Elevated left ventricular filling pressure (measured as mean pulmonary capillary wedge pressure) at rest or with exercise is diagnostic of heart failure with preserved ejection fraction. However, the capacity of the right ventricle to compensate for a high mean pulmonary capillary wedge pressure and thus maintain an appropriate transpulmonary gradient (TPG) and perfusion of the pulmonary capillaries is likely an important contributor to gas exchange efficiency and exercise capacity. Therefore, this study aimed to determine whether a higher TPG at peak exercise is associated with superior exercise capacity and gas exchange. Gas exchange data from dyspneic patients referred for exercise right heart catheterization were retrospectively analyzed and patients were split into two groups based on TPG. Patients with a higher TPG at peak exercise had a higher peak VO2 (1025 +/- 227 vs 823 +/- 276, P = .038), end-tidal partial pressure of carbon dioxide (42.2 +/- 7.9 vs 38.0 +/- 4.7, P = .044), and gas exchange estimates of pulmonary vascular capacitance (408 +/- 90 vs 268 +/- 108, P = .001). A higher TPG at peak exercise correlated with a higher peak oxygen uptake, O-2 pulse, and stroke volume (R = 0.42, 0.44 and 0.42, respectively, all P < 0.05). These findings indicate that a greater TPG with exercise might be important for improving exercise capacity in heart failure with preserved ejection fraction.

Heart failure (HF) has traditionally been defined by symptoms of fluid accumulation and poor perfusion, but it is now recognized that specific HF classifications hold prognostic and therapeutic relevance. Specifically, HF with reduced ejection fraction is characterized by reduced left ventricular systolic pump function and dilation and HF with preserved ejection fraction is characterized primarily by abnormal left ventricular filling (diastolic failure) with relatively preserved left ventricular systolic function. These forms of HF are distributed equally among patients with HF and likely require distinctly different strategies to mitigate the morbidity, mortality, and medical resource utilization of this disease. In particular, HF is a significant medical issue within the US Department of Veterans Affairs (VA) hospital system and constitutes a major translational research priority for the VA. Because a common underpinning of both HF with reduced ejection fraction and HF with preserved ejection fraction seems to be changes in the structure and function of the myocardial extracellular matrix, a conference was convened sponsored by the VA, entitled, Targeting Myocardial Fibrosis in Heart Failure to explore the extra-cellular matrix as a potential therapeutic target and to propose specific research directions. The conference was conceptually framed around the hypothesis that although HF with reduced ejection fraction and HF with preserved ejection fraction clearly have distinct mechanisms, they may share modifiable pathways and biological mediators in common. Inflammation and extracellular matrix were identified as major converging themes. A summary of our discussion on unmet challenges and possible solutions to move the field forward, as well as recommendations for future research opportunities, are provided.

Background: Although left atrial (LA) mechanical dysfunction in heart failure with preserved ejection fraction (HFpEF) is associated with poor clinical outcomes, the influence of LA myopathy on temporal changes in cardiovascular biomarkers is unclear. Methods and Results: We evaluated biomarker correlates of LA myopathy, as defined by reduced LA strain, and the associations of LA strain with longitudinal changes in biomarkers among participants in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial. LA speckle-tracking was performed on baseline echocardiograms of RELAX participants to measure LA reservoir and LA contractile strain. Of the 216 RELAX participants, 169 (78%) had measurable LA strain and biomarker data. Participants with LA reservoir strain below median (13.5%, interquartile range: 10%-22.5%) were older, more likely to have atrial fibrillation, and had higher jugular venous pressure (P < .05 for all). At baseline, higher levels of endothelin-1, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and troponin I were independently associated with lower LA reservoir and contractile strain (P-adjusted < .05 for all comparisons). Higher LA reservoir strain (beta coefficient per 1-unit increase: -21.2, 95% CI: -38.8, -3.7; P = .02) was independently associated with reduction in NT-proBNP at 24 weeks. Conclusion: In HFpEF, LA myopathy is characterized by elevation in biomarkers of neurohormonal activation and myocardial necrosis. Lower LA function is associated with continued elevation in NT-proBNP over time, suggesting that LA myopathy is associated with persistent congestion in HFpEF.