Sex differences in right ventricular function between Groups 1 and 3 pulmonary hypertension.

Group 3 pulmonary hypertension (PH) patients have disproportionate right ventricular dysfunction (RVD) compared to pulmonary arterial hypertension. We evaluated how sex and PH etiology modulated RVD. Strain echocardiography showed no intrasex differences between PH types. Heightened RVD in Group 3 PH may be due to a greater male proportion.

Effect of Combination of Balloon Pulmonary Angioplasty and Medical Therapy on Reverse Right Ventricular Remodeling and Hemodynamics in Chronic Thromboembolic Pulmonary Hypertension.

INTRODUCTION: Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive and debilitating disorder that results from incomplete resolution of vascular obstructions resulting in pulmonary hypertension. Surgical pulmonary thromboendarterectomy (PTE) is the treatment of choice for CTEPH. Unfortunately, many CTEPH patients are ineligible for PTE or do not have access to an expert surgical center. Medical therapy imparts important symptomatic and exercise benefits for CTEPH patients, but it does not extend survival. Balloon pulmonary angioplasty (BPA) is an emerging transcatheter approach that is both safe and efficacious. However, the potential synergy between upfront BPA and medical therapy treatment approaches in patients with inoperable CTEPH is unknown. Here, we evaluated how the combination of BPA and medical therapy compared to medical therapy alone in a newly established BPA program. METHODS: Twenty-one patients with inoperable or residual CTEPH were evaluated in this single-center observational study. Ten patients underwent upfront BPA and medical therapy while 11 patients were treated with medical therapy alone. Hemodynamic and echocardiographic assessments were performed at baseline and at least 1 month after completion of therapy. Continuous variables were compared using t-test or Mann-Whitney U-test. Categorical variables were analyzed with Chi squared and Fisher's exact test where appropriate. RESULTS: Combination therapy significantly reduced mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR), but medical therapy only significantly lowered PVR. Comprehensive echocardiographic analysis revealed a more robust reverse right ventricular (RV) remodeling effect and augmentation of RV function with combination therapy. At the end of study, the combination therapy group had lower mPAP and PVR and better RV function. Importantly, there were no significant adverse effects in patients treated with BPA. CONCLUSION: Combination therapy significantly improves hemodynamics and RV function in inoperable CTEPH while carrying an acceptable risk profile, even in a newly developed program. Further studies comparing upfront combination therapy to medical therapy with larger, long-term, and randomized approaches should be considered.

Intermittent Fasting Activates AMP-Kinase to Restructure Right Ventricular Lipid Metabolism and Microtubules.

Intermittent fasting (IF) extends life span via pleotropic mechanisms, but one important molecular mediator is adenosine monophosphate-activated protein kinase (AMPK). AMPK enhances lipid metabolism and modulates microtubule dynamics. Dysregulation of these molecular pathways causes right ventricular (RV) failure in patients with pulmonary arterial hypertension. In rodent pulmonary arterial hypertension, IF activates RV AMPK, which restores mitochondrial and peroxisomal morphology and restructures mitochondrial and peroxisomal lipid metabolism protein regulation. In addition, IF increases electron transport chain protein abundance and activity in the right ventricle. Echocardiographic and hemodynamic measures of RV function are positively associated with fatty acid oxidation and electron transport chain protein levels. IF also combats heightened microtubule density, which normalizes transverse tubule structure.

Junctophilin-2 Regulates Mitochondrial Metabolism.

Right ventricular dysfunction (RVD) is a risk factor for mortality in multiple cardiovascular diseases, but approaches to combat RVD are lacking. Therapies used for left heart failure are largely ineffective in RVD, and thus the identification of molecules that augment RV function could improve outcomes in a wide-array of cardiac limitations. Junctophilin-2 (JPH2) is an essential protein that plays important roles in cardiomyocytes, including calcium handling/maintenance of t-tubule structure and gene transcription. Additionally, JPH2 may regulate mitochondrial function as Jph2 knockout mice exhibit cardiomyocyte mitochondrial swelling and cristae derangements. Moreover, JPH2 knockdown in embryonic stem cell-derived cardiomyocytes induces downregulation of the mitochondrial protein mitofusin-2 (MFN2), which disrupts mitochondrial cristae structure and transmembrane potential. Impaired mitochondrial metabolism drives RVD, and here we evaluated the mitochondrial role of JPH2. We showed JPH2 directly interacts with MFN2, ablation of JPH2 suppresses mitochondrial biogenesis, oxidative capacity, and impairs lipid handling in iPSC-CM. Gene therapy with AAV9-JPH2 corrects RV mitochondrial morphological defects, mitochondrial fatty acid metabolism enzyme regulation, and restores the RV lipidomic signature in the monocrotaline rat model of RVD. Finally, AAV-JPH2 improves RV function without altering PAH severity, showing JPH2 provides an inotropic effect to the dysfunction RV.

Ferroptosis Promotes Pulmonary Hypertension.

Background: Mitochondrial dysfunction, characterized by impaired lipid metabolism and heightened reactive oxygen species (ROS) generation, results in lipid peroxidation-induced ferroptosis. Ferroptosis is an inflammatory mode of cell death as it both promotes complement activation and recruits macrophages. In pulmonary arterial hypertension (PAH), pulmonary arterial endothelial cells exhibit disrupted lipid metabolism and increased ROS production, and there is ectopic complement deposition and inflammatory macrophage accrual in the surrounding vasculature. However, the integrative effects of ferroptosis on metabolism, cellular landscape changes in the lung, complement induction, and pulmonary vascular remodeling are unknown. Methods: Multi-omics analyses in rodents and a genetic association study in humans evaluated the role of ferroptosis in PAH. Results: Ferrostatin-1, a small-molecule ferroptosis inhibitor, mitigated PAH severity and improved right ventricular function in monocrotaline rats. RNA-seq and proteomics analyses demonstrated ferroptosis was induced with increasingly severe PAH. Metabolomics and proteomics data showed ferroptosis inhibition restructured lung metabolism and altered phosphatidylcholine and phosphatidylethanolamine levels. RNA-seq, proteomics, and confocal microscopy revealed complement activation and pro-inflammatory cytokines/chemokines were suppressed by ferrostatin-1. Additionally, ferrostatin-1 combatted changes in endothelial, smooth muscle, and interstitial macrophage abundances and gene activation patterns in the lungs as revealed by deconvolution RNA-seq. Finally, the presence of six single-nucleotide polymorphisms in ferroptosis genes were independently associated with pulmonary hypertension severity in the Vanderbilt BioVU repository. Conclusions: Rodent and human data nominate ferroptosis as a PAH regulating pathway via its ability to modulate lung lipid metabolism, repress pathogenic complement activation, dampen interstitial macrophage infiltration, and restore the lung cellular environment.

Pulmonary Arterial Hypertension Patients Have a Proinflammatory Gut Microbiome and Altered Circulating Microbial Metabolites.

Rationale: Inflammation drives pulmonary arterial hypertension (PAH). Gut dysbiosis causes immune dysregulation and systemic inflammation by altering circulating microbial metabolites; however, little is known about gut dysbiosis and microbial metabolites in PAH. Objectives: To characterize the gut microbiome and microbial metabolites in patients with PAH. Methods: We performed 16S ribosomal RNA gene and shotgun metagenomics sequencing on stool from patients with PAH, family control subjects, and healthy control subjects. We measured markers of inflammation, gut permeability, and microbial metabolites in plasma from patients with PAH, family control subjects, and healthy control subjects. Measurements and Main Results: The gut microbiome was less diverse in patients with PAH. Shannon diversity index correlated with measures of pulmonary vascular disease but not with right ventricular function. Patients with PAH had a distinct gut microbial signature at the phylogenetic level, with fewer copies of gut microbial genes that produce antiinflammatory short-chain fatty acids (SCFAs) and secondary bile acids and lower relative abundances of species encoding these genes. Consistent with the gut microbial changes, patients with PAH had relatively lower plasma concentrations of SCFAs and secondary bile acids. Patients with PAH also had enrichment of species with the microbial genes that encoded the proinflammatory microbial metabolite trimethylamine. The changes in the gut microbiome and circulating microbial metabolites between patients with PAH and family control subjects were not as substantial as the differences between patients with PAH and healthy control subjects. Conclusions: Patients with PAH have proinflammatory gut dysbiosis, in which lower circulating SCFAs and secondary bile acids may facilitate pulmonary vascular disease. These findings support investigating modulation of the gut microbiome as a potential treatment for PAH.

Glyoxylase-1 combats dicarbonyl stress and right ventricular dysfunction in rodent pulmonary arterial hypertension.

Background: Heightened glycolytic flux is associated with right ventricular (RV) dysfunction in pulmonary arterial hypertension (PAH). Methylglyoxal, a glycolysis byproduct, is a highly reactive dicarbonyl that has toxic effects via non-enzymatic post-translational modifications (protein glycation). Methylglyoxal is degraded by the glyoxylase system, which includes the rate-limiting enzyme glyoxylase-1 (GLO1), to combat dicarbonyl stress. However, the potential consequences of excess protein glycation on RV function are unknown. Methods: Bioinformatics analysis of previously identified glycated proteins predicted how protein glycation regulated cardiac biology. Methylglyoxal treatment of H9c2 cardiomyocytes evaluated the consequences of excess protein glycation on mitochondrial respiration. The effects of adeno-associated virus serotype 9-mediated (AAV9) GLO1 expression on RV function in monocrotaline rats were quantified with echocardiography and hemodynamic studies. Immunoblots and immunofluorescence were implemented to probe the effects of AAV-Glo1 on total protein glycation and fatty acid oxidation (FAO) and fatty acid binding protein levels. Results: In silico analyses highlighted multiple mitochondrial metabolic pathways may be affected by protein glycation. Exogenous methylglyoxal minimally altered mitochondrial respiration when cells metabolized glucose, however methylglyoxal depressed FAO. AAV9-Glo1 increased RV cardiomyocyte GLO1 expression, reduced total protein glycation, partially restored mitochondrial density, and decreased lipid accumulation. In addition, AAV9-Glo1 increased RV levels of FABP4, a fatty acid binding protein, and hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunits alpha and beta (HADHA and HADHB), the two subunits of the mitochondrial trifunctional protein for FAO. Finally, AAV9-Glo1 blunted RV fibrosis and improved RV systolic and diastolic function. Conclusion: Excess protein glycation promotes RV dysfunction in preclinical PAH, potentially through suppression of FAO.

Macrophage-NLRP3 Activation Promotes Right Ventricle Failure in Pulmonary Arterial Hypertension.

Rationale: 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. Objectives: Evaluating the contribution of the NLRP3 inflammasome in RV macrophages to PAH RVF. Methods: 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 in vitro 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. Measurements and Main Results: 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. In vivo, 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. Conclusions: 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.

Ingenuity pathway analysis of the human cardiac cell Atlas identifies differences between right and left ventricular cardiomyocytes.

Pharmaceuticals for left ventricular (LV) dysfunction do not have similar success in right ventricular (RV) failure, which may reflect biological differences between the ventricles. In this study, we performed Ingenuity Pathway Analysis of the Human Cell Atlas to understand how the transcriptomic signatures of the RV and LV differ.

Inflammatory Glycoprotein 130 Signaling Links Changes in Microtubules and Junctophilin-2 to Altered Mitochondrial Metabolism and Right Ventricular Contractility.

BACKGROUND: Right ventricular dysfunction (RVD) is the leading cause of death in pulmonary arterial hypertension (PAH), but no RV-specific therapy exists. We showed microtubule-mediated junctophilin-2 dysregulation (MT-JPH2 pathway) causes t-tubule disruption and RVD in rodent PAH, but the druggable regulators of this critical pathway are unknown. GP130 (glycoprotein 130) activation induces cardiomyocyte microtubule remodeling in vitro; however, the effects of GP130 signaling on the MT-JPH2 pathway and RVD resulting from PAH are undefined. METHODS: Immunoblots quantified protein abundance, quantitative proteomics defined RV microtubule-interacting proteins (MT-interactome), metabolomics evaluated the RV metabolic signature, and transmission electron microscopy assessed RV cardiomyocyte mitochondrial morphology in control, monocrotaline, and monocrotaline-SC-144 (GP130 antagonist) rats. Echocardiography and pressure-volume loops defined the effects of SC-144 on RV-pulmonary artery coupling in monocrotaline rats (8-16 rats per group). In 73 patients with PAH, the relationship between interleukin-6, a GP130 ligand, and RVD was evaluated. RESULTS: SC-144 decreased GP130 activation, which normalized MT-JPH2 protein expression and t-tubule structure in the monocrotaline RV. Proteomics analysis revealed SC-144 restored RV MT-interactome regulation. Ingenuity pathway analysis of dysregulated MT-interacting proteins identified a link between microtubules and mitochondrial function. Specifically, SC-144 prevented dysregulation of electron transport chain, Krebs cycle, and the fatty acid oxidation pathway proteins. Metabolomics profiling suggested SC-144 reduced glycolytic dependence, glutaminolysis induction, and enhanced fatty acid metabolism. Transmission electron microscopy and immunoblots indicated increased mitochondrial fission in the monocrotaline RV, which SC-144 mitigated. GP130 antagonism reduced RV hypertrophy and fibrosis and augmented RV-pulmonary artery coupling without altering PAH severity. In patients with PAH, higher interleukin-6 levels were associated with more severe RVD (RV fractional area change 23±12% versus 30±10%, P=0.002). CONCLUSIONS: GP130 antagonism reduces MT-JPH2 dysregulation, corrects metabolic derangements in the RV, and improves RVD in monocrotaline rats.

With No Lysine Kinase 1 Promotes Metabolic Derangements and RV Dysfunction in Pulmonary Arterial Hypertension.

Small molecule inhibition of with no lysine kinase 1 (WNK1) (WNK463) signaling activates adenosine monophosphate-activated protein kinase signaling and mitigates membrane enrichment of glucose transporters 1 and 4, which decreases protein O-GlcNAcylation and glycation. Quantitative proteomics of right ventricular (RV) mitochondrial enrichments shows WNK463 prevents down-regulation of several mitochondrial metabolic enzymes. and metabolomics analysis suggests multiple metabolic processes are corrected. Physiologically, WNK463 augments RV systolic and diastolic function independent of pulmonary arterial hypertension severity. Hypochloremia, a condition of predicted WNK1 activation in patients with pulmonary arterial hypertension, is associated with more severe RV dysfunction. These results suggest WNK1 may be a druggable target to combat metabolic dysregulation and may improve RV function and survival in pulmonary arterial hypertension.

Intermittent Fasting Enhances Right Ventricular Function in Preclinical Pulmonary Arterial Hypertension.

Background Intermittent fasting (IF) confers pleiotropic cardiovascular benefits including restructuring of the gut microbiome and augmentation of cellular metabolism. Pulmonary arterial hypertension (PAH) is a rare and lethal disease characterized by right ventricular (RV) mitochondrial dysfunction and resultant lipotoxicity and microbiome dysbiosis. However, the effects of IF on RV function in PAH are unexplored. Therefore, we investigated how IF altered gut microbiota composition, RV function, and survival in the monocrotaline model of PAH. Methods and Results Male Sprague Dawley rats were randomly allocated into 3 groups: control, monocrotaline-ad libitum feeding, and monocrotaline-IF (every other day feeding). Echocardiography and invasive hemodynamics showed IF improved RV systolic and diastolic function despite no significant change in PAH severity. IF prevented premature mortality (30% mortality rate in monocrotaline-ad libitum versus 0% in monocrotaline-IF rats, P=0.04). IF decreased RV cardiomyocyte hypertrophy and reduced RV fibrosis. IF prevented RV lipid accrual on Oil Red O staining and ceramide accumulation as determined by metabolomics. IF mitigated the reduction in jejunum villi length and goblet cell abundance when compared with monocrotaline-ad libitum. The 16S ribosomal RNA gene sequencing demonstrated IF changed the gut microbiome. In particular, there was increased abundance of Lactobacillus in monocrotaline-IF rats. Metabolomics profiling revealed IF decreased RV levels of microbiome metabolites including bile acids, aromatic amino acid metabolites, and gamma-glutamylated amino acids. Conclusions IF directly enhanced RV function and restructured the gut microbiome. These results suggest IF may be a non-pharmacological approach to combat RV dysfunction, a currently untreatable and lethal consequence of PAH.

Hemodynamic Characteristics and Outcomes of Pulmonary Hypertension in Patients Undergoing Tricuspid Valve Repair or Replacement.

BACKGROUND: The impact of pulmonary hypertension (PH) on outcomes after surgical tricuspid valve replacement (TVR) and repair (TVr) is unclear. We sought to characterize PH in patients undergoing TVR/TVr, based on invasive hemodynamics and evaluate the effect of PH on mortality. METHODS: We identified 86 consecutive patients who underwent TVR/TVr with invasive hemodynamic measurements within 3 months before surgery. We used Kaplan-Meier survival and restricted mean survival time (RMST) analyses to quantify the effects of PH on survival. RESULTS: The mean age was 63 ± 13 years, 59% were female, 45% had TVR, 55% had TVr, 39.5% had isolated TVR/TVr, and 60.5% had TVR/TVr concomitant with other cardiac surgeries). Eighty-six percent of these patients had PH with a mean pulmonary artery pressure of 30 ± 10 mm Hg, pulmonary vascular resistance (PVR) of 2.5 (interquartile range: 1.5-3.9) Wood units (WU), pulmonary arterial compliance of 2.3 (1.6-3.6) mL/mm Hg, and pulmonary arterial elastance of 0.8 (0.6-1.2) mm Hg/mL. Cardiac output was mildly reduced at 4.0 ± 1.4 L/min, with elevated right-atrial pressure (14 ± 12 mm Hg) and pulmonary capillary wedge pressure (19 ± 7 mm Hg). Over a median follow-up of 6.3 years, 22% of patients died. Patients with PVR ≥ 2.5 WU had lower RMST over 5 years compared with patients with PVR < 2.5 WU. CONCLUSION: PH is common in patients undergoing TVR/TVr, with combined pre- and postcapillary being the most common type. PVR ≥ 2.5 WU is associated with lower survival at 5-year follow-up.

CONTEXTE: On connaît mal les répercussions de l'hypertension pulmonaire (HP) chez les patients qui ont subi une intervention chirurgicale de remplacement de la valve tricuspide (RVT) ou de réparation de la valve tricuspide (rVT). Nous avons tenté de caractériser l'HP chez les patients ayant subi un RVT ou une rVT en fonction des paramètres de surveillance hémodynamique effractive et d'évaluer l'effet de l'HP sur la mortalité. MÉTHODOLOGIE: Nous avons relevé 86 patients consécutifs ayant subi un RVT ou une rVT qui avaient fait l'objet de mesures hémodynamiques effractives dans les trois mois précédant l'intervention chirurgicale. Pour quantifier les effets de l'HP sur la survie, nous avons analysé la survie au moyen de la méthode de Kaplan-Meier et de la survie moyenne restreinte. RÉSULTATS: Les patients avaient en moyenne 63 ± 13 ans; 59 % d'entre eux étaient des femmes; 45 % avaient subi un RVT et 55 %, une rVT; 39,5 % avaient subi seulement un RVT ou une rVT lors de l'intervention chirurgicale; 60,5 % avaient subi un RVT ou une rVT en même temps qu'une autre intervention cardiaque. Quatre-vingt-six pour cent de ces patients présentaient une HP avec une pression artérielle pulmonaire moyenne de 30 ± 10 mmHg, une résistance vasculaire pulmonaire (RVP) de 2,5 (intervalle interquartile : 1,5 à 3,9) unités de Wood (UW), une compliance artérielle pulmonaire de 2,3 (1,6 à 3,6) ml/mmHg et une élastance artérielle pulmonaire de 0,8 (0,6 à 1,2) mmHg/ml. On a observé une légère baisse du débit cardiaque à 4,0 ± 1,4 L/min, ainsi qu'une augmentation de la pression auriculaire droite (14 ± 12 mmHg) et de la pression artérielle pulmonaire d'occlusion (19 ± 7 mmHg). Sur une période médiane de suivi de 6,3 ans, 22 % des patients sont décédés. Le taux de survie moyenne restreinte à 5 ans était plus faible chez les patients présentant une RVP ≥ 2,5 UW que chez les patients présentant une RVP < 2,5 UW. CONCLUSION: L'HP est fréquente chez les patients subissant un RVT ou une rVT, le type le plus courant étant l'HP mixte (pré-capillaire et post-capillaire). Une RVP ≥ 2,5 UW est associée à un taux de survie à 5 ans plus faible.

Excess Protein O-GlcNAcylation Links Metabolic Derangements to Right Ventricular Dysfunction in Pulmonary Arterial Hypertension.

The hexosamine biosynthetic pathway (HBP) converts glucose to uridine-diphosphate-N-acetylglucosamine, which, when added to serines or threonines, modulates protein function through protein O-GlcNAcylation. Glutamine-fructose-6-phosphate amidotransferase (GFAT) regulates HBP flux, and AMP-kinase phosphorylation of GFAT blunts GFAT activity and O-GlcNAcylation. While numerous studies demonstrate increased right ventricle (RV) glucose uptake in pulmonary arterial hypertension (PAH), the relationship between O-GlcNAcylation and RV function in PAH is unexplored. Therefore, we examined how colchicine-mediated AMP-kinase activation altered HBP intermediates, O-GlcNAcylation, mitochondrial function, and RV function in pulmonary artery-banded (PAB) and monocrotaline (MCT) rats. AMPK activation induced GFAT phosphorylation and reduced HBP intermediates and O-GlcNAcylation in MCT but not PAB rats. Reduced O-GlcNAcylation partially restored the RV metabolic signature and improved RV function in MCT rats. Proteomics revealed elevated expression of O-GlcNAcylated mitochondrial proteins in MCT RVs, which fractionation studies corroborated. Seahorse micropolarimetry analysis of H9c2 cardiomyocytes demonstrated colchicine improved mitochondrial function and reduced O-GlcNAcylation. Presence of diabetes in PAH, a condition of excess O-GlcNAcylation, reduced RV contractility when compared to nondiabetics. Furthermore, there was an inverse relationship between RV contractility and HgbA1C. Finally, RV biopsy specimens from PAH patients displayed increased O-GlcNAcylation. Thus, excess O-GlcNAcylation may contribute to metabolic derangements and RV dysfunction in PAH.

Comparison of Balloon Pulmonary Angioplasty and Pulmonary Vasodilators for Inoperable Chronic Thromboembolic Pulmonary Hypertension: A Systematic Review and Meta-Analysis.

Treatment options for chronic thromboembolic pulmonary hypertension (CTEPH) that is not amenable to thromboendarterectomy or is recurrent/persistent after thromboendarterectomy (inoperable CTEPH) include pulmonary vasodilators or balloon pulmonary angioplasty (BPA). We compared efficacy and safety outcomes of BPA with or without pulmonary vasodilators to pulmonary vasodilator therapy alone in patients with inoperable CTEPH. Observational and randomized trial data reporting outcomes for >5 patients with inoperable CTEPH were sought. Single-arm random effects meta-analyses were performed. The primary outcome was change in six-minute walk distance (6MWD). Secondary outcomes included safety; World Health Organization functional class (WHO FC); and change in mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), and cardiac index. Thirty-four studies with 1604 patients were eligible for analyses. Both treatments resulted in significant improvement in 6MWD (71.0 meters, 95% CI: 47.4-94.5 meters with BPA versus 47.8 meters, 95% CI: 34.5-61.2 meters with pulmonary vasodilators), PVR [-3.1 Wood Units (WU), 95% CI: -4.9 to -1.4 WU versus -1.6 WU, 95% CI: -2.4 to -0.8 WU] and mPAP (-14.8 mmHg, 95% CI: -18.2 to -11.5 mmHg versus -4.9 mmHg, 95% CI: -6.9 to -2.8 mmHg). Cardiac index was similar and most patients were WHO FC II and III after their respective interventions. More complications occurred in the BPA arm. In conclusion, BPA and pulmonary vasodilators both improve 6MWD and hemodynamics in patients with inoperable CTEPH. While BPA may offer greater functional and hemodynamic improvements, this technique carries the accompanying risks of an invasive procedure.

Hypochloremia Is a Noninvasive Predictor of Mortality in Pulmonary Arterial Hypertension.

Background Pulmonary arterial hypertension (PAH) is a lethal disease. In resource-limited countries PAH outcomes are worse because therapy costs are prohibitive. To improve global outcomes, noninvasive and widely available biomarkers that identify high-risk patients should be defined. Serum chloride is widely available and predicts mortality in left heart failure, but its prognostic utility in PAH requires further investigation. Methods and Results In this study 475 consecutive PAH patients evaluated at the University of Minnesota and Vanderbilt University PAH clinics were examined. Clinical characteristics were compared by tertiles of serum chloride. Both the Kaplan-Meier method and Cox regression analysis were used to assess survival and predictors of mortality, respectively. Categorical net reclassification improvement and relative integrated discrimination improvement compared prediction models. PAH patients in the lowest serum chloride tertile (≤101 mmol/L: hypochloremia) had the lowest 6-minute walk distance and highest right atrial pressure despite exhibiting no differences in pulmonary vascular disease severity. The 1-, 3-, and 5-year survival was reduced in hypochloremic patients when compared with the middle- and highest-tertile patients (86%/64%/44%, 95%/78%/59%, and, 91%/79%/66%). After adjustment for age, sex, diuretic use, serum sodium, bicarbonate, and creatinine, the hypochloremic patients had increased mortality when compared with the middle-tertile and highest-tertile patients. The Minnesota noninvasive model (functional class, 6-minute walk distance, and hypochloremia) was as effective as the French noninvasive model (functional class, 6-minute walk distance, and elevated brain natriuretic peptide or N-terminal pro-brain natriuretic peptide) for predicting mortality. Conclusions Hypochloremia (≤101 mmol/L) identifies high-risk PAH patients independent of serum sodium, renal function, and diuretic use.

Sex Differences in Right Ventricular Dysfunction: Insights From the Bench to Bedside.

There are inherent distinctions in right ventricular (RV) performance based on sex as females have better RV function than males. These differences are magnified and have very important prognostic implications in two RV-centric diseases, pulmonary hypertension (PH), and arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). In both PH and ARVC/D, RV dysfunction results in poor patient outcomes. However, there are no currently approved therapies specifically targeting the failing RV, an important unmet need for these two life-threatening disorders. In this review, we highlight human data demonstrating divergent RV phenotypes in healthy, PH, and ARVC/D patients based on sex. Furthermore, we discuss the links between estrogen (the female predominant sex hormone), testosterone (the male predominant sex hormone), and dehydroepiandrosterone (a precursor hormone for multiple sex hormones in males and females) and RV function in both disorders. To provide potential mechanistic insights into sex differences in RV function, we review data that investigate how sex hormones combat or contribute to pathophysiological changes in the RV. Finally, we highlight the ongoing clinical trials in pulmonary arterial hypertension targeting estrogen and dehydroepiandrosterone signaling. Hopefully, a greater understanding of the factors that promote superior RV function in females will lead to novel therapeutic approaches to combat RV dysfunction in PH and ARVC/D.

Treatment Targets for Right Ventricular Dysfunction in Pulmonary Arterial Hypertension.

Right ventricle (RV) dysfunction is the strongest predictor of mortality in pulmonary arterial hypertension (PAH), but, at present, there are no therapies directly targeting the failing RV. Although there are shared molecular mechanisms in both RV and left ventricle (LV) dysfunction, there are important differences between the 2 ventricles that may allow for the development of RV-enhancing or RV-directed therapies. In this review, we discuss the current understandings of the dysregulated pathways that promote RV dysfunction, highlight RV-enriched or RV-specific pathways that may be of particular therapeutic value, and summarize recent and ongoing clinical trials that are investigating RV function in PAH. It is hoped that development of RV-targeted therapies will improve quality of life and enhance survival for this deadly disease.