Nesiritide: past, present, and future.

B-type natriuretic peptide (BNP) is an endogenous cardiac neurohormone, produced in the ventricles in response to pressure and volume elevation. Nesiritide is identical to endogenous BNP and is synthesized using recombinant DNA technology. It is currently used in the treatment of acute decompensated heart failure. In clinical trials, nesiritide has been shown to decrease pulmonary capillary wedge pressure, pulmonary artery pressure, right atrial pressure, and systemic vascular resistance, as well as increase cardiac index and stroke volume index. Infusions of nesiritide have led to increased diuresis and natriuresis. Patients treated with nesiritide have reported improvements in global clinical status, dyspnea, and fatigue. Therapy with nesiritide has resulted in decreased plasma renin, aldosterone, norepinephrine, and endothelin-1 levels, as well as reduced ventricular ectopy and ventricular tachycardia. Heart rate variability also improved with nesiritide. Patients with acute coronary syndromes, serious arrhythmia, renal disease, diastolic dysfunction, or vasopressor dependence have been safely managed with nesiritide. Early treatment with nesiritide in the emergency department may lead to decreased length of hospital stay and reduced readmission rates compared to standard care. Outpatient serial infusions of nesiritide in severe heart failure patients on optimal medical therapy may result in improved clinical status, increased ejection fraction, reduced aldosterone and endothelin-1 levels, and decreased hospitalizations. Potential future uses of nesiritide include treatment of acute coronary syndromes, pulmonary hypertension, bronchospasm in chronic lung disease, and as antifibrotic/anti-remodeling therapy or bridge to cardiac transplant. The possibility of subcutaneous injections of nesiritide has been studied in both animals and humans.

Diabetes and the occurrence of ventricular arrhythmic events in patients with severe left ventricular dysfunction.

AIMS/HYPOTHESIS: Diabetes is associated with a higher risk of ischaemic heart disease and heart failure, which frequently lead to rhythm disorders. However, experimental and clinical studies are inconsistent with regard to the risk of arrhythmic events in patients with diabetes. We studied the frequency of ventricular arrhythmic events in patients with and without diabetes. METHODS: The study group included 207 patients with severe heart failure. The severity of ventricular arrhythmias was assessed by 24-h Holter monitoring, using prospectively defined measures of ventricular arrhythmic burden. RESULTS: Patients with diabetes comprised 48% of the study group. All measures of ventricular ectopy were much lower in patients with diabetes. Mean hourly ventricular pairs (13.3+/-3.7 vs 7.2+/-2.0, p=0.03), mean hourly repetitive ventricular beats (32+/-9 vs 17+/-5, p=0.01), and the frequency of ventricular tachycardia episodes per 24 h (36+/-13 vs 16+/-6, p=0.01) were lower in patients with diabetes. After inclusion of clinical variables and drug therapies in a multivariate analysis, the negative relationship between diabetes and the frequency of ventricular pairs (p=0.03), repetitive ventricular beats (p=0.04), and ventricular tachycardia (p=0.03) remained independent. In multivariate logistic regression, the risk of developing ventricular tachycardia was lower in patients with diabetes with an adjusted odds ratio of 0.41 (95% CI, 0.22 to 0.75, p=0.004). CONCLUSION/INTERPRETATION: Diabetes confers a protective effect with regard to the occurrence of ventricular arrhythmias in the setting of decompensated heart failure. The precise mechanism of this phenomenon requires further investigation.

Blunted sympathetic response in diabetic patients with decompensated congestive heart failure.

BACKGROUND: The risk for congestive heart failure is strongly increased in diabetes, and the prognosis of diabetic patients with established heart failure is worse compared to nondiabetic patients. Heart failure entails complex alterations in autonomic and neurohormonal responses, which exert a direct deleterious effect on the heart and contribute to progressive circulatory failure. Altered neurohumoral physiology may underlie the poor prognosis of diabetic patients with heart failure. METHODS: We studied 88 patients (mean age 61+/-13 years) admitted for decompensated heart failure. Neurohormonal and cytokine profiles, including plasma renin activity, aldosterone, norepinephrine, endothelin-1, tumor necrosis factor-alpha, and interleukin-6, were obtained in all patients. In addition, a 24-h Holter recording was performed, and time and frequency domain heart rate variability indices were calculated. RESULTS: Of 88 patients, 48 were classified as having diabetes based on history, diet therapy, or use of oral hypoglycemic agents or insulin. The only difference in the neurohormonal and cytokine profile between the diabetic and nondiabetic groups was a significantly lower norepinephrine level in diabetic patients (668+/-64 vs. 489+/-50 pg/ml, P=0.009). Heart rate variability analysis revealed that the low-frequency power in normalized units (an index of sympathetic modulation) was significantly lower in diabetic patients (4.7+/-1.4 vs. 5.9+/-0.9, P=0.04). No significant differences occurred in any of the time (the percentage of RR intervals with >50 ms variation and the square root of mean squared differences of successive RR intervals) or frequency domain (high frequency power) indices of parasympathetic modulation between the two groups. CONCLUSIONS: Patients with diabetes mellitus exhibit a blunted sympathetic response during heart failure decompensation. Blunted sympathetic activation in the setting of symptomatic heart failure may impair the ability of the myocardium to compensate and contribute to the high incidence of symptomatic heart failure among diabetic patients.

Low risk of significant echocardiographic valvulopathy in patients treated with anorectic drugs.

BACKGROUND: Phentermine--fenfluramine and dexfenfluramine use for weight loss has been previously associated with increased prevalence of valvular heart disease. This association was initially based on small numbers of patients, limited data on dose and duration of drug therapy, and no correlation with matched controls. METHODS: Our investigation involved 343 obese subjects enrolled in a prospective, strict weight loss, research protocol from September 1994 to September 1997. All subjects underwent transthoracic echocardiography for significant valvular lesions within a mean of 121 days from the manufacturer's announcement of the voluntary withdrawal of fenfluramine and dexfenfluramine from the market. All echocardiograms were interpreted by 2 independent readers. RESULTS: The study population included 281 females and 62 males with a mean age of 46.7+/-9.1 years and mean initial body mass index of 40.1+/-8.1 kg/m(2). Using the Food and Drug Administration's criteria, only 21 subjects (6.1%) had significant valvular lesions. Aortic regurgitation was detected in 18 subjects, mitral regurgitation in 3 subjects, and both aortic and mitral regurgitation in 1 subject; no one had severe regurgitation. Significant valvular disease did not correlate with age, gender, initial/ending body mass index, the drug dose, duration of drug therapy, or serotonin reuptake inhibitors. CONCLUSIONS: Anorexigen therapy is associated with a low prevalence of significant valvular regurgitation. Late valvular abnormalities from drug treatment await long term prospective studies.

Comparison of the occurrence of ventricular arrhythmias in patients with acutely decompensated congestive heart failure receiving dobutamine versus nesiritide therapy.

Ventricular arrhythmias are common in patients with congestive heart failure (CHF) and may be exacerbated by positive inotropic therapy. Because human B-type natriuretic peptide (nesiritide), an arterial and venodilator, inhibits sympathetic activity, it may decrease the incidence of arrhythmias. Our investigation compares the arrhythmogenicity of dobutamine with nesiritide. A total of 305 patients with decompensated CHF requiring intravenous vasoactive therapy were randomized to receive standard therapy (n = 102) or nesiritide (0.015 microg/kg/min [n = 103] or 0.030 microg/kg/min [n = 100]) to gain additional data on the relative safety and efficacy of nesiritide compared with standard parenteral care. Dobutamine was chosen as the standard care agent in 58 subjects. During study drug infusion, all patients had continuous clinical hemodynamic and electrocardiographic monitoring. The dobutamine and nesiritide groups were similar with respect to baseline use of antiarrhythmic agents, including beta blockers. Serious arrhythmias and the incidence of cardiac arrest were more common in patients who received dobutamine than in those taking nesiritide: sustained ventricular tachycardia, 4 (7%) versus 2 (1%), respectively (p = 0.014); nonsustained ventricular tachycardia, 10 (17%) versus 23 (11%), respectively (p = 0.029); cardiac arrest, 3 (5%) versus 0, respectively (p = 0.011). We conclude that among patients with decompensated CHF for whom dobutamine is selected as standard therapy, the incidence of serious ventricular arrhythmias and cardiac arrest is significantly greater than the incidence of these events in patients randomized to nesiritide.

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.

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.

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.

Effect of beta-blockade on autonomic modulation of heart rate and neurohormonal profile in decompensated heart failure.

BACKGROUND: One of the putative mechanisms for the salutary effects of beta-blockers in patients with congestive heart failure (CHF) 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 (HRV) in decompensated CHF. METHODS: Time and frequency domain HRV indices were obtained from 24-hour Holter recordings and compared to assess the role of beta-blockade in 199 patients (mean age 60 +/- 14 years) with decompensated CHF. Neurohormonal differences were assessed by measuring norepinephrine, endothelin-1, tumor necrosis factor-alpha, and interleukin-6 in a subset of 64 patients. RESULTS: All HRV 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 R-R 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 R-R 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). Norepinephrine and interleukin-6 levels were substantially lower in patients on beta-blockers (28% and 61%, respectively). However, these differences did not reach statistical significance. CONCLUSIONS: Beta-blockers improve the impaired cardiac autonomic regulation during high sympathetic stress of decompensated CHF. This effect may play an important role in protecting the myocardium and preventing arrhythmias during transient increases in sympathetic activity.

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 diabetes mellitus on heart rate variability in patients with congestive heart failure.

This study sought to determine if the severity of autonomic perturbations in patients with heart failure are affected by the presence of diabetes. Decreased HRV is frequent in diabetic patients free of clinically apparent heart disease and has been invoked as a risk factor for sudden cardiac death. However, reduced HRV is also commonly present in patients with left ventricular dysfunction. The effect of diabetes on autonomic dysfunction in this setting is not known. Holter ECGs from 69 diabetic patients and 85 nondiabetic control subjects with heart failure were analyzed. The severity of autonomic dysfunction was assessed using 24-hour time- and frequency-domain HRV analysis. Prognostically important time- and frequency-domain HRV measures (SDNN, SDANN5, total power, and ultra-low frequency power) were not different between the two groups. Time- and frequency-domain parameters modulated by parasympathetic tone (pNN50, RMSSD, and HF power) were depressed to a similar degree in the diabetic and the nondiabetic groups. The low frequency power was significantly lower in diabetic patients (5.8 +/- 0.7 vs 5.3 +/- 1.0, P = 0.02). The ratio of low to high frequency power was substantially lower in the diabetic group (2.2 +/- 0.2 vs 1.4 +/- 0.2, P < 0.0001). These differences were more apparent in insulin-treated diabetics. In the presence of heart failure, HRV parameters that are most predictive of adverse outcome are similar in diabetic and nondiabetic patients. Furthermore, during increased sympathetic stimulation in the setting of heart failure, diabetes does not worsen parasympathetic withdrawal but may mitigate sympathetic activation.

Role of endothelin in modulation of heart rate variability in patients with decompensated heart failure.

Endothelin-1 (ET-1) can modulate central and peripheral sympathetic outflow. However, if increased ET-1 levels contribute to autonomic perturbations in the setting of congestive heart failure (CHF) is not known. The purpose of this study was to determine if increased ET-1 levels contribute to the depressed HRV in patients with CHF. Sixty-four patients were admitted to the hospital for treatment of decompensated CHF (mean age 59+/-12 years, NYHA Classes III [72%] and IV [28%]). Time- and frequency-domain HRV measures were obtained from 24-hour Holter recordings. Neurohormonal activation was assessed by measuring plasma renin activity (PRA), aldosterone, norepinephrine, and ET-1 levels. Among the time-domain HRV indices, ET-1 correlated negatively with the standard deviation of RR intervals (SDNN) (r = - 0.38, P = 0.002) and standard deviation of all 5-minute mean RR intervals (SDANN5) (r = - 0.48, P < 0.0001), but not with time-domain indices indicative of parasympathetic modulation. Among the frequency-domain HRV indices, ET-1 correlated negatively with the total power (r = - 0.32, P = 0.01) and ultralow frequency power (ULF) (r = - 0.43, P = 0.0004), but not with indices of parasympathetic (high frequency) or sympathovagal (low frequency) modulation. Using multiple linear regression, adjusting for clinical parameters, drug therapies, and other neurohormones, the strong negative relationship between ET-1 and SDNN (P = 0.027), SDANN5 (P = 0.002), and ULF power (P = 0.017) persisted. In conclusion, ET-1 may play an important role in the autonomic dysfunction characteristic of CHF. The correlation between ET-1 levels and prognostically important indices of overall HRV suggests that these HRV measures are better markers of neurohormonal activation in CHF, which may partially account for their greater discriminatory power for risk stratification.

BNP in decompensated heart failure: diagnostic, prognostic and therapeutic potential.

B-type or brain natriuretic peptide (BNP) is a balanced vasodilator with no inotropic nor chronotropic properties. Plasma levels can be used in diagnosis and prognosis of patients with heart failure, hypertension, myocardial infarction, right ventricular dysfunction and cor pulmonale. Intravenous therapy with BNP (nesiritide) in nearly 1000 patients demonstrated significant dose-dependent reductions in pulmonary capillary wedge pressure and systemic vascular resistance, as well as increased cardiac index. Compared to dobutamine, it is not pro-arrhythmic and has no effect on heart rate. Compared to standard therapy, it improves dyspnea by 3 h of therapy and leads to fewer headaches and arrhythmias than the commonly used intravenous agents nitroglycerin and dobutamine, respectively. Current research suggests an important role for use of nesiritide in the treatment of decompensated heart failure.

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.

Safety and efficacy of an accelerated dobutamine stress echocardiography protocol in the evaluation of coronary artery disease.

Although dobutamine requires up to 10 minutes to achieve steady state, dobutamine stress echocardiography is routinely performed using stepwise increments at 3-minute intervals. Consequently, the full effect of any infusion rate is not attained before the dobutamine dose is advanced to the next level. This study sought to test the safety and efficiency of high-dose continuous dobutamine infusion. One hundred consecutive patients underwent an accelerated protocol using a constant infusion of 50 microg/kg/min. In the absence of a stress echocardiographic end point (>/=85% of maximal predicted heart rate, new wall motion abnormalities, hypotension, arrhythmia, or intolerable symptoms), dobutamine infusion was discontinued at 10 minutes. Hemodynamic responses and adverse effect profile were compared with 100 patients who underwent a standard stepwise dobutamine stress protocol. Peak heart rate (140 +/- 16 vs 140 +/- 19 beats/min, p = 0.95) and systolic blood pressure (169 +/- 32 vs 162 +/- 31 mm Hg, p = 0.08) were similar in both protocols. Accelerated dobutamine administration produced a rapid increase in heart rate (12.5 +/- 6.2 vs 5.7 +/- 2.6 beats/min, p <0.001), and a substantial reduction in test duration (6.4 +/- 2.4 vs 12.9 +/- 3.0 minutes, p <0.001). The mean weight-adjusted cumulative dobutamine dose was lower in the accelerated protocol group (320 +/- 111 vs 353 +/- 133 microg/kg, p = 0.016). No significant differences were noted between the 2 groups with respect to various side effects. These data demonstrate that a high-dose, single-stage dobutamine echocardiographic stress protocol is a feasible, well-tolerated alternative to standard dobutamine stress echocardiography, and results in a substantial reduction in test time while maintaining a low complication rate.

Low incidence of embolic strokes with atrial septal aneurysms: A prospective, long-term study.

BACKGROUND: Previous retrospective studies have suggested that atrial septal aneurysms (ASA) are associated with embolic strokes. The purpose of this study was to evaluate prospectively the embolic potential of ASA. METHODS: Of 846 consecutive patients undergoing cardiac surgery from December 1990 to March 1993, we identified 42 patients who had ASA as an incidental finding on intraoperative transesophageal echocardiography. Patency was determined by color and/or contrast echocardiography. The majority of patients were given aspirin postoperatively. Patients were monitored by personal and/or telephone interviews, and their clinical conditions were confirmed by their personal physicians. Any patient with any question of a neurologic event had a detailed neurologic history, examination, and computed tomographic or magnetic resonance imaging scan. RESULTS: The incidence of ASA in our population was 4.9%; there were 22 men and 20 women with a mean age of 72 years. Oscillating ASA were present in 28 patients and fixed aneurysm in 10. The mean diameter of the ASA was 21 +/- 4 mm. Eighteen (56%) of 32 patients had a patent ASA. Patients were monitored for a mean period of 69.5 months (56 to 85 months). No patient had a cerebrovascular event or systemic embolization. CONCLUSION: The risk of cerebrovascular events or embolic strokes in our patient population with incidental ASA was low. If treatment is needed for this condition, aspirin appears to be effective therapy.

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.

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 manufacturer's 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.

Circadian patterns of heart rate variability, fibrinolytic activity, and hemostatic factors in type I diabetes mellitus with cardiac autonomic neuropathy.

Diabetes mellitus is associated with a marked increase in the risk of coronary events but with an altered circadian distribution that demonstrates an absent morning peak and higher infarction rate during the evening hours. To elucidate the mechanism of this phenomenon, the circadian pattern of heart rate variability was evaluated in 22 type I diabetic patients with diabetic autonomic neuropathy in conjunction with circadian changes of fibrinolytic and hemostatic factors. The circadian pattern (6 A.M. to 10 P.M. vs 10 P.M. to 6 A.M.) of 3 indexes of parasympathetic tone was evaluated using 24-hour heart rate variability analysis. The high-frequency power (3.0 +/- 0.2 vs 3.3 +/- 0.2 ms2, p = 0.08) and the percentage of RR intervals with >50 ms variation (0.47 +/- 0.18 vs 0.69 +/- 0.33 ms, p = 0.52) demonstrated no significant circadian variation. The square root of mean squared differences of successive RR intervals showed a small but significant increase during nighttime (8.5 +/- 0.7 vs 9.7 +/- 1.1 ms, p = 0.02). Fibrinolytic activity was significantly lower at 8 A.M. than at 4 P.M. (166.4 +/- 12.5 to 200.2 +/- 9.3 mm2, p = 0.0003), but with a low amplitude. Plasminogen activator inhibitor 1 showed no circadian variation. Factor VII and fibrinogen demonstrated a significant reduction from 8 A.M. to 4 P.M., but both peak and nadir values were elevated. The von Willebrand factor was markedly elevated with no circadian variation. Thus, diabetic autonomic neuropathy is associated with a loss of both the nocturnal predominance of parasympathetic activity and a prothrombotic state that persists throughout the day. These abnormalities may attenuate the relative protection from coronary events during the afternoon and nighttime.