Publications by authors named "Todd M Kolb"

58 Publications

A novel approach to perioperative risk assessment for patients with pulmonary hypertension.

ERJ Open Res 2021 Jul 19;7(3). Epub 2021 Jul 19.

Dept of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA.

Rationale: Pulmonary hypertension (PH) is associated with significant perioperative morbidity and mortality. We hypothesised that pulmonary arterial hypertension (PAH) composite risk assessment scores could estimate perioperative risk for PH patients when adjusted for inherent procedural risk.

Methods: We identified patients in the Johns Hopkins PH Center Registry that had noncardiac surgery (including endoscopies) between September 2015 and January 2020. We collected information on preoperative patient-level and procedural variables and used logistic regression to evaluate associations with a composite outcome of death within 30 days or serious postoperative complication. We generated composite patient-level risk assessment scores for each subject and used logistic regression to estimate the association with adverse surgical outcomes. We adjusted multivariable models for inherent procedural risk of major cardiovascular events and used these models to generate a numerical PH perioperative risk (PHPR) score.

Results: Among 150 subjects, 19 (12.7%) reached the primary outcome, including 7 deaths (4.7%). Individual patient-level and procedural variables were associated with the primary outcome (all p<0.05). A composite patient-level risk assessment score built on three noninvasive parameters was strongly associated with reduced risk for poor outcomes (OR=0.4, p=0.03). This association was strengthened after adjusting the model for procedural risk. A PHPR score derived from the multivariable model stratified patients into low (0%), intermediate (≤10%), or high (>10%) risk of reaching the primary outcome.

Conclusion: Composite PAH risk assessment scores can predict perioperative risk for PH patients after accounting for inherent procedural risk. Validation of the PHPR score in a multicentre, prospective cohort is warranted.
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http://dx.doi.org/10.1183/23120541.00257-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287131PMC
July 2021

Associations of Angiopoietins With Heart Failure Incidence and Severity.

J Card Fail 2021 Jul 17;27(7):786-795. Epub 2021 Apr 17.

University of Washington, Department of Medicine, Seattle, WA; University of Washington, Department of Epidemiology, Seattle, WA. Electronic address:

Background: Angiopoietin-1 and 2 (Ang1, Ang2) are important mediators of angiogenesis. Angiopoietin levels are perturbed in cardiovascular disease, but it is unclear whether angiopoietin signaling is causative, an adaptive response, or merely epiphenomenon of disease activity.

Methods And Results: In a cohort free of cardiovascular disease at baseline (Multi-Ethnic Study of Atherosclerosis [MESA]), relationships between angiopoietins, cardiac morphology, and subsequent incidence of heart failure or cardiovascular death were evaluated. In cohorts with pulmonary arterial hypertension or left heart disease, associations between angiopoietins, invasive hemodynamics, and adverse clinical outcomes were evaluated. In MESA, Ang2 was associated with a higher incidence of heart failure or cardiovascular death (hazard ratio 1.21 per standard deviation, P < .001). Ang2 was associated with increased right atrial pressure (pulmonary arterial hypertension cohort) and increased wedge pressure and right atrial pressure (left heart disease cohort). Elevated Ang2 was associated with mortality in the pulmonary arterial hypertension cohort.

Conclusions: Ang2 was associated with incident heart failure or death among adults without cardiovascular disease at baseline and with disease severity in individuals with existing heart failure. Our finding that Ang2 is increased before disease onset and that elevations reflect disease severity, suggests Ang2 may contribute to heart failure pathogenesis.
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http://dx.doi.org/10.1016/j.cardfail.2021.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277723PMC
July 2021

Exercise right ventricular ejection fraction predicts right ventricular contractile reserve.

J Heart Lung Transplant 2021 Jun 17;40(6):504-512. Epub 2021 Feb 17.

Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address:

Background: Right ventricular (RV) contractile reserve shows promise as an indicator of occult RV dysfunction in pulmonary vascular disease. We investigated which measure of RV contractile reserve during exercise best predicts occult RV dysfunction and clinical outcomes.

Methods: We prospectively studied RV contractile reserve in 35 human subjects referred for right heart catheterization for known or suspected pulmonary hypertension. All underwent cardiac magnetic resonance imaging, echocardiography, and supine invasive cardiopulmonary exercise testing with concomitant RV pressure-volume catheterization. Event-free survival was prospectively adjudicated from time of right heart catheterization for a 4-year follow-up period.

Results: RV contractile reserve during exercise, as measured by a positive change in end-systolic elastance (Ees) during exertion, was associated with elevation in pulmonary pressures but preservation of RV volumes. Lack of RV reserve, on the other hand, was tightly coupled with acute RV dilation during exertion (R = 0.76, p< 0.001). RV Ees and dilation changes each predicted resting RV-PA dysfunction. RV ejection fraction during exercise, which captured exertional changes in both RV Ees and RV dilation, proved to be a robust surrogate for RV contractile reserve. Reduced exercise RV ejection fraction best predicted occult RV dysfunction among a variety of resting and exercise RV measures, and was also associated with clinical worsening.

Conclusions: RV ejection fraction during exercise, as an index of RV contractile reserve, allows for excellent identification of occult RV dysfunction, more so than resting measures of RV function, and may predict clinical outcomes as well.
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http://dx.doi.org/10.1016/j.healun.2021.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169559PMC
June 2021

Anesthetic techniques for patients with pulmonary hypertension undergoing ophthalmologic procedures: A case series.

J Clin Anesth 2021 Aug 2;71:110220. Epub 2021 Mar 2.

Department of Anesthesiology and Critical Care Medicine, Division of Adult Cardiothoracic Anesthesia, Division of Pediatric Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.

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http://dx.doi.org/10.1016/j.jclinane.2021.110220DOI Listing
August 2021

Insulin-like growth factor binding protein-2: a new circulating indicator of pulmonary arterial hypertension severity and survival.

BMC Med 2020 10 6;18(1):268. Epub 2020 Oct 6.

Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University, 720 Rutland Ave. Ross RM 1143, Baltimore, MD, 21205, USA.

Background: Pulmonary arterial hypertension (PAH) is a fatal disease that results from cardio-pulmonary dysfunction with the pathology largely unknown. Insulin-like growth factor binding protein 2 (IGFBP2) is an important member of the insulin-like growth factor family, with evidence suggesting elevation in PAH patients. We investigated the diagnostic and prognostic value of serum IGFBP2 in PAH to determine if it could discriminate PAH from healthy controls and if it was associated with disease severity and survival.

Methods: Serum IGFBP2 levels, as well as IGF1/2 levels, were measured in two independent PAH cohorts, the Johns Hopkins Pulmonary Hypertension program (JHPH, N = 127), NHLBI PAHBiobank (PAHB, N = 203), and a healthy control cohort (N = 128). The protein levels in lung tissues were determined by western blot. The IGFBP2 mRNA expression levels in pulmonary artery smooth muscle cells (PASMC) and endothelial cells (PAEC) were assessed by RNA-seq, secreted protein levels by ELISA. Association of biomarkers with clinical variables was evaluated using adjusted linear or logistic regression and Kaplan-Meier analysis.

Results: In both PAH cohorts, serum IGFBP2 levels were significantly elevated (p < 0.0001) compared to controls and discriminated PAH from controls with an AUC of 0.76 (p < 0.0001). A higher IGFBP2 level was associated with a shorter 6-min walk distance (6MWD) in both cohorts after adjustment for age and sex (coefficient - 50.235 and - 57.336 respectively). Cox multivariable analysis demonstrated that higher serum IGFBP2 was a significant independent predictor of mortality in PAHB cohort only (HR, 3.92; 95% CI, 1.37-11.21). IGF1 levels were significantly increased only in the PAHB cohort; however, neither IGF1 nor IGF2 had equivalent levels of associations with clinical variables compared with IGFBP2. Western blotting shown that IGFBP2 protein was significantly increased in the PAH vs control lung tissues. Finally, IGFBP2 mRNA expression and secreted protein levels were significantly higher in PASMC than in PAEC.

Conclusions: IGFBP2 protein expression was increased in the PAH lung, and secreted by PASMC. Elevated circulating IGFBP2 was associated with PAH severity and mortality and is a potentially valuable prognostic marker in PAH.
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http://dx.doi.org/10.1186/s12916-020-01734-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537100PMC
October 2020

Multi-Beat Right Ventricular-Arterial Coupling Predicts Clinical Worsening in Pulmonary Arterial Hypertension.

J Am Heart Assoc 2020 05 8;9(10):e016031. Epub 2020 May 8.

Department of Medicine Medical University of South Carolina Charleston SC.

Background Although right ventricular (RV) to pulmonary arterial (RV-PA) coupling is considered the gold standard in assessing RV dysfunction, its ability to predict clinically significant outcomes is poorly understood. We assessed the ability of RV-PA coupling, determined by the ratio of multi-beat (MB) end-systolic elastance (Ees) to effective arterial elastance (Ea), to predict clinical outcomes. Methods and Results Twenty-six subjects with pulmonary arterial hypertension (PAH) underwent same-day cardiac magnetic resonance imaging, right heart catheterization, and RV pressure-volume assessment with MB determination of Ees/Ea. RV ejection fraction (RVEF), stroke volume/end-systolic volume, and single beat-estimated Ees/Ea were also determined. Patients were treated with standard therapies and followed prospectively until they met criteria of clinical worsening (CW), as defined by ≥10% decline in 6-minute walk distance, worsening World Health Organization (WHO) functional class, PAH therapy escalation, RV failure hospitalization, or transplant/death. Subjects were 57±14 years, largely WHO class III (50%) at enrollment, with preserved average RV ejection fraction (RVEF) (47±11%). Mean follow-up was 3.2±1.3 years. Sixteen (62%) subjects met CW criteria. MB Ees/Ea was significantly lower in CW subjects (0.7±0.5 versus 1.3±0.8, =0.02). The optimal MB Ees/Ea cut-point predictive of CW was 0.65, defined by ROC (AUC 0.78, =0.01). MB Ees/Ea below this cut-point was significantly associated with time to CW (hazard ratio 5.1, =0.001). MB Ees/Ea remained predictive of outcomes following multivariate adjustment for timing of PAH diagnosis and PAH diagnosis subtype. Conclusions RV-PA coupling as measured by MB Ees/Ea has prognostic significance in human PAH, even in a cohort with preserved RVEF.
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http://dx.doi.org/10.1161/JAHA.119.016031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660856PMC
May 2020

Diffusing Capacity Is an Independent Predictor of Outcomes in Pulmonary Hypertension Associated With COPD.

Chest 2020 08 14;158(2):722-734. Epub 2020 Mar 14.

Johns Hopkins University Division of Pulmonary and Critical Care, Baltimore, MD. Electronic address:

Background: Patients with COPD who experience pulmonary hypertension (PH) have worse mortality than those with COPD alone. Predictors of poor outcomes in COPD-PH are not well-described. Diffusing capacity of the lung (Dlco) assesses the integrity of the alveolar-capillary interface and thus may be a useful prognostic tool among those with COPD-PH.

Research Question: Using a single center registry, we sought to evaluate Dlco as a predictor of mortality in a cohort of patients with COPD-PH.

Study Design And Methods: This retrospective cohort study analyzed 71 COPD-PH patients from the Johns Hopkins Pulmonary Hypertension Registry with right-sided heart catheterization (RHC)-proven PH and pulmonary function testing data within one year of diagnostic RHC. Transplant-free survival was calculated from index RHC. Adjusted transplant-free survival was modelled using Cox proportional hazard methods; age, pulmonary vascular resistance, FEV, oxygen use, and N-terminal pro-brain natriuretic peptide were included as covariates.

Results: Overall unadjusted transplant-free 1-, 3-, and 5-year survivals were 87%, 60%, and 51%, respectively. Survival was associated with reduced Dlco across the observed range of pulmonary artery pressures and pulmonary vascular resistance. Severe Dlco impairment was associated with poorer survival (log-rank χ 13.07) (P < .001); adjusting for covariates, for every percent predicted decrease in Dlco, mortality rates increased by 4% (hazard ratio, 1.04; 95% CI, 1.01-1.07).

Interpretation: Among patients with COPD-PH, severe gas transfer impairment is associated with higher mortality, even with adjustment for airflow obstruction and hemodynamics, which suggests that Dlco may be a useful prognostic marker in this population. Future studies are needed to further investigate the association between Dlco and morbidity and to determine the utility of Dlco as a biomarker for disease risk and severity in COPD-PH.
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http://dx.doi.org/10.1016/j.chest.2020.02.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173778PMC
August 2020

Functional Impact of Human Genetic Variants of /Endostatin on Pulmonary Endothelium.

Am J Respir Cell Mol Biol 2020 04;62(4):524-534

Division of Pulmonary and Critical Care Medicine, Department of Medicine, and.

Pulmonary arterial hypertension (PAH) is an incurable disease characterized by disordered and dysfunctional angiogenesis leading to small-vessel loss and an obliterative vasculopathy. The pathogenesis of PAH is not fully understood, but multiple studies have demonstrated links between elevated angiostatic factors, disease severity, and adverse clinical outcomes. ES (endostatin), one such circulating angiostatic peptide, is the cleavage product of the proteoglycan (collagen α1[XVIII] chain). Elevated serum ES is associated with increased mortality and disease severity in PAH. A nonsynonymous variant of ES (aspartic acid-to-asparagine substitution at amino acid 104; p.D104N) is associated with differences in PAH survival. Although /ES expression is markedly increased in remodeled pulmonary vessels in PAH, the impact of ES on pulmonary endothelial cell (PEC) biology and molecular contributions to PAH severity remain undetermined. In the present study, we characterized the effects of exogenous ES on human PEC biology and signaling. We demonstrated that ES inhibits PEC migration, proliferation, and cell survival, with significant differences between human variants, indicating that they are functional genetic variants. ES promotes proteasome-mediated degradation of the transcriptional repressor ID1, increasing expression and release of TSP-1 (thrombospondin 1). ES inhibits PEC migration via an ID1/TSP-1/CD36-dependent pathway, in contrast to proliferation and apoptosis, which require both CD36 and CD47. Collectively, the data implicate ES as a novel negative regulator of ID1 and an upstream propagator of an angiostatic signal cascade converging on CD36 and CD47, providing insight into the cellular and molecular effects of a functional genetic variant linked to altered outcomes in PAH.
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http://dx.doi.org/10.1165/rcmb.2019-0056OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7110972PMC
April 2020

Serum uric acid as a marker of disease risk, severity, and survival in systemic sclerosis-related pulmonary arterial hypertension.

Pulm Circ 2019 Jul-Sep;9(3):2045894019859477. Epub 2019 Jul 29.

Department of Medicine Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA.

The object of this paper is to assess associations between serum uric acid (UA) and pulmonary arterial hypertension (PAH) risk, disease severity, and mortality in a well-characterized cohort of systemic sclerosis (SSc) patients referred for evaluation of possible PAH. Consecutive SSc patients aged >18 years with serum UA drawn within two weeks of a diagnostic right heart catheterization (RHC) were included. Associations between baseline serum UA and PAH at RHC were examined using logistic regression and receiver operating characteristic curves. Relationships between UA levels and metrics of disease severity were assessed using Pearson and Spearman correlation. Associations between UA and survival were assessed using Kaplan-Meier analysis and Cox proportional hazard modeling. A total of 162 SSc patients were included; 82 received a diagnosis of PAH at RHC. Patients found to have PAH had significantly higher UA than those without PAH. Elevated baseline UA was associated with significantly increased odds of PAH diagnosis at RHC (odds ratio [OR] = 4.07, 95% confidence interval [CI] = 2.11-7.87,  < 0.001). Each mg/dL higher UA was associated with a 14% increase in mortality (hazard ratio [HR] = 1.14, 95% CI = 1.02-1.28,  < 0.05). In multivariable models adjusting for potential confounders of the relationship between UA and survival, UA > 6.3 mg/dL remained significantly associated with increased mortality (HR = 1.84, 95% CI = 1.02-3.32,  < 0.05). Among SSc patients with suspected PAH, elevated serum UA is associated with increased risk of SSc-PAH. Among individuals diagnosed with SSc-PAH by RHC, UA is associated with disease severity and survival. These results indicate UA is a useful predictor of PAH risk and prognosis in SSc.
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http://dx.doi.org/10.1177/2045894019859477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6664664PMC
July 2019

SU5416 does not attenuate early RV angiogenesis in the murine chronic hypoxia PH model.

Respir Res 2019 Jun 17;20(1):123. Epub 2019 Jun 17.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, 1830 E. Monument Street, 5th Floor, Baltimore, MD, 21205, USA.

Background: Right ventricular (RV) angiogenesis has been associated with adaptive myocardial remodeling in pulmonary hypertension (PH), though molecular regulators are poorly defined. Endothelial cell VEGFR-2 is considered a "master regulator" of angiogenesis in other models, and the small molecule VEGF receptor tyrosine kinase inhibitor SU5416 is commonly used to generate PH in rodents. We hypothesized that SU5416, through direct effects on cardiac endothelial cell VEGFR-2, would attenuate RV angiogenesis in a murine model of PH.

Methods: C57 BL/6 mice were exposed to chronic hypoxia (CH-PH) to generate PH and stimulate RV angiogenesis. SU5416 (20 mg/kg) or vehicle were administered at the start of the CH exposure, and weekly thereafter. Angiogenesis was measured after one week of CH-PH using a combination of unbiased stereological measurements and flow cytometry-based quantification of myocardial endothelial cell proliferation. In complementary experiments, primary cardiac endothelial cells from C57 BL/6 mice were exposed to recombinant VEGF (50 ng/mL) or grown on Matrigel in the presence of SU5416 (5 μM) or vehicle.

Result: SU5416 directly inhibited VEGF-mediated ERK phosphorylation, cell proliferation, and Kdr transcription, but not Matrigel tube formation in primary murine cardiac endothelial cells in vitro. SU5416 did not inhibit CH-PH induced RV angiogenesis, endothelial cell proliferation, or RV hypertrophy in vivo, despite significantly altering the expression profile of genes involved in angiogenesis.

Conclusions: These findings demonstrate that SU5416 directly inhibited VEGF-induced proliferation of murine cardiac endothelial cells but does not attenuate CH-PH induced RV angiogenesis or myocardial remodeling in vivo.
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http://dx.doi.org/10.1186/s12931-019-1079-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580559PMC
June 2019

Validation of the REVEAL Prognostic Equation and Risk Score Calculator in Incident Systemic Sclerosis-Associated Pulmonary Arterial Hypertension.

Arthritis Rheumatol 2019 10 26;71(10):1691-1700. Epub 2019 Aug 26.

The Johns Hopkins University School of Medicine, Baltimore, Maryland.

Objective: A prognostic equation and risk score calculator derived from the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL) are being used to predict 1-year survival in patients with pulmonary arterial hypertension (PAH), but little is known about the performance of these REVEAL survival prediction tools in systemic sclerosis (SSc)-associated PAH (SSc-PAH).

Methods: Prospectively gathered data from the Johns Hopkins Pulmonary Hypertension Program and Pulmonary Hypertension Assessment and Recognition of Outcome in Scleroderma Registries were used to evaluate the predictive accuracy of the REVEAL models for predicting the probability of 1-year survival in patients with SSc-PAH. Model discrimination was assessed by comparison of the Harrell's C-index, model fit was assessed using multivariable regression techniques, and model calibration was assessed by comparing predicted to observed survival estimates.

Results: The validation cohort consisted of 292 SSc-PAH patients with a 1-year survival rate of 87.4%. The C-index for predictive accuracy of the REVEAL prognostic equation (0.734, 95% confidence interval [95% CI] 0.652-0.816) and for the risk score (0.743, 95% CI 0.663-0.823) demonstrated good discrimination, comparable to that in the model development cohort. The calibration slope was 0.707 (95% CI 0.400-1.014), indicating that the overall model fit was marginal (P = 0.06). The magnitude of risk assigned to low distance on the 6-minute walk test (6MWD) and elevated serum levels of brain natriuretic peptide (BNP) was lower in the validation cohort than was originally seen in the REVEAL derivation cohort. Model calibration was poor, particularly for the highest risk groups.

Conclusion: In predicting 1-year survival in patients newly diagnosed as having SSc-PAH, the REVEAL prognostic equation and risk score provide very good discrimination but poor calibration. REVEAL prediction scores should be interpreted with caution in newly diagnosed SSc-PAH patients, particularly those with higher predicted risk of poor 1-year survival resulting from a low 6MWD or a high BNP serum level.
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http://dx.doi.org/10.1002/art.40918DOI Listing
October 2019

A nonapoptotic endothelial barrier-protective role for caspase-3.

Am J Physiol Lung Cell Mol Physiol 2019 06 25;316(6):L1118-L1126. Epub 2019 Mar 25.

Department of Medicine, Johns Hopkins University School of Medicine , Baltimore, Maryland.

Noncanonical roles for caspase-3 are emerging in the fields of cancer and developmental biology. However, little is known of nonapoptotic functions of caspase-3 in most cell types. We have recently demonstrated a disassociation between caspase-3 activation and execution of apoptosis with accompanying cytoplasmic caspase-3 sequestration and preserved endothelial barrier function. Therefore, we tested the hypothesis that nonapoptotic caspase-3 activation promotes endothelial barrier integrity. Human lung microvascular endothelial cells were exposed to thrombin, a nonapoptotic stimulus, and endothelial barrier function was assessed using electric cell-substrate impedance sensing. Actin cytoskeletal rearrangement and paracellular gap formation were assessed using phalloidin staining. Cell stiffness was evaluated using magnetic twisting cytometry. In addition, cell lysates were harvested for protein analyses. Caspase-3 was inhibited pharmacologically with pan-caspase and a caspase-3-specific inhibitor. Molecular inhibition of caspase-3 was achieved using RNA interference. Cells exposed to thrombin exhibited a cytoplasmic activation of caspase-3 with transient and nonapoptotic decrease in endothelial barrier function as measured by a drop in electrical resistance followed by a rapid recovery. Inhibition of caspases led to a more pronounced and rapid drop in thrombin-induced endothelial barrier function, accompanied by increased endothelial cell stiffness and paracellular gaps. Caspase-3-specific inhibition and caspase-3 knockdown both resulted in more pronounced thrombin-induced endothelial barrier disruption. Taken together, our results suggest cytoplasmic caspase-3 has nonapoptotic functions in human endothelium and can promote endothelial barrier integrity.
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http://dx.doi.org/10.1152/ajplung.00487.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620669PMC
June 2019

Disconnect between Fibrotic Response and Right Ventricular Dysfunction.

Am J Respir Crit Care Med 2019 06;199(12):1550-1560

1 Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.

Remodeling and fibrosis of the right ventricle (RV) may cause RV dysfunction and poor survival in patients with pulmonary hypertension. To investigate the consequences of RV fibrosis modulation and the accompanying cellular changes on RV function. Expression of fibrotic markers was assessed in the RV of patients with pulmonary hypertension, the murine pulmonary artery banding, and rat monocrotaline and Sugen5416/hypoxia models. Invasive hemodynamic and echocardiographic assessment was performed on galectin-3 knockout or inhibitor-treated mice. Established fibrosis was characterized by marked expression of galectin-3 and an enhanced number of proliferating RV fibroblasts. Galectin-3 genetic and pharmacologic inhibition or antifibrotic treatment with pirfenidone significantly diminished RV fibrosis progression in the pulmonary artery banding model, without improving RV functional parameters. RV fibrotic regions were populated with mesenchymal cells coexpressing vimentin and PDGFRα (platelet-derived growth factor receptor-α), but generally lacked αSMA (α-smooth muscle actin) positivity. Serum levels of galectin-3 were increased in patients with idiopathic pulmonary arterial hypertension but did not correlate with cardiac function. No changes of galectin-3 expression were observed in the lungs. We identified extrapulmonary galectin-3 as an important mediator that drives RV fibrosis in pulmonary hypertension through the expansion of PDGFRα/vimentin-expressing cardiac fibroblasts. However, interventions effectively targeting fibrosis lack significant beneficial effects on RV function.
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http://dx.doi.org/10.1164/rccm.201809-1737OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580669PMC
June 2019

Risk assessment in scleroderma patients with newly diagnosed pulmonary arterial hypertension: application of the ESC/ERS risk prediction model.

Eur Respir J 2018 10 18;52(4). Epub 2018 Oct 18.

Johns Hopkins University, Division of Pulmonary and Critical Care Medicine, Dept of Medicine, Baltimore, MD, USA.

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http://dx.doi.org/10.1183/13993003.00497-2018DOI Listing
October 2018

Assessment of Right Ventricular Function in the Research Setting: Knowledge Gaps and Pathways Forward. An Official American Thoracic Society Research Statement.

Am J Respir Crit Care Med 2018 08;198(4):e15-e43

Background: Right ventricular (RV) adaptation to acute and chronic pulmonary hypertensive syndromes is a significant determinant of short- and long-term outcomes. Although remarkable progress has been made in the understanding of RV function and failure since the meeting of the NIH Working Group on Cellular and Molecular Mechanisms of Right Heart Failure in 2005, significant gaps remain at many levels in the understanding of cellular and molecular mechanisms of RV responses to pressure and volume overload, in the validation of diagnostic modalities, and in the development of evidence-based therapies.

Methods: A multidisciplinary working group of 20 international experts from the American Thoracic Society Assemblies on Pulmonary Circulation and Critical Care, as well as external content experts, reviewed the literature, identified important knowledge gaps, and provided recommendations.

Results: This document reviews the knowledge in the field of RV failure, identifies and prioritizes the most pertinent research gaps, and provides a prioritized pathway for addressing these preclinical and clinical questions. The group identified knowledge gaps and research opportunities in three major topic areas: 1) optimizing the methodology to assess RV function in acute and chronic conditions in preclinical models, human studies, and clinical trials; 2) analyzing advanced RV hemodynamic parameters at rest and in response to exercise; and 3) deciphering the underlying molecular and pathogenic mechanisms of RV function and failure in diverse pulmonary hypertension syndromes.

Conclusions: This statement provides a roadmap to further advance the state of knowledge, with the ultimate goal of developing RV-targeted therapies for patients with RV failure of any etiology.
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http://dx.doi.org/10.1164/rccm.201806-1160STDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6835085PMC
August 2018

Supply and Demand: Micro(vascular) Economics of the Right Ventricle in Pulmonary Hypertension.

Am J Respir Cell Mol Biol 2018 10;59(4):410-411

1 Department of Medicine Johns Hopkins University School of Medicine Baltimore, Maryland.

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http://dx.doi.org/10.1165/rcmb.2018-0203EDDOI Listing
October 2018

Pulmonary Effective Arterial Elastance as a Measure of Right Ventricular Afterload and Its Prognostic Value in Pulmonary Hypertension Due to Left Heart Disease.

Circ Heart Fail 2018 04;11(4):e004436

Division of Cardiology (E.T., B.W.K., E.K.K., D.A.K., R.J.T.) and Division of Pulmonary and Critical Care Medicine (T.M.K., R.D., S.C.M., P.M.H.), Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD. Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (S.J.S., H.H.P.). Division of Cardiology, Mayo Clinic, Rochester, MN (B.A.B., W.L.M.). Division of Pulmonary, Critical Care, and Sleep Medicine, University of Washington, Seattle (P.J.L.). Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston (B.A.H., R.J.T.).

Background: Patients with combined post- and precapillary pulmonary hypertension due to left heart disease have a worse prognosis compared with isolated postcapillary. However, it remains unclear whether increased mortality in combined post- and precapillary pulmonary hypertension is simply a result of higher total right ventricular load. Pulmonary effective arterial elastance (Ea) is a measure of total right ventricular afterload, reflecting both resistive and pulsatile components. We aimed to test whether pulmonary Ea discriminates survivors from nonsurvivors in patients with pulmonary hypertension due to left heart disease and if it does so better than other hemodynamic parameters associated with combined post- and precapillary pulmonary hypertension.

Methods And Results: We combined 3 large heart failure patient cohorts (n=1036) from academic hospitals, including patients with pulmonary hypertension due to heart failure with preserved ejection fraction (n=232), reduced ejection fraction (n=335), and a mixed population (n=469). In unadjusted and 2 adjusted models, pulmonary Ea more robustly predicted mortality than pulmonary vascular resistance and the transpulmonary gradient. Along with pulmonary arterial compliance, pulmonary Ea remained predictive of survival in patients with normal pulmonary vascular resistance. The diastolic pulmonary gradient did not predict mortality. In addition, in a subset of patients with echocardiographic data, Ea and pulmonary arterial compliance were better discriminators of right ventricular dysfunction than the other parameters.

Conclusions: Pulmonary Ea and pulmonary arterial compliance more consistently predicted mortality than pulmonary vascular resistance or transpulmonary gradient across a spectrum of left heart disease with pulmonary hypertension, including patients with heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, and pulmonary hypertension with a normal pulmonary vascular resistance.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.117.004436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5901761PMC
April 2018

Pulmonary arterial hypertension and atrial arrhythmias: incidence, risk factors, and clinical impact.

Pulm Circ 2018 Apr-Jun;8(2):2045894018769874. Epub 2018 Mar 26.

1 Division of Pulmonary and Critical Care Medicine, 1466 Department of Medicine, Johns Hopkins University, Baltimore , MD, USA.

Atrial arrhythmia (AA) occurrence in pulmonary arterial hypertension (PAH) may determine clinical deterioration and affect prognosis. In this study we assessed AA incidence in idiopathic (IPAH) and systemic sclerosis related PAH (SSc-PAH) and evaluated risk factors, management, and impact on mortality. We collected baseline data from consecutive IPAH or SSc-PAH patients prospectively enrolled in the Johns Hopkins Pulmonary Hypertension Registry between January 2000 and July 2016. During follow-up AA onset, treatment, and outcome were recorded. Among 317 patients (201 SSc-PAH, 116 IPAH), 42 developed AA (19 atrial fibrillation, 10 flutter-fibrillation, 9 atrial flutter, and 4 atrial ectopic tachycardia) with a 13.2% cumulative incidence. Most events were associated with hospitalization (90.5%). Electrical or pharmacological cardioversion was attempted in most cases. Patients with AA had higher right atrial pressure, pulmonary wedge pressure ( P < 0.005), NT-proBNP ( P < 0.05), and thyroid disease prevalence ( P < 0.005). Higher mortality was observed in patients with AA, though not statistically significant (LogRank P = 0.323). Similar long-term mortality between IPAH with AA and SSc-PAH without AA was observed (LogRank P = 0.098). SSc-PAH with AA had the worst prognosis. In PAH patients AA occurrence is a matter of significant concern. Therapeutic strategies aimed at restoring sinus rhythm may represent an important goal.
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http://dx.doi.org/10.1177/2045894018769874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5912291PMC
March 2018

Focused Review of Perioperative Care of Patients with Pulmonary Hypertension and Proposal of a Perioperative Pathway.

Cureus 2018 Jan 15;10(1):e2072. Epub 2018 Jan 15.

Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine.

Morbidity and mortality risk increase considerably for patients with pulmonary hypertension (PH) undergoing non-cardiac surgery. Unfortunately, there are no comprehensive, evidence-based guidelines for perioperative evaluation and management of these patients. We present a brief review of the literature on perioperative outcomes for patients with PH and describe the implementation of a collaborative perioperative management program for these high-risk patients at a tertiary academic center.
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http://dx.doi.org/10.7759/cureus.2072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5854330PMC
January 2018

Right Ventricular Myofilament Functional Differences in Humans With Systemic Sclerosis-Associated Versus Idiopathic Pulmonary Arterial Hypertension.

Circulation 2018 05 19;137(22):2360-2370. Epub 2018 Jan 19.

Divisions of Cardiology (S.H., K.M.K.-S., M.M., D.A.K.).

Background: Patients with systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) have a far worse prognosis than those with idiopathic PAH (IPAH). In the intact heart, SSc-PAH exhibits depressed rest and reserve right ventricular (RV) contractility compared with IPAH. We tested whether this disparity involves underlying differences in myofilament function.

Methods: Cardiac myocytes were isolated from RV septal endomyocardial biopsies from patients with SSc-PAH, IPAH, or SSc with exertional dyspnea but no resting PAH (SSc-d); control RV septal tissue was obtained from nondiseased donor hearts (6-7 per group). Isolated myocyte passive length-tension and developed tension-calcium relationships were determined and correlated with in vivo RV function and reserve. RV septal fibrosis was also examined.

Results: Myocyte passive stiffness from length-tension relations was similarly increased in IPAH and SSc-PAH compared with control, although SSc-PAH biopsies had more interstitial fibrosis. More striking disparities were found between active force-calcium relations. Compared with controls, maximal calcium-activated force (F) was 28% higher in IPAH but 37% lower in SSc-PAH. F in SSc-d was intermediate between control and SSc-PAH. The calcium concentration required for half-maximal force (EC) was similar between control, IPAH, and SSc-d but lower in SSc-PAH. This disparity disappeared in myocytes incubated with the active catalytic subunit of protein kinase A. Myocyte F directly correlated with in vivo RV contractility assessed by end-systolic elastance ( =0.46, =0.002) and change in end-systolic elastance with exercise ( =0.49, =0.008) and was inversely related with exercise-induced chamber dilation ( =0.63, <0.002), which also was a marker of depressed contractile reserve.

Conclusions: A primary defect in human SSc-PAH resides in depressed sarcomere function, whereas this is enhanced in IPAH. These disparities correlate with in vivo RV contractility and contractile reserve and are consistent with worse clinical outcomes in SSc-PAH. The existence of sarcomere disease before the development of resting PAH in patients with SSc-d suggests that earlier identification and intervention may prove useful.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.033147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976528PMC
May 2018

The impact of ambrisentan and tadalafil upfront combination therapy on cardiac function in scleroderma associated pulmonary arterial hypertension patients: cardiac magnetic resonance feature tracking study.

Pulm Circ 2018 Jan-Mar;8(1):2045893217748307. Epub 2017 Dec 18.

1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

The aim of this study was to evaluate the effect of upfront combination therapy with ambrisentan and tadalafil on left ventricular (LV) and right ventricular (RV) function in patients with systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH). LV and RV peak longitudinal and circumferential strain and strain rate (SR), which consisted of peak systolic SR (SRs), peak early diastolic SR (SRe), and peak atrial-diastolic SR (SRa) were analyzed using cardiac magnetic resonance imaging (CMRI) data from the recently published ATPAHSS-O trial (ambrisentan and tadalafil upfront combination therapy in SSc-PAH). Twenty-one patients completed the study protocol. Measures of RV systolic function (RV free wall [RVFW] peak longitudinal strain [pLS], RVFW peak longitudinal SRs [pLSRs]) and RV diastolic function (RVFW peak longitudinal SRa [pLSRa], RVFW peak circumferential SRe) were improved after treatment. LV systolic function (LV peak global longitudinal strain [pGLS]) and diastolic function (LV peak global longitudinal SRe [pGLSRe]) were also significantly improved at follow-up. Increased 6-min walk distance was significantly correlated with RVFW pLS and pLSRs, while the decrease in N-terminal pro-brain natriuretic peptide was correlated with LV pGLS. Increased cardiac index was associated with improved LV pGLSRe, and reduction in mean right atrial pressure was correlated with improved RVFW pLS and pLSRa. Combination therapy was associated with a significant improvement in both RV and LV function as assessed by CMR-derived strain and SR. Importantly, the improvement in RV and LV strain and SR correlated with improvements in known prognostic markers of PAH. (Approved by clinicaltrials.gov [NCT01042158] before patient recruitment.).
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http://dx.doi.org/10.1177/2045893217748307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018906PMC
December 2017

XOR inhibition with febuxostat accelerates pulmonary endothelial barrier recovery and improves survival in lipopolysaccharide-induced murine sepsis.

Physiol Rep 2017 Aug;5(15)

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Sepsis is a leading cause of death among patients in the intensive care unit, resulting from multi-organ failure. Activity of xanthine oxidoreductase (XOR), a reactive oxygen species (ROS) producing enzyme, is known to be elevated in nonsurvivors of sepsis compared to survivors. We have previously demonstrated that XOR is critical for ventilator-induced lung injury. Using febuxostat, a novel nonpurine inhibitor of XOR, we sought to determine the role of XOR inhibition in a murine model of sepsis-induced lung injury and mortality. C57BL/6J mice were subjected to intravenous (IV) lipopolysaccharide (LPS) for various time points, and lungs were harvested for analyses. Subsets of mice were treated with febuxostat, pre or post LPS exposure, or vehicle. Separate groups of mice were followed up for mortality after LPS exposure. After 24 hr of IV LPS mice exhibited an increase in XOR activity in lung tissue and a significant increase in pulmonary endothelial barrier disruption. Pretreatment of animals with febuxostat before exposure to LPS, or treatment 4 h after LPS, resulted in complete abrogation of XOR activity. Inhibition of XOR with febuxostat did not prevent LPS-induced pulmonary vascular permeability at 24 h, however, it accelerated recovery of the pulmonary endothelial barrier integrity in response to LPS exposure. Furthermore, treatment with febuxostat resulted in significant reduction in mortality. Inhibition of XOR with febuxostat accelerates recovery of the pulmonary endothelial barrier and prevents LPS-induced mortality, whether given before or after exposure to LPS.
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http://dx.doi.org/10.14814/phy2.13377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555900PMC
August 2017
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