James M.M. Neilson

Prospective Study of Heart Rate Variability and Mortality in Chronic Heart Failure Results of the United Kingdom Heart Failure Evaluation and Assessment of Risk Trial (UK-Heart)

BACKGROUND Patients with chronic heart failure (CHF) have a continuing high mortality. Autonomic dysfunction may play an important role in the pathophysiology of cardiac death in CHF. UK-HEART examined the value of heart rate variability (HRV) measures as independent predictors of death in CHF. METHODS AND RESULTS In a prospective study powered for mortality, we recruited 433 outpatients 62+/-9.6 years old with CHF (NYHA functional class I to III; mean ejection fraction, 0.41+/-0.17). Time-domain HRV indices and conventional prognostic indicators were related to death by multivariate analysis. During 482+/-161 days of follow-up, cardiothoracic ratio, SDNN, left ventricular end-systolic diameter, and serum sodium were significant predictors of all-cause mortality. The risk ratio for a 41.2-ms decrease in SDNN was 1.62 (95% CI, 1.16 to 2.44). The annual mortality rate for the study population in SDNN subgroups was 5.5% for >100 ms, 12.7% for 50 to 100 ms, and 51.4% for <50 ms. SDNN, creatinine, and serum sodium were related to progressive heart failure death. Cardiothoracic ratio, left ventricular end-diastolic diameter, the presence of nonsustained ventricular tachycardia, and serum potassium were related to sudden cardiac death. A reduction in SDNN was the most powerful predictor of the risk of death due to progressive heart failure. CONCLUSIONS CHF is associated with autonomic dysfunction, which can be quantified by measuring HRV. A reduction in SDNN identifies patients at high risk of death and is a better predictor of death due to progressive heart failure than other conventional clinical measurements. High-risk subgroups identified by this measurement are candidates for additional therapy after prescription of an ACE inhibitor.

Predicting death due to progressive heart failure in patients with mild-to-moderate chronic heart failure

OBJECTIVES The aim of this study was to explore the value of noninvasive predictors of death/mode of death in ambulant outpatients with chronic heart failure (HF). BACKGROUND Mortality in chronic HF remains high, with a significant number of patients dying of progressive disease. Identification of these patients is important. METHODS We recruited 553 ambulant outpatients age 63 +/- 10 years with symptoms of chronic HF (New York Heart Association functional class, 2.3 +/- 0.5) and objective evidence of left ventricular dysfunction (ejection fraction <45%, cardiothoracic ratio >0.55, or pulmonary edema on chest radiograph). After 2,365 patient-years of follow-up, 201 patients had died, with 76 events due to progressive HF. RESULTS Independent predictors of all-cause mortality assessed with the Cox proportional hazards model were as follows: a low standard deviation of all normal-to-normal RR intervals (SDNN); lower serum sodium and higher creatinine levels; higher cardiothoracic ratio; nonsustained ventricular tachycardia; higher left ventricular end-systolic diameter; left ventricular hypertrophy; and increasing age. Independent predictors of death specific to progressive HF were SDNN, serum sodium and creatinine levels. The hazard ratio of progressive HF death for a 10% decrease in SDNN was 1.06 (95% confidence interval [CI], 1.01 to 1.12); for a 2 mmol/l decrease in serum sodium, 1.22 (95% CI, 1.08 to 1.38); and for a 10 micromol/l increase in serum creatinine, 1.14 (95% CI, 1.09 to 1.19) (all p < 0.01). CONCLUSIONS In ambulant outpatients with chronic HF, low serum sodium and SDNN and high serum creatinine identify patients at increased risk of death due to progressive HF.

Heart rate variability in patients with ventricular arrhythmias: Effect of antiarrhythmic drugs

The purpose of this study was to investigate whether heart rate variability could be reliably assessed in patients with ventricular arrhythmias and to evaluate whether it is affected by antiarrhythmic drugs. The study was based on an analysis of 239 ambulatory electrocardiographic (ECG) recordings obtained from 67 patients with frequent and complex ventricular arrhythmias enrolled in the Antiarrhythmic Drug Evaluation Group (ADEG) study. In each recording, after exclusion of premature ventricular complexes, the number of times during a 24 h period in which two consecutive sinus RR intervals differed by more than 50 ms was calculated. The total 24 h count from each recording was then used as an index of heart rate variability. This method is a reliable marker of cardiac parasympathetic activity. Recordings were analyzed at baseline (n = 56), during longterm treatment with amiodarone (n = 17), flecainide (n = 22) or propafenone (n = 17) and after washout in selected patients (n = 5). Despite the presence of a different number of arrhythmias, total 24 h counts in the same patient appeared reproducible over time (r = 0.83 between two different recordings, n = 49, p Baseline counts (median 1,698, range 26 to 13,648) were not correlated (r = 0.15) with the number of arrhythmias. The three antiarrhythmic drugs had a disparate effect on total 24 h counts: no change was observed in patients treated with amiodarone (median percent change [Δ%]-8, p = NS), whereas a significant (p These results indicate that heart rate variability can reliably be assessed by this total 24 h counts method in patients with frequent ventricular arrhythmias. The presence or suppression of arrhythmias itself did not modify heart rate variability. Class IC antiarrhythmic drugs may significantly affect heart rate variability, and this influence may contribute to the overall effect of these agents on mortality.

Effect of captopril on cardiac parasympathetic activity in chronic cardiac failure secondary to coronary artery disease

Thirty-two patients with chronic cardiac failure underwent 24-hour ambulatory electrocardiographic monitoring on 2 separate occasions: 20 patients before and during treatment with captopril, and 12 acting as controls. Heart rate variability was calculated by counting the number of times successive RR interval differences were greater than 50 ms (this measurement being a reliable index of cardiac parasympathetic activity). During treatment with captopril, group mean total counts increased to 1,032 (range 48 to 7,437) from 482 (range 23 to 6,120) (p = 0.002). There was no change in mean hourly waking or sleeping heart rates. In the control group, no changes were seen: group mean total counts on the first occasion were 340 (range 120 to 3,255) and on the second occasion 400 (range 154 to 3,300) (p = not significant). These results show that treatment with angiotensin-converting enzyme inhibitors increases cardiac parasympathetic activity in patients with chronic cardiac failure. This may be relevant to the improved prognosis of this group of patients when treated with angiotensin-converting enzyme inhibitors.

Measurement of parasympathetic activity from 24-hour ambulatory electrocardiograms and its reproducibility and sensitivity in normal subjects, patients with symptomatic myocardial ischemia, and patients with diabetes mellitus

The parasympathetic nervous system plays a major role in the pathophysiology of many cardiovascular disease, particularly in modulating myocardial electrical stability. Measurements of heart rate variability have been widely used to assess parasympathetic activity. The reproducibility of measurements obtained from 24-hour ambulatory electrocardiograms has not been well documented. We have developed a technique for measuring parasympathetic activity from clinical quality 24-hour ambulatory electrocardiograms by counting beat-to-beat increases in RR interval that are > 50 ms. To determine the reproducibility and sensitivity of our technique, we analyzed repeated 24-hour electrocardiograms of 173 subjects (19 normal subjects, 67 patients with ischemic heart disease, and 87 diabetics) followed up over periods of 2 to 16 weeks. In all subject groups, mean values for repeated measurements were virtually identical. Measurements were stable in all 3 groups throughout the course of the study, as assessed by intraclass correlation coefficients. This technique is sensitive enough to detect relatively small changes in parasympathetic activity in subjects, as demonstrated by the calculated Bland and Altman coefficients of repeatability. Reproducibility and sensitivity of our technique are particularly good in normal subjects and in patients with ischemic heart disease. The results obtained with this technique imply that other related measurements of parasympathetic activity will show similar excellent short- and long-term reproducibility and sensitivity.

Differing patterns of cardiac parasympathetic activity and their evolution in selected patients with a first myocardial infarction

OBJECTIVES The purpose of the study was to compare cardiac parasympathetic activity during the early and convalescent phases of acute anterior and inferior myocardial infarction. BACKGROUND Previous studies have shown that cardiac parasympathetic activity may vary with the site of infarction and that recovery may occur after infarction. METHODS Cardiac parasympathetic activity was measured from 24-h electrocardiograms by counting the number of times that successive RR intervals (counts) differed by > 50 ms. Recordings began within 12 h of admission and at 7, 42 and 140 days after acute myocardial infarction in 20 patients (mean age 57 +/- 7.9 years). All patients were treated with streptokinase, aspirin and oral beta-adrenergic blocking agents. RESULTS For the entire group, mean total 24-h RR counts increased from 592 (range 78 to 3,812) at 48 h to 648 (range 109 to 5,473) at 7 days, 1,145 (range 162 to 6,268) at 42 days and 1,958 (range 344 to 9,632) at 140 days. Patients with anterior infarction had significantly lower counts (mean 277, range 78 to 2,708; n = 11) compared with those with inferior infarction (mean 2,172, range 897 to 3,812; n = 9) at 48 h (p < 0.05). There was no significant difference in counts between patients with anterior (mean 1,051, range 212 to 6,268) and inferior (mean 1,321, range 162 to 3,265) infarction after 42 or after 140 days (anterior: mean 1,655, range 344 to 9,632; inferior: mean 2,588, range 1,700 to 5,767). CONCLUSIONS These data suggest that after anterior myocardial infarction there is impaired cardiac parasympathetic function that improves within 6 weeks, whereas in inferior infarction there is relative preservation of cardiac parasympathetic function.

The correction of autonomic dysfunction in cirrhosis by captopril

BACKGROUND/AIMS Vagal dysfunction is reported in about 70% of patients with cirrhosis, irrespective of aetiology, as detected by cardiovascular reflex tests. We have previously shown that RR-variability on 24-h ECG is a more sensitive marker of vagal dysfunction in cirrhosis. Angiotensin II inhibits vagal function in animals, and it is elevated in cirrhosis and may be the cause of the vagal dysfunction. Our aim was to observe the effect of captopril on vagal dysfunction in cirrhosis. METHODS Eight patients with cirrhosis (biopsy proven, male two, female six, mean age 54.25) had 24-h ECG RR-variability performed. They then received captopril 25 mg t.d.s. for 48 h. The 24-h ECG was repeated on therapy. RESULTS Mean blood pressure remained unchanged: baseline 89.8 +/- 4.8 mmHg (mean +/- sem) versus 91.8 +/- 5.9 mmHg, p = not significant. Median baseline RR-variability was 791 (range 18-5344) counts/24 h and increased in all but one patient, with captopril, to 1548 (56-4824) p = 0.008. Three increased into the normal range. CONCLUSION The vagal dysfunction of cirrhosis is caused by neuromodulation by angiotensin II and is not due to a neuropathy.

The impact of QT lag compensation on dynamic assessment of ventricular repolarization: reproducibility and the impact of lead selection.

LANG, C.C.E., et al.: The Impact of QT Lag Compensation on Dynamic Assessment of Ventricular Repolarization: Reproducibility And The Impact of Lead Selection. In cardiac disease, abnormalities exist in the rate‐corrected QT interval and the relationship between QT and heart rate. The QT/RR relationship is known to be dynamic and show circadian variation. The availability of automated methods for measurement of QT and RR intervals allows monitoring of the QT/RR relationship and may provide insights into arrhythmia onset. Using a method for analyzing 24‐hour recordings that incorporates beat‐by‐beat QT and RR measurement and an automated mechanism for compensating for lag in adaptation of QT to changes in RR, the authors evaluated the impact of lag compensation on assessment of the QT/RR relationship, reproducibility, and the effect of lead selection in 15 normal subjects. The QT/RR relationship is continuously estimated from the lag compensated data over a 5‐minute scrolling time frame. The relationship is expressed as an exponential formula, QT = QTo · RRJ where QTo is the QT interval at a standardized RR interval of 1 second and J is a variable exponent. We found that the use of lag compensation significantly improves the mean 24‐hour correlation between QT and RR data (r = 0.87 vs 0.65). The 24‐ hour mean of QTo and J were highly reproducible (coefficients of variation 2% and 8%, respectively). The mean 24‐hour QT/RR relationship for the population was QT = 0.415 · (RR)0.32. There was a small difference between leads in QTo and J. Compensating for QT adaptation lag provides a means of assessing the QT/RR relationship over long and short periods. This method allows investigation of the effect of acute interventions on the dynamic QT/RR relationship, which has previously been restricted by the presence of QT hysteresis.

Effects of digoxin on time domain measures of heart rate variability in patients with stable chronic cardiac failure: withdrawal and comparison group studies

The effect on heart rate variability of adding digoxin to a diuretic and ACE inhibitor was studied in patients with chronic stable cardiac failure. Digoxin was found to increase heart rate variability, especially those measures of heart rate variability thought to represent parasympathetic activity. The withdrawal of digoxin led to a decrease in heart rate variability to pre-treatment levels. Whilst digoxin in standard doses does not alter prognosis in chronic cardiac failure, it does have potentially beneficial neurohumoral effects. If the increase in heart rate variability, which represents beneficial neurohumoral modulation, can be divorced from the potentially detrimental effects, perhaps by using smaller doses, then there may be a role for digoxin in the treatment of chronic cardiac failure.

Abnormalities of the repolarization characteristics of patients with heart failure progress with symptom severity.

Background: Congestive heart failure is a common condition with high mortality. Many of these deaths are sudden and unexpected. Ventricular action potential, surface repolarization (QT interval), and dispersion of repolarization are prolonged in the failing heart, contributing to arrhythmogenesis and sudden death. We studied the relationship between QT and heart rate (RR interval) from ambulatory recordings using a novel method in patients with ischemic heart disease and varying degrees of left‐ventricular impairment (IHD) and compared them to healthy subjects (HS). We compare the degree of abnormality with the functional impairment and ejection fraction.