Publications by authors named "Marc A Simon"

100 Publications

A clinically applicable strategy to estimate the in vivo distribution of mechanical material properties of the right ventricular wall.

Int J Numer Method Biomed Eng 2021 Nov 1:e3548. Epub 2021 Nov 1.

Department of Civil and Environmental Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

A clinically applicable approach to estimate the in vivo mechanical material properties of the heart wall is presented. This optimization-based inverse estimation approach applies a shape-based objective functional combined with rigid body registration and incremental parameterization of heterogeneity to use standard clinical imaging data along with simplified representations of cardiac function to provide consistent and physically meaningful solution estimates. The capability of the inverse estimation algorithm is evaluated through application to two clinically obtained human datasets to estimate the passive elastic mechanical properties of the heart wall, with an emphasis on the right ventricle. One dataset corresponded to a subject with normal heart function, while the other corresponded to a subject with severe pulmonary hypertension, and therefore expected to have a substantially stiffer right ventricle. Patient-specific pressure-driven bi-ventricle finite element analysis was used as the forward model and the endocardial surface of the right ventricle was used as the target data for the inverse problem. By using the right ventricle alone as the target of the inverse problem the relative sensitivity of the objective function to the right ventricle properties is increased. The method was able to identify material properties to accurately match the corresponding shape of the simplified forward model to the clinically obtained target data, and the properties obtained for the example cases are consistent with the clinical expectation for the right ventricle. Additionally, the material property estimates indicate significant heterogeneity in the heart wall for both subjects, and more so for the subject with pulmonary hypertension.
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http://dx.doi.org/10.1002/cnm.3548DOI Listing
November 2021

Right Ventricular Shape Feature Quantification for Evaluation of Pulmonary Hypertension: Feasibility and Preliminary Associations With Clinical Outcome Submitted for Publication.

J Biomech Eng 2022 Apr;144(4)

Department of Civil and Environmental Engineering, University of Pittsburgh, Pittsburgh, PA 15261.

This study aimed to demonstrate feasibility of statistical shape analysis techniques to identify distinguishing features of right ventricle (RV) shape as related to hemodynamic variables and outcome data in pulmonary hypertension (PH). Cardiovascular magnetic resonance images were acquired from 50 patients (33 PH, 17 non-PH). Contemporaneous right heart catheterization data were collected for all individuals. Outcome was defined by all-cause mortality and hospitalization for heart failure. RV endocardial borders were manually segmented, and three-dimensional surfaces reconstructed at end diastole and end systole. Registration and harmonic mapping were then used to create a quantitative correspondence between all RV surfaces. Proper orthogonal decomposition was performed to generate modes describing RV shape features. The first 15 modes captured over 98% of the total modal energy. Two shape modes, 8 (free wall expansion) and 13 (septal flattening), stood out as relating to PH state (mode 13: r = 0.424, p = 0.002; mode 8: r = 0.429, p = 0.002). Mode 13 was significantly correlated with outcome (r = 0.438, p = 0.001), more so than any hemodynamic variable. Shape analysis techniques can derive unique RV shape descriptors corresponding to specific, anatomically meaningful features. The modes quantify shape features that had been previously only qualitatively related to PH progression. Modes describing relevant RV features are shown to correlate with clinical measures of RV status, as well as outcomes. These new shape descriptors lay the groundwork for a noninvasive strategy for identification of failing RVs, beyond what is currently available to clinicians.
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http://dx.doi.org/10.1115/1.4052495DOI Listing
April 2022

Exercise Intolerance in Older Adults With Heart Failure With Preserved Ejection Fraction: JACC State-of-the-Art Review.

J Am Coll Cardiol 2021 Sep;78(11):1166-1187

Wake Forest School of Medicine, Winston-Salem, North Carolina, USA. Electronic address:

Exercise intolerance (EI) is the primary manifestation of chronic heart failure with preserved ejection fraction (HFpEF), the most common form of heart failure among older individuals. The recent recognition that HFpEF is likely a systemic, multiorgan disorder that shares characteristics with other common, difficult-to-treat, aging-related disorders suggests that novel insights may be gained from combining knowledge and concepts from aging and cardiovascular disease disciplines. This state-of-the-art review is based on the outcomes of a National Institute of Aging-sponsored working group meeting on aging and EI in HFpEF. We discuss aging-related and extracardiac contributors to EI in HFpEF and provide the rationale for a transdisciplinary, "gero-centric" approach to advance our understanding of EI in HFpEF and identify promising new therapeutic targets. We also provide a framework for prioritizing future research, including developing a uniform, comprehensive approach to phenotypic characterization of HFpEF, elucidating key geroscience targets for treatment, and conducting proof-of-concept trials to modify these targets.
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http://dx.doi.org/10.1016/j.jacc.2021.07.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8525886PMC
September 2021

Role of Internal Jugular Venous Ultrasound in suspected or confirmed Heart Failure: A Systematic Review.

J Card Fail 2021 Aug 19. Epub 2021 Aug 19.

UPMC Heart and Vascular Institute, Pittsburgh, Pennsylvania; Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, Pittsburgh, Pennsylvania; Department of Bioengineering, Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.

Background: Few data are available on the use of internal jugular vein (IJV) ultrasound parameters to assess central venous pressure and clinical outcomes among patients with suspected or confirmed heart failure (HF).

Methods: We performed electronic searches on PubMed, The Cochrane Library, EMBASE, EBSCO, Web of Science, and CINAHL databases from the inception through January 9, 2021, to identify studies evaluating the accuracy and reliability of the IJV ultrasound parameters and exploring its correlation with central venous pressure and clinical outcomes in adult patients with suspected or confirmed acutely decompensated HF. The studies' report quality was assessed by Quality Assessment of Diagnostic Accuracy Studies-2 scale.

Results: A total of 11 studies were eligible for final analysis (n = 1481 patients with HF). The studies were segregated into 3 groups: (1) the evaluation of patients presenting to the emergency department with dyspnea, (2) the evaluation of patients presenting to the HF clinic for follow-up, and (3) the evaluation of hospitalized patients with acutely decompensated HF or undergoing right heart catheterization. US parameters included IJV height, IJV diameter, IJV diameter ratio, IJV cross-sectional area, respiratory compressibility index, and compression compressibility index.

Conclusions: The findings of this systematic review suggest a significant role for ultrasound interrogation of the IJV in evaluation of patients in the emergency department presenting with dyspnea, in the outpatient clinic for poor clinical outcomes in HF, and in determining the timing of discharge for patients admitted with acutely decompensated HF. Further studies are warranted for testing the reliability of the reported ultrasound indices.
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http://dx.doi.org/10.1016/j.cardfail.2021.08.009DOI Listing
August 2021

Pulmonary Hypertension in the Context of Heart Failure With Preserved Ejection Fraction.

Chest 2021 Aug 12. Epub 2021 Aug 12.

Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, SC. Electronic address:

Heart failure with preserved ejection fraction (HFpEF) is the most common form of heart failure and frequently is associated with pulmonary hypertension (PH). HFpEF associated with PH may be difficult to distinguish from precapillary forms of PH, although this distinction is crucial because therapeutic pathways are divergent for the two conditions. A comprehensive and systematic approach using history, clinical examination, and noninvasive and invasive evaluation with and without provocative testing may be necessary for accurate diagnosis and phenotyping. After diagnosis, HFpEF associated with PH can be subdivided into isolated postcapillary pulmonary hypertension (IpcPH) and combined postcapillary and precapillary pulmonary hypertension (CpcPH) based on the presence or absence of elevated pulmonary vascular resistance. CpcPH portends a worse prognosis than IpcPH. Despite its association with reduced functional capacity and quality of life, heart failure hospitalizations, and higher mortality, therapeutic options focused on PH for HFpEF associated with PH remain limited. In this review, we aim to provide an updated overview on clinical definitions and hemodynamically characterized phenotypes of PH, pathophysiologic features, therapeutic strategies, and ongoing challenges in this patient population.
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http://dx.doi.org/10.1016/j.chest.2021.08.039DOI Listing
August 2021

Health disparities and treatment approaches in portopulmonary hypertension and idiopathic pulmonary arterial hypertension: an analysis of the Pulmonary Hypertension Association Registry.

Pulm Circ 2021 Jul-Sep;11(3):20458940211020913. Epub 2021 May 17.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.

Compared to idiopathic pulmonary arterial hypertension (IPAH), patients with portopulmonary hypertension (POPH) have worse survival. Health disparities may contribute to these differences but have not been studied. We sought to compare socioeconomic factors in patients with POPH and IPAH and to determine whether socioeconomic status and/or POPH diagnosis were associated with treatment and health-care utilization. We performed a cross-sectional study of adults enrolled in the Pulmonary Hypertension Association Registry. Patients with IPAH (n = 344) and POPH (n = 57) were compared. Compared with IPAH, patients with POPH were less likely to be college graduates (19.6% vs. 34.9%, p = 0.02) and more likely to be unemployed (54.7% vs. 30.5%, p < 0.001) and have an annual household income below poverty level (45.7% vs. 19.0%, p < 0.001). Patients with POPH had similar functional class, quality of life, 6-min walk distance, and mean pulmonary arterial pressure with a higher cardiac index. Compared with IPAH, patients with POPH were less likely to receive combination therapy (46.4% vs. 62.2%, p = 0.03) and endothelin receptor antagonists (28.6% vs. 55.1%, p < 0.001) at enrollment with similar treatment at follow-up. Patients with POPH had more emergency department visits (1.7 ± 2.1 vs. 0.9 ± 1.2, p = 0.009) and hospitalizations in the six months preceding enrollment (1.5 ± 2.1 vs. 0.8 ± 1.1, p = 0.02). Both POPH diagnosis and lower education level were independently associated with a higher number of emergency department visits. Compared to IPAH, patients with POPH have lower socioeconomic status, are less likely to receive initial combination therapy and endothelin receptor antagonists but have similar treatment at follow-up, and have increased health-care utilization.
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http://dx.doi.org/10.1177/20458940211020913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186121PMC
May 2021

Current Understanding of the Right Ventricle Structure and Function in Pulmonary Arterial Hypertension.

Front Physiol 2021 28;12:641310. Epub 2021 May 28.

Division of Cardiology, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States.

Pulmonary arterial hypertension (PAH) is a disease resulting in increased right ventricular (RV) afterload and RV remodeling. PAH results in altered RV structure and function at different scales from organ-level hemodynamics to tissue-level biomechanical properties, fiber-level architecture, and cardiomyocyte-level contractility. Biomechanical analysis of RV pathophysiology has drawn significant attention over the past years and recent work has found a close link between RV biomechanics and physiological function. Building upon previously developed techniques, biomechanical studies have employed multi-scale analysis frameworks to investigate the underlying mechanisms of RV remodeling in PAH and effects of potential therapeutic interventions on these mechanisms. In this review, we discuss the current understanding of RV structure and function in PAH, highlighting the findings from recent studies on the biomechanics of RV remodeling at organ, tissue, fiber, and cellular levels. Recent progress in understanding the underlying mechanisms of RV remodeling in PAH, and effects of potential therapeutics, will be highlighted from a biomechanical perspective. The clinical relevance of RV biomechanics in PAH will be discussed, followed by addressing the current knowledge gaps and providing suggested directions for future research.
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http://dx.doi.org/10.3389/fphys.2021.641310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194310PMC
May 2021

A pilot study of oral treprostinil pharmacogenomics and treatment persistence in patients with pulmonary arterial hypertension.

Ther Adv Respir Dis 2021 Jan-Dec;15:17534666211013688

Pharmacogenomics Center of Excellence, Institute for Personalized Medicine, Department of Pharmacy and Therapeutics, Center for Clinical Pharmaceutical Sciences and the Clinical and Translational Science Institute, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.

Background And Aims: Treprostinil is a prostacyclin analog used to treat pulmonary arterial hypertension. Dosing is empiric and based on tolerability. Adverse effects are common and can affect treatment persistence. Pharmacogenomic variants that may affect treprostinil metabolism and transport have not been well-characterized. We aimed to investigate the pharmacogenomic sources of variability in treatment persistence and dosing.

Methods: Patients were prospectively recruited from an IRB approved biobank registry at a single pulmonary hypertension center. A cohort of patients who received oral treprostinil were screened for participation. Pharmacogenomic analysis was for variants in , , and . A retrospective review was conducted for demographics, clinical status, dosing, and response. Fisher's exact test was used for categorical data and Kruskal-Wallis test or Wilcoxon rank sum were used for continuous data.

Results: A total of 15 patients received oral treprostinil and were consented. Their median age was 53 years, 73% were female, and 93% were White. The median total daily dose was 22.5 mg (13.5, 41) at last clinical observation. 40% of patients discontinued treatment with a majority due to adverse effects. Approximately 27% of patients had a loss-of-function variant in (*1/*3 or *1/*4), whereas 47% of patients had a loss-of-function variant in (*1/*2, *1/*3, or *2/*2). Minor allele frequencies for (rs1751034 and rs3742106) were 0.17 and 0.43, respectively. Survival analysis showed that increased CYP2C9 activity score was associated with decreased risk for treatment discontinuation [hazard ratio (HR): 0.13; 95% confidence interval (CI): 0.02, 0.91;  = 0.04]. Genetic variants were not significantly associated with dosing.

Conclusion: Genetic variants responsible for the metabolism and transport of oral treprostinil were common. Increased CYP2C9 activity score was associated with decreased risk for treatment discontinuation. However, dosing was not associated with genetic variants in metabolizing enzymes for treprostinil. Our findings suggest significant variability in treatment persistence to oral treprostinil, with pharmacogenomics being a potentially important contributor.
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http://dx.doi.org/10.1177/17534666211013688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111525PMC
April 2021

Levosimendan Improves Hemodynamics and Exercise Tolerance in PH-HFpEF: Results of the Randomized Placebo-Controlled HELP Trial.

JACC Heart Fail 2021 05 7;9(5):360-370. Epub 2021 Apr 7.

Northwestern University, Chicago, Illinois, USA.

Objectives: The purpose of this study was to evaluate the effects of intravenous levosimendan on hemodynamics and 6-min walk distance (6MWD) in patients with pulmonary hypertension and heart failure with preserved ejection fraction (PH-HFpEF).

Background: There are no proven effective treatments for patients with PH-HFpEF.

Methods: Patients with mean pulmonary artery pressure (mPAP) ≥35 mm Hg, pulmonary capillary wedge pressure (PCWP) ≥20 mm Hg, and LVEF ≥40% underwent 6MWD and hemodynamic measurements at rest, during passive leg raise, and supine cycle exercise at baseline and after an open-label 24-h levosimendan infusion (0.1 μg/kg/min). Hemodynamic responders (those with ≥4 mm Hg reduction of exercise-PCWP) were randomized (double blind) to weekly levosimendan infusion (0.075 to 0.1 ug/kg/min for 24 h) or placebo for 5 additional weeks. The primary end point was exercise-PCWP, and key secondary end points included 6MWD and PCWP measured across all exercise stages.

Results: Thirty-seven of 44 patients (84%) met responder criteria and were randomized to levosimendan (n = 18) or placebo (n = 19). Participants were 69 ± 9 years of age, 61% female, and with resting mPAP 41.0 ± 9.3 mm Hg and exercise-PCWP 36.8 ± 11.3 mm Hg. Compared with placebo, levosimendan did not significantly reduce the primary end point of exercise-PCWP at 6 weeks (-1.4 mm Hg; 95% confidence interval [CI]: -7.8 to 4.8; p = 0.65). However, levosimendan reduced PCWP measured across all exercise stages (-3.9 ± 2.0 mm Hg; p = 0.047). Levosimendan treatment resulted in a 29.3 m (95% CI: 2.5 to 56.1; p = 0.033) improvement in 6MWD compared with placebo.

Conclusions: Six weeks of once-weekly levosimendan infusion did not affect exercise-PCWP but did reduce PCWP incorporating data from rest and exercise, in tandem with increased 6MWD. Further study of levosimendan is warranted as a therapeutic option for PH-HFpEF. (Hemodynamic Evaluation of Levosimendan in Patients With PH-HFpEF [HELP]; NCT03541603).
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http://dx.doi.org/10.1016/j.jchf.2021.01.015DOI Listing
May 2021

The Prognostic Value of Right Atrial Strain Imaging in Patients with Precapillary Pulmonary Hypertension.

J Am Soc Echocardiogr 2021 08 24;34(8):851-861.e1. Epub 2021 Mar 24.

Division of Cardiology, Washington University in St. Louis, St. Louis, Missouri; Penn State University College of Medicine, Hershey Medical Center, Hershey, Pennsylvania. Electronic address:

Background: Right ventricular (RV) failure in patients with pulmonary hypertension (PH) is associated with unfavorable clinical events and a poor prognosis. Elevation of right atrial (RA) pressure is established as a marker for RV failure. However, the additive prognostic value of RA mechanical function is unclear.

Methods: The authors tested the hypothesis that RA function by strain echocardiography has prognostic usefulness by studying 165 consecutive patients with precapillary PH defined invasively: mean pulmonary artery pressure ≥ 25 mm Hg and pulmonary capillary wedge pressure < 15 mm Hg. Speckle-tracking strain analyses of the right atrium and right ventricle were performed, along with routine measures. Peak RA strain values from six segments using generic speckle-tracking software were averaged to RA peak longitudinal strain, representing RA global reservoir function. The primary end point was all-cause mortality during 5 years of follow-up. RA strain was similarly analyzed in a control group of 16 normal subjects for comparison.

Results: There were 151 patients with PH (mean age, 55 ± 16 years; 73% women; mean World Health Organization functional class, 2.6 ± 0.6), after 14 exclusions (three with atrial septal defects and 11 with left ventricular ejection fractions < 50%). RA strain measurement was feasible in 93% of patients and RV strain measurement in 88%. RA peak longitudinal strain was significantly reduced in patients with PH compared with control subjects, as expected (P < .001). During 5-year follow-up, 73 patients (48%) died. Patients with RA peak strain in the lowest quartile (<25%) had a significant risk for death (P = .006), even after correcting for confounding variables. RA strain was independently associated with survival in multivariate analysis (P = .039) and had additive prognostic value to RV strain (log-rank P = .01) in subgroup analysis.

Conclusions: RA peak longitudinal strain had additive prognostic usefulness to other clinical measures, including RV strain, RA area, and RA pressure, in patients with PH. RA mechanical function by strain imaging has potential for clinical applications in patients with PH.
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http://dx.doi.org/10.1016/j.echo.2021.03.007DOI Listing
August 2021

Creation and Validation of a Novel Sex-Specific Mortality Risk Score in LVAD Recipients.

J Am Heart Assoc 2021 04 25;10(7):e020019. Epub 2021 Mar 25.

Division of Cardiology Department of Medicine Emory Clinical Cardiovascular Research InstituteEmory University School of Medicine Atlanta GA.

Background Prior studies have shown that women have worse 3-month survival after receiving a left ventricular assist device compared with men. Currently used prognostic scores, including the Heartmate II Risk Score, do not account for the increased residual risk in women. We used the IMACS (International Society for Heart and Lung Transplantation Mechanically Assisted Circulatory Support) registry to create and validate a sex-specific risk score for early mortality in left ventricular assist device recipients. Methods and Results Adult patients with a continuous-flow LVAD from the IMACS registry were randomly divided into a derivation cohort (DC; n=9113; 21% female) and a validation cohort (VC; n=6074; 21% female). The IMACS Risk Score was developed in the DC to predict 3-month mortality, from preoperative candidate predictors selected using the Akaike information criterion, or significant sex × variable interaction. In the DC, age, cardiogenic shock at implantation, body mass index, blood urea nitrogen, bilirubin, hemoglobin, albumin, platelet count, left ventricular end-diastolic diameter, tricuspid regurgitation, dialysis, and major infection before implantation were retained as significant predictors of 3-month mortality. There was significant ischemic heart failure × sex and platelet count × sex interaction. For each quartile increase in IMACS risk score, men (odds ratio [OR], 1.86; 95% CI, 1.74-2.00; <0.0001), and women (OR, 1.93; 95% CI, 1.47-2.59; <0.0001) had higher odds of 3-month mortality. The IMACS risk score represented a significant improvement over Heartmate II Risk Score (IMACS risk score area under the receiver operating characteristic curve: men: DC, 0.71; 95% CI, 0.69-0.73; VC, 0.69; 95% CI, 0.66-0.72; women: DC, 0.73; 95% CI, 0.70-0.77; VC, 0.71 [95% CI, 0.66-0.76; <0.01 for improvement in receiver operating characteristic) and provided excellent risk calibration in both sexes. Removal of sex-specific interaction terms resulted in significant loss of model fit. Conclusions A sex-specific risk score provides excellent risk prediction in LVAD recipients.
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http://dx.doi.org/10.1161/JAHA.120.020019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174331PMC
April 2021

Right ventricular load and contractility in HIV-associated pulmonary hypertension.

PLoS One 2021 23;16(2):e0243274. Epub 2021 Feb 23.

Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States of America.

Background: People living with human immunodeficiency virus (PLWH) are at risk of developing pulmonary hypertension (PH) and right ventricular (RV) dysfunction, but understanding of the relationship of RV function to afterload (RV-PA coupling) is limited. We evaluated the clinical and hemodynamic characteristics of human immunodeficiency virus (HIV)-associated PH.

Methods: We performed a retrospective review of patients with a diagnosis of HIV undergoing right heart catheterization (RHC) from 2000-2016 in a tertiary care center. Inclusion criteria were diagnosis of HIV, age ≥ 18 years and availability of RHC data. PH was classified as either pulmonary arterial hypertension (PAH; mean pulmonary arterial pressure [mPAP] ≥ 25mmHg with pulmonary artery wedge pressure [PAWP] ≤ 15mmHg) or pulmonary venous hypertension (PVH; mPAP ≥ 25mmHg with PAWP > 15). We collected demographics, CD4 cell count, HIV viral load, RHC and echocardiographic data. The single beat method was used to calculate RV-PA coupling from RHC.

Results: Sixty-two PLWH with a clinical likelihood for PH underwent RHC. Thirty-two (52%) met PH criteria (15 with PAH, 17 with PVH). Average time from diagnosis of HIV to diagnosis of PH was 11 years. Eleven of 15 individuals with PAH were on antiretroviral therapy (ART) while all 17 patients with PVH were on ART. Compared to PLWH without PH, those with PH had an increased likelihood of having a detectable HIV viral load and lower CD4 cell counts. PLWH with PAH or PVH had increased RV afterload with normal RV contractility, and preserved RV-PA coupling.

Conclusion: PLWH with PH (PAH or PVH) were more likely to have a detectable HIV viral load and lower CD4 count at the time of RHC. PLWH with PAH or PVH had increased RV afterload, normal RV contractility, with preserved RV-PA coupling suggestive of an early onset, mild, and compensated form of PH. These results should be confirmed in larger studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243274PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901734PMC
July 2021

An exploratory assessment of stretch-induced transmural myocardial fiber kinematics in right ventricular pressure overload.

Sci Rep 2021 02 11;11(1):3587. Epub 2021 Feb 11.

Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA.

Right ventricular (RV) remodeling and longitudinal fiber reorientation in the setting of pulmonary hypertension (PH) affects ventricular structure and function, eventually leading to RV failure. Characterizing the kinematics of myocardial fibers helps better understanding the underlying mechanisms of fiber realignment in PH. In the current work, high-frequency ultrasound imaging and structurally-informed finite element (FE) models were employed for an exploratory evaluation of the stretch-induced kinematics of RV fibers. Image-based experimental evaluation of fiber kinematics in porcine myocardium revealed the capability of affine assumptions to effectively approximate myofiber realignment in the RV free wall. The developed imaging framework provides a noninvasive modality to quantify transmural RV myofiber kinematics in large animal models. FE modeling results demonstrated that chronic pressure overload, but not solely an acute rise in pressures, results in kinematic shift of RV fibers towards the longitudinal direction. Additionally, FE simulations suggest a potential protective role for concentric hypertrophy (increased wall thickness) against fiber reorientation, while eccentric hypertrophy (RV dilation) resulted in longitudinal fiber realignment. Our study improves the current understanding of the role of different remodeling events involved in transmural myofiber reorientation in PH. Future experimentations are warranted to test the model-generated hypotheses.
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http://dx.doi.org/10.1038/s41598-021-83154-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878470PMC
February 2021

Induced bioresistance via BNP detection for machine learning-based risk assessment.

Biosens Bioelectron 2021 Mar 16;175:112903. Epub 2020 Dec 16.

Department of Electrical and Computer Engineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA, 15261, USA. Electronic address:

Machine Learning (ML) is a powerful tool for big data analysis that shows substantial potential in the field of healthcare. Individual patient data can be inundative, but its value can be extracted by ML's predictive power and ability to find trends. A great area of interest is early diagnosis and disease management strategies for cardiovascular disease (CVD), the leading cause of death in the world. Treatment is often inhibited by analysis delays, but rapid testing and determination can help improve frequency for real time monitoring. In this research, an ML algorithm was developed in conjunction with a flexible BNP sensor to create a quick diagnostic tool. The sensor was fabricated as an ion-selective field effect transistor (ISFET) in order to be able to quickly gather large amounts of electrical data from a sample. Artifical samples were tested to characterize the sensors using linear sweep voltammetry, and the resulting data was utilized as the initial training set for the ML algorithm, an implementation of quadratic discriminant analysis (QDA) written in MATLAB. Human blood serum samples from 30 University of Pittsburgh Medical Center (UPMC) patients were tested to evaluate the effective sorting power of the algorithm, yielding 95% power in addition to ultra fast data collection and determination.
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http://dx.doi.org/10.1016/j.bios.2020.112903DOI Listing
March 2021

SCUBE1 Controls BMPR2-Relevant Pulmonary Endothelial Function: Implications for Diagnostic Marker Development in Pulmonary Arterial Hypertension.

JACC Basic Transl Sci 2020 Nov 4;5(11):1073-1092. Epub 2020 Nov 4.

Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology and Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

Utilizing publicly available ribonucleic acid sequencing data, we identified as a BMPR2-related gene differentially expressed between induced pluripotent stem cell-endothelial cells derived from pulmonary arterial hypertension (PAH) patients carrying pathogenic BMPR2 mutations and control patients without mutations. Endothelial SCUBE1 expression was decreased by known triggers of PAH, and its down-regulation recapitulated known BMPR2-associated endothelial pathophenotypes in vitro. Meanwhile, SCUBE1 concentrations were reduced in plasma obtained from PAH rodent models and patients with PAH, whereas plasma concentrations were tightly correlated with hemodynamic markers of disease severity. Taken together, these data implicate SCUBE1 as a novel contributor to PAH pathogenesis with potential therapeutic, diagnostic, and prognostic applications.
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http://dx.doi.org/10.1016/j.jacbts.2020.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691287PMC
November 2020

Clinical Differences and Outcomes between Methamphetamine-associated and Idiopathic Pulmonary Arterial Hypertension in the Pulmonary Hypertension Association Registry.

Ann Am Thorac Soc 2021 04;18(4):613-622

Department of Medicine and.

Single-center studies demonstrated that methamphetamine use is associated with pulmonary arterial hypertension (Meth-APAH). We used the Pulmonary Hypertension Association Registry to evaluate the national distribution of Meth-APAH and to compare its impact on patient-reported and clinical outcomes relative to idiopathic PAH. To determine if patients with Meth-APAH differ from those with idiopathic PAH in demographics, regional distribution in the United States, hemodynamics, health-related quality of life, PAH-specific treatment, and health care use. The Pulmonary Hypertension Association Registry is a U.S.-based prospective cohort of patients new to care at a Pulmonary Hypertension Care Center. The registry collects baseline demographics, clinical parameters, and repeated measures of health-related quality of life, World Health Organization functional class, 6-minute walk distance, therapy, and health care use. Repeated measures of functional class, health-related quality of life, type of therapy, emergency department visits, and hospitalizations were compared using generalized estimating equations. Of 541 participants included, 118 had Meth-APAH; 83% of Meth-APAH arose in the western United States. The Meth-APAH group was younger and had a poorer socioeconomic status and lower cardiac index than the idiopathic PAH group, despite no difference in mean pulmonary artery pressure or pulmonary vascular resistance. The Meth-APAH group had a more advanced functional class in longitudinal models (0.22 points greater; 95% confidence interval [CI], 0.07 to 0.37) and worse PAH-specific (emPHasis-10) health-related quality of life (-5.4; 95% CI, -8.1 to -2.8). There was no difference in dual combination therapy; however, participants with Meth-APAH were less likely to be initiated on triple therapy (odds ratio [OR], 0.43; 95% CI, 0.24 to 0.77) or parenteral therapy (OR, 0.10; 95% CI, 0.04 to 0.24). Participants with Meth-APAH were more likely to seek care in the emergency department (incidence rate ratio, 2.30; 95% CI, 1.71 to 3.11) and more likely to be hospitalized (incidence rate ratio, 1.42; 95% CI, 1.10 to 1.83). Meth-APAH represents a unique clinical phenotype of PAH, most common in the western United States. It accounts for a notable proportion of PAH in expert centers. Assessment for methamphetamine use is necessary in patients with PAH.
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http://dx.doi.org/10.1513/AnnalsATS.202007-774OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174020PMC
April 2021

Gender Differences in Mortality After Left Ventricular Assist Device Implant: A Causal Mediation Analysis Approach.

ASAIO J 2021 06;67(6):614-621

From the Division of Cardiology, Department of Medicine, Emory Clinical Cardiovascular Research Institute, Emory University School of Medicine, Atlanta, Georgia.

We used the International Society for Heart and Lung Transplantation (ISHLT) Registry for Mechanically Assisted Circulatory Support (IMACS) database to examine 1) gender differences in post-left ventricular assist device (LVAD) mortality in the contemporary era and 2) preimplant clinical factors that might mediate any observed differences. Adults who received continuous-flow (CF)-LVAD from January 2013 to September 2017 (n = 9,565, age: 56.2 ± 13.2 years, 21.6% female, 31.1% centrifugal pumps) were analyzed. An inverse probability weighted Cox proportional hazards model was used to estimate association of female gender with all-cause mortality, adjusting for known covariates. Causal mediation analysis was performed to test plausible preimplant mediators mechanistically underlying any association between female gender and mortality. Females had higher mortality after LVAD (adjusted hazard ratio [HR]: 1.36; p < 0.0001), with significant gender × time interaction (p = 0.02). An early period of increased risk was identified, with females experiencing a higher risk of mortality during the first 4 months after implant (adjusted HR: 1.74; p < 0.0001), but not after (adjusted HR: 1.18; p = 0.16). More severe tricuspid regurgitation and smaller left ventricular end-diastolic diameter at baseline mediated ≈21.9% of the increased early hazard of death in females; however, most of the underlying mechanisms remain unexplained. Therefore, females have increased mortality only in the first 4 months after LVAD implantation, partially driven by worsening right ventricular dysfunction and LV-LVAD size mismatch.
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http://dx.doi.org/10.1097/MAT.0000000000001288DOI Listing
June 2021

Nationwide variability in the use of induction immunosuppression for adult heart transplantation.

J Card Surg 2020 Nov 5;35(11):3053-3061. Epub 2020 Oct 5.

Division of Cardiac Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

Background: Institutional factors have been shown to impact outcomes following orthotopic heart transplantation (OHT). This study evaluated center variability in the utilization of induction therapy for OHT and its implications on clinical outcomes.

Methods: Adult OHT patients between 2010 and 2018 were identified from the United Network for Organ Sharing registry. Transplant centers were stratified based on their rates of induction therapy utilization. Mixed-effects logistic regression models were created with drug-treated rejection within 1 year as primary endpoint and individual centers as a random parameter. Risk-adjusted Cox regression was used to evaluate patient-level mortality outcomes.

Results: In 17,524 OHTs performed at 100 centers, induction therapy was utilized in 48.6% (n = 8411) with substantial variability between centers (interquartile range, 21.4%-79.1%). There were 36, 30, and 34 centers in the low (<29%), intermediate (29%-66%), and high (>67%) induction utilization terciles groups, respectively. Induction therapy did not account for the observed variability in the treated rejection rate at 1 year among centers after adjusting for donor and recipient factors (p = .20). No differences were observed in postoperative outcomes among induction utilization centers groups (all, p > .05). Furthermore, there was a weak correlation between the percentage of induction therapy utilization at the center-level and recipients found to have moderate (r = .03) or high (r = .04) baseline risks for acute rejection at 1 year.

Conclusions: This analysis demonstrates that there is substantial variability in the use of induction therapy among OHT centers. In addition, there was a minimal correlation with baseline recipient risk or 1-year rejection rates, suggesting a need for better-standardized practices for induction therapy use in OHT.
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http://dx.doi.org/10.1111/jocs.15075DOI Listing
November 2020

PROVIDE-HF primary results: Patient-Reported Outcomes inVestigation following Initiation of Drug therapy with Entresto (sacubitril/valsartan) in heart failure.

Am Heart J 2020 12 24;230:35-43. Epub 2020 Sep 24.

Duke Clinical Research Institute, Durham, NC; Duke University School of Medicine, Durham, NC.

Background: In PARADIGM-HF, sacubitril/valsartan improved quality of life (QOL) versus enalapril in heart failure with reduced ejection fraction (HFrEF), yet limited data are available regarding QOL changes after sacubitril/valsartan initiation in routine practice.

Methods: PROVIDE-HF was a prospective study within a national research network (Patient-Centered Outcomes Research Network) of HFrEF outpatients recently initiated on sacubitril/valsartan versus controls with recent angiotensin-converting enzyme inhibitor/angiotensin receptor blocker initiation/dose change. The primary end point was mean Kansas City Cardiomyopathy Questionnaire (KCCQ) change through 12 weeks. Other end points included responder analyses: ≥5-point and ≥20-point KCCQ increase. Adjusted QOL change was estimated after propensity score weighting.

Results: Overall, 270 patients had both baseline and 12-week KCCQ data (151 sacubitril/valsartan; 119 control). The groups had similar demographics and HF details: median EF 28% and N-terminal pro-brain natriuretic peptide 1083 pg/mL. Sacubitril/valsartan patients had larger improvements in KCCQ (mean difference +4.76; P = .027) and were more likely to have a ≥5-point and ≥20-point response (all P < .05). Adjusted comparisons demonstrated similar numerical improvements in the change in KCCQ (+4.55; 95% CI -0.89 to 9.99; P = .101) and likelihood of ≥5-point increase (odds ratio 1.55; 95% CI: 0.84-2.86; P = .16); ≥20-point increase remained statistically significant (odds ratio 3.79; 95% CI 1.47-9.73; P = .006).

Conclusions: In this prospective HFrEF study of sacubitril/valsartan initiation compared with recent angiotensin-converting enzyme inhibitor/angiotensin receptor blocker initiation/dose change, the between-group difference in the primary end point, mean KCCQ change at 12 weeks was not statistically significant following adjustment, but sacubitril/valsartan initiation was associated with early improvements in QOL and a higher likelihood of ≥20-point improvement in KCCQ at 12 weeks. These data add additional real-world evidence related to patient-reported outcomes following the initiation of sacubitril/valsartan in routine clinical practice.
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http://dx.doi.org/10.1016/j.ahj.2020.09.012DOI Listing
December 2020

Metformin in Pulmonary Hypertension in Left Heart Disease.

Front Med (Lausanne) 2020 19;7:425. Epub 2020 Aug 19.

Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, United States.

Metformin is ubiquitously used in the management of Type II Diabetes Mellitus (DMII). Over the years, our growing knowledge of its therapeutic potential has broadened its use to the treatment of infertility in polycystic ovarian syndrome, gestational diabetes, and even obesity. Recently, it has been suggested as a novel therapy in cardiovascular disease (CVD). Given that CVD is the leading cause of death in patients with DMII, with ~ 75% dying from a cardiovascular event, the intersection of DMII and CVD provides a unique therapeutic target. In particular, pulmonary hypertension (PH) related to CVD (Group II PH) may be an optimal target for metformin therapy. The objective of this review article is to provide an overview of the pathophysiology of PH related to left heart disease (PH-LHD), outline the proposed pathophysiologic mechanism of insulin resistance in heart failure and PH-LHD, and evaluate the role metformin may have in heart failure and PH-LHD.
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http://dx.doi.org/10.3389/fmed.2020.00425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466644PMC
August 2020

Diversity, Equity, and Inclusiveness in Medicine and Cardiology: Next Steps for .

J Am Heart Assoc 2020 10 17;9(20):e019307. Epub 2020 Sep 17.

Department of Biostatistics Boston University School of Public Health Boston MA USA.

We, the Editors of the , sincerely regret the publication of the article "Diversity, Inclusion, and Equity: Evolution of Race and Ethnicity Considerations for the Cardiology Workforce in the United States of America From 1969 to 2019". We are aware that the publication of this flawed and biased article has caused a great deal of unnecessary pain and anguish to a number of parties, and reflects extremely poorly on us. We fully support the retraction of this article.
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http://dx.doi.org/10.1161/JAHA.120.019307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763382PMC
October 2020

Clearing Our Vision for Discerning Precapillary From Postcapillary Pulmonary Hypertension With the OPTICS Risk Score.

J Am Heart Assoc 2020 08 31;9(15):e017685. Epub 2020 Jul 31.

Département de Cardiologie Cliniques Universitaires de Bruxelles-Hôpital Erasme Brussels Belgium.

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http://dx.doi.org/10.1161/JAHA.120.017685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792237PMC
August 2020

Angiotensin Receptor-Neprilysin Inhibition Attenuates Right Ventricular Remodeling in Pulmonary Hypertension.

J Am Heart Assoc 2020 07 18;9(13):e015708. Epub 2020 Jun 18.

Department of BioengineeringUniversity of PittsburghPA.

BackgroundPulmonary hypertension (PH) results in increased right ventricular (RV) afterload and ventricular remodeling. Sacubitril/valsartan (sac/val) is a dual acting drug, composed of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker valsartan, that has shown promising outcomes in reducing the risk of death and hospitalization for chronic systolic left ventricular heart failure. In this study, we aimed to examine if angiotensin receptor-neprilysin inhibition using sac/val attenuates RV remodeling in PH.Methods and ResultsRV pressure overload was induced in Sprague-Dawley rats via banding the main pulmonary artery. Three different cohorts of controls, placebo-treated PH, and sac/val-treated PH were studied in a 21-day treatment window. Terminal invasive hemodynamic measurements, quantitative histological analysis, biaxial mechanical testing, and constitutive modeling were employed to conduct a multiscale analysis on the effects of sac/val on RV remodeling in PH. Sac/val treatment decreased RV maximum pressures (29% improvement, =0.002), improved RV contractile (30%, =0.012) and relaxation (29%, =0.043) functions, reduced RV afterload (35% improvement, =0.016), and prevented RV-pulmonary artery uncoupling. Furthermore, sac/val attenuated RV hypertrophy (16% improvement, =0.006) and prevented transmural reorientation of RV collagen and myofibers (=0.011). The combined natriuresis and vasodilation resulting from sac/val led to improved RV biomechanical properties and prevented increased myofiber stiffness in PH (61% improvement, =0.032).ConclusionsSac/val may prevent maladaptive RV remodeling in a pressure overload model via amelioration of RV pressure rise, hypertrophy, collagen, and myofiber reorientation as well as tissue stiffening both at the tissue and myofiber level.
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http://dx.doi.org/10.1161/JAHA.119.015708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670537PMC
July 2020

The Effects of Inhaled Sodium Nitrite on Pulmonary Vascular Impedance in Patients With Pulmonary Hypertension Associated with Heart Failure With Preserved Ejection Fraction.

J Card Fail 2020 Aug 22;26(8):654-661. Epub 2020 May 22.

Department of Bioengineering; Vascular Medicine Institute; Division of Pulmonary, Allergy and Critical Care Medicine; Division of Cardiology and Heart and Vascular Institute. Electronic address:

Background: The severity of pulmonary hypertension (PH) is monitored by measuring pulmonary vascular resistance, which is a steady-state measurement and ignores the pulsatile load encountered by the right ventricle (RV). Pulmonary vascular impedance (PVZ) can depict both steady-state and pulsatile forces, and thus may better predict clinical outcomes. We sought to calculate PVZ in patients with PH associated with heart failure with preserved ejection fraction who were administered inhaled sodium nitrite to better understand the acute effects on afterload.

Methods And Results: Fourteen patients with PH associated with heart failure with preserved ejection fraction underwent right heart catherization and were administered inhaled sodium nitrite. A Fourier transform was used to calculate PVZ for both before and after nitrite for comparison. Inhaled sodium nitrite decreased characteristic impedance (inversely related to proximal pulmonary artery compliance) and total work performed by the RV. RV efficiency improved, defined by a reduction in the total work divided by cardiac output. There was a mild decrease in pulmonary steady-state resistance after the administration of inhaled sodium nitrite, but this effect was not significant.

Conclusions: PVZ analysis showed administration of inhaled sodium nitrite was associated with an improvement in pulmonary vascular compliance via a decrease in characteristic impedance, more so than pulmonary steady-state resistance. This effect was associated with improved RV efficiency and total work.
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http://dx.doi.org/10.1016/j.cardfail.2020.04.006DOI Listing
August 2020

The Preimplantation Psychosocial Evaluation and Prediction of Clinical Outcomes During Mechanical Circulatory Support: What Information Is Most Prognostic?

Transplantation 2021 03;105(3):608-619

Heart and Vascular Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, PA.

Background: Psychosocial evaluations are required for long-term mechanical circulatory support (MCS) candidates, no matter whether MCS will be destination therapy (DT) or a bridge to heart transplantation. Although guidelines specify psychosocial contraindications to MCS, there is no comprehensive examination of which psychosocial evaluation domains are most prognostic for clinical outcomes. We evaluated whether overall psychosocial risk, determined across all psychosocial domains, predicted outcomes, and which specific domains appeared responsible for any effects.

Methods: A single-site retrospective analysis was performed for adults receiving MCS between April 2004 and December 2017. Using an established rating system, we coded psychosocial evaluations to identify patients at low, moderate, or high overall risk. We similarly determined risk within each of 10 individual psychosocial domains. Multivariable analyses evaluated whether psychosocial risk predicted clinical decisions about MCS use (DT versus bridge), and postimplantation mortality, transplantation, rehospitalization, MCS pump exchange, and standardly defined adverse medical events (AEs).

Results: In 241 MCS recipients, greater overall psychosocial risk increased the likelihood of a DT decision (odds ratio, 1.76; P = 0.017); and postimplantation pump exchange and occurrence of AEs (hazard ratios [HRs] ≥ 1.25; P ≤ 0.042). The individual AEs most strongly predicted were cardiac arrhythmias and device malfunctions (HRs ≥ 1.39; P ≤ 0.032). The specific psychosocial domains predicting at least 1 study outcome were mental health problem severity, poorer medical adherence, and substance use (odds ratios and HRs ≥ 1.32; P ≤ 0.010).

Conclusions: The psychosocial evaluation predicts not only clinical decisions about MCS use (DT versus bridge) but important postimplantation outcomes. Strategies to address psychosocial risk factors before or soon after implantation may help to reduce postimplantation clinical risks.
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http://dx.doi.org/10.1097/TP.0000000000003287DOI Listing
March 2021

Outcomes of Pulmonary Arterial Hypertension Are Improved in a Specialty Care Center.

Chest 2020 07 25;158(1):330-340. Epub 2020 Feb 25.

Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA; Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Pittsburgh, PA; Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA. Electronic address:

Background: Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressures and is managed by vasodilator therapies. Current guidelines encourage PAH management in specialty care centers (SCCs), but evidence is sparse regarding improvement in clinical outcomes and correlation to vasodilator use with referral.

Research Question: Is PAH management at SCCs associated with improved clinical outcomes?

Study Designand Methods: A single-center, retrospective study was performed at the University of Pittsburgh Medical Center (UPMC; overseeing 40 hospitals). Patients with PAH were identified between 2008 and 2018 and classified into an SCC or non-SCC cohort. Cox proportional hazard modeling was done to compare for all-cause mortality, as was negative binomial regression modeling for hospitalizations. Vasodilator therapy was included to adjust outcomes.

Results: Of 580 patients with PAH at UPMC, 455 (78%) were treated at the SCC, comprising a younger (58.8 vs 64.8 years; P < .001) and more often female (68.4% vs 51.2%; P < .001) population with more comorbidities without differences in race or income. SCC patients demonstrated improved survival (hazard ratio, 0.68; P = .012) and fewer hospitalizations (incidence ratio, 0.54; P < .001), and provided more frequent disease monitoring. Early patient referral to SCC (< 6 months from time of diagnosis) was associated with improved outcomes compared with non-SCC patients. SCC patients were more frequently prescribed vasodilators (P < .001) and carried more diagnostic PAH coding (P < .001). Vasodilators were associated with improved outcomes irrespective of location but without statistical significance when comparing between locations (P > .05).

Interpretation: The UPMC SCC demonstrated improved outcomes in mortality and hospitalizations. The SCC benefit was multifactorial, with more frequent vasodilator therapy and disease monitoring. These findings provide robust evidence for early and regular referral of patients with PAH to SCCs.
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http://dx.doi.org/10.1016/j.chest.2020.01.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339236PMC
July 2020

mTORC1 in Pulmonary Arterial Hypertension. At the Crossroads between Vasoconstriction and Vascular Remodeling?

Am J Respir Crit Care Med 2020 05;201(10):1177-1179

Division of Pulmonary, Critical Care, and Sleep MedicineUniversity of California, San DiegoLa Jolla, California.

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http://dx.doi.org/10.1164/rccm.202001-0087EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233339PMC
May 2020

Use of Tricuspid Annular Plane Systolic Excursion/Pulmonary Artery Systolic Pressure As a Non-Invasive Method to Assess Right Ventricular-PA Coupling in Patients With Pulmonary Hypertension.

Circ Cardiovasc Imaging 2019 09 10;12(9):e009648. Epub 2019 Sep 10.

Division of Cardiology, Department of Medicine, University of Pittsburgh Medical Center, Pennsylvania (M.J.B., M.A.S.).

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http://dx.doi.org/10.1161/CIRCIMAGING.119.009648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859895PMC
September 2019
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