Attenuated Heart Rate Research Articles

Reduced Cardiac Beta 1 Receptor Expression and Function in a Mouse Model of Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disorder. HCMis characterized by cardiac hypertrophy, fibrosis, and an increased risk of fatalarrhythmias and sudden cardiac death. Previous studies in humans with HCM havedemonstrated increased cardiac norepinephrine spillover and reduced beta-1 receptor(B1R) expression in the left ventricle (LV). We have previously demonstrated thatcardiac sympathetic tone is elevated in an alpha-tropomyosin mutant mouse model ofHCM. We hypothesized that HCM mice would demonstrate reduced B1R expression inthe LV and attenuated heart rate (HR) and dP/dt max responses to ramped infusion of theB1R agonist, dobutamine. First, we utilized western blot to measure B1R proteinexpression in LV tissue from HCM and littermate wild-type (WT) mice (n=4 male micein each group). B1R expression was significantly reduced in the LV of HCM micecompared to WT littermate controls (HCM 60±1% vs. WT 100±4%; paired t-test, p<0.05). Next, we recorded left ventricular pressure in male and female HCM andlittermate WT control (n=5 male mice, each group; n=6 female mice, each group) miceanesthetized with isoflurane (2% in O2). Data were analyzed by 2-way ANOVA withgenotype and sex as factors. Baseline HR and dP/dt max were significantly lower inHCM compared to WT mice (genotype p<0.05), however, there were no sex differencesin either variable (sex p>0.05). Next, in order to assess cardiac B1R function, we firstinfused the ganglionic blocker chlorisondamine (6ug/g) to eliminate autonomic reflexfunction in HCM and littermate WT mice (n=4 mice, each group). Then, we performed adobutamine stress test via ramped infusion of dobutamine starting at 2ng/g/min andincreasing the dose in 2ng/g/min increments every 2 minutes up to 12ng/g/min via aprogrammable syringe pump. Data were analyzed by 2-way ANOVA with dose andgenotype as factors. Contrary to our hypothesis, ramped infusion of dobutamine resultedin a similar, significant (dose p<0.05) increase in HR in both HCM and WT mice(genotype p>0.05). Peak increases in HR occurred during the highest dose ofdobutamine (12ng/g/min; ΔHR HCM 58±19 vs. WT 70±20 beats/min) in both groups.Consistent with our hypothesis, increases in dP/dt max were significantly blunted inHCM mice compared to littermate WT controls (dose x genotype p<0.05). Peakincreases in dP/dt max occurred at a lower dose of dobutamine for HCM (4ng/g/min;ΔdP/dt max 1129±767 mmHg/s) compared to WT (8ng/g/min; ΔdP/dt max 4882±499mmHg/s). In summary, LV B1R expression is reduced in HCM mice. Increases in HR inresponse to ramped infusion of dobutamine were similar between HCM and WT micewhereas increases in dP/dt max were attenuated in HCM mice. We speculate that thedifferential inotropic and chronotropic responses to dobutamine could be due to regionaldifferences in B1R expression or contractile dysfunction in HCM mice. Michigan Technological University Startup. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

1034 Attenuated Heart Rate Change as Potential Sleep Digital Biomarker in Lewy Body Dementia

1034 Attenuated Heart Rate Change as Potential Sleep Digital Biomarker in Lewy Body Dementia

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.

Icanbelimod (CBP-307), a next-generation Sphingosine-1-phosphate receptor modulator, in healthy men: pharmacokinetics, pharmacodynamics, safety, and tolerability in a randomized trial in Australia.

Icanbelimod (formerly CBP-307) is a next-generation S1PR modulator, targeting S1PR1. In this first-in-human study, icanbelimod was investigated in healthy men in Australia. Participants were randomized 3:1, double-blind, to icanbelimod or placebo in four single-dose cohorts (0.1 mg, 0.25 mg, 0.5 mg [n=8 per cohort], 2.5 mg [n=4]) or for 28-days once-daily treatment in two cohorts (0.15 mg, 0.25 mg [n=8 per cohort]). Participants in the 0.25-mg cohort received 0.1 mg on Day 1. Treatments were administered orally after fasting; following one-week washout, icanbelimod was administered after breakfast in the 0.5-mg cohort. Icanbelimod exposure increased rapidly and dose-dependently with single and multiple dosing (Tmax 4-7 hours). Lymphocyte counts decreased rapidly after single (-11%, 0.1 mg; -40%, 0.25 mg; -71%, 0.5 mg; -77%, 2.5 mg) and multiple doses (-49%, 0.15 mg; -75%, 0.25 mg), and recovered quickly, 7 days after dosing. After single-dose 0.5 mg, although a high-fat breakfast versus fasting did not affect maximal decrease, lymphocyte counts tended to be lower after breakfast across most timepoints up to 72 hours. Twenty-eight participants (63.6%) experienced mainly mild treatment-emergent adverse events (TEAEs). After single-dose icanbelimod, the most common TEAEs were headache (28.6%, n=6) and dizziness (19.0%, n=4). Three participants experienced transient bradycardia, with one serious, following single-dose 2.5 mg icanbelimod. After multiple-dose icanbelimod, the most common TEAEs were headache (50.0%, n=6) and lymphopenia (41.7%, n=5), and two participants withdrew due to non-serious TEAEs. Up-titration attenuated heart rate reductions. Icanbelimod was well-tolerated up to 0.5 mg and effectively reduced lymphocyte counts. ClinicalTrials.gov, identifier NCT02280434.b.

EXERCISE IMPROVES HEART RATE RECOVERY GREATER THAN STANDARD CARE IN TYPE 2 DIABETES

https://youtu.be/HRw1f_DoX-Q INTRODUCTION An attenuated heart rate recovery (HRR) immediately after exercise is considered an index of autonomic imbalance and is a predictor of all cause mortality in patients with type 2 diabetes (T2D). Because autonomic dysfunction in T2D patients has shown to be reversible with glycemic control, weight loss, and fitness gain, we investigated the effect of a 12 week aerobic exercise (AE) intervention compared to standard care on HRR in patients with T2D. METHODS T2D patients (n=32) were randomized to a 12-week AE intervention (n=19) or standard of care (n=13). The AE intervention consisted of supervised exercise training for 1h/day 5/wk for 12 weeks at 80% VO2peak. All subjects completed body composition analysis (DEXA), oral glucose tolerance test (OGTT), and maximal exercise testing before and after the study period. HRR was measured every minute for 10 minutes after cessation of maximal exercise testing. RESULTS Baseline HRR 1-minute values were negatively associated with ASCVD Risk (rho = 0.623; p = 0.002) and positively associated with VO2peak (rho = 0.361; p = 0.042). Body weight was unchanged in both control (p = 0.989) and AE group (p = 0.248) after the study period. Following AE training intervention, VO2peak increased by 7.4 ± 1.9% (p &amp;lt; 0.001), glucose metabolism, as measured by OGTT area under the curve (AUC), improved by 11.6 ± 6.0% (p = 0.040), and HRR 1-minute increased by 10.4 ± 6.1% (p = 0.234). The control group showed no significant changes as VO2peak increased by 0.7 ± 2.6% (p = 0.826), AUC improved by 3.1 ± 3.5% (p = 0.585), and HRR 1-minute increased 3.9 ± 9.0% (p = 0.915). Baseline HRR predicted change in HRR after the study period in the control group (rho = −0.817; p = 0.002) but not in the AE group (rho = −0.054, p = 0.860). Upon controlling for baseline HRR, AE group possessed a significantly higher post intervention HRR 1-minute value than control by 28.5% (p = 0.036). We found the AE group also had higher HRR values than control during the post-intervention 10-minute recovery resulting in a main effect of group (p &amp;lt; 0.001). CONCLUSIONS T2D patients with higher HRR, only receiving standard of care, are more susceptible to chronic detriments in HRR indicative of gradual autonomic function loss. To our knowledge these are the first data showing regular moderate-vigorous intensity exercise, which improved glycemic control and fitness gain independent of weight loss, outperforms standard of care alone for greater HRR.

The Respiratory Muscle Metaboreflex: Effects Of Sex And Aging

High levels of respiratory muscle work evoke a sympathetically mediated pressor reflex (e.g. metaboreflex), and young females demonstrate an attenuated heart rate and blood pressure response relative to males. It is unclear what the inter-relationships are between the effects of healthy aging and female sex hormones on the respiratory muscle metaboreflex. PURPOSE: We tested the hypothesis that the pressor response to inspiratory work would be similar between older men and women, and higher relative to their younger counterparts. METHODS: Healthy, normotensive young (26 ± 3 y) males (YM; n = 10) and females (YF; n = 9) and aged (63 ± 6 y) males (OM; n = 5) and females (OF; n = 10, post-menopausal) participated. YF were tested in the mid-luteal phase of the menstrual cycle. Participants performed inspiratory pressure threshold loading (PTL; 60% maximal inspiratory mouth pressure, breathing frequency = 15 bpm, 0.70 inspiratory duty cycle) to task failure. Mean arterial pressure (MAP) and heart rate (HR) were recorded continuously. RESULTS:Time to task failure was different between groups (YF = 19 ± 8. YM = 18 ± 9, OF = 13 ± 6, OM = 8 ± 5 min, p = 0.036). The absolute pressure time product, per minute was also different between groups (p = 0.005); of which, OM generated significantly greater pressures than YW (p = 0.018). There was a significant age (p = 0.002) and sex (p = 0.030) effect in the MAP response to PTL. Peak MAP between OF (+25 ± 10 mmHg) and OM (+17 ± 4 mmHg) were similar (p = 0.999). Peak MAP in OF was greater than YF (+8 ± 6 mmHg, p = 0.010) and was similar to YM (+19 ± 15 mmHg, p = 0.475). The peak MAP response was greater in YM compared to YW (p = 0.009). There was a significant sex, time interaction in the HR response to PTL (p = 0.007). YM showed the greatest peak HR response to PTL (+27 ± 11 bpm) though not significantly different to YF (+15 ± 12 bpm), OF (+17 ± 7 bpm), or OM (+18 ± 6 bpm). CONCLUSIONS:Healthy aging is associated with a heightened respiratory muscle metaboreflex compared to young men and women. The cardiovascular response to the respiratory muscle metaboreflex is similar between older males and post-menopausal females.Support: NSERC

Abstract P1105: Inflammatory Bowel Disease Induced Autonomic Dysregulation Increases The Risk For Atrial Fibrillation

Introduction: Ulcerative colitis causes inflammation of the innermost lining of the colon and rectum. The disease has a relapsing and remitting course and is accompanied by extraintestinal manifestations such as an increased risk for atrial fibrillation (AF). Here we will test the hypothesis that during active colitis, dysregulation of parasympathetic signaling increases the propensity for atrial arrhythmic events. Methods: Dextran Sulfate Sodium (DSS: 3%, 7days) treated mice (C57BL/6) exhibit disrupted intestinal barrier function that mimics the disease phenotype of active colitis. Changes in atrial electrophysiology was quantified in-vivo (EKG) and in the Langendorff (LD)-perfused heart (atrial electrograms) during peak inflammation (DSS A ) and remission (DSS R ). Results: During peak inflammation, structural remodeling was reflected in a decreased heart weight to tibia length ratio (Control (CTL A ): 9.9±0.4 mg/mm, n=10; DSS A : 8.8±0.3 mg/mm, n=12; p&lt;0.05) whereas electrophysiological atrial remodeling was supported by a prolonged P-wave duration (CTL A : 25.5±0.6 ms, n=10; DSS A : 31.2±0.6 ms, n=24; p&lt;0.0001) and shortened atrial effective refractory period (CTL A : 27.3±1.7 ms, n=4; DSS A : 19.3±0.6 ms, n=4; p&lt;0.01). In comparison to CTL A , DSS A mice exhibited autonomic dysregulation reflected in an attenuated heart rate (HR) variability and a decreased change in HR in response to the muscarinic receptor blocker atropine (CTL A : 7.6±1.8 %, n=5; DSS A : 2.2±0.7 %, n=7; p&lt;0.01). The decreased vagal tone in DSS A coincided with an exaggerated response to the parasympathomimetic carbachol (CCh, 150ng/g) that resulted in a larger decrease in HR (in vivo: CTL A : -12.3±3.1 %, n=10; DSS A : -46.0±5.6 %, n=10; p&lt;0.0001) and increased number of spontaneous arrhythmic events (CTL A : 1.7±0.6 events/min, n=10; DSS A : 9.8±3.8 events/min, n=10; p&lt;0.05) in vivo and in the LD-configuration. The susceptibility for pacing induced AF trended to be increased in DSS A animals. Structural and electrophysiological changes were reversible upon remission. Conclusion: Active colitis induces transient structural and electrophysiological remodeling. We propose that dysregulation of cholinergic signaling drives the increased propensity for atrial arrhythmia.

Impacts of imagery-enhanced versus verbally-based cognitive behavioral group therapy on psychophysiological parameters in social anxiety disorder: Results from a randomized-controlled trial

Social anxiety disorder (SAD) is associated with marked physiological reactivity in social-evaluative situations. However, objective measurement of biomarkers is rarely evaluated in treatment trials, despite potential utility in clarifying disorder-specific physiological correlates. This randomized controlled trial sought to examine the differential impact of imagery-enhanced vs. verbal-based cognitive behavioral group therapy (IE-CBGT, n = 53; VB-CBGT, n = 54) on biomarkers of emotion regulation and arousal during social stress in people with SAD (pre- and post-treatment differences in heart rate variability (HRV) and skin conductance). We acquired psychophysiological data from randomized participants across four social stress test phases (baseline, speech preparation, speech, interaction) at pre-treatment, and 1- and 6-months post-treatment. Analyses revealed that IE-CBGT selectively attenuated heart rate as indexed by increases in median heart rate interval (median-RR) compared to VB-CBGT at post-treatment, whereas one HRV index showed a larger increase in the VB-CBGT condition before but not after controlling for median-RR. Other psychophysiological indices did not differ between conditions. Lower sympathetic arousal in the IE-CBGT condition may have obviated the need for parasympathetic downregulation, whereas the opposite was true for VB-CBGT. These findings provide preliminary insights into the impact of imagery-enhanced and verbally-based psychotherapy for SAD on emotion regulation biomarkers.

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.

40-min nap opportunity attenuates heart rate and perceived exertion and improves physical specific abilities in elite basketball players

ABSTRACT The effect of a 40-min nap opportunity on physiological responses and specific abilities was investigated. Twelve high-level professional basketball players (26.33±5.2 years; 193.17±7.1 m; 87.48±11.2 kg) undertook randomly 40-min nap opportunity (NAP) and control condition (CON). Wellness (Hooper Index) and Epworth Sleepiness Scale (ESS) were measured before and after both conditions. Defensive (DA) and offensive (OA) agility and upper body power (UBP) were assessed after both conditions. Shooting skill (SST) performance was evaluated prior and after a fatiguing task (FT). Heart rate (HR) and rating of perceived exertion (RPE) were recorded during SST-test, FT and SST-retest. ESS, Hooper’s stress and fatigue score were significantly lower after nap compared to those before nap (0.009 ≤ p ≤ 0.03). Better performance was obtained in NAP compared to CON condition for DA, OA and UBP (0.0005 ≤ p ≤ 0.02). SST performance was significantly higher in NAP compared to CON in the retest session (p = 0.003, Δ = 20.2%). The improved performance was associated with significant lower HRpeak (p = 0.01, Δ = 5.25%) and RPE (p = 0.003, Δ = 15.12%). In conclusion, NAP reduced sleepiness and stress and fatigue and enhances physical outcomes of specific skills in elite basketball players.

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.

Heart Rate Recovery Following Exercise Testing in Pediatric Patients with Acyanotic Repaired Congenital Heart Disease.

Attenuated heart rate recovery (HRR) following peak exercise has been shown to be a predictor of mortality in populations of adults with Fontan palliation, coronary artery disease, heart failure, and heart transplantation. However, few have studied HRR in children and adolescents with congenital heart disease (CHD). This case-controlstudy compared HRR patterns from exercise stress testing in children and adolescents with and withoutrepaired acyanotic CHD (raCHD). Retrospective analysis included patients aged 10-18years who had exercise testing between 2007 and 2017. The raCHD cohort included patients with Tetralogy of Fallot, transposition of the great arteries, coarctation, truncus arteriosus, atrioventricular septal defect, pulmonary outflow obstruction, aortic stenosis and/or insufficiency, or septal defects. Those in the control cohort were matched for age, sex, BMI, peak METs achieved, and peak heart rate (HR). HR at 1-min intervals throughout the 10-min recovery period and HRR patterns were analyzed. The study included n = 584 individuals (raCHD: n = 146), median age 14years old, 67.1% male. The cohorts had similar resting and peak HRs. Linear mixed-effects models (LMM) suggested statistically significant cohort-by-time interaction for HR in exercise recovery, with the largest mean difference at minute-6 (2.9bpm, p = 0.008). When comparing lesion types, LMM found no cohort or cohort-by-time interaction. While minute-6 of exercise recovery was statistically significant, the difference was 2.9bpm and may not have clinical significance. These results suggest that HRR in pediatric raCHD patients should not vary from their healthy peers, and an attenuated HRR may not be directly attributed to underlying raCHD.

Heart Rate Recovery at 1 Min after Exercise Is a Marker of Disease Severity and Prognosis in Chronic Thromboembolic Pulmonary Hypertension

Background: Attenuated heart rate recovery at 1 min (HRR1) was demonstrated to correlate with poor prognosis in patients with pulmonary arterial hypertension, whereas its role in patients with chronic thromboembolic pulmonary hypertension (CTEPH) remains unclear. Objectives: The aim of this study was to investigate the correlations between HRR1 and functional status, echocardiography, hemodynamics, and prognosis of CTEPH. Methods: We retrospectively enrolled patients with CTEPH who underwent right heart catheterization and cardiopulmonary exercise test between June 2014 to October 2020 in Fuwai hospital. The primary outcome was clinical worsening. Linear regression was performed to assess the association between HRR1 and established markers of CTEPH severity. Receiver operating characteristic curve analysis was performed to determine the optimal cutoff of HRR1. Cox regression models were used to assess the association between HRR1 and clinical worsening. Results: A total of 211 patients with CTEPH were included in the study. After adjusting for confounders, HRR1 positively correlated with 6-min walk distance, mixed venous oxygen saturation, and peak oxygen consumption, and negatively correlated with NT-proBNP, pulmonary vascular resistance, and ventilatory equivalent of carbon dioxide. Compared with patients with HRR1 ≥16 beats, patients with HRR1 <16 beats had approximately a 3-fold risk of experiencing clinical worsening and the risk escalated with time. Conclusion: HRR1 could reflect disease severity and was independently associated with prognosis in patients with CTEPH.

Abstract 14228: Mechanism of Atrial Fibrillation in an Animal Model of Inflammatory Bowel Disease

Introduction: Ulcerative colitis (UC) is an i nflammatory bowel disease with a relapsing and remitting course. UC has extraintestinal manifestations and UC patients exhibit twice the risk for atrial fibrillation (AF) during acute disease activity. The mechanism of AF due to UC remains to be determined. Hypothesis: During acute UC a dysregulation of vagal signaling increases a patients propensity for AF. Methods: Mice (male, C57BL/6) were treated with Dextran Sulfate Sodium (DSS: 3%) supplemented drinking water for 7days that disrupts intestinal barrier function and mimics the disease phenotype of acute UC. Changes in atrial electrophysiology were quantified in vivo (EKG), on the whole heart (Langendorff configuration) and the cellular level (Fluo-4AM) during peak inflammation (DSS A ) and remission (DSS R ). Results: DSS A mice exhibited an attenuated heart rate (HR) in vivo (CTL: 491 ± 11 bpm, n=10; DSS A : 448 ± 11 bpm, n=16; p&lt;0.05) and in excised perfused hearts (Langendorff configuration: CTL: 321 ± 15 bpm, n = 3; DSS A : 256 ± 17 bpm, n = 4; p &lt; 0.05). The P-wave duration was prolonged (in vivo, CTL: 25.5 ± 0.6 ms, n=10; DSS A : 30.2 ± 0.5 ms, n=16; p &lt; 0.0001) and HR variability time-domain measure RR-corrected SDNN was attenuated (CTL: 11.3 ± 1.1 ms, n=10; DSS A : 8.2 ± 0.7 ms, n=16; p &lt; 0.05). The latter is an indicator for an attenuated vagal tone in DSS A mice and coincided with an increased sensitivity to the vagal agonist Carbachol in-vivo (CCh 150 ng/g, change in HR: CTL: -3.8 ± 4.4 %, n=6; DSS A : -42.2 ± 4.8 %, n=10; p &lt; 0.0001). After burst pacing DSS A hearts exhibited a prolonged RR-corrected sinus node recovery time (CTL: 11.2 ± 1.4 ms, n=3; DSS A : 25.5 ± 2.1 ms, n=4; p &lt; 0.0001), an increased AF propensity, and prolonged duration of AF episodes (CTL: 0.8 ± 0.17 s, n=3; DSS A : 2.4 ± 0.31 s, n=4; p &lt; 0.05) even in the absence of CCh. No changes in atrial myocyte Ca handling properties were determined. After remission HR, P-wave duration, and HRV in DSS R returned to control values. Conclusions: The data suggests that acute UC increases the risk for AF likely as a consequence of an attenuated sinus rhythm and atrial conduction velocity where vagal stimuli could exacerbate the risk for reentry of excitation. If these changes are the direct consequence of the attenuated vagal tone remains to be determined.

Cancer classification using machine learning and HRV analysis: preliminary evidence from a pilot study

Most cancer patients exhibit autonomic dysfunction with attenuated heart rate variability (HRV) levels compared to healthy controls. This research aimed to create and evaluate a machine learning (ML) model enabling discrimination between cancer patients and healthy controls based on 5-min-ECG recordings. We selected 12 HRV features based on previous research and compared the results between cancer patients and healthy individuals using Wilcoxon sum-rank test. Recursive Feature Elimination (RFE) identified the top five features, averaged over 5 min and employed them as input to three different ML. Next, we created an ensemble model based on a stacking method that aggregated the predictions from all three base classifiers. All HRV features were significantly different between the two groups. SDNN, RMSSD, pNN50%, HRV triangular index, and SD1 were selected by RFE and used as an input to three different ML. All three base-classifiers performed above chance level, RF being the most efficient with a testing accuracy of 83%. The ensemble model showed a classification accuracy of 86% and an AUC of 0.95. The results obtained by ML algorithms suggest HRV parameters could be a reliable input for differentiating between cancer patients and healthy controls. Results should be interpreted in light of some limitations that call for replication studies with larger sample sizes.

Cardiorespiratory Abnormalities in Patients Recovering from Coronavirus Disease 2019

BackgroundA large number of patients around the world are recovering from coronavirus disease 2019 (COVID-19); many of them report persistence of symptoms. The aim of this study was to test pulmonary, cardiovascular, and peripheral responses to exercise in patients recovering from COVID-19.MethodsPatients who recovered from COVID-19 were prospectively evaluated using a combined anatomic and functional assessment. All patients underwent clinical examination, laboratory tests, and combined stress echocardiography and cardiopulmonary exercise testing. Left ventricular volumes, ejection fraction, stroke volume, heart rate, E/e′ ratio, right ventricular function, oxygen consumption (Vo2), lung volumes, ventilatory efficiency, oxygen saturation, and muscle oxygen extraction were measured in all effort stages and compared with values in historical control subjects.ResultsA total of 71 patients were assessed 90.6 ± 26 days after the onset of COVID-19 symptoms. Only 23 (33%) were asymptomatic. The most common symptoms were fatigue (34%), muscle weakness or pain (27%), and dyspnea (22%). Vo2 was lower among post-COVID-19 patients compared with control subjects (P = .03, group-by-time interaction P = .007). Reduction in peak Vo2 was due to a combination of chronotropic incompetence (75% of post-COVID-19 patients vs 8% of control subjects, P < .0001) and an insufficient increase in stroke volume during exercise (P = .0007, group-by-time interaction P = .03). Stroke volume limitation was mostly explained by diminished increase in left ventricular end-diastolic volume (P = .10, group-by-time interaction P = .03) and insufficient increase in ejection fraction (P = .01, group-by-time interaction P = .01). Post-COVID-19 patients had higher peripheral oxygen extraction (P = .004) and did not have significantly different respiratory and gas exchange parameters compared with control subjects.ConclusionsPatients recovering from COVID-19 have symptoms associated with objective reduction in peak Vo2. The mechanism of this reduction is complex and mainly involves a combination of attenuated heart rate and stroke volume reserve.

Can Physical Exercise Attenuate Heart Rate Variability Decline Produced By Cancer?

As cancer therapies have evolved, survival rates have increased, yet side-effects still exist. Cardiotoxicity and neurotoxicity have negative effects on the autonomic nervous system and create cardiovascular dysfunction. Heart rate variability (HRV), a marker of autonomic modulation, negatively decreases with cancer, and is associated with fatigue, depression, and mortality. Exercise appears to attenuate the decline in HRV. PURPOSE: This review analyzes the effects of exercise programs on HRV of cancer patients and survivors. METHODS: PRISMA guidelines were followed by searching Web of Science articles and PubMed databases. The quality of the articles was assessed by PEDro scale. Statistical procedures used Revman 5.3. RESULTS: Six studies fulfilled the inclusion/exclusion criteria and included 272 participants, 30 to 75 years old. Exercise programs had a mean length of 10.4 wks, a frequency of 3.1 d/wk, and a mean duration of 78 min/session. In the time domain HRV measures, exercise increased in Standard deviation of NN intervals (p < 0.00001; MD = 12.79 ms [95% CI = 9.03 to 16.55]) and decreased Root mean square of successive RR interval differences (p = 0.002; MD = 13.08 ms [95% CI = 4.90 to 21.27]) compared to controls. Frequency domain data reveal that significant differences between control and exercise groups could be reached in low-frequency (absolute power: p < 0.0001; SMD = 0.97 [95% CI = 0.61 to 1.34]; relative power: p = 0.04; MD = -7.70 [95%CI = -15.4 to -0.36]) high-frequency (absolute power: p = 0.001, SMD = 1.49 [95% CI = 0.32 to 2.66]; relative power: p = 0.04, MD = 8.00 nu [95% CI = 0.20 to 15.80]) and HF/LF ratio (p = 0.007; MD = -0.32 [95% CI = -0.55 to -0.09). CONCLUSIONS: Exercise programs can lead to positive effects on HRV of cancer patients and survivors, with more positive changes realized with resistance and endurance workouts. However, the overall small sample size studying exercise and HRV in cancer patients warrants further study to confirm these results.

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.

Attenuated heart rate recovery is associated with higher arrhythmia recurrence and mortality following atrial fibrillation ablation.

Heart rate recovery (HRR), the decrease in heart rate occurring immediately after exercise, is caused by the increase in vagal activity and sympathetic withdrawal occurring after exercise and is a powerful predictor of cardiovascular events and mortality. The extent to which it impacts outcomes of atrial fibrillation (AF) ablation has not previously been studied. The aim of this study is to investigate the association between attenuated HRR and outcomes following AF ablation. We studied 475 patients who underwent EST within 12 months of AF ablation. Patients were categorized into normal (>12 b.p.m.) and attenuated (≤12 b.p.m.) HRR groups. Our main outcomes of interest included arrhythmia recurrence and all-cause mortality. During a mean follow-up of 33 months, 43% of our study population experienced arrhythmia recurrence, 74% of those with an attenuated HRR, and 30% of those with a normal HRR (P < 0.0001). Death occurred in 9% of patients in the attenuated HRR group compared to 4% in the normal HRR cohort (P = 0.001). On multivariable models adjusting for cardiorespiratory fitness (CRF), medication use, left atrial size, ejection fraction, and renal function, attenuated HRR was predictive of increased arrhythmia recurrence (hazard ratio 2.54, 95% confidence interval 1.86-3.47, P < 0.0001). Heart rate recovery provides additional valuable prognostic information beyond CRF. An impaired HRR is associated with significantly higher rates of arrhythmia recurrence and death following AF ablation.

Ketamine: yay or neigh? Implications for cardiovascular regulation and considerations for field use.

Ketamine: yay or neigh? Implications for cardiovascular regulation and considerations for field use.