Arrhythmogenic Remodeling in the Failing Heart

Chronic heart failure is a clinical syndrome with multiple etiologies, associated with significant morbidity and mortality. Cardiac arrhythmias, including ventricular tachyarrhythmias and atrial fibrillation, are common in heart failure. A number of cardiac diseases including heart failure alter the expression and regulation of ion channels and transporters leading to arrhythmogenic electrical remodeling. Myocardial hypertrophy, fibrosis and scar formation are key elements of arrhythmogenic structural remodeling in heart failure. In this article, the mechanisms responsible for increased arrhythmia susceptibility as well as the underlying changes in ion channel, transporter expression and function as well as alterations in calcium handling in heart failure are discussed. Understanding the mechanisms of arrhythmogenic remodeling is key to improving arrhythmia management and the prevention of sudden cardiac death in patients with heart failure.

Abrogation of CC Chemokine Receptor 9 Ameliorates Ventricular Electrical Remodeling in Mice After Myocardial Infarction

Introduction: Myocardial infarction (MI) triggers structural and electrical remodeling. CC chemokine receptor 9 (CCR9) mediates chemotaxis of inflammatory cells in MI. In our previous study, CCR9 knockout has been found to improve structural remodeling after MI. Here, we further investigate the potential influence of CCR9 on electrical remodeling following MI in order to explore potential new measures to improve the prognosis of MI.Methods and Results: Mice was used and divided into four groups: CCR9+/+/Sham, CCR9−/−/Sham, CCR9+/+/MI, CCR9−/−/MI. Animals were used at 1 week after MI surgery. Cardiomyocytes in the infracted border zone were acutely dissociated and the whole-cell patch clamp was used to record action potential duration (APD), L-type calcium current (ICa,L) and transient outward potassium current (Ito). Calcium transient and sarcoplasmic reticulum (SR) calcium content under stimulation of Caffeine were measured in isolated cardiomyocytes by confocal microscopy. Multielectrode array (MEA) was used to measure the conduction of the left ventricle. The western-blot was performed for the expression level of connexin 43. We observed prolonged APD90, increased ICa,L and decreased Ito following MI, while CCR9 knockout attenuated these changes (APD90: 50.57 ± 6.51 ms in CCR9−/−/MI vs. 76.53 ± 5.98 ms in CCR9+/+/MI, p < 0.05; ICa,L: −13.15 ± 0.86 pA/pF in CCR9−/−/MI group vs. −17.05 ± 1.11 pA/pF in CCR9+/+/MI, p < 0.05; Ito: 4.01 ± 0.17 pA/pF in CCR9−/−/MI group vs. 2.71 ± 0.16 pA/pF in CCR9+/+/MI, p < 0.05). The confocal microscopy results revealed CCR9 knockout reversed the calcium transient and calcium content reduction in sarcoplasmic reticulum following MI. MEA measurements showed improved conduction velocity in CCR9−/−/MI mice (290.1 ± 34.47 cm/s in CCR9−/−/MI group vs. 113.2 ± 14.4 cm/s in CCR9+/+/MI group, p < 0.05). Western-blot results suggested connexin 43 expression was lowered after MI while CCR9 knockout improved its expression.Conclusion: This study shows CCR9 knockout prevents the electrical remodeling by normalizing ion currents, the calcium homeostasis, and the gap junction to maintain APD and the conduction function. It suggests CCR9 is a promising therapeutic target for MI-induced arrhythmia, which warrants further investigation.

Kv1.3 Channel Blockade Improves Inflammatory Profile, Reduces Cardiac Electrical Remodeling, and Prevents Arrhythmia in Type 2 Diabetic Rats

Purpose Kv1.3 channel regulates the activity of lymphocytes, macrophages, or adipose tissue and its blockade reduces inflammatory cytokine secretion and improves insulin sensitivity in animals with metabolic syndrome and in genetically obese mice. Thus, Kv1.3 blockade could be a strategy for the treatment of type 2 diabetes. Elevated circulating levels of TNFα and IL-1b mediate the higher susceptibility to cardiac arrhythmia in type 2 diabetic rats. We hypothesized that Kv1.3 channel blockade with the psoralen PAP1 could have immunomodulatory properties that prevent QTc prolongation and reduce the risk of arrhythmia in type 2 diabetic rats. Methods Type 2 diabetes was induced to Sprague-Dawley rats by high-fat diet and streptozotocin injection. Diabetic animals were untreated, treated with metformin, or treated with PAP1 for 4 weeks. Plasma glucose, insulin, cholesterol, triglycerides, and cytokine levels were measured using commercial kits. ECG were recorded weekly, and an arrhythmia-inducing protocol was performed at the end of the experimental period. Action potentials were recorded in isolated ventricular cardiomyocytes. Results In diabetic animals, PAP1 normalized glycaemia, insulin resistance, adiposity, and lipid profile. In addition, PAP1 prevented the diabetes-induced repolarization defects through reducing the secretion of the inflammatory cytokines IL-10, IL-12p70, GM-CSF, IFNγ, and TNFα. Moreover, compared to diabetic untreated and metformin-treated animals, those treated with PAP1 had the lowest risk of developing the life-threatening arrhythmia Torsade de Pointes under cardiac challenge. Conclusion Kv1.3 inhibition improves diabetes and diabetes-associated low-grade inflammation and cardiac electrical remodeling, resulting in more protection against cardiac arrhythmia compared to metformin.

Ventricular arrhythmia susceptibility in a new porcine model of heart failure (HF) with reduced ejection fraction

Introduction Sudden death secondary to ventricular arrhythmias is common in HF patients, with no effective treatment available outside of implantable cardiac defibrillators. While animal models are essential for the discovery of anti-arrhythmic drugs, no reliable large animal HF models with associated ventricular arrhythmias have been described so far. Objectives We aimed at evaluating ventricular remodeling and arrhythmia susceptibility in an HF pig model with reduced ejection fraction (EF) following myocardial infarction (MI). Methods MI was induced in 53 male Göttingen minipigs (12–15 months, 20–25 kg) by coronary embolization in mid-left anterior descending and mid-left circumflex coronary arteries using endovascular coils. Seven other pigs underwent sham operation and were used as control. Two weeks after surgery, cardiac function was assessed by echocardiography, and animals were included based on EF<50% (n=15/53), assigned either to 12 weeks of vehicle (n=9) or perindopril (n=6, 1 mg/kg/d, per os) group. At the end of the study, their left ventricular (LV) electrical remodeling was studied by echocardiography/electrocardiography and a programmed-electrical stimulation protocol was performed to evaluate the susceptibility to develop ventricular arrhythmias. Results At the end of the study, animals in the vehicle group had a significant LV remodeling associated with a reduced EF (p<0.05 vs. sham, see table). This remodeling was associated with cardio-pulmonary congestion, significant increases in LV end-diastolic pressure, left atrial volume, and lung mass (all p<0.05 vs. sham, see table), fully prevented by perindopril treatment. They had also an electrical remodeling as evidenced by an increase in PR, QRS, and QTc intervals, as well as LV effective refractory period (+18%, 14%, 33%, and 13%, respectively, p<0.05, compared to sham animals). Electrical changes were mitigated by perindopril treatment (p=NS vs. sham). LV mechanical dispersion measured with speckle-tracking echocardiography was significantly increased in vehicle group (58±5 vs. 22±1 ms in sham group, respectively) as well as in perindopril group. Programmed-electrical stimulations induced in 6/8 vehicle animals either non-sustained (n=3) or sustained (n=2) ventricular tachycardia, or ventricular fibrillation (n=1). In sham group only 1/7 animal had a ventricular fibrillation. No inducible ventricular arrhythmia was observed in animals treated with Perindopril. Conclusion In this new pig model of congestive HF with reduced EF, LV remodeling was associated with electrical remodeling and susceptibility to develop arrhythmias. Chronic angiotensin-converting enzyme inhibitor treatment prevented congestion, mitigated electrical remodeling, and suppressed arrhythmia susceptibility. FUNDunding Acknowledgement Type of funding sources: Private company. Main funding source(s): Servier Research Institute - CardioVascular & Metabolic Diseases Center for Therapeutic Innovation Table 1

Influence of miR-221/222 on cardiomyocyte calcium handling and function

Background Cardiovascular disease is the leading cause of death worldwide. Cardiac electrical remodeling including altered ion channel expression and imbalance of calcium homeostasis can have detrimental effects on cardiac function. While it has been extensively reported that miR-221/222 are involved in structural remodeling, their role in electrical remodeling still has to be evaluated. We previously reported that subunits of the L-type Ca2+ channel (LTCC) are direct targets of miR-221/222. Furthermore, HL-1 cells transfected with miR-221 or -222 mimics showed a reduction in LTCC current density while the voltage-dependence of activation was not altered. The aim of the present study was to determine the influence of miR-221/222 on cardiomyocyte calcium handling and function. Results Transient transfection of HL-1 cells with miR-221/222 mimics led to slower depolarization-dependent Ca2+ entry and increased proportion of non-responding cells. Angiotensin II-induced Ca2+ release from the SR was not affected by miR-221/222. In miR-222-transfected neonatal cardiomyocytes the isoprenaline-induced positive inotropic effect on the intracellular Ca2+ transient was lost and the positive chronotropic effect on spontaneous beating activity was strongly reduced. This could have severe consequences for cardiomyocytes and could lead to a reduced contractility and systolic dysfunction of the whole heart. Conclusions This study adds a new role of miR-221/222 in cardiomyocytes by showing the impact on β-adrenergic regulation of LTCC function, calcium handling and beating frequency. Together with the previous report that miR-221/222 reduce GIRK1/4 function and LTCC current density, it expands our knowledge about the role of these miRs on cardiac ion channel regulation.