Effects of Experimental Heart Failure on Atrial Cellular and Ionic Electrophysiology

Li, Danshi; Melnyk, Peter; Feng, Jianlin; Wang, Zhiguo; Petrecca, Kevin; Shrier, Alvin; Nattel, Stanley

doi:10.1161/01.cir.101.22.2631

Cited by 331 publications

(337 citation statements)

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“…Atrial cardiomyocytes were isolated enzymatically as previously described 18. After anesthetized with sodium pentobarbital (3%; 30 mg/kg), the heart was quickly removed from the torso and was placed in cold perfusion fluid (4°C).…”

Section: Methodsmentioning

confidence: 99%

Xanthine Oxidase Inhibitor Allopurinol Prevents Oxidative Stress‐Mediated Atrial Remodeling in Alloxan‐Induced Diabetes Mellitus Rabbits

Yang

Zhao

Qiu

et al. 2018

JAHA

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BackgroundThere are several mechanisms, including inflammation, oxidative stress and abnormal calcium homeostasis, involved in the pathogenesis of atrial fibrillation. In diabetes mellitus (DM), increased oxidative stress may be attributable to higher xanthine oxidase activity. In this study, we examined the relationship between oxidative stress and atrial electrical and structural remodeling, and calcium handling abnormalities, and the potential beneficial effects of the xanthine oxidase inhibitor allopurinol upon these pathological changes.Methods and ResultsNinety rabbits were randomly and equally divided into 3 groups: control, DM, and allopurinol‐treated DM group. Echocardiographic and hemodynamic assessments were performed in vivo. Serum and tissue markers of oxidative stress and atrial fibrosis, including the protein expression were examined. Atrial interstitial fibrosis was evaluated by Masson trichrome staining. ICaL was measured from isolated left atrial cardiomyocytes using voltage‐clamp techniques. Confocal microscopy was used to detect intracellular calcium transients. The Ca2+ handling protein expression was analyzed by Western blotting. Mitochondrial‐related proteins were analyzed as markers of mitochondrial function. Compared with the control group, rabbits with DM showed left ventricular hypertrophy, increased atrial interstitial fibrosis, oxidative stress and fibrosis markers, ICaL and intracellular calcium transient, and atrial fibrillation inducibility. These abnormalities were alleviated by allopurinol treatment.ConclusionsAllopurinol, via its antioxidant effects, reduces atrial mechanical, structural, ion channel remodeling and mitochondrial synthesis abnormalities induced by DM‐related increases in oxidative stress.

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Section: Methodsmentioning

confidence: 99%

Xanthine Oxidase Inhibitor Allopurinol Prevents Oxidative Stress‐Mediated Atrial Remodeling in Alloxan‐Induced Diabetes Mellitus Rabbits

Yang

Zhao

Qiu

et al. 2018

JAHA

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“…In vitro analyses of ion currents have shown that the minor changes in AERP observed in RVP dogs are due to inhibition of depolarizing currents being offset by the inhibition of repolarizing currents (22).…”

Section: Chronic Consequences Of Savp Versus Rvpmentioning

confidence: 99%

Experimental studies of atrial fibrillation: a comparison of two pacing models

Laurent¹,

Moe²,

Hu³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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is a well-established animal model of atrial fibrillation (AF). However, this model is limited by a high mortality rate and severe heart failure. The purpose of our study was to assess a new canine model of inducible AF. We performed acute, short-term, simultaneous atrioventricular pacing (SAVP) and RVP (in random order) in 14 dogs for 30 s. SAVP produced more echocardiographic pulmonary venous flow reversal, a greater increase in mean pulmonary capillary wedge pressure, and a significantly greater decrease in left atrial emptying function (Ϫ84.4 Ϯ 38.6% vs. Ϫ23.7 Ϯ 27.1%, P Ͻ 0.05) than RVP. Thirty dogs were randomized to three, longer-term, study groups: eight dogs in the control group (no pacing), eight dogs in the RVP group (2 wk at 240 beats/min followed by 3 wk at 220 beats/min), and fourteen dogs in the SAVP group (2 wk at 220 beats/min). SAVP induced less left ventricular dysfunction but more left atrial dysfunction than RVP. SAVP dogs had similar atrial effective refractory periods as RVP dogs but more heterogeneity in conduction and more AF inducibility (83% vs. 40%, P Ͻ 0.05) and maintenance (median 1,660 vs. 710 s, P Ͻ 0.05) than RVP dogs. SAVP induced more collagen turnover and was associated with a significantly greater increase in type III collagen in the atria compared with RVP dogs (6.9 Ϯ 1.5 vs. 4.8 Ϯ 1.6, respectively, P Ͻ 0.05 vs. 1.1 Ϯ 0.7 in unpaced control dogs). In conclusion, the SAVP model induced profound mechanical and substrate atrial remodeling and reproducible sustained AF. This new model is clinically relevant and may be useful for testing AF interventions. experimental atrial arrhythmia; extracellular matrix; remodeling ATRIAL FIBRILLATION (AF) is the most common sustained cardiac arrhythmia and frequently causes cardiovascular morbidity and mortality. Although AF can occur in patients with normal hearts (lone AF), the majority of patients with AF have coexisting structural heart disease, most commonly hypertension or heart failure (1). To better understand the relationship between the atrial substrate and AF vulnerability and to evaluate therapies for AF, multiple animal models of AF have been developed. They include sterile pericarditis, acute atrial ischemia, atrial volume overload, mitral regurgitation, pacemakerinduced atrial tachycardia, and ventricular pacing-induced heart failure (25).One of the most commonly used models employs rapid atrial pacing (RAP) at 400 beats/min with control of the ventricular response (atrioventricular node ablation) (24). This model helps to understand the mechanisms underlying the tendency of paroxysmal AF to become persistent but does not relate closely to the most frequent clinical conditions associated with AF, in which the left atrium (LA) dilates and is fibrosed, exhibiting conduction slowing (14, 21). The other commonly used model is rapid ventricular pacing (RVP) to induce heart failure (240 -280 beats/min for 3-8 wk), sometimes combined with RAP (RVP at 240 beats/min for 2 wk combined with additional RAP at 400 beats/min during the sec...

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“…1 Congestive heart failure (CHF) is an important cause of AF and also causes ionic remodeling. 7 Like AT, CHF also decreases I to ; however, CHF-induced remodeling differs from AT remodeling in that CHF reduces I Ca to a lesser extent, decreases the slow delayed-rectifier (I Ks ), and increases the Na ϩ -Ca 2ϩ exchanger (I NCX ). 7 Consequently, instead of decreasing action potential duration, CHF leaves atrial action potential duration unchanged or increased.…”

mentioning

confidence: 99%

“…7 Like AT, CHF also decreases I to ; however, CHF-induced remodeling differs from AT remodeling in that CHF reduces I Ca to a lesser extent, decreases the slow delayed-rectifier (I Ks ), and increases the Na ϩ -Ca 2ϩ exchanger (I NCX ). 7 Consequently, instead of decreasing action potential duration, CHF leaves atrial action potential duration unchanged or increased. 7 Whereas AT-induced ionic remodeling promotes atrial reentry by decreasing the wavelength in a spatially heterogeneous fashion, 1 CHF-induced ionic remodeling increases the wavelength and may contribute to AF promotion by inducing afterdepolarization-related ectopic activity due to enhanced I NCX .…”

mentioning

confidence: 99%

Atrial Ionic Remodeling Induced by Atrial Tachycardia in the Presence of Congestive Heart Failure

et al. 2004

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Background-Atrial fibrillation (AF) and congestive heart failure (CHF) produce discrete forms of atrial ionic remodeling.The in vivo effects of atrial tachycardia (AT) remodeling are altered by CHF. This study evaluated underlying mechanisms at the level of ionic remodeling. Methods and Results-We studied 4 groups of dogs: (1) unpaced controls (CTLs); (2) CHF caused by 2-week ventricular tachypacing (VTP, 240 bpm); (3) AT (400 bpm ϫ7 days); and (4) CHFϩAT (2-week VTP with AT for the last 7 days). CHF and CHFϩAT groups equally increased left atrial pressure. AF duration was increased in all paced groups. Effective refractory period (ERP) was decreased by 42% in AT versus CTL but by only 24% in ATϩCHF versus CHF. CHF reduced L-type Ca 2ϩ (I Ca ), transient-outward (I to ), and the slow delayed-rectifier (I Ks ) currents while increasing the Na ϩ -Ca 2ϩ exchanger (I NCX ) and not affecting the inward-rectifier (I K1 ) current. AT reduced I to and I Ca while increasing I K1 and leaving I Ks unaltered. The addition of AT to CHF failed to alter I to , I Ks , or I NCX beyond the effect of CHF alone, decreased I Ca slightly compared with CHF alone, but had smaller effects on I Ca and I K1 compared with AT alone. Thus, CHFϩAT, as would occur in a CHF patient who develops AF, produced an ionic remodeling pattern different from that of CHF or AT alone and from what would have been predicted from additive effects of CHF and AT. Conclusions-The presence of CHF alters AT-induced ionic remodeling. Thus, the ionic remodeling caused by cardiac arrhythmias in the presence of cardiac pathology is not necessarily predictable from the effects of either alone, with important potential implications for understanding the pathophysiology of arrhythmias in the diseased heart.

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Effects of Experimental Heart Failure on Atrial Cellular and Ionic Electrophysiology

Cited by 331 publications

References 44 publications

Xanthine Oxidase Inhibitor Allopurinol Prevents Oxidative Stress‐Mediated Atrial Remodeling in Alloxan‐Induced Diabetes Mellitus Rabbits

Xanthine Oxidase Inhibitor Allopurinol Prevents Oxidative Stress‐Mediated Atrial Remodeling in Alloxan‐Induced Diabetes Mellitus Rabbits

Experimental studies of atrial fibrillation: a comparison of two pacing models

Atrial Ionic Remodeling Induced by Atrial Tachycardia in the Presence of Congestive Heart Failure

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