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Background: Peak oxygen consumption and oxygen pulse along with their respective percent predicted measures are gold standards of exercise capacity. To date, no studies have investigated the relationship between percent predicted peak oxygen pulse (%PredO 2 P) and ventricular-vascular response (VVR) and the association of %PredO 2 P with all-cause mortality in heart failure with preserved ejection fraction (HFpEF) patients., Objectives: The authors investigated the association between: 1) CPET measures of %PredO 2 P and VVR; and 2) %PredO 2 P and all-cause mortality in HFpEF patients., Methods: Our cohort of 154 HFpEF patients underwent invasive CPET and were grouped into %PredO 2 P tertiles. The association between percent predicted Fick components and markers of VVR (ie, proportionate pulse pressure, effective arterial elastance) was determined with correlation analysis. The Cox proportional hazards model was used to identify predictors of mortality., Results: The participants' mean age was 57 ± 15 years. Higher %PredO 2 P correlated with higher exercise capacity. In terms of VVR, higher %PredO 2 P correlated with a lower pressure for a given preload (effective arterial elastance r = -0.45, P  < 0.001 and proportionate pulse pressure r = -0.22, P  = 0.008). %PredO 2 P distinguished normal and abnormal percent predicted peak stroke volume and correlated positively with %PredVO 2 (r = 0.61, P  < 0.001). Participants had a median follow-up time of 5.6 years and 15% death. Adjusted for age and body mass index, there was a 5% relative reduction in mortality (HR: 0.95, 95% CI: 0.92-0.98, P  = 0.003) for every percent increase in %PredO 2 P., Conclusions: In HFpEF, %PredO 2 P is a VVR marker that can stratify invasive parameters such as percent predicted peak stroke volume. %PredO 2 P is an independent prognostic marker for all-cause mortality and those with higher %PredO 2 P exhibited longer survival., Competing Interests: Dr Malhotra was supported by the National Heart, Lung, and Blood Institute (R01HL142809, R01HL159514, and R01HL162928), the American Heart Association (22TPA969625), and the Wild Family Foundation. Dr Malhotra has received research funding from Angea Biotherapeutics and Amgen; and serves as a consultant for Myokardia/BMS, Renovacor, Epizon Pharma, and Third Pole. Dr Malhotra is a co-founder of Patch, Inc; is a co-inventor for a patent on pharmacologic BMP inhibitors (along with Mass General Brigham) for which he receives royalties; and has received royalties from UpToDate for scientific content authorship. Dr Nayor was supported by NIH grants K23-HL138260, R01-HL156975, and R01-HL131029 and by a Career Investment Award from the Department of Medicine, Boston University School of Medicine; and has received speaking honoraria from Cytokinetics. Dr Lewis has received research funding from the National Institutes of Health R01-HL 151841, R01-HL131029, R01-HL159514, American Heart Association 15GPSGC-24800006 and Amgen, Cytokinetics, Applied Therapeutics, AstraZeneca, and SoniVie; has received honoraria for advisory boards outside of the current study from Pfizer, Merck, Boehringer Ingelheim, NXT, American Regent, Cyclerion, Cytokinetics, and Amgen; and has received royalties from UpToDate for scientific content authorship related to exercise physiology. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: Whether systemic oxygen levels (SaO 2 ) during exercise can provide a window into invasively derived exercise hemodynamic profiles in patients with undifferentiated dyspnea on exertion is unknown., Methods: We performed cardiopulmonary exercise testing with invasive hemodynamic monitoring and arterial blood gas sampling in individuals referred for dyspnea on exertion. Receiver operator analysis was performed to distinguish heart failure with preserved ejection fraction from pulmonary arterial hypertension., Results: Among 253 patients (mean ± SD, age 63 ± 14 years, 55% female, arterial O 2 [PaO 2 ] 87 ± 14 mmHg, SaO 2 96% ± 4%, resting pulmonary capillary wedge pressure [PCWP] 18 ± 4mmHg, and pulmonary vascular resistance [PVR] 2.7 ± 1.2 Wood units), there was no exercise PCWP threshold, measured up to 49 mmHg, above which hypoxemia was consistently observed. Exercise PaO 2 was not correlated with exercise PCWP (rho = 0.04; P = 0.51) but did relate to exercise PVR (rho = -0.46; P < 0.001). Exercise PaO 2 and SaO 2 levels distinguished left-heart-predominant dysfunction from pulmonary-vascular-predominant dysfunction with an area under the curve of 0.89 and 0.89, respectively., Conclusion: Systemic O 2 levels during exercise distinguish relative pre- and post-capillary pulmonary hemodynamic abnormalities in patients with undifferentiated dyspnea. Hypoxemia during upright exercise should not be attributed to isolated elevation in left heart filling pressures and should prompt consideration of pulmonary vascular dysfunction., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: This study aimed to evaluate hemodynamic correlates of inducible blood pressure (BP) pulsatility with exercise in heart failure with preserved ejection fraction (HFpEF), to identify relationships to outcomes, and to compare this with heart failure with reduced ejection fraction (HFrEF)., Background: In HFpEF, determinants and consequences of exercise BP pulsatility are not well understood., Methods: We measured exercise BP in 146 patients with HFpEF who underwent invasive cardiopulmonary exercise testing. Pulsatile BP was evaluated as proportionate pulse pressure (PrPP), the ratio of pulse pressure to systolic pressure. We measured pulmonary arterial catheter pressures, Fick cardiac output, respiratory gas exchange, and arterial stiffness. We correlated BP changes to central hemodynamics and cardiovascular outcome (nonelective cardiovascular hospitalization) and compared findings with 57 patients with HFrEF from the same referral population., Results: In HFpEF, only age (standardized beta = 0.593; P < 0.001), exercise stroke volume (standardized beta = 0.349; P < 0.001), and baseline arterial stiffness (standardized beta = 0.182; P = 0.02) were significant predictors of peak exercise PrPP in multivariable analysis (R = 0.661). In HFpEF, lower PrPP was associated with lower risk of cardiovascular events, despite adjustment for confounders (HR:0.53 for PrPP below median; 95% CI: 0.28-0.98; P = 0.043). In HFrEF, lower exercise PrPP was not associated with arterial stiffness but was associated with lower peak exercise stroke volume (P = 0.013) and higher risk of adverse cardiovascular outcomes (P = 0.004)., Conclusions: In HFpEF, greater inducible BP pulsatility measured using exercise PrPP reflects greater arterial stiffness and higher risk of adverse cardiovascular outcomes, in contrast to HFrEF where inducible exercise BP pulsatility relates to stroke volume reserve and favorable outcome., Competing Interests: Funding Support and Author Disclosures Dr Namasivayam is supported by a Clinical and Research Fellowship from the Division of Cardiology, Massachusetts General Hospital, Harvard Medical School; and is a recipient of the St. Vincent’s Clinic Travelling Fellowship Award. Dr Lewis is supported by the American Heart Association Award 15GPSGC24800006 and by the National Heart, Lung and Blood Institute Awards R01-HL 131029 and R01-HL151841. Dr Nayor is supported by National Institutes of Health/National Heart, Lung, and Blood Institute K23-HL138260. Dr Ho is supported by National Institutes of Health/National Heart, Lung, and Blood Institute R01-HL134893 and R01-HL140224. Dr Malhotra is supported by Transformation Project Award 18TPA34230025 from the American Heart Association and grant R01-HL142809 from the National Heart, Lung, and Blood Institute. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022. Published by Elsevier Inc.)

Background: Obesity has multifactorial effects on lung function and exercise capacity. The contributions of obesity-related inflammatory pathways to alterations in lung function remain unclear., Research Question: To examine the association of obesity-related inflammatory pathways with pulmonary function, exercise capacity, and pulmonary-specific contributors to exercise intolerance., Method: We examined 695 patients who underwent cardiopulmonary exercise testing (CPET) with invasive hemodynamic monitoring at Massachusetts General Hospital between December 2006-June 2017. We investigated the association of adiponectin, leptin, resistin, IL-6, CRP, and insulin resistance (HOMA-IR) with pulmonary function and exercise parameters using multivariable linear regression., Results: Obesity-related inflammatory pathways were associated with worse lung function. Specifically, higher CRP, IL-6, and HOMA-IR were associated with lower percent predicted FEV 1 and FVC with a preserved FEV 1 /FVC ratio suggesting a restrictive physiology pattern (P ≤ 0.001 for all). For example, a 1-SD higher natural-logged CRP level was associated with a nearly 5% lower percent predicted FEV 1 and FVC (beta -4.8, s.e. 0.9 for FEV1; beta -4.9, s.e. 0.8 for FVC; P < 0.0001 for both). Obesity-related inflammatory pathways were associated with worse pulmonary vascular distensibility (adiponectin, IL-6, and CRP, P < 0.05 for all), as well as lower pulmonary artery compliance (IL-6 and CRP, P ≤ 0.01 for both)., Interpretation: Our findings highlight the importance of obesity-related inflammatory pathways including inflammation and insulin resistance on pulmonary spirometry and pulmonary vascular function. Specifically, systemic inflammation as ascertained by CRP, IL-6 and insulin resistance are associated with restrictive pulmonary physiology independent of BMI. In addition, inflammatory markers were associated with lower exercise capacity and pulmonary vascular dysfunction., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Importance: Heart failure with preserved ejection fraction (HFpEF) is a joint metabolic and cardiovascular disorder with significant noncardiac contributions., Objective: To define and quantify the metabolic cost of initiating exercise in individuals with and without HFpEF and its functional consequences., Design, Setting, and Participants: This prospective cohort study included individuals with hemodynamically confirmed HFpEF from the Massachusetts General Hospital Exercise Study (MGH-ExS) and community-dwelling participants from the Framingham Heart Study (FHS). Analysis began April 2016 and ended November 2020., Exposures: Internal work (IW), a measure of work equivalents required to initiate movement., Main Outcomes and Measures: Using breath-by-breath oxygen uptake (V̇o2) measurements and V̇o2-work rate associations, cost of initiating exercise (IW) in patients with HFpEF (MGH-ExS) and in community-dwelling individuals (FHS) was quantified. Linear regression was used to estimate associations between IW and clinical/hemodynamic measures., Results: Of 3231 patients, 184 (5.7%) had HFpEF and were from MGH-ExS, and 3047 (94.3%) were community-dwelling individuals from FHS. In the MGH-ExS cohort, 86 (47%) were women, the median (interquartile range) age was 63 (53-72) years, and the median (interquartile range) peak V̇o2 level was 13.33 (11.77-15.62) mL/kg/min. In the FHS cohort, 1620 (53%) were women, the median (interquartile range) age was 54 (48-60) years, and the median (interquartile range) peak V̇o2 level was 22.2 (17.85-27.35) mL/kg/min. IW was higher in patients with HFpEF and accounted for 27% (interquartile range, 21%-39%) of the total work (IW + measured external workload on the cycle), compared with 15% (interquartile range, 12%-20%) of that in FHS participants. Body mass index accounted for greatest explained variance in patients with HFpEF from MGH-ExS and FHS participants (22% and 18%, respectively), while resting cardiac output and biventricular filling pressures were not significantly associated with variance in IW in patients with HFpEF. A higher IW in patients with HFpEF was associated with a greater increase in left- and right-sided cardiac filing pressure during unloaded exercise, despite similar resting hemodynamic measures across IW., Conclusions and Relevance: This study found that internal work, a new body mass index-related measure reflecting the metabolic cost of initiating movement, is higher in individuals with HFpEF compared with middle-aged adults in the community and is associated with steep, early increases in cardiac filling pressures. These findings highlight the importance of quantifying heterogeneous responses to exercise initiation when evaluating functional intolerance in individuals at risk for or with HFpEF.

Background: Arterial stiffness is thought to contribute to the pathophysiology of heart failure with preserved ejection fraction (HFpEF). We sought to examine arterial stiffness in HFpEF and hypertension and investigate associations of arterial and left ventricular hemodynamic responses to exercise., Methods and Results: A total of 385 symptomatic individuals with an EF of ≥50% underwent upright cardiopulmonary exercise testing with invasive hemodynamic assessment of arterial stiffness and load (aortic augmentation pressure, augmentation index, systemic vascular resistance index, total arterial compliance index, effective arterial elastance index, and pulse pressure amplification) at rest and during incremental exercise. An abnormal hemodynamic response to exercise was defined as a steep increase in pulmonary capillary wedge pressure relative to cardiac output (∆PCWP/∆CO > 2 mm Hg/L/min). We compared rest and exercise measures between HFpEF and hypertension in multivariable analyses. Among 188 participants with HFpEF (mean age 61 ± 13 years, 56% women), resting arterial stiffness parameters were worse compared with 94 hypertensive participants (mean age 55 ± 15 years, 52% women); these differences were accentuated during exercise in HFpEF (all P ≤ .0001). Among all participants, exercise measures of arterial stiffness correlated with worse ∆PCWP/∆CO. Specifically, a 1 standard deviation higher exercise augmentation pressure was associated with 2.15-fold greater odds of abnormal LV hemodynamic response (95% confidence interval 1.52-3.05; P < .001). Further, exercise measures of systemic vascular resistance index, elastance index, and pulse pressure amplification correlated with a lower peak oxygen consumption., Conclusions: Exercise accentuates the increased arterial stiffness found in HFpEF, which in turn correlates with left ventricular hemodynamic responses. Unfavorable ventricular-vascular interactions during exercise in HFpEF may contribute to exertional intolerance and inform future therapeutic interventions., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Ventilatory efficiency (minute ventilation required to eliminate carbon dioxide, VE/VCO2) during exercise potently predicts outcomes in advanced heart failure with reduced ejection fraction, but its prognostic significance for at-risk individuals with preserved left ventricular systolic function is unclear. We aimed to characterize mechanistic determinants and prognostic implications of VE/VCO2 in a single-center dyspneic referral cohort (MGH-ExS [Massachusetts General Hospital Exercise Study]) and in a large sample of community-dwelling participants in the FHS (Framingham Heart Study)., Methods: Maximum incremental cardiopulmonary exercise tests were performed. VE/VCO2 was assessed as the slope pre- and post-ventilatory anaerobic threshold (VE/VCO2 pre-VATslope , VE/VCO2 post-VATslope ), the slope throughout exercise (VE/VCO2 overall-slope ), and as the lowest 30-second value (VE/VCO2 nadir )., Results: In the MGH-ExS (N=493, age 56±15 years, 61% women, left ventricular ejection fraction 64±8%), higher VE/VCO2 nadir was associated with lower peak exercise cardiac output and steeper increases in exercise pulmonary capillary wedge pressure (both P <0.0001). VE/VCO2 nadir (hazard ratio, 1.34 per 1-SD unit [95% CI, 1.10-1.62] P =0.003) was associated with future cardiovascular hospitalization/death and outperformed classical VE/VCO2 measures used in heart failure with reduced ejection fraction (VE/VCO2 overall-slope ). In FHS (N=1936, age 54±9 years, 53% women), VE/VCO2 measures taken in low-to-moderate intensity exercise (including VE/VCO2 pre-VATslope , VE/VCO2 nadir ) were directly associated with cardiovascular risk factor burden (smoking, Framingham cardiovascular disease risk score, and lower fitness; all P <0.001)., Conclusions: Impaired ventilatory efficiency is associated with cardiovascular risk in the community and with adverse hemodynamic profiles and future hospitalizations/death in a referral population, highlighting the prognostic importance of easily acquired submaximum exercise ventilatory gas exchange measurements in broad populations with preserved left ventricular systolic function.

Background: Abnormal pulmonary arterial pressure (PAP) responses to exercise have been described in select individuals; however, clinical and prognostic implications of exercise pulmonary hypertension (exPH) among broader samples remains unclear., Objectives: This study sought to investigate the association of exPH with clinical determinants and outcomes., Methods: The authors studied individuals with chronic exertional dyspnea and preserved ejection fraction who underwent cardiopulmonary exercise testing with invasive hemodynamic monitoring. Exercise pulmonary hypertension was ascertained using minute-by-minute PAP and cardiac output (CO) measurements to calculate a PAP/CO slope, and exPH defined as a PAP/CO slope >3 mm Hg/l/min. The primary outcome was cardiovascular (CV) hospitalization or all-cause mortality., Results: Among 714 individuals (age 57 years, 59% women), 296 (41%) had abnormal PAP/CO slopes. Over a mean follow-up of 3.7 ± 2.9 years, there were 208 CV or death events. Individuals with abnormal PAP/CO slope had a 2-fold increased hazard of future CV or death event (multivariable-adjusted hazard ratio: 2.03; 95% confidence interval: 1.48 to 2.78; p < 0.001). The association of abnormal PAP/CO slope with outcomes remained significant after excluding rest PH (n = 146, hazard ratio: 1.75; 95% confidence interval: 1.21 to 2.54; p = 0.003). Both pre- and post-capillary contributions to exPH independently predicted adverse events (p < 0.001 for both)., Conclusions: Exercise pulmonary hypertension is independently associated with CV event-free survival among individuals undergoing evaluation of chronic dyspnea. These findings suggest incremental value of exercise hemodynamic assessment to resting measurements alone in characterizing the burden of PH in individuals with dyspnea. Whether PH and PH subtypes unmasked by exercise can be used to guide targeted therapeutic interventions requires further investigation., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Since 1993, WHO has recommended a strategy through which national governments can meet their responsibility to treat patients and to prevent the spread of tuberculosis (TBI). Four of the major elements of the strategy, which came to be known as DOTS, were political commitment by governments, improved laboratory services, a continuous supply of good-quality drugs, and a reporting system to document the progress (and failure) of treatment for individual patients and of the programme. The fifth element, effective case management via direct observation of treatment by an independent and trained third party, was a response to decades of reports documenting the failure of patients to complete treatment. Put simply: direct observation of treatment is an integral and essential component of DOTS. The value of the direct observation component of DOTS has been questioned in a recent systematic review, in which it was suggested that direct observation of treatment is unnecessary and disrespectful of patients. Both self-administered treatment and treatment observation by a family member have been proposed as acceptable alternatives. This article challenges the validity of these assertions on the basis that, firstly, direct observation requires strong leadership and a lengthy commitment of human resources, which as yet is not universally employed. Secondly, it is believed that the ultimate ethical and legal responsibility for ensuring treatment completion and cure of a communicable disease belongs to the public health system and the community, and not to the individual patient. TB, this article will seek to argue, can be controlled when appropriate policies are implemented and continued, even in the absence of an outbreak or media attention. Just as patients may be tempted to change or stop an effective treatment regimen because of the long duration of treatment, public health policy-makers may be tempted to alter key elements of DOTS because of the persistence required to maintain effective programmes.

Respiratory tract infections (RTIs) are expensive for MCOs and cause significant morbidity among their members. Although awareness of resistance to antibiotics is increasing, antibiotic selection for community-acquired RTIs remains largely empiric. When making formulary decisions, Pharmacy and Therapeutics Committees may want to consider the spectrum of coverage that an antibiotic provides and its vulnerability to resistance development. Through appropriate formulary management and provider education, MCOs can promote successful clinical and economic outcomes. This article examines the current status of antibiotic therapy for community-acquired RTIs and encourages the incorporation of new parameters into MCO formulary decision processes.