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Our data reveal for the first time that associations between aerobic fitness and resting muscle sympathetic nerve activity are sex and age specific; inverse relationships are evident in younger males (

Patients with sympathetic excess are those most likely to benefit from novel interventions targeting the autonomic nervous system. To inform such personalized therapy, we identified determinants of augmented muscle sympathetic nerve activity (MSNA) in heart failure, versus healthy controls.We compared data acquired in 177 conventionally-treated, stable non-diabetic patients in sinus rhythm, aged 18-79 years (149 males; 28 females; LVEF: 25±11% [mean±SD]; range 5-60%), and, concurrently, under similar conditions, in 658 healthy, normotensive volunteers (398 males; 260 females; aged 18-81 years). In heart failure, MSNA ranged between 7 and 90 bursts·minBurst frequency and incidence exceeded normative values in only ~53% and ~33% of patients. Such diversity encourages selective deployment of sympatho-modulatory therapies. Clinical characteristics can highlight individuals who may benefit from future personalized interventions targeting pathological sympathetic activation.

Background: Heart failure with reduced ejection fraction (HFrEF) is associated with reduced cardiac β-adrenergic signal transduction in response to chronic elevations in neurally released and circulating norepinephrine. Whether elevations in muscle sympathetic nerve activity (MSNA) are accompanied by attenuated α-adrenoceptor–mediated vasoconstriction remains unclear. Therefore, the objective of the current work was to compare transduction of sympathetic firing into blood pressure (BP) in treated patients with HFrEF and healthy controls. Methods: Twenty-three treated patients with HFrEF (4 females, left ventricular ejection fraction: 28±2%) and 22 healthy controls (6 females) underwent a 7-minute resting measurement of continuous beat-to-beat BP (finger photoplethysmography), heart rate (electrocardiography), and MSNA (microneurography). Sympathetic-BP transduction was quantified using both signal averaging, whereby the BP response to each MSNA burst was serially tracked over 15 cardiac cycles and averaged to derive the peak change in BP, and cross-spectral analysis of low-frequency (0.04–0.15 Hz) MSNA and BP oscillations. Results: Compared with controls, patients with HFrEF had less sympathetic-BP transduction (0.7±0.3 versus 0.2±0.3 mm Hg; P 2 ; P 2 ; P P =0.01) and further attenuated (0.1±0.1 mm Hg; P =0.03) in patients with HFrEF with elevated resting MSNA. Conclusions: Treated HFrEF is associated with lower sympathetic-BP transduction, even when MSNA is not elevated, and diminishes further with disease progression. These adaptations may serve to limit the adverse consequences of oscillatory surges in sympathetic vasoconstrictor discharge on stroke volume.

Elevated large-artery stiffness is recognized as an independent predictor of cardiovascular and all-cause mortality. The mechanisms responsible for such stiffening are incompletely understood. Several recent cross-sectional and acute experimental studies have examined whether sympathetic outflow, quantified by microneurographic measures of muscle sympathetic nerve activity (MSNA), can modulate large-artery stiffness in humans. A major methodological challenge of this research has been the capacity to evaluate the independent neural contribution without influencing the dynamic blood pressure dependence of arterial stiffness. The focus of this review is to summarize the evidence examining 1) the relationship between resting MSNA and large-artery stiffness, as determined by carotid-femoral pulse wave velocity or pulse wave reflection characteristics (i.e., augmentation index) in men and women; 2) the effects of acute sympathoexcitatory or sympathoinhibitory maneuvers on carotid-femoral pulse wave velocity and augmentation index; and 3) the influence of sustained increases or decreases in sympathetic neurotransmitter release or circulating catecholamines on large-artery stiffness. The present results highlight the growing evidence that the sympathetic nervous system is capable of modulating arterial stiffness independent of prevailing hemodynamics and vasomotor tone.

Key points Ventilatory long-term facilitation (vLTF) refers to respiratory neuroplasticity that develops following intermittent hypoxia in both healthy and clinical populations. A sustained hypercapnic background is argued to be required for full vLTF expression in humans. We determined whether acute intermittent hypercapnic hypoxia elicits vLTF during isocapnic-normoxic recovery in healthy males and females. We further assessed whether tonic peripheral chemoreflex drive is necessary and contributes to the expression of vLTF. Following 40-minutes of intermittent hypercapnic hypoxia, minute ventilation was increased throughout 50-minutes of isocapnic-normoxic recovery. Inhibition of peripheral chemoreflex drive with hyperoxia attenuated the magnitude of vLTF. Males and females achieve vLTF through different respiratory recruitment patterns. Abstract Ventilatory long-term facilitation (vLTF) refers to respiratory neuroplasticity that manifests as increased minute ventilation (VI ) following intermittent hypoxia. In humans, hypercapnia sustained throughout intermittent hypoxia and recovery is considered necessary for vLTF expression. We examined whether acute intermittent hypercapnic hypoxia (IHH) induces vLTF, and if peripheral chemoreflex drive contributes to vLTF throughout isocapnic-normoxic recovery. In 19 individuals (9 females, age: 22±3, mean±SD), measurements of tidal volume (VT ), breathing frequency (fB ), VI , and end-tidal gases (PET O2 and PET CO2 ), were made at baseline, during IHH and 50-minutes of recovery. Totalling 40-minutes, IHH included 1-minute intervals of 40-s hypercapnic hypoxia (target PET O2 = 50 mmHg and PET CO2 = +4 mmHg above baseline) and 20-s normoxia. During baseline and recovery, dynamic end-tidal forcing maintained resting PET O2 and PET CO2 and delivered 1-minute of hyperoxia (PET O2 : 355±7 mmHg) every 5-minutes. The depression in VI during hyperoxia was considered an index of peripheral chemoreflex drive. Throughout recovery VI was increased 4.6±3.7 l/min from baseline (P

BACKGROUND Hypoestrogenemia due to menopause is associated with increased cardiovascular disease risk, in part due to elevated indexes of aortic wave reflection (AWRI) and central (aortic) blood pressure. We sought to investigate whether AWRI and central blood pressure are also augmented in hypoestrogenic exercise-trained premenopausal women with functional hypothalamic amenorrhea (ExFHA). METHODS In age- (pooled mean ± SEM, 24 ± 1 years), BMI- (21 ± 1 kg/m2 ), and cardiorespiratory fitness-matched (45 ± 2 ml/kg/min) eumenorrheic ovulatory (ExOv; n = 11) and ExFHA women (n = 10), we assessed aortic blood pressure and waveform characteristics (augmentation index and wave reflection amplitude) obtained from radial pressure waves (applanation tonometry). Doppler ultrasound determined cardiac output (CO) and total peripheral resistance (TPR). Measures were recorded before and 1 hour after 45 minutes of moderate intensity exercise to determine the influence of exercise-induced increases in nitric oxide. RESULTS Pre-exercise, AIx75, central systolic BP (SBPc), and CO were lower (P .05) in ExFHA but was lowered (P

Objective:To more precisely and comprehensively estimate the genetic and environmental correlations between various indices of obesity and BP.Methods:We estimated heritability and genetic correlations of obesity indices with BP in the Oman family study (n=1231). Ambulatory and office beat-to-beat BP was measured and mean values for SBP and DBP during daytime, sleep, 24-h and 10min at rest were calculated. Different indices were used to quantify obesity and fat distribution: BMI, percentage of body fat (%BF), waist circumference and waist-to-height ratio (WHtR). SOLAR software was used to perform univariate and bivariate quantitative genetic analyses adjusting for age, age2, sex, age-sex and age2- sex interactions.Results:Heritabilities of BP ranged from 30.2 to 38.2% for ambulatory daytime, 16.8 - 21.4% for sleeping time, 32.1 - 40.4% for 24-h and 22 - 24.4% for office beat-to-beat measurements. Heritabilities for obesity indices were 67.8% for BMI, 52.2% for %BF, 37.3% for waist circumference and 37.9% for WHtR. All obesity measures had consistently positive phenotypic correlations with ambulatory and office beat-to-beat SBP and DBP (r-range: 0.14 - 0.32). Genetic correlations of obesity indices with SBP and DBP were higher than environmental correlations (rG: 0.16 - 0.50; rE: 0.01 - 0.31).Conclusion:The considerable genetic overlap between a variety of obesity indices and both ambulatory and office beat-to-beat BP highlights the relevance of pleiotropic genes. Future GWAS analyses should discover the specific genes both influencing obesity indices and BP to help unravel their shared genetic background.

No abstract available.

Atrial fibrillation is the most common sustained arrhythmia and is associated with significant morbidity and mortality. The autonomic nervous system has a significant role in the milieu predisposing to the triggers, perpetuators and substrate for atrial fibrillation. It has direct electrophysiological effects and causes alterations in atrial structure. In a significant portion of patients with atrial fibrillation, the autonomic nervous system activity is likely a composite of reflex excitation due to atrial fibrillation itself and contribution of concomitant risk factors such as hypertension, obesity and sleep-disordered breathing. We review the role of autonomic nervous system activation, with focus on changes in reflex control during atrial fibrillation and the role of combined sympatho-vagal activation for atrial fibrillation initiation, maintenance and progression. Finally, we discuss the potential impact of combined aggressive risk factor management as a strategy to modify the autonomic nervous system in patients with atrial fibrillation and to reverse the arrhythmogenic substrate. (c) 2018 Elsevier B.V. All rights reserved.

KEY POINTS Central chemoreceptor stimulation, by hypercapnia (acidosis), and peripheral, by hypoxia plus hypercapnia, evoke reflex increases in ventilation and sympathetic outflow. The assumption that central or peripheral chemoreceptor-mediated sympathetic activation elicited when PCO2 increases parallels concurrent ventilatory responses is unproven. Applying a modified rebreathing protocol that equilibrates central and peripheral chemoreceptor PCO2 whilst clamping O2 tension at either hypoxic or hyperoxic concentrations, the independent ventilatory and muscle sympathetic stimulus-response properties of the central and peripheral chemoreflexes were quantified and compared in young men. The novel findings were that ventilatory and sympathetic responses to central and peripheral chemoreflex stimulation are initiated at similar PCO2 recruitment thresholds but individual specific sympathetic responsiveness cannot be predicted from the ventilatory sensitivities of either chemoreceptor reflex. Such findings in young men, if replicated in heart failure or hypertension, should temper present enthusiasm for trials targeting the peripheral chemoreflex based solely on ventilatory responsiveness to non-specific chemoreceptor stimulation. ABSTRACT In humans, stimulation of peripheral or central chemoreceptor reflexes is assumed to evoke equivalent ventilatory and sympathetic responses. We evaluated whether central or peripheral chemoreceptor-mediated sympathetic activation elicited by increases in CO2 tension ( PCO2 ) parallels concurrent ventilatory responses. Twelve healthy young men performed a modified rebreathing protocol designed to equilibrate central and peripheral chemoreceptor PCO2 tensions with end-tidal PCO2 ( PETCO2 ) at two isoxic end-tidal PO2 ( PETO2 ) such that central responses can be segregated, by hyperoxia, from the net response (hypoxia minus hyperoxia). Ventilation and muscle sympathetic nerve activity (MSNA) were recorded continuously during rebreathing at isoxic PETO2 of 150 and 50 mmHg. During rebreathing, the PETCO2 values at which ventilation (L min-1 ) and total MSNA (units) began to rise were identified ( PETCO2 recruitment thresholds) and their slopes above the recruitment threshold were determined (sensitivity). The central chemoreflex recruitment threshold for ventilation (46 ± 3 mmHg) and MSNA (45 ± 4 mmHg) did not differ (P = 0.55) and slopes were 2.3 ± 0.9 L min-1 mmHg-1 and 2.1 ± 1.5 units mmHg-1 , respectively. The peripheral chemoreflex recruitment thresholds, at 41 ± 3 mmHg for both ventilation and MSNA were lower (P

Fluid that shifts out of the legs and into the neck when supine can contribute to upper-airway narrowing. The present study investigates the relative contributions of vascular and extravascular fluid to the total accumulation of neck fluid volume (NFV). In 22 healthy awake participants (8 women), aged 42 ± 9 yr, we measured NFV with bioelectrical impedance, internal jugular vein volume (IJVV) with ultrasound, and extravascular NFV (NFVEV) as the difference between NFV and IJVV. Participants were randomly allocated to control and intervention, both of which were conducted on the same day. Measurements were made at baseline and every 5 min thereafter during control and intervention. During intervention, participants received 40 mmHg lower-body positive pressure (LBPP) when supine, followed by LBPP plus 10° Trendelenburg position, then LBPP when supine again, followed by recovery. During control, participants lay supine for equal time. LBPP and LBPP plus Trendelenburg position both increased NFV from baseline compared with control ( P < 0.001), with significant contributions from IJVV ( P < 0.001). Returning to supine with LBPP, IJVV returned to baseline, but NFV remained elevated because of accumulation of NFVEV. These findings suggest that contributions of IJVV to NFV are immediate but transient, whereas sustained elevation in NFV when supine is likely a result of NFVEV. These findings add new insights into the mechanism by which fluid accumulates in the neck by rostral fluid shift. NEW & NOTEWORTHY This study demonstrates that lying supine for 30 min as well as increased fluid shift out of the legs to simulate nocturnal rostral fluid shift causes fluid to accumulate mainly in the extravascular space of the neck rather than in the internal jugular veins. Therefore, in subjects without fluid-retaining states, extravascular neck fluid accumulation overnight might play a more significant role in the pathophysiology of upper-airway narrowing than intravascular fluid accumulation.

Defined as a structural or functional cardiac abnormality accompanied by symptoms, signs, or biomarkers of altered ventricular pressures or volumes, heart failure also is a state of autonomic disequilibrium. A large body of evidence affirms that autonomic disturbances are intrinsic to heart failure; basal or stimulated sympathetic nerve firing or neural norepinephrine (NE) release more often than not exceed homeostatic need, such that an initially adaptive adrenergic or vagal reflex response becomes maladaptive. The magnitude of such maladaptation predicts prognosis. This Ludwig lecture develops two theses: the elucidation and judiciously targeted amelioration of maladaptive autonomic disturbances offers opportunities to complement contemporary guideline-based heart failure therapy, and serendipitous single-participant insights, acquired in the course of experimental protocols with entirely different intent, can generate novel insight, inform mechanisms, and launch entirely new research directions. I précis six elements of our current synthesis of the causes and consequences of maladaptive sympathetic disequilibrium in heart failure, shaped by patient-inspired epiphanies: arterial baroreceptor reflex modulation, excitation stimulated by increased cardiac filling pressure, paradoxical muscle sympathetic activation as a peripheral neurogenic constraint on exercise capacity, renal sympathetic restraint of natriuresis, coexisting sleep apnea, and augmented chemoreceptor reflex sensitivity and then conclude by envisaging translational therapeutic opportunities.

In healthy young volunteers, acquisition of blood oxygen level-dependent (BOLD) magnetic resonance (MR) and muscle sympathetic nerve (MSNA) signals during simulation of obstructive or central sleep apnea identified cortical cardiovascular autonomic regions in which the BOLD signal changed synchronously with acute noradrenergic excitation. In the present work, we tested the hypothesis that such Mueller maneuvers (MM) and breath-holds (BH) would elicit greater concomitant changes in mean efferent nerve firing and BOLD signal intensity in patients with moderate to severe obstructive sleep apnea (OSA) relative to age- and sex-matched individuals with no or only mild OSA (Apnea Hypopnea Index, AHI, ∗-weighted echo planar functional MR imaging. MSNA at rest was greater in those with OSA (65 ± 19 vs. 48 ± 17 bursts per 100 heart beats; p < 0.01). MM and BH elicited similar heart rate, blood pressure, and MSNA responses in the two cohorts; group mean BOLD data were concordant, detecting no between-group differences in cortical autonomic region signal activities. The present findings do not support the concept that recurring episodes of cyclical apnea during sleep alter cortical or peripheral neural responsiveness to their simulation during wakefulness by volitional Mueller maneuvers or breath-holds.

Multiunit recordings of postganglionic sympathetic outflow to muscle yield otherwise imperceptible insights into sympathetic neural modulation of human vascular resistance and blood pressure. This Corcoran Lecture will illustrate the utility of microneurography to investigate neurogenic cardiovascular regulation; review data concerning muscle sympathetic nerve activity of women and men with normal and high blood pressure; explore 2 concepts, central upregulation of muscle sympathetic outflow and cortical autonomic neuroplasticity; present sleep apnea as an imperfect model of neurogenic hypertension; and expose the paradox of sympathetic excitation without hypertension. In awake healthy normotensive individuals, resting muscle sympathetic nerve activity increases with age, sleep fragmentation, and obstructive apnea. Its magnitude is not signaled by heart rate. Age-related changes are nonlinear and differ by sex. In men, sympathetic nerve activity increases with age but without relation to their blood pressure, whereas in women, both rise concordantly after age 40. Mean values for muscle sympathetic nerve activity burst incidence are consistently higher in cohorts with hypertension than in matched normotensives, yet women’s sympathetic nerve traffic can increase 3-fold between ages 30 and 70 without causing hypertension. Thus, increased sympathetic nerve activity may be necessary but is insufficient for primary hypertension. Moreover, its inhibition does not consistently decrease blood pressure. Despite a half-century of microneurographic research, large gaps remain in our understanding of the content of the sympathetic broadcast from brain to blood vessel and its specific individual consequences for circulatory regulation and cardiovascular, renal, and metabolic risk.

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)

Postural orthostatic tachycardia syndrome (POTS) is accompanied by reduced brain blood flow, autonomic dysfunction, and orthostatic intolerance. We hypothesized that wearing a neck compression collar would attenuate orthostatic symptoms, increase brain blood flow, and influence autonomic reflexes. Ten participants with POTS (9 women, age: 36 ± 10) underwent two trials of supine rest, paced deep breathing (6 breaths/min), Valsalva maneuver (40 mmHg for 15 s), and 70° upright tilt. For one trial, participants wore a neck compression device (Q30 Innovations). Blood pressure, heart rate (HR), brain blood flow velocity, stroke volume, respiratory rate, and end-tidal gases were continuously measured. The Vanderbilt Orthostatic Symptom Score was compiled at the end of tilt. The use of the collar reduced the orthostatic symptom score of participants with POTS during upright tilt (26.9 ± 12.5 to 18.7 ± 13.1, P = 0.04). Collar compression in the supine condition reduced the low-frequency domain of HR variability (60 ± 18 to 51 ± 23 normalized units, P = 0.04) and increased the change in HR (15 ± 5 to 17 ± 6 bpm, P = 0.02) and E:I ratio (1.2 ± 0.1 to 1.3 ± 0.1, P = 0.01) during paced deep breathing. Throughout tilt, wearing the collar reduced respiratory rate (baseline: 13 ± 3 to 12 ± 4 breath/min; tilt: 18 ± 5 to 15 ± 5 breath/min; main effect of collar P = 0.048), end-tidal oxygen (baseline: 115 ± 5 to 112 ± 5 mmHg; tilt: 122 ± 10 to 118 ± 11 mmHg; main effect of collar P = 0.026). In participants with POTS, wearing the Q-collar reduced orthostatic symptoms, increased the HR response to deep breathing, and decreased resting ventilation. NEW & NOTEWORTHY We found that using a neck compression collar alleviated orthostatic symptoms in upright posture in participants with postural orthostatic tachycardia syndrome (POTS). This could be due to compression of the baroreceptors and subsequent changes in autonomic function. Indeed, we observed increased heart rate responsiveness to paced deep breathing and reductions of respiratory rate and end-tidal O2 (suggesting reduced ventilation). Further, wearing the collar reduced mean blood velocity in the brain during Valsalva perhaps due to higher brain blood volume.

Study Objectives: In heart failure (HF), we observed two patterns of hyperpnea during Cheyne-Stokes respiration with central sleep apnea (CSR-CSA): a positive pattern where end-expiratory lung volume remains at or above functional residual capacity, and a negative pattern where it falls below functional residual capacity. We hypothesized the negative pattern is associated with worse HF. Methods: Patients with HF underwent polysomnography. During CSR-CSA, hyperpnea, apnea-hyperpnea cycle, and lung to finger circulation times (LFCT) were measured. Plasma N-terminal prohormone of brain natriuretic peptide (NT-proBNP) concentration and left ventricular ejection fraction (LVEF) were assessed. Results: Of 33 patients with CSR-CSA (31 men, mean age 68 years), 9 had a negative hyperpnea pattern. There was no difference in age, body mass index, and apnea-hypopnea index between groups. Patients with a negative pattern had longer hyperpnea time (39.5 ± 6.4 versus 25.8 ± 5.9 seconds, P < .01), longer cycle time (67.8 ± 15.9 versus 51.7 ± 9.9 seconds, P < .01), higher NT-proBNP concentrations (2740 [6769] versus 570 [864] pg/ml, P = .01), and worse New York Heart Association class (P = .02) than those with a positive pattern. LFCT and LVEF did not differ between groups. Conclusions: Patients with HF and a negative CSR-CSA pattern have evidence of worse cardiac function than those with a positive pattern. Greater positive expiratory pressure during hyperpnea is likely generated during the negative pattern and might support stroke volume in patients with worse cardiac function. Commentary: A commentary on this article appears in this issue on page 1227. Clinical Trial Registration: The trial is registered with Current Controlled Trials (www.controlled-trials.com; ISRCTN67500535) and Clinical Trials (www. clinicaltrials.gov; NCT01128816).

The beneficial effects of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (ANG II) receptor antagonists in patients with heart failure secondary to reduced ejection fraction (HFrEF) are felt to result from prevention of the adverse effects of ANG II on systemic afterload and renal homeostasis. However, ANG II can activate the sympathetic nervous system, and part of the beneficial effects of ACE inhibitors and ANG II antagonists may result from their ability to inhibit such activation. We examined the acute effects of the ACE inhibitor captopril (25 mg, n = 9) and the ANG II receptor antagonist losartan (50 mg, n = 10) on hemodynamics as well as total body and cardiac norepinephrine spillover in patients with chronic HFrEF. Hemodynamic and neurochemical measurements were made at baseline and at 1, 2, and 4 h after oral dosing. Administration of both drugs caused significant reductions in systemic arterial, cardiac filling, and pulmonary artery pressures ( P < 0.05 vs. baseline). There was no significant difference in the magnitude of those hemodynamic effects. Plasma concentrations of ANG II were significantly decreased by captopril and increased by losartan ( P < 0.05 vs. baseline for both). Total body sympathetic activity increased in response to both captopril and losartan ( P < 0.05 vs. baseline for both); however, there was no change in cardiac sympathetic activity in response to either drug. The results of the present study do not support the hypothesis that the acute inhibition of the renin-angiotensin system has sympathoinhibitory effects in patients with chronic HFrEF.

Despite improvements in medical therapy and device-based treatment, heart failure (HF) continues to impose enormous burdens on patients and health care systems worldwide. Alterations in autonomic nervous system (ANS) activity contribute to cardiac disease progression, and the recent development of invasive techniques and electrical stimulation devices has opened new avenues for specific targeting of the sympathetic and parasympathetic branches of the ANS. The Heart Failure Association of the European Society of Cardiology recently organized an expert workshop which brought together clinicians, trialists and basic scientists to discuss the ANS as a therapeutic target in HF. The questions addressed were: (i) What are the abnormalities of ANS in HF patients? (ii) What methods are available to measure autonomic dysfunction? (iii) What therapeutic interventions are available to target the ANS in patients with HF, and what are their specific strengths and weaknesses? (iv) What have we learned from previous ANS trials? (v) How should we proceed in the future?

Introduction Both types of sleep-disordered breathing (SDB), obstructive and central sleep apnoea (OSA and CSA, respectively), are common in patients with heart failure and reduced ejection fraction (HFrEF). In such patients, SDB is associated with increased cardiovascular morbidity and mortality but it remains uncertain whether treating SDB by adaptive servo-ventilation (ASV) in such patients reduces morbidity and mortality. Aim ADVENT-HF is designed to assess the effects of treating SDB with ASV on morbidity and mortality in patients with HFrEF. Methods ADVENT-HF is a multicentre, multinational, randomized, parallel-group, open-label trial with blinded assessment of endpoints of standard medical therapy for HFrEF alone vs. with the addition of ASV in patients with HFrEF and SDB. Patients with a history of HFrEF undergo echocardiography and polysomnography. Those with a left ventricular ejection fraction ≤45% and SDB (apnoea–hypopnoea index ≥15) are eligible. SDB is stratified into OSA with ≥50% of events obstructive or CSA with >50% of events central. Those with OSA must not have excessive daytime sleepiness (Epworth score of ≤10). Patients are then randomized to receive or not receive ASV. The primary outcome is the composite of all-cause mortality, cardiovascular hospital admissions, new-onset atrial fibrillation requiring anti-coagulation but not hospitalization, and delivery of an appropriate discharge from an implantable cardioverter-defibrillator not resulting in hospitalization during a maximum follow-up time of 5 years. Conclusion The ADVENT-HF trial will help to determine whether treating SDB by ASV in patients with HFrEF improves morbidity and mortality.

We investigated the impact of short-acting and extended release nifedipine on sympathetic activity using radiotracer methodology in patients with stable coronary artery disease in order to more accurately document the response of the sympathetic nervous system to different formulations of this dihydropyridine calcium channel antagonist. Participants were randomized to placebo, short-acting or extended release nifedipine for 7–10 days. On the final day, systemic blood pressure, cardiac filling pressures, cardiac output, plasma norepinephrine (NE) and total body NE spillover were measured at baseline (time 0) and repeated at intervals for 6 hours. There were no differences in baseline measures between groups. Following the morning dose of study medication there were no changes in hemodynamics or sympathetic activity in the placebo group. However, there was a significant fall in blood pressure and a significant increase in total body NE spillover in both nifedipine groups. Importantly, the increase in sympathetic activity in response to short-acting nifedipine began earlier (30 minutes) and was much greater than that observed in the extended release group, which occurred later (270 minutes). These findings confirm that sustained therapy with nifedipine is associated with activation of the sympathetic nervous system which is dependent on the pharmacokinetics of the formulation.

As with blood pressure, age-related changes in muscle sympathetic nerve activity (MSNA) may differ nonlinearly between sexes. Data acquired from 398 male (age: 39±17; range: 18–78 years [mean±SD]) and 260 female (age: 37±18; range: 18–81 years) normotensive healthy nonmedicated volunteers were analyzed using linear regression models with resting MSNA burst frequency as the outcome and the predictors sex, age, MSNA, blood pressure, and body mass index modelled with natural cubic splines. Age and body mass index contributed 41% and 11%, respectively, of MSNA variance in females and 23% and 1% in males. Overall, changes in MSNA with age were sigmoidal. At age 20, mean MSNA of males and females were similar, then diverged significantly, reaching in women a nadir at age 30. After 30, MSNA increased nonlinearly in both sexes. Both MSNA discharge and blood pressure were lower in females until age 50 (17±9 versus 25±10 bursts·min −1 ; P −19 ; 106±11/66±8 versus 116±7/68±9 mm Hg; P −1 ; P =0.17; 119±15/71±13 versus 120±13/72±9 mm Hg; P >0.56). Compared with age 30, MSNA burst frequency at age 70 was 57% higher in males but 3-fold greater in females; corresponding increases in systolic blood pressure were 1 (95% CI, −4 to 5) and 12 (95% CI, 6–16) mm Hg. Except for concordance in females beyond age 40, there was no systematic change with age in any resting MSNA-blood pressure relationship. In normotensive adults, MSNA increases after age 30, with ascendance steeper in women.

Muscle sympathetic nerve activity (MSNA) decreases during low-intensity dynamic one-leg exercise in healthy subjects but increases in patients with heart failure with reduced ejection fraction (HFrEF). We hypothesized that increased peak oxygen uptake (V̇o2peak) after aerobic training would be accompanied by less sympathoexcitation during both mild and moderate one-leg dynamic cycling, an attenuated muscle metaboreflex, and greater skin vasodilation. We studied 27 stable, treated HFrEF patients (6 women; mean age: 65 ± 2 SE yr; mean left ventricular ejection fraction: 30 ± 1%) and 18 healthy age-matched volunteers (6 women; mean age: 57 ± 2 yr). We assessed V̇o2peak (open-circuit spirometry) and the skin microcirculatory response to reactive hyperemia (laser flowmetry). Fibular MSNA (microneurography) was recorded before and during one-leg cycling (2 min unloaded and 2 min at 50% of V̇o2peak) and, to assess the muscle metaboreflex, during posthandgrip ischemia (PHGI). HFrEF patients were evaluated before and after 6 mo of exercise-based cardiac rehabilitation. Pretraining V̇o2peak and skin vasodilatation were lower ( P < 0.001) and resting MSNA higher ( P = 0.01) in HFrEF than control subjects. Training improved V̇o2peak (+3.0 ± 1.0 mL·kg−1·min−1; P < 0.001) and cutaneous vasodilation and diminished resting MSNA (−6.0 ± 2.0, P = 0.01) plus exercise MSNA during unloaded (−4.0 ± 2.5, P = 0.04) but not loaded cycling (−1.0 ± 4.0 bursts/min, P = 0.34) and MSNA during PHGI ( P < 0.05). In HFrEF patients, exercise training lowers MSNA at rest, desensitizes the sympathoexcitatory metaboreflex, and diminishes MSNA elicited by mild but not moderate cycling. Training-induced downregulation of resting MSNA and attenuated reflex sympathetic excitation may improve exercise capacity and survival.

STUDY OBJECTIVES: In patients with heart failure (HF) and reduced left ventricular ejection fraction (HFrEF), stroke volume (SV) falls during hyperpnea of Cheyne-Stokes respiration with central sleep apnea (CSR-CSA). We have identified two distinct patterns of hyperpnea: positive, in which end-expiratory lung volume (EELV) remains at or above functional residual capacity (FRC), and negative, in which EELV falls below FRC. The increase in expiratory intrathoracic pressure generated by the latter should have effects on the heart analogous to external chest compression. To test the hypotheses that in HFrEF patients, CSR-CSA with the negative pattern has an auto-resuscitation effect such that compared with the positive pattern, it is associated with a smaller fall in SV and a smaller increase in cardiac workload (product of heart rate and systolic blood pressure). METHODS: In 15 consecutive HFrEF patients with CSR-CSA during polysomnography, hemodynamic data derived from digital photoplethysmography during positive and negative hyperpneas were compared. RESULTS: Compared to the positive, negative hyperpneas were accompanied by reductions in the maximum and mean relative fall in SV of 30% (p = 0.002) and 10% (p = 0.031), respectively, and by reductions in the degree of increases in heart rate and rate pressure product during hyperpnea of 46% (p < 0.001) and 13% (p = 0.007), respectively. CONCLUSIONS: Our findings suggest the novel concept that the negative pattern of CSR-CSA may constitute a form of auto-resuscitation that acts as a compensatory mechanism to maintain SV in patients with severe HF.

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.

Muscle sympathetic nerve activity (MSNA) at rest increases with age. However, the influence of age on MSNA recorded during dynamic leg exercise is unknown. We tested the hypothesis that aging attenuates the sympatho-inhibitory response observed in young subjects performing mild to moderate 1-leg cycling. After predetermining peak oxygen uptake, we compared contra-lateral fibular nerve MSNA during 2 min each of mild (unloaded) and moderate (30%–40% of the work rate at peak oxygen uptake, halved for single leg) 1-leg cycling in 18 young (age, 23 ± 1 years (mean ± SE)) and 18 middle-aged (age, 57 ± 2 years) sex-matched healthy subjects. Mean height, weight, resting heart rate, systolic blood pressure, and percent predicted peak oxygen uptake were similar between groups. Middle-aged subjects had higher resting MSNA burst frequency and incidence (P < 0.001) and diastolic blood pressure (P = 0.04). During moderate 1-leg cycling, older subjects’ systolic blood pressure increased more (+21 ± 5 vs. +10 ± 1 mm Hg; P = 0.02) and their fall in MSNA burst incidence was amplified (−19 ± 2 vs. −11 ± 2 bursts/100 heart beats; P = 0.01) but because heart rate rose less (+15 ± 3 vs. +19 ± 2 bpm; P = 0.03), exercise induced similar reductions in burst frequency (P = 0.25). Contrary to our initial hypothesis, with advancing age, mild- to moderate-intensity dynamic leg exercise elicits a greater rise in systolic blood pressure and a larger fall in MSNA.

Introduction:Individual differences in heart rate variability (HRV) can be partly attributed to genetic factors that may be more pronounced during stress. Using data from the Oman Family Study (OFS), we aimed to estimate and quantify the relative contribution of genes and environment to the variance of HRV at rest and during stress; calculate the overlap in genetic and environmental influences on HRV at rest and under stress using bivariate analyses of HRV parameters and heart rate (HR).Methods:Time and frequency domain HRV variables and average HR were measured from beat-to-beat HR obtained from electrocardiogram recordings at rest and during two stress tests [mental: Word Conflict Test (WCT) and physical: Cold Pressor Test (CPT)] in the OFS - a multigenerational pedigree consisting of five large Arab families with a total of 1326 participants. SOLAR software was used to perform quantitative genetic modelling.Results:Heritability estimates for HRV and HR ranged from 0.11 to 0.31 for rest, 0.09-0.43 for WCT, and 0.07-0.36 for CPT. A large part of the genetic influences during rest and stress conditions were shared with genetic correlations ranging between 0.52 and 0.86 for rest-WCT and 0.60-0.92 for rest-CPT. Nonetheless, genetic rest-stress correlations for most traits were significantly smaller than 1 indicating some stress-specific genetic effects.Conclusion:Genetic factors significantly influence HRV and HR at rest and under stress. Most of the genetic factors that influence HRV at rest also influence HRV during stress tests, although some unique genetic variance emerges during these challenging conditions.

Synchronization of molecular, metabolic, and cardiovascular circadian oscillations is fundamental to human health. Sleep-disordered breathing, which disrupts such temporal congruence, elicits hemodynamic, autonomic, chemical, and inflammatory disturbances with acute and long-term consequences for heart, brain, and circulatory and metabolic function. Sleep apnea afflicts a substantial proportion of adult men and women but is more prevalent in those with established cardiovascular diseases and especially fluid-retaining states. Despite the experimental, epidemiological, observational, and interventional evidence assembled in support of these concepts, this substantial body of work has had relatively modest pragmatic impact, thus far, on the discipline of cardiology. Contemporary estimates of cardiovascular risk still are derived typically from data acquired during wakefulness. The impact of sleep-related breathing disorders rarely is entered into such calculations or integrated into diagnostic disease-specific algorithms or therapeutic recommendations. Reasons for this include absence of apnea-related symptoms in most with cardiovascular disease, impediments to efficient diagnosis at the population level, debate as to target, suboptimal therapies, difficulties mounting large randomized trials of sleep-specific interventions, and the challenging results of those few prospective cardiovascular outcome trials that have been completed and reported. The objectives of this review are to delineate the bidirectional interrelationship between sleep-disordered breathing and cardiovascular disease, consider the findings and implications of observational and randomized trials of treatment, frame the current state of clinical equipoise, identify principal current controversies and potential paths to their resolution, and anticipate future directions.

Abnormal renal function is common in acute and chronic congestive heart failure (CHF) and is related to the severity of congestion. However, treatment of congestion often leads to worsening renal function. Our objective was to explore basal determinants of renal function and their response to hemodynamic interventions. Thirty-seven patients without CHF and 59 patients with chronic CHF (ejection fraction; 23 ± 8%) underwent right heart catheterization, measurements of glomerular filtration rate (GFR; inulin) and renal plasma flow (RPF; para-aminohippurate), and radiotracer estimates of renal sympathetic activity. A subset (26 without, 36 with CHF) underwent acute pharmacological intervention with dobutamine or nitroprusside. We explored the relationship between baseline and drug-induced hemodynamic changes and changes in renal function. In CHF, there was an inverse relationship among right atrial mean pressure (RAM) pressure, RPF, and GFR. By contrast, mean arterial pressure (MAP), cardiac index (CI), and measures of renal sympathetic activity were not significant predictors. In those with CHF there was also an inverse relationship among the drug-induced changes in RAM as well as pulmonary artery mean pressure and the change in GFR. Changes in MAP and CI did not predict the change in GFR in those with CHF. Baseline values and changes in RAM pressure did not correlate with GFR in those without CHF. In the CHF group there was a positive correlation between RAM pressure and renal sympathetic activity. There was also an inverse relationship among RAM pressure, GFR, and RPF in patients with chronic CHF. The observation that acute reductions in RAM pressure is associated with an increase in GFR in patients with CHF has important clinical implications.

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 …