Ventricular remodeling: Difference between revisions
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==[[Ventricular remodeling pathophysiology|Pathophysiology]]== | ==[[Ventricular remodeling pathophysiology|Pathophysiology]]== | ||
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. | |||
==[[Ventricular remodeling causes|Causes]]== | ==[[Ventricular remodeling causes|Causes]]== | ||
Revision as of 16:42, 27 November 2013
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Ventricular Remodeling |
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Differentiating Ventricular Remodeling From Other Conditions |
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Diagnosis |
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Treatment |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor-in-Chief: Mohammad I. Barouqa, M.D.
Synonyms and keywords: Left ventricular remodeling, LV remodeling
Overview
The Left Ventricle has an enormous ability to respond to any type of stress or pathological process. Such a response includes a complex a 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.
Historical Perspective
Classification
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.
Pathophysiology
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.
Causes
Differentiating Ventricular remodeling from other Diseases
Epidemiology and Demographics
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.
Risk Factors
Natural History, Complications and Prognosis
Diagnosis
History and Symptoms | Physical Examination | Laboratory Findings | Other Imaging Findings | Other Diagnostic Studies
Treatment
Medical Therapy | Surgery | Primary Prevention | Secondary Prevention | Future or Investigational Therapies
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.