Andrew J. Burger

Relationship Between Reactive Pulmonary Hypertension and Mortality in Patients With Acute Decompensated Heart Failure

Background— In patients with heart failure, pulmonary hypertension (PH) predicts higher risk for morbidity and mortality. However, few data are available on the prognostic implications of reactive (precapillary) PH superimposed on passive (postcapillary) PH. Methods and Results— We performed a subgroup analysis of 242 patients with acute decompensated heart failure assigned to pulmonary artery catheter placement in the Vasodilation in the Management of Acute Congestive Heart Failure trial. Patients were classified into 3 groups, using the final (posttreatment) hemodynamic measurements: (1) no PH (mean pulmonary artery pressure ⩽25 mm Hg; (2) passive PH (mean pulmonary artery pressure >25, pulmonary capillary wedge pressure >15 mm Hg, and pulmonary vascular resistance⩽3 Wood units); and (3) reactive PH (mean pulmonary artery pressure >25, pulmonary capillary wedge pressure >15 mm Hg, and pulmonary vascular resistance >3 Wood units). Fifty-eight patients were classified as normal mean pulmonary artery pressure, 124 with passive PH and 60 with reactive PH. During follow-up of 6 months, 5 (8.6%), 27 (21.8%), and 29 (48.3%) deaths occurred in patients without PH, patients with passive PH, and with reactive PH, respectively (P<0.0001). After multivariable adjustments, reactive PH remained an independent predictor of death, with an adjusted hazard ratio of 4.8 compared with patients without PH, and 2.8 compared with patients with passive PH (95% confidence interval, 1.7 to 4.7, P=0.0001). Similar results were obtained when reactive PH was defined on the basis of transpulmonary gradient. Conclusions— Reactive PH is common among patients with acute decompensated heart failure after initial diuretic and vasodilator therapy. The adverse outcome associated with PH is predominantly due to increased mortality rates in the subgroup of patients with reactive PH.

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

Interleukin‐6 and Heart Rate Variability. 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.

The relationship between transient and persistent worsening renal function and mortality in patients with acute decompensated heart failure.

BACKGROUND Worsening renal function (WRF) is an ominous complication in patients with acute heart failure syndrome (AHFS). Few data are available with regard to the clinical implications of transient versus persistent WRF in this setting. METHODS AND RESULTS We studied 467 patients with AHFS and creatinine measurements at baseline and on days 2, 5, 14, and 30. WRF (>/= 0.5 mg/dL increase in serum creatinine above baseline at any time point) was defined as persistent when serum creatinine remained >/= 0.5 mg/dL above baseline throughout day 30, and transient when creatinine levels subsequently decreased to < 0.5 mg/dL above baseline. WRF occurred in 115 patients, and was transient in 39 patients (33.9%). The 6-month mortality rates were 17.3%, 20.5%, and 46.1% in patients without WRF, transient WRF, and persistent WRF, respectively. In a multivariable Cox model, compared with patients with stable renal function, the adjusted hazard ratio for mortality was 0.8 (95% CI 0.4-1.7; P = .58) in patients with transient WRF and 3.2 (95% CI 2.1-5.0; P < .0001) in patients with persistent WRF. CONCLUSION Transient WRF is frequent among patients with AHFS. Whereas persistent WRF portends increased mortality, transient WRF appears to be associated with a better outcome as compared with persistent renal failure.

Effect of Glycemic Control on Heart Rate Variability in Type I Diabetic Patients With Cardiac Autonomic Neuropathy

Diabetic cardiac autonomic neuropathy (CAN) is associated with a high risk of cardiovascular events. Previous studies have shown that strict glycemic control slows the deterioration of CAN as assessed by standard autonomic function tests but fails to show reversibility. The aim of this study was to evaluate the effect of glycemic control on early and advanced CAN in type I diabetic patients using power spectral analysis of heart rate variability (HRV). Ten patients with early and 13 patients with advanced CAN were enrolled in a program of intensified insulin treatment. Standard autonomic function tests and 24-hour time and frequency domain HRV parameters were obtained at baseline, 3, 6, and 12 months. Hemoglobin A1C decreased from 9.5 +/- 0.4% to 8.4 +/- 0.5% (p = 0.02) in the early CAN group, and from 9.3 +/- 0.4% to 8.2 +/- 0.5% (p = 0.006) in the advanced CAN group. In general, both time and frequency domain HRV indexes tended to improve in patients with early CAN but continued to deteriorate in patients with advanced CAN. The low- and high-frequency power increased in patients with early CAN (229 +/- 95 to 626 +/- 563 ms2 and 62 +/- 30 to 183 +/- 168 ms2, respectively). The high-frequency power significantly improved at 12 months over baseline (p = 0.04), indicating increased parasympathetic tone. By contrast, these parameters continued to deteriorate in patients with advanced CAN (65 +/- 32 to 46 +/- 8 ms2 and 193 +/- 75 to 144 +/- 33 ms2, respectively). Autonomic function tests showed no significant change in both groups. These data show that a reversible metabolic component of CAN exists in patients with early CAN. Power spectral analysis of HRV allows early identification of potential reversibility as early as 1 year after the institution of strict glycemic control.

Low prevalence of valvular heart disease in 226 phentermine-fenfluramine protocol subjects prospectively followed for up to 30 months.

OBJECTIVES This investigation sought to determine the effect of phentermine-fenfluramine (phen-fen) on the prevalence of valvular heart disease in 226 obese subjects enrolled in a prospective, strict weight loss, research protocol. BACKGROUND Early reports have suggested that the use of phen-fen for weight loss may be associated with increased valvular heart disease. Such reports were based on small numbers of patients, limited data on dose and duration of phen-fen therapy, and no correlation with matched controls. METHODS All subjects underwent transthoracic echocardiography for significant valvular lesions within a mean of 97 days from the manufacturers announcement of the voluntary withdrawal of fenfluramine and dexfenfluramine. All echocardiograms were interpreted by two independent readers. RESULTS The study population included 183 women and 43 men with a mean age of 46.9 +/- 8.9 years and mean starting body mass index of 39.8 +/- 7.7 kg/m2. Using the Food and Drug Administration criteria, significant aortic regurgitation was detected in 15 subjects (6.6%) and mitral regurgitation in 3 subjects (1.3%). Only one patient had significant regurgitation of both aortic and mitral valves. No valves had severe regurgitation. Significant valvular disease did not correlate with the dose or duration of phen-fen therapy. Furthermore, the prevalence of valvular regurgitation is comparable to the normal offspring in the Framingham Heart Study, who are similar in age, gender, and geographical location. CONCLUSIONS Phen-fen therapy is associated with a low prevalence of significant valvular regurgitation. Valvular regurgitation in our subjects may reflect age-related degenerative changes.

Early cardioversion of atrial fibrillation facilitated by transesophageal echocardiography: short-term safety and impact on maintenance of sinus rhythm at 1 year

BACKGROUND For patients presenting with atrial fibrillation of only a few weeks duration, the use of transesophageal echocardiography offers the opportunity to markedly abbreviate the duration of atrial fibrillation before cardioversion. We sought to determine if the shorter duration of atrial fibrillation allowed by a transesophageal echocardiography strategy had an impact on the recurrence of atrial fibrillation and prevalence of sinus rhythm during the first year following cardioversion. METHODS Transesophageal echocardiography was attempted in 539 patients (292 men, 247 women; 71.6 +/- 13.0 years.) with atrial fibrillation > or =2 days (66.1% <3 weeks) or of unknown duration before elective cardioversion of atrial fibrillation. Therapeutic anticoagulation at the time of transesophageal echocardiography was present in 94.6% of patients, and 73.4% of subjects were discharged on warfarin. RESULTS Atrial thrombi were identified in 70 (13.1%) patients. Successful cardioversion in 413 patients without evidence of atrial thrombi was associated with clinical thromboembolism in 1 patient (0.24%, 95% confidence interval: 0.0--0.8%). In patients with atrial fibrillation <3 weeks at the time of cardioversion (a duration incompatible with conventional therapy of 3 to 4 weeks of warfarin before cardioversion), the 1-year atrial fibrillation recurrence rate was lower (41.1% vs. 57.9%, P <0.01), and the prevalence of sinus rhythm at 1 year was increased (65.8% vs. 51.3%, P <0.03). No other clinical or echocardiographic index was associated with recurrence of atrial fibrillation or sinus rhythm at 1 year. CONCLUSIONS Early cardioversion facilitated by transesophageal echocardiography has a favorable safety profile and provides the associated benefit of reduced recurrence of atrial fibrillation for patients in whom the duration of atrial fibrillation is <3 weeks.

Circadian patterns of heart rate variability in normals, chronic stable angina and diabetes mellitus

The purpose of our investigation was to compare circadian patterns of heart rate variability as assessed by 24-h ambulatory electrocardiographic (ECG) recordings in normal subjects, chronic stable angina, and Type 1 diabetes mellitus. The study population consisted of three groups: 12 normal subjects, 23 chronic angina patients, and 23 Type 1 diabetics. For purposes of analyzing circadian variation, the ECG recordings were divided into daytime (08:00-00.00 h) and night-time (00:00-08:00 h) periods. Analysis was performed for all time and frequency domain measures of heart rate variability, attempting to identify differences in day-to-night variability among these three groups. All time domain parameters except standard deviation of all 5-min mean RR intervals, and all frequency domain indices maintain significant circadian variations (P<0.0001), with the greatest day to night variation seen in normals, the least in diabetics, and intermediate values in chronic angina. These changes in heart rate variability circadian rhythms reflect significant reductions in cardiac parasympathetic activity with the most marked reduction in nocturnal vagal activity. Given the circadian pattern of myocardial ischemia and infarction, these data suggest that quantification of the magnitude of circadian variation in heart rate variability may have the potential to further risk stratify chronic angina and diabetes for future cardiac events.

Short- and long-term reproducibility of heart rate variability in patients with long-standing type I diabetes mellitus

Heart rate variability (HRV) has been used to assess cardiac autonomic function noninvasively, understand the pathophysiologic mechanisms of heart disease, evaluate therapy, and assess long-term prognosis. We examined both the short- and long-term reproducibility of the time and frequency domain HRV parameters in 23 type I diabetics over a 12-month interval. Entry criteria included juvenile onset diabetes before age 35 years, >24-year duration of diabetes, diabetes difficult to control, and albuminuria. Standardized noninvasive autonomic testing and 24-hour ambulatory electrocardiographic recordings were obtained. Fifteen men and 8 women (mean age 36.7 years) were enrolled. Fifty-three percent of the men and 75% of the women were smokers, and women had higher cholesterol than men. All HRV parameters were markedly decreased when compared with normal persons. Using Pearson correlation, the time domain indicators of parasympathetic activity demonstrated very strong correlations at 3 and 6 months compared with baseline, with good correlations at 1 year. The average SD of all 5-minute RR intervals maintained a very strong correlation for the entire year (r >0.94). In the frequency domain, the measures of parasympathetic and sympathetic activity maintained a solid correlation for the entire study period. Reproducibility of HRV was also examined using repeated-measures analysis of variance. The time and frequency domain parameters demonstrated very little variation over the study period of 12 months. Thus, our investigation demonstrated that HRV in long-term diabetics using 24-hour ambulatory recordings is abnormal and reproducible over a 12-month interval; very little variation in all HRV parameters, especially in parameters of parasympathetic activity, occurred during the study period.

Intravenous nesiritide (human B-type natriuretic peptide) reduces plasma endothelin-1 levels in patients with decompensated congestive heart failure.

LQT2 as well as LQT3 models of the long QT syndrome. Circulation 1997;96: 2038–2047. 9. Tanabe Y, Inagaki M, Kurita T, Nagaya N, Taguchi A, Suyama K, Aihara N, Kamakura S, Sunagawa K, Nakamura K, et al. Sympathetic stimulation produces a greater increase in both transmural and spatial dispersion of repolarization in LQT1 than LQT2 forms of congenital long QT syndrome. J Am Coll Cardiol 2001;37:911–919. 10. Shimizu W, Ohe T, Kurita T, Takaki H, Aihara N, Kamakura S, Matsuhisa M, Shimomura K. Early afterdepolarizations induced by isoproterenol in patients with congenital long QT syndrome. Circulation 1991;84:1915–1923. 11. Schwartz PJ, Priori SG, Locati EH, Napolitano C, Cantu F, Towbin JA, Keating MT, Hammoude H, Brown AM, Chen LS. Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na channel blockade and to increase in heart rate. Implications for gene-specific therapy. Circulation 1995;92:3381–3386. 12. Chinushi M, Caref EB, Restivo M, Noll G, Aizawa Y, El-Sherif N. Cyclelength associated modulation of the regional dispersion of ventricular repolarization in a canine model of long QT syndrome. Pacing Clin Electrophysiol 2001;24:1247–1257. 13. El-Sherif N, Chinushi M, Caref EB, Restivo M. Electrophysiological mechanism of the characteristics electrocardiographic morphology of torsade de pointes tachyarrhythmias in the long QT syndrome. Circulation 1997;96:4392– 4399. 14. El-Sherif N, Caref EB, Chinushi M, Restivo M. Mechanism of arrhythmogenicity of the short-long cardiac sequence that precedes ventricular tachyarrhythmias in the long QT syndrome. J Am Coll Cardiol 1999;33:1415–1423. 15. Ejima J, Martin D, Engle C, Sherman Z, Kunimoto S, Gettes LS. Ability of activation recovery intervals to assess action potential duration during acute no-flow ischemia in the in situ porcine heart. J Cardiovasc Electrophysiol 1998;9:832–844. 16. Davidenko JM, Antzelevitch C. Electrophysiological mechanisms underlying rate-dependent changes of refractoriness in normal and segmentally depresses canine Purkinje fibers: the characteristics of post-repolarization refractoriness. Circ Res 1986;58:257–268. 17. Surawicz B. Electrophysiological substrate of torsade de pointes: dispersion of repolarization or early afterdepolarizations? J Am Coll Cardiol 1989;14:172– 184. 18. Gbadebo TD, Trimble RW, Khoo MSC, Temple J, Roden DM, Anderson ME. Calmodulin inhibitor W-7 unmasks a novel electrocardiographic parameter that predicts initiation of torsade de pointes. Circulation 2002;105:770–774. 19. Wu J, Wu J, Zipes DP. Early after depolarizations, U wave, and torsades de pointes. Circulation 2002;105:675–676.

Effect of beta-blockade on heart rate variability in decompensated heart failure

BACKGROUND One of the putative mechanisms for the salutary effects of beta-blockers in patients with congestive heart failure is their ability to improve autonomic dysfunction. However, patients with profound neurohumoral abnormalities derive little survival benefit from beta-blockers. The purpose of the current study was to evaluate the effect of beta-blockers on heart rate variability in decompensated heart failure. METHODS Time and frequency domain heart rate variability indices were obtained from 24-h Holter recordings and compared to assess the role of beta-blockade in 199 patients (mean age 60+/-14 years [range 21 to 87]) with decompensated heart failure (New York Heart Association functional class III [66%] and IV [34%]). RESULTS All heart rate variability indices were markedly suppressed but were substantially higher in patients who were on beta-blockers. Time domain measures of parasympathetic cardiac activity, the percentage of RR intervals with >50 ms variation (4.9+/-0.6 vs. 7.7+/-1.2%, P=0.006) and the square root of mean squared differences of successive RR intervals (22.7+/-2.0 vs. 31.6+/-4.1 ms, P=0.004), were higher in the beta-blocker group. Spectral analysis revealed that the total power and the ultra low frequency power were significantly higher in patients on beta-blockers (82% and 59%, respectively). The high frequency power, a spectral index of parasympathetic modulation, was 41% higher in the beta-blocker group (121+/-25 vs. 171+/-27 ms(2), P=0.02). Multiple linear regression, adjusted for clinical parameters and drug therapies, revealed a strong positive relationship between beta-blockade and higher values of time and frequency domain measures. The mean number of ventricular tachycardia episodes were significantly lower in patients on beta-blocker therapy (3.6+/-1.5 vs. 19.0+/-5.3, P=0.04). CONCLUSIONS beta-blockers improve the impaired cardiac autonomic regulation during high sympathetic stress of decompensated heart failure.