The recent randomized clinical trials have shown that neurohumoral activation starts early in the natural history of left ventricular dysfunction and that the levels of circulating factors such as atrial natriuretic peptide, norepinephrine, plasma renin activity, and endothelin-1 increase with heart failure severity. The Survival And Ventricular Enlargement (SAVE) study (1994) showed that the levels of atrial natriuretic peptide, renin, aldosterone, and arginine vasopressin were independent predictors of the combined end points of cardiovascular death, development of severe congestive heart failure, and recurrent myocardial infarction.
Cohn et al, on behalf of the Vasodilator-Heart Failure Trial (V-HeFT) investigators, showed that plasma norepinephrine was an independent prognostic factor in heart failure. However, the Studies Of Left Ventricular Dysfunction (SOLVD) Registry showed a weak correlation between plasma norepinephrine and left ventricular ejection fraction in an expanded cohort with a broader spectrum of left ventricular dysfunction; it only found a significant increase in norepinephrine in patients deteriorating to New York Heart Association class IV. Absolute plasma norepinephrine levels in heart failure are influenced by alterations in neuronal uptake and the clearance and metabolism of norepinephrine released from sympathetic nerve endings.
Plasma renin activity
The SOLVD Registry showed that plasma renin activity increased as ejection fraction declined, in a relationship independent of diuretic or angiotensin-converting enzyme inhibitor therapy. Although several studies have reported stimulation of the renin-angiotensin system in heart failure, there is no agreement as to its frequency or magnitude in relation to disease severity. Dzau et al reported marked system activation in acute decompensation, falling to near normal levels during recovery. Plasma renin activity may thus reflect compensation or decompensation status. Diuretic therapy and sodium restriction affect the renin-angiotensin system and increase plasma renin activity. However, Anand et al found elevated plasma renin activity in five of eight patients with advanced untreated heart failure and marked salt and water retention, confirming a similar report in untreated heart failure by Brown et al. Thus, plasma renin activity can vary significantly depending on the severity and treatment of the study cohort. The SOLVD data, covering varying stages and therapies in heart failure, found a correlation with the ejection fraction. This suggests that the degree of left ventricular dysfunction modulates plasma renin activity, directly (inadequate renal perfusion) and/or indirectly (renal sympathetic stimulation and renin release).
Atrial natriuretic peptide
Atrial natriuretic peptide is synthesized in the myocardium and released mainly in response to increased atrial stretching. Plasma levels increase with increased atrial pressure and atrial stretch in worsening heart failure. Hara et al found a negative correlation with the ejection fraction and a positive correlation with heart failure severity. Rouleau et al also found a negative correlation with the cardiac index. SOLVD confirmed the negative correlation with the ejection fraction and identified atrial natriuretic peptide as the hormone most closely correlating with left atrial and left ventricular systolic and diastolic dimensions and the cardiothoracic ratio.
In SOLVD, plasma arginine vasopressin levels showed virtually no increase compared with normal subjects, and thus no significant association with ejection fraction or functional class, despite earlier evidence to the contrary. The mechanism of arginine vasopressin release in heart failure is unclear, but is believed to be nonosmotic. Levels often parallel those of plasma renin activity because of compromised end-organ perfusion. Baroreceptor stimulation is a common stimulus for the release of both hormones, and increases in angiotensin II may directly stimulate the hypophyseal production of arginine vasopressin. However, in SOLVD, despite progressive increases in plasma renin activity with increased left ventricular dysfunction, arginine vasopressin levels remained stable. This suggests that arginine vasopressin release is not a primary mechanism for maintaining peripheral resistance in most patients with heart failure, and that nonosmotic mechanisms effect only limited release.
Endothelin-1 is a potent endothelial cell-derived peptide with multifunctional properties, including venous and arterial vasoconstriction, modulation of inotropy, and induction of hypertrophy and gene expression. Elevated levels have been reported in heart failure. Pacher et al and Tsutamoto et al showed that endothelin-1 is a potent independent predictor of mortality in severe heart failure. Pousset et al extended this finding to mild and moderate heart failure.
Brain-type natriuretic peptide
Brain-type natriuretic peptide (BNP) is a neurohormone secreted by the ventricles in response to volume expansion and pressure overload. Maeda et al and Cleri-co et al showed that levels increase with clinical severity in heart failure due to left ventricular systolic dysfunction, and correlate with hemodynamic parameters such as pulmonary capillary wedge pressure and left ventricular ejection fraction.
The contributions of prostaglandins, the kallikrein-kinin system, growth hormone, and calcitonin gene-related peptide to the pathophysiology of heart failure await elucidation.