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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)

OBJECTIVE Delayed heart rate (HR) recovery in the immediate postexercise period has been linked to adverse cardiovascular prognosis. The after effects of an acute bout of exercise on HR modulation in postmenopausal women (PMW) and the influence of estrogen therapy are unknown. METHODS In 13 sedentary PMW (54 ± 2 y, mean ± SEM), we assessed HR variability (HRV)--an index of HR modulation--and the influence of estrogen therapy on HRV. HRV in the frequency domain was quantified during supine rest and again 60 minutes after treadmill exercise for 45 minutes, at 60% VO2peak. PMW were studied before and after 4 weeks of oral estradiol. To obtain reference values for the after effects of exercise on HRV in healthy young women, 14 premenopausal women (PreM) completed the identical exercise protocol. RESULTS Compared with PreM, PMW demonstrated lower high frequency (vagal modulation) and total HRV (P < 0.05) at rest. In PreM, all HRV values were similar before and after exercise. In contrast, in PMW after exercise, despite having identical HR to PreM, high frequency and total HRV were all lower (all P ≤ 0.01) compared with pre-exercise HRV values. Estrogen therapy had no effect on pre or postexercise values for HRV. CONCLUSIONS When compared with PreM, PMW have identical HR, but lower vagal HR modulation at rest and delayed HRV recovery after exercise. Estrogen does not restore baseline HRV or accelerate HRV recovery postexercise, suggesting aging rather than estrogen deficiency per se may lower HRV in PMW.

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 …

Our prior observations in normotensive postmenopausal women stimulated the hypotheses that compared with eumenorrheic women, active hypoestrogenic premenopausal women with functional hypothalamic amenorrhea would demonstrate attenuated reflex renin–angiotensin–aldosterone system responses to an orthostatic challenge, whereas to defend blood pressure reflex increases in muscle, sympathetic nerve activity would be augmented. To test these hypotheses, we assessed, in recreationally active women, 12 with amenorrhea (ExFHA; aged 25±1 years; body mass index 20.7±0.7 kg/m 2 ; mean±SEM) and 17 with eumenorrhea (ExOv; 24±1 years; 20.9±0.5 kg/m 2 ), blood pressure, heart rate, plasma renin, angiotensin II, aldosterone, and muscle sympathetic nerve activity at supine rest and during graded lower body negative pressure (−10, −20, and −40 mm Hg). At baseline, heart rate and systolic blood pressure were lower ( P P >0.05). In response to graded lower body negative pressure, heart rate increased ( P P P P P >0.05). Muscle sympathetic nerve activity burst incidence increased reflexively in both groups, but more so in ExFHA ( P

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.

Objective:Several studies have reported a small yet significant decrease in blood pressure (BP) with continuous positive airway pressure (CPAP) application in patients with obstructive sleep apnea (OSA). We investigated the long-term efficiency of CPAP in the management of hypertensive patients with

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 …

Purpose: Muscle sympathetic nerve activity (MSNA) is increased in older endurance-trained men, yet the reflex sympathetic forearm vasoconstrictor response to graded lower body negative pressure (LBNP) diminishes with age. The aim of this study was to assess the influence of aerobic exercise capacity on this altered neurovascular coupling. We hypothesized that during graded LBNP, the forearm vascular resistance (FVR)�MSNA relationship would be steeper in sedentary versus fit men. Methods: We therefore studied 20 healthy middle-age men (age = 52 ± 2 yr, mean ± SE), 10 physically active (FIT) and 10 sedentary (SED) (129% ± 4% vs 85% ± 3% of predicted peak oxygen uptake) during 4 min each of LBNP at -5, -10, -20, and -40 mm Hg, applied in a random order. We determined HR, plasma norepinephrine, and MSNA (microneurography) and derived FVR from blood pressure and forearm blood flow (plethysmography). The FVR�MSNA relationship was determined by linear regression in each group separately, and groups were compared using multiple linear regression. Results: MSNA burst frequency and FVR at rest and during LBNP (P < 0.003) were similar in the two groups, whereas HR was significantly lower (P < 0.002) both at rest and during LBNP in FIT men (P < 0.05). FVR during LBNP correlated positively with MSNA in the SED group (r = 0.44, P < 0.001) but not in the FIT group (r = 0.19, P = 0.10). Multiple linear regression confirmed that both MSNA (P < 0.001) and fitness level (P = 0.04) contribute to the forearm vascular response. Conclusions: Thus, during simulated orthostasis, middle-age SED men exhibit a significant FVR�MSNA relationship, which is not evident in age-matched FIT men. This alteration in neurovascular coupling may potentially affect cardiovascular risk in middle-age men.

It is not established whether behavioral interventions add benefit to pharmacological therapy for hypertension. We hypothesized that behavioral neurocardiac training (BNT) with heart rate variability biofeedback would reduce blood pressure further by modifying vagal heart rate modulation during reactivity and recovery from standardized cognitive tasks (“mental stress”). This randomized, controlled trial enrolled 65 patients with uncomplicated hypertension to BNT or active control (autogenic relaxation), with six 1-hour sessions over 2 months with home practice. Outcomes were analyzed with linear mixed models that adjusted for antihypertensive drugs. BNT reduced daytime and 24-hour systolic blood pressures (−2.4±0.9 mm Hg, P =0.009, and −2.1±0.9 mm Hg, P =0.03, respectively) and pulse pressures (−1.7±0.6 mm Hg, P =0.004, and −1.4±0.6 mm Hg, P =0.02, respectively). No effect was observed for controls ( P >0.10 for all indices). BNT also increased RR-high-frequency power (0.15 to 0.40 Hz; P =0.01) and RR interval ( P P =0.29), and RR interval decreased ( P =0.03). Neither intervention altered spontaneous baroreflex sensitivity ( P >0.10). In contrast to relaxation therapy, BNT with heart rate variability biofeedback modestly lowers ambulatory blood pressure during wakefulness, and it augments tonic vagal heart rate modulation. It is unknown whether efficacy of this treatment can be improved with biofeedback of baroreflex gain. BNT, alone or as an adjunct to drug therapy, may represent a promising new intervention for hypertension.

Background— Higher blood pressure in acute heart failure has been associated with improved survival; however, the relationship between blood pressure and survival in stabilized patients at hospital discharge has not been established. Methods and Results— In 7448 patients with heart failure (75.2�11.5 years; 49.9% men) discharged from the hospital in Ontario, Canada, we examined the association of systolic blood pressure (SBP) and diastolic blood pressure with long-term survival. Parametric survival analysis was performed, and survival time ratios were determined according to discharge blood pressure group. A total of 25 427 person-years of follow-up were examined. In those with left ventricular ejection fraction ≤40%, median survival was decreased by 17% (survival time ratio, 0.83; 95% CI, 0.71 to 0.98; P =0.029) when discharge SBP was 100 to 119 mm Hg and decreased by 23% (survival time ratio, 0.77; 95% CI, 0.62 to 0.97; P =0.024) when discharge SBP was P =0.007) and 0.75 (95% CI, 0.53 to 1.07; P =0.12) when discharge SBPs were 140 to 159 and ≥160 mm Hg, respectively. In those with left ventricular ejection fraction >40%, survival time ratios were 0.69 (95% CI, 0.51 to 0.93), 0.83 (95% CI, 0.71 to 0.99), 0.95 (95% CI, 0.80 to 1.14), and 0.76 (95% CI, 0.61 to 0.95) for discharge SBPs Conclusions— In this long-term population-based study of patients with heart failure, the association of discharge SBP with mortality followed a U-shaped distribution. Survival was shortened in those with reduced or increased values of discharge SBP.

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, …

Sympathetic activation and sleep apnea are present in most patients with symptomatic systolic heart failure (HF). Acutely, obstructive and central apneas increase muscle sympathetic activity (MSNA) during sleep by eliciting recurrent hypoxia, hypercapnia, and arousal. In obstructive sleep apnea patients with normal systolic function, this increase persists after waking. Whether coexisting sleep apnea augments daytime MSNA in HF is unknown. We tested the hypothesis that its presence exerts additive effects on MSNA during wakefulness. Overnight sleep studies and morning MSNA recordings were performed on 60 subjects with ejection fraction P =0.005; 58±2 versus 50±3 bursts/min, P =0.037), irrespective of its etiology (the mean difference for central sleep apnea was 17 bursts per 100 heartbeats; n=14; P =0.006; and for obstructive sleep apnea, 11 bursts per 100 heartbeats; n=29; P =0.032). In a subgroup (n=8), treatment of obstructive sleep apnea lowered MSNA by 12 bursts per 100 heartbeats ( P =0.003). Convergence of independent excitatory influences of HF and sleep apnea on central sympathetic neurons results in higher MSNA during wakefulness in HF patients with coexisting sleep apnea. This additional stimulus to central sympathetic outflow may accelerate the progression of HF; its attenuation by treatment of sleep apnea represents a novel nonpharmacological opportunity.

To determine, in sedentary normotensive postmenopausal women, the after-effects of exercise on systemic and regional hemodynamics, and whether changes in total peripheral conductance after exercise relate to changes in brachial artery flow-mediated vasodilation (FMD).In 13 sedentary postmenopausal women, the blood pressure (BP), cardiac output, total peripheral resistance and total peripheral conductance, calf vascular resistance and FMD were measured during baseline rest, and again commencing 45 min after treadmill exercise. Fourteen premenopausal women completed the identical protocol to obtain reference values for the after-effects of exercise in healthy females.In postmenopausal women, exercise was followed by falls in systolic BP (P0.01) and diastolic BP (P0.001). BP did not fall after exercise in premenopausal women. In both groups the cardiac output (P0.01) increased and the calf vascular resistance (P0.01) and total peripheral resistance (P0.05) decreased after exercise, but resistance fell more (P0.05) in postmenopausal women. Baseline FMD was greater in premenopausal women (12.1 +/- 1.5 versus 5.3 +/- 1.3%, P0.01), and similar before and after exercise, whereas prior exercise nearly doubled the FMD of postmenopausal women (to 9.9 +/- 1.4%, P0.01). These increases in FMD correlated with baseline values (r = -0.75, P0.01) and with relative changes in total peripheral conductance (r = 0.72, P0.02). The latter relationship was absent in premenopausal women (r = -0.29).In postmenopausal women, acute dynamic exercise elicits sustained increases in FMD that could facilitate post-exercise hypotension in this population. These observations reinforce the concept of exercise as an important non-pharmacological intervention to modify cardiovascular risk in postmenopausal women.

BACKGROUND Dihydropyridines have both sympathoexcitatory and sympathoinhibitory effects. To date, the latter have been characterized only in animals. During chronic treatment with long-acting dihydropyridines, sympathoexcitatory effects mediated via the arterial baroreflex are unlikely. However, increases in plasma angiotensin II in response to dihydropyridines could contribute to increases in sympathetic activity during chronic treatment. Such increases may be less in older than in young patients. METHODS We evaluated the effects of 4 weeks of treatment with low-dose nifedipine gastrointestinal therapeutic system (GITS; 20 mg/day) compared with placebo on muscle sympathetic nerve activity and plasma noradrenaline, in relation to changes in plasma renin activity and plasma angiotensin II and blood pressure in young and older patients with mild hypertension. RESULTS Nifedipine GITS decreased systolic and diastolic blood pressures significantly, by 10 +/- 3 mmHg and 7 +/- 2 mmHg respectively, in older patients (age 67 +/- 2 years), but not in younger patients (age 45 +/- 2 years) (decreases of 1 +/- 3 mmHg and 1 +/- 2 mmHg, respectively). Nifedipine GITS caused only minor changes in plasma renin activity and plasma angiotensin II in young and older patients. Compared with changes in response to placebo (-5.7 +/- 2.4 bursts/min), sympathetic activity was increased significantly by nifedipine GITS in the young patients (2.0 +/- 1.7 bursts/min; P < 0.05), but not in older patients (5.4 +/- 1.3 bursts/min by placebo compared with 4.1 +/- 3.5 bursts/min by nifedipine GITS). CONCLUSION We conclude that age-related differences in the response of muscle sympathetic nerve activity (and plasma noradrenaline) to low-dose nifedipine GITS in patients with mild hypertension are unlikely to be mediated by plasma angiotensin II. An increase in sympathetic activity may contribute to the absent blood pressure response in young patients with hypertension.

Long-term nocturnal hemodialysis, which uses longer and more frequent sessions than conventional hemodialysis, lowers clinic blood pressure and left ventricular mass. We tested the hypotheses that short-term nocturnal hemodialysis would (1) reduce ambulatory blood pressure; (2) cause peripheral vasodilation; (3) lower plasma norepinephrine concentration; and (4) improve the arterial response to reactive hyperemia (a marker of endothelium-dependent vasodilation). We studied 18 consecutive patients (age, 41±2; [mean±SEM]) before and 1 and 2 months after conversion from conventional (three 4-hour sessions per week) to nocturnal (six 8-hour sessions per week) hemodialysis. As the dialysis dose per session (Kt/V) increased from 1.24±0.06 to 2.04±0.08 after 2 months ( P =0.02), symptomatic hypotension developed and most antihypertensive medications were withdrawn. Nocturnal hemodialysis nonetheless lowered 24-hour mean arterial pressure (from 102±3 to 90±2 mm Hg after 2 months; P =0.01), total peripheral resistance (from 1967±235 to 1499±191 dyne · s · cm −5 ; P P =0.04). Endothelium-dependent vasodilation could not be elicited during conventional hemodialysis (−2.7±1.8%) but was restored (+8.0±1.0%; P =0.001) after 2 months of nocturnal hemodialysis. The brachial artery response to nitroglycerin also improved (from 6.9±2.8 to 15.7±1.6%; P

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 …

See related article, pp 319–325 Chronic sympathetic hyperactivity, characteristic of the majority of patients with hypertension or heart failure, can contribute to cardiovascular morbidity and mortality via a number of actions. Pharmacological strategies to prevent these adverse effects have had variable success. β-Blockers clearly benefit patients with heart failure but have less definitive effects in patients with hypertension, whereas α1-blockers or centrally acting agents have shown mixed results, and all of these classes can cause bothersome adverse effects. Device-based approaches, such as baroreflex activation therapy and renal denervation, have been shown to lower sympathetic activity in patients with hypertension, but beneficial actions on cardiovascular outcomes have yet to be demonstrated. So, where do the central nervous system (CNS) actions of angiotensin II (Ang II), aldosterone, and, hence, Ang II type 1 (AT1) receptor and mineralocorticoid receptor (MR) blockers fit in? Experimental studies have demonstrated that both circulating Ang II and aldosterone act within the CNS to cause sympatho-excitation and raise blood pressure.1,2 Ang II stimulates AT1 receptors in nuclei of the lamina terminalis and thereby activates mainly angiotensinergic pathways to the paraventricular nucleus (PVN) and rostral ventrolateral medulla. Circulating Ang II, in addition, activates an MR-endogenous ouabain pathway. This slowly acting, neuromodulatory pathway appears responsible for most of the persistent neuronal activation in, for example, the PVN, and the progressive hypertension induced by circulating Ang II. Studies using central infusions of an aldosterone synthase inhibitor suggest that the CNS MR activation by Ang II largely depends on locally produced aldosterone rather than circulation-derived aldosterone.1 However, the progressive hypertension caused by a chronic increase in circulating aldosterone can also be prevented by specific CNS blockade of either MR or AT1 receptors,2 suggesting that both circulating aldosterone and Ang II may activate …

It has been demonstrated elsewhere that circulating renin angiotensin system (RAS) components peak when plasma estrogen levels are highest, during the luteal phase of the normal menstrual cycle. This phenomenon has been attributed to "activation" of the RAS. The end-organ vasoconstrictive response to this phenomenon has not been well established. In two related experiments, the RAS was studied in healthy, premenopausal women during predefined phases of the normal menstrual cycle. In the first experiment, the circulating components of the RAS and the systemic hemodynamic response to incremental lower body negative pressure (LBNP) during the follicular and luteal phases of the menstrual cycle were examined. Response variables included mean arterial pressure (MAP), renin, plasma renin activity (PRA), angiotensin II (AngII), and aldosterone. Baseline levels of renin, PRA, and aldosterone were significantly higher in the luteal phase. In response to LBNP, there were significant increases in all variables in both phases; however, the humoral response to this stimulus was significantly augmented in the luteal phase compared with the follicular phase. Despite these elevations in circulating components of the RAS during the luteal phase, subjects were unable to maintain MAP in response to LBNP, exhibiting a dramatic depressor response that did not occur during the follicular phase. In the second experiment, renal and peripheral hemodynamic function at baseline, and in response to AngII blockade with losartan, were examined in women during these high and low estrogen phases of the menstrual cycle. The renal and peripheral hemodynamic responses were similar in the luteal phase and the follicular phase. These results demonstrate that, despite an increase in circulating RAS components during the luteal phase of the menstrual cycle, the system is blunted rather than "activated," at least at a tissue level. Further studies are needed to clarify this mechanism.

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.

OBJECTIVES To determine the acute effects of continuous positive airway pressure (CPAP) on baroreceptor reflex sensitivity (BRS) for heart rate during sleep in congestive heart failure (CHF) patients with obstructive sleep apnea (OSA). DESIGN AND METHODS In eight CHF patients with OSA not previously treated with CPAP, spontaneous BRS was assessed during overnight polysomnography prior to the onset of sleep, and during stage 2 non-rapid eye movement sleep (NREM) before, during and after application of CPAP. RESULTS CPAP alleviated OSA and acutely increased the slope of BRS (median, 25%,75%) [from 3.9 (3.5, 4.8) to 6.2 (4.6, 26.2) ms/mmHg, P

Summary: Previous studies have shown that atrial natriuretic peptide (ANP) has relative sympathoinhibitory effects that are of potential benefit in patients with congestive heart failure (CHF). In this study, cardiac and systemic sympathetic responses to ANP were evaluated and compared with responses to sodium nitroprusside (SNP) in patients with CHF. Right- and left-heart hemodynamics were obtained simultaneously with cardiac (CANESP) and total body (TBNESP) norepinephrine spillover; these were measured by using the radiotracer technique. Reductions in arterial blood pressure and cardiac filling pressures were similar with both drugs. ANP and SNP caused a significant and similar increase in TBNESP. Mean values for CANESP did not change in either group, but the response of individual patients was dependent on the effect on diastolic blood pressure (r = −0.71, p < 0.01). These results do not provide evidence for a sympathoinhibitory effect of ANP, but suggest that in patients with CHF, cardiac sympathoexcitatory response to arterial baroreceptor unloading may be countered by a potential sympathoinhibitory effect caused by a reduction in cardiac filling pressures. In the setting of CHF, vasodilator therapy may decrease cardiac sympathetic activity if systemic hypotension is avoided.

Having obstructive sleep apnea (OSA) increases the relative odds of also having coronary artery disease by 27% and of having suffered a stroke by 58%.1 Approximately 50% of individuals with OSA are also hypertensive, and those who are not initially so have an ≈3-fold increase in their likelihood of developing hypertension after 4 years if their apnea-hypopnea index (AHI) is ≥15 events per hour.2–4 Some of this propensity to cardiovascular events may accrue from site-specific consequences of OSA. For example, if transmission of the acoustic energy generated by snoring stimulated the development of carotid atherosclerosis,5 conceivably this action could increase the odds for stroke but not for myocardial infarction. Conversely, during each futile effort to breathe against the occluded pharynx, mechanical strain elicited by the abrupt generation of negative intrathoracic (and, hence, augmented epicardial artery transmural) pressure6 could rupture coronary plaques.7 A parallel increase in left ventricular wall stress, accompanied by oxygen desaturation during apnea, might induce myocardial ischemia, or non-ST segment elevation infarction.3 These cardiac effects of OSA could increase coronary risk but should not affect the likelihood of cerebrovascular events, whereas simultaneous increases in left atrial transmural pressure and concurrent fluctuations in autonomic tone might well raise the odds of developing embolic stroke by triggering atrial fibrillation.8 Over the long term, more important than these local actions may be the immediate and sustained systemic consequences of OSA. These include recurrent cycles of apnea and hyperpnea, sympathetic excitation and withdrawal, hypoxia reoxygenation and oxidative stress, impaired tonic and reflex vagal heart rate modulation, platelet aggregation, activation of inflammatory pathways, oxidation of lipoproteins, expression of adhesion molecules, hyperaldosteronism, impaired endothelial responsiveness and vascular smooth muscle proliferation.3,4 By modifying vascular function or structure, or by initiating or promoting atherosclerosis, these stimuli, acting individually …

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.

Obstructive sleep apnea (OSA), a common disorder, increases the 4-year risk of developing hypertension by ≈3-fold.1 In an uncontrolled trial, treatment of OSA when present in drug-resistant hypertension by nasal continuous positive airway pressure (CPAP) achieved substantial reductions in both nighttime and daytime blood pressure (BP).2 However, in controlled and uncontrolled studies involving small cohorts of patients with OSA with stage 1 hypertension, prehypertension, or normal BP, the short-term use of CPAP had less or no effect on BP. A meta-analysis in the present issue of Hypertension 3 attempts to estimate the effect of this intervention on BP. The authors identified all of the published trials that reported BP as a primary or a secondary end point in which adults with OSA diagnosed by polysomnography were randomly allocated to therapeutic CPAP or not for ≥2 weeks. These 16 trials involved 818 participants (86.3% men; mean age: 51 years; mean apnea-hypopnea index: 36.2 events per hour) treated for ≤24 weeks. From the 15 trials that reported systolic and diastolic BP, the authors calculated a significant mean net reduction of 2.46/1.83 mm Hg with CPAP and, from the 7 trials that reported mean arterial BP, a significant net reduction of 2.22 mm Hg. By comparison, in a previous meta-analysis restricted to 12 trials in which the primary variable of interest was 24-hour mean ambulatory BP, the calculated net decrease was still significant at 1.69 mm Hg.4 In the present analysis by Bazzano et al,3 the mean net change in systolic BP tended to correlate with the average nightly CPAP use (Figure 5 in Reference 3; P =0.13). These authors concluded that CPAP decreases BP among those with OSA, and treating OSA with CPAP may help prevent hypertension. There is increasing awareness of the adverse interactions between OSA …

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: Patients with obstructive sleep apnea (OSA) exhibit impaired brachial artery flow-mediated dilation during wakefulness, a phenomenon that has been attributed to a carryover into the awake state of the consequences of recurrent cycles of hypoxia and reperfusion during sleep, resulting in decreased NO bioavailability and vascular inflammation.1 However, recent prospective studies have failed to identify clearly an independent predictive relationship between markers of oxidative stress and endothelial function.2 Our unanticipated detection of retrograde arterial flow during spontaneous obstructive apnea in an experimental subject who fell asleep when studied during the daytime leads us to propose a novel, additional mechanism for the development of this marker of endothelial dysfunction. A 67-year–old man (blood pressure: 142/84 mm Hg; heart rate: 49 bpm) with known severe untreated OSA (apnea-hypopnea index: 63 events per hour) and treated hypertension (40 mg of fosinopril), whose apneas precipitated …

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.

To the Editor, Cardiovascular mortality remains the leading cause of death in ESRD patients.1 Several of the abnormalities that accrue in ESRD have the potential to attenuate endothelium-dependent vasodilation (EDV).2 These include, but are not restricted to, uremia, hypertension, and increased plasma concentrations of asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase3,4 that has been recently associated independently with increased cardiovascular event rates.5 Nocturnal hemodialysis (NHD) (5 to 6 sessions per week, 8 hours per session) is a novel mode of renal replacement therapy that increases both the frequency and dose of dialysis.6 Within 1 to 2 months after ESRD patients are converted from CHD to NHD, hypertension resolves, EDV improves markedly, and vasodilator responsiveness to sublingual glyceryl trinitrate (GTN) is enhanced.7 ADMA inhibits competitively all 3 isoforms of NO synthase.8 When infused into healthy humans, ADMA decreases forearm blood flow and cardiac output and increases systemic vascular …

OBJECTIVE To determine the effects of prior exercise and naloxone on haemodynamics, muscle sympathetic nerve activity, pituitary hormones and ambulatory blood pressure. METHODS We studied 14 mild hypertensive and 14 normotensive subjects on two days. After baseline measurements, subjects were randomly allocated to vehicle or naloxone (0.4 mg/kg) 30 min before 45 min treadmill exercise. RESULTS In both groups blood pressure, stroke volume, and calf and total peripheral resistances were lower 1 h after exercise, whereas sympathetic activity was unchanged. In normotensive subjects naloxone abolished this calf vasodilation without altering muscle sympathetic nerve activity, and attenuated these haemodynamic aftereffects of exercise, implying a peripheral opioidergic mechanism. Naloxone had no haemodynamic effect in hypertensive subjects. In normotensives there was an inverse relationship between changes in blood pressure and sympathetic activity after vehicle and exercise. This was transformed by naloxone into a positive relationship (r = 0.69, P < 0.02) similar to that observed in hypertensives after vehicle and exercise. Naloxone did not alter the latter positive relationship. Naloxone altered exercise-induced changes in prolactin and luteinizing hormone, but only in normotensive males. In both groups ambulatory blood pressures and heart rates over 2 h after subjects left the laboratory were higher than the values recorded at baseline or 1 h after exercise, and were unaffected by naloxone. CONCLUSIONS The depressor effect of exercise is due to peripheral vasodilation, occurs in the absence of sympathetic withdrawal and is short-lived. Endogenous opioids, activated by running, participate in the haemodynamic, sympathoneural and pituitary hormone aftereffects of exercise in normotensive subjects, whereas in hypertensives these aftereffects of exercise are achieved through non-opioidergic mechanisms. These observations are consistent with the concept that activation of endogenous opioid systems by exercise is impaired in mild hypertension.

We measured intraarterial, ambulatory blood pressure over a 24-h period in 12 subjects 24--63 years (mean 47.6) of age with newly diagnosed untreated hypertension. Measurements were performed both before and after 2--9 months of once-daily treatment with atenolol, a cardioselective beta-adrenoceptor antagonist. Significant reductions in arterial pressure (p less than 0.005) during treatment with atenolol (dose range 50--200 mg) were observed over the full 24-h period.