death with [[mycophenolate]] when compared to [[azathioprine]] <ref name="pmid15896747">{{cite journal| author=Eisen HJ, Kobashigawa J, Keogh A, Bourge R, Renlund D, Mentzer R et al.| title=Three-year results of a randomized, double-blind, controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant recipients. | journal=J Heart Lung Transplant | year= 2005 | volume= 24 | issue= 5 | pages= 517-25 | pmid=15896747 | doi=10.1016/j.healun.2005.02.002 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15896747 }} </ref>.
* Side effect profile: [[chest pain]], [[hypertension]]/[[hypotension]], [[tachycardia]], [[peripheral edema]], [[headache]], [[fever]], [[rash]], [[abdominal pain]], [[nausea]], [[diarrhea]]/[[constipation]], [[leukopenia]], [[anemia]], [[thrombocytopenia]], [[liver function test]] abnormalities, abnormal [[creatinine]] and [[BUN]], increased risk for infections
====Calcineurin inhibitors====
* The use of [[Immunosuppressive drugs#Drugs Acting on Immunophilins|calcineurin inhibitors]] i.e [[cyclosporin]] and [[tacrolimus]] have not been shown to lower the risk of developing CAV.
* This suggests that other immunological pathways may exists that play a role in the pathogenesis of CAV. Moreover, side effects from use of these drugs leads to a high incidence of not only [[chronic renal disease]] but also [[hypertension]] and [[hyperlipidemia]] which in turn may accelerate the process of CAV.

===Non-Immunosuppressive therapy===
Non-immunosuppressive therapy includes:
* Lipid lowering therapy with [[statins]]
* [[Anti-hypertensive]] medications to optimize blood pressure
* Optimal glucose control in [[diabetes|diabetic]] patients
* Anti-cytomegalovirus therapy
* [[Antioxidants]]

====Statins====
* [[Obesity]], elevated levels of [[cyclosporine]], use of [[steroids]] and [[insulin resistance]] all contribute to the development of hyperlipidemia in cardiac transplant patients. Use of statins have proven to reduce mortality in multiple randomized controlled trials.
* Immunomodulatory effects of [[statins]] include:
** Inhibition of [[smooth muscle]] proliferation
*** By inhibiting lipid production, statins halt the intra-cellular signal transduction and consequently protein synthesis
*** By inhibiting expression of genes for [[growth factor]]s essential for proliferation of smooth muscles
** Direct influence on gene expression of endothelin-1, leading to improved endothelial function thereby protecting against [[atherogenesis]].
** Prevents attachment of [[monocytes]] to endothelium, which is the first step in [[atherogenesis]] <ref name="pmid12515749">{{cite journal| author=Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Krobot K et al.| title=Simvastatin initiated early after heart transplantation: 8-year prospective experience. | journal=Circulation | year= 2003 | volume= 107 | issue= 1 | pages= 93-7 | pmid=12515749 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12515749 }} </ref>
** In the presence of immunosuppressants like [[cyclosporin A]], statins reduce [[natural killer cell]] activity, [[T cell]] proliferation and activity in vitro. Moreover, statin induced LDL receptor activation leads to increase in intracellularly available LDL-bound cyclosporin A <ref name="pmid8880225">{{cite journal| author=Kurakata S, Kada M, Shimada Y, Komai T, Nomoto K| title=Effects of different inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, pravastatin sodium and simvastatin, on sterol synthesis and immunological functions in human lymphocytes in vitro. | journal=Immunopharmacology | year= 1996 | volume= 34 | issue= 1 | pages= 51-61 | pmid=8880225 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8880225 }} </ref>.
* Long term effects of [[simvastatin]]: The effects of [[simvastatin]] over a period of 8 years was studied in a randomized controlled trial by Wenke and colleagues <ref name="pmid12515749">{{cite journal| author=Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Krobot K et al.| title=Simvastatin initiated early after heart transplantation: 8-year prospective experience. | journal=Circulation | year= 2003 | volume= 107 | issue= 1 | pages= 93-7 | pmid=12515749 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12515749 }} </ref> in which the study group received simvastatin on the fourth post-operative day, whereas the control group was managed with dietary therapy alone.
** At the end of 8 years, the [[Kaplan-Meier estimator|Kaplan-Meier]] survival rate was 88.6% in the simvastatin group versus 59.5% in the control group (P< 0.006 by log rank, HR 0.24,95% CI, 0.08-0.71). The incidence of angiographically proven CAV was also found to be lower in the simvastatin group compared to the control group.
* Long term effects of [[pravastatin]]: Another randomized controlled trial by Kobashigawa and colleagues studied the effects of [[pravastatin]] at one year <ref name="pmid7637722">{{cite journal| author=Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman L, Wang XM et al.| title=Effect of pravastatin on outcomes after cardiac transplantation. | journal=N Engl J Med | year= 1995 | volume= 333 | issue= 10 | pages= 621-7 | pmid=7637722 | doi=10.1056/NEJM199509073331003 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7637722 }} </ref> and at the end of ten years <ref name="pmid16297773">{{cite journal| author=Kobashigawa JA, Moriguchi JD, Laks H, Wener L, Hage A, Hamilton MA et al.| title=Ten-year follow-up of a randomized trial of pravastatin in heart transplant patients. | journal=J Heart Lung Transplant | year= 2005 | volume= 24 | issue= 11 | pages= 1736-40 | pmid=16297773 | doi=10.1016/j.healun.2005.02.009 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16297773 }} </ref>.
** After 1 year of follow up, the patients in pravastatin group had reduced incidence of severe episodes of transplant rejections causing hemodynamic instability as well as CAV determined by angiography and autopsy. This group also had better survival compared to the non-pravastatin group.
** These significant differences also persisted in a 10 year follow up of the same study cohort which, similar to the above mentioned study, demonstrated survival benefits and reduced incidence of CAV by angiography in an intention to treat analysis.

====Calcium Channel Blockers and ACE inhibitors====
* Mechanisms by which [[calcium channel blockers]] (CCB's) and [[ACE inhibitors]] are thought to prevent CAV are as follows <ref name="pmid12176600">{{cite journal| author=Weis M| title=Cardiac allograft vasculopathy: prevention and treatment options. | journal=Transplant Proc | year= 2002 | volume= 34 | issue= 5 | pages= 1847-9 | pmid=12176600 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12176600 }} </ref>:
** Preservation of endothelial function
** Reduced oxidative stress
** Suppression of [[smooth muscle]] cell migration and proliferation
** Additionally [[nifedipine]] has been shown to cause [[vasodilatation]] in coronary arteries with endothelial dysfunction and inhibition of [[endothelin]] production <ref name="pmid11791002">{{cite journal| author=Weis M, Pehlivanli S, von Scheidt W| title=Vasodilator response to nifedipine in human coronary arteries with endothelial dysfunction. | journal=J Cardiovasc Pharmacol | year= 2002 | volume= 39 | issue= 2 | pages= 172-80 | pmid=11791002 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11791002 }} </ref>.
* In a study by Schroeder and colleagues<ref name="pmid8417382">{{cite journal| author=Schroeder JS, Gao SZ, Alderman EL, Hunt SA, Johnstone I, Boothroyd DB et al.| title=A preliminary study of diltiazem in the prevention of coronary artery disease in heart-transplant recipients. | journal=N Engl J Med | year= 1993 | volume= 328 | issue= 3 | pages= 164-70 | pmid=8417382 | doi=10.1056/NEJM199301213280303 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8417382 }} </ref> involving 57 cardiac transplant patients randomized to either receive [[diltiazem]] or placebo, showed that the coronary artery diameter decreased at a slower rate in patients receiving diltiazem compared to placebo at 1 year follow-up. However the overall survival at the end of 2 years remained unchanged.
* Synergistic effect of calcium channel blockers and ACE inhibitors: This was suggested by Erinc et al. when their study involving 82 heart transplant patients showed that combined use of CCB's and ACE inhibitors was associated with improvement in [[IVUS]] indices of CAV. These patients were randomized to receive either calcium channel blockers or ACE inhibitors or both or placebo.

==References==
{{reflist|2}}
{{WH}}
{{WS}}

Cardiac allograft vasculopathy prevention

2014-12-07T04:58:20Z

Aarti Narayan: /* Calcium Channel Blockers and ACE inhibitors */

__NOTOC__
{{Cardiac allograft vasculopathy}}
{{CMG}}; {{AE}} {{AN}} {{RT}}

==Overview==

==Prevention==
As the pathogenesis of CAV consists of both immunological and non-immunological insults, it has been suggested that preventative strategies should consist of control of risk factors for CAV and optimal [[immunosuppressive therapy]]. However, the best preventative strategy to delay development of CAV is yet to be determined.

===Optimization of Immunosuppressive Therapy===
The [[rapamycin]] derivatives, [[sirolimus]] and [[everolimus]], have been proven to have significant benefit in the prevention of CAV in addition to [[statins]]. Other options for immunosuppressive therapy include <ref name="pmid16686747">{{cite journal| author=Mehra MR| title=Contemporary concepts in prevention and treatment of cardiac allograft vasculopathy. | journal=Am J Transplant | year= 2006 | volume= 6 | issue= 6 | pages= 1248-56 | pmid=16686747 | doi=10.1111/j.1600-6143.2006.01314.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16686747 }} </ref>:
* [[Corticosteroids]]
* [[Mycophenolate mofetil]]

====Everolimus and Sirolimus====
* Act by inhibiting mTOR (mammalian target), thereby having anti-proliferative effects in response to allo-antigens.
* Everolimus is currently not FDA approved for clinical use in the United States.
* Associated with significantly reduced incidence of [[graft rejection]].
* Serial [[IVUS]] studies to evaluate intimal proliferation demonstrated smaller increase in maximal intimal thickness and intimal index in patients taking [[everolimus]] <ref name="pmid12944570">{{cite journal| author=Eisen HJ, Tuzcu EM, Dorent R, Kobashigawa J, Mancini D, Valantine-von Kaeppler HA et al.| title=Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. | journal=N Engl J Med | year= 2003 | volume= 349 | issue= 9 | pages= 847-58 | pmid=12944570 | doi=10.1056/NEJMoa022171 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12944570 }} </ref>. Similar results were found in trials that studied [[sirolimus]] <ref name="pmid23856215">{{cite journal| author=Matsuo Y, Cassar A, Yoshino S, Flammer AJ, Li J, Gulati R et al.| title=Attenuation of cardiac allograft vasculopathy by sirolimus: Relationship to time interval after heart transplantation. | journal=J Heart Lung Transplant | year= 2013 | volume= 32 | issue= 8 | pages= 784-91 | pmid=23856215 | doi=10.1016/j.healun.2013.05.015 | pmc=PMC3727915 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23856215 }} </ref>.
* Side effect profile:
** Everolimus: increase in [[serum creatinine]] levels, [[hyperlipidemia]], [[anemia]], [[thrombocytopenia]], [[peripheral edema]], [[hypertension]]. However, opportunistic viral infections less often seen.
** Sirolimus: Similar to everolimus, however recent reports of impaired wound healing have been reported in renal transplant patients.

====Mycophenolate mofetil====
* Studies have shown trend towards a lower maximal intimal thickness on [[IVUS]], lower incidence of retransplantation and death with [[mycophenolate]] when compared to [[azathioprine]] <ref name="pmid15896747">{{cite journal| author=Eisen HJ, Kobashigawa J, Keogh A, Bourge R, Renlund D, Mentzer R et al.| title=Three-year results of a randomized, double-blind, controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant recipients. | journal=J Heart Lung Transplant | year= 2005 | volume= 24 | issue= 5 | pages= 517-25 | pmid=15896747 | doi=10.1016/j.healun.2005.02.002 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15896747 }} </ref>.
* Side effect profile: [[chest pain]], [[hypertension]]/[[hypotension]], [[tachycardia]], [[peripheral edema]], [[headache]], [[fever]], [[rash]], [[abdominal pain]], [[nausea]], [[diarrhea]]/[[constipation]], [[leukopenia]], [[anemia]], [[thrombocytopenia]], [[liver function test]] abnormalities, abnormal [[creatinine]] and [[BUN]], increased risk for infections
====Calcineurin inhibitors====
* The use of [[Immunosuppressive drugs#Drugs Acting on Immunophilins|calcineurin inhibitors]] i.e [[cyclosporin]] and [[tacrolimus]] have not been shown to lower the risk of developing CAV.
* This suggests that other immunological pathways may exists that play a role in the pathogenesis of CAV. Moreover, side effects from use of these drugs leads to a high incidence of not only [[chronic renal disease]] but also [[hypertension]] and [[hyperlipidemia]] which in turn may accelerate the process of CAV.

===Non-Immunosuppressive therapy===
Non-immunosuppressive therapy includes:
* Lipid lowering therapy with [[statins]]
* [[Anti-hypertensive]] medications to optimize blood pressure
* Optimal glucose control in [[diabetes|diabetic]] patients
* Anti-cytomegalovirus therapy
* [[Antioxidants]]

====Statins====
* [[Obesity]], elevated levels of [[cyclosporine]], use of [[steroids]] and [[insulin resistance]] all contribute to the development of hyperlipidemia in cardiac transplant patients. Use of statins have proven to reduce mortality in multiple randomized controlled trials.
* Immunomodulatory effects of [[statins]] include:
** Inhibition of [[smooth muscle]] proliferation
*** By inhibiting lipid production, statins halt the intra-cellular signal transduction and consequently protein synthesis
*** By inhibiting expression of genes for [[growth factor]]s essential for proliferation of smooth muscles
** Direct influence on gene expression of endothelin-1, leading to improved endothelial function thereby protecting against [[atherogenesis]].
** Prevents attachment of [[monocytes]] to endothelium, which is the first step in [[atherogenesis]] <ref name="pmid12515749">{{cite journal| author=Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Krobot K et al.| title=Simvastatin initiated early after heart transplantation: 8-year prospective experience. | journal=Circulation | year= 2003 | volume= 107 | issue= 1 | pages= 93-7 | pmid=12515749 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12515749 }} </ref>
** In the presence of immunosuppressants like [[cyclosporin A]], statins reduce [[natural killer cell]] activity, [[T cell]] proliferation and activity in vitro. Moreover, statin induced LDL receptor activation leads to increase in intracellularly available LDL-bound cyclosporin A <ref name="pmid8880225">{{cite journal| author=Kurakata S, Kada M, Shimada Y, Komai T, Nomoto K| title=Effects of different inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, pravastatin sodium and simvastatin, on sterol synthesis and immunological functions in human lymphocytes in vitro. | journal=Immunopharmacology | year= 1996 | volume= 34 | issue= 1 | pages= 51-61 | pmid=8880225 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8880225 }} </ref>.
* Long term effects of [[simvastatin]]: The effects of [[simvastatin]] over a period of 8 years was studied in a randomized controlled trial by Wenke and colleagues <ref name="pmid12515749">{{cite journal| author=Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Krobot K et al.| title=Simvastatin initiated early after heart transplantation: 8-year prospective experience. | journal=Circulation | year= 2003 | volume= 107 | issue= 1 | pages= 93-7 | pmid=12515749 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12515749 }} </ref> in which the study group received simvastatin on the fourth post-operative day, whereas the control group was managed with dietary therapy alone.
** At the end of 8 years, the [[Kaplan-Meier estimator|Kaplan-Meier]] survival rate was 88.6% in the simvastatin group versus 59.5% in the control group (P< 0.006 by log rank, HR 0.24,95% CI, 0.08-0.71). The incidence of angiographically proven CAV was also found to be lower in the simvastatin group compared to the control group.
* Long term effects of [[pravastatin]]: Another randomized controlled trial by Kobashigawa and colleagues studied the effects of [[pravastatin]] at one year <ref name="pmid7637722">{{cite journal| author=Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman L, Wang XM et al.| title=Effect of pravastatin on outcomes after cardiac transplantation. | journal=N Engl J Med | year= 1995 | volume= 333 | issue= 10 | pages= 621-7 | pmid=7637722 | doi=10.1056/NEJM199509073331003 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7637722 }} </ref> and at the end of ten years <ref name="pmid16297773">{{cite journal| author=Kobashigawa JA, Moriguchi JD, Laks H, Wener L, Hage A, Hamilton MA et al.| title=Ten-year follow-up of a randomized trial of pravastatin in heart transplant patients. | journal=J Heart Lung Transplant | year= 2005 | volume= 24 | issue= 11 | pages= 1736-40 | pmid=16297773 | doi=10.1016/j.healun.2005.02.009 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16297773 }} </ref>.
** After 1 year of follow up, the patients in pravastatin group had reduced incidence of severe episodes of transplant rejections causing hemodynamic instability as well as CAV determined by angiography and autopsy. This group also had better survival compared to the non-pravastatin group.
** These significant differences also persisted in a 10 year follow up of the same study cohort which, similar to the above mentioned study, demonstrated survival benefits and reduced incidence of CAV by angiography in an intention to treat analysis.

====Calcium Channel Blockers and ACE inhibitors====
* Mechanisms by which [[calcium channel blockers]] and [[ACE inhibitors]] are thought to prevent CAV are as follows <ref name="pmid12176600">{{cite journal| author=Weis M| title=Cardiac allograft vasculopathy: prevention and treatment options. | journal=Transplant Proc | year= 2002 | volume= 34 | issue= 5 | pages= 1847-9 | pmid=12176600 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12176600 }} </ref>:
** Preservation of endothelial function
** Reduced oxidative stress
** Suppression of [[smooth muscle]] cell migration and proliferation
** Additionally [[nifedipine]] has been shown to cause [[vasodilatation]] in coronary arteries with endothelial dysfunction and inhibition of [[endothelin]] production <ref name="pmid11791002">{{cite journal| author=Weis M, Pehlivanli S, von Scheidt W| title=Vasodilator response to nifedipine in human coronary arteries with endothelial dysfunction. | journal=J Cardiovasc Pharmacol | year= 2002 | volume= 39 | issue= 2 | pages= 172-80 | pmid=11791002 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11791002 }} </ref>.
* In a study by Schroeder and colleagues<ref name="pmid8417382">{{cite journal| author=Schroeder JS, Gao SZ, Alderman EL, Hunt SA, Johnstone I, Boothroyd DB et al.| title=A preliminary study of diltiazem in the prevention of coronary artery disease in heart-transplant recipients. | journal=N Engl J Med | year= 1993 | volume= 328 | issue= 3 | pages= 164-70 | pmid=8417382 | doi=10.1056/NEJM199301213280303 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8417382 }} </ref> involving 57 cardiac transplant patients randomized to either receive [[diltiazem]] or placebo, showed that the coronary artery diameter decreased at a slower rate in patients receiving diltiazem compared to placebo at 1 year follow-up. However the overall survival at the end of 2 years remained unchanged.

==References==
{{reflist|2}}
{{WH}}
{{WS}}

Cardiac allograft vasculopathy prevention

2014-12-07T04:56:36Z

Aarti Narayan: /* Calcium Channel Blockers and ACE inhibitors */

__NOTOC__
{{Cardiac allograft vasculopathy}}
{{CMG}}; {{AE}} {{AN}} {{RT}}

==Overview==

==Prevention==
As the pathogenesis of CAV consists of both immunological and non-immunological insults, it has been suggested that preventative strategies should consist of control of risk factors for CAV and optimal [[immunosuppressive therapy]]. However, the best preventative strategy to delay development of CAV is yet to be determined.

===Optimization of Immunosuppressive Therapy===
The [[rapamycin]] derivatives, [[sirolimus]] and [[everolimus]], have been proven to have significant benefit in the prevention of CAV in addition to [[statins]]. Other options for immunosuppressive therapy include <ref name="pmid16686747">{{cite journal| author=Mehra MR| title=Contemporary concepts in prevention and treatment of cardiac allograft vasculopathy. | journal=Am J Transplant | year= 2006 | volume= 6 | issue= 6 | pages= 1248-56 | pmid=16686747 | doi=10.1111/j.1600-6143.2006.01314.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16686747 }} </ref>:
* [[Corticosteroids]]
* [[Mycophenolate mofetil]]

====Everolimus and Sirolimus====
* Act by inhibiting mTOR (mammalian target), thereby having anti-proliferative effects in response to allo-antigens.
* Everolimus is currently not FDA approved for clinical use in the United States.
* Associated with significantly reduced incidence of [[graft rejection]].
* Serial [[IVUS]] studies to evaluate intimal proliferation demonstrated smaller increase in maximal intimal thickness and intimal index in patients taking [[everolimus]] <ref name="pmid12944570">{{cite journal| author=Eisen HJ, Tuzcu EM, Dorent R, Kobashigawa J, Mancini D, Valantine-von Kaeppler HA et al.| title=Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. | journal=N Engl J Med | year= 2003 | volume= 349 | issue= 9 | pages= 847-58 | pmid=12944570 | doi=10.1056/NEJMoa022171 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12944570 }} </ref>. Similar results were found in trials that studied [[sirolimus]] <ref name="pmid23856215">{{cite journal| author=Matsuo Y, Cassar A, Yoshino S, Flammer AJ, Li J, Gulati R et al.| title=Attenuation of cardiac allograft vasculopathy by sirolimus: Relationship to time interval after heart transplantation. | journal=J Heart Lung Transplant | year= 2013 | volume= 32 | issue= 8 | pages= 784-91 | pmid=23856215 | doi=10.1016/j.healun.2013.05.015 | pmc=PMC3727915 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23856215 }} </ref>.
* Side effect profile:
** Everolimus: increase in [[serum creatinine]] levels, [[hyperlipidemia]], [[anemia]], [[thrombocytopenia]], [[peripheral edema]], [[hypertension]]. However, opportunistic viral infections less often seen.
** Sirolimus: Similar to everolimus, however recent reports of impaired wound healing have been reported in renal transplant patients.

====Mycophenolate mofetil====
* Studies have shown trend towards a lower maximal intimal thickness on [[IVUS]], lower incidence of retransplantation and death with [[mycophenolate]] when compared to [[azathioprine]] <ref name="pmid15896747">{{cite journal| author=Eisen HJ, Kobashigawa J, Keogh A, Bourge R, Renlund D, Mentzer R et al.| title=Three-year results of a randomized, double-blind, controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant recipients. | journal=J Heart Lung Transplant | year= 2005 | volume= 24 | issue= 5 | pages= 517-25 | pmid=15896747 | doi=10.1016/j.healun.2005.02.002 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15896747 }} </ref>.
* Side effect profile: [[chest pain]], [[hypertension]]/[[hypotension]], [[tachycardia]], [[peripheral edema]], [[headache]], [[fever]], [[rash]], [[abdominal pain]], [[nausea]], [[diarrhea]]/[[constipation]], [[leukopenia]], [[anemia]], [[thrombocytopenia]], [[liver function test]] abnormalities, abnormal [[creatinine]] and [[BUN]], increased risk for infections
====Calcineurin inhibitors====
* The use of [[Immunosuppressive drugs#Drugs Acting on Immunophilins|calcineurin inhibitors]] i.e [[cyclosporin]] and [[tacrolimus]] have not been shown to lower the risk of developing CAV.
* This suggests that other immunological pathways may exists that play a role in the pathogenesis of CAV. Moreover, side effects from use of these drugs leads to a high incidence of not only [[chronic renal disease]] but also [[hypertension]] and [[hyperlipidemia]] which in turn may accelerate the process of CAV.

===Non-Immunosuppressive therapy===
Non-immunosuppressive therapy includes:
* Lipid lowering therapy with [[statins]]
* [[Anti-hypertensive]] medications to optimize blood pressure
* Optimal glucose control in [[diabetes|diabetic]] patients
* Anti-cytomegalovirus therapy
* [[Antioxidants]]

====Statins====
* [[Obesity]], elevated levels of [[cyclosporine]], use of [[steroids]] and [[insulin resistance]] all contribute to the development of hyperlipidemia in cardiac transplant patients. Use of statins have proven to reduce mortality in multiple randomized controlled trials.
* Immunomodulatory effects of [[statins]] include:
** Inhibition of [[smooth muscle]] proliferation
*** By inhibiting lipid production, statins halt the intra-cellular signal transduction and consequently protein synthesis
*** By inhibiting expression of genes for [[growth factor]]s essential for proliferation of smooth muscles
** Direct influence on gene expression of endothelin-1, leading to improved endothelial function thereby protecting against [[atherogenesis]].
** Prevents attachment of [[monocytes]] to endothelium, which is the first step in [[atherogenesis]] <ref name="pmid12515749">{{cite journal| author=Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Krobot K et al.| title=Simvastatin initiated early after heart transplantation: 8-year prospective experience. | journal=Circulation | year= 2003 | volume= 107 | issue= 1 | pages= 93-7 | pmid=12515749 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12515749 }} </ref>
** In the presence of immunosuppressants like [[cyclosporin A]], statins reduce [[natural killer cell]] activity, [[T cell]] proliferation and activity in vitro. Moreover, statin induced LDL receptor activation leads to increase in intracellularly available LDL-bound cyclosporin A <ref name="pmid8880225">{{cite journal| author=Kurakata S, Kada M, Shimada Y, Komai T, Nomoto K| title=Effects of different inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, pravastatin sodium and simvastatin, on sterol synthesis and immunological functions in human lymphocytes in vitro. | journal=Immunopharmacology | year= 1996 | volume= 34 | issue= 1 | pages= 51-61 | pmid=8880225 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8880225 }} </ref>.
* Long term effects of [[simvastatin]]: The effects of [[simvastatin]] over a period of 8 years was studied in a randomized controlled trial by Wenke and colleagues <ref name="pmid12515749">{{cite journal| author=Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Krobot K et al.| title=Simvastatin initiated early after heart transplantation: 8-year prospective experience. | journal=Circulation | year= 2003 | volume= 107 | issue= 1 | pages= 93-7 | pmid=12515749 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12515749 }} </ref> in which the study group received simvastatin on the fourth post-operative day, whereas the control group was managed with dietary therapy alone.
** At the end of 8 years, the [[Kaplan-Meier estimator|Kaplan-Meier]] survival rate was 88.6% in the simvastatin group versus 59.5% in the control group (P< 0.006 by log rank, HR 0.24,95% CI, 0.08-0.71). The incidence of angiographically proven CAV was also found to be lower in the simvastatin group compared to the control group.
* Long term effects of [[pravastatin]]: Another randomized controlled trial by Kobashigawa and colleagues studied the effects of [[pravastatin]] at one year <ref name="pmid7637722">{{cite journal| author=Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman L, Wang XM et al.| title=Effect of pravastatin on outcomes after cardiac transplantation. | journal=N Engl J Med | year= 1995 | volume= 333 | issue= 10 | pages= 621-7 | pmid=7637722 | doi=10.1056/NEJM199509073331003 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7637722 }} </ref> and at the end of ten years <ref name="pmid16297773">{{cite journal| author=Kobashigawa JA, Moriguchi JD, Laks H, Wener L, Hage A, Hamilton MA et al.| title=Ten-year follow-up of a randomized trial of pravastatin in heart transplant patients. | journal=J Heart Lung Transplant | year= 2005 | volume= 24 | issue= 11 | pages= 1736-40 | pmid=16297773 | doi=10.1016/j.healun.2005.02.009 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16297773 }} </ref>.
** After 1 year of follow up, the patients in pravastatin group had reduced incidence of severe episodes of transplant rejections causing hemodynamic instability as well as CAV determined by angiography and autopsy. This group also had better survival compared to the non-pravastatin group.
** These significant differences also persisted in a 10 year follow up of the same study cohort which, similar to the above mentioned study, demonstrated survival benefits and reduced incidence of CAV by angiography in an intention to treat analysis.

====Calcium Channel Blockers and ACE inhibitors====
* Mechanisms by which [[calcium channel blockers]] and [[ACE inhibitors]] are thought to prevent CAV are as follows <ref name="pmid12176600">{{cite journal| author=Weis M| title=Cardiac allograft vasculopathy: prevention and treatment options. | journal=Transplant Proc | year= 2002 | volume= 34 | issue= 5 | pages= 1847-9 | pmid=12176600 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12176600 }} </ref>:
** Preservation of endothelial function
** Suppression of [[smooth muscle]] cell migration and proliferation
** Additionally [[nifedipine]] has been shown to cause [[vasodilatation]] in coronary arteries with endothelial dysfunction and inhibition of [[endothelin]] production <ref name="pmid11791002">{{cite journal| author=Weis M, Pehlivanli S, von Scheidt W| title=Vasodilator response to nifedipine in human coronary arteries with endothelial dysfunction. | journal=J Cardiovasc Pharmacol | year= 2002 | volume= 39 | issue= 2 | pages= 172-80 | pmid=11791002 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11791002 }} </ref>.
* In a study by Schroeder and colleagues<ref name="pmid8417382">{{cite journal| author=Schroeder JS, Gao SZ, Alderman EL, Hunt SA, Johnstone I, Boothroyd DB et al.| title=A preliminary study of diltiazem in the prevention of coronary artery disease in heart-transplant recipients. | journal=N Engl J Med | year= 1993 | volume= 328 | issue= 3 | pages= 164-70 | pmid=8417382 | doi=10.1056/NEJM199301213280303 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8417382 }} </ref> involving 57 cardiac transplant patients randomized to either receive [[diltiazem]] or placebo, showed that the coronary artery diameter decreased at a slower rate in patients receiving diltiazem compared to placebo at 1 year follow-up. However the overall survival at the end of 2 years remained unchanged.

==References==
{{reflist|2}}
{{WH}}
{{WS}}

Cardiac allograft vasculopathy prevention

2014-12-07T04:55:13Z

Aarti Narayan: /* Calcium Channel Blockers and ACE inhibitors */

__NOTOC__
{{Cardiac allograft vasculopathy}}
{{CMG}}; {{AE}} {{AN}} {{RT}}

==Overview==

==Prevention==
As the pathogenesis of CAV consists of both immunological and non-immunological insults, it has been suggested that preventative strategies should consist of control of risk factors for CAV and optimal [[immunosuppressive therapy]]. However, the best preventative strategy to delay development of CAV is yet to be determined.

===Optimization of Immunosuppressive Therapy===
The [[rapamycin]] derivatives, [[sirolimus]] and [[everolimus]], have been proven to have significant benefit in the prevention of CAV in addition to [[statins]]. Other options for immunosuppressive therapy include <ref name="pmid16686747">{{cite journal| author=Mehra MR| title=Contemporary concepts in prevention and treatment of cardiac allograft vasculopathy. | journal=Am J Transplant | year= 2006 | volume= 6 | issue= 6 | pages= 1248-56 | pmid=16686747 | doi=10.1111/j.1600-6143.2006.01314.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16686747 }} </ref>:
* [[Corticosteroids]]
* [[Mycophenolate mofetil]]

====Everolimus and Sirolimus====
* Act by inhibiting mTOR (mammalian target), thereby having anti-proliferative effects in response to allo-antigens.
* Everolimus is currently not FDA approved for clinical use in the United States.
* Associated with significantly reduced incidence of [[graft rejection]].
* Serial [[IVUS]] studies to evaluate intimal proliferation demonstrated smaller increase in maximal intimal thickness and intimal index in patients taking [[everolimus]] <ref name="pmid12944570">{{cite journal| author=Eisen HJ, Tuzcu EM, Dorent R, Kobashigawa J, Mancini D, Valantine-von Kaeppler HA et al.| title=Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. | journal=N Engl J Med | year= 2003 | volume= 349 | issue= 9 | pages= 847-58 | pmid=12944570 | doi=10.1056/NEJMoa022171 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12944570 }} </ref>. Similar results were found in trials that studied [[sirolimus]] <ref name="pmid23856215">{{cite journal| author=Matsuo Y, Cassar A, Yoshino S, Flammer AJ, Li J, Gulati R et al.| title=Attenuation of cardiac allograft vasculopathy by sirolimus: Relationship to time interval after heart transplantation. | journal=J Heart Lung Transplant | year= 2013 | volume= 32 | issue= 8 | pages= 784-91 | pmid=23856215 | doi=10.1016/j.healun.2013.05.015 | pmc=PMC3727915 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23856215 }} </ref>.
* Side effect profile:
** Everolimus: increase in [[serum creatinine]] levels, [[hyperlipidemia]], [[anemia]], [[thrombocytopenia]], [[peripheral edema]], [[hypertension]]. However, opportunistic viral infections less often seen.
** Sirolimus: Similar to everolimus, however recent reports of impaired wound healing have been reported in renal transplant patients.

====Mycophenolate mofetil====
* Studies have shown trend towards a lower maximal intimal thickness on [[IVUS]], lower incidence of retransplantation and death with [[mycophenolate]] when compared to [[azathioprine]] <ref name="pmid15896747">{{cite journal| author=Eisen HJ, Kobashigawa J, Keogh A, Bourge R, Renlund D, Mentzer R et al.| title=Three-year results of a randomized, double-blind, controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant recipients. | journal=J Heart Lung Transplant | year= 2005 | volume= 24 | issue= 5 | pages= 517-25 | pmid=15896747 | doi=10.1016/j.healun.2005.02.002 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15896747 }} </ref>.
* Side effect profile: [[chest pain]], [[hypertension]]/[[hypotension]], [[tachycardia]], [[peripheral edema]], [[headache]], [[fever]], [[rash]], [[abdominal pain]], [[nausea]], [[diarrhea]]/[[constipation]], [[leukopenia]], [[anemia]], [[thrombocytopenia]], [[liver function test]] abnormalities, abnormal [[creatinine]] and [[BUN]], increased risk for infections
====Calcineurin inhibitors====
* The use of [[Immunosuppressive drugs#Drugs Acting on Immunophilins|calcineurin inhibitors]] i.e [[cyclosporin]] and [[tacrolimus]] have not been shown to lower the risk of developing CAV.
* This suggests that other immunological pathways may exists that play a role in the pathogenesis of CAV. Moreover, side effects from use of these drugs leads to a high incidence of not only [[chronic renal disease]] but also [[hypertension]] and [[hyperlipidemia]] which in turn may accelerate the process of CAV.

===Non-Immunosuppressive therapy===
Non-immunosuppressive therapy includes:
* Lipid lowering therapy with [[statins]]
* [[Anti-hypertensive]] medications to optimize blood pressure
* Optimal glucose control in [[diabetes|diabetic]] patients
* Anti-cytomegalovirus therapy
* [[Antioxidants]]

====Statins====
* [[Obesity]], elevated levels of [[cyclosporine]], use of [[steroids]] and [[insulin resistance]] all contribute to the development of hyperlipidemia in cardiac transplant patients. Use of statins have proven to reduce mortality in multiple randomized controlled trials.
* Immunomodulatory effects of [[statins]] include:
** Inhibition of [[smooth muscle]] proliferation
*** By inhibiting lipid production, statins halt the intra-cellular signal transduction and consequently protein synthesis
*** By inhibiting expression of genes for [[growth factor]]s essential for proliferation of smooth muscles
** Direct influence on gene expression of endothelin-1, leading to improved endothelial function thereby protecting against [[atherogenesis]].
** Prevents attachment of [[monocytes]] to endothelium, which is the first step in [[atherogenesis]] <ref name="pmid12515749">{{cite journal| author=Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Krobot K et al.| title=Simvastatin initiated early after heart transplantation: 8-year prospective experience. | journal=Circulation | year= 2003 | volume= 107 | issue= 1 | pages= 93-7 | pmid=12515749 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12515749 }} </ref>
** In the presence of immunosuppressants like [[cyclosporin A]], statins reduce [[natural killer cell]] activity, [[T cell]] proliferation and activity in vitro. Moreover, statin induced LDL receptor activation leads to increase in intracellularly available LDL-bound cyclosporin A <ref name="pmid8880225">{{cite journal| author=Kurakata S, Kada M, Shimada Y, Komai T, Nomoto K| title=Effects of different inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, pravastatin sodium and simvastatin, on sterol synthesis and immunological functions in human lymphocytes in vitro. | journal=Immunopharmacology | year= 1996 | volume= 34 | issue= 1 | pages= 51-61 | pmid=8880225 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8880225 }} </ref>.
* Long term effects of [[simvastatin]]: The effects of [[simvastatin]] over a period of 8 years was studied in a randomized controlled trial by Wenke and colleagues <ref name="pmid12515749">{{cite journal| author=Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Krobot K et al.| title=Simvastatin initiated early after heart transplantation: 8-year prospective experience. | journal=Circulation | year= 2003 | volume= 107 | issue= 1 | pages= 93-7 | pmid=12515749 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12515749 }} </ref> in which the study group received simvastatin on the fourth post-operative day, whereas the control group was managed with dietary therapy alone.
** At the end of 8 years, the [[Kaplan-Meier estimator|Kaplan-Meier]] survival rate was 88.6% in the simvastatin group versus 59.5% in the control group (P< 0.006 by log rank, HR 0.24,95% CI, 0.08-0.71). The incidence of angiographically proven CAV was also found to be lower in the simvastatin group compared to the control group.
* Long term effects of [[pravastatin]]: Another randomized controlled trial by Kobashigawa and colleagues studied the effects of [[pravastatin]] at one year <ref name="pmid7637722">{{cite journal| author=Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman L, Wang XM et al.| title=Effect of pravastatin on outcomes after cardiac transplantation. | journal=N Engl J Med | year= 1995 | volume= 333 | issue= 10 | pages= 621-7 | pmid=7637722 | doi=10.1056/NEJM199509073331003 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7637722 }} </ref> and at the end of ten years <ref name="pmid16297773">{{cite journal| author=Kobashigawa JA, Moriguchi JD, Laks H, Wener L, Hage A, Hamilton MA et al.| title=Ten-year follow-up of a randomized trial of pravastatin in heart transplant patients. | journal=J Heart Lung Transplant | year= 2005 | volume= 24 | issue= 11 | pages= 1736-40 | pmid=16297773 | doi=10.1016/j.healun.2005.02.009 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16297773 }} </ref>.
** After 1 year of follow up, the patients in pravastatin group had reduced incidence of severe episodes of transplant rejections causing hemodynamic instability as well as CAV determined by angiography and autopsy. This group also had better survival compared to the non-pravastatin group.
** These significant differences also persisted in a 10 year follow up of the same study cohort which, similar to the above mentioned study, demonstrated survival benefits and reduced incidence of CAV by angiography in an intention to treat analysis.

====Calcium Channel Blockers and ACE inhibitors====
* Mechanisms by which [[calcium channel blockers]] and [[ACE inhibitors]] are thought to prevent CAV are as follows <ref name="pmid12176600">{{cite journal| author=Weis M| title=Cardiac allograft vasculopathy: prevention and treatment options. | journal=Transplant Proc | year= 2002 | volume= 34 | issue= 5 | pages= 1847-9 | pmid=12176600 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12176600 }} </ref>:
** Preservation of endothelial function
** Suppression of [[smooth muscle]] cell migration and proliferation
** Additionally [[nifedipine]] has been shown to cause [[vasodilatation]] in coronary arteries with endothelial dysfunction and inhibition of [[endothelin]] production <ref name="pmid11791002">{{cite journal| author=Weis M, Pehlivanli S, von Scheidt W| title=Vasodilator response to nifedipine in human coronary arteries with endothelial dysfunction. | journal=J Cardiovasc Pharmacol | year= 2002 | volume= 39 | issue= 2 | pages= 172-80 | pmid=11791002 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11791002 }} </ref>.
* In a study by Schroeder and colleagues<ref name="pmid8417382">{{cite journal| author=Schroeder JS, Gao SZ, Alderman EL, Hunt SA, Johnstone I, Boothroyd DB et al.| title=A preliminary study of diltiazem in the prevention of coronary artery disease in heart-transplant recipients. | journal=N Engl J Med | year= 1993 | volume= 328 | issue= 3 | pages= 164-70 | pmid=8417382 | doi=10.1056/NEJM199301213280303 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8417382 }} </ref> involving 57 cardiac transplant patients randomized to either receive [[diltiazem]] or placebo, showed that the coronary artery diameter decreased at a slower rate in patients receiving diltiazem compared to placebo at 1 year follow-up.

==References==
{{reflist|2}}
{{WH}}
{{WS}}

Cardiac allograft vasculopathy prevention

2014-12-07T03:36:31Z

Aarti Narayan: /* Calcium Channel Blockers and ACE inhibitors */

__NOTOC__
{{Cardiac allograft vasculopathy}}
{{CMG}}; {{AE}} {{AN}} {{RT}}

==Overview==

==Prevention==
As the pathogenesis of CAV consists of both immunological and non-immunological insults, it has been suggested that preventative strategies should consist of control of risk factors for CAV and optimal [[immunosuppressive therapy]]. However, the best preventative strategy to delay development of CAV is yet to be determined.

===Optimization of Immunosuppressive Therapy===
The [[rapamycin]] derivatives, [[sirolimus]] and [[everolimus]], have been proven to have significant benefit in the prevention of CAV in addition to [[statins]]. Other options for immunosuppressive therapy include <ref name="pmid16686747">{{cite journal| author=Mehra MR| title=Contemporary concepts in prevention and treatment of cardiac allograft vasculopathy. | journal=Am J Transplant | year= 2006 | volume= 6 | issue= 6 | pages= 1248-56 | pmid=16686747 | doi=10.1111/j.1600-6143.2006.01314.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16686747 }} </ref>:
* [[Corticosteroids]]
* [[Mycophenolate mofetil]]

====Everolimus and Sirolimus====
* Act by inhibiting mTOR (mammalian target), thereby having anti-proliferative effects in response to allo-antigens.
* Everolimus is currently not FDA approved for clinical use in the United States.
* Associated with significantly reduced incidence of [[graft rejection]].
* Serial [[IVUS]] studies to evaluate intimal proliferation demonstrated smaller increase in maximal intimal thickness and intimal index in patients taking [[everolimus]] <ref name="pmid12944570">{{cite journal| author=Eisen HJ, Tuzcu EM, Dorent R, Kobashigawa J, Mancini D, Valantine-von Kaeppler HA et al.| title=Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. | journal=N Engl J Med | year= 2003 | volume= 349 | issue= 9 | pages= 847-58 | pmid=12944570 | doi=10.1056/NEJMoa022171 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12944570 }} </ref>. Similar results were found in trials that studied [[sirolimus]] <ref name="pmid23856215">{{cite journal| author=Matsuo Y, Cassar A, Yoshino S, Flammer AJ, Li J, Gulati R et al.| title=Attenuation of cardiac allograft vasculopathy by sirolimus: Relationship to time interval after heart transplantation. | journal=J Heart Lung Transplant | year= 2013 | volume= 32 | issue= 8 | pages= 784-91 | pmid=23856215 | doi=10.1016/j.healun.2013.05.015 | pmc=PMC3727915 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23856215 }} </ref>.
* Side effect profile:
** Everolimus: increase in [[serum creatinine]] levels, [[hyperlipidemia]], [[anemia]], [[thrombocytopenia]], [[peripheral edema]], [[hypertension]]. However, opportunistic viral infections less often seen.
** Sirolimus: Similar to everolimus, however recent reports of impaired wound healing have been reported in renal transplant patients.

====Mycophenolate mofetil====
* Studies have shown trend towards a lower maximal intimal thickness on [[IVUS]], lower incidence of retransplantation and death with [[mycophenolate]] when compared to [[azathioprine]] <ref name="pmid15896747">{{cite journal| author=Eisen HJ, Kobashigawa J, Keogh A, Bourge R, Renlund D, Mentzer R et al.| title=Three-year results of a randomized, double-blind, controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant recipients. | journal=J Heart Lung Transplant | year= 2005 | volume= 24 | issue= 5 | pages= 517-25 | pmid=15896747 | doi=10.1016/j.healun.2005.02.002 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15896747 }} </ref>.
* Side effect profile: [[chest pain]], [[hypertension]]/[[hypotension]], [[tachycardia]], [[peripheral edema]], [[headache]], [[fever]], [[rash]], [[abdominal pain]], [[nausea]], [[diarrhea]]/[[constipation]], [[leukopenia]], [[anemia]], [[thrombocytopenia]], [[liver function test]] abnormalities, abnormal [[creatinine]] and [[BUN]], increased risk for infections
====Calcineurin inhibitors====
* The use of [[Immunosuppressive drugs#Drugs Acting on Immunophilins|calcineurin inhibitors]] i.e [[cyclosporin]] and [[tacrolimus]] have not been shown to lower the risk of developing CAV.
* This suggests that other immunological pathways may exists that play a role in the pathogenesis of CAV. Moreover, side effects from use of these drugs leads to a high incidence of not only [[chronic renal disease]] but also [[hypertension]] and [[hyperlipidemia]] which in turn may accelerate the process of CAV.

===Non-Immunosuppressive therapy===
Non-immunosuppressive therapy includes:
* Lipid lowering therapy with [[statins]]
* [[Anti-hypertensive]] medications to optimize blood pressure
* Optimal glucose control in [[diabetes|diabetic]] patients
* Anti-cytomegalovirus therapy
* [[Antioxidants]]

====Statins====
* [[Obesity]], elevated levels of [[cyclosporine]], use of [[steroids]] and [[insulin resistance]] all contribute to the development of hyperlipidemia in cardiac transplant patients. Use of statins have proven to reduce mortality in multiple randomized controlled trials.
* Immunomodulatory effects of [[statins]] include:
** Inhibition of [[smooth muscle]] proliferation
*** By inhibiting lipid production, statins halt the intra-cellular signal transduction and consequently protein synthesis
*** By inhibiting expression of genes for [[growth factor]]s essential for proliferation of smooth muscles
** Direct influence on gene expression of endothelin-1, leading to improved endothelial function thereby protecting against [[atherogenesis]].
** Prevents attachment of [[monocytes]] to endothelium, which is the first step in [[atherogenesis]] <ref name="pmid12515749">{{cite journal| author=Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Krobot K et al.| title=Simvastatin initiated early after heart transplantation: 8-year prospective experience. | journal=Circulation | year= 2003 | volume= 107 | issue= 1 | pages= 93-7 | pmid=12515749 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12515749 }} </ref>
** In the presence of immunosuppressants like [[cyclosporin A]], statins reduce [[natural killer cell]] activity, [[T cell]] proliferation and activity in vitro. Moreover, statin induced LDL receptor activation leads to increase in intracellularly available LDL-bound cyclosporin A <ref name="pmid8880225">{{cite journal| author=Kurakata S, Kada M, Shimada Y, Komai T, Nomoto K| title=Effects of different inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, pravastatin sodium and simvastatin, on sterol synthesis and immunological functions in human lymphocytes in vitro. | journal=Immunopharmacology | year= 1996 | volume= 34 | issue= 1 | pages= 51-61 | pmid=8880225 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8880225 }} </ref>.
* Long term effects of [[simvastatin]]: The effects of [[simvastatin]] over a period of 8 years was studied in a randomized controlled trial by Wenke and colleagues <ref name="pmid12515749">{{cite journal| author=Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Krobot K et al.| title=Simvastatin initiated early after heart transplantation: 8-year prospective experience. | journal=Circulation | year= 2003 | volume= 107 | issue= 1 | pages= 93-7 | pmid=12515749 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12515749 }} </ref> in which the study group received simvastatin on the fourth post-operative day, whereas the control group was managed with dietary therapy alone.
** At the end of 8 years, the [[Kaplan-Meier estimator|Kaplan-Meier]] survival rate was 88.6% in the simvastatin group versus 59.5% in the control group (P< 0.006 by log rank, HR 0.24,95% CI, 0.08-0.71). The incidence of angiographically proven CAV was also found to be lower in the simvastatin group compared to the control group.
* Long term effects of [[pravastatin]]: Another randomized controlled trial by Kobashigawa and colleagues studied the effects of [[pravastatin]] at one year <ref name="pmid7637722">{{cite journal| author=Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman L, Wang XM et al.| title=Effect of pravastatin on outcomes after cardiac transplantation. | journal=N Engl J Med | year= 1995 | volume= 333 | issue= 10 | pages= 621-7 | pmid=7637722 | doi=10.1056/NEJM199509073331003 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7637722 }} </ref> and at the end of ten years <ref name="pmid16297773">{{cite journal| author=Kobashigawa JA, Moriguchi JD, Laks H, Wener L, Hage A, Hamilton MA et al.| title=Ten-year follow-up of a randomized trial of pravastatin in heart transplant patients. | journal=J Heart Lung Transplant | year= 2005 | volume= 24 | issue= 11 | pages= 1736-40 | pmid=16297773 | doi=10.1016/j.healun.2005.02.009 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16297773 }} </ref>.
** After 1 year of follow up, the patients in pravastatin group had reduced incidence of severe episodes of transplant rejections causing hemodynamic instability as well as CAV determined by angiography and autopsy. This group also had better survival compared to the non-pravastatin group.
** These significant differences also persisted in a 10 year follow up of the same study cohort which, similar to the above mentioned study, demonstrated survival benefits and reduced incidence of CAV by angiography in an intention to treat analysis.

====Calcium Channel Blockers and ACE inhibitors====
* Mechanisms by which [[calcium channel blockers]] and [[ACE inhibitors]] are thought to prevent CAV are as follows <ref name="pmid12176600">{{cite journal| author=Weis M| title=Cardiac allograft vasculopathy: prevention and treatment options. | journal=Transplant Proc | year= 2002 | volume= 34 | issue= 5 | pages= 1847-9 | pmid=12176600 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12176600 }} </ref>:
** Preservation of endothelial function
** Suppression of [[smooth muscle]] cell migration and proliferation
** Additionally [[nifedipine]] has been shown to cause [[vasodilatation]] in coronary arteries with endothelial dysfunction and inhibition of [[endothelin]] production <ref name="pmid11791002">{{cite journal| author=Weis M, Pehlivanli S, von Scheidt W| title=Vasodilator response to nifedipine in human coronary arteries with endothelial dysfunction. | journal=J Cardiovasc Pharmacol | year= 2002 | volume= 39 | issue= 2 | pages= 172-80 | pmid=11791002 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11791002 }} </ref>.

==References==
{{reflist|2}}
{{WH}}
{{WS}}

Cardiac allograft vasculopathy prevention

2014-12-07T03:34:12Z

Aarti Narayan: /* Calcium Channel Blockers and ACE inhibitors */

Cardiac allograft vasculopathy prevention

2014-12-07T03:29:18Z

Aarti Narayan: /* Non-Immunosuppressive therapy */

Cardiac allograft vasculopathy prevention

2014-12-07T03:28:51Z

Aarti Narayan: /* Non-Immunosuppressive therapy */

Cardiac allograft vasculopathy prevention

2014-12-06T22:31:56Z

Aarti Narayan: /* Statins */

Cardiac allograft vasculopathy prevention

2014-12-06T20:27:37Z

Aarti Narayan: /* Statins */

Cardiac allograft vasculopathy prevention

2014-12-06T20:25:25Z

Aarti Narayan: /* Statins */

Cardiac allograft vasculopathy prevention

2014-12-06T20:19:11Z

Aarti Narayan: /* Statins */

Cardiac allograft vasculopathy prevention

2014-12-06T20:06:50Z

Aarti Narayan: /* Statins */

Cardiac allograft vasculopathy prevention

2014-12-06T19:57:43Z

Aarti Narayan: /* Statins */

Cardiac allograft vasculopathy prevention

2014-12-06T19:56:42Z

Aarti Narayan: /* Statins */

Cardiac allograft vasculopathy prevention

2014-12-06T19:55:24Z

Aarti Narayan: /* Statins */

Cardiac allograft vasculopathy prevention

2014-12-04T14:11:32Z

Aarti Narayan: /* Statins */

Cardiac allograft vasculopathy prevention

2014-12-04T14:10:24Z

Aarti Narayan: /* Statins */

Cardiac allograft vasculopathy prevention

2014-12-04T14:00:18Z

Aarti Narayan: /* Statins */