Abstract 206: Mechanisms of Sudden Death in Right Heart Failure Caused by Chronic Pulmonary Arterial Hypertension
Introduction: Right heart failure (RHF) in pulmonary arterial hypertension (PAH) is associated with increased incidence of sudden death by a mechanism that remains poorly explored. We hypothesized that RHF promotes dispersion of repolarization (DR) and triggered activity (TA) leading to mixed focal and reentrant ventricular fibrillation (VF).
Methods: Chronic PAH-associated RHF was induced in rats by single s.c. injection of 60 mg/kg monocrotaline (N=24) and compared to saline treated (Control) rats (N=13). At the end of the 4th week, the hearts were studied in either isolated-perfused Langendorff or in isolated myocyte patch-clamp setting. RV epicardial activation pattern was optically mapped using fluorescent voltage-sensitive dye (RH 237). SERCA-2a was determined by Western Blot and tissue fibrosis assessed by Masson trichrome staining.
Results: At the end of the 4th week, 10 RHF rats (40%) died suddenly but none in the Control. On optical mapping, RHF hearts (N=4) manifested spontaneous VF during normal Tyrode's perfusion with wavefronts that had the characteristics of both focal and reentrant multiple wavelet patterns. No VF was initiated in any of the control hearts (N=5). Isolated myocytes from RHF showed significantly greater DR (30 ms vs. 20 ms) as assessed by the gradient of max-min action potential duration (APD) and had their mean APD 90 percent repolarization increased from 33±6 ms to 57±8 ms (P<0.05). Long duration (2000 ms) depolarizing current pulses promoted TA in the RHF that had faster frequency than in Control (4.2±0.37 vs. 2.5±0.28 per pulse, P<0.05) with higher peak amplitudes (65.2±4.7 mV vs. 45±3.5 mV, P<0.05). Western Blot showed a significant reduction (∼15 fold) in SERCA-2a protein levels in RHF (0.06±0.01) vs. Control (1±0.26). RHF showed mild to moderate RV fibrosis and echocardiography showed significant reduction in RV ejection fraction (RVEF) from 65±1 to 33±3% with normal non-fibrotic LV structure and normal LVEF.
Conclusions: RHF manifests increased RV fibrosis and greater susceptibility to VF by multiple interacting mechanisms involving increased TA and DR, prolonged APD and altered calcium cycling (i.e., reduced SERCA-2a) and reduced RVEF promoting spontaneous VF by mixed focal and reentrant mechanisms.
- © 2010 by American Heart Association, Inc.