Attenuated Heart Rate Response Research Articles

Chronotropic Incompetence During Exercise Testing as a Marker of Autonomic Dysfunction in Individuals with Early Parkinson's Disease.

An attenuated heart rate response to exercise, termed chronotropic incompetence, has been reported in Parkinson's disease (PD). Chronotropic incompetence may be a marker of autonomic dysfunction and a cause of exercise intolerance in early stages of PD. To investigate the relationship between chronotropic incompetence, orthostatic blood pressure change (supine - standing), and exercise performance (maximal oxygen consumption, VO2peak) in individuals with early PD within 5 years of diagnosis not on dopaminergic medications. We performed secondary analyses of heart rate and blood pressure data from the Study in Parkinson's Disease of Exercise (SPARX). 128 individuals were enrolled into SPARX (63.7±9.3 years; 57.0% male, 0.4 years since diagnosis [median]). 103 individuals were not taking chronotropic medications, of which 90 had a normal maximal heart rate response to exercise testing (155.3±14.0 bpm; PDnon-chrono) and 13 showed evidence of chronotropic incompetence (121.3±11.3 bpm; PDchrono, p < 0.05). PDchrono had decreased VO2peak compared to PDnon-chrono (19.7±4.5 mL/kg/min and 24.3±5.8 mL/kg/min, respectively, p = 0.027). There was a positive correlation between peak heart rate during exercise and the change in systolic blood pressure from supine to standing (r = 0.365, p < 0.001). A subgroup of individuals with early PD not on dopaminergic medication had chronotropic incompetence and decreased VO2peak, which may be related to autonomic dysfunction. Evaluation of both heart rate responses to incremental exercise and orthostatic vital signs may serve as biomarkers of early autonomic impairment and guide treatment. Further studies should investigate whether cardiovascular autonomic dysfunction affects the ability to exercise and whether exercise training improves autonomic dysfunction.

Cardiometabolic Effects of DOCA-Salt in Mice Dependent on Ambient Temperature.

Mice prefer warmer environments than humans. For this reason, behavioral and physiological thermoregulatory responses are engaged by mice in response to a standard room temperature of 22 to 24 °C. Autonomic mechanisms mediating thermoregulatory responses overlap with mechanisms activated in hypertension, and, therefore, we hypothesized that housing at thermoneutral temperatures (TNs; 30 °C) would modify the cardiometabolic effects of deoxycorticosterone acetate (DOCA)-salt in mice. The effects of DOCA-salt treatment upon ingestive behaviors, energy expenditure, blood pressure, heart rate (HR), and core temperature were assessed in C57BL/6J mice housed at room temperature or TN. Housing at TN reduced food intake, energy expenditure, blood pressure, and HR and attenuated HR responses to acute autonomic blockade by chlorisondamine. At room temperature, DOCA-salt caused expected increases in fluid intake, sodium retention in osmotically inactive pools, blood pressure, core temperature, and also caused expected decreases in fat-free mass, total body water, and HR. At TN, the effects of DOCA-salt upon fluid intake, fat gains, hydration, and core temperature were exaggerated, but effects on energy expenditure and HR were blunted. Effects of DOCA-salt upon blood pressure were similar for 3 weeks and exaggerated by TN housing in the fourth week. Ambient temperature robustly influences behavioral and physiological functions in mice, including metabolic and cardiovascular phenotype development in response to DOCA-salt treatment. Studying cardiometabolic responses of mice at optimal ambient temperatures promises to improve the translational relevance of rodent models.

Cardiac baroreflex sensitivity and heart rate variability are lower in humans with high affinity hemoglobin compared to typical affinity hemoglobin

BackgroundHumans with high O2 affinity hemoglobin (HAH) have a markedly lower partial pressure of O2at which 50% of hemoglobin is saturated (P50) and a leftward shift of the oxy‐hemoglobin dissociation curve. Humans with HAH have attenuated heart rate responses during both acute and chronic hypoxic exposure relative to humans with typical P50. Despite the attenuated heart rate responses to hypoxia, there are typically no blood pressure differences found in humans with HAH relative to humans with typical P50. Due to the blunted heart rate and normal blood pressure responses to hypoxia in humans with HAH, this study aimed to investigate the impact of HAH on cardiac autonomic function during normoxia and hypoxia. We hypothesized that humans with HAH would have lower cardiac baroreflex sensitivity (cBRS) and heart rate variability (HRV) during normoxia and hypoxia relative to individuals with typical P50.MethodsNine humans with a HAH mutation (6 female, Age: 40±12yrs, P50: 16±1 mmHg) and 12 controls with typical affinity hemoglobin (6 female, Age: 40±10yrs, P50: 26±1 mmHg) laid supine for 10‐minutes prior to 20‐minutes of isocapnic hypoxia, titrated to reduce arterial O2 pressure to ~50 mmHg (Avg. FiO2 = 11.9±0.0%). Beat‐to‐beat arterial pressures (arterial catheter) and heart rate (electrocardiogram) were continuously recorded. Data were averaged in five‐minute segments starting with the last five minutes of supine normoxic rest. Spontaneous cBRS was quantified using the sequence method. HRV was measured in time and frequency domains. Standard deviation of the RR interval (SDRR) was calculated as the standard deviation of all RR intervals in a data segment. Low frequency (LF) HRV was calculated using Fast Fourier Transformation and assessed as absolute spectral intensity in the LF band (0.04‐0.15Hz).ResultsArterial oxygen (PaO2) and carbon dioxide (PaCO2) pressures were not different between humans with HAH and controls during normoxia or isocapnic hypoxia [PaO2: (HAH vs. Control): 48±3 vs. 47±2 mmHg, p=0.612; PaCO2: (HAH vs. Control): 40±3 vs. 39±1 mmHg, p=0.328] exposure. cBRS was lower in humans with HAH compared to controls in normoxia and throughout isocapnic hypoxia [normoxia (HAH vs. Control): 7±4 vs. 16±10 ms/mmHg; hypoxia minutes 15‐20 (HAH vs. Control): 4±3 vs. 14±11 ms/mmHg; Hb type, p=0.024]. Several metrics of HRV were lower in humans with HAH relative to control (SDRR: Hb type, p≤0.001; LF: Hb type, p=0.030) and HRV was blunted to a similar extent in both groups with hypoxia (SDRR: time effect, p=0.009).ConclusionThe findings of this study are twofold. Compared to controls, humans with HAH have: 1) attenuated cardiac baroreflex sensitivity and 2) lower heart rate variability in both normoxia and isocapnic hypoxia.

Transcutaneous vagus nerve stimulation attenuates autoantibody-mediated cardiovagal dysfunction and inflammation in a rabbit model of postural tachycardia syndrome.

Previous studies demonstrated M2 muscarinic acetylcholine receptor-activating autoantibodies (M2R-AAb) were present in some patients with postural tachycardia syndrome (POTS). This study examines how these autoantibodies might contribute to the pathophysiology of POTS, and whether low-level tragus stimulation (LLTS) can ameliorate autoantibody-mediated autonomic dysregulation in the rabbit. Five New Zealand white rabbits were immunized with a M2R second extracellular loop peptide to produce cholinomimetic M2R-AAb. Tilt test and infusion studies were performed on conscious rabbits before immunization, 6weeks after immunization, and 8weeks after immunization with 2-week daily LLTS treatment. Each rabbit served as its own control. Compared to preimmune state, an enhanced heart rate increase and decreased parasympathetic activity upon tilting were observed in immunized rabbits. Furthermore, these rabbits demonstrated an attenuated heart rate-slowing response to infusion of the M2R orthosteric agonist arecaidine propargyl ester (APE), suggesting an inhibitory allosteric effect of M2R-AAb. There was also a significant increase in serum inflammatory cytokines in immunized rabbits. LLTS treatment suppressed the postural tachycardia, improved the sympathovagal balance with increased acetylcholine secretion, reduced the levels of inflammatory cytokines, and reversed the attenuated heart rate response to APE in immunized rabbits. No suppression of M2R-AAb expression by LLTS was found during this short-term study period. Receptor-modulating activity of M2R-AAb produced in immunized rabbits was confirmed with in vitro bioassay. Autoantibody inhibition of cholinergic ligand activity may be involved in the development of cardiovagal dysfunction and inflammation associated with POTS, both of which can be improved by vagal stimulation.

Frailty is associated with impaired cerebral oxygenation recovery during

Abstract Frailty is associated with impaired peripheral circulatory responses to standing in older adults. However, little is known about how frailty affects cerebrovascular function during such activities of daily living. Here we investigate the association between frailty and cerebral oxygenation during standing in a large clinical cohort of fallers and fainters. Participants were recruited from a national Falls and Syncope unit and underwent an active stand test (5–10 minutes lying supine, 3 minutes standing) with concurrent monitoring of continuous blood pressure (BP) and heart rate (HR) and tissue saturation index (TSI) using near-infrared spectroscopy (NIRS). Frailty was measured using a count of deficits (27 morbidities). Robust linear regression was applied to study the association between features of dynamic cerebral oxygenation (changes from baseline at nadir, overshoot, 30s and steady state; and recovery rate) and frailty while correcting for covariates. A p-value &amp;lt;0.05 was considered significant. Frailty was associated with deficits in TSI at 30s after standing (β: −0.165, CI: (−0.261, −0.069), p=0.005), as well as a lower diastolic BP at 30s (β: −1.346, CI: (−2.287, −0.405), p=0.032) and standing steady-state (β: −1.182, CI: (−2.038, −0.325), p=0.032). When stratified by gender, frailty was associated in women with a lower TSI at overshoot (β: −0.174, CI: (−0.312, −0.037), p=0.043) and 30s (β: −0.216 (−0.344, −0.089), p=0.010), and impaired DBP recovery at overshoot (β: −1.623, CI: (−2.865, −0.391), p=0.045) and attenuated HR response at 30s (β: −0.701, CI: (−1.246, −0.155), p=0.036). No associations were found in men. Impaired cerebral oxygenation and BP responses to standing are associated with frailty in patients with falls and syncope, with stronger effects in women, suggesting that frailty may increase risk of hypoperfusion and consequent syncope, falls, and brain ageing. Our results demonstrate the clinical utility and feasibility of using NIRS in this context which can be used to further personalise patient management. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Irish Research Council Cerebral oxygenation and frailty

Tibetans at intermediate altitude exhibit lower hemoglobin concentration and distinct responses to poikilocapnic hypoxia relative to Han Chinese residents

People with high-altitude ancestry exhibit distinct cellular, respiratory, and cardiovascular adaptive phenotypes relative to individuals with lowland ancestry. For example, Tibetans at high altitude exhibit higher ventilatory responses to hypoxia relative to Han Chinese at comparable altitude. We hypothesize Tibetans living at intermediate altitude maintain responses similar to those at high altitude. We measured levels of total hemoglobin ([Hb]), carboxyhemoglobin saturation (SpCO), and methemoglobin (MetHb), as well as the hypoxic and heart rate responses to acute hypoxia (HVR and HHR, respectively) under isocapnic and poikilocapnic conditions, in 21 individuals of Tibetan (n = 21) and Han Chinese (n = 16) ancestry residing at ~1300 m (~4327 ft) in Salt Lake City, Utah. To study ventilatory and heart rate responses to changes of CO2 during hypoxia (ΔVI /ΔEtCO2 and ΔHR/ΔEtCO2 respectively), we measured the difference in ventilation and heart rate between isocapnic (constant End-tidal CO2) and poikilocapnic (with decreased End-tidal CO2 due to hyperventilation) hypoxic conditions. Tibetans had lower [Hb] (p < 0.002), higher SpCO (p < 0.004), and higher MetHb (p < 0.02) levels compared to Han Chinese. [Hb] is negatively correlated with HHR in the Han Chinese (p < 0.05), but this was not observed in Tibetans. We did not find significant differences in HVR between Tibetans and Han Chinese, in contrast to previous reports at high altitude; however, we found that Tibetans exhibited a blunted HHR during poikilocapnic hypoxia (p < 0.03) relative to Han Chinese. We did not find differences in the ΔVI /ΔEtCO2 between the two groups, but Tibetans had lower ΔHR/ΔEtCO2 with more negative values compared to Han Chinese (p < 0.01). We also found that the correlation between HVR and HHR is similar for both groups during isocapnia, but the slopes of these correlations are significantly different in poikilocapnia (p < 0.003) with a positive relationship observed only in Tibetans (p < 0.006). Our results show that, at intermediate altitude, individuals with Tibetan ancestry have lower levels of [Hb], higher levels of Hb metabolites, and exhibit an attenuated heart rate response to hypoxia. The correlation between ventilatory and heart rate responses to hypoxia is similar between groups during isocapnia but is decreased during poikilocapnic hypoxia (with lower levels of CO2 due to hyperventilation) in Han Chinese but not Tibetans, suggesting a CO2-dependent effect on HR in Han Chinese but not in Tibetans. Therefore, Hb levels and metabolism but not the HVR to hypoxia may be maintained in individuals with Tibetan ancestry at intermediate altitudes. Correlations in poikilocapnic vs. isocapnic hypoxia may suggest an attenuated effect of CO2 on heart rate during hypoxia in people with Tibetan ancestry.

Tibetans resident at intermediate altitude (1300 m, 4327 ft) show similar hypoxic ventilatory responses but blunted heart rate responses to poikilocapnic hypoxia

Population living at high altitudes for hundreds of generations exhibit distinct respiratory and cardiovascular responses to hypoxia relative to other populations. The extent of these differences at intermediate altitude is less understood and could provide important insight into ancestry specific physiological responses in the absence of hypoxia. We hypothesized that Tibetans living at intermediate altitude (1300 m, 4327 ft) exhibit an increased hypoxic ventilatory response (HVR) and an elevated hypoxic heart rate response (HHR) compared to Han Chinese examined at the same altitude. To estimate O2 sensitivity, we measured ventilation (VI), heart rate (HR) and O2 saturation (Sat) under hyperoxic conditions (30% O2) and then during a hypoxic stimulus (10% minimum desaturation) keeping end‐tidal CO2 (EtCO2) levels constant (isocapnia) or allowing changes in the EtCO2 (poikilocapnia). We quantified HVR and HHR as change in VI and HR between hyperoxia and hypoxia standardized per the change in O2 Sat (ΔVI/ΔSat and ΔHR/ΔSat respectively). To estimate CO2 sensitivity, we measured changes in VI and HR responses between poikilocapnic and isocapnic hypoxia and standardized these changes per change in EtCO2 (ΔVI/ΔEtCO2 and ΔHR/ΔEtCO2 respectively). We did not find significant differences in ΔVI/ΔSat and ΔVI/ΔEtCO2 between Tibetan and Han Chinese during isocapnic and poikilocapnic hypoxia. The ΔHR/ΔSat between populations during isocapnic hypoxia was also not significantly different. However, Tibetans exhibited a blunted ΔHR/ΔSat during poikilocapnic hypoxia compared to Han Chinese (35.8% decrease, p &lt; 0.02) with a significant ancestry effect in women (37.6% decrease, p &lt; 0.009). The mean value of ΔHR/ΔEtCO2 was positive in the Han Chinese group but negative in Tibetan (169% difference, p &lt; 0.02), indicating that Tibetans had a blunted HR response when CO2 is not controlled. Our results show that HVR responses in Tibetan individuals with high‐altitude ancestry is not different than Han Chinese residents at comparable intermediate altitude, but the HHR to hypoxia during poikilocapnia is blunted in individuals with Tibetan ancestry. These results suggest that, at intermediate altitude, individuals with Tibetan ancestry exhibit an attenuated heart rate response to hypoxia due to an increased contribution of the CO2 chemosensory response.Support or Funding InformationSupported by NIH 1RO1HL145470 and R01 HL‐081823.

Spinal Cord Injury Impairs Cardiovascular Capacity in Elite Wheelchair Rugby Athletes.

To examine differences in heart rate (HR) responses during international wheelchair rugby competition between athletes with and without a cervical spinal cord injury (SCI) and across standardized sport classifications. Observational study. The 2015 Parapan American Games wheelchair rugby competition. Forty-three male athletes (31 ± 8 years) with a cervical SCI (n = 32) or tetraequivalent impairment (non-SCI, n = 11). Average and peak HR (HRavg and HRpeak, respectively). To characterize HR responses in accordance with an athletes' International Wheelchair Rugby Federation (IWRF) classification, we separated athletes into 3 groups: group I (IWRF classification 0.5-1.5, n = 15); group II (IWRF classification 2.0, n = 15); and group III (IWRF classification 2.5-3.5, n = 13). Athletes with SCI had lower HRavg (111 ± 14 bpm vs 155 ± 13 bpm) and HRpeak (133 ± 12 bpm vs 178 ± 13 bpm) compared with non-SCI (both P < 0.001). Average HR was higher in group III than in I (136 ± 25 bpm vs 115 ± 20 bpm, P = 0.045); however, SCI athletes showed no difference in HRavg or HRpeak between groups. Within group III, SCI athletes had lower HRavg (115 ± 6 bpm vs 160 ± 8 bpm) and HRpeak (135 ± 11 bpm vs 183 ± 11 bpm) than non-SCI athletes (both P < 0.001). This study is the first to demonstrate attenuated HR responses during competition in SCI compared with non-SCI athletes, likely due to injury to spinal autonomic pathways. Among athletes with SCI, IWRF classification was not related to differences in HR. Specific assessment of autonomic function after SCI may be able to predict HR during competition and consideration of autonomic impairments may improve the classification process.

Interleukin-10 treatment attenuates sinus node dysfunction caused by streptozotocin-induced hyperglycaemia in mice

Diabetes, characterized by hyperglycaemia, causes sinus node dysfunction (SND) in several rodent models. Interleukin (IL)-10, which is a potent anti-inflammatory cytokine, has been reported to decrease in obese and diabetic patients. We tested the hypothesis that administration of IL-10 inhibits the development of SND caused by hyperglycaemia in streptozotocin (STZ)-induced diabetic mice. Six-week old CL57/B6 (WT) mice were divided into the following groups: control, STZ injection, and STZ injection with systemic administration of IL-10. IL-10 knockout mice were similarly treated. STZ-induced hyperglycaemia for 8 weeks significantly depressed serum levels of IL-10, but increased several proinflammatory cytokines in WT mice. STZ-induced hyperglycaemia-reduced resting heart rate (HR), and attenuated HR response to isoproterenol in WT mice. In isolated perfused heart experiments, corrected-sinus node recovery time was prolonged in WT mice with STZ injection. Sinus node tissue isolated from the WT-STZ group showed fibrosis, abundant infiltration of macrophages, increased production of reactive oxygen species (ROS), and depressed hyperpolarization activated cyclic nucleotide-gated potassium channel 4 (HCN4). However, the changes observed in the WT-STZ group were significantly attenuated by IL-10 administration and were further exaggerated in IL-10 knockout mice. In cultured cells, preincubation of IL-10 suppressed hyperglycaemia-induced apoptotic and profibrotic signals, and overproduction of ROS. IL-10 markedly inhibited the high glucose-induced p38 activation, and activated signal transducer and activator of transcription (STAT) 3 phosphorylation. Our results suggest that IL-10 attenuates ROS production, inflammation and fibrosis, and plays an important role in the inhibition of hyperglycaemia-induced SND by suppression of HCN4 downregulation. In addition, IL-10-mediated inhibition of p38 is dependent on STAT3 phosphorylation.

Mineralocorticoid receptor antagonists attenuate exaggerated exercise pressor reflex responses in hypertensive rats.

Exaggerated heart rate (HR) and blood pressure responses to exercise in hypertension are mediated, in part, by overactivity of the exercise pressor reflex (EPR). The mechanisms underlying this EPR dysfunction have not been fully elucidated. Previous studies have shown that stimulation of mineralocorticoid receptors (MRs) with exogenous administration of aldosterone in normal, healthy rats reproduces the EPR overactivity characteristic of hypertensive animals. Conversely, the purpose of this study was to examine whether antagonizing MR with spironolactone (SPIR) or eplerenone (EPL) in decerebrated hypertensive rats ameliorates abnormal EPR function. Changes in mean arterial pressure (MAP) and HR induced by EPR or muscle mechanoreflex (a component of EPR) activation were assessed in normotensive Wistar-Kyoto rats and spontaneously hypertensive rats (SHRs) fed normal chow (NC) or a customized diet containing either SPIR or EPL for 3 wk. SHRs treated with SPIR or EPL had significantly attenuated MAP responses to EPR (NC: 45 ± 7 mmHg, SPIR: 26 ± 4 mmHg, and EPL: 24 ± 5 mmHg, P = 0.02) and mechanoreflex (NC: 34 ± 9 mmHg, SPIR: 17 ± 3 mmHg, and EPL: 15 ± 3 mmHg, P = 0.03) activation. SHRs treated with SPIR or EPL also showed significantly attenuated HR responses to EPR (NC: 17 ± 3 beats/min, SPIR: 9 ± 1 beats/min, and EPL: 9 ± 2 beats/min, P = 0.01) and mechanoreflex (NC: 15 ± 3 beats/min, SPIR: 6 ± 1 beats/min, and EPL: 7 ± 1 beats/min, P = 0.01) activation. Wistar-Kyoto rats treated with SPIR did not demonstrate significant differences in MAP or HR responses to EPR or mechanoreflex activation. The data suggest that antagonizing MRs may be an effective strategy for the treatment of EPR overactivity in hypertension.NEW & NOTEWORTHY Exaggerated cardiovascular responses to exercise in hypertensive patients are linked with overactive exercise pressor reflexes (EPRs). Administration of low-dose mineralocorticoid receptor antagonists (spironolactone or eplerenone) effectively ameliorates abnormal EPR function in hypertension. Effective treatment of EPR overactivity may reduce the cardiovascular risks associated with physical activity in hypertension.

Dual-task performance under acute stress in female adolescents with borderline personality disorder.

Research to elucidate early alterations of higher cognitive processes in adolescents with BPD is rare. This study investigated differences in dual-task performance in adolescents with BPD during stress and non-stress conditions. The study sample comprised 30 female adolescents with BPD and 34 healthy controls. The impact of stress on dual-task performance was measured using a standardized stressor. Self-reports of distress and measures of heart rate (HR) were obtained to measure stress reactivity. There were no group differences in task performance. Under stress conditions, the performance on the auditory task decreased in both groups but without significant group differences. Healthy controls showed an increase of mean HR after stress induction compared to no change in the BPD group. The finding of attenuated HR response to acute stress in adolescent patients with BPD may contradict current theories that the affective hyperresponsivity in BPD is based on a biologically determined mechanism.

Reduced high intensity training distance had no effect on VLa4 but attenuated heart rate response in 2-3-year-old Standardbred horses.

BackgroundTraining of Standardbred race horses aims to improve cardiovascular and metabolic functions but studies on the effects of different training strategies from breaking till racing are lacking. Sixteen horses with the goal to race as 3-year-olds were studied from breaking (1-year-olds) to December as 3-year-olds. Horses were allocated to either a control (C) or reduced (R) training program from 2 years of age. The aim was to evaluate the effect of reducing the distance of high intensity exercise by 30% with respect to velocity at lactate concentration 4 mmol/l (VLa4), blood lactate and cardiovascular response. All training sessions were documented and heart rate (HR) was recorded. A standardized exercise test of 1,600 m was performed 10 times and a VLa4 test was performed five times.ResultsC horses initially exercised for a longer time with a HR >180 beats per minute compared to R horses (P < 0.05) but after 6–9 months, time with HR >180 bpm decreased in C and were similar in the two groups (P > 0.05). Over the 2-year period, recovery HR after the 1,600 m-test decreased in both groups but was within 2 months lower in C than in R (P < 0.05). C horses also had lower resting HR as 3-year-olds (P < 0.01) than R horses. In C, post exercise hematocrit was higher than in R (P < 0.05). There was a tendency (P < 0.1) towards a larger aortic diameter in C as 3-year-olds (C: 1.75 ± 0.05, R: 1.70 ± 0.05 cm/100 kg BW). Left ventricle diameter and blood volume (in December as 2-year-olds) did not differ between groups. There were no differences between groups in post exercise blood lactate concentration or in VLa4. Both groups were equally successful in reaching the goal of participation in races.ConclusionsHorses subjected to a reduced distance of high intensity training from the age of 2 showed an attenuated heart rate response, but were able to maintain the same VLa4 and race participation as horses subjected to longer training distances.

Relationship between chronotropic incompetence and β-blockers based on changes in chronotropic response during cardiopulmonary exercise testing

BackgroundChronotropic incompetence (CI), an attenuated heart rate (HR) response to exercise, is common in patients with cardiovascular disease. The aim of this study was to assess changes in the chronotropic response (CR) during cardiopulmonary exercise testing (CPET) in patients undergoing cardiac rehabilitation and investigate the effects of β-blockers. MethodsPatients undergoing cardiac rehabilitation performed CPET. Failure to achieve 80% of the age-predicted maximal HR (APMHR) defined CI. Values of the metabolic chronotropic relationship (MCR) were calculated from the ratio of the HR reserve to metabolic reserve at 4 stages, warm-up (MCR-Wu), anaerobic threshold (MCR-AT), respiratory compensation (MCR-Rc), and peak point (MCR-Pk), using the Wilkoff model. In patients who showed an increase in MCR at ≥3 of the 4 exercise stages, CR was considered to have improved. ResultsPatients with high BNP levels (≥80pg/ml) had a lower MCR at all stages compared with those with low BNP levels (<80pg/ml). Of the 80 patients, 47 showed an increase in both peak VO2 and AT, and of these 31 (66.0%) were taking β-blockers. Improvement in CR was observed in 30 of 47 patients with CI, and 70% of these were taking β-blockers. In patients not taking β-blockers, MCR-AT was lower than MCR-Rc, whereas in those taking β-blockers MCR-AT was higher than MCR-Rc. ConclusionsAn attenuated HR response may occur during the early stages of exercise. The HR response according to the presence or absence of β-blockers is clearly identifiable by comparing MCR-AT and MCR-Rc using the Wilkoff model.

Effect of DOCA/salt hypertension on CRF expression in the amygdala and the autonomic stress response in conscious rats.

The effects of DOCA/salt treatment on amygdala-area CRF gene expression and the autonomic response to air jet stress (AJS) were evaluated in conscious male Sprague Dawley (SD) rats. Fifteen days of DOCA/salt treatment significantly increased resting arterial pressure (AP), decreased resting heart rate (HR) and significantly reduced regional CRF mRNA compared to controls (23±7% vs. 100±26%) independent of changes in regional CRF receptor expression. Twenty min of AJS elicited a rise in AP (~15mmHg) that was similar in both DOCA/salt animals (n=11) and controls (n=6). Alternatively, increases in HR were significantly different in the DOCA/salt animals compared to controls; including one group of DOCA/salt animals (n=5) which responded with an attenuated HR response at the onset of AJS (low-responders) and a second group (n=6) which demonstrated an elevated HR response to AJS (high-responders), specifically during the last 10min of AJS. The divergent HR responses to AJS in the DOCA/salt animals were linked to differences in resting heart rate variability. During recovery HR returned to baseline within 10min in both control and the low responder DOCA group but indicators of spontaneous baroreflex gain only increased significantly in controls. HR in the high-responder DOCA animals did not return to baseline during the same period. These results show that DOCA/salt treatment triggers downregulation of CRF gene expression in the region of the amygdala and significantly alters the HR response to acute stress but does not alter the pressor response to stress compared to normotensive controls.

Assessing cerebrovascular autoregulation from critical closing pressure and resistance area product during upright posture in aging and hypertension.

Static cerebral autoregulation (sCA) is believed to be resistant to aging and hypertensive pathology. However, methods to characterize autoregulation commonly rely on beat-by-beat mean hemodynamic measures and do not consider within-beat pulse wave characteristics that are impacted by arterial stiffening. We examined the role of critical closing pressure (CrCP) and resistance area product (RAP), two measures derived from the pulse wave, across supine lying, sitting, and standing postures in young adults, normotensive older adults, and older adults with controlled and uncontrolled hypertension (N = 80). Traditional measures of sCA, using both intracranial and extracranial methods, indicated similar efficiency across all groups, but within-beat measures suggested different mechanisms of regulation. At rest, RAP was increased in hypertension compared with young adults (P < 0.001), but CrCP was similar. In contrast, the drop in CrCP was the primary regulator of change in cerebrovascular resistance upon adopting an upright posture. Both CrCP and RAP demonstrated group-by-posture interaction effects (P < 0.05), with older hypertensive adults exhibiting a rise in RAP that was absent in other groups. The posture-related swings in CrCP and RAP were related to changes in both the pulsatile and mean components of arterial pressure, independent of age, cardiac output, and carbon dioxide. Group-by-posture differences in pulse pressure were mediated in part by an attenuated heart rate response in older hypertensive adults (P = 0.002). Examination of pulsatile measures in young, elderly, and hypertensive adults identified unique differences in how cerebral blood flow is regulated in upright posture.

Effect of Mildly Attenuated Heart Rate Response During Treadmill Exercise Testing on Cardiovascular Outcome in Healthy Men and Women

Attenuated heart rate (HR) response during exercise is associated with adverse cardiovascular outcome. The acceptable value for HR response is 85% of the age-predicted maximal HR (APMHR). This study hypothesized that mild attenuation of HR response during exercise among healthy subjects is associated with increased cardiovascular risk. The study population comprised 10,323 healthy men and women without known cardiovascular disease (CVD) or diabetes mellitus who underwent a yearly screening program and were followed up during a mean period of 4.3 years. Participants were grouped to 3 tertiles based on the percentage of their APMHR reached at the baseline stress test. The primary end point was the occurrence of CVD or cerebrovascular disease. A total of 1,015 incident cases of CVD occurred during follow-up. A multivariate Cox proportional hazards regression model showed that the CVD risk of subjects who reached 60% to 96% of their APMHR was 35% greater compared with those who reached their APMHR (p = 0.001). A subgroup analysis among subjects who reached 85% of their APMHR showed that even mildly attenuated heart response (in the range of 85% to 96% APMHR) was independently associated with 36% increase in CVD risk (p <0.001). In conclusion, attenuated HR response during exercise is a powerful and independent predictor of adverse cardiovascular events during long-term follow-up among healthy men and women. The prognostic implications of attenuated HR response in this population are apparent even with a minor decrease of the maximal HR to <96% of the APMHR.

Reduced sympathetic activity in idiopathic rapid-eye-movement sleep behavior disorder and Parkinson's disease

More than 50% of patients with idiopathic REM sleep behavior disorder (iRBD) will develop Parkinson's disease or Lewy body dementia. In a previous study, we found attenuated heart rate responses in iRBD and Parkinson's disease patients during sleep. The current study aimed to evaluate heart rate variability further in order to identify possible changes in these components during wakefulness and sleep in patients with iRBD and Parkinson's disease. We evaluated heart rate variability in 5-minute electrocardiography segments from wakefulness, and non-REM and REM sleep in 11 iRBD patients and 23 Parkinson's disease patients, and compared these with 10 control subjects. Patients with iRBD had attenuated sympathetic nervous system activity compared with controls and this was more pronounced in patients with Parkinson's disease. The cardiac parasympathetic nervous system seems to be relatively well preserved in patients with iRBD and Parkinson's disease. The progressive reduction of sympathetic nervous activity is in line with the postganglionic sympathetic nervous dysfunction seen in early Parkinson's disease.

Impaired chronotropic response to 6-min walk test and reduced survival in interstitial lung disease

Reduced chronotropic response to maximal exercise has been associated with poor survival in people without respiratory disease. The contribution of chronotropic response to exercise limitation and survival in interstitial lung disease (ILD) is not well defined. This study investigated the relationships between chronotropic response during 6-min walk test, exercise capacity and survival in ILD. Eligible participants had ILD, were ambulant and free of heart failure and beta blocker therapy. Chronotropic response during the 6-min walk test was defined as peak heart rate (HR) minus resting HR. Survival was recorded at four years. Sixty-two participants (40 idiopathic pulmonary fibrosis) were included, with mean (SD) TLCO 50(18)% predicted and 6-min walk distance (6MWD) 377 (127) metres. A smaller chronotropic response was associated with reduced 6MWD (r=0.65, p<0.001). Independent predictors of 6MWD were chronotropic response, peak oxygen uptake on cardiopulmonary exercise test; right ventricular systolic pressure on echocardiogram; and age. This model explained 83% of the variance in 6MWD, with 24% of the variance attributable to chronotropic response. A chronotropic response during 6-min walk test of less than 20 beats per minute was an independent predictor of death at four years (odds ratio 10.71, 95% confidence interval 2.67-42.94) in a model that also included oxygen desaturation and forced vital capacity. Impaired chronotropic response to 6-min walk test is associated with reduced 6MWD and reduced survival in ILD, independent of physical fitness and pulmonary hypertension. Investigation of the mechanisms underlying attenuated HR response to exercise in ILD is warranted.

Attenuated Heart Rate Response is Associated with Hypocretin Deficiency in Patients with Narcolepsy

Several studies have suggested that hypocretin-1 may influence the cerebral control of the cardiovascular system. We analyzed whether hypocretin-1 deficiency in narcolepsy patients may result in a reduced heart rate response. We analyzed the heart rate response during various sleep stages from a 1-night polysomnography in patients with narcolepsy and healthy controls. The narcolepsy group was subdivided by the presence of +/- cataplexy and +/- hypocretin-1 deficiency. Sleep laboratory studies conducted from 2001-2011. In total 67 narcolepsy patients and 22 control subjects were included in the study. Cataplexy was present in 46 patients and hypocretin-1 deficiency in 38 patients. None. All patients with narcolepsy had a significantly reduced heart rate response associated with arousals and leg movements (P < 0.05). Heart rate response associated with arousals was significantly lower in the hypocretin-1 deficiency and cataplexy groups compared with patients with normal hypocretin-1 levels (P < 0.04) and patients without cataplexy (P < 0.04). Only hypocretin-1 deficiency significantly predicted the heart rate response associated with arousals in both REM and non-REM in a multivariate linear regression. Our results show that autonomic dysfunction is part of the narcoleptic phenotype, and that hypocretin-1 deficiency is the primary predictor of this dysfunction. This finding suggests that the hypocretin system participates in the modulation of cardiovascular function at rest.

Attenuated heart rate response in REM sleep behavior disorder and Parkinson's disease

The objective of this study was to determine whether patients with Parkinson's disease with and without rapid-eye-movement sleep behavior disorder and patients with idiopathic rapid-eye-movement sleep behavior disorder have an attenuated heart rate response to arousals or to leg movements during sleep compared with healthy controls. Fourteen and 16 Parkinson's patients with and without rapid-eye-movement sleep behavior disorder, respectively, 11 idiopathic rapid-eye-movement sleep behavior disorder patients, and 17 control subjects underwent 1 night of polysomnography. The heart rate response associated with arousal or leg movement from all sleep stages was analyzed from 10 heartbeats before the onset of the sleep event to 15 heartbeats following onset of the sleep event. The heart rate reponse to arousals was significantly lower in both parkinsonian groups compared with the control group and the idiopathic rapid-eye-movement sleep behavior disorder group. The heart rate response to leg movement was significantly lower in both Parkinson's groups and in the idiopathic rapid-eye-movement sleep behavior disorder group compared with the control group. The heart rate response for the idiopathic rapid-eye-movement sleep behavior disorder group was intermediate with respect to the control and the parkinsonian groups. The attenuated heart rate response may be a manifestation of the autonomic deficits experienced in Parkinson's disease. The idiopathic rapid-eye-movement sleep behavior disorder patients not only exhibited impaired motor symptoms but also incipient autonomic dysfunction, as revealed by the attenuated heart rate response.