Challenging the Hemodynamic Hypothesis in Heart Failure With Preserved Ejection Fraction: Is Exercise Capacity Limited by Elevated Pulmonary Capillary Wedge Pressure?

BACKGROUND: Exercise intolerance is a defining characteristic of heart failure with preserved ejection fraction (HFpEF). A marked rise in pulmonary capillary wedge pressure (PCWP) during exertion is pathognomonic for HFpEF and is thought to be a key cause of exercise intolerance. If true, acutely lowering PCWP should improve exercise capacity. To test this hypothesis, we evaluated peak exercise capacity with and without nitroglycerin to acutely lower PCWP during exercise in patients with HFpEF. METHODS: Thirty patients with HFpEF (70±6 years of age; 63% female) underwent 2 bouts of upright, seated cycle exercise dosed with sublingual nitroglycerin or placebo control every 15 minutes in a single-blind, randomized, crossover design. PCWP (right heart catheterization), oxygen uptake (breath × breath gas exchange), and cardiac output (direct Fick) were assessed at rest, 20 Watts (W), and peak exercise during both placebo and nitroglycerin conditions. RESULTS: PCWP increased from 8±4 to 35±9 mm Hg from rest to peak exercise with placebo. With nitroglycerin, there was a graded decrease in PCWP compared with placebo at rest (-1±2 mm Hg), 20W (-5±5 mm Hg), and peak exercise (-7±6 mm Hg; drug × exercise stage P=0.004). Nitroglycerin did not affect oxygen uptake at rest, 20W, or peak (placebo, 1.34±0.48 versus nitroglycerin, 1.32±0.46 L/min; drug × exercise P=0.984). Compared with placebo, nitroglycerin lowered stroke volume at rest (-8±13 mL) and 20W (-7±11 mL), but not peak exercise (0±10 mL). CONCLUSIONS: Sublingual nitroglycerin lowered PCWP during submaximal and maximal exercise. Despite reduction in PCWP, peak oxygen uptake was not changed. These results suggest that acute reductions in PCWP are insufficient to improve exercise capacity, and further argue that high PCWP during exercise is not by itself a limiting factor for exercise performance in patients with HFpEF. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04068844.

Ventilatory Responses to Exercise by Age, Sex, and Health Status.

ABSTRACT: An understanding of the normal pulmonary responses to incremental exercise is requisite for appropriate interpretation of findings from clinical exercise testing. The purpose of this review is to provide concrete information to aid the interpretation of the exercise ventilatory response in both healthy and diseased populations. We begin with an overview of the normal exercise ventilatory response to incremental exercise in the healthy, normally trained young-to-middle aged adult male. The exercise ventilatory responses in two nonpatient populations (females, elderly) are then juxtaposed with the responses in healthy males. The review concludes with overviews of the exercise ventilatory responses in four patient populations (obesity, chronic obstructive pulmonary disease, asthma, congestive heart failure). Again, we use the normal response in healthy adults as the framework for interpreting the responses in the clinical groups. For each healthy and clinical population, recent, impactful research findings will be presented.

Sex differences in the ventilatory responses to exercise in mild to moderate obesity.

NEW FINDINGS: What is the central question of the study? What are the sex differences in ventilatory responses during exercise in adults with obesity? What is the main finding and its importance? Tidal volume and expiratory flows are lower in females when compared with males at higher levels of ventilation despite small increases in end-expiratory lung volumes. Since dyspnoea on exertion is a frequent complaint, particularly in females with obesity, careful attention should be paid to unpleasant respiratory symptoms and mechanical ventilatory constraints while prescribing exercise. ABSTRACT: Obesity is associated with altered ventilatory responses, which may be exacerbated in females due to the functional consequences of sex-related morphological differences in the respiratory system. This study examined sex differences in ventilatory responses during exercise in adults with obesity. Healthy adults with obesity (n = 73; 48 females) underwent pulmonary function testing, underwater weighing, magnetic resonance imaging (MRI), a graded exercise test to exhaustion, and two constant work rate exercise tests; one at a fixed work rate (60 W for females and 105 W for males) and one at a relative intensity (50% of peak oxygen uptake, V ̇ O 2 peak ${\dot{V}}_{{{\rm{O}}}_{\rm{2}}{\rm{peak}}}$ ). Metabolic, respiratory and perceptual responses were assessed during exercise. Compared with males, females used a smaller proportion of their ventilatory capacity at peak exercise (69.13 ± 14.49 vs. 77.41 ± 17.06% maximum voluntary ventilation, P = 0.0374). Females also utilized a smaller proportion of their forced vital capacity (FVC) at peak exercise (tidal volume: 48.51 ± 9.29 vs. 54.12 ± 10.43%FVC, P = 0.0218). End-expiratory lung volumes were 2-4% higher in females compared with males during exercise (P < 0.05), while end-inspiratory lung volumes were similar. Since the males were initiating inspiration from a lower lung volume, they experienced greater expiratory flow limitation during exercise. Ratings of perceived breathlessness during exercise were similar between females and males at comparable levels of ventilation. In summary, sex differences in the manifestations of obesity-related mechanical ventilatory constraints were observed. Since dyspnoea on exertion is a common complaint in patients with obesity, particularly in females, exercise prescriptions should be tailored with the goal of minimizing unpleasant respiratory sensations.

Cardiac perturbations after high-intensity exercise are attenuated in middle-aged compared with young endurance athletes: diminished stress or depleted stimuli?

Strenuous exercise elicits transient functional and biochemical cardiac imbalances. Yet, the extent to which these responses are altered owing to aging is unclear. Accordingly, echocardiograph-derived left ventricular (LV) and right ventricular (RV) global longitudinal strain (GLS) and high-sensitivity cardiac troponin I (hs-cTnI) were assessed before (pre) and after (post) a 60-min high-intensity cycling race intervention (CRIT60) in 11 young (18-30 yr) and 11 middle-aged (40-65 yr) highly trained male cyclists, matched for cardiorespiratory fitness. LV and RV GLS were measured at rest and during a semirecumbent exercise challenge performed at the same intensity (young: 93 ± 10; middle-aged: 85 ± 11 W, P = 0.60) pre- and post-CRIT60. Augmentation (change from rest-to-exercise challenge) of LV GLS (pre: -2.97 ± 0.65; post: -0.82 ± 0.48%, P = 0.02) and RV GLS (pre: -2.08 ± 1.28; post: 3.08 ± 2.02%, P = 0.01) was attenuated and completely abolished, in the young following CRIT60, while augmentation of LV GLS (pre: -3.21 ± 0.41; post: -3.99 ± 0.55%, P = 0.22) and RV GLS (pre: -3.47 ± 1.44; post: -1.26 ± 1.00%, P = 0.27) was preserved in middle-aged following CRIT60. While serum hs-cTnI concentration increased followingCRIT60 in the young (pre: 7.3 ± 1.6; post: 17.7 ± 1.6 ng/L, P < 0.01) and middle-aged (pre: 4.5 ± 0.6; post: 10.7 ± 2.0 ng/L, P < 0.01), serum hs-cTnI concentration increased to a greater extent in the young than in the middle-aged following CRIT60 (P < 0.01). These findings suggest that functional and biochemical cardiac perturbations induced by high-intensity exercise are attenuated in middle-aged relative to young individuals. Further study is warranted to determine whether acute exercise-induced cardiac perturbations alter the adaptive myocardial remodeling response.NEW & NOTEWORTHY High-intensity endurance exercise elicits acute cardiac imbalances that may be an important stimulus for adaptive cardiac remodeling. This study highlights that following a bout of high-intensity exercise that is typical of routine day-to-day cycling training, exercise-induced autonomic, biochemical, and functional cardiac imbalances are attenuated in middle-aged relative to young well-trained cyclists. These findings suggest that aging may alter exercise-induced stress stimulus response that initiates cardiac remodeling in athlete's heart.

Folic acid supplementation improves vascular endothelial function, yet not skin blood flow during exercise in the heat, in patients with heart failure.

Heart failure (HF) patients are susceptible to heat strain during exercise, secondary to blunted skin blood flow (SkBF) responses, which may be explained by impaired nitric oxide (NO)-dependent vasodilation. Folic acid improves vascular endothelial function and SkBF through NO-dependent mechanisms in healthy older individuals and patients with cardiovascular disease. We examined the effect of folic acid supplementation (5 mg/day for 6 wk) on vascular function [brachial artery flow-mediated dilation (FMD)] and SkBF responses [cutaneous vascular conductance (CVC)] during 60 min of exercise at a fixed metabolic heat production (300 WHprod) in a 30°C environment in 10 patients with HF (New York Heart Association Class I-II) and 10 healthy controls (CON). Serum folic acid concentration increased in HF [preintervention (pre): 1.4 ± 0.2; postintervention (post): 8.9 ± 6.7 ng/ml, P = 0.01] and CON (pre: 1.3 ± 0.6; post: 5.2 ± 4.9 ng/ml, P = 0.03). FMD improved by 2.1 ± 1.3% in HF ( P < 0.01), but no change was observed in CON postintervention ( P = 0.20). During exercise, the external workload performed on the cycle ergometer to attain the fixed level of heat production for exercise was similar between groups (HF: 60 ± 13; CON: 65 ± 20 external workload, P = 0.52). Increases in CVC during exercise were similar in HF (pre: 0.89 ± 0.43; post: 0.83 ± 0.45 au/mmHg, P = 0.80) and CON (pre: 2.01 ± 0.79; post: 2.03 ± 0.72 au/mmHg, P = 0.73), although the values were consistently lower in HF for both pre- and postintervention measurement intervals ( P < 0.05). These findings demonstrate that folic acid improves vascular endothelial function in patients with HF but does not enhance SkBF during exercise at a fixed metabolic heat production in a warm environment.

Heart Failure and Thermoregulatory Control: Can Patients With Heart Failure Handle the Heat?

Upon heat exposure, the thermoregulatory system evokes reflex increases in sweating and skin blood flow responses to facilitate heat dissipation and maintain heat balance to prevent the continuing rise in core temperature. These heat dissipating responses are mediated primarily by autonomic and cardiovascular adjustments; which, if attenuated, may compromise thermoregulatory control. In patients with heart failure (HF), the neurohumoral and cardiovascular dysfunction that underpins this condition may potentially impair thermoregulatory responses and, consequently, place these patients at a greater risk of heat-related illness. The aim of this review is to describe thermoregulatory mechanisms and the factors that may increase the risk of heat-related illness in patients with HF. An understanding of the mechanisms responsible for impaired thermoregulatory control in HF patients is of particular importance, given the current and projected increase in frequency and intensity of heat waves, as well as the promotion of regular exercise as a therapeutic modality. Furthermore, novel therapeutic strategies that may improve thermoregulatory control in HF, and the clinical relevance of this work in this population will be discussed.

Pediatric patients diagnosed as overweight and obese have an elevated risk of dyspnea.

We investigated whether pediatric patients with overweight and obesity are more likely to have dyspnea compared with those who are non-overweight. We collected de-identified data from TriNetX, a global federated multicenter research database, using both the UT Southwestern Medical Center and multinational Research Networks. Our analysis focused on patients aged 8-12 years. We identified overweight and obesity using ICD-10-CM codes E66 and dyspnea using code R06.0. Patients with overweight and obesity had a significantly higher risk of dyspnea compared with those who were non-overweight. This association was observed in both the UT Southwestern Network (risk ratio: 1.81, p < 0.001) and the Research Network (risk ratio: 2.70, p < 0.001). Furthermore, within the UT Southwestern Network, the risk was found to be higher in females compared with males (risk ratio: 2.17 vs. 1.67). These results have significant clinical implications, suggesting that clinicians should consider overweight and obesity as independent risk factors for dyspnea in pediatric patients after excluding other possible contributing factors.

Comparing the Physiological Responses to the 6-Minute Walk Test, Timed Up and Go Test, and Treadmill Cardiopulmonary Exercise Test.

Purpose: To compare physiological responses during a treadmill cardiopulmonary exercise test (CPX), 6-minute walk test (6MWT), and timed up and go test (TUGT) in individuals referred for unexplained breathlessness and symptom limited treadmill exercise testing. Methods: Heart rate (HR), oxygen consumption (V̇O2), carbon dioxide production (V̇CO2), respiratory exchange ratio (RER), minute ventilation (V̇E), systolic blood pressure (SBP), and rating of perceived exertion (RPE) were recorded throughout each test. Results: Each test demonstrated a significant increase (p < 0.01) in the cardiopulmonary (V̇O2, V̇CO2 and V̇E, RPE, SBP, and HR) and perceptual (RPE) responses from rest to end exercise. The increase in cardiopulmonary and perceptual responses was greatest for the CPX with significantly smaller responses demonstrated during the 6MWT (p < 0.01) and even smaller responses for the TUGT (p < 0.01 vs CPX and 6MWT). Conclusion: Not surprisingly, the treadmill CPX results is the greatest physiological response in our group. Despite being of short duration, the TUGT results in an increased physiological response.

Respiratory symptom perception during exercise in patients with heart failure with preserved ejection fraction.

We investigated whether central or peripheral limitations to oxygen uptake elicit different respiratory sensations and whether dyspnea on exertion (DOE) provokes unpleasantness and negative emotions in patients with heart failure with preserved ejection fraction (HFpEF). 48 patients were categorized based on their cardiac output (Q̇c)/oxygen uptake (V̇O2) slope and stroke volume (SV) reserve during an incremental cycling test. 15 were classified as centrally limited and 33 were classified as peripherally limited. Ratings of perceived breathlessness (RPB) and unpleasantness (RPU) were assessed (Borg 0-10 scale) during a 20 W cycling test. 15 respiratory sensations statements (1-10 scale) and 5 negative emotions statements (1-10) were subsequently rated. RPB (Central: 3.5±2.0 vs. Peripheral: 3.4±2.0, p=0.86), respiratory sensations, or negative emotions were not different between groups (p>0.05). RPB correlated (p<0.05) with RPU (r=0.925), "anxious" (r=0.610), and "afraid" (r=0.383). While DOE provokes elevated levels of negative emotions, DOE and respiratory sensations seem more related to a common mechanism rather than central and/or peripheral limitations in HFpEF.

Identifying the Mechanisms of a Peripherally Limited Exercise Phenotype in Patients With Heart Failure With Preserved Ejection Fraction.

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 (VO2) 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/VO2 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 VO2, 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 VO2 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 mLO2/dL blood; P<0.001). During single leg knee extension, there was no difference in peak leg VO2 (P=0.306), but the peripherally limited group had greater blood flow/VO2 ratio (P=0.024), lower arterial-to-venous oxygen content difference (central: 12.3±2.5 versus peripheral: 10.3±2.2 mLO2/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/V̇O2 ratio and poor muscle diffusive capacity. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04068844.

Static respiratory mechanics are unaltered in males and females with obesity.

We tested the hypothesis that independent of the obesity-related shift in lung volume subdivisions, obesity would not reduce the interrelationships of expiratory flow, lung volume, and static lung elastic recoil pressure in males and females. Simultaneous measurements of expiratory flow, volume, and transpulmonary pressure were continuously recorded while flow-volume loops of varying expiratory efforts were performed in a pressure-corrected, volume-displacement body plethysmograph in males and females with obesity. Static compliance curves were collected using the occlusion technique. Flow-volume, static pressure-volume, and static pressure-flow relationships were examined. Isovolume pressure-flow curves were constructed for the determination of the critical pressure for maximal flow. Data were compared with that collected in lean males and females. Individuals with obesity displayed a notable decrease in functional residual capacity. The interrelationships of flow, lung volume, static elastic recoil pressure, and the minimum pressure required for maximal expiratory flow in males and females with obesity were not different from that in lean males and females (all P > 0.05). Obesity does not alter the interrelationships of flow-volume-pressure of the lung in adult males and females (all P > 0.05). We further explored potential sex differences in static mechanics independent of obesity and observed that females have lower maximal expiratory flow due to a combination of smaller lungs and greater upstream flow resistance compared with males (all P ≤ 0.05).NEW & NOTEWORTHY The potential influence of obesity on the interrelationships between maximal expiratory flow, lung volume, and static lung elastic recoil pressure is unclear. These data show that the presence of obesity does not alter the relationship of flow and pressure across the mid-expiratory range in males and females. In addition, independent of obesity, females have smaller lungs and greater upstream flow resistance, which contributes to reduced maximal flow, when compared with males.

Ventilatory limitations in patients with HFpEF and obesity.

Heart failure with preserved ejection fraction (HFpEF) patients have an increased ventilatory demand. Whether their ventilatory capacity can meet this increased demand is unknown, especially in those with obesity. Body composition (DXA) and pulmonary function were measured in 20 patients with HFpEF (69 ± 6 yr;9 M/11 W). Cardiorespiratory responses, breathing mechanics, and ratings of perceived breathlessness (RPB, 0-10) were measured at rest, 20 W, and peak exercise. FVC correlated with %body fat (R2 =0.51,P = 0.0006), V̇O2peak (%predicted,R2 =0.32,P = 0.001), and RPB (R2 =0.58,P = 0.0004). %Body fat correlated with end-expiratory lung volume at rest (R2 =0.76,P < 0.001), 20 W (R2 =0.72,P < 0.001), and peak exercise (R2 =0.74,P < 0.001). Patients were then divided into two groups: those with lower ventilatory reserve (FVC<3 L,2 M/10 W) and those with higher ventilatory reserve (FVC>3.8 L,7 M/1 W). V̇O2peak was ∼22% less (p < 0.05) and RPB was twice as high at 20 W (p < 0.01) in patients with lower ventilatory reserve. Ventilatory reserves are limited in patients with HFpEF and obesity; indeed, the margin between ventilatory demand and capacity is so narrow that exercise capacity could be ventilatory limited in many patients.

Elevated risk of dyspnea in adults with obesity.

We investigated whether older adults (OA) with obesity are more likely to have dyspnea compared with OA without obesity, and whether OA with obesity are at a greater risk of having dyspnea compared with middle-aged (MA) and younger adults (YA) with obesity. We obtained de-identified data from the TriNetX UT Southwestern Medical Center database. We identified obesity and dyspnea using ICD-10-CM codes E66 and R06.0, respectively. Patients were separated into three age groups: OA, (65-75 y.o.), MA (45-55 y.o.), and YA (25-35 y.o). Within these groups, those with and without obesity or dyspnea were identified for analysis. The risk of dyspnea was greater in OA (risk ratio: 3.64), MA (risk ratio: 3.52), and YA (risk ratio: 2.76) with obesity compared with age-matched patients without obesity (all p < 0.01). The risk of dyspnea was greater in OA and MA with obesity compared with YA with obesity (both p < 0.001 vs. YA). These findings suggest that clinicians should consider obesity as an independent risk factor for dyspnea.

Inhibiting regional sweat evaporation modifies the ventilatory response to exercise: interactions between core and skin temperature.

In humans, elevated body temperatures can markedly increase the ventilatory response to exercise. However, the impact of changing the effective body surface area (BSA) for sweat evaporation (BSAeff) on such responses is unclear. Ten healthy adults (9 males, 1 female) performed eight exercise trials cycling at 6 W/kg of metabolic heat production for 60 min. Four conditions were used where BSAeff corresponded to 100%, 80%, 60%, and 40% of BSA using vapor-impermeable material. Four trials (one at each BSAeff) were performed at 25°C air temperature, and four trials (one at each BSAeff) at 40°C air temperature, each with 20% humidity. The slope of the relation between minute ventilation and carbon dioxide elimination (V̇E/V̇co2 slope) assessed the ventilatory response. At 25°C, the V̇E/V̇co2 slope was elevated by 1.9 and 2.6 units when decreasing BSAeff from 100 to 80 and to 40% (P = 0.033 and 0.004, respectively). At 40°C, V̇E/V̇co2 slope was elevated by 3.3 and 4.7 units, when decreasing BSAeff from 100 to 60 and to 40% (P = 0.016 and P < 0.001, respectively). Linear regression analyses using group average data from each condition demonstrated that end-exercise mean body temperature (integration of core and mean skin temperature) was better associated with the end-exercise ventilatory response, compared with core temperature alone. Overall, we show that impeding regional sweat evaporation increases the ventilatory response to exercise in temperate and hot environmental conditions, and the effect is mediated primarily by increases in mean body temperature.NEW & NOTEWORTHY Exercise in the heat increases the slope of the relation between minute ventilation and carbon dioxide elimination (V̇E/V̇co2 slope) in young healthy adults. An indispensable role for skin temperature in modulating the ventilatory response to exercise is noted, contradicting common belief that internal/core temperature acts independently as a controller of ventilation during hyperthermia.

Reducing Pulmonary Capillary Wedge Pressure During Exercise Exacerbates Exertional Dyspnea in Patients With Heart Failure With Preserved Ejection Fraction: Implications for V˙/Q˙ Mismatch.

BACKGROUND: The primary cause of dyspnea on exertion in heart failure with preserved ejection fraction (HFpEF) is presumed to be the marked rise in pulmonary capillary wedge pressure during exercise; however, this hypothesis has never been tested directly. Therefore, we evaluated invasive exercise hemodynamics and dyspnea on exertion in patients with HFpEF before and after acute nitroglycerin (NTG) treatment to lower pulmonary capillary wedge pressure. RESEARCH QUESTION: Does reducing pulmonary capillary wedge pressure during exercise with NTG improve dyspnea on exertion in HFpEF? STUDY DESIGN AND METHODS: Thirty patients with HFpEF performed two invasive 6-min constant-load cycling tests (20 W): one with placebo (PLC) and one with NTG. Ratings of perceived breathlessness (0-10 scale), pulmonary capillary wedge pressure (right side of heart catheter), and arterial blood gases (radial artery catheter) were measured. Measurements of V˙/Q˙ matching, including alveolar dead space (Vdalv; Enghoff modification of the Bohr equation) and the alveolar-arterial Po2 difference (A-aDO2; alveolar gas equation), were also derived. The ventilation (V˙e)/CO2 elimination (V˙co2) slope was also calculated as the slope of the V˙e and V˙co2 relationship, which reflects ventilatory efficiency. RESULTS: Ratings of perceived breathlessness increased (PLC: 3.43 ± 1.94 vs NTG: 4.03 ± 2.18; P = .009) despite a clear decrease in pulmonary capillary wedge pressure at 20 W (PLC: 19.7 ± 8.2 vs NTG: 15.9 ± 7.4 mm Hg; P < .001). Moreover, Vdalv (PLC: 0.28 ± 0.07 vs NTG: 0.31 ± 0.08 L/breath; P = .01), A-aDO2 (PLC: 19.6 ± 6.7 vs NTG: 21.1 ± 6.7; P = .04), and V˙e/V˙co2 slope (PLC: 37.6 ± 5.7 vs NTG: 40.2 ± 6.5; P < .001) all increased at 20 W after a decrease in pulmonary capillary wedge pressure. INTERPRETATION: These findings have important clinical implications and indicate that lowering pulmonary capillary wedge pressure does not decrease dyspnea on exertion in patients with HFpEF; rather, lowering pulmonary capillary wedge pressure exacerbates dyspnea on exertion, increases V˙/Q˙ mismatch, and worsens ventilatory efficiency during exercise in these patients. This study provides compelling evidence that high pulmonary capillary wedge pressure is likely a secondary phenomenon rather than a primary cause of dyspnea on exertion in patients with HFpEF, and a new therapeutic paradigm is needed to improve symptoms of dyspnea on exertion in these patients.

Six Months of Exercise Training Improves Ventilatory Responses during Exercise in Adults with Well-Healed Burn Injuries.

INTRODUCTION: Pulmonary function is lower after a severe burn injury, which could influence ventilatory responses during exercise. It is unclear whether exercise training improves pulmonary function or ventilatory responses during exercise in adults with well-healed burn injuries. Therefore, we tested the hypothesis that exercise training improves pulmonary function and ventilatory responses during exercise in adults with well-healed burn injuries. METHODS: Thirty-nine adults (28 with well-healed burn injuries and 11 non-burn-injured controls) completed 6 months of unsupervised, progressive exercise training including endurance, resistance, and high-intensity interval components. Before and after exercise training, we performed comprehensive pulmonary function testing and measured ventilatory responses during cycling exercise. We compared variables using two-way ANOVA (group-time; i.e., preexercise/postexercise training (repeated factor)). RESULTS: Exercise training did not increase percent predicted spirometry, lung diffusing capacity, or airway resistance measures (time: P ≥ 0.14 for all variables). However, exercise training reduced minute ventilation ( V̇E ; time: P ≤ 0.05 for 50 and 75 W) and the ventilatory equivalent for oxygen ( V̇E /V̇O 2 ; time: P < 0.001 for 75 W) during fixed-load exercise for both groups. The ventilatory equivalent for carbon dioxide ( V̇E /V̇CO 2 ) during exercise at 75 W was reduced after exercise training (time: P = 0.04). The percentage of age-predicted maximum heart rate at the ventilatory threshold was lower in adults with well-healed burn injuries before ( P = 0.002), but not after ( P = 0.22), exercise training. Lastly, exercise training increased V̇E and reduced V̇E /V̇O 2 during maximal exercise (time: P = 0.005 for both variables). CONCLUSIONS: These novel findings demonstrate that exercise training can improve ventilatory responses during exercise in adults with well-healed burn injuries.

Repeatability of dyspnea measurements during exercise in women with obesity.

While the 0-10 Borg scale to rate perceived breathlessness (RPB) is widely used to assess dyspnea on exertion, the repeatability of RPB in women with obesity is unknown. We examined the repeatability of RPB in women with obesity during submaximal constant-load cycling following at least 10 weeks of normal daily life. Seventeen women (37 ± 7 yr; 34.6 ± 4.5 kg/m2) who rated their breathlessness as 3 on the Borg scale (i.e., "moderate") during 60 W submaximal cycling repeated the same test following 19 ± 9 weeks of normal living. Mean body weight (93.8 ± 16.1 vs. 93.6 ± 116.8 kg, p = 0.94) and RPB (3.0 ± 0.0 vs. 3.1 ± 1.4, p = 0.80) did not differ between pre- and post-normal living periods. We demonstrate that subjective ratings of breathlessness are repeatable for the majority of subjects and can be used to accurately assess DOE during submaximal constant-load cycling in women with obesity.

Physiological dead space during exercise in patients with heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is associated with cardiopulmonary abnormalities that may increase physiological dead space to tidal volume (VD/VT) during exercise. However, studies have not corrected VD/VT for apparatus mechanical dead space (VDM), which may confound the accurate calculation of VD/VT. We evaluated whether calculating physiological dead space with (VD/VTVDM) and without (VD/VT) correcting for VDM impacts the interpretation of gas exchange efficiency during exercise in HFpEF. Fifteen HFpEF (age: 69 ± 6 yr; V̇o2peak: 1.34 ± 0.45 L/min) and 12 controls (70 ± 3 yr; V̇o2peak: 1.70 ± 0.51 L/min) were studied. Pulmonary gas exchange and arterial blood gases were analyzed at rest, submaximal (20 W for HFpEF and 40 W for controls), and peak exercise. VD/VT was calculated as [Formula: see text] - [Formula: see text]/[Formula: see text]. VD/VTVDM was calculated as [Formula: see text] - [Formula: see text]/[Formula: see text] - VDM/VT. VD/VT decreased from rest (HFpEF: 0.54 ± 0.07; controls: 0.32 ± 0.07) to submaximal exercise (HFpEF: 0.46 ± 0.07; controls: 0.25 ± 0.06) in both groups (P < 0.05), but remained stable (P > 0.05) thereafter to peak exercise (HFpEF: 0.46 ± 0.09; controls: 0.22 ± 0.05). In HFpEF, VD/VTVDM did not change (P = 0.58) from rest (0.29 ± 0.07) to submaximal exercise (0.29 ± 0.06), but increased (P = 0.02) thereafter to peak exercise (0.33 ± 0.06). In controls, VD/VTVDM remained stable such that no change was observed (P > 0.05) from rest (0.17 ± 0.06) to submaximal exercise (0.14 ± 0.06), or thereafter to peak exercise (0.14 ± 0.05). Calculating physiological dead space with and without a VDM correction yields quantitively and qualitatively different results, which could have impact on the interpretation of gas exchange efficiency in HFpEF. Further investigation is required to uncover the clinical consequences and the mechanism(s) explaining the increase in VD/VTVDM during exercise in HFpEF.NEW & NOTEWORTHY Calculating VD/VT with and without correcting for VDM yields quantitively and qualitatively different results, which could have an important impact on the interpretation of V/Q mismatch in HFpEF. The finding that V/Q mismatch and gas exchange efficiency worsened, as reflected by an increase in VD/VTVDM during exercise, has not been previously demonstrated in HFpEF. Thus, further studies are needed to investigate the mechanisms explaining the increase in VD/VTVDM during exercise in patients with HFpEF.

Alveolar Dead Space Is Augmented During Exercise in Patients With Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Patients with heart failure with preserved ejection fraction (HFpEF) exhibit many cardiopulmonary abnormalities that could result in V˙/Q˙ mismatch, manifesting as an increase in alveolar dead space (VDalveolar) during exercise. Therefore, we tested the hypothesis that VDalveolar would increase during exercise to a greater extent in patients with HFpEF compared with control participants. RESEARCH QUESTION: Do patients with HFpEF develop VDalveolar during exercise? STUDY DESIGN AND METHODS: Twenty-three patients with HFpEF and 12 control participants were studied. Gas exchange (ventilation [V˙E], oxygen uptake [V˙o2], and CO2 elimination [V˙co2]) and arterial blood gases were analyzed at rest, twenty watts (20W), and peak exercise. Ventilatory efficiency (evaluated as the V˙E/V˙co2 slope) also was measured from rest to 20W in patients with HFpEF. The physiologic dead space (VDphysiologic) to tidal volume (VT) ratio (VD/VT) was calculated using the Enghoff modification of the Bohr equation. VDalveolar was calculated as: (VD / VT × VT) - anatomic dead space. Data were analyzed between groups (patients with HFpEF vs control participants) across conditions (rest, 20W, and peak exercise) using a two-way repeated measures analysis of variance and relationships were analyzed using Pearson correlation coefficient. RESULTS: VDalveolar increased from rest (0.12 ± 0.07 L/breath) to 20W (0.22 ± 0.08 L/breath) in patients with HFpEF (P < .01), whereas VDalveolar did not change from rest (0.01 ± 0.06 L/breath) to 20W (0.06 ± 0.13 L/breath) in control participants (P = .19). Thereafter, VDalveolar increased from 20W to peak exercise in patients with HFpEF (0.37 ± 0.16 L/breath; P < .01 vs 20W) and control participants (0.19 ± 0.17 L/breath; P = .03 vs 20W). VDalveolar was greater in patients with HFpEF compared with control participants at rest, 20W, and peak exercise (main effect for group, P < .01). Moreover, the increase in VDalveolar correlated with the V˙E/V˙co2 slope (r = 0.69; P < .01), which was correlated with peak V˙o2peak (r = 0.46; P < .01) in patients with HFpEF. INTERPRETATION: These data suggest that the increase in V˙/Q˙ mismatch may be explained by increases in VDalveolar and that increases in VDalveolar worsens ventilatory efficiency, which seems to be a key contributor to exercise intolerance in patients with HFpEF.

Estimating exercise PaCO2 in patients with heart failure with preserved ejection fraction.

Patients with heart failure with preserved ejection fraction (HFpEF) exhibit cardiopulmonary abnormalities that could affect the predictability of exercise [Formula: see text] from the Jones corrected partial pressure of end-tidal CO2 (PJCO2) equation (PJCO2 = 5.5 + 0.9 × [Formula: see text] - 2.1 × VT). Since the dead space to tidal volume (VD/VT) calculation also includes [Formula: see text] measurements, estimates of VD/VT from PJCO2 may also be affected. Because using noninvasive estimates of [Formula: see text] and VD/VT could save patient discomfort, time, and cost, we examined whether partial pressure of end-tidal CO2 ([Formula: see text]) and PJCO2 can be used to estimate [Formula: see text] and VD/VT in 13 patients with HFpEF. [Formula: see text] was measured from expired gases measured simultaneously with radial arterial blood gases at rest, constant-load (20 W), and peak exercise. VD/VT[art] was calculated using the Enghoff modification of the Bohr equation, and estimates of VD/VT were calculated using [Formula: see text] (VD/VT[ET]) and PJCO2 (VD/VT[J]) in place of [Formula: see text]. [Formula: see text] was similar to [Formula: see text] at rest (-1.46 ± 2.63, P = 0.112) and peak exercise (0.66 ± 2.56, P = 0.392), but overestimated [Formula: see text] at 20 W (-2.09 ± 2.55, P = 0.020). PJCO2 was similar to [Formula: see text] at rest (-1.29 ± 2.57, P = 0.119) and 20 W (-1.06 ± 2.29, P = 0.154), but underestimated [Formula: see text] at peak exercise (1.90 ± 2.13, P = 0.009). VD/VT[ET] was similar to VD/VT[art] at rest (-0.01 ± 0.03, P = 0.127) and peak exercise (0.01 ± 0.04, P = 0.210), but overestimated VD/VT[art] at 20 W (-0.02 ± 0.03, P = 0.025). Although VD/VT[J] was similar to VD/VT[art] at rest (-0.01 ± 0.03, P = 0.156) and 20 W (-0.01 ± 0.03, P = 0.133), VD/VT[J] underestimated VD/VT[art] at peak exercise (0.03 ± 0.04, P = 0.013). Exercise [Formula: see text] and VD/VT[ET] provides better estimates of [Formula: see text] and VD/VT[art] than PJCO2 and VD/VT[J] does at peak exercise. Thus, estimates of [Formula: see text] and VD/VT should only be used if sampling arterial blood during CPET is not feasible.NEW & NOTEWORTHY [Formula: see text] provides a better estimate of [Formula: see text] than PJCO2 at peak exercise, and VD/VT[ET] provides a better estimate of VD/VT[art] than VD/VT[J] at peak exercise. Although we reported significant correlations, we did not find an identity between [Formula: see text] and estimates of [Formula: see text], nor did we find an identity between VD/VT[art] and estimates of VD/VT[art]. Thus, caution should be taken and estimates of [Formula: see text] and VD/VT should only be used if sampling arterial blood during CPET is not feasible.