ABSTRACT
The conceptual model for heart failure has changed radically over the past 20 years. No longer a simple hemodynamic paradigm of pump dysfunction, heart failure is now characterized as a complex clinical syndromewith release of many neurohormones (1) and cytokines (2), which are believed to be most responsible for progression of the disease (3). This change in the understanding of the pathophysiology of heart failure has important therapeutic implications. Interventions aimed solely at correcting low cardiac output or reduced blood flow do not necessarily slow heart failure progression or reduce
mortality. Neurohormonal activation and cardiac remodeling (4) are now recognized as important aspects of cardiovascular disease progression and are, therefore, emerging as therapeutic targets in heart failure. Many data confirm that the neurohormonal and possibly the cytokine hypothesis of heart failure in adults may be valid in children with heart failure as well. Neurohormonal activation seems to be the final common pathway of different cardiovascular disorders caused by myocardial insufficiency, valvular or congenital heart disease; that may explain comparable clinical symptoms despite differences in the hemodynamic trigger. However, nearly 20 years after Cohn’s finding that neurohormonal activation predicts prognosis in chronic heart failure (5), we have no comparable
data in pediatric cardiology. A retrospective life-table analysis of 438 children based on initial measurements of renin activity confirm the high impact of neurohormonal activation on prognosis in children with congenital heart disease (Fig. 1) and should be a challenge to transfer this ‘‘new’’ model of adult heart failure to pediatric heart failure. Pediatric cardiologists have to realize that the most promising drugs in clinical heart failure trials-angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, beta-blockers, and aldosterone antagonists-are inhibitors of the neurohormonal system (Fig. 2). New drugs under investigation in current clinical trials-recombinant b-type natriuretic peptide, endothelin receptor, and vasopressin antagonists-are also based on the neurohormonal model of heart failure. Hemodynamic medical interventions in chronic heart failure with inotropes like phosphodiesterase inhibitors or vasodilators like calcium antagonists have shown disappointing results in clinical trials and an increased mortality. These results in adult patients should be a warning for any further ‘‘off label’’ use of these drugs in children with heart failure.
