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Introduction: Elevated muscle sympathetic nerve activity (MSNA) both at rest and during dynamic cycling relates inversely to peak oxygen uptake (VO 2peak ) in patients with heart failure due to a reduced ejection fraction (HFrEF). We observed a drop in MSNA both rest (-6±2 bursts/min) and mild exercise (-4±2) in HFrEF patients after 6 months of cardiac rehabilitation. Hypothesis: We hypothesized that after training those HFrEF patients with LOW VO2peak (less than median 74% of age predicted) would have a larger decrease in MSNA during dynamic exercise than those with HIGH VO2peak (over 74%). Methods: In 21 optimally treated HFrEF patients (5 Female) (13 HIGH: mean VO 2peak =26 ml·kg/min; 98% of predicted; 8 LOW VO 2peak =12; 50%) we assessed VO 2peak (open-circuit spirometry), heart rate variability (HRV) and fibular MSNA (microneurography) at rest, during 1-leg cycling (2 min each of mild and moderate intensity upright 1-leg cycling, n=19) and recovery before and after 6 months of exercise training (45 min aerobic exercise, 5 days/ wk at 60-70 % of VO 2peak; and resistance training 2 days/wk). Results: HIGH and LOW groups had similar age (63±3 vs 63±4 years) , LVEF (30±2 vs 28±3%), BMI, resting heart rate (HR), blood pressure and MSNA (52±3 vs 50±3 bursts/min). Training increased VO 2peak in both groups (main effect P=0.009), with no group difference in HR response or ratings of perceived exertion. MSNA at rest tended to decrease after training in the HIGH but not LOW group (interaction P=0.08). MSNA during cycling increased in both HIGH (P=0.04) and LOW (P Conclusions: Contrary to our hypothesis, the sympatho-inhibitory effect of 6 months of exercise-based cardiac rehabilitation favours HFrEF patients with an already normal VO 2peak . This suggests that increasing initially low VO 2peak may be insufficient to trigger beneficial exercise and recovery autonomic modulation and altered training paradigms may be required in such patients. Funded by Canadian Institutes for Health Research (CIHR)

Efferent sympathetic nerve discharge is both gated to the cardiac cycle and inhibited by afferent input from cardiac, aortic, and carotid mechanoreceptors stimulated by rhythmic atrial and conduit artery distension. In patients with chronic heart failure as a consequence of impaired systolic function, both this gating and the blood pressure–muscle sympathetic nerve activity (MSNA) relationship are preserved.1–3 The evolution of mechanical left ventricular support from devices that generate a pulse wave to those that propel blood continuously thus raises a number of intriguing questions about the body’s adaptation to this alien physiology: What effect does short- or long-term diminution or loss of arterial pulse pressure have on the neural regulation of the heart and circulation by the baroreceptor reflex? What impact do such changes have on endothelial biology, autoregulation of regional blood flow, and tissue or organ perfusion? Article see p 2316 The first of these questions is the subject of a contribution from the Levine laboratory to the present issue of Circulation .4 These investigators focused their attention on the effect of acute alterations in mean and pulse pressures on 1 efferent limb of the arterial baroreceptor reflex arc, postganglionic sympathetic discharge to calf skeletal muscle, which they recorded directly from the fibular nerve. In a previously published experiment by this group, MSNA was recorded under 2 conditions, supine rest and 60° head-up tilt, in 6 patients with implanted left ventricular assist devices (LVADs) providing pulsatile flow and from 11 with nonpulsatile LVADs. In those with nonpulsatile compared with pulsatile LVADs, MSNA was 80% higher at rest and 70% higher during tilt, a difference these investigators attributed to diminished arterial mechanoreceptor stretch.5 Cornwell et al4 now report the findings of a protocol involving 13 patients with implanted Heartmate II continuous axial-flow devices designed …

Background— Muscle sympathetic activation in heart failure with reduced ejection fraction (HFrEF) has been attributed, on the basis of multiunit recordings, to attenuated inhibitory feedback from stretch-sensitive cardiopulmonary mechanoreceptors. However, such preparations integrate 2 populations of single units exhibiting directionally opposite firing when atrial pressure is perturbed. We tested the hypothesis that the proportion of single units firing paradoxically when filling pressure increases is augmented in HFrEF. Methods and Results— Muscle sympathetic nerve activity and estimated central venous pressure were recorded during nonhypotensive lower body negative pressure (LBNP; -10 mm Hg) and nonhypertensive positive pressure (LBPP; +10 mm Hg) in 11 treated HFrEF (left ventricular ejection fraction 25±6% [mean±standard deviation]) patients and 14 similarly aged controls. Single-unit muscle sympathetic nerve activity discharge was termed either anticipated, if firing frequency exhibited classic negative-feedback responses, or paradoxical. LBNP and LBPP had no heart rate, stroke volume, or blood pressure effects ( P >0.05). Estimated central venous pressure decreased with LBNP ( P P P P =0.0001). Consequently, LBPP increased mean single-unit firing frequency ( P P Conclusion— These findings provide the first evidence in human HFrEF for an augmented excitatory cardiopulmonary–muscle sympathetic nerve activity reflex response to increased preload, incorporating 2 distinct single-unit populations with differing firing properties.

Sleep apnea occurs in ≈5% to 10% of the general population, regardless of race and ethnicity.1 By contrast, in patients with cardiovascular diseases (CVDs), its prevalence, depending on the specific disorder surveyed, can range between 47% and 83%.2–4 One form, central sleep apnea (CSA), is rare in the general population, but is detected often in conditions characterized by sodium and water retention, such as heart failure (HF).2 Such epidemiological observations raise several important and as yet unresolved questions: What accounts for this remarkable concentration of sleep apnea among patients with CVD and its association with fluid retaining states? Does obstructive sleep apnea (OSA) predispose at-risk individuals to develop, over time, hypertension, coronary artery disease, stroke, or HF? Conversely, could mechanisms engaged by CVD, such as activation of the sympathetic nervous and renin-angiotensin-aldosterone systems, with consequences including renal sodium retention, contribute over time to the development or exacerbation of sleep apnea? From the clinical perspective, is sleep apnea, when present in patients with CVD an epiphenomenon, perhaps related to ageing, or a causal contributor to worse prognosis? And if so, are there now sufficient data to recommend randomized controlled trials to determine whether specific treatment of sleep apnea can reduce mortality or cardiovascular event rates? Our objectives, in this review, are to provide novel insight into each of these specific questions by integrating into our contemporary understanding of relationships between sleep apnea and CVD5 newer epidemiological, observational, mechanistic, and trial data; to introduce a hypothetical model of bidirectional causality; and to consider directions for future research. In healthy subjects, during non–rapid eye movement sleep (which constitutes ≈85% of total sleep time), efferent sympathetic nerve activity (SNA) diminishes and vagal tone increases, resulting in reductions in metabolic rate, blood pressure (BP), and heart rate (HR).6 …

Sleep-related breathing disorders are highly prevalent in patients with established cardiovascular disease. Obstructive sleep apnea (OSA) affects an estimated 15 million adult Americans and is present in a large proportion of patients with hypertension and in those with other cardiovascular disorders, including coronary artery disease, stroke, and atrial fibrillation.1–14 In contrast, central sleep apnea (CSA) occurs mainly in patients with heart failure.15–19 The purpose of this Scientific Statement is to describe the types and prevalence of sleep apnea and its relevance to individuals who either are at risk for or already have established cardiovascular disease. Special emphasis is given to recognizing the patient with cardiovascular disease who has coexisting sleep apnea, to understanding the mechanisms by which sleep apnea may contribute to the progression of the cardiovascular condition, and to identifying strategies for treatment. This document is not intended as a systematic review but rather seeks to highlight concepts and evidence important to understanding the interactions between sleep apnea and cardiovascular disease, with particular attention to more recent advances in patient-oriented research. Implicit in this first American Heart Association/American College of Cardiology Scientific Statement on Sleep Apnea and Cardiovascular Disease is the recognition that, although holding great promise, this general area is in need of a substantially expanded knowledge base. Specific questions include whether sleep apnea is important in initiating the development of cardiac and vascular disease, whether sleep apnea in patients with established cardiovascular disease accelerates disease progression, and whether treatment of sleep apnea results in clinical improvement, fewer cardiovascular events, and reduced mortality. Experimental approaches directed at addressing these issues are limited by several considerations. First, the close association between obesity and OSA often obscures differentiation between the effects of obesity, the effects of OSA, and the effects of synergies between these conditions. Second, multiple comorbidities, …

Sleep-related breathing disorders are highly prevalent in patients with established cardiovascular disease. Obstructive sleep apnea (OSA) affects an estimated 15 million adult Americans and is present in a large proportion of patients with hypertension and in those with other cardiovascular disorders, including coronary artery disease, stroke, and atrial fibrillation.1–14 In contrast, central sleep apnea (CSA) occurs mainly in patients with heart failure.15–19 The purpose of this Scientific Statement is to describe the types and prevalence of sleep apnea and its relevance to individuals who either are at risk for or already have established cardiovascular disease. Special emphasis is given to recognizing the patient with cardiovascular disease who has coexisting sleep apnea, to understanding the mechanisms by which sleep apnea may contribute to the progression of the cardiovascular condition, and to identifying strategies for treatment. This document is not intended as a systematic review but rather seeks to highlight concepts and evidence important to understanding the interactions between sleep apnea and cardiovascular disease, with particular attention to more recent advances in patient-oriented research. Implicit in this first American Heart Association/American College of Cardiology Scientific Statement on Sleep Apnea and Cardiovascular Disease is the recognition that, although holding great promise, this general area is in need of a substantially expanded knowledge base. Specific questions include whether sleep apnea is important in initiating the development of cardiac and vascular disease, whether sleep apnea in patients with established cardiovascular disease accelerates disease progression, and whether treatment of sleep apnea results in clinical improvement, fewer cardiovascular events, and reduced mortality. Experimental approaches directed at addressing these issues are limited by several considerations. First, the close association between obesity and OSA often obscures differentiation between the effects of obesity, the effects of OSA, and the effects of synergies between these conditions. Second, multiple comorbidities, …

Heart failure (HF) affects 5 to 6 million North Americans and is increasing in prevalence.1 Mortality remains high. In Ontario, for example, between 1994 and 1997, approximately 33% of patients diagnosed with HF on first admission to hospital died within 1 year.2 Reductions in mortality demonstrated in randomized clinical trials of pharmacological agents, such as β-receptor blockers3 and angiotensin-converting enzyme inhibitors,4 have been slow to translate into substantial reductions in death and hospitalization rates in community-based HF populations. These figures have remained relatively constant between 1948 and 1997.2,5–7 In more recent clinical trials, the addition of newer agents has had a marginal, neutral, or even adverse impact on the high residual mortality of optimally treated patients.8,9 Accordingly, investigators such as Massie10 have raised the concern that there may be limits to the benefits achievable through conventional pharmacological strategies. Resource-intensive interventions, such as left ventricular assist devices or heart transplantation, are available to only a small minority of patients. Therefore, there remains a need to develop novel, widely applicable, and cost-effective approaches to the therapy of HF. An important limitation to the current guidelines for the evaluation and management of chronic HF is their focus on the patient as he/she presents while awake.1 This approach presupposes that any mechanisms that might contribute to the pathophysiology or progression of HF are quiescent during sleep. Our objective in this review, therefore, is to highlight the pathophysiological and therapeutic implications of co-existing sleep apnea in patients with HF. There are 2 major forms of sleep apnea: obstructive sleep apnea (OSA) and central sleep apnea (CSA). Because their pathophysiologies and clinical implications in the setting of HF are quite different, OSA and CSA will be dealt with separately in the 2 parts of this review. In Part …

Background— Heart failure with reduced ejection fraction and obstructive sleep apnea (OSA), 2 states of increased metabolic demand and sympathetic nervous system activation, often coexist. Continuous positive airway pressure (CPAP), which alleviates OSA, can improve ventricular function. It is unknown whether this is due to altered oxidative metabolism or presynaptic sympathetic nerve function. We hypothesized that short-term (6–8 weeks) CPAP in patients with OSA and heart failure with reduced ejection fraction would improve myocardial sympathetic nerve function and energetics. Methods and Results— Forty-five patients with OSA and heart failure with reduced ejection fraction (left ventricular ejection fraction 35.8±9.7% [mean±SD]) were evaluated with the use of echocardiography and 11 C-acetate and 11 C-hydroxyephedrine positron emission tomography before and ≈6 to 8 weeks after randomization to receive short-term CPAP (n=22) or no CPAP (n=23). Work metabolic index, an estimate of myocardial efficiency, was calculated as follows: (stroke volume index×heart rate×systolic blood pressure÷K mono ), where K mono is the monoexponential function fit to the myocardial 11 C-acetate time-activity data, reflecting oxidative metabolism. Presynaptic sympathetic nerve function was measured with the use of the 11 C-hydroxyephedrine retention index. CPAP significantly increased hydroxyephedrine retention versus no CPAP (Δretention: +0.012 [0.002, 0.021] versus −0.006 [−0.013, 0.005] min −1 ; P =0.003). There was no significant change in work metabolic index between groups. However, in those with more severe OSA (apnea-hypopnea index >20 events per hour), CPAP significantly increased both work metabolic index and systolic blood pressure ( P Conclusions— In patients with heart failure with reduced ejection fraction and OSA, short-term CPAP increased hydroxyephedrine retention, indicating improved myocardial sympathetic nerve function, but overall did not affect energetics. In those with more severe OSA, CPAP may improve cardiac efficiency. Further outcome-based investigation of the consequences of CPAP is warranted. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00756366.

Background Activation of the sympathetic nervous system has important prognostic implications in chronic heart failure. Nonselective versus selective β-adrenergic receptor antagonists may have differential effects on norepinephrine release from nerve terminals mediated by prejunctional β 2 -adrenergic receptors. Methods and Results — Thirty-six patients with chronic heart failure were randomized to the nonselective β-blocker carvedilol or the selective β-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 P P 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 β-blocker, caused its sympathoinhibitory effect by blocking peripheral, prejunctional β-adrenergic receptors.

Background —The purpose of this study was to determine if atrial natriuretic peptide (ANP) exerts a relative inhibitory effect on muscle sympathetic nerve activity (MSNA) at rest and during nonhypotensive lower body negative pressure (LBNP) in heart failure, as in healthy subjects. Methods and Results —Fifteen men (age 39±2 years [mean±SE]) with dilated cardiomyopathy (ejection fraction 18±3%) received intravenous ANP (50 μg bolus, then 50 ng · kg −1 · min −1 ) and nitroglycerin (NTG, 8 mg/min) as a hemodynamic control. During each infusion MSNA, blood pressure (BP), central venous pressure (CVP), and heart rate (HR) were recorded before and during LBNP at −6 and −12 mm Hg. NTG and ANP caused similar and significant reductions in CVP and diastolic BP, but resting MSNA did not increase with either infusion. LBNP at −6 mm Hg lowered CVP ( P P P P =NS). Conclusions —These observations are consistent with the concept that ANP exerts a sympathoinhibitory action in heart failure. This is most evident in response to reductions in atrial pressures that do not affect systemic BP.

Background —The objectives of this study were to determine the effects of continuous positive airway pressure (CPAP) on blood pressure (BP) and systolic left ventricular transmural pressure (LVP tm ) during sleep in congestive heart failure (CHF) patients with obstructive sleep apnea (OSA). In CHF patients with OSA, chronic nightly CPAP treatment abolishes OSA and improves left ventricular (LV) ejection fraction. We hypothesized that one mechanism whereby CPAP improves cardiac function in CHF patients with OSA is by lowering LV afterload during sleep. Methods and Results —Eight pharmacologically treated CHF patients with OSA were studied during overnight polysomnography. BP and esophageal pressure (P es ) (ie, intrathoracic pressure) were recorded before the onset of sleep and during stage 2 non–rapid eye movement sleep before, during, and after CPAP application. OSA was associated with an increase in systolic BP (from 120.4±7.8 to 131.8±10.6 mm Hg, P tm (from 124.4±7.7 to 137.2±10.8 mm Hg, P P tm to 117.4±8.5 mm Hg ( P es amplitude, and respiratory rate. Conclusions —In CHF patients with OSA, LV afterload increases from wakefulness to stage 2 sleep. By alleviating OSA, CPAP reduces LV afterload and heart rate, unloads inspiratory muscles, and improves arterial oxygenation during stage 2 sleep. CPAP is a nonpharmacological means of further reducing afterload and heart rate during sleep in pharmacologically treated CHF patients with OSA.

Background There are α-adrenergic receptors on human myocardium that exert positive inotropic effects. The effect of α-adrenergic receptor blockade on human left ventricular (LV) performance has not been fully explored. Although α-adrenergic receptor blockade might have effects on LV function that are mediated via blockade of postsynaptic myocardial α-adrenergic receptors, it is also possible that blockade of presynaptic α 2 -adrenergic receptors and subsequent increased release of norepinephrine would have effects on LV performance. In the present study, we explored the effects of nonselective α-adrenergic receptor blockade on LV performance and transcardiac norepinephrine concentrations in a group of patients with normal LV function and in a group of patients with congestive heart failure secondary to dilated cardiomyopathy. Methods and Results Using an intracoronary drug infusion technique, we administered the nonselective α-adrenergic antagonist phentolamine to 13 patients with normal LV function and 19 patients with congestive heart failure secondary to dilated cardiomyopathy. With a high-fidelity LV catheter, the systolic (+dP/dt) and diastolic (−dP/dt and Tau) LV function responses to intracoronary infusion of phentolamine (0.2 mg/min×5 minutes) were assessed. In 8 patients with normal ventricular function and 10 patients with congestive heart failure, arterial and coronary sinus blood samples were drawn to determine the effects of phentolamine on catecholamine concentrations. Phentolamine had no measurable effect on LV performance or catecholamine concentrations in the normal ventricular function group. In patients with congestive heart failure, intracoronary phentolamine caused a significant increase in +dP/dt and the rate of isovolumic LV relaxation (−dP/dt and Tau). These hemodynamic effects were accompanied by a significant increase in coronary sinus norepinephrine concentration but no change in arterial norepinephrine concentration. Conclusions Myocardial α-adrenergic receptor blockade causes significant inotropic and lusitropic effects in the failing but not the nonfailing human LV. These effects appear to be mediated by increased release of norepinephrine from cardiac nerves secondary to blockade of presynaptic α 2 -adrenergic receptors. Differences in the responses of the failing and nonfailing human LV appear to reflect the higher level of sympathetic activation that is seen in the group with congestive heart failure. This suggests that the presynaptic α 2 -adrenergic receptor exerts a tonic inhibitory effect on the release of norepinephrine from cardiac nerves in patients with congestive heart failure.

Sympathetic activation in heart failure is intimately linked to disease progression and to adverse outcome.1–3⇓⇓ Contemporary management of heart failure relies on three antiadrenergic strategies, predicated on the hypothesis that interventions that counter sympathetic overactivity will improve both symptoms and prognosis. First, excessive central sympathetic outflow to the heart and periphery can be reduced by normalizing elevated cardiac filling pressures,4 by abolishing coexisting obstructive sleep apnea with nocturnal continuous positive airway pressure,5 or by attenuating sympathoexcitatory reflexes activated by exercising muscle through conditioning. Although rational, thus far these interventions have not been proven to improve survival. See p 1797 A second approach has been to modulate the neural regulation of norepinephrine (NE) release. Examples include digitalis glycosides, which appear to sensitize acutely and therefore increase the discharge of arterial baroreceptors, and ACE inhibitors, which should diminish or block the prejunctional facilitatory effects of angiotensin II on NE release. However, the impact of ACE inhibitors on plasma NE (PNE) concentrations is relatively modest,6,7⇓ suggesting that their mortality benefit accrues primarily through nonadrenergic mechanisms. Third, sympathetic activation may be addressed indirectly, by blocking the actions of catecholamines on postjunctional adrenergic receptors. A series of placebo-controlled trials has demonstrated the symptomatic, hemodynamic, and mortality benefits of β-adrenoceptor antagonists.8–10⇓⇓ β1 blockade, as exerted by metoprolol or bisoprolol, may be sufficient to achieve these effects. Whether concomitant β2-adrenoceptor antagonism, as with carvedilol or bucindolol, confers any additional benefit is the subject of an ongoing comparative mortality trial. Although carvedilol is also classified as an α1 antagonist, this action does not appear to be functionally important during long-term treatment.11 Thus, long-term β-blockade leaves α-adrenoceptor–mediated vasoconstriction and renal sodium retention unopposed. Moreover, β-blockade does not shield the heart and periphery from neuropeptide …

To the Editor: We read with interest the recent report from Mozaffarian et al1 that consumption of ω-3 fatty acid containing fish is associated with increased heart rate variability (HRV) markers of vagal heart rate modulation. Importantly, in their analysis, higher HRV was accompanied by a lower risk of subsequent cardiac death. Their findings, which demonstrate the potential use of HRV indices as surrogate or secondary measures of treatment efficacy when evaluating preventive strategies for cardiovascular disease, raise 2 important questions for research on the HRV response to interventions such as diet. First, how would one characterize the magnitude of treatment effects such …

Introduction: Past studies showed that in patients with heart failure (HF), sleep apnea (SA) increases mortality risk, but these patients were not characterized on the basis of HF etiology. Hypothesis: Since patients with ischemic HF may suffer greater adverse consequences of SA-related hypoxia and hypertension than those with non-ischemic HF, SA will increase risk of death in patients with ischemic, but not in those with non-ischemic HF. Methods: From 1997 to 2004, consecutive HF patients with ejection fraction (EF) ≤ 45% had sleep studies and were divided into those with SA (apnea-hypopnea index ≥ 15/hr of sleep) and those without SA. They were followed prospectively to determine all-cause mortality rate. Results: Of 218 patients enrolled, follow up data were obtained in 95%. Of these, 87 (40%) had ischemic HF. SA was found in 53% of those with ischemic HF and in 41% of those with non-ischemic HF. 14 patients with obstructive sleep apnea on CPAP therapy were excluded from the analysis. Of the remaining 193 patients, 34 (18%) died during a mean follow up of 32 months. In the non-ischemic HF group, there was no difference in mortality between those with, and those without SA (Figure ). In contrast, in the ischemic group, mortality was significantly higher in those with SA than those without it (18.9 vs. 4.6 deaths/100 patient-years, P = 0.003). After adjusting for age, EF, New York Heart Association class, β-blocker use, and the presence of diabetes using multivariate Cox analysis, SA remained a significant independent risk for death (HR 3.02, 95%CI 1.07– 8.59, P = 0.037). Conclusions: These data show that ischemic etiology identifies those HF patients with SA at increased risk of death.

In the first part of this 2-part review, we provided a synopsis of the cardiovascular effects of normal sleep and an overview of the diagnostic, pathophysiological, and therapeutic implications of obstructive sleep apnea (OSA) in the setting of heart failure (HF). In this second part, we turn our attention to central sleep apnea (CSA), commonly referred to as Cheyne-Stokes respiration. This breathing disorder has a strikingly higher prevalence in patients with HF as compared with the general population with normal left ventricular function, and when present appears to have adverse prognostic implications. Our objective in Part II of this review is to provide a broad perspective of the pathophysiological and clinical significance of CSA in HF. CSA associated with Cheyne-Stokes respiration is a form of periodic breathing in which central apneas and hypopneas alternate with periods of hyperventilation that have a waxing-waning pattern of tidal volume. Figure 1 illustrates the proposed mechanisms that underlie periodic oscillations in ventilation in HF. Unlike OSA, CSA likely arises as a consequence of HF. Thus, the presence of CSA may alert the physician to the necessity of intensifying HF therapy. The current debate is whether CSA is simply a reflection of severely compromised cardiac function with elevated left ventricular filling pressures, or whether, for the same degree of cardiac dysfunction, CSA exerts unique and independent pathological effects on the failing myocardium. Although there are not yet sufficient data to resolve this controversy within the confines of this review, we will discuss evidence on both sides of this issue. Figure 1. Pathophysiology of central sleep apnea in heart failure (HF). HF leads to increased left ventricular (LV) filling pressure. The resulting pulmonary congestion activates lung vagal irritant receptors, which stimulate hyperventilation and hypocapnia. Superimposed arousals cause further abrupt increases in ventilation and drive PaCO2 …

Abstract Alternation in the amplitude of muscle sympathetic nerve activity (MSNA) was documented in three patients with severe heart failure. In the index patient with pulsus alternans, the amplitude of MSNA was inversely related to changes in the preceding diastolic pressure with a lag time of 1.2 to 1.3 seconds, indicating that oscillations in burst amplitude are determined primarily by changes in this component of blood pressure. Spectral analysis of the blood pressure and MSNA signals identified two spectral peaks, one at the cardiac frequency and a second peak, with greater spectral power, at the alternans frequency (ie, at half the heart rate). The latter peak for both blood pressure and MSNA disappeared when alternans was abolished by nitroglycerin. The presence of sympathetic alternans in synchrony with pulsus alternans and the rapid transduction of changes in the diastolic blood pressure afferent signal to the amplitude of sympathetic outflow indicate that the arterial baroreflex control of MSNA must be active and rapidly responsive in human heart failure.