TARGET: Chronic Heart Failure
   
 

DISEASE STATE

Heart failure is a progressive disorder manifested by a diminished ability of the heart to pump enough blood to meet the demands of the body’s tissues. The disorder is characterized by fluid retention, shortness of breath, fatigue, and cardiac arrhythmias. The body attempts to compensate by gradually remodeling the heart, resulting in an enlarged, poorly contracting heart. Unfortunately, these changes can increase strain and lead to further deterioration in the heart’s pumping function, resulting in a vicious cycle of deterioration of function.
  Heart failure can result from a number of disease processes and is a principle complication of nearly all forms of heart disease.
   
 

PREVALENCE

Chronic heart failure is the most common cause of mortality and morbidity, afflicting an estimated 5-10 million people in the United States and 7.5 million people in Japan and Western Europe. In the United States, the occurrence of chronic heart failure is estimated to double during each decade between the ages of 50 and 90.
The 1-year mortality for advanced heart failure exceeds 50%.
   
 

THE ROLE OF RYCALS™ IN HEART FAILURE

Rycal™ compounds may help improve function in heart failure by improving cardiac contractility without increasing energy demands* and by inducing reverse remodeling of the heart. Rycal™ compounds may also be anti-arrhythmic, and it is hypothesized that they may improve exercise capacity by direct action on leaky RyR channels in skeletal muscle that can occur in heart failure.
   
 

CLINICAL STATUS

In preclinical studies, Rycal™ compounds have been shown to act directly on ryanodine receptors (RyR)/calcium release channels in the heart to increase cardiac function, to suppress fatal cardiac arrhythmias, and to act on RyR channels in skeletal muscle to improve exercise capacity. Based on these promising results, ARMGO™ is planning to launch human clinical trials to study Rycal™ compounds in patients with chronic heart failure.
 
 
Marx SO, Reiken S, Hisamatsu Y, et al. PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell. 2000;101:365-376.
 
Wehrens XHT, Lehnart SE, Reiken SR, et al. Enhancing calstabin binding to ryanodine receptors improves both cardiac and skeletal muscle function in heart failure. Proc Natl Acad Sci U S A. 2005;102:9607-9612.
 
Wehrens T, Lehnart S, Marks A. Intracellular calcium release and cardiac disease. Annu Rev Physiol. 2005;67:69-98.
 
 
*Rycal™ compounds are NOT inotropes. When infused at high doses in animals (eg, pig, dog), they have no measurable affect on heart rate, blood pressure, or cardiac function. In preclinical models, Rycal™ compounds have additive activity when given with either angiotensin-converting enzyme inhibitors or beta blockers. Uniquely, Rycal™ compounds target the 3 major causes of mortality and morbidity in heart failure: decreased cardiac contractility, impaired exercise capacity, and arrhythmias.

Current News


 

ARMGO™ Pharma Receives $1 Million Award from MDA to Support Advancement of Rycal™ Compound ARM210 as a Novel Treatment for Duchenne Muscular Dystrophy   Link to Article

 

ARMGO™ Pharma, Inc. announces the appointment of Dr. Sapan Shah as CEO   Link to Article

 

Kushnir A, Marks AR. The ryanodine receptor in cardiac physiology and disease. Adv Pharmacol. 2010;59:1-30.   Link to Article

 

Kushnir A, Shan J, Betzenhauser MJ, Reiken S, Marks AR. Role of CaMKlldelta phosphorylation of the cardiac ryanodine receptor in the force frequency relationship and heart failure. Proc Natl Acad Sci U S A. 2010 Jun1;107(22):10274-9.   Link to Article

 

Kushnir A, Betzenhauser MJ, Marks AR. Ryanodine receptor studies using genetically engineered mice.FEBS Lett. 2010 May 17;584(10):1956-65.   Link to Article

 

Betzenhauser MJ, Marks AR. Ryanodine Receptor channelopathies Pflugers Arch. 2010 Jul;460(2):467-80.   Link to Article

 

Fauconnier J, Thireau J, Reiken S, Cassan C, Richard S, Matecki S, Marks AR,Lacampagne A.- Leaky RyR2 trigger ventricular arrhythmias in Duchenne muscular dystrophy.Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1559-64.4-9.   Link to Article

Prof. Andrew Marks presentation on, "Mechanism-Based Therapies for Heart Failure and Cardiac Arrhythmias" from the Henry Stewart Talks, Series, "Calcium Signalling: Regulation, Mechanisms, Effectors, Role in Disease and Recent Advances".
Link to Presentation