Omer Yiginer

Hydralazine and Organic Nitrates Restore Impaired Excitation-Contraction Coupling by Reducing Calcium Leak Associated with Nitroso-Redox Imbalance

Background: Hydralazine and organic nitrates have clinical benefits for heart failure, but the underlying mechanism is controversial. Results: Hydralazine reduced sarcoplasmic reticulum Ca2+ leak and improved Ca2+ cycling and contractility; nitroglycerin enhanced contractile efficiency; both were impaired by nitroso-redox imbalance. Conclusion: These agents exert complementary effects on nitroso-redox imbalance. Significance: New mechanistic insights for redox-targeted treatments of heart failure. Although the combined use of hydralazine and isosorbide dinitrate confers important clinical benefits in patients with heart failure, the underlying mechanism of action is still controversial. We used two models of nitroso-redox imbalance, neuronal NO synthase-deficient (NOS1−/−) mice and spontaneously hypertensive heart failure rats, to test the hypothesis that hydralazine (HYD) alone or in combination with nitroglycerin (NTG) or isosorbide dinitrate restores Ca2+ cycling and contractile performance and controls superoxide production in isolated cardiomyocytes. The response to increased pacing frequency was depressed in NOS1−/− compared with wild type myocytes. Both sarcomere length shortening and intracellular Ca2+ transient (Δ[Ca2+]i) responses in NOS1−/− cardiomyocytes were augmented by HYD in a dose-dependent manner. NTG alone did not affect myocyte shortening but reduced Δ[Ca2+]i across the range of pacing frequencies and increased myofilament Ca2+ sensitivity thereby enhancing contractile efficiency. Similar results were seen in failing myocytes from the heart failure rat model. HYD alone or in combination with NTG reduced sarcoplasmic reticulum (SR) leak, improved SR Ca2+ reuptake, and restored SR Ca2+ content. HYD and NTG at low concentrations (1 μm), scavenged superoxide in isolated cardiomyocytes, whereas in cardiac homogenates, NTG inhibited xanthine oxidoreductase activity and scavenged NADPH oxidase-dependent superoxide more efficiently than HYD. Together, these results revealed that by reducing SR Ca2+ leak, HYD improves Ca2+ cycling and contractility impaired by nitroso-redox imbalance, and NTG enhanced contractile efficiency, restoring cardiac excitation-contraction coupling.

Melatonin protects against ischemic heart failure in rats

Ischemic injury, which occurs as a result of sympathetic hyperactivity, plays an important role in heart failure. Melatonin is thought to have antiatherogenic, antioxidant, and vasodilatory effects. In this study, we investigated whether melatonin protects against ischemic heart failure (HF). In Wistar albino rats, HF was induced by left anterior descending (LAD) coronary artery ligation and rats were treated with either vehicle or melatonin (10 mg/kg) for 4 weeks. At the end of this period, echocardiographic measurements were recorded and the rats were decapitated to obtain plasma and cardiac tissue samples. Lactate dehydrogenase, creatine kinase, aspartate aminotransferase, alanine aminotransferase, and lysosomal enzymes (β‐D‐glucuronidase, β‐galactosidase, β‐D‐N‐acetyl‐glucosaminidase, acid phosphatase, and cathepsin‐D) were studied in plasma samples, while malondialdehyde and glutathione levels and Na+, K+‐ATPase, caspase‐3 and myeloperoxidase activities were determined in the cardiac samples. Sarco/endoplasmic reticulum calcium ATPase (SERCA) and caveolin‐3 levels in cardiac tissues were evaluated using Western blot analyses. Furthermore, caveolin‐3 levels were also determined by histological analyses. In the vehicle‐treated HF group, cardiotoxicity resulted in decreased cardiac Na+, K+‐ATPase and SERCA activities, GSH contents and caveolin‐3 levels, while plasma LDH, CK, and lysosomal enzyme activities and cardiac MDA and Myeloperoxidase (MPO) activities were found to be increased. On the other hand, melatonin treatment reversed all the functional and biochemical changes. The present results demonstrate that Mel ameliorates ischemic heart failure in rats. These observations highlight that melatonin is a promising supplement for improving defense mechanisms in the heart against oxidative stress caused by heart failure.

Intervalo QT corrigido e dispersão do intervalo QT corrigido são válidos quando interpretados com outras mensurações de repolarização

We read the article entitled ‘‘The effect of esmolol on corrected-QT interval, corrected-QT interval dispersion changes seen during anesthesia induction in hypertensive patients taking an angiotensin-converting enzyme inhibitor’’ by Ceker et al. with interest.1 The authors investigated the effects of esmolol on the hemodynamic, correctedQT (QTc) interval and corrected-QT interval dispersion (QTcD) changes during anesthesia induction in hypertensive patients. Finally, they concluded that prolonging effect of endotracheal intubation and anesthesia induction on QTc and QTcD can be prevented by esmolol administration. We would like to thank to the authors for their valuable contribution. Electrical inhomogeneity of myocardium may lead potentially life threatening cardiac arrhythmias. There are some invasive and non-invasive methods to determine the myocardial inhomogenity. QTd and QTcd are well known noninvasive parameters and can be measured on surface ECG by manually or on digital platform. Unfortunately reproducibility of QT measurements is low both in manual and automatic measurements.2,3 Additionally, in manuel measurements, interand intraobserver variability of QTd is very high.3 In this study, it is unknown whether the measurements were done manually or in digital platform. It would have been better if the authors had mentioned the measurement type. Transmural dispersion of repolarization (TDR) quantifies myocardial inhomogeneity in addition to QTd.4 Isolated cells from different layers of the myocardium revealed that myocardium consists of three different myocyte types: (i) endocardial, (ii) epicardial, and (iii) midmyocardial M cells.5 These myocyte structures have various electrophysiological characteristics. This heterogeneity may cause to electrical instability and are measurable on surface ECG. Epicardial repolarization phase ends at the peak of the T-wave, M cells repolarization continues until the end of the T wave.5 Thus, the distance between the peak and end of the T wave is entitled as Tp-e interval, which reflects TDR. Previously, we presented that TDR was increased in patients with E

Corrected QT interval and corrected QT interval dispersion is worthwhile when interpreted with other repolarization measurements

Lemos com interesse o artigo intitulado ‘‘Efeito de esmolol sobre o intervalo QT corrigido e alterações da dispersão do intervalo QT corrigido observadas durante a indução da anestesia em pacientes hipertensos que receberam um inibidor da enzima conversora de angiotensina’’ escrito por Ceker et al. Os autores investigaram os efeitos de esmolol sobre as alterações na hemodinâmica, intervalo QT corrigido (QTc) e dispersão do intervalo QT corrigido (QTcD) durante a indução da anestesia em pacientes hipertensos. Finalmente, concluíram que o efeito prolongado da intubação traqueal e da indução da anestesia sobre o QTc e QTcD pode ser evitado com a administração de esmolol. Gostaríamos de agradecer aos autores por sua valiosa contribuição. A não homogeneidade elétrica do miocárdio pode, potencialmente, levar a arritmias cardíacas fatais. Existem alguns métodos invasivos e não invasivos para determinar a homogeneidade do miocárdio. Os QTd (dispersão do QT) e QTcd são parâmetros não invasivos bem conhecidos e podem ser medidos no ECG de superfície manualmente ou em plataforma digital. Infelizmente, a reprodutibilidade das mensurações do QT é baixa, em mensurações tanto manuais quanto automáticas. Além disso, em mensurações manuais, a variabilidade inter e intraobservador da QTd é muito alta. Nesse estudo, não se sabe se as mensurações foram feitas manualmente ou em plataforma digital. Seria melhor se os autores tivessem mencionado o tipo de mensuração. A dispersão transmural da repolarização (DTR) quantifica a falta de homogeneidade do miocárdio além da QTd. Células isoladas a partir de diferentes camadas do miocárdio revelaram que o miocárdio consiste em três tipos diferentes de miócitos: (i) endocárdio, (ii) epicárdio e (iii) células M do miocárdio médio. Essas estruturas do miócito têm várias características eletrofisiológicas. Essa heterogeneidade pode causar instabilidade elétrica e é mensurável no ECG de superfície. A fase de repolarização do epicárdio termina no pico da onda T, a repolarização das células M continua até o fim da onda T. Assim, a distância entre o pico e o fim da onda T é denominada intervalo Tp-e, que reflete a DTR. Previamente, demonstramos que a DTR era aumentada em pacientes com apneia obstrutiva do sono e exposição crônica ao arsênico por meio da água potável. Foi demonstrado também que a DTR é aumentada no infarto do miocárdio com elevação do ST. Adicionar as mensurações da DTR teria sido melhor para determinar a falta de homogeneidade do miocárdio. Acreditamos que o estudo de Ceker et al. levará a novos estudos sobre a heterogeneidade e instabilidade do miocárdio. No entanto, a avaliação do intervalo Tp-e tornaria esse estudo mais preciso.

An Issue Waiting to be Clarified: Effects of the QT Prolonging Drugs on Tp-e Interval

We read the article ‘Impact of Psychotropic Drugs on QT Interval Dispersion in Adult Patients’ by Claudio et al. with great interest1. They investigated in this study the effects of psychotropic drugs on QT interval (QTI), corrected QT interval (QTc), and QT dispersion (QTd). They concluded that psychotropic drugs increased QTd and QTc interval. QTd is the most frequently used non-invasive method to quantify electrical myocardial heterogeneity. However, there are variable results in studies related to QTI due to the technical limitations in measurements2. It is well-known that the reproducibility of QTI measurements is low both in manual and automatic measurements2. In this study, the measurements were performed digitally by four cardiologists using the Preview software with a magnification of 300%. We appreciated the method used in this study in order to obtain more accurate data. It is recommended that measurements be done digitally at least by two cardiologists2. Quantifying electrical myocardial heterogeneity and transmural dispersion of repolarization (TDR) was introduced in the beginning of 2000’s3. The myocardium comprises 3 distinct myocyte types - namely, endocardial, epicardial, and midmyocardial M cells3. Although these myocytes are morphologically similar, they exhibit different electrophysiological characteristics. M cells have typically the longest action potential. Furthermore, when myocardium is exposed to conditions prolonging the repolarization phase, such as bradycardia or agents, the action potential duration of the M cells are more prolonged than in the other cells3. While repolarization of the epicardial region ends at the peak of T-wave, repolarization phase of M cells ends at the end of T wave3. Therefore, the time between the peak and end of the T wave is called Tp-e interval, as an index of TDR. The role of the TDR in the prediction of possible life‑threatening arrhythmic events has been demonstrated in the Brugada, short-QT and long-QT syndromes and coronary artery disease3. Previously, we showed that TDR was increased in patients with obstructive sleep apnea and chronic arsenic exposure4,5. However, there is no study investigating the effects of QT prolonging drugs on TDR. The repolarization phase of myocytes in midmyocardial and endocardial layers may be more influenced by the drugs. In this context, psychotropic drugs may be increasing QT interval duration via Tp-e interval prolongation. In conclusion, it seems that adding the data related to Tp-e interval to the study results might have completely illuminated the effects of psychotropic drugs on electrical heterogeneity of myocardium in many respects.