Arrhythmogenic substrate in hearts of rats with monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy

Benoist, David; Stones, Rachel; Drinkhill, Mark J.; Bernus, Olivier; White, Ed

doi:10.1152/ajpheart.01226.2010

Cited by 67 publications

(74 citation statements)

References 40 publications

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“…MCT animals were killed (23 Ϯ 1 days after MCT injection) by cervical dislocation following stunning when they expressed clinical signs of HF including weight loss, tachypnea, lethargy, cold extremities and piloerection. These have been shown to correlate with decompensated RV dysfunction in this model (3,19). CON animals were kept for the same period of time as MCT and killed on corresponding days.…”

Section: Methodsmentioning

confidence: 99%

Regional skeletal muscle remodeling and mitochondrial dysfunction in right ventricular heart failure

Wüst¹,

Myers

Stones³

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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ance is a cardinal symptom of right ventricular heart failure (RV HF) and skeletal muscle adaptations play a role in this limitation. We determined regional remodeling of muscle structure and mitochondrial function in a rat model of RV HF induced by monocrotaline injection (MCT; 60 mg·kg Ϫ1 ; n ϭ 11). Serial sections of the plantaris were stained for fiber type, succinate dehydrogenase (SDH) activity and capillaries. Mitochondrial function was assessed in permeabilized fibers using respirometry, and isolated complex activity by blue native gel electrophoresis (BN PAGE). All measurements were compared with saline-injected control animals (CON; n ϭ 12). Overall fiber cross-sectional area was smaller in MCT than CON: 1,843 Ϯ 114 vs. 2,322 Ϯ 120 m 2 (P ϭ 0.009). Capillary-to-fiber ratio was lower in MCT in the oxidative plantaris region (1.65 Ϯ 0.09 vs. 1.93 Ϯ 0.07; P ϭ 0.03), but not in the glycolytic region. SDH activity (P ϭ 0.048) and maximal respiratory rate (P ϭ 0.012) were each ϳ15% lower in all fibers in MCT. ADP sensitivity was reduced in both skeletal muscle regions in MCT (P ϭ 0.032), but normalized by rotenone. A 20% lower complex I/IV activity in MCT was confirmed by BN PAGE. MCT-treatment was associated with lower mitochondrial volume density (lower SDH activity), quality (lower complex I activity), and fewer capillaries per fiber area in oxidative skeletal muscle. These features are consistent with structural and functional remodeling of the determinants of oxygen supply potential and utilization that may contribute to exercise intolerance and reduced quality of life in patients with RV HF. bioenergetics; exercise; mitochondrial complex I; respirometry; monocrotaline AN INCREASE IN PULMONARY ARTERIAL pressure increases the loading on the right ventricle of the heart. If sustained, pulmonary arterial hypertension (PAH) results in right ventricular hypertrophy and ultimately to right ventricular heart failure (RV HF), the major cause of death in sufferers of PAH (5, 21). Mortality rates of patients with PAH and RV HF are very high: 20 to 40% in the first 3 years after diagnosis (5). PAH and HF are characterized by a reduced tolerance to muscular exercise despite new therapies (2,19,21,33). Interestingly, the reduction in the maximal oxygen uptake (V O 2max ) is a better predictor of mortality than the central hemodynamic deficit or other traditional risk factors (36). Consequently, correction of the central blood flow limitation by heart transplantation does not consistently resolve functional limitations in patients with HF (43), supporting the view that skeletal muscle remodeling plays an important role in exercise intolerance and mortality in many chronic disease states including PAH and RV HF (17,33,54).A common observation in patients with LV (32) and RV (33) HF is muscle atrophy and weakness, that contributes to a loss of power generating capacity. This may be accompanied by a shift in muscle fiber type expression away from fatigueresistant type I fibers, towards type II (33, 42, 44) and changes i...

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Section: Methodsmentioning

confidence: 99%

Regional skeletal muscle remodeling and mitochondrial dysfunction in right ventricular heart failure

Wüst¹,

Myers

Stones³

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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“…In those patients with demonstrable fibrosis in the right ventricle there is a poor outcome although there is no evidence to link this directly to arrhythmias [19]. Animal studies have also shown remodelling in the right ventricle with increased fibrosis, myocardial fibre disarray and alterations in the ion channels, connexins and calcium handling proteins critical for impulse generation and propagation [20].…”

Section: Reviewmentioning

confidence: 99%

Arrhythmias in pulmonary arterial hypertension

Temple¹

2017

J Congenit Heart Dis

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Pulmonary arterial hypertension is a condition associated with raised right heart pressures and subsequent remodelling of the right atrium and ventricle with relative preservation of left heart function. There is a high incidence of arrhythmias including atrial fibrillation, atrial flutter and atrioventricular nodal re-entrant tachycardia. Despite recent advances in medical therapy for pulmonary arterial hypertension arrhythmias continue to have a high morbidity and mortality. Treatment includes medical therapy, cardioversion and catheter ablation.

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“…The progressive vasculopathy leads to intraluminal narrowing and obstruction of the resistance vasculature, leading to sustained increases in pulmonary vascular resistance and pulmonary arterial pressure. In an attempt to compensate for the increased afterload and wall stress, the right ventricle undergoes structural and electrical remodeling (Malenfant et al, 2013;Simon, 2013), creating proarrhythmic substrates and triggers for arrhythmias (Benoist et al, 2011(Benoist et al, , 2012Rocchetti et al, 2014). Although the extent of the vascular pathology in PAH can determine morbidity and mortality, RV dysfunction is now recognized as the key determinant of disease outcome (Voelkel et al, 2012;Archer et al, 2013;Rain et al, 2013Rain et al, , 2014.…”

Section: Introductionmentioning

confidence: 99%

Ranolazine Reduces Remodeling of the Right Ventricle and Provoked Arrhythmias in Rats with Pulmonary Hypertension

Liles

Hoyer

Oliver

et al. 2015

J Pharmacol Exp Ther

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Pulmonary arterial hypertension (PAH) is a progressive disease that often results in right ventricular (RV) failure and death. During disease progression, structural and electrical remodeling of the right ventricle impairs pump function, creates proarrhythmic substrates, and triggers for arrhythmias. Notably, RV failure and lethal arrhythmias are major contributors to cardiac death in patients with PAH that are not directly addressed by currently available therapies. Ranolazine (RAN) is an antianginal, antiischemic drug that has cardioprotective effects in experimental and clinical settings of left-sided heart dysfunction. RAN also has antiarrhythmic effects due to inhibition of the late sodium current in cardiomyocytes. We therefore hypothesized that RAN could reduce the maladaptive structural and electrical remodeling of the right ventricle and could prevent triggered ventricular arrhythmias in the monocrotaline rat model of PAH. Indeed, in both in vivo and ex vivo experimental settings, chronic RAN treatment reduced electrical heterogeneity (right ventricular-left ventricular action potential duration dispersion), shortened heart-rate corrected QT intervals in the right ventricle, and normalized RV dysfunction. Chronic RAN treatment also dose-dependently reduced ventricular hypertrophy, reduced circulating levels of B-type natriuretic peptide, and decreased the expression of fibrotic markers. In addition, the acute administration of RAN prevented isoproterenol-induced ventricular tachycardia/ventricular fibrillation and subsequent cardiovascular death in rats with established PAH. These results support the notion that RAN can improve the electrical and functional properties of the right ventricle, highlighting its potential benefits in the setting of RV impairment.

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Arrhythmogenic substrate in hearts of rats with monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy

Cited by 67 publications

References 40 publications

Regional skeletal muscle remodeling and mitochondrial dysfunction in right ventricular heart failure

Regional skeletal muscle remodeling and mitochondrial dysfunction in right ventricular heart failure

Arrhythmias in pulmonary arterial hypertension

Ranolazine Reduces Remodeling of the Right Ventricle and Provoked Arrhythmias in Rats with Pulmonary Hypertension

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