Sodium-Calcium Exchanger Inhibition Results in Ventricular Fibrillation in Hearts with Pressure Overload Induced Hypertrophy

Introduction: 5.1 million people in the United States have heart failure (HF). Improved treatment of heart failure is critically important because approximately half of patients diagnosed with HF die within 5 years. Cardiac myocyte calcium (Ca2+) imbalance is a characteristic of HF and may cause diastolic dysfunction and focal arrhythmias. During contraction, ryanodine receptors release Ca2+, which is primarily removed by the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) and the sarcolemmal sodium calcium exchanger (NCX) to initiate relaxation. There is evidence that NCX activity is elevated in failing hearts to compensate for reduced SERCA activity. We tested the hypothesis that NCX inhibition in HF hearts would result in greater contractile dysfunction and arrhythmias than in sham hearts. Methods: Rats underwent either sham or trans-aortic constriction (TAC) surgery to induce pressure-overload HF. Rat hearts were excised and Langendorff perfused with a Krebs-Hensleit solution, pH=7.4, oxygenated with 95%O2/5%CO2. Left ventricular developed pressure (LVDP), heart rate, and coronary flow rate were acquired. After a stabilization period, increasing concentrations of the NCX inhibitor SEA0400 were added. In a subset of hearts, Western blots were performed using SERCA, NCX, and Cx43 antibodies. Results: During perfusion, baseline LVDP was reduced in TAC animals compared to the sham animals (75.5±19.6 vs 136.2±5.4 mmHg), while heart rate did not differ (222±25 vs 199±22 bpm). Immediately after the final addition of SEA0400, heart rate remained constant (231±21 vs 215±26 bpm). However, approximately one minute after the final concentration of SEA0400 was added, 3 out of the 4 TAC hearts experienced ventricular fibrillation (VF). Western blot analysis did not show a significant change in SERCA or NCX protein expression in the TAC model. Conclusion: Most notably, NCX inhibition resulted in VF for 3 out of 4 TAC hearts, while no sham (n=3) hearts experienced VF. LVDP dropped to 84±4% of baseline in TAC hearts, while sham hearts exhibited no change in LVDP. Surprisingly, this decrease in LVDP was not accompanied by an increase in diastolic pressure (7.6±1.7 vs 6.5±2.6 mmHg). Our results suggest that the sodium calcium exchanger is more important for maintaining contractile function in failing hearts than in healthy hearts. As inhibition of NCX results in decreased LVDP and induces VF in TAC hearts, it is likely that increased NCX activity compensates for decreased SERCA activity in hypertrophic/failing hearts

Glibenclamide Prevents APD Shortening During Deoxygenation in Left Ventricular Working Hearts

Intro: Sarcolemmal ATP-sensitive K+ channels (KATP) open in response to low [ATP]/[ADP] to link cardiac energetics and action potential duration (APD). The effect of workload and oxygenation on KATP activation in excised working hearts is important for arrhythmia mechanisms, yet is unknown. Using novel motion-corrected ratiometric optical mapping, we hypothesized that, due to KATP activation, APD shortening in LV working (LVW) hearts during hypoxia is more severe than in unloaded Langendorff perfused hearts (LANG). Methods: Epicardial APDs were measured from LVW and LANG rabbit hearts (n=11) using di-4-ANEPPS excitation ratiometry and a motion-tracking algorithm. Circulating perfusate was gradually deoxygenated by bubbling with N2 gas. Perfusate %O2 was measured. In a subset of studies, 10µM glibenclamide (GLIB) was added to identify the level of APD shortening attributed to KATP. Results: APD dropped more rapidly in LVW than LANG hearts during gradual deoxygenation. Between 75 to 50 %O2, LVW APD dropped at a rate of 1.33±0.84 %O2/msec while LANG APD was constant. LANG APD dropped most rapidly at 50 %O2. GLIB diminished APD shortening in LVW hearts to a rate of 0.61±0.11 %O2/msec until 45 %O2, when APD dropped rapidly. In LVW hearts with GLIB, the APD vs. %O2 curve closely mirrored the LANG curve. Conclusion: APD shortens severely in LVW hearts during deoxygenation. High workload precipitates a mismatch of O2 supply:demand sooner, and to a greater extent, than in unloaded hearts. GLIB blocks KATP to decouple energetics and electrical activity to align the deoxygenation curves of loaded and unloaded hearts

Neurotransmission to parasympathetic cardiac vagal neurons in the brain stem is altered with left ventricular hypertrophy-induced heart failure

© 2015 the American Physiological Society. Hypertension, cardiac hypertrophy, and heart failure (HF) are widespread and debilitating cardiovascular diseases that affect nearly 23 million people worldwide. A distinctive hallmark of these cardiovascular diseases is autonomic imbalance, with increased sympathetic activity and decreased parasympathetic vagal tone. Recent device-based approaches, such as implantable vagal stimulators that stimulate a multitude of visceral sensory and motor fibers in the vagus nerve, are being evaluated as new therapeutic approaches for these and other diseases. However, little is known about how parasympathetic activity to the heart is altered with these diseases, and this lack of knowledge is an obstacle in the goal of devising selective interventions that can target and selectively restore parasympathetic activity to the heart. To identify the changes that occur within the brain stem to diminish the parasympathetic cardiac activity, left ventricular hypertrophy was elicited in rats by aortic pressure overload using a transaortic constriction approach. Cardiac vagal neurons (CVNs) in the brain stem that generate parasympathetic activity to the heart were identified with a retrograde tracer and studied using patch-clamp electrophysiological recordings in vitro. Animals with left cardiac hypertrophy had diminished excitation of CVNs, which was mediated both by an augmented frequency of spontaneous inhibitory GABAergic neurotransmission (with no alteration of inhibitory glycinergic activity) as well as a diminished amplitude and frequency of excitatory neurotransmission to CVNs. Opportunities to alter these network pathways and neurotransmitter receptors provide future targets of intervention in the goal to restore parasympathetic activity and autonomic balance to the heart in cardiac hypertrophy and other cardiovascular diseases

Neurotransmission to Parasympathetic Cardiac Vagal Neurons in the Brainstem is Altered With Left Ventricular Hypertrophy Induced Heart Failure.

© 2015 the American Physiological Society. Hypertension, cardiac hypertrophy, and heart failure (HF) are widespread and debilitating cardiovascular diseases that affect nearly 23 million people worldwide. A distinctive hallmark of these cardiovascular diseases is autonomic imbalance, with increased sympathetic activity and decreased parasympathetic vagal tone. Recent device-based approaches, such as implantable vagal stimulators that stimulate a multitude of visceral sensory and motor fibers in the vagus nerve, are being evaluated as new therapeutic approaches for these and other diseases. However, little is known about how parasympathetic activity to the heart is altered with these diseases, and this lack of knowledge is an obstacle in the goal of devising selective interventions that can target and selectively restore parasympathetic activity to the heart. To identify the changes that occur within the brain stem to diminish the parasympathetic cardiac activity, left ventricular hypertrophy was elicited in rats by aortic pressure overload using a transaortic constriction approach. Cardiac vagal neurons (CVNs) in the brain stem that generate parasympathetic activity to the heart were identified with a retrograde tracer and studied using patch-clamp electrophysiological recordings in vitro. Animals with left cardiac hypertrophy had diminished excitation of CVNs, which was mediated both by an augmented frequency of spontaneous inhibitory GABAergic neurotransmission (with no alteration of inhibitory glycinergic activity) as well as a diminished amplitude and frequency of excitatory neurotransmission to CVNs. Opportunities to alter these network pathways and neurotransmitter receptors provide future targets of intervention in the goal to restore parasympathetic activity and autonomic balance to the heart in cardiac hypertrophy and other cardiovascular diseases

Chronic Activation of Hypothalamic Oxytocin Neurons Improves Cardiac Function During Left Ventricular Hypertrophy-Induced Heart Failure.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: [email protected]. Aims: A distinctive hallmark of heart failure (HF) is autonomic imbalance, consisting of increased sympathetic activity, and decreased parasympathetic tone. Recent work suggests that activation of hypothalamic oxytocin (OXT) neurons could improve autonomic balance during HF. We hypothesized that a novel method of chronic selective activation of hypothalamic OXT neurons will improve cardiac function and reduce inflammation and fibrosis in a rat model of HF.Methods and results: Two groups of male Sprague-Dawley rats underwent trans-ascending aortic constriction (TAC) to induce left ventricular (LV) hypertrophy that progresses to HF. In one TAC group, OXT neurons in the paraventricular nucleus of the hypothalamus were chronically activated by selective expression and activation of excitatory DREADDs receptors with daily injections of clozapine N-oxide (CNO) (TAC + OXT). Two additional age-matched groups received either saline injections (Control) or CNO injections for excitatory DREADDs activation (OXT NORM). Heart rate (HR), LV developed pressure (LVDP), and coronary flow rate were measured in isolated heart experiments. Isoproterenol (0.01 nM-1.0 µM) was administered to evaluate β-adrenergic sensitivity. We found that increases in cellular hypertrophy and myocardial collagen density in TAC were blunted in TAC + OXT animals. Inflammatory cytokine IL-1β expression was more than twice higher in TAC than all other hearts. LVDP, rate pressure product (RPP), contractility, and relaxation were depressed in TAC compared with all other groups. The response of TAC and TAC + OXT hearts to isoproterenol was blunted, with no significant increase in RPP, contractility, or relaxation. However, HR in TAC + OXT animals increased to match Control at higher doses of isoproterenol.Conclusions: Activation of hypothalamic OXT neurons to elevate parasympathetic tone reduced cellular hypertrophy, levels of IL-1β, and fibrosis during TAC-induced HF in rats. Cardiac contractility parameters were significantly higher in TAC + OXT compared with TAC animals. HR sensitivity, but not contractile sensitivity, to β-adrenergic stimulation was improved in TAC + OXT hearts