Trimetazidine in heart failure with preserved ejection fraction: a randomized controlled cross-over trial.

AIMS: Impaired myocardial energy homeostasis plays an import role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). Left ventricular relaxation has a high energy demand, and left ventricular diastolic dysfunction has been related to impaired energy homeostasis. This study investigated whether trimetazidine, a fatty acid oxidation inhibitor, could improve myocardial energy homeostasis and consequently improve exercise haemodynamics in patients with HFpEF. METHODS AND RESULTS: The DoPING-HFpEF trial was a phase II single-centre, double-blind, placebo-controlled, randomized cross-over trial. Patients were randomized to trimetazidine treatment or placebo for 3 months and switched after a 2-week wash-out period. The primary endpoint was change in pulmonary capillary wedge pressure, measured with right heart catheterization at multiple stages of bicycling exercise. Secondary endpoint was change in myocardial phosphocreatine/adenosine triphosphate, an index of the myocardial energy status, measured with phosphorus-31 magnetic resonance spectroscopy. The study included 25 patients (10/15 males/females; mean (standard deviation) age, 66 (10) years; body mass index, 29.8 (4.5) kg/m2 ); with the diagnosis of HFpEF confirmed with (exercise) right heart catheterization either before or during the trial. There was no effect of trimetazidine on the primary outcome pulmonary capillary wedge pressure at multiple levels of exercise (mean change 0 [95% confidence interval, 95% CI -2, 2] mmHg over multiple levels of exercise, P = 0.60). Myocardial phosphocreatine/adenosine triphosphate in the trimetazidine arm was similar to placebo (1.08 [0.76, 1.76] vs. 1.30 [0.95, 1.86], P = 0.08). There was no change by trimetazidine compared with placebo in the exploratory parameters: 6-min walking distance (mean change of -6 [95% CI -18, 7] m vs. -5 [95% CI -22, 22] m, respectively, P = 0.93), N-terminal pro-B-type natriuretic peptide (5 (-156, 166) ng/L vs. -13 (-172, 147) ng/L, P = 0.70), overall quality-of-life (KCCQ and EQ-5D-5L, P = 0.78 and P = 0.51, respectively), parameters for diastolic function measured with echocardiography and cardiac magnetic resonance, or metabolic parameters. CONCLUSIONS: Trimetazidine did not improve myocardial energy homeostasis and did not improve exercise haemodynamics in patients with HFpEF.

Right Atrial Adaptation to Precapillary Pulmonary Hypertension: Pressure-Volume, Cardiomyocyte, and Histological Analysis.

BACKGROUND: Precapillary pulmonary hypertension (precPH) patients have altered right atrial (RA) function and right ventricular (RV) diastolic stiffness. OBJECTIVES: This study aimed to investigate RA function using pressure-volume (PV) loops, isolated cardiomyocyte, and histological analyses. METHODS: RA PV loops were constructed in control subjects (n = 9) and precPH patients (n = 27) using magnetic resonance and catheterization data. RA stiffness (pressure rise during atrial filling) and right atrioventricular coupling index (RA minimal volume / RV end-diastolic volume) were compared in a larger cohort of patients with moderate (n = 39) or severe (n = 41) RV diastolic stiffness. Cardiomyocytes were isolated from RA tissue collected from control subjects (n = 6) and precPH patients (n = 9) undergoing surgery. Autopsy material was collected from control subjects (n = 6) and precPH patients (n = 4) to study RA hypertrophy, capillarization, and fibrosis. RESULTS: RA PV loops showed 3 RA cardiac phases (reservoir, passive emptying, and contraction) with dilatation and elevated pressure in precPH. PrecPH patients with severe RV diastolic stiffness had increased RA stiffness and worse right atrioventricular coupling index. Cardiomyocyte cross-sectional area was increased 2- to 3-fold in precPH, but active tension generated by the sarcomeres was unaltered. There was no increase in passive tension of the cardiomyocytes, but end-stage precPH showed reduced number of capillaries per mm2 accompanied by interstitial and perivascular fibrosis. CONCLUSIONS: RA PV loops show increased RA stiffness and suggest atrioventricular uncoupling in patients with severe RV diastolic stiffness. Isolated RA cardiomyocytes of precPH patients are hypertrophied, without intrinsic sarcomeric changes. In end-stage precPH, reduced capillary density is accompanied by interstitial and perivascular fibrosis.

Right Ventricular Function During Exercise After Pulmonary Endarterectomy for Chronic Thromboembolic Pulmonary Hypertension.

Background Pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension improves resting hemodynamics and right ventricular (RV) function. Because exercise tolerance frequently remains impaired, RV function may not have completely normalized after PEA. Therefore, we performed a detailed invasive hemodynamic study to investigate the effect of PEA on RV function during exercise. Methods and Results In this prospective study, all consenting patients with chronic thromboembolic pulmonary hypertension eligible for surgery and able to perform cycle ergometry underwent cardiac magnetic resonance imaging, a maximal cardiopulmonary exercise test, and a submaximal invasive cardiopulmonary exercise test before and 6 months after PEA. Hemodynamic assessment and analysis of RV pressure curves using the single-beat method was used to determine load-independent RV contractility (end systolic elastance), RV afterload (arterial elastance), RV-arterial coupling (end systolic elastance-arterial elastance), and stroke volume both at rest and during exercise. RV rest-to-exercise responses were compared before and after PEA using 2-way repeated-measures analysis of variance with Bonferroni post hoc correction. A total of 19 patients with chronic thromboembolic pulmonary hypertension completed the entire study protocol. Resting hemodynamics improved significantly after PEA. The RV exertional stroke volume response improved 6 months after PEA (79±32 at rest versus 102±28 mL during exercise; P<0.01). Although RV afterload (arterial elastance) increased during exercise, RV contractility (end systolic elastance) did not change during exercise either before (0.43 [0.32-0.58] mm Hg/mL versus 0.45 [0.22-0.65] mm Hg/mL; P=0.6) or after PEA (0.32 [0.23-0.40] mm Hg/mL versus 0.28 [0.19-0.44] mm Hg/mL; P=0.7). In addition, mean pulmonary artery pressure-cardiac output and end systolic elastance-arterial elastance slopes remained unchanged after PEA. Conclusions The exertional RV stroke volume response improves significantly after PEA for chronic thromboembolic pulmonary hypertension despite a persistently abnormal afterload and absence of an RV contractile reserve. This may suggest that at mildly elevated pulmonary pressures, stroke volume is less dependent on RV contractility and afterload and is primarily determined by venous return and conduit function.

Idiopathic pulmonary arterial hypertension patients with a high H2FPEF-score: Insights from the Amsterdam UMC PAH-cohort.

BACKGROUND: The idiopathic pulmonary arterial hypertension (iPAH) phenotype is changing from a predominantly young female patient to an older, frequently obese patient of either sex. Many newly diagnosed iPAH-patients have risk factors for left ventricular diastolic dysfunction (LVDD), possibly affecting management and treatment. AIM: To determine whether the H2FPEF-score identifies a subgroup of iPAH-patients with blunted response to PAH-targeted treatment. STUDY DESIGN AND METHODS: We performed a retrospective analysis of 253 treatment-naïve iPAH-patients (1989-2019) with a confirmed diagnosis after right heart catheterization by a multidisciplinary team. Follow-up RHC measurements were available in 150 iPAH-patients. iPAH-patients were stratified by the H2FPEF-score; a score ≥5 identified a higher possibility of (concealed) LVDD. RESULTS: The presence of a high H2FPEF-score in incident iPAH-patients rose 30% in thirty years. Patients with a H2FPEF-score ≥5 were older, more often male and/or obese, and had more comorbidities than patients with a H2FPEF-score ≤1. A high H2FPEF-score was associated with worse survival and poor functional capacity. Right ventricular function was equally depressed among iPAH-groups. Imaging and invasive hemodynamic measurements suggested concealed LVDD in iPAH patients with a high H2FPEF-score. At follow-up, hemodynamic and functional responses were similar in iPAH-patients with a high or low H2FPEF-score. CONCLUSIONS: While a high H2FPEF-score in iPAH is associated with a worse prognosis and signs of LVDD, hemodynamic and functional responses to PAH treatment are not predicted by the H2FPEF-score.

The Value of Passive Leg Raise During Right Heart Catheterization in Diagnosing Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Because of limited accuracy of noninvasive tests, diastolic stress testing plays an important role in the diagnostic work-up of patients with heart failure with preserved ejection fraction (HFpEF). Exercise right heart catheterization is considered the gold standard and indicated when HFpEF is suspected but left ventricular filling pressures at rest are normal. However, performing exercise during right heart catheterization is not universally available. Here, we examined whether pulmonary capillary wedge pressure (PCWP) during a passive leg raise (PLR) could be used as simple and accurate method to diagnose or rule out occult-HFpEF. METHODS: In our tertiary center for pulmonary hypertension and HFpEF, all patients who received a diagnostic right heart catheterization with PCWP-measurements at rest, PLR, and exercise were evaluated (2014-2020). The diagnostic value of PCWPPLR was compared with the gold standard (PCWPEXERCISE). Cut-offs derived from our cohort were subsequently validated in an external cohort (N=74). RESULTS: Thirty-nine non-HFpEF, 33 occult-HFpEF, and 37 manifest-HFpEF patients were included (N=109). In patients with normal PCWPREST (<15 mmHg), PCWPPLR significantly improved diagnostic accuracy compared with PCWPREST (AUC=0.82 versus 0.69, P=0.03). PCWPPLR ≥19 mmHg (24% of cases) had a specificity of 100% for diagnosing occult-HFpEF, irrespective of diuretic use. PCWPPLR ≥11 mmHg had a 100% sensitivity and negative predictive value for diagnosing occult-HFpEF. Both cut-offs retained a 100% specificity and 100% sensitivity in the external cohort. Absolute change in PCWPPLR or V-wave derived parameters had no incremental value in diagnosing occult-HFpEF. CONCLUSIONS: PCWPPLR is a simple and powerful tool that can help to diagnose or rule out occult-HFpEF.

Interplay of sex hormones and long-term right ventricular adaptation in a Dutch PAH-cohort.

BACKGROUND: To investigate the association between altered sex hormone expression and long-term right ventricular (RV) adaptation and progression of right heart failure in a Dutch cohort of Pulmonary Arterial Hypertension (PAH)-patients across a wide range of ages. METHODS: In this study we included 279 PAH-patients, of which 169 females and 110 males. From 59 patients and 21 controls we collected plasma samples for sex hormone analysis. Right heart catheterization (RHC) and/or cardiac magnetic resonance (CMR) imaging was performed at baseline. For longitudinal data analysis, we selected patients that underwent a RHC and/or CMR maximally 1.5 years prior to an event (death or transplantation, N = 49). RESULTS: Dehydroepiandrosterone-sulfate (DHEA-S) levels were reduced in male and female PAH-patients compared to controls, whereas androstenedione and testosterone were only reduced in female patients. Interestingly, low DHEA-S and high testosterone levels were correlated to worse RV function in male patients only. Subsequently, we analyzed prognosis and RV adaptation in females stratified by age. Females ≤45years had best prognosis in comparison to females ≥55years and males. No differences in RV function at baseline were observed, despite higher pressure-overload in females ≤45years. Longitudinal data demonstrated a clear distinction in RV adaptation. Although females ≤45years had an event at a later time point, RV function was more impaired at end-stage disease. CONCLUSIONS: Sex hormones are differently associated with RV function in male and female PAH-patients. DHEA-S appeared to be lower in male and female PAH-patients. Females ≤45years could persevere pressure-overload for a longer time, but had a more severe RV phenotype at end-stage disease.

Validation of the 2016 ASE/EACVI Guideline for Diastolic Dysfunction in Patients With Unexplained Dyspnea and a Preserved Left Ventricular Ejection Fraction.

Background Echocardiography is considered the cornerstone of the diagnostic workup of heart failure with preserved ejection fraction. Thus far, validation of the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging (ASE/EACVI) echo-algorithm for evaluation of diastolic (dys)function in a patient suspected of heart failure with preserved ejection fraction has been limited. Methods and Results The diagnostic performance of the 2016 ASE/EACVI algorithm was assessed in 204 patients evaluated for unexplained dyspnea or pulmonary hypertension with echocardiogram and right heart catheterization. Invasively measured pulmonary capillary wedge pressure (PCWP) was used as the gold standard. In addition, the diagnostic performance of H2FPEF score and NT-proBNP (N-terminal pro-B-type natriuretic peptide) were evaluated. There was a poor correlation between indexed left atrial volume, E/e' (septal and average) or early mitral inflow (E), and PCWP (r=0.25-0.30, P values all <0.01). No correlation was found in our cohort between e' (septal or lateral) or tricuspid valve regurgitation and PCWP. The correlation between diastolic function grades of the ASE/EACVI algorithm and PCWP was poor (r=0.17, P<0.05). The ASE/EACVI algorithm had a sensitivity and specificity of 35% and 87%, respectively; an accuracy of 67% and an area under the curve of 0.56. Moreover, in 30% of cases the algorithm was not applicable or indeterminate. H2FPEF score had a modest correlation with PCWP (r=0.44, P<0.0001), and accuracy was 73%; NT-proBNP correlated weakly with PCWP (r=0.24, P<0.001), and accuracy was 57%. Conclusions The 2016 ASE/EACVI algorithm for the assessment of diastolic function has a limited diagnostic accuracy in patients evaluated for unexplained dyspnea and/or pulmonary hypertension, and especially sensitivity to detect diastolic dysfunction was low.

Hemodynamic Effects of Pulmonary Arterial Hypertension-Specific Therapy in Patients With Heart Failure With Preserved Ejection Fraction and With Combined Post- and Precapillay Pulmonary Hypertension.

BACKGROUND: Drugs approved for pulmonary arterial hypertension have been considered for patients with heart failure with preserved ejection fraction and combined post- and precapillary pulmonary hypertension (Cpc-PH). We aimed to study changes in cardiac volumes, cardiac load and left ventricular (LV) filling pressures in patients with heart failure with preserved ejection fraction and Cpc-PH in response to pulmonary arterial hypertension-specific treatment. METHODS AND RESULTS: In this prospective study, 23 patients with heart failure with preserved ejection fraction and Cpc-PH underwent right-heart catheterization, including acute provocation testing (fluid loading and inhaled nitric oxide) and cardiac MRI at baseline. Right-heart catheterization and cardiac MRI were repeated after 4 months of treatment. At baseline, acutely increasing preload by fluid loading resulted in a significant increase in pulmonary arterial wedge pressure (PAWP), whereas reducing right ventricular (RV) afterload and increasing LV distensability by acute administration of inhaled nitric oxide had no effect on PAWP. After 4 months of treatment, we observed a significant reduction in RV and LV afterload and increased RV and LV stroke volume, but PAWP significantly increased. CONCLUSIONS: In patients with heart failure with preserved ejection fraction and Cpc-PH, 4 months of pulmonary arterial hypertension-specific treatment increased RV and LV stroke volume at the expense of increased PAWP. This increase in PAWP was similarly observed acutely after fluid loading.

Pulmonary arterial hypertension, a novelty in idiopathic inflammatory myopathies: insights and first experiences with vasoactive therapy.

To characterise the different types of pulmonary hypertension (PH) among idiopathic inflammatory myopathy (IIM). A retrospective case series with assessment of PH by right heart catheterisation, extent of interstitial lung disease (ILD) and outcome of vasoactive therapy.The group of patients with IIM with PH (n=9) showed a median age at PH diagnosis of 62 years (IQR 48-71 years; eight women), seven diagnosed with polymyositis and two with dermatomyositis; median disease duration of 5.7 years and five patients with a positive anti-Jo1 antibody. We found one patient to be classified in PH WHO group 2 (left heart disease), five patients in WHO group 3 (lung disease) and three patients in WHO group 1 (pulmonary arterial hypertension (PAH)). During median observed follow-up of 24 months, mortality for the total group was 44%. Surprisingly, we found a relevant group (33%) of patients with IIM who suffered from non-ILD-PH, which reflects the presence of PAH phenotype. This result should lead to more awareness among treating physicians that complaints of dyspnoea among patient with IIM could be related to PAH and not only ILD. The role of vasoactive therapy remains to be defined in patients with IIM suffering from PAH or PH-ILD.

Serial assessment of right ventricular systolic function in patients with precapillary pulmonary hypertension using simple echocardiographic parameters: A comparison with cardiac magnetic resonance imaging.

BACKGROUND: Although cardiac magnetic resonance imaging (CMRI) is the gold standard for the (serial) assessment of right ventricular (RV) function, the technique has several drawbacks: CMRI is relatively expensive, has a limited availability, and the analyses are time consuming. Echocardiography (echo) can overcome several of these issues. The aim of this study was to compare simple echo-derived parameters of RV systolic function with CMRI-derived RV ejection fraction (RVEF) in patients with precapillary pulmonary hypertension (PH) and to determine which echo parameters best followed the change in CMRI-derived-RVEF during follow-up. METHODS: CMRI and echo were performed in 96 precapillary PH patients. In 38 patients a second set of a CMRI and echo were available. Retrospectively, echo-derived right ventricular fractional area change (RVFAC), tricuspid annulus plane systolic excursion (TAPSE), fractional transversal (FTWM), and longitudinal wall motion (FLWM) were assessed and compared with CMRI-derived-RVEF. Furthermore, the changes in RVFAC, TAPSE, FTWM, and FLWM during follow-up were compared with the change in CMRI-derived-RVEF. RESULTS: All four echo parameters were significantly correlated to CMRI-derived-RVEF. The strongest relationship was seen between CMRI-derived-RVEF and RVFAC (r2=0.567). However, sensitivity for predicting a deterioration in CMRI-derived RVEF was poor for all four echo-derived parameters (ranging from 33% to 56%). CONCLUSIONS: Although RVFAC, TAPSE, FTWM, and FLWM were significantly correlated to CMRI-derived-RVEF, all four echo parameters showed a low sensitivity for predicting a deterioration in CMRI-derived RVEF during follow-up. Therefore, RVFAC, TAPSE, FTWM, and FLWM are not suitable parameters for the serial assessment of RV systolic function in patients with precapillary PH.

A critical appraisal of transpulmonary and diastolic pressure gradients.

Pulmonary hypertension (PH) resulting from left heart failure is an increasingly recognized clinical entity. To distinguish isolated postcapillary PH from combined post- and precapillary PH, the use of a diastolic pressure gradient (DPG = diastolic Pulmonary Artery Pressure - Pulmonary Arterial Wedge Pressure, dPAP - PAWP) has been advocated over the transpulmonary pressure gradient (TPG = mean Pulmonary Artery Pressure - PAWP, mPAP - PAWP) since DPG was suggested to be independent of cardiac output (CO) and only slightly related to PAWP, while TPG depends on both. We quantitatively derived and compared the DPG and TPG Using right heart catheterization data (n = 1054), we determined systolic pulmonary artery pressure (sPAP), dPAP and mPAP, PAWP, and CO From this data, we derived TPG and DPG and tested their dependence on PAWP and CO We found that dPAP and sPAP are proportional with mPAP over a wide range of PAWP (1-31 mmHg), with dPAP = 0.62mPAP and sPAP = 1.61mPAP As a consequence, TPG and DPG are equally dependent on PAWP: TPG = mPAP - PAWP, and DPG = 0.62mPAP - PAWP Furthermore, we showed that both TPG and DPG depend on CO The absolute increase in DPG with CO is 62% of the TPG increase with CO, but the relative dependence is the same. Both TPG and DPG depend on PAWP and CO Thus, in principle, there are no major advantages for using DPG to distinguish postcapillary pulmonary hypertension from combined post- and precapillary pulmonary hypertension.

The effects of exercise on right ventricular contractility and right ventricular-arterial coupling in pulmonary hypertension.

RATIONALE: Exercise tolerance is decreased in patients with pulmonary hypertension (PH). It is unknown whether exercise intolerance in PH coincides with an impaired rest-to-exercise response in right ventricular (RV) contractility. OBJECTIVES: To investigate in patients with PH the RV exertional contractile reserve, defined as the rest-to-exercise response in end-systolic elastance (ΔEes), and the effects of exercise on the matching of Ees and RV afterload (Ea) (i.e., RV-arterial coupling; Ees/Ea). In addition, we compared ΔEes with a recently proposed surrogate, the rest-to-exercise change in pulmonary artery pressure (ΔPAP). METHODS: We prospectively included 17 patients with precapillary PH and 7 control subjects without PH who performed a submaximal invasive cardiopulmonary exercise test between January 2013 and July 2014. Ees and Ees/Ea were assessed using single-beat pressure-volume loop analysis. MEASUREMENTS AND MAIN RESULTS: Exercise data in 16 patients with PH and 5 control subjects were of sufficient quality for analysis. Ees significantly increased from rest to exercise in control subjects but not in patients with PH. Ea significantly increased in both groups. As a result, exercise led to a decrease in Ees/Ea in patients with PH, whereas Ees/Ea was unaffected in control subjects (Pinteraction = 0.009). In patients with PH, ΔPAP was not related to ΔEes but significantly correlated to the rest-to-exercise change in heart rate. CONCLUSIONS: In contrast to control subjects, patients with PH were unable to increase Ees during submaximal exercise. Failure to compensate for the further increase in Ea during exercise led to deterioration in Ees/Ea. Furthermore, ΔPAP did not reflect ΔEes but rather the change in heart rate.

Changes in right ventricular function measured by cardiac magnetic resonance imaging in patients receiving pulmonary arterial hypertension-targeted therapy: the EURO-MR study.

BACKGROUND: Most measures that predict survival in pulmonary hypertension (PH) relate directly to, or correlate with, right ventricular (RV) function. Direct assessment of RV function using noninvasive techniques such as cardiac MRI may therefore be an appropriate way of determining response to therapy and monitoring disease progression in PH. METHODS AND RESULTS: In this pan-European study, 91 patients with PH (mean pulmonary arterial pressure 46±15 mm Hg) underwent clinical and cardiac MRI assessments at baseline and after 12 months of disease-targeted therapy (predominantly endothelin receptor antagonists [47.3%] or phosphodiesterase type-5 inhibitors [25.3%]). At month 12, functional class had improved in 21 patients, was unchanged in 63 patients, and had deteriorated in 7 patients. Significant improvements were achieved in RV and left ventricular ejection fraction (P<0.001 and P=0.0007, respectively), RV stroke volume index (P<0.0001), and left ventricular end-diastolic volume index (P=0.0015). Increases in 6-minute walk distance were significant (P<0.0001) and correlated with change in RV ejection fraction and left ventricular end-diastolic volume, although correlation coefficients were low (r=0.28, P=0.01 and r=0.26, P=0.02, respectively). CONCLUSIONS: On-treatment changes in cardiac MRI-derived variables from left and right sides of the heart reflected changes in functional class and survival in patients with PH. Direct measurement of RV function using cardiac MRI can fully assess potential benefits of treatment in PH.

Right atrial pressure affects the interaction between lung mechanics and right ventricular function in spontaneously breathing COPD patients.

INTRODUCTION: It is generally known that positive pressure ventilation is associated with impaired venous return and decreased right ventricular output, in particular in patients with a low right atrial pressure and relative hypovolaemia. Altered lung mechanics have been suggested to impair right ventricular output in COPD, but this relation has never been firmly established in spontaneously breathing patients at rest or during exercise, nor has it been determined whether these cardiopulmonary interactions are influenced by right atrial pressure. METHODS: Twenty-one patients with COPD underwent simultaneous measurements of intrathoracic, right atrial and pulmonary artery pressures during spontaneous breathing at rest and during exercise. Intrathoracic pressure and right atrial pressure were used to calculate right atrial filling pressure. Dynamic changes in pulmonary artery pulse pressure during expiration were examined to evaluate changes in right ventricular output. RESULTS: Pulmonary artery pulse pressure decreased up to 40% during expiration reflecting a decrease in stroke volume. The decline in pulse pressure was most prominent in patients with a low right atrial filling pressure. During exercise, a similar decline in pulmonary artery pressure was observed. This could be explained by similar increases in intrathoracic pressure and right atrial pressure during exercise, resulting in an unchanged right atrial filling pressure. CONCLUSIONS: We show that in spontaneously breathing COPD patients the pulmonary artery pulse pressure decreases during expiration and that the magnitude of the decline in pulmonary artery pulse pressure is not just a function of intrathoracic pressure, but also depends on right atrial pressure.