CHF: circulatory homeostasis gone awry.

The role of the renin-angiotensin-aldosterone system (RAAS) is integral to salt and water retention, particularly by the kidneys. Over time, positive sodium balance leads first to intra- and then to extravascular volume expansion, with subsequent symptomatic heart failure. This report examines the role of the RAAS in regulating a less well recognized component essential to circulatory homeostasis--central blood volume. The regulation of central blood volume draws on integrative cardiorenal physiology and a key role played by the RAAS in its regulation. In presenting insights into the role of the RAAS in regulating central blood volume, this review also addresses other sodium-retaining states with a predisposition to edema formation, such as cirrhosis and nephrosis.

Diastolic dysfunction in the elderly--the interstitial issue.

Diastolic dysfunction is increasingly recognized as a cause of congestive heart failure. Meta-analyses of earlier studies of this disorder suggest that 40%-50% of patients with the congestive heart failure syndrome have preserved left ventricular systolic function, with current estimates ranging up to 74%. Among patients >or=65 years of age with congestive heart failure, 55% of all subjects and 67% of women had normal systolic function. Histopathologic evaluation reveals a maladaptive remodeling of the interstitium associated with aging, resulting in an increase in interstitial collagen content. The interstitium normally plays a critical role in the generation of early diastolic suction. When there is a significant enough increase in myocardial collagen volume fraction, with its increased viscoelastic burden, this normal early diastolic suction is compromised and diastolic pressures increase. Left ventricular diastolic dysfunction ensues. Neurohumoral abnormalities associated with diastolic dysfunction include activation of the renin-angiotensin-aldosterone system, including increased elaboration of myocardial aldosterone. This excess of aldosterone appears to play a major role in the development of myocardial fibrosis. Recent observations in animal models and humans have demonstrated regression of interstitial collagen volume fraction in response to inhibition of the renin-angiotensin-aldosterone system by angiotensin-converting enzyme inhibitors and aldosterone inhibition, with improvement in diastolic function. Therapeutic implications of these observations suggest targeting the maladaptive remodeling of the interstitium via inhibition of the renin-angiotensin-aldosterone system.

Cardiac fibrosis as a cause of diastolic dysfunction.

BACKGROUND: Diastolic dysfunction is increasingly recognized as a cause of symptomatic heart failure, including the clinical syndrome congestive heart failure (CHF). Meta-analyses of earlier studies of this disorder suggest 40-50% of patients with congestive heart failure have preserved left ventricular systolic function. Conditions associated with diastolic dysfunction are diverse and most commonly include ischemic cardiomyopathy with previous myocardial infarction(s) and hypertensive heart disease. PATHOPHYSIOLOGY: An underlying histopathologic finding in each of these entities is an adverse accumulation and structural remodeling of the heart's fibrillar collagen matrix expressed as cardiac fibrosis. In ventricular tissue fibrosis serves to impose a viscoelastic burden that compromises all of diastole, including the rate of relaxation, diastolic suction and passive stiffness. Various factors contribute to the abnormal accumulation of this fibrillar matrix. Of particular importance are effector hormones of the renin-angiotensin-aldosterone system. TREATMENT: In experimental studies, pharmacologic interference with each of these circulating hormones, either through ACE inhibition or respective receptor antagonism, proves cardioprotective by preventing fibrosis while preserving diastolic function. Additionally, a regression of established cardiac fibrosis by its presumptive proteolytic digestion induced by ACE inhibition or AT receptor antagonism has been demonstrated. This cardioreparative strategy improves tissue stiffness and suggests diastolic dysfunction is reversible.