Simultaneous Application of Interstitial Flow and Cyclic Mechanical Strain to a Three-Dimensional Cell-Seeded Hydrogel

The present study describes the design and validation of a simple apparatus to apply simultaneous mechanical and fluidic stress to three-dimensional (3D) cell-seeded collagen hydrogels. Constructs were formed in wells in a silicone substrate that could be stretched cyclically, and were also fitted with inlet ports to apply fluid flow. Acid etching was used to retain adhesion of the gels to the walls of the well, and an acellular layer of collagen hydrogel was used to distribute flow evenly. Finite element modeling showed that 5% uniaxial strain applied to the entire silicone substrate resulted in -6.5% strain in each of the gel constructs. Permeability testing and flow observation showed that acellular hydrogels were fourfold more permeable than cardiac fibroblast-seeded gels, and that the fluid distributed evenly in the acellular layer before entering the cell-seeded gel. Viability testing and imaging demonstrated that cells remained viable with expected fibroblast morphology for the 120-h duration of the experiments. These results demonstrate that this simple bioreactor can be used to study the effects of mechanical strain and interstitial flow in 3D protein hydrogels. Such 3D tissue models have utility in studying cell and tissue responses to their mechanical environment.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90463/1/ten-2Etec-2E2010-2E0547.pd

Subacute pericardial abscess after aortic valve replacement: a case report

BACKGROUND: Purulent pericarditis is an infectious disease, frequently caused by gram-positive bacteria, that is rarely observed in healthy individuals, and is often associated with predisposing conditions. CASE PRESENTATION: Here, we present the case of an Escherichia coli post-surgical localized purulent pericarditis complicated by transient constrictive pericarditis and its diagnostic and therapeutic management. CONCLUSIONS: Our case report focuses on the importance of imaging-guided treatment of purulent pericardial diseases, in particular on the emerging role of 18\u2009F-labelled 2-fluoro-2-deoxy-D-glucose Positron Emission Tomography/Computed Tomography in pericardial diseases and on the management of transient constrictive pericarditis, often seen after thoracic surgery

Genetics and clinical phenotype of Erdheim–Chester disease: A case report of constrictive pericarditis and a systematic review of the literature

Background: Erdheim–Chester disease (ECD) is a rare form of histiocytosis. An increasing number of genetic mutations have been associated with this syndrome, confirming its possible neoplastic origin. Recently, a connection between the BRAF mutational status and a specific phenotype was described; however, no studies have yet evaluated the correlations between other mutations and the clinical features of the disease. Objectives: This study aims to clarify the association between the clinical phenotype and genetic mutations identified in the neoplastic cell lines of ECD. Methods: We describe a case of ECD characterized by pericardial involvement and a KRAS mutation shared with chronic myelomonocytic leukemia. Hence, through a meta-analysis of individual participant data of all genetically and clinically described cases of ECD in the literature, we aimed to elucidate the association between its clinical phenotype and baseline genetic mutations. Results: Of the 760 studies screened, our review included 133 articles published from 2012 to April 2021. We identified 311 ECD patients whose genotype and phenotype were described. We found five main genes (BRAF, KRAS, NRAS, PIK3CA, and MAP2K1) whose mutation was reported at least three times. Mutation of BRAF led to a neurological disease (183 of 273 patients, 67%; p < 0.001); KRAS- and NRAS-mutated patients mainly showed cutaneous (five of six patients, 83.3%, p < 0.004) and pleural (four of nine patients, 44%, p = 0.002) involvement, respectively; PIK3CA was not associated with specific organ involvement; and MAP2K1 mutations caused the disease to primarily involve the peritoneum and retroperitoneum (4 of 11, 36.4%, p = 0.01). Conclusion: This work implies a possible influence of baseline mutation over the natural history of ECD, underscoring the importance of a thorough genetic analysis in all cases with the ultimate goal of identifying a possible targeted therapy for each patient

Treprostinil increases the number and angiogenic potential of endothelial progenitor cells in children with pulmonary hypertension

Background Pulmonary vasodilators in general and prostacyclin therapy in particular, have markedly improved the outcome of patients with pulmonary arterial hypertension (PAH). As endothelial dysfunction is a key feature of PAH, and as endothelial progenitor cells (EPC) may contribute to vascular repair in PAH, we suspected that prostacyclin therapy might enhance EPC numbers and functions. In the present study, objectives were to determine whether EPC may contribute to vasodilator treatment efficacy in PAH. Methods We quantified CD34+ cells, CFU-Hill and ECFC (endothelial colony forming cells) in peripheral blood from children with idiopathic PAH (n = 27) or PAH secondary to congenital heart disease (n = 52). CD34+ were enumerated by flow cytometry, CFU-Hill and ECFC by a culture assay. ECFC grown ex vivo were tested for their angiogenic capacities before and after prostacyclin analog therapy (subcutaneous treprostinil). Results ECFC counts were significantly enhanced in the 8 children treated with treprostinil, while no change was observed in children receiving oral therapy with endothelin antagonists and/or PDE5 inhibitors. CD34+ cell and CFU-Hill counts were unaffected. ECFC from patients treated with treprostinil had a hyperproliferative phenotype and showed enhanced angiogenic potential in a nude mouse preclinical model of limb ischemia. Conclusions ECFC may partly mediate the clinical benefits of prostanoids in pulmonary arterial hypertension

Primary malignant pericardial tumour in Lynch syndrome

Background: This case represents the first report of malignant primary cardiac tumour in a patient with Lynch Syndrome associated with MSH2 pathogenic variant. Case presentation: A 57-year-old woman with previous ovarian cystadenocarcinoma was admitted to the emergency room for hematic pericardial effusion. Multimodal diagnostic imaging revealed two solid pericardial vascularized masses. After pericardiectomy, the final histological diagnosis was poorly differentiated pleomorphic sarcomatoid carcinoma. During follow-up she developed an ampulla of Vater adenocarcinoma. Genetic analysis identified an MSH2 pathogenic variant. Conclusion: This case contributes to expand the tumour spectrum of Lynch syndrome, suggesting that MSH2 pathogenic variants cause a more complex multi-tumour cancer syndrome than the classic Lynch Syndrome. In MSH2 variant carriers, symptoms such as dyspnoea and chest discomfort might alert for rare tumours and a focused cardiac evaluation should be considered

Secondary prevention medical therapy and outcomes in patients with myocardial infarction with non-obstructive coronary artery disease

Background: Myocardial infarction with non-obstructive coronary arteries (MINOCA) is a heterogeneous entity with relevant long-term major cardiovascular events. Several trials have demonstrated that dual antiplatelet therapy (DAPT), b-blocker, renin-angiotensin-aldosterone system (RAAS) inhibitor and statin therapy improve the prognosis in patients with obstructive myocardial infarction (ob-MI). However, evidence on the best medical therapy for secondary prevention in MINOCA patients is lacking. Purpose: To investigate the effects of secondary prevention treatments at discharge on mid-term outcomes in MINOCA. Methods: Patients with acute myocardial infarction (MI) undergoing early coronary angiography between 2016 and 2018 were extracted from a clinical database. The diagnosis of MINOCA was made according to 2016 ESC MINOCA Position Paper criteria. Second-level diagnostic work-up including cardiac magnetic resonance was performed to exclude non-ischemic troponin elevation cause. The relationship between treatments and outcomes was evaluated by using Kaplan-Meier survival analysis and Cox regression models. All confirmed MINOCA were followed in our outpatient clinics. The primary endpoints were all-cause mortality, re-hospitalization for MI and a composite outcome including all-cause mortality, hospitalization for MI and ischemic stroke (MACE). Results: Out of 1,141 AMI who underwent coronary angiography, 134 were initially diagnosed as MINOCA. Patients with MINOCA were less likely to receive secondary prevention treatments than patients with obstructive coronary artery disease (CAD) MI (respectively, 42.1% vs 81.8% for DAPT; 75.5% vs 89.6% for b-blockers; 64.7% vs 80.3% for RAAS inhibitor and 63.9% vs 83% for statins). Based on the diagnostic work-up completed during the first month after discharge, a final sample of 88 patients had confirmed MINOCA. During an average follow-up of 19.35 \ub1 10.65 months, all-cause mortality occurred in 11 (12.5%) patients, recurrence of MI in 4 (4.5%), and MACE in 15 (17.0%) patients. Patients treated with RAAS inhibitors and statins had a significantly longer survival. On the contrary, no increase in survival was found in patients treated with b-blockers or DAPT. Cox multivariable analysis, including all secondary prevention drugs, showed that only RAAS inhibitors were associated with reduced all cause-mortality and MACE. Conclusion: This prospective study suggests that RAAS inhibitor therapy provides midterm beneficial effects on outcomes in MINOCA patients; in contrast, dual antiplatelet, b-blocker and statin therapy had no effects on mortality and MACE. These results should be considered preliminary and warrant confirmation from larger studies

Secondary prevention medical therapy and outcomes in patients with myocardial infarction with non-obstructive coronary artery disease

Background: Myocardial infarction with non-obstructive coronary arteries (MINOCA) is a heterogeneous entity with relevant long-term major cardiovascular events. Several trials have demonstrated that dual antiplatelet therapy (DAPT), b-blocker, renin-angiotensin-aldosterone system (RAAS) inhibitor and statin therapy improve the prognosis in patients with obstructive myocardial infarction (ob-MI). However, evidence on the best medical therapy for secondary prevention in MINOCA patients is lacking. Purpose: To investigate the effects of secondary prevention treatments at discharge on mid-term outcomes in MINOCA. Methods: Patients with acute myocardial infarction (MI) undergoing early coronary angiography between 2016 and 2018 were extracted from a clinical database. The diagnosis of MINOCA was made according to 2016 ESC MINOCA Position Paper criteria. Second-level diagnostic work-up including cardiac magnetic resonance was performed to exclude non-ischemic troponin elevation cause. The relationship between treatments and outcomes was evaluated by using Kaplan-Meier survival analysis and Cox regression models. All confirmed MINOCA were followed in our outpatient clinics. The primary endpoints were all-cause mortality, re-hospitalization for MI and a composite outcome including all-cause mortality, hospitalization for MI and ischemic stroke (MACE). Results: Out of 1,141 AMI who underwent coronary angiography, 134 were initially diagnosed as MINOCA. Patients with MINOCA were less likely to receive secondary prevention treatments than patients with obstructive coronary artery disease (CAD) MI (respectively, 42.1% vs 81.8% for DAPT; 75.5% vs 89.6% for b-blockers; 64.7% vs 80.3% for RAAS inhibitor and 63.9% vs 83% for statins). Based on the diagnostic work-up completed during the first month after discharge, a final sample of 88 patients had confirmed MINOCA. During an average follow-up of 19.35 ± 10.65 months, all-cause mortality occurred in 11 (12.5%) patients, recurrence of MI in 4 (4.5%), and MACE in 15 (17.0%) patients. Patients treated with RAAS inhibitors and statins had a significantly longer survival. On the contrary, no increase in survival was found in patients treated with b-blockers or DAPT. Cox multivariable analysis, including all secondary prevention drugs, showed that only RAAS inhibitors were associated with reduced all cause-mortality and MACE. Conclusion: This prospective study suggests that RAAS inhibitor therapy provides midterm beneficial effects on outcomes in MINOCA patients; in contrast, dual antiplatelet, b-blocker and statin therapy had no effects on mortality and MACE. These results should be considered preliminary and warrant confirmation from larger studies

Prognostic value of high-sensitivity cardiac troponin I early after coronary artery bypass graft surgery

Background: The diagnosis of periprocedural myocardial infarction (PMI) after coronary artery bypass graft (CABG) is based on biochemical markers along with clinical and instrumental findings. However, there is not a clear cutoff value of high-sensitivity cardiac troponin (hs-cTn) to identify PMI. We hypothesized that isolated hs-cTn concentrations in the first 24 h following CABG could predict cardiac adverse events (in-hospital death and PMI) and/or left ventricular ejection fraction (LVEF) decrease. Methods: We retrospectively enrolled all consecutive adult patients undergoing CABG, alone or in association with other cardiac surgery procedures, over 1 year. Hs-cTn I concentrations (Access, Beckman Coulter) were serially measured in the post-operative period and analyzed according to post-operative outcomes. Results: 300 patients were enrolled; 71.3% underwent CABG alone, 33.7% for acute coronary syndrome. Most patients showed hs-cTn I values superior to the limit required by the latest guidelines for the diagnosis of PMI. Five patients (1.7%) died, 8% developed a PMI, 10.6% showed a LVEF decrease ≥ 10%. Hs-cTn I concentrations did not significantly differ with respect to death and/or PMI whereas they were associated with LVEF decrease ≥ 10% (p value < 0.005 at any time interval), in particular hs-cTn I values at 9–12 h post-operatively. A hs-cTn I cutoff of 5556 ng/L, a value 281 (for males) and 479 (for females) times higher than the URL, at 9–12 h post-operatively was identified, representing the best balance between sensitivity (55%) and specificity (79%) in predicting LVEF decrease ≥ 10%. Conclusions: Hs-cTn I at 9–12 h post-CABG may be useful to early identify patients at risk for LVEF decrease and to guide early investigation and management of possible post-operative complications

Cumulative subgroup analysis to reduce waste in clinical research for individualised medicine

Background: Although subgroup analyses in clinical trials may provide evidence for individualised medicine, their conduct and interpretation remain controversial. Methods: Subgroup effect can be defined as the difference in treatment effect across patient subgroups. Cumulative subgroup analysis refers to a series of repeated pooling of subgroup effects after adding data from each of related trials chronologically, to investigate the accumulating evidence for subgroup effects. We illustrated the clinical relevance of cumulative subgroup analysis in two case studies using data from published individual patient data (IPD) meta-analyses. Computer simulations were also conducted to examine the statistical properties of cumulative subgroup analysis. Results: In case study 1, an IPD meta-analysis of 10 randomised trials (RCTs) on beta blockers for heart failure reported significant interaction of treatment effects with baseline rhythm. Cumulative subgroup analysis could have detected the subgroup effect 15 years earlier, with five fewer trials and 71% less patients, than the IPD meta-analysis which first reported it. Case study 2 involved an IPD meta-analysis of 11 RCTs on treatments for pulmonary arterial hypertension that reported significant subgroup effect by aetiology. Cumulative subgroup analysis could have detected the subgroup effect 6 years earlier, with three fewer trials and 40% less patients than the IPD meta-analysis. Computer simulations have indicated that cumulative subgroup analysis increases the statistical power and is not associated with inflated false positives. Conclusions: To reduce waste of research data, subgroup analyses in clinical trials should be more widely conducted and adequately reported so that cumulative subgroup analyses could be timely performed to inform clinical practice and further research