Cardiovascular remodelling in response to exercise training in patients after the Fontan procedure: a pilot study.

BACKGROUND: The cardiovascular adaptations associated with structured exercise training in Fontan patients remain unknown. We hypothesised that short-term training causes cardiac remodelling and parallel improvement in maximal exercise capacity (VO2 max) in these patients. METHODS AND RESULTS: Five patients, median age 19.5 (17.6-21.3) years, with a history of Fontan operation meeting inclusion/exclusion criteria, participated in a 3-month training programme designed to improve endurance. Magnetic resonance images for assessment of cardiac function, fibrosis, cardiac output, and liver elastography to assess stiffness were obtained at baseline and after training. Maximal exercise capacity (VO2 max) and cardiac output Qc (effective pulmonary blood flow) at rest and during exercise were measured (C2H2 rebreathing) at the same interval. VO2 max increased from median (IQR) 27.2 (26-28.7) to 29.6 (28.5-32.2) ml/min/kg (p = 0.04). There was an improvement in cardiac output (Qc) during maximal exercise testing from median (IQR) 10.3 (10.1-12.3) to 12.3 (10.9-14.9) l/min, but this change was variable (p = 0.14). Improvement in VO2 max correlated with an increase in ventricular mass (r = 0.95, p = 0.01), and improvement in Quality-of-life inventory (PedsQL) Cardiac scale scores for patient-reported symptoms (r = 0.90, p = 0.03) and cognitive problems (r = 0.89, p = 0.04). The correlation between VO2 max and Qc showed a positive trend but was not significant (r = 0.8, p = 0.08). No adverse cardiac or liver adaptations were noted. CONCLUSION: Short-term training improved exercise capacity in this Fontan pilot without any adverse cardiac or liver adaptations. These results warrant further study in a larger population and over a longer duration of time. TRIAL REGISTRATION NUMBER: NCT03263312, Unique Protocol ID: STU 122016-037; Registration Date: 18 January, 2017.

Central Command and the Regulation of Exercise Heart Rate Response in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Chronotropic incompetence is common in heart failure with preserved ejection fraction (HFpEF) and is linked to impaired aerobic capacity. Whether upstream autonomic signaling pathways responsible for raising exercise heart rate are impaired in HFpEF is unknown. We investigated the integrity of central command and muscle metaboreceptor function, 2 predominant mechanisms responsible for exertional increases in heart rate, in patients with HFpEF and senior controls. METHODS: Fourteen healthy senior controls (7 men, 7 women) and 20 carefully screened patients with HFpEF (8 men, 12 women) underwent cardiopulmonary exercise testing (peak Vo2) and static handgrip exercise at 40% of maximal voluntary contraction to fatigue with postexercise circulatory arrest for 2 minutes to assess central command and metaboreceptor function, respectively. RESULTS: Peak Vo2 (13.1±3.4 versus 22.7±4.0 mL/kg/min; P<0.001) and heart rate (122±20 versus 155±14 bpm; P<0.001) were lower in patients with HFpEF than senior controls. There were no significant differences in peak heart rate response during static handgrip between groups (patients with HFpEF versus controls: 90±13 versus 93±10 bpm; P=0.49). Metaboreceptor function, defined as mean arterial blood pressure at the end of postexercise circulatory arrest, was not significantly different between groups. CONCLUSIONS: Central command (vagally mediated) and metaboreceptor function (sympathetically mediated) in patients with HFpEF were not different from those in healthy senior controls despite significantly lower peak whole-body exercise heart rates. These results demonstrate key reflex autonomic pathways regulating exercise heart rate responsiveness are intact in HFpEF.

One-Year Committed Exercise Training Reverses Abnormal Left Ventricular Myocardial Stiffness in Patients With Stage B Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Individuals with left ventricular (LV) hypertrophy and elevated cardiac biomarkers in middle age are at increased risk for the development of heart failure with preserved ejection fraction. Prolonged exercise training reverses the LV stiffening associated with healthy but sedentary aging; however, whether it can also normalize LV myocardial stiffness in patients at high risk for heart failure with preserved ejection fraction is unknown. In a prospective, randomized controlled trial, we hypothesized that 1-year prolonged exercise training would reduce LV myocardial stiffness in patients with LV hypertrophy. METHODS: Forty-six patients with LV hypertrophy (LV septum >11 mm) and elevated cardiac biomarkers (N-terminal pro-B-type natriuretic peptide [>40 pg/mL] or high-sensitivity troponin T [>0.6 pg/mL]) were randomly assigned to either 1 year of high-intensity exercise training (n=30) or attention control (n=16). Right-heart catheterization and 3-dimensional echocardiography were performed while preload was manipulated using both lower body negative pressure and rapid saline infusion to define the LV end-diastolic pressure-volume relationship. A constant representing LV myocardial stiffness was calculated from the following: P=S×[Exp {a (V-V0)}-1], where "P" is transmural pressure (pulmonary capillary wedge pressure - right atrial pressure), "S" is the pressure asymptote of the curve, "V" is the LV end-diastolic volume index, "V0" is equilibrium volume, and "a" is the constant that characterizes LV myocardial stiffness. RESULTS: Thirty-one participants (exercise group [n=20]: 54±6 years, 65% male; and controls (n=11): 51±6 years, 55% male) completed the study. One year of exercise training increased max by 21% (baseline 26.0±5.3 to 1 year later 31.3±5.8 mL·min-1·kg-1, P<0.0001, interaction P=0.0004), whereas there was no significant change in max in controls (baseline 24.6±3.4 to 1 year later 24.2±4.1 mL·min-1·kg-1, P=0.986). LV myocardial stiffness was reduced (right and downward shift in the end-diastolic pressure-volume relationship; LV myocardial stiffness: baseline 0.062±0.020 to 1 year later 0.031±0.009), whereas there was no significant change in controls (baseline 0.061±0.033 to 1 year later 0.066±0.031, interaction P=0.001). CONCLUSIONS: In patients with LV hypertrophy and elevated cardiac biomarkers (stage B heart failure with preserved ejection fraction), 1 year of exercise training reduced LV myocardial stiffness. Thus, exercise training may provide protection against the future risk of heart failure with preserved ejection fraction in such patients. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03476785.

Increased Myocardial Stiffness in Patients With High-Risk Left Ventricular Hypertrophy: The Hallmark of Stage-B Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Individuals with left ventricular hypertrophy (LVH) and elevated cardiac biomarkers in middle age are at high risk for the development of heart failure with preserved ejection fraction (HFpEF). However, it is unknown what the pathophysiological underpinnings of this high-risk state may be. We tested the hypothesis that patients with LVH and elevated cardiac biomarkers would demonstrate elevated left ventricular (LV) myocardial stiffness in comparison with healthy controls as a key marker for future HFpEF. METHODS: Forty-six patients with LVH (LV septum >11 mm) and elevated cardiac biomarkers (N-terminal pro-B-type natriuretic peptide [>40 pg/mL] or troponin T [>0.6 pg/mL]) were recruited, along with 61 age- and sex-matched (by cohort) healthy controls. To define LV pressure-volume relationships, right heart catheterization and 3-dimensional echocardiography were performed while preload was manipulated using lower body negative pressure and rapid saline infusion. RESULTS: There were significant differences in body size, blood pressure, and baseline pulmonary capillary wedge pressure between groups (eg, pulmonary capillary wedge pressure: LVH, 13.4±2.7 versus control, 11.7±1.7 mm Hg, P<0.0001). The LV was less distensible in LVH than in controls (smaller volume for the same filling pressure). When preload was expressed as transmural filling pressure (pulmonary capillary wedge pressure - right atrial pressure), LV myocardial stiffness was nearly 30% greater in LVH than in controls (LVH stiffness constant, 0.053±0.027 versus controls, 0.042±0.020, P=0.028). CONCLUSIONS: LV myocardial stiffness in patients with LVH and elevated biomarkers (stage-B HFpEF) is greater than in age- and sex-matched controls and thus appears to represent a transitional state from a normal healthy heart to HFpEF. Although the LV myocardial stiffness of patients with LVH is greater than that of healthy controls at this early stage, further studies are required to clarify whether interventions such as exercise training to improve LV compliance may prevent the full manifestation of the HFpEF syndrome in these high-risk individuals. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT03476785 and NCT02039154.

Left Atrial Electromechanical Remodeling Following 2 Years of High-Intensity Exercise Training in Sedentary Middle-Aged Adults.

BACKGROUND: Moderate intensity exercise is associated with a decreased incidence of atrial fibrillation. However, extensive training in competitive athletes is associated with an increased atrial fibrillation risk. We evaluated the effects of 24 months of high intensity exercise training on left atrial (LA) mechanical and electric remodeling in sedentary, healthy middle-aged adults. METHODS: Sixty-one participants (53±5 years) were randomized to 10 months of exercise training followed by 14 months of maintenance exercise or stretching/balance control. Fourteen Masters athletes were added for comparison. Left ventricular (LV) and LA volumes underwent 3D echocardiographic assessment, and signal-averaged electrocardiographs for filtered P-wave duration and atrial late potentials were completed at 0, 10, and 24 months. Extended ambulatory monitoring was performed at 0 and 24 months. Within and between group differences from baseline were compared using mixed-effects model repeated-measures analysis. RESULTS: Fifty-three participants completed the study (25 control, 28 exercise) with 88±11% adherence to assigned exercise sessions. In the exercise group, both LA and LV end diastolic volumes increased proportionately (19% and 17%, respectively) after 10 months of training (peak training load). However, only LA volumes continued to increase with an additional 14 months of exercise training (LA volumes 55%; LV end diastolic volumes 15% at 24 months versus baseline; P<0.0001 for all). The LA:LV end diastolic volumes ratio did not change from baseline to 10 months, but increased 31% from baseline in the Ex group ( P<0.0001) at 24 months, without a change in controls. There were no between group differences in the LA ejection fraction, filtered P-wave duration, atrial late potentials, and premature atrial contraction burden at 24 months and no atrial fibrillation was detected. Compared with Masters athletes, the exercise group demonstrated lower absolute LA and LV volumes, but had a similar LA:LV ratio after 24 months of training. CONCLUSIONS: Twenty-four months of high intensity exercise training resulted in LA greater than LV mechanical remodeling with no observed electric remodeling. Together, these data suggest different thresholds for electrophysiological and mechanical changes may exist in response to exercise training, and provide evidence supporting a potential mechanism by which high intensity exercise training leads to atrial fibrillation. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02039154.

The impact of 2 years of high-intensity exercise training on a model of integrated cardiovascular regulation.

KEY POINTS: Heart rate variability, a common and easily measured index of cardiovascular dynamics, is the output variable of complicated cardiovascular and respiratory control systems. Both neural and non-neural control mechanisms may contribute to changes in heart rate variability. We previously developed an innovative method using transfer function analysis to assess the effect of prolonged exercise training on integrated cardiovascular regulation. In the present study, we modified and applied this to investigate the effect of 2 years of high-intensity training on circulatory components to tease out the primary effects of training. Our method incorporated the dynamic Starling mechanism, dynamic arterial elastance and arterial-cardiac baroreflex function. The dynamic Starling mechanism gain and arterial-cardiac baroreflex gain were significantly increased in the exercise group. These parameters remained unchanged in the controls. Conversely, neither group experienced a change in dynamic arterial elastance. The integrated cardiovascular regulation gain in the exercise group was 1.34-fold larger than that in the control group after the intervention. In these previously sedentary, otherwise healthy, middle-aged adults, 2 years of high-intensity exercise training improved integrated cardiovascular regulation by enhancing the dynamic Starling mechanism and arterial-cardiac baroreflex sensitivity. ABSTRACT: Assessing the effects of exercise training on cardiovascular variability is challenging because of the complexity of multiple mechanisms. In a prospective, parallel-group, randomized controlled study, we examined the effect of 2 years of high-intensity exercise training on integrated cardiovascular function, which incorporates the dynamic Starling mechanism, dynamic arterial elastance and arterial-cardiac baroreflex function. Sixty-one healthy participants (48% male, aged 53 years, range 52-54 years) were randomized to either 2 years of exercise training (exercise group: n = 34) or control/yoga group (controls: n = 27). Before and after 2 years, subjects underwent a 6 min recording of beat-by-beat pulmonary artery diastolic pressure (PAD), stroke volume index (SV index), systolic blood pressure (sBP) and RR interval measurements with controlled respiration at 0.2 Hz. The dynamic Starling mechanism, dynamic arterial elastance and arterial-cardiac baroreflex function were calculated by transfer function gain between PAD and SV index; SV index and sBP; and sBP and RR interval, respectively. Fifty-three participants (controls: n = 25; exercise group: n = 28) completed the intervention. After 2 years, the dynamic Starling mechanism gain (Group × Time interaction: P = 0.008) and the arterial-cardiac baroreflex gain (P = 0.005) were significantly increased in the exercise group but remained unchanged in the controls. There was no change in dynamic arterial elastance in either of the two groups. The integrated cardiovascular function gain in the exercise group increased 1.34-fold, whereas there was no change in the controls (P = 0.02). In these previously sedentary, otherwise healthy middle-aged adults, a 2 year programme of high-intensity exercise training improved integrated cardiovascular regulation by enhancing the dynamic Starling mechanism and arterial-cardiac baroreflex sensitivity, without changing dynamic arterial elastance.

SERCA2a Agonist Effects on Cardiac Performance During Exercise in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Impaired ventricular relaxation influences left ventricular pressures during exercise in heart failure with preserved ejection fraction (HFpEF). Sarco/endoplasmic reticulum calcium-adenosine triphosphatase (SERCA2a) facilitates myocardial relaxation by increasing calcium reuptake and is impaired in HFpEF. OBJECTIVES: This study sought to investigate the effects of istaroxime, a SERCA2 agonist, on lusitropic and hemodynamic function during exercise in patients with HFpEF and control subjects. METHODS: Eleven control subjects (7 male, 4 female) and 15 patients with HFpEF (8 male, 7 female) performed upright cycle exercise with right-sided heart catheterization. Participants received istaroxime (0.5 µg/kg/min) or saline placebo (single-blind, crossover design). Cardiac output, pulmonary capillary wedge pressure (PCWP), and diastolic function were measured at rest and during submaximal exercise. In an exploratory analysis (Hedge's g), 7 patients with HFpEF received higher-dose istaroxime (1.0 µg/kg/min). End-systolic elastance (Ees) was calculated by dividing systolic blood pressure (SBP) × 0.9 by end-systolic volume (ESV) (on 3-dimensional echocardiography). RESULTS: Patients with HFpEF had higher PCWP (25 ± 10 mm Hg vs 12 ± 5 mm Hg; P < 0.001) and lower tissue Doppler velocities during exercise. Istaroxime (0.5 µg/kg/min) had no effect on resting or exercise measures in patients with HFpEF or control subjects. Control subjects had a larger increase in Ees (Δ 1.55 ± 0.99 mm Hg/mL vs Δ 0.86 ± 1.31 mm Hg/mL; P = 0.03), driven by lower ESV. Comparing placebo and istaroxime 1.0 µg/kg/min during exercise, PCWP during the 1.0 µg/kg/min istaroxime dose was slightly lower (Δ 2.2 mm Hg; Hedge's g = 0.30). There were no effects on diastolic function, but there were increases in SBP and s', suggesting a mild inotropic effect. CONCLUSIONS: Low-dose istaroxime had no effect on cardiac filling pressure or parameters of relaxation in patients with HFpEF during exercise. Higher doses of istaroxime may have been more effective in reducing exercise PCWP in patients with HFpEF. (Hemodynamic Response to Exercise in HFpEF Patients After Upregulation of SERCA2a; NCT02772068).

Randomized Controlled Trial of Moderate- and High-Intensity Exercise Training in Patients With Hypertrophic Cardiomyopathy: Effects on Fitness and Cardiovascular Response to Exercise.

Background Moderate intensity exercise training (MIT) is safe and effective for patients with hypertrophic cardiomyopathy, yet the efficacy of high intensity training (HIT) remains unknown. This study aimed to compare the efficacy of HIT compared with MIT in patients with hypertrophic cardiomyopathy. Methods and Results Patients with hypertrophic cardiomyopathy were randomized to either 5 months of MIT, or 1 month of MIT followed by 4 months of progressive HIT. Peak oxygen uptake (V˙O2; Douglas bags), cardiac output (acetylene rebreathing), and arteriovenous oxygen difference (Fick equation) were measured before and after training. Left ventricular outflow gradient and volumes were measured by echocardiography. Fifteen patients completed training (MIT, n=8, age 52±7 years; HIT, n=7, age 42±8 years). Both HIT and MIT improved peak V˙O2 by 1.3 mL/kg per min (P=0.009). HIT (+1.5 mL/kg per min) had a slightly greater effect than MIT (+1.1 mL/kg per min) but with no statistical difference (group×exercise P=0.628). A greater augmentation of arteriovenous oxygen difference occurred with exercise (Δ1.6 mL/100 mL P=0.005). HIT increased left ventricular end-diastolic volume (+17 mL, group×exercise P=0.015) compared with MIT. No serious arrhythmias or adverse cardiac events occurred. Conclusions This randomized trial of exercise training in patients with hypertrophic cardiomyopathy demonstrated that both HIT and MIT improved fitness without clear superiority of either. Although the study was underpowered for safety outcomes, no serious adverse events occurred. Exercise training resulted in salutary peripheral and cardiac adaptations. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03335332.

Isolated knee extensor exercise training improves skeletal muscle vasodilation, blood flow, and functional capacity in patients with HFpEF.

Patients with HFpEF experience severe exercise intolerance due in part to peripheral vascular and skeletal muscle impairments. Interventions targeting peripheral adaptations to exercise training may reverse vascular dysfunction, increase peripheral oxidative capacity, and improve functional capacity in HFpEF. Determine if 8 weeks of isolated knee extension exercise (KE) training will reverse vascular dysfunction, peripheral oxygen utilization, and exercise capacity in patients with HFpEF. Nine HFpEF patients (66 ± 5 years, 6 females) performed graded IKE exercise (5, 10, and 15 W) and maximal exercise testing (cycle ergometer) before and after IKE training (3x/week, 30 min/leg). Femoral blood flow (ultrasound) and leg vascular conductance (LVC; index of vasodilation) were measured during graded IKE exercise. Peak pulmonary oxygen uptake (V̇O2 ; Douglas bags) and cardiac output (QC ; acetylene rebreathe) were measured during graded maximal cycle exercise. IKE training improved LVC (pre: 810 ± 417, post: 1234 ± 347 ml/min/100 mmHg; p = 0.01) during 15 W IKE exercise and increased functional capacity by 13% (peak V̇O2 during cycle ergometry; pre:12.4 ± 5.2, post: 14.0 ± 6.0 ml/min/kg; p = 0.01). The improvement in peak V̇O2 was independent of changes in Q̇c (pre:12.7 ± 3.5, post: 13.2 ± 3.9 L/min; p = 0.26) and due primarily to increased a-vO2 difference (pre: 10.3 ± 1.6, post: 11.0 ± 1.7; p = 0.02). IKE training improved vasodilation and functional capacity in patients with HFpEF. Exercise interventions aimed at increasing peripheral oxidative capacity may be effective therapeutic options for HFpEF patients.

1 Year HIIT and Omega-3 Fatty Acids to Improve Cardiometabolic Risk in Stage-A Heart Failure.

OBJECTIVES: This study aims to determine whether 1 year of high-intensity interval training (HIIT) and omega-3 fatty acid (n-3 FA) supplementation would improve fitness, cardiovascular structure/function, and body composition in obese middle-aged adults at high-risk of heart failure (HF) (stage A). BACKGROUND: It is unclear if intensive lifestyle interventions begun in stage A HF can improve key cardiovascular and metabolic risk factors. METHODS: High-risk obese adults (n = 80; age 40 to 55 years; N-terminal pro-B-type natriuretic peptide >40 pg/mL or high-sensitivity cardiac troponin T >0.6 pg/mL; visceral fat >2 kg) were randomized to 1 year of HIIT exercise or attention control, with n-3 FA (1.6 g/daily omega-3-acid ethyl esters) or placebo supplementation (olive oil 1.6 g daily). Outcome variables were exercise capacity quantified as peak oxygen uptake (V.O2), left ventricular (LV) mass, LV volume, myocardial triglyceride content (magnetic resonance spectroscopy), arterial stiffness/function (central pulsed-wave velocity; augmentation index), and body composition (dual x-ray absorptiometry scan). RESULTS: Fifty-six volunteers completed the intervention. There was no detectible effect of HIIT on visceral fat or myocardial triglyceride content despite a reduction in total adiposity (Δ: -2.63 kg, 95% CI: -4.08 to -0.46, P = 0.018). HIIT improved exercise capacity by ∼24% (ΔV.O2: 4.46 mL/kg per minute, 95% CI: 3.18 to 5.56; P < 0.0001), increased LV mass (Δ: 9.40 g, 95% CI: 4.36 to 14.44; P < 0.001), and volume (Δ: 12.33 mL, 95 % CI: 5.61 to 19.05; P < 0.001) and reduced augmentation index (Δ: -4.81%, 95% CI: -8.63 to -0.98; P = 0.009). There was no independent or interaction effect of n-3 FA on any outcome. CONCLUSIONS: One-year HIIT improved exercise capacity, cardiovascular structure/function, and adiposity in stage A HF with no independent or additive effect of n-3 FA administration. (Improving Metabolic Health in Patients With Diastolic Dysfunction [MTG]; NCT03448185).

Evidence of Reduced Efferent Renal Sympathetic Innervation After Chemical Renal Denervation in Humans.

BACKGROUND: Renal denervation (RDN) is effective at lowering blood pressure. However, it is unknown if ablative procedures elicit sympathetic denervation of the kidneys in humans. The aim of this investigation was to assess sympathetic innervation of the renal cortex following perivascular chemical RDN, which may be particularly effective at ablating perivascular efferent and afferent nerves. METHODS: Seven hypertensive patients (4F:3M; 50-65 years) completed PET-CT sympathetic neuroimaging of the renal cortex using 11C-methylreboxetine (11C-MRB, norepinephrine transporter ligand) and 6-[18F]-fluorodopamine (18F-FDA; substrate for the cell membrane norepinephrine transporter) before and 8 weeks after chemical RDN (Peregrine System Infusion Catheter, Ablative Solutions; n = 4; 2F:2M) or control renal angiography (n = 3; 2F:1M). Patients completed physiological phenotyping including 24-hour ambulatory blood pressure, hemodynamics, muscle sympathetic nerve activity, and 24-hour urine collection. RESULTS: RDN decreased 11C-MRB-derived radioactivity by ~30% (Δ  11C-MRB/chamber: -0.95 a.u. confidence interval (CI): -1.36 to -0.54, P = 0.0002), indicative of efferent RDN. In contrast, 18F-FDA-derived radioactivity increased (Δ  18F-FDA/chamber: 2.72 a.u. CI: 0.73-4.71, P = 0.009), consistent with reduced vesicular turnover. Controls showed no change in either marker. Ambulatory systolic pressure decreased in 3 of 4 patients (-9 mm Hg CI: -27 to 9, P = 0.058), and central systolic pressure decreased in all patients (-23 mm Hg CI: -51 to 5, P = 0.095). CONCLUSIONS: These results are the first to show efferent sympathetic denervation of the renal cortex following RDN in humans. Further studies of mechanisms underlying variable blood pressure lowering in the setting of documented RDN may provide insights into inconsistencies in clinical trial outcomes. CLINICAL TRIALS REGISTRATION: Trial Number NCT03465917.

Impact of severe obesity on exercise performance in heart failure with preserved ejection fraction.

BACKGROUND: Obesity plays an important role in functional impairment in HFpEF. The mechanisms underlying decreased functional capacity in obese HFpEF are not clear. We assessed the cardiac and peripheral determinants of exercise performance in HFpEF patients with class 2 obesity in the upright position, representative of posture when performing functional activities. METHODS AND RESULTS: Thirty-two HFpEF patients were divided into two groups by presence of class 2 obesity (C2, BMI ≥ 35 kg/m2 , n = 14) and non-C2 (BMI < 35 kg/m2 , n = 18). Participants performed a bout of submaximal exercise followed by incremental stages of treadmill exercise to determine peak aerobic power (peak VO2 ). Peak VO2 and Ve/VCO2 were measured using Douglas bags while cardiac output (Qc) and stroke volume (SV) were measured by acetylene rebreathing. The C2 group were younger than the non-C2 group (67 ± 6 versus 73 ± 6 years; p = .009). Comorbid condition burden was similar between groups. Peak VO2 indexed to body mass was not significantly different between groups. Absolute peak VO2 was higher in the C2 group secondary to a larger peak Qc (14.3 versus 11.0 L/min; p = .012). SV reserve was also higher in the C2 group (72 versus 49%; p = .038). CONCLUSION: HFpEF patients with severe obesity had similar cardiorespiratory fitness compared to patients with lower BMI with similar comorbidity burden. Absolute VO2 was actually higher in the severely obese driven by larger Qc and SV reserve arguing against significant effects from obesity per se on aerobic performance. The presence of a larger "cardiac engine" may offer potential for fat-loss strategies to improve impairments in functional capacity in obese patients with HFpEF.

Elevated exercise blood pressure in middle-aged women is associated with altered left ventricular and vascular stiffness.

Women are at higher risk for developing heart failure with preserved ejection fraction (HFpEF). We examined the utility of peak exercise blood pressure (BP) in identifying preclinical features of HFpEF, namely vascular and cardiac stiffness in middle-aged women. We studied 47 healthy, nonobese middle-aged women (53 ± 5 yr). Oxygen uptake (V̇o2) and BP were assessed at rest and maximal treadmill exercise. Resting cardiac function and stiffness were assessed by echocardiography and invasive measurement (right heart catheterization) of left ventricular (LV) filling pressure under varying preloads. LV stiffness was calculated by curve fit of the diastolic portion of the pressure-volume curve. Aortic pulse-wave velocity was measured by arterial tonometry. Body fat was measured using dual-energy X-ray absorptiometry. Subjects in the highest exercise BP tertile had peak systolic BP of 201 ± 11 compared with 142 ± 19 mmHg in the lowest tertile (P < 0.001). Higher exercise BP was associated with increased age, percentage body fat, smaller LV size, slower LV relaxation, and increased LV and vascular stiffness. After adjustment, LV and arterial stiffness remained significantly associated with peak exercise BP. There was a trend toward increased body fat and slowed LV relaxation (both P < 0.07). In otherwise healthy middle-aged women, elevated exercise BP was independently associated with increased vascular stiffness and a smaller, stiffer LV, functional and structural risk factors characteristic for stages A and B HFpEF.NEW & NOTEWORTHY Women are at increased risk for heart failure with preserved ejection fraction (HFpEF) largely due to higher prevalence of arterial and cardiac stiffening. We were able to identify several subclinical markers of early (stages A and B) HFpEF pathophysiology largely on the basis of exercise blood pressure (BP) response in otherwise healthy middle-aged women. Exercise BP response may be an inexpensive screening tool to identify women at highest risk for developing future HFpEF.

Safety, hemodynamic effects, and detection of acute xenon inhalation: rationale for banning xenon from sport.

This study aimed to quantify the sedative effects, detection rates, and cardiovascular responses to xenon. On 3 occasions, participants breathed xenon (FiXe 30% for 20 min; FiXe 50% for 5 min; FiXe 70% for 2 min) in a nonblinded design. Sedation was monitored by a board-certified anesthesiologist. During 70% xenon, participants were also verbally instructed to operate a manual value with time-to-task failure being recorded. Beat-by-beat hemodynamics were measured continuously by ECG, photoplethysmography, and transcranial Doppler. Over 48 h postadministration, xenon was measured in blood and urine by gas chromatography-mass spectrometry. Xenon caused variable levels of sedation and restlessness. Task failure of the self-operating value occurred at 60-90 s in most individuals. Over the first minute, 50% and 70% xenon caused a substantial reduction in total peripheral resistance (P < 0.05). All dosages caused an increase in cardiac output (P < 0.05). By the end of xenon inhalation, slight hypertension was observed after all three doses (P < 0.05), with an increase in middle cerebral artery velocity (P < 0.05). Xenon was consistently detected, albeit in trace amounts, up to 3 h after all three doses of xenon inhalation in blood and urine with variable results thereafter. Xenon inhalation caused sedation incompatible with self-operation of a breathing apparatus, thus causing a potential life-threatening condition in the absence of an anesthesiologist. Yet, xenon can only be reliably detected in blood and urine up to 3 h postacute dosing.NEW & NOTEWORTHY Breathing xenon in dosages conceivable for doping purposes (FiXe 30% for 20 min; FiXe 50% for 5 min; FiXe 70% for 2 min) causes an initial rapid fall in total peripheral resistance with tachycardia and thereafter a mild hypertension with elevated middle cerebral artery velocity. These dose duration intervals cause sedation that is incompatible with operating a breathing apparatus and can only be detected in blood and urine samples with a high probability for up to ~3 h.

Effect of acute and chronic xenon inhalation on erythropoietin, hematological parameters, and athletic performance.

This study aimed to assess the efficacy of acute subanesthetic dosages of xenon inhalation to cause erythropoiesis and determine the effect of chronic xenon dosing on hematological parameters and athletic performance. To assess the acute effects, seven subjects breathed three subanesthetic concentrations of xenon: 30% fraction of inspired xenon (FiXe) for 20 min, 50% FiXe for 5 min, and 70% FiXe for 2 min. Erythropoietin (EPO) was measured at baseline, during, and after xenon inhalation. To determine the chronic effects, eight subjects breathed 70% FiXe for 2 min on 7 consecutive days, and EPO, total blood, and plasma volume were measured. Phase II involved assessment of 12 subjects for EPO, total blood volume, maximal oxygen uptake, and 3-km time before and after random assignment to 4 wk of xenon or sham gas inhalation. FiXe 50% and 70% stimulated an increase in EPO at 6 h [+2.3 mIU/mL; 95% confidence interval (CI) 0.1-4.5; P = 0.038] and at 192 h postinhalation (+2.9 mIU/mL; 95% CI 0.6-5.1; P = 0.017), respectively. Seven consecutive days of dosing significantly elevated plasma volume (+491 mL; 95% CI 194-789; P = 0.002). Phase II showed no significant effect on EPO, hemoglobin mass, plasma volume, maximal oxygen uptake, or 3-km time. Acute exposure to subanesthetic doses of xenon caused a consistent increase in EPO, and 7 consecutive days of xenon inhalation significantly expanded plasma volume. However, this physiological response appeared to be transient, and 4 wk of xenon inhalation did not stimulate increases in plasma volume or erythropoiesis, leaving cardiorespiratory fitness and athletic performance unchanged.NEW & NOTEWORTHY This is the first study to examine each element of the cascade by which xenon inhalation is purported to take effect, starting with measurement of the hypoxia-inducible factor effector, erythropoietin, to hemoglobin mass and blood volume and athletic performance. We found that acute exposure to xenon increased serum erythropoietin concentration, although major markers of erythropoiesis remained unchanged. While daily dosing significantly expanded plasma volume, no physiological or performance benefits were apparent following 4 wk of dosing.

Carotid baroreflex responsiveness in normotensive African Americans is attenuated at rest and during dynamic leg exercise.

Evidence suggests differences between African Americans (AAs) and Caucasian Americans (CAs) in cardiovascular responsiveness to physiological stressors. This study tested the hypothesis that carotid baroreflex (CBR) control of heart rate (HR) and blood pressure is reduced in AAs compared to CAs during exercise. Mean arterial pressure (MAP) and HR were continuously recorded at rest and during leg cycling in 23 non-hypertensive male subjects (12 AA; 11 CA; age 19-26 years). CBR control of HR and MAP was assessed with 5-s pulses of neck pressure (NP, simulated hypotension) and neck suction (NS, simulated hypertension) ranging from +45 to -80 Torr. Across all NS stimuli (-20, -40, -60, -80 Torr) at rest, the AA group demonstrated attenuated CBR-mediated reductions in HR (AA, -8.9 ± 1.9 vs. CA, -14.1 ± 2.3 bpm; P < 0.001) and MAP (AA, -6.4 ± 1 vs. CA, -7.8 ± 0.8 mmHg; P < 0.05). Despite similar gain and magnitude of resetting observed in the modeled stimulus response curves, an attenuation among AAs persisted in HR (AA, -8.2 ± 1.6 vs. CA, -11.8 ± 3 bpm; P < 0.05) and MAP (AA, -6.8 ± 0.9 vs. CA, -8.2 ± 1.1 mmHg; P < 0.05) responses to NS during exercise. No differences in CBR-mediated HR and MAP responses to NP were detected between groups at rest or during exercise. These data suggest impairment in the ability to defend against a hypertensive challenge among AAs during steady-state exercise compared to their CA counterparts.