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Preclinical testing using animal models is indispensable in cardiovascular research. However, the translation to clinical practice of these animal models is questionable since it is not always clear how representative they are. This systematic review intends to summarize the interspecies differences in the coagulation profile of animal models used in cardiovascular research. It aims to guide future research in choosing the optimal animal species. A literature search of PubMed, Embase, Web of Science (Core Collection) and Cochrane Library was performed using a search string that was well defined and not modified during the study. An overview of the search terms used in each database can be found in the appendix. Articles describing coagulation systems in large animals were included. We identified 30 eligible studies of which 15 were included. Compared to humans, sheep demonstrated a less active external pathway of coagulation. Sheep had a higher platelet count but the platelet activatability and response to biomaterials were lower. Both sheep and pigs displayed no big differences in the internal coagulation system compared to humans. Pigs showed results very similar to those of humans, with the exception of a higher platelet count and stronger platelet aggregation in pigs. Coagulation profiles of different species used for preclinical testing show strong variation. Adequate knowledge of these differences is key in the selection of the appropriate species for preclinical cardiovascular research. Future thrombogenicity research should compare sheep to pig in an identical experimental setup.

IntroductionIschaemic cold static storage (ICSS) is the gold standard in donor heart preservation. This ischaemic time frame renders a time constraint and risk for primary graft dysfunction. Cold oxygenated heart perfusion, known as non-ischaemic heart preservation (NIHP), theoretically limits the ischaemic time, while holding on to the known advantage of hypothermia and cardioplegia, a low metabolic rate.Methods and analysisThe NIHP 2019 study is an international, randomised, controlled, open, multicentre clinical trial in 15 heart transplantation centres in 8 European countries and includes 202 patients undergoing heart transplantation, allocated 1:1 to NIHP or ICSS. Enrolment is estimated to be 30 months after study initiation. The patients are followed for 12 months after transplantation.The primary objective is to evaluate the effect of NIHP on survival, allograft function and rejection episodes within the first 30 days after transplantation. The secondary objectives are to compare treatment groups with respect to survival, allograft function, cardiac biomarkers, rejection episodes, allograft vasculopathy, adverse events and adverse device effects within 12 months.Ethics and disseminationThis protocol was approved by the Ethics Committee (EC) for Research UZ/KU Leuven, Belgium, the coordinating EC in Germany (Bei Der LMU München), the coordinating EC in the UK (West Midlands—South Birmingham Research), the EC of Hospital Puerta de Hierro, Madrid, Spain, the EC of Göteborg, Sweden, the coordinating EC in France, the EC of Padova, Italy and the EC of the University of Vienna, Austria. This study will be conducted in accordance with current local regulations and international applicable regulatory requirements according to the principles of the Declaration of Helsinki and ISO14155:2020. Main primary and secondary outcomes will be published on modified intention-to-treat population and per-protocol population.Trial registration numberNCT03991923.

ObjectivesAtrial secondary mitral regurgitation (ASMR) is a clinically distinct form of Carpentier type I mitral regurgitation (MR), rooted in excessive atrial and mitral annular dilation in the absence of left ventricular dysfunction. Mitral valve annuloplasty (MVA) is expected to provide a more durable solution for ASMR than for ventricular secondary MR (VSMR). Yet data on MR recurrence and outcome after MVA for ASMR are scarce. This study sought to investigate surgical outcomes and repair durability in patients with ASMR, as compared with a contemporary group of patients with VSMR.MethodsClinical and echocardiographic data from consecutive patients who underwent MVA to treat ASMR or VSMR in an academic centre were retrospectively analysed. Patient characteristics, operative outcomes, time to recurrence of ≥moderate MR and all-cause mortality were compared between patients with ASMR versus VSMR.ResultsOf the 216 patients analysed, 97 had ASMR opposed to 119 with VSMR and subvalvular leaflet tethering. Patients with ASMR were typically female (68.0% vs 33.6% in VSMR, p<0.001), with a history of atrial fibrillation (76.3% vs 33.6% in VSMR, p<0.001), paralleling a larger left atrial size (p<0.033). At a median follow-up of 3.3 (IQR 1.0–7.3) years, recurrence of ≥moderate MR was significantly lower in ASMR versus VSMR (7% vs 25% at 2 years, overall log-rank p=0.001), also when accounting for all-cause death as competing risk (subdistribution HR 0.50 in ASMR, 95% CI 0.29 to 0.88, p=0.016). Moreover, ASMR was associated with better overall survival compared with VSMR (adjusted HR 0.43 95% CI 0.22 to 0.82, p=0.011), independent from baseline European System for Cardiac Operative Risk Evaluation II surgical risk score.ConclusionPrognosis following MVA to treat ASMR is better, compared with VSMR as reflected by lower all-cause mortality and MR recurrence. Early distinction of secondary MR towards underlying ventricular versus atrial disease has important therapeutic implications.

Cardiac surgeries may expose pulmonary arterial tissue to systemic conditions, potentially resulting in failure of that tissue. Our goal was to quantitatively assess pulmonary artery adaptation due to changes in mechanical environment. In 17 sheep, we placed a pulmonary autograft in aortic position, with or without macroporous mesh reinforcement. It was exposed to systemic conditions for 6 months. All sheep underwent 3 ECG-gated MRI’s. Explanted tissue was subjected to mechanical and histological analysis. Results showed progressive dilatation of the unreinforced autograft, while reinforced autografts stabilized after two months. Some unreinforced pulmonary autograft samples displayed more aorta-like mechanical behavior with increased collagen deposition. The mechanical behavior of reinforced autografts was dominated by the mesh. The decrease in media thickness and loss of vascular smooth muscle cells was more pronounced in reinforced than in unreinforced autografts. In conclusion, altering the mechanical environment of a pulmonary artery causes changes in its mechano-biological properties.

Valvular heart disease is a common disease often necessitating valve replacement. Mechanical heart valves (MHVs) are often used in younger patients because of their longer durability. Their main disadvantage is the need for lifelong anticoagulation. Warfarin is considered a standard treatment, but it is far from perfect. Direct oral anticoagulants (DOACs) are a new and more patient-friendly alternative to warfarin when anticoagulation is required, but have not yet been approved for the indication of mechanical valves. Evidence acquisition: A literature search of Pubmed, Embase, Web of Science (Core Collection), and Cochrane Library (from inception to May 2023) was performed using a search string that was well defined and not modified during the study. An extensive overview of the search terms used in each database can be found in the Appendix. Only prospective clinical trials were included in this review. A total of 10 publications were included in this review. Relevance to clinical practice: This systematic review summarizes the different types of DOACs and their possible use in the anticoagulation of mechanical valves. We aim to propose future directions in anticoagulation research for mechanical valves. Conclusions: DOAC use in MHVs has been halted due to the failure of both dabigatran and apixaban in two major clinical trials. However, rivaroxaban was successful in two small clinical trials. Ample research is still needed to explore new valve designs as well as new anticoagulation targets.

Aims Information on the prevalence, outcome and factors associated with heart failure in patients with adult congenital heart disease (CHD) (ACHD‐HF) is lacking. We aimed at assessing the prevalence and outcome of ACHD‐HF, the variables associated with ACHD‐HF, and the differences between major anatomical/pathophysiological ACHD subgroups. Methods and results We included 3905 patients (age 35.4 ± 13.2 years) under active follow‐up in our institution (last visit >2010). Outcome of ACHD‐HF cases was compared with sex‐ and age‐matched cases. Univariable and multivariable binary logistic regression with ACHD‐HF diagnosis as a dependent variable was performed. Overall prevalence of ACHD‐HF was 6.4% (mean age 49.5 ± 16.7 years), but was higher in patients with cyanotic CHD (41%), Fontan circulation (30%), and a systemic right ventricle (25%). All‐cause mortality was higher in ACHD‐HF cases when compared with controls (mortality rate ratio 4.67 (2.36–9.27); P = 0.0001). In multivariable logistic regression analysis, age at latest follow‐up [per 10 years; odds ratio (OR) 1.52; 95% confidence interval (CI) 1.31–1.77], infective endocarditis (OR 4.11; 95%CI 1.80–9.38), history of atrial arrhythmia (OR 3.52; 95%CI 2.17–5.74), pacemaker implantation (OR 2.66; 95% CI 1.50–4.72), end‐organ dysfunction (OR 2.41; 95% CI 1.03–5.63), New York Heart Association class (OR 9.28; 95% CI 6.04–14.25), heart rate (per 10 bpm; OR 1.27; 95% CI 1.08–1.50), ventricular dysfunction (OR 3.62; 95% CI 2.54–5.17), and pulmonary hypertension severity (OR 1.66; 95% CI 1.21–2.30) were independently related to the presence of ACHD‐HF. Some variables (age, atrial arrhythmia, pacemaker, New York Heart Association, and ventricular dysfunction) were related to ACHD‐HF in all anatomical/physiological subgroups, whereas others were not. Conclusions ACHD‐HF is prevalent especially in complex CHD and is associated with poor prognosis. Our data provide insight in the factors related to ACHD‐HF including differences between specific anatomical and physiological subgroups.

Background Cardiac fibrosis is a key feature of pathological cardiac remodelling that significantly impacts heart function through contributing to stiffness, diastolic dysfunction, and arrhythmias, ultimately leading to heart failure (HF). Despite extensive research into fibrosis-related matrix alterations, therapeutic advancements are limited, in part owing to the different nature (reparative vs interstitial) and tissue distribution of fibrosis involved. To identify unique features of fibrosis phenotypes, we investigated fibroblast (FB) heterogeneity and spatial distribution in left ventricular myocardium in HF patients with ischemic (ICM) and dilated cardiomyopathy (DCM). Infarct scar was also analysed. Methods We performed single-nucleus RNA sequencing of 20 human left ventricular tissue samples: from non-failing, NF ( N  = 4), DCM ( N  = 6) and ICM ( N  = 5) hearts, and from the ICM scar region ( N  = 5). The data was subjected to bioinformatic analysis, included clustering, differential expression, ligand-receptor inference, and pseudotime trajectory mapping to delineate FB transitions and regional fibrosis signatures. To identify localisations of FB states and cellular neighbourhoods, data was integrated with publicly available spatial transcriptomics datasets. Results We identified distinct FB subpopulations across failing and non-failing hearts. Resident FB states showed preferential perivascular and interstitial distribution in NF and exhibited significant depletion in HF, giving rise to different disease states. We identified shared and unique activation ligands driving the onset of FB transitions as well as transcriptional differences between scar and interstitial fibrosis, and between ICM and DCM interstitial fibrosis. Trajectory analysis revealed distinct differentiation pathways for FB depending on its originating resident FB, with specific transcription factors guiding each transition. Conclusions These findings provide a comprehensive framework for understanding fibroblast dynamics, highlighting the heterogeneity and spatial complexity of fibrosis in human end-stage HF, and offering potential therapeutic targets to mitigate fibrosis while preserving scar integrity.

The role of immunosuppressive therapy on SARS-CoV-2 infection risk and COVID-19 severity remains unclear in unvaccinated solid organ transplant recipients. We included 1957 organ transplant recipients between July 2020 and April 2021 to analyze whether baseline immunosuppressive therapy and other risk factors are associated with SARS-CoV-2 infection and severe COVID-19. In total, 247 (12.6%) had SARS-CoV-2 (defined as positive nasopharyngeal swab and/or positive antibody titer). Of these, 57 (23.1%) had severe COVID-19, defined as oxygen supplementation, intensive care unit admission or death. Multivariable analysis identified diabetes (hazard ratio (HR) 1.39 (95% confidence interval (CI) 1.05–1.83)), chronic lung disease (HR 1.71 (95% CI 1.13–2.60)) and contact with a COVID-19 positive individual (HR 3.61 (95% CI 2.61–4.99) as independent risk factors for SARS-CoV-2 infection. There was no association between immunosuppressive therapy and infection risk. Severe COVID-19 was multivariably associated with hypertension (OR 5.45 (95% CI 1.66–17.84)), chronic kidney disease (OR 3.55 (95% CI 1.75–7.19)), corticosteroid use (OR 2.93 (95% CI 1.03–2.55)) and having a COVID-19 positive housemate (OR 6.77 (95% CI 2.65–17.28)). In conclusion, baseline corticosteroid use, but no other immunosuppressive agent, is independently associated with severe COVID-19 in unvaccinated SOT recipients after correction for hypertension, chronic kidney disease, housemates affected by COVID-19 and transplant type.

Right-sided mechanical support of the Fontan circulation by existing devices has been compounded by the cross-sectional design of vena cava anastomosis to both pulmonary arteries. Our purpose was to investigate whether increasing inferior vena cava (IVC) flow with a rotary blood pump in the IVC only in an ovine animal model of Fontan would lead to acceptable superior vena cava (SVC) pressure. To achieve this, a Fontan circulation was established in four female sheep by anastomosing the SVC to the main pulmonary artery (MPA) and by interposing a Dacron graft between the IVC and the MPA. A rotary blood pump was then introduced in the graft, and the effect of incremental flows was observed at increasing flow regimen. Additionally, to stimulate increased pulmonary resistance, the experience was repeated in each animal with the placement of a restrictive band on the MPA distally to the SVC and Dacron graft anastomosis. Circulatory support of IVC flow alone increased the systemic cardiac output significantly, both with and without banding, indicating the feasibility of mechanical support of the Fontan circulation by increasing the flow only in the inferior vena cava. The increase in SVC pressure remained within acceptable limits, indicating the potential effectiveness of this mode of support. The findings suggest that increasing the flow only in the inferior vena cava is a feasible method for mechanical support of the Fontan circulation, potentially leading to an increase in cardiac output with acceptable increases in superior vena cava pressure.

During the Renaissance, Leonardo Da Vinci was the first person to successfully detail the anatomy of the aortic root and its adjacent structures. Ever since, novel insights into morphology, function, and their interplay have accumulated, resulting in advanced knowledge on the complex functional characteristics of the aortic valve (AV) and root. This has shifted our vision from the AV as being a static structure towards that of a dynamic interconnected apparatus within the aortic root as a functional unit, exhibiting a complex interplay with adjacent structures via both humoral and mechanical stimuli. This paradigm shift has stimulated surgical treatment strategies of valvular disease that seek to recapitulate healthy AV function, whereby AV disease can no longer be seen as an isolated morphological pathology which needs to be replaced. As prostheses still cannot reproduce the complexity of human nature, treatment of diseased AVs, whether stenotic or insufficient, has tremendously evolved, with a similar shift towards treatments options that are more hemodynamically centered, such as the Ross procedure and valve-conserving surgery. Native AV and root components allow for an efficient Venturi effect over the valve to allow for optimal opening during the cardiac cycle, while also alleviating the left ventricle. Next to that, several receptors are present on native AV leaflets, enabling messenger pathways based on their interaction with blood and other shear-stress-related stimuli. Many of these physiological and hemodynamical processes are under-acknowledged but may hold important clues for innovative treatment strategies, or as potential novel targets for therapeutic agents that halt or reverse the process of valve degeneration. A structured overview of these pathways and their implications for cardiothoracic surgeons and cardiologists is lacking. As such, we provide an overview on embryology, hemodynamics, and messenger pathways of the healthy and diseased AV and its implications for clinical practice, by relating this knowledge to current treatment alternatives and clinical decision making.