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==Diagnosis of plaque-related disease==
Areas of severe narrowing, [[stenosis]], detectable by angiography, and to a lesser extent "stress testing" have long been the focus of human diagnostic techniques for [[cardiovascular disease]], in general. However, these methods focus on detecting only severe [[stenosis|narrowing]], not the underlying atherosclerosis disease.  As demonstrated by human clinical studies, most severe events occur in locations with heavy plaque, yet little or no lumen [[stenosis|narrowing]] present before debilitating events suddenly occur. Plaque rupture can lead to artery lumen occlusion within seconds to minutes, and potential permanent debility and sometimes sudden death.
Greater than 75% lumen [[stenosis]] used to be considered by cardiologists as the hallmark of clinically significant disease because it is typically only at this severity of narrowing of the larger heart arteries that recurring episodes of [[Angina pectoris|angina]] and detectable abnormalities by stress testing methods are seen. However, clinical trials have shown that only about 14% of clinically-debilitating events occur at locations with this, or greater severity of [[stenosis|narrowing]]. The majority of events occur due to atheroma plaque rupture at areas without [[stenosis|narrowing]] sufficient enough to produce any [[Angina pectoris|angina]] or stress test abnormalities. Thus, since the later-1990s, greater attention is being focused on the "vulnerable plaque."
Though any artery in the body can be involved, usually only severe [[stenosis|narrowing]] or obstruction of some arteries, those that supply more critically-important organs are recognized. Obstruction of arteries supplying the heart muscle result in a [[myocardial infarction|heart attack]]. Obstruction of arteries supplying the brain result in a [[stroke]]. These events are life-changing, and often result in irreversible loss of function because lost heart muscle and brain cells do not grow back to any significant extent, typically less than 2%.
Over the last couple of decades, methods other than angiography and stress-testing have been increasingly developed as ways to better detect atherosclerotic disease before it becomes symptomatic. These have included both (a) anatomic detection methods and (b) physiologic measurement methods.
'''Examples of anatomic methods include''':
(1) coronary calcium scoring by CT,
(2) carotid IMT (intimal medial thickness) measurement by ultrasound, and
(3) IVUS.
'''Examples of physiologic methods include''':
(1) lipoprotein subclass analysis,
(2) HbA1c,
(3) hs-CRP, and
(4) homocysteine.
The example of the metabolic syndrome combines both anatomic (abdominal girth) and physiologic (blood pressure, elevated blood glucose) methods.
Advantages of these two approaches: The anatomic methods directly measure some aspect of the actual atherosclerotic disease process itself, thus offer potential for earlier detection, including before symptoms start, disease staging and tracking of disease progression. The physiologic methods are often less expensive and safer and changing them for the better may slow disease progression, in some cases with marked improvement.
Disadvantages of these two approaches: The anatomic methods are generally more expensive and several are invasive, such as IVUS. The physiologic methods do not quantify the current state of the disease or directly track progression. For both, clinicians and third party payers have been slow to accept the usefulness of these newer approaches.


==Physiologic factors that increase risk==
==Physiologic factors that increase risk==

Revision as of 18:34, 22 February 2013

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]

Physiologic factors that increase risk

Various anatomic, physiological & behavioral risk factors for atherosclerosis are known. These can be divided into various categories: congenital vs acquired, modifiable or not, classical or non-classical. The points labelled '+' in the following list form the core components of "metabolic syndrome":

Treatment

If atherosclerosis leads to symptoms, some symptoms such as angina pectoris can be treated. Non-pharmaceutical means are usually the first method of treatment, such as cessation of smoking and practicing regular exercise. If these methods do not work, medicines are usually the next step in treating cardiovascular diseases, and with improvements, have increasingly become the most effective method over the long term. However, medicines are criticized for their expense, patented control and occasional undesired effects.

Lipoprotein imbalances, upper normal and especially elevated blood sugar, i.e. diabetes, high blood pressure, homocysteine, stopping smoking, taking anticoagulants (anti-clotting agents) which target clotting factors, taking omega 3 oils from fatty fish or plant oils such as flax or canola oils, exercising and losing weight are the usual focus of treatments which have proved to be helpful in clinical trials. The target serum cholesterol level is ideally equal or less than 4mmol/L (160 mg/dL) and triglycerides equal or less than 2mmol/L 180 (mg/dL).

In general, the group of medications referred to as statins has seen popularity yet they are not approved in most jurisdictions for treating atherosclerosis. They have relatively few short-term undesirable side-effects and have shown some effect in reducing atherosclerotic disease 'events' in some but not all studies such as ALLHAT.

The newest statin, rosuvastatin, has been the first to demonstrate regression of atherosclerotic plaque within the coronary arteries by IVUS evaluation,[2] see the Effect of Very High-Intensity Statin Therapy reference below. The study was not set up to demonstrate clinical benefit or harm. However, for most people, changing their physiologic behaviors, from the usual high risk to greatly reduced risk, requires a combination of several compounds, taken on a daily basis and indefinitely. More and more human treatment trials have been done and are ongoing which demonstrate improved outcome for those people using more complex and effective treatment regimens which change physiologic behaviour patterns to more closely resemble those humans exhibit in childhood at a time before fatty streaks begin forming.

Lowering lipoprotein little a, a genetic variant of LDL, can be achieved with large daily doses of vitamin B3, niacin. Niacin also tends to shift LDL particle distribution to larger particle size and improve HDL functioning. Work on increasing HDL particle concentration and function, beyond the niacin effect, perhaps even more important, is slowly advancing. Combinations of statins, niacin, intestinal cholesterol absorption inhibiting supplements (ezetimibe and others, and to a much lesser extent fibrates have been the most successful in changing dyslipidemia patterns and but, in the case of inhibitors and fibrates without improving clinical outcomes in secondary prevention. In primary prevention, cholesterol lowering agents have not reduced the mortality rates, for example the AFCAPS/TexCAPS and EXCEL trials and the 2 main trials with atorvastatin, Lipitor, as in the ASCOT and SPARCL studies. Dietary changes to achieve benefit have been more controversial, generally far less effective and less widely adhered to with success.

Evidence has increased that people with diabetes, despite not having clinically detectable atherosclotic disease, have more severe debility from atherosclerotic events over time than even non-diabetics who have already suffered atherosclerotic events. Thus diabetes has been upgraded to be viewed as an advanced atherosclerotic disease equivalent.

Lowering homocysteine levels, including within the normal range and dietary supplements of Omega 3 oils, especially those from the muscle of some deep salt water living fish species, also have clinical evidence of significant protective effects as confirmed by 6 double blind placebo controlled human clinical trials.

Medical treatments often focus predominantly on the symptoms. However, over time, the treatments which focus on decreasing the underlying atherosclerosis processes, as opposed to simply treating the symptoms resulting from the atherosclerosis, have been shown by clinical trials to be more effective.

Other physical treatments, helpful in the short term, include minimally invasive angioplasty procedures to physically expand narrowed arteries and major invasive surgery, such as bypass surgery, to create additional blood supply connections which go around the more severely narrowed areas.

High dose supplements of vitamin E or C, with the goal of improving antioxidant protection, have failed to produce any beneficial trends in human, double blind, clinical research trials. However, these trials have consistently used lower doses than those claimed to be effective and have ignored the short half life of high intakes of vitamin C in the body.

On the other hand, the statins, and some other medications have been shown to have antioxidant effects, possibly part of their basis for some of their therapeutic success in reducing cardiac 'events'.

The success of statin drugs in clinical trials is based on some reductions in mortality rates, however never in women or people over the age of 70 CMAJ. For example, in 4S, the first large placebo controlled, randomized clinical trial of a statin in people with advanced disease who had already suffered a heart attack, the overall mortality rate reduction for those taking the statin, vs. placebo, was 30%. For the subgroup of people in the trial who had Diabetes Mellitus, the mortality rate reduction between statin and placebo was 54%. 4S was a 5.4 year trial which started in 1989 and was published in 1995 after completion. There were 3 more dead women at trial's end on statin than in the group on placebo drug. The |ASTEROID trial, mentioned above and in reference 3, has been the first to show actual disease volume regression (see page 8 of the paper which shows cross-sectional areas of the total heart artery wall at start and 2 years of rosuvastatin 40 mg/day treatment); however, its design was not able to "prove" the mortality reduction issue since it has no placebo group.

In summary, the key to the more effective approaches has been better understanding of the widespread and insidious nature of the disease and to combine multiple different treatment strategies, not rely on just one or a few approaches. Additionally, for those approaches, such as lipoprotein transport behaviors, which have been shown to produce the most success, adopting more aggressive combination treatment strategies has generally produced better results, both before and especially after people are symptomatic. However, treating asymptomatic people remains controversial in the medical community.

Patients at risk for atherosclerosis-related diseases are increasingly being treated prophylactically with low-dose aspirin and a statin. The high incidence of cardiovascular disease led Wald and Law[3] to propose a Polypill, a once-daily pill containing these two types of drugs in addition to an ACE inhibitor, diuretic and beta blocker and folic acid. They maintain that high uptake by the general population by such a Polypill would reduce cardiovascular mortality by 80%. It must be emphasized however that this is purely theoretical, as the Polypill has never been tested in a clinical trial.

Recent research

Methods to increase high density lipoprotein (HDL) particle concentrations, which in some animal studies largely reverses and remove atheromas, are being developed and researched. Niacin has HDL raising effects (by 10 - 30%) and showed clinical trial benefit in the Coronary Drug Project, however, the drug torcetrapib most effectively raising HDL (by 60%) also raised deaths by 60% and all studies regarding this drug were halted in December 2006.[3]

An indication of the role of HDL on atherosclerosis has been with the rare Apo-A1 Milano human genetic variant of this HDL protein. Ongoing work starting in the 1990s may lead to human clinical trials probably by about 2008, on using either synthesized Apo-A1 Milano HDL directly or by gene-transfer methods to pass the ability to synthesize the Apo-A1 Milano HDL protein.

The ASTEROID trial used a high-dose of a powerful statin, rosuvastatin, and found plaque (intima + media volume) reduction; see the Effect of Very High-Intensity Statin Therapy reference below. No attempt has yet been made to compare this drug with placebo regarding clinical benefit.

Since about 2002, progress in understanding and developing techniques for modulating immune system function so as to significantly suppress the action of macrophages to drive atherosclerotic plaque progression are being developed with considerable success in reducing plaque development in both mice and rabbits. Plans for human trials, hoped for by about 2008, are in progress. Generally these techniques are termed immunomodulation of atherosclerosis.

Genetic expression and control mechanism research, including (a) the PPAR peroxisome proliferator activated receptors known to be important in blood sugar and variants of lipoprotein production and function and (b) of the multiple variants of the proteins which form the lipoprotein transport particles, is progressing.

Some controversial research has suggested a link between atherosclerosis and the presence of several different nanobacteria in the arteries, e.g. Chlamydophila pneumoniae, though trials of current antibiotic treatments known to be usually effective in suppressing growth or killing these bacteria have not been successful in improving outcomes.

The immunomodulation approaches mentioned above, because they deal with innate responses of the host to promote atherosclerosis, have far greater prospects for success. [4] [5]

Pathological Findings

Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology







Saphenous Vein Graft


Coronary Arteries

Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology




Aorta

Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

Carotid Artery

Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

Lung

Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

Pulmonary Artery

Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

Brain

Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

Liver

Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

Kidney

Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

Spleen

Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

References

  1. Deepak L. Bhatt, MD; Eric J. Topol, MD Need to Test the Arterial Inflammation Hypothesis, 2002, referenced on 4/1/06
  2. [1], "Effect of Very High-Intensity Statin Therapy on Regression of Coronary Atherosclerosis".
  3. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003;326:1419. PMID.
  4. Stevens, Karen M.J. Douglas, Athanasios N. Saratzis and George D. Kitas Inflammation and atherosclerosis in rheumatoid arthritis Robert J. Expert Rev. Mol. Med. Vol. 7, Issue 7
  5. Mol, A 2002 _The Body Multiple: Ontology in medical practice_ London: Duke University Press

See also


cs:Ateroskleróza da:Åreforkalkning de:Arteriosklerose ko:동맥경화 it:Aterosclerosi he:טרשת עורקים nl:Atheromatose no:Åreforkalkning fi:Ateroskleroosi sv:Åderförkalkning

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