Sildenafil, a phosphodiesterase 5 inhibitor, is currently under investigation for therapy of pulmonary hypertension. This study was designed to investigate chronic effects of sildenafil in monocrotaline (MCT)-induced pulmonary hypertension in rats. Four weeks after a single subcutaneous injection of MCT, the animals displayed nearly threefold elevated pulmonary artery pressure and vascular resistance values, with a concomitant decline in central venous oxygen saturation and arterial oxygenation. Marked right heart hypertrophy was evident, and massive thickening of the precapillary artery smooth muscle layer was histologically apparent. Further deterioration of pulmonary hypertension occurred 6 weeks after MCT injection, with some animals dying during this period because of right heart failure. When chronically administered from Days 14-28, sildenafil significantly increased plasma cyclic guanosine monophosphate and inhibited the development of pulmonary hypertension and right heart hypertrophy, with preservation of gas exchange and systemic arterial pressure. A corresponding efficacy profile was also noted for long-term feeding with sildenafil from Days 28-42. Moreover, the death rate significantly decreased in those animals treated with sildenafil. We conclude that sildenafil attenuates MCT-induced pulmonary hypertension and cor pulmonale in rats.

Abstract-Severe pulmonary hypertension is a disabling disease with high mortality. We investigated acute and chronic effects of iloprost, a long-acting prostacyclin analogue, and the dual-selective phosphodiesterase 3/4 inhibitor tolafentrine in monocrotaline-induced pulmonary hypertension in rats. Twenty-eight and 42 days after administration of the alkaloid, right ventricular systolic pressure increased from 25.8Ϯ2.0 to 62.9Ϯ3.4 and 70.5Ϯ7.4 mm Hg, with concomitant decline in cardiac index, central venous oxygen saturation, and arterial oxygenation. Marked right heart hypertrophy was demonstrated by the strongly elevated ratio of right ventricle/left ventricle plus septum weight, and massive thickening of the precapillary artery smooth muscle layer was shown histologically. Western blot analysis demonstrated increased levels of matrix metalloproteinases (MMPs) -2 and -9 and increased gelatinolytic activities in isolated pulmonary arteries. In these animals, both intravenous iloprost and tolafentrine displayed characteristic features of pulmonary vasodilators. When chronically infused from days 14 to 28, both agents significantly attenuated all monocrotaline-induced hemodynamic and gas exchange abnormalities as well as right heart hypertrophy. Full normalization of all variables including right ventricle size was achieved on combined administration of both agents during this period. This was also true for MMP-2 and MMP-9 expression and activity. Moreover, when iloprost plus tolafentrine was used for late therapeutic intervention, with infusion from days 28 to 42 after full establishment of severe pulmonary hypertension and cor pulmonale, hemodynamic, gas exchange, and cardiac and pulmonary vascular remodeling changes were significantly reversed. We conclude that the combined administration of iloprost and a dual-selective phosphodiesterase 3/4 inhibitor prevents and reverses the development of pulmonary hypertension and cor pulmonale in response to monocrotaline in rats. This regimen may therefore offer a possible antiremodeling therapy in severe pulmonary hypertension. Key Words: iloprost Ⅲ pulmonary hypertension Ⅲ monocrotaline Ⅲ phosphodiesterase Ⅲ tolafentrine P ulmonary arterial hypertension (PAH) is a severe disabling disease characterized by elevation of pulmonary artery pressure and death attributable to circulatory failure. 1,2 Predominant features of the pathology of PAH include intimal lesions, medial hypertrophy, and adventitial thickening of precapillary pulmonary arteries and right ventricular hypertrophy. Imbalances of vasodilatory and vasoconstrictor agents have been implicated in both the predominance of increased vasomotor tone and the chronic remodeling of resistance vessels, including vascular smooth muscle cell growth. In patients with primary pulmonary hypertension, a reduced excretion of prostaglandin and an enhanced excretion of thromboxane metabolites has been noted. 3 Moreover, enhanced activities of phosphodiesterases (PDEs), which hydrolyze the prostaglandin-and NO-induced second mes...

Background There is scarce data about the long‐term mortality as well as the prognostic value of cardiovascular magnetic resonance and late gadolinium enhancement (LGE) in patients with biopsy‐proven viral myocarditis. We sought to investigate: (1) mortality and (2) prognostic value of LGEcardiovascular magnetic resonance (location, pattern, extent, and distribution) in a >10‐year follow‐up in patients with biopsy‐proven myocarditis. Methods and Results Two‐hundred three consecutive patients with biopsy‐proven viral myocarditis and cardiovascular magnetic resonance were enrolled; 183 patients were eligible for standardized follow‐up. The median follow‐up was 10.1 years. End points were all‐cause death, cardiac death, and sudden cardiac death (SCD). We found substantial long‐term mortality in patients with biopsy‐proven myocarditis (39.3% all cause, 27.3% cardiac, and 10.9% SCD); 101 patients (55.2%) demonstrated LGE. The presence of LGE was associated with a more than a doubled risk of death (hazard ratio [HR], 2.40; 95% CI], 1.30–4.43), escalating to a HR of 3.00 (95% CI, 1.41–6.42) for cardiac death, and a HR of 14.79 (95% CI, 1.95–112.00) for SCD; all P ≤0.009. Specifically, midwall, (antero‐) septal LGE, and extent of LGE were highly associated with death, all P <0.001. Septal LGE was the best independent predictor for SCD (HR, 4.59; 95% CI, 1.38–15.24; P =0.01). Conclusions In patients with biopsy‐proven viral myocarditis, the presence of midwall LGE in the (antero‐) septal segments is associated with a higher rate of mortality (including SCD) compared with absent LGE or other LGE patterns, underlining the prognostic benefit of a distinct LGE analysis in these patients.

Objective: Patients with coronary artery disease (CAD) are at increased risk for cardiac death and respiratory failure following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Platelets are crucially involved in pathogenesis of CAD and might also contribute to pathophysiology of SARS-CoV-2 infection. Approach and Results: We enrolled a cohort of 122 participants from February 2020 to July 2020 including 55 patients with preexisting CAD and acute SARS-CoV-2 infection (CAD-SARS-CoV-2 positive ), 28 patients with CAD and without SARS-CoV-2 (CAD-SARS-CoV-2 negative ), and 39 healthy controls. Clinical and cardiac examination of the CAD-SARS-CoV-2 positive group included blood sampling, echocardiography, and electrocardiography within 24 hours after hospital admission. Phenotyping of platelets was performed by flow cytometry; plasma levels of chemokines were analyzed by ELISA. Respiratory failure of patients was stratified by the Horovitz index as moderately/severely impaired when Horovitz index <200 mm Hg. The clinical end point was defined as Horovitz index <200 mm Hg with subsequent mechanical ventilation within a follow-up of 60 days. CAD-SARS-CoV-2 positive patients display a significant enhanced platelet activation and hyper-inflammation early at time of hospital admission. Circulating platelet/leukocyte co-aggregates correlate with plasma levels of cytokines/chemokines like IL (interleukin)-6, CCL2, and CXCL10 as well as activation of platelets is associated with CCL5 and elevation of pulmonary artery pressure. Furthermore, furin is stored and released from activated platelets. High furin plasma levels are associated with poor clinical prognosis in CAD-SARS-CoV-2 positive patients. Conclusions: Patients with CAD and SARS-CoV-2 infection exhibit elevated systemic platelet activation and enhanced plasma levels of the subtilisin-like proprotein convertase furin, which may contribute to an unfavorable clinical prognosis.

Introduction. Paraproteinemia has been associated with both thromboembolic and bleeding complications. Previous retrospective analyses and case reports report on a direct correlation of serum immunoglobulin levels (especially IgM and IgA) with critical bleeding events. Underlying mechanisms include interference with platelet function, immune thrombocytopenia, clotting factor deficiencies, and acquired von Willebrand disease (AVWD). Methods. Laboratory data, including qualitative and quantitative analyses of von Willebrand Factor (vWF), collagen binding assay (CBA) and PFA-100 closure time from 132 patients with diagnosis of multiple myeloma between 2003 and 2015 were retrieved, and cases were retrospectively evaluated for bleeding complications. Coagulation abnormalities were correlated with clinical history and disease parameters. Results. 70 out of 132 patients (53%) displayed bleeding complications including multiple hematomas (n=41), epistaxis (n=10), or perioperative bleeding (n=9). Bleeding vs. non-bleeding patients showed no differences regarding age, gender, previous chemotherapy, or immunoglobulin isotypes. Special coagulation lab results of patients with bleeding events are shown in table 1. Table 1. Pathological coag labs in 70 patients with bleeding Normal Abnormal Sensitivity(95% CI) Specificity(95% CI) PPV*(95% CI) NPV*(95% CI) PLT (<50x103/µl) 70 0 0 1 0 0.47 (0.38-0.56) PT, aPTT 68 2 0.06 (0.02-0.1) 0.95 (0.85-0.99) 0.57 (0.2-0.88) 0.47 (0.38-0.56) vWF:Ag or RCoF 64 6 0.09 (0.04-0.18) 0.95 (0.86-0.99) 0.67 (0.3-0.9) 0.48 (0.39-0.9) PFA-100 27 43 0.61 (0.49-0.73) 0.97 (0.88-0.99) 0.96 (0.84-99) 0.69 (0.58-0.78) CBA/vWF 45 25 0.35 (0.25-0.48) 0.98 (0.9-0.99) 0.96 (0.78-1) 0.58 (0.48-0.67) PFA-100 or CBA/vWF 52 18 0.74 (0.62-0.84) 0.95 (0.86-0.99) 0.94 (0.84-1) 0.76 (0.65-0.85) *PPV = positive predictive value, NPV = negative predictive value Serum free light-chain, but not complete Ig paraprotein levels were significantly associated with bleeding events (p<0.001), prolonged PFA-100 closure time (p<0.001), and pathological CBA/vWF-ratio (p<0.05). Conclusions. Bleeding events were most commonly due to defects of primary hemostasis. Global coagulation tests as well as vWF:Ag and RCo were insufficient in predicting bleeding. When the results of both PFA-100 and CBA/vWF-ratio were considered, 74% of the bleeding patients could be detected. We suggest that both PFA-100 and CBA/vWF-ratio should be determined in patients with multiple myeloma and signs of bleeding in order to rule out AVWD with sufficient sensitivity. Serum free light-chain levels were correlated with hemorrhage and detectable AVWD. Therefore, free Ig light-chains may play a role in the pathophysiology of bleeding. Disclosures Weisel: Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Travel Support, Research Funding; Noxxon: Consultancy; Onyx: Consultancy, Honoraria; Novartis: Other: Travel Support; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel Support; BMS: Consultancy, Honoraria, Other: Travel Support.