Smith, Joshua R

Aims Patients with hypertrophic obstructive cardiomyopathy (HOCM) have impaired exercise capacity. The gold standard therapy for patients with HOCM is septal myectomy surgery; however, changes in maximum oxygen uptake (VO2peak) following myectomy are variable, with VO2peak decreasing in some patients. Therefore, we evaluated changes in VO2peak following surgical myectomy to determine clinical predictors of those exhibiting decreased VO2peak post-myectomy. Methods HOCM patients ( N = 295) who performed symptom limited cardiopulmonary exercise testing prior to and following surgical myectomy were included for analysis. The VO2peak non-responder group ( n = 128) was defined as <0% change in VO2peak from pre- to post-myectomy. Step-wise regression models using demographics, clinical, and physiologic characteristics were created to determine predictors of hypertrophic cardiomyopathy patients in the VO2peak non-responder group. Results Independent predictors of the VO2peak non-responder group included higher pre-myectomy VO2peak (% predicted), older age, women, history of dyslipidemia, lack of cardiac rehabilitation enrollment, and lower body mass index (all p < 0.03). Forty-three (14.6%) patients reached the primary end-point of all-cause mortality during a median follow up of 11.25 years (interquartile range 6.94 to 16.40). After adjustment for age, sex, beta-blocker use, coronary artery disease history, and body mass index, the VO2peak non-responder group had greater risk of death compared with the VO2peak responder group (adjusted hazard ratio: 1.77, 95% confidence interval: 1.06–3.34, p = 0.01). Conclusion This large hypertrophic cardiomyopathy cohort demonstrated that demographic (i.e. female sex), lack of cardiac rehabilitation enrollment, and cardiovascular risk factors (i.e. history of dyslipidemia) are predictive of those patients that did not exhibit increases in VO2peak following septal myectomy surgery.

It is unknown whether central hemodynamics are impaired during exercise in chronic obstructive pulmonary disease (COPD) patients. We hypothesized that, at a similar absolute V̇o2 during exercise, COPD patients would have a lower stroke volume and cardiac output compared with healthy controls. Furthermore, we hypothesized that greater static hyperinflation [ratio of inspiratory capacity to total lung capacity (IC/TLC)] and expiratory intrathoracic pressure would be significantly related to the lower cardiac output and stroke volume responses in COPD patients. Clinically stable COPD ( n = 13; FEV1/FVC: 52 ± 13%) and controls ( n = 10) performed constant workload submaximal exercise at an absolute V̇o2 of ~1.3 L/min. During exercise, inspiratory capacity maneuvers were performed to determine operating lung volumes and cardiac output (via open-circuit acetylene rebreathe technique) and esophageal pressure were measured. At similar absolute V̇o2 during exercise ( P = 0.81), COPD had lower cardiac output than controls (COPD: 11.0 ± 1.6 vs. control: 12.2 ± 1.2 L/min, P = 0.03) due to a lower stroke volume (COPD: 107 ± 13 vs. control: 119 ± 19 mL, P = 0.04). The heart rate response during exercise was not different between groups ( P = 0.66). FEV1 (%predicted) and IC/TLC were positively related to stroke volume ( r = 0.68, P = 0.01 and r = 0.77, P < 0.01). Last, esophageal pressure-time integral during inspiration was positively related to cardiac output ( r = 0.56, P = 0.047). These data demonstrate that COPD patients have attenuated cardiac output and stroke volume responses during exercise compared with control. Furthermore, these data suggest that the COPD patients with the most severe hyperinflation and more negative inspiratory intrathoracic pressures have the most impaired central hemodynamic responses. NEW & NOTEWORTHY Chronic obstructive pulmonary disease leads to cardiac structural changes and pulmonary derangements that impact the integrative response to exercise. However, it is unknown whether these pathophysiological alterations influence the cardiac response during exercise. Herein, we demonstrate that COPD patients exhibit impaired central hemodynamics during exercise that are worsened with greater hyperinflation.

The measurement of peak oxygen uptake (VO2peak) is an important metric for evaluating cardiac transplantation (HTx) eligibility. However, it is unclear which factors (e.g., recipient demographics, clinical parameters, cardiac rehabilitation (CR) participation) influence VO2peak following HTx. Consecutive HTx patients with cardiopulmonary exercise testing (CPET) between 2007–2016 were included. VO2peak was measured from CPET standard protocol. Regression analyses determined predictors of the highest post-HTx VO2peak (i.e., quartile 4: VO2peak > 20.1 mL/kg/min). One hundred-forty HTx patients (women: n = 41 (29%), age: 52 ± 12 years, body mass index (BMI): 27 ± 5 kg/m2) were included. History of diabetes (Odds Ratio (OR): 0.17, 95% Confidence Interval (CI): 0.04–0.77, p = 0.021), history of dyslipidemia (OR: 0.42, 95% CI: 0.19–0.93, p = 0.032), BMI (OR: 0.90, 95% CI: 0.82–0.99, p = 0.022), hemoglobin (OR: 1.29, 95% CI: 1.04–1.61, p = 0.020), white blood cell count (OR: 0.81, 95% CI: 0.66–0.98, p = 0.033), CR exercise sessions (OR: 1.10, 95% CI: 1.04–1.15, p < 0.001), and pre-HTx VO2peak (OR: 1.17, 95% CI: 1.07–1.29, p = 0.001) were significant predictors. Multivariate analysis showed CR exercise sessions (OR: 1.10, 95% CI: 1.03–1.16, p = 0.002), and pre-HTx VO2peak (OR: 1.16, 95% CI: 1.04–1.30, p = 0.007) were independently predictive of higher post-HTx VO2peak. Pre-HTx VO2peak and CR exercise sessions are predictive of a greater VO2peak following HTx. These data highlight the importance of CR exercise session attendance and pre-HTx fitness in predicting VO2peak post-HTx.

Hypertrophic obstructive cardiomyopathy (HOCM) patients exhibit compromised peak exercise capacity (VO2peak). Importantly, severely reduced VO2peak is directly related to increased morbidity and mortality in these patients. Therefore, we sought to determine clinical predictors of VO2peak in HOCM patients. HOCM patients who performed symptom-limited cardiopulmonary exercise testing between 1995 and 2016 were included for analysis. Peak VO2 was reported as absolute peak VO2, indexed to body weight and analyzed as quartiles, with quartile 1 representing the lowest VO2peak. Step-wise regression models using demographic features and clinical and physiologic characteristics were created to determine predictors of HOCM patients with the lowest VO2peak. We included 1177 HOCM patients (age: 53 ± 14 years; BMI: 24 ± 12 kg/m2) with a VO2peak of 18.0 ± 5.6 mL/kg/min. Significant univariate predictors of the lowest VO2peak included age, female sex, New York Health Association (NYHA) class, BMI, left atrial volume index, E/e’, E/A, hemoglobin, N-terminal pro b-type natriuretic peptide (NT-proBNP), and a history of diabetes, hypertension, stroke, atrial fibrillation, or coronary artery disease. Independent predictors of the lowest VO2peak included age (OR, CI: 1.03, 1.02–1.06; p < 0.0001), women (4.66, 2.94–7.47; p = 0.001), a history of diabetes (2.05, 1.17–3.60; p = 0.01), BMI (0.94, 0.92–0.96; p < 0.0001), left atrial volume index (1.07, 1.05–1.21; p = 0.04), E/e’ (1.05, 1.01–1.08; p = 0.004), hemoglobin (0.76, 0.65–0.88; p = 0.0004), and NT-proBNP (1.72, 1.42–2.11; p < 0.0001). These findings demonstrate that demographic factors (i.e., age and sex), comorbidities (e.g., diabetes and obesity), echocardiography indices, and biomarkers (e.g., hemoglobin and NT-proBNP) are predictive of severely compromised VO2peak in HOCM patients.

New Findings What is the central question of this study? The goal of this study was to investigate the effect of alterations in tidal volume and alveolar volume on the elevated physiological dead space and the contribution of ventilatory constraints thereof in heart failure patients during submaximal exercise. What is the main finding and its importance? We found that physiological dead space was elevated in heart failure via reduced tidal volume and alveolar volume. Furthermore, the degree of ventilatory constraints was associated with physiological dead space and alveolar volume. AbstractPatients who have heart failure with reduced ejection fraction (HFrEF) exhibit impaired ventilatory efficiency [i.e. greater ventilatory equivalent for carbon dioxide () slope] and elevated physiological dead space (VD/VT). However, the impact of breathing strategy on VD/VT during submaximal exercise in HFrEF is unclear. The HFrEF (n = 9) and control (CTL, n = 9) participants performed constant‐load cycling exercise at similar ventilation (). Inspiratory capacity, operating lung volumes and arterial blood gases were measured during submaximal exercise. Arterial blood gases were used to derive VD/VT, alveolar volume, dead space volume, alveolar ventilation and dead space ventilation. During submaximal exercise, HFrEF patients had greater slope and VD/VT than CTL subjects (P = 0.01). At similar , HFrEF patients had smaller tidal volumes and alveolar volumes (HFrEF 1.11 ± 0.33 litres versus CTL 1.66 ± 0.37 litres; both P ≤ 0.01), whereas dead space volume was not different (P = 0.47). The augmented breathing frequency in HFrEF patients resulted in greater dead space ventilation compared with CTL subjects (HFrEF 15 ± 4 l min−1 versus CTL 10 ± 5 l min−1; P = 0.048). The HFrEF patients exhibited greater increases in expiratory reserve volume and lower inspiratory capacity (as a percentage of predicted) than CTL subjects (both P < 0.05), which were significantly related to VD/VT and alveolar volume in HFrEF patients (all P < 0.03). In HFrEF, the reduced tidal volume and alveolar volume elevate physiological dead space during submaximal exercise, which is worsened in those with the greatest ventilatory constraints. These findings highlight the negative consequences of ventilatory constraints on physiological dead space during submaximal exercise in HFrEF.

It is unknown whether the greater total work of breathing (WOB) with aging is due to greater elastic and/or resistive WOB. We hypothesized that older compared with younger adults would exhibit a greater total WOB at matched ventilations (V̇e) during graded exercise, secondary to greater inspiratory resistive and elastic as well as expiratory resistive WOB. Older (OA: 60 ± 8 yr; n = 9) and younger (YA: 38 ± 7 yr; n = 9) adults performed an incremental cycling test to volitional fatigue. Esophageal pressure, inspiratory (IRV) and expiratory reserve volumes (ERV), expiratory flow limitation (EFL), and ventilatory variables were measured at matched V̇e (i.e., 25, 50, and 75 l/min) during exercise. The inspiratory resistive and elastic as well as expiratory resistive WOB were quantified using the Otis method. At V̇e of 75 l/min, older adults had greater %EFL and larger tidal volumes to inspiratory capacity but smaller relative IRV ( P ≤ 0.03) than younger adults. Older compared with younger adults had greater total WOB at V̇Eof 50 and 75 l/min (OA: 90 ± 43 vs. YA: 49 ± 21 J/min; P < 0.04 for both). At V̇e of 75 l/min, older adults had greater inspiratory elastic and resistive WOB (OA: 44 ± 27 vs. YA: 24 ± 22 and OA: 23 ± 15 vs. YA: 11 ± 3 J/min, respectively, P < 0.03 for both) and expiratory resistive WOB (OA: 23 ± 19 vs. YA: 14 ± 9 J/min, P = 0.02) than younger adults. These data demonstrate that aging-induced pulmonary alterations result in greater inspiratory elastic and resistive as well as expiratory resistive WOB, which may have implications for the integrated response during exercise.NEW & NOTEWORTHY Aging-induced changes to the pulmonary system result in increased work of breathing (WOB) during exercise. However, it is not known whether this higher WOB with aging is due to differences in elastic and/or resistive WOB. Herein, we demonstrate that older adults exhibited greater inspiratory elastic and resistive as well as expiratory resistive WOB during exercise.

AbstractAimIn contrast to knowledge that heart failure (HF) patients demonstrate peak exercise uncoupling across ventilation, gas exchange and cardiac haemodynamics, whether this dyssynchrony follows that at the exercise on‐transition is unclear. This study tested whether exercise on‐transition temporal lag for ventilation relative to gas exchange and oxygen pulse (O2pulse) couples with effects from abnormal pulmonary gaseous oxygen store (O2store) contributions to O2 to interdependently precipitate persistently elevated ventilatory demand and low oxidative metabolic capacity in HF.MethodsBeat‐to‐beat HR and breath‐to‐breath ventilation and gas exchange were continuously acquired in HF (N = 9, ejection fraction = 30 ± 9%) and matched controls (N = 10) during square‐wave ergometry at 60% O2peak (46 ± 14 vs 125 ± 54‐W, P < .001). Temporal responses across E, O2 and O2pulse were assessed for the exercise on‐transition using single exponential model Phase II on‐kinetic time constants (τ = time to reach 63% steady‐state rise). Breath‐to‐breath gas fractions and respiratory flows were used to determine O2stores.ResultsHF vs controls: τ for E (137 ± 93 vs 74 ± 40‐seconds, P = .03), O2 (60 ± 40 vs 23 ± 5‐seconds, P = .03) and O2pulse (28 ± 18 vs 23 ± 15‐seconds, P = .59). Within HF, τ for E differed from O2pulse (P < .02), but not O2. Exercise E rise (workload indexed) differed in HF vs controls (545 ± 139 vs 309 ± 88‐mL min−1 W−1, P < .001). Exercise on‐transition O2store depletion in HF exceeded controls, generally persisting to end‐exercise.ConclusionThese data suggest HF demonstrated exercise on‐transition O2store depletion (high O2store contribution to O2) coupled with dyssynchronous E, O2 and O2pulse kinetics—not attributable to prolonged cardiac haemodynamics. Persistent high ventilatory demand and low oxidative metabolic capacity in HF may be precipitated by physiological uncoupling occurring within the exercise on‐transition.

New Findings What is the central question of this study? Premenopausal women have an attenuated inspiratory muscle metaboreflex‐induced increase in arterial blood pressure compared with men. It is unclear whether sympathetic vasomotor outflow during dynamic exercise with increased inspiratory muscle activation is less in young women than in men. What is the main finding and its importance? The magnitude of increased sympathetic vasomotor outflow during leg cycling with inspiratory resistance was smaller in women than in men. Less sympathetic vasomotor outflow with inspiratory muscle metaboreflex activation could be one of the mechanisms for the attenuated inspiratory muscle‐induced metaboreflex during exercise in young women. AbstractWe compared changes in muscle sympathetic nerve activity (MSNA) and cardiovascular variables during leg cycle exercise with increased inspiratory muscle resistance in men and women. We hypothesized that sympathetic vasomotor outflow during exercise with increased inspiratory resistance would be attenuated in young women compared with age‐matched men. Eight women and seven men completed the study. The subjects performed two 10 min exercise bouts at 40% peak oxygen uptake using a cycle ergometer in a semirecumbent position [spontaneous breathing for 5 min and voluntary hyperventilation with or without inspiratory resistive breathing for 5 min (breathing frequency 50 breaths min−1 with a 50% duty cycle; inspiratory resistance 30% of maximal inspiratory pressure)]. Mean arterial blood pressure (MAP) was acquired using finger photoplethysmography. The MSNA was recorded via microneurography of the right median nerve at the cubital fossa. During leg cycle exercise with inspiratory resistive breathing, MSNA burst frequency was increased, accompanied by an increase in MAP in both men and women. Women, compared with men, had less of an increase in MAP (women +22.8 ± 12.3 mmHg versus men +32.2 ± 5.4 mmHg; P < 0.05) and MSNA burst frequency (women +9.6 ± 2.9 bursts min−1 versus men +14.6 ± 6.4 bursts min−1; P < 0.05). These results suggest that the attenuated inspiratory muscle‐induced metaboreflex during exercise in young women is attributable, in part, to a lesser sympathetic vasomotor outflow compared with men.