Elsevier

Cardiology Clinics

Volume 19, Issue 1, 1 February 2001, Pages 113-126
Cardiology Clinics

APOPTOSIS AND THE SYSTOLIC DYSFUNCTION IN CONGESTIVE HEART FAILURE: Story of Apoptosis Interruptus and Zombie Myocytes

https://doi.org/10.1016/S0733-8651(05)70198-3Get rights and content

Congestive heart failure (CHF) affects approximately 5 million people in the United States and is a contributing factor in more than 250,000 deaths annually. It is diagnosed in 400,000 Americans each year and is the primary diagnosis for more than 900,000 hospitalizations annually. CHF is the single most frequent cause of hospitalization for people age 65 and older (American Heart Association 1998). The direct health care costs (drugs, nursing home care, professional services) have been estimated as approximately $17.8 billion each year. These numbers likely will increase as the US population ages. In 1990, the age-adjusted death rate from CHF was 106.4 per 100,000, more than that from acquired immunodeficiency syndrome (AIDS) and breast cancer combined.18a The median survival after the diagnosis of heart failure is 1.7 years in men and 3.2 years in women, with a 5-year survival rate of less than 50%.25 Cardiac transplantation remains the only effective management option for end-stage heart failure. Approximately, 2000 transplants are performed in the country every year (American Heart Association 1998). Therefore, there is need for identifying the cascade of molecular and cellular events that contribute to left ventricular dysfunction, which likely may provide novel targets for preventing disease progression in heart failure.

The syndrome of CHF is characterized by hemodynamic abnormalities, impaired exercise capacity, neurohormonal activation but, most importantly, a relentless progression. This progressive nature of the disease accounts for its significant morbidity and its high mortality.42 It is interesting to note that a relatively long interval exists between the initial event causing myocardial damage and development of CHF. Even in patients with a large myocardial infarction (MI), the commonest cause of heart failure, symptoms often take years to appear.68 In the Framingham Heart Study,30 15% to 25% of all subjects with MI developed symptoms of CHF over a period of 5 years. Similarly, in the Multicenter Diltiazem Postinfarction Research Group trial,38 which examined the effect of a calcium antagonist in patients following a non-Q-MI, 24% of asymptomatic subjects in the placebo group developed CHF in 2.5 years. It is not clear what changes occur during this long interval that mediate the progression of heart failure or what influences the variable rate of progression.

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]

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