Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malignant ventricular tachyarrhythmias are common among patients with hypertrophy and heart failure, and these arrhythmias can initiate by triggered activity. Abnormal repolarization and disturbed calcium handling due to remodeling processes are common features of the hypertrophied and failing heart that conspire to facilitate triggering events. These changes have a different cellular origin in compensated hypertrophy as compared with failure, which underscores the complexity of mechanisms that predispose the remodeled heart to arrhythmias. This hampers the identification of the vulnerable patient and adequate antiarrhythmic pharmacotherapy. Beat-to-beat variability of repolarization has been proposed as an early (noninvasive) electrographic detection method of triggered activity. An increase of variability heralds an enhanced risk of arrhythmias, and controlling this repolarization parameter by pharmacological agents is antiarrhythmic. Different drugs (flunarizine, ranolazine, K201, calmodulin kinase blockers) that are able to prevent and/or suppress triggered arrhythmias by specific mechanisms of action will be discussed.
 ...
PMID:Cellular basis for triggered ventricular arrhythmias that occur in the setting of compensated hypertrophy and heart failure: considerations for diagnosis and treatment. 1799 35

In excitable cells such as skeletal and cardiac myocytes excitation-contraction coupling is an important intermediate step between initiation of the action potential and induction of contraction. This process is predominantly controlled by Ca(2+) release from the sarcoplasmic reticulum via the ryanodine receptor. This very large protein (MW 560 kDa) exists as a homotetramer (~2.2 MDa) and is expressed in three isoforms: RyR1, expressed in skeletal muscle; RyR2, expressed in cardiac muscle; and RyR3, expressed in various cells at lower levels than the other isoforms. Release of Ca(2+) via RyR2 is induced by Ca(2+) influx through L-type Ca(2+) channels and is modulated by multiple factors, including phosphorylation of RyR2 protein by protein kinase A, calmodulin kinase II and FKBP12.6, and stimulation via the beta-adrenergic receptor signaling pathway. Hyperphosphorylation of RyR2 induces Ca(2+) leak during diastole, which can cause fatal arrhythmias and lead to heart failure. This makes RyR2 an important therapeutic target. Although there are few commercially available drugs that inhibit Ca(2+) leak from RyR2, K201 (JTV-519), a benzothiazepine derivative, has emerged as a new ryanodine receptor-selective agent that prevents atrial fibrillation, ventricular arrhythmias, heart failure and exercise-induced sudden cardiac death. In this review, we discuss recent advances in our understanding of the basic structure and function of ryanodine receptors, their involvement in heart disease, and the development of drugs to prevent ryanodine receptor malfunction and recent patents.
 ...
PMID:Ryanodine receptor: a novel therapeutic target in heart disease. 1822 Nov 9

Recent studies on cardiac hypertrophy animal model suggest that inter-domain interactions within the ryanodine receptor (RyR2) become defective concomitant with the development of hypertrophy (e.g. de-stabilization of the interaction between N-terminal and central domains of RyR2; T. Oda, M. Yano, T. Yamamoto, T. Tokuhisa, S. Okuda, M. Doi, T. Ohkusa, Y. Ikeda, S. Kobayashi, N. Ikemoto, M. Matsuzaki, Defective regulation of inter-domain interactions within the ryanodine receptor plays a key role in the pathogenesis of heart failure, Circulation 111 (2005) 3400-3410). To determine if de-stabilization of the inter-domain interaction in fact causes hypertrophy, we introduced DPc10 (a peptide corresponding to the G(2460)-P(2495) region of RyR2, which is known to de-stabilize the N-terminal/central domain interaction) into rat neonatal cardiomyocytes by mediation of peptide carrier BioPORTER. After incubation for 24h the peptide induced hypertrophy, as evidenced by significant increase in cell size and [(3)H]leucine uptake. K201 or dantrolene, the reagents known to correct the de-stabilized inter-domain interaction to a normal mode, prevented the DPc10-induced hypertrophy. These results suggest that disruption of the normal N-terminal/central inter-domain interaction within the RyR2 is a causative mechanism of cardiomyocyte hypertrophy.
 ...
PMID:Defective regulation of the ryanodine receptor induces hypertrophy in cardiomyocytes. 1928 93

K201 is a 1,4-benzothiazepine derivative that is a promising new drug with a strong cardioprotective effect. We initially discovered K201 as an effective suppressant of sudden cardiac cell death due to calcium overload. K201 is a non-specific blocker of sodium, potassium and calcium channels, and its cardioprotective effect is more marked than those of nicorandil, prazosine, propranolol, verapamil and diltiazem. Recently, K201 has also been shown to have activities indicated for treatment of atrial fibrillation, ventricular fibrillation, heart failure and ischemic heart disease, including action as a multiple-channel blocker, inhibition of diastolic Ca(2+) release from the sarcoplasmic reticulum, suppression of spontaneous Ca(2+) sparks and Ca(2+) waves, blockage of annexin V and provision of myocardial protection, and improvement of norepinephrine-induced diastolic dysfunction. Here, we describe the pharmacological characteristics and clinical applications of K201.
 ...
PMID:Pharmacological characteristics and clinical applications of K201. 1944 77

In heart failure, intracellular Ca2+ leak from cardiac ryanodine receptors (RyR2s) leads to a loss of Ca2+ from the sarcoplasmic reticulum (SR) potentially contributing to decreased function. Experimental data suggest that the 1,4-benzothiazepine K201 (JTV-519) may stabilise RyR2s and thereby reduce detrimental intracellular Ca2+ leak. Whether K201 exerts beneficial effects in human failing myocardium is unknown. Therefore, we have studied the effects of K201 on muscle preparations from failing human hearts. K201 (0.3 microM; extracellular [Ca2+]e 1.25 mM) showed no effects on contractile function and micromolar concentrations resulted in negative inotropic effects (K201 1 microM; developed tension -9.8 +/- 2.5% compared to control group; P < 0.05). Interestingly, K201 (0.3 microM) increased the post-rest potentiation (PRP) of failing myocardium after 120 s, indicating an increased SR Ca2+ load. At high [Ca2+]e concentrations (5 mmol/L), K201 increased PRP already at shorter rest intervals (30 s). Strikingly, treatment with K201 (0.3 microM) prevented diastolic dysfunction (diastolic tension at 5 mmol/L [Ca2+]e normalised to 1 mmol/L [Ca2+]e: control 1.26 +/- 0.06, K201 1.01 +/- 0.03, P < 0.01). In addition at high [Ca2+]e) K201 (0.3 microM) treatment significantly improved systolic function [developed tension +27 +/- 8% (K201 vs. control); P < 0.05]. The beneficial effects on diastolic and systolic functions occurred throughout the physiological frequency range of the human heart rate from 1 to 3 Hz. Upon elevated intracellular Ca2+ concentration, systolic and diastolic contractile functions of terminally failing human myocardium are improved by K201.
 ...
PMID:K201 improves aspects of the contractile performance of human failing myocardium via reduction in Ca2+ leak from the sarcoplasmic reticulum. 1971 43

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.
 ...
PMID:Cardiac ryanodine receptor in metabolic syndrome: is JTV519 (K201) future therapy? 2256 49