Publications by authors named "Gustavo A Heresi"

76 Publications

Direct oral anticoagulants in chronic thromboembolic pulmonary hypertension.

J Thromb Thrombolysis 2021 Apr 9. Epub 2021 Apr 9.

Division of Pulmonary and Critical Care Medicine, Cedars Sinai Medical Center, Los Angeles, CA, USA.

Chronic thromboembolic pulmonary hypertension (CTEPH) represents the later stage consequence of at least one or more unresolved episodes of acute pulmonary embolism; thus, indefinite anticoagulation is strongly recommended by current practice guidelines. Historically, vitamin K antagonists have been widely used in these patients. However, recent data indicate a shift toward direct oral anticoagulants (DOACs), despite lack of data on the safety and efficacy in this patient population. Herein, we briefly discuss the current rationale for oral anticoagulation use in CTEPH, addressing important issues and controversies involved with the use of DOACs, opening a strategy for further clinical research in the field of oral anticoagulation.
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http://dx.doi.org/10.1007/s11239-021-02445-zDOI Listing
April 2021

Incidence of symptomatic venous thromboembolism following hospitalization for coronavirus disease 2019: Prospective results from a multi-center study.

Thromb Res 2021 02 11;198:135-138. Epub 2020 Dec 11.

Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Background: Thrombosis and pulmonary embolism appear to be major causes of mortality in hospitalized coronavirus disease 2019 (COVID-19) patients. However, few studies have focused on the incidence of venous thromboembolism (VTE) after hospitalization for COVID-19.

Methods: In this multi-center study, we followed 1529 COVID-19 patients for at least 45 days after hospital discharge, who underwent routine telephone follow-up. In case of signs or symptoms of pulmonary embolism (PE) or deep vein thrombosis (DVT), they were invited for an in-hospital visit with a pulmonologist. The primary outcome was symptomatic VTE within 45 days of hospital discharge.

Results: Of 1529 COVID-19 patients discharged from hospital, a total of 228 (14.9%) reported potential signs or symptoms of PE or DVT and were seen for an in-hospital visit. Of these, 13 and 12 received Doppler ultrasounds or pulmonary CT angiography, respectively, of whom only one patient was diagnosed with symptomatic PE. Of 51 (3.3%) patients who died after discharge, two deaths were attributed to VTE corresponding to a 45-day cumulative rate of symptomatic VTE of 0.2% (95%CI 0.1%-0.6%; n = 3). There was no evidence of acute respiratory distress syndrome (ARDS) in these patients. Other deaths after hospital discharge included myocardial infarction (n = 13), heart failure (n = 9), and stroke (n = 9).

Conclusions: We did not observe a high rate of symptomatic VTE in COVID-19 patients after hospital discharge. Routine extended thromboprophylaxis after hospitalization for COVID-19 may not have a net clinical benefit. Randomized trials may be warranted.
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http://dx.doi.org/10.1016/j.thromres.2020.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836837PMC
February 2021

COVID-19 and Pulmonary Arterial Hypertension: Early Data and Many Questions.

Ann Am Thorac Soc 2020 12;17(12):1528-1530

Department of Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, Ohio.

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http://dx.doi.org/10.1513/AnnalsATS.202008-1014EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706598PMC
December 2020

Follow-Up Functional Class and 6-Minute Walk Distance Identify Long-Term Survival in Pulmonary Arterial Hypertension.

Lung 2020 12 19;198(6):933-938. Epub 2020 Nov 19.

United Therapeutics, Durham, NC, USA.

Purpose: Guidelines recommend specific treatment goals for pulmonary arterial hypertension (PAH) patients: functional class I or II, 6-min walk distance (6MWD) ≥ 380 to 440 m, normal natriuretic peptide levels, and normal right-sided invasive hemodynamics. Only observational registry data support this recommendation. Our aim was to test these goals in a large group 1 PAH cohort against long-term survival.

Methods: We analyzed the PHIRST and TRIUMPH populations (n = 563, age 53.5 ± 14.7 years, female sex 79%). The predictor variables were the treatment goals measured at the end of the placebo-controlled phase (16 and 12 weeks, respectively). The primary outcome was all-cause mortality at the end of follow-up during the open-label extension phase.

Results: There were 73 deaths during median follow of 1072 days (range 27 to 2177). Patients who achieved a functional class I or II had better survival. Both a 6MWD ≥ 380 m and ≥ 440 m were associated with lower mortality, but survival was better in patients able to walk ≥ 440 m. The best long-term survival was achieved with functional class I or II and 6MWD ≥ 440 m. In a subset of the population, cardiac index > 2.5 L/min/m was weakly associated with better survival.

Conclusion: WHO functional class I or II, 6MWD ≥ 440 m and CI > 2.5 L/min/m measured 12-16 weeks after the introduction of PAH-targeted therapy are associated with better long-term survival in PAH. Best survival is observed by reaching both the functional class and the 6MWD goals.
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http://dx.doi.org/10.1007/s00408-020-00402-wDOI Listing
December 2020

[Pulmonary embolism or pulmonary thrombosis in situ in severe pneumonic COVID-19 associated coagulopathy: does systemic thrombolysis have a role?]

Medicina (B Aires) 2020 ;80(5):581-582

Medicina Respiratoria, Hospital Ramón y Cajal, Universidad de Alcalá (IRYCIS), Madrid, España.

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October 2020

Morphologic and Functional Dual-Energy CT Parameters in Patients With Chronic Thromboembolic Pulmonary Hypertension and Chronic Thromboembolic Disease.

AJR Am J Roentgenol 2020 12 29;215(6):1335-1341. Epub 2020 Sep 29.

Sections of Thoracic and Cardiovascular Imaging Laboratory, Imaging Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195.

The objective of our study was to compare morphologic and functional dual-energy CT (DECT) parameters in patients with chronic thromboembolic disease (CTED) and chronic thromboembolic pulmonary hypertension (CTEPH). Using the local CTEPH registry, we identified 28 patients with CTED and 72 patients with CTEPH. On each DECT examination, a clot burden score was calculated by assigning the following scores for chronic changes by location: pulmonary trunk, 5; each main pulmonary artery (MPA), 4; each lobar branch, 3; each segmental branch, 2; and each subsegmental branch, 1. The total clot burden score was calculated by adding the individual scores from both lungs. Functional parameters were assessed using perfused blood volume (PBV) maps and included lung enhancement (in Hounsfield units), percentage of PBV, MPA peak enhancement (in Hounsfield units), maximum enhancement corresponding to 100, and the ratio of MPA peak enhancement to lung enhancement. A perfusion defect (PD) score was calculated by assigning 1 point to each segmental PD. Patients with CTED and patients with CTEPH were matched using propensity score matching to account for potential confounders. After matching, the CTEPH group showed a higher PD score than the CTED group and unilateral disease was more common in the CTED group than in the CTEPH group. In the unmatched sample, patients with CTED showed increased percentages of PBV for both lungs (PBV total) and for the right lung as compared with the CTEPH group (adjusted = 0.040 and 0.028, respectively); after adjustment for clot burden, the difference between groups was still noted but was not statistically significant. No statistically significant differences were noted in the various functional DECT parameters after propensity score matching. Patients with CTED show anatomic and functional changes in the pulmonary vasculature and lung parenchyma similar to those seen in patients with CTEPH. Functional DECT parameters support the observation that CTED is an intermediate clinical phenotype in the population with chronic pulmonary embolism.
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http://dx.doi.org/10.2214/AJR.19.22743DOI Listing
December 2020

Refining Risk Stratification in Pulmonary Embolism: A Step Forward.

Chest 2020 Sep;158(3):858-859

Department of Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, OH. Electronic address:

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http://dx.doi.org/10.1016/j.chest.2020.04.001DOI Listing
September 2020

Acute pulmonary embolism multimodality imaging prior to endovascular therapy.

Int J Cardiovasc Imaging 2021 Jan 30;37(1):343-358. Epub 2020 Aug 30.

Section of Interventional Radiology, Imaging Institute, Cleveland Clinic Main Campus, Cleveland, OH, USA.

The manuscript discusses the application of CT pulmonary angiography, ventilation-perfusion scan, and magnetic resonance angiography to detect acute pulmonary embolism and to plan endovascular therapy. CT pulmonary angiography offers high accuracy, speed of acquisition, and widespread availability when applied to acute pulmonary embolism detection. This imaging modality also aids the planning of endovascular therapy by visualizing the number and distribution of emboli, determining ideal intra-procedural catheter position for treatment, and signs of right heart strain. Ventilation-perfusion scan and magnetic resonance angiography with and without contrast enhancement can also aid in the detection and pre-procedural planning of endovascular therapy in patients who are not candidates for CT pulmonary angiography.
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http://dx.doi.org/10.1007/s10554-020-01980-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456521PMC
January 2021

Comparison of 4 Acute Pulmonary Embolism Mortality Risk Scores in Patients Evaluated by Pulmonary Embolism Response Teams.

JAMA Netw Open 2020 08 3;3(8):e2010779. Epub 2020 Aug 3.

Department of Emergency Medicine, Massachusetts General Hospital, Boston.

Importance: The risk of death from acute pulmonary embolism can range as high as 15%, depending on patient factors at initial presentation. Acute treatment decisions are largely based on an estimate of this mortality risk.

Objective: To assess the performance of risk assessment scores in a modern, US cohort of patients with acute pulmonary embolism.

Design, Setting, And Participants: This multicenter cohort study was conducted between October 2016 and October 2017 at 8 hospitals participating in the Pulmonary Embolism Response Team (PERT) Consortium registry. Included patients were adults who presented with acute pulmonary embolism and had sufficient information in the medical record to calculate risk scores. Data analysis was performed from March to May 2020.

Main Outcomes And Measures: All-cause mortality (7- and 30-day) and associated discrimination were assessed by the area under the receiver operator curve (AUC).

Results: Among 416 patients with acute pulmonary embolism (mean [SD] age, 61.3 [17.6] years; 207 men [49.8%]), 7-day mortality in the low-risk groups ranged from 1.3% (1 patient) to 3.1% (4 patients), whereas 30-day mortality ranged from 2.6% (1 patient) to 10.2% (13 patients). Among patients in the highest-risk groups, the 7-day mortality ranged from 7.0% (18 patients) to 16.3% (7 patients), whereas 30-day mortality ranged from 14.4% (37 patients) to 26.3% (26 patients). Each of the risk stratification tools had modest discrimination for 7-day mortality (AUC range, 0.616-0.666) with slightly lower discrimination for 30-day mortality (AUC range, 0.550-0.694).

Conclusions And Relevance: These findings suggest that commonly used risk tools for acute pulmonary embolism have modest estimating ability. Future studies to develop and validate better risk assessment tools are needed.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.10779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450352PMC
August 2020

CT-Based Biomarkers for Prediction of Chronic Thromboembolic Pulmonary Hypertension After an Acute Pulmonary Embolic Event.

AJR Am J Roentgenol 2020 10 18;215(4):800-806. Epub 2020 Aug 18.

Section of Thoracic Imaging, Imaging Institute, Cleveland Clinic, L-10, 413-4, 9500 Euclid Ave, Cleveland, OH 44195.

The purpose of this study is to assess CT-based markers predictive of the development of chronic thromboembolic pulmonary hypertension (CTEPH) after acute pulmonary embolism. Identified from a search of local registries, 48 patients who had CTEPH develop were included in the study group, and 113 patients who had complete resolution of acute pulmonary embolism were included in the control group. Baseline CT scans obtained at the time of the initial pulmonary embolism event were evaluated for the degree of clot-induced vessel obstruction, the quantitative Walsh score, the ratio of the right ventricle diameter to the left ventricle diameter, the right atrium diameter, the pulmonary artery diameter, right heart thrombus, pericardial effusion, lung infarction, and mosaic attenuation. Classification and regression tree analysis was used to create a decision tree. The decision tree was externally validated on an anonymized cohort of 50 control subjects and 50 patients with CTEPH. During univariable analysis, an increase in the degree occlusive clot on initial imaging, a decrease in the Walsh score, absence of pericardial effusion, presence of lung infarction, and the presence of mosaic attenuation were associated with an increased probability of CTEPH development. In the final decision tree, the occlusive nature of the clot remained. Two patients in the cohort used for external validation had nondiagnostic findings and were excluded. The decision process correctly classified 33% (16/48) of patients who had CTEPH develop and 86% (43/50) of patients who did not have CTEPH develop, for an odds ratio of 3.1 (95% CI, 1.1-8.3). The presence of an occlusive clot on initial imaging is associated with an increased probability of CTEPH development. Presence of mosaic attenuation and lung infarction may also predict CTEPH development, although additional studies are needed.
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http://dx.doi.org/10.2214/AJR.19.22541DOI Listing
October 2020

Mixed Venous Oxygen Saturation Is a Better Prognosticator Than Cardiac Index in Pulmonary Arterial Hypertension.

Chest 2020 Dec 3;158(6):2546-2555. Epub 2020 Jul 3.

Department of Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, OH. Electronic address:

Background: European Society of Cardiology (ESC) and European Respiratory Society (ERS) guidelines include thermodilution cardiac index (TDCI) and mixed venous oxygen saturation (SvO) as two of the three hemodynamic determinations used in risk assessment of patients with pulmonary arterial hypertension (PAH). SvO may be a better measurement than TDCI to assess prognosis in patients with either idiopathic or heritable PAH.

Research Question: What is the concordance between TDCI and SvO ESC/ERS risk group allocation and their prognostic value in patients with PAH?

Study Design And Methods: In this retrospective study, we assessed the correlation between SvO and TDCI in patients with idiopathic and heritable PAH. We determined concordance in the ESC/ERS risk group allocation and association with survival, both at baseline and follow-up.

Results: A total of 158 patients (mean age, 58 ± 17 years; 72% women) with idiopathic (91%) and heritable (9%) PAH were included. There was moderate association between TDCI and SvO (r = 0.50; 95% CI, 0.37-0.62). Weighted kappa revealed a fair agreement between TDCI and SvO (κ = 0.30; 95% CI, 0.18-0.42), with concordance in risk group allocation in 49% of patients. During a median follow-up of 45 months (interquartile range, 23-105), 62 patients (39%) died. Using Kaplan-Meier analysis, survival was impacted by the SvO (log rank = 0.002) but not by the TDCI risk group allocation (log-rank = 0.51). Using the Cox proportional hazard model, adjusted for age and sex, SvO (but not TDCI) was associated with mortality (hazard ratio per 1% change, 0.94; 95% CI, 0.91-0.97; P < .001).

Interpretation: When using the cutoffs proposed by the ESC/ERS guidelines, we noted poor concordance in risk score allocation between TDCI and SvO. In patients with idiopathic or heritable PAH, SvO measurements are superior to TDCI in predicting long-term mortality.
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http://dx.doi.org/10.1016/j.chest.2020.06.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768941PMC
December 2020

Assessment of ventilation-perfusion scans in patients with chronic thromboembolic pulmonary hypertension before and after surgery and correlation with clinical parameters.

Clin Imaging 2020 Oct 11;66:147-152. Epub 2020 May 11.

Imaging Institute, Cleveland Clinic, United States of America. Electronic address:

Purpose: We did a comparative analysis of matched and mismatched defects in pre- and post-operative V/Q scans in CTEPH patients. We correlated the number of these defects with pre-operative clinical and hemodynamic parameters.

Methods: This was a retrospective study on 27 patients with CTEPH who underwent surgery. Pre- and post-operative V/Q scans were graded for each lung segment as normal, matched or mismatched defect. Additional pre- and post-operative clinical and hemodynamic parameters that were collected include New York Heart Association functional class, six-minute walk distance in feet, N-terminal pro b-type natriuretic peptide, forced expiratory volume in one second/forced vital capacity, diffusing capacity of the lung for carbon monoxide, pulmonary arterial pressure (systolic, diastolic and mean), right atrial pressure, cardiac output and cardiac index. Pulmonary vascular resistance was then calculated.

Results: On a segmental basis, 176 mismatched defects were noted in 27 patients, of which 111 improved post-surgery (63%). 22 of the 34 matched defects improved following surgery (64%). 31 new mismatched defects were observed. The number of pre-operative matched defects per patient ranged from 0 to 6. No statistically significant associations were observed between the number of pre-operative matched defects and pre-operative clinical parameters. No statistically significant associations were observed between the number of improved matched defects and the change in clinical parameters (pre- to post-surgery).

Conclusion: Both matched and mismatched defects on preoperative V/Q scans can show normalization post-surgery. The extent of matched defects on a preoperative V/Q scan does not correlate significantly with other clinical and hemodynamic parameters.
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http://dx.doi.org/10.1016/j.clinimag.2020.04.041DOI Listing
October 2020

Inpatient Initiation of Oral Treprostinil in an Academic Medical System.

Cardiovasc Drugs Ther 2020 08;34(4):547-553

Department of Pharmacy, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44095, USA.

Purpose: Clinicians may transition patients on parenteral or inhaled prostacyclins to oral treprostinil for ease of use or to avoid adverse effects related to parenteral therapy. However, few data are available to guide these transitions in inpatients. The purpose of this analysis is to describe the inpatient initiation of oral treprostinil at an academic medical system.

Methods: This is a retrospective cohort analysis of patients newly initiated on oral treprostinil at Cleveland Clinic Heath System from 2015 to 2017. Demographic information regarding pulmonary arterial hypertension (PAH) history and previous PAH therapies were recorded. Outcomes evaluated included doses of oral treprostinil utilized, adverse effects related to therapy, and measures of clinical and functional status before and after the initiation of oral treprostinil.

Results: Overall, 29 patients were prescribed oral treprostinil, of which 15 patients were included in the analysis. Common reasons for initiation of oral treprostinil included disease progression (6, 40%) and patient desire (4, 25%). The median duration of transition/initiation of oral treprostinil was 4 days (range, 3-11 days). Median daily dose of oral treprostinil on day 1 of initiation was 2 mg (0.25-4 mg). By day 7, median daily dose was 15 mg (0.75-27.75 mg). Common adverse effects related to therapy were gastrointestinal (7, 47%) and headache (4, 27%). No patients required discontinuation of oral treprostinil due to adverse effects within 90 days of initiation.

Conclusion: Inpatient initiation/transition to oral treprostinil was relatively well tolerated. Future studies should evaluate clinical outcomes surrounding the transitioning to oral treprostinil.
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http://dx.doi.org/10.1007/s10557-020-06992-0DOI Listing
August 2020

Estrogen Signaling and Portopulmonary Hypertension: The Pulmonary Vascular Complications of Liver Disease Study (PVCLD2).

Hepatology 2021 Feb 29;73(2):726-737. Epub 2020 Sep 29.

Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.

Background And Aims: Portopulmonary hypertension (POPH) was previously associated with a single-nucleotide polymorphism (SNP) rs7175922 in aromatase (cytochrome P450 family 19 subfamily A member 1 [CYP19A1]). We sought to determine whether genetic variants and metabolites in the estrogen signaling pathway are associated with POPH.

Approach And Results: We performed a multicenter case-control study. POPH patients had mean pulmonary artery pressure >25 mm Hg, pulmonary vascular resistance >240 dyn-sec/cm , and pulmonary artery wedge pressure ≤15 mm Hg without another cause of pulmonary hypertension. Controls had advanced liver disease, right ventricular (RV) systolic pressure <40 mm Hg, and normal RV function by echocardiography. We genotyped three SNPs in CYP19A1 and CYP1B1 using TaqMan and imputed SNPs in estrogen receptor 1 using genome-wide markers. Estrogen metabolites were measured in blood and urine samples. There were 37 patients with POPH and 290 controls. Mean age was 57 years, and 36% were female. The risk allele A in rs7175922 (CYP19A1) was significantly associated with higher levels of estradiol (P = 0.02) and an increased risk of POPH (odds ratio [OR], 2.36; 95% confidence interval [CI], 1.12-4.91; P = 0.02) whereas other SNPs were not. Lower urinary 2-hydroxyestrogen/16-α-hydroxyestrone (OR per 1-ln decrease = 2.04; 95% CI, 1.16-3.57; P = 0.01), lower plasma levels of dehydroepiandrosterone-sulfate (OR per 1-ln decrease = 2.38; 95% CI, 1.56-3.85; P < 0.001), and higher plasma levels of 16-α-hydroxyestradiol (OR per 1-ln increase = 2.16; 95% CI, 1.61-2.98; P < 0.001) were associated with POPH.

Conclusions: Genetic variation in aromatase and changes in estrogen metabolites were associated with POPH.
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http://dx.doi.org/10.1002/hep.31314DOI Listing
February 2021

Mimickers of chronic thromboembolic pulmonary hypertension on imaging tests: a review.

Pulm Circ 2020 Jan-Mar;10(1):2045894019882620. Epub 2020 Mar 26.

Respiratory Institute, Cleveland Clinic, Cleveland, OH, USA.

Chronic thromboembolic pulmonary hypertension (CTEPH) is caused by mechanical obstruction of large pulmonary arteries secondary to one or more episodes of pulmonary embolism. Ventilation perfusion scan is the recommended initial screening test for this condition and typically shows multiple large mismatched perfusion defects. However, not all patients with an abnormal ventilation perfusion scan have CTEPH since there are other conditions that be associated with a positive ventilation perfusion scan. These conditions include in situ thrombosis, pulmonary artery sarcoma, fibrosing mediastinitis, pulmonary vasculitis and sarcoidosis, among others. Although these conditions cannot be distinguished from CTEPH using a ventilation perfusion scan, they have certain characteristic radiological features that can be demonstrated on other imaging techniques such as computed tomography scan and can help in differentiation of these conditions. In this review, we have summarized some key clinical and radiological features that can help differentiate CTEPH from the CTEPH mimics.
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http://dx.doi.org/10.1177/2045894019882620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103595PMC
March 2020

Plasma metabolomic profile in chronic thromboembolic pulmonary hypertension.

Pulm Circ 2020 Jan-Mar;10(1):2045894019890553. Epub 2020 Feb 4.

Department of Inflammation and Immunity, Lerner Research Institute, Cleveland, OH, USA.

We aimed to characterize the plasma metabolome of chronic thromboembolic pulmonary hypertension patients using a high-throughput unbiased omics approach. We collected fasting plasma from a peripheral vein in 33 operable chronic thromboembolic pulmonary hypertension patients, 31 healthy controls, and 21 idiopathic pulmonary arterial hypertension patients matched for age, gender, and body mass index. Metabolomic analysis was performed using an untargeted approach (Metabolon Inc. Durham, NC). Of the total of 862 metabolites identified, 362 were different in chronic thromboembolic pulmonary hypertension compared to controls: 178 were higher and 184 were lower. Compared to idiopathic pulmonary arterial hypertension, 147 metabolites were different in chronic thromboembolic pulmonary hypertension: 45 were higher and 102 were lower. The plasma metabolome allowed us to distinguish subjects with chronic thromboembolic pulmonary hypertension and healthy controls with a predictive accuracy of 89%, and chronic thromboembolic pulmonary hypertension versus idiopathic pulmonary arterial hypertension with 80% accuracy. Compared to idiopathic pulmonary arterial hypertension and healthy controls, chronic thromboembolic pulmonary hypertension patients had higher fatty acids and glycerol; while acyl cholines and lysophospholipids were lower. Compared to healthy controls, both idiopathic pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension patients had increased acyl carnitines, beta-hydroxybutyrate, amino sugars and modified amino acids and nucleosides. The plasma global metabolomic profile of chronic thromboembolic pulmonary hypertension suggests aberrant lipid metabolism characterized by increased lipolysis, fatty acid oxidation, and ketogenesis, concomitant with reduced acyl choline and phospholipid moieties. Future research should investigate the pathogenetic and therapeutic potential of modulating lipid metabolism in chronic thromboembolic pulmonary hypertension.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000865PMC
February 2020

Lipids and ketones dominate metabolism at the expense of glucose control in pulmonary arterial hypertension: a hyperglycaemic clamp and metabolomics study.

Eur Respir J 2020 04 9;55(4). Epub 2020 Apr 9.

Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

Individuals with idiopathic pulmonary arterial hypertension (PAH) display reduced oral glucose tolerance. This may involve defects in pancreatic function or insulin sensitivity but this hypothesis has not been tested; moreover, fasting nutrient metabolism remains poorly described in PAH. Thus, we aimed to characterise fasting nutrient metabolism and investigated the metabolic response to hyperglycaemia in PAH.12 participants (six PAH, six controls) were administered a hyperglycaemic clamp, while 52 (21 PAH, 31 controls) underwent plasma metabolomic analysis. Glucose, insulin, C-peptide, free fatty acids and acylcarnitines were assessed from the clamp. Plasma metabolomics was conducted on fasting plasma samples.The clamp verified a reduced insulin response to hyperglycaemia in PAH (-53% control), but with similar pancreatic insulin secretion. Skeletal muscle insulin sensitivity was unexpectedly greater in PAH. Hepatic insulin extraction was elevated in PAH (+11% control). Plasma metabolomics identified 862 metabolites: 213 elevated, 145 reduced in PAH (p<0.05). In both clamp and metabolomic cohorts, lipid oxidation and ketones were elevated in PAH. Insulin sensitivity, fatty acids, acylcarnitines and ketones correlated with PAH severity, while hepatic extraction and fatty acid:ketone ratio correlated with longer six-min walk distance.Poor glucose control in PAH could not be explained by pancreatic β-cell function or skeletal muscle insulin sensitivity. Instead, elevated hepatic insulin extraction emerged as an underlying factor. In agreement, nutrient metabolism in PAH favours lipid and ketone metabolism at the expense of glucose control. Future research should investigate the therapeutic potential of reinforcing lipid and ketone metabolism on clinical outcomes in PAH.
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http://dx.doi.org/10.1183/13993003.01700-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263739PMC
April 2020

Impact of Multidisciplinary Pulmonary Embolism Response Team Availability on Management and Outcomes.

Am J Cardiol 2019 11 7;124(9):1465-1469. Epub 2019 Aug 7.

Section of Vascular Medicine, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio.

Treatment strategies for complex patients with pulmonary embolism (PE) are often debated given patient heterogeneity, multitude of available treatment modalities, and lack of consensus guidelines. Although multidisciplinary Pulmonary Embolism Response Teams (PERT) are emerging to address this lack of consensus, their impact on patient outcomes is not entirely clear. This analysis was conducted to compare outcomes of all patients with PE before and after PERT availability. We analyzed all adult patients admitted with acute PE diagnosed on computed tomography scans in the 18 months before and after the institution of PERT at a large tertiary care hospital. Among 769 consecutive inpatients with PE, PERT era patients had lower rates of major or clinically relevant nonmajor bleeding (17.0% vs 8.3%, p = 0.002), shorter time-to-therapeutic anticoagulation (16.3 hour vs 12.6 hour, p = 0.009) and decreased use of inferior vena cava filters (22.2% vs 16.4%, p = 0.004). There was an increase in the use of thrombolytics/catheter-based strategies, however, this did not achieve statistical significance (p = 0.07). There was a significant decrease in 30-day/inpatient mortality (8.5% vs 4.7%, p = 0.03). These differences in outcomes were more pronounced in intermediate and high-risk patients (mortality 10.0% vs 5.3%, p = 0.02). The availability of multidisciplinary PERT was associated with improved outcomes including 30-day mortality. Patients with higher severity of PE seemed to derive most benefit from PERT availability.
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http://dx.doi.org/10.1016/j.amjcard.2019.07.043DOI Listing
November 2019

Pulmonary Edema Following Initiation of Parenteral Prostacyclin Therapy for Pulmonary Arterial Hypertension: A Retrospective Study.

Chest 2019 07 15;156(1):45-52. Epub 2019 Feb 15.

Department of Pulmonary Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, OH. Electronic address:

Background: Pulmonary edema may complicate the use of pulmonary arterial hypertension (PAH)-targeted therapies. We aimed to determine the proportion of patients who develop pulmonary edema after initiation of parenteral prostacyclin therapy, to identify its risk factors, and to assess its implications for hospital length of stay and mortality.

Methods: A retrospective cohort study of patients with PAH at the initiation of parenteral prostacyclin between 1997 and 2015 enrolled in the Cleveland Clinic PAH registry. Pulmonary edema was defined as at least one symptom or clinical sign and radiographic evidence of pulmonary edema. We determined patient characteristics predictive of pulmonary edema as well as the association between pulmonary edema and hospital length of stay (LOS) and 6-month mortality.

Results: One hundred and fifty-five patients were included (median age, 51 years; female, 72%; white, 85%; idiopathic, 64%; and connective tissue disease [CTD], 23%). Pulmonary edema developed in 33 of 155 patients (21%). Independent predictors of pulmonary edema were high right atrial pressure (RAP), CTD etiology, and the presence of three or more risk factors for left heart disease (LHD). Pulmonary edema was associated with a 4.5-day increase in hospital LOS (95% CI, 1.4-7.5 days; P < .001) and a 4-fold increase in 6-month mortality (OR, 4.3; 95% CI, 1.28-14.36; P = .031).

Conclusions: Pulmonary edema occurred in 21% of patients with PAH initiated on parenteral prostacyclin. Three or more risk factors for LHD, CTD-PAH, and a high baseline RAP were independent predictors of pulmonary edema. Pulmonary edema was associated with a prolonged hospital LOS and increased 6-month mortality.
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http://dx.doi.org/10.1016/j.chest.2019.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607426PMC
July 2019

Evaluation of Vascular Parameters in Patients With Pulmonary Thromboembolic Disease Using Dual-energy Computed Tomography.

J Thorac Imaging 2019 Nov;34(6):367-372

Section of Thoracic Imaging, Imaging Institute, Cleveland Clinic.

Purpose: The purpose of this study was to evaluate patterns of vascular and lung parenchymal enhancement in patients with suspected chronic thromboembolic pulmonary hypertension (CTEPH) and in those with acute pulmonary embolism (PE) and compare those two groups.

Materials And Methods: We retrospectively studied 186 thoracic DECT studies referred for evaluation of CTEPH or pulmonary hypertension. A total of 80 of these patients had a negative scan (control group), 13 had acute PE, and 53 had chronic thromboembolic disease (CTED)/CTEPH. Five different DECT-based parameters were evaluated that highlight patterns of vascular kinetics. Specifically, total DECT-based parenchymal attenuation in Hounsfield Unit (HU) (LungHU), percentage of perfused blood volume (PBV), peak enhancement of main pulmonary artery (PApeak in HU), maximum enhancement corresponding to 100 (PAmax), and the ratio of PApeak to LungHU were calculated.

Results: Compared with patients with negative CT, patients with CTED/CTEPH tended to have lower LungHU (median: 27 vs. 38, P<0.001), lower PBV (median: 39 vs. 51, P=0.003), and higher PApeak/LungHU ratio (median: 17 vs. 13, P=0.003). Compared with patients with acute PE, patients with CTED/CTEPH tended to have lower LungHU (median: 27 vs. 39, P=0.006), lower PBV (median: 39 vs. 62, P=0.023), and higher PApeak/LungHU ratio (median: 17 vs. 11, P=0.023). No statistically significant differences were observed between patients with acute PE and those with negative CT.

Conclusions: DECT-based vascular parameters offer the potential to differentiate patients with acute versus chronic PE. These various anatomic and functional vascular DECT-based parameters might be reflective of the state of the underlying vascular bed.
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http://dx.doi.org/10.1097/RTI.0000000000000383DOI Listing
November 2019

Pulmonary Embolism Response Teams: A Novel Approach for the Care of Complex Patients With Pulmonary Embolism.

Clin Appl Thromb Hemost 2018 Dec 19;24(9_suppl):48S-55S. Epub 2018 Nov 19.

Division of Pulmonary and Critical Care Medicine; University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Pulmonary embolism represents the third most common cause of cardiovascular death in the United States. Reperfusion therapeutic strategies such as systemic thrombolysis, catheter directed therapies, surgical pulmonary embolectomy, and cardiopulmonary support devices are currently available for patients with high- and intermediate-high-risk pulmonary embolism. However, deciding on optimal therapy may be challenging. Pulmonary embolism response teams have been designed to facilitate multidisciplinary decision-making with the goal to improve quality of care for complex cases with pulmonary embolism. Herein, we discuss the current role and strategies on how to leverage the strengths from pulmonary embolism response teams, its possible worldwide adoption, and implementation to improve survival and change the paradigm in the care of a potentially deadly disease.
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http://dx.doi.org/10.1177/1076029618812954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714822PMC
December 2018

Comparative assessment of qualitative and quantitative perfusion with dual-energy CT and planar and SPECT-CT V/Q scanning in patients with chronic thromboembolic pulmonary hypertension.

Cardiovasc Diagn Ther 2018 Aug;8(4):414-422

Department of Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, OH, USA.

Background: The purpose of this study was to compare the qualitative and quantitative assessment of perfusion on dual-energy CT (DECT) and planar and single photon emission computed tomography (SPECT)-CT V/Q scanning in patients with chronic thromboembolic pulmonary hypertension (CTEPH).

Methods: Nineteen patients with known CTEPH underwent both DECT and SPECT-CT V/Q scanning. Sixteen of these patients underwent planar V/Q imaging concurrently. Two readers independently graded DECT-perfused blood volume (PBV) defects on a four-point scale (0= normal, 1= mild <25%, 2= moderate 25-50%, 3= severe >50%). A grade was given for each lung lobe and for each of 18 lung segments. One reader graded the SPECT-CT images similarly. Quantitative measurements of lung perfusion were calculated with DECT and planar V/Q scanning for 16 of these patients.

Results: The inter-reader agreement on DECT was strong with agreement in 85% (258/304) of segments (kappa =0.86) and 84% (80/95) of lobes (kappa =0.82). The inter-modality agreement between DECT and SPECT-CT was lower. Readers 1 and 3 agreed in only 34% (103/304) of segments (kappa =0.25) and 33% (31/94) of lobes (kappa =0.22). Agreement between readers 2 and 3 was similar. Correlation between quantitative measurements with DECT and planar V/Q imaging was poor and ranged from 0.01 to 0.45.

Conclusions: Inter-observer agreement in subjective grading of PBV maps is excellent. However, inter-modality agreement between DECT and SPECT-CT is modest. Automated quantification values of PBV maps correlate poorly with established tools like planar V/Q imaging. These differences need to be kept in mind during clinical decision making.
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http://dx.doi.org/10.21037/cdt.2018.05.07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129841PMC
August 2018

Diagnosis of Deep Venous Thrombosis and Pulmonary Embolism: New Imaging Tools and Modalities.

Clin Chest Med 2018 09;39(3):493-504

Department of Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Mail Code A90, 9500 Euclid Avenue, Cleveland, OH 44195, USA.

Imaging continues to be the modality of choice for the diagnosis of venous thromboembolic disease, particularly when incorporated into diagnostic algorithms. Improvement in imaging techniques as well as new imaging modalities and processing methods have improved diagnostic accuracy and additionally are being leveraged in prognostication and decision making for choice of intervention. In this article, we review the role of imaging in diagnosis and prognostication of venous thromboembolism. We also discuss emerging imaging approaches that may in the near future find clinical usefulness in improving diagnosis and prognostication as well as differentiating disease phenotypes.
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http://dx.doi.org/10.1016/j.ccm.2018.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317734PMC
September 2018

Survival After an ICU Hospitalization for Pulmonary Hypertension.

Chest 2018 07;154(1):229-231

Pulmonary and Critical Care Faculty, Cleveland Clinic, Cleveland, OH. Electronic address:

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http://dx.doi.org/10.1016/j.chest.2018.03.028DOI Listing
July 2018

Myeloperoxidase aggravates pulmonary arterial hypertension by activation of vascular Rho-kinase.

JCI Insight 2018 06 7;3(11). Epub 2018 Jun 7.

Heart Center, Department of Cardiology.

Pulmonary arterial hypertension (PAH) remains a disease with limited therapeutic options and dismal prognosis. Despite its etiologic heterogeneity, the underlying unifying pathophysiology is characterized by increased vascular tone and adverse remodeling of the pulmonary circulation. Myeloperoxidase (MPO), an enzyme abundantly expressed in neutrophils, has potent vasoconstrictive and profibrotic properties, thus qualifying as a potential contributor to this disease. Here, we sought to investigate whether MPO is causally linked to the pathophysiology of PAH. Investigation of 2 independent clinical cohorts revealed that MPO plasma levels were elevated in subjects with PAH and predicted adverse outcome. Experimental analyses showed that, upon hypoxia, right ventricular pressure was less increased in Mpo-/- than in WT mice. The hypoxia-induced activation of the Rho-kinase pathway, a critical subcellular signaling pathway yielding vasoconstriction and structural vascular remodeling, was blunted in Mpo-/- mice. Mice subjected to i.v. infusion of MPO revealed activation of Rho-kinase and increased right ventricular pressure, which was prevented by coinfusion of the Rho-kinase inhibitor Y-27632. In the Sugen5416/hypoxia rat model, PAH was attenuated by the MPO inhibitor AZM198. The current data demonstrate a tight mechanistic link between MPO, the activation of Rho-kinase, and adverse pulmonary vascular function, thus pointing toward a potentially novel avenue of treatment.
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http://dx.doi.org/10.1172/jci.insight.97530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124430PMC
June 2018

A pulmonary embolism response team (PERT) approach: initial experience from the Cleveland Clinic.

J Thromb Thrombolysis 2018 Aug;46(2):186-192

Respiratory Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, A90, Cleveland, OH, 44195, USA.

Management of intermediate and high risk acute pulmonary embolism (PE) is challenging. The role of multidisciplinary teams for the care of these patients is emerging. Herein, we report our experience with a pulmonary embolism response team (PERT). We conducted a retrospective chart review on all patients admitted to the Cleveland Clinic main campus who required activation of the (PERT) from October 1, 2014 to September 1, 2016. We extracted data pertaining to clinical presentation, bleeding complications, and pre- and post-discharge imaging. Patients were classified as low, intermediate or high risk PE. Descriptive and continuous variables were collected and analyzed. There were 134 PERT activations. PE was confirmed by CT-PA in 118 patients. Fifteen (13%) patients were classified as low risk, 80 (68%) intermediate risk PE and 23 (19%) high risk PE. Fourteen (12%) patients were treated with catheter directed rtPA, 6 (5%) received full dose (100 mg rtPA), 16 (13%) received systemic half-dose (50 mg rtPA), 6 (5%) underwent a surgical embolectomy and 4 (3%) underwent mechanical thrombectomy. 65 (55%) patients received anticoagulation only, and 8 (7%) patients were managed conservatively without any anticoagulation or advanced therapy. 11 (9%) patients died while during the hospitalization. Fourteen patients had major bleeding events. There were no bleeding events among patients who received systemic low dose or full dose rtPA. A multidisciplinary approach to cases of intermediate risk and high risk PE can be implemented successfully. We saw a relatively low rate of bleeding events with use of rtPA.
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http://dx.doi.org/10.1007/s11239-018-1686-2DOI Listing
August 2018

Plasma levels of high density lipoprotein cholesterol and outcomes in chronic thromboembolic pulmonary hypertension.

PLoS One 2018 29;13(5):e0197700. Epub 2018 May 29.

Department of Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.

Background: High Density Lipoprotein Cholesterol (HDL-C) has various anti-inflammatory, anti-atherogenic, anti-oxidant and anti-coagulant properties that improve vascular function. The utility of HDL-C as a biomarker of severity and predictor of survival was described in patients with pulmonary arterial hypertension (PAH). No prior study has assessed the utility of HDL-C in patients with Chronic Thromboembolic Pulmonary Hypertension (CTEPH).

Objectives: We aim to measure HDL-C levels in CTEPH patients and compare it to those in PAH patients and controls and determine HDL-C associations with markers of disease severity, hemodynamics and mortality in CTEPH.

Methods: We retrospectively included patients with CTEPH, identified from the Cleveland Clinic Pulmonary Hypertension Registry. All patients had right heart catheterization (RHC) and imaging studies consistent with CTEPH. We collected demographics, co-morbidities, baseline laboratory data including plasma HDL-C, six-minute walk test (6MWT), echocardiography and RHC. HDL-C levels were compared to a cohort of patients with cardiovascular risk factors and a previously published PAH cohort.

Results: HDL-C levels were available for 90 patients with CTEPH (age: 57.4±13.9 years; female 40%), 69 patients with PAH (age: 46.7±12.8 years; female 90%) and 254 control subjects (age: 56.7±13 years; female 48%). HDL-C levels in CTEPH patients were lower compared to controls and higher compared to PAH patients (median, IQR: CTEPH: 44, 34-57 mg/dl; PAH: 35.3, 29-39 mg/dl; Control: 49, 40-60 mg/dl; p < 0.01 for both pairwise comparisons). In CTEPH, higher HDL-C was associated with decreased prevalence of right ventricular dilation on echocardiography (p = 0.02). 57 patients with CTEPH underwent pulmonary thromboendarterectomy, higher HDL-C was associated with a larger decrement in postoperative pulmonary vascular resistance (PVR) (r = 0.37, p = 0.049). HDL-C was not associated with mortality or other markers of disease severity.

Conclusions: HDL-C levels in CTEPH patients were lower compared to control subjects, but higher compared to PAH patients. Higher HDL-C in CTEPH was associated with less right ventricular dilation and greater decrement in postoperative PVR. These data suggest that HDL-C may be a useful marker of small vessel disease in CTEPH.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197700PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5973565PMC
December 2018