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Background: Single measurements of left ventricular filling pressure at rest lack sensitivity for identifying heart failure with preserved ejection fraction (HFpEF) in patients with dyspnea on exertion. We hypothesized that exercise hemodynamic measurements (ie, changes in pulmonary capillary wedge pressure [PCWP] indexed to cardiac output [CO]) may more sensitively differentiate HFpEF and non-HFpEF disease states, reflect aerobic capacity, and forecast heart failure outcomes in individuals with normal PCWP at rest., Methods and Results: We studied 175 patients referred for cardiopulmonary exercise testing with hemodynamic monitoring: controls (n=33), HFpEF with resting PCWP≥15 mm Hg (n=32), and patients with dyspnea on exertion with normal resting PCWP and left ventricular ejection fraction (DOE-nlrW; n=110). Across 1835 paired PCWP-CO measurements throughout exercise, we used regression techniques to define normative bounds of "PCWP/CO slope" in controls and tested the association of PCWP/CO slope with exercise capacity and composite cardiac outcomes (defined as cardiac death, incident resting PCWP elevation, or heart failure hospitalization) in the DOE-nlrW group. Relative to controls (PCWP/CO slope, 1.2±0.4 mm Hg/L/min), patients with HFpEF had a PCWP/CO slope of 3.4±1.9 mm Hg/L/min. We used a threshold (2 SD above the mean in controls) of 2 mm Hg/L/min to define abnormal. PCWP/CO slope >2 in DOE-nlrW patients was common (n=45/110) and was associated with reduced peak Vo 2 ( P <0.001) and adverse cardiac outcomes after adjustment for age, sex, and body mass index (hazard ratio, 3.47; P =0.03) at a median 5.3-year follow-up., Conclusions: Elevated PCWP/CO slope during exercise (>2 mm Hg/L/min) is common in DOE-nlrW and predicts exercise capacity and heart failure outcomes. These findings suggest that current definitions of HFpEF based on single measures during rest are insufficient and that assessment of exercise PCWP/CO slope may refine early HFpEF diagnosis., (© 2018 American Heart Association, Inc.)

Introduction: Pulmonary edema with low systemic oxygen (O2) levels is a hallmark of acute decompensated heart failure (HF) related to elevated left heart filling pressures. However, less is known about arterial O2 (PaO2) responses during exercise in patients with heart failure with preserved ejection fraction (HFpEF). Hypothesis: We hypothesized that changes in PaO2 in response to exercise are governed by extra-cardiac organ systems rather than the degree of elevation in pulmonary capillary wedge pressure (PCWP). Methods: We performed maximum incremental cardiopulmonary exercise testing with invasive hemodynamic monitoring in 411 patients (age 58±2.9, 61% female, BMI 29.7±0.7, LVEF 66±2.6 %; mean±SEM) with HFpEF defined by ACC/AHA criteria with exclusion of patients with O2-dependent lung disease. Results: Exercise PaO2 was associated with peak VO2 (r=0.22, p<0.001) but average PaO2 increased only modestly from rest to peak exercise (3.1±0.7mmHg) and overt O2 desaturation was uncommon (1.5% of patients had PaO2<55mmHg and O2sat ≤ 88%). Exercise change in PaO2 was not associated with resting PCWP (r=0.05, p=0.27) or exercise PCWP (r<0.01, P=0.7) (Figure). Change in PaO2was correlated with % predicted diffusion capacity of the lungs (DLCO) (r=0.28, p<0.001) despite relatively normal average spirometry values (FVC 93±1, FEV1 89±5, FVC/FEV 96±5, % predicted mean±SEM). Pulmonary artery pressure (PAP) and transpulmonary pressure gradient (TPG) were also associated with change in PaO2 (r=-0.18 (PAP), r=-0.25 (TPG), p<0.001) in multivariable models adjusting for age, sex, and BMI. Conclusions: Pulmonary and pulmonary vascular function, but not left sided filling pressures, relate to changes in PaO2 during incremental exercise in HFpEF. These findings highlight the important role of extra-cardiac organ systems, specifically the lungs, in mediating systemic O2 bioavailability during exercise in HFpEF. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. Background: Heart failure with preserved ejection fraction (HFpEF) is common, yet there is currently no consensus on how to define HFpEF according to various society and clinical trial criteria. How clinical and hemodynamic profiles of patients vary across definitions is unclear. We sought to determine clinical characteristics, as well as physiologic and prognostic implications of applying various criteria to define HFpEF. Methods: We examined consecutive patients with chronic exertional dyspnea (New York Heart Association class II to IV) and ejection fraction ≥50% referred for comprehensive cardiopulmonary exercise testing with invasive hemodynamic monitoring. We applied societal and clinical trial HFpEF definitions and compared clinical profiles, exercise responses, and cardiovascular outcomes. Results: Of 461 patients (age 58±15 years, 62% women), 416 met American College of Cardiology/American Heart Association (ACC/AHA), 205 met European Society of Cardiology (ESC), and 55 met Heart Failure Society of America (HFSA) criteria for HFpEF. Clinical profiles and exercise capacity varied across definitions, with peak oxygen uptake of 16.2±5.2 (ACC/AHA), 14.1±4.2 (ESC), and 12.7±3.1 mL·kg-1·min-1 (HFSA). A total of 243 patients had hemodynamic evidence of HFpEF (abnormal rest or exercise filling pressures), of whom 222 met ACC/AHA, 161 met ESC, and 41 met HFSA criteria. Over a mean follow-up of 3.8 years, the incidence of cardiovascular outcomes ranged from 75 (ACC/AHA) to 298 events per 1000 person-years (HFSA). Application of clinical trial definitions of HFpEF similarly resulted in distinct patient classification and prognostication. Conclusions: Use of different HFpEF classifications variably enriches for future cardiovascular events, but at the expense of not including up to 85% of individuals with physiologic evidence of HFpEF. Comprehensive phenotyping of patients with suspected heart failure highlights the limitations and heterogeneity of current HFpEF definitions and may help to refine HFpEF subgrouping to test therapeutic interventions. [ABSTRACT FROM AUTHOR]