Synonyms and keywords: Left ventricular remodeling, LV remodeling, Cardiac Remodeling, Ventricle Remodeling, Cardiac Hypertrophy, Ventricular Myocardial Remodeling, Myocardial Remodeling, Ventricular Remodeling
The Left Ventricle has an enormous ability to respond to any type of stress or pathological process. Such a response includes a complex of wide range of transcriptional, signaling, structural, electrophysiological and functional events of cardiac myocytes as well as other cells within the ventricle.
Ventricular remodeling is classified as Pathological or Physiological.
Ventricular remodeling can be either physiological or pathological. Physiological changes occur in cases of pregnancy, exercise and post-natal growth and considered to be normal, whereas pathological remodeling occur due to cardiac injury and can end up with cardiac arrhythmia and heart failure.
Remodeling has three patterns. Concentric remodeling where there is an increase in relative wall thickness (Ventricular wall thickness compared to cavity size) and with or without increase cardiac mass.This change is noticed in cases of pressure overload.Eccentric Hypertrophy where there is an increase in cardiac mass and chamber volume with relative wall thickness varying between being decreased, the same or increased. This change is noticed in cases of volume overload, after infarction and isotonic exercise. Mixed Concentric and Eccentric changes as in Myocardial Infarction (MI), Where there is a combined volume and pressure overload on noninfarcted areas.
Remodeling can be classified as adaptive or maladaptive.
Recent studies identified some cardiac myocytes in the LV that have the ability to re enter the cell cycle and proliferate. However, the majority of the cardiac cells cannot,and respond to stress by remodeling. Cardiac progenitors are localized to the epicardial surface of the heart and believed to contribute to the formation of coronary blood vessels during embryogenesis. These cells have the ability to express c-Kit,Sca-1 or Islet-1 on their surfaces.
As cardiac myocytes stretch there is an increase in the local production or release of Angiotensin II (ANG II), Norepinephrine and endothelin. These neurohormonal proteins stimulate expression of proteins and cardiac myocytes hypertrophy. Increases in ANG II, aldosterone and cytokines stimulate collagen synthesis leading into fibrosis and remodeling of the cardiac extracellular matrix, while reduced nitric oxide will allow more cellular and interstitial growth as it is a negative inhibitor of remodeling.
The connective tissue network connecting myocytes together is made from fibrillar collagen. Cardiac fibrosis contributes to morbidity and mortality and the amount of fibrotic tissue in the heart is directly proportional to cardiac arrhythmias and sudden cardiac death.
Human and animals models showed that in case of pathological stress, fibroblasts proliferate and differentiate in myofibroblasts that lay down collagen I, collagen III and fibronectin after myocardial infarction and lead to fibrosis ,which in its turn will form a scar and replace injured cardiac myocytes. This scar will prevent ventricular rupture. In contrast, fibrosis arising due to hypertension-induced pressure overload is reactive and can lead to a decrease in compliance and oxygen diffusion capacity.
Also, The enzyme collagenase is present in an inactive form in the ventricle and its activation after myocardial injury will lead into collagen degradation and hence an increase in chamber dimensions.MMPs (Matrix Metalloproteinases) is one type of the collagenase enzymes that play a role in remodeling ,where MMP-1 in hypertensive patients with systolic dysfunction lead to heart failure faster than those with diastolic function.Hence it is directly correlated with end-diastolic volume and inversely correlated with Left Ventricular Ejection Fraction.
Neurohormonal activation in the form of increased release of Renin, Norepinephrine and antidiuretic hormones plays an important role in the process of remodeling. Although, it is initially a compensatory process and adaptive, such activation will lead into decompensation over the long term.
Angiotensin II is one of the hormones that contribute to cardiac remodeling,where it is released from cardiac myocytes due to mechanical stretch as well as it is generated systemically. Angiotensin II binds AT1 receptors on human fibroblasts and promotes collagen synthesis along with protein synthesis and lead to hypertrophic changes. Besides,it enhances the action of aldosterone hormone which binds to mineralocorticoid receptors on cardiac cells and contributes to the process of remodeling.
AT2 receptors activated by Angiotensin II leads into vasodilation and blunt cardiac remodeling. This suggests that AT1 & AT2 receptors have opposite effects to each other.
Endothelin and Vasopressin are also activated during heart failure, where Vasopressin V1A receptor activation can lead to an increase in Ca2+ level intracellulary and promotes cardiac myocytes hypertrophy and remodeling.Also,the activation of Endothelin-1 increases the contractility and stimulate growth of cardiac myocytes which can lead to cardiac hypertrophy.
Other factors as Proinflammatory cytokines promote hypertrophy, apoptosis and extracellular matrix remodeling. Elevated levels of cytokines are now an indication to poor clinical prognosis.
Left Ventricular remodeling can occur due to neurohormonal activation,hypertension,myocardial injury and cardiomyopathy.
The cardiac myocyte is the major cell involved. However, the interstium .fibroblasts, collagen, and coronary vasculature also play an important role. Remodeling is mainly affected by hemodynamic load and neurohormonal activation. Remodeling after Myocardial Infarction (MI) usually begins within the first few hours after infarct and progresses over time. The entire heart may be involved as thinning and dilatation in the infarct region is associated with distortion in shape of the entire heart,with volume overload hypertrophy of noninfarcted myocardium.The extent and location of myocardial damage affect the process of remodeling and its enormity.
Remodeling after MI occurs in stages. After interruption of blood supply to a certain area, the cardiac myocytes will immediately die either via necrosis, apoptosis or autophagy. These dying cells will release intracellular proteins(cardiac troponins and creatine kinase) into the circulation and trigger an inflammatory response. Neutrophils,macrophages,monocyes and Lymphocytes infiltrate the cardiac tissue to remove cardiac myocytes.
Once this inflammatory stage ends, cardiac fibroblasts start proliferating and synthesizing extra cellular proteins such as collagen type I in order to form the scar and replace the dead cardiac cells.Such a process will prevent cardiac rupture. The remodeling here will continue in response to increases in wall stress.
Negative T waves can predict post infarction prognosis. lack of negative T waves resolution or late appearance of new negative T-waves are associated with less recovery and more remodeling.
Hypertension is the most important factor for heart failure. The pressure overload taking place will shift the heart to increase its wall thickness according to Laplace Law such that the demand on oxygen will decrease. This change is adaptive initially but a persistent high pressure stress will eventually lead into decompensation and heart failure.
Atrophic remodeling is also one of the changes that take place in the heart, as the cardiac myocytes are capable of shrinking. Such remodeling can reduce the Left Ventricular (LV) mass, Mechanical unloading (prolonged bed rest and weightlessness during space travel) or increased catabolic state as in cancer are important factors that contribute to atrophic remodeling. Apoptosis is an energy dependent pathway taken by the cells and does not involve the release of any intracellular content that can lead to inflammatory reaction.
Metabolic remodeling also plays a crucial role in patients of diabetes mellitus and obesity, where these patients are more prone to develop hypertension ,coronary artery disease and heart failure.Normally,cardiac cells metabolize fatty acids and glucose and to a lesser extent lactate and ketone bodies.However,the onset of insulin resistance and obesity-driven type II diabetes mellitus shift the cardiac cells to utilize fatty acids more than glucose leading to myopathy characterized by ventricular dilatation,cardiac myocytes hypertrophy and death, as well as interstitial fibrosis and dysfunctional changes in diastolic relaxation.
Recent studies focused on a paradox termed as obesity paradox where obese patients with heart failure manifest improvements in survival compared to normal weight patients and higher body mass indexes are related to lower mortality risk. Such association is attributed to depression of the neurohormonal system or to an increase in nutritional or metabolic reserve.
Electrophysiological Remodeling in patients with LV hypertrophy develop malignant arrhythmias. Sustained ventricular tachycardia or ventricular fibrillation can occur immediately after myocardial infarction, during remodeling and later after injury. Alterations in transmembrane Ca2+ fluxes are believed to contribute to the pathogenesis of hypertrophy and failure by abnormally activating Ca2+ responsive signaling pathway. Ventricular arrhythmia have different mechanisms but they all arise from a disordered electrical currents due to prolongation of ventricular action potentials, and delay in the recovery of excitability, which is observed in cardiac hypertrophy, lead to early and late afterdepolarizations and exacerbate arrhythmias.
Premature Ventricular Contractions: The most common type of cardiac arryhytmias, where a premature QRS complex is noted on ECG with abnormal duration and shape.It has no clinical significance in the absence of heart disease.
Right Ventricular Failure: Failure of the right ventricle associated with venous engorgement,subcutaneous edema and hepatic enlargement.
Maladaptive remodeling is age dependent and the mortality rate resulting from Myocardial Infarction increases with age.
Coronary artery disease which is the leading cause of heart failure with reduced systolic function occurs more in males than females.However, heart failure with preserved systolic function affects females more than males with a ratio of 2:1
Cardiac Remodeling is both an adaptive and maladaptive process during which the heart responds to injury.When the remodeling is adaptive, the heart will be able to maintain function in response to pressure or overload pressure especially during the acute phase of myocardial injury.For instance, the heart has the ability to remodel during mitral insufficiency,where there is an increase in the ventricular load or preload, to keep the flow of blood forward.On the other hand, Progressive remodeling is associated with poor prognosis. The time needed for the transition of any adaptive to maladaptive remodeling is not specific and can vary among patients. Once this transition is established, the remodeling process will contribute to Heart Failure progression.
The survival rate of patients with heart failure depends on age, gender, race and cause of cardiomyopathy.
The mortality rate in treated patients with heart failure increases with age as noted by a community-based review of over 5500 persons from the Cardiovascular Health Study and the Framingham study.Also, gender has an effect on the mortality rate, where women has generally a better prognosis than men with 3.2 years median survival rate compared to 1.7 years in men.
The effect of race on the mortality rate of patients with heart failure is still uncertain as different studies noted the following:
- Higher mortality in black patients with asymptomatic LV dysfunction or overt Heart failure as a post hoc analysis from the SOLVD trial of enalpril noted.
- Lower mortality rate in black patients with heart failure treated in 1998-1999 as noted in a study carried out on 30,000 Medicare beneficiaries hospitalized.
- No difference noted between black and white patients as noted by a post hoc analysis from the DIG trial of digoxin therapy.
Cardiomyopathy also has a role in determining the mortality rate where patients with peripartum cardiomyopathy has a better prognosis compared to patients with myocardial disease, particularly amyloidosis or hemochromatosis, HIV infection, doxorubicin therapy, ischemic heart disease, or connective tissue disease.On the other hand, hypertension, myocarditis, sarcoidosis, substance abuse have no effect on the mortality rate of patients with heart failure.
Several studies showed that there is a seasonal variation affecting the mortality rate.Deaths from heart failure seems to peak in winter months of January and December more than any other summer month.
Left Ventricular Systolic Dysfunction is difficult to be diagnosed solely on the basis of signs and symptoms. Studies showed that remodeling can occur without clinical symptoms. Cardiac remodeling can be assessed using echocardiography and radionuclide imaging. These two imaging studies identify LV systolic Dysfunction.
Although echocardiography is reliable in clinical trials, there is still some variations in its readings and good images are easier said than done in obese patients or those with respiratory diseases. Such difficulties make MRI a better method to provide more accurate images .Nevertheless, MRI is considered to be expensive for routine use.
Among the biomarkers used to evaluate patients of Heart Failure with Preserved Ejection Fraction are Brain Natriuretic Peptide (BNP) and N-terminal pro-BNP. Other circulating biomarkers used to diagnose Heart Failure with Preserved Ejection Fraction include Procollagen,Interleukin-6,Interleukin-8,Tumor Necrosis Factor-α,matrix metaloproteinase,triiodothyronine,Troponin T,heart-type fatty acid binding proteins and carbohydrate antigen-125.These Biomarkers and their implications still need to be studied more thoroughly.
Cardiac Troponin T and I are cardiac enzymes that are released after myocardial injury. These enzymes elevation are used as indicators for progressive decline in left ventricular function in patients of Heart Failure, even in the absence of coronary artery disease.
ACE inhibitors and ARBs used to treat hypertension have the ability to target cardiac remodeling and reduce heart failure morbidity and mortality. Recent studies targeted Renin, the rate limiting step of Angiotensin II production, using Aliskiren and showed an ability to blunt cardiac remodeling in infarcted mice hearts. The addition of Mineralocorticoid Receptors Antagonists (MRA) in low doses revealed that there is an improvement in the symptoms of patients with moderately severe or severe heart failure,especially those of recent decompensation or left ventricular dysfunction early after infarction.Spironolactone and Eplerenone are among the MRA drugs used. However, Spironolactone has adverse metabolic and endocrine side effects making eplerenone use to become more convenient.MRA therapy can lead to an increased level of aldosterone,which in its turn can lead to deleterious effects on the heart through non-mineralocorticoid receptors.
β-adrenergic receptor blockers are also among drugs used treat hypertension, cardiac arrhythmias and cardiac remodeling. Cardiac myocytes express β1 receptors and respond to β1-selective inhibitors.Nevertheless, fibroblasts express β2-receptors making the mechanism to which β-blockers act to become indefinable.
Positive inotropic agents used to control symptoms in decompensated heart failure showed to have an increase in mortality over the long term, and the use of Digoxin did not affect the mortality rate in the long run. However, two new nonglycoside inotropic agents are studied more thoroughly now.One is to deliver cDNA of the sacroplasmic reticulum Ca2+ pump via an Adeno-associated virus in order to refill the downregulated sacroplasmic reticulum Ca2+ levels and showed safety and benefits in advanced heart failure. The second is a Luso-inotropic compound, Istaroxime, which inhibits Na/K ATPase that can lead to accumulation of Na+ intracellulary and decrease the activity of Na-Ca ions exchanger to remove cystolic Ca2+, and hence activates the sacromeric contraction. This process showed a decrease in capillary wedge pressure and heart rate during phase II clinical trial.
HMG-CoA reductase inhibitors originally used to lower cholesterol level can provide protection to patients with ischemic heart disease. And anti-remodeling effects can occur when they are added to ACE inhibitors and β-blockers.
Vasopressin receptor antagonists such as conivaptan, Lixivaptan, Mozavaptan and Tolvaptan showed no effect on Heart failure long-term mortality and morbidity when used for acute treatment of hospitalized Heart failure patients. However, the addition of Tolvaptan in its oral form to standard therapy improved the symptoms of some Heart failure patients without series cardiac events.
Stem cells being considered for myocardial regeneration can be derived from bone marrow , circulating pools of progenitor cells and tissue-resident stem cells derived from adipose tissue, skeletal muscle ,myocardium and epicardium.The majority of clinical trials using stem cells derived from bone marrow showed safety and benefits in the treatment of ischemic heart disease beyond the standard therapy.However,some studies did not show any efficacy as patients receiving autologous adult stem cells are in advanced age and with different comorbidities such as hypertension and diabetes mellitus.Such comorbidities have effects on the viability of stem cells.
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