Behavioural modification of the cholinergic anti-inflammatory response to C-reactive protein in patients with hypertension.

OBJECTIVES: A central hypothesis of the cholinergic anti-inflammatory reflex model is that innate immune activity is inhibited by the efferent vagus. We evaluated whether changes in markers of tonic or reflex vagal heart rate modulation following behavioural intervention were associated inversely with changes in high-sensitivity C-reactive protein (hsCRP) or interleukin-6 (IL-6). DESIGN: Subjects diagnosed with hypertension (n = 45, age 35-64 years, 53% women) were randomized to an 8-week protocol of behavioural neurocardiac training (with heart rate variability biofeedback) or autogenic relaxation. Assessments before and after intervention included pro-inflammatory factors (hsCRP, IL-6), markers of vagal heart rate modulation [RR high-frequency (HF) power within 0.15-0.40 Hz, baroreflex sensitivity and RR interval], conventional measures of lipoprotein cholesterol and 24-h ambulatory systolic and diastolic blood pressure. RESULTS: Changes in hsCRP and IL-6 were not associated with changes in lipoprotein cholesterol or blood pressure. After adjusting for anti-inflammatory drugs and confounding factors, changes in hsCRP related inversely to changes in HF power (ß = -0.25±0.1, P = 0.02), baroreflex sensitivity (ß = -0.33±0.7, P = 0.04) and RR interval (ß = -0.001 ± 0.0004, P = 0.02). Statistically significant relationships were not observed for IL-6. CONCLUSIONS: Changes in hsCRP were consistent with the inhibitory effect of increased vagal efferent activity on pro-inflammatory factors predicted by the cholinergic anti-inflammatory reflex model. Clinical trials for patients with cardiovascular dysfunction are warranted to assess whether behavioural interventions can contribute independently to the chronic regulation of inflammatory activity and to improved clinical outcomes.

Studying semblances of a true killer: experimental model of human ventricular fibrillation.

It is unknown whether ventricular fibrillation (VF) studied in experimental models represents in vivo human VF. First, we examined closed chest in vivo VF induced at defibrillation threshold testing (DFT) in four patients with ischemic cardiomyopathy pretransplantation. We examined VF in these same four hearts in an ex vivo human Langendorff posttransplantation. VF from DFT was compared with VF from the electrodes from a similar region in the right ventricular endocardium in the Langendorff using two parameters: the scale distribution width (extracted from continuous wavelet transform) and VF mean cycle length (CL). In a second substudy group where multielectrode phase mapping could be performed, we examined early VF intraoperatively (in vivo open chest condition) in three patients with left ventricular cardiomyopathy. We investigated early VF in the hearts of three patients in an ex vivo Langendorff and compared findings with intraoperative VF using two metrics: dominant frequency (DF) assessed by the Welch periodogram and the number of phase singularities (lasting >480 ms). Wavelet analysis (P = 0.9) and VF CL were similar between the Langendorff and the DFT groups (225 ± 13, 218 ± 24 ms; P = 0.9), indicating that wave characteristics and activation rate of VF was comparable between the two models. Intraoperative DF was slower but comparable with the Langendorff DF over the endocardium (4.6 ± 0.1, 5.0 ± 0.4 Hz; P = 0.9) and the epicardium (4.5 ± 0.2, 5.2 ± 0.4 Hz; P = 0.9). Endocardial phase singularity number (9.6 ± 5, 12.1 ± 1; P = 0.6) was lesser in number but comparable between in vivo and ex vivo VF. VF dynamics in the limited experimental human studies approximates human in vivo VF.

Shift in sleep apnoea type in heart failure patients in the CANPAP trial.

In patients with heart failure (HF), the predominant type of sleep apnoea can change over time in association with alterations in circulation time. The aim of this study was to determine whether, in some patients with HF, a spontaneous shift from mainly central (>50% central events) to mainly obstructive (>50% obstructive events) sleep apnoea (CSA and OSA, respectively) over time coincides with improvement in left ventricular ejection fraction (LVEF). Therefore, sleep studies and LVEFs of HF patients with CSA from the control arm of the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure (CANPAP) trial were examined to determine whether some converted to mainly OSA and, if so, whether this was associated with an increase in LVEF. Of 98 patients with follow-up sleep studies and LVEFs, 18 converted spontaneously to predominantly OSA. Compared with those in the nonconversion group, those in the conversion group had a significantly greater increase in the LVEF (2.8% versus -0.07%) and a significantly greater fall in the lung-to-ear circulation time (-7.6 s versus 0.6 s). In patients with HF, spontaneous conversion from predominantly CSA to OSA is associated with an improvement in left ventricular systolic function. Future studies will be necessary to further examine this relationship.

Relationship between sleep apnoea and mortality in patients with ischaemic heart failure.

OBJECTIVE: To determine whether the influence of sleep apnoea (SA) on the risk of death differs in patients with ischaemic and in those with non-ischaemic heart failure (HF). DESIGN: Prospective observational study. PATIENTS: Consecutive patients with HF with left ventricular ejection fraction < or =45% newly referred to the HF clinic between 1 September 1997 and 1 December 2004. MAIN OUTCOME MEASURES: Patients underwent sleep studies and were divided into those with moderate to severe SA (apnoea-hypopnoea index > or =15/h of sleep) and those with mild to no SA (apnoea-hypopnoea index <15/h of sleep). They were followed up for a mean of 32 months to determine all-cause mortality rate. RESULTS: Of 193 patients, 34 (18%) died. In the ischaemic group, mortality risk adjusted for confounding factors was significantly higher in those with SA than in those without it (18.9 vs 4.6 deaths/100 patient-years, hazards ratio (HR) = 3.03, 95% CI 1.04 to 8.84, p = 0.043). In contrast, in the non-ischaemic HF group, there was no difference in adjusted mortality risk between those with, and those without, SA (3.9 vs 4.0 deaths/100 patient-years, p = 0.929). CONCLUSIONS: In patients with HF, the presence of SA is independently associated with an increased risk of death in those with ischaemic, but not in those with non-ischaemic, aetiology. These findings suggest that patients with ischaemic cardiomyopathy are more susceptible to the adverse haemodynamic, autonomic and inflammatory consequences of SA than are those with non-ischaemic cardiomyopathy.

Discordance between microneurographic and heart-rate spectral indices of sympathetic activity in pulmonary arterial hypertension.

OBJECTIVES: To determine, in patients with pulmonary arterial hypertension (PAH), whether there is a relationship: (1) between sympathetic nerve firing rate and spectral indices of sympathetic neural heart rate modulation; and (2) between heart rate variability (HRV) and right atrial pressure, a stimulus to sinoatrial node stretch. DESIGN: Characterisation of patients and healthy controls. SETTING: Teaching hospital-based study. PATIENTS: 9 PAH patients without elevated pulmonary capillary wedge pressure and nine age-matched control subjects. INTERVENTIONS: Heart rate (HR) and muscle sympathetic nerve activity (MSNA) were recorded during 10 min of supine rest in both PAH patients studied after right heart catheterisation, and healthy volunteers. Coarse-graining spectral analysis determined HR spectral power. MAIN OUTCOME MEASURES: (1) Low-frequency (PL) spectral component of HRV; (2) MSNA burst frequency; and in PAH patients: (3) right atrial pressure. RESULTS: MSNA burst frequency was higher in PAH patients (48 (24) and 29 (11) bursts/min, respectively; mean (SD); p = 0.05), whereas total power (p = 0.01), its fractal (p<0.01) and harmonic (p = 0.04) components, and PL (p = 0.01) were all reduced. PL related inversely to both MSNA burst frequency (r = -0.86, p = 0.005) and right atrial systolic pressure (r = -0.77, p = 0.04). CONCLUSIONS: Thus, in PAH (as in patients with left ventricular systolic dysfunction) loss of PL relates inversely to gain in MSNA burst frequency. Diminished sympathetic neural heart rate modulation and increased right atrial stretch may combine to attenuate HRV, an adverse prognostic marker.

Should sleep apnoea be a specific target of therapy in chronic heart failure?

Sleep apnoea is a common and important co-morbidity in heart failure. It affects survival adversely by: (1) causing nocturnal hypoxia and oxidative stress; (2) raising nocturnal and daytime sympathetic activity and blood pressure and blunting vagal tone; and (3) increasing left ventricular transmural pressure (that is, afterload) and myocardial oxygen demand. Although its abolition by positive airway pressure counters these mechanisms of increased cardiovascular risk and augments ejection fraction, this device therapy has not been adopted widely in cardiovascular practice. An adequately powered outcome trial is required to determine whether sleep apnoea should be a specific therapeutic target in heart failure.

Effect of continuous positive airway pressure on ventricular ectopy in heart failure patients with obstructive sleep apnoea.

BACKGROUND: Obstructive sleep apnoea (OSA) elicits a number of cardiovascular perturbations that could lead acutely or chronically to increased ventricular ectopy in patients with heart failure (HF). We tested the hypothesis that treatment of OSA with continuous positive airway pressure (CPAP) in patients with HF would reduce the frequency of ventricular premature beats (VPBs) during sleep in association with reduced sympathetic nervous system activity. METHODS: Following optimisation of medical treatment, 18 HF patients with OSA and >10 VPBs per hour of sleep were randomised to a control group (n = 8) or a treatment group who received CPAP (n = 10). The frequency of VPBs and urinary norepinephrine (noradrenaline) concentrations during total sleep time were determined at baseline and after 1 month. RESULTS: Control patients did not experience any significant changes in apnoea-hypopnoea index (AHI), mean nocturnal O(2) saturation, or the frequency of VPBs. In contrast, there was a significant reduction in AHI (p<0.001), an increase in minimum O(2) saturation (p = 0.05), a reduction in urinary norepinephrine concentrations (p = 0.009), and a 58% reduction in the frequency of VPBs during total sleep (from mean (SE) 170 (65) to 70 (28) per hour, p = 0.011) after 1 month of CPAP treatment. CONCLUSIONS: In patients with HF, treatment of co-existing OSA by CPAP reduces the frequency of VPBs during sleep. These data suggest that reductions in VPBs and other ventricular arrhythmias through treatment of OSA might improve the prognosis in patients with HF.

Impaired brachial artery endothelium dependent flow mediated dilation in systemic lupus erythematosus: preliminary observations.

Our objective was to compare brachial artery endothelium dependent and independent vasodilation in lupus patients and healthy females, by means of high-resolution noninvasive brachial artery ultrasound. Endothelially mediated vasodilation was estimated noninvasively by examination of brachial artery responses to postischemic reactive hyperemia and endothelial independent vasodilation from response to sublingual glycerlynitrate (GTN) using high-resolution external vascular ultrasound. Five patients with known coronary artery disease (CAD), five with subclinical CAD, five with no CAD and five control subjects were assessed. Endothelium dependent vasodilation was significantly blunted in lupus patients with CAD as compared with healthy female controls (0.11 versus 11.1%, P = 0.018). Corresponding values for lupus patients with subclinical CAD and no CAD were 11 and 9.6%, respectively. For each subject, endothelium dependent vasodilation (EDV) was related to endothelium independent vasodilation (EIV) to adjust for varying vascular smooth muscle responses to GTN in individual subjects. This ratio was markedly depressed in lupus patients with CAD as compared with control subjects (0.12 versus 1.15). The corresponding EDV/EIV ratios for patients with subclinical CAD and no CAD were similar at 0.69 and 0.65, respectively. The conclusion was that flow mediated vasodilation in lupus patients with coronary artery disease is markedly depressed as compared to healthy subjects.

Efectos cardiovascularesde la presión positiva continuaen la vía aérea en pacientes on insuficiencia cardíacay apnea del sueño / Cardiovascular effects of continuos positive airway pressure in patients with heart failure and obstructive sleep apnea

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Refractory hypertension and sleep apnoea: effect of CPAP on blood pressure and baroreflex.

This study was undertaken to determine whether abolition of obstructive sleep apnoea (OSA) by continuous positive airway pressure (CPAP) could reduce blood pressure (BP) in patients with refractory hypertension. In 11 refractory hypertensive patients with OSA, the acute effects of CPAP on nocturnal BP were studied during sleep and its longer term effects on 24-h ambulatory BP after 2 months. During a single night's application, CPAP abolished OSA and reduced systolic BP in stage 2 sleep from 138.3 +/- 6.8 to 126.0 +/- 6.3 mmHg. There was also a trend towards a reduction in average diastolic BP (from 77.7 +/- 4.5 to 72.9 +/- 4.5). CPAP usage for 2 months was accompanied by an 11.0 +/- 4.4 mmHg reduction in 24-h systolic BP. In addition, both the nocturnal and daytime components of systolic BP fell significantly by 14.4 +/- 4.4 and 9.3 +/- 3.9 mmHg, respectively. Diastolic BP was reduced significantly at night by 7.8 +/- 3.0 mmHg. In patients with refractory hypertension, acute abolition of obstructive sleep apnoea by continuous positive airway pressure reduces nocturnal blood pressure. These data also suggest that continuous positive airway pressure may reduce nocturnal and daytime systolic blood pressure chronically. Randomised trials are needed to confirm the latter results.

Sympathetic activation in human heart failure: diverse mechanisms, therapeutic opportunities.

Plasma noradrenaline (NA) concentrations relate both to the severity of heart failure, and to its impact on survival, but have shortcomings that limit their usefulness as measures of sympathetic discharge. Neural recordings and the isotopic dilution method for determining organ-specific rates of NA spillover into plasma have enhanced our understanding of mechanisms responsible for sympathetic activation. Because the arterial baroreceptor reflex control of heart rate is impaired in heart failure, a parallel reduction in the reflex inhibition of sympathetic outflow has been assumed. However, human heart failure is characterized by rapidly responsive arterial baroreflex regulation of muscle sympathetic nerve activity (MSNA), attenuated cardiopulmonary reflex modulation of MSNA, and activation of a cardiac-specific sympatho-excitatory reflex related to increased cardiopulmonary filling pressures. Together, these baroreceptor mediated mechanisms account only, in part, for the time course and magnitude of adrenergic activation in heart failure. Non-baroreflex sympatho-excitatory mechanisms include: a metaboreflex arising from exercising skeletal muscle, mediated, in part, by adenosine, co-existing sleep apnoea, and pre-junctional facilitation of NA release. Thus, sympathetic activation in the setting of impaired systolic function reflects the net balance and interaction between augmented excitatory and diminished inhibitory influences. Variation, between patients, in the dynamics, magnitude and progression of sympathetic activation mandates an individualized approach to investigation and therapy. Excessive sympathetic outflow to the heart and periphery can be addressed by several complimentary strategies: attenuating these sympatho-excitatory stimuli, modulating the neural regulation of NA release, and blocking the actions of catecholamines at post-junctional receptors.

Peak oxygen uptake is not determined by cardiac noradrenaline spillover in heart failure.

AIMS: We recently found that resting muscle sympathetic nerve activity is inversely related to peak oxygen uptake (VO(2) peak) in patients with heart failure, suggesting a peripheral neurogenic limit to exercise in heart failure. No such relationship was observed in healthy controls. To determine whether this observation is specific to sympathetic discharge to skeletal muscle, we tested the null hypothesis that VO(2) peak would not relate to resting cardiac noradrenaline spillover, which is also elevated in heart failure. METHODS AND RESULTS: We measured cardiac noradrenaline spillover at rest by a radiotracer technique and VO(2) peak, during cycle ergometry, by open circuit spirometry in 49 heart failure patients (mean age 54.4+/-1.4 (SE)). There was a significant relationship between age and peak VO(2) (P=0.022). There was no significant relationship between cardiac noradrenaline spillover and either absolute or relative VO(2) peak (P=0.136), with age included in a multiple linear regression model, and none between cardiac noradrenaline spillover and the percent predicted VO2) peak achieved (P=0.34). CONCLUSIONS: Reduced exercise capacity in heart failure relates more closely to sympathetic traffic to skeletal muscle than to cardiac sympathetic outflow, as assessed by noradrenaline spillover. This finding lends further support to the concept of a predominantly peripheral neurogenic limit to exercise.

Lack of evidence for peripheral alpha(1)- adrenoceptor blockade during long-term treatment of heart failure with carvedilol.

OBJECTIVES: The purpose of this study was to determine whether carvedilol's alpha(1)-adrenoceptor antagonism persists during long-term therapy of patients with congestive heart failure (CHF). BACKGROUND: Carvedilol and metoprolol differ in that carvedilol also antagonizes beta(2)- and alpha(1)-adrenoceptors. We hypothesized that in contrast to metoprolol, carvedilol would increase calf vascular conductance (CVC), blunt neurally mediated vasoconstriction and attenuate neuroeffector transfer function gain. METHODS: We randomized 36 patients with CHF (age 55 +/- 1 years, ejection fraction 19 +/- 1%, means +/- SE) to either drug. Blood pressure (BP), heart rate, muscle sympathetic nerve activity (MSNA) and CVC were assessed before and after four months of treatment. The variability of BP and MSNA was determined using fast Fourier transformation. RESULTS: Paired data were obtained in 23 (carvedilol, 13; metoprolol, 10) subjects. Both beta-blockers decreased heart rate, but neither affected mean BP or CVC (carvedilol: 0.016 +/- 0.002 to 0.018 +/- 0.003 U; metoprolol: 0.020 +/- 0.002 to 0.020 +/- 0.004 U). Isometric handgrip exercise (30% of maximum) increased heart rate, mean BP and MSNA. The calf vasoconstrictor response to handgrip exercise was not affected by carvedilol (from 16 +/- 6 resistance U to 25 +/- 10 resistance U, NS). The gain of the transfer of oscillations in MSNA into BP under resting conditions was not attenuated by carvedilol. CONCLUSIONS: Carvedilol did not increase CVC, blunt the calf vasoconstrictor response to handgrip or attenuate the gain of the neuroeffector transfer function, indicating the absence of functionally important peripheral alpha(1)-adrenoceptor antagonism during long-term treatment of CHF.

Nonselective versus selective beta-adrenergic receptor blockade in congestive heart failure: differential effects on sympathetic activity.

BACKGROUND: Activation of the sympathetic nervous system has important prognostic implications in chronic heart failure. Nonselective versus selective beta-adrenergic receptor antagonists may have differential effects on norepinephrine release from nerve terminals mediated by prejunctional beta(2)-adrenergic receptors. METHODS AND RESULTS: Thirty-six patients with chronic heart failure were randomized to the nonselective beta-blocker carvedilol or the selective beta-blocker metoprolol (double-blind). Measurements of hemodynamics and cardiac and systemic norepinephrine spillover as well as microneurographic recordings of muscle sympathetic nerve traffic were made before and after 4 months of therapy. In the carvedilol group (n=17), there were significant reductions in both total body (-1.7+/-0.5 nmol/min, P<0.01) and cardiac norepinephrine spillover (-87+/-29 pmol/min, P<0.01). By contrast, in the metoprolol group (n=14), there were no significant changes in total body or cardiac norepinephrine spillover. Responses in the carvedilol group were significantly different from those observed in the metoprolol group (P<0.05). Both agents caused a reduction in heart rate and increases in pulse pressure, although mean arterial pressure did not change. Importantly, microneurographic measures of sympathetic nerve traffic to skeletal muscle did not change in either group. CONCLUSIONS: Therapy with carvedilol caused significant decreases in systemic and cardiac norepinephrine spillover, an indirect measure of norepinephrine release. Such changes were not observed in patients treated with metoprolol. There was no effect of either agent on sympathetic efferent neuronal discharge to skeletal muscle. These findings suggest that carvedilol, a nonselective beta-blocker, caused its sympathoinhibitory effect by blocking peripheral, prejunctional beta-adrenergic receptors.

Effect of adenosine receptor blockade with caffeine on sympathetic response to handgrip exercise in heart failure.

Adenosine (Ado) increases muscle sympathetic nerve activity (MSNA) reflexively. Plasma Ado and MSNA are elevated in heart failure (HF). We tested the hypothesis that Ado receptor blockade by caffeine would attenuate reflex MSNA responses to handgrip (HG) and posthandgrip ischemia (PHGI) and that this action would be more prominent in HF subjects than in normal subjects. We studied 12 HF subjects and 10 age-matched normal subjects after either saline or caffeine (4 mg/kg) infusion during isometric [30% of maximal voluntary contraction (MVC)] and isotonic (10%, 30%, and 50%) HG exercise, followed by 2 min of PHGI. In normal subjects, caffeine did not block increases in MSNA during PHGI after 50% HG. In HF subjects, caffeine abolished MSNA responses to PHGI after both isometric and 50% isotonic exercise (P < 0.05) but MSNA responses during HG were unaffected. These findings are consistent with muscle metaboreflex stimulation by endogenous Ado during ischemic or intense nonischemic HG in HF and suggest an important sympathoexcitatory role for endogenous Ado during exercise in this condition.

Differential sympathetic nerve and heart rate spectral effects of nonhypotensive lower body negative pressure.

Lower body negative pressure (LBNP; -5 and -15 mmHg) was applied to 14 men (mean age 44 yr) to test the hypothesis that reductions in preload without effect on stroke volume or blood pressure increase selectively muscle sympathetic nerve activity (MSNA), but not the ratio of low- to high-frequency harmonic component of spectral power (P(L)/P(H)), a coarse-graining power spectral estimate of sympathetic heart rate (HR) modulation. LBNP at -5 mmHg lowered central venous pressure and had no effect on stroke volume (Doppler) or systolic blood pressure but reduced vagal HR modulation. This latter finding, a manifestation of arterial baroreceptor unloading, refutes the concept that low levels of LBNP interrogate, selectively, cardiopulmonary reflexes. MSNA increased, whereas P(L)/P(H) and HR were unchanged. This discordance is consistent with selectivity of efferent sympathetic responses to nonhypotensive LBNP and with unloading of tonically active sympathoexcitatory atrial reflexes in some subjects. Hypotensive LBNP (-15 mmHg) increased MSNA and P(L)/P(H), but there was no correlation between these changes within subjects. Therefore, HR variability has limited utility as an estimate of the magnitude of orthostatic changes in sympathetic discharge to muscle.

Arterial baroreceptor and cardiopulmonary reflex control of sympathetic outflow in human heart failure.

Several observations indicate that the arterial baroreflex control of sympathetic nerve activity is preserved, even in advanced heart failure. These include: (1) augmentation of muscle sympathetic nerve activity burst amplitude and duration following a premature beat; (2) rapid recognition of changes in blood pressure induced by ventricular arrhythmias; (3) muscle sympathetic alternans and a steep inverse relationship between changes in diastolic pressure and the subsequent sympathetic burst amplitude during pulsus alternans; (4) similar inhibition of muscle sympathetic nerve activity in subjects with normal and impaired left ventricular systolic function by increases in intrathoracic aortic transmural pressure; (5) documentation, by cross-spectral analysis, of similar gain in the transfer function between blood pressure and muscle sympathetic nerve activity in these two groups; and (6) during sodium nitroprusside infusion, similar reflex increases in total body norepinephrine spillover in normal and heart-failure subjects. When nonhypotensive lower-body negative pressure was applied to test the hypothesis that selective reduction of atrial and pulmonary pressures would exert a cardiac sympathoinhibitory response in heart failure, there was no effect in control subjects, but cardiac norepinephrine spillover fell by 25% (P < .05) in those with systolic dysfunction. In summary, human heart failure is characterized by a rapidly responsive and sensitive arterial baroreflex, and by activation of a cardiac sympathoexcitatory reflex related to increased cardiopulmonary filling pressures.

Rationale and design of the Canadian Continuous Positive Airway Pressure Trial for Congestive Heart Failure patients with Central Sleep Apnea--CANPAP.

BACKGROUND: Cheyne-Stokes respiration with central sleep apnea (CSR-CSA) is commonly observed in patients with congestive heart failure (CHF), in which it is an independent risk factor for death. Treating CSR-CSA may, therefore, improve outcomes in patients with CHF. OBJECTIVE: The Canadian Continuous Positive Airway Pressure Trial for Congestive Heart Failure Patients with Central Sleep Apnea (CANPAP) is a multicentre, randomized, controlled clinical trial designed to test the hypothesis that treating CSR-CSA with continuous positive airway pressure (CPAP) will reduce the combined rate of all-cause mortality and cardiac transplantation in patients with CHF. Secondary outcomes include the severity of CSR-CSA, left ventricular volumes and function, submaximal exercise capacity, quality of life and hospital admissions. PATIENTS AND METHODS: The aim is to enroll 408 patients with CHF (New York Heart Association class II to IV and left ventricular ejection fraction of less than 40%) and CSR-CSA over a five-year period. Patients are randomly assigned to either standard medical therapy for CHF or standard medical therapy plus CPAP. The trial has 80% power to detect a 35% between-group treatment difference for the all-cause mortality-cardiac transplantation rate. Substudies will assess the role of oximetry as a screening tool for detecting CSR-CSA in patients with CHF, and the effects of CPAP on cardiac arrhythmias and plasma concentrations of natriuretic peptides and catecholamines. CONCLUSIONS: The CANPAP trial will help to define the role of CPAP better as a nonpharmacological intervention for the treatment of patients with CHF who have CSR-CSA.

Hemodynamic effects of simulated obstructive apneas in humans with and without heart failure.

STUDY OBJECTIVES: To determine whether generation of negative intrathoracic pressure during apnea would cause more pronounced and sustained reductions in cardiac output in patients with congestive heart failure (CHF) than in healthy subjects. DESIGN: Physiologic intervention study. SETTING: Cardiorespiratory physiology laboratory. PARTICIPANTS: Nine patients with CHF and nine healthy control subjects matched for age and sex. INTERVENTIONS: Patients with CHF and healthy subjects generated - 30 cm H(2)O of intrathoracic pressure during 15-s Mueller maneuvers (MMs) to simulate the acute hemodynamic effects and aftereffects of obstructive apneas. RESULTS: In both groups, MMs caused an immediate rise in left ventricular transmural pressure during systole (LVPtmsys) [p < 0.05], but in CHF patients, this immediate increase was followed by a significant drop in LVPtmsys (p < 0.05), associated with significantly greater reductions in systolic BP and cardiac index than in healthy subjects (- 25 +/- 3 mm Hg vs - 11 +/- 2 mm Hg [p < 0.05] and - 0.53 +/- 0.11 L/min/m(2) vs - 0.15 +/- 0.11 L/min/m(2) [p < 0.05], respectively). Healthy subjects recovered promptly, but in CHF patients, these adverse hemodynamic effects were sustained following release of the MM. CONCLUSIONS: CHF patients experience more pronounced and sustained reductions in BP and cardiac output both during and following the MM than do healthy subjects. These findings suggest the potential for adverse hemodynamic effects and aftereffects of negative intrathoracic pressure generation during obstructive sleep apnea in patients with CHF.