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Cited by 399Cardiac electrophysiology and arrhythmiasCardiac Arrhythmias and TreatmentsIon Transport and Channel Regulation

Upregulation of Na+/Ca2+Exchanger Expression and Function in an Arrhythmogenic Rabbit Model of Heart Failure

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Pogwizd, Steven M., Qi, Ming, Yuan, Weilong, Samarel, Allen M., Bers, Donald M.·1999·Circulation Research
DOI 10.1161/01.res.85.11.1009
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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 2+from the sarcoplasmic reticulum (SR) and consequent activation of an inward Na+/Ca 2+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 1.43±0.03 to 1.97±0.05 cm) and severely depressed function (fractional shortening reduced from 37% to 26%,P<0.02). Heart-to-body weight was increased by 79% in HF. Western blots showed a 93% increase in NaCaX protein in HF (P<0.04). 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. The amplitude of caffeine-induced contractures, used to assess SR Ca 2+load, was not significantly different in HF. Relaxation and [Ca 2+]i decline during caffeine-induced contractures is attributable to Ca 2+transport by NaCaX and was 61% and 45% faster in HF (P<0.05), respectively. NaCaX current measured under controlled voltage clamp conditions was also 2-fold higher in HF cells. SR Ca 2+-ATPase mRNA and protein levels and Ca 2+current density were not significantly altered in HF. Twitch amplitudes from HF myocytes were 26% smaller compared with control (P<0.02), but twitch relaxation and [Ca 2+]i decline (due largely to SR Ca 2+-ATPase) were not altered. Thus myocytes and myocardium from HF rabbits exhibit enhanced NaCaX expression and function. The enhanced NaCaX activity may contribute to depressed contractions, increased transient inward current (for a given SR Ca 2+release), delayed afterdepolarizations, and nonreentrant initiation of ventricular tachycardia in this arrhythmogenic model of HF.

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  • Myocardial function in intact rabbits can be assessed with established in vivo quantitative and imaging techniques such as echocardiography, hemodynamic catheterization, electrocardiography, and cardiac MRI.

    “various in vivo quantitative and imaging techniques such as echocardiography (Pogwizd, Qi, Yuan, Samarel, & Bers, 1999), hemodynamic cardiac catheterization (Mahaffey, Raya, Pennock, Morkin, & Goldman, 1995; A. S. Shah, et al., 2000), electrocardiography (Pogwizd, et al., 1999), and cardiac magnetic resonance imaging (Jung, et al., 2012) are well established and are routinely performed in rabbits.”

    From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Pogwizd, et al., 1999

  • Various methods are available to generate rabbit heart failure models, including pacing-induced failure, combined aortic insufficiency-induced volume overload and aortic constriction-induced pressure overload, and coronary ligation.

    “Various methods for generating rabbit heart failure models are available including pacing-induced failure (D. Liu, Gao, Roy, Cornish, & Zucker, 2006), combined aortic insufficiency induced volume overload and aortic constriction induced pressure overload (Pogwizd, et al., 1999), and coronary ligation (Maurice, et al., 1999; D. C. White, et al., 2000).”

    From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Pogwizd, et al., 1999

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Research works printed but not linked: 2

  1. Hatem SN, Sham JSK, Morad M. Enhanced Na ϩ -Ca 2ϩ exchange activity in cardio-myopathic Syrian hamster. Circ Res. 1994;74:253-261.
  2. Pieske B, Maier LS, Bers DM, Hasenfuss G. Ca 2ϩ handling and SR Ca 2ϩ content in isolated failing and nonfailing human myocardium Circ Res. 1999;85:38 -46.

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Authors
Pogwizd, S. M., Qi, M., Yuan, W., Samarel, A. M., & Bers, D. M.
Affiliations
Loyola University Chicago (US)
ORCID
Venue
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
1999-11-26
Volume
85
Issue
11
Pages
1009-1019
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
DOI
10.1161/01.res.85.11.1009
OpenAlex
W2147959747
Cited by
399
References
49
Citations by year
2026: 3 · 2025: 2 · 2024: 4 · 2023: 6 · 2022: 6 · 2021: 12 · 2020: 10 · 2019: 12 · 2018: 11 · 2017: 9 · 2016: 9 · 2015: 17 · 2014: 18 · 2013: 17 · 2012: 19
FWCI
16.99
Type
journal article
Language
en
Open access
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Heart Association
  • National Institutes of Health (5r01hl052478-05)
  • University of Illinois at Chicago
  • National Heart, Lung, and Blood Institute (HL46929, HL52478, HL30077)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Arrhythmias and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
Keywords
Na+/Ca2+ exchanger, heart failure, ventricular arrhythmias, delayed afterdepolarizations, non-ischemic cardiomyopathy, sarcoplasmic reticulum calcium release, sarcoplasmic reticulum Ca2+-ATPase, caffeine-induced contracture, aortic regurgitation, aortic constriction, rabbit model, gene expression
MeSH terms
Animals, Aortic Valve Insufficiency, Arrhythmias, Cardiac, Caffeine, Calcium, Constriction, Disease Models, Animal, Gene Expression Regulation, Cardiomegaly, Heart Failure, Heart Ventricles, Molecular Weight, Myocardial Contraction, Rabbits, RNA, Messenger, Sodium, Ion Transport, Myocardial Ischemia, Sodium-Calcium Exchanger

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