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Background: Left ventricular thrombus formation is a complication of acute myocardial infarction. However, the incidence and risk of systemic thromboembolism in the era of primary angioplasty for ST elevation myocardial infarction (STEMI) is unclear. This study aims to determine clinical outcomes in patients with STEMI treated with primary angioplasty and left ventricular thrombus at 1 year., Methods: Patients who underwent primary angioplasty for STEMI and had a transthoracic echocardiogram were recruited. The primary endpoint was a composite of all-cause mortality, stroke, and systemic thromboembolism at 1 year. For the primary endpoint, the difference between the presence and absence of left ventricular thrombus was compared using a logistic regression, adjusting for minimization variables including age, diabetes mellitus, hypertension, and previous stroke., Results: Of 2608 patients who underwent primary angioplasty for STEMI, 1645 (63%) patients had a transthoracic echocardiogram performed during the index hospital admission. Forty patients (2.4%) had evidence of left ventricular thrombus on transthoracic echocardiography. Patients with left ventricular thrombus were more likely to develop atrial fibrillation in the immediate postinfarction period (6 [15%] vs 87 [5.4%], P = 0.025). At 1 year, the primary endpoint occurred in 4 (10%) patients with left ventricular thrombus and 146 (9.1%) who did not (logistic regression hazard ratio 0.79, 95% confidence interval 0.23-2.70)., Conclusions: In the contemporary era of mechanical reperfusion for STEMI, echocardiographic detection of left ventricular thrombus was observed in <3% patients. The presence of left ventricular thrombus was not associated with an increased risk of systemic thromboembolism., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

We have previously shown a reduction in HF events with cardiac resynchronization therapy with defibrillator (CRT-D) in patients with mild heart failure (HF) and diabetes mellitus (DM). It remains unknown whether HF remission in DM patients with CRT-D translates into reduced mortality. The effects of CRT-D versus an implantable cardioverter-defibrillator (ICD) alone to reduce long-term mortality were assessed in patients with left bundle branch block with DM (n = 386) and without DM (n = 982), enrolled in the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT). We further subdivided DM patients by insulin and noninsulin therapy. Kaplan-Meier survival analyses and multivariate cox proportional hazards regression models were utilized. At the 7-year follow-up, CRT-D was associated with a lower mortality in DM patients compared with ICD alone (21% vs 42%, p = 0.02), similar to non-DM patients (16 vs 24%, p = 0.014). CRT-D was associated with a 41% reduction in the risk of long-term all-cause mortality in DM patients (hazard ratio [HR] 0.59, 95% confidence interval 0.36 to 0.96, p = 0.033) and a similar reduction in non-DM patients (HR 0.69, 95% confidence interval 0.48 to 0.99, p = 0.045, treatment-diabetes interaction p = 0.611). Among DM patients, mortality benefit was evident in insulin-treated patients only (HR 0.40, p = 0.030). Reductions in HF events were present in all groups. In the MADIT-CRT, patients with mild HF with DM derive significant long-term survival benefit from CRT-D, similar to those without DM. The mortality benefit from CRT-D within the DM subgroup seems to be confined to patients with insulin treated diabetes., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Rare, high-arousal negative emotions are known triggers of sudden death in individuals with preexisting heart disease. Whether everyday fluctuations in emotional arousal influence arrhythmia risk is unknown., Methods: We studied 160 patients with the congenital long QT syndrome, 199 patients with coronary artery disease, and 2 groups of matched healthy volunteers (n = 52 and 50, respectively). Three-day home visits including a 12-hour Holter recording each day were completed. Subjects engaged in typical daily activities and were paged 10 times per day. On each occasion, subjects rated the intensity of 16 different emotions during the 5 minutes preceding the page. Holter data over those 5-minute epochs were analyzed for heart rate and QT interval corrected for heart rate (QTc). Analyses focused on within-subject covariation of momentary emotion and QTc., Results: In patients with long QT syndrome, activated positive affect and activated negative affect were associated with QTc shortening, whereas low arousal positive affect (calm and relaxed) was associated with QTc lengthening, which at times exceeded 500 msec. Findings were not affected by beta-blocker status or observed in younger healthy subjects. Findings were 3 to 8 times stronger in the LQT2 genotype, known to be prone to emotion-induced events, relative to the LQT1 genotype. Findings in patients with long QT syndrome for activated positive affect and low arousal positive affect were replicated in patients with coronary artery disease relative to older healthy subjects., Conclusion: These findings suggest that even subtle changes in emotional arousal may alter repolarization reserve and contribute to sudden death risk in vulnerable individuals., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Patients with long QT syndrome (LQTS) are at a high risk of cardiac events. Many patients with LQTS are treated with antidepressant drugs (ADs). We investigated the LQTS genotype-specific risk of recurrent cardiac arrhythmic events (CAEs) associated with AD therapy. The study included 59 LQT1 and 72 LQT2 patients from the Rochester-based LQTS Registry with corrected QT (QT c ) prolongation and a history of AD therapy. Using multivariate Anderson-Gill models, we estimated the LQTS genotype-specific risk of recurrent CAEs (ventricular tachyarrhythmias, aborted cardiac arrest, or sudden cardiac death) associated with time-dependent ADs. Specifically, we examined the risk associated with all ADs, selective serotonin reuptake inhibitor (SSRI), and ADs classified on the CredibleMeds list (www.CredibleMeds.org) as "Conditional" or "Known risk of Torsades de pointes (TdP)." After adjusting for baseline QT c duration, sex, and time-dependent beta-blocker usage, there was an increased risk of recurrent CAEs associated with ADs in LQT1 patients (hazard ratio = 3.67, 95% confidence interval 1.98-6.82, p < 0.001) but not in LQT2 patients (hazard ratio = 0.89, 95% confidence interval 0.49-1.64, p = 0.716; LQT1 vs LQT2 interaction, p < 0.001). Similarly, LQT1 patients who were on SSRIs or ADs with "Known risk of TdP" had a higher risk of recurrent CAEs than those patients off all ADs, whereas there was no association in LQT2 patients. ADs with "Conditional risk of TdP" were not associated with the risk of recurrent CAEs in any of the groups. In conclusion, the risk of recurrent CAEs associated with time-dependent ADs is higher in LQT1 patients but not in LQT2 patients. Results suggest a LQTS genotype-specific effect of ADs on the risk of arrhythmic events., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Guidelines support cardiac resynchronization therapy with a defibrillator (CRT-D) in mild heart failure (HF) patients with left bundle branch block (LBBB). However, not all patients demonstrate echocardiographic or clinical response to CRT-D. We aimed to evaluate the long-term outcomes of echocardiographic hypo-responders and clinical hypo-responders to CRT-D with LBBB in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy. Five-hundred thirty-four patients with LBBB in the CRT-D arm were followed for 5.6 years (median). Clinical hypo-response was defined as HF event in the first year after CRT-D implantation. Echocardiographic hypo-response was defined as ≤35% reduction (median) in left ventricular end-systolic volume 1 year after CRT-D implantation without evidence of clinical hypo-response. Echocardiographic and clinical response was observed in 257 patients (48%). Two-hundred fifty patients (47%) were echocardiographic hypo-responders and 27 patients (5%) were clinical hypo-responders. Echocardiographic hypo-responders had increased risk of all-cause mortality compared with echocardiographic + clinical responders (hazard ratio [HR] 2.85, 95% confidence interval [CI]: 1.37 to 5.94, p = 0.005). Clinical hypo-responders had increased risk of mortality compared with echocardiographic + clinical responders (HR 7.49, 95% CI: 2.88 to 19.48, p <0.0001) and compared with echocardiographic hypo-responders (HR 2.63, 95% CI: 1.17 to 5.92, p = 0.020). In conclusion, during long-term follow-up, patients with mild HF and LBBB who have echocardiographic hypo-response to CRT, with or without clinical signs of worsening HF, have increased risk of mortality. This study emphasizes the prognostic significance of echocardiographic assessment of left ventricular volume after CRT implantation in LBBB patients with mild HF., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Cardiac-related clinical practice guidelines have become an integral part of the practice of cardiology. Unfortunately, these guidelines are often long, complex, and difficult for practicing cardiologists to use. Guidelines should be condensed and their format upgraded, so that the key messages are easier to comprehend and can be applied more readily by those involved in patient care. After presenting the historical background and describing the guideline structure, we make several recommendations to make clinical practice guidelines more user-friendly for clinical cardiologists. Our most important recommendations are that the clinical cardiology guidelines should focus exclusively on (1) class I recommendations with established benefits that are supported by randomized clinical trials and (2) class III recommendations for diagnostic or therapeutic approaches in which quality studies show no benefit or possible harm. Class II recommendations are not evidence based but reflect expert opinions related to published clinical studies, with potential for personal bias by members of the guideline committee. Class II recommendations should be published separately as "Expert Consensus Statements" or "Task Force Committee Opinions," so that both majority and minority expert opinions can be presented in a less dogmatic form than the way these recommendations currently appear in clinical practice guidelines., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The temporal effect of heart failure (HF) hospitalization occurring at different time periods before implantation has not yet been studied in detail. The aim of the present study was to investigate the potential association between time from last HF hospitalization to device implantation and effects on subsequent outcomes and benefit from cardiac resynchronization therapy with a defibrillator (CRT-D). Multivariate Cox models were used to determine the temporal influence of previous HF hospitalization on the end point of HF or death within all left bundle branch block implantable cardioverter-defibrillator (ICD) and CRT-D patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT) trial (n = 1,250) and to evaluate the clinical benefit of CRT-D implantation, comparing CRT-D patients with ICD patients within each previous HF hospitalization group. The patients with previous HF hospitalization ≤12 months before device implantation had the greatest incidence of HF or death during 4-year follow-up (31%), while those with previous HF hospitalization >12 months and those with no previous HF hospitalization had similar lower rates of HF or death (22% and 24%, respectively). All patients treated with CRT-D derived significant clinical benefit compared with their ICD counterparts, regardless of time of previous hospitalization (hazard ratios 0.38 [no previous hospitalization], 0.49 (≤12 months), and 0.45 (>12 months); p for interaction = 0.67). In conclusion, in the present study of patients with mild HF with prolonged QRS intervals and LBBB, a previous HF hospitalization ≤12 months was associated with increased risk for HF or death compared with >12 months and no previous HF hospitalizations. The clinical benefit of CRT-D was evident in all patients regardless of time from last HF hospitalization to implantation compared with ICD only., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Unaffected long-QT syndrome family members (FMs) frequently experience syncope. The aims of this study were to test the hypothesis that syncope events in FMs are benign events and to compare clinical characteristics, triggers eliciting the syncope events, and long-term outcomes between FMs and those with LQT1 or LQT2 mutations from the international Long QT Syndrome Registry. A total of 679 FMs, 864 LQT1 patients, and 782 LQT2 patients were included. Seventy-eight FMs (11%) experienced cardiovascular events. Almost all cardiovascular events were nonfatal syncope; only 1 FM, with an additional mitral valve prolapse, experienced aborted cardiac arrest during exercise. The mean age at first syncope in FMs was 17 years, and female FMs experienced syncope more frequently than male FMs (14% vs 9%, p = 0.027). Syncope was more frequently triggered by exercise in LQT1 patients (43% in LQT1 patients vs 5% in FMs, p <0.001), while syncope triggered by a variety of other triggers was more frequent in FMs (54% in FMs vs 22% in LQT1 patients and 30% in LQT2 patients, p <0.001 for both). None of the FMs experienced aborted cardiac arrest or sudden cardiac death after the first syncopal episode. In conclusion, syncope is frequently present in FMs, and these syncopal events occurred more frequently in female than in male FMs, with an increased incidence in midadolescence. Triggers eliciting the syncopal events were different between FMs and patients with long-QT syndrome mutations. Hence, the type of trigger is useful in distinguishing between high- and low-risk syncope. These data indicate that FMs from families with LQTS have a benign form of syncope, most likely related to vasovagal syncope and not ventricular tachyarrhythmic syncope., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Low pulse pressure (PP) is associated with poor outcome in hospitalized patients with systolic heart failure (HF). However, the relation between PP and response to cardiac resynchronization therapy with defibrillator (CRT-D) is unknown. We aimed to evaluate the relation between preimplantation PP and echocardiographic response to CRT-D and subsequent clinical outcome after 1 year. The relation between preimplantation PP and echocardiographic response to CRT-D (defined as >15% reduction in left ventricular (LV) end-systolic volume at 1 year) was evaluated in 754 patients with CRT-D with left bundle branch block enrolled in Multicenter Automatic Defibrillator Cardioverter Defibrillator Implantation Trial-Cardiac Resynchronization Therapy. The association between PP at 1 year and the risk for subsequent HF or death was evaluated using multivariate Cox model. Patients with high versus low PP (>40 vs ≤40 mm Hg [lower quartile]) had a significantly greater reduction in LV end-systolic volume, LV end-diastolic volume, and LV dyssynchrony (p<0.01 for all comparisons). In multivariate analysis, the presence of high PP was associated with a 3.5-fold (p<0.001) increase in the likelihood of a positive echocardiographic response to CRT-D. Patients with high PP (>40 mm Hg, >lower quartile) 1 year after CRT-D implantation experienced a 50% reduction in the risk of subsequent HF or death (p=0.001) and 63% reduction in death only (p=0.001), compared with patients with low PP. In conclusion, high baseline PP is an independent predictor of echocardiographic response to CRT-D, and high PP after device implantation is associated with improved subsequent clinical outcome., (Copyright © 2014 Elsevier Inc. All rights reserved.)

We hypothesized that the response to cardiac resynchronization therapy with a defibrillator (CRT-D) in patients with mildly symptomatic heart failure (HF) is more favorable than the commonly referenced figure of 70%. This study involves the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) study population in which paired echocardiograms from baseline and 1-year follow-up were available in 621 implantable cardioverter-defibrillator-treated patients and 749 patients treated with CRT-D. We prespecified CRT-D responders as the patients who at 1-year follow-up had a reduction in left ventricular end-systolic volume (LVESV) that corresponded to the top (best) quintile of LVESV reduction in the implantable cardioverter-defibrillator-treated patients, that is, a ≥17% reduction in LVESV. Using this metric, 88% of patients treated with CRT-D and 91% of the patients treated with CRT-D with left bundle branch block (LBBB) were identified as cardiac resynchronization therapy responders. Landmark multivariate Cox model analyses revealed a significant interaction (p=0.038) involving LVESV (responders vs nonresponders) and LBBB (present vs not present) in risk reduction for HF or death. The interaction finding indicates that cardiac resynchronization therapy responders with LBBB have a significantly lower risk for HF or death (hazard ratio [HR] 0.24) than patients without LBBB (HR 0.62). In the patients treated with CRT-D, LVESV response was associated with reduction in the risk of death (HR 0.20, p<0.001). An increasing percent reduction in LVESV was associated with progressively lower rates of HF or death, a finding consistent with a dose-response relation. In conclusion, approximately 90% of CRT-D-treated patients in MADIT-CRT had a significant and meaningful reduction in LVESV, and these LVESV responders had reduced rates of cardiac events during long-term follow-up., (Copyright © 2014 Elsevier Inc. All rights reserved.)

There are limited data regarding risk factors for the development of ischemic events (IEs) among patients with ischemic cardiomyopathy (IC) who receive cardiac resynchronization therapy with a defibrillator (CRT-D) and their effect on the efficacy of the device. The present study population comprised 1,045 patients with IC enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy. We used multivariate Cox proportional hazards regression modeling to identify risk factors for the development of IE (comprising hospitalization for acute coronary syndromes and/or coronary interventions during the trial) among study patients. Time-dependent analysis was performed to identify the effect of IE on the risk for subsequent heart failure (HF) or death in CRT-D recipients. Independent predictors for the development of IE among study patients included previous revascularization (coronary artery bypass surgery: hazard ratio [HR] 1.88, p = 0.003; percutaneous coronary intervention: HR 3.21, p <0.001) and increased systolic blood pressure (HR 1.67, p = 0.02), whereas a left bundle branch block pattern on the baseline electrocardiogram was associated with reduced risk for IE (HR 0.62, p = 0.02). Treatment with CRT-D did not have a significant effect on IE risk compared with defibrillator-only therapy (HR 0.87, p = 0.51). Time-dependent analysis showed that the development of IEs among CRT-D recipients was associated with more than twofold (p = 0.01) increased risk for subsequent heart failure or death. In conclusion, our data suggest that treatment with CRT-D does not reduce the risk of IE in patients with IC and that the benefit of CRT-D is attenuated after the development of IEs in this population., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Cardiac resynchronization therapy (CRT) is effective for the treatment of patients with heart failure and a wide QRS duration, particularly left bundle branch block. However, subjects with right bundle branch block (RBBB) do not appear to benefit from CRT. The aim of this study was to determine whether patients with specific RBBB conduction patterns responded to CRT in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) trial. In the present post hoc analysis, patients with RBBB who received CRT with an implantable cardioverter defibrillator (n = 132) were divided into 2 groups according to the baseline QRS morphology in the inferior and high lateral leads: group 1: left anterior fascicular block (LAFB) pattern (n = 80; 60.6%); and group 2: non-LAFB pattern (n = 52; 39.4%). Subjects with RBBB who received an implantable cardioverter defibrillator served as the control group (n = 87). The primary end point was echocardiographic response to CRT, defined as percent change in left ventricular (LV) and left atrial volumes from baseline to 1 year. The secondary end point was heart failure or death. The non-LAFB group demonstrated a significantly larger percent reduction in LV end-diastolic volume, LV end-systolic volume, and left atrial volume compared to controls (-11%, p <0.0001; -17%, p <0.0001; -15%, p <0.0001, respectively) and LAFB (-5%, p = 0.028; -7%, p = 0.019; -6%; p = 0.022; respectively) by multivariate analysis. No difference was found in the 3-year crude event rates for death or heart failure among the LAFB (22%), non-LAFB (21%), or ICD-only (20%) groups (p = NS). In conclusion, conduction patterns influence echocardiographic response to CRT in patients with RBBB, with favorable reductions in the LV and left atrial volumes in those without an LAFB conduction pattern. This echocardiographic benefit did not translate into a reduction in heart failure or death during a 3-year follow-up period., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Patients with congenital structural heart disease (CSHD) and inherited arrhythmias (IAs) are at high risk of ventricular tachyarrhythmias and sudden cardiac death. The present study was designed to evaluate the short- and long-term outcomes of patients with CSHD and IA who received a wearable cardioverter-defibrillator (WCD) for the prevention of sudden cardiac death. The study population included 162 patients with CSHD (n = 43) and IA (n = 119) who were prospectively followed up in a nationwide registry from 2005 to 2010. The mortality rates were compared using Kaplan-Meier survival analysis. The mean age of the study patients was 38 ± 27 years. The patients with CSHD had a greater frequency of left ventricular dysfunction (ejection fraction <30%) than did the patients with IA (37% vs 5%, respectively; p = 0.002). The predominant indication for WCD was pending genetic testing in the IA group and transplant listing in the CSHD group. Compliance with the WCD was similar in the 2 groups (91%). WCD shocks successfully terminated 3 ventricular tachyarrhythmias in the patients with IA during a median follow-up of 29 days of therapy (corresponding to 23 appropriate WCD shocks per 100 patient-years). No arrhythmias occurred in the patients with CSHD during a median follow-up of 27 days. No patients died while actively wearing the WCD. At 1 year of follow-up, the survival rates were significantly lower among the patients with CSHD (87%) than among the patients with IA (97%, p = 0.02). In conclusion, our data suggest that the WCD can be safely used in high-risk adult patients with IA and CSHD. Patients with IA showed a greater rate of ventricular tachyarrhythmias during therapy but significantly lower long-term mortality rates., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Obesity has been identified as a risk factor for cardiovascular disease and heart failure. However, data regarding the relation of body mass index (BMI) to outcome in patients with established heart failure are conflicting. We examined the risk of all-cause mortality and sudden cardiac death (SCD) in 1,231 patients after myocardial infarction with left ventricular dysfunction enrolled the Multicenter Automatic Defibrillator Implantation Trial-II (MADIT-II). Interaction-term analysis was used to assess the benefit of the implantable cardioverter-defibrillator (ICD) in upper (obese > or =30 kg/m(2), n = 361) and lower (nonobese <30 kg/m(2), n = 870) BMI categories. Mean BMI in the study population was 27.9 +/- 5.1 kg/m(2). In multivariate analysis, decreased BMI was shown to be independently associated with an increase in the risk of all-cause mortality (23% risk increase per 5-U BMI decreased, p = 0.009) and SCD (41% risk increase per 5-U BMI decrease, p = 0.01). Consistently, patients with BMI <30 kg/m(2) exhibited 46% (p = 0.03) and 76% (p = 0.04) increases in risk of all-cause mortality and SCD, respectively, compared to patients who had higher BMI values. The benefit of the ICD was pronounced in higher-risk patients with BMI <30 kg/m(2) (hazard ratio 0.68, p = 0.017) and maintained in the lower-risk subgroup of patients with BMI > or =30 kg/m(2) (hazard ratio 0.73, p = 0.32; p = 0.86 for ICD-by-BMI interaction). In conclusion, our findings suggest an independent inverse association between BMI values and risk of all-cause mortality and SCD in patients after myocardial infarction with left ventricular dysfunction enrolled in the MADIT-II trial., (Copyright 2010 Elsevier Inc. All rights reserved.)

The clinical course of patients with 2 relatively common long QT syndrome type 3 mutations has not been well described. In the present study, we investigated the mutational-specific risk in patients with deletional (DeltaKPQ) and missense (D1790G) mutations involving the SCN5A gene. The study population involved 50 patients with the DeltaKPQ mutation and 35 patients with the D1790G mutation. The cumulative probability of a first cardiac event (syncope, aborted cardiac arrest, or long QT syndrome-related sudden death) was evaluated using the Kaplan-Meier method. The Cox proportional hazards survivorship model was used to determine the independent contribution of clinical and genetic factors to the first occurrence of cardiac events from birth through 40 years of age. The Andersen-Gill proportional intensity regression model was used to analyze the factors associated with recurrent syncope. Patients with a DeltaKPQ mutation had a significantly greater probability of a first cardiac event from birth through 40 years of age (34%) than those with the D1790G mutation (20%; p <0.001). Multivariate analysis demonstrated an increased risk of cardiac events among DeltaKPQ carriers compared to D1790G carriers (hazard ratio 2.42, p <0.0001) after adjustment for gender and QTc duration. Patients with DeltaKPQ mutations also had an increased risk of recurrent syncope (hazard ratio 5.20, p <0.001). In conclusion, the clinical course of patients with long QT syndrome type with DeltaKPQ mutations was shown to be more virulent than those with D1790G mutations, and this effect was independent of QTc duration. The findings highlight the importance of knowing the specific mutation in risk stratification of patients with long QT syndrome type 3., (Copyright 2010 Elsevier Inc. All rights reserved.)

The Medtronic Sprint Fidelis leads (models 6930, 6931, 6948, 6949) are 6.6-F bipolar high-voltage implantable cardioverter-defibrillator electrodes that were first introduced in September 2004. In October 2007, Fidelis leads were removed from the market. We sought to determine the time-dependent hazard of the Fidelis failure rate to date. A retrospective chart review was conducted in all patients who underwent implantation of a Sprint Fidelis lead (426 leads) at our center. We primarily implanted models 6931 and 6949. With 1,056 years of combined follow-up (average 2.3 +/- 1), 38 of 426 (8.92%) Sprint Fidelis leads failed (3.6%/year). The hazard of fracture increased exponentially over time by a power of 2.13 (95% confidence interval [CI] 1.98 to 2.27, p <0.001) and the 3-year survival was 90.8% (95% CI 87.4 to 94.3). If a Fidelis lead was functioning normally at 1 year, the chance it would survive another year was 97.4% (95% CI 95.7 to 99.1); if functioning at 2 years, the chance of surviving another year was 94.7% (95% CI 91.8 to 97.7); and if functioning at 3 years, the chance of surviving 1 more year was 86.7% (95% CI 78.8 to 95.5). Other commonly used implantable cardioverter-defibrillator leads showed no evidence of increased failure rates. In conclusion, to date, the hazard of Fidelis lead fracture is increasing exponentially with time and, based on our data, occurring at a higher rate than the latest manufacturer's performance update. Further accumulative data are needed because it remains unknown if the fracture rate will level off or continue to increase.

Diabetes mellitus can affect ventricular repolarization, and we investigated the impact of diabetes on the risk for cardiac events in older patients with long QT syndrome (LQTS). The study population consisted of 1,152 patients with QTc interval >/=450 ms who were enrolled in the United States portion of the International Long QT Syndrome Registry and survived >40 years of age. Patients were categorized as having diabetes if they received oral diabetic medication or insulin. End points after 40 years of age included first cardiac event (syncope, aborted cardiac arrest, sudden cardiac death, whichever occurred first) and all-cause mortality. Follow-up extended from 41 to 75 years of age. Risk factors for end points were evaluated by the Cox model. During follow-up, 193 patients had a first cardiac event, and 99 patients died. Of patients with LQTS, development of diabetes in adult patients with LQTS was not associated with an increased risk of first cardiac events dominated by syncope. Risk factors for mortality were syncope before 41 years of age, QTc interval > or =500 ms, heart rate >80 beats/min, and diabetes; there was no mortality interaction involving diabetes and QTc interval > or =500 ms. In conclusion, diabetes and prolonged QTc interval contributed independent mortality risks in adult patients with LQTS, with no interaction between these 2 risk factors.

The clinical course and risk factors associated with beta(2)-agonist therapy for asthma have not been investigated previously in patients with the long-QT syndrome (LQTS). The risk of a first LQTS-related cardiac event due to beta(2)-agonist therapy was examined in 3,287 patients enrolled in the International LQTS Registry with QTc > or = 450 ms. The Cox proportional hazards model was used to assess the independent contribution of clinical factors for first cardiac events (syncope, aborted cardiac arrest, or sudden death) from birth through age 40. Time-dependent beta(2)-agonist therapy for asthma was associated with an increased risk for cardiac events (hazard ratio [HR] = 2.00, 95% confidence interval 1.26 to 3.15, p = 0.003) after adjustment for relevant covariates including time-dependent beta-blocker use, gender, QTc, and history of asthma. This risk was augmented within the first year after the initiation of beta(2)-agonist therapy (HR = 3.53, p = 0.006). The combined use of beta(2)-agonist therapy and anti-inflammatory steroids was associated with an elevated risk for cardiac events (HR = 3.66, p <0.01); beta-blocker therapy was associated with a reduction in cardiac events in those using beta(2) agonists (HR = 0.14, p = 0.05). In conclusion, beta(2)-agonist therapy was associated with an increased risk for cardiac events in patients with asthma with LQTS, and this risk was diminished in patients receiving beta blockers.

There are limited data regarding gender-related differences in electrocardiographic (ECG) presentation in patients after myocardial infarction (MI) and the prognostic value of ECG variables in women. A series of ECG parameters were analyzed in 838 patients (216 women, 622 men) using standard electrocardiography performed 5 to 7 days after first MI, and their associations with gender and risk for cardiac events, defined as cardiac death, nonfatal MI, or unstable angina, were evaluated. Heart rate was faster and QTc duration was longer, whereas QRS duration was shorter in women compared with men. Women had more lateral ST depressions and more T-wave inversions in the anterior and lateral regions. During mean 2-year follow-up, there were 138 events in men and 65 in women; women had a 38% greater risk for recurrent events (adjusted hazard ratio [HR] 1.38, p = 0.031). In multivariate Cox regression analysis, ST-segment elevation in leads V(1) to V(4) on the fifth to seventh day after MI was associated with increased risk for recurrent events in women (adjusted HR 2.16, p = 0.003) but not in men (adjusted HR = 0.81, p = 0.32). ST depressions in leads V(5), V(6), I, or aVL (adjusted HR 1.70, p = 0.006) in men but not in women (adjusted HR 0.98, p = 0.93) were identified as a risk factor for recurrent events. In conclusion, there are gender-related differences in ECG presentation and the prognostic significance of ECG findings after MI. ST-segment elevation in anterior leads is a significant predictor of events in women, whereas ST depression in lateral leads is a significant predictor in men.

There are limited data regarding the prognostic value of QRS complex fragmentation, defined as changes in QRS morphology (<120 ms) with different RSR' patterns: additional R waves, notched S wave, or >1 R' wave. The purpose of our analysis was to assess the prognostic value of presence of Q waves and QRS fragmentation for predicting recurrent cardiac events, defined as cardiac death, nonfatal myocardial infarction (MI), or unstable angina, whichever occurs first, in 350 patients with first Q-wave MI. In follow-up (2 months on average) electrocardiograms (ECGs), 277 patients (79%) had persistent Q waves and 73 (21%) had resolution of Q waves. Independently of Q waves, presence of QRS complex fragmentation was found in 187 patients (53%). Resolved Q waves on 2-month ECGs was associated with worsened prognosis (adjusted hazard ratio [HR] 2.33, p = 0.007), whereas presence of any fragmented QRS did not increase risk of recurrent cardiac events (adjusted HR 0.93, p = 0.79). Among patients for whom Q waves disappeared on 2-month ECGs, patients with QRS fragmentation (n = 37) had over twofold higher risk of recurrent events (adjusted HR 2.68, p = 0.004) compared with those without fragmented QRS and persistent Q waves. In conclusion, presence of fragmented QRS independently of Q waves was not associated with increased risk of recurrent events in the general population of patients after MI. However, among patients with resolved Q waves, fragmented QRS was associated with increased risk of cardiac events. Fragmented QRS complex should not be neglected in patients with transient Q waves after myocardial infarction.

In young patients, the accumulative burden of traditional cardiovascular risk factors may not be as significant as in an older population. Genetic risk factors were suggested to have a role in the early development of myocardial infarction (MI). However, data about the association between polymorphisms in heart disease-related genes and the early onset of a first MI are limited. In the present study, age at onset of a first MI was related to individual single-nucleotide polymorphisms in each of 18 prespecified candidate genes in a cohort of 814 patients enrolled in the Thrombogenic Factors and Recurrent Coronary Events (THROMBO) Study. Multivariate regression analysis showed in patients who had the high-risk genotypes of paraoxonase 1 (PON1) Q192R and endothelial nitric oxide synthase (eNOS) E298D that ages at onset of a first MI were 1.8 (p = 0.02) and 3.5 years (p = 0.02) earlier than in noncarriers of the genotypes, respectively. Consistently, high-risk genotypes of the PON1 Q192R and eNOS E298D polymorphisms were significantly associated with onset of a first MI at age <50 years (adjusted odds ratio 1.70, p = 0.005, adjusted odds ratio 2.15, p = 0.01, respectively). In conclusion, our findings suggest that high-risk genotypes of the PON1 Q192R and eNOS E298D polymorphisms are independently associated with a significantly earlier occurrence of coronary events.

Location (anterior) and type (Q wave) of myocardial infarction (MI) might be considered of prognostic significance when predicting mortality. However, there are limited data regarding the prognostic significance of type and location of MI in patients with severely depressed left ventricular function. In 1,221 patients in the MADIT II, Q-wave MI was observed in 763 patients (62%), 115 (10%) had non-Q-wave MI, and 343 (28%) had conduction abnormalities. In patients with Q-wave MI, anterior MI was present in 430 (57%), inferior in 155 (20%), and combined in 178 (23%) patients. Study end points included all-cause mortality, hospitalization or death due to worsening congestive heart failure, and episodes of ventricular tachycardia or ventricular fibrillation requiring implantable cardioverter-defibrillator therapy. In a multivariate Cox proportional hazard model predicting mortality, the following clinical variables entered the predictive model at a p value <0.10: treatment (implantable cardioverter-defibrillator vs conventional therapy), age dichotomized at 65 years, angina pectoris, ejection fraction dichotomized at 25%, serum urea nitrogen dichotomized at 25 mg/dl, and beta-blocker use. After adjustment for these covariates, risk of mortality was not significantly different in non-Q-wave MI versus Q-wave MI. However, when analyzing location of MI, inferior wall MI was associated with a significantly (hazard ratio 1.58, p = 0.048) higher risk of mortality than anterior wall MI. In addition, patients with conduction abnormalities had a higher risk of mortality (hazard ratio 1.36, p = 0.088) than patients with anterior wall MI. In conclusion, in the setting of severely depressed ejection fraction (< or =30%), inferior wall MI was associated with a significantly higher risk of mortality than anterior wall MI.

This study compared different measurements of repolarization duration in patients after infarction with and without conduction disturbances and evaluated the prognostic significance of repolarization parameters for predicting mortality in patients with conduction abnormalities. The study population consisted of 3,282 patients after recent myocardial infarction. Repolarization duration was measured using Bazett QTc and JTc (QTc minus QRS) and Rautaharju QT and JT(RR) formulas. All-cause mortality was the end point of the predictive models. In 259 patients with conduction disturbances, 76 (2.3%) had indeterminate ventricular conduction disturbances, 126 (3.8%) had right bundle branch block, and 47 (1.4%) had left bundle branch block. Patients with left bundle branch block demonstrated excessive prolongation of the QTc interval, which was not observed when using the JT(RR) interval. There were no significant differences in repolarization duration by gender in patients with conduction abnormalities. Repolarization parameters were uniformly dichotomized at the 75th percentile (QTc interval >490 ms, JTc interval >360 ms, QT(RR,QRS) interval >433 ms, JT(RR) interval >359 ms) to determine their prognostic significance for predicting mortality. After adjustment for significant clinical predictors of mortality, the hazard ratios were 1.65 for QTc interval (p = 0.062), 1.46 for JTc interval (p = 0.168), 1.71 for QT(RR,QRS) interval (p = 0.043), and 1.70 for JT(RR) interval (p = 0.044)(.) In conclusion, patients with left bundle branch block, right bundle branch block, or indeterminate ventricular conduction disturbances show longer repolarization duration than patients without these conduction disturbances, and QT(RR,QRS) and JT(RR) intervals reflect better than QTc repolarization duration in patients with conduction disturbances. QT(RR) and JT(RR) intervals significantly and independently predict mortality in patients after infarction with conduction disturbances.

The aim of this study was to examine the effectiveness of implantable cardioverter-defibrillator (ICD) therapy in whites and blacks who were enrolled in the Multicenter Automatic Defibrillator Implantation Trial-II (MADIT-II). The study population involved 1,232 subjects, with 1,073 white patients (87%) and 102 black patients (8%). Univariate analyses revealed a significant reduction in mortality in white patients treated with ICD therapy (p <0.02), but not in black patients (p = 0.96). White patients had a significant reduction of sudden cardiac death (p <0.01), but no benefit was evident in black patients (p = 0.62). Adjusting for relevant covariates, the ICD therapy/conventional therapy hazard ratios for total mortality were favorable in whites (0.75, 95% confidence interval [CI] 0.55 to 1.02), but not in blacks (1.25, 95% CI 0.42 to 3.60); the hazard ratios for sudden cardiac death were significantly (p = 0.04) lower in whites (0.29, 95% CI 0.17 to 0.49) than in blacks (1.71, 95% CI 0.33 to 8.84). Interaction analyses revealed a pattern of progressive improvement in ICD efficacy in whites as the end point became more specific for arrhythmic death, with exactly the reverse for blacks. In conclusion, ICD therapy in MADIT-II was associated with a reduction in total mortality, cardiac death, and sudden cardiac death in whites but not in blacks.

Implanted cardioverter defibrillator therapy has been shown to be associated with a significant reduction in the risk of sudden cardiac death (SCD) in patients with ischemic left ventricular dysfunction. However, data on the relation between renal function and SCD in this population are limited, and the effect of renal dysfunction on the implanted cardioverter defibrillator benefit has not been determined. We performed a retrospective analysis of the outcome associated with renal dysfunction, as determined by the estimated glomerular filtration rate (eGFR), in patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial-II. Multivariate analysis in conventionally treated patients showed that for each 10-U reduction in eGFR, the risk of all-cause mortality and SCD increased by 16% (p = 0.005) and 17% (p = 0.03), respectively. Defibrillator therapy was associated with a survival benefit in each eGFR category of > or = 35 ml/min/1.73 m2 (overall risk reduction for all-cause mortality 32%, p = 0.01 and for SCD 66%, p < 0.001). However, no implanted cardioverter defibrillator benefit was shown among patients with an eGFR < 35 ml/min/1.73 m2 (all-cause mortality hazard ratio 1.09, p = 0.84; SCD hazard ratio 0.95, p = 0.95). In conclusion, in patients with high-risk cardiac disease enrolled in the Multicenter Automatic Defibrillator Implantation Trial-II, a significant increase was found in the risk of SCD with declining renal function. Defibrillator therapy was associated with a significant survival benefit among the study patients with mild to moderate or no renal disease, but no benefit was shown among patients with more advanced renal dysfunction.

This study examined the effects of beta blockers on (1) appropriate implantable cardioverter defibrillator (ICD) therapy for ventricular tachycardia (VT) or ventricular fibrillation (VF), (2) inappropriate ICD therapy for atrial fibrillation or supraventricular tachycardia, and (3) survival in 691 patients who received ICDs in the Multicenter Automatic Defibrillator Implantation Trial-II. The study population involved 258 patients who were not receiving beta blockers and 433 who were receiving metoprolol (n = 192), atenolol (n = 58), or carvedilol (n = 182). Patients receiving beta blockers were divided into the upper quartile and lower 3 quartiles of the drug doses they were taking. Patients receiving the higher doses of beta blockers (those in the top quartile of doses) had a significant reduction in the risk for VT or VF requiring ICD therapy compared with patients not receiving beta blockers (hazard ratio 0.48, p = 0.02). The frequency of inappropriate ICD therapy for supraventricular tachyarrhythmias was not significantly different among the 3 treatment groups (p = 0.32). Beta-blocker use at the 2 dosage levels was associated with significant improvement in survival compared with the nonuse of beta blockers (hazard ratios 0.42 to 0.44, p <0.01). In conclusion, beta blockers reduce the risk for VT or VF and improve survival in ICD-treated patients with ischemic cardiomyopathy.

In the second Multicenter Automatic Defibrillator Implantation Trial, patients with a previous myocardial infarction and left ventricular ejection fraction < or =0.30 benefited significantly from prophylactic implantable cardioverter-defibrillator (ICD) placement. Diabetic patients who had a myocardial infarction had a worse prognosis compared with nondiabetics. The present study used data from the second Multicenter Automatic Defibrillator Implantation Trial to assess the efficacy of ICD placement on survival in diabetic patients. Of the 1,232 patients in the second Multicenter Automatic Defibrillator Implantation Trial, 489 were characterized as diabetic. They were more likely to be New York Heart Association class II to IV, be hypertensive, have renal dysfunction, have an increased body mass index, and to take diuretic drugs. Diabetic patients had a 24% greater adjusted risk of death than nondiabetic patients. The hazard ratio (HR) for the risk of death in patients treated with the ICD compared with conventional therapy was similar in diabetics (HR 0.61; 95% confidence interval [CI] 0.38 to 0.98) and nondiabetics (HR 0.71; 95% CI 0.49 to 1.05), with no evidence of interaction. Thus, diabetic patients derive a similar benefit from ICD therapy despite being sicker and having a higher mortality rate overall.

The association of a group of prespecified atherosclerotic risk genotypes with recurrent coronary events (coronary-related death, nonfatal myocardial infarction, or unstable angina) was investigated in a cohort of 1,008 patients after infarction during an average follow-up of 28 months. We used a carrier-ship approach with time-dependent survivorship analysis to evaluate the average risk of each carried genotype. Contrary to expectation, the hazard ratio for recurrent coronary events per carried versus noncarried genotype was 0.89 (95% confidence interval 0.80 to 0.99, p = 0.03) after adjustment for relevant genetic, clinical, and environmental covariates. This hazard ratio, derived from the 7 prespecified genotypes, indicated an average 11% reduction in the risk of recurrent coronary events per carried versus noncarried genotype. At 1 year after hospital discharge, the cumulative probability of recurrent coronary events was 26% in those who carried < or =1, 20% for those with 2 to 4, and 13% for those with > or =5 of these genotypes (p = 0.02). This unexpected risk reversal is a likely consequence of changes in the mix of risk factors in pre- and postinfarction populations. In conclusion, this under appreciated, population-based, risk-reversal phenomenon may explain the inconsistent associations of genetic risk factors with outcome events in previous reports involving coronary populations with different risk attributes.

The Multicenter Automatic Defibrillator Implantation Trial II demonstrated a significant 31% reduction in the risk of mortality in postinfarction patients with low ejection fraction (EF < or =30%). Recently, results from the Sudden Death in Heart Failure Trial indicated that a subgroup of patients with New York Heart Association (NYHA) class III heart failure had less benefit from an implantable cardioverter-defibrillator (ICD) than patients with less advanced heart failure. This study evaluates the association between NYHA class, EF, and blood urea nitrogen (BUN) levels as measures of heart failure and left ventricular dysfunction, and ICD benefit in reducing mortality as well as the association of these parameters with ICD therapy for ventricular tachyarrhythmias. NYHA class I was identified in 442 patients (36%), class II in 425 (35%), and class III in 350 patients (29%). EF < or =20% was present in 472 patients (38%), EF of 21% to 25% in 359 patients (29%), and EF of 26% to 30% in 401 patients (33%). BUN < or =25 mg/dl was present in 850 patients (70%) and >25 mg/dl in 368 patients (30%). Patients with higher NYHA class and BUN had higher mortality (34%) and a higher risk of arrhythmic events (33% to 35%) than patients in lower functional groups (16% to 20%). EF did not differentiate the risk. There was no evidence for significant interactions between mortality, ICD therapy, and tested parameters. In conclusion, patients with more advanced heart failure have a higher risk of mortality and arrhythmic events than patients with less severe disease. However, there is no significant difference in the benefit from ICD therapy among the above subgroups of patients in the Multicenter Automatic Defibrillator Implantation Trial.

In this study, we detail our recent experience with 2 successful Internet-based virtual cardiac symposia that focused on the Brugada syndrome and the long QT syndrome. The responses from cardiologists around the world exceeded our expectations, and clearly, this approach answered an unmet need and has major educational potential. Although we initiated the Virtual Cardiac Symposia with the idea of assisting cardiologists caring for patients with relatively infrequent cardiac conditions, we believe that this Internet-based educational approach will have similar applicability and value for cardiologists caring for patients with common cardiac disorders.

The present study retrospectively explored the reasons for delay in the onset of survival benefit from the implanted cardioverter defibrillator (ICD) in the Second Multicenter Automatic Defibrillator Implantation Trial. The cumulative probability of cause-specific death over time was estimated by the Kaplan-Meier method and by proportional hazards regression analysis. Early cardiac death survival curves were similar by treatment assignment in the 0- to 12-month period (p = 0.76). Late cardiac death survival curves by treatment assignment in the >12- to 52-month follow-up period were divergent with a lower probability of late cardiac death in the ICD arm compared with conventional therapy group (p <0.001). The time-specific hazard ratios of ICD to conventional therapy for cardiac death in the early and late periods were significantly different from each other (nominal p = 0.004). There was a significant decrease in sudden cardiac death with ICD therapy in the early (p = 0.012) and late (p <0.001) groups. In the early period, the rate of nonsudden cardiac death was significantly higher in the ICD group than in the conventional therapy group (p = 0.003). Rates of late nonsudden cardiac death were similar in the 2 treatment arms (p = 0.11).

Comprehensive information about the independent value of different electrocardiographic (ECG) variables in predicting cardiac events after acute myocardial infarction (AMI) in the era of modern therapy is limited. Patients (n = 1,034) underwent standard electrocardiography from 5 to 7 days after an AMI. Several time intervals and PQRST abnormalities were analyzed from the electrocardiogram. During a mean +/- SD follow-up of 752 +/- 301 days on average, 42 patients (4%) experienced cardiac death, and 259 patients (25%) a cardiac death, nonfatal AMI, or unstable angina. Several ECG variables had a significant association with cardiac events in univariate comparisons. After adjustment for all risk variables in the Cox hazards model, lateral ST-segment depression (hazard ratio [HR] 4.76, 95% confidence interval [CI] 2.40 to 9.44, p <0.0001) and atrial abnormality with a terminal deflection of the P wave > or =0.1 mV deep and > or =40 ms in duration in lead V(1) (HR 2.46, 95% CI 1.25 to 4.82, p = 0.009) were the only ECG variables that independently predicted cardiac death. Lateral ST-segment depression also predicted the combined end point of cardiac death/nonfatal AMI/unstable angina in this model (HR 1.49, 95% CI 1.14 to 1.94, p = 0.003). In conclusion, lateral ST depression and atrial abnormality on the electrocardiogram are independent predictors of cardiac death after AMI. Lateral ST depression is also associated with ischemic cardiac events.

Increasing evidence implicates inflammation as a risk factor for coronary artery disease. We determined whether an elevated leukocyte count is associated with an increased risk of death or reinfarction in stable patients with a past acute myocardial infarction (AMI). The current analysis is a substudy of the Multicenter Diltiazem Postinfarction Trial, which investigated the effect of diltiazem on mortality and reinfarction in 2,466 patients hospitalized for AMI. We included 1,294 patients in whom a leukocyte count was obtained 6 months after the index AMI. The composite end point of reinfarction or death was used as the primary end point of the study and reinfarction or cardiac death was used as a secondary end point. The study population was divided into 4 quartiles (Q1, Q2, Q3, and Q4) based on the leukocyte count. During a mean follow-up period of 25 months, 163 patients reached the primary end point: 8.7%, 10.9%, 14.0%, and 16.7%, in Q1, Q2, Q3, and, Q4 respectively (p = 0.01). After adjusting for potential covariates, Cox proportional-hazards analysis revealed that an increased leukocyte count was associated with an increased risk of both the primary end point (hazard ratio/1 quartile increase in leukocyte count, 1.26; p = 0.003; 95% confidence interval 1.08 to 1.47) and secondary end point (hazard ratio, 1.18/1-quartile increase; p = 0.05; 95% confidence interval 1.00 to 1.40). In conclusion, an increased leukocyte count measured in the stable post-AMI period is associated with an increased risk of cardiac events. These findings indicate that the leukocyte count may be another marker of an atherosclerotic inflammatory process that contributes to cardiac events in postinfarction patients.

Although improved patient survival has been reported in several randomized trials with the implanted cardioverter-defibrillator, <15% of patients treated with defibrillators during trials receive life-saving benefit from this therapy. We evaluated the survival benefit from defibrillator therapy in relation to the severity of the mortality risk in patients with coronary heart disease. Using data from the Multicenter Automatic Defibrillator Implantation Trial, we partitioned the study population into high- and low-risk subsets for each of 3 physiologically meaningful risk factors (ejection fraction, QRS duration, and history of heart failure requiring therapy). Risk of death was evaluated by Cox proportional-hazards regression analyses in patients with single and multiple risk factors. The defibrillator was associated with a significant (p = 0.002) reduction in mortality only in high-risk subsets with ejection fraction <0.26, QRS duration > or =0.12 second, and history of heart failure requiring treatment. The Cox hazard ratio for the risk of death progressively increased >1.0 as a function of the number of risk factors present. Defibrillator therapy was associated with a progressive reduction in the hazard ratio <1.0 (improved survival) at each increased level of mortality risk. Patients at the highest mortality risk (all 3 risk factors; hazard ratio 4.33) achieved the largest mortality reduction (hazard ratio 0.20) from defibrillator therapy. In patients with chronic coronary heart disease, the magnitude of the survival benefit from the implanted defibrillator is directly related to the severity of cardiac dysfunction and its associated mortality risk.

Carriership analysis is a statistical approach for detecting the average increase in risk (hazard ratio) for adverse time-dependent events per number of prespecified phenotypic or genotypic risk factors carried by subjects in limited-sized populations. This carriership approach was applied to phenotypic risk factor analysis in a postinfarction population, and simulated genetic modeling was performed to show how carriership analysis could be used to identify a group of oligogenic factors in common polygenic disorders.

Cigarette smoking is linked to increased cardiac morbidity and mortality, and has been shown to affect both lipid profiles and thrombotic factors in healthy subjects. However, the influence of smoking on the atherothrombotic environment has not been studied in a large population of patients after acute myocardial infarction (AMI). Blood samples and medical history, including smoking status, were obtained from 1,045 patients at a 2-month visit after AMI. Smokers were asked to refrain 24 hours before the visit, but not all complied. Measurements included total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, apolipoprotein-B, apolipoprotein-A, triglycerides, factor VII, factor VIIa, von Willebrand factor, D-dimer, and plasminogen activator inhibitor. There were 247 current, 443 past, and 349 nonsmokers. After adjustment for clinical variables, current smokers had higher levels of total cholesterol and apolipoprotein-B than past and nonsmokers (p <0.01). High-density lipoprotein cholesterol and apolipoprotein-A levels were similar between groups. Fibrinogen was elevated in current (p = 0.001) and past (p = 0.029) smokers, compared with nonsmokers. Smokers who smoked within 24 hours of blood sampling had higher apolipoprotein-B (p = 0.005), total cholesterol (p = 0.001), and fibrinogen (p = 0.015) levels than those who refrained from smoking. In conclusion, postinfarction patients, who historically have higher levels of atherogenic lipids than healthy subjects, have increased levels of these lipids attributed to active smoking. After smoking cessation, lipid profiles approach nonsmoker levels, but fibrinogen remains elevated. Smoking within 24 hours of blood sampling was associated with further adverse prothrombotic and lipogenic effects.

Thrombosis contributes to recurrent coronary events in patients after acute myocardial infarction (AMI), but prognostic significance of thrombogenic factors by gender is unknown. This study aimed to determine gender-related differences in the prognostic significance of thrombogenic factors for predicting cardiac events (nonfatal reinfarction or cardiac death) in postinfarction patients. Blood levels of the following factors were measured 2 months after AMI in 791 men and 254 women: fibrinogen, von Willebrand factor, factor VII and VIIa, plasminogen activator inhibitor, D-dimer, cholesterol, apolipoprotein A-1, apolipoprotein B, lipoprotein(a), triglycerides, and high-density lipoprotein cholesterol. After adjustment for clinical covariates, levels of apolipoprotein A, high-density lipoprotein cholesterol, fibrinogen, and factor VIIa were significantly higher in postinfarction women than men. During a mean 26-month follow-up, there were 67 cardiac events (8.5%) in men and 14 (5.5%) in women (p = 0.11). In the multivariate Cox model, elevated levels of factor VIIa were a significant predictor of cardiac events in women (p = 0.022) but not in men (p = 0.80), with significant gender-related effect (hazard ratio 2.80 vs 0.92, respectively; p <0.05). D-dimer had prognostic value in men (p = 0. 006) but not in women (p = 0.36), although the difference between hazard ratios for men and women was not significant (2.35 vs 1.58, respectively; p = 0.49). In conclusion, elevated levels of factor VIIa are associated with an increased risk of recurrent cardiac events in postinfarction women, but not in men. D-dimer is more predictive for cardiac events in postinfarction men than women. These observations indicate possible gender-related differences in the pathophysiologic mechanisms of recurrent cardiac events.

In patients with the long QT syndrome (LQTS), the occurrence of cardiac events (syncope or cardiac arrest) is frequently associated with acute arousal caused by exercise, swimming, emotion, or noise. However, cardiac events may also occur during sleep or with ordinary daily activities. The purpose of this study was to determine whether there are differential clinical, electrocardiographic, and genetic features among LQTS patients who experienced cardiac events with and without acute arousal. We identified 1,325 patients with cardiac events from the International LQTS Registry. Based on the precipitating conditions of the first event, 427 patients were classified as arousal, 345 as nonarousal, and the remaining 553 were unknown (not classifiable). Gene linkage was known in 78 of the 772 patients with classifiable first events. The age at first cardiac event was significantly younger in the arousal than the nonarousal group (11.7 vs. 15.5 years, respectively; p<0.001). The arousal-type patients had a higher rate of subsequent cardiac events during follow-up after the index event than the nonarousal-type patients (p = 0.02). Arousal-related cardiac events occurred in 85% of LQT1, 67% of LQT2, and 33% of LQT3 patients (p = 0.008). This study provides evidence that the genotype is an important determinant of the LQTS phenotype in terms of arousal and nonarousal-related cardiac events.

Although elevated body mass index (BMI) was found to be associated with QT prolongation in healthy subjects, electrocardiographic findings in coronary patients in relation to BMI have not been investigated. We studied 936 coronary patients whose electrocardiographic parameters were compared according to their BMI and found that BMI did not affect the overall QT duration, but QT dispersion was significantly higher in normal-weight coronary patients than in obese patients.

While acquiring data for the International Long QT Syndrome Registry, we noticed that a number of patients referred for long QT syndrome (LQTS) were affected by asthma. The effect of asthma comorbidity on clinical course of LQTS has not been studied. This study aimed to evaluate the prevalence of asthma in patients with LQTS, determine the influence of asthma comorbidity on outcome of LQTS patients, and to investigate the confounding effects of beta mimetics and beta blockers on the occurrence of cardiac events in asthmatic patients. The influence of asthma on risk of cardiac events (syncope, aborted cardiac arrest, or LQTS death) was evaluated after accounting for age, gender, QTc, and RR interval duration, beta-blocker and beta-mimetic use. Asthma was identified in 226 (5.2%) of 4,310 studied LQTS family members. Longer QTc duration was associated with higher incidence of asthma (p <0.001). Asthma was independently associated with significantly increased risk of cardiac events in affected LQTS patients (hazard ratio 1.32; p = 0.048) and in borderline-affected family members (hazard ratio 2.08; p = 0.004) after adjustment for QTc, RR interval, and gender. An increased risk of cardiac events in asthmatic patients observed before beta-blocker therapy was reduced after initiation of treatment with beta blockers. In conclusion, the occurrence of asthma in LQTS patients increases with QTc duration. Asthma comorbidity in LQTS patients is associated with an increased risk of cardiac events. The asthma-associated increase in the risk of LQTS-related cardiac events is diminished after initiation of beta-blocker therapy, suggesting a possible role of beta-receptor modulation underlying asthma-LQTS association.