Bradley A Maron

Partners HealthCare · Department of Medicine

Aims: To develop a suite of quality indicators (QIs) for the evaluation of the care and outcomes for adults with pulmonary arterial hypertension (PAH). Methods and results: We followed the ESC methodology for the development of QIs. This included the 1) identification of key domains of care for the management of PAH, 2) proposal of candidate QIs...

Cardiovascular diseases (CVD) are the leading cause of death worldwide and display complex phenotypic heterogeneity caused by many convergent processes, including interactions between genetic variation and environmental factors. Despite the identification of a large number of associated genes and genetic loci, the precise mechanisms by which these...

In pulmonary arterial hypertension (PAH), inflammation promotes a fibroproliferative pulmonary vasculopathy. Reductionist studies emphasizing single biochemical reactions suggest a shift toward glycolytic metabolism in PAH; however, key questions remain regarding the metabolic profile of specific cell types within PAH vascular lesions in vivo. We u...

Prompt initiation of therapy after pulmonary arterial hypertension (PAH) diagnosis is critical to improve outcomes; yet delays in PAH treatment are common. Prior research demonstrates that individuals with PAH belonging to socially disadvantaged groups experience worse clinical outcomes. Whether these poor outcomes are mediated by delays in care or...

Background Pulmonary arterial hypertension (PAH) is a heterogenous and complex pulmonary vascular disease associated with substantial morbidity. Machine learning algorithms (used in many PAH risk calculators) can combine established parameters with thousands of circulating biomarkers to optimize PAH prognostication, but these approaches do not offe...

Background: Elevated mean pulmonary artery pressure (mPAP) is common in patients with hypertrophic cardiomyopathy (HCM) and heart failure symptoms. However, dynamic left ventricular (LV) outflow tract obstruction may confound interpretation of pulmonary hypertension (PH) pathophysiology in HCM when relying on resting invasive hemodynamic data alon...

Pathogenic DNA methylation changes may be involved in pulmonary arterial hypertension (PAH) onset and its progression, but there is no data on potential associations with patient-derived hemodynamic parameters. The reduced representation bisulfite sequencing (RRBS) platform identified N = 631 differentially methylated CpG sites which annotated to N...

Inhaled treprostinil was approved recently for interstitial lung disease‐pulmonary hypertension (PH); however, efficacy in 'real‐world' populations is not known. We designed a protocol and report our experience evaluating 10 patients referred for therapy. Misdiagnosis at presentation was common; ultimately, three patients (30%) were prescribed drug...

Background PVDOMICS (Pulmonary Vascular Disease Phenomics) is a precision medicine initiative to characterize pulmonary vascular disease (PVD) using deep phenotyping. PVDOMICS tests the hypothesis that integration of clinical metrics with omic measures will enhance understanding of PVD and facilitate an updated PVD classification. Objectives The p...

This science advisory focuses on the need to better understand the epidemiology, pathophysiology, and treatment of pulmonary hypertension in patients with heart failure with preserved ejection fraction. This clinical phenotype is important because it is common, is strongly associated with adverse outcomes, and lacks evidence-based therapies. Our go...

Hypertrophic cardiomyopathy (HCM) is a global and relatively common cause of patient morbidity and mortality and is among the first reported monogenic cardiac diseases. For 30 years, the basic etiology of HCM has been attributed largely to variants in individual genes encoding cardiac sarcomere proteins, with the implication that HCM is fundamental...

Abstract The pathobiology of in situ pulmonary thrombosis in acute respiratory distress syndrome (ARDS) due to severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection is incompletely characterized. In human pulmonary artery endothelial cells (HPAECs), hypoxia increases neural precursor cell expressed, developmentally downregulated 9...

The cardiopulmonary hemodynamic profile observed during exercise may identify patients with early stage pulmonary vascular and primary cardiac diseases, and is used clinically to inform prognosis. However, a standardised approach to interpreting hemodynamics is lacking. We performed a systematic literature search according to PRISMA guidelines to i...

Treating Veterans with chronic obstructive pulmonary disease complicated by pulmonary hypertension (COPD‐PH) using phosphodiesterase type‐5 inhibitor pharmacotherapy is common, but efficacy data are lacking. To address this further, patients with COPD‐PH from five Department of Veterans Affairs hospitals were randomized (1∶1) to receive placebo or...

Aims The minute ventilation–carbon dioxide production relationship (VE/VCO2 slope) is widely used for prognostication in heart failure (HF) with reduced left ventricular ejection fraction (LVEF). This study explored the prognostic value of VE/VCO2 slope across the spectrum of HF defined by ranges of LVEF. Methods and results In this single-centre...

Despite impressive efforts invested in epigenetic research in the last 50 years, clinical applications are still lacking. Only a few university hospital centers currently use epigenetic biomarkers at the bedside. Moreover, the overall concept of precision medicine is not widely recognized in routine medical practice and the reductionist approach re...

Introduction: Advanced-stage pulmonary arterial hypertension (asPAH) is characterized by endothelial dysfunction and fibrotic remodeling of pulmonary arterioles that promotes irreversible right heart failure. Thus, identifying mechanisms that regulate vascular fibrosis in early PAH (esPAH) may have translational importance. Hypothesis: We hypothesi...

It is important for both the patient and physician communities to have timely access to information recognizing rapid progress in the diagnosis and treatment of familiar but relatively uncommon cardiovascular diseases. Patients with 3 cardiovascular diseases (ie, hypertrophic cardiomyopathy, pulmonary arterial hypertension, and transthyretin (TTR)...

Myocardial injury after noncardiac surgery is defined by elevated postoperative cardiac troponin concentrations that exceed the 99th percentile of the upper reference limit of the assay and are attributable to a presumed ischemic mechanism, with or without concomitant symptoms or signs. Myocardial injury after noncardiac surgery occurs in ≈20% of p...

Purpose of Review Chronic thromboembolic pulmonary hypertension (CTEPH) is an uncommon complication of acute pulmonary embolism (PE), in which the red, platelet-rich thrombus does not resolve but forms into an organized yellow, fibrotic scar-like obstruction in the pulmonary vasculature. Here we review the pathobiology of CTEPH. Recent Findings Ou...

Purpose of Review Chronic thromboembolic pulmonary hypertension (CTEPH), included in group 4 PH, is an uncommon complication of acute pulmonary embolism (PE), in which emboli in the pulmonary vasculature do not resolve but rather form into an organized scar-like obstruction which can result in right ventricular (RV) failure. Here we provide an over...

Pulmonary hypertension is associated with increased morbidity and mortality, and growing evidence suggests that even mild elevations in pulmonary artery pressure estimated with echocardiography are linked to increased mortality. In healthy individuals who undergo right heart catheterisation, the average pulmonary artery systolic pressure ranges fro...

Background Pulmonary hypertension is a heterogeneous disease and a significant portion of patients at risk for it have available computed tomography (CT) imaging. Advanced automated processing techniques could be leveraged to for early detection, screening and development of quantitative phenotypes. Pruning and vascular tortuosity have been previou...

Aims There is a wide spectrum of diseases associated with pulmonary hypertension, pulmonary vascular remodelling, and right ventricular dysfunction. The NIH-sponsored PVDOMICS network seeks to perform comprehensive clinical phenotyping and endophenotyping across these disorders to further evaluate and define pulmonary vascular disease. Methods and...

Right ventricular dysfunction is a hallmark of advanced pulmonary vascular, lung parenchymal, and left heart disease, yet the underlying mechanisms that govern (mal)adaptation remain incompletely characterized. Owing to the knowledge gaps in our understanding of the right ventricle (RV) in health and disease, the National Heart, Lung, and Blood Ins...

The diagnosis and management of pulmonary arterial hypertension (PAH) includes several advances, such as broader recognition of extra-pulmonary vascular organ system involvement, validated point-of-care clinical assessment tools, and a focus on early-initiation of multiple pharmacotherapeutics in appropriate patients. Indeed, a principal goal in PA...

Opioid overdose is the leading cause of death for Americans 25 to 64 years of age, and opioid use disorder affects >2 million Americans. The epidemiology of opioid-associated out-of-hospital cardiac arrest in the United States is changing rapidly, with exponential increases in death resulting from synthetic opioids and linear increases in heroin de...

Progress in precision medicine is limited by insufficient knowledge of transcriptomic or proteomic features in involved tissues that define pathobiological differences between patients. Here, myectomy tissue from patients with obstructive hypertrophic cardiomyopathy and heart failure is analyzed using RNA-Seq, and the results are used to develop in...

Rationale: Data on the molecular mechanisms that regulate platelet-pulmonary endothelial adhesion under conditions of hypoxia are lacking, but may have important therapeutic implications. Objectives: Identify a hypoxia-sensitive, modifiable mediator of platelet-pulmonary artery endothelial cell adhesion and thrombotic remodeling. Methods and Measur...

Pulmonary hypertension (PH) is an independent risk factor for adverse clinical outcome, particularly in left heart disease (LHD) patients. Recent advances have clarified the mean pulmonary artery pressure (mPAP) range that is above normal and is associated with clinical events, including mortality. This progress has for the first time resulted in a...

Background The renin-angiotensin-aldosterone system (RAAS) contributes to pulmonary hypertension (PH) pathogenesis. While animal data suggest RAAS inhibition attenuates PH, it is unknown if RAAS inhibition is beneficial in PH patients. Research question Is RAAS inhibitor use associated with lower mortality in a large cohort of patients with hemody...

Network Medicine is now an established scientific discipline, having generated key insights on integrated mechanisms underlying complex human diseases. The next discovery phase will emphasize innovating analytics that optimize networks for advancing precision medicine. Accomplishing this goal will require organizing a scientifically diverse team st...

Background In pulmonary hypertension subgroups, elevated pulmonary vascular resistance (PVR) of 3·0 Wood units or more is associated with poor prognosis. However, the spectrum of PVR risk in pulmonary hypertension is not known. To address this area of uncertainty, we aimed to analyse the relationship between PVR and adverse clinical outcomes in pul...

The coronavirus disease 2019 (COVID‐19) pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2), marks a global event that will permanently reshape implementation of intensive care medicine. As of June 4, 2020, there are 6,606,455 reported cases of COVID‐19 including 388,556 fatalities spanning 215 countries and territories...

Pulmonary (arterial) hypertension (PH/PAH) is a life-threatening cardiopulmonary disorder. Experimental evidence suggests involvement of inflammatory and autoimmune processes in pathogenesis of PH/PAH, however the triggering and disease-promoting mechanisms remain unknown. The complement system is a key arm of innate immunity implicated in various...

Advanced phenotyping of cardiovascular diseases has evolved with the application of high-resolution omics screening to populations enrolled in large-scale observational and clinical trials. This strategy has revealed that considerable heterogeneity exists at the genotype, endophenotype, and clinical phenotype levels in cardiovascular diseases, a fe...

Pulmonary vascular disease, including pulmonary arterial hypertension (PAH), is increasingly recognized to be affected by systemic alterations including up‐regulation of the renin‐angiotensin‐aldosterone system and perturbations to metabolic pathways, particularly glucose and fat metabolism. There is increasing pre‐clinical and clinical data that e...

Background: Pulmonary arterial hypertension (PAH) is a highly morbid disease characterized by elevated pulmonary vascular resistance (PVR) and pathogenic right ventricular remodeling. Endothelial expression of the prometastatic protein NEDD9 is increased in fibrotic PAH arterioles, and NEDD9 inhibition decreases PVR in experimental PAH. We hypothe...

Rationale: Pulmonary (arterial) hypertension (PH/PAH) is a life-threatening cardiopulmonary disorder where inflammation and immunity have emerged as critical early pathogenic elements. Although pro-inflammatory processes in PH/PAH are the focus of extensive investigation, the initiating mechanisms remain elusive. Objectives: We tested whether ac...

Importance Current guidelines recommend evaluation for echocardiographically estimated right ventricular systolic pressure (RVSP) greater than 40 mm Hg; however, this threshold does not capture all patients at risk. Objectives To determine if mild echocardiographic pulmonary hypertension (ePH) is associated with reduced right ventricular (RV) func...

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...

Background Minute ventilation-carbon dioxide production relationship (VE/VCO2 slope), as assessed by cardiopulmonary exercise testing (CPET), strongly predicts outcomes in heart failure (HF). High VE/VCO2 slope can indicate ventilatory inefficiency. A single VE/VCO2 slope threshold defining abnormal of ≥ 34 to 36 is used clinically across HF catego...

Background: At the recent 6th World Symposium on Pulmonary Hypertension (PH), the definition of PH was redefined to include lower pulmonary artery pressures in the setting of elevated pulmonary vascular resistance (PVR). However, the relevance of this change to subjects with PH due to left-heart disease as well as the preoperative assessment of he...

Hypertrophic cardiomyopathy (HCM) has been considered a heterogeneous cardiac disease ascribed solely to single sarcomere gene mutations. However, limitations of this hypothesis suggest that sarcomere mutations alone do not adequately explain all HCM clinical and pathobiological features. Disease-causing sarcomere mutations are absent in ∼70% of pa...

Transcriptomic analysis of pulmonary microvascular endothelial cells from experimental models offers insight into pulmonary arterial hypertension (PAH) pathobiology. However, culturing may alter the molecular profile of endothelial cells prior to analysis, limiting the translational relevance of results. Here we present a novel and validated method...

This document contains details regarding flow cytometry setup, endothelial cell isolation methods, as well as sources and characteristics of commercial primary cells. (DOCX)

Raw electropherograms for rat PMVEC RNA isolated from control and monocrotaline-PAH animals are provided in this document. (DOCX)

Detection of CD31 and α-smooth muscle actin by immunocytochemistry was similar with acetone or methanol cell fixation. Peripheral rat lung tissue was treated with mechanical and enzymatic dissociation, and the cell pellet was cultured in endothelial-selective medium. Presumed rat PMVECs were fixed in acetone or methanol and analyzed using anti-CD31...

CD31 and von Willebrand Factor colocalize in human pulmonary arterial endothelial cells and presumed rat pulmonary microvascular endothelial cells. (A) Human pulmonary artery endothelial cells were labeled with either anti-CD31 Ab #1 or anti-von Willebrand Factor Ab #6 and analyzed using confocal microscopy to determine colocalization thresholds. (...

Detailed gating strategy for the identification of confirmed rat pulmonary microvascular endothelial cells by CD31 and Griffonia simplicifolia isolectin 1-B4 flow cytometry. Presumed rat PMVECs were isolated without cell culture by mechanical and enzymatic digestion and immunomagnetic bead selection for CD31. Presumed rat PMVECs were labeled with a...

Background Recent studies have demonstrated a continuum in clinical risk related to mean pulmonary artery pressure that begins at >19 mm Hg, which is below the traditional threshold used to define pulmonary hypertension (PH) of 25 mm Hg. Because of the implications on patient diagnosis and prognosis, the generalizability and validity of these data...

Germline mutations involving small mothers against decapentaplegic-transforming growth factor-β (SMAD-TGF-β) signaling are an important but rare cause of pulmonary arterial hypertension (PAH), which is a disease characterized, in part, by vascular fibrosis and hyperaldosteronism (ALDO). We developed and analyzed a fibrosis protein-protein network (...

Background: Pulmonary vascular remodeling is an angiogenic-related process involving changes in smooth muscle cell (SMC) homeostasis, which is frequently observed in chronic obstructive pulmonary disease (COPD). MicroRNAs (miRNAs) are small non-coding RNAs that regulate mRNA expression levels of many genes leading to the manifestation of cell iden...

Rationale: Current methods assessing clinical risk due to exercise intolerance in cardiopulmonary disease patients rely on a small subset of traditional variables. Alternative strategies incorporating the spectrum of factors underlying prognosis in at-risk patients may be useful clinically, but are lacking. Objective: Use unbiased analyses to id...

A methodical approach to pulmonary hypertension (PH) assessment in clinical practice is critical to ensure the correct diagnosis, determine disease severity, and initiate appropriate therapy. Data from epidemiological, clinical, and survey studies suggest that practice patterns vary widely across geographic regions, hospitals, and even within the e...

Women have an increased risk of pulmonary hypertension (PH) but better survival compared to men. Few studies have explored sex-based differences in population-based cohorts with PH. We sought to determine whether sex was associated with hemodynamics and survival in US veterans with PH (mean pulmonary artery pressure [mPAP] ≥ 25 mm Hg) from the Vete...

Significance: All cellular metabolic processes are tied to the cellular redox environment. Therefore, maintaining redox homeostasis is critically important for normal cell function. Indeed, redox stress contributes to the pathobiology of many human diseases. The cellular redox response system is composed of numerous interconnected components, incl...