Marc Klapholz, MD, associate professor of medicine and director, Division of Cardiology, UMDNJ-New Jersey Medical School

Originally thought to be a disease simply of hemodynamic instability, systolic dysfunction heart failure is now recognized as a syndrome with a multitude of neurohormonal, cytokine, sympathetic and other cellular abnormalities. The challenge has been to identify therapeutic targets to slow or reverse these abnormalities and/or to augment myocardial contractility. Neurohormonal derangements described in heart failure include elevated levels of angiotensin II, aldosterone, endothelin and vasopressin. Angiotensin-converting enzyme inhibitors and aldosterone antagonists improve symptoms and increase survival, validating the importance of neurohormonal modulation in patients with heart failure. While the treatment of chronic heart failure has undergone numerous advances over the past two decades, the management of acutely decompensated heart failure, particularly in association with a low cardiac output syndrome, has remained elusive.

The mainstay of therapy in these patients has been either the use of beta receptor agonists such as Dobutamine or phosphodiesterase inhibitors (PDEI) such as Milrinone or Amrinone. These inotropes acutely augment myocardial contractility by increasing intracellular cyclic AMP (adenosine monophosphate), which leads to increases in intracellular calcium, enhancing myocardial inotropy. Dobutamine mediates its effect by directly increasing production of cyclic AMP while Milrinone and Amrinone work by decreasing metabolism of cyclic AMP (see fig. 1). However, flooding the cell with calcium is often associated with serious adverse events, such as life-threatening cardiac arrhythmias. Both the beta agonists and the PDEIs have been associated with increased mortality, particularly when used repeatedly over the long term. Newer approaches to inotropic therapy center on augmenting cardiac contractility without increasing the calcium load to the cell. These inotropes focus on improving efficiency of calcium use within the cell. Two distinct mechanisms for increasing calcium efficiency are currently being researched.

Enlarge the image Figure 1: Dobutamine, Milrinone and Digoxin all augment myocardial contractility by increasing intracellular calcium

In the steady state, calcium is released from its intracellular store in the sarcoplasmic reticulum and binds to troponin C, a member of the troponin complex, which is composed of troponin C, T and I. Binding of calcium to troponin C induces a conformational change in the troponin complex which causes the displacement of tropomyosin from actin. The displacement of tropomyosin from actin unmasks actin binding sites, which are then free to interact with myosin, leading to myocyte shortening. The myosin actin complex is the fundamental contractile component of the myocardium. The dissociation constant of the calcium troponin C complex is high, leading to a very short-lived interaction. Once calcium is released from troponin C, it is shuttled back into the sarcoplasmic reticulum through the sarcoplasmic reticulum calcium (SERCA) pump. Two therapeutic approaches that have emerged include stabilization of the calcium-troponin C interaction and augmentation of the SERCA pump. Stabilizing the calcium-troponin C complex leads to a longer and more stable interaction between actin and myosin, greater myofilament shortening and enhanced contractility. By augmenting SERCA, which is down regulated in heart failure, more calcium is taken up into the sarcoplasmic reticulum during diastole. Consequently, this additional calcium is available for release from the sarcoplasmic reticulum during the subsequent cardiac systole. In both approaches total intracellular calcium is not increased, but the effect of calcium is magnified by its more efficient use.

Calcium Channel Sensitizers

Enlarge the image Figure 2: Levosimendan stabilizes the calcium troponin C complex, enhancing contractility.

Levosimendan (Orion Pharmaceuticals) is the prototypical calcium channel sensitizer which works by stabilizing the interactions between calcium and troponin C (see fig. 2). Levosimendan has been studied in several trials that have shown that Levosimendan exerts a similar hemodynamic effect to Dobutamine, including increases in cardiac output and decrements in pulmonary capillary wage pressures. While these early studies were not designed to detect mortality differences, follow-up of patients treated with Levosimendan as compared to those treated with Dobutamine showed improvement in survival at both 30 and 180 days post pretreatment.

The current study entitled "Randomized Multicenter Evaluation of Intravenous Levosimendan Efficacy vs. Placebo in the Short Term Treatment of Decompensated Chronic Heart Failure (REVIVE)," is designed to ascertain the proportion of patients improved or worsened at 24 hours and five days after start of drug infusion. We used a composite scale for patients and classified them as improved, worse or unchanged. The pre-specified, secondary endpoints include patient global assessment at six hours, time to death, or worsening of heart failure during the first 31 days, and all cause mortality during the first 90 days. Inclusion criteria for this study are men or women greater than 18 years of age who are hospitalized for worsening heart failure, have shortness of breath at rest and a left ventricular ejection fraction of less than 35%. Planned enrollment for this double blind, randomized, placebo-controlled trial is 1,000 patients and is nearly complete with results forthcoming in mid-2005.

SERCA Agonist

PST2744 (Sigma Tau Pharmaceuticals) is the first compound in the class of SERCA agonists to be developed for clinical trials. This drug augments sarcoplasmic reticulum calcium ATPase (adenosine triphosphatase), which is the enzyme responsible for mediating the uptake of calcium into the sarcoplasmic reticulum during diastole.

The efficacy and safety of PST2744 has been evaluated in numerous animal studies and has shown consistent increases in myocardial contractility, improvement in ventricular relaxation and lowering of preload and afterload. Intravenous bolus administration of PST2744 induces a prompt increase in +dP/dt max in vivo in a dose- related fashion, supporting its inotropic effect. Negative dP/dt is similarly increased, suggesting that the compound has beneficial lucitropic properties. The study currently underway is a Phase 1 trial to evaluate the safety and tolerability of PST2744 in patients with chronic heart failure. Patients with stable class II-III heart failure and a systolic left ventricular ejection fraction of less than or equal to 40% will be eligible. The primary objective of the study is to establish the safety and tolerability of this new compound. The secondary objectives are to assess the hemodynamic effects of this compound by measuring right ventricular pressures, pulmonary artery pressures, cardiac output and vascular resistances. Additional objectives include characterizing the pharmacokinetic profile of this compound in patients with heart failure. The study is a randomized, dose escalating study with three sequential cohorts of patients. As this is the first trial conducted in humans, careful attention is being paid to safety parameters with external review at each dose level prior to advancing to the next level.

Marc Klapholz, MD, is the director of the division of cardiology at NJMS. Dr. Klapholz received his medical degree from Albert Einstein College of Medicine of Yeshiva University in New York. He completed his residency in internal medicine, an NIH-sponsored cardiology fellowship and general cardiology fellowship at Albert Einstein College of Medicine of Yeshiva University and the Bronx Municipal Hospital. Dr. Klapholz has been a principal investigator in more than 70 clinical trials relating to heart failure. His major research interests include evaluation of novel therapeutic agents for the treatment of heart failure, diastolic dysfunction, and hemodynamic and functional correlates of serum levels of brain natriuretic peptide in heart failure. Dr. Klapholz has authored and co-authored numerous articles, book chapters, monographs, and reviews. §