Publications by authors named "Jane A Leopold"

127 Publications

Digital health device measured sleep duration and ideal cardiovascular health: an observational study.

BMC Cardiovasc Disord 2021 10 14;21(1):497. Epub 2021 Oct 14.

Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, NRB0630K, Boston, MA, 02115, USA.

Background: Studies relying on self-reported sleep data suggest that there is an association between short and long sleep duration and less than ideal cardiovascular health. Evidence regarding the feasibility of using digital health devices to measure sleep duration and assess its relationship to ideal cardiovascular health are lacking. The objective of the present study was to utilize digital health devices to record sleep duration and examine the relationship between sleep duration and ideal cardiovascular health.

Methods: A total of 307 participants transmitted sleep duration data from digital health devices and answered the Life's Simple 7 survey instrument to assess ideal cardiovascular health. Sleep duration was defined as adequate (7 to < 9 h per night) or non-adequate (< 7 h and ≥ 9 h).

Results: We identified three sleep-cardiovascular health phenogroups: resilient (non-adequate sleep and ideal cardiovascular health), uncoupled (adequate sleep and non-ideal cardiovascular health) or concordant (sleep and cardiovascular health metrics were aligned). Participants in the resilient phenogroup (n = 83) had better cardiovascular health factor profiles (blood pressure, blood glucose and cholesterol levels) and behaviors (healthy weight, diet, exercise, smoking) than participants in the concordant (n = 171) and uncoupled (n = 53) phenogroups. This was associated with higher Life's Simple 7 Health Scores in the resilient phenogroup compared to the concordant and uncoupled phenogroups (7.8 ± 0.8 vs. 7.0 ± 1.4 vs. 5.6 ± 0.7, P < 0.01).

Conclusion: This study identified three distinct sleep-ideal cardiovascular health phenogroups and highlights the advantage of incorporating sleep assessments into studies of cardiovascular health. Future studies should focus on the relationship between sleep-cardiovascular phenogroups and clinical outcomes. Clinical Trial Registration Clinicaltrials.gov NCT02958098. Date of registration: November 11, 2016.
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http://dx.doi.org/10.1186/s12872-021-02284-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8518231PMC
October 2021

Inflammation and Heart Failure: Friend or Foe?

Circulation 2021 Oct 11;144(15):1241-1243. Epub 2021 Oct 11.

Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (J.A.L.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.056628DOI Listing
October 2021

Initial Triple Pharmacotherapy in Pulmonary Arterial Hypertension: Is More Necessarily Better?

Authors:
Jane A Leopold

J Am Coll Cardiol 2021 Oct;78(14):1404-1406

Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jacc.2021.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8637933PMC
October 2021

Diagnosis and Treatment of Right Heart Failure in Pulmonary Vascular Diseases: A National Heart, Lung, and Blood Institute Workshop.

Circ Heart Fail 2021 06 15;14(6). Epub 2021 Jun 15.

Division of Lung Diseases, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD.

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 Institute (NHLBI) commissioned a working group to identify current challenges in the field. These included a need to define and standardize normal RV structure and function in populations; access to RV tissue for research purposes and the development of complex experimental platforms that recapitulate the environment; and the advancement of imaging and invasive methodologies to study the RV within basic, translational, and clinical research programs. Specific recommendations were provided, including a call to incorporate precision medicine and innovations in prognosis, diagnosis, and novel RV therapeutics for patients with pulmonary vascular disease.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.007975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375628PMC
June 2021

Nanoparticle-Facilitated Gene Delivery in Congenital Pulmonary Vascular Disease: Roadmap for Other Forms of Pulmonary Hypertension.

Authors:
Jane A Leopold

Circulation 2021 Aug 16;144(7):556-558. Epub 2021 Aug 16.

Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.055345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371906PMC
August 2021

A precision medicine approach to sex-based differences in ideal cardiovascular health.

Sci Rep 2021 07 21;11(1):14848. Epub 2021 Jul 21.

Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, NRB0630K, Boston, MA, 02115, USA.

Cardiovascular disease risk factor profiles and health behaviors are known to differ between women and men. Sex-based differences in ideal cardiovascular health were examined in the My Research Legacy study, which collected cardiovascular health and lifestyle data via Life's Simple 7 survey and digital health devices. As the study overenrolled women (n = 1251) compared to men (n = 310), we hypothesized that heterogeneity among women would affect comparisons of ideal cardiovascular health. We identified 2 phenogroups of women in our study cohort by cluster analysis. The phenogroups differed significantly across all 7 cardiovascular health and behavior domains (all p < 0.01) with women in phenogroup 1 having a lower Life's Simple 7 Health Score than those in phenogroup 2 (5.9 ± 1.3 vs. 7.6 ± 1.3, p < 0.01). Compared to men, women in phenogroup 1 had a higher burden of cardiovascular disease risk factors, exercised less, and had lower ideal cardiovascular health scores (p < 0.01). In contrast, women in phenogroup 2 had fewer cardiovascular risk factors but similar exercise habits and higher ideal cardiovascular health scores than men (p < 0.01). These findings suggest that heterogeneity among study participants should be examined when evaluating sex-based differences in ideal cardiovascular health.
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http://dx.doi.org/10.1038/s41598-021-93966-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295282PMC
July 2021

Quantification of Arterial and Venous Morphologic Markers in Pulmonary Arterial Hypertension Using CT Imaging.

Chest 2021 Jul 13. Epub 2021 Jul 13.

Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Background: Pulmonary hypertension is a heterogeneous disease, and a significant portion of patients at risk for it have CT imaging available. Advanced automated processing techniques could be leveraged for early detection, screening, and development of quantitative phenotypes. Pruning and vascular tortuosity have been previously described in pulmonary arterial hypertension (PAH), but the extent of these phenomena in arterial vs venous pulmonary vasculature and in exercise pulmonary hypertension (ePH) have not been described.

Research Question: What are the arterial and venous manifestations of pruning and vascular tortuosity using CT imaging in PAH, and do they also occur in ePH?

Study Design And Methods: A cohort of patients with PAH and ePH and control subjects with available CT angiograms were retrospectively identified to examine the differential arterial and venous presence of pruning and tortuosity in patients with precapillary pulmonary hypertension not confounded by lung or thromboembolic disease. The pulmonary vasculature was reconstructed, and an AI method was used to separate arteries and veins and to compute arterial and venous vascular volumes and tortuosity.

Results: A total of 42 patients with PAH, 12 patients with ePH, and 37 control subjects were identified. There was relatively lower (median [interquartile range]) arterial small vessel volume in subjects with PAH (PAH 14.7 [11.7-16.2; P < .0001]) vs control subjects (16.9 [15.6-19.2]) and venous small vessel volume in subjects with PAH and ePH (PAH 8.0 [6.5-9.6; P < .0001]; ePH, 7.8 [7.5-11.4; P = .004]) vs control subjects (11.5 [10.6-12.2]). Higher large arterial volume, however, was only observed in the pulmonary arteries (PAH 17.1 [13.6-23.4; P < .0001] vs control subjects 11.4 [8.1-15.4]). Similarly, tortuosity was higher in the pulmonary arteries in the PAH group (PAH 3.5 [3.3-3.6; P = .0002] vs control 3.2 [3.2-3.3]).

Interpretation: Lower small distal pulmonary vascular volume, higher proximal arterial volume, and higher arterial tortuosity were observed. These can be quantified by using automated techniques from clinically acquired CT scans of patients with ePH and resting PAH.
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http://dx.doi.org/10.1016/j.chest.2021.06.069DOI Listing
July 2021

Ideal Cardiovascular Health in Former Smokers.

J Clin Med 2021 Jun 1;10(11). Epub 2021 Jun 1.

Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.

Former smokers remain at increased risk for cardiovascular diseases compared to never smokers, but have lower risk than current smokers. We therefore hypothesized that former smokers would have an ideal cardiovascular health phenotype that was intermediate between current and never smokers. Differences in ideal cardiovascular health between never ( = 1025), former ( = 428), and current ( = 108) smokers were evaluated in the My Research Legacy study, which collected cardiovascular health data from the Life's Simple 7 survey and digital health devices. Former smokers had a higher burden of prevalent cardiovascular disease, hypertension, diabetes mellitus, and hypercholesterolemia compared to current and never smokers (all < 0.01). Former smokers' Life's Simple 7 Health Scores, a measure of ideal cardiovascular health, were intermediate between current and never smokers (4.9 ± 1.3 vs. 6.3 ± 1.5 vs. 7.0 ± 1.4, < 0.01). As former smokers shared similarities with both current and never smokers, we performed a cluster analysis, which identified two phenogroups of former smokers. The phenogroups differed significantly across all 7 cardiovascular health and behavior categories (all < 0.01). These findings suggest that former smokers are a heterogeneous group and increased attention to cardiovascular health factors and behaviors is warranted to achieve ideal cardiovascular health.
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http://dx.doi.org/10.3390/jcm10112450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198985PMC
June 2021

Comprehensive echocardiographic evaluation of the right heart in patients with pulmonary vascular diseases: the PVDOMICS experience.

Eur Heart J Cardiovasc Imaging 2021 Jun 7. Epub 2021 Jun 7.

Bluhm Cardiovascular Institute, Northwestern University, 676 N Saint Clair, Chicago Illinois 60611 USA.

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 Results: Echocardiography represents the primary non-invasive method to phenotype cardiac anatomy, function, and haemodynamics in these complex patients. However, comprehensive right heart evaluation requires the use of multiple echocardiographic parameters and optimized techniques to ensure optimal image acquisition. The PVDOMICS echo protocol outlines the best practice approach to echo phenotypic assessment of the right heart/pulmonary artery unit.

Conclusion: Novel workflow processes, methods for quality control, data for feasibility of measurements, and reproducibility of right heart parameters derived from this study provide a benchmark frame of reference. Lessons learned from this protocol will serve as a best practice guide for echocardiographic image acquisition and analysis across the spectrum of right heart/pulmonary vascular disease.
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http://dx.doi.org/10.1093/ehjci/jeab065DOI Listing
June 2021

NHLBI-CMREF Workshop Report on Pulmonary Vascular Disease Classification: JACC State-of-the-Art Review.

J Am Coll Cardiol 2021 04;77(16):2040-2052

Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

The National Heart, Lung, and Blood Institute and the Cardiovascular Medical Research and Education Fund held a workshop on the application of pulmonary vascular disease omics data to the understanding, prevention, and treatment of pulmonary vascular disease. Experts in pulmonary vascular disease, omics, and data analytics met to identify knowledge gaps and formulate ideas for future research priorities in pulmonary vascular disease in line with National Heart, Lung, and Blood Institute Strategic Vision goals. The group identified opportunities to develop analytic approaches to multiomic datasets, to identify molecular pathways in pulmonary vascular disease pathobiology, and to link novel phenotypes to meaningful clinical outcomes. The committee suggested support for interdisciplinary research teams to develop and validate analytic methods, a national effort to coordinate biosamples and data, a consortium of preclinical investigators to expedite target evaluation and drug development, longitudinal assessment of molecular biomarkers in clinical trials, and a task force to develop a master clinical trials protocol for pulmonary vascular disease.
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http://dx.doi.org/10.1016/j.jacc.2021.02.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065203PMC
April 2021

Non-invasive characterization of complex coronary lesions.

Sci Rep 2021 04 14;11(1):8145. Epub 2021 Apr 14.

Department of Biomedical Engineering, Duke University, Durham, NC, 27705, USA.

Conventional invasive diagnostic imaging techniques do not adequately resolve complex Type B and C coronary lesions, which present unique challenges, require personalized treatment and result in worsened patient outcomes. These lesions are often excluded from large-scale non-invasive clinical trials and there does not exist a validated approach to characterize hemodynamic quantities and guide percutaneous intervention for such lesions. This work identifies key biomarkers that differentiate complex Type B and C lesions from simple Type A lesions by introducing and validating a coronary angiography-based computational fluid dynamic (CFD-CA) framework for intracoronary assessment in complex lesions at ultrahigh resolution. Among 14 patients selected in this study, 7 patients with Type B and C lesions were included in the complex lesion group including ostial, bifurcation, serial lesions and lesion where flow was supplied by collateral bed. Simple lesion group included 7 patients with lesions that were discrete, [Formula: see text] long and readily accessible. Intracoronary assessment was performed using CFD-CA framework and validated by comparing to clinically measured pressure-based index, such as FFR. Local pressure, endothelial shear stress (ESS) and velocity profiles were derived for all patients. We validates the accuracy of our CFD-CA framework and report excellent agreement with invasive measurements ([Formula: see text]). Ultra-high resolution achieved by the model enable physiological assessment in complex lesions and quantify hemodynamic metrics in all vessels up to 1mm in diameter. Importantly, we demonstrate that in contrast to traditional pressure-based metrics, there is a significant difference in the intracoronary hemodynamic forces, such as ESS, in complex lesions compared to simple lesions at both resting and hyperemic physiological states [n = 14, [Formula: see text]]. Higher ESS was observed in the complex lesion group ([Formula: see text] Pa) than in simple lesion group ([Formula: see text] Pa). Complex coronary lesions have higher ESS compared to simple lesions, such differential hemodynamic evaluation can provide much the needed insight into the increase in adverse outcomes for such patients and has incremental prognostic value over traditional pressure-based indices, such as FFR.
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http://dx.doi.org/10.1038/s41598-021-86360-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047040PMC
April 2021

Data from Digital Health Devices Informs Ideal Cardiovascular Health.

J Pers Med 2021 Mar 10;11(3). Epub 2021 Mar 10.

Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.

Ideal cardiovascular health is associated with a decrease in adverse cardiovascular events. The My Research Legacy study examined ideal cardiovascular health using the Life's Simple 7 survey and data from digital health devices. We hypothesized that digital devices provide a more objective view of overall cardiovascular health status than self-reported measures. Therefore, we analyzed weight and activity data recorded by digital devices to recalculate the Life's Simple 7 Health Score. All study participants ( = 1561) answered the survey, while a subgroup ( = 390) provided data from digital devices. Individuals with digital devices had a lower body mass index (BMI) and higher weekly minutes of vigorous exercise than participants without digital devices ( < 0.01). Baseline Health Scores were higher in individuals with digital devices compared to those without (7.0 ± 1.6 vs. 6.6 ± 1.6, < 0.01). Data from digital devices reveal both increases and decreases in measured vs. self-reported BMI ( < 0.04) and weekly minutes of moderate and vigorous exercise activity ( < 0.01). Using these data, a significant difference was found between the recalculated and the self-reported Life's Simple 7 Health Score ( < 0.05). These findings suggest that incorporation of digital health devices should be considered as part of a precision medicinal approach to assessing ideal cardiovascular health.
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http://dx.doi.org/10.3390/jpm11030189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998383PMC
March 2021

Integrative Omics to Characterize and Classify Pulmonary Vascular Disease.

Clin Chest Med 2021 03 12;42(1):195-205. Epub 2021 Jan 12.

Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, T1218 Medical Center North, 1161 21st Avenue South, Nashville, TN 37232, USA.

Advances in high-throughput biotechnologies have facilitated omics profiling, a key component of precision phenotyping, in patients with pulmonary vascular disease. Omics provides comprehensive information pertaining to genes, transcripts, proteins, and metabolites. The resulting omics big datasets may be integrated for more robust results and are amenable to analysis using machine learning or newer analytical methodologies, such as network analysis. Results from fully integrated multi-omics datasets combined with clinical data are poised to provide novel insight into pulmonary vascular disease as well as diagnose the presence of disease and prognosticate outcomes.
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http://dx.doi.org/10.1016/j.ccm.2020.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875152PMC
March 2021

Inhibiting Jak2 Ameliorates Pulmonary Hypertension: Fulfilling the Promise of Precision Medicine.

Authors:
Jane A Leopold

Am J Respir Cell Mol Biol 2021 01;64(1):12-13

Brigham and Women's Hospital Harvard Medical School Boston, Massachusetts.

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http://dx.doi.org/10.1165/rcmb.2020-0384EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780993PMC
January 2021

Endocrine Delivery of MicroRNA-210: A Trusted Traveler That Mediates Pulmonary Hypertension.

Authors:
Jane A Leopold

Circ Res 2020 08 13;127(5):693-695. Epub 2020 Aug 13.

From the Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

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http://dx.doi.org/10.1161/CIRCRESAHA.120.317625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880541PMC
August 2020

PCSK9 and Calcific Aortic Valve Stenosis: Moving Beyond Lipids.

Authors:
Jane A Leopold

JACC Basic Transl Sci 2020 Jul 27;5(7):662-664. Epub 2020 Jul 27.

Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1016/j.jacbts.2020.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393421PMC
July 2020

Pulmonary vascular resistance and clinical outcomes in patients with pulmonary hypertension: a retrospective cohort study.

Lancet Respir Med 2020 09 27;8(9):873-884. Epub 2020 Jul 27.

Providence Veterans Affairs Medical Center, Providence, RI, USA; Division of Cardiovascular Medicine, Warren Alpert Medical School of Brown University, Providence, RI, USA.

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 pulmonary hypertension.

Methods: We did a retrospective cohort study of all patients undergoing right heart catheterisation (RHC) in the US Veterans Affairs health-care system (Oct 1, 2007-Sep 30, 2016). Patients were included in the analyses if data from a complete RHC and at least 1 year of follow-up were available. Both inpatients and outpatients were included, but individuals with missing mean pulmonary artery pressure (mPAP), pulmonary artery wedge pressure, or cardiac output were excluded. The primary outcome measure was time to all-cause mortality assessed by the Veteran Affairs vital status file. Cox proportional hazards models were used to assess the association between PVR and outcomes, and the mortality hazard ratio was validated in a RHC cohort from Vanderbilt University Medical Center (Sept 24, 1998-June 1, 2016).

Findings: The primary cohort (N=40 082; 38 751 [96·7%] male; median age 66·5 years [IQR 61·1-73·5]; median follow-up 1153 days [IQR 570-1971]), included patients with a history of heart failure (23 201 [57·9%]) and chronic obstructive pulmonary disease (13 348 [33·3%]). We focused on patients at risk for pulmonary hypertension based on a mPAP of at least 19 mm Hg (32 725 [81·6%] of 40 082). When modelled as a continuous variable, the all-cause mortality hazard for PVR was increased at around 2·2 Wood units compared with PVR of 1·0 Wood unit. Among patients with a mPAP of at least 19 mm Hg and pulmonary artery wedge pressure of 15 mm Hg or less, the adjusted hazard ratio (HR) for mortality was 1·71 (95% CI 1·59-1·84; p<0·0001) and for heart failure hospitalisation was 1·27 (1·13-1·43; p=0·0001), when comparing PVR of 2·2 Wood units or more to less than 2·2 Wood units. The validation cohort (N=3699, 1860 [50·3%] male, median age 60·4 years [49·5-69·2]; median follow-up 1752 days [IQR 1281-2999]) included 2870 patients [77·6%] with mPAP of at least 19 mm Hg (1418 [49·4%] male). The adjusted mortality HR for patients in the mPAP of 19 mm Hg or more group and with PVR of 2·2 Wood units or more and pulmonary artery wedge pressure of 15 mm or less Hg (1221 [42·5%] of 2870) was 1·81 (95% CI 1·33-2·47; p=0·0002).

Interpretation: These data widen the continuum of clinical risk for mortality and heart failure in patients referred for RHC with elevated pulmonary artery pressure to include PVR of around 2.2 Wood units and higher. Testing the generalisability of these findings in at-risk populations with fewer cardiopulmonary comorbidities is warranted.

Funding: None.
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http://dx.doi.org/10.1016/S2213-2600(20)30317-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219057PMC
September 2020

Editorial commentary: Premature peripheral arterial disease: A consequence of accelerated vascular aging due to less than ideal cardiovascular health?

Authors:
Jane A Leopold

Trends Cardiovasc Med 2021 08 9;31(6):359-360. Epub 2020 Jul 9.

Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, NRB0630K, Boston, MA 02115, United States. Electronic address:

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http://dx.doi.org/10.1016/j.tcm.2020.06.011DOI Listing
August 2021

Network determinants of cardiovascular calcification and repositioned drug treatments.

FASEB J 2020 08 8;34(8):11087-11100. Epub 2020 Jul 8.

Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Ectopic cardiovascular calcification is a highly prevalent pathology for which there are no effective novel or repurposed pharmacotherapeutics to prevent disease progression. We created a human calcification endophenotype module (ie, the "calcificasome") by mapping vascular calcification genes (proteins) to the human vascular smooth muscle-specific protein-protein interactome (218 nodes and 632 edges, P < 10 ). Network proximity analysis was used to demonstrate that the calcificasome overlapped significantly with endophenotype modules governing inflammation, thrombosis, and fibrosis in the human interactome (P < 0.001). A network-based drug repurposing analysis further revealed that everolimus, temsirolimus, and pomalidomide are predicted to target the calcificasome. The efficacy of these agents in limiting calcification was confirmed experimentally by treating human coronary artery smooth muscle cells in an in vitro calcification assay. Each of the drugs affected expression or activity of their predicted target in the network, and decreased calcification significantly (P < 0.009). An integrated network analytical approach identified novel mediators of ectopic cardiovascular calcification and biologically plausible candidate drugs that could be repurposed to target calcification. This methodological framework for drug repurposing has broad applicability to other diseases.
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http://dx.doi.org/10.1096/fj.202001062RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497212PMC
August 2020

Accelerating massively parallel hemodynamic models of coarctation of the aorta using neural networks.

Sci Rep 2020 06 11;10(1):9508. Epub 2020 Jun 11.

Department of Biomedical Engineering, Duke University, Durham, NC, USA.

Comorbidities such as anemia or hypertension and physiological factors related to exertion can influence a patient's hemodynamics and increase the severity of many cardiovascular diseases. Observing and quantifying associations between these factors and hemodynamics can be difficult due to the multitude of co-existing conditions and blood flow parameters in real patient data. Machine learning-driven, physics-based simulations provide a means to understand how potentially correlated conditions may affect a particular patient. Here, we use a combination of machine learning and massively parallel computing to predict the effects of physiological factors on hemodynamics in patients with coarctation of the aorta. We first validated blood flow simulations against in vitro measurements in 3D-printed phantoms representing the patient's vasculature. We then investigated the effects of varying the degree of stenosis, blood flow rate, and viscosity on two diagnostic metrics - pressure gradient across the stenosis (ΔP) and wall shear stress (WSS) - by performing the largest simulation study to date of coarctation of the aorta (over 70 million compute hours). Using machine learning models trained on data from the simulations and validated on two independent datasets, we developed a framework to identify the minimal training set required to build a predictive model on a per-patient basis. We then used this model to accurately predict ΔP (mean absolute error within 1.18 mmHg) and WSS (mean absolute error within 0.99 Pa) for patients with this disease.
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http://dx.doi.org/10.1038/s41598-020-66225-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289812PMC
June 2020

Comprehensive Diagnostic Evaluation of Cardiovascular Physiology in Patients With Pulmonary Vascular Disease: Insights From the PVDOMICS Program.

Circ Heart Fail 2020 03 24;13(3):e006363. Epub 2020 Feb 24.

Division of Pulmonary, Allergy, Critical Care & Sleep Medicine, Department of Medicine (F.P.R.).

Background: Invasive hemodynamic evaluation through right heart catheterization plays an essential role in the diagnosis, categorization, and risk stratification of patients with pulmonary hypertension.

Methods: Subjects enrolled in the PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) program undergo an extensive invasive hemodynamic evaluation that includes repeated measurements at rest and during several provocative physiological challenges. It is a National Institutes of Health/National Heart, Lung, and Blood Institute initiative to reclassify pulmonary hypertension groups based on clustered phenotypic and phenomic characteristics. At a subset of centers, participants also undergo an invasive cardiopulmonary exercise test to assess changes in hemodynamics and gas exchange during exercise.

Conclusions: When coupled with other physiological testing and blood -omic analyses involved in the PVDOMICS study, the comprehensive right heart catheterization protocol described here holds promise to clarify the diagnosis and clustering of pulmonary hypertension patients into cohorts beyond the traditional 5 World Symposium on Pulmonary Hypertension groups. This article will describe the methods applied for invasive hemodynamic characterization in the PVDOMICS program. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02980887.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046052PMC
March 2020

Circulating NEDD9 is increased in pulmonary arterial hypertension: A multicenter, retrospective analysis.

J Heart Lung Transplant 2020 04 31;39(4):289-299. Epub 2019 Dec 31.

Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address:

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 hypothesized that circulating NEDD9 is increased in PAH and informs the clinical profile of patients.

Methods: Clinical data and plasma samples were analyzed retrospectively for 242 patients from 5 referral centers (2010-2017): PAH (n = 139; female 82%, 58 [48-67] years), non-PAH pulmonary hypertension (PH) (n = 54; female 56%, 63.4 ± 12.2 years), and dyspnea non-PH controls (n = 36; female 75%, 54.2 ± 14.0 years).

Results: Compared with controls, NEDD9 was increased in PAH by 1.82-fold (p < 0.0001). Elevated NEDD9 correlated with PVR in idiopathic PAH (ρ = 0.42, p < 0.0001, n = 54), connective tissue disease (CTD)-PAH (ρ = 0.53, p < 0.0001, n = 53), and congenital heart disease-PAH (ρ = 0.68, p < 0.0001, n = 10). In CTD-PAH, NEDD9 correlated with 6-minute walk distance (ρ = -0.35, p = 0.028, n = 39). In contrast to the PAH biomarker N-terminal pro-brain natriuretic peptide (n = 38), NEDD9 correlated inversely with exercise pulmonary artery wedge pressure and more strongly with right ventricular ejection fraction (ρ = -0.41, p = 0.006, n = 45) in a mixed population. The adjusted hazard ratio for lung transplant-free survival was 1.12 (95% confidence interval [CI], 1.02-1.22, p = 0.01) and 1.75 (95% CI, 1.12-2.73, p = 0.01) per 1 ng/ml and 5 ng/ml increase in plasma NEDD9, respectively, by Cox proportional hazard model.

Conclusions: In PAH, plasma NEDD9 is increased and associates with key prognostic variables. Prospective studies that include hard end points are warranted to validate NEDD9 as a novel PAH biomarker.
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http://dx.doi.org/10.1016/j.healun.2019.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605895PMC
April 2020

The application of big data to cardiovascular disease: paths to precision medicine.

J Clin Invest 2020 01;130(1):29-38

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 feature of the most common diseases that has not been elucidated by conventional reductionism. In this discussion, we address genomic context and (endo)phenotypic heterogeneity, and examine commonly encountered cardiovascular diseases to illustrate the genotypic underpinnings of (endo)phenotypic diversity. We highlight the existing challenges in cardiovascular disease genotyping and phenotyping that can be addressed by the integration of big data and interpreted using novel analytical methodologies (network analysis). Precision cardiovascular medicine will only be broadly applied to cardiovascular patients once this comprehensive data set is subjected to unique, integrative analytical strategies that accommodate molecular and clinical heterogeneity rather than ignore or reduce it.
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http://dx.doi.org/10.1172/JCI129203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934200PMC
January 2020

Metabolic syndrome, neurohumoral modulation, and pulmonary arterial hypertension.

Br J Pharmacol 2020 04 18;177(7):1457-1471. Epub 2020 Feb 18.

Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.

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 preclinical and clinical data that each of these pathways can promote pulmonary vascular disease and right heart failure and are not simply disease markers. More recently, trials of therapeutics aimed at neurohormonal activation or metabolic dysfunction are beginning to shed light on how interventions in these pathways may affect patients with PAH. This review will focus on underlying mechanistic data that supports neurohormonal activation and metabolic dysfunction in the pathogenesis of PAH and right heart failure as well as discussing early translational data in patients with PAH.
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http://dx.doi.org/10.1111/bph.14968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060367PMC
April 2020

Immunoglobulin-driven Complement Activation Regulates Proinflammatory Remodeling in Pulmonary Hypertension.

Am J Respir Crit Care Med 2020 01;201(2):224-239

Division of Critical Care Medicine and Cardiovascular Pulmonary Research, Departments of Pediatrics and Medicine.

Pulmonary hypertension (PH) is a life-threatening cardiopulmonary disorder in which inflammation and immunity have emerged as critical early pathogenic elements. Although proinflammatory processes in PH and pulmonary arterial hypertension (PAH) are the focus of extensive investigation, the initiating mechanisms remain elusive. We tested whether activation of the complement cascade is critical in regulating proinflammatory and pro-proliferative processes in the initiation of experimental hypoxic PH and can serve as a prognostic biomarker of outcome in human PAH. We used immunostaining of lung tissues from experimental PH models and patients with PAH, analyses of genetic murine models lacking specific complement components or circulating immunoglobulins, cultured human pulmonary adventitial fibroblasts, and network medicine analysis of a biomarker risk panel from plasma of patients with PAH. Pulmonary perivascular-specific activation of the complement cascade was identified as a consistent critical determinant of PH and PAH in experimental animal models and humans. In experimental hypoxic PH, proinflammatory and pro-proliferative responses were dependent on complement (alternative pathway and component 5), and immunoglobulins, particularly IgG, were critical for activation of the complement cascade. We identified Csf2/GM-CSF as a primary complement-dependent inflammatory mediator. Furthermore, using network medicine analysis of a biomarker risk panel from plasma of patients with PAH, we demonstrated that complement signaling can serve as a prognostic factor for clinical outcome in PAH. This study establishes immunoglobulin-driven dysregulated complement activation as a critical pathobiological mechanism regulating proinflammatory and pro-proliferative processes in the initiation of experimental hypoxic PH and demonstrates complement signaling as a critical determinant of clinical outcome in PAH.
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http://dx.doi.org/10.1164/rccm.201903-0591OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961733PMC
January 2020

A novel secreted-cAMP pathway inhibits pulmonary hypertension via a feed-forward mechanism.

Cardiovasc Res 2020 07;116(8):1500-1513

Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1030, New York, NY 10029, USA.

Aims: Cyclic adenosine monophosphate (cAMP) is the predominant intracellular second messenger that transduces signals from Gs-coupled receptors. Intriguingly, there is evidence from various cell types that an extracellular cAMP pathway is active in the extracellular space. Herein, we investigated the role of extracellular cAMP in the lung and examined whether it may act on pulmonary vascular cell proliferation and pulmonary vasculature remodelling in the pathogenesis of pulmonary hypertension (PH).

Methods And Results: The expression of cyclic AMP-metabolizing enzymes was increased in lungs from patients with PH as well as in rats treated with monocrotaline and mice exposed to Sugen/hypoxia. We report that inhibition of the endogenous extracellular cAMP pathway exacerbated Sugen/hypoxia-induced lung remodelling. We found that application of extracellular cAMP induced an increase in intracellular cAMP levels and inhibited proliferation and migration of pulmonary vascular cells in vitro. Extracellular cAMP infusion in two in vivo PH models prevented and reversed pulmonary and cardiac remodelling associated with PH. Using protein expression analysis along with luciferase assays, we found that extracellular cAMP acts via the A2R/PKA/CREB/p53/Cyclin D1 pathway.

Conclusions: Taken together, our data reveal the presence of an extracellular cAMP pathway in pulmonary arteries that attempts to protect the lung during PH, and suggest targeting of the extracellular cAMP signalling pathway to limit pulmonary vascular remodelling and PH.
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http://dx.doi.org/10.1093/cvr/cvz244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314640PMC
July 2020

The importance of side branches in modeling 3D hemodynamics from angiograms for patients with coronary artery disease.

Sci Rep 2019 06 20;9(1):8854. Epub 2019 Jun 20.

Department of Biomedical Engineering, Duke University, Durham, 27708, USA.

Genesis of atherosclerotic lesions in the human arterial system is critically influenced by the fluid mechanics. Applying computational fluid dynamic tools based on accurate coronary physiology derived from conventional biplane angiogram data may be useful in guiding percutaneous coronary interventions. The primary objective of this study is to build and validate a computational framework for accurate personalized 3-dimensional hemodynamic simulation across the complete coronary arterial tree and demonstrate the influence of side branches on coronary hemodynamics by comparing shear stress between coronary models with and without these included. The proposed novel computational framework based on biplane angiography enables significant arterial circulation analysis. This study shows that models that take into account flow through all side branches are required for precise computation of shear stress and pressure gradient whereas models that have only a subset of side branches are inadequate for biomechanical studies as they may overestimate volumetric outflow and shear stress. This study extends the ongoing computational efforts and demonstrates that models based on accurate coronary physiology can improve overall fidelity of biomechanical studies to compute hemodynamic risk-factors.
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http://dx.doi.org/10.1038/s41598-019-45342-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586809PMC
June 2019

Precision Medicine in Pulmonary Arterial Hypertension.

Circ Res 2019 03;124(6):832-833

From the Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

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http://dx.doi.org/10.1161/CIRCRESAHA.119.314757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6419751PMC
March 2019

Computing the ankle-brachial index with parallel computational fluid dynamics.

J Biomech 2019 01 19;82:28-37. Epub 2018 Oct 19.

Department of Biomedical Engineering, Duke University, Durham, NC, USA. Electronic address:

The ankle-brachial index (ABI), a ratio of arterial blood pressure in the ankles and upper arms, is used to diagnose and monitor circulatory conditions such as coarctation of the aorta and peripheral artery disease. Computational simulations of the ABI can potentially determine the parameters that produce an ABI indicative of ischemia or other abnormalities in blood flow. However, 0- and 1-D computational methods are limited in describing a 3-D patient-derived geometry. Thus, we present a massively parallel framework for computational fluid dynamics (CFD) simulations in the full arterial system. Using the lattice Boltzmann method to solve the Navier-Stokes equations, we employ highly parallelized and scalable methods to generate the simulation domain and efficiently distribute the computational load among processors. For the first time, we compute an ABI with 3-D CFD. In this proof-of-concept study, we investigate the dependence of ABI on the presence of stenoses, or narrowed regions of the arteries, by directly modifying the arterial geometry. As a result, our framework enables the computation a hemodynamic factor characterizing flow at the scale of the full arterial system, in a manner that is extensible to patient-specific imaging data and holds potential for treatment planning.
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http://dx.doi.org/10.1016/j.jbiomech.2018.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6666426PMC
January 2019

Safety and long-term efficacy of AAV1.SERCA2a using nebulizer delivery in a pig model of pulmonary hypertension.

Pulm Circ 2018 Oct-Dec;8(4):2045894018799738. Epub 2018 Aug 21.

1 Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Nebulization delivery of adeno-associated virus serotype 1 encoding sarcoplasmic reticulum Ca-ATPase2a (AAV1.SERCA2a) gene was examined in a Yukatan miniature swine model of chronic pulmonary hypertension (n = 13). Nebulization of AAV1.SERCA2a resulted in homogenous distribution of vectors, lower pulmonary vascular resistance, and a trend towards better long-term survival compared to control animals.
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http://dx.doi.org/10.1177/2045894018799738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6146327PMC
August 2018
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