Role of Amino Acids and Genetic Disorder in Pathogenesis of Heart Failure

Heart Failure

pathogenesis of heart failure, cardiac ryanodine Receptor 2, Amino acids

Heart failure (HF) is a continuously growing public health problem. The study aim to provide novel insights into the role of amino acids in pathogenesis of heart failure, to obtain a better understanding of cardiac ryanodine Receptor 2 role as an essential player in excitation-contraction coupling in pathogenesis of heart failure and clarify the potential value of these markers as targets for heart failure therapy

Heart failure (HF) is a continuously growing public health problem. Presently, almost 40 million people are affected by heart failure worldwide. According to World Health Organization (WHO), cardiovascular diseases are number one cause of deaths globally . In developed countries, the prevalence of heart failure is approximately 1-2% of the adult population. In Egypt, the prevalence of HF with preserved ejection fraction represents about 34.2 % while heart failure with reduced ejection fraction represents 65.8 % of total heart failure cases . A broad range of cardiac diseases, inherited disorders, and systematic diseases can result in heart failure. The situation is even more complex, as heart failure can have mixed etiologies. Heart failure itself represents a final common pathway in response to genetic and/or environmental influences. A clear genetic identification can positively influence patient treatment and, thereby, improve prognosis. Besides, understanding the pathogenesis of genetically induced heart failure at it molecular level may lead to the development of specific individual heart failure therapies in the future. The human heart uses large amounts of amino acids (AAs) as regulators of both myocardium protein turnover and energy metabolism, but uses few AAs as substrates for direct energy production .The heart's reliance on AAs increases during heart failure because of high myocardium anabolic activity and cardiomyocyte energy shortage. Anabolic activity of the ventricle wall is induced by both high levels of ventricular pressure and a myocardial substrate shift from fatty acid oxidation (FAOX) to glucose oxidation (GLUOX). Various mechanisms may potentially be operating during CHF to impair arterial AAs, including inadequate protein-energy intake, body AA overconsumption, particularly in hyper metabolic states, increased remodeling activity of the heart and lung and finally, the development of pathogenic gut flora. Understanding arterial AA levels could be useful to understand whether heart anabolic activity and remaining heart capacity of energy production are being threatened by low AA s and furthermore may allow us to correct altered AAs through diet and/or supplementation of specific free AAs. A reduction in essential AAs in CHF subjects, shows the disease severity-related decline of arterial levels of those non-essential (and essential methionine) AAs with the greatest impact on myocardium energetics, anti-oxidative capacity and myocardial protein remodeling. Calcium cycling protein and heart failure Ca2+-dependent signaling is highly regulated in cardiomyocytes and determines the force of cardiac muscle contraction. Ca2+ cycling refers to the release and reuptake of intracellular Ca2+ that drives muscle contraction and relaxation in failing hearts. Ca2+ cycling is profoundly altered, resulting in impaired contractility and fatal cardiac arrhythmias. The key defects in Ca2+ cycling occur at the level of the sarcoplasmic reticulum (SR), a Ca2+ storage organelle in muscle. Defects in the regulation of Ca2+ cycling proteins including the ryanodine receptor 2 (RyR2) a cardiac Ca2+ release channel macromolecular complexes and the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase2a (SERCA2a) contribute to heart failure. Phosphorylation of the cardiac ryanodine receptor (RyR2) phospho-site S2808 has hallmark of heart failure (HF) and a critical mediator of the physiological fight or flight response of the heart. In support of this hypothesis, mice unable to undergo phosphorylation at RyR2-S2808 (S2808A) were significantly protected against HF and displayed a blunted response to adrenergic stimulation.

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