Heart failure with preserved ejection fraction: Boosting Diagnostics and Myocardial Metabolism

In Chapter 2, we evaluated the diagnostic performance of the ASE/EACVI echo-algorithm and other diagnostic tools for diastolic dysfunction, using invasive right heart catheterization as gold standard reference. In a retrospective study of 204 patients evaluated for unexplained dyspnea or pulmonary hypertension with echocardiography and right heart catheterization, echocardiography, NT-proBNP and the H2FPEF score were compared against invasively measured pulmonary capillary wedge pressure (PCWP). The ASE/EACVI algorithm had a low sensitivity (35%) but high specificity (87%) to detect elevated filling pressures in patients with a preserved ejection fraction. In addition, individual echo-parameters of the algorithm had no significant or only modest correlations with invasively measured filling pressures. The H2FPEF score had a sensitivity of 88% and a specificity of 59%. These results warrant caution for ruling out the diagnosis HFpEF solely based on the ASE/EACVI algorithm and supports the use of the H2FPEF score in the diagnostic work-up for HFpEF. Chapter 3 explored whether a passive leg raise (PLR) maneuver during right heart catheterization could be used to increase diagnostic accuracy for occult HFpEF, and potentially allow deferment of exercise right heart catheterization in some cases. In this study we showed that PLR could be used to accurately diagnose or rule out occult HFpEF. Based on our cohort (n=109) and validated in an external cohort from the Mayo Clinic (n=74), we established that PCWP during PLR below 11 mmHg could be used to rule out occult HFpEF and a PCWP during PLR of 19 mmHg and above could be used to diagnose occult HFpEF with 100% accuracy. In Chapter 4, we postulated that differences between HFpEF and HFrEF in the hemodynamic response on afterload reduction are an additional explanation for the neutral results of angiotensine-neprilysin inhibition in HFpEF found in the PARAGON-HF trial. Compared to HFrEF, HFpEF is characterized by a steeper end-systolic pressure volume relationship (contractility is relatively spared), a steeper slope of the end-diastolic pressure volume relationship (increased stiffness), and a smaller left ventricular end-diastolic volume. We argued that, due to these differences, a similar reduction in afterload would cause a lesser increase in stroke volume and a more pronounced decrease in blood pressure in HFpEF, compared to HFrEF. In Chapter 5 we performed a meta-analysis evaluating differences between HFpEF and HFrEF in long-term hemodynamic response and the effect on reverse remodeling of foundational heart failure pharmacotherapy. Chapter 6 comprises the rationale and trial design of a randomized controlled crossover intervention study, the DoPING-HFpEF trial, examining whether 3 months of trimetazidine – a fatty acid beta-oxidation inhibitor – treatment can improve left ventricular diastolic function in HFpEF, by altering myocardial substrate use and improving the myocardial energy status. Chapter 7 reports the results of the DoPING-HFpEF trial (N=25). Trimetazidine did not improve myocardial energy status as measured by myocardial PCr/ATP and other metabolic biomarkers. In addition, trimetazidine did not decrease PCWP at multiple levels of exercise in patients with HFpEF, nor did it improve other cardiac endpoint measured by echocardiography, magnetic resonance imaging, 6-minute walk test, quality-of-life questionnaires or biochemical markers. In Chapter 8 we performed a systematic review and meta-analysis of current literature on trimetazidine in heart failure, including all types of heart failure, and both English and non-English literature. In Chapter 9, we report the results of the randomized controlled IRON-HFpEF trial. We investigated whether intravenous iron supplementation in patients with HFpEF and iron deficiency could improve myocardial energy homeostasis and consequently improve diastolic function (as measured by exercise right heart catheterization and echocardiography).