Hisako Tsuji

Impact of Reduced Heart Rate Variability on Risk for Cardiac Events The Framingham Heart Study

BACKGROUND Although heart rate variability (HRV) is altered in a variety of pathological conditions, the association of reduced HRV with risk for new cardiac events has not been studied in a large community-based population. METHODS AND RESULTS The first 2 hours of ambulatory ECG recordings obtained on subjects of the Framingham Heart Study who were free of clinically apparent coronary heart disease or congestive heart failure were reprocessed to assess HRV. Five frequency-domain measures and three time-domain measures were obtained. The associations between HRV measures and the incidence of new cardiac events (angina pectroris, myocardial infarction, coronary heart disease death, or congestive heart failure) were assessed with proportional hazards regression analyses. There were 2501 eligible subjects with a mean age of 53 years. During a mean follow-up of 3.5 years, cardiac events occurred in 58 subjects. After adjustment for age, sex, cigarette smoking, diabetes, left ventricular hypertrophy, and other relevant risk factors, all HRV measures except the ratio of low-frequency to high-frequency power were significantly associated with risk for a cardiac event (P = .0016 to .0496). A one-standard deviation decrement in the standard deviation of total normal RR intervals (natural log transformed) was associated with a hazard ratio of 1.47 for new cardiac events (95% confidence interval of 1.16 to 1.86). CONCLUSIONS The estimation of HRV by ambulatory monitoring offers prognostic information beyond that provided by the evaluation of traditional cardiovascular disease risk factors.

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.

Determinants of heart rate variability

OBJECTIVES This study sought to examine clinical determinants of heart rate variability and to report normative reference values for eight heart rate variability measures. BACKGROUND Although the clinical implications of heart rate variability have been described, clinical determinants and normative values of heart rate variability measures have not been studied systematically in a large community-based population. METHODS The first 2 h of ambulatory electrocardiographic recordings obtained in Framingham Heart Study subjects attending a routine examination were reprocessed for heart rate variability. Recordings with transient or persistent nonsinus rhythm, premature beats > 10% of total beats, < 1-h recording time or processed time < 50% of recorded time were excluded; subjects receiving antiarrhythmic medications also were excluded. Among five frequency domain and three time domain measures that were obtained, low frequency power (0.04 to 0.15 Hz), high frequency power (0.15 to 0.40 Hz) and the standard deviation of total normal RR intervals based on 2-h recordings were selected for the principal analyses. Variables with potential physiologic effects or possible technical influences on heart rate variability measures were chosen for multiple linear regression analysis. Normative values, derived from a subset of healthy subjects, were adjusted for age and heart rate. RESULTS There were 2,722 eligible subjects with a mean age (+/-SD) of 55 +/- 14 years. Three separate multiple linear regression analyses revealed that higher heart rate, older age, beta-adrenergic blocking agent use, history of myocardial infarction or congestive heart failure, diuretic use, diastolic blood pressure > or = 90 mm Hg, diabetes mellitus, consumption of three or more cups of coffee per day and smoking were associated with lower values of one or more heart rate variability measures, whereas longer processed time, start time in the morning, frequent supraventricular and ventricular premature beats, female gender and systolic blood pressure > or = 160 mm Hg were associated with higher values. Age and heart rate were the major determinants of all three selected heart rate variability measures (partial R2 values 0.125 to 0.389). Normative reference values for all eight heart rate variability measures are presented. CONCLUSIONS Age and heart rate must be taken into account when assessing heart rate variability.

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.

Heritability of Heart Rate Variability

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.

The associations of levels of serum potassium and magnesium with ventricular premature complexes (the Framingham Heart Study)

There are conflicting data regarding the impact of serum potassium and magnesium levels on susceptibility to ventricular premature complexes (VPCs) in the clinical setting. The associations of serum potassium and magnesium levels with the prevalence of complex or frequent (> 30/hour, multiform or repetitive) VPCs were examined after adjusting for age, sex, smoking, caffeinated coffee consumption, alcohol consumption, and left ventricular mass in Framingham Offspring Study subjects who were free of clinically apparent heart disease. There were 3,327 eligible subjects (mean age 44 years). Complex or frequent VPCs were present in 183 subjects (5.5%). When age-adjusted prevalences of complex or frequent VPCs were compared among quartiles of serum potassium and magnesium using a trend test, lower potassium (p = 0.002) and lower magnesium (p = 0.010) levels were associated with higher prevalence rates of arrhythmia. In logistic regression analyses that included potassium and magnesium simultaneously, potassium (p = 0.0021) and magnesium (p = 0.0311) levels were inversely associated with the occurrence of complex or frequent VPCs after adjustment for age, sex, smoking, coffee and alcohol consumption, diuretic use, and systolic blood pressure. These associations remained significant after accounting for left ventricular mass. A 1 SD decrement in potassium (0.48 mEq/liter) or magnesium (0.16 mEq/liter) level was associated with a 27% (95% confidence interval 6% to 51%) and a 20% (95% confidence interval 3% to 41%) greater odds of complex or frequent VPCs, respectively. Lower levels of serum potassium and magnesium were concurrently associated with higher prevalence rates of ventricular arrhythmias.

Atrial fibrillation in acute myocardial infarction

To elucidate the genesis and effect of atrial fibrillation (AF), 102 patients with acute myocardial infarction were studied. Eighteen patients had AF during the first 72 hours in the coronary care unit. The hospital mortality rate was 23%. Discriminant analysis was used to determine the important variables contributing to the genesis of AF and hospital mortality based on the following variables: cardiac output, pulmonary capillary wedge pressure, right atrial pressure, systolic blood pressure (at admission and before the onset of AF or most abnormal value), age, location of infarction, sex and pericarditis. Pulmonary capillary wedge pressure, right atrial pressure and age were the important factors contributing to AF, whereas pulmonary capillary wedge pressure and age were important for hospital mortality. Therefore, the hemodynamic change imposed on the left atrium and aging are the major factors related to the occurrence of AF and hospital mortality.

Genome scan linkage results for heart rate variability (the Framingham Heart Study)

There is a substantial heritable component to the beat-to-beat variation in heart rate. However, the molecular mechanisms underlying the control of heart rate variability (HRV) remain unknown. The present study sought to identify chromosomal regions linked to HRV phenotypes. The first 2 hours of ambulatory electrocardiographic recordings obtained from Framingham Heart Study subjects attending a routine examination were processed for HRV. HRV variables analyzed included very-low-frequency power, low-frequency power, and high-frequency power. Gender-specific residuals were used for log-transformed HRV data after adjustment for age, HR, systolic and diastolic blood pressures, and coffee and alcohol consumption. In conjunction with a 10-cM genome-wide scan, HRV data were available for 725 subjects in 230 extended families, including 390 sibling pairs. Variance component log-of-the-odds (LOD) scores were obtained. The highest multipoint LOD scores were obtained for log very-low frequency on chromosome 15 at 62 cM (LOD 1.84) and for log low frequency on chromosome 2 at 153 cM (LOD 1.81). These data suggest there may be influential genetic regions contributing to HRV. Further studies are warranted to identify genes in these regions that may influence autonomic tone. Recognition of the genetic determinants of HRV may provide additional insights into the pathophysiology of the autonomic nervous system and offer clues to its modulation.

Prognosis of subjects with Brugada-type electrocardiogram in a population of middle-aged Japanese diagnosed during a health examination.

There is controversy about the clinical significance of an incidental finding of a Brugada-type electrocardiogram (ECG) pattern. To assess the prognosis of subjects with a diagnosis of a Brugada-type ECG pattern during a health examination, 13,904 subjects (mean age 58 +/- 10 years) who had the annual health examination including an ECG offered to adult citizens of Moriguchi City, Osaka, Japan, in 1997 were studied. A Brugada-type ECG pattern was found in 98 subjects, and 37 subjects had type 1. During a mean follow-up of 7.8 +/- 1.6 years, there were 4 deaths (4.1%) and 1 cardiovascular death (1.0%) in subjects with a Brugada-type ECG pattern, whereas there were 612 deaths (4.4%) and 142 cardiovascular deaths (1.0%) in those without. One cardiovascular death in a subject with a Brugada-type ECG pattern was sudden death. Unadjusted proportional hazards regression analyses showed that Brugada-type ECG pattern was not associated with either all-cause (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.34 to 2.41) or cardiovascular mortality (HR 0.97, 95% CI 0.14 to 6.93). After adjustment for cardiovascular risk factors, Brugada-type ECG pattern had no association with either all-cause (HR 0.77, 95% CI 0.29 to 2.07) or cardiovascular mortality (HR 1.01, 95% CI 0.14 to 7.31). In conclusion, Brugada-type ECG patterns diagnosed during a health examination in a middle-aged population had a low risk of sudden death and were not associated with increased risk of either cardiovascular or all-cause mortality.

Haemoglobin level influences plasma brain natriuretic peptide concentration.

Objective — It has been demonstrated that the haemoglobin (Hb) level is associated with the prognosis of congestive heart failure (CHF). Correction of anaemia has improved CHF outcomes even in patients without anaemia. Lower Hb level may play a more important role in left ventricular (LV) dysfunction than previously recognized. This study aimed to evaluate the association of Hb level with plasma brain natriuretic peptide (BNP) level as a marker of LV function adjusted for known determinants of BNP. Methods and results — Association of Hb level with plasma BNP level was studied in 279 outpatients of cardiology (mean age 61 ± 16, 54% men) using multivariate regression analysis. Mean Hb level was 13.7 ± 1.5 g/dl and 14% of patients had anaemia. Median BNP level was 28 pg/ml (range < 4 to 580 pg/ml). In total subjects, the multivariate model adjusted for age, sex, history of CHF, atrial fibrillation, serum creatinine level, LV wall motion abnormality, end-diastolic LV dimension, LV mass index, and cardiovascular risk factors showed that a lower Hb level was significantly associated with higher BNP level (p = 0.0243). In “normal” subjects who did not have a history of CHF, atrial fibrillation, LV wall motion abnormality, LV dilatation, valvular abnormality, or LV hypertrophy, a lower Hb level was significantly associated with a higher BNP level (p = 0.0012) after adjustment for age, sex, serum creatinine level, and cardiovascular risk factors. Conclusions — Lower Hb levels are associated with higher plasma BNP levels independent of age, sex, serum creatinine level, LV wall motion abnormality, LV hypertrophy, history of CHF, atrial fibrillation, and cardiovascular risk factors.