Design, manufacturing and testing of a green non-isocyanate polyurethane prosthetic heart valve.

The sole effective treatment for most patients with heart valve disease is valve replacement by implantation of mechanical or biological prostheses. However, mechanical valves represent high risk of thromboembolism, and biological prostheses are prone to early degeneration. In this work, we aim to determine the potential of novel environmentally-friendly non-isocyanate polyurethanes (NIPUs) for manufacturing synthetic prosthetic heart valves. Polyhydroxyurethane (PHU) NIPUs are synthesized via an isocyanate-free route, tested in vitro, and used to produce aortic valves. PHU elastomers reinforced with a polyester mesh show mechanical properties similar to native valve leaflets. These NIPUs do not cause hemolysis. Interestingly, both platelet adhesion and contact activation-induced coagulation are strongly reduced on NIPU surfaces, indicating low thrombogenicity. Fibroblasts and endothelial cells maintain normal growth and shape after indirect contact with NIPUs. Fluid-structure interaction (FSI) allows modeling of the ideal valve design, with minimal shear stress on the leaflets. Injection-molded valves are tested in a pulse duplicator and show ISO-compliant hydrodynamic performance, comparable to clinically-used bioprostheses. Poly(tetrahydrofuran) (PTHF)-NIPU patches do not show any evidence of calcification over a period of 8 weeks. NIPUs are promising sustainable biomaterials for the manufacturing of improved prosthetic valves with low thrombogenicity.

Protective Effect of Ticagrelor Against Infective Endocarditis Induced by Virulent Staphylococcus aureus in Mice.

In addition to its potent antiplatelet activity, ticagrelor possesses antibacterial properties against gram-positive bacteria. We wondered whether the typical clinical dosage of ticagrelor could prevent the development of infective endocarditis caused by highly virulent Staphylococcus aureus. Ticagrelor prevented vegetation formation in a mouse model of inflammation-induced endocarditis. The dosage achieved in patients under ticagrelor therapy altered bacterial toxin production and adherence on activated endothelial cells, thereby mitigating bacterial virulence. Besides the previously described bactericidal activity at high doses, ticagrelor at typical clinical doses possesses antivirulence activity against S aureus. Ticagrelor antiplatelet activity further interferes with the interplay between platelets and bacteria.

Exercise-induced myocardial T1 increase and right ventricular dysfunction in recreational cyclists: a CMR study.

PURPOSE: Although cardiac troponin I (cTnI) increase following strenuous exercise has been observed, the development of exercise-induced myocardial edema remains unclear. Cardiac magnetic resonance (CMR) native T1/T2 mapping is sensitive to the pathological increase of myocardial water content. Therefore, we evaluated exercise-induced acute myocardial changes in recreational cyclists by incorporating biomarkers, echocardiography and CMR. METHODS: Nineteen male recreational participants (age: 48 ± 5 years) cycled the 'L'étape du tour de France" (EDT) 2021' (175 km, 3600 altimeters). One week before the race, a maximal graded cycling test was conducted to determine individual heart rate (HR) training zones. One day before and 3-6 h post-exercise 3 T CMR and echocardiography were performed to assess myocardial native T1/T2 relaxation times and cardiac function, and blood samples were collected. All participants were asked to cycle 2 h around their anaerobic gas exchange threshold (HR zone 4). RESULTS: Eighteen participants completed the EDT stage in 537 ± 58 min, including 154 ± 61 min of cycling time in HR zone 4. Post-race right ventricular (RV) dysfunction with reduced strain and increased volumes (p < 0.05) and borderline significant left ventricular global longitudinal strain reduction (p = 0.05) were observed. Post-exercise cTnI (0.75 ± 5.1 ng/l to 69.9 ± 41.6 ng/l; p < 0.001) and T1 relaxation times (1133 ± 48 ms to 1182 ± 46 ms, p < 0.001) increased significantly with no significant change in T2 (p = 0.474). cTnI release correlated with increase in T1 relaxation time (p = 0.002; r = 0.703), post-race RV dysfunction (p < 0.05; r = 0.562) and longer cycling in HR zone 4 (p < 0.05; r = 0.607). CONCLUSION: Strenuous exercise causes early post-race cTnI increase, increased T1 relaxation time and RV dysfunction in recreational cyclists, which showed interdependent correlation. The long-term clinical significance of these changes needs further investigation. TRIAL REGISTRATION NUMBERS AND DATE: NCT04940650 06/18/2021. NCT05138003 06/18/2021.

Bioactive surface coating for preventing mechanical heart valve thrombosis.

BACKGROUND: Prosthetic heart valves are the only treatment for most patients with severe valvular heart disease. Mechanical valves, made of metallic components, are the most long-lasting type of replacement valves. However, they are prone to thrombosis and require permanent anticoagulation and monitoring, which leads to higher risk of bleeding and impacts the patient's quality of life. OBJECTIVES: To develop a bioactive coating for mechanical valves with the aim to prevent thrombosis and improve patient outcomes. METHODS: We used a catechol-based approach to produce a drug-releasing multilayer coating adherent to mechanical valves. The hemodynamic performance of coated Open Pivot valves was verified in a heart model tester, and coating durability in the long term was assessed in a durability tester producing accelerated cardiac cycles. Coating antithrombotic activity was evaluated in vitro with human plasma or whole blood under static and flow conditions and in vivo after surgical valve implantation in a pig's thoracic aorta. RESULTS: We developed an antithrombotic coating consisting of ticagrelor- and minocycline-releasing cross-linked nanogels covalently linked to polyethylene glycol. We demonstrated the hydrodynamic performance, durability, and hemocompatibility of coated valves. The coating did not increase the contact phase activation of coagulation, and it prevented plasma protein adsorption, platelet adhesion, and thrombus formation. Implantation of coated valves in nonanticoagulated pigs for 1 month efficiently reduced valve thrombosis compared with noncoated valves. CONCLUSION: Our coating efficiently inhibited mechanical valve thrombosis, which might solve the issues of anticoagulant use in patients and the number of revision surgeries due to valve thrombosis despite anticoagulation.

Abduction Arthro-Fluoroscopy in Adhesive Capsulitis of the Shoulder.

This technical note describes a method of diagnosing adhesive capsulitis of the shoulder based on the real-time study of abduction movement under fluoroscopy control after opacification of the joint cavity with contrast media. This movement passively or actively shows a limitation of the abduction, a scapulohumeral block, or a weak or even an absence of rolling of the humeral head in the glenoid cavity, transforming the abduction into a shoulder elevation.

Pulmonary Artery Sling Blurs the Distal Trachea on Frontal Chest Radiography.

Teaching Point: The pulmonary artery sling can be suspected on frontal chest radiography, not only by ancillary findings like lobe/lung emphysema or persisting atelectasis, but also blurring of the distal trachea or carina.

Semi-Quantitative Versus Visual Analysis of Adenosine Perfusion Magnetic Resonance Imaging in Intermediate-Grade Coronary Artery Stenosis Using Fractional Flow Reserve as the Reference: A Pilot Study.

Background: To evaluate the diagnostic accuracy of semi-quantitative adenosine perfusion magnetic resonance imaging (MRI) to determine fractional flow reserve (FFR) ≤ 0.80 intermediate-grade coronary stenoses as compared to visual analysis. Methods: Forty-six patients (mean age 61 ± 9 years; 33 males) with 49 intermediate-grade stenoses (59 ± 7.6%; range, 42-70% minimal diameter reduction) underwent adenosine perfusion MRI and FFR measurement within four months in this retrospective study. MRI was visually assessed by two experienced readers twice with one-year interval, the second time with the knowledge of the diseased artery. The stress subendocardial myocardial enhancement maximal upslope was evaluated distal to the coronary stenosis (=RISK) and divided by the same value in remote myocardium supplied by normal arteries (=REMOTE) to obtain the relative myocardial perfusion index (RMPI). Results: The average FFR value was 0.84 ± 0.09 and 15/49(31%) intermediate-grade stenoses were FFR ≤ 0.80. The kappa-values for interobserver agreement assessing inducible perfusion defects on visual readings was 0.20 on the first reading and increased to 0.62 with the knowledge of the stenosis location. Consensus readings had a diagnostic accuracy of 82%(40/49) in identifying FFR ≤ 0.80 stenoses on both blinded and unblinded readings with regards to the knowledge of the stenosis location. Meanwhile, stress subendocardial RMPI had higher accuracy (43/49[88%]) than visual readings to predict FFR ≤ 0.80 stenoses, using a cutoff value of 0.84. Conclusion: By assessing perfusion changes in remote myocardium, semi-quantitative MRI analysis using stress subendocardial RMPI can provide an equal or more accurate alternative to visual analysis in identifying FFR ≤ 0.80 intermediate-grade stenoses. Larger cohorts of patients are required to validate this approach.

Differential Biological Effects of Dietary Lipids and Irradiation on the Aorta, Aortic Valve, and the Mitral Valve.

Aims: Dietary cholesterol and palmitic acid are risk factors for cardiovascular diseases (CVDs) affecting the arteries and the heart valves. The ionizing radiation that is frequently used as an anticancer treatment promotes CVD. The specific pathophysiology of these distinct disease manifestations is poorly understood. We, therefore, studied the biological effects of these dietary lipids and their cardiac irradiation on the arteries and the heart valves in the rabbit models of CVD. Methods and Results: Cholesterol-enriched diet led to the thickening of the aortic wall and the aortic valve leaflets, immune cell infiltration in the aorta, mitral and aortic valves, as well as aortic valve calcification. Numerous cells expressing α-smooth muscle actin were detected in both the mitral and aortic valves. Lard-enriched diet induced massive aorta and aortic valve calcification, with no detectable immune cell infiltration. The addition of cardiac irradiation to the cholesterol diet yielded more calcification and more immune cell infiltrates in the atheroma and the aortic valve than cholesterol alone. RNA sequencing (RNAseq) analyses of aorta and heart valves revealed that a cholesterol-enriched diet mainly triggered inflammation-related biological processes in the aorta, aortic and mitral valves, which was further enhanced by cardiac irradiation. Lard-enriched diet rather affected calcification- and muscle-related processes in the aorta and aortic valve, respectively. Neutrophil count and systemic levels of platelet factor 4 and ent-8-iso-15(S)-PGF2α were identified as early biomarkers of cholesterol-induced tissue alterations, while cardiac irradiation resulted in elevated levels of circulating nucleosomes. Conclusion: Dietary cholesterol, palmitic acid, and cardiac irradiation combined with a cholesterol-rich diet led to the development of distinct vascular and valvular lesions and changes in the circulating biomarkers. Hence, our study highlights unprecedented specificities related to common risk factors that underlie CVD.

Regular Dietary Intake of Palmitate Causes Vascular and Valvular Calcification in a Rabbit Model.

Aims: Palmitic acid (PA) and oleic acid (OA) are two main dietary fatty acids. Dietary intake of PA has been associated with cardiovascular disease risk, and the effect of OA remains uncertain. Our study aimed to assess the effect of a short-term intake of lard, as source of PA and OA, on aorta and aortic valve. Methods and Results: Rabbits were fed with two lard-enriched diets, containing either elevated levels of PA or of both PA and OA as compared to chow diet. After 16 weeks of each diet, calcification was observed in the aortic intima and in the aortic valve. The extent of calcification did not differ between the two diets. In contrast, rabbits fed chow diet did not develop any calcification. In blood, PA enrichment resulted in decreased lymphocyte and monocyte counts and increased levels of hemoglobin and haematocrit. Levels of the calcification inhibitor fetuin-A were also diminished, whereas creatinine levels were raised. Of note, none of the diets changed cholesterol levels in LDL or HDL. Comprehensive quantitative lipidomics analysis identified diet-related changes in plasma lipids. Dietary PA enrichment led to a drop of polyunsaturated fatty acids (PUFA), in particular of linoleic acid in cholesteryl esters, triglycerides and diacylglycerols (DAG). Ratios of PA to 18-carbon PUFA in DAG were positively correlated with the extent of aortic valve calcification, and inversely with monocyte counts. PA content in blood correlated with aorta calcification. Conclusions: Regular dietary PA intake induces vascular and valvular calcification independently of traditional risk factors. Our findings raise awareness about PA-rich food consumption and its potential deleterious effect on cardiovascular health.

Case Series: Pulmonary Artery Intramural Hematoma in Stanford Type A Acute Aortic Dissection.

Main Teaching Point: Diagnosing acute ascending aortic dissection in patients with equivocal radiologic data may rely on associated findings such as pulmonary artery intramural hematoma. The immediate diagnosis of aortic dissection is paramount in its management. Its diagnosis may be challenging on computed tomography when the intimal flap, pathognomonic of dissection, is not readily visualized. Pulmonary artery intramural hematoma may arise from rupture of the posterior wall of the ascending aorta into the common aortopulmonary adventitia as a result of acute dissection. The clinical significance of pulmonary artery hematoma is unknown, but its presence may facilitate the diagnosis of acute dissection when other radiologic findings are equivocal. Herein, we present four cases of pulmonary artery intramural hematoma associated with Stanford type A acute aortic dissection, among whom patient outcomes depended mainly on the prompt treatment the dissection.

Synthesis of ticagrelor analogues belonging to 1,2,3-triazolo[4,5-d]pyrimidines and study of their antiplatelet and antibacterial activity.

Based on the recent observation that the antiplatelet agent ticagrelor and one of its metabolite exert bactericidal activity against gram-positive bacteria, a series of 1,2,3-triazolo[4,5-d]pyrimidines structurally related to ticagrelor were synthesized and examined as putative antiplatelet and antibacterial agents. The aim was to assess the possibility of dissociating the two biological properties and to find novel 1,2,3-triazolo[4,5-d]pyrimidines expressing antiplatelet activity and devoid of in vitro antibacterial activity. The new compounds synthesized were known metabolites of ticagrelor as well as structurally simplified analogues. Some of them were found to express antiplatelet activity and to lose the antibacterial activity, supporting the view that the two activities were not necessarily linked.

Dexfenfluramine and Pergolide Cause Heart Valve Disease via Valve Metabolic Reprogramming and Ongoing Matrix Remodeling.

Several clinical reports indicate that the use of amphetaminic anorectic drugs or ergot derivatives could cause valvular heart disease (VHD). We sought to investigate whether valvular lesions develop in response to long-term oral administration of these drugs and to identify drug-targeted biological processes that may lead to VHD. Treatment of New Zealand White rabbits with pergolide, dexfenfluramine, or high-dose serotonin for 16 weeks induced valvular alterations characterized by extracellular matrix remodeling. Transcriptome profiling of tricuspid valves using RNA sequencing revealed distinct patterns of differentially expressed genes (DEGs) that clustered according to the different treatments. Genes that were affected by the three treatments were functionally enriched for reduced cell metabolism processes. The two drugs yielded more changes in gene expression than serotonin and shared most of the DEGs. These DEGs were mostly enriched for decreased biosynthetic processes, increased cell-matrix interaction, and cell response to growth factors, including TGF-ß, which was associated with p38 MAPK activation. Treatment with pergolide specifically affected genes involved in homeostasis, which was corroborated by the activation of the master regulator of cell energy homeostasis, AMPK-α, as well as decreased levels of metabolism-related miR-107. Thus, both pergolide and dexfenfluramine may cause VHD through valve metabolic reprogramming and matrix remodeling.