Search

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

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

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.

Microneurographic recordings of muscle sympathetic nerve activity (MSNA) are generally analyzed over discrete epochs, usually in minutes. This is sufficient for determining resting sympathetic outflow but may obscure physiologically relevant information regarding temporal changes during an acute stress, such as exercise. To address this limitation, we applied a moving average to examine continuously the effects of one-leg cycling on MSNA in 22 participants with (n=11) and without (n=11) heart failure with reduced ejection fraction (HFrEF). MSNA burst frequency and incidence were acquired over an 8 minute period: 2 minutes of baseline, zeroload cycling, moderate intensity cycling (50% of VO2 peak), and recovery. MSNA was analyzed in 30 second epochs, advancing in five-second increments to create a 91 point overlapping moving average plot. Area under the curve analysis demonstrated that both MSNA burst frequency and incidence were higher in HFrEF than controls during zeroload and moderate intensity cycling ...

The reflex fibular muscle sympathetic nerve (MSNA) response to dynamic handgrip exercise is elicited at a lower threshold in heart failure with reduced ejection fraction (HFrEF). The present aim was to test the hypothesis that the contralateral MSNA response to mild to moderate dynamic one-legged exercise is augmented in HFrEF relative to age- and sex-matched controls. Heart rate (HR), blood pressure and MSNA were recorded in 16 patients with HFrEF (left ventricular ejection fraction = 31 ± 2%; age 62 ± 3 years, mean ± SE) and 13 healthy control subjects (56 ± 2 years) before and during 2 min of upright one-legged unloaded cycling followed by 2 min at 50% of peak oxygen uptake (). Resting HR and blood pressure were similar between groups whereas MSNA burst frequency was higher (50.0 ± 2.0 vs. 42.3 ± 2.7 bursts min−1, P = 0.03) and lower (18.0 ± 2.0 vs. 32.6 ± 2.8 ml kg−1 min−1, P

Nolan RP, Floras JS, Ahmed L, Harvey PJ, Hiscock N, Hendrickx H, Talbot D (University Health Network and University of Toronto; Women’s College Hospital, University of Toronto, Toronto, ON, Canada; and Unilever Discover, Colworth Science Park, Sharnbrook, UK). Behavioural modification of the cholinergic anti-inflammatory response to C-reactive protein in patients with hypertension. J Intern Med 2012; 272: 161–169. Objectives. A central hypothesis of the cholinergic anti-inflammatory reflex model is that innate immune activity is inhibited by the efferent vagus. We evaluated whether changes in markers of tonic or reflex vagal heart rate modulation following behavioural intervention were associated inversely with changes in high-sensitivity C-reactive protein (hsCRP) or interleukin-6 (IL-6). Design. Subjects diagnosed with hypertension (n = 45, age 35–64 years, 53% women) were randomized to an 8-week protocol of behavioural neurocardiac training (with heart rate variability biofeedback) or autogenic relaxation. Assessments before and after intervention included pro-inflammatory factors (hsCRP, IL-6), markers of vagal heart rate modulation [RR high-frequency (HF) power within 0.15–0.40 Hz, baroreflex sensitivity and RR interval], conventional measures of lipoprotein cholesterol and 24-h ambulatory systolic and diastolic blood pressure. Results. Changes in hsCRP and IL-6 were not associated with changes in lipoprotein cholesterol or blood pressure. After adjusting for anti-inflammatory drugs and confounding factors, changes in hsCRP related inversely to changes in HF power (β =−0.25±0.1, P = 0.02), baroreflex sensitivity (β = −0.33±0.7, P = 0.04) and RR interval (β = −0.001 ± 0.0004, P = 0.02). Statistically significant relationships were not observed for IL-6. Conclusions. Changes in hsCRP were consistent with the inhibitory effect of increased vagal efferent activity on pro-inflammatory factors predicted by the cholinergic anti-inflammatory reflex model. Clinical trials for patients with cardiovascular dysfunction are warranted to assess whether behavioural interventions can contribute independently to the chronic regulation of inflammatory activity and to improved clinical outcomes.

The arterial baroreflex is important for buffering blood pressure (BP) responses to stress. Whether the sensitivity of the arterial baroreflex (BRS) is associated with hemodynamic responses to ment...

Background Erectile dysfunction is common in patients with chronic heart failure and sildenafil is an effective treatment option in this population. Sildenafil has been reported to increase sympathetic outflow in normal volunteers. To date, experience with sildenafil in patients with congestive heart failure is limited and the impact of phosphodiesterase-5 inhibition on sympathetic activity in this population has not been evaluated. Methods and results 10 patients with heart failure (ejection fraction 23±3%) were studied. Generalized and cardiac sympathetic activity responses to an intravenous infusion of sildenafil were measured by the norepinephrine spillover method. In response to sildenafil, there was a significant reduction in mean pulmonary artery (− 26±5%, P

We have documented a pre-junctional beta-2 adrenoceptor mediated reduction in cardiac norepinephrine spillover (CNES) in heart failure patients receiving chronic beta-blockade. Our present objective was to ascertain the consequence of this decrease for vagal heart rate (HR) regulation by determining CNES, arterial baroreflex sensitivity for HR (BRS) and arterial baroreflex modulation of muscle sympathetic nerve activity (MSNA) before and upon 4 months of beta-blockade with either carvedilol or metoprolol. In 19 heart failure patients in sinus rhythm (age: 55+/-2 [mean+/-S.E.]; ejection fraction: 20+/-2%), beta-blockade increased BRS from 4.8+/-0.9 to 7.9+/-1.3 ms/mm Hg (P0.005) but had no effect on arterial baroreflex modulation of MSNA. Changes in CNES and BRS were inversely related (r=-0.52; n=16, P0.05). Chronic beta-blockade in heart failure augments reflex vagal control of HR at an efferent site of interaction involving blockade of cardiac sympathetic pre-junctional beta-2 adrenoceptors that facilitate NE release.

Background: Non-selective and selective β-blockers have been shown to improve outcomes in chronic heart failure (CHF). Recent data suggests the non-selective β-blockers have a more favourable effect on outcomes than β1-selective agents. We sought to examine the differential effects of non-selective versus selective β-blockade on myocardial substrate utilization in patients with CHF. Methods and results: Twenty-two patients with CHF were randomised to the non-selective β-blocker carvedilol or the selective β-blocker metoprolol (double-blind). Measurement of hemodynamics, arterial and coronary sinus free fatty acid (FFA) and lactate levels, and cardiac norepinephrine spillover (CANESP) were made before and after 4 months of therapy. In the carvedilol group (n=11), there was a significant reduction in myocardial FFA uptake (0.12±0.02 to 0.1±0.02 mmol/l, P

Nocturnal hemodialysis (NHD)[8 hrs, 6/week] is a novel renal replacement therapy that lowers daytime blood pressure and plasma norepinephrine and corrects uremic related sleep apnea. Our aim was to test the hypothesis that NHD would lower sympathetic modulation of sino-atrial node discharge during sleep as assessed by power spectral analysis of heart rate variability (HRV). We conducted a case-control study comprising 9 patients (age: 44 ± 2)[mean ± SEM] before and after conversion from conventional hemodialysis (CHD)[4 hrs,3/week] to NHD and 10 normal subjects (age: 45 ± 3). Overnight polysomnography was used to assess heart rate, sleep stages and episodes of apnea and hypopnea per hour of sleep. Fast Fourier transformation was employed to compute frequency domain analysis of HRV (low frequency (LF)[0.05–0.15Hz] and high frequency (HF)[0.15–0.5Hz] power) during stage 2 non rapid eye movement sleep. LF/LF + HF, HF/HF + LF and LF/HF were used to estimate sympathetic and vagal modulation of heart rate and their ratio respectively. While on CHD, each subject was examined twice (1 day prior to and same night of CHD session). After conversion to NHD, each patient was studied once, on a non-dialysis night. Frequency of apnea and hypopnea decreased significantly after conversion from CHD to NHD (from 29.2 ± 9.9 to 7.2 ± 3.3 episodes per hour, p = 0.04). Subjects RR interval (ms) HF LF/HF+LF HF/HF+LF LF/HF a:p

In light of the known modulatory effects of estrogen on neurohumoral control of blood pressure (BP), we tested the hypothesis that muscle sympathetic nerve activity (MSNA) and serum renin angiotensin aldosterone system (RAAS) levels would differ between estrogen deficient physically active women with functional hypothalamic amenorrhea (ExFHA) and eumenorrheic estrogen replete women. MSNA, serum RAAS components (renin, angiotensin II and aldosterone), and brachial artery BP (mmHg) were recorded at baseline and during graded lower body negative pressure (LBNP; -10, -20, and -40mmHg) in 17 recreationally active eumenorrheic women (ExOv; 24±1 years; body mass index 20.9±0.5kg/m2; mean±SEM) and 12 ExFHA women (25±1 years; 20.7±0.7 kg/m2). At baseline, heart rate (HR; b/min) and systolic BP (SBP) were lower (p0.05) between the groups. In response to graded LBNP, HR was increased (p

We read with interest the recent work of Fisher et al. (2010), who demonstrated, in healthy young men, that muscle metaboreflex-induced sympathetic excitation contributes to the heart rate response to ischaemic handgrip exercise in a graded manner. This effect, masked at lower intensity of exercise by parasympathetic reactivation at the cessation of handgrip, was unmasked by glycopyrrolate during post-handgrip ischaemia, which prolongs metaboreflex stimulation of muscle afferents independently of central command and muscle mechanoreflex influences, and abolished by β-blockade. The authors interpret their findings as indicating that heart rate returns to resting values during ischaemia after moderate exercise because of an overwhelming effect of parasympathetic reactivation, which counters metaboreflex increases in cardiac sympathetic activity. However, after more intense handgrip, cardiac sympathetic activity predominates and the impact of parasympathetic restoration is less obvious. Although this concept has been supported by animal work (O’Leary, 1993), it has not been investigated directly in humans as in the present study (Fisher et al. 2010). Fisher et al. (2010) speculate that in the absence of parasympathetic reactivation, increased cardiac sympathetic nerve activity should delay the post-exercise recovery of heart rate and propose heart failure, which is characterized by augmented cardiac sympathetic activation and diminished cardiac vagal heart rate modulation (Floras, 2009), as an important clinical condition where this independent predictor of mortality (Cole et al. 1999) may be particularly evident. Our own studies of post-handgrip ischaemia provide independent validation of the mechanism tested by Fisher which is of potential concern in heart failure. Our principal findings were: first, that in heart failure the muscle metaboreflex elicits a greater increase in muscle sympathetic nerve activity during ischaemic or intense non-ischaemic handgrip exercise than in age-matched healthy controls; second, that this excitatory reflex response occurs at a lower threshold in heart failure than in healthy subjects; and third, that the magnitude of this effect is a function of exercise capacity (Notarius et al. 2001). Importantly, unlike the young men studied by Fisher et al. (2010), in our series all subjects were of middle age. As we commented upon in the Discussion in our paper, in contrast to the lower intensities of dynamic handgrip (10% and 30% MVC), heart rate did not return to baseline in these heart failure patients after ischaemic (30% MVC) and intense non-ischaemic (50% MVC) handgrip exercise. A graded response to ischaemic and non-ischaemic handgrip also was observed in simultaneously acquired microneurographic recordings of sympathetic nerve traffic directed at calf skeletal muscle. Our findings are therefore consistent with Fisher's hypothesis that diminished vagal drive in heart failure may be insufficient to counter the cardiac sympathetic excitatory response to metaboreflex stimulation once exercise ceases. Together, these clinical and experimental studies (O’Leary, 1993; Notarius et al. 2001; Fisher et al. 2010) offer compelling evidence in favour of a role for the muscle metaboreflex in stimulating the accelerated heart rate response to ischaemic handgrip exercise and intense dynamic exercise, and suggest that this mechanism may be of particular clinical relevance in conditions such as heart failure (Floras, 2009) or hypertension (Esler, 2010) that exhibit cardiac sympathetic excitation and blunted parasympathetic tone.

Hyperphosphatemia and poor uremia control are established cardiovascular risk factors in patients with end-stage renal disease (ESRD) associated with impaired endothelial dependent and independent vasodilation (EDV and EIV). Nocturnal hemodialysis [6 × 8 h/week] augments dialysis dose and offers normal phosphate (Pi) balance. We hypothesized that NHD would restore EDV (endothelial function) and EIV (vascular smooth muscle cell function) by simultaneously improving uremia and Pi control. 2 groups of ESRD patients (mean age 41 ± 2 years) stratified according to their baseline plasma Pi levels (normal Pi 1.8 mM) were studied. Dialysis dose (Kt/V per session), plasma Pi, blood pressure (BP) and brachial artery responses to reactive hyperemia (EDV), and sublingual nitroglycerin (EIV) were examined before, 1 and 2 months after conversion from conventional hemodialysis (CHD) [3 × 4 h/week] to NHD. After 2 months, NHD increased dialysis dose (from 1.24 ± 0.06 to 2.04 ± 0.08; p = 0.02) and lowered BP (from 140 ± 5/82 ± 3 to 119 ± 1/71 ± 3, p = 0.01) in all patients. In patients with adequate Pi control during CHD, EDV was normalized after 1 month of NHD. In contrast, in the high Pi group, 1 month of NHD was sufficient to reduce plasma phosphate levels, but 2 months of NHD was required for EDV to improve. Variables Normal Pi (n=10) CHD NHD (1month) NHD (2months) High Pi (n=8) CHD NHD (1month) NHD (2 months) * p

Vasopressin facilitates the baroreflex control of the circulation. The peptide may act at several sites to augment the baroreflex. In this study we examined the effect of vasopressin on aortic baroreceptors in anaesthetized rabbits and on left ventricular mechanoreceptors in anaesthetized cats. Vasopressin (16 mu./kg. min) did not change resting nerve discharge in single fibres from aortic baroreceptors. Vasopressin (16 mu./kg. min) significantly enhanced the response of single aortic nerve fibre discharge to elevation in arterial pressure. The slope relating nerve activity to mean arterial pressure increased from 0.24 +/- 0.05 (mean +/- S.E. of mean) to 0.50 +/- 0.16 impulses/cardiac cycle. mmHg (P less than 0.05) in ten aortic medullated fibres and from 0.06 +/- 0.03 to 0.18 +/- 0.04 impulses/cardiac cycle. mmHg (P less than 0.05) in three non-medullated fibres. Vasopressin (16 mu./kg. min) did not change resting nerve discharge in single fibres from left ventricular mechanoreceptors. Vasopressin (16 mu./kg. min) significantly enhanced the response of single nerve fibre discharge from left ventricular mechanoreceptors in response to elevation of left ventricular end-diastolic pressure. The slope relating nerve activity to left ventricular end-diastolic pressure increased from 0.24 +/- 0.07 to 0.32 +/- 0.07 impulses/cardiac cycle. mmHg (P less than 0.05) in six medullated fibres and from 0.10 +/- 0.01 to 0.15 +/- 0.02 impulses/cardiac cycle. mmHg (P less than 0.05) in four non-medullated fibres. These data show that vasopressin sensitizes high and low pressure baroreceptors and suggest a mechanism by which vasopressin may facilitate the baroreflex control of the circulation.