Macrophage-NLRP3 Activation Promotes Right Ventricle Failure in Pulmonary Arterial Hypertension. American journal of respiratory and critical care medicine Pulmonary arterial hypertension (PAH) often results in death from right ventricular failure (RVF). NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3)-macrophage activation may promote RVF in PAH. Evaluating the contribution of the NLRP3 inflammasome in RV macrophages to PAH RVF. Rats with decompensated RV hypertrophy (monocrotaline [MCT] and Sugen-5416 hypoxia [SuHx]) were compared with compensated RV hypertrophy rats (pulmonary artery banding). Echocardiography and right heart catheterization were performed. Macrophages, atrial natriuretic peptides, and fibrosis were evaluated by microscopy or flow cytometry. NLRP3 inflammasome activation and cardiotoxicity were confirmed by immunoblot and strategies. MCT rats were treated with SC-144 (a GP130 antagonist) or MCC950 (an NLRP3 inhibitor). Macrophage-NLRP3 activity was evaluated in patients with PAH RVF. Macrophages, fibrosis, and atrial natriuretic peptides were increased in MCT and SuHx RVs but not in left ventricles or pulmonary artery banding rats. Although MCT RV macrophages were inflammatory, lung macrophages were antiinflammatory. CCR2 macrophages (monocyte-derived) were increased in MCT and SuHx RVs and highly expressed NLRP3. The macrophage-NLRP3 pathway was upregulated in patients with PAH with decompensated RVs. Cultured MCT monocytes showed NLRP3 activation, and in coculture experiments resulted in cardiomyocyte mitochondrial damage, which MCC950 prevented. , MCC950 reduced NLRP3 activation and regressed pulmonary vascular disease and RVF. SC-144 reduced RV macrophages and NLRP3 content, prevented STAT3 (signal transducer and activator of transcription 3) activation, and improved RV function without regressing pulmonary vascular disease. NLRP3-macrophage activation occurs in the decompensated RV in preclinical PAH models and patients with PAH. Inhibiting GP130 or NLRP3 signaling improves RV function. The concept that PAH RVF results from RV inflammation rather than solely from elevated RV afterload suggests a new therapeutic paradigm. 10.1164/rccm.202110-2274OC

Enhanced pulmonary vasodilator reserve and abnormal right ventricular: pulmonary artery coupling in heart failure with preserved ejection fraction. Andersen Mads J,Hwang Seok-Jae,Kane Garvan C,Melenovsky Vojtech,Olson Thomas P,Fetterly Kenneth,Borlaug Barry A Circulation. Heart failure BACKGROUND:Pulmonary hypertension and right ventricular (RV) dysfunction are common in patients with advanced heart failure with preserved ejection fraction (HFpEF), yet their underlying mechanisms remain poorly understood. We sought to examine RV-pulmonary artery (PA) functional reserve responses and RV-PA coupling at rest and during β-adrenergic stimulation in subjects with earlier stage HFpEF. METHODS AND RESULTS:In a prospective trial, subjects with HFpEF (n=39) and controls (n=18) underwent comprehensive invasive and noninvasive hemodynamic assessment using high fidelity micromanometer catheters, echocardiography, and expired gas analysis at rest and during dobutamine infusion. HFpEF subjects displayed similar RV structure but significantly impaired RV systolic (lower RV dP/dtmax/IP and s') and diastolic function (higher RV τ) coupled with more severe pulmonary vascular disease, manifest by higher PA pressures, higher PA resistance, and lower PA compliance compared with controls. Dobutamine infusion caused greater pulmonary vasodilation in HFpEF compared with controls, with enhanced reductions in PA resistance, greater increase in PA compliance, and a more negative slope in the PA pressure-flow relationship when compared with controls (all P<0.001). RV-PA coupling analysis revealed that dobutamine improved RV ejection in HFpEF subjects through afterload reduction alone, rather than through enhanced contractility, indicating RV systolic reserve dysfunction. CONCLUSIONS:Pulmonary hypertension in early stage HFpEF is related to partially reversible pulmonary vasoconstriction coupled with RV systolic and diastolic dysfunction, even in the absence of RV structural remodeling. Pulmonary vascular tone is more favorably responsive to β-adrenergic stimulation in HFpEF than controls, suggesting a potential role for β-agonists in the treatment of patients with HFpEF and pulmonary hypertension. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01418248. 10.1161/CIRCHEARTFAILURE.114.002114

Right ventricular dysfunction in left-sided heart failure with preserved versus reduced ejection fraction. Bosch Lena,Lam Carolyn S P,Gong Lingli,Chan Siew Pang,Sim David,Yeo Daniel,Jaufeerally Fazlur,Leong Kui Toh Gerard,Ong Hean Yee,Ng Tze Pin,Richards Arthur Mark,Arslan Fatih,Ling Lieng H European journal of heart failure BACKGROUND:Right ventricular (RV) dysfunction is recognized as a major prognostic factor in left-sided heart failure (HF). However, the relative contribution of RV dysfunction in HF with preserved (HFpEF) vs. reduced ejection fraction (HFrEF) is unclear. METHODS AND RESULTS:Right ventricular longitudinal strain (RVLS), tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PASP) were determined by echocardiography in 657 age- and gender-matched groups of patients with HFpEF [left ventricular ejection fraction (LVEF) ≥50%; n=219] and HFrEF (LVEF <50%; n=219) and in controls without HF (n=219) from an Asian population-based cohort study. Across control to HFpEF and HFrEF groups, RV function deteriorated as measured by RVLS (-26.7 ± 5%, -22.7±6.6% and -18.2 ± 6.7%, respectively) and TAPSE (21.0 ± 3.9, 17.5 ± 5.1 and 14.7 ± 4.7 mm, respectively), whereas PASP increased (26.8 ± 7.1, 34.5 ± 11.9 and 39.3 ± 16.2 mmHg, respectively) (all P<0.001). Controlling for PASP in control, HFpEF and HFrEF subjects, the magnitude of RVLS/PASP (-1.06 ± 0.32, -0.75 ± 0.32 and -0.56 ± 0.36, respectively) and TAPSE/PASP ratios (0.83 ± 0.23, 0.54 ± 0.24 and 0.55 ± 0.29, respectively) similarly decreased across groups. Right ventricular dysfunction (by both TAPSE and RVLS) was independently associated with left ventricular systolic dysfunction and atrial fibrillation, but not with PASP. Among patients with HF, both TAPSE/PASP and RVLS/PASP ratios were related to the composite endpoint of all-cause death and HF hospitalization, even after multivariable adjustment [hazard ratio (HR) 0.33; 95% confidence interval (CI) 0.14-0.74 and HR 3.09; 95% CI 1.52-6.26, respectively], with no difference between HFrEF and HFpEF. CONCLUSIONS:Right ventricular dysfunction is present in HFpEF and is even more pronounced in HFrEF for any given degree of pulmonary hypertension. It is independently predicted by left ventricular dysfunction but not by PASP. Right ventricular-arterial coupling is prognostically important in HF regardless of LVEF. 10.1002/ejhf.873

Right ventricular dysfunction in heart failure with preserved ejection fraction: a systematic review and meta-analysis. Gorter Thomas M,Hoendermis Elke S,van Veldhuisen Dirk J,Voors Adriaan A,Lam Carolyn S P,Geelhoed Bastiaan,Willems Tineke P,van Melle Joost P European journal of heart failure AIMS:Right ventricular (RV) dysfunction and pulmonary hypertension (PH) are increasingly recognized in heart failure with preserved ejection fraction (HFpEF). The prevalence and prognostic value of RV dysfunction in HFpEF have been widely but variably reported. We therefore conducted a systematic review and meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses. METHODS AND RESULTS:English literature until May 2016 was evaluated for prevalence of RV dysfunction [i.e. tricuspid annular plane systolic excursion (TAPSE) <16 mm, fractional area change (FAC) <35%, or tricuspid annular systolic velocity (RV S') <9.5 cm/s)] and PH [i.e. mean pulmonary artery pressure (MPAP) ≥25 mmHg or pulmonary artery systolic pressure (PASP) ≥35 mmHg]. Combined hazard ratios (HRs) for outcomes were calculated. A total of 38 studies was included. In studies with stringent HFpEF criteria, prevalence of RV dysfunction was 28% for TAPSE, 18% for FAC, and 21% for RV S'. Prevalence of PH was 68% for both increased MPAP and PASP. TAPSE (HR 1.26/5 mm decrease; P < 0.0001), FAC (HR 1.15/5% decrease; P < 0.0001), MPAP (HR 1.26/5 mmHg increase; P < 0.0001), and PASP (1.16/5 mmHg increase; P < 0.0001) were all univariably associated with mortality. HRs for RV S' were not reported. CONCLUSION:RV dysfunction and PH are highly prevalent and are both associated with poor outcome in patients with HFpEF. 10.1002/ejhf.630