Patients with long QT syndrome (LQTS) who harbor multiple mutations (i.e. ≥ 2 mutations in ≥ 1 LQTS-susceptibility gene) may experience increased risk for life-threatening cardiac events.
The present ...study was designed to compare the clinical course of LQTS patients with multiple mutations to those with a single mutation.
The risk for life-threatening cardiac events (comprising aborted cardiac arrest, implantable defibrillator shock, or sudden cardiac death) from birth through age 40 years, by the presence of multiple vs. single mutations, was assessed among 403 patients from the LQTS Registry.
Patients with multiple mutations (n=57) exhibited a longer QTc at enrollment compared with those with a single mutation (mean ± SD: 506 ± 72 vs. 480 ± 56 msec, respectively; P=0.003) and had a higher rate of life threatening cardiac events during follow-up (23% vs. 11%, respectively; p=0.031). Consistently, multivariate analysis demonstrated that patients with multiple mutations had a 2.3-fold (P=0.015) increased risk for life threatening cardiac events as compared to patients with a single mutation. The presence of multiple mutations in a single LQTS gene was associated with a 3.2-fold increased risk for life threatening cardiac events (P=0.010) whereas the risk associated with multiple mutation status involving >1 LQTS gene was not significantly different from the risk associated with a single mutation (HR 1.7, P=0.26).
LQTS patients with multiple mutations have a greater risk for life-threatening cardiac events as compared to patients with a single mutation.
There are limited data regarding the effect of age on the risk of ventricular tachyarrhythmias (VTAs). The present study was designed to compare the risk for VTAs in young and older patients with ...left bundle branch block (LBBB) and mildly symptomatic heart failure who receive device therapy. The risk of the first ventricular tachycardia (VT) or ventricular fibrillation (VF) event and the risk of first appropriate implantable cardioverter defibrillator (ICD) shock was compared between young (<75 years, n = 1,037) and older (≥75 years, n = 227) patients with LBBB enrolled in Multicenter Automatic Implantation Trial with Cardiac Resynchronization Therapy. The cumulative incidence of a first VTA through 2 years of follow-up was significantly lower in older patients than in younger patients. Multivariate analysis showed that older patients experienced a significantly lower risk of VT/VF (hazard ratio 0.38, 95% confidence interval 0.22 to 0.64, p <0.001) and a significantly lower risk of appropriate ICD shocks (hazard ratio 0.37, 95% confidence interval 0.17 to 0.82, p = 0.014) compared with younger patients. Each increasing decade of life was associated with a 19% (p = 0.002) and 22% (p = 0.018) reduction in the risk of VT/VF and appropriate ICD shocks, respectively. The lower risk of VT/VF and appropriate ICD shocks in older patients was evident in patients implanted with an ICD only and in those implanted with a cardiac resynchronization therapy with defibrillator. In conclusion, in patients with LBBB and mild symptoms of heart failure, aging is associated with a significant decrease in the incidence of VT/VF and ICD shocks.
Abstract Background Data regarding cardiac resynchronization therapy (CRT) in patients with multiple comorbidities are limited. Objectives This study evaluated the association of multiple ...comorbidities with the benefits of CRT over implantable cardioverter-defibrillator (ICD) alone. Methods We examined 1,214 MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy) study patients with left bundle branch block (LBBB) and 0, 1, 2, or ≥3 comorbidities, including renal dysfunction, hypertension (HTN), diabetes, coronary artery disease, history of atrial arrhythmias, history of ventricular arrhythmias, current smoking, and cerebrovascular accident. In an adjusted analysis, we analyzed risk of heart failure (HF) events or death by comorbidity group in all patients and in patients with CRT with defibrillator (CRT-D) versus ICD. Then we examined percent change in left ventricular (LV) end-diastolic volume, LV end-systolic volume, LV ejection fraction, left atrial volume, and LV dyssynchrony at 1-year in CRT-D patients by comorbidity group. Results There was an inverse relationship between comorbidity burden and improvements in LV end-systolic volume, LV end-diastolic volume, left ventricular ejection fraction, left atrial volume, and LV dyssynchrony. In an adjusted model, there was an increasing risk of death or nonfatal HF events with increasing comorbidity burden regardless of treatment group (p < 0.001). During a mean follow-up of 4.65 years, there was no interaction with respect to comorbidity burden and the benefit of CRT-D versus ICD only for death or nonfatal HF events (interaction p = 0.943). In the groups with greatest comorbidity burden (2 and ≥3), the absolute risk reduction associated with CRT-D over ICD alone appeared greater than that seen for groups with less comorbidity burden (0 and 1). Conclusions During long-term follow-up of MADIT-CRT study patients with LBBB randomized to CRT-D, there were differences in HF or death risk and in the degree of reverse remodeling among comorbidity groups. However, the burden of comorbidity does not appear to compromise the clinical benefits of CRT-D compared with ICD alone.
There is limited data regarding the relationship between age and inappropriate therapy among patients with an implantable cardioverter-defibrillator (ICD) and resynchronization therapy.
We aimed to ...investigate this relationship and the effect of ICD programming on inappropriate therapy by age.
In the Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy (MADIT-RIT) 1500 patients were randomized to 3 ICD programming arms: (A) conventional with ventricular tachycardia (VT) therapy ≥170; (B) high-rate cutoff with VT therapy ≥200, and (C) prolonged 60-second delay for VT therapy ≥170. We investigated the relationship between age, the risk of inappropriate ICD therapy (including antitachycardia pacing ATP or shock), and ICD programming.
Cumulative incidence function Kaplan-Meier graphs showed an inverse relationship between increasing quartiles of age (Q1: ≤55, Q2: 56-64, Q3: 65-71, and Q4: ≥72 years) and the risk for inappropriate therapy. Multivariate analyses showed that each increasing decade of life was associated with 34% (P < .001), 27% (P < .001), and 26% (P < .001) reduction in the risk of inappropriate shock, inappropriate ATP, and any inappropriate therapy, respectively. Treatment arms B and C as compared with arm A were associated with a significant reduction in the risk of inappropriate therapies across all age quartiles (P < .001 for all).
Among patients with a primary prevention indication for an ICD, there is an inverse relationship between age and inappropriate ICD therapy. Innovative ICD programming of high-rate cutoff or prolonged delay for VT therapy is associated with significant reductions in inappropriate therapy among all age groups.
In long QT syndrome type 1 (LQT1), the location and type of mutations have been shown to affect the clinical outcome. Although haploinsufficiency, including stop-codon and frameshift mutations, has ...been associated with a lower risk of cardiac events in patients with LQT1, nonsense mutations have been presumed functionally equivalent.
The purpose of this study was to evaluate clinical differences between patients with nonsense mutations.
The study sample comprised 1090 patients with genetically confirmed mutations. Patients were categorized into 5 groups, depending on mutation type and location: missense not located in the high-risk cytoplasmic loop (c-loop) (n = 698), which is used as reference; missense c-loop (n = 192); stop-codon (n = 67); frameshift (n = 39); and others (n = 94). The primary outcome was a composite end point of syncope, aborted cardiac arrest, and long QT syndrome-related death (cardiac events). Outcomes were evaluated using the multivariate Cox proportional hazards regression analysis. Standard patch clamp techniques were used.
Compared to patients with missense non-c-loop mutations, the risk of cardiac events was reduced significantly in patients with stop-codon mutations (hazard ratio HR 0.57; 95% confidence interval CI 0.34-0.96; P = .035), but not in patients with frameshift mutations (HR 1.01; 95% CI 0.58-1.77; P = .97). Our data suggest that currents of the most common stop-codon mutant channel (Q530X) were larger than those of haploinsufficient channels (wild type: 42 ± 6 pA/pF, n = 20; Q530X+wild type: 79 ± 14 pA/pF, n = 20; P < .05) and voltage dependence of activation was altered.
Stop-codon mutations are associated with a lower risk of cardiac events in patients with LQT1, while frameshift mutations are associated with the same risk as the majority of the missense mutations. Our data indicate functional differences between these previously considered equivalent mutation subtypes.
Abnormal heart rate turbulence (HRT) has been documented as a strong predictor of total mortality and sudden death in postinfarction patients, but data in patients with congestive heart failure (CHF) ...are limited.
The aim of this study was to evaluate the prognostic significance of HRT for predicting mortality in CHF patients in New York Heart Association (NYHA) class II-III.
In 651 CHF patients with sinus rhythm enrolled into the MUSIC (Muerte Subita en Insuficiencia Cardiaca) study, the standard HRT parameters turbulence onset (TO) and slope (TS), as well as HRT categories, were assessed for predicting total mortality and sudden death.
HRT was analyzable in 607 patients, mean age 63 years (434 male), 50% of ischemic etiology. During a median follow up of 44 months, 129 patients died, 52 from sudden death. Abnormal TS and HRT category 2 (HRT2) were independently associated with increased all-cause mortality (HR: 2.10, CI: 1.41 to 3.12, P <.001 and HR: 2.52, CI: 1.56 to 4.05, P <.001; respectively), sudden death (HR: 2.25, CI: 1.13 to 4.46, P = .021 for HRT2), and death due to heart failure progression (HR: 4.11, CI: 1.84 to 9.19, P <.001 for HRT2) after adjustment for clinical covariates in multivariate analysis. The prognostic value of TS for predicting total mortality was similar in various groups dichotomized by age, gender, NYHA class, left ventricular ejection fraction, and CHF etiology. TS was found to be predictive for total mortality only in patients with QRS > 120 ms.
HRT is a potent risk predictor for both heart failure and arrhythmic death in patients with class II and III CHF.
Previous studies suggested that statin therapy reduces the risk of occurrence and recurrence of atrial fibrillation mainly in patients with coronary artery disease. Data regarding the effect of ...statins on the risk for the entire range of supraventricular arrhythmias (SVA) in mild heart failure (HF) with different disease causes are lacking. Multivariate Cox proportional hazards regression models were used to assess the effect of statin therapy, evaluated as a time-dependent covariate, on the risk of SVA and recurrent SVA (defined as atrial fibrillation, atrial flutter, atrial tachycardia, and supraventricular tachycardia) that were inappropriately treated with implantable cardioverter-defibrillator device in 1,790 patients enrolled in the Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy trial. Statin users constituted 68% of the study patients (n = 1209). They were older and more frequently men; they were more likely to have ischemic cardiomyopathy, diabetes, hypertension, and previous atrial arrhythmias. During the 3.7-year median follow-up time, 160 patients had an SVA event, and the total number of recurrent events was 335. Time-dependent statin therapy was independently associated with a significant 29% reduction of the first SVA event (p = 0.046) and 33% reduction of recurrent SVA events (p = 0.003), consistent across all prespecified subgroups. In conclusion, in mild HF with either cardiac resynchronization therapy with a defibrillator or an implantable cardioverter-defibrillator device, statin therapy was associated with significant reduction of occurrence and recurrence of inappropriately treated SVA.
Diabetes mellitus (DM) modify outcome in patients with heart failure (HF). We aimed to analyze the risk for death, HF alone, combined end point HF/death, and ventricular tachycardia/ventricular ...fibrillation (VT/VF) in patients with mild HF without DM and in those with DM, further stratified by the presence of insulin treatment. We determined whether cardiac resynchronization therapy with defibrillator (CRT-D) versus implantable cardioverter defibrillator improves clinical outcomes in these 3 subgroups. Cox proportional hazards regression models were used to analyze 1,278 patients with left bundle branch block in the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy trial. Treatment with CRT-D versus implantable cardioverter defibrillator was associated with 76% risk reduction in all-cause mortality (hazard ratio 0.24; 95% confidence interval 0.08 to 0.74, p = 0.012) in subgroup of diabetic patients treated with insulin only (interaction p = 0.043). Significant risk reduction in HF alone, HF/death, and the VT/VF after CRT-D was observed across investigated groups and similar left ventricular reverse remodeling to CRT-D. In conclusion, patients with mild HF with DM treated with insulin derive significant risk reduction in mortality, in HF, and VT/VF after implantation of CRT-D. Diabetic patients not receiving insulin benefit from CRT-D by reduction of HF events.
There are limited data on the significance of left ventricular (LV) lead pacing polarity to predict clinical outcomes.
We aimed to determine the association between the LV lead pacing polarity for ...heart failure (HF) or death and ventricular tachyarrhythmias (VTA) in patients enrolled in MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy), receiving a cardiac resynchronization therapy device with implanted cardioverter-defibrillator (CRT-D).
We retrospectively analyzed LV pacing polarity. Patients with LV bipolar leads paced between LV ring and LV tip were identified as True Bipolar, while those with LV bipolar leads paced between LV tip or LV ring and right ventricular coil or unipolar leads were identified as Unipolar/Extended Bipolar. Kaplan-Meier survival analyses and multivariate Cox proportional hazards regression models were used.
Of the 969 patients, 421 had True Bipolar pacing while the remainder (n = 548) had Unipolar/Extended Bipolar pacing. Among patients with left bundle branch block (LBBB), True Bipolar pacing was associated with lower cumulative incidence of death (P = .022) and HF/death (P = .046) compared to those with Unipolar/Extended Bipolar LV pacing. After adjustment for clinical covariates, bipolar LV pacing in LBBB patients was associated with 54% lower risk for death (HR: 0.46; 95% CI: 0.24-0.88; P = .020) and 32% lower risk for HF/death (HR: 0.68; 95% CI: 0.46-1.00; P = .048) compared to Unipolar/Extended Bipolar LV pacing, but not in those with non-LBBB. No association was seen with risk of ventricular tachyarrhythmia.
True Bipolar LV pacing configuration is associated with a significantly lower risk of HF/death and all-cause mortality in CRT-D patients with LBBB.
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