New THERAPEUTIC strategies for heart failure management

By: M. Mohsen Ibrahim, MD

Prof. of Cardiology - Cairo University

President of the Egyptian Hypertension Society

Over the past decade mechanisms underlying the vicious circle of progressive heart failure were clarified. A large number of neurohormonal modulators and cytokines were identified as the major contributors to the malignant nature of congestive heart failure. Excessive loading on the myocardium due to hemodynamic factors or loss of cardiac myocytes initiates a cascade of events which is initially adaptive to maintain the cardiac pumping ability and cardiac output. Later these initial compensatory events become maladaptive due to excessive and inappropriate activation of neurohormones and cytokines. The most important systems involved include the rennin-angiotensin- aldosterone system, the adrenergic nervous system, endothelin and argenine- vasopressin pathways, and cytokines.

Furthermore, there is an alteration of the myocardial genetic program with regression to fetal phenotype. The outcome of these different processes is structural and functional myocardial changes known as remodeling.  During this process there is progressive loss of cardiac myocytes secondary to both necrosis and apoptosis and an increase in collagen tissue formation and deposition producing diffuse myocardial fibrosis. The heart changes into a dilated, globular structure with fibrosis, myocyte hypertrophy and myocyte loss. It is the progressive nature of this process of cardiac remodeling that leads to the vicious circle of irreversible heart failure and death. In addition to the central cardiac changes, the vascular endothelium is abnormal in heart failure patients. This impairment in endothelial function is responsible for many of the manifestations of heart failure independent of failure of the cardiac muscle pumping ability.

Therapeutic Targets in Heart Failure Management   

Cardiac Remodeling

An important goal of modern heart failure therapy is to slow, arrest or if possible reverse the remodeling process. This objective can be achieved through effective neurohormonal and cytokine blockade aiming at preventing the cytotoxic and deleterious effects of the maladaptive activation of these systems. Angiotensin- converting- enzyme (ACE) inhibitors, beta adrenergic blockers (BB), angiotensin receptor blockers and aldosterone antagonists proved effective in attenuating the remodeling process, slowing or preventing myocardial fibrosis and myocyte loss and prolonging life. Beta adrenergic blockers are the only agents which proved experimentally to reverse the cardiac remodeling. Agents that interfere with other neurohormonal and cytokine activation are undergoing clinical trials, however, there are mixed results from completed studies. A number of endothelin receptor antagonists are under evaluation. Although they seem to have a favorable acute hemodynamic effect, their effects on clinical status, morbidity and mortality are not clear. The results of recent trials were disappointing.

A new group of drugs which contain a combination of ACE-inhibitor and neutral endopeptidase inhibitor (responsible for degradation of natriuretic peptide) seem theoretically advantageous, however recent trials with omapatrilat, a representative of this group showed no advantage over enalapril. Furthermore, this group carries the increased risk of angioneurotic edema because of excess bradykinin production.

Although there is some evidence that anticytokine interventions improve hemodynamic and clinical status in heart failure, the result of clinical trials using etanercept- an antitumor necrosis factor agent- were not encouraging. Another agent, infliximab- an antitumor necrosis factor antibody- was found to increases mortality and hospitalization.

Vascular Endothelium

Approaches to improve endothelial function include exercise training and correction of atherosclerotic risk factors. Physical exercise improves functional capacity, neurohormonal activity and skeletal muscle performance.

Contractile Machinery

Interventions directed to improve myocardial contractile machinery include inotropic drugs, multisite cardiac pacing, ventricular assist devices and myocyte implantation. Based upon their mode of action, direct myocardial inotropes are classified into cyclic AMP dependent and cyclic AMP independent agents. The first group includes direct adrenergic beta stimulants (e.g., dobutamine and ibopamine) and phosphodiasterase inhibitors (e.g., milrinone, enoximone, and vesnarinone). These agents can tide the patient over a short critical period, they produce acute hemodynamic improvement but they have no value and are deleterious on long term since they increase mortality. The second group includes calcium sensitizers which have the advantage of increasing myocardial contractility without augmenting oxygen requirements. Levosimendan is a well studied calcium sensitizers that proved more effective than dobutamine and improved short and long term mortality in severe heart failure patients.

Multisite cardiac pacing is useful intervention in heart failure patients with prolonged P-R interval or wide QRS duration. By resynchronizing cardiac contraction it improves left ventricular performance.

Implantation of LV assist devices can improve survival and can reverse remodeling.

Conclusion        

The new therapeutic strategy in heart failure is targeting cardiac remodeling, vascular endothelial function and contractile machinery. Agents successful in improving survival are ACE-I, BB and aldosterone antagonists. Among the new inotropes, levosimendan seems a promising drug in patients with severe heart failure. Multisite pacing and LV assist devices improve LV pumping function and prolong survival.