Pulmonary embolism response team.

The Pulmonary Embolism Response Team (PERT) is a multidisciplinary team that quickly evaluates, coordinates diagnosis, and optimizes management for patients with pulmonary embolism (PE), a serious public health problem. The classification and management of PE has evolved over recent years. Despite updated guidelines by major medical organizations, classification and management relies heavily on expert opinion. Given the complexity of patients with PE and the variety of clinical presentations and treatment options, a multidisciplinary team is warranted.

Relationship of soluble ST2 to pulmonary hypertension severity in patients undergoing cardiac resynchronization therapy.

BACKGROUND: Pulmonary hypertension (PH) is an adverse prognostic marker in patients undergoing cardiac resynchronization therapy (CRT). We sought to determine the relation of biomarkers of fibrosis [soluble ST2 (sST2), galectin-3], wall stretch [amino terminal pro-brain natriuretic peptide (NT-proBNP)], and necrosis [high-sensitivity troponin-I (hsTnI)] to PH severity in CRT patients. METHODS: Biomarkers and right ventricular systolic pressure (RVSP) were measured at CRT implant and 6-month later (n=111). PH was categorized into 3 groups based on RVSP: no (<35 mmHg), mild-moderate (35-60 mmHg), and severe (>60 mmHg). Patients were categorized as progressors (worsened PH), persistent PH (no change) and regressors (improved PH). Endpoints were 6-month CRT response and 2-year major adverse cardiac event (MACE). RESULTS: RVSP was associated with CRT nonresponse (P=0.02) and MACE (P=0.03). Severe PH patients had 5-fold increase risk for CRT nonresponse (OR 5.0, P=0.04) and MACE (HR 5.7, P=0.04) over non-PH patients. Progressors and persistent PH patients had >2-fold odds for CRT non-response (OR 2.8, P=0.45) and >11-fold increase in MACE compared to no PH patients or regressors (HR 11.6, P=0.02). Only NT-proBNP and sST2 were discernable between PH groups, with graded increase based on PH severity (both P≤0.02), and lower values in regressors versus non-regressors (both P≤0.01). Levels of sST2 decreased at 6 months in regressors (15 ng/mL, P=0.03) and increased slightly (3-8 ng/mL) in non-regressors, without difference for NT-proBNP (P=0.08). CONCLUSIONS: sST2 levels are related with PH severity in CRT patients. Serial sST2 changes after CRT implant suggests potential role to monitor PH after CRT.

A four-tier classification system of pulmonary artery metrics on computed tomography for the diagnosis and prognosis of pulmonary hypertension.

BACKGROUND: We aimed to develop a severity classification system of the main pulmonary artery diameter (mPA) and its ratio to the ascending aorta diameter (ratio PA) for the diagnosis and prognosis of pulmonary hypertension (PH) on computed tomography (CT) scans. METHODS: In 228 patients (136 with PH) undergoing right heart catheterization (RHC) and CT for dyspnea, we measured mPA and ratio PA. In a derivation cohort (n = 114), we determined cutpoints for a four-tier severity grading system that would maximize sensitivity and specificity, and validated it in a separate cohort (n = 114). Cutpoints for mPA were defined with ≤27 mm(F) and ≤29 mm(M) as the normal reference range; mild as >27 to <31 mm(F) and >29 to <31 mm(M); moderate≥31-34 mm; and severe>34 mm. Cutpoints for ratio PA were defined as normal ≤0.9; mild>0.9 to 1.0; moderate>1.0 to 1.1; and severe>1.1. RESULTS: Sensitivities for normal tier were 99% for mPA and 93% for ratio PA; while specificities for severe tier were 98% for mPA>34 mm and 100% for ratio PA>1.1. C-statistics for four-tier mPA and ratio PA were both 0.90 (derivation) and both 0.85 (validation). Severity of mPA and ratio PA corresponded to hemodynamics by RHC and echocardiography (both p < 0.001). Moderate-severe mPA values of ≥31 mm and ratio PA>1.1 had worse survival than normal values (all p ≤ 0.01). CONCLUSION: A CT-based four-tier severity classification system of PA diameter and its ratio to the aortic diameter has high accuracy for PH diagnosis with increased mortality in patients with moderate-severe severity grades. These results may support clinical utilization on chest and cardiac CT reports.

Relationship Between Measures of Adiposity, Arterial Inflammation, and Subsequent Cardiovascular Events.

BACKGROUND: The objective of this study was to evaluate how different measures of adiposity are related to both arterial inflammation and the risk of subsequent cardiovascular events. METHODS AND RESULTS: We included individuals who underwent (18)F-fluorodeoxyglucose positron emission tomography/computed tomography imaging for oncological evaluation. Subcutaneous adipose tissue (SAT) volume, visceral adipose tissue (VAT) volume, and VAT/SAT ratio were determined. Additionally, body mass index, metabolic syndrome, and aortic (18)F-fluorodeoxyglucose uptake (a measure of arterial inflammation) were determined. Subsequent development of cardiovascular disease (CVD) events was adjudicated. The analysis included 415 patients with a median age of 55 (P25-P75: 45-65) and a median body mass index of 26.4 (P25-P75: 23.4-30.9) kg/m(2). VAT and SAT volume were significantly higher in obese individuals. VAT volume (r=0.290; P<0.001) and VAT/SAT ratio (r=0.208; P<0.001) were positively correlated with arterial inflammation. Thirty-two subjects experienced a CVD event during a median follow-up of 4 years. Cox proportional hazard models showed that VAT volume and VAT/SAT ratio were associated with CVD events (hazard ratio [95% confidence interval]: 1.15 [1.06-1.25]; P<0.001; 3.60 [1.88-6.92]; P<0.001, respectively). Body mass index, metabolic syndrome, and SAT were not predictive of CVD events. CONCLUSIONS: Measures of visceral fat are positively related to arterial inflammation and are independent predictors of subsequent CVD events. Individuals with higher measures of visceral fat as well as elevated arterial inflammation are at highest risk for subsequent CVD events. The findings suggest that arterial inflammation may explain some of the CVD risk associated with adiposity.

Atrial fibrillation is associated with hematopoietic tissue activation and arterial inflammation.

Inflammation is associated with the development of atrial fibrillation (AF). Activity in hematopoietic tissues, which produce inflammatory leukocytes, is closely related to systemic inflammation, arterial inflammation and cardiovascular events, but its relationship to AF is unknown. Using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging, we examined the relationships between AF, splenic metabolic activity and vascular inflammation. We conducted a cross sectional study of 70 participants: 35 with AF, who were matched (by age, sex and history of active cancer) to 35 controls without AF. Splenic metabolic activity and vascular aortic inflammation were measured by the mean FDG maximum standard uptake values (SUV Max) by PET. We examined (1) the association between AF and splenic activity, and (2) AF and aortic inflammation. The mean age of the population was 68.13 (standard deviation (SD) 8.98) years and 46 (65 %) participants were male. Splenic activity was higher in AF participants [2.31 (SD 0.45) vs. 2.07 (SD 0.37), p = 0.024], and remained significant after adjusting for demographic and clinical covariates. Aortic inflammation was also higher in AF participants [2.22 (SD 0.44) vs. 1.91 (SD 0.44), p = 0.004], and remained significant on multivariable analysis. Aortic inflammation and splenic activity were highly correlated (Pearson R = 0.61, p < 0.001). Atrial fibrillation is associated with higher hematopoietic tissue activation and arterial inflammation. Further studies are needed to clarify the mechanisms by which this cardio-splenic axis is implicated in AF.

Increased arterial inflammation in individuals with stage 3 chronic kidney disease.

PURPOSE: While it is well known that patients with chronic kidney disease (CKD) are at increased risk for the development and progression of atherosclerosis, it is not known whether arterial inflammation is increased in mild CKD. The aim of this study was to compare arterial inflammation using 18F-FDG PET/CT in patients with CKD and in matched controls. METHODS: This restrospective study included 128 patients undergoing FDG PET/CT imaging for clinical indications, comprising 64 patients with stage 3 CKD and 64 control patients matched by age, gender, and cancer history. CKD was defined according to guidelines using a calculated glomerular filtration rate (eGFR). Arterial inflammation was measured in the ascending aorta as FDG uptake on PET. Background FDG uptake (venous, subcutaneous fat and muscle) were recorded. Coronary artery calcification (CAC) was assessed using the CT images. The impact of CKD on arterial inflammation and CAC was then assessed. RESULTS: Arterial inflammation was higher in patients with CKD than in matched controls (standardized uptake value, SUV: 2.41 ± 0.49 vs. 2.16 ± 0.43; p = 0.002). Arterial SUV correlated inversely with eGFR (r = -0.299, p = 0.001). Venous SUV was also significantly elevated in patients with CKD, while subcutaneous fat and muscle tissue SUVs did not differ between groups. Moreover, arterial SUV remained significantly elevated in patients with CKD compared to controls after correcting for muscle and fat background, and also remained significant after adjusting for clinical risk factors. Further, CKD was associated with arterial inflammation (SUV) independent of the presence of subclinical atherosclerosis (CAC). CONCLUSION: Moderate CKD is associated with increased arterial inflammation beyond that of controls. Further, the increased arterial inflammation is independent of presence of subclinical atherosclerosis. Current risk stratification tools may underestimate the presence of atherosclerosis in patients with CKD and thereby the risk of cardiovascular events.

Circulating MicroRNA-30d Is Associated With Response to Cardiac Resynchronization Therapy in Heart Failure and Regulates Cardiomyocyte Apoptosis: A Translational Pilot Study.

BACKGROUND: Biomarkers that predict response to cardiac resynchronization therapy (CRT) in heart failure patients with dyssynchrony (HFDYS) would be clinically important. Circulating extracellular microRNAs (miRNAs) have emerged as novel biomarkers that may also play important functional roles, but their relevance as markers for CRT response has not been examined. METHODS AND RESULTS: Comprehensive miRNA polymerase chain reaction arrays were used to assess baseline levels of 766 plasma miRNAs in patients undergoing clinically indicated CRT in an initial discovery set (n=12) with and without subsequent echocardiographic improvement at 6 months after CRT. Validation of candidate miRNAs in 61 additional patients confirmed that baseline plasma miR-30d was associated with CRT response (defined as an increase in left ventricular ejection fraction ≥10%). MiR-30d was enriched in coronary sinus blood and increased in late-contracting myocardium in a canine model of HFDYS, indicating cardiac origin with maximal expression in areas of high mechanical stress. We examined the functional effects of miR-30d in cultured cardiomyocytes and determined that miR-30d is expressed in cardiomyocytes and released in vesicles in response to mechanical stress. Overexpression of miR-30d in cultured cardiomyocytes led to cardiomyocyte growth and protected against apoptosis by targeting the mitogen-associated kinase 4, a downstream effector of tumor necrosis factor. In HFDYS patients, miR-30d plasma levels inversely correlated with high-sensitivity troponin T, a marker of myocardial necrosis. CONCLUSIONS: Baseline plasma miR-30d level is associated with response to CRT in HFDYS in this translational pilot study. MiR-30d increase in cardiomyocytes correlates with areas of increased wall stress in HFDYS and is protective against deleterious tumor necrosis factor signaling.

Splenic metabolic activity predicts risk of future cardiovascular events: demonstration of a cardiosplenic axis in humans.

OBJECTIVES: This study sought to determine whether splenic activation after acute coronary syndrome (ACS) is linked to leukocyte proinflammatory remodeling and whether splenic activity independently predicts the risk of cardiovascular disease (CVD) events. BACKGROUND: Pre-clinical data suggest the existence of a cardiosplenic axis, wherein activation of hematopoietic tissues (notably in the spleen) results in liberation of proinflammatory leukocytes and accelerated atherosclerotic inflammation. However, it is presently unknown whether a cardiosplenic axis exists in humans and whether splenic activation relates to CVD risk. METHODS: (18)F-fluorodeoxyglucose ((18)FDG)-positron emission tomography (PET) imaging was performed in 508 individuals across 2 studies. In the first study, we performed FDG-PET imaging in 22 patients with recent ACS and 22 control subjects. FDG uptake was measured in spleen and arterial wall, whereas proinflammatory gene expression of circulating leukocytes was assessed by quantitative real-time polymerase chain reaction. In a second study, we examined the relationship between splenic tissue FDG uptake with subsequent CVD events during follow-up (median 4 years) in 464 patients who previously had undergone FDG-PET imaging. RESULTS: Splenic activity increased after ACS and was significantly associated with multiple indices of inflammation: 1) up-regulated gene expression of proinflammatory leukocytes; 2) increased C-reactive protein; and 3) increased arterial wall inflammation (FDG uptake). Moreover, in the second study, splenic activity (greater than or equal to the median) was associated with an increased risk of CVD events (hazard ratio [HR]: 3.3; 95% confidence interval [CI]: 1.5 to 7.3; p = 0.003), which remained significant after adjustment for CVD risk factors (HR: 2.26; 95% CI: 1.01 to 5.06; p = 0.04) and for arterial FDG uptake (HR: 2.68; 95% CI: 1.5 to 7.4; p = 0.02). CONCLUSIONS: Our findings demonstrate increased splenic metabolic activity after ACS and its association with proinflammatory remodeling of circulating leukocytes. Moreover, we observed that metabolic activity of the spleen independently predicted risk of subsequent CVD events. Collectively, these findings provide evidence of a cardiosplenic axis in humans similar to that shown in pre-clinical studies.

Coronary sinus biomarker sampling compared to peripheral venous blood for predicting outcomes in patients with severe heart failure undergoing cardiac resynchronization therapy: the BIOCRT study.

BACKGROUND: A significant minority of patients receiving cardiac resynchronization therapy (CRT) remain nonresponsive to this intervention. OBJECTIVE: This study aimed to determine whether coronary sinus (CS) or baseline peripheral venous (PV) levels of established and emerging heart failure (HF) biomarkers are predictive of CRT outcomes. METHODS: In 73 patients (aged 68 ± 12 years; 83% men; ejection fraction 27% ± 7%) with CS and PV blood samples drawn simultaneously at the time of CRT device implantation, we measured amino-terminal pro-B-type natriuretic peptide (NT-proBNP), galectin-3 (gal-3), and soluble ST2 (sST2) levels. NT-proBNP concentrations >2000 pg/mL, gal-3 concentrations >25.9 ng/mL, and sST2 concentrations >35 ng/mL were considered positive on the basis of established PV cut points for identifying "high-risk" individuals with HF. CRT response was adjudicated by the HF Clinical Composite Score. A major adverse cardiovascular event (MACE) was defined as the composite end point of death, cardiac transplant, left ventricular assist device, and HF hospitalization at 2 years. RESULTS: NT-proBNP concentrations were 20% higher in the CS than in the periphery, while gal-3 and sST2 concentrations were 10% higher in the periphery than in the CS (all P < .001). There were 45% CRT nonresponders at 6 months and 16 (22%) patients with MACE. Triple-positive CS values yielded the highest specificity of 95% for predicting CRT nonresponse. Consistently, CS strategies identified patients at higher risk of developing MACE, with >11-fold adjusted increase for triple-positive CS patients compared to triple-negative patients (all P ≤ .04). PV strategies were not predictive of MACE. CONCLUSION: Our findings suggest that CS sampling of HF biomarkers may be better than PV sampling for predicting CRT outcomes. Larger studies are needed to confirm our findings.

Measurement of arterial activity on routine FDG PET/CT images improves prediction of risk of future CV events.

OBJECTIVES: This study sought to determine whether arterial inflammation measured by (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET) improves prediction of cardiovascular disease (CVD) beyond traditional risk factors. BACKGROUND: It is unknown whether arterial (18)F-FDG uptake measured with routine PET imaging provides incremental value for predicting CVD events beyond Framingham risk score (FRS). METHODS: We consecutively identified 513 individuals from 6,088 patients who underwent (18)F-FDG-PET and computed tomography (CT) imaging at Massachusetts General Hospital between 2005 and 2008 and who met additional inclusion criteria: ≥30 years of age, no prior CVD, and free of cancer. CVD events were independently adjudicated, while blinded to clinical data, using medical records to determine incident stroke, transient ischemic attack, acute coronary syndrome, revascularization, new-onset angina, peripheral arterial disease, heart failure, or CVD death. FDG uptake was measured in the ascending aorta (as target-to-background-ratio [TBR]), while blinded to clinical data. RESULTS: During follow-up (median 4.2 years), 44 participants developed CVD (2 per 100 person-years at risk). TBR strongly predicted subsequent CVD independent of traditional risk factors (hazard ratio: 4.71; 95% confidence interval [CI]: 1.98 to 11.2; p < 0.001) and (hazard ratio: 4.13; 95% CI: 1.59 to 10.76; p = 0.004) after further adjustment for coronary calcium score. Addition of arterial PET measurement to FRS scores improved the C-statistic (mean ± standard error 0.62 ± 0.03 vs. 0.66 ± 0.03). Further, incorporation of TBR into a model with FRS variables resulted in an integrated discrimination of 5% (95% CI: 0.36 to 9.87). Net reclassification improvements were 27.48% (95% CI: 16.27 to 39.92) and 22.3% (95% CI: 11.54 to 35.42) for the 10% and 6% intermediate-risk cut points, respectively. Moreover, TBR was inversely associated with the timing of CVD (beta -0.096; p < 0.0001). CONCLUSIONS: Arterial FDG uptake, measured from routinely obtained PET/CT images, substantially improved incident CVD prediction beyond FRS among individuals undergoing cancer surveillance and provided information on the potential timing of such events.