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˙O ₂ ; 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˙O ₂ 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.

BACKGROUND: We identified peripherally limited patients using cardiopulmonary exercise testing and measured skeletal muscle oxygen transport and utilization during invasive single leg exercise testing to identify the mechanisms of the peripheral limitation. METHODS: Forty-five patients with heart failure with preserved ejection fraction (70±7 years, 27 females) completed seated upright cardiopulmonary exercise testing and were defined as having a (1) peripheral limitation to exercise if cardiac output/oxygen consumption (VO ₂ ) was elevated (≥6) or 5 to 6 with a stroke volume reserve >50% (n=31) or (2) a central limitation to exercise if cardiac output/VO ₂ slope was ≤5 or 5 to 6 with stroke volume reserve <50% (n=14). Single leg knee extension exercise was used to quantify peak leg blood flow (Doppler ultrasound), arterial-to-venous oxygen content difference (femoral venous catheter), leg VO ₂ , and muscle oxygen diffusive conductance. In a subset of participants (n=36), phosphocreatine recovery time was measured by magnetic resonance spectroscopy to determine skeletal muscle oxidative capacity. RESULTS: Peak VO ₂ during cardiopulmonary exercise testing was not different between groups (central: 13.9±5.7 versus peripheral: 12.0±3.1 mL/min per kg; P =0.135); however, the peripheral group had a lower peak arterial-to-venous oxygen content difference (central: 13.5±2.0 versus peripheral: 11.1±1.6 mLO ₂ /dL blood; P <0.001). During single leg knee extension, there was no difference in peak leg VO ₂ ( P =0.306), but the peripherally limited group had greater blood flow/VO ₂ ratio ( P =0.024), lower arterial-to-venous oxygen content difference (central: 12.3±2.5 versus peripheral: 10.3±2.2 mLO ₂ /dL blood; P =0.013), and lower muscle oxygen diffusive conductance ( P =0.021). A difference in magnetic resonance spectroscopy–derived phosphocreatine recovery time was not detected ( P =0.199). CONCLUSIONS: Peripherally limited patients with heart failure with preserved ejection fraction identified by cardiopulmonary exercise testing have impairments in oxygen transport and utilization at the level of the skeletal muscle quantified by invasive knee extension exercise testing, which includes an increased blood flow/V̇O ₂ ratio and poor muscle diffusive capacity. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04068844.

Background: We tested the hypothesis that patients with heart failure with preserved ejection fraction (HFpEF) would have greater muscle sympathetic nerve activity (MSNA) at rest and sympathetic reactivity during a cold pressor test compared with non–heart failure controls. Further, given the importance of the baroreflex modulation of MSNA in the control of blood pressure (BP), we hypothesized that patients with HFpEF would exhibit a reduced sympathetic baroreflex sensitivity. METHODS: Twenty-eight patients with HFpEF and 44 matched controls (mean±SD: 71±8 versus 70±7 years; 9 men/19 women versus 16 men/28 women) were studied. BP, heart rate, and MSNA (microneurography) were measured during 6 to 10 minutes of supine rest and the 2-minute cold pressor test. Spontaneous sympathetic baroreflex sensitivity was assessed during supine rest. Results: Patients with HFpEF had higher resting MSNA burst frequency (39±14 versus 31±12 bursts/min; P =0.020) and lower sympathetic baroreflex sensitivity (−2.83±0.76 versus −3.57±1.19 bursts/100 heartbeats/mm Hg; P =0.019) than controls, but burst incidence was not different between groups (56±19 versus 50±20 bursts/100 heartbeats; P =0.179). During the cold pressor test, increases in MSNA indices did not differ between groups ( P =0.135–0.998), but patients had a smaller increase in diastolic BP (Δ4±6 versus Δ14±11 mm Hg; P <0.001) compared with controls. Conclusions: Despite augmented resting MSNA burst frequency, burst incidence was not significantly different between groups, and sympathetic baroreflex sensitivity was reduced in patients with HFpEF. Furthermore, patients had preserved sympathetic reactivity but attenuated diastolic BP responses during the cold pressor test. These data suggest that, during physiological stress, sympathetic reactivity is intact, but the peripheral pathway for sympathetic vasoconstriction may be impaired in HFpEF.

Patients with hypertrophic cardiomyopathy (HCM) often have reduced exercise capacity, and it is unclear whether cardiovascular regulation during exercise is intact in these patients. We aimed to determine the relationship between cardiac output (Q̇_c) and oxygen uptake (V̇o₂), and stroke volume (SV) reserve in HCM compared with healthy participants and participants with left ventricular hypertrophy (LVH) but not HCM. Sixteen patients with HCM (48 ± 7 yr, 44% female), 16 participants with LVH (49 ± 5 yr, 44% female), and 61 healthy controls (CON: 52 ± 5 yr, 52% female) completed submaximal steady-state treadmill exercise followed by a maximal exercise test. V̇o₂, Q̇_c, SV, and arteriovenous oxygen difference were measured during rest and exercise, and Q̇_c/V̇o₂ slopes were constructed, The Q̇_c/V̇o₂ slope was blunted in HCM compared with CON and LVH [HCM 4.9 ± 0.7 vs. CON 5.5 ± 1.0 (P = 0.027) vs. LVH 6.0 ± 1.0 AU (P = 0.002)] and participants with HCM had a lower SV reserve (HCM 53 ± 33%, controls 83 ± 33%, LVH 82 ± 22%; HCM vs. controls P = 0.002; HCM vs. LVH P = 0.015). Despite a blunted Q̇_c/V̇o₂ slope, 75% of patients with HCM achieved ≥80% predicted V̇o_2max by augmenting a-vo₂ difference at maximal exercise (16.0 ± 0.8 mL/100 mL vs. 13.8 ± 2.7 mL/100 mL, P = 0.021). Patients with HCM do not appropriately match Q̇_c to metabolic demand, primarily due to inadequate stroke volume augmentation. Despite this central limitation, many patients achieve normal exercise capacities by significantly increasing peripheral oxygen extraction. NEW & NOTEWORTHY Through state-of-the-art hemodynamic and oxygen uptake methodologies, this study found the cardiac output response to increasing metabolic demand is blunted among patients with hypertrophic cardiomyopathy (HCM), primarily due to a reduced stroke volume reserve. Many patients with HCM augment their peripheral oxygen extraction during maximal exercise to achieve normal exercise capacity and overcome ineffective matching of cardiac output. Peripheral adaptations that compensate for cardiac limitations may contribute to the heterogeneity of functional limitations observed within this patient population.