Pulmonary hypertension (PH) associated with left heart failure (LHF) (PH-LHF) is one of the most common causes of PH. It directly contributes to symptoms and reduced functional capacity and negatively affects right heart function, ultimately leading to a poor prognosis. There are no specific treatments for PH-LHF, despite the high number of drugs tested so far. This scientific document addresses the main knowledge gaps in PH-LHF with emphasis on pathophysiology and clinical trials. Key identified issues include better understanding of the role of pulmonary venous versus arteriolar remodelling, multidimensional phenotyping to recognize patient subgroups positioned to respond to different therapies, and conduct of rigorous pre-clinical studies combining small and large animal models. Advancements in these areas are expected to better inform the design of clinical trials and extend treatment options beyond those effective in pulmonary arterial hypertension. Enrichment strategies, endpoint assessments, and thorough haemodynamic studies, both at rest and during exercise, are proposed to play primary roles to optimize early-stage development of candidate therapies for PH-LHF.

• Keywords
• Drug, Heart failure, Pulmonary hypertension, Therapy, Translational,
• MeSH
• Ventricular Function, Right * physiology   MeSH
• Humans MeSH
• Hypertension, Pulmonary * physiopathology   etiology   therapy   MeSH
• Pulmonary Circulation * physiology   MeSH
• Heart Failure * physiopathology   complications   therapy   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

AIMS: The determinants and relevance of right ventricular (RV) mechanical dyssynchrony in heart failure with reduced ejection fraction (HFrEF) are poorly understood. We hypothesized that increased afterload may adversely affect the synchrony of RV contraction. METHODS AND RESULTS: A total of 148 patients with HFrEF and 36 controls underwent echocardiography, right heart catheterization, and gated single-photon emission computed tomography to measure RV chamber volumes and mechanical dyssynchrony (phase standard deviation of systolic displacement timing). Exams were repeated after preload (N = 135) and afterload (N = 15) modulation. Patients with HFrEF showed higher RV dyssynchrony compared with controls (40.6 ± 17.5° vs. 27.8 ± 9.1°, P < 0.001). The magnitude of RV dyssynchrony in HFrEF correlated with larger RV and left ventricular (LV) volumes, lower RV ejection fraction (RVEF) and LV ejection fraction, reduced intrinsic contractility, increased heart rate, higher pulmonary artery (PA) load, and impaired RV-PA coupling (all P ≤ 0.01). Low RVEF was the strongest predictor of RV dyssynchrony. Left bundle branch block (BBB) was associated with greater RV dyssynchrony than right BBB, regardless of QRS duration. RV afterload reduction by sildenafil improved RV dyssynchrony (P = 0.004), whereas preload change with passive leg raise had modest effect. Patients in the highest tertiles of RV dyssynchrony had an increased risk of adverse clinical events compared with those in the lower tertile [T2/T3 vs. T1: hazard ratio 1.98 (95% confidence interval 1.20-3.24), P = 0.007]. CONCLUSIONS: RV dyssynchrony is associated with RV remodelling, dysfunction, adverse haemodynamics, and greater risk for adverse clinical events. RV dyssynchrony is mitigated by acute RV afterload reduction and could be a potential therapeutic target to improve RV performance in HFrEF.

• Keywords
• Heart failure with reduced ejection fraction, Pulmonary hypertension, Right ventricular dyssynchrony, Right ventricular failure, SPECT,
• MeSH
• Ventricular Dysfunction, Left * MeSH
• Echocardiography methods   MeSH
• Ventricular Function, Left MeSH
• Humans MeSH
• Heart Ventricles diagnostic imaging   MeSH
• Heart Failure * MeSH
• Stroke Volume MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

INTRODUCTION: Phosphodiesterase-5a inhibition (PDE5i) leads to favorable changes in pulmonary hemodynamic and cardiac output (CO) in patients with advanced heart failure (HF) and reduced ejection fraction (HFrEF). The hemodynamic response to PDE5i could be heterogeneous and the clinical variables associated with these changes are scarcely investigated. MATERIALS AND METHODS: Of 260 patients with advanced HFrEF referred for advanced therapies [cardiac transplant/left ventricular assist device (LVAD)], 55 had pulmonary hypertension (PH) and fulfilled the criteria for the PDE5i vasoreactivity test. Right heart catheterization (RHC) was performed as a part of clinical evaluation before and after 20-mg intravenous sildenafil. Absolute and relative changes in pulmonary vascular resistance (PVR) were evaluated to assess hemodynamic response to PDE5i. Clinical, biochemical, and hemodynamic factors associated with PVR changes were identified. RESULTS: Sildenafil administration reduced PVR (- 45.3%) and transpulmonary gradient (TPG; - 34.8%) and increased CO (+ 13.6%). Relative change analysis showed a negative moderate association between baseline plasma potassium and changes in PVR (r = - 0.48; p = 0.001) and TPG (r = - 0.43; p = 0.005) after PDE5i. Aldosterone concentration shows a direct moderate association with PVR changes after PDE5i. A significant moderate association was also demonstrated between CO improvement and the severity of mitral (r = 0.42; p = 0.002) and tricuspid (r = 0.39; p = 0.004) regurgitation. CONCLUSION: We identified plasma potassium, plasma aldosterone level, and atrioventricular valve regurgitations as potential cofounders of hemodynamic response to acute administration of PDE5i. Whether modulation of potassium levels could enhance pulmonary vasoreactivity in advanced HFrEF deserves further research.

• Keywords
• heart failure, phospodiesterase inhibitors, potassium, pulmonary hypertension, pulmonary vascular resistance,
• Publication type
• Journal Article MeSH