The failing heart: a new therapeutic approach

Heart failure is one of major cause of death among people both in developed and developing countries. After 40 years of age, the lifetime risk of developing heart failure is 20% for both women and men. In its most common manifestation, heart failure is marked by a decrease in cardiac contractility and called systolic heart failure. To preserve cardiac output, the body increases sympathetic tone and activates neurohormonal pathways (a cascade of intracellular events occurring inside the cardiac muscle cells). These compensatory mechanisms can, however, accelerate the decline of cardiac systolic function. Patients die because of progressive weakening of the heart leading to cardiac remodelling, which further weakens it and can also cause deadly arrhythmias (irregular heartbeat or abnormal heart rhythm). Therefore a group of scientists thought that if the failing heart could be strengthened, the outcome might be more favorable. This group of researchers working at Cytokinetics, Inc., San Francisco, CA, a pharmaceutical company, recently published their exciting and very promising findings about  a small-molecule drug — omecamtiv mecarbil — that selectively enhances the activity of the motor protein myosin, the main force-generating protein of the heart.

Let us first understand the underlying mechanism of heartbeat. The sarcoplasmic reticulum (a organelle inside the striated muscle cell), major functions of which is to  release calcium ions (Ca²⁺) into the cytoplasm of the heart-muscle cells in a synchronized manner  as shown in following figure (Source: Bers & Harris, Nature 2011, 473; 36–39). The Ca²⁺ activates myofilaments — organized structures in the cytoplasm composed of interlocked (like the fingers of folded hands) filaments of either actin or myosin proteins. On activation, each myosin filament simultaneously grabs and pulls on an actin filament, in a process that uses the cellular energy molecule ATP. The coordinated contractile activity of the myofilaments develops the forceful muscle contraction that ejects blood from the heart. In heart failure, a reduced amount of Ca²⁺ is available for release by the sarcoplasmic reticulum, contributing to weaker myofilament activation and contraction.     

First line of drugs to teat heart failures were, inotropic drugs —that enhance contraction at a given ventricular volume — by enhancing the Ca²⁺ signal that activates contraction. But many of these drugs actually overload cardiac muscle cells with Ca²⁺, increasing both energy consumption and the risk of arrhythmias and therefore worsen a patient's prognosis. Now these drugs are not that widely used these days. Most widely used type of drugs to treat patients with chronic heart failure are β-blockers, ACE inhibitors, and ARBs, which are not inotropic drugs. These drugs block neurohumoral signalling by adrenergic and renin–angiotensin pathways. Heart failure is accompanied by a neurohumoral storm that activates these pathways by fuelling progressive remodelling and dysfunction. Thus blocking these pathways can slow the progress of heart failure. However, these drugs also increase heart rate and myocardial oxygen consumption and can produce arrhythmias and hypotension or low blood pressure, which contributes to higher mortality.

Dr. Fady Malik and co-investigators hypothesized that directly activating the contractility of the cardiac sarcomere (the smallest functional unit of cardiac muscle fiber) would improve cardiac performance while avoiding the adverse effects of indirect mechanisms. The sarcomere is made up of interdigitating thin and thick filaments. Myosin, the main component of the thick filament, uses chemical energy derived from ATP hydrolysis to produce force for contraction. Myosin motors act upon thin filaments composed of actin and the troponin-tropomyosin regulatory complex. In resting muscle, the free calcium concentration is low, and the regulatory proteins prevent myosin from interacting with actin. During each heartbeat, calcium is released transiently from the sarcoplasmic reticulum into the cytoplasm, where it binds to troponin and allows myosin to interact with actin filaments and to produce contraction. The muscle relaxes as calcium is removed from the cytoplasm.

In this report recently published in Science, (2011, 331 (6023): 1439-1443) this team established that omecamtiv mecarbil — also an inotropic drug — increases heartbeat strength by selectively enhancing the ability of the myosin molecule to generate force (see above figure). They demonstrated that omecamtiv mecarbil enhances cardiac output without changing the level of consumption of oxygen and ATP (molecular unit of cellular/chemical energy) by the heart. As the heart weakens, it receives less nutritive, oxygen-rich blood (that is, the heart pumps blood through its own coronary arteries), which further limits cardiac contraction. By augmenting force while avoiding extra energetic costs, omecamtiv mecarbil increases the apparent efficiency of cardiac contraction and preserves the energy supply–demand balance.

Though tested in a dog model of heart failure, omecamtiv mecarbil holds lot of promises as a selective activator of cardiac myosin, and a rare example of a drug whose action depends on activation rather than inhibition of an enzyme, an approach that may have broader application for therapeutic intervention. Further studies in patients with heart failure will eventually define the clinical benefit and risk profile of cardiac myosin activation in a condition that is still marked by substantial rates of mortality and morbidity. Also this drug gives a new direction of research in which more drugs need to be developed to activate cardiac myosin as a new therapeutic approach to treat heart failure conditions.

For details, please read the article:
http://www.sciencemag.org/content/331/6023/1439.full