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Introduction:HFpEF is more prevalent in women compared to men, yet mechanisms underlying these sex differences are poorly understood. We sought to examine sex differences in the relationship between exercise pulmonary capillary wedge pressure (PCWP) responses and baseline and exercise measures of arterial stiffness.Methods:We studied 83 men (mean age 62) and 107 women (mean age 60) with HFpEF who underwent CPET with invasive hemodynamic monitoring. Measures of central arterial stiffness (aortic augmentation pressure [AP], augmentation index [Aix], and aortic pulse pressure [AoPP]) were obtained using application of a validated generalized transfer function to invasive radial arterial waveforms. Data was collected at rest, 30 watts and peak exercise. Sex differences were compared using multivariable linear regression. We next examined the association of arterial stiffness with abnormally steep PCWP to exercise (?PCWP/?CO > 2 mmHg/L/min) using logistic regression models.Results:Women had higher indices of arterial stiffness both at rest and during exercise (Figure). At rest, AP was nearly 10mmHg higher in women (P<0.001), a difference that persisted in multivariable analyses, as well as at 30W and peak exercise. Resting measures of arterial stiffness were associated with an abnormally steep PCWP response to exercise (?PCWP/?CO > 2) in women, but not men. Specifically, a 1-SD increase in AP was associated with a >3-fold increased odds of abnormally steep PCWP exercise response in women (AP: OR 3.16, 95% CI 1.34-7.42, p=0.008 [women] vs OR 2.07, 95% CI 0.95-5.49, p=0.15 [men]) with similar findings for Aix and AoPP.Conclusions:In patients with HFpEF, arterial stiffness is significantly higher in women both at rest and during exercise. Resting arterial stiffness is associated with abnormally steep increases in PCWP with exercise in women. These findings highlight an important phenotypic sex difference in patients with HFpEF.

Introduction:A resting supine pulmonary capillary wedge pressure (rsPCWP) of ? 15 mmHg is considered a hemodynamic ?gold standard? criteria for diagnosing heart failure with preserved ejection fraction (HFpEF). Whether normal upright exercise PCWP confers a favorable prognosis when rsPCWP is elevated is unknown.Hypothesis:Among patients with elevated rsPCWP and a normal PCWP increase relative to cardiac output (PCWP/CO < 2 mmHg/L/min) during exercise will have superior HF-event free survival compared to individuals with elevated rsPCWP and abnormal PCWP/CO ? 2mmHg/L/min.Methods:We performed upright maximum incremental ramp cycle ergometry cardiopulmonary exercise testing with invasive hemodynamic monitoring in patients referred to a single center for evaluation of exertional dyspnea. At rest and each minute of exercise direct Fick CO and PCWP were measured to derive PCWP/CO slopes and patient outcomes were assessed with Cox regression models.Results:In 182 patients with rsPCWP ? 15mmHg and normal LVEF (age 60?14, 54% female, BMI 31?7, LVEF 65?7%; mean?SD) PCWP/CO slope was < 2 mmHg/L/min in 72 patients and ? 2mmHg/L/min in 110. After adjustment for age, sex, and BMI (Figure), PCWP/CO< 2mmHg/L/min was associated with a lower hazard for combined HF or death (hazard ratio HR=0.29, p=0.007), HF alone (HR=0.35, trend at p=0.067), and death (HR=0.29, p=0.028) in comparison with PCWP/CO ? 2mmHg/L/min. The 95% confidence intervals were [0.119, 0.716], [0.113,1.08] and [0.072, 0.829], respectively.Conclusion:A normal upright PCWP/CO slope of < 2 mmHg/L/min is associated with favorable outcomes in patients with elevated rsPCWP. These findings highlight a potentially important role of assessing exercise hemodynamics in patients with suspected HFpEF, even when rsPCWP is elevated.

Introduction:Exercise intolerance in patients with heart failure with preserved ejection fraction (HFpEF) reflects multi-organ dysfunction characteristic of a systemic disorder. We sought to determine if oxygen uptake (VO2) kinetic patterns may aid in resolution of cardiac-specific impairment during exercise.Hypothesis:Delayed kinetics of VO2recovery will predict cardiac performance and heart failure (HF) outcomes in patients with suspected HFpEF.Methods:We performed upright maximum incremental ramp cycle ergometry cardiopulmonary exercise testing with invasive hemodynamic monitoring in patients referred to a single center for evaluation of exertional dyspnea. Pulmonary capillary wedge pressure (PCWP), and direct Fick cardiac output (CO) were measured at rest and during each minute of exercise to derive ?PCWP/?CO slopes (WQ). We assessed recovery O2kinetics by measuring VO2recovery delay (VO2RD), defined as the time it took for VO2 to fall below peak VO2 (defined by the highest 30 second median within the final minute of exercise). VO2RD >25s was evaluated as a prognostic cut point based on recent data linking VO2RD >25s to increased risk of mortality in HF with reduced LVEF. HF hospitalization and HF event-free survival were assessed by Cox regression models.Results:Among 342 patients with measured VO2 kinetics and normal LVEF (age 58?14.0, 55% female, BMI 29.5?6.2, LVEF 65?6.9%, mean?SD), VO2RD >25s was present in 72 patients (27%). VO2RD increased across quartiles of WQ (Figure, ANOVA p<0.0001). After adjustment for age, sex, and BMI, VO2RD>25s was associated with a higher hazard for HF hospitalization (HR 3.35, 95% CI 1.28-8.76, p=0.014) and combined HF or death (HR 2.1, 95% CI 1.04-4.18, p=0.039).Conclusion:In patients undergoing evaluation of dyspnea on exertion, abnormal VO2recovery kinetics are associated with a steep increment in PCWP in response to exercise and lower HF-free survival.

Introduction:Adverse exertional hemodynamic responses in HFpEF include increases in pulmonary capillary wedge pressure (PCWP) and inadequate augmentation of stroke volume (SV). Blood pressure is an integral part of the ventricular-vascular response to exercise in HFpEF.Hypothesis:We hypothesized that blood pressure responses during exercise would be associated with PCWP and SV responses in patients with HFpEF.Methods:We evaluated 146 patients with HFpEF who underwent invasive cardiopulmonary exercise testing. Hemodynamic changes were measured during seated cycle exercise. PCWP and SV were measured using a Swan-Ganz catheter. SBP, DBP and PP were measured using a radial artery catheter. Proportionate pulse pressure (PrPP) was calculated as PP/SBP. Relationships between exertional BP changes and PCWP and SV changes were evaluated with multivariable linear regression. Models were adjusted for age, sex, BMI, heart rate change and maximum workload (watts).Results:Cohort profile was mean age 63 years (SD 13 years), 50% male. SBP and DBP changes during exercise were significantly positively correlated with changes in PCWP. In contrast, PrPP changes were significantly positively correlated with maximal SV. Findings persisted after multivariate correction (Table). Standardized beta coefficients for SBP and DBP changes were higher than for all other covariates (age, sex, BMI, heart rate change and maximal workload) in multivariate PCWP models, while standardized beta coefficient for change in PrPP was higher than those for age and sex, but less than those for BMI, heart rate change and workload.Conclusions:In patients with HFpEF, the nature of blood pressure response during exercise was closely associated with exertional PCWP and SV. Exertional blood pressure response patterns may provide a window into mechanisms of ventricular-vascular interaction in HFpEF.

Introduction:During exercise, the systemic vasculature must vasodilate to accommodate increased cardiac output and delivery of oxygen to the peripheral tissues. Systemic vascular distensibility (SVD) represents the ability of systemic arterioles to vasodilate for a given increase in pressure. However, the effects of SVD on exercise performance in patients with heart failure with preserved ejection fraction (HFpEF) are unknown. We hypothesized that abnormal SVD is an important determinant of exercise performance in HFpEF.Methods:Patients with HFpEF (n= 309, LVEF? 50%, and supine PCWP ? 15 mmHg or PCWP/Cardiac output slope ? 2.0 mmHg/L/min) and controls (n= 119, peak VO2> 80% predicted, with LVEF? 50%, supine PCWP <15mmHg, and PCWP/CO slope < 2.0) underwent cardiopulmonary exercise testing with invasive hemodynamic monitoring. A distensible vessel model was used to calculate the systemic vascular pressure-flow relationship, using measures of mean arterial pressure, right atrial pressure, and cardiac output at rest and multiple points during exercise. Utilizing an iterative approach with least-squares methodology we determined SVD.Results:SVD was lower in the HFpEF group (Figure, 0.27?0.12% per mmHg, mean, SD) than in the control group (0.32?0.12% per mmHg, p<0.0001). SVD was associated with cardiac output at peak exercise as well as augmentation of cardiac output both in the control population (?=0.22, p=0.019) and HFpEF population (?=0.15 p=0.009). Higher SVD was associated with improved ventilatory efficiency measured by VE/VCO2 slope in the HFpEF population (?=-0.18, p=0.0017).Conclusions:Systemic vascular distensibility is lower in patients with HFpEF compared to controls and is a predictor of cardiac output augmentation and ventilatory efficiency in patients with HFpEF. We conclude that SVD is an important determinant of exercise performance in HFpEF.

Background:Patients with repaired Tetralogy of Fallot (rTOF) often develop pulmonary regurgitation leading to progressive right ventricular (RV) dilatation and dysfunction resulting in chronic heart failure (HF). RV reserve is known to predict outcomes in a population with congenital right heart disease. This study aims to characterize RV reserve in adults with rTOF and to evaluate RV reserve before and after pulmonic valve replacement (PVR) in a select subset.Methods:We performed a retrospective study evaluating rTOF patients (n = 83) who underwent cardiopulmonary exercise testing with first pass radionuclide ventriculography at a single tertiary care center. RV reserve was categorized as normal or abnormal, defined as right ventricle ejection fraction (RVEF) <45% at peak exercise or inability to augment RVEF by 5% from rest.Results:Mean age was 42 years and 45% were female. 69% had impaired RV reserve. Compared to the normal reserve group, patients with impaired RV reserve were older (43 vs 38 years, p = 0.04), had a longer QRS duration (153 vs 132ms, p < 0.001) and were more likely to have had repair after age 1 year (84% vs 65%, p = 0.05). Of this group, 69 (83%) underwent cardiac CT or MRI. Patients with impaired RV reserve had lower mean RVEF (42% vs 48%, p = 0.03) with similar resting indexed RV end-diastolic volume (134 vs 142 ml/m2, p = 0.3). With respect to gas exchange, both groups had similar peak oxygen consumption as predicted for gender and age (57% vs 60%, p = 0.5). 11 patients had assessment of RV reserve pre- and post-PVR. After PVR there was a statistically significant increase in resting RVEF (42% vs 38%, p = 0.02) and RVEF at peak exercise (44% vs 38%) with a decrease in RV reserve impairment in this subgroup.Conclusions:Impaired RV reserve is associated with traditional predictors of poor outcomes in rTOF (older age, prolonged QRS, later age of repair). Assessment of RV reserve identifies asymptomatic patients with RV dysfunction who have resting RV function and volumes that would not meet indications for reoperation per existing guidelines. Current practice utilizes MRI to assess RV function and dilatation at rest to determine timing of PVR. Assessment of RV reserve may aid clinicians in identifying asymptomatic rTOF patients who may regain RV function with PVR.