Pelvic Vein Obstruction in Chronic Thromboembolic Pulmonary Hypertension: A Novel Association.

Background: Pelvic venous obstruction (PVO), defined as greater than 50% stenosis or occlusion of pelvic veins, is a known risk factor for deep vein thrombosis (DVT). DVT is a known risk factor for chronic thromboembolic pulmonary hypertension (CTEPH), but the prevalence of PVO in CTEPH is unknown. Methods: This cross-sectional study at Temple University's tertiary referral center for Pulmonary Hypertension, Right Heart Failure, and CTEPH sought to identify the presence of PVO in patients with CTEPH who underwent cardiac catheterization, pulmonary angiography, and venography. Results: A total of 193 CTEPH patients were referred for pulmonary angiography, and among these, 148 underwent venography. PVO was identified in 65 (44%) patients. Lower extremity (LE) DVT was associated with PVO (p = 0.004). The severity of pulmonary hypertension was similar with and without PVO (mean pulmonary artery pressure 43.0 ± 10.3 mm Hg vs. 43.8 ± 12.4 mm Hg, p = 0.70), as was the need for pulmonary thromboendarterectomy (69.2% vs. 61.4%, p = 0.32). Conclusions: Pelvic vein obstruction is common and a novel clinical association in patients with CTEPH, particularly in patients with a history of LE DVT. PVO and its role in CTEPH warrants further study, including the potential role of revascularization to mitigate further risk.

Virtual Echocardiography Screening Tool Identifies Pulmonary Arterial Hypertension Significantly Earlier Than High-Risk Clinical Diagnosis.

Pulmonary arterial hypertension (PAH) is often a progressive, fatal disease. Because of nonspecificity of symptoms and limited awareness of PAH, patients are often diagnosed and referred late to accredited pulmonary hypertension (PH) centers, contributing to worsening survival and overall prognosis. The objective of the present study was to determine if the virtual echocardiography screening tool (VEST), a simple scoring system using routinely reported echocardiographic metrics, could capture earlier diagnoses of PAH before clinical recognition and referral to expert PH centers. This study is a retrospective analysis of 132 patients with PAH evaluated consecutively at 2 accredited referral PH centers. VEST scores and time to evaluation at PH center were quantified based on the first available echocardiogram before referral. Clinical risk assessment was calculated at initial evaluation by the PH center using the REVEAL (Registry to Evaluate Early and Long-term PAH Disease Management) 2.0 calculator. An overwhelming majority (93%) of the study participants had markedly abnormal VEST scores predictive of PAH before evaluation at a PH referral center. The median delay from VEST to evaluation was >6 months at 206 days (quartile 1, quartile 3: 55, 757). At initial evaluation, 72% were intermediate or high-risk based on REVEAL 2.0 risk assessment. In conclusion, we propose that VEST is a powerful yet simple scoring tool that can capture high-risk patients with PAH, prompting earlier diagnosis and referrals to accredited PH centers, and allowing for earlier expert implementation of PH medical therapies.

Risk Stratification of Patients with Pulmonary Arterial Hypertension: The Role of Echocardiography.

Background: Given the morbidity and mortality associated with pulmonary arterial hypertension (PAH), risk stratification approaches that guide therapeutic management have been previously employed. However, most patients remain in the intermediate-risk category despite initial therapy. Herein, we sought to determine whether echocardiographic parameters could improve the risk stratification of intermediate-risk patients. Methods: Prevalent PAH patients previously enrolled in observational studies at 3 pulmonary hypertension centers were included in this study. A validated PAH risk stratification approach was used to stratify patients into low-, intermediate-, and high-risk groups. Right ventricular echocardiographic parameters were used to further stratify intermediate-risk patients into intermediate-low- and intermediate-high-risk groups based on transplant-free survival. Results: From a total of 146 patients included in our study, 38 patients died over a median follow-up of 2.5 years. Patients with intermediate-/high-risk had worse echocardiographic parameters. Tricuspid annular plane systolic excursion (TAPSE) and the degree of tricuspid regurgitation (TR) were highly associated with survival (p < 0.01, p = 0.04, respectively) and were subsequently used to further stratify intermediate-risk patients. Among intermediate-risk patients, survival was worse for patients with TAPSE < 19 mm compared to those with TAPSE ≥ 19 mm (estimated one-year survival 74% vs. 96%, p < 0.01) and for patients with moderate/severe TR compared to those with no/trace/mild TR (estimated one-year survival 70% vs. 93%, p < 0.01). Furthermore, among intermediate-risk patients, those with both TAPSE < 19 mm and moderate/severe TR had an estimated one-year survival (56%) similar to that of high-risk patients (56%), and those with both TAPSE ≥ 19 mm and no/trace/mild TR had an estimated one-year survival (97%) similar to that of low-risk patients (95%). Conclusions: Echocardiography, a routinely performed, non-invasive imaging modality, plays a pivotal role in discriminating distinct survival phenotypes among prevalent intermediate-risk PAH patients using TAPSE and degree of TR. This can potentially help guide subsequent therapy.

May-Thurner Anatomy in Patients With Chronic Thromboembolic Pulmonary Hypertension: An Important Clinical Association.

OBJECTIVES: The aim of this study was to investigate the incidence of May-Thurner anatomy (MTA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and identify its predictors. BACKGROUND: MTA is an anatomical variant characterized by compression of left common iliac vein by the overlying right iliac artery. Over time, this leads to venous intimal scarring, blood flow stasis, and the development of deep vein thrombosis (DVT). DVT is a known risk factor for the development of CTEPH. The prevalence of this anatomical variation in patients with CTEPH is unknown. METHODS: A retrospective chart review was conducted in patients referred to Temple University Hospital's cardiac catheterization laboratory for the evaluation of CTEPH between January 2016 and June 2020. Among these patients, those who underwent invasive venography were evaluated for the presence of angiographic MTA. Multivariate regression was used to identify factors associated with presence of MTA. RESULTS: A total of 193 patients with CTEPH were referred for pulmonary angiography, of whom 148 patients underwent invasive venography. MTA was identified in 44 patients (29.7%). Factors associated with the presence of MTA were lower extremity DVT (odds ratio: 3.5; 95% confidence interval: 1.58-7.8; P = 0.002), and left lower extremity post-thrombotic syndrome (odds ratio: 2.0; 95% confidence interval: 0.98-4.1; P = 0.05). Patients with MTA were more likely to undergo pulmonary thromboendarterectomy than patients without MTA (79.5% vs 58.7%; P = 0.015). CONCLUSIONS: MTA is very common in patients with CTEPH. History of lower extremity DVT and or left lower extremity post-thrombotic syndrome was associated with the presence of MTA.

Virtual echocardiography screening tool to differentiate hemodynamic profiles in pulmonary hypertension.

This study validated a novel virtual echocardiography screening tool (VEST), which utilized routinely reported echocardiography parameters to predict hemodynamic profiles in pulmonary hypertension (PH) and identify PH due to pulmonary vascular disease (PHPVD). Direct echocardiography imaging review has been shown to predict hemodynamic profiles in PH; however, routine use often overemphasizes Doppler-estimated pulmonary artery systolic pressure (PASPDE), which lacks discriminatory power among hemodynamically varied PH subgroups. In patients with PH of varying subtypes at a tertiary referral center, reported echocardiographic findings needed for VEST, including left atrial size, E:e' and systolic interventricular septal flattening, were obtained. Receiver operating characteristic analyses assessed the predictive performance of VEST vs. PASPDE in identifying PHPVD, which was later confirmed by right heart catheterization. VEST demonstrated far superior discriminatory power than PASPDE in identifying PHPVD. A positive score was 80.0% sensitive and 75.6% specific for PHPVD with an area under the curve of 0.81. PASPDE exhibited poorer discriminatory power with an area under the curve of 0.56. VEST's strong discriminatory ability remained unchanged when validated in a second cohort from another tertiary center. We demonstrated that this novel VEST using three routine parameters that can be easily extracted from standard echocardiographic reports can successfully capture PH patients with a high likelihood of PHPVD. During the Covid-19 pandemic, when right heart catheterization and timely access to experts at accredited PH centers may have limited widespread availability, this may assist physicians to rapidly and remotely evaluate PH patients to ensure timely and appropriate care.

A comprehensive echocardiographic method for risk stratification in pulmonary arterial hypertension.

QUESTION ADDRESSED: Echocardiography is not currently considered as providing sufficient prognostic information to serve as an integral part of treatment goals in pulmonary arterial hypertension (PAH). We tested the hypothesis that incorporation of multiple parameters reflecting right heart function would improve the prognostic value of this imaging modality. METHODS AND MAIN RESULTS: We pooled individual patient data from a total of 517 patients (mean age 52±15 years, 64.8% females) included in seven observational studies conducted at five European and United States academic centres. Patients were subdivided into three groups representing progressive degrees of right ventricular dysfunction based on a combination of echocardiographic measurements, as follows. Group 1 (low risk): normal tricuspid annular plane systolic excursion (TAPSE) and nonsignificant tricuspid regurgitation (TR) (n=129); group 2 (intermediate risk): normal TAPSE and significant TR or impaired TAPSE and nondilated inferior vena cava (IVC) (n=256); group 3 (high risk): impaired TAPSE and dilated IVC (n=132). The 5-year cumulative survival rate was 82% in group 1, 63% in group 2 and 43% in group 3. Low-risk patients had better survival rates than intermediate-risk patients (log-rank Chi-squared 12.25; p<0.001) and intermediate-risk patients had better survival rates than high-risk patients (log-rank Chi-squared 26.25; p<0.001). Inclusion of other parameters such as right atrial area and pericardial effusion did not provide added prognostic value. ANSWER TO THE QUESTION: The proposed echocardiographic approach integrating the evaluation of TAPSE, TR grade and IVC is effective in stratifying the risk for all-cause mortality in PAH patients, outperforming the prognostic parameters suggested by current guidelines.

Leiomyosarcoma Tumor Embolism Masquerading as Thrombus in Transit.

BACKGROUND Tumor embolism is a rare neoplastic complication that occurs when there is intravenous invasion by a benign or malignant tumor. We present the case of an asymptomatic patient with an incidentally discovered leiomyosarcoma tumor emboli, which was initially misdiagnosed as "thrombus in transit." CASE REPORT The patient was a 58-year-old woman who was incidentally found on echocardiogram to have a large tubular mass within the inferior vena cava and right atrium. Although initially characterized as "thrombus in transit", this mobile right atrial mass was present without clinical, echocardiographic, or radiographic evidence of pulmonary embolism or increased pulmonary arterial impedance. Given that a thrombus in transit is nearly always associated with submassive or massive pulmonary emboli and their attendant right heart sequelae, these pertinent negative findings led us to seek an alternative diagnosis. After a trial of conservative management with anticoagulation and attempted removal of the mass with the AngioVac system, the patient ultimately underwent median sternotomy and surgical embolectomy on cardiopulmonary bypass to remove the mass, which was later identified on pathology as a leiomyosarcoma. CONCLUSIONS With rare exceptions, "thrombus in transit" is accompanied by large pulmonary emboli and the presence of increased pulmonary artery pressure and right heart strain. The absence of clinical, echocardiographic, or radiographic evidence of these hemodynamic sequelae should raise suspicion for an alternative diagnosis. Tumor embolism should be considered in the differential diagnosis of any patient with a history of malignancy who presents with evidence of intracardiac mass or embolism.

Cangrelor and Heparin for Pulmonary Thromboendarterectomy in Heparin-Induced Thrombocytopenia.

Perioperative anticoagulation management for patients with heparin-induced thrombocytopenia requiring cardiopulmonary bypass and deep hypothermic circulatory arrest presents a clinical challenge. Alternative anticoagulants have been used but can cause significant postoperative bleeding. We report the successful use of cangrelor and heparin in a 30-year-old patient with severe heparin-induced thrombocytopenia undergoing urgent pulmonary thromboendarterectomy.

Right ventricular outflow tract velocity time integral-to-pulmonary artery systolic pressure ratio: a non-invasive metric of pulmonary arterial compliance differs across the spectrum of pulmonary hypertension.

Pulmonary arterial compliance (PAC), invasively assessed by the ratio of stroke volume to pulmonary arterial (PA) pulse pressure, is a sensitive marker of right ventricular (RV)-PA coupling that differs across the spectrum of pulmonary hypertension (PH) and is predictive of outcomes. We assessed whether the echocardiographically derived ratio of RV outflow tract velocity time integral to PA systolic pressure (RVOT-VTI/PASP) (a) correlates with invasive PAC, (b) discriminates heart failure with preserved ejection-associated PH (HFpEF-PH) from pulmonary arterial hypertension (PAH), and (c) is associated with functional capacity. We performed a retrospective cohort study of patients with PAH (n = 70) and HFpEF-PH (n = 86), which was further dichotomized by diastolic pressure gradient (DPG) into isolated post-capillary PH (DPG < 7 mmHg; Ipc-PH, n = 54), and combined post- and pre-capillary PH (DPG ≥ 7 mm Hg; Cpc-PH, n = 32). Of the 156 patients, 146 had measurable RVOT-VTI or PASP and were included in further analysis. RVOT-VTI/PASP correlated with invasive PAC overall (ρ = 0.61, P < 0.001) and for the PAH (ρ = 0.38, P = 0.002) and HFpEF-PH (ρ = 0.63, P < 0.001) groups individually. RVOT-VTI/PASP differed significantly across the PH spectrum (PAH: 0.13 [0.010-0.25] vs. Cpc-PH: 0.20 [0.12-0.25] vs. Ipc-PH: 0.35 [0.22-0.44]; P < 0.001), distinguished HFpEF-PH from PAH (AUC = 0.72, 95% CI = 0.63-0.81) and Cpc-PH from Ipc-PH (AUC = 0.78, 95% CI = 0.68-0.88), and remained independently predictive of 6-min walk distance after multivariate analysis (standardized ß-coefficient = 27.7, 95% CI = 9.2-46.3; P = 0.004). Echocardiographic RVOT-VTI/PASP is a novel non-invasive metric of PAC that differs across the spectrum of PH. It distinguishes the degree of pre-capillary disease within HFpEF-PH and is predictive of functional capacity.

Case series of seven women with uterine fibroids associated with venous thromboembolism and chronic thromboembolic disease.

Uterine fibroids have been described as an associate to acute venous thromboembolism (VTE), with case reports showing an association between large uterine fibroids, acute deep venous thrombosis (DVT), and acute pulmonary embolism (PE). However, there is little known about the association or causation between uterine fibroids, chronic thromboembolic disease (CTED), and chronic thromboembolic pulmonary hypertension (CTEPH). We report on six women with uterine fibroids and CTEPH, as well as one woman with CTED, all of whom presented with exertional dyspnea, lower extremity swelling, and in the cases of CTEPH, clinical, echocardiographic, and hemodynamic evidence of pulmonary hypertension and right heart failure. Compression of the pelvic veins by fibroids was directly observed with invasive venography or contrast-enhanced computed tomography in five cases. All seven women underwent pulmonary thromboendarterectomy (PTE) followed by marked improvement in functional, clinical, and hemodynamic status.

Using all-cause mortality to define severe RV dilation with RV/LV volume ratio.

Right ventricular (RV) end-diastolic volume (EDV) to left ventricular (LV) EDV ratio using cardiovascular magnetic resonance imaging (CMR) is an important parameter for RV size evaluation in additional to indexed EDV. We explore the severity partition for RV dilation using mortality in a population of 62 patients with pulmonary hypertension (PH). Cine short-axis images were acquired with a 1.5 T MR scanner using a steady-state free precession sequence. The optimal cutoff to classify severe RV dilation was determined by a receiver-operating curve (ROC) analysis based on mortality. We further defined mild and moderate categories by the standard deviation distance between normal and severely dilated and found the categories RV dilation by RV/LV volume ratio to be "mild" (1.27-1.69), "moderate" (1.70-2.29) and "severe" (≥2.30). There were significant differences in RVEDV and RV ejection fraction between "mild", "moderate" and "severe" groups (p < 0.001). The "severe" category had a significantly higher mortality when compared to the "non-severe" categories (p < 0.001) while there was no difference among the "non-severe" dilated groups. We have shown that severe RV dilation partition can be defined using mortality with RV/LV volume ratio, which offers an outcome based grading of the "severe" category of RV dilation.

Initial Right Ventricular Dysfunction Severity Identifies Severe Peripartum Cardiomyopathy Phenotype With Worse Early and Overall Outcomes: A 24-Year Cohort Study.

BACKGROUND: Outcomes in peripartum cardiomyopathy (PPCM) vary. We sought to determine whether severity of left or right ventricular dysfunction (RVD) at PPCM diagnosis differentially associates with adverse outcomes. METHODS AND RESULTS: We conducted a single-center retrospective cohort study of 53 patients with PPCM. The primary outcome was a composite of left ventricular assist device implantation, cardiac transplantation, or death. We used Kaplan-Meier curves to examine event-free survival and Cox proportional hazards models to examine associations of left ventricular (LV) ejection fraction <30%, LV end-diastolic diameter ≥60 mm, and moderate-to-severe RVD at PPCM diagnosis with the primary outcome. Median (interquartile range) follow-up time was 3.6 (1.4-7.3) years. Seventeen patients (32%) experienced the primary outcome, of whom 11 had moderate-to-severe RVD at time of PPCM diagnosis. Overall event-free survival differed by initial RVD severity and LV ejection fraction <30%, but not by LV end-diastolic diameter ≥60 mm. In univariable analyses, LV ejection fraction <30% and moderate-to-severe RVD were associated with the outcome (hazard ratios [95% confidence intervals] of 4.85 [1.11-21.3] and 4.26 [1.47-11.6], respectively). In a multivariable model with LV ejection fraction <30%, LV end-diastolic diameter ≥60 mm, and moderate-to-severe RVD, only moderate-to-severe RVD was independently associated with the outcome (hazard ratio [95% confidence interval], 3.21 [1.13-9.10]). Although most outcomes occurred within the first year, nearly a third occurred years after PPCM diagnosis. CONCLUSIONS: Initial moderate-to-severe RVD is associated with a more advanced cardiomyopathy phenotype and increased risk of adverse outcomes in PPCM, within and beyond the first year of diagnosis. By identifying a worse PPCM phenotype, initial moderate-to-severe RVD may prompt earlier consideration of advanced heart replacement therapies.

Rationale and design of the ranolazine PH-RV study: a multicentred randomised and placebo-controlled study of ranolazine to improve RV function in patients with non-group 2 pulmonary hypertension.

Introduction: A major determining factor on outcomes in patients with pulmonary arterial hypertension (PAH) is right ventricular (RV) function. Ranolazine, which is currently approved for chronic stable angina, has been shown to improve RV function in an animal model and has been shown to be safe in small human studies with PAH. We aim to study the effect of ranolazine on RV function using cardiovascular magnetic resonance (CMR) in patients with pulmonary hypertension (non-group 2 patients) and monitor the effect of ranolazine on metabolism using metabolic profiling and changes of microRNA. Methods and analysis: This study is a longitudinal, randomised, double-blind, placebo-controlled, multicentre proof-of-concept study in 24 subjects with pulmonary hypertension and RV dysfunction treated with ranolazine over 6 months. Subjects who meet the protocol definition of RV dysfunction (CMR RV ejection fraction (EF) <45%) will be randomised to ranolazine or placebo with a ratio of 2:1. Enrolled subjects will be assessed for functional class, 6 min walk test and health outcome based on SF-36 tool. Peripheral blood will be obtained for N-terminal-pro brain natriuretic peptide, metabolic profiling, and microRNA at baseline and the conclusion of the treatment period. CMR will be performed at baseline and the conclusion of the treatment period. The primary outcome is change in RVEF. The exploratory outcomes include clinical, other CMR parameters, metabolic and microRNA changes. Ethics and dissemination: The trial protocol was approved by Institutional Review Boards. The trial findings will be disseminated in scientific journals and meetings. Trial registration numbers: NCT01839110 and NCT02829034; Pre-results.

Follow-up tricuspid annular plane systolic excursion predicts survival in pulmonary arterial hypertension.

Few studies have examined the utility of serial echocardiography in the evaluation, management, and prognosis of patients with pulmonary arterial hypertension (PAH). Therefore, we sought to evaluate the prognostic significance of follow-up tricuspid annular plane systolic excursion (TAPSE) in PAH. We prospectively studied 70 consecutive patients with PAH who underwent baseline right heart catheterization (RHC) and transthoracic echocardiogram, who survived to follow-up echocardiogram after initiation of PAH therapy. Baseline TAPSE was 1.6 ± 0.5 cm which increased to 2.0 ± 0.4 cm on follow-up ( P < 0.0001). The cohort was dichotomized by TAPSE at one-year follow-up: Group 1 (n = 37): follow-up TAPSE ≥ 2 cm; Group 2 (n = 33): follow-up TAPSE < 2 cm. Group 1 participants were significantly more likely to reach WHO functional class I-II status and achieve a higher six-minute walk distance on follow-up. Of the 68 patients who survived more than one year, 18 died (26.5%) over a median follow-up of 941 days (range, 3-2311 days), with significantly higher mortality in Group 2 versus Group 1 (41.9% vs. 13.5%; P = 0.003). While baseline TAPSE stratified at 2 cm did not predict survival in this cohort, TAPSE ≥ 2 cm at follow-up strongly predicted survival in bivariable models (hazard ratio, 0.21; 95% confidence interval, 0.08-0.60). In conclusion, follow-up TAPSE ≥ 2 cm is a prognostic marker and potential treatment target in a PAH population.

Assessment of the physiologic contribution of right atrial function to total right heart function in patients with and without pulmonary arterial hypertension.

Total right heart function requires normal function of both the right ventricle and the right atrium. However, the degree to which right atrial (RA) function and right ventricular (RV) function each contribute to total right heart function has not been quantified. In this study, we aimed to quantify the contribution of RA function to total right heart function in a group of pulmonary arterial hypertension (PAH) patients compared to a cohort of normal controls without cardiovascular disease. The normal cohort comprised 35 subjects with normal clinical echocardiograms, while the PAH cohort included 37 patients, of whom 31 had echocardiograms before and after initiation of PAH-specific therapy. Total right heart function was measured via tricuspid annular plane excursion (TAPSE). TAPSE was broken down into two components, the excursion occurring during RA contraction (TAPSERA) and that occurring before RA contraction (TAPSERV). RA fractional area change (RA-FAC) was also compared between the two groups. In the PAH cohort, more than half of the total TAPSE occurred during atrial systole, compared to less than one-third in the normal cohort (51.0% vs. 32.1%; P < 0.0001). There was a significant correlation between RA-FAC and TAPSE in the PAH cohort but not in the normal cohort. TAPSE improved significantly in the posttreatment cohort (1.7 vs. 2.1 cm), but TAPSERA continued to account for about half of the total TAPSE after treatment. RA function accounts for a significantly greater proportion of total right heart function in patients with PAH than in normal subjects.