Peripheral vascular disease:

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CONCLUSIONS: These results show that ALDH1A1 is downregulated in calcified valves, hence promoting VIC transition into an osteoblastic phenotype. Retinoic acid receptor alpha agonists, including all-trans retinoic acid through a drug repositioning strategy, represent a promising and innovative pharmacological approach to prevent calcification of native aortic valves and BPV.

Platelets are among the most abundant cells in the body and play important roles in coagulation and immunity. Platelets are formed when hematopoietic stem cells proliferate and differentiate into megakaryocytes via the regulation of various cytokines. After the megakaryocytes mature in the bone marrow cavity, proplatelets are released into the blood circulation where they eventually remodel into mature platelets. Given that the production and functions of platelets involve the regulation of many factors-such as hematopoietic stem cells, the hematopoietic microenvironment, and cytokines-the causes and mechanisms of platelet-related diseases are diverse, often involving platelet production, clearance, and distribution. In this review, we examined the regulation of platelet production and summarized common disorders affecting platelet quantity, namely, thrombocytopenia and thrombocytosis. In addition, we reviewed previous clinical studies and summarized the medication strategies commonly used for the treatment of different platelet disorders in different clinical scenarios.

CONCLUSIONS: Moderate expression of cardiac β3AR, at levels observed in human cardiac myocardium, exerts metabolic and antioxidant effects through activation of the pentose-phosphate pathway and NRF2 pathway through S-nitrosation of Keap1, thereby preserving myocardial oxidative metabolism, function, and integrity under pathophysiological stress.

High-throughput sequencing, with its capacity to simultaneously sequence large volumes of genomic data, has evolved from a research-focused technology to a clinical tool. This review outlines key steps in the development of a clinical haemostasis and thrombosis genetics service leveraging a multigene panel. We discuss its value across inherited bleeding, platelet, and thrombotic disorders (BPTDs) in the context of published studies utilizing multigene panels in these conditions. Benefits of sequencing include establishing a diagnosis through the simultaneous assessment of multiple candidate genes, exclusion of genocopies and predictions of phenotype to deliver targeted therapy. The presence of concomitant variants may modify phenotype; however, predictions on disease course from oligogenic modifiers are not yet used to guide patient care or counselling. Limitations in the widespread roll out of multigene panels for clinical diagnostics of BPTDs exist. These challenges relate to detection of structural variants, variable diagnostic hit rates and management of incidental findings. Variants of uncertain significance (VUS) also frustrate diagnostic yield. Family segregation studies, in vitro characterisation, and protein modelling aid interpretation of variant pathogenicity. While multigene panels offer substantial opportunities to improve BTPDs diagnostics, their implementation should be guided by appropriate expertise and in conjunction with clinical research to ensure safe and ethical care.

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Angiogenesis, the formation of new blood vessels, is a fundamental biological process with implications for both physiological functions and pathological conditions. While the transcriptional regulation of angiogenesis, mediated by factors such as HIF-1α (hypoxia-inducible factor 1-alpha) and VEGF (vascular endothelial growth factor), is well-characterized, the translational regulation of this process remains underexplored. Bioinformatics has emerged as an indispensable tool for advancing our understanding of translational regulation, offering predictive models that leverage large data sets to guide research and optimize experimental approaches. However, a significant gap persists between bioinformatics experts and other researchers, limiting the accessibility and utility of these tools in the broader scientific community. To address this divide, user-friendly bioinformatics platforms are being developed to democratize access to predictive analytics and empower researchers across disciplines. Translational control, compared with transcriptional control, offers a more energy-efficient mechanism that facilitates rapid cellular responses to environmental changes. Furthermore, transcriptional regulators themselves are often subject to translational control, emphasizing the interconnected nature of these regulatory layers. Investigating translational regulation requires advanced, accessible bioinformatics tools to analyze RNA structures, interacting micro-RNAs, long noncoding RNAs, and RBPs (RNA-binding proteins). Predictive platforms such as RNA structure, human internal ribosome entry site Atlas, and RBPSuite enable the study of RNA motifs and RNA-protein interactions, shedding light on these critical regulatory mechanisms. This review highlights the transformative role of bioinformatics using widely accessible user-friendly tools with a Web-browser interface to elucidate translational regulation in angiogenesis. The bioinformatics tools discussed extend beyond angiogenesis, with applications in diverse fields, including clinical care. By integrating predictive models and experimental insights, researchers can streamline hypothesis generation, reduce experimental costs, and find novel translational regulators. By bridging the bioinformatics knowledge gap, this review aims to empower researchers worldwide to adopt bioinformatics tools in their work, fostering innovation and accelerating scientific discovery.

Abstract: Chronic heart failure (CHF) involves skeletal muscle abnormalities, including atrophy, inflammation, mitochondrial dysfunction, and fibrosis, which impair contractile function. This study examines whether muscle deterioration correlates with CHF disease severity by assessing the relationship between circulating N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) concentrations, left ventricular ejection fraction (LVEF), and muscle characteristics in CHF patients. In 36 patients with CHF (LVEF≤45%, NYHA class I-III), we measured circulating NT-proBNP concentrations, LVEF, muscle strength and functional measures, and myocellular features, including fiber type-specific cross-sectional area (CSA), muscle stem cell (MuSC) and myonuclei content, and capillary density. Also, muscle mitochondrial function was evaluated. The concentration of NT-proBNP inversely correlated with muscle strength (R=0.25, P<0.01), mean fiber CSA (R=0.15, P=0.04), and MuSC content (R=0.37, P<0.01). Moreover, a non-significant inverse correlation was observed for capillary density (R=0.12, P=0.06). The strength of associations between NT-proBNP, fiber CSA and capillary density was primarily driven by fiber type-specific correlations. Associations to MuSC content was equally strong across fiber types. No corelation was observed for measures of mitochondrial function. For LVEF, a non-significant correlation was observed only for overall MuSC content (R=0.11 P=0.07). Skeletal muscle deterioration in patients with CHF correlates with NT-proBNP, but not LVEF, suggesting that NT-proBNP concentration constitutes a stronger indicator of the link between CHF severity and skeletal muscle decline than LVEF as function parameter. Our findings highlights circulating NTpro-BNP concentrations as a potential biomarker for identification of patients at risk of experiencing skeletal muscle deterioration.

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Populations most affected by cardiovascular health disparities, including underrepresented populations with lower socioeconomic status, people with disabilities, and those living in underserved rural communities, are disproportionately exposed to adverse social determinants of health. Specifically, economic instability and suboptimal living conditions within the neighborhood and built environment directly determine access to resources and opportunities for healthful behaviors. In this scientific statement, we examined the technology-enabled interventions that address cardiovascular health behaviors from adolescence to adulthood in populations most affected by health disparities. We used a broad definition of technology, including wearables, applications, and telehealth, for behavior tracking. Aligning with Life's Essential 8, we focused on interventions targeting behavior change related to physical activity, sedentary time, dietary intake, tobacco cessation, and sleep health to improve cardiovascular health. The digital determinants of health are important adjuncts to the social determinants and operate at the individual, interpersonal, community, and societal levels. The digital determinants of health include the impact of digital technologies (eg, wearables, telemedicine) across health outcomes. Evidence of effective interventions using technology to improve cardiovascular health through positive behavior change is critical for preventing cardiovascular disease events. Stronger evidence is needed to inform and implement effective approaches that are scalable and cost-effective across communities and health care institutions to advance digital equity in cardiovascular health. Dissemination of digital solutions to improve cardiovascular health in communities or across health care systems must ensure effective, feasible, available, and affordable solutions for populations most in need.

CONCLUSIONS: Our study revealed that maternal genetic factors and plasma aspirin hydrolysis are not among the decisive factors in determining the effectiveness of low-dose aspirin in preventing preeclampsia among high-risk women. Instead, placental GLYAT appears to play a key role by limiting the effect of salicylic acid in the placenta.

Abstract: While resting heart rate (RHR) is associated with multiple diseases, conflicting information exists on the association between RHR and venous thromboembolism (VTE). We, therefore, aimed to investigate the association between RHR and risk of VTE in a population-based cohort.Participants ( = 36,395) were followed from inclusion in the Tromsø 4 to 7 surveys (1994-2016) throughout 2020. RHR was measured in beats per minute (bpm) at each survey (repeated measurements for those attending several surveys). All first-time VTEs during follow-up were recorded. Hazard ratios (HR) for VTE with 95% confidence intervals (CIs) according to RHR categories (61-70, 71-80, and >80 bpm) with ≤60 bpm as reference were estimated using Cox regression models, and adjusted for age, sex, body mass index, cardiovascular disease, cancer, and physical activity. We also performed age-stratified analyses (<60 and ≥60 years).During a median of 6.6 years of follow-up, 1,072 participants experienced a VTE. Fully adjusted HRs (95% CI) for overall VTE were 1.12 (0.93-1.35), 1.35 (1.11-1.63), and 1.19 (0.97-1.47) for RHR categories 61 to 70, 71 to 80, and >80 bpm, respectively. Corresponding HRs for unprovoked VTE were 1.56 (1.14-2.14), 1.76 (1.28-2.43), and 1.60 (1.13-2.25), whereas no association was observed for provoked VTE. The association was more consistent in those ≥60 years, with HRs for overall VTE, >80 bpm versus ≤60 bpm of 1.30 (1.02-1.65) and for unprovoked VTE of 1.86 (1.24-2.81).Our findings suggest that higher RHR may be a risk factor for VTE and more consistently so for those ≥60 years. The VTE risk by higher RHR was particularly pronounced for unprovoked events.

Baroreflex regulates blood pressure and heartbeat through specific mechanosensitive baroreceptors. However, the current knowledge is derived only from animal experiments. No data about human aortic baroreceptors have been reported so far. Therefore, in this study, we performed extended histological, proteomics and transcriptomics analyses of the aortic arch to identify potential human baroreceptors. Three healthy human aortic arches from autopsies, six abdominal aortic aneurysms and four control abdominal aortic tissue samples from our vascular biobank were analysed. For histological analyses, antibodies against various neuronal markers were used. Laser capture microdissection and macrodissection were performed to selectively analyse nerves in the adventitia of the human aorta using proteomics and RNA sequencing. Histological analysis revealed a heterogeneous distribution of nerves in the adventitia along the entire aortic arch, predominantly in the ascending aorta up to the left subclavian artery. Proteome analysis identified three putative human baroreceptors PIEZO1, TRPV2, and TRPM4. Transcriptomics confirmed that these ion channels do not originate from cells within the aortic wall but presumably from the cell body of the vagus nerve. Interestingly, these ion channels were also detected in the healthy abdominal aorta and abdominal aneurysm without any significant differences in their abundance. Our study identified, for the first time, putative baroreceptors in the human aortic arch. Further studies are necessary to validate our current results and elucidate the role of these putative baroreceptors in the human aortic arch.

CONCLUSIONS: Echocardiography-guided induction of myocardial IR enables high-throughput induction of myocardial IR injury with precise echocardiographic definition of the occlusion level and immediate evaluation of cardiac function during ischemia. The method provides a more clinically relevant assessment of IR sequelae and offers notable animal welfare advantages by eliminating the need for ventilation and thoracotomy, thereby mitigating potential surgery-related confounders.

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Mitral regurgitation and tricuspid regurgitation are the most common valvular heart diseases in patients with heart failure and have independent prognostic value. Transcatheter interventions are now available for the treatment of valvular heart disease, and their efficacy and safety have been tested in randomized controlled trials. However, evidence is still limited and sometimes inconclusive because several aspects of these trials limit their interpretation or consistency. These include heterogeneity in the pathogenesis and clinical characteristics of patients, the dynamic nature of secondary atrioventricular valve disease severity, the role of heart failure medications and devices, dependency on procedural results and operators' skills, smaller number of patients enrolled and the power to detect differences in trials, and limitations to use patients' reported outcomes with unblinded study protocols. These specific aspects of trials in patients with atrioventricular valve disease are reviewed in this article with a focus on possible solutions to generate further evidence for the efficacy and safety for transcatheter treatments of atrioventricular valve disease in patients with heart failure.

CONCLUSIONS: The canonical ketogenic enzyme, HMGCS2, mediates the therapeutic effects of the oxidized form of nicotinamide adenine dinucleotide repletion in HFpEF by restoring normal lipid metabolism and mitochondrial function.

Significant hemodynamic changes occur within the neonatal transition period including a sudden increase in pulmonary blood flow, disappearance of fetal shunts and increase in systemic vascular resistance. How this affects left ventricular (LV) physiology and intraventricular flow dynamics is still poorly understood. Blood speckle tracking is a novel high frame rate echocardiographic technique that allows to visualize two-dimensional intraventricular flow dynamics. In this study longitudinal changes in LV diastolic flow dynamics were explored in a prospective single-center design analyzing a total of 176 echocardiographic examinations in 36 healthy newborns from birth until six months of age. Kinetic energy, energy loss, vorticity and intraventricular pressure difference increased significantly from birth until six-eight weeks of age (p < 0.001 for all parameters). The increase in IVPD continued until six months of age while no further significant changes in the other quantitative LV flow parameters could be observed beyond six-to-eight weeks. Early after birth, diastolic vorticity was predominantly located at the anterior mitral valve leaflet while at six months of age, vorticity was similar at the anterior compared to the posterior mitral valve leaflet. Overall, these results indicate that LV diastolic physiology and flow dynamics undergo substantial changes in early life. The observed changes in diastolic LV properties are likely associated with increased LV filling in the presence of increased pulmonary blood flow.

Patients with interrupted inferior vena cava (I-IVC) and azygos continuation who undergo Fontan completion via hepatoazygos shunting (HAS) exhibit unique hemodynamic challenges. This study evaluates age-related shifts in systemic venous return dominance, hepatic flow distribution (HFD), power loss (PL), and flow disturbances using patient-specific computational fluid dynamics (CFD). Data analysis from 95 I-IVC patients showed a non-linear shift in upper-to-lower body systemic flow dominance with ratios of 2, 1, and 0.5 (correlating to ages ~3, ~10, and ~20 respectively). CFD simulations for 17 selected patients revealed a trend of increasing HFD toward the right pulmonary artery (RPA), with median splits of 45%-49%, 48%-52%, and 40%-60% for the respective flow ratios. Power loss increased significantly with lower-body flow dominance. Median values for absolute PL were 4.75 mW (ratio 2), 16.5 mW (ratio 1), and 33.7 mW (ratio 0.5). Indexed PL showed a similar trend, rising from 0.04 mW/m² to 0.11 mW/m² across the flow ratios. Vorticity (VOR) and viscous dissipation rates (VDR), key metrics of flow disturbances, also increased with lower-body flow dominance, showing strong correlations with PL (R = 0.58-0.76). Kruskal-Wallis based statistical analysis identified significant statistical differences in absolute PL (p = 0.0045) and flow disturbances (p < 0.001), emphasizing the impact of age-related flow dynamics on Fontan efficiency. Our findings emphasize the need for targeted interventions in patients with I-IVC with azygos continuation to mitigate evolving hemodynamic inefficiencies and optimize Fontan outcomes during critical growth periods.