Fokozott aritmiaérzékenységgel társuló kamrai szívizom-remodelling vizsgálata sportszív nagyállatmodellben

A közelmúltban több tanulmány is rámutatott arra, hogy az intenzív sporttevékenység szívritmuszavarok kialakulására hajlamosíthat és akár hirtelen szívhalálhoz is vezethet, azonban a háttérben húzódó elektrofiziológiai mechanizmusok kevéssé ismertek. Munkánk során a tartós állóképességi edzés indukálta szívizom-átépülést (ún. „remodelling”) és aritmiaérzékenységet vizsgáltuk kutya sportszív-modellben. Beagle-kutyákat véletlenszerűen „kontroll” és „edzett” csoportokba soroltunk (n=12/csoport), ez utóbbi egy 4 hónapos intenzív edzésprogramban vett részt. A szívizom-remodellációt és a ritmuszavar-érzékenységet számos in vivo és in vitro technikával vizsgáltuk (elektrokardiográfia, echokardiográfia, közvetlen kamrai „burst” ingerlés, patch-clamp, immunocitokémia, szövettani vizsgálatok). Az edzésprogram hatására nőtt a szeptális falvastagság (8,1±0,2 mm vs. 7,4±0,2 mm; p<0,05), a bal kamrai végdisztolés átmérő (32,0±0,7 mm vs. 30,4±0,7 mm; p<0,05) és a bal kamrai tömegindex (125,8±4,3 g/m2 vs. 97,7±6,4 g/m2 ; p<0,05). Megnyúlt kamrai repolarizációt figyeltünk meg in vivo és in vitro körülmények között (QTc: 237,1±3,4 ms vs. 213,6±2,8 ms; APD90: 472,8±29,6 ms vs. 370,1±32,7 ms; p<0,05), amelyek a repolarizáció emelkedett rövid távú variabilitásával társultak. Az edzett állatok szívéből izolált bal kamrai szívizomsejtek tranziens kifelé irányuló K+-áramának amplitúdója csökkent (6,4±0,5 pA/pF vs. 8,8±0,9 pA/ pF, 50 mV; p<0,05), mindemellett a bal kamrai fibrózis mértéke, illetve a HCN4-fehérje expressziója is emelkedett. Fokozott ektópiás aktivitást és aritmiaérzékenységet figyeltünk meg az edzett állatokban. Modellünkben egyértelmű strukturális és elektrofiziológiai szívizom-átalakulás jelentkezett. Szívmorfológiai megfigyeléseink összhangban állnak a humán állóképességi élsportolókban megfigyeltekkel. Tanulmányunkban a repolarizáció diszperziójának fokozódása, a fibrózis emelkedett mértéke és a HCN4-túlexpresszió a modell aritmiák iránti fokozott érzékenységét jelzik

Acetylcholine Reduces L-Type Calcium Current without Major Changes in Repolarization of Canine and Human Purkinje and Ventricular Tissue

Vagal nerve stimulation (VNS) holds a strong basis as a potentially effective treatment modality for chronic heart failure, which explains why a multicenter VNS study in heart failure with reduced ejection fraction is ongoing. However, more detailed information is required on the effect of acetylcholine (ACh) on repolarization in Purkinje and ventricular cardiac preparations to identify the advantages, risks, and underlying cellular mechanisms of VNS. Here, we studied the effect of ACh on the action potential (AP) of canine Purkinje fibers (PFs) and several human ventricular preparations. In addition, we characterized the effects of ACh on the L-type Ca2+ current (I-CaL) and AP of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and performed computer simulations to explain the observed effects. Using microelectrode recordings, we found a small but significant AP prolongation in canine PFs. In the human myocardium, ACh slightly prolonged the AP in the midmyocardium but resulted in minor AP shortening in subepicardial tissue. Perforated patch-clamp experiments on hiPSC-CMs demonstrated that 5 mu M ACh caused an approximate to 15% decrease in I-CaL density without changes in gating properties. Using dynamic clamp, we found that under blocked K+ currents, 5 mu M ACh resulted in an approximate to 23% decrease in AP duration at 90% of repolarization in hiPSC-CMs. Computer simulations using the O'Hara-Rudy human ventricular cell model revealed that the overall effect of ACh on AP duration is a tight interplay between the ACh-induced reduction in I-CaL and ACh-induced changes in K+ currents. In conclusion, ACh results in minor changes in AP repolarization and duration of canine PFs and human ventricular myocardium due to the concomitant inhibition of inward I-CaL and outward K+ currents, which limits changes in net repolarizing current and thus prevents major changes in AP repolarization

Fokozott aritmiaérzékenységgel társuló kamrai szívizom-remodelling vizsgálata sportszív nagyállatmodellben = Ventricular myocardial remodeling associated with increased arrhythmia sensitivity in a large animal athlete’s heart model

A közelmúltban több tanulmány is rámutatott arra, hogy az intenzív sporttevékenység szívritmuszavarok kialakulására hajlamosíthat és akár hirtelen szívhalálhoz is vezethet, azonban a háttérben húzódó elektrofiziológiai mechanizmusok kevéssé ismertek. Munkánk során a tartós állóképességi edzés indukálta szívizom-átépülést (ún. „remodelling”) és aritmiaérzékenységet vizsgáltuk kutya sportszív-modellben. Beagle-kutyákat véletlenszerűen „kontroll” és „edzett” csoportokba soroltunk (n=12/csoport), ez utóbbi egy 4 hónapos intenzív edzésprogramban vett részt. A szívizom-remodellációt és a ritmuszavar-érzékenységet számos in vivo és in vitro technikával vizsgáltuk (elektrokardiográfia, echokardiográfia, közvetlen kamrai „burst” ingerlés, patch-clamp, immunocitokémia, szövettani vizsgálatok). Az edzésprogram hatására nőtt a szeptális falvastagság (8,1±0,2 mm vs. 7,4±0,2 mm; p<0,05), a bal kamrai végdisztolés átmérő (32,0±0,7 mm vs. 30,4±0,7 mm; p<0,05) és a bal kamrai tömegindex (125,8±4,3 g/m2 vs. 97,7±6,4 g/m2; p<0,05). Megnyúlt kamrai repolarizációt figyeltünk meg in vivo és in vitro körülmények között (QTc: 237,1±3,4 ms vs. 213,6±2,8 ms; APD90: 472,8±29,6 ms vs. 370,1±32,7 ms; p<0,05), amelyek a repolarizáció emelkedett rövid távú variabilitásával társultak. Az edzett állatok szívéből izolált bal kamrai szívizomsejtek tranziens kifelé irányuló K+-áramának amplitúdója csökkent (6,4±0,5 pA/pF vs. 8,8±0,9 pA/pF, 50 mV; p<0,05), mindemellett a bal kamrai fibrózis mértéke, illetve a HCN4-fehérje expressziója is emelkedett. Fokozott ektópiás aktivitást és aritmiaérzékenységet figyeltünk meg az edzett állatokban. Modellünkben egyértelmű strukturális és elektrofiziológiai szívizom-átalakulás jelentkezett. Szívmorfológiai megfigyeléseink összhangban állnak a humán állóképességi élsportolókban megfigyeltekkel. Tanulmányunkban a repolarizáció diszperziójának fokozódása, a fibrózis emelkedett mértéke és a HCN4-túlexpresszió a modell aritmiák iránti fokozott érzékenységét jelzik. Abstract: Several recent studies have highlighted that high-intensity training may predispose to cardiac arrhythmias and, in severe cases, sudden cardiac death, but the underlying electrophysiological mechanisms are poorly understood. Our study investigated cardiac remodeling and susceptibility to ventricular arrhythmias induced by sustained endurance training in a canine model of elite exercise. Beagle dogs were randomized to a “control” or a “trained” group (n=12/group). The trained group participated in a 4-month intensive training program. Cardiac remodeling and arrhythmia susceptibility were investigated using various in vivo and in vitro methods (elect-rocardiography, echocardiography, ventricular burst stimulation, patch-clamp, immunocytochemistry and histopathological studies). The training program led to increased septal wall thickness (8.13±0.2 mm vs. 7.4±0.2 mm; p<0.05), left ventricular end-diastolic dia-meter (32.0±0.7 mm vs. 30.4±0.7 mm; p<0.05), and left ventricular mass index (125.8±4.3 g/m2 vs. 97.7±6.4 g/m2; p<0.05). In trained animals, prolonged ventricular repolarization was detected under in vivo and in vitro conditions (QTc: 237.1±3.4 ms vs. 213.6±2.8 ms, n=12; APD90: 472.8±29.6 ms vs. 370.1±32.7 ms; p<0.05), accompanied with increased short-term variability of repolarization. The amplitude of the transient outward K+-current in left ventricular myocytes isolated from the hearts of the trained animals was reduced (6.4±0.5 pA/pF vs. 8.8±0.9 pA/pF, at 50 mV; p<0.05), additionally, the degree of left ventricular fibrosis and HCN4 protein expression were increased. Additionally, there was a notable increase in ectopic activity in trained dogs. The exercise program resulted in clear cardiac structural and electrophysiological alterations. Our study suggests that increased repolarization dispersion, elevated fibrosis, and overexpression of HCN4 indicate increased susceptibility of the model to arrhythmias

Effect of ivabradine in heart failure : a meta-analysis of heart failure patients with reduced versus preserved ejection fraction

In clinical trials of heart failure reduced ejection fraction (HFrEF), ivabradine seemed to be an effective heart rate lowering agent associated with lower risk of cardiovascular death. In contrast, ivabradine failed to improve cardiovascular outcomes in heart failure preserved ejection fraction (HFpEF) despite the significant effect on heart rate. This meta-analysis is the first to compare the effects of ivabradine on heart rate and mortality parameters in HFpEF versus HFrEF. We screened three databases: PubMed, Embase, and Cochrane Library. The outcomes of these studies were mortality, reduction in heart rate, and left ventricular function improvement. We compared the efficacy of ivabradine treatment in HFpEF versus HFrEF. Heart rate analysis of pooled data showed decrease in both HFrEF (-17.646 beats/min) and HFpEF (-11.434 beats/min), and a tendency to have stronger bradycardic effect in HFrEF (p = 0.094) in randomized clinical trials. Left ventricular ejection fraction analysis revealed significant improvement in HFrEF (5.936, 95% CI: [4.199-7.672], p < 0.001) when compared with placebo (p < 0.001). We found that ivabradine significantly improves left ventricular performance in HFrEF, at the same time it exerts a tendency to have improved bradycardic effect in HFrEF. These disparate effects of ivabradine and the higher prevalence of non-cardiac comorbidities in HFpEF may explain the observed beneficial effects in HFrEF and the unchanged outcomes in HFpEF patients after ivabradine treatment

Application of ventricular tachyarrhythmia definitions of the updated Lambeth Conventions provides incompatibility with earlier results, masks antifibrillatory activity and reduces inter-observer agreement.

The Lambeth Conventions (LC I), a landmark guidance document for arrhythmia research was updated and arrhythmia definitions were changed in the new Lambeth Conventions II (LC II). This study examined whether the arrhythmia definitions of LC I and LC II yield the same qualitative results and whether LC II improves inter-observer agreement. Two independent investigators performed blinded arrhythmia analysis of the electrocardiograms of isolated, Langendorff rat hearts subjected to regional ischemia and perfused with Class I antiarrhythmics with 3 or 5 mM K+ in the perfusate. Data obtained with arrhythmia definitions of LC I and LC II were compared within and between observers. Applying ventricular fibrillation (VF) definition of LC II significantly increased VF incidence and reduced VF onset time irrespective of treatment by detecting 'de novo' VF episodes not found by LC I. LC II reduced the number of ventricular tachycardia (VT) episodes and simultaneously increased the number of VF episodes as compared with the respective values obtained according to LC I. Using VF definition of LC II masked the significant antifibrillatory effects of flecainide and the high K+ concentration identified with the VF definition of LC I. When VF incidence was tested, a very strong inter-observer agreement was found according to LC I, whereas using VF definition of LC II reduced inter-observer agreement. It is concluded that LC II shifts some tachyarrhythmias from VT to VF class, and thus results obtained by arrhythmia definitions of LC I and LC II are not compatible; VF definition of LC II may change the conclusion of pharmacological, physiological and pathophysiological arrhythmia investigations and may reduce inter-observer agreement. Thus, VT and VF definitions of LC II should be amended in order to increase compatibility and inter-observer agreement

Long-Term Endurance Exercise Training Alters Repolarization in a New Rabbit Athlete’s Heart Model

In the present study, the effect of long-term exercise training was investigated on myocardial morphological and functional remodeling and on proarrhythmic sensitivity in a rabbit athlete’s heart model. New-Zealand white rabbits were trained during a 12-week long treadmill running protocol and compared with their sedentary controls. At the end of the training protocol, echocardiography, in vivo and in vitro ECG recordings, proarrhythmic sensitivity with dofetilide (nM) were performed in isolated hearts, and action potential duration (APD) measurements at different potassium concentrations (4.5 and 2 mM) were made in the isolated papillary muscles. Expression levels of the slow component of delayed rectifier potassium current and fibrosis synthesis and degradation biomarkers were quantified. Echocardiography showed a significantly dilated left ventricle in the running rabbits. ECG PQ and RR intervals were significantly longer in the exercised group (79 ± 2 vs. 69 ± 2 ms and 325 ± 11 vs. 265 ± 6 ms, p < 0.05, respectively). The in vivo heart rate variability (HRV) (SD of root mean square: 5.2 ± 1.4 ms vs. 1.4 ± 0.2 ms, p < 0.05) and Tpeak-Tend variability were higher in the running rabbits. Bradycardia disappeared in the exercised group in vitro. Dofetilide tended to increase the QTc interval in a greater extent, and significantly increased the number of arrhythmic beats in the trained animals in vitro. APD was longer in the exercised group at a low potassium level. Real-time quantitative PCR (RT-qPCR) showed significantly greater messenger RNA expression of fibrotic biomarkers in the exercised group. Increased repolarization variability and higher arrhythmia incidences, lengthened APD at a low potassium level, increased fibrotic biomarker gene expressions may indicate higher sensitivity of the rabbit “athlete’s heart” to life-threatening arrhythmias

Endurance training-induced cardiac remodeling in a guinea pig athlete's heart model

Besides the health benefits of regular exercise, high-level training - above an optimal level -may have adverse effects. In this study, we investigated the effects of long-term vigorous training and its potentially detrimental structural-functional changes in a small animal athlete's heart model. Thirty-eight 4-month-old male guinea pigs were randomised into sedentary and exercised groups. The latter underwent a 15-week-long endurance-training program. To investigate the effects of the intense long-term exercise, in vivo (echocardiography, electrocardiography), ex vivo and in vitro (histopathology, patch-clamp) measurements were performed. Following the training protocol, the exercised animals exhibited structural left ventricular enlargement and significantly higher degree of myocardial fibrosis. Furthermore, resting bradycardia accompanied by elevated heart rate variability occurred, representing increased parasympathetic activity in the exercised hearts. The observed prolonged QTc intervals and increased repolarization variability parameters may raise the risk of electrical instability in exercised animals. Complex arrhythmias did not occur in either group and there were no differences between the groups in ex vivo or in cellular electrophysiological experiments. Accordingly, the high parasympathetic activity may promote impaired repolarization in conscious exercised animals. The detected structural-functional changes share similarities with the human athlete's heart, therefore, this model might be useful for investigations on cardiac remodeling

Increased Ca2+ content of the sarcoplasmic reticulum provides arrhythmogenic trigger source in swimming-induced rat athlete's heart model

Sudden cardiac death among top athletes is very rare, however, it is 2-4 times more frequent than in the age-matched control population. In the present study, the electrophysiological consequences of long-term exercise training were investigated on Ca2+ homeostasis and ventricular repolarization, together with the underlying alterations of ion channel expression, in a rat athlete's heart model. 12-week swimming exercise-trained and control Wistar rats were used. Electrophysiological data were obtained by using ECG, patch clamp and fluorescent optical measurements. Protein and mRNA levels were determined by the Western immunoblot and qRT-PCR techniques. Animals in the trained group exhibited significantly lower resting heart rate, higher incidence of extrasystoles and spontaneous Ca2+ release events. The Ca2+ content of the sarcoplasmic reticulum (SR) and the Ca2+ transient amplitude were significantly larger in the trained group. Intensive physical training is associated with elevated SR Ca2+ content, which could be an important part of physiological cardiac adaptation mechanism to training. However, it may also sensitize the heart for the development of spontaneous Ca2+ release and extrasystoles. Training-associated remodeling may promote elevated incidence of life threatening arrhythmias in top athletes