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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 (

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.

In heart failure with reduced ejection fraction (HFrEF), diminished tonic and reflex vagal heart rate modulation and exaggerated sympathetic outflow and neural norepinephrine release are evident from disease inception. Each of these disturbances of autonomic regulation has been independently associated with shortened survival, and β-adrenoceptor antagonism and therapeutic autonomic modulation by other means have been demonstrated, in clinical trials, to lessen symptoms and prolong survival. In contrast, data concerning the autonomic status of patients with heart failure with preserved ejection fraction (HFpEF) are comparatively sparse. Little is known concerning the prognostic consequences of autonomic dysregulation in such individuals, and therapies applied with success in HFrEF have in most trials failed to improve symptoms or survival of those with HFpEF. A recent HFpEF Expert Scientific Panel report emphasised that without a deeper understanding of the pathophysiology of HFpEF, establishing effective treatment will be challenging. One aspect of such pathology may be cardiovascular autonomic disequilibrium, often worsened by acute exercise or routine daily activity. This review aims to summarise existing knowledge concerning parasympathetic and sympathetic function of patients with HFpEF, consider potential mechanisms and specific consequences of autonomic disturbances that have been identified, and propose hypotheses for future investigation.

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

BackgroundIn recent summers, some populous mid-latitude to high-latitude regions have experienced greater heat intensity, more at night than by day. Such warming has been associated with increased cause-specific adult mortality. Sex-specific and age-specific associations between summer nocturnal surface air temperatures (SAT) and cardiovascular disease (CVD) deaths have yet to be established.MethodsA monthly time series analysis (June–July, 2001–2015) was performed on sex-specific CVD deaths in England and Wales of adults aged 60–64 and 65–69 years. Using negative binomial regression with autocorrelative residuals, associations between summer (June–July) nocturnal SAT anomalies (primary exposure) and CVD death rates (outcome) were computed, controlling for key covariates. To explore external validity, similar associations with respect to CVD death in King County, Washington, USA, also were calculated, but only for men aged 60–64 and 65–69 years. Results are reported as incidence rate ratios.ResultsFrom 2001 to 2015, within these specific cohorts, 39 912 CVD deaths (68.9% men) were recorded in England and Wales and 488 deaths in King County. In England and Wales, after controlling for covariates, a 1°C rise in anomalous summer nocturnal SAT associated significantly with a 3.1% (95% CI 0.3% to 5.9%) increased risk of CVD mortality among men aged 60–64, but not older men or either women age groups. In King County, after controlling for covariates, a 1°C rise associated significantly with a 4.8% (95% CI 1.7% to 8.1%) increased risk of CVD mortality among those ConclusionIn two mid-latitude regions, warmer summer nights are accompanied by an increased risk of death from CVD among men aged 60–64 years.

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

Background Reflected arterial waves contribute to left ventricular (LV) afterload. Heart failure patients with reduced ejection fraction (HFrEF) are afterload sensitive and sympathetically activated. We tested the hypothesis that HFrEF patients exhibit a positive relationship between sympathetic vasoconstrictor discharge and aortic wave reflection. Methods Sixteen treated patients with HFrEF (61 ± 9 years of age, left ventricular ejection fraction 30 ± 7%, 3 women) and 16 similar-aged healthy control subjects (57 ± 7 years of age, 4 women) underwent noninvasive measurements of radial pulse waveforms (applanation tonometry) to calculate central blood pressures and aortic wave reflection characteristics: augmentation pressure (AP), augmentation index (AIx), and AIx corrected to a heart rate of 75 beats/min (AIx@75). Muscle sympathetic nerve activity (MSNA) burst frequency was recorded from the fibular nerve (microneurography). Results HFrEF patients had higher AIx (26 ± 9 vs 17 ± 15%; P .05), AP (11 ± 5 vs 7 ± 8 mm Hg; P = 0.11), or AIx@75 (19 ± 9 vs 13 ± 11%,-P = 0.14). MSNA correlated positively with AP (r = 0.50; P 0.49). Conclusions In patients with HFrEF, but not similarly aged healthy subjects, indices of aortic wave reflection correlate positively with MSNA. By increasing LV afterload, such neurovascular coupling could impair LV performance and worsen heart failure symptoms. Therapies that attenuate neurogenic vasoconstriction may benefit HFrEF patients by diminishing arterial wave reflection.

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.

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.

During 1-leg cycling, contralateral muscle sympathetic nerve activity (MSNA) falls in healthy adults but increases in most with reduced ejection fraction heart failure (HFrEF). We hypothesized that their peak oxygen uptake (

The sympathetic nervous system coordinates the cardiovascular response to exercise. This regulation is impaired in both experimental and human heart failure with reduced ejection fraction (HFrEF), resulting in a state of sympathoexcitation which limits exercise capacity and contributes to adverse outcome. Exercise training can moderate sympathetic excess at rest. Recording sympathetic nerve firing during exercise is more challenging. Hence, data acquired during exercise are scant and results vary according to exercise modality. In this review we will: (1) describe sympathetic activity during various exercise modes in both experimental and human HFrEF and consider factors which influence these responses; and (2) summarise the effect of exercise training on sympathetic outflow both at rest and during exercise in both animal models and human HFrEF. We will particularly highlight studies in humans which report direct measurements of efferent sympathetic nerve traffic using intraneural recordings. Future research is required to clarify the neural afferent mechanisms which contribute to efferent sympathetic activation during exercise in HFrEF, how this may be altered by exercise training, and the impact of such attenuation on cardiac and renal function.

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.

Sleep disordered breathing (SDB) is highly prevalent in patients with atrial fibrillation, heart failure and hypertension and is associated with increased risk of mortality, cardiovascular (CV) events and arrhythmias. Current assessment of the severity of SDB is mainly based on the apnea-hypopnea index (AHI) representing the number of hypopneas and apneas per hour of sleep. However, this event-based parameter alone may not sufficiently reflect the complex pathophysiological mechanisms underlying SDB potentially contributing to CV outcome risk. In this review article, we highlight important limitations and pitfalls of current assessment, quantification and interpretation of SDB-severity in patients with CV disease and will discuss pathophysiological considerations from preclinical and clinical mechanistic studies and possible clinical implications.

Blood pressure responses to graded exercise testing can provide important diagnostic and prognostic information. While published guidelines outline what constitutes a "normal" and "abnormal" (i.e., exaggerated) blood pressure response to exercise testing, the widespread use of exaggerated blood pressure responses as a clinical tool is limited due to sparse and inconsistent data. A review of the original sources from these guidelines reveals an overall lack of empirical evidence to support both the normal blood pressure responses and their upper limits. In this current opinion, we critically evaluate the current exercise blood pressure guidelines including (1) the normal blood pressure responses to graded exercise testing; (2) the upper limits of this normal response; (3) the blood pressure criteria for test termination; and (4) the thresholds for exaggerated blood pressure responses. We provide evidence that exercise blood pressure responses vary according to subject characteristics, and subsequently a re-evaluation of what constitutes normal and abnormal responses is necessary to strengthen the clinical utility of this assessment.

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.

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.

Rationale: End-stage renal disease (ESRD) patients have high annual mortality mainly due to cardiovascular causes. The acute effects of obstructive and central sleep apnea on cardiac function in ESRD patients have not been determined. We therefore tested, in patients with ESRD, the hypotheses that (1) sleep apnea induces deterioration in cardiac function overnight and (2) attenuation of sleep apnea severity by ultrafiltration (UF) attenuates this deterioration. Methods: At baseline, ESRD patients, on conventional hemodialysis, with left ventricular ejection fraction (LVEF) >45% had polysomnography (PSG) performed on a non-dialysis day to determine the apnea-hypopnea index (AHI). Echocardiography was performed at the bedside, before and after sleep. Isovolumetric contraction time divided by left ventricular ejection time (IVCT/ET) and isovolumetric relaxation time divided by ET (IVRT/ET) were measured by tissue doppler imaging. The myocardial performance index (MPI), a composite of systolic and diastolic function was also calculated. One week later, subjects with sleep apnea (AHI ≥15) had fluid removed by UF, followed by repeat PSG and echocardiography. ­Results: Fifteen subjects had baseline measurements, of which 7 had an AHI p = 0.008, 0.007 and 0.031, respectively), indicating deterioration in systolic and diastolic function. Following fluid removal by UF in the sleep-apnea group, the AHI decreased by 48.7% (p = 0.012) and overnight increases in MPI, IVCT/ET and IVRT/ET observed at baseline were abolished. Conclusions: In ESRD, cardiac function deteriorates overnight in those with sleep apnea, but not in those without sleep apnea. This overnight deterioration in the sleep-apnea group may be at least partially due to sleep apnea, since attenuation of sleep apnea by UF was accompanied by elimination of this deleterious overnight effect.

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.

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.

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.

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 …

Obstructive sleep apnea (OSA), present in ~15% of the general population, increases the risks of stroke, heart failure, and premature death. Importantly, individuals with cardiovascular disease have a higher prevalence yet they often have few symptoms to alert clinicians to its presence. OSA with an apnea-hypopnea index (AHI) ≥15 events/hour is present in ≥30% of patients with primary hypertension and in up to 80% of those with drug resistant hypertension, suggesting that the neural, hormonal, inflammatory and vascular cascades triggered by OSA may elevate blood pressure chronically. The purpose of this review is to summarize: (1) the epidemiology of OSA and its relation to cardiovascular risk; (2) potential mechanisms by which OSA could promote conditions known to increase the risk of hypertension or contribute to its development and progression; (3) evidence for and against a pro-hypertensive effect of OSA; and, (4) the impact of treatment with continuous positive airway pressure (CPAP) on blood pressure and blood pressure-related morbidities. The prevailing view that the effect of treatment on blood pressure is modest arises from the inability of most contemporary technology to measure accurately the true impact of CPAP on OSA-entrained surges in nocturnal blood pressure. Moreover the exclusive focus on blood pressure, as if this is the principal determinant of cardiovascular event rates in this population, is naïve. The capacity to reduce cardiovascular risk by treating OSA with CPAP likely transcends a simple blood pressure effect; formal testing of this hypothesis will require adequately powered randomized clinical trials.

Obstructive sleep apnea is more prevalent in patients with hypertension than in the general population and many with obstructive sleep apnea also have hypertension. Obstructive sleep apnea increases the risk of hypertension-related morbidities such as stroke, heart failure, and premature death. Are such associations coincidental or causal and if the latter, what are their implications for clinical practice? Despite compelling epidemiological and mechanistic links between obstructive sleep apnea and hypertension, the effect in clinical trials of the treatment of obstructive sleep apnea on blood pressure has been modest and variable. The purpose of this review is to summarize our present understanding of: (1) the relevant epidemiology and mechanisms that might be responsible for the bidirectional relationship between obstructive sleep apnea and hypertension; and (2) available evidence regarding the effect of treating obstructive sleep apnea on blood pressure.

We previously showed in heart failure (HF) patients that obstructive respiratory events during sleep and generation of negative intrathoracic pressure during Mueller manoeuvres, mimicking obstructive apneas, acutely reduced stroke volume (SV). We also showed that treating obstructive sleep apnea (OSA) with continuous positive airway pressure (CPAP) increased left ventricular ejection fraction over a 1-month period. We therefore hypothesized that, in HF patients, those with OSA would have greater overnight declines in SV and cardiac output (CO) than in those without sleep apnea, and that therapy of OSA using CPAP would prevent these declines.We examined overnight percent change in SV and CO in 32 HF patients with and 28 without OSA using digital photoplethysmography. Among patients with OSA, we also examined changes in SV and CO during a CPAP titration study.During the baseline polysomnogram SV and CO decreased more overnight in those with OSA than in those without sleep apnea (-12.6 ± 7.7% vs -3.2 ± 6.8%; P0.001 and -16.2 ± 9.9% vs -3.7 ± 8.3%; P0.001, respectively). Overnight changes in SV and CO correlated inversely with total apnea-hypopnea index (r = -0.551; P0.001 and r = -0.522; P0.001, respectively). In 21 patients with OSA, CPAP reduced the total apnea-hypopnea index from 37.7 ± 21.4 to 15.0 ± 16.0 (P0.001) in association with attenuation of the overnight reduction of SV (from -14.0 ± 7.9% to -3.4 ± 9.8%; P = 0.002) and CO (from -17.2 ± 9.0% to -9.7 ± 10.7%; P = 0.042).In patients with HF, coexisting OSA causes overnight declines in SV and CO that are prevented through reversal of OSA by CPAP.

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

Study Objectives: Postoperative development of obstructive sleep apnea (OSA) has been attributed to the fluid overloaded state of patients during the postoperative period. In this context, alterations in cardiac autonomic regulation caused by OSA may explain the increased postoperative risk for adverse cardiovascular events. This study tests the hypothesis that individuals with fluid overload-induced OSA will experience autonomic dysregulation, compared to those without fluid overload-induced OSA. Methods: Twenty-one normotensive, nonobese (mean body mass index 24.5 kg/m2) males (mean age 37 years) underwent a sleep study. Participants were randomly assigned to infusion with saline during sleep either at the minimum rate (control) or as a bolus of 22 mL/kg body weight (intervention). Participants were blinded to the intervention and crossed over to the other study arm after 1 week. Measures of heart rate variability were calculated from electrocardiography recordings presaline and postsaline infusion in the intervention arm. Heart rate variability measures computed were: standard deviation of the RR interval; root mean square of successive differences; low-frequency, high-frequency, and total power; and the ratio of low-frequency to highfrequency power. Results: Although presaline infusion values were similar, postsaline infusion values of the standard deviation of the RR interval and high-frequency power were lower in the group whose apnea-hypopnea index increased in response to saline infusion, compared to the group whose apnea-hypopnea index did not increase in response to saline infusion (P

Hypertension in pregnancy impacts ≈10% of all pregnancies.1 Hypertensive disorders of pregnancy include chronic hypertension, gestational hypertension (new-onset hypertension with blood pressure

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.

Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (−0.74, Heart rate variability (HRV) describes the individual variation in cardiac cycle duration and is a measure of vagal control of heart rate. Here, the authors identify seventeen single-nucleotide polymorphisms associated with HRV, lending new insight into the vagal regulation of heart rhythm.

Sleep-disordered breathing (SDB) occurs in approximately 50% of patients with reduced left ventricular ejection fraction receiving contemporary heart failure (HF) therapies. Obstructive (OSA) and central sleep apneas (CSA) interrupt breathing by different mechanisms but impose qualitatively similar autonomic, chemical, mechanical, and inflammatory burdens on the heart and circulation. Because contemporary evidence-based drug and device HF therapies have little or no mitigating effect on the acute or long-term consequences of such stimuli, there is a sound mechanistic rationale for targeting SDB to reduce cardiovascular event rates and prolong life. However, the promise of observational studies and randomized trials of small size and duration describing a beneficial effect of treating SDB in HF via positive airway pressure was not realized in 2 recent randomized outcome-driven trials: SAVE, which evaluated the cardiovascular effect of treating OSA in a cohort without HF, and SERVE-HF, which reported the results of a strategy of random allocation of minute-ventilation-triggered adaptive servo-ventilation (ASV) for HF patients with CSA. Whether effective treatment of either OSA or CSA improves the HF trajectory by reducing cardiovascular morbidity or mortality has yet to be definitively established. ADVENT-HF, designed to determine the effect of treating both CSA and non-sleepy OSA HF patients with a peak-airflow triggered ASV algorithm, could resolve this present clinical equipoise concerning the treatment of SDB.

Atrial mechanoreceptors, stimulated by increased pressure or volume, elicit in healthy humans a net sympathoinhibitory response. The co-existence of an atrial reflex eliciting muscle sympathoexcitation has been postulated but undetected by conventional multi-unit muscle sympathetic nerve activity (MSNA). We hypothesized that in response to a selective increase in atrial pressure, single-unit MSNA would reveal a subpopulation of efferent sympathetic neurons with firing patterns opposite to the integrated multi-unit MSNA envelope. Multi- and single-unit MSNA recordings were acquired in eight healthy middle-aged subjects (age, 57 ± 8 years; body mass index, 25 ± 2 kg/m2) submitted to selective decreases or increases in atrial pressure by nonhypotensive lower body negative pressure (LBNP; −10 mmHg) or nonhypertensive lower body positive pressure (LBPP; +10 mmHg), respectively. Single-unit MSNA firing responses were classified as anticipated if spike frequency and incidence increased with LBNP or decreased with LBPP and paradoxical if they decreased with LBNP or increased with LBPP. LBNP decreased (3.2 ± 2.8 to 1.4 ± 3.1 mmHg, P < 0.01) and LBPP increased (3.3 ± 2.7 to 4.9 ± 2.8 mmHg, P < 0.01) estimated central venous pressure without affecting stroke volume, systemic pressure, or resistance. Multi-unit MSNA increased with LBNP (31 ± 17 to 38 ± 19 bursts/min, P < 0.01) and diminished with LBPP (33 ± 15 to 28 ± 15 bursts/min, P < 0.01). Of 21 single-units identified, 76% exhibited firing responses to both LBNP and LBPP concordant with multi-unit MSNA, whereas 24% demonstrated discordant or paradoxical responses. The detection of two subpopulations of single-units within the multi-unit MSNA recording, exhibiting opposite firing characteristics, establishes the first evidence in humans for the existence of an excitatory cardiac-muscle sympathetic reflex activated by increasing atrial pressure.

The development of gestational diabetes and even milder forms of dysglycemia during pregnancy represents a maternal phenotype at increased subsequent risk for developing type 2 diabetes mellitus, metabolic syndrome, and, with time, overt cardiovascular disease. A careful and systematic dissection of the hormonal, metabolic, and vascular changes occurring in such women during pregnancy and over the postpartum years provides a unique opportunity to identify conventional and novel conditions and biomarkers whose modification may attenuate adverse long-term outcomes, particularly cardiovascular risk. The purpose of this review is to summarize current understanding of the magnitude of such risk and its potential causes, with a particular focus on postpartum alterations in endothelial and vascular smooth muscle responsiveness.

Blood pressure is a continuous, not a static, variable. Individuals exhibiting similar clinic or home blood pressure can differ considerably with respect to their average day and nighttime values, beat-by-beat blood pressure variation during wakefulness and sleep, responses to mental and physical stimuli, and intersession and seasonal variation. There now is evidence that several such representations of blood pressure variability, if augmented, increase cardiovascular risk independent of the average of conventionally acquired blood pressure readings. As well, recent retrospective analyses of published trial data have concluded that antihypertensive drug classes differ in their effects on intersession blood pressure variability and associated risk of stroke. If the goal of the hypertension community is to optimize personalized cardiovascular risk assessment and to attenuate fully such risk, future efforts should be directed at determining which representation of blood pressure variability estimates individual cardiovascular risk best, establishing "normal" and "high- risk" variability distributions, testing the hypothesis that attenuating such variability specifically through drug or device therapy reduces cardiovascular risk more than blood pressure reduction per se, and integrating such data into clinical practice.