Heart failure: a hemodynamic disorder complicated by maladaptive proliferative responses

Abstract

Heart failure has traditionally been viewed as a hemodynamic syndrome characterized by fluid retention, high venous pressure, and low cardiac output. Over the past decade, however, it has become clear that because of deterioration and progressive dilatation (remodeling) of the diseased heart, this is also a rapidly fatal syndrome. The importance of prognosis came to be appreciated when clinical trials showed that therapy which initially improves such functional abnormalities, as high venous pressure and low cardiac output, often fail to improve survival, and that some drugs which improve hemodynamics worsen long-term prognosis. The latter is true for most vasodilators which, in spite of alleviating the adverse short-term consequences of high afterload, shorten survival. Notable exceptions are ACE inhibitors, whose vasodilator effects do not explain their ability to prolong survival; instead, these drugs slow both deterioration and remodeling of the failing heart. Inotropic agents, while providing immediate relief of symptoms, generally shorten long-term survival, whereas β-blockers slow deterioration and remodeling, and reduce mortality. Aldosterone antagonists exert beneficial effects on prognosis that are not easily explained by their diuretic effects, but instead can be explained by their ability to inhibit signaling pathways that stimulate maladaptive hypertrophy, remodeling, apoptosis and other deleterious responses that cause deterioration of the failing heart. These and other findings demonstrate that heart failure is more than a hemodynamic disorder; these patients suffer from maladaptive proliferative responses that cause cardiac cell death and progressive dilatation that play a key role in determining the poor prognosis in this syndrome.

A comparative serial echocardiographic analysis of cardiac structure and function in rats subjected to pressure or volume overload

“…Traditional definitions, which prevailed throughout most of the 20th Century, defined heart failure as a hemodynamic disorder due to impairment or failure of the heart's pumping mechanism. Thus, increased pulmonary and systemic venous pressures, fluid retention and low cardiac output (CO) were encompassed in such a definition (15 Hypertension is associated with both systolic and diastolic dysfunction (17) and is the most common cause of diastolic dysfunction leading to heart failure (20). Hypertension leads to both LV hypertrophy and fibrosis that causes reduced myocardial complian ce (20).…”

CHIP protects against cardiac pressure overload through regulation of AMPK

“…Pathological cardiac hypertrophy (subsequently referred to as cardiac hypertrophy) is an adaptive response to increased afterload brought about by hypertension, decreased arterial compliance, and other cardiac stressors (1). During the development of cardiac hypertrophy, numerous cellular processes come into play, including protein synthesis and proteolysis to account for the structural changes that accompany hypertrophy, as well as changes in cardiac metabolism to cope with increased energy demands.…”

Effects of Novel Vasopressin Receptor Antagonists on Renal Function and Cardiac Hypertrophy in Rats with Experimental Congestive Heart Failure

“…In particular, the dominant role of the renin angiotensin aldosterone system (RAAS) and sympathetic nervous system (SNS) in the development of cardiovascular and renal dysfunction in CHF has been established and angiotensin-converting enzyme inhibitors and ␤-blockers serve as key therapies in clinical CHF (Packer, 1992;Shigematsu et al, 2001;Jessup and Brozena, 2003;Katz, 2003). Although playing an important compensatory role in the early stages of the disease, prolonged activation of these systems has detrimental effects on the kidney and cardiovascular system.…”