BACKGROUND: Adaptation of the right ventricle is a key determinant of outcomes in pulmonary arterial hypertension (PAH). Despite a compelling rationale to develop targeted therapies for the right ventricle in PAH, no such treatments exist. H2-receptor antagonism is a potential myocardial-focused paradigm in heart failure. RESEARCH QUESTION: Do H2-receptor antagonists improve outcomes in patients with PAH? STUDY DESIGN AND METHODS: We conducted a 24-week, single-center, 1:1 randomized, double-masked, placebo-controlled trial of the H2-receptor antagonist famotidine in patients with a diagnosis of PAH. The primary outcome was change in 6-minute walk distance (6MWD) at 24 weeks. Secondary end points included B-type natriuretic peptide levels, New York Heart Association functional class, right ventricular parameters measured from echocardiography, health-related quality of life, and escalation in PAH-focused care. RESULTS: From May 2019 through July 2023, 80 participants were randomized with 79 receiving study drug. No significant difference in the primary outcome of 6MWD at 24 weeks was found, with an increase of 4.7 m seen in the placebo arm vs a decrease of 17.0 m in the famotidine arm (P 1/4 .24). Also no differences were found in secondary end points at 24 weeks. Study drug was well tolerated, and safety profiles were similar between arms. Adherence and study conduct were good overall. Participants with methamphetamineassociated PAH were similar in all aspects to the study participants more broadly. INTERPRETATION: The results of this trial do not support the routine use of famotidine 20 mg daily as an adjunct therapy for the treatment of PAH. The findings of the Repurposing a Histamine Antagonist to Benefit Patients With Pulmonary Hypertension (REHAB-PH) trial argue against the practice of avoiding participants with methamphetamine-associated PAH in randomized clinical trials of novel therapies.

Background: Pulmonary arterial hypertension (PAH) is a complex disease characterized by progressive right ventricular (RV) failure leading to significant morbidity and mortality. Investigating metabolic features and pathways associated with RV dilation, mortality, and measures of disease severity can provide insight into molecular mechanisms, identify subphenotypes, and suggest potential therapeutic targets. Methods: We collected data from a prospective cohort of PAH participants and performed untargeted metabolomic profiling on 1045 metabolites from circulating blood. Analyses were intended to identify metabolomic differences across a range of common metrics in PAH (eg, dilated versus nondilated RV). Partial least squares discriminant analysis was first applied to assess the distinguishability of relevant outcomes. Significantly altered metabolites were then identified using linear regression, and Cox regression models (as appropriate for the specific outcome) with adjustments for age, sex, body mass index, and PAH cause. Models exploring RV maladaptation were further adjusted for pulmonary vascular resistance. Pathway enrichment analysis was performed to identify significantly dysregulated processes. Results: A total of 117 participants with PAH were included. Partial least squares discriminant analysis showed cluster differentiation between participants with dilated versus nondilated RVs, survivors versus nonsurvivors, and across a range of NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, REVEAL 2.0 composite scores, and 6-minute-walk distances. Polyamine and histidine pathways were associated with differences in RV dilation, mortality, NT-proBNP, REVEAL score, and 6-minute walk distance. Acylcarnitine pathways were associated with NT-proBNP, REVEAL score, and 6-minute walk distance. Sphingomyelin pathways were associated with RV dilation and NT-proBNP after adjustment for pulmonary vascular resistance. Conclusions: Distinct plasma metabolomic profiles are associated with RV dilation, mortality, and measures of disease severity in PAH. Polyamine, histidine, and sphingomyelin metabolic pathways represent promising candidates for identifying patients at high risk for poor outcomes and investigation into their roles as markers or mediators of disease progression and RV adaptation.

Introduction: Balloon pulmonary angioplasty (BPA) is a less invasive treatment alternative for patients with chronic thromboembolic pulmonary hypertension (CTEPH) who are unable to move forward with pulmonary thromboendarterectomy. This report describes a single-center experience with a nascent BPA program in the United States (US). Methods: All patients who underwent BPA between August 2018-2021 were included in this retrospective, single-center observational cohort. Pre-and post -procedure clinical information was collected, along with procedural characteristics. Results: Thirty patients began their BPA series during the study period. The majority of patients had segmental disease (n - 25, 83.3%). A total of 135 BPA procedures were performed on 417 segments. On average, patients completed 4.5 sessions and the majority of patients (n = 23, 76.7%) underwent more than 2. There were 24 episodes of hemoptysis and 20 procedural events that required treatment, typically with either heparin reversal or balloon tamponade. Of 26 participants with completed series, mean PA pressure (-6 mmHg, 95% CI-9 to-4 mmHg, p = 0.0001), PVR (-1.9 Wood units, 95% CI -2.9 to-1.0, p = 0.0002), and pulmonary compliance (-1.0 mL/mmHg, 95% CI-1.5 to-0.5, p = 0.0002) improved. Improvement was also seen in NYHA functional classification and walk distance (p = 0.01). Two deaths occurred, with one death peri-procedurally. Conclusion: This paper describes an early experience with BPA at a single US center. Improvement in non-invasive and invasive metrics were seen without adding a significant morbidity to an already high-risk patient population.

Introduction Pulmonary arterial hypertension (PAH) remains a serious and life-threatening illness. Thyroid dysfunction is relatively understudied in individuals with PAH but is known to affect cardiac function and vascular tone in other diseases. The aim of this observational study was to evaluate the association between thyroid-stimulating hormone (TSH), mortal and non-mortal outcomes in individuals with PAH. Methods The Seattle Right Ventricle Translational Science (Servetus) Study is an observational cohort that enrolled participants with PAH between 2014 and 2016 and then followed them for 3 years. TSH was measured irrespective of a clinical suspicion of thyroid disease for all participants in the cohort. Linear regression was used to estimate the relationships between TSH and right ventricular basal diameter, tricuspid annular plane systolic excursion and 6-minute walk distance. Logistic regression was used to estimate the relationship with New York Heart Association Functional Class, and Cox proportional hazards were used to estimate the relationship with mortality. Staged models included unadjusted models and models accounting for age, sex at birth and aetiology of pulmonary hypertension with or without further adjustment for N-terminal-pro hormone brain natriuretic peptide. Results Among 112 participants with PAH, TSH was strongly associated with mortality irrespective of adjustment. There was no clear consistent association between TSH and other markers of severity in a cohort with PAH. Discussion This report reinforces the important observation that TSH is associated with survival in patients with PAH, and future study of thyroid dysfunction as a potential remediable contributor to mortality in PAH is warranted.

BACKGROUND: Subtypes of pulmonary arterial hypertension (PAH) differ in both fundamental disease features and clinical outcomes. Angiogenesis and inflammation represent disease features that may dif-fer across subtypes and are of special interest in connective tissue disease-associated PAH (CTD-PAH). We compared inflammatory and angiogenic biomarker profiles across different etiologies of PAH and related them to clinical outcomes.METHODS: Participants with idiopathic PAH, CTD-PAH, toxin-associated PAH (tox-PAH), or congenital heart disease-associated PAH (CHD-PAH) were enrolled into a prospective observational cohort. Baseline serum con-centrations of 33 biomarkers were related to 3-year mortality, echocardiogram, REVEAL score, and 6-minute walk distance (6MWD). Findings were validated using plasma proteomic data from the UK PAH Cohort Study.RESULTS: One hundred twelve patients were enrolled: 45 idiopathic, 27 CTD-PAH, 20 tox-PAH, and 20 CHD-PAH. Angiogenic and inflammatory biomarkers were distinctly elevated within the CTD-PAH cohort. Six bio-markers were associated with mortality within the entire PAH cohort: interleukin-6 (IL-6, HR:1.6, 95% CI:1.18-2.18), soluble fms-like tyrosine kinase 1 (sFlt-1, HR:1.35, 95% CI:1.02-1.80), placental growth factor (PlGF, HR:1.55, 95% CI:1.07-2.25), interferon gamma-induced protein 10 (IP-10, HR:1.44, 95% CI:1.04-1.99), tumor necrosis factor-beta (TNF-b, HR:1.81, 95% CI:1.11-2.95), and NT-proBNP (HR:2.19, 95% CI:1.52-3.14). Only IL-6 and NT-proBNP remained significant after controlling for multiple comparisons. IL-6, IP-10, and sFlt-1 sig-nificantly associated with mortality in CTD-PAH, but not non-CTD-PAH subgroups. In the UK cohort, IP-10, PlGF, TNF-b, and NT-proBNP significantly associated with 5-year survival.

HomeJournal of the American Heart AssociationVol. 11, No. 14Risk Prediction and Right Ventricular Dilation in a Single‐Institution Pulmonary Arterial Hypertension Cohort Open AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citations ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toOpen AccessLetterPDF/EPUBRisk Prediction and Right Ventricular Dilation in a Single‐Institution Pulmonary Arterial Hypertension Cohort Hongyang Pi, MD, MS, Selma D. Carlson, MD, Lia M. Barros, ARNP, Laurie Hogl, RRT, James N. Kirkpatrick, MD, Stephanie Nolley, RN, David D. Ralph, MD, Samuel G. Rayner, MD and Peter J. Leary, MD, PhD Hongyang PiHongyang Pi , Department of Medicine, , University of Washington, , Seattle, , WA, , Selma D. CarlsonSelma D. Carlson , Department of Medicine, , Veterans Administration Minneapolis, , Minneapolis, , MN, , Lia M. BarrosLia M. Barros , Department of Medicine, , University of Washington, , Seattle, , WA, , Laurie HoglLaurie Hogl , Department of Medicine, , University of Washington, , Seattle, , WA, , James N. KirkpatrickJames N. Kirkpatrick , Department of Medicine, , University of Washington, , Seattle, , WA, , Stephanie NolleyStephanie Nolley , Department of Medicine, , University of Washington, , Seattle, , WA, , David D. RalphDavid D. Ralph , Department of Medicine, , University of Washington, , Seattle, , WA, , Samuel G. RaynerSamuel G. Rayner https://orcid.org/0000-0002-2541-4221 , Department of Medicine, , University of Washington, , Seattle, , WA, and Peter J. LearyPeter J. Leary *Correspondence to: Peter J. Leary, MD, PhD, University of Washington Medical Center, 1959 NE Pacific St., AMDG BB‐1361, Box 356522, Seattle, WA 98195‐6522. Email: E-mail Address: [email protected] https://orcid.org/0000-0001-5716-248X , Department of Medicine, , University of Washington, , Seattle, , WA, , Department of Epidemiology, , University of Washington, , Seattle, , WA, Originally published13 Jul 2022https://doi.org/10.1161/JAHA.122.025521Journal of the American Heart Association. 2022;11:e025521Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: July 13, 2022: Ahead of Print Therapies for patients with pulmonary arterial hypertension (PAH) have dramatically expanded. This expansion is welcome but has raised important questions about when to deploy therapies. To inform treatment decisions, risk‐assessment tools have been developed and guidelines advocate for formal risk stratification.1 Risk‐scores are heavily weighted in patient and clinician education on treatment escalation (eg, www.pahinitiative.com/pah‐information‐support).Nevertheless, discrepancies between physician gestalt and risk scores exist.2 Divergent impressions arising from gestalt may represent fallibility in subjective decision making, a more comprehensive clinical synthesis, or both. Results from cardiac imaging may contribute to divergent impressions. Cardiac imaging is recommended for guideline‐concordant care but not strongly represented in risk‐assessment tools.3 Using a single‐institution cohort, we evaluated right ventricular (RV) dilation alongside risk scores to further inform risk stratification. RV dilation was chosen as an approachable example to inform the hypothesis that routinely available clinical information may meaningfully modify impressions from formal risk assessment.The Servetus (Seattle Right Ventricle Translational Science) study includes a prospective cohort of participants with PAH enrolled and consented at the University of Washington between 2014 and 2016 (institutional review board number 3387). All participants had RV basal diameter measured on echocardiography and completed questionnaires every 3 months for 3 years. Vital status was confirmed for participants who died or did not return questionnaires. REVEAL 2.0 risk scores from the follow‐up visit most proximate to the echocardiogram were calculated using established methods (at least 7 variables were used).3In parametric analyses, unadjusted Cox proportional hazards estimated associations between risk scores and hazard of death over 3 years. Proportional hazards were confirmed using the Therneau and Grambsch test of non‐zero slope. In complementary analyses, log‐rank testing compared survival at 3 years (fixed time point) in nonparametric analyses. Two risk‐assessment approaches were used. Standard REVEAL 2.0 risk scores were used in the first set of analyses. The presence of RV dilation was used to further subdivide the large group of high‐risk REVEAL participants in the second set of analyses. Analyses were performed using Stata 15.0 (StataCorp, College Station, TX). Data supporting the findings are available from the corresponding author upon reasonable request.Ninety‐two participants were included. Most were on dual‐agent PAH therapy (44.6%), and many used 3 agents (20.6%). Participants with a high‐risk REVEAL 2.0 score comprised the largest subset (45.7%). The table reports associations between standard REVEAL 2.0 scores and outcomes (Table). Low‐ and intermediate‐risk scores did not differentiate outcomes; however, high‐risk scores clearly identified a group with increased risk for poor outcomes.Table . Survival Using 2 Different Risk Stratification Approaches for Participants With Pulmonary Arterial HypertensionRisk strataNHazard of deathSurvival at 3 yearsHR (95% CI)P valueSurvivalP valueStandard REVEAL 2.0 risk scoreLow risk30Referent97%ReferentIntermediate risk201.5 (0.1–24.1)0.7795%0.77High risk4211.0 (1.4–84.2)0.0269%0.004Alternative approachLow risk30Referent97%ReferentIntermediate risk201.5 (0.1–24.1)0.7795%0.77High risk (RVd <5 cm)266.2 (0.7–52.8)0.1081%0.06High risk (RVd ≥5 cm)1621.9 (2.7–176.0)0.00450%0.002HR indicates hazard ratio; and RVd, right ventricular basal diameter in diastole.When the high‐risk group was further stratified by RV size, 26 participants had mild or moderate RV dilation (<5 cm) and 16 had severe RV dilation (≥5 cm) defined as the upper quartile of dilation. The high‐risk group without severe RV dilation was not statistically different from intermediate‐ or low‐risk groups. The high‐risk group with severe RV dilation had worse survival compared with all other groups.These data reinforce previous work demonstrating that REVEAL risk scores, particularly high‐risk scores, predict poor outcomes in prevalent patients with PAH. We add to this by showing that readily available clinical results further delineate risk.We do not believe these findings undermine the value of formal risk‐assessment in routine care. The correct approach to titrating PAH therapy is in flux, and some evidence suggests both high‐risk groups (with and without RV dilation) might benefit from aggressive therapy.4 Conversely, the value of rapid escalation to 3 pulmonary vasodilators including parenteral therapy is not clearly established; side effects are common, and the possibility for harm is present.5 Given this uncertainty, identifying 2 high‐risk subgroups (one with 50% and one with 81% survival) likely crosses thresholds where patients and clinicians might variably choose a more incremental or aggressive approach.There are clear limitations. This was a small, single‐institution cohort. Insufficient power and small cohort size may have contributed to the lack of significance when comparing the high‐risk group without RV dilation and intermediate‐risk group to the low‐risk group. Nevertheless, despite its size, the cohort was well‐phenotyped, had several years of follow‐up, and demonstrated significant differences in survival and thus adequate power between high‐risk participants with and without RV dilation. This underscores the large survival difference between these 2 high‐risk groups. There is also no validation cohort. Risk assessment derivation requires large cohorts, careful attention to model specification, and rigorous validation. Our intent was not to develop a competing risk score or specifically focus on RV basal diameter. Instead, we believe these results are an example where routine clinical data may alter clinical gestalt in a manner that is important and not well‐captured in current risk scores.In summary, formal risk‐assessment to guide therapeutic escalation is widely promoted in academic and industry‐sponsored education. In this real‐world single institution cohort, most participants were considered high risk by risk score alone. We provide data that reinforce a paradigm where formal risk assessment is an important decision aid but does not supplant clinical synthesis and decision making.Sources of FundingThis work was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award KL2TR000421.DisclosuresDr Rayner received research funding from Bayer Pharmaceuticals. Dr Leary has received research funding from the National Institutes of Health, the American Heart Association, and Bayer Pharmaceuticals; salary support from the Cystic Fibrosis Foundation Therapeutic Development Network; and consulting fees from Bayer Pharmaceuticals. The remaining authors have no disclosures to report.Footnotes*Correspondence to: Peter J. Leary, MD, PhD, University of Washington Medical Center, 1959 NE Pacific St., AMDG BB‐1361, Box 356522, Seattle, WA 98195‐6522. Email: [email protected]eduFor Sources of Funding and Disclosures, see page 2.References1 Boucly A, Weatherald J, Humbert M, Sitbon O. Risk assessment in pulmonary arterial hypertension. Eur Respir J. 2018; 51:1800279. doi: 10.1183/13993003.00279-2018CrossrefMedlineGoogle Scholar2 Sahay S, Tonelli AR, Selej M, Watson Z, Benza RL. Risk assessment in patients with functional class II pulmonary arterial hypertension: comparison of physician gestalt with ESC/ERS and the REVEAL 2.0 risk‐score. PLoS One. 2020; 15:e0241504. doi: 10.1371/journal.pone.0241504CrossrefMedlineGoogle Scholar3 Benza RL, Gomberg‐Maitland M, Elliott CG, Farber HW, Foreman AJ, Frost AE, McGoon MD, Pasta DJ, Selej M, Burger CD, et al. Predicting survival in patients with pulmonary arterial hypertension: the REVEAL risk‐score calculator 2.0 and comparison with ESC/ERS‐based risk assessment strategies. Chest. 2019; 156:323–337. doi: 10.1016/j.chest.2019.02.004CrossrefMedlineGoogle Scholar4 Weatherald J, Boucly A, Sahay S, Humbert M, Sitbon O. The low‐risk profile in pulmonary arterial hypertension. Time for a paradigm shift to goal‐oriented clinical trial endpoints?Am J Respir Crit Care Med. 2018; 197:860–868. doi: 10.1164/rccm.201709-1840PPCrossrefMedlineGoogle Scholar5 Galie N, Sitbon O, Doelberg M, Gibbs JSR, Hoeper MM, Martin N, Mathai SC, McLaughlin V, Perchenet L, Simonneau G, et al. Long‐term outcomes in newly diagnosed pulmonary arterial hypertension (PAH) patients receiving initial triple oral combination therapy: insights from the randomised controlled TRITON study. Eur Heart J. 2020; 41:ehaa946.2288. doi: 10.1093/ehjci/ehaa946.2288CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails July 19, 2022Vol 11, Issue 14Article InformationMetrics Copyright © 2022 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley BlackwellThis is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.https://doi.org/10.1161/JAHA.122.025521PMID: 35861845 Manuscript receivedJanuary 24, 2022Manuscript acceptedJune 13, 2022Originally publishedJuly 13, 2022 Keywordspulmonary hypertensionbasal diameterechocardiographyPDF download SubjectsHeart Failure

Background Angiopoietin-1 and 2 (Ang1, Ang2) are important mediators of angiogenesis. Angiopoietin levels are perturbed in cardiovascular disease, but it is unclear whether angiopoietin signaling is causative, an adaptive response, or merely epiphenomenon of disease activity. Methods and Results In a cohort free of cardiovascular disease at baseline (Multi-Ethnic Study of Atherosclerosis [MESA]), relationships between angiopoietins, cardiac morphology, and subsequent incidence of heart failure or cardiovascular death were evaluated. In cohorts with pulmonary arterial hypertension or left heart disease, associations between angiopoietins, invasive hemodynamics, and adverse clinical outcomes were evaluated. In MESA, Ang2 was associated with a higher incidence of heart failure or cardiovascular death (hazard ratio 1.21 per standard deviation, P < .001). Ang2 was associated with increased right atrial pressure (pulmonary arterial hypertension cohort) and increased wedge pressure and right atrial pressure (left heart disease cohort). Elevated Ang2 was associated with mortality in the pulmonary arterial hypertension cohort. Conclusions Ang2 was associated with incident heart failure or death among adults without cardiovascular disease at baseline and with disease severity in individuals with existing heart failure. Our finding that Ang2 is increased before disease onset and that elevations reflect disease severity, suggests Ang2 may contribute to heart failure pathogenesis.

Disease-specific metabolomic signatures have been associated with mortality in pulmonary arterial hypertension (PAH). We explore whether this reflects right ventricular (RV) dysfunction. We analyzed quantitative targeted profiling of over 300 metabolites from a prospective cohort of PAH patients.

Rationale: Patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) typically undergo frequent clinical evaluation. The incidence and outcomes of coronavirus disease (COVID-19) and its impact on routine management for patients with pulmonary vascular disease is currently unknown.Objectives: To assess the cumulative incidence and outcomes of recognized COVID-19 for patients with PAH/CTEPH followed at accredited pulmonary hypertension centers, and to evaluate the pandemic's impact on clinic operations at these centers.Methods: A survey was e-mailed to program directors of centers accredited by the Pulmonary Hypertension Association. Descriptive analyses and linear regression were used to analyze results.Results: Seventy-seven center directors were successfully e-mailed a survey, and 58 responded (75%). The cumulative incidence of COVID-19 recognized in individuals with PAH/CTEPH was 2.9 cases per 1,000 patients, similar to the general U.S. population. In patients with PAH/CTEPH for whom COVID-19 was recognized, 30% were hospitalized and 12% died. These outcomes appear worse than the general population. A large impact on clinic operations was observed including fewer clinic visits and substantially increased use of telehealth. A majority of centers curtailed diagnostic testing and a minority limited new starts of medical therapy. Most centers did not use experimental therapies in patients with PAH/CTEPH diagnosed with COVID-19.Conclusions: The cumulative incidence of COVID-19 recognized in patients with PAH/CTEPH appears similar to the broader population, although outcomes may be worse. Although the total number of patients with PAH/CTEPH recognized to have COVID-19 was small, the impact of COVID-19 on broader clinic operations, testing, and treatment was substantial.

BACKGROUND:Circulating levels of endothelin-1 (ET1) are elevated in heart failure and predict poor prognosis. However, it is not clear whether ET1 elevation is an adaptive response, maladaptive response, or an epiphenomenon of heart failure. In this study, we evaluated the relationships between ET1, cardiac morphology, and incident heart failure or cardiovascular death in participants with no evidence of clinical cardiovascular disease at the time ET1 was measured. METHODS AND RESULTS:ET1 was measured in 1,361 participants in the Multi-Ethnic Study of Atherosclerosis Angiogenesis Sub-Study. As suggested by linear regression, participants with lower circulating ET1 levels tended to be older, non-white, more likely to have smoked heavily, and less likely to report intentional exercise. Participants with higher ET1 levels had smaller left ventricular end-diastolic volumes (8.9 ml smaller per log increase in ET1, 95% confidence interval 17.1-0.7, p = 0.03) with an increased left ventricular ejection fraction (2.8% per log increase in ET1, 95% confidence interval 0.5%-5.2%, p = 0.02). As suggested by Cox Proportional Hazards estimates, participants with higher ET1 levels had a lower risk for the composite outcome of heart failure or cardiovascular death in models that were unadjusted or had limited adjustment (p = 0.03 and p = 0.05, respectively). Lower risk for heart failure with higher ET1 levels could not be clearly shown in a model including health behaviors. CONCLUSIONS:These results suggest, but do not confirm, that elevated levels of circulating ET1 are associated with a more favorable cardiac phenotype. The relationship between ET1 and outcomes was not fully independent of one or more covariates.

Definition of abbreviations: CABG = coronary artery bypass graft; H2RA = H2 receptor antagonist; MI = myocardial infarction; PCI = percutaneous coronary intervention; PS = propensity score.Data are mean 6 SD, unless otherwise specified.*Pulmonary vascular resistance [(mean pulmonary artery pressure 2 wedge pressure)/cardiac output] was determined for each participant and then averaged.

Myocardial H2 receptor activation contributes to heart failure (HF) in preclinical models, and H2 receptor antagonists are associated with decreased HF incidence. This study evaluated whether H2 histamine receptor (HRH2) single nucleotide polymorphisms (SNPs) are associated with HF incidence and whether myocardial transcript abundance is associated with HF recovery. The association of SNPs in HRH2 with incident HF was characterized using Cox proportional hazards regression among participants in the Multi-Ethnic Study of Atherosclerosis. Differences in myocardial HRH2 transcripts were characterized in participants with dilated cardiomyopathy comparing 6 "super-responders" with 6 nonresponders to β blockade in the Beta-Blocker Effect on Remodeling and Gene Expression Trial. In MESA, no candidate SNP was associated with HF in black, Hispanic, or white participants. The rs2241562 minor allele was present only in Chinese participants and the adjusted HF hazard among those with 1 or more copies of this allele was 3.7, 95% confidence interval 1.0 to 13.4. In BORG, super-responders to β blockade had higher levels of myocardial HRH2 transcript at baseline compared with nonresponders (fragments per kilobase per transcript per million mapped reads: Variant 2, 5.5 ± 1.1 compared with 3.2 ± 0.8 in nonresponders, p = 0.002; Variant 1 + 2, 32.1 ± 7.4 compared with 23.3 ± 4.2 in nonresponders, p = 0.04). In conclusion, the presence of a minor allele at rs2241562 was associated with increased HF incidence in Chinese participants. Differences in myocardial HRH2 transcript abundance were seen in participants with dilated cardiomyopathy who responded to β blockade. These observations support the hypothesis that HRH2 is involved in the pathogenesis of HF.

BackgroundAdverse drug events (ADEs) with pulmonary vasodilator use in pulmonary arterial hypertension (PAH) are common. ADEs may contribute to worse quality of life; however, their relationship to prognosis is unknown. The objective of this study was to determine whether common ADEs after initiating subcutaneous treprostinil were associated with prognosis in PAH.MethodsWe assembled a retrospective cohort of participants from four clinical trials of treprostinil for PAH, including 908 participants who received subcutaneous treprostinil and 243 who received placebo at the time ADEs were ascertained. The occurrences of four common early ADEs (infusion reactions, headaches, jaw pain, or gastrointestinal side effects) were assessed during the eight weeks after starting the infusion. We used Cox proportional hazards to estimate associations between ADEs and mortality.ResultsNo ADEs related to placebo were associated with mortality. In participants who received treprostinil, infusion reactions, headaches, and jaw pain were not associated with mortality. Gastrointestinal side effects occurring during the first eight weeks following treprostinil infusion were associated with a 57% increase in the hazard of mortality (95% CI: 14–118%). This relationship was unchanged after adjusting for demographic differences and differences in baseline PAH severity.ConclusionsGastrointestinal ADEs after starting subcutaneous treprostinil were associated with an increased risk for mortality. Increased mortality was not observed with other early ADEs or with gastrointestinal symptoms in participants who were not receiving treprostinil at the time. This hypothesis-generating association suggests ADEs may identify different phenotypes in PAH.

Case 1 A 66-year-old woman with a history of hypertension presented with acute chest pain and was found to have a right ventricular (RV) myocardial infarction. Her ECG demonstrated ST elevations in the inferior leads (II, III, and aVF) and reciprocal depressions in the anterior precordial leads (V2–V4). A bedside echocardiogram revealed akinesis of the basal inferior wall and septum with severely reduced RV systolic function. Left ventricular (LV) function was preserved. The estimated pulmonary artery systolic pressure by echocardiogram was 14 to 19 mm Hg. Emergent cardiac catheterization revealed multivessel coronary disease, including a completely occluded right coronary artery, which was revascularized with drug-eluting stents leading to restoration of Thrombolysis in Myocardial Infarction (TIMI) 2 to 3 flow (Figure 1). After revascularization, the patient was hypotensive (86/51 mm Hg) and

BACKGROUND Myocardial H-2 receptor activation may promote cardiac fibrosis and apoptosis in pre-clinical models and histamine H-2 receptor antagonist (H2RA) use may improve symptoms in participants with heart failure (HF); however, relationships between H2RA use, incident HF, and longitudinal change in left ventricular (LV) morphology are not known.OBJECTIVES This study sought to determine whether H2RA use is associated with incident HF and change in LV morphology over time.METHODS We included 6,378 men and women from MESA (Multi-Ethnic Study of Atherosclerosis), a multicenter prospective observational cohort of participants without cardiovascular disease at baseline. Cox proportional hazards were used to estimate the association between H2RA use and incident HF in adjusted models. In participants with cardiac magnetic resonance imaging, associations between H2RA use, baseline LV morphology (n = 4,691), and longitudinal change in the LV (n = 2,806) were estimated using linear regression.RESULTS H2RAs were used by 313 participants but not by the other 6,065 individuals. During a median follow-up of 11.2 years, 236 participants developed HF. In adjusted models, baseline H2RA use relative to nonuse was associated with 62% lower risk for incident HF (p = 0.02). H2RA use was associated with preserved stroke volume, LV end-diastolic volume, and mass/volume ratio as measured by cardiac magnetic resonance imaging over approximately 10 years (all p < 0.05). There were no associations between H2RA use and LV mass or ejection fraction.CONCLUSIONS H2RA use was associated with reduced risk for incident HF. Left heart morphology over time suggests less age-related change in H2RA users. These associations suggest histamine signaling may be important in the pathogenesis of HF. (Multi-Ethnic Study of Atherosclerosis [MESA]; NCT00005487) (C) 2016 by the American College of Cardiology Foundation.

RATIONALE:H2 receptor antagonist (H2RA) use is common and may act directly on the heart through myocardial H2 receptors or indirectly through changes in pulmonary vascular resistance. OBJECTIVES:To determine the relationship between histamine H2RA use and right ventricular (RV) morphology. METHODS:We studied 4,122 participants in the Multi-Ethnic Study of Atherosclerosis without clinical cardiovascular disease who had magnetic resonance imaging assessment of RV morphology and ascertainment of medication use. Multivariable linear regression estimated cross-sectional associations between H2RA use and RV morphology after adjusting for demographics, anthropometrics, smoking status, diabetes mellitus, and hypertension. Further adjustments for co-medication use, left ventricular parameters, lung structure and function, renal function, or inflammatory markers were considered in separate models. Analyses in a subcohort restricted to H2RA or proton pump inhibitor users accounted for confounding by the indication of gastroesophageal reflux disease. MEASUREMENTS AND MAIN RESULTS:H2RA use was associated with lower RV mass (-0.7 g; 95% confidence interval, -1.2 to -0.2 g; P = 0.004) and smaller RV end-diastolic volume (-4.2 ml; 95% confidence interval, -7.2 to -1.2 ml; P = 0.006). This relationship was unchanged with adjustment for co-medication use, lung structure and function, renal function, and inflammation. The relationship with RV mass was independent of left ventricular mass. Results were similar in the smaller cohort restricted to proton pump inhibitor and H2RA users. CONCLUSIONS:H2RA use was associated with lower RV mass and smaller RV end-diastolic volume. Additional study of histamine and H2 receptors in cardiopulmonary diseases affecting the RV may have direct clinical relevance.

Right ventricular (RV) failure is a key determinant of morbidity and mortality in pulmonary hypertension (PH). The present study aims to add to existing descriptions of RV structural and functional changes in PH through a comprehensive three-dimensional (3D) shape analysis. We performed 3D echocardiography on 53 subjects with PH and 19 normal subjects. Twenty short-axis slices from apex to tricuspid centroid were measured to characterize regional shape: apical angle, basal bulge, eccentricity, and area. Transverse shortening was assessed by fractional area change (FAC) in each short-axis slice, longitudinal contraction was assessed by tricuspid annular plane systolic excursion (TAPSE) and global function by RV ejection fraction. Multivariate logistic analysis was used to compare the association of RV parameters with New York Heart Association (NYHA) class. Compared to normal, RV function in PH is characterized by decreased stroke volume index (SVi), fractional area change and ejection fraction. Increased eccentricity, apical rounding and bulging at the base characterize the shape of the RV in PH. Increased SVi, ejection fraction and mid-ventricular FAC were associated with less severe NYHA class in adjusted analyses. The RV in idiopathic PH (iPAH) was observed to have a larger end-diastolic volume and decreased function compared with connective tissue disease associated PH (ctd-PH). This work describes increased eccentricity and decreased systolic function in subjects with PH. Functional parameters were associated with NYHA class and heterogeneity in the phenotype was noted between subjects with iPAH and ctd-PH.