The relation of ventricular arrhythmia electrophysiological characteristics to cardiac phenotype and circadian patterns in hypertrophic cardiomyopathy.

BACKGROUND: The triggers of ventricular arrhythmias (VAs) leading to sudden cardiac death in hypertrophic cardiomyopathy (HCM) are ill defined. We sought to examine the electrophysiological characteristics of VAs in HCM and study their relation to cardiac phenotype and circadian patterns using stored intracardiac electrocardiograms from implantable cardioverter defibrillators (ICDs). METHODS AND RESULTS: A single centre, observational cohort study of 230 consecutively evaluated ICD recipients with HCM [median age 42 years, 97% primary prevention, 51% with anti-tachycardia pacing (ATP)]. Fifty-six non-clustered VAs (39 initially treated with ATP and 17 with shocks) from 29 patients were analysed. Monomorphic ventricular tachycardia was the culprit arrhythmia in 86% of cases, ventricular fibrillation/flutter in 9%, and polymorphic ventricular tachycardia in 5%. Prior to the onset of VA the rhythm was sinus in 67%, atrial fibrillation/flutter in 19%, and 15% were paced ventricularly; tachycardia (cycle length <600 ms) was present in 25%. Ventricular arrhythmias were triggered by premature ventricular complexes (PVCs) in 72%, which were late-coupled (84%). Short-long-short initiation was seen in 2% and 26% of VAs were sudden-onset without preceding PVCs. Ventricular arrhythmia peaked at midday (with 20% occurring between 2300 and 0700), on Sundays and in May. The cardiac phenotype and time of the day did not predict the mode of initiation. Age at ICD implantation was the only independent predictor of VA cycle length (linear regression coefficient 0.67, 95% CI 0.02-1.32, P= 0.04). Anti-tachycardia pacing terminated 67% of VAs, but patients with ATP therapy had a similar incidence of appropriate shocks (log-rank test P= 0.25) and syncope (log rank P= 0.23) to patients with shock as initial therapy. CONCLUSIONS: Most VAs are monomorphic ventricular tachycardias triggered by late-coupled PVCs. They are frequently terminated by ATP, but ATP does not reduce the frequency of ICD shocks. Younger HCM patients have more rapid VAs, which may explain the peak of sudden cardiac death in early adulthood. The circadian periodicity is different from that observed in ischaemic heart disease, and is likely to relate to the distinct character of the arrhythmogenic substrate in HCM and its modulators.

The long-term survival and the risks and benefits of implantable cardioverter defibrillators in patients with hypertrophic cardiomyopathy.

OBJECTIVE: Implantable cardioverter defibrillators (ICDs) are routinely used to prevent sudden cardiac death (SCD) in selected hypertrophic cardiomyopathy (HCM) patients, but the determinants of device-related complications, therapies and long-term cardiovascular mortality in ICD recipients are not known. DESIGN: Retrospective observational cohort study. SETTING: Single-centre tertiary referral cardiomyopathy clinic. Patients 334 consecutively evaluated HCM patients (median age 40 years, 62% male, 92% primary prevention) at risk of SCD treated with ICD. Thirty-six patients (11%) received concurrent cardiac resynchronisation therapy for heart failure symptoms. RESULTS: During the 1286 patient-years of follow-up, cardiovascular mortality (including transplantation) occurred in 22 (7%) patients (1.7%/year) and was associated with New York Heart Association (NYHA) class III/IV (adjusted HR=9.38, 95% CI 3.31 to 26.55, p≤0.001), percentage fractional shortening (HR=0.92, 95% CI 0.87 to 0.96, p=0.001) and implantation for secondary prevention (HR=0.07, 95% CI 0.01 to 0.86, p=0.04). There were no SCD. Twenty-eight (8%) patients received appropriate shocks (2.3%/year), which were predicted by baseline fractional shortening (HR=0.96, 95% CI 0.92 to 0.99, p=0.04). Fifty-five (16%) patients received inappropriate shocks (4.6%/year). Sixty (18%) patients experienced implant-related complications (5.1%/year), including two deaths. Adverse ICD-related events (inappropriate shocks and/or implant complications) were seen in 101 (30%) patients (8.6%/year). Patients with cardiac resynchronisation therapy were more likely to develop implant complications than those with single-chamber ICDs (HR=4.39, 95% CI 1.44 to 13.35, p=0.009) and had a higher 5-year cardiovascular mortality than did the rest of the cohort (21% vs 6%, p<0.001). CONCLUSIONS: HCM patients with an ICD have a significant cardiovascular mortality and are exposed to frequent inappropriate shocks and implant complications. These data suggest that new strategies are required to improve patient selection for ICDs and to prevent disease progression in those that receive a device.

Acute administration of vitamin C abrogates protection from ischemic preconditioning in rabbits.

Vitamin C is considered to be an antioxidant agent that is broadly used. Free radicals are involved in the protective mechanism of preconditioning (PC), but some antioxidant compounds abolish this benefit. The aim of the present study was to evaluate the effect of vitamin C on the protective effect of PC with respect to infarct size and oxidative stress in anesthetized rabbits. Male rabbits were randomly divided into six groups and subjected to 30 min of myocardial ischemia and 3h of reperfusion with the following interventions per group: (1) Control (no intervention), (2) Vit C 150 group (i.v. vitamin C at a total dose of 150 mg/kg for 75 min, starting 40 min before the onset of long ischemia and lasting up to the 5th min of reperfusion), (3) Vit C 300 group (i.v. vitamin C at a total dose of 300 mg/kg as previously described), (4) PC group (two cycles of 5 min ischemia and 10 min reperfusion), (5) combined PC-Vit C 150 group and (6) combined PC-Vit C 300 group. Blood samples were taken at different time points for malondialdehyde (MDA) assessment as a lipid peroxidation marker and for superoxide dismutase (SOD) activity. At the end of the experiment the infarct size was determined. Vitamin C, at both doses, did not reduce the infarct size (35.5+/-4.1%, 38.3+/-7.0% vs. 44.9+/-3.3% in the control group) and diminished the protection afforded by PC (32.0+/-2.7%, 43.8+/-3.3% vs. 15.7+/-2.9% in the PC group, P<0.05). At reperfusion there was an elevation of circulating MDA levels in the control and PC groups while in both vitamin C groups the levels were decreased. SOD activity was enhanced in the PC group compared to the controls; vitamin C did not change SOD activity during ischemia-reperfusion. Vitamin C abrogates the beneficial effect of ischemic PC on infarct size and elicits antioxidant properties during ischemia-reperfusion.

Acute administration of vitamin E triggers preconditioning via K(ATP) channels and cyclic-GMP without inhibiting lipid peroxidation.

Vitamin E (VitE) is considered an antioxidant agent. One or more brief periods of ischemia (isc), followed by short reperfusion (rep), increase the tolerance of the heart to a subsequent prolonged ischemia, a phenomenon known as ischemic preconditioning (PC). Mitochondrial KATP channels (mitoKATP), cyclic-GMP (cGMP), and free radicals are involved in the mechanism of PC, whereas some antioxidants abolish this benefit. The purpose of this study was to evaluate the effect of VitE on infarct size, PC, and the oxidative status in vivo. Male rabbits were divided into seven groups and were subjected to myocardial ischemia (isc) and reperfusion (rep) with the following interventions: (1) control (no intervention); (2) E150 (iv VitE at a dose of 150 mg/kg for 75 min, starting 40 min before index isc and lasting through 5 min of rep); (3) E300 (iv VitE 300 mg/kg as previously described); (4) PC (two cycles of 5 min isc and 10 min rep), (5) combined E150-PC; and (6) combined E300-PC. In the last two groups VitE was given 40 min before index ischemia. Blood samples were taken for malondialdehyde (MDA) and conjugated dienes (CDs) measurement. In a second series of experiments heart tissue samples were taken at the time of long ischemia for MDA and CD determination and for cGMP assay. In order to test whether combined treatment with VitE (as the E150 group) and the mitoKATP blocker 5-hydroxydecanoic acid (5-HD) changes the infarct size, an additional group was assessed in the first series of experiments. Tissue VitE concentration was evaluated in myocardium. VitE at both doses reduced the infarct size (19.7 +/- 2.8% for E150 and 18.8 +/- 4.9% for E300 vs 47.4 +/- 2.6% in control, P < 0.05) without attenuating the effect of PC (10.2 +/- 3.1% for E150-PC, 12.4 +/- 2.2% for E300-PC, vs 13.5 +/- 3.3% for PC). Combined VitE and 5-HD treatment abrogates this benefit (37.4 +/- 6.5%, P < 0.05 vs E150 and NS vs control). VitE increases intracellular cGMP and CDs levels (P < 0.05 vs control) to the same extent as PC (P < 0.05 vs control), with no effect on MDA (P = NS between all the groups). Peripheral markers of oxidative stress are increased during reperfusion in all groups (P < 0.05 vs baseline). Overall, VitE limits infarct size via mitoKATP and cGMP, while preserving the benefit of ischemic PC.