Jagmeet P. Singh

Prevalence and clinical determinants of mitral, tricuspid, and aortic regurgitation (the Framingham Heart Study)

Little information is available on the prevalence and determinants of valvular regurgitation in the general population. This study sought to assess the prevalence and clinical determinants of mitral (MR), tricuspid (TR), and aortic (AR) regurgitation in a population-based cohort. Color Doppler echocardiography was performed in 1,696 men and 1,893 women (aged 54 +/- 10 years) attending a routine examination at the Framingham Study. After excluding technically poor echocardiograms, MR, TR, and AR were qualitatively graded from trace to severe. Multiple logistic regression analysis was used to examine the association of clinical variables with MR and TR (more than or equal to mild severity) and AR (more than or equal to trace severity). MR and TR of more than or equal to mild severity was seen in 19.0% and 14.8% of men and 19.1% and 18.4% of women, respectively, and AR of more than or equal to trace severity in 13.0% of men and 8.5% of women. The clinical determinants of MR were age (odds ratio [OR] 1.3/9.9 years, 95% confidence interval [CI] 1.2 to 1.5), hypertension (OR 1.6; 95% CI 1.2 to 2.0), and body mass index (OR 0.8/4.3 kg/m2; 95% CI 0.7 to 0.9). The determinants of TR were age (OR 1.5/9.9 years; 95% CI 1.3 to 1.7), body mass index (OR 0.7/4.3 kg/m2; 95% CI 0.6 to 0.8), and female gender (OR 1.2; 95% CI 1.0 to 1.6). The determinants of AR were age (OR 2.3/9.9 years; 95% CI 2.0 to 2.7) and male gender (OR 1.6; 95% CI 1.2 to 2.1). A substantial proportion of healthy men and women had detectable valvular regurgitation by color Doppler echocardiography. These data provide population-based estimates for comparison with patients taking anorectic drugs.

Reduced heart rate variability and new-onset hypertension: insights into pathogenesis of hypertension: the Framingham Heart Study.

Heart rate variability (HRV) is a useful noninvasive tool to assess cardiac autonomic function. The purpose of this study was to (1) compare measures of HRV between hypertensive and normotensive subjects and (2) examine the role of HRV as a predictor of new-onset hypertension. The first 2 hours of ambulatory ECG recordings obtained from 931 men and 1111 women attending a routine examination at the Framingham Heart Study were processed for HRV. Three time-domain and 5 frequency-domain variables were studied: standard deviation of normal RR intervals (SDNN), percentage of differences between adjacent normal RR intervals exceeding 50 milliseconds, square root of the mean of squared differences between adjacent normal RR intervals, total power (0.01 to 0.40 Hz), high frequency power (HF, 0.15 to 0.40 Hz), low frequency power (LF, 0.04 to 0.15 Hz), very low frequency power (0.01 to 0.04 Hz), and LF/HF ratio. On cross-sectional analysis, HRV was significantly lower in hypertensive men and women. Among 633 men and 801 women who were normotensive at baseline (systolic blood pressure <140 mm Hg and diastolic blood pressure <90 mm Hg and not receiving antihypertensive treatment), 119 men and 125 women were newly hypertensive at follow-up 4 years later. After adjustment for factors associated with hypertension, multiple logistic regression analysis revealed that LF was associated with incident hypertension in men (odds ratio per SD decrement [OR], 1.38; 95% confidence interval [CI], 1.04 to 1.83) but not in women (OR, 1.12; 95% CI, 0.86 to 1.46). SDNN, HF, and LF/HF were not associated with hypertension in either sex. HRV is reduced in men and women with systemic hypertension. Among normotensive men, lower HRV was associated with greater risk for developing hypertension. These findings are consistent with the hypothesis that autonomic dysregulation is present in the early stage of hypertension.

Left Ventricular Lead Position and Clinical Outcome in the Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT) Trial

Background— An important determinant of successful cardiac resynchronization therapy for heart failure is the position of the left ventricular (LV) pacing lead. The aim of this study was to analyze the impact of the LV lead position on outcome in patients randomized to cardiac resynchronization-defibrillation in the Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT) study. Methods and Results— The location of the LV lead was assessed by means of coronary venograms and chest x-rays recorded at the time of device implantation. The LV lead location was classified along the short axis into an anterior, lateral, or posterior position and along the long axis into a basal, midventricular, or apical region. The primary end point of MADIT-CRT was heart failure (HF) hospitalization or death, whichever came first. The LV lead position was assessed in 799 patients, (55% patients ≥65 years of age, 26% female, 10% LV ejection fraction ⩽25%, 55% ischemic cardiomyopathy, and 71% left bundle-branch block) with a follow-up of 29±11 months. The extent of cardiac resynchronization therapy benefit was similar for leads in the anterior, lateral, or posterior position (P=0.652). The apical lead location compared with leads located in the nonapical position (basal or midventricular region) was associated with a significantly increased risk for heart failure/death (hazard ratio=1.72; 95% confidence interval, 1.09 to 2.71; P=0.019) after adjustment for the clinical covariates. The apical lead position was also associated with an increased risk for death (hazard ratio=2.91; 95% confidence interval, 1.42 to 5.97; P=0.004). Conclusion— LV leads positioned in the apical region were associated with an unfavorable outcome, suggesting that this lead location should be avoided in cardiac resynchronization therapy. Clinical Trial Registration— URL: http://clinicaltrials.gov. Unique identifier: NCT00180271.

Cardiac-Resynchronization Therapy in Heart Failure with a Narrow QRS Complex

BACKGROUND Cardiac-resynchronization therapy (CRT) reduces morbidity and mortality in chronic systolic heart failure with a wide QRS complex. Mechanical dyssynchrony also occurs in patients with a narrow QRS complex, which suggests the potential usefulness of CRT in such patients. METHODS We conducted a randomized trial involving 115 centers to evaluate the effect of CRT in patients with New York Heart Association class III or IV heart failure, a left ventricular ejection fraction of 35% or less, a QRS duration of less than 130 msec, and echocardiographic evidence of left ventricular dyssynchrony. All patients underwent device implantation and were randomly assigned to have CRT capability turned on or off. The primary efficacy outcome was the composite of death from any cause or first hospitalization for worsening heart failure. RESULTS On March 13, 2013, the study was stopped for futility on the recommendation of the data and safety monitoring board. At study closure, the 809 patients who had undergone randomization had been followed for a mean of 19.4 months. The primary outcome occurred in 116 of 404 patients in the CRT group, as compared with 102 of 405 in the control group (28.7% vs. 25.2%; hazard ratio, 1.20; 95% confidence interval [CI], 0.92 to 1.57; P=0.15). There were 45 deaths in the CRT group and 26 in the control group (11.1% vs. 6.4%; hazard ratio, 1.81; 95% CI, 1.11 to 2.93; P=0.02). CONCLUSIONS In patients with systolic heart failure and a QRS duration of less than 130 msec, CRT does not reduce the rate of death or hospitalization for heart failure and may increase mortality. (Funded by Biotronik and GE Healthcare; EchoCRT ClinicalTrials.gov number, NCT00683696.).

Blood Pressure Response During Treadmill Testing as a Risk Factor for New-Onset Hypertension The Framingham Heart Study

BACKGROUND Although systolic blood pressure (SBP) response to exercise has been shown to predict subsequent hypertension in small samples of men, this association has not been studied in a large population-based sample of middle-aged men and women. The purpose of this study was to examine, in normotensive subjects, the relations of SBP and diastolic blood pressure (DBP) during the exercise and recovery periods of a graded treadmill test to the risk of developing new-onset hypertension. METHODS AND RESULTS BP data from exercise testing in 1026 men and 1284 women (mean age, 42+/-10 years; range, 20 to 69 years) from the Framingham Offspring Study who were normotensive at baseline were related to the incidence of hypertension 8 years later. New-onset hypertension, defined as an SBP >/=140 mm Hg or DBP >/=90 mm Hg or the initiation of antihypertensive drug treatment, occurred in 228 men (22%) and 207 women (16%). Exaggerated SBP (Ex-SBP 2) and DBP (Ex-DBP 2) response and delayed recovery of SBP (R-SBP 3) and DBP (R-DBP 3) were defined as an age-adjusted BP greater than the 95th percentile during the second stage of exercise and third minute of recovery, respectively. After multivariable adjustment, Ex-DBP 2 was highly predictive of incident hypertension in both men (OR, 4.16; 95% CI, 2.15, 8.05) and women (OR, 2.17; CI, 1.19, 3.96). R-SBP 3 was predictive of hypertension in men in a multivariable model that included exercise duration and peak exercise BP (OR, 1.92; CI, 1.00, 3.69). Baseline resting SBP (chi2, 23.4 in men and 34.7 in women) and DBP (chi2, 11.3 in men and 13.1 in women) had stronger associations with new-onset hypertension than exercise DBP (chi2, 16.4 in men and 6.1 in women) and recovery SBP (chi2, 6.5 in men and 2.1 in women) responses. CONCLUSIONS An exaggerated DBP response to exercise was predictive of risk for new-onset hypertension in normotensive men and women. An elevated recovery SBP was predictive of hypertension in men. These findings may reflect subtle pathophysiological features in the preclinical stage of hypertension.

Association of Hyperglycemia With Reduced Heart Rate Variability (The Framingham Heart Study)

This study was designed to examine the association of heart rate variability (HRV) with blood glucose levels in a large community-based population. Previous reports have shown HRV to be reduced in diabetics, suggesting the presence of abnormalities in neural regulatory mechanisms. There is scant information about HRV across the spectrum of blood glucose levels in a population-based cohort. One thousand nine hundred nineteen men and women from the Framingham Offspring Study, who underwent ambulatory electrocardiographic recordings at a routine examination, were eligible. HRV variables included the SD of normal RR intervals (SDNN), high-frequency (HF, 0.15 to 0.40 Hz) and low-frequency (LF, 0.04 to 0.15 Hz) power, and LF/HF ratio. Fasting plasma glucose levels were used to classify subjects as normal (<110 mg/dl; n = 1, 779), as having impaired fasting glucose levels (110 to 125 mg/dl; n = 56), and as having diabetes mellitus (DM >/=126 mg/dl or receiving therapy; n = 84). SDNN, LF and HF power, and LF/HF ratio were inversely related to plasma glucose levels (p <0.0001). SDNN and LF and HF powers were reduced in DM subjects (4.28 +/- 0.03, 6.03 +/- 0. 08, and 4.95 +/- 0.09) and in subjects with impaired fasting glucose levels (4.37 +/- 0.04, 6.26 +/- 0.10, and 5.06 +/- 0.11) compared with those with normal fasting glucose (4.51 +/- 0.01, 6.77 +/- 0.02, and 5.55 +/- 0.02, all p <0.005), respectively. After adjusting for covariates (age, sex, heart rate, body mass index, antihypertensive and cardiac medications, systolic and diastolic blood pressures, smoking, and alcohol and coffee consumption), LF power and LF/HF ratio were lower in DM subjects than in those with normal fasting glucose (p <0.005). HRV is inversely associated with plasma glucose levels and is reduced in diabetics as well as in subjects with impaired fasting glucose levels. Additional research is needed to determine if low HRV contributes to the increased cardiovascular morbidity and mortality described in subjects with hyperglycemia.

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.

2012 EHRA/HRS expert consensus statement on cardiac resynchronization therapy in heart failure: implant and follow-up recommendations and management

2012 EHRA/HRS expert consensus statement on cardiac resynchronization therapy in heart failure : implant and follow-up recommendations and management

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.

Heritability of heart rate variability: the Framingham heart study

BACKGROUND There is evolving evidence that heart rate (HR) is genetically determined. Heart rate variability (HRV) measured by power spectral analysis provides quantitative phenotypic markers of autonomic nervous system activity. Reported determinants of HR and HRV only partially explain their variability in the population. The purpose of this study was to assess the heritability of HR and HRV and estimate the contribution of genetic factors to their variance. METHODS AND RESULTS Subjects who underwent ambulatory recordings at a routine examination were eligible; subjects with congestive heart failure, coronary artery disease, diabetes mellitus, and those taking cardioactive medications were excluded. We analyzed high-frequency power, low-frequency power, very low-frequency power, total power, low-frequency/high-frequency ratio, and the standard deviation of normal R-R intervals from 2-hour continuous ECG recordings. Heritability analysis was done by studying correlations between siblings (n=682, in 291 sibships, 517 pairs) and between spouse pairs (n=206 pairs) after adjusting for important covariates. Results from separate models were combined to estimate the components of variance attributable to measured covariates, additive genetic effects (heritability), and household effects. After adjusting for covariates, the correlations were consistently higher among siblings (0.21 to 0.26) compared with spouses (0.01 to 0.19). The measured covariates in general accounted for 13% to 40% of the total phenotypic variance, whereas genetic factors accounted for 13% to 23% of the variation among HR and HRV measures. CONCLUSIONS Heritable factors may explain a substantial proportion of the variance in HR and HRV. These results highlight the contribution of genetic versus environmental factors to autonomic nervous system activity.