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Comparative Study
, 5 (1), 181-90

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

Affiliations
Comparative Study

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

Soban Umar et al. Circ Arrhythm Electrophysiol.

Abstract

Background: Right ventricular failure (RVF) in pulmonary hypertension (PH) is associated with increased incidence of sudden death by a poorly explored mechanism. 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 (control, n=17). Activation pattern of the 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 approximately day 30. Rats manifested increased mortality, and ≈30% rats died suddenly and precipitously during 23-32 days after 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 reentrant wave fronts. Microelectrode recordings from the RV-epicardium at the onset of focal activity showed early afterdepolarization-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 left ventricular 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 control 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 early afterdepolarization-mediated triggered activity.

Conflict of interest statement

Conflict of Interest Disclosures: None

Figures

Figure 1
Figure 1
Cardiac hemodynamics and mortality in rats with PH. Panel A shows echocardiographic images of B-mode (left panel), M-mode of heart (middle panel), and pulsed-wave Doppler of pulmonary artery (PA) flow (right panel) where EDD is RV end-diastolic diameter. Arrows in the pulsed-wave Doppler signals show mid-systolic notch in the pulmonary artery flow in PH (n=7 for CTRL and n=6 for PH). Panels B shows Hematoxylin-eosin staining of heart cross-sections of CTRL and PH (n=7 for CTRL and n=6 for PH). Panel C shows combined time-course of mortality (including sudden unexpected deaths, black squares) and RVEF (black circles) in the PH group (n=24).
Figure 2
Figure 2
Cardiac structural changes associated with PH-induced RV-failure. A. RV, LV and IVS sections stained with wheat germ agglutinin (red) in CTRL and PH hearts. B. Myocyte cross sectional diameter (CSD) of RV, LV and IVS comparing CTRL and PH groups. ***p<0.001 vs. CTRL. (n=3 rats per group and at least 60 cells per group). C. Masson trichrome staining of RV and LV-sections in CTRL and PH; blue color indicates fibrosis. Quantification of RV and LV-endocardial and epicardial fibrosis (%) is shown in the right panels. **p<0.01 vs. CTRL (n=3 rats per group). D. Representative immunoblots of RV and LV from CTRL and PH labelled with anti-caspase-3 and anti-vinculin antibodies. Mean levels of cleaved caspase-3 protein normalized to vinculin in CTRL (black bar) and PH (red) are shown at the right (**p<0.01 vs. CTRL, n=4–7 rats per group)
Figure 3
Figure 3
Emergence of RV epicardial EADs, triggered activity and VF in a heart isolated 29 days after MCT injection. In each panel the recordings from top to bottom are: pseudo-ECG, LV and left atrial bipolar electrograms (LV Beg and LA Beg), and the bottom tracing is single cell microelectrode recording from the RV epicardial base. Panel A shows the emergence of an EAD on two consecutive sinus beats (two downward arrows) 28 min after mounting the heart with regular sinus rhythm (SR) at a mean cycle length of 254±18 ms. The EAD associated with the third sinus beat triggers an action potential at a coupling interval of 85 ms (upward arrow) causing a premature ventricular depolarization (PVD) on the pseudo-ECG (arrow). Notice that the emergence of RV epicardial cell EAD is associated with isoelectric interval of the LA Beg, LV Beg and pseudo-ECG recordings indicating absence of electrical activity elsewhere in the heart during the emergence of EADs in the RV. Panel B shows recordings 29 min after tissue mounting (1 min after panel A) with the third sinus beat associated with EAD-mediated triggered activity (upward arrow) causing non-sustained ventricular tachycardia (NSVT) (arrow on pseudo-ECG). Panel C shows recordings made 2 min after panel B showing EAD-mediated triggered activity to cause VT (~18 beats) which then degenerates to irregular pattern signalling the onset of VF. The VF was then terminated by electrical shock (not shown). Panel D shows magnified view of part of the lower 2 recordings of A.
Figure 4
Figure 4
Optical snap shots, isochronal maps and optical action potentials recorded from the RV epicardium in a heart 29 days after MCT injection. Panel A (left) are snapshots during RV pacing from the base at a cycle length of 200 ms and during sinus rhythm (right 3 snap shots) showing total RV epicardial activation within 10 ms. Asterisk at the base of the RV is the pacing site (downward white arrow indicates the direction of propagation) Notice the absence of conduction block during pacing and during sinus rhythm. Time zero is chosen arbitrarily for both pacing and sinus rhythm snapshots. Panel B is a schematic drawing of optical action potential (OAP) with blue denoting repolarization and red depolarization. Panel C are isochronal maps during pacing (left) and during sinus rhythm (right) of the corresponding snap shots shown in panel A. Arrows in panel C indicate the direction of wavefront propagation. Panel D shows simultaneous 8 OAPs recorded from equally spaced sites (1 to 8) identified in panel C (black arrow). Downward pointing red arrow indicates the direction of wavefront propagation during RV pacing from the base and upward pointing red arrow indicates sinus beats. The lower 4 panels in panel D are simultaneous recordings of pseudo-ECG, left ventricular and atrial bipolar electrograms (LV Beg and LA Beg, respectively) and pacing stimulus artefact (bottom tracing). Six paced beats at a cycle length of 200 ms are followed by five beats of sinus origin with a cycle length of ~310 ms.
Figure 5
Figure 5
Optical imaging during spontaneous VF in a heart isolated 29 days after MCT injection. Open stars indicate the two foci, white arrows indicate propagation from foci and black arrows indicate propagation from existing waves. Panel A shows the pseudo-ECG of the onset of the spontaneous VF. The heart was imaged about 15 seconds after onset. The pECG of the imaged period is shown in the second part of the trace, after the 10s break. The red double arrow indicates the period shown in panel B. Panel B shows snap shots of activation during 144 ms of imaged time. The red dots in the first image indicate the locations of the OAPs shown in panel D. See panel D for the color scale of the snap shots in relation to the OAPs. Panel C shows the frequency map with two sample OAPs at the closed circle and square. Panel D shows OAPs highlighting the propagation from the foci 1 (OAPs a and b) and 2 (OAPs c, d and e) indicated in panel B. Panel E shows the phase (π) map of the 7 Hz activity. The activity continued and arrived at the apex beyond the end of the period (i.e., the foci had already fired the second time), so this late activity near the apex was unwrapped to the 2π complement for clarity.
Figure 6
Figure 6
APD prolongation and triggered activity in isolated RV cardiomyocytes. A. Bar graph showing mean action potential duration at 90% repolarization (APD90) in RV and LV cardiomyocytes from CTRL (white bar) and PH (black bar) (***p<0.001 vs. CTRL, n=16–20 cells for RV and n=5 cells for LV from 5 rats/group). B. Bar graphs showing rate of depolarizing current-induced triggered activity (TA) (per second) in RV and LV cardiomyocytes from CTRL (white bar) and PH (black bar) (**p<0.01 vs. CTRL n=5 cells from 5 rats/group). C. Depolarizing current-induced triggered activity in isolated RV-cardiomyocytes from CTRL and PH.
Figure 7
Figure 7
Alteration of Kv1.5 and KCNE2 expression in PH. A. Relative transcript levels of Kv1.5 and Kv 2.1 in CTRL (white bar), and PH (black bar) normalized to CTRL are shown (*p<0.05 vs. CTRL, n=3–4/group). B. Representative immunoblots of RV and LV (left panel) from CTRL and PH labelled with anti-Kv1.5 and anti-GAPDH antibodies. Mean protein levels of Kv1.5 protein (right panel) normalized to GAPDH in CTRL (white bar) and PH (black) are shown (*p<0.05 vs. CTRL, n=3–4/group). C. Immunofluorescence images of isolated RV and LV cardiomyocytes stained for Kv1.5 are shown from CTRL and PH. D. Representative immunoblots of RV and LV (left panel) from CTRL and PH labelled with anti-KCNE2 and anti-GAPDH antibodies. Mean protein levels of KCNE2 normalized to GAPDH (right panel) in CTRL (white bar) and PH (black) are shown. (*p<0.05 vs. CTRL, n=3–4/group). E. Immunofluorescence images of isolated cardiomyocytes stained for KCNE2 are shown from CTRL and PH of RV (left panel) and LV (right panel).

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