Depressed Heart Rate Variability as an Independent Predictor of Death in Chronic Congestive Heart Failure Secondary to Ischemic or Idiopathic Dilated Cardiomyopathy

After acute myocardial infarction, depressed heart rate variability (HRV) has been proven to be a powerful independent predictor of a poor outcome. Although patients with chronic congestive heart failure (CHF) have also markedly impaired HRV, the prognostic value of HRV analysis in these patients remains unknown. The aim of this study was to investigate whether HRV parameters could predict survival in 102 consecutive patients with moderate to severe CHF (90 men, mean age 58 years, New York Heart Association [NYHA] class II to IV, CHF due to idiopathic dilated cardiomyopathy in 24 patients and ischemic heart disease in 78 patients, ejection fraction [EF], 26%; peak oxygen consumption, 16.9 ml/kg/min) after exclusion of patients in atrial fibrilation with diabetes or with chronic renal failure. In the prognostic analysis (Cox proportional-hazards model, Kaplan-Meier survival analysis), the following factors were investigated: age, CHF etiology, NYHA class, EF, peak oxygen consumption, presence of ventricular tachycardia on Holter monitoring, and HRV measures derived from 24-hour electrocardiography monitoring, calculated in the time (standard deviation of all normal RR intervals [SDNN], standard deviation of 5-minute RR intervals [SDANN], mean of all 5-minute standard deviations of RR intervals [SD], root-mean-square of difference of successive RR intervals [rMSSD], and percentage of adjacent RR intervals >50 ms different [pNN50]) and frequency domain (total power [TP], power within low-frequency band [LF], and power within high-frequency band [HF]). During follow-up of 584 ± 405 days (365 days in all who survived), 19 patients (19%) died (mean time to death: 307 ± 315 days, range 3 to 989). Cox's univariate analysis identified the following factors to be predictors of death: NYHA (p = 0.003), peak oxygen consumption (p = 0.01), EF (p = 0.02), ventricular tachycardia on Holter monitoring (p = 0.05), and among HRV measures: SDNN (p = 0.004), SDANN (p = 0.003), SD (p = 0.02), and LF (p = 0.003). In multivariate analysis, HRV parameters (SDNN, SDANN, LF) were found to predict survival independently of NYHA functional class, EF, peak oxygen consumption, and ventricular tachycardia on Holter monitoring. The Kaplan-Meier survival curves revealed SDNN <100 ms to be a useful risk factor; 1-year survival in patients with SDNN <100 ms was 78% when compared with 95% in those with SDNN >100 ms (p = 0.008). The coexistence of SDNN <100 ms and a peak oxygen consumption <14 ml/kg/min allowed identification of a group of 18 patients with a particularly poor prognosis (1-year survival 63% vs 94% in the remaining patients, p <0.001). We conclude that depressed HRV on 24-hour ambulatory electrocardiography monitoring is an independent risk factor for a poor prognosis in patients with CHF. Whether analysis of HRV could be recommended in the risk stratification for better management of patients with CHF needs further investigation.

In 102 consecutive patients with stable chronic congestive heart failure and sinus rhythm, several heart rate variability measures derived from 24-hour electrocardiographic recording were significant prognostic risk markers, independent of clinical variables (New York Heart Association class, peak oxygen consumption, left ventricular ejection fraction). The coexistence of the standard deviation of all normal RR intervals <100 ms and peak oxygen consumption <14 ml/kg/min had the worst prognosis, and it is concluded that heart rate variability analysis is useful for noninvasive heart transplant assessment.     

Interleukin-6 levels are inversely correlated with heart rate variability in patients with decompensated heart failure

INTRODUCTION: Increased local and systemic elaboration of cytokines have an important role in the pathogenesis of congestive heart failure (CHF) through diverse mechanisms. Because cytokines are known to act at the neuronal level in both the peripheral and central nervous system, we sought to determine whether increased cytokine levels are associated with the autonomic dysfunction that characterizes CHF. METHODS AND RESULTS: We studied 64 patients admitted for decompensated CHF (mean age 59+/-12 years). Autonomic function was assessed using time- and frequency-domain heart rate variability (HRV) measures, obtained from 24-hour Holter recordings. In addition, norepinephrine, tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) were measured in all patients. TNF-alpha levels did not correlate with any of the HRV measures. IL-6 inversely correlated with the time-domain parameters of standard deviation of RR intervals (SDNN) (r = -0.36, P = 0.004) and standard deviation of all 5-minute mean RR intervals (SDANN) (r = -0.39, P = 0.001), and with the frequency-domain parameters of total power (TP) (r = -0.37, P = 0.003) and ultralow-frequency (ULF) power (r = -0.43, P = 0.001). No correlation was found between IL-6 and indices of parasympathetic modulation. Using multiple linear regression models, adjusting for clinical variables and drug therapies, the strong inverse relationship between IL-6 and SDNN (P = 0.006), SDANN (P = 0.001), TP (P = 0.04), and ULF power (P = 0.0007) persisted. CONCLUSION: Reduction of long-term HRV indices is associated with increased levels of IL-6 in patients with decompensated heart failure. The ability of long-term HRV parameters to better reflect activation of diverse hormonal systems may explain their greater prognostic power for risk stratification in patients with CHF.     

Effect of metoprolol on heart rate variability in symptomatic patients with mitral valve prolapse

Metoprolol is widely used to eliminate symptoms in patients with mitral valve prolapse (MVP), a condition associated with enhanced sympathetic tone. In this study, effects of metoprolol on heart rate variability (HRV) indices were investigated in symptomatic patients with MVP. Thirty-nine symptomatic patients with MVP (26 women, mean age 26 +/- 7 years) and 16 age- and gender-matched controls were studied. After a baseline 24-hour Holter evaluation in all subjects, patients with MVP were started on metoprolol succinate therapy at a dose of 25 to 100 mg/d, and Holter analysis was repeated at the end of 3 months of metoprolol therapy. At the basal evaluation, all time-domain HRV indices with the exception of proportion of adjacent RR intervals differing by >50 ms in the 24-hour recording were significantly lower in patients with MVP than controls (SD of all normal-to-normal [NN] intervals, p = 0.013; SD of average NN intervals calculated during 5-minute periods of the entire recording, p = 0.03; triangular index, p = 0.025; and square root of mean squared differences in successive NN intervals, p = 0.026). After metoprolol treatment, all HRV indices significantly improved compared with baseline (SD of all NN intervals, p = 0.028; SD of average NN intervals calculated during 5-minute periods of the entire recording, p = 0.043; triangular index, p = 0.004; square root of the mean squared differences in successive NN intervals, p = 0.021; and proportion of adjacent RR intervals differing by >50 ms in the 24-hour recording, p = 0.014), and HRV indices after metoprolol treatment were similar to those of the control group (p >0.05). In conclusion, metoprolol significantly improved impaired HRV parameters in symptomatic patients with MVP.     

Trans-Fatty Acid consumption and heart rate variability in 2 separate cohorts of older and younger adults

Background- Trans-fatty acid (TFA) consumption is associated with risk of coronary heart disease, and trans-18:2, but not trans-18:1, in red blood cell membranes has been associated with sudden cardiac arrest. Abnormal heart rate variability (HRV) reflects autonomic dysfunction and predicts cardiac death. Relationships between TFA consumption and HRV remain understudied. We determined whether total TFA consumption, as well as trans-18:1 and trans-18:2 TFA consumption, was independently associated with HRV in 2 independent cohorts in the United States and Portugal. Methods and Results- In 2 independent cohorts of older US adults (Cardiovascular Health Study [CHS], age 72±5 years, 1989/1995) and young Portuguese adults (Porto, age 19±2 years, 2008/2010), we assessed habitual TFA intake by food frequency questionnaires in CHS (separately estimating trans-18:1 and trans-18:2) and multiple 24-hour recalls in Porto (estimating total TFA only, which in a subset correlated with circulating trans-18:2 but not trans-18:1, suggesting that we captured the former). HRV was assessed using 24-hour Holters in CHS (n=1076) and repeated short-term (5-minute) ECGs in Porto (n=160). We used multivariate-adjusted linear regression to relate TFA consumption to HRV cross-sectionally (CHS, Porto) and longitudinally (CHS). In CHS, higher trans-18:2 consumption was associated with lower 24-hour SD of all normal-to-normal intervals both cross-sectionally (-12%; 95% CI, -19% to -6%; P=0.001) and longitudinally (-15%; 95% CI, -25% to -4%; P= 0.009) and lower 24-hour SD of 5-minute average N-N intervals and mean of the 5-minute SD of N-N intervals calculated over 24 hours (P<0.05 each). Higher trans-18:1 consumption in CHS was associated with more favorable 24-hour HRV in particular time-domain indices (24-hour SD of all normal-to-normal intervals, SD of 5-minute average N-N intervals, mean of the 5-minute SD of N-N intervals calculated over 24 hours; P<0.05 each). In Porto, each higher SD TFA consumption was associated with 4% lower 5-minute 24-hour SD of all normal-to-normal intervals (95% CI, -8% to -1%; P=0.04) and 7% lower 5-minute square root of the mean of the squares of successive N-N differences (95% CI, -13% to -1%; P=0.04). Conclusions- Trans-18:2 consumption is associated with specific, less favorable indices of HRV in both older and young adults. Trans-18:1 consumption is associated with more favorable HRV indices in older adults. Our results support the need to investigate potential HRV-related mechanisms, whereby trans-18:2 may increase arrhythmic risk.     

Fractal analysis and time- and frequency-domain measures of heart rate variability as predictors of mortality in patients with heart failure

Time-domain measures of heart rate (HR) variability provide prognostic information among patients with congestive heart failure (CHF). The prognostic power of spectral and fractal analytic methods of HR variability has not been studied in the patients with chronic CHF. The aim of this study was to assess whether traditional and fractal analytic methods of HR variability predict mortality among a population of patients with CHF. The standard deviation of RR intervals, HR variability index, frequency-domain indexes, and the short-term fractal scaling exponent of RR intervals were studied from 24-hour Holter recordings in 499 patients with CHF and left ventricular ejection fraction < or =35%. During a mean follow-up of 665 +/- 374 days, 210 deaths (42%) occurred in this population. Conventional and fractal HR variability indexes predicted mortality by univariate analysis. For example, a short-term fractal scaling exponent <0.90 had a risk ratio (RR) of 1.9 (95% confidence interval [CI] 1.4 to 2.5) and the SD of all RR intervals <80 ms had an RR of 1.7 (95% CI 1.2 to 2.1). After adjusting for age, functional class, medication, and left ventricular ejection fraction in the multivariate proportional-hazards analysis, the reduced short-term fractal exponent remained the independent predictor of mortality, RR 1.4 (95% CI 1.0 to 1.9; p <0.05). All HR variability indexes were more significant univariate predictors of mortality in functional class II than in class III or IV. Among patients with moderate heart failure, HR variability measurements provide prognostic information, but all HR variability indexes fail to provide independent prognostic information in patients with the most severe functional impairment.     

Incidence and clinical predictors of pulmonary embolism in severe heart failure patients admitted to a coronary care unit

OBJECTIVES: To determine the incidence of clinical pulmonary embolism (PE) in a population with severe congestive heart failure (CHF) admitted to a coronary care unit (CCU), and to identify clinical predictors of PE in this population. DESIGN AND SETTING: Prospective, observational study performed in a CCU of a tertiary care hospital between July 2001 and March 2003. PATIENTS: One hundred ninety-eight patients with severe decompensated CHF. MEASUREMENTS AND RESULTS: Of 198 patients recruited, 18 patients (9.1%) received a diagnosis of PE during their hospitalization. Deep vein thrombosis was demonstrated in 8 of 18 patients (44.4%) with PE. Thromboprophylaxis was used by 12 of 18 patients (66.7%) with PE and 126 of 180 patients (70%) without PE (p = 0.77). Both groups were similar with respect to mean age (68.2 +/- 14.1 years vs 69.6 +/- 13.4 years [+/- SD]), proportion of male patients (61.1% vs 55.1%), markers of CHF severity (New York Heart Association functional class > II, ejection fraction < 30%, Na < 136 mEq/L, ischemic etiology), and comorbid conditions (diabetes mellitus, atrial fibrillation, chronic renal failure, hypertension) [p = not significant]. The presence of PE was significantly associated with cancer (relative risk [RR], 8.4; 95% confidence interval [CI], 3.9 to 18.1), immobilization (RR, 5.4; 95% CI, 2.0 to 14.4), previous venous thromboembolism (VTE) [RR, 4.4; 95% CI, 1.7 to 11.3], COPD (RR, 3.1; 95% CI, 1.03 to 9.2), and right ventricle (RV) abnormality (RR, 3.3; 95% CI, 1.3 to 8.0). In a multiple logistic regression analysis, only cancer (odds ratio [OR], 26.9; 95% CI, 4.9 to 146.8), RV abnormality (OR, 9.7; 95% CI, 2.2 to 42.6), and previous VTE (OR, 9.1; 95% CI, 1.28 to 64.7) remained independently associated with PE. CONCLUSIONS: In patients with severe decompensated CHF admitted to a CCU, the incidence of clinical PE is very high despite adequate prophylaxis. Traditional risk factors seemed to play an important role in determining the risk of PE in this population.     

Predictors of congestive heart failure mortality in elderly people from the general population

Congestive heart failure (CHF) is highly prevalent in the elderly. The aim of this study was to identify the predictors of CHF mortality in patients over 65 years of age who were free of CHF at initial screening. A total of 3,282 elderly subjects were recruited in a population-based frame and 12-year events were recorded. Continuous items were divided into tertiles and for each tertile adjusted the relative risk (RR) with 95% confidence intervals (CI) was derived in both genders from multivariate Cox analysis of CHF mortality. Age > or = 72 years ([RR]: 2.24; 95% CI 1.56 - 3.24), male gender ([RR]: 1.4; 95%CI 1.02 - 1.76), clinical history of coronary artery disease ([RR]: 1.25; 95% CI 1.02 - 1.76), pulse pressure > or = 79 mmHg ([RR]: 1.33; 95% CI 1.03 - 1.87), heart rate > or = 81 bpm ([RR]: 1.32; 95% CI 1.10 - 1.96), atrial fibrillation ([RR]: 1.82; 95% CI 1.18 - 2.81), left ventricular hypertrophy ([RR]: 1.42; 95% CI 1.01 - 2.02), diabetes ([RR]: 1.35; 95% CI 1.02 - 1.78), vital capacity < or = 81% of the theoretical value ([RR]: 2.50; 95% CI 1.88 - 3.32), forced expiratory volume in 1 second < or = 72% of the theoretical value ([RR]: 2.02; 95% CI 1.55 - 2.72) and serum sodium level < or = 139 mmol/L ([RR]: 1.95; 95% CI 1.44 - 2.63) predicted CHF mortality. This model is able to identify elderly people at increased risk of death from CHF.     

Persistent high NTpro-BNP concentration as a negative prognostic factor in patients with decompensated heart failure

INTRODUCTION: Monitoring of natriuretic peptide concentration may be useful for the identification of high-risk patients presenting with decompensated chronic heart failure (CHF). AIM: Assessment of the predicting value of a significant decrease (by > or =20% vs. baseline) of N-terminal proBNP (NTpro-BNP, ROCHE) concentration during hospitalisation in patients with decompensated CHF. METHODS: This study involved 54 patients admitted to our centre because of CHF decompensation. Concentration of NTpro-BNP was measured on admission and at discharge from hospital. Primary end-points of this study were overall mortality and mortality with a number of cardiovascular-related readmissions. RESULTS: Mean NTpro-BNP concentration on admission was 7435+/-10040 pg/ml and at the time of discharge from hospital -- 4816+/-7822 pg/ml. In 31 (57%) patients a significant decrease (> or =20% vs baseline value) in NTpro-BNP level (mean: -58%+/-21%) was noted, while in the remainder (23 patients; 43%) neither an increase nor a decrease in NTpro-BNP levels was observed (mean: +72%+/-132%) despite optimal treatment and stabilisation of the clinical status. The mean follow-up duration was 358+/-240 days. Cox analysis showed that the absence of significant NTpro-BNP level decrease was associated with an increased risk of death -- RR: 3.69 (95% CI: 1.10-12.37; p=0.035) and was the single independent risk factor for readmission due to cardiovascular-related reasons and/or death -- RR: 2.29 (95% CI: 1.20-4.35; p=0.01). In the group of 23 patients with an increase or decrease in NTpro-BNP concentration of more than or equal to 20%, the survival rate was 65% vs. 87% in the remainder (p=0.02). CONCLUSIONS: The lack of a significant (> or =20%) decrease of NTpro-BNP level during hospitalisation correlates with a higher mortality and rate of readmissions. NTpro-BNP level monitoring may be of clinical importance for risk stratification in patients hospitalised for decompensated CHF.     

Gender-related differences in modulation of heart rate in patients with congestive heart failure

INTRODUCTION: The prognosis of women with congestive heart failure (CHF) is better than that for men, but the mechanisms underlying the female survival advantage are not well understood. CHF is characterized by profound abnormalities in cardiac autonomic control that contribute to progressive circulatory failure and influence survival. METHODS AND RESULTS: Time- and frequency-domain heart rate variability (HRV) indexes were obtained from 24-hour Holter recordings and compared to assess the role of gender in 131 men and 68 women with CHF (mean age 60 +/- 13.6 years, range 21 to 87; New York Heart Association Functional Class III [66%] and IV [34%]). Gender-related differences in HRV were observed only in the subset of patients with nonischemic heart failure (55 men and 39 women). Among the time-domain indexes, the SD of the RR intervals (76 +/- 5.3 msec vs 55.3 +/- 3.2 msec, P < 0.0001) and indexes denoting parasympathetic modulation, the percentage of RR intervals with >50 msec variation (4.0% +/- 1.0% vs 6.5% +/- 1.3%, P = 0.02), and the square root of mean squared differences of successive RR intervals (19.1 +/- 3.3 vs 28.4 +/- 3.8, P = 0.004) were higher in women. Among the frequency-domain indexes, the total power (7.5 +/- 0.13 ln-msec2 vs 8.3 +/- 0.14 ln-msec2, P = 0.0002), the ultralow-frequency power (7.2 +/- 0.11 ln-msec2 vs 8.0 +/- 0.14 In-msec2, P < 0.0001), the low-frequency power (3.8 +/- 0.25 ln-msec2 vs 4.8 +/- 0.28 ln-msec2, P = 0.006), and the high-frequency power (3.8 +/- 0.24 ln-msec2, vs 4.6 +/- 0.26 ln-msec2, P = 0.003) were greater in women than in men. CONCLUSION: Women with nonischemic CHF have an attenuated sympathetic activation and parasympathetic withdrawal compared with men. Gender-based differences in autonomic responses in the setting of CHF may be related to the female survival advantage.     

Minor myocardial damage detected by troponin T is a powerful predictor of long-term prognosis in patients with acute decompensated heart failure

BACKGROUND: The progression of chronic heart failure (CHF) is characterized by frequent exacerbation requiring hospitalization and high mortality. Clinical deterioration is triggered by many factors that could promote ongoing myocytes injury. We sought to determine whether a specific marker of cardiac injury, troponin T (cTnT), is associated with prognosis in acute decompensated heart failure (ADHF). METHODS: One hundred and eighty-four consecutive patients with ADHF were enrolled in the absence of an acute coronary syndrome. A cTnT value> or =0.1 ng/ml in samples drawn at 6, 12 or 24 h after hospital admission was considered abnormal. RESULTS: Increased levels of cTnT were found in 58 patients (31.5%, group 1). There were no significant differences between group 1 and patients with cTnT<0.1 ng/ml (group 2) in terms of demographic and clinical characteristics, although ischemic etiology was more prevalent in group 1 (51.7% vs. 31.7%, p=0.009). During follow-up, the mortality in groups 1 and 2 was 31% and 17.5% (p=0.038, OR=2.13, 95% CI: 1.03-4.69), respectively. The 3-year free-CHF readmission survival in group 1 and 2 was 25% and 53% (log rank test p=0.015). In a Cox proportional hazard model, poor tissue perfusion (HR=2.46, 95% CI=1.31-4.6), previous infarction (HR=1.99, 95% CI=1.02-3.9) and cTnT> or =0.1 ng/ml (HR=1.74, 95% CI=1.05-2.9) emerged as the independent predictors of long-term outcome. CONCLUSIONS: One third of patients with decompensated CHF had elevated levels of cTnT. Troponin T was an independent long-term prognostic marker of morbidity and mortality and it suggests a role of biochemical risk stratification in this setting.     

Effect of nesiritide (human b-type natriuretic peptide) and dobutamine on heart rate variability in decompensated heart failure

Background

Previous studies have suggested that natriuretic peptides may have direct sympathoinhibitory effects. Nesiritide (recombinant human B-type natriuretic peptide) has been recently approved for treatment of decompensated congestive heart failure (CHF). We sought to assess the effects of nesiritide compared with dobutamine on time-domain indices of heart rate variability (HRV) in patients with decompensated CHF.

Methods

The study population consisted of 185 patients, who were randomized to intravenous nesiritide at a low (0.015 μg/kg/min, n = 56) or high (0.03 μg/kg/min, n = 58) dose, or to dobutamine (≥ 5 μg/kg/min, n = 58). Time-domain HRV indices were obtained from 24-hour Holter recordings immediately before and during study drug therapy.

Results

Dobutamine therapy resulted in a decrease in standard deviation of the R-R intervals over a 24-hour period (SDNN), standard deviation of all 5-minute mean R-R intervals (SDANN), and the percentage of R-R intervals with >50 ms variation (pNN50) (all P < .05). Low-dose nesiritide induced an increase in SDNN (P < .05), and high-dose nesiritide resulted in a nonsignificant decrease in all measures of HRV. A significant interaction was noted between baseline HRV and the effect of vasoactive therapy on HRV (P = .028). Therefore, the effect of nesiritide and dobutamine was analyzed in relation to baseline HRV. In the dobutamine group, patients with moderately depressed HRV at baseline displayed a reduction in SDNN (P = .01), SDANN (P = .01), pNN50 (P = .04), and the square root of mean squared differences of successive R-R intervals (RMSSD) (P = .05), whereas no significant changes occurred in patients with severely depressed HRV. In the low-dose nesiritide group, patients with severely depressed HRV displayed an increase in SDNN (P = .001), SDANN (P = .02), and RMSSD (P = .01), with no significant changes in patients with moderately depressed HRV. HRV response to high-dose nesiritide was similar to that of dobutamine.

Conclusions

Low-dose nesiritide therapy in patients with decompensated CHF improves indices of overall HRV and parasympathetic modulation, particularly if HRV is severely depressed at baseline. Dobutamine and possibly high-dose nesiritide can potentially lead to further deterioration of autonomic dysregulation.     

Prognostic value of iodine-123-metaiodobenzylguanidine myocardial uptake and heart rate variability in chronic congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy

Autonomic nervous system dysfunction is common in congestive heart failure (CHF) and is believed to predispose patients to an increased risk of death. This study aimed to assess the prognostic significance of heart rate variability (HRV) measurements in conjunction with scintigraphic imaging using metaiodobenzylguanidine (MIBG) labeled with iodine-123 (I-123-MIBG), which detects abnormalities in autonomic nervous activity, in patients with stable CHF during optimal medical treatment. The study population included 52 patients (56 +/- 12 years of age) with a mean left ventricular ejection fraction of 31 +/- 12%. All underwent I-123-MIBG scanning and 24-hour ambulatory electrocardiographic monitoring for the analysis of HRV on entrance into the study. The heart/mediastinum MIBG uptake ratio was calculated. HRV analysis included the assessment of time- and frequency-domain variables. During the 2-year follow-up, 14 patients (27%) died. MIBG uptake at 1 hour was less (1.39 +/- 0.10) in nonsurvivors than in survivors (1.50 +/- 0.16; p = 0.013). In univariate Cox regression analysis, MIBG uptake was a significant prognostic factor (p = 0.038, hazard ratio [HR] 0.017, 95% confidence interval [CI] 0.00 to 0.79). Time- and frequency-domain variables were similar in survivors and nonsurvivors. However, high-frequency power was associated with an increased risk for sudden death (HR 0.310, 95% CI 0.101 to 0.954, p = 0.041) but not with all-cause mortality. In conclusion, cardiac I-123-MIBG imaging identifies patients with CHF at high risk of dying and may be a more reliable predictor of overall mortality than HRV.     

Reproducibility and relation to mean heart rate of heart rate variability in normal subjects and in patients with congestive heart failure secondary to coronary artery disease

Before heart rate (HR) variability can be used for predictive purposes in the clinical setting, day-to-day variation and reproducibility need to be defined as do relations to mean HR. HR variability and mean HR were therefore determined in 2 successive 24-hour ambulatory electrocardiograms obtained from 33 normal subjects (age 34 ± 7 years, group I), and 22 patients with coronary disease and stable congestive heart failure (CHF) (age 59 ± 7 years, group II). Three measures were used: (1) SDANN (standard deviation of all mean 5-minute normal sinus RR intervals in successive 5-minute recording periods over 24 hours); (2) SD (the mean of the standard deviation of all normal sinus RR intervals in successive 5-minute recording periods over 24 hours); and (3) CV (coefficient of variation of the SD measure), a new measure that compensates for HR effects. Group mean HR was higher and HR variability lower in group II than in group I (80 ±10 vs 74 ± 9 beats/min, p < 0.04). Mean group values for HR and HR variability showed good correlations between days 1 and 2 (mean RR, R = 0.89, 0.97; SDANN, R = 0.87, 0.87; SD, R = 0.93, 0.97; CV, R = 0.95, 0.97 in groups I and II, respectively). In contrast, considerable individual day-to-day variation occurred (group I, 0 to 46%; group II, 0 to 51%). Low HR variability values were more consistent than high values. SDANN and SD correlated moderately with HR in both groups (r = 0.50 to 0.64). The CV measure minimizes HR effects on HR variability. In conclusion (1) mean group differences in HR variability between normal subjects and patients with CHF are highly reproducible, but considerable day-to-day variations may occur in some subjects, particularly normal persons with high HR variability; (2) mean HR is higher and HR variability lower in patients with CHF; and (3) mean HR must be considered when interpreting changes in HR variability. The CV measure minimizes this problem.     

Activity of the neurohormonal system and its relationship to autonomic abnormalities in decompensated heart failure.

BACKGROUND: The syndrome of congestive heart failure (CHF) entails complex autonomic and hormonal responses. Profound abnormalities in autonomic function, characterized by sympathetic overactivity and parasympathetic withdrawal, exert direct deleterious effects on the heart and contribute to progressive circulatory failure. We investigated the relationship of heart rate variability (HRV) with levels of neurohormones in plasma. METHODS AND RESULTS: We studied 64 patients admitted to the hospital for treatment of decompensated CHF (mean age, 59 +/- 2 years; New York Heart Association class III [72%] and IV [28%]). Time- and frequency-domain HRV indices were obtained from 24-hour Holter recordings. Neurohormonal activation was assessed by measuring plasma renin activity and aldosterone and norepinephrine levels. In the time domain, norepinephrine correlated negatively with average NN interval (r = -.34; P =.007), SDNN (r = -.35; P =.005), and SDANN (r = -.36; P =.004). In the frequency domain, norepinephrine was negatively associated with the total power (r = -.39; P =.001) and ultralow power (r = -.43; P =.0005). No correlation was found between indices indicative of parasympathetic modulation, except for a borderline correlation with the high-frequency power (r = -.25; P =.048). CONCLUSIONS: Reduced HRV may be associated with increased norepinephrine levels in patients with severe CHF. The ability of long-term HRV parameters to reflect in part the activation of diverse hormonal systems may explain their greater prognostic power for risk stratification in patients with CHF.     

B-type natriuretic peptide and peak exercise oxygen consumption provide independent information for risk stratification in patients with stable congestive heart failure

OBJECTIVES: The aim of this study was to compare the prognostic value of peak oxygen consumption (VO(2)) and B-type natriuretic peptide (BNP) in patients with stable congestive heart failure (CHF). BACKGROUND: Previous studies have demonstrated that both peak VO(2) and BNP are useful for risk stratification in patients with CHF. No study has compared the respective prognostic value of these two parameters in a large series of patients receiving a combination of angiotensin-converting enzyme inhibitors and of beta-blockers. METHODS: Patients with stable CHF underwent radionuclide angiography, echocardiography, 24-h Holter monitoring, and a cardiopulmonary exercise test. Blood samples were drawn for standard measurements and for hormonal determinations. RESULTS: After a median follow-up period of 787 days, there were 75 cardiac-related deaths and three urgent transplantations. Independent predictors of cardiac survival were percent of maximal predicted VO(2) (%VO(2), relative risk [RR] = 2.84 [95% confidence interval, CI = 1.73 to 4.65], p < 0.00001), BNP (RR = 3.17 [95% CI 1.68 to 5.96], p = 0.0004), left atrial diameter (LAD) (RR = 2.04 [95% CI 1.25 to 3.34], p = 0.004), age (RR = 1.93 [95% CI 1.22 to 3.05], p = 0.005), and aldosterone (RR = 1.84 [95% CI 1.12 to 3.00], p = 0.015). In patients with infra-median levels of BNP (<109 pg/ml), age was the only independent predictor of cardiac survival. However, in patients with supra-median levels of BNP, independent predictors of cardiac survival were %VO(2) (RR = 3.76 [95% CI 2.19 to 6.45], p < 0.00001) and LAD (RR = 1.90 [95% CI 1.10 to 3.28], p = 0.02). CONCLUSIONS: B-type natriuretic peptide, in combination with %VO(2), improves risk stratification of patients with stable CHF.     

扩张型心肌病患者心率变异性的临床分析

目的探讨心率变异性(HRV)在扩张型心肌病(DCM)患者中的变化规律及其对扩张型心肌病患者心血管事件的预测价值。方法对90例扩张型心肌病患者和50例健康人行24h动态心电图心率变异性对比分析及随访。心率变异性(HRV)分析包括正常RR间期标准差(SDNN),5min平均RR间期标准差(SDANN)等。90例扩张型心肌病患者平均随访21.2±7.3个月(10天～32个月),确定有无心血管事件发生。计算心率变异性(HRV)指标在预测扩张型心肌病患者发生心血管事件中的比值比(OR)和95%可信区间(95%CI)。结果健康人的心率变异性有明显的昼夜变化规律,心率变异性夜间>白天;扩张型心肌病患者的心率变异性明显低于健康组,昼夜节律性丧失,且与病情及心功能明显相关;11例扩张型心肌病患者发生心血管事件。心率变异性时域指标SDNN<100ms和SDANN<100ms发生心血管事件的比值比(OR)和95%可信区间(95%CI)分别为6.05和1.98～18.47及5.00和1.43～17.54。对性别和年龄进行校正后,SDNN<100ms的比值比(OR)和95%可信区间(95%CI)为3.13和1.16～8.47。结论扩张型心肌病患者在总体心率变异性显著降低的基础上,以迷走神经张力低下和心率变异性昼夜节律丧失为突出表现;扩张型心肌病合并心力衰竭患者心率变异性的变化,反映患者病情变化;24h心率变异性的SDNN可能是预测扩张型心肌病患者发生心血管事件的独立危险因素。     

Heart rate variability in healthy children and in those with congenital heart disease both before and after operation

There are no reports of standard measures of heart rate variability (HRV) in pediatric patients with heart disease. Time domain (standard deviation of all normal RR intervals [SDNN], standard deviation of all 5-minute mean RR intervals, average standard deviation of all 5-minute RR intervals, and frequency domain (total, low- [LF], and high-frequency [HF] power) measures of HRV were (1) obtained in 45 healthy children, (2) compared between 36 children with congenital heart disease and age-matched controls, (3) compared before and after surgery, and (4) compared between age-matched postoperative patients staying <7 days (group I, n = 16) and those staying longer (group II, n = 16). In healthy children, SDNN increased rapidly during infancy and more gradually thereafter, while the LH/HF ratio decreased until preschool age, with a later increase into adolescence. Compared with controls, preoperative patients had decreased total (53 ± 55 vs 84 ± 75 beats/min²/Hz, p = 0.01) and HF (12 ± 14 vs 29 ± 46 beats/min²/Hz, p = 0.03) power despite having similar heart rates. In the immediate postoperative period, all measures of HRV were decreased from preoperative values. Groups I and II did not differ in mean RR interval or HRV preoperatively; however, postoperatively, HRV was decreased in group II when compared with group I (SDNN 53 ± 17 vs 40 ± 14 ms, p = 0.01), although the mean RR interval remained comparable (499 ± 81 vs 481 ± 62 ms, p = 0.3). It is concluded that (1) there are significant age-related changes in HRV in healthy children, (2) preoperatively, children with congenital heart disease have reduced total and HF power when compared with healthy controls, (3) HRV is further reduced postoperatively in all patients, and (4) prolonged postoperative hospitalization is associated with a greater reduction in HRV.     

Determinants of late-onset heart failure in myocardial infarction survivors: GISSI Prevenzione trial results

INTRODUCTION AND OBJECTIVES: Improvement in the early phase of myocardial infarction (MI) is associated with a higher rate of late complications, including late-onset heart failure (LHF). The factors predicting LHF are not well understood. Our aims were to identify the factors predicting LHF and to determine the survival rate in these patients. PATIENTS AND METHOD: The GISSI-Prevenzione trial involved 11,323 low-risk patients (NYHA class < or = II) who had had a recent MI (< 3 months). It was a multicenter, open-label, clinical trial of the efficacy of treatment with polyunsaturated fatty acids, vitamin E, both, or neither. Patients with heart failure at baseline and those whose ejection fraction was unknown (n = 2908) were excluded from the present analysis. Late-onset heart failure was defined prospectively as hospital admission due to heart failure. A Cox regression model adjusted for major covariates was used for risk analysis. RESULTS: The study included 8415 patients. During 3.5 years of follow-up, 192 (2.3%) developed LHF. The risk of LHF could be predicted from readily available parameters: age (per year; RR=1.07; 95% CI, 1.05-1.09), ejection fraction (per 1% increment; RR=0.96; 95% CI, 0.94-0.97), heart rate (> or = 74 beats/min; RR=1.62; 95% CI, 1.21-2.16), white blood cell count (> or = 8900 per ml; RR=1.42; 95% CI, 1.05-1.94), diabetes (RR=1.62; 95% CI, 1.17-2.24), hypertension (RR=1.76; 95% CI, 1.33-2.34), peripheral artery disease (RR=2.11; 95% CI, 1.32-3.37), and reinfarction (RR=2.09; 95% CI, 1.28-3.39). LHF was associated with poor survival: (RR=2.34; 95% CI, 1.63-3.36). CONCLUSIONS: The risk of LHF in post-MI patients can be predicted from readily available parameters. LHF was associated with a poor prognosis.     

Compromise of the cardiac autonomic nervous system in patients with Fontan-type circulation: preliminary data

BACKGROUND: Rhythm disturbances are frequent after Fontan operations. Arrhythmias related to reduced heart rate variability (HRV) have been described in various cardiovascular diseases. METHODS: We attempted to investigate HRV in 12 patients who underwent Fontan operation (age 11.4 +/- 3 years). Results were compared to a control group of 13 children matched for age, sex and heart rate (10.4 +/- 3 years). All patients underwent 24-hour Holter monitoring. The following time domain indexes were calculated: mean duration of RR intervals, standard deviation of all RR intervals (SD), square root of the mean squared differences of successive RR intervals (r-MSSD), percentage of differences between adjacent RR intervals > 50 msec (pNN50). The following frequency domain indexes were calculated: total power (TP), low frequency (LF), high frequency (HF), LF/HF ratio. RESULTS: The following indexes were significantly reduced in Fontan patients: SD (p < 0.0001), r-MSSD (p < 0.0001), pNN50 (p = 0.0002), TP (p < 0.0001), LF (p < 0.0001), HF (p = 0.0001). LF/HF increased significantly (p = 0.04). No differences were detected according to the type of operation (cavopulmonary connection vs atriopulmonary connection) or clinical status. CONCLUSIONS: Patients with Fontan circulation had a significantly reduced HRV and particularly abnormal sympatho-vagal balance. Surgery on the caval veins and the atria alters the intracardiac ganglia that are abundant at the cavo-atrial junction and in the myocardium of the right atrium. Abnormalities of HRV in Fontan patients may act as a co-factor in the initiation of arrhythmia in these patients.     

Relation of heart rate variability to serum levels of C-reactive protein in patients with unstable angina pectoris

Heart rate variability (HRV) and systemic markers of inflammation have prognostic value in patients with unstable angina pectoris (UAP). However, it is unknown whether any relation exists between HRV parameters and indexes of inflammation in this clinical context. We assessed HRV on 24-hour electrocardiographic Holter recordings, performed within 24 hours of admission, and measured C-reactive protein (CRP) serum levels by a high-sensitivity assay on admission, in 531 patients with UAP (65+/-10 years of age; 347 men) who were enrolled in the prospective multicenter study Stratificazione Prognostica dell'Angina Instabile (SPAI). A significant inverse correlation was found between CRP levels and all HRV parameters, with the highest r coefficient shown with SD of all RR intervals (r= -0.23; p<0.001) in the time domain and with very low-frequency amplitude (r= -0.22; p<0.001) in the frequency domain. When patients were categorized into 4 groups according to CRP quartile levels, statistically significant lower HRV values were observed in the upper CRP quartile. On separate multiple regression analyses, including the most important clinical and laboratory variables, SD of all RR intervals and very low-frequency amplitude were the most significant predictors of increasing CRP levels (p<0.001 for the 2 comparisons). In contrast, in models with SD of all RR intervals and very low-frequency amplitude as dependent variables, CRP was a strong predictor of impaired cardiac autonomic function (p<0.001 for the 2 comparisons). Thus, our data show that, in patients with UAP, high levels of serum CRP levels are significantly associated with decreased HRV, suggesting a possible pathophysiologic link between cardiac autonomic dysfunction and inflammatory activity.