Blunted Heart Rate Response Research Articles

Heart rate response and recovery in bicycle exercise testing - reference values and association with mortality

Abstract Introduction Chronotropic incompetence and impaired heart rate (HR) recovery are related to mortality. Guidelines lack specific recommendations for reference values on HR recovery assessment. Purpose To define normal values for HR response and recovery in individuals referred for a bicycle exercise stress test and to relate these factors to risk of mortality. Methods We included 9,917 subjects (46% females) aged 18–85 years who performed a bicycle exercise test. We defined age- and sex-specific reference equations for peak HR, HR reserve, and HR recovery at 1 and 2 minutes (HRR1 and HRR2) using a subgroup of individuals without apparent cardiovascular (CV) risk nor comorbidities (N=2,774). Associations between blunted HR indices (<5thpercentile) and mortality were analysed using Cox regression in all subjects and in individuals with normal exercise capacity (N=8,070). Results All HR indices were age-dependent. The 5th percentiles of HR reserve, HRR1, and HRR2 correlated weakly with previously reported reference values. During median follow-up of 8.6 years 1,110 (11%) died. HR recovery variables were the strongest predictors of all-cause (HRR1, hazard ratio 1.66 (95% confidence interval, 1.45–1.90)) and CV mortality (HRR2, 1.59 (1.26–2.00)) after adjustments for potential confounders. Blunted HR response (peak HR) increased risk of all-cause (1.32 (1.14–1.53)) and CV mortality (1.41 (1.09–1.83)). Combined blunted HRR1 and HRR2 or HR response and HRR1 further increased risk of all-cause (1.92 (1.64–2.24) and 1.85 (1.55–2.22), respectively) and CV mortality (1.95 (1.50–2.54) and 1.94 (1.42–2.65), respectively). HR recovery variables (HRR1, 1.97 (1.63–2.39) and HRR2, 1.76 (1.46–2.12)) remained stronger predictors of mortality than peak HR (1.38 (1.10–1.72)) in individuals with normal exercise capacity. Conclusions All HR variables were age-dependent and associated with mortality. Blunted HR recovery was more strongly related to mortality than chronotropic incompetence, and their combination added prognostic value. Furthermore, blunted HR recovery variables, rather than blunted HR response, remained strongly associated with mortality even in the presence of normal exercise capacity.

Chronotropic Incompetence across Heart Failure Categories.

The HF syndrome is characterized by an autonomic unbalance with sympathetic hyperactivity which contributes to increased myocardial oxygen demand, oxidative stress, peripheral vasoconstriction, afterload mismatch with a progressive desensitization and down-regulation of cardiac β1-receptors. These changes, together with a few other structural and peripheral changes, lead to chronotropic incompetence (CI), such as the inability to increase heart rate (HR) consistently with activity or demand. CI, regardless of the method and cut-off adopted to define it, is associated with reduced exercise capacity and a worse prognosis. Furthermore, different pharmacological classes might interfere with the physiologic exercise-induced HR response, thus generating some confusion. In particular, the β-blockers, albeit lowering peak HR, are known to improve prognosis and left ventricular inotropic reserve so that their withdrawal should be avoided at least in HF with reduced and mildly reduced ejection fraction. Similarly, a still debated strategy to counterbalance a blunted exercise-induced HR response, is represented by rate-adapting pacing. The present review, besides supplying an overview on possible CI definitions, discusses the clinical impact of CI and potential pharmacological and non-pharmacological therapeutic strategies.

Cardiac Comorbidity and Exercise Intolerance in Bilateral Lung Transplant Recipients Followed at a Pediatric Center.

Reduced exercise capacity is common in young bilateral lung transplantation (Bi-LTx) recipients, but longer-term data on cardiac comorbidities are limited. We evaluate potential cardiac contributions to long-term exercise intolerance in this population. All Bi-LTx recipients at a single pediatric center, who completed routine clinical post-transplant cardiac assessment, including echocardiogram, cardiac exam, and cardiopulmonary exercise testing (CPET), were included. Cardiac risk factors (CRFs) were assessed by history and laboratory tests. CPET-derived peak and percent-predicted peak myocardial oxygen consumption (VO2 peak, ppVO2 peak) were used to quantitate exercise capacity. Percent-predicted peak oxygen pulse (pp peak O2 pulse) assessed stroke volume. 15 patients (67% M; median age 21.6years, median follow-up from Bi-LTx 7.0years) were included. Almost all patients (14, 93%) had multiple CRFs; hypertension and hyperlipidemia/dyslipidemia were the most common. On CPET, 93% (n = 14) had abnormal (≤ 85%) ppVO2 peak (median 59%). 73% (n = 11) had abnormal pp peak O2 pulse (median 74%). Ten had blunted heart rate response to exercise. Nine had left ventricular diastolic dysfunction (LV-DD) on echocardiogram. Median percent-predicted forced expiratory volume in one second was 70%. One had severe chronic lung allograft dysfunction. Cardiac risk factors and exercise intolerance are common among young Bi-LTx recipients years post-transplant, even among those without significant pulmonary dysfunction. High prevalence of multiple CRFs, LV-DD, chronotropic dysfunction, and abnormal stroke volume suggest cardiac comorbidities may contribute to intolerance. Medical management of CRFs and tailored exercise may decrease cardiac risk and improve functional capacity for Bi-LTx survivors.

Heart rate response and recovery in cycle exercise testing - normal values and association with mortality.

Chronotropic incompetence and impaired heart rate (HR) recovery are related to mortality. Guidelines lack specific reference values for HR recovery. We defined normal values and studied blunted HR response and recovery, and mortality risk. We included 9,917 subjects (45% females) aged 18-85 years who performed a cycle exercise test. We defined normal values for peak HR, HR reserve, and HR recovery at 1 and 2 minutes (HRR1 and HRR2) based on individuals apparently healthy (N=2,242). Associations between blunted HR indices (<5th percentile) and mortality over a median follow-up of 8.6 years were analysed using Cox regression and competing risk analysis. All HR indices were age-dependent and independent predictors of all-cause and CV mortality. The 5th percentiles of HR reserve, HRR1, and HRR2 correlated weakly with existing reference values. HR recovery variables were the strongest predictors of all-cause mortality (HRR1, hazard ratio 1.70 [95% confidence interval, 1.49-1.94] and HRR2, 1.57 [1.37-1.79]), including in subjects with normal exercise capacity (HRR1, 1.96 [1.61-2.39] and HRR2, 1.76 [1.46-2.12]). Combining HR indices appeared to increase the risk of all-cause (HRR1 and HRR2, 1.96 [1.68-2.29] and peak HR and HRR1, 1.87 [1.56-2.23]) and CV mortality, although no specific combination was superior for predicting CV mortality. All HR variables were age-dependent and associated with all-cause and CV mortality. Blunted HR recovery variables were the strongest predictors of all-cause mortality, even in subjects with normal exercise capacity. Combined blunted HR indices appeared to add prognostic value.

Assessment of cardiorespiratory fitness in Chinese patients with early to mid-stage Parkinson’s disease

Purpose To evaluate cardiorespiratory fitness in patients with early to mid-stage Parkinson’s disease by cardiopulmonary exercise test (CPET) on a stationary cycle ergometer. Methods To compare the differences in each index of the cardiopulmonary exercise test between the two groups of subjects; general data such as disease duration, medication use and exercise habits were also collected. Results (1) Finally, 36 Parkinson’s disease patients and 12 healthy controls successfully completed the cardiopulmonary exercise test without any adverse events. (2) The V’O2peak, Metspeak, RERpeak, MVVpeak, Wpeak, HRpeak, HRpeak/pre, percentage of HRR-1 min decay > 12 bpm, SBPpeak in the Parkinson’s disease group were lower than those in the control group (p < .05, each). Detailed data: V’O2peak (15.7 ± 4.5vs21.5 ± 3.6 ml/kg/min, p < .01), Metspeak (4.5 ± 1.3 vs 6.1 ± 1.0, p < .01), RERpeak (1.04 ± 0.10 vs 1.15 ± 0.10, p = .001), MVVpeak (37.22 ± 11.58 vs 53.00 ± 16.85L/min, p = .009), Wpeak (49.17 ± 29.72 vs 49.17 ± 29.72W, p < .01), HRpeak (111.08 ± 16.67 vs 111.08 ± 16.67bpm, p < .01), HRpeak/pre (71.19 ± 10.06 vs 96.00 ± 21.13, p = .002), percentage of HRR-1min decay > 12bpm (33.3% vs 100%, p < .01), systolic blood pressure (155.81 ± 31.83 vs 175.83 ± 17.84 mmHg, p = .01). (3) Divided Parkinson’s disease patients into high V’O2peak group (V’O2peak ≥ 15 mL/kg/min) and low V’O2peak group (V’O2peak < 15 mL/kg/min). The age of patients, Hoehn–Yahr grade and incidence of symptom fluctuation in high V’O2peak group were lower (p < .05, respectively), percentage of males and percentage of HRR-1 min decay > 12 bpm were higher (p < .05, respectively); p < .05 is considered a statistically significant difference. Detailed data: age of patients(61.05 ± 6.93 vs 68.57 ± 7.99 years, p = .005), Hoehn–Yahr grade(1.75 ± 0.48 vs 2.18 ± 0.64, p = .028), incidence of symptom fluctuation (59.1 vs 92.9%, p = .03), percentage of males (77.7 vs 42.9%, p = .041), percentage of HRR-1 min decay > 12 bpm (50 vs 7.1%, p = .008). Conclusions Cardiopulmonary exercise test was safe to perform and the cardiorespiratory fitness is significantly reduced in patients with early and middle stage Parkinson’s disease. Patients with Parkinson’s disease presented blunted heart rate and systolic blood pressure responses to exercise test. Females, older age, fluctuating symptoms, high H-Y staging and higher activities of daily living may be associated with lower oxygen uptake.

Paradoxical increase in global longitudinal strain by handgrip exercise despite left ventricular diastolic dysfunction.

Although global longitudinal strain (GLS) is recognized as a sensitive marker of intrinsic left ventricular (LV) dysfunction, its afterload dependency has also been pointed. We hypothesized that decrease in GLS during handgrip exercise could be more sensitive marker of intrinsic myocardial dysfunction. Handgrip exercise-stress echocardiography was performed in 90 cardiovascular disease patients with preserved LV ejection fraction. LV diastolic function was graded according to the guidelines. Diastolic wall stress (DWS) and ratio of left atrial (LA) volume index to late-diastolic mitral annular velocity (LAVI/a') were measured at rest as LV stiffness. As well, LA strains were measured to assess LA function. GLS was expressed as absolute value and significant changes in GLS by handgrip exercise was defined as changes over prespecified mean absolute test-retest variability (2.65%). While mean value of GLS did not change by the exercise, substantial patients showed significant changes in GLS: decreased (group I, n=28), unchanged (group II, n=34), and increased (group III, n=28). Unexpectedly, patients in group I did not show any clinical and echocardiographic characteristics, while those in group III were characterized by elevated natriuretic peptide levels, blunted heart rate response to handgrip exercise, and advanced LV diastolic dysfunction. Multivariable analyses revealed that DWS, left atrial booster strain, and grade II or more diastolic dysfunction determined the increase in GLS even after adjustment for elevated natriuretic peptides and the changes in heart rate by the exercise. In contrast to our hypothesis, paradoxical increase in GLS by handgrip exercise could be associated with advanced LV diastolic dysfunction in cardiovascular patients with preserved LV ejection fraction. Our findings suggest that HG exercise for heart failure patients does not enhance the afterload straightforward, resulting in variable changes of GLS according to the individual conditions.

Safety, feasibility, and hemodynamic response of regadenoson for stress perfusion CMR

Owing to its pharmacodynamics and posology, the use of regadenoson for stress cardiac magnetic resonance (CMR) has potential advantages over other vasodilators. We sought to evaluate the safety, hemodynamic response and diagnostic performance of regadenoson stress-CMR in routine clinical practice. All regadenoson stress-CMR examinations performed between May 2017 and July 2020 at our institution were retrospectively reviewed. A total of 698 studies were included for the final analysis. A conventional stress/rest protocol was performed using a 1.5T MRI scanner (Magnetom Aera, Siemens Healthineers, Erlangen, Germany). Adverse events, clinical symptoms, and hemodynamic response were assessed. Diagnostic accuracy of the test was evaluated in patients who underwent invasive coronary angiography. Nearly half of patients (48.5%) remained asymptomatic. Most common clinical symptoms included dyspnea (137, 19.6%), chest pain (116, 16.6%) and flushing (44, 6.3%). Two patients (0.28%) could not complete the examination due to severe hypotension or unbearable chest pain. Overall, an increase in heart rate (HR) response (36.2% [IQR: 22.5?50.9]) and a decrease in systolic and diastolic blood pressure (BP) (median systolic BP response of -5% [IQR: -11.5-0.6]; median diastolic BP response of -6.3 mmHg [IQR: -13.4-0]) was observed. Patients with symptoms induced by regadenoson showed higher HR response (40.3%, IQR: 26.4?56.1 vs. 32.4%, IQR: 19-45.6, p < 0.001), whereas a blunted HR response was observed in diabetic (29.6%, IQR: 18.4?42 p < 0.001), obese (31.7%, IQR: 20.7?46.2 p = 0.005) and patients aged 70 years or older (32.9%, IQR: 22.6?43.1 p < 0.001). Overall, regadenoson stress-CMR showed 95.65% (IQ 91.49?99.81) sensitivity, 54.84% (IQ 35.71?73.97) specificity, 86.99% (IQ 82.74?94.68) positive predictive value, and 77.27% (IQ 57.49?97.06) negative predictive value for detecting significant coronary stenosis as compared with invasive coronary angiography. Regadenoson is a well-tolerated vasodilator that can be safely employed for stress perfusion CMR, with high diagnostic performance.

Feasibility of physiological pacing rate in cardiac resynchronization therapy.

Although cardiac resynchronization therapy (CRT) improves functional capacity in heart failure patients, a blunted heart rate (HR) response remains after treatment. So we aimed to evaluate the feasibility of the physiological pacing rate (PPR) in CRT patients. A cohort of 30 clinical mildly symptomatic CRT patients underwent the six-minute walk test (6MWT). During the 6MWT, HR, blood pressure, and maximum walking distance were assessed. The measurements were obtained in a pre to post manner, with CRT at nominal settings and with the physiological phase (CRT PPR), in which HR was increased by 10% above the maximum HR achieved previously. The CRT cohort also comprised a matched control group (CRT CG). In the CRT CG, the 6MWT was repeated after the standard evaluation with no PPR. The evaluations were blinded for patients and for the 6MWT evaluator. During the 6MWT, CRT PPR led to an increase in walking distance of 40.5m (9.2%; P<0.0001) when compared with baseline trial. Additionally, CRT PPR increased the maximum walking distance compared with CRT CG 479.3±68.9m vs. 420.3±44.8m, respectively, P=0.001. In the CRT CG, CRT PPR increased the variation in walking distance, compared with baseline trials, respectively 2.40±3.8% vs. 9.25±7.0%, P=0.007. In mildly symptomatic CRT patients PPR is feasible, leading to improvements in functional capacity. In this regard, the efficacy of PPR must be confirmed by controlled randomized trials.

Effects of peer vicarious experience and low effortful control on children's anxiety in social performance situations.

Two experiments investigated perceived and physiological changes in anxiety in children (7-11 years; N = 222; 98 female) in a performance situation after they observed another child in a similar situation with a negative or neutral outcome. The sample's London, United Kingdom, school catchment areas ranged from low to high socioeconomic statuses with 31% to 49% of children from ethnic minority backgrounds. In Study 1, participants watched one of two films of a child playing a simple musical instrument (a kazoo). In one film, an audience of peers responds negatively to the performance. In the other film, the audience response was neutral. Participants were then filmed playing the instrument themselves and measures of perceived and actual heart rate were taken along with individual differences in trait social anxiety, anxiety sensitivity, and effortful control. To better understand findings from Study 1, Study 2 replicated Study 1 but added a manipulation check and measures of effortful control and self-reported anxiety. Multiple regression analyses found watching a negative performance film, compared with a neutral one, was associated with a blunted heart rate response for children with low effortful control (Study 1 and 2). These findings suggest that children who are low in effortful control may disengage during performance tasks if the situation's social threat is elevated. Hierarchical regression analyses found that, compared to the neutral film, the negative performance film elevated children's self-report anxiety (Study 2). Overall, the findings indicated that anxiety in performance situations can be elevated after observing peers' negative experiences. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Down syndrome patients with normal hearts: are they really normal?

Even though congenital heart disease is a common finding in down syndrome (DS) patients, some of them have anatomically normal hearts. However, the term "normal" might not be suitable, as these patients usually suffer from functional cardiac dysfunction. Several research highlighted that despite the absence of anatomical heart defects, subtle cardiac function derangements are present in DS patients. We aim to assess cardiac functions by Two-dimensional echocardiography and tissue Doppler imaging (TDI) in pediatric DS patients who have anatomically normal hearts. One hundred seventy-two patients with karyotyping confirmed DS with anatomically normal hearts and 165 healthy normal control children were enrolled in the current study. Their cardiac functions were assessed using both 2-dimensional echocardiography and TDI. Both patients and controls had structurally and anatomically normal hearts. In DS patients, the right side of the heart showed a significant reduction in both systolic and diastolic functions. Systolic dysfunction was evident by significantly decreased levels of Tricuspid annular plane systolic excursion and systolic wave by TDI. Diastolic dysfunction of the right ventricle was evident by prolonged deceleration time by conventional echocardiography and a significant decrease in annular tissue doppler velocity during early diastole/late diastole ratio by TDI. The E/De ratio was significantly increased. Even with anatomically normal hearts, DS patients should undergo cardiac function assessment by echocardiography & TDI. TDI is superior to conventional echocardiography in detecting subtle cardiac dysfunction especially left ventricular diastolic dysfunction in DS patients. TDI showed a significant decrease in the early/atrial ratio of mitral valve annulus and prolongation of left ventricle isometric relaxation time in DS children. Also, the left ventricle E/De ratio was prolonged denoting elevated filling pressures and diastolic dysfunction. This indicates that the TDI has higher sensitivity to detect diastolic dysfunction than conventional Echocardiography. Biventricular TDI-derived myocardial performance index was found to be significantly increased in DS children.

PS-B10-5: EFFECTS OF CHRONIC ACETYLCHOLINESTERASE INHIBITION WITH PYRIDOSTIGMINE ON CARDIOVASCULAR SYSTEM AND AUTONOMIC BALANCE IN SPONTANEOUSLY HYPERTENSIVE RATS

Objective: The imbalance in autonomic nervous system, characterized by increased sympathetic and attenuated parasympathetic activity, plays an important role in the pathogenesis of hypertension. The spontaneously hypertensive rats (SHR) which are one of the most studied animal models of essential hypertension, are characterized by autonomic nervous system imbalance. Our study was aimed to determine the effect of chronic inhibition of acetylcholinesterase with pyridostigmine on cardiovascular parameters and sympatho-vagal balance in SHR and Wistar-Kyoto (WKY) rats. Design and method: Adult male SHR and WKY rats were treated with pyridostigmine (25 mg/kg/day) in drinking solution for 2 weeks. The rats were implanted with telemetric transducers to measure blood pressure (BP) and heart rate (HR). Autonomic balance was evaluated by power spectral analysis of systolic blood pressure variability (SBPV) and heart rate variability (HRV). Sympatho-vagal balance was also evaluated pharmacologically by administration of methylatropine (antagonist of muscarinic acetylcholine receptors) and propranolol (antagonist of beta-adrenergic receptors) in a separate set of rats. Results: SHR have elevated BP, increased vascular sympathetic activity (low frequency component of SBPV), and reduced HRV compared to WKY. Pyridostigmine significantly reduced HR in rats of both strains (during both dark and light phase) and BP during the dark (active) phase compared to untreated controls. Acetylcholinesterase activity in plasma was significantly reduced by pyridostigmine treatment in both strains (SHR 53 ± 3%, WKY 46 ± 3%). Sympatho-vagal balance examination revealed reduced cardiac vagal tone in SHR as evidenced by blunted HR response to the muscarinic receptor blocker methylatropine and increased cardiac sympathetic tone as evidenced by elevated HR response to the beta-blocker propranolol. Pyridostigmine treatment increased cardiac vagal tone and decreased cardiac sympathetic tone in SHR to the levels of untreated WKY. Moreover, pyridostigmine increased HRV and reduced low frequency component of SBPV in SHR indicating the restoration of autonomic balance. The reduction of sympathetic tone in pyridostigmine-treated rats was also evident from the reduction of plasma levels of noradrenaline. The potentiation of cardiac parasympathetic activity by pyridostigmine treatment was confirmed by the attenuation of restraint stress-induced tachycardia in both strains. Conclusions: Chronic stimulation of peripheral cholinergic system with pyridostigmine leads to the improvement of autonomic nervous system balance in SHR by increasing cardiac vagal tone and reducing sympathetic tone. Thus, chronic treatment with acetylcholinesterase inhibitors seems to be a promising therapeutic strategy for the restoration of autonomic balance in cardiovascular diseases.

Autonomic Dysfunction Impairs Baroreflex Function in an Alzheimer's Disease Animal Model.

Alzheimer's disease (AD) patients frequently present with orthostatic hypotension. This inability to reflexively increase blood pressure on standing is a serious health concern and increases the risk of stroke and cardiovascular diseases. Since there are no clear mechanisms for orthostatic hypotension in human AD, the present study assessed the autonomic changes that could explain this comorbidity in an AD animal model. We used the established streptozotocin-induced rat model of AD (STZ-AD), which mimics many hallmark symptoms of sporadic AD in humans. Baroreflex responses were analyzed in anesthetized STZ-AD rats using femoral catheterization for blood pressure and heart rate, and autonomic activity was assessed using specific blockers and splanchnic sympathetic nerve recordings. Expression levels of autonomic receptors at the heart were examined using the western blot technique. Baroreflex function in STZ-AD showed a blunted heart rate (HR) response to low blood pressure challenges, and the maximal sympathetic nerve activity was reduced. Conversely, HR responses to high blood pressure were similar to control, indicating no change in parasympathetic nerve activity. Under resting conditions, autonomic blockade demonstrated a baseline shift to increased sympathetic tone in STZ-AD. Protein expression levels of beta-1 adrenergic receptor and muscarinic acetylcholine receptor M2 in the heart were unchanged. Our study provides the first data on the pathological influence of AD on baroreflex function, which primarily affected the sympathetic nervous system in STZ-AD. These results represent the first mechanisms that may correlate with the orthostatic hypotension in human AD.

Cardiac Screening - Soccer

HISTORY: 18 year old male collegiate soccer player presented for routine physical for varsity soccer team. Unremarkable past medical history aside from an adenectomy as a child. Negative sickle cell disease screening and up to date on vaccinations. Screening EKG notable for a prolonged QT/QTc 520/510ms. He denied any cardiac symptoms, but noted a syncopal event at age 16, when he went from sitting to standing, associated with blurry vision and dizziness. At that time, he had quick return of consciousness and did not seek medical attention. Denied use use of any performance-enhancing drugs PHYSICAL EXAMINATION: General: athletic young man HEENT: midline trachea, no thyroid enlargement Respiratory: lungs clear to auscultation and percussion Cardiovascular: sinus bradycardia, no murmurs Abdomen: non-tender without organomegaly Extremities: no edema DIFFERENTIAL DIAGNOSIS: Congenital LQTS; Acquired LQTS; Bradyarrhythmia (AV block) TEST AND RESULTS: BMP and TSH normal; Repeat EKG significant for bradycardia, uncorrected QT 520ms, broad-based T wave. Echocardiogram with ejection fraction 62%, structurally normal. Wore a Zio patch: range of 33bpm-176bpm, average 61bpm. Predominantly sinus. Underwent stress testing, reached 81.2% predicted MHR, BP 178/75, no chest discomfort, normal ST segment response to stress. Referred to Genetic Counsellor for Diagnostic Testing. The pathogenic variant, c.1552CT (p.Arg518*), was identified in KCNQ1 (AD/AR arrhythmia conditions), as well as variants of uncertain significance in MYH6 and RBM20. FINAL WORKING DIAGNOSIS: Congenital long QT syndrome (LQTS) due to heterozygous mutation at KCNQ1, Exon 12, c.1552C >T (p.Arg518*). This pathogenic mutation causes a premature translational stop signal at codon 518 of KCNQ1 gene, this is known to cause LQTS. Heterozygous carriers with typically mild clinical manifestions. TREATMENT AND OUTCOMES: The athlete was started on nadolol 40mg tablet once daily, then uptitrated to 80mg shortly thereafter. A repeat EKG showed sinus bradycardia and a shorter QT 480ms. Repeat stress testing notable for a blunted heart rate response (as expected on a beta-blocker), QT of 380ms with no QT prolongation during maximal exercise. The athlete’s family purchased a defibrillator for home use, and he has been cleared to return to varsity athletics.

Effects of circulating estradiol on physiological, behavioural, and subjective correlates of anxiety: A double-blind, randomized, placebo-controlled trial

Anxiety-related behaviours as well as the prevalence of anxiety disorders show a large sex difference in humans. Clinical studies in humans as well as behavioural studies in rodents suggest that estradiol may have anxiolytic properties. In line with this, anxiety symptoms fluctuate with estradiol levels along the menstrual cycle. However, the influence of estradiol on subjective, behavioural, as well as physiological correlates of anxiety has never been systematically addressed in humans.We ran a double-blind, randomized, placebo-controlled study (N = 126) to investigate the effects of estradiol on anxiety in men and women. In healthy volunteers, circulating estradiol levels were elevated through estradiol administration over two consecutive days to simulate the rise in estradiol levels around ovulation. Subjective, behavioral, as well as, physiological correlates of anxiety were assessed using a virtual reality elevated plus-maze (EPM).Estradiol treatment reduced the physiological stress response with blunted heart rate response and lower cortisol levels compared to placebo treatment in both sexes. In contrast, respiration frequency was only reduced in women after estradiol treatment. Behavioural measures of anxiety as well as subjective anxiety on the EPM were not affected by estradiol treatment. In general, women showed more avoidance and less approach behavior and reported higher subjective anxiety levels on the EPM than men.These results highlight the limited anxiolytic properties of circulating levels of estradiol in humans, which influence physiological markers of anxiety but not approach and avoidance behaviour or subjective anxiety levels.

Regadenoson stress CMR: safety, feasibility and hemodynamic response

Abstract Background and objectives The use of regadenoson for stress cardiac magnetic resonance (CMR) has potential advantages over other vasodilators. We sought to evaluate the safety, feasibility and hemodynamic response (heart rate and blood pressure) of regadenoson in an unselected population undergoing stress CMR for clinical work-up. Methods A total of 603 regadenoson stress CMR clinical examinations performed between May 2017 and May 2020 in our institution were retrospectively reviewed. Studies were performed using a conventional stress/rest CMR protocol with a 1.5T MRI scanner. A fixed dose of 5 ml of regadenoson was employed as stressor. As part of the protocol, 200 mg of theophylline was administered between stress and rest acquisitions to reverse the vasodilator effect of regadenoson. Adverse events, clinical symptoms, and hemodynamic response were assessed. Results In our cohort, no severe adverse events requiring hospitalization were observed, and only 5 adverse events were reported (0.83%). Only two patients (0.3%) did not complete the test due to adverse events or symptoms related to regadenoson administration (one case presented severe hypotension; the other presented unbearable chest pain). There were no cases of bronchospasm, stress-induced arrhythmia or death. Over half of patients reported mild symptoms after drug administration (52%, n=314), more frequently dyspnea (19%, n=112), chest pain (18%, n=106) and flushing (6%, n=34). All symptoms resolved after theophylline administration. Overall, an increase in heart rate (mean increase and (standard deviation) = 24 (12.6) bpm and a mild decrease in systolic (−8.2 (17.1) mmHg) and diastolic (−4.9 (10.2) mmHg) blood pressure were observed as response to regadenoson. A blunted heart rate response was observed in elderly (p&amp;lt;0.01), diabetic (p&amp;lt;0.01) and obese (p=0.01) patients. Only 46 patients (7.8%) did not show tachycardization response. Conclusions The use of regadenoson in stress CMR proved to be safe and feasible in the vast majority of patients. Adverse events were not frequent with regadenoson and symptoms were transient and well tolerated, while premature ending of the test related to drug administration was very rare. Funding Acknowledgement Type of funding sources: None. Hemodynamic response

Mortality among patients undergoing dipyridamole 99mTc Sestamibi SPECT: impact of blunted heart rate response and abnormal scans

Abstract Background Blunted heart rate response (BHRR) caused by cardiac neuropathy associated with dipyridamole stress, has been linked to cardiovascular (CV) outcome events. Whether BHRR is necessarily associated with abnormal perfusion is unknown. The aim of the study was to assess the incremental prognostic value of BHRR in a single center population undergoing Dipyridamole 99mTc Sestamibi SPECT test (DSPECT) for predicting late CV events. Methods 388 patients (aged 73±10 years, 45% females, 51% with known coronary disease) that underwent DSPECT over 3 years period were included. Abnormal DSPECT and BHRR were evaluated in relation to late death. Results Mean follow up period was 1560±565 (15–2431) days. During follow up period, 90 patients died. Mode of death was CV in 20 and non-CV in 70. BHRR (&amp;lt;20% heart rate increase), abnormal DSPECT, post-stress LVEF &amp;lt;60% and reversible defects were observed in 63%, 41%, 23% and 20% of patients, respectively. BHRR (HR -2.41, p&amp;lt;0.0006) and abnormal DSPECT (HR-1.62, p=0.02) were predictors of all-cause death. BHRR had incremental prognostic value over abnormal DSPECT (Figure, p&amp;lt;0.0005). Multivariable analysis identified age, dyspnea, insulin treated diabetes mellitus and dialysis as independent predictors of death while DSPECT and BHRR did not. However, BHRR remained a significant predictor of CV death [HR 8.1 (1.06, 62.0), p&amp;lt;0.05]. Conclusions In this contemporary DSPECT cohort, BHRR and DSPECT failed to predict all-cause mortality. However, BHRR was an independent predictor of CV death. Funding Acknowledgement Type of funding sources: None. BHRR stratifies abnormal DSPECT

OSA and cardiorespiratory fitness: a review.

Powell TA, Mysliwiec V, Brock MS, Morris MJ. OSA and cardiorespiratory fitness: a review. J Clin Sleep Med. 2022;18(1):279-288.

B-PO02-020 PDE4D MEDIATES DESENSITIZATION OF Β-ADRENERGIC RECEPTORS IN THE SINOATRIAL NODE IN HYPERTENSIVE HEART DISEASE

Chronotropic incompetence is common in hypertensive heart disease due to impaired β-adrenergic receptor (β-AR) responsiveness of the sinoatrial node (SAN). To determine the mechanism for impaired β-AR signaling in the SAN of angiotensin II (AngII) induced hypertensive heart disease. C57BL/6 mice were infused with saline or AngII (2.5mg/kg/day) for 21 days to induce hypertensive heart disease. Heart rate (HR) and SAN function in response to the β-AR agonist isoproterenol (ISO) were studied by in vivo electrocardiography, in isolated atrial preparations by optical mapping, in isolated SAN myocytes by patch-clamping, and by molecular techniques. AngII infused mice had impaired HR increases in response to ISO (100mg/kg) in vivo (171.1±7.1 vs. 134±9.8 bpm; n=5-6 mice; P<0.05) and in isolated atrial preparations (10μM ISO; 160.4±9.7 vs. 96.6±7.8, n=5-6 hearts; P<0.05). ISO (10μM) induced increases in SAN conduction velocity were also smaller in AngII infused hearts (1.6±0.1 vs. 1.1±0.1 cm/s, n=5-6 hearts; P<0.05). The effects of ISO (10μM) in isolated SAN myocytes after AngII infusion were impaired as indicated by smaller increases in spontaneous action potential (AP) firing (54.5±4.6 vs. 28.3±2.7 AP/min; P<0.001), diastolic depolarization (DD) slope (33.2±3.8 vs. 19.0±3.5 mV/s; P<0.05), peak “funny” current (-3.7±0.2 vs. -1.8±0.1 pA/pF; P<0.05), and peak L-type Ca2+ current (-6.9±1.3 vs. -3.5±0.7 pA/pF; P<0.05; n=7-15 cells). SAN myocytes from AngII infused mice had diminished cAMP generation in response to ISO (126.5±4.7 vs. 103.7±5.3 nM/1000 cells; P<0.05). No differences were seen in the protein expression of β1- or β2-ARs (both n=6; P>0.05); however, AngII infused mice had increased SAN PDE4 activity (1.4±0.3 vs. 3.9±0.9 pmol/mg/min, n=5; P<0.05). Total PDE4 expression was unaltered in the SAN of AngII infused mice but localization of PDE4D surrounding both β1- and β2-ARs was increased (n=6; P<0.05). Acute application of the PDE4 inhibitor rolipram (10μM) normalized ISO (10nM) induced increases in AP firing and DD slope in SAN myocytes (n=8-10) from AngII infused mice. AngII infusion results in blunted HR responses to β-AR stimulation due to upregulation of PDE4D specifically around β-ARs in the SAN.

Amyotrophic Lateral Sclerosis, Resistance Training, Endurance Exercise, Tolerance, and Compliance

Amyotrophic Lateral Sclerosis, Resistance Training, Endurance Exercise, Tolerance, and Compliance

395 Exercise Capacity is Maintained in Older Military Personnel with Moderate to Severe Obstructive Sleep Apnea

Abstract Introduction The relationship between moderate to severe OSA and exercise capacity remains unclear. Prior studies showing a reduction in VO2 max in this population have mostly involved middle-aged and overweight patients. We looked to determine if this trend in VO2 max was present in a similarly aged population of military personnel with previously undiagnosed moderate to severe OSA. Methods We studied 170 middle-aged male military members who underwent cardiopulmonary exercise testing (CPET) and polysomnography (PSG) as a part of a comprehensive evaluation for an established military program. For analysis, patients were categorized either into an OSA group (apnea-hypopnea index (AHI) ≥ 15 events/h) or control group (AHI &amp;lt; 15 events/h). VO2 max was compared between groups. Results Mean AHI was 29.0 in the OSA group (n =58) versus 7.4 in the controls (n = 112). Patients were of similar age (53.1 vs. 53.7 years) and BMI was slightly higher in the OSA group (27.5kg/m2 versus 26.3 kg/m2, P = .0077). Percent-predicted VO2 max was supernormal in both groups, though was comparatively lower in the OSA group (117% vs. 125%; P &amp;lt;.001). There was a trend toward a blunted heart rate response to exercise in the OSA group as represented by peak heart rate (163 vs. 178; p=0.07). Conclusion Older military personnel with moderate to severe OSA have normal exercise capacity. This may suggest that the low-arousal OSA phenotype often noted in military personnel does not significantly influence exercise capacity or that regular exercise helps limit its impact. It remains likely that the effect of untreated OSA on exercise capacity is influenced by several variables including age, BMI, OSA phenotype, and regularity of exercise. Trends in VO2 max and peak heart rate noted in this study may suggest that untreated OSA in certain populations can negatively impact exercise capacity Support (if any) No external funding