Timothy E. Meyer

Effect of Obesity and Insulin Resistance on Myocardial Substrate Metabolism and Efficiency in Young Women

Background—Obesity is a risk factor for impaired cardiac performance, particularly in women. Animal studies suggest that alterations in myocardial fatty acid metabolism and efficiency in obesity can cause decreased cardiac performance. In the present study, we tested the hypothesis that myocardial fatty acid metabolism and efficiency are abnormal in obese women. Methods and Results—We studied 31 young women (body mass index [BMI] 19 to 52 kg/m2); 19 were obese (BMI >30 kg/m2). Myocardial oxygen consumption (M&OV0312;o2) and fatty acid uptake (MFAUp), utilization (MFAU), and oxidation (MFAO) were quantified by positron emission tomography. Cardiac work was measured by echocardiography, and efficiency was calculated as work/M &OV0312;o2. BMI correlated with M &OV0312;o2 (r =0.58, P =0.0006), MFAUp (r =0.42, P <0.05), and efficiency (r = −0.40, P <0.05). Insulin resistance, quantified by the glucose area under the curve (AUC) during an oral glucose tolerance test, correlated with MFAUp (r =0.55, P <0.005), MFAU (r =0.62, P <0.001), and MFAO (r =0.58, P <0.005). A multivariate, stepwise regression analysis showed that BMI was the only independent predictor of M&OV0312;o2 and efficiency (P =0.0005 and P <0.05, respectively). Glucose AUC was the only independent predictor of MFAUp, MFAU, and MFAO (P <0.05, <0.005, and <0.005, respectively). Conclusions—In young women, obesity is a significant predictor of increased M&OV0312;o2 and decreased efficiency, and insulin resistance is a robust predictor of MFAUp, MFAU, and MFAO. This increase in fatty acid metabolism and decrease in efficiency is concordant with observations made in experimental models of obesity. These metabolic changes may play a role in the pathogenesis of decreased cardiac performance in obese women.

Long-Term Outcome After ICD and CRT Implantation and Influence of Remote Device Follow-Up: The ALTITUDE Survival Study

Background— Outcome data for patients receiving implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy-defibrillator (CRT-D) devices treated outside of clinical trials are lacking. No clinical trial has evaluated mortality after device implantation or after shock therapy in large numbers of patients with implanted devices that regularly transmit device data over a network. Methods and Results— Survival status in patients implanted with ICD and CRT devices across the United States from a single manufacturer was assessed. Outcomes were compared between patients followed in device clinic settings and those who regularly transmit remote data collected from the device an average of 4 times monthly. Shock delivery and electrogram analysis could be ascertained from patients followed on the network, enabling survival after ICD shock to be evaluated. One- and 5-year survival rates in 185 778 patients after ICD implantation were 92% and 68% and were 88% and 54% for CRT-D device recipients. In 8228 patients implanted with CRT-only devices, survival was 82% and 48% at 1 and 5 years, respectively. For the 69 556 ICD and CRT-D patients receiving remote follow-up on the network, 1- and 5-year survival rates were higher compared with those in the 116 222 patients who received device follow-up in device clinics only (50% reduction; P<0.0001). There were no differences between patients followed on or off the remote network for the characteristics of age, gender, implanted device year or type, and economic or educational status. Shock therapy was associated with subsequent mortality risk for both ICD and CRT-D recipients. Conclusions— Survival after ICD and CRT-D implantation in patients treated in naturalistic practice compares favorably with survival rates observed in clinical trials. Remote follow-up of device data is associated with excellent survival, but arrhythmias that result in device therapy in this population are associated with a higher mortality risk compared with patients who do not require shock therapy.

Primary Results From the SmartDelay Determined AV Optimization: A Comparison to Other AV Delay Methods Used in Cardiac Resynchronization Therapy (SMART-AV) Trial A Randomized Trial Comparing Empirical, Echocardiography-Guided, and Algorithmic Atrioventricular Delay Programming in Cardiac Resynchronization Therapy

Background— One variable that may influence cardiac resynchronization therapy response is the programmed atrioventricular (AV) delay. The SmartDelay Determined AV Optimization: A Comparison to Other AV Delay Methods Used in Cardiac Resynchronization Therapy (SMART-AV) Trial prospectively randomized patients to a fixed empirical AV delay (120 milliseconds), echocardiographically optimized AV delay, or AV delay optimized with SmartDelay, an electrogram-based algorithm. Methods and Results— A total of 1014 patients (68% men; mean age, 66±11 years; mean left ventricular ejection fraction, 25±7%) who met enrollment criteria received a cardiac resynchronization therapy defibrillator, and 980 patients were randomized in a 1:1:1 ratio. All patients were programmed (DDD-60 or DDDR-60) and evaluated after implantation and 3 and 6 months later. The primary end point was left ventricular end-systolic volume. Secondary end points included New York Heart Association class, quality-of-life score, 6-minute walk distance, left ventricular end-diastolic volume, and left ventricular ejection fraction. The medians (quartiles 1 and 3) for change in left ventricular end-systolic volume at 6 months for the SmartDelay, echocardiography, and fixed arms were −21 mL (−45 and 6 mL), −19 mL (−45 and 6 mL), and −15 mL (−41 and 6 mL), respectively. No difference in improvement in left ventricular end-systolic volume at 6 months was observed between the SmartDelay and echocardiography arms (P=0.52) or the SmartDelay and fixed arms (P=0.66). Secondary end points, including structural (left ventricular end-diastolic volume and left ventricular ejection fraction) and functional (6-minute walk, quality of life, and New York Heart Association classification) measures, were not significantly different between arms. Conclusions— Neither SmartDelay nor echocardiography was superior to a fixed AV delay of 120 milliseconds. The routine use of AV optimization techniques assessed in this trial is not warranted. However, these data do not exclude possible utility in selected patients who do not respond to cardiac resynchronization therapy. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00677014.

Primary Results From the SmartDelay Determined AV Optimization: A Comparison to Other AV Delay Methods Used in Cardiac Resynchronization Therapy (SMART-AV) Trial

Background— One variable that may influence cardiac resynchronization therapy response is the programmed atrioventricular (AV) delay. The SmartDelay Determined AV Optimization: A Comparison to Other AV Delay Methods Used in Cardiac Resynchronization Therapy (SMART-AV) Trial prospectively randomized patients to a fixed empirical AV delay (120 milliseconds), echocardiographically optimized AV delay, or AV delay optimized with SmartDelay, an electrogram-based algorithm. Methods and Results— A total of 1014 patients (68% men; mean age, 66±11 years; mean left ventricular ejection fraction, 25±7%) who met enrollment criteria received a cardiac resynchronization therapy defibrillator, and 980 patients were randomized in a 1:1:1 ratio. All patients were programmed (DDD-60 or DDDR-60) and evaluated after implantation and 3 and 6 months later. The primary end point was left ventricular end-systolic volume. Secondary end points included New York Heart Association class, quality-of-life score, 6-minute walk distance, left ventricular end-diastolic volume, and left ventricular ejection fraction. The medians (quartiles 1 and 3) for change in left ventricular end-systolic volume at 6 months for the SmartDelay, echocardiography, and fixed arms were −21 mL (−45 and 6 mL), −19 mL (−45 and 6 mL), and −15 mL (−41 and 6 mL), respectively. No difference in improvement in left ventricular end-systolic volume at 6 months was observed between the SmartDelay and echocardiography arms (P=0.52) or the SmartDelay and fixed arms (P=0.66). Secondary end points, including structural (left ventricular end-diastolic volume and left ventricular ejection fraction) and functional (6-minute walk, quality of life, and New York Heart Association classification) measures, were not significantly different between arms. Conclusions— Neither SmartDelay nor echocardiography was superior to a fixed AV delay of 120 milliseconds. The routine use of AV optimization techniques assessed in this trial is not warranted. However, these data do not exclude possible utility in selected patients who do not respond to cardiac resynchronization therapy. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00677014.

The relationship between ventricular electrical delay and left ventricular remodelling with cardiac resynchronization therapy

Aims The aim of the present study was to evaluate the relationship between left ventricular (LV) electrical delay, as measured by the QLV interval, and outcomes in a prospectively designed substudy of the SMART-AV Trial. Methods and results This was a multicentre study of patients with advanced heart failure undergoing cardiac resynchronization therapy (CRT) defibrillator implantation. In 426 subjects, QLV was measured as the interval from the onset of the QRS from the surface ECG to the first large peak of the LV electrogram. Left ventricular volumes were measured by echocardiography at baseline and after 6 months of CRT by a blinded core laboratory. Quality of life (QOL) was assessed by a standardized questionnaire. When separated by quartiles based on QLV duration, reverse remodelling response rates (>15% reduction in LV end systolic volume) increased progressively from 38.7 to 68.4% and QOL response rate (>10 points reduction) increased from 50 to 72%. Patients in the highest quartile of QLV had a 3.21-fold increase (1.58–6.50, P = 0.001) in their odds of a reverse remodelling response after correcting for QRS duration, bundle branch block type, and clinical characteristics by multivariate logistic regression analysis. Conclusion Electrical dyssynchrony, as measured by QLV, was strongly and independently associated with reverse remodelling and QOL with CRT. Acute measurements of QLV may be useful to guide LV lead placement.

Timing of cardiac transplantation in patients with heart failure receiving β-adrenergic blockers

BACKGROUND Previous work shows that patients with heart failure patients who have peak oxygen consumption (VO2 peak) >14 ml/kg/min do not derive a survival benefit from cardiac transplantation. However, this was shown before beta-blocker therapy for patients with systolic heart failure became common, and beta-blockers improve survival in patients with heart failure without changing VO(2) peak. Our purpose was to re-evaluate the utility of VO(2) peak >14 ml/kg/min as an indicator of the need for cardiac transplantation in patients with heart failure who are taking beta-blockers. METHODS Actuarial, hemodynamic, and exercise ventilatory data were collected from 540 patients with heart failure, 256 of whom were taking beta-blockers. We tracked death and cardiac transplantation. We stratified the percentage of patients event-free 1 and 3 years after VO(2) peak study by their VO(2) peak and beta-blocker status, and compared 1- and 3-year post-transplant survival (United Network of Organ Sharing [UNOS] data). We also compared total mortality for the patients with heart failure as stratified by beta-blocker stats and VO(2) peak (excluding the 42 who underwent transplantation) with UNOS post-transplant survival. RESULTS Patients with heart failure who were receiving beta-blockers and whose VO(2) peak was > or =12 ml/kg/min had greater 1- and 3-year event-free survival rates (95% confidence intervals, 92.6%-96.6% and 85.8%-96.0%) than did post-transplant patients (83.9%-86.3% and 75.4%-76.6%). However, in patients with heart failure not taking beta-blockers, VO(2) peak <14 ml/kg/min was associated with worse 3-year survival (38.9 - 62.1%) than that for post-transplant patients. Excluding the 42 patients with heart failure in our study who underwent transplantation and then evaluating survival of the remaining patients with heart failure (not event-free survival) did not substantially change these results. CONCLUSIONS Patients with heart failure who are receiving beta-blockers do not derive a survival advantage at 1 and 3 years after cardiac transplantation if VO(2) peak is > or =12 ml/kg/min. Patients not taking beta-blockers whose VO(2) peak is <14 ml/kg/min have superior survival with cardiac transplantation.

Caloric restriction may reverse age‐related autonomic decline in humans

Caloric restriction (CR) retards aging in laboratory rodents. No information is available on the effects of long‐term CR on physiologic markers of aging and longevity in humans. Heart rate variability (HRV) is a marker for cardiac autonomic functioning. The progressive decline in HRV with aging and the association of higher HRV with better health outcomes are well established. Heart rate variability assessment is a reliable tool by which the effects of CR on autonomic function can be assessed. Time‐ and frequency‐domain analyses compared 24‐h HRV in 22 CR individuals aged 35–82 years and 20 age‐matched controls eating Western diets (WD). The CR group was significantly leaner than the WD group. Heart rate was significantly lower, and virtually, all HRV values were significantly higher in the CR group than in the WD group (P < 0.002). Heart rate variability in the CR individuals was comparable with published norms for healthy individuals 20 years younger. In addition, when differences in heart rate (HR) and HRV between CR and WD were compared with previously published changes in HRV induced in healthy adults given atenolol, percent differences in each measure were generally similar in direction and magnitude and suggested declines in sympathetic and increases in parasympathetic modulation of HR and increased circadian variability associated with CR. These findings provide evidence that CR has direct systemic effects that counter the expected age‐associated changes in autonomic function so that HRV indexes in CR individuals are similar to those of individuals 20 years younger eating WDs.

The effect of β-adrenergic blockers on the prognostic value of peak exercise oxygen uptake in patients with heart failure ☆

Abstract Objectives Our aim was to determine the effect of β-adrenergic blockade on the prognostic value of peak oxygen consumption testing in patients with heart failure. Background Peak oxygen consumption has been shown to be a useful prognostic tool in patients with heart failure. However, studies demonstrating the utility of peak oxygen consumption were conducted before β-blocker therapy became widespread. Thus, our objective was to determine the effect of β-blockers on the prognostic value of peak oxygen consumption in patients with heart failure. Methods Actuarial, anthropomorphic, hemodynamic and exercise ventilatory data were collected from 369 patients with heart failure. Death and orthotopic heart transplants were the events tracked. Patients were divided into those taking β-blockers and those not taking them. Event-free survival days were calculated. Results One hundred ninety-nine patients on β-blockers and 170 not on β-blockers were studied. There were 40 orthotopic heart transplants and 82 deaths during follow-up. Peak oxygen consumption (milliliters per kilogram per minute) trended toward being an independent predictor of event-free survival ( p = 0.055). In patients on and not on β-blockers, a peak oxygen consumption of >14 ml/kg·min was associated with a 1-year event rate of approximately half of that associated with a peak oxygen consumption ≤14 ml/kg·min. However, for every level of peak oxygen consumption, the event rate was lower in the group taking β-blockers. Conclusions β-blocker status does not change the predictive power of peak oxygen consumption in patients with heart failure, but β-blocker status is important to consider when using peak oxygen consumption to predict event-free survival in patients with heart failure.

Potential mechanisms underlying the effect of gender on response to cardiac resynchronization therapy: Insights from the SMART-AV multicenter trial

BACKGROUND Recent studies demonstrate that women may respond more favorably to cardiac resynchronization therapy (CRT) than do men. The mechanisms remain unclear. OBJECTIVES To describe the effects of gender on response to CRT and to explore potential mechanisms behind these differences. METHODS Data for 846 patients from the SMART-AV trial were used to evaluate the mechanisms behind the effects of gender on CRT response. Atrioventricular optimization (AVO) was performed via SmartDelay or echocardiography. Baseline and 6-month left ventricular end systolic volume index (LVESVi) were fitted to a linear regression model with gender predicting change in LVESVi and adjusted for baseline covariates significantly differing by gender. The interaction variable for AVO and gender was also assessed for its effect on change in LVESVi. RESULTS Baseline variables, including age, body mass index, left ventricular ejection fraction, QRS width, and severity of heart failure symptoms, were comparable between men and women. Women had a higher incidence of left bundle branch block conduction and nonischemic cardiomyopathy and exhibited greater reductions in LVESVi even after adjustment for these differences (13.4 mL/m(2) vs 8.5 mL/m(2); P = .002). In addition, women had greater percentages of biventricular pacing and appeared to derive greater reductions in left ventricular volume with AVO than did men. CONCLUSIONS Women demonstrated greater reductions in LVESVi with CRT than did men. These observations are not explained by differences in baseline characteristics. Greater degrees of biventricular pacing and enhanced response to AVO in women may partly explain the reason for the gender effect on CRT response.

The effect of left ventricular electrical delay on AV optimization for cardiac resynchronization therapy

BACKGROUND The role of atrioventricular optimization (AVO) for cardiac resynchronization therapy (CRT) is controversial. Identifying subgroups that benefit from optimization is important to improve CRT outcomes. Pacing at sites of late electrical activation, as assessed by the QLV interval, improves remodeling with CRT. OBJECTIVE To evaluate whether pacing at sites of long left ventricular (LV) electrical delay increases the effectiveness of AVO. METHODS This substudy of the SMART-AV trial included 280 subjects who were randomized to either an electrogram-based AVO (SmartDelay) or nominal atrioventricular delay (120 ms). The QLV interval was defined as the time from the onset of QRS to the LV electrogram peak. CRT response was defined prospectively as a >15% reduction in left ventricular end systolic volume from implant to 6 months. RESULTS The cohort was 68% men, with a mean age of 66 ± 11 years and LV ejection fraction of 28% ± 8%. Longer QLV durations were significantly associated with CRT response (P < .01) for the entire cohort. Moreover, the benefit of AVO increased as QLV prolonged. At the longest QLV quartile, there was more than a 6-fold increase in the likelihood of a remodeling response compared with nominal atrioventricular delays. CONCLUSIONS Baseline electrical dyssynchrony, as measured by the QLV interval, predicted CRT response. At long QLV intervals, AVO can increase the likelihood of structural response to CRT. AVO and QLV optimized that LV lead location may work synergistically to maximize CRT response.