Rutaecarpine targets hERG channels and participates in regulating electrophysiological properties leading to ventricular arrhythmia.

Drug-mediated or medical condition-mediated disruption of hERG function accounts for the main cause of acquired long-QT syndrome (acLQTs), which predisposes affected individuals to ventricular arrhythmias (VA) and sudden death. Many Chinese herbal medicines, especially alkaloids, have risks of arrhythmia in clinical application. The characterized mechanisms behind this adverse effect are frequently associated with inhibition of cardiac hERG channels. The present study aimed to assess the potent effect of Rutaecarpine (Rut) on hERG channels. hERG-HEK293 cell was applied for evaluating the effect of Rut on hERG channels and the underlying mechanism. hERG current (IhERG ) was measured by patch-clamp technique. Protein levels were analysed by Western blot, and the phosphorylation of Sp1 was determined by immunoprecipitation. Optical mapping and programmed electrical stimulation were used to evaluate cardiac electrophysiological activities, such as APD, QT/QTc, occurrence of arrhythmia, phase singularities (PSs), and dominant frequency (DF). Our results demonstrated that Rut reduced the IhERG by binding to F656 and Y652 amino acid residues of hERG channel instantaneously, subsequently accelerating the channel inactivation, and being trapped in the channel. The level of hERG channels was reduced by incubating with Rut for 24 hours, and Sp1 in nucleus was inhibited simultaneously. Mechanismly, Rut reduced threonine (Thr)/ tyrosine (Tyr) phosphorylation of Sp1 through PI3K/Akt pathway to regulate hERG channels expression. Cell-based model unables to fully reveal the pathological process of arrhythmia. In vivo study, we found that Rut prolonged QT/QTc intervals and increased induction rate of ventricular fibrillation (VF) in guinea pig heart after being dosed Rut for 2 weeks. The critical reasons led to increased incidence of arrhythmias eventually were prolonged APD90 and APD50 and the increase of DF, numbers of PSs, incidence of early after-depolarizations (EADs). Collectively, the results of this study suggest that Rut could reduce the IhERG by binding to hERG channels through F656 and Y652 instantaneously. While, the PI3K/Akt/Sp1 axis may play an essential role in the regulation of hERG channels, from the perspective of the long-term effects of Rut (incubating for 24 hours). Importantly, the changes of electrophysiological properties by Rut were the main cause of VA.

Biventricular dyssynchrony on cardiac magnetic resonance imaging and its correlation with myocardial deformation, ventricular function and objective exercise capacity in patients with repaired tetralogy of Fallot.

BACKGROUND: Electrical dyssynchrony and prolonged QRS duration are common in patients with repaired tetralogy of Fallot (ToF). It has been linked to increased risk of sudden cardiac death and right ventricular (RV) dysfunction. We investigated myocardial dyssynchrony using cardiac magnetic resonance imaging (CMR) and feature tracking analysis (FT) in this setting and compared it to myocardial deformation, conventional parameters of ventricular dysfunction and clinical parameters. METHODS AND RESULTS: Patients underwent standardized CMR investigations as part of a nationwide study. We prospectively assessed myocardial deformation and analysed regional wall motion abnormalities of the RV and the left ventricle (LV) using CMR-FT. The main measure of dyssynchrony was the maximal time difference (wall motion delay) of the regional strain as a parameter of mechanical biventricular dyssynchrony. In addition, clinical parameters and measures of cardiopulmonary exercise capacity were available. Overall 345 patients were included. Parameters of biventricular wall motion delay correlated significantly with global FT-strain parameters (p < 0.0001 for all imaging planes assessed). Furthermore, we found a significant correlation between circumferential RV motion delay and QRS duration (p = 0.006). Higher LV and RV wall motion delay parameters were also associated with lower peak oxygen consumption (p < 0.05) and a worse LV and RV ejection fraction (p < 0.02). CONCLUSIONS: Assessment of mechanical dyssynchrony is feasible using CMR-FT in ToF patients. Parameters of mechanical dyssynchrony correlate with electrical dyssynchrony, biventricular function and objective exercise capacity in this setting. Due to the weak degree of correlation, however, the clinical significance of these findings remains to be clarified by further studies.

All-Trans Retinoic Acid supplementation prevents cardiac fibrosis and cytokines induced by Methylglyoxal.

Methylglyoxal (MG), a metabolic intermediate of glycolysis is a precursor for endogeneous production of advanced glycation end-products. The increased production of MG have negative influence over the structure and function of different biomolecules and thus plays an important role in the pathogenesis of diabetic cardiac complications. Retinoic acid (RA), an active metabolite of vitamin A, has a major role in preventing cardiac remodeling and ventricular fibrosis. Hence, the objective of the present study was to determine whether rats administered with all-trans retinoic acid (RA) could attenuate MG induced pathological effects. Wistar rats were divided into 4 groups. Group 1 rats were kept as control; Group 2 rats were administrated with MG (75 mg/kg/day) for 8 weeks. Group 3 rats were given RA (Orally, 1.0 mg/kg/day) along with MG; Group 4 rats received RA alone. Cardiac antioxidant status, induction of fibrosis, AGE receptor (RAGE) and cytokines expression was evaluated in the heart tissues. Administration of MG led to depletion of antioxidant enzymes, induction of fibrosis (p < 0.001), up-regulated expression of RAGE (3.5 fold), TGF-ß (4.4 fold), SMAD2 (3.7 fold), SMAD3 (6.0 fold), IL-6 (4.3 fold) and TNF-α (5.5 fold) in the heart tissues compared to control rats. Moreover, the exogenous administration of MG caused significant (p < 0.001) increase in the circulating CML levels. Whereas, RA treatment prevented the induction of fibrosis and restored the levels of cytokines and RAGE expression. Methylglyoxal-induced fibrosis can lead to pathological effects in the heart tissues. RA attenuates the effects of MG in the heart, suggesting that it can be of added value to usual diabetic therapy.

Vulnerable windows define susceptibility to alternans and spatial discordance.

Electrophysiological alternans is a beat-to-beat alternation of the action potential duration and/or Ca(2+) transient amplitude and is linked to ventricular arrhythmias. We investigated the significance of various rate parameters under different experimental conditions with respect to alternans incidence and the propensity for spiral wave formation. Voltage and Ca(2+) were optically mapped in monolayers of neonatal rat ventricular myocytes. Alternans did not occur at physiological temperature, but its incidence increased significantly at lowered temperatures. Pacing cycle length for spatially concordant alternans onset (PCL(C)), PCL for spatially discordant alternans onset (PCL(D)), and minimum cycle length for loss of 1:1 or 2:2 capture (MCL) also significantly increased with lower temperature but in a way such that the differences between PCL(C) and MCL and between PCL(D) and MCL widened. These results provided the rationale to identify the former difference as the alternans vulnerable window (AVW; in ms) and the latter difference as the discordant alternans vulnerable window (AVW(D); in ms). Computational simulations showed that interventions that widen AVW, including altered Ca(2+) cycling and enhanced K(+) currents, also promote alternans, regardless of whether PCL(C) or MCL increased or decreased. The simulation results were confirmed experimentally by addition of the ATP-sensitive K(+) channel agonist pinacidil. Mathematical analysis provided a theoretical basis linking the size of AVW to the incidence of alternans. Finally, experiments showed that the size of AVW(D) is related to the incidence of spatially discordant alternans and, additionally, to the incidence of spiral wave formation. In conclusion, vulnerable windows can be defined that are strongly correlated with alternans incidence, spatial discordance, and spiral wave formation.

Hypocalcemic heart failure in thalassemic patients.

Hypocalcemic cardiomyopathy in primary or secondary hypoparathyroidism is usually refractory to conventional treatment of cardiac failure. We report the case of a thalassemic patient with severe cardiac failure that might have been attributed to several factors, such as hemosiderosis, hypomagnesemia, and hypocalcemia, refractory to conventional cardiac therapy. Cardiac echocardiography showed impaired biventricular performance, and laboratory analyses revealed hypoparathyroidism due to hemosiderosis. When concomitant treatment of heart failure and calcium supplementation was initiated, correction of hypocalcemia resulted in clinical and laboratory improvement, providing strong evidence in support of our hypothesis about hypocalcemic myocardiopathy.

Chronic treatment with carvedilol improves ventricular function and reduces myocyte apoptosis in an animal model of heart failure.

BACKGROUND: Beta blocker treatment has emerged as an effective treatment modality for heart failure. Interestingly, beta-blockers can activate both pro-apoptotic and anti-apoptotic pathways. Nevertheless, the mechanism for improved cardiac function seen with beta-blocker treatment remains largely unknown. Carvedilol is a non-selective beta-blocker with alpha-receptor blockade and antioxidant properties. We therefore studied the impact of the effects of carvedilol in an animal model of end-stage heart failure. RESULTS: To test whether chronic treatment with beta-blockade decreases apoptosis, we treated myopathic turkeys with two dosages of carvedilol, 1 mg/kg (DCM1) and 20 mg/kg (DCM20), for four weeks and compared them to non-treated DCM animals (DCM0) and to control turkeys (CON). Echocardiographic measurements showed that non-treated DCM animals had a significantly lower fractional shortening (FS) when compared to CON (68.73 +/- 1.37 vs. 18.76 +/- 0.59%, p < 0.001). Both doses of carvedilol significantly improved FS (33.83 +/- 10.11 and 27.73 +/- 6.18% vs. 18.76 +/- 0.59% for untreated DCM, p < 0.001). DCM left ventricles were characterized by a higher percentage of apoptotic nuclei when compared to CON (5.64 +/- 0.49 vs. 1.72 +/- 0.12%, respectively p < 0.001). Both doses of carvedilol significantly reduced the number of apoptotic nuclei (2.32 +/- 0.23% and 2.36 +/-6% 1 mg and 20 mg/kg respectively). CONCLUSIONS: Carvedilol improves ventricular function. Furthermore, treatment with carvedilol decreased the incidence of apoptosis in cardiac myocytes from failing hearts at both doses. These data suggest that the inhibition of apoptosis with carvedilol may lead to improvement in ventricular function and may underlie a beneficial effect of beta-blockade independent of heart rate lowering effects.

Symptomatic systolic ventricular failure.

Over the past 20 to 30 years there have been significant advances in the management of heart failure related to improved understanding of pathophysiology, better methods of assessment, and improved drug treatments. The aims of treatment have broadened, with increased emphasis on earlier intervention. Clinical research activity in this area has been considerable, increasingly allowing an evidence-based approach to management. Most earlier trials of treatment were relatively short-term, small-group studies with various clinical end points, including severity of symptoms, exercise performance, and left ventricular function assessment; however, increasingly a higher standard of evidence has been required, including a provision of reliable, large-scale mortality trial data. This has been further encouraged, if not mandated, by the relatively recent appreciation that some agents may demonstrate dissociation of treatment effects, possibly dose related, with improved short-term outcomes but adverse effects on survival with prolonged treatment. The general principles of management of congestive heart failure encompass patient evaluation and confirmation of the diagnosis, consideration, and correction of underlying remediable causes and precipitating factors, pharmacological treatment, patient education and counseling, and planned follow-up, as summarized in recently published guidelines. This review focuses primarily on the available randomized controlled clinical trial evidence related to the pharmacological treatment of the clinical congestive heart failure syndrome. Other aspects of management, such as patient education, counseling, and planned follow-up, should be regarded as complementary to pharmacological treatment and important to ensure compliance and optimal long-term outcomes.