Background—The purpose of this study was to determine the relative contribution of fibrosis-mediated and myofibril-mediated stiffness in rats with mild and severe right ventricular (RV) dysfunction. Methods and Results—By performing pulmonary artery banding of different diameters for 7 weeks, mild RV dysfunction (Ø=0.6 mm) and severe RV dysfunction (Ø=0.5 mm) were induced in rats. The relative contribution of fibrosis- and myofibril-mediated RV stiffness was determined in RV trabecular strips. Total myocardial stiffness was increased in trabeculae from both mild and severe RV dysfunction in comparison to controls. In severe RV dysfunction, increased RV myocardial stiffness was explained by both increased fibrosis-mediated stiffness and increased myofibril-mediated stiffness, whereas in mild RV dysfunction, only myofibril-mediated stiffness was increased in comparison to control. Histological analyses revealed that RV fibrosis gradually increased with severity of RV dysfunction, whereas the ratio of collagen I/III expression was only elevated in severe RV dysfunction. Stiffness measurements in single membrane-permeabilized RV cardiomyocytes demonstrated a gradual increase in RV myofibril stiffness, which was partially restored by protein kinase A in both mild and severe RV dysfunction. Increased expression of compliant titin isoforms was observed only in mild RV dysfunction, whereas titin phosphorylation was reduced in both mild and severe RV dysfunction. Conclusions—RV myocardial stiffness is increased in rats with mild and severe RV dysfunction. In mild RV dysfunction, stiffness is mainly determined by increased myofibril stiffness. In severe RV dysfunction, both myofibril- and fibrosis-mediated stiffness contribute to increased RV myocardial stiffness.

Background: We provide the first multicenter analysis of patients cared for by eight Pulmonary Embolism Response Teams (PERTs) in the United States (US); describing the frequency of team activation, patient characteristics, pulmonary embolism (PE) severity, treatments delivered, and outcomes.Methods: We enrolled patients from the National PERT Consortium™ multicenter registry with a PERT activation between 18 October 2016 and 17 October 2017. Data are presented combined and by PERT institution. Differences between institutions were analyzed using chi‐squared test or Fisher's exact test for categorical variables, and ANOVA or Kruskal‐Wallis test for continuous variables, with a two‐sided P value < 0.05 considered statistically significant.Results: There were 475 unique PERT activations across the Consortium, with acute PE confirmed in 416 (88%). The number of activations at each institution ranged from 3 to 13 activations/month/1000 beds with the majority originating from the emergency department (281/475; 59.3%). The largest percentage of patients were at intermediate–low (141/416, 34%) and intermediate–high (146/416, 35%) risk of early mortality, while fewer were at high‐risk (51/416, 12%) and low‐risk (78/416, 19%). The distribution of risk groups varied significantly between institutions (P = 0.002). Anticoagulation alone was the most common therapy, delivered to 289/416 (70%) patients with confirmed PE. The proportion of patients receiving any advanced therapy varied between institutions (P = 0.0003), ranging from 16% to 46%. The 30‐day mortality was 16% (53/338), ranging from 9% to 44%.Conclusions: The frequency of team activation, PE severity, treatments delivered, and 30‐day mortality varies between US PERTs. Further research should investigate the sources of this variability.

To provide a systematic review of catheter-based therapies of acute pulmonary embolism. Studies published in peer-reviewed journals before February 2017 were included and categorized according to the mechanism of thrombus removal: fragmentation, rheolytic therapy, aspiration or catheter-directed thrombolysis. Strengths, challenges and the level of evidence of each device were evaluated. We found 16 different catheter-based therapies for acute PE; all but one being used off-label. The majority of procedures involve catheter-directed thrombolysis. Aspiration therapy shows promise, but limited data are available. Rheolytic therapy should be used with caution, if at all, due to the high number of associated complications. Catheter-based therapies show promise as a treatment for acute PE, though evidence is lacking. Further research into the efficacy and safety of devices is needed.

Acute pulmonary embolism (PE) is the third most common cardiovascular cause of death after acute myocardial infarction and stroke. Patients are, however, often under‐treated due to the risks associated with systemic thrombolysis and surgical embolectomy. Novel pharmacological and catheter‐based treatment strategies show promise, but the data supporting their use in patients are sparse. We therefore aimed to develop an in vivo model of acute PE enabling controlled evaluations of efficacy and safety of novel therapies. Danish Landrace pigs (n = 8) were anaesthetized and mechanically ventilated. Two pre‐formed autologous PEs (PE1, PE2, 20 × 1 cm) were administered consecutively via the right external jugular vein. The intact nature and central location were visualized in situ by magnetic resonance imaging (MRI). The hemodynamic and biochemical responses were evaluated at baseline (BL) and after each PE by invasive pressure measurements, MRI, plus arterial and venous blood analysis. Pulmonary arterial pressure increased after administration of the PEs (BL: 16.3 ± 1.2, PE1: 27.6 ± 2.9, PE2: 31.6 ± 3.1 mmHg, BL vs. PE1: P = 0.0027, PE1 vs. PE2: P = 0.22). Animals showed signs of right ventricular strain evident by increased end systolic volume (BL: 60.9 ± 5.1, PE1: 83.3 ± 5.0, PE2: 99.4 ± 6.5 mL, BL vs. PE1: P = 0.0005, PE1 vs. PE2: P = 0.0045) and increased plasma levels of Troponin T. Ejection fraction decreased (BL: 58.9 ± 2.4, PE1: 46.4 ± 2.9, PE2: 37.3 ± 3.5%, BL vs. PE1: p = 0.0008, PE1 vs. PE2: P = 0.009) with a compensatory increase in heart rate preserving cardiac output and systemic blood pressure. The hemodynamic and biochemical responses were comparable to that of patients suffering from intermediate‐high‐risk PE. This porcine model mirrors the anatomical and physiologic changes seen in human patients with intermediate‐high‐risk PE, and may enable testing of future therapies for this disease.

Objectives: We investigated whether the vasopressin-analog, terlipressin induces systemic vasoconstriction and pulmonary vasodilation in a porcine model of acute pulmonary embolism. Design: Controlled, animal study. Setting: Tertiary medical center research laboratory. Subjects: Female pigs (n = 12, Cross of Land Race, Duroc, and Yorkshire ~ 60 kg). Interventions: Acute pulmonary embolism was induced by administration of three large autologous emboli. Animals then received four increasing doses of either terlipressin (n = 6) or vehicle (n = 6). Measurements and Main Results: Effects were evaluated in vivo at baseline, after pulmonary embolism and after each dose by invasive hemodynamic measures, transesophageal echocardiography, and blood analysis. Isolated pulmonary arteries were evaluated ex vivo in a myograph. Pulmonary embolism caused a four-fold increase in pulmonary vascular resistance (p < 0.0001) and a two-fold increase in mean pulmonary arterial pressure (p < 0.0001) compared with baseline. Terlipressin increased mean systemic blood pressure (28 ± 5 mm Hg; p < 0.0001) and systemic vascular resistance (1,320 ± 143 dynes; p < 0.0001) compared with vehicle. In the pulmonary circulation, terlipressin decreased mean pulmonary arterial pressure (–6.5 ± 1.8 mm Hg; p = 0.005) and tended to decrease pulmonary vascular resistance (–83 ± 33 dynes; p = 0.07). Terlipressin decreased cardiac output (–2.5 ± 0.5 L/min; p < 0.0001) and increased plasma lactate (2.7 ± 0.2 mmol/L; p < 0.0001), possibly indicating systemic hypoperfusion. A biomarker of cerebral ischemia, S100b, remained unchanged, suggesting preserved cerebral perfusion (0.17 ± 0.11 µg/L; p = 0.51). Ex vivo, terlipressin relaxed pulmonary and constricted mesenteric arteries. Conclusions: Terlipressin caused systemic vasoconstriction and pulmonary vasodilation in a porcine in vivo model of acute pulmonary embolism and vasorelaxation in isolated pulmonary arteries. Despite positive vascular effects, cardiac output declined and plasma lactate increased probably due to a predominantly systemic vasoconstrictor effect of terlipressin. These findings should warrant careful translation to the clinical setting and does not suggest routine use in acute pulmonary embolism.