Article

Cardiac ryanodine receptor in metabolic syndrome: is JTV519 (K201) future therapy?

Department of Pharmacology, Ufuk University School of Medicine. Mevlana Bulvari, Balgat, Ankara, Turkey.
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 01/2012; 5:89-99. DOI: 10.2147/DMSO.S30005
Source: PubMed

ABSTRACT Metabolic syndrome is characterized by a combination of obesity, hypertension, insulin resistance, dyslipidemia, and impaired glucose tolerance. This multifaceted syndrome is often accompanied by a hyperdynamic circulatory state characterized by increased blood pressure, total blood volume, cardiac output, and metabolic tissue demand. Experimental, epidemiological, and clinical studies have demonstrated that patients with metabolic syndrome have significantly elevated cardiovascular morbidity and mortality rates. One of the main and frequent complications seen in metabolic syndrome is cardiovascular disease. The primary endpoints of cardiometabolic risk are coronary and peripheral arterial disease, myocardial infarction, congestive heart failure, arrhythmia, and stroke. Alterations in expression and/or functioning of several key proteins involved in regulating and maintaining ionic homeostasis can cause cardiac disturbances. One such group of proteins is known as ryanodine receptors (intracellular calcium release channels), which are the major channels through which Ca(2+) ions leave the sarcoplasmic reticulum, leading to cardiac muscle contraction. The economic cost of metabolic syndrome and its associated complications has a significant effect on health care budgets. Improvements in body weight, blood lipid profile, and hyperglycemia can reduce cardiometabolic risk. However, constant hyperadrenergic stimulation still contributes to the burden of disease. Normalization of the hyperdynamic circulatory state with conventional therapies is the most reasonable therapeutic strategy to date. JTV519 (K201) is a newly developed 1,4-benzothiazepine drug with antiarrhythmic and cardioprotective properties. It appears to be very effective in not only preventing but also in reversing the characteristic myocardial changes and preventing lethal arrhythmias. It is also a unique candidate to improve diastolic heart failure in metabolic syndrome.

0 Bookmarks
 · 
191 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cardiac pathologies remain the main cause of mortality worldwide. Among them the most common cause is cardiac ischemia. The rapid reperfusion after coronary occlusion has considerably improved the cardiac outcome, however reperfusion per se has deleterious effect also called reperfusion injuries. Cytosolic calcium overload is now well admitted as an essential pathophysiological mechanism involved in reperfusion injuries although the source and origin of calcium remain to be determined. Recent works have pointed out the potential defect of sarcoplasmic reticulum calcium release channels (ryanodine receptor, RyR) as a primary cause of calcium overload during ischemia-reperfusion. This finding opens new pharmacological perspectives in limiting reperfusion injuries since allosteric modulators able to restore and prevents RyR dysfunction have been developed during the last decade.
    Pharmacology [?] Therapeutics 02/2013; · 7.79 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The cardiac ryanodine receptor (RyR2), a Ca2+ release channel on the membrane of the sarcoplasmic reticulum (SR), plays a key role in determining the strength of the heartbeat by supplying Ca2+ required for contractile activation. Abnormal RyR2 function is recognized as an important part of the pathophysiology of heart failure (HF). While in the normal heart, the balance between the cytosolic and intra-SR Ca2+ regulation of RyR2 function maintains the contraction-relaxation cycle, in HF, this behaviour is compromised by excessive post-translational modifications of the RyR2. Such modification of the Ca2+ release channel impairs the ability of the RyR2 to properly deactivate leading to a spectrum of Ca2+-dependent pathologies that include cardiac systolic and diastolic dysfunction, arrhythmias, and structural remodelling. In this article, we present an overview of recent advances in our understanding of the underlying causes and pathological consequences of abnormal RyR2 function in the failing heart. We also discuss the implications of these findings for HF therapy.
    Cardiovascular research 03/2013; · 5.80 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Heart failure has become increasingly prevalent and poses a significant socioeconomic burden in the developed world. Approximately half of heart failure patients have preserved ejection fraction (HFpEF) and experience an increased morbidity and mortality which are in part attributed to the lack of effective therapies, as well as to the presence of comorbidities. Suppression of neurohormonal activation by beta-blockers and renin-angiotensin-aldosterone system inhibitors is the cornerstone in the pharmacotherapy of heart failure with reduced ejection fraction (HFrEF). However these medications are not associated with significant clinical benefit in the HFpEF group. In this review, we provide an in-depth pathophysiology-based update on novel pharmacotherapies of HFpEF. A deeper insight into the pathophysiologic mechanisms of HFpEF may create opportunities for novel pharmacological interventions.
    Pharmacology [?] Therapeutics 06/2013; · 7.79 Impact Factor

Full-text (2 Sources)

View
8 Downloads
Available from
May 31, 2014