Outcome of patients with congestive heart failure treated with standard versus high doses of enalapril: a multicenter study. High Enalapril Dose Study Group

OBJECTIVES

We sought to prospectively and randomly compare survival with clinical and hemodynamic variables in patients with congestive heart failure (CHF) treated with standard versus high doses of enalapril.

BACKGROUND

Angiotensin-converting enzyme (ACE) inhibitors produce hemodynamic and symptomatic benefits in patients with CHF, but there is still controversy about the optimal dose in this clinical setting.

METHODS

Two hundred and forty-eight patients with advanced CHF (age 56.3 ± 12 years) were randomized to receive a maximal tolerated dose of enalapril, up to 20 mg/day in group 1 (mean dose achieved 17.9 ± 4.3 mg/day, N = 122) and 60 mg/day in group 2 (mean dose achieved 42 ± 19.3 mg/day, N = 126).

RESULTS

At enrollment, patients in group 1 were in New York Heart Association (NYHA) functional class 2.6 ± 0.7 and had a mean systolic blood pressure (SBP) of 117 ± 18 mm Hg, a mean heart rate (HR) of 85 ± 16 beats/min and a left ventricular ejection fraction (LVEF) of 20.0 ± 9.8%. In group 2, patients were in NYHA class 2.6 ± 0.7; their SBP was 118 ± 17 mm Hg, HR 83 ± 15 beats/min and LVEF 18.8 ± 8.1%. There were no significant differences in these characteristics between the two groups of patients at enrollment. After 12 months of follow-up, 22 (18%) of 122 patients in group 1 and 23 (18%) of 126 patients in group 2 had died (p = 0.995, with 80% power of the study to detect a delta difference of 13%). The NYHA class was the same (1.9 ± 0.7) in both groups; SBP was 111 ± 16 and 111 ± 17 mm Hg, HR 77 ± 12 and 79 ± 13 beats/min and LVEF 31 ± 19% and 30 ± 12% in groups 1 and 2, respectively. These differences were not statistically significant. The study had a power of 80% to detect (p = 0.05) the following changes: 13% in death rate, 0.25 units in NYHA class, 6 mm Hg in SBP, 5 beats/min in HR and 6% in LVEF.

CONCLUSIONS

No significant differences were found in survival and clinical and hemodynamic variables between patients receiving standard and those receiving high doses of enalapril.     

Electronic home monitoring of congestive heart failure patients: design and feasibility

The efficacy of electronic monitoring in the home care of heart failure (HF) patients has not been widely reported. We developed a Vital Sign System (VSS) monitoring device capable of measuring the weight, blood pressure, and heart rate of congestive heart failure (CHF) patients in the home and transmitting these measurements via modem to a World Wide Web server. In this study of 22 CHF patients, we tested the reliability of the VSS electronic measurements compared to manual measurements taken by visiting home care nurses and ease of use of the VSS units as rated by both patients and home care nurses. The correlation of electronic to manual measurements was high (weight r=0.99; systolic blood pressure [SBP] r=0.84; diastolic blood pressure [DBP] r=0.54; heart rate [HR] r=0.88). The mean difference between electronic and manual measurements was within an acceptable range for clinical surveillance and care of CHF patients (weight 1.6 lbs; SBP 8.8 mm Hg; DBP 9.2 mm Hg; HR 0.7 bpm) The devices were rated favorably by both nurses and patients. The VSS monitoring device is a reliable, feasible, and favorably rated technology for home surveillance of CHF patients. (c)1999 by CHF, Inc.     

Effects of calcium antagonist, angiotensin-converting enzyme inhibitors and beta-blocker on hemodynamic and sympathetic nerve responses to exercise in essential hypertension]

To investigate the effects of antihypertensive drugs on hemodynamic and sympathetic nerve responses to exercise, graded ergometer exercise tests were performed before and after two-week administration of nifedipine, captopril and metoprolol in 18 patients with essential hypertension. The arterial pressure, heart rates (HR), and left ventricular functions as obtained by echocardiography, and the plasma norepinephrine (PNE) levels, were evaluated at rest and during submaximal exercise before and after two-week treatment with nifedipine (40 mg/day, 5 cases), captopril (37.5-75 mg/day, 6 cases) and metoprolol (60 mg/day, 7 cases). These 3 drugs significantly reduced systolic (SBP) and diastolic (DBP) blood pressures but caused no significant changes in resting PNE levels. Nifedipine produced no significant changes in HR and cardiac output (CO) at rest, but augmented the increase in HR (delta HR) and SBP (delta SBP) during submaximal exercise. The increase in PNE (delta PNE) was also augmented by nifedipine. Captopril reduced left ventricular end-diastolic volume and CO without changes in HR and fractional shortening (FS) at rest; whereas, it did not affect delta HR, delta CO, delta SBP or delta PNE during exercise. Metoprolol reduced HR and CO at rest, and also resulted in a decrease in delta FS and delta CO during submaximal exercise. delta SBP was unchanged and delta PNE was increased by treatment with metoprolol. These results indicate that, in hypertensive subjects, the effects on the hemodynamic and sympathetic nerve responses to exercise are different among these 3 antihypertensive drugs despite their identical effects on blood pressure.     

Assessment of autonomic regulation in chronic congestive heart failure by heart rate spectral analysis

Neurohumoral modulation of cardiovascular function is an important component of the hemodynamic alterations in patients with chronic congestive heart failure (CHF). Analysis of heart rate (HR) variability is a noninvasive means of investigating the autonomic control of the heart. The variability of HR and respiratory signals, both derived from ambulatory electrocardiographic recordings, were analyzed with power spectral analysis to evaluate autonomic control in 25 patients with chronic stable CHF (class III or IV) and 21 normal control subjects. In the patients with CHF, HR spectral power was markedly reduced (p less than 0.0001) at all frequencies examined (0.01 to 1.0 Hz, period 1 to 100 seconds) and virtually absent at frequencies greater than 0.04 Hz. Heart rate fluctuations at very low frequencies (0.01 to 0.04 Hz) less effectively differentiated CHF patients from control subjects, due to discrete (about 65 seconds, 0.015 Hz) oscillation in HR, which was associated with a similar pattern in respiratory activity in many of the patients with CHF. These findings demonstrate a marked derangement of HR modulation in patients with severe CHF. The frequency characteristics of HR fluctuations in these patients are consistent with abnormal baroreflex responsiveness to physiologic stimuli, and suggest that there is diminished vagal, but relatively preserved sympathetic, modulation of HR.     

Adrenal pheochromocytoma associated with dramatic cyclic hemodynamic fluctuations

A 52-year-old woman with a right adrenal pheochromocytoma had repetitive attacks of symptomatic hypotension/shock with systolic blood pressure (SBP)<50 mmHg followed by hypertension/hypertensive crises with SBP>300 mmHg. A non-invasive recording of beat-to-beat SBP, diastolic blood pressure (DBP), heart rate (HR), stroke volume (SV), cardiac output (CO) and total peripheral resistance (TPR) was collected for 346 min. Twenty hemodynamic cycles occurred during this time, lasting 17 min on average, with the most dramatic changes of TPR. The ratio of the highest to the lowest observed values was nearly 12:1 for TPR, over 6:1 for both SBP and DBP, over 4:1 for CO, and nearly 4:1 for SV and 2:1 for HR. The fluctuations of TPR preceded changes of all other hemodynamic variables.     

Circulatory autoregulation in chronic congestive heart failure: responses to head-up tilt in 41 patients

To evaluate mechanisms that regulate the response to postural change in patients with chronic congestive heart failure (CHF), the hemodynamic and vasoactive hormonal responses to head-up tilt were examined in 41 patients. Peripheral venous pooling was present in only 18 patients and was inversely correlated with baseline pulmonary wedge pressure. Baseline supine hemodynamic indexes of these 18 patients indicated less severe CHF compared with those of the 23 patients who did not demonstrate venous pooling. The 18 patients with intact afferent pooling also had lower levels of plasma renin activity and demonstrated increases in both plasma renin activity and norepinephrine on tilt; these reflex increases in vasoactive hormones were not seen in the 23 patients with severe CHF. Overall, 3 patterns could be identified. Of the 18 patients with venous pooling, 12 maintained many of the elements of normal postural response, with increases in systemic vascular resistance and circulating norepinephrine that maintain blood pressure constant. Six patients did not increase resistance in response to peripheral venous pooling and had major decreases in blood pressure analogous to idiopathic orthostatic hypotension. The larger group of 23 patients with more severe CHF did not have peripheral venous pooling and, hence, no afferent stimulus for reflex changes. Thus, the hemodynamic and neurohormonal responses to head-up tilt in CHF are heterogeneous and may be influenced by the severity of disease. The abnormalities of response may reflect the progression of vascular adaptation with loss of myocardial pump function and are important in terms of the pathophysiology and treatment of chronic heart failure.     

Vasopeptidase inhibition with omapatrilat in chronic heart failure: acute and long-term hemodynamic and neurohumoral effects

OBJECTIVES: We investigated the acute and long-term hemodynamic and neurohumoral effects of the vasopeptidase inhibitor omapatrilat in human heart failure. BACKGROUND: Angiotensin-converting enzyme (ACE) inhibition constitutes a major advance in the treatment of chronic heart failure (CHF). Simultaneous inhibition of both neutral endopeptidase and ACE with omapatrilat may represent a new treatment strategy in CHF. METHODS: Three hundred and sixty-nine patients with symptomatic heart failure were randomized to double-blind treatment with omapatrilat (first 190 patients: 2.5 mg, 5 mg or 10 mg; last 179 patients: 2.5 mg, 20 mg or 40 mg once daily) for 12 weeks. RESULTS: Acutely, the 10 mg, 20 mg and 40 mg doses of omapatrilat produced greater reductions in pulmonary capillary wedge pressure (PCWP), systolic blood pressure (SBP) and systemic vascular resistance compared with 2.5 mg. Higher doses were associated with greater increases in vasodilator and natriuretic peptides, in addition to ACE inhibition. After 12 weeks, omapatrilat 20 mg and 40 mg showed greater falls from baseline in PCWP (40 mg: 0 h to 12 h average change -7.3 +/- 0.8 mm Hg) and SBP (40 mg: -11.7 +/- 1.7 mm Hg) than 2.5 mg (both p < 0.01 vs. 2.5 mg). The incidence of adverse experiences and patient withdrawal were similar in all groups. CONCLUSIONS: In CHF, the acute hemodynamic benefit seen with higher doses of omapatrilat was associated with increases in plasma vasodilator and natriuretic peptide levels in addition to ACE inhibition. After 12 weeks, the hemodynamic benefit was maintained. Omapatrilat may be a promising new agent in CHF.     

米力农治疗充血性心力衰竭的血流动力学变化及临床疗效观察

目的　观察米力农对充血性心力衰竭患者血流动力学的影响及临床治疗效果。方法　应用米力农治疗充血性心力衰竭患者 5 0例 ,观察治疗前后心功能级别变化 ,并进行血流动力学及超声心动图指标测定。结果　应用米力农治疗后 1 5分钟起血流动力学指标 RAP、MPP、PCWP、PVR、SVR即较前有明显下降 ( P<0 .0 5 ) ,CI增加 ( P<0 .0 5 ) ,作用持续到 8小时后。对 HR、 SBP、 DBP无影响 ( P>0 .0 5 )。治疗后超声心动图测定显示 SV、 CO、 EF、 FS、E峰较治前明显增加 ( P<0 .0 5 )。A峰明显下降 ( P<0 .0 5 ) ,LVD、RVD、LAD显著缩小 ( P<0 .0 5 )。心功能改善 4 8例 ,总有效率 96 %。结论　米力农能增加心肌收缩力 ,改善心脏舒张功能 ,且有扩血管作用 ,对心力衰竭有明显疗效。     

Peripheral sympathetic control during dobutamine infusion: effects of aging and heart failure

OBJECTIVES: We assessed the effects of beta-adrenergic agonism on muscle sympathetic nerve activity (MSNA) in patients with congestive heart failure (CHF) and young and matched controls. BACKGROUND: Myocardial response to beta-adrenergic stimulation decreases with aging and with CHF. METHODS: In CHF patients, we measured cardiac hemodynamics and MSNA (microneurography) before, with short-term (n = 5), and after 48-h (n = 9) of dobutamine infusion (10 microg/kg/min). In eight young controls and nine controls matched to the CHF patients, we measured cardiac hemodynamics and MSNA during randomized short-term dobutamine (10 microg/kg/min) and placebo infusions. RESULTS: In CHF patients, short-term dobutamine infusion did not modify mean blood pressure (MBP), MSNA, or heart rate (HR). Moreover, 48-h dobutamine infusion increased cardiac index (3.1 +/- 0.2 vs. 2.2 +/- 0.2 l/min/m(2), p = 0.006), decreased mean pulmonary pressure (28 +/- 7 vs. 38 +/- 7 mm Hg, p = 0.0001) and peripheral resistance (1,099 +/- 112 vs. 1,759 +/- 263, p = 0.03), but did not change MBP, HR, or MSNA in the patients. In matched controls, dobutamine increased HR (87 +/- 5 vs. 65 +/- 2 beats/min, p = 0.0009) but did not change MBP or MSNA. In young controls, dobutamine increased MBP (102 +/- 2 vs. 90 +/- 2 mm Hg, p = 0.0003) and decreased MSNA (28 +/- 5 vs. 35 +/- 3 bursts/min, p = 0.03) but did not change HR (p = 0.054). In the controls, the largest increases in MBP with dobutamine were associated with the most marked reductions in MSNA (r = -0.49, p = 0.04) and the smallest increases in HR (r = -0.70, p = 0.001). CONCLUSIONS: Arterial baroreceptor activation during increases in MBP inhibits MSNA and limits the HR response to dobutamine in controls. This mechanism, together with peripheral vasodilation, probably contributes to the absence of peripheral sympathetic withdrawal despite substantial hemodynamic improvements in CHF patients.     

Safety profile and hemodynamic responses to beta-adrenergic stimulation by dobutamine in heart transplant patients

STUDY OBJECTIVE: Dobutamine stress echocardiography (DSE) has been used as a screening tool for coronary artery disease after heart transplantation and in the identification of patients at risk for development of cardiac events. However, the safety profile of high-dose dobutamine in heart transplant patients has not been systematically examined. Accordingly, we studied the safety profile and hemodynamic responses to escalating doses of dobutamine to determine the influence of denervation. DESIGN: We assessed the hemodynamic responses, heart rate (HR), and arterial BP indexes (mean arterial pressure, systolic BP [SBP], diastolic BP [DBP], and pulse pressure) to dobutamine in 87 heart transplant patients ([mean +/- SD] age, 51 +/- 1 years) and compared the results with 97 nontransplant patients (age, 63.0 +/- 1 years) who served as innervated control subjects. MEASUREMENTS AND RESULTS: The baseline HR (84 +/- 2 vs 69 +/- 1 beats/minute, respectively; p < 0.001) and peak HR response (144 +/- 2 vs 117 +/- 2 beats/minute, respectively; p < 0.001) were significantly higher in heart transplant patients than in the nontransplant patients. SBP was lower in heart transplant patients than in nontransplant patients at baseline (131 +/- 2 vs 138 +/- 2 mm Hg, respectively; p < 0.02) and at peak (150 +/- 3 vs 158 +/- 3 mm Hg, respectively; p < 0.03). However, baseline DBP was higher in transplant patients than in nontransplant patients (86 +/- 1 vs 77 +/- 1 mm Hg, respectively; p < 0.001). The decrease in DBP was similar in both groups (15 mm Hg). The dose-response curve for HR was shifted leftward in heart transplant patients. Heart transplant patients attained a higher absolute HR at each infusion stage and higher rates of increase, but the decrease in DBP was not significantly different in the two groups. CONCLUSIONS: These results show that there is augmented chronotropic response and expected decline in DBP in response to dobutamine infusion in heart transplant patients. This increase in myocardial oxygen demand and a decrease in coronary perfusion pressure may be important mechanisms in the development of ischemic abnormalities that are detectable as regional dysynergy on echocardiography.     

Aspirin Inhibits the Acute Arterial and Venous Vasodilator Response to Captopril in Patients with Chronic Heart Failure

Summary Purpose: The potentially beneficial hemodynamic effects of angiotensin-converting enzyme (ACE) inhibitors in heart failure may relate, in part, to their ability to increase the production of vasodilator prostanoids. Low dose aspirin is commonly prescribed in CHF and may attenuate the vasodilator effects of ACE inhibitors. We sought to determine the effects of low dose aspirin on the peripheral hemodynamic effects of captopril in patients with chronic heart failure (CHF). Methods: Nine patients with chronic heart failure were randomized in a placebo controlled, cross over study, to 75 mg of aspirin daily or placebo. After 7 days treatment the response to 25 mg of captopril was evaluated over 180 min using venous occlusion plethysmography. Forearm blood flow (FBF) and forearm venous capacitance (FVC) were measured. Results: Mean arterial pressure and heart rate did not change. After placebo, FBF increased in response to captopril (+18%, 95%CI 24.2, 11.8), a response inhibited by aspirin (−1.4%, 2.9, −5.7), p < 0.005. After placebo, FVC increased in response to captopril (+7.6%, 9.8, 5.4), which was also inhibited by aspirin (+2.0%, 4.6, −0.6), aspirin vs. placebo, p = 0.02). Conclusion: In patients with chronic heart failure even low dose aspirin inhibits both the acute arterial and venous dilator responses to captopril. This action of aspirin may reduce the long-term clinical benefits of ACE inhibitors     

Immersion in warm water induces improvement in cardiac function in patients with chronic heart failure

BACKGROUND: The effects of immersion and training of patients with chronic heart failure (CHF) in warm water has not been thoroughly investigated. The aim of this study was to assess the acute hemodynamic response of immersion and peripheral muscle training in elderly patients with CHF. METHODS: Thirteen CHF patients and 13 healthy subjects underwent echocardiography on land and in a temperature-controlled swimming pool (33-34 degrees C). RESULTS: Rest. Heart rate decreased (CHF, p=0.01; control, p=0.001) and stroke volume increased (CHF, p=0.01; control, p=0.001) during water immersion in both groups, with no change in systolic or diastolic blood pressure. Ejection fraction (p<0.05) and transmitral Doppler E/A ratio (p=0.01) increased in the CHF group, with no changes in left ventricular volumes. The healthy subjects had similar responses, but also displayed an increase in cardiac output (p<0.01) and left ventricular volumes (p<0.001). Exercise. Cardiac output and systolic blood pressure increased significantly in water, in both groups. CONCLUSION: A general increase in early diastolic filling was accompanied by a decrease in heart rate, leading to an increase in stroke volume and ejection fraction in most patients with CHF during warm water immersion. These beneficial hemodynamic effects might be the reason for the previously observed good tolerability of this exercise regime.     

New aspects for the role of physical training in the management of patients with chronic heart failure

Recent experimental and clinical data have shown that physical training is an important therapeutic intervention in the management of patients with chronic heart failure (CHF), improving central hemodynamics and attenuating peripheral abnormalities (endothelial dysfunction and skeletal myopathy) characterizing the progression of the syndrome. Additionally, physical training seems to beneficially modulate peripheral immune responses of CHF expressed by elevated circulating proinflammatory cytokines, soluble cellular adhesion molecules and soluble apoptosis signaling molecules, resulting in improvement in exercise capacity of CHF patients. This article summarizes current knowledge about the beneficial role of physical training in CHF, as well as about traditional and novel mechanisms contributing to the physical training-induced improvement in clinical performance of CHF patients.     

Possible role of dopamine in ventilatory acclimatization to high altitude

Ventilatory acclimatization to high altitude is accompanied by increased hypoxic (HVR) and hypercapnic (HCVR) ventilatory responses which may reflect increased carotid body chemosensitivity. Dopamine is an inhibitory neuromodulator of the carotid body and its activity may be reduced by hypoxic exposure. To determine whether decreased dopaminergic activity could account for the increased chemosensitivity of acclimatization, we examined the response to peripheral dopamine receptor (D₂) blockade with domperidone on HVR and HCVR in awake cats before and after exposure to simulated altitude of 14000 ft for 2 days. During anesthesia, we also examined the effects of domperidone on carotid body responses to hypoxia and hypercapnia in acclimatized and low altitude cats. Two days' exposure to hypobaric hypoxia produced an increase in HVR and HCVR. Before acclimatization, domperidone augmented HVR and HCVR, but there was no effect after acclimatization. In anesthetized low altitude cats, domperidone increased carotid body responses to hypoxia and hypercapnia, but had no effect in acclimatized cats. These results indicate that decreased endogenous dopaminergic activity may contribute to increased ventilatory and chemoreceptor responsiveness to hypoxia and hypercapnia during hypoxic ventilatory acclimatization.     

Impaired chronotropic response to exercise in patients with congestive heart failure. Role of postsynaptic beta-adrenergic desensitization

The mechanism responsible for the attenuated heart rate (HR) response to exercise in patients with congestive heart failure (CHF) was investigated in 46 normal subjects and 59 patients with CHF stratified by peak exercise oxygen consumption (VO2). The peak exercise HR and the increment in HR from rest to peak exercise were decreased in CHF patients, and both correlated strongly with peak VO2 (r = 0.810, p less than 0.0001; r = 0.863, p less than 0.0001, respectively). Peak exercise norepinephrine level (NE) and the increment in NE from rest to peak exercise were not attenuated in CHF patients. Resting NE was elevated in CHF patients and correlated inversely with peak VO2 (r = -0.595, p less than 0.001). However, no significant correlation occurred between peak VO2 and either peak exercise NE or the exercise increment in NE. The ratio of the exercise increments in HR and NE, and indirect index of sinoatrial node sympathetic responsiveness, was markedly reduced in CHF patients and was inversely related to the severity of exercise impairment. Likewise, the HR response to a graded isoproterenol infusion was markedly reduced in CHF patients. Age-matching of normal subjects and CHF patients did not affect the foregoing observations. Infusion of CHF patients with the phosphodiesterase inhibitor milrinone caused a significant increase in the ratio of the exercise increments in HR and NE. These data strongly suggest that the attenuated HR response to exercise in CHF patients is due, at least in part, to postsynaptic desensitization of the beta-adrenergic receptor pathway.     

Heart failure in diabetes and related conditions

BackgroundDespite advances in therapy for congestive heart failure (CHF), mortality remains 40% to 80% higher for diabetics with CHF than nondiabetics. Diabetes prevalence is increasing worldwide with prevalence of diabetes among patients with CHF increasing at an even faster pace.Methods and ResultsAlthough multiple mechanisms are responsible for development of CHF in diabetes, ischemic heart disease plays a major role. In the foreseeable future, physicians will have to deal with increasing numbers of subjects with diabetes, coronary disease, and heart failure. Several recent developments in the field of heart failure have revolutionized the way patients are treated for CHF with improvements in quality of life and mortality. Although long-term prospective studies specifically addressing heart failure in diabetes are lacking, extrapolation of data from recent large trials has shed light on management of CHF in diabetes.ConclusionsThis review summarizes new developments in the field of CHF among subjects with diabetes, metabolic syndrome, and obesity.     

Responses of the second derivative of the finger photoplethysmogram indices and hemodynamic parameters to anesthesia induction

The finger photoplethysmogram (PTG) is a non-invasive method for pulse-wave analysis. The second derivative wave of the PTG (SDPTG) enables evaluation of atherosclerosis and cardiovascular aging. Responses of SDPTG indices and hemodynamic parameters to anesthesia induction are unknown. A total of 42 patients aged 40 years, who may have had atherosclerotic change, and who underwent elective oral surgery, were analyzed. Patients were divided into sevoflurane (S group; N=22) and sevoflurane with remifentanil (R group; N=20) groups. Systolic and diastolic blood pressure (SBP, DBP), heart rate (HR) and SDPTG were measured at four time points: before induction, after loss of consciousness, after tracheal intubation and 30?min after induction. At postintubation, b/a was elevated (that is, large arterial stiffness was increased), and d/a was reduced (that is, peripheral vascular resistance was increased) in the S group compared with the R group. SBP, DBP and HR were increased in the S group compared with those in the R group. In the S group, preanesthetic b/a and the aging index (AGI) were positively correlated with SBP at immediate postintubation, and preanesthetic d/a was negatively correlated with SBP and DBP at immediate postintubation. It is suggested that usage of remifentanil, a potent μ-opioid analgesic, with sevoflurane anesthesia prevented an increase in blood pressure and HR in response to laryngoscopy and tracheal intubation, which was accompanied by suppression of both elevation of b/a and the AGI and reduction of d/a. SDPTG indices are useful for predicting hypertension during induction of sevoflurane anesthesia, regardless of a history of hypertension or hypertensive factors.     

Brain natriuretic peptide is a potent vasodilator in aged human microcircula-tion and shows a blunted response in heart failure patients

Background Brain natriuretic peptide （BNP） is normally present in low levels in the circulation, but it is elevated in parallel with the degree of congestion in heart failure subjects （CHF）. BNP has natriuretic effects and is a potent vasodilator. It is suggested that BNP could be a therapeutic alternative in CHF. However, we postulated that the high levels of circulating BNP in CHF may downregulate the response of microvascular natriuretic receptors. This was tested by comparing 15 CHF patients （BNP 〉 3000 ng/L） with 10 matched, healthy controls. Methods Cutaneous microvascular blood flow in the forearm was measured by laser Doppler Flowmetry. Local heating （＋44°C, 10 min） was used to evoke a maximum local dilator response. Results Non-invasive iontophoretic administration of either BNP or acetylcholine （ACh）, a known endothelium-dependent dilator, elicited an increase in local flow. The nitric oxide synthase inhibitor, l-N-Arginine- methyl-ester （L-NAME）, blocked the BNP response （in controls）. Interestingly, responses to BNP in CHF patients were reduced to about one third of those seen in healthy controls （increase in flow： 251% in CHF vs. 908% in controls; P 〈 0.001）. In contrast, the vasodilator responses to ACh and to local heating were only somewhat attenuated in CHF patients. Thus, dilator capacity and nitric oxide signalling were not af- fected to the same extent as BNP-mediated dilation, indicating a specific downregulation of the latter response. Conclusions The findings show for the first time that microvascular responses to BNP are markedly reduced in CHF patients. This is consistent with the hypothesis of BNP receptor function is downregulated in CHF.     

Biomarkers of endothelial dysfunction are elevated and related to prognosis in chronic heart failure patients with diabetes but not in those without diabetes

BACKGROUND: Biomarkers of endothelial dysfunction, such as soluble E-selectin, and von Willebrand factor (vWf) are elevated in patients with chronic heart failure (CHF). The impact of diabetes mellitus (DM) on these biomarkers, and their relation to prognosis remains unknown. AIMS: to investigate the impact of DM on plasma levels and the prognostic value of E-selectin and vWf in patients with CHF. METHODS AND RESULTS: Plasma levels of E-selectin and vWf were measured in 195 CHF patients with (n=48, 24.5%), and without DM, and in 116 age-matched healthy controls. Compared with controls, median plasma E-selectin levels were higher in CHF patients with DM (P=0.012), but not in CHF patients without DM (P=0.45); vWf levels were also higher in CHF patients with DM (P<0.001), but not without DM (P=0.108). E-selectin was associated with risk of recurrent ischaemic cardiovascular events among CHF patients with DM (HR 2.60; P=0.009), but not among patients without DM (HR 1.09; P=0.60) per 1 SD increment in log transformed variable. vWf was not related with outcome in CHF patients with or without DM. CONCLUSIONS: Plasma levels of E-selectin and vWf are elevated in CHF patients with DM but not in those without DM. High E-selectin levels may be associated with ischaemic events in patients with DM.     

A comparison of ambulatory oxygen consumption during circuit training and aerobic exercise in patients with chronic heart failure.

PURPOSE: This study compared the exercise intensity of a combined aerobic and resistance exercise circuit training session with the exercise intensity of continuous aerobic exercise in patients with chronic heart failure (CHF). METHODS: Peak oxygen consumption (VO2peak) and muscular strength (1 repetition maximum) were assessed in six CHF patients (age 62 +/- 3 years). Heart rate, rate of perceived exertion (RPE), blood pressures, ambulatory oxygen consumption (VO2), and ventilatory data were measured during two types of exercise: continuous cycling on a bicycle ergometer (aerobic [AER] session) and combined AER and resistance exercise (circuit training [CIR] session). RESULTS: There were no significant differences in VO2, RPE, heart rate, or hemodynamic responses (rate pressure product, diastolic blood pressure, or mean arterial pressure) during exercise, between the two sessions. Systolic blood pressure was significantly lower during CIR (P < 0.05). Minute ventilation and tidal volume were significantly higher (P < 0.0001 and P < 0.01, respectively) and respiratory frequency significantly lower (P < 0.005) during CIR. During CIR, RPE significantly correlated with VO2 (P < 0.01), whereas heart rate did not. Conversely, during the AER session HR correlated with VO2 (P < 0.01), but RPE did not. CONCLUSIONS: Circuit training is a well-tolerated form of exercise training for CHF patients that is associated with similar oxygen and hemodynamic demand to aerobic exercise. Results suggest that RPE may be a better method of prescribing and monitoring exercise intensity during CIR, with heart rate the preferred measure of intensity during aerobic exercise.