Upregulation of Na ⁺ /Ca ²⁺ Exchanger Expression and Function in an Arrhythmogenic Rabbit Model of Heart Failure

Abstract

Abstract-Three-dimensional cardiac mapping in rabbits with nonischemic cardiomyopathy has shown that ventricular arrhythmias initiate by a nonreentrant mechanism that may be due to triggered activity from delayed afterdepolarizations. Delayed afterdepolarizations are thought to be due to spontaneous release of Ca 2ϩ from the sarcoplasmic reticulum (SR) and consequent activation of an inward Na ϩ /Ca 2ϩ exchange (NaCaX) current. The goal of this study was to determine whether there is enhanced NaCaX gene expression and functional activity that may contribute to nonreentrant activation. Heart failure (HF) was induced in rabbits by combined aortic insufficiency and aortic constriction. HF rabbits had left ventricular enlargement (left ventricular end-diastolic dimension increased from 1.43Ϯ0.03 to 1.97Ϯ0.05 cm) and severely depressed function (fractional shortening reduced from 37% to 26%, PϽ0.02). Heart-to-body weight was increased by 79% in HF. Western blots showed a 93% increase in NaCaX protein in HF (PϽ0.04). NaCaX mRNA (7-kb transcript) was increased by 104% relative to the 18S rRNA in HF. A 14-kb NaCaX transcript was also seen in the HF rabbits, raising total NaCaX mRNA to 2.7-fold compared with controls. Key Words: heart failure Ⅲ Na ϩ /Ca 2ϩ exchange Ⅲ ventricular tachycardia Ⅲ delayed afterdepolarization Ⅲ Ca 2ϩ S udden death in patients with congestive heart failure (HF) is commonly due to lethal ventricular arrhythmias, including ventricular tachycardia (VT) and ventricular fibrillation. 1,2 However, very little is known about the electrophysiologic and molecular mechanisms underlying arrhythmogenesis in HF. An understanding will require 1) development of arrhythmogenic animal models of HF, 2) delineation of the arrhythmic mechanisms in these animal models, 3) validation of these mechanisms by studies in the human heart, and 4) assessment of the function and expression of the channels and carrier proteins that may underlie these arrhythmic mechanisms.There are a considerable number of experimental animal models of HF, 3 but very few are arrhythmogenic. An arrhythmogenic experimental model of nonischemic cardiomyopathy has recently been developed in rabbits, combining aortic insufficiency and aortic constriction. 4,5 These HF rabbits develop severe depression of left ventricular (LV) function, pathologic alterations similar to that in patients with nonischemic cardiomyopathy, and spontaneously-occurring VT. 3 Using 3D cardiac mapping, Pogwizd 5 has demonstrated that the spontaneously-occurring VT in these HF rabbits initiates by a nonreentrant mechanism. Recent 3D mapping studies in failing human hearts at the time of heart transplantation in patients with idiopathic dilated cardiomyopathy have demonstrated that spontaneous and induced VT in these patients also initiates by a focal nonreentrant mechanism. 6 The nature of this nonreentrant mechanism in the myopathic heart is unknown. Vermeulen et al 7 have demonstrated that failing myocardium from rabbits with aortic insufficiency and aortic stenosis demo...

Suppression of Early and Late Afterdepolarizations by Heterozygous Knockout of the Na + /Ca 2+ Exchanger in a Murine Model

“…2,3 However, others have suggested that DADs and EADs share a common mechanism that may be NCX dependent. 4 To date, the role of chronically altered NCX expression in the generation of arrhythmia has been limited to models with increased NCX expression 5 and to animal models of heart failure or hypertrophy 1,[6][7][8][9][10] in which NCX is known to be overexpressed. Yet, in heart failure, a multitude of proarrhythmic alterations other than the upregulation of NCX has been identified, 11 most importantly a reduction of K + currents 12,13 which promote a prolongation of AP duration and the occurrence of arrhythmia.…”

Intracellular Na + Concentration Is Elevated in Heart Failure But Na/K Pump Function Is Unchanged

“…Specifically, HF cardiac myocytes exhibit depressed and prolonged Ca 2ϩ transients. 1 These changes can be explained by reductions in sarcoplasmic reticulum (SR) Ca 2ϩ -ATPase 2 and increased Na/Ca exchange (NCX) [3][4][5][6] function.…”

Mutation in sodium–calcium exchanger 1 (NCX1) causes cardiac fibrillation in zebrafish

“…Relaxation is accomplished by resequestering of calcium to the sarcoplasmic reticulum by sarcoendoplasmic reticular Ca 2ϩ -ATPase2 (SERCA2) and extrusion of calcium from the cell by NCX1 and plasma membrane Ca 2ϩ -ATPase (PMCA). Abnormal calcium handling caused by altered expression levels or protein activities of NCX1 and SERCA2, or by mutations in ryanodine receptors, have been associated with cardiac diseases, such as heart failure and arrhythmia, and with sudden death in humans and animal models (1)(2)(3)(4)(5)(6). In addition, genetic studies in the zebrafish demonstrate that L-type calcium channels and the sodium pump (a modulator of NCX activity) are indispensable for embryonic cardiac function (7,8).…”

“…NCX1 is highly expressed in the heart and is considered to be the primary mechanism for calcium extrusion in cardiomyocytes. In fact, elevated NCX1 activity has been noted in patients with heart failure and is associated with arrhythmia in patients and animal models (1,2). The embryonic role of NCX1, however, is not well understood.…”