Spontaneous Ventricular Fibrillation in Right Ventricular Failure Secondary to Chronic Pulmonary Hypertension

Abstract

Background Right ventricular failure (RVF) in pulmonary hypertension (PH) is associated with increased incidence of sudden death by a poorly explored mechanism. Here we test the hypothesis that PH promotes spontaneous ventricular fibrillation (VF) during a critical post-PH onset period characterized by a sudden increase in mortality. Methods and Results Rats received either a single subcutaneous dose of monocrotaline (MCT, 60 mg/kg) to induce PH-associated RVF (PH, n=24) or saline (CTRL, n=17). Activation pattern of RV-epicardial surface was mapped using voltage-sensitive dye in isolated Langendorff-perfused hearts along with single glass-microelectrode and ECG-recordings. MCT-injected rats developed severe PH by day-21 and progressed to RVF by ~day-30. Rats manifested increased mortality and ~30% rats died suddenly and precipitously during 23–32 days post-MCT. This fatal period was associated with the initiation of spontaneous VF by a focal mechanism in the RV which was subsequently maintained by both focal and incomplete re-entrant wavefronts. Microelectrode recordings from the RV-epicardium at the onset of focal activity showed early afterdepolarization (EAD)-mediated triggered activity that led to VF. The onset of the RV cellular triggered beats preceded left ventricular depolarizations by 23±8 ms. The RV but not the LV cardiomyocytes isolated during this fatal period manifested significant action potential duration prolongation, dispersion and an increased susceptibility to depolarization-induced repetitive activity. No spontaneous VF was observed in any of the CTRL hearts. RVF was associated with significantly reduced RV ejection fraction (p<0.001), RV hypertrophy (p<0.001) and RV fibrosis (p<0.01). The hemodynamic function of the LV and its structure were preserved. Conclusions PH-induced RVF is associated with a distinct phase of increased mortality characterized by spontaneous VF arising from the RV by an EAD-mediated triggered activity.

Transmural dispersion of repolarization and cardiac remodeling in ventricles of rabbit with right ventricular hypertrophy

“…predominantly in RVH rabbits (Panyasing et al, 2010). It has been demonstrated previously that electrical remodeling especially in the right ventricle is the proximate cause of arrhythmias (Benoist, Stones, Drinkhill, Bernus, & White, 2011;Tanaka, Takase, & Yao, 2013;Umar et al, 2012). In the current study, both prolongation of repolarization and increased transmural dispersion of repolarization were observed in rabbits with RVH suggesting the tendency to increase arrhythmogenic risk in PAB rabbits.…”

“…Previous studies demonstrated that right ventricular failure following pulmonary hypertension and right ventricular hypertrophy is associated with increased incidence of cardiac sudden death; however, the underlying mechanism is unclear (Umar et al, 2012). Therefore, there is a need for an animal model of right ventricular hypertrophy.…”

“…Recently, Humbert, Sitbon, and Chaouat (2010) reported that the overall mortality rate of patients with RVH due to PAH was 30-50% in which 17-28% of that mortality rate was sudden cardiac death. The major cause of the sudden cardiac death may result from spontaneous ventricular fibrillation (Umar et al, 2012). This arrhythmia has been demonstrated to associate with electrical and structural remodeling of the right ventricle (Lee, Kodoma, Anno, Kamiya, & Toyama, 1997;Umar et al, 2012).…”

“…The major cause of the sudden cardiac death may result from spontaneous ventricular fibrillation (Umar et al, 2012). This arrhythmia has been demonstrated to associate with electrical and structural remodeling of the right ventricle (Lee, Kodoma, Anno, Kamiya, & Toyama, 1997;Umar et al, 2012).…”

Stem and Progenitor Cell Therapy for Pulmonary Arterial Hypertension: Effects on the Right Ventricle (2013 Grover Conference Series)

“…The LVs of these hearts did not develop fibrosis. 33 Yen et al 34 found that 3 weeks after MCT injection, the rats suffered from RV fibrosis, had high expression of fibrotic biomarkers (transforming growth factor β [TGFβ], p-SMAD3) in the RV, and low expression of antifibrotic biomarkers (bone morphogenetic protein 2 [BMP2], p-SMAD1/5). Treatment with a combination of sildenafil and bone marrow-derived EPCs was able to reverse these changes to levels almost equal to those of healthy rats, and this combination was more potent than either of the two therapies alone.…”