APOPTOSIS AND THE SYSTOLIC DYSFUNCTION IN CONGESTIVE HEART FAILURE: Story of Apoptosis Interruptus and Zombie Myocytes
Section snippets
WHAT MEDIATES CONTINUED MYOCARDIAL DAMAGE IN CONGESTIVE HEART FAILURE?
Heart failure is caused by many etiologic conditions, each with different pathogenic mechanisms. Although ventricular dysfunction is transient in some conditions, others result in progressive worsening of myocardial structure and function even when the noxious factors responsible for initial injury no longer exist.71 Such a situation typically is represented by an aftermath of acute MI. It is unclear why the left ventricle should continue to fail following a single episode of regional wall
CAN APOPTOSIS OCCUR IN HEART FAILURE?
Various cardiovascular disorders that result in CHF are characterized by volume or pressure overload, or loss of contractile myocardial mass. The initial hemodynamic compensation in these disorders is accomplished by neurohormonal and cytokine activation, which leads to myocardial hypertrophy and dilatation.18, 32 At the cellular level, there is progressive lengthening of cells with much less increase in cell width.3, 18, 21 Such mechanical adaptations initially reduce wall stress and serve to
DO TRANSGENIC MODELS OF HEART FAILURE SUBSTANTIATE THE APOPTOTIC HYPOTHESIS?
The occurrence of apoptosis has been confirmed in various transgenic animal models, which also have allowed better understanding of the pathogenetic basis of apoptosis in ventricular myocardium. The transgenic strategies have included induction of active caspases, overexpression of inducers of apoptosis, and underexpression of survival factors.28 The transgenic models also have addressed the relationship between myocardial hypertrophy and apoptosis. The most convincing animal model is based on
DOES APOPTOSIS OCCUR IN HUMAN HEART FAILURE?
Demonstration of apoptosis in human heart failure is the logical extension of the apoptosis hypothesis observed in the animal models of heart failure. Narula et al47 first demonstrated apoptosis in the hearts explanted during cardiac transplantation. Seven cardiomyopathic hearts were examined; all patients had severe CHF for 1.5 to 6.5 years and were New York Heart Association (NYHA) class IV symptomatic. Hemodynamic studies47 before transplantation demonstrated moderate-to-severe pulmonary
WHAT IS SO PECULIAR ABOUT APOPTOSIS IN HEART FAILURE?
Although foregoing studies have demonstrated reproducibly the occurrence of apoptosis by the TUNEL-based evidence of DNA fragmentation, more recent investigations have claimed that TUNEL staining in myocytes does not truly represent apoptosis. Kanoh et al29 studied endomyocardial biopsy specimens from 20 patients of dilated cardiomyopathy (with variable functional class) and compared them with 20 control biopsy specimens. Evidence of apoptosis was observed in 15% of biopsy specimens in
CAN INTERRUPTED APOPTOSIS LEAD TO MYOCARDIAL DYSFUNCTION?
It is logical to assume that terminally differentiated cells, which do not possess the capability of renewal, should not be able to undergo programmed cell death. From the foregoing discussion, however, it is clear that the apoptotic process is initiated in failing cardiomyocyte. The initiating receptor complexes are altered and regulators of apoptosis are imbalanced. Cytochrome c is released from mitochondria, which leads to activation of apoptotic caspases.49 Subsequent damage to nucleus may
SUMMARY
Although previously it was believed that apoptosis could not occur in the terminally differentiated tissue, such as adult heart muscle cells, recent studies in endomyocardial biopsies from patients with dilated cardiomyopathy and in explanted hearts from patients with end-stage heart failure undergoing cardiac transplantation have demonstrated histologic evidence of apoptosis. Whereas neurohormonal activation during heart failure leads to compensatory hemodynamic alterations, coupled with
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Address reprint requests to Jagat Narula MD, DM, PhD, Division of Cardiology, MCP-Hahnemann University Hospital, Broad and Vine, MS115–742NT, Philadelphia, PA 19102–1192, e-mail: [email protected]