Forrester A. Lee

Circadian variation of sustained ventricular tachycardia in patients with coronary artery disease and implantable cardioverter-defibrillators.

While previous studies using epidemiological data and ambulatory ECG monitoring have shown peak occurrence of sudden death and nonsustained ventricular tachycardia in the morning, none have examined circadian variation of potentially life-threatening ventricular tachycardia (VT), nor has any study observed circadian behavior of any arrhythmias in individuals followed longitudinally. We used the event memory of multiprogrammable implantable cardioverter- defibrillators to evaluate the circadian pattern of sustained VT over time. Methods and ResultsData were reviewed from 32 consecutive patients with coronary artery disease and sustained VT who had received the Ventak PRX (CPI, Inc) cardioverterdefibrillator between May 1991 and August 1993 and had experienced at least one episode of VT terminated by their device. Mean follow-up was 14±7 months. Among the 2558 episodes recorded by the device logs, VT occurrence peaked between 6 AM and noon (P = .007 by ANOVA among four 6-hour time periods). Harmonic regression revealed a morning peak at 9 AM (P < .01). This morning peak occurred in patients with both frequent and infrequent events. Among 21 patients who experienced more than four VT events, 8 (38%) had an AM peak of VT occurrence (>35% of VT between 6 AM and noon). Neither age, ejection fraction, event frequency, presenting arrhythmia, nor drug therapy distinguished patients who displayed the AM VT peak. ConclusionsIn patients with coronary artery disease, sustained VT displays circadian variation with peak frequency in the morning, similar to that for sudden death. Individual patients who display specific patterns of circadian variation over time can be identified using defibrillator logs. Investigation of circadian variation of other phenomena to elucidate mechanisms of VT should focus on these patients.

Effects of propranolol on recovery of heart rate variability following acute myocardial infarction and relation to outcome in the Beta-Blocker Heart Attack Trial.

This study evaluated the effects of propranolol on recovery of heart rate variability (HRV) after acute myocardial infarction and its relation to outcome in the Beta-blocker Heart Attack Trial (BHAT). Beta blockers improve mortality after acute myocardial infarction, but through an unknown mechanism. Depressed HRV, a measure of autonomic tone, predicts mortality after acute myocardial infarction. Whether beta blockers influence recovery of HRV after acute myocardial infarction, and thereby improve outcome, is unknown. We compared 24-hour HRV parameters at 1 week after acute myocardial infarction and after 6 weeks of treatment with propanolol (n = 88) or placebo (n = 96). The relation between 25-month outcome (death/acute myocardial infarction/congestive heart failure), propranolol treatment, and HRV was further analyzed. After 6 weeks, high-frequency (HF) power (log-normalized), an index of vagal tone, increased more in propranolol-treated patients (4.28 +/- 0.1 to 5.17 +/- 0.09 ms(2)) than in placebo-treated patients (4.26 +/- 0.09 to 4.77 +/- 0.1 ms(2), p <0.05). Sympathovagal balance measured by the low-frequency (LF) to HF ratio increased in placebo-treated patients (3.55 +/- 0.24 to 3.86 +/- 0.24) but decreased in those treated with propranolol (3.76 +/- 0.29 to 3.17 +/- 0.23, p <0.01). Other frequency-domain parameters increased over time but were not affected by propranolol. Propranolol blunted the morning increase in the LF/HF ratio. Recovery of HF, the strongest HRV predictor of outcome, and propranolol therapy independently predicted outcome. In summary, after acute myocardial infarction, propranolol therapy improves recovery of parasympathetic tone, which correlates with improved outcome, and decreases morning sympathetic predominance. These findings may elucidate the mechanisms by which beta blockers decrease mortality and reduce the early morning risk of sudden death after acute myocardial infarction.

Decreased heart rate variability is associated with higher levels of inflammation in middle-aged men

BACKGROUND Many traditional risk factors for coronary artery disease (CAD) are associated with altered autonomic function. Inflammation may provide a link between risk factors, autonomic dysfunction, and CAD. We examined the association between heart rate variability (HRV), a measure of autonomic function, and inflammation, measured by C-reactive protein (CRP) and interleukin-6 (IL-6). METHODS We examined 264 middle-aged male twins free of symptomatic CAD. All underwent ambulatory electrocardiogram monitoring and 24-hour ultra low, very low, low, and high-frequency power were calculated using power spectral analysis. C-reactive protein and IL-6 were measured, and risk factors including age, smoking, hypertension, lipids, diabetes, body mass index (BMI), depression, and physical activity were assessed. RESULTS Physical activity, BMI, high-density lipoprotein cholesterol, smoking, depression, and hypertension were directly associated with CRP and IL-6 and inversely associated with one or more HRV variables. There was a graded inverse relationship between all HRV parameters (except high frequency) and CRP and IL-6. After adjustment for age, BMI, activity, high-density lipoprotein, smoking, hypertension, depression, and diabetes, ultra low frequency and very low frequency remained significant predictors of CRP (P < .01). CONCLUSIONS C-reactive protein is associated with decreased HRV, even after controlling for traditional CAD risk factors. Autonomic dysregulation leading to inflammation may represent one pathway through which traditional risk factors promote development of CAD.

Peak filling rate normalized to mitral stroke volume: A new Doppler echocardiographic filling index validated by radionuclide angiographic techniques

The noninvasive measurement of left ventricular filling has relied predominantly on radionuclide-derived peak filling rate normalized to end-diastolic volume. Doppler echocardiography also has the ability to measure peak filling rate, but wide application of this technique has been limited by technical errors involved in quantitative echocardiographic determination of mitral anulus cross-sectional area and ventricular volumes. For Doppler echocardiography, normalization of peak filling rate to mitral stroke volume rather than end-diastolic volume permits the derivation of a diastolic filling index that is relatively free of errors caused by geometric assumptions, diameter measurements and sample volume positioning. This normalization process can be achieved by simply dividing early peak filling velocity by the time velocity integral of mitral inflow. To validate this new Doppler echocardiographic filling index, Doppler echocardiographic and radionuclide-derived peak filling rate, both normalized to mitral stroke volume, were compared in 30 patients; there was an excellent correlation (r = 0.91, SEE = 0.88). This variable was not influenced by the position of the sample volume in relation to the mitral apparatus in contrast to early filling velocity, which increased 37%, and early/late filling (E/A) ratio, which increased 43% as the sample volume was moved from the anulus to the tips of the mitral leaflets. In a cohort of 22 normal patients, the mean peak filling rate normalized to mitral stroke volume (SV) was 5.25 +/- 1.47 SV/s. The mean peak filling rate for a subgroup of eight normal patients aged 57 to 89 years (mean 71 +/- 9) was 3.9 +/- 1 SV/s.(ABSTRACT TRUNCATED AT 250 WORDS)

Depressive symptoms and heart rate variability: Evidence for a shared genetic substrate in a study of twins

Objective: To clarify the relationship between depression and heart rate variability (HRV) in a sample of twins. Reduced HRV, a measure of autonomic dysfunction, has been linked to depression but many studies have inadequately controlled for familial and environmental factors. Furthermore, little is known about whether depression and HRV share common genetic pathways. Methods: We performed power spectral analysis on 24-hour ambulatory electrocardiograms in 288 middle-aged male twins. Log-normalized ultra low, very low, low, high frequency, and total power were calculated. A lifetime history of major depressive disorder (MDD) was determined, using the Structured Clinical Interview for Psychiatry Disorders, and current depressive symptoms were measured with the Beck Depression Inventory. Mixed-effect regression models were used to account for intrapair variability and estimate within-pair effects at the same time controlling for potential confounders. Results: Both current depressive symptoms and a history of MDD were significantly associated with lower HRV. There was a graded effect, and power in each frequency band was 29% to 36% lower in the lowest band compared with the highest BDI category. All HRV measures except high frequency remained significantly associated with current depressive symptoms in multivariable analysis, but not with lifetime history of MDD. When analyses were stratified by zygosity, a significant within-pair association between BDI score and HRV was found in the dizygotic but not in the monozygotic twins, suggesting a genetic influence on the association. Conclusions: A shared, genetically influenced biological pathway underlies the association between depression and lower HRV. These two phenotypes may be the expression of a generalized neurobiological perturbation. BDI = Beck Depression Inventory; CAD = coronary artery disease; DZ = dizygotic; HRV = heart rate variability; MDD = major depressive disorder; MZ = monozygotic; PTSD = posttraumatic stress disorder.

Onset of altered interventricular septal motion during cardiac surgery. Assessment by continuous intraoperative transesophageal echocardiography.

Abnormal motion of the interventricular septum is frequently observed after uncomplicated cardiac surgery. We sought to elucidate the mechanism underlying this phenomenon by using continuous echocardiographic imaging of the heart from a constant transesophageal location in 21 patients undergoing their first cardiac operation. Quantitative global and regional functional analyses were performed in each patient at baseline (stage 1), after median sternotomy (stage 2), after sternal retraction (stage 3), after pericardiotomy (stage 4), after completion of cardiopulmonary bypass (stage 5), and after chest closure (stage 6). During the first four surgical stages, mean left ventricular fractional shortening varied little among regions with a fixed reference system (maximum range, 31.6-39.2%; p = NS) but changed dramatically after the discontinuation of cardiopulmonary bypass (stage 5). The apparent medial hypokinesis that was observed (4.9 +/- 4.7% [SD]) was accompanied by lateral hyperkinesis (65.2 +/- 4.1%, p less than 0.0001). These regional differences were completely eliminated with a floating reference system (33.6 +/- 2.7% for medial, and 34.8 +/- 1.7% for lateral; p = NS), suggesting cardiac translation. Quantitative curvature analysis supported this conclusion, with preservation of baseline regional curvature seen throughout the procedure. The mean length of individual translational vectors (reflecting systolic movement of the endocardial centroid) remained minimal (less than or equal to 1.0 mm) through stage 4 but increased more than fourfold at stage 5, continuing in a medial direction after chest closure (5.2 +/- 3.0 mm and 271 +/- 6 degrees from anterior). Thus, abnormal postoperative septal motion is not caused by removal of restraining forces of the pericardium or anterior mediastinum but rather appears to be directly related to events occurring during cardiopulmonary bypass.

A bending energy model for measurement of cardiac shape deformity

An approach to analyzing and quantifying the shape characteristics of the endocardial contour of the left ventricle of the heart is described. The computation begins by finding the local curvature differences between the contour under consideration and the mean normal contour at each of 100 equidistant points. The weighted square of these differences, summed over a set of points, is shown to be the regional or, global bending energy required to deform the mean normal contour to the characteristic shape of the analyzed contour. Resampling, smoothing and curvature computation issues are considered for the image-derived digital contours that are used in the analysis. Experiments were performed on artificial contour data and data derived from contrast ventriculographic (CV) studies of humans. It is also shown that the method has been adapted to measure endocardial shape form equilibrium radionuclide angiocardiography.

Home continuous positive inotropic infusion as a bridge to cardiac transplantation in patients with end-stage heart failure

BACKGROUND The clinical use of positive inotropic therapy at home in patients awaiting cardiac transplantation has not been reported since United Network for Organ Sharing (UNOS) regulations were changed to allow home infusions in Status 1B patients. METHODS We observed 21 consecutive patients with UNOS 1B status during positive inotropic therapy at home. We used hemodynamic monitoring at the initiation of therapy to optimize dosing. We selected for home therapy patients with stable clinical status and improved functional capacity during inotropic treatment. Implantable cardioverter defibrillators were placed in all but 1 patient before discharge. RESULTS Initial positive inotropic therapy included dobutamine in 12 patients (mean dose, 4.5 mcg/kg/min; range, 2.5-7.5 mcg/kg/min), milrinone in 8 patients (mean dose, 0.44 mcg/kg/min; range, 0.375-0.55 mcg/kg/min), and dopamine at a dose of 3 mcg/kg/min in 1 patient. Patients had improved functional capacity (New York Heart Association Class 3.7 +/- 0.1 to 2.4 +/- 0.2, p < 0.01), improved renal function (serum creatinine, 1.5 +/- 0.1 to 1.3 +/- 0.1, p < 0.01), improved resting hemodynamics, and decreased number of hospitalizations during positive inotropic infusion therapy when compared with pre-treatment baseline. Implantable cardioverter defibrillator discharges were infrequent (0.19 per 100 patient days of follow-up). Actuarial survival to transplantation at 6 and 12 months was 84%. CONCLUSIONS Continuous positive inotropic therapy at home was safe and was associated with decreased health care costs in selected patients awaiting cardiac transplantation.

Prognostic value of noninvasive testing one year after orthotopic cardiac transplantation

OBJECTIVES We sought to evaluate the prognostic value of routine noninvasive testing--stress thallium-201 imaging, rest two-dimensional echocardiography and rest equilibrium radionuclide angiography--1 year after cardiac transplantation. BACKGROUND Coronary artery vasculopathy is the most important cause of late death after orthotopic cardiac transplantation. Several clinical variables have been identified as risk factors for development of coronary vasculopathy. Traditional noninvasive diagnostic testing has been shown to be relatively insensitive for identifying patients with angiographic vasculopathy. METHODS Results of prospectively acquired noninvasive testing in 47 consecutive transplant recipients alive 1 year after transplantation were related to subsequent survival. Other clinical variables previously shown to be associated with the development of coronary artery vasculopathy were also included in the analysis. RESULTS The 5-year survival rate after cardiac transplantation was 81%. By univariate analysis, echocardiography (chi-square 9.21) and stress thallium-201 myocardial perfusion imaging (chi-square 16.76) were predictive for survival, whereas rest equilibrium radionuclide angiography was not. Clinical contributors to survival were donor age (chi-square 4.56), number of human leukocyte antigen mismatches (chi-square 3.06) and cold ischemic time (chi-square 3.23). By multivariate analysis, stress myocardial imaging remained the only significant predictor of survival (risk ratio 0.27; 95% confidence interval 0.06 to 0.89). CONCLUSIONS Normal thallium-201 stress myocardial perfusion imaging 1 year after cardiac transplantation is an important predictor of 5-year survival.

Common Genes Contribute to Depressive Symptoms and Heart Rate Variability: The Twins Heart Study

Depression and reduced heart rate variability (HRV) are predictors of coronary artery disease (CAD), and highly correlated with each other. However, little is known to what extend this correlation can be explained by common genetic components. We examined 198 middle-aged male twins (121 monozygotic and 77 dizygotic) from the Vietnam Era Twin Registry. Current depressive symptoms were assessed using the Beck Depression Inventory-II and HRV was assessed on 24-hour electrocardiographic Holter recordings. Five frequency domain variables were used, including ultra low frequency (ULF), very low frequency (VLF), low frequency (LF), high frequency (HF) and total power (TPow). Structural equation modeling was used to estimate shared genetic effects for depressive symptoms and the HRV frequency domains. Both depressive symptoms (h(2)=.5) and all measurements of HRV showed high heritability (h(2)=.43-.63). A significant inverse correlation was found between depressive symptoms and all HRV indices except LF and HF, with the highest coefficient (r) for TPow (r = -.24, P = .01) and ULF (r = -.24, P = .01). Bivariate genetic modeling revealed significant genetic correlations between depressive symptoms and TPow (r(A) = -.21, P = .04), as well as ULF (r(A) = -.23, P = .02). Of the total covariance between depressive symptoms and these two HRV indices, over 80% was due to the same genetic factors. In conclusion, depressive symptoms are associated with decreased HRV and this association is due, in large part, to a shared genetic effect. These results suggest that a common neurobiological dysfunction links depression and autonomic dysregulation.