Jeffrey N. Rottman

Frequency domain measures of heart period variability and mortality after myocardial infarction.

BackgroundWe studied 715 patients 2 weeks after myocardial infarction to establish the associations between six frequency domain measures of heart period variability (HPV) and mortality during 4 years of follow-up. Methods and ResultsEach measure of HPV had a significant and at least moderately strong univariate association with all-cause mortality, cardiac death, and arrhythmic death. Power in the lower-frequency bands–ultra low frequency (ULF) and very low frequency (VLF) power–had stronger associations with all three mortality end points than power in the higher-frequency bands-low frequency (LF) and high frequency (HF) power. The 24-hour total power also had a significant and strong association with all three mortality end points. VLF power was the only variable that was more strongly associated with arrhythmic death than with cardiac death or all-cause mortality. In multivariate Cox regression models using a step-up approach to evaluate the independent associations between frequency domain measures of heart period variability and death of all causes, ULF power was selected first (i.e., was the single component with the strongest association). Adding VLF or LF power to the Cox regression model significantly improved the prediction of outcome. With both ULF and VLF power in the Cox regression model, the addition of the other two components, LF and HF power, singly or together, did not significantly improve the prediction of all-cause mortality. We explored the relation between the heart period variability measures and all-cause mortality, cardiac death, and arrhythmic death before and after adjusting for five previously established postinfarction risk predictors: age, New York Heart Association functional class, rales in the coronary care unit, left ventricular ejection fraction, and ventricular arrhythmias detected in a 24-hour Holter ECG recording ConclusionsAfter adjustment for the five risk predictors, the association between mortality and total, ULF, and VLF power remained significant and strong, whereas LF and HF power were only moderately strongly associated with mortality. The tendency for VLF power to be more strongly associated with arrhythmic death than with all-cause or cardiac death was still evident after adjusting for the five covariates. Adding measures of HPV to previously known predictors of risk after myocardial infarction identifies small subgroups with a 2.5-year mortality risk of approximately 50%.

Correlations among time and frequency domain measures of heart period variability two weeks after acute myocardial infarction

Seven hundred fifteen participants from a multicenter natural history study of acute myocardial infarction were studied (1) to determine the correlations among time and frequency domain measures of heart period variability, (2) to determine the correlations between the measures of heart period variability and previously established post-infarction risk predictors, and (3) to determine the predictive value of time domain measures of heart period variability for death during follow-up after acute myocardial infarction. Twenty-four hour electrocardiographic recordings obtained 11 +/- 3 days after acute myocardial infarction were analyzed and 11 measures of heart period variability were computed. Each of 4 bands in the heart period power spectrum had 1 or 2 corresponding variables in the time domain that correlated with it so strongly (r greater than or equal to 0.90) that the variables were essentially equivalent: ultra low frequency power with SDNN* and SDANN index,* very low frequency power and low-frequency power with SDNN index,* and high-frequency power with r-MSSD* and pNN50.* As expected from theoretical considerations, SDNN and the square root of total power were almost perfectly correlated. Correlations between the time and frequency domain measures of heart period variability and previously identified postinfarction risk predictors, e.g., left ventricular ejection fraction and ventricular arrhythmias, are remarkably weak. Time domain measures of heart period variability, especially those that measure ultra low or low-frequency power, are strongly and independently associated with death during follow-up. * Defined in Table II.

Time Domain Measurements of Heart Rate Variability

Assessment of HRV through time domain variables is a simple and practical method of assessing autonomic function. In this capacity its utility has been demonstrated in normal subjects and in diverse cardiac and noncardiac pathologic states. It can be used to assess the effects of drugs and other interventions, including exercise and psychological and physical stress on cardiac autonomic tone. Importantly, decreased HRV is almost uniformly associated with adverse outcome. The prognostic information appears to incorporate both alterations in autonomic tone and longer term components and is best assessed using ambulatory ECG recordings. Defining the clinical applicability and physiologic mechanisms of changes in HRV remain active areas of research.

Severe depression is associated with markedly reduced heart rate variability in patients with stable coronary heart disease

OBJECTIVE The purpose of this study was to investigate the relationship between depression and heart rate variability in cardiac patients. METHODS Heart rate variability was measured during 24-hour ambulatory electrocardiographic (ECG) monitoring in 40 medically stable out-patients with documented coronary heart disease meeting current diagnostic criteria for major depression, and 32 nondepressed, but otherwise comparable, patients. Patients discontinued beta-blockers and antidepressant medications at the time of study. Depressed patients were classified as mildly (n = 21) or moderately-to-severely depressed (n = 19) on the basis of Beck Depression Inventory scores. RESULTS There were no significant differences among the groups in age, gender, blood pressure, history of myocardial infarction, diabetes, or smoking. Heart rates were higher and nearly all indices of heart rate variability were significantly reduced in the moderately-to-severely versus the nondepressed group. Heart rates were also higher and mean values for heart rate variability lower in the mildly depressed group compared with the nondepressed group, but these differences did not attain statistical significance. CONCLUSION The association of moderate to severe depression with reduced heart rate variability in patients with stable coronary heart disease may reflect altered cardiac autonomic modulation and may explain their increased risk for mortality.

Chronic Treatment With Sildenafil Improves Energy Balance and Insulin Action in High Fat–Fed Conscious Mice

Stimulation of nitric oxide–cGMP signaling results in vascular relaxation and increased muscle glucose uptake. We show that chronically inhibiting cGMP hydrolysis with the phosphodiesterase-5 inhibitor sildenafil improves energy balance and enhances in vivo insulin action in a mouse model of diet-induced insulin resistance. High-fat–fed mice treated with sildenafil plus l-arginine or sildenafil alone for 12 weeks had reduced weight and fat mass due to increased energy expenditure. However, uncoupling protein-1 levels were not increased in sildenafil-treated mice. Chronic treatment with sildenafil plus l-arginine or sildenafil alone increased arterial cGMP levels but did not adversely affect blood pressure or cardiac morphology. Sildenafil treatment, with or without l-arginine, resulted in lower fasting insulin and glucose levels and enhanced rates of glucose infusion, disappearance, and muscle glucose uptake during a hyperinsulinemic (4 mU · kg−1 · min−1)–euglycemic clamp in conscious mice. These effects occurred without an increase in activation of muscle insulin signaling. An acute treatment of high fat–fed mice with sildenafil plus l-arginine did not improve insulin action. These results show that phosphodiesterase-5 is a potential target for therapies aimed at preventing diet-induced energy imbalance and insulin resistance.

Comparison of baroreflex sensitivity and heart period variability after myocardial infarction

In animals, baroreflex sensitivity is inversely related to the likelihood of ventricular fibrillation during myocardial ischemia. After myocardial infarction in human patients, reduced baroreflex sensitivity is associated with increased mortality. A reduced standard deviation of normal RR intervals over a 24 h period is also associated with reduced survival after myocardial infarction. Therefore, 32 normotensive men who had survived their first myocardial infarction were studied to define the relation between baroreflex sensitivity assessed with phenylephrine injection and three Holter electrocardiographic measures of tonic vagal activity: the percent of successive normal RR intervals greater than 50 ms, the root mean square successive difference of normal RR intervals and the power in the high frequency energy of the normal RR interval power spectrum. Correlations among the Holter measures of heart period variability were greater than or equal to 0.94, indicating that these measures are so strongly correlated that any one of them can be used to represent the others. Baroreflex sensitivity showed weaker correlations with the three Holter variables (0.57 to 0.63), indicating that the Holter measures did not accurately predict baroreflex sensitivity. Baroreflex sensitivity showed a stronger correlation with the three Holter variables during the night than during the day. Baroreflex sensitivity and tonic vagal activity reflected by Holter variables were reduced more in patients with inferior myocardial infarction than in those with anterior infarction. The relative utility of baroreflex sensitivity and Holter measures of tonic vagal activity in predicting sudden cardiac death after myocardial infarction needs to be evaluated in a large prospective study.

Differing Effects of Age on Heart Rate Variability in Men and Women

Gender and age are both known to affect heart rate variability (HRV). Their interaction is not known. HRV, determined from 24-hour Holter recordings, was compared between gender-matched older (15 men and 15 women, aged 67 +/- 3 years, range 64 to 76) and younger (15 men and 15 women, aged 33 +/- 4 years, range 26 to 42) subjects selected for an age difference of approximately 35 years. HRV for older and younger subjects was compared separately by gender. HRV was also compared by gender within groups. Heart rates were significantly higher, and all time and frequency domain indexes of HRV were significantly lower among the older than among the younger men. Among the women only the shorter term indexes of HRV were significantly lower in the older group. When HRV was compared by gender within age groups, there were no significant differences between men and women in the older group. In the younger group, men had lower heart rates, and all 24-hour time domain indexes of HRV, except those that reflect vagal modulation of heart rate, were significantly higher than those in women. We conclude that HRV is comparable in older men and women. However, HRV is differently affected by age. In men, for whom initial levels of HRV are significantly higher, older age is associated with a global reduction in HRV, reflecting reductions in both sympathetic and parasympathetic modulation and a loss of circadian variability. In women, older age is associated mainly with a decline in shorter term indexes of HRV without significant changes in circadian variability.

Triggering of Nocturnal Arrhythmias by Sleep-Disordered Breathing Events

OBJECTIVES This study sought to evaluate respiratory disturbances as potential triggers for arrhythmia in patients with sleep-disordered breathing (SDB). BACKGROUND SDB is associated with an increased risk of atrial fibrillation and nonsustained ventricular tachycardia (NSVT) as well as a predilection for sudden cardiac death during nocturnal sleeping hours. However, prior research has not established whether respiratory disturbances operate as triggers for nocturnal arrhythmias. METHODS Overnight polysomnograms from the Sleep Heart Health Study (n = 2,816) were screened for paroxysmal atrial fibrillation and NSVT. We used the case-crossover design to determine whether apneas and/or hypopneas are temporally associated with episodes of paroxysmal atrial fibrillation or NSVT. For each arrhythmia, 3 periods of sinus rhythm were identified as control intervals. Polysomnograms were examined for the presence of respiratory disturbances, oxygen desaturations, and cortical arousals within a 90-s hazard period preceding each arrhythmia or control period. RESULTS Fifty-seven participants with a wide range of SDB contributed 62 arrhythmias (76% NSVT). The odds of an arrhythmia after a respiratory disturbance were nearly 18 times (odds ratio: 17.5; 95% confidence interval: 5.3 to 58.4) the odds of an arrhythmia occurring after normal breathing. The absolute rate of arrhythmia associated with respiratory disturbances was low (1 excess arrhythmia per 40,000 respiratory disturbances). Neither hypoxia nor electroencephalogram-defined arousals alone increased arrhythmia risk. CONCLUSIONS Although the absolute arrhythmia rate is low, the relative risk of paroxysmal atrial fibrillation and NSVT during sleep is markedly increased shortly after a respiratory disturbance. These results support a direct temporal link between SDB events and the development of these arrhythmias.

Mechanisms of Death in the CABG Patch Trial A Randomized Trial of Implantable Cardiac Defibrillator Prophylaxis in Patients at High Risk of Death After Coronary Artery Bypass Graft Surgery

BACKGROUND The CABG Patch trial compared prophylactic implantable cardiac-defibrillator (ICD) implantation with no antiarrhythmic therapy in coronary bypass surgery patients who had a left ventricular ejection fraction <0.36 and an abnormal signal-averaged ECG. There were 102 deaths among the 446 ICD group patients and 96 deaths among the 454 control group patients, a hazard ratio of 1.07 (P=0.63). The mechanisms of death were classified, and hypotheses were tested about the effects of ICD therapy on arrhythmic and nonarrhythmic cardiac deaths in the CABG Patch Trial and the Multicenter Automatic Defibrillator Implantation Trial (MADIT). METHODS AND RESULTS The 198 deaths in the trial were reviewed by an independent Events Committee and classified by the method of Hinkle and Thaler. Only 54 deaths (27%) occurred out of hospital; 145 deaths (73%) were witnessed. Seventy-nine (82%) of the 96 deaths in the control group and 76 (75%) of the 102 deaths in the ICD group were due to cardiac causes. Cumulative arrhythmic mortality at 42 months was 6.9% in the control group and 4.0% in the ICD group (P=0. 057). Cumulative nonarrhythmic cardiac mortality at 42 months was 12. 4% in the control group and 13.0% in the ICD group (P=0.275). Death due to pump failure was significantly associated with death >1 hour from the onset of symptoms, dyspnea within 7 days of death, and overt heart failure within 7 days of death. CONCLUSIONS In the CABG Patch Trial, ICD therapy reduced arrhythmic death 45% without significant effect on nonarrhythmic deaths. Because 71% of the deaths were nonarrhythmic, total mortality was not significantly reduced.

Effect of exercise training on heart rate variability in healthy older adults

OBJECTIVE To determine the effect of exercise training on cardiac autonomic modulation in normal older adults by using analysis of heart rate variability. SUBJECTS The exercise group consisted of 7 men and 9 women aged 66 +/- 4 years. The comparison group consisted of 7 men and 9 women also aged 66 +/- 4 years. METHOD Heart rate variability was determined from 24-hour Holter recordings before and after 12 months of supervised exercise, which consisted of 3 months of stretching and 9 months of 5 hours/week aerobic exercise at approximately 70% of maximal oxygen uptake. Heart rate variability was measured at baseline and 12 months later in the comparison group, who had not changed their usual activity level. RESULTS In the exercise group maximal oxygen consumption increased from 1.8 +/- 0.5 L/min to 2.2 +/- 0.7 L/min (P <.05). The standard deviation of normal interbeat intervals increased from 126 +/- 21 ms to 142 +/- 25 ms. Mean nighttime heart rate decreased from 67 +/- 6 beats/min to 63 +/- 5 beats/min. Increased fitness level had little effect on indexes of heart rate variability, which reflect parasympathetic or mixed sympathetic/parasympathetic modulation of heart rate. There was no change in heart rate or heart rate variability in the comparison group. CONCLUSIONS Exercise training increases total heart rate variability in normal older adults. The most marked alterations are in nocturnal heart rate. Heart rate variability is stable over a 1-year period in older adults who do not alter their activity level.