An endothelial regulatory module links blood pressure regulation with elite athletic performance.

The control of transcription is crucial for homeostasis in mammals. A previous selective sweep analysis of horse racing performance revealed a 19.6 kb candidate regulatory region 50 kb downstream of the Endothelin3 (EDN3) gene. Here, the region was narrowed to a 5.5 kb span of 14 SNVs, with elite and sub-elite haplotypes analyzed for association to racing performance, blood pressure and plasma levels of EDN3 in Coldblooded trotters and Standardbreds. Comparative analysis of human HiCap data identified the span as an enhancer cluster active in endothelial cells, interacting with genes relevant to blood pressure regulation. Coldblooded trotters with the sub-elite haplotype had significantly higher blood pressure compared to horses with the elite performing haplotype during exercise. Alleles within the elite haplotype were part of the standing variation in pre-domestication horses, and have risen in frequency during the era of breed development and selection. These results advance our understanding of the molecular genetics of athletic performance and vascular traits in both horses and humans.

Aortic events and relative survival in patients with moderately dilated proximal thoracic aorta.

Objectives. This study describes growth, local and remote aortic events, and survival in patients with proximal (root, ascending) aortic diameters just below threshold for operation. Methods. Patients with proximal aortic diameter of 4.5 to 5.4 cm at baseline, were followed with serial computed tomography studies and data collected retrospectively. Aortic growth rate was estimated using mixed effects modelling. Clinical and radiological features associated with outcomes (all-cause death, aortic death, local or remote aortic events (dissection, rupture, intramural hematoma, or intervention)) were assessed with Cox analysis. Survival and freedom from events were estimated using Kaplan-Meier methods. Results. 80 patients underwent 274 CT scans during 265 patient-years. Median proximal aortic growth was 0.2 cm in 3 years. 32 events occurred in 28 patients (35%). Eleven events were local, all elective proximal aortic surgery. Nine events were remote: 5 type B aortic dissections, 3 descending aneurysms undergoing elective repair, and one infrarenal aortic rupture. Twelve patients died, half of type B aortic dissection. Relative survival compared to a matched normal population was 82% (95% confidence limits 55-98%) at 10 years. In Cox analysis, increased descending aortic diameter was an independent predictor of all-cause death (hazard ratio [HR], 1.39) and aortic death (HR 1.96). Conclusions. Descending, but not proximal, aortic growth was predictive of lethal events. The decreased relative survival, the substantial number of remote aortic events and aortic deaths strongly suggest continuous serial CT surveillance of the entire aorta. Other indicators than proximal aortic diameter appear needed to improve management of this patient group.

Comparative Long-Term Clinical Performance of Mechanical Aortic Valve Prostheses.

Importance: Aggregated data and long-term follow-up in national health data registers offer the opportunity to compare the performance of mechanical aortic prostheses within the same population. Objective: To investigate the clinical performance of mechanical aortic valve prostheses. Design, Setting, and Participants: This nationwide cohort study included all 5224 patients who underwent primary mechanical aortic valve replacement in Sweden between January 1, 2003, and December 31, 2018. Statistical analysis was performed between May and September 2023. Exposures: Surgical aortic valve replacement with the On-X, Carbomedics, Bicarbon, Standard, Regent, Open Pivot, Masters, or Advantage valve models. Main Outcomes and Measures: The primary outcome was all-cause mortality, and secondary outcomes were reintervention, heart failure, major bleeding, stroke, and embolic events. Regression standardization was used to account for baseline differences. Results: Overall, 5224 patients (mean [SD] age, 56.8 [11.7] years; 3908 men [74.8%]) were included. Total follow-up time was 43 982 person-years (mean [SD], 8.4 [4.6] years; maximum, 17.2 years). After regression standardization, there was a significant difference in 10-year mortality between the Carbomedics model group (17%; 95% CI, 15%-18%), Regent model group (17%; 95% CI, 13%-20%), and Standard model group (17%; 95% CI, 14%-19%) compared with the Bicarbon model group (27%; 95% CI, 21%-34%). Conclusions and Relevance: In this cohort study of mechanical valve surgical aortic replacement outcomes in Sweden, the rate of all-cause mortality was higher in the Bicarbon group than in the Carbomedics, Regent, and Standard model groups. These findings warrant further research on the long-term clinical performance of the Bicarbon valve.

The effect of continuous bilateral parasternal block with lidocaine on patient-controlled analgesia opioid requirement and recovery after open heart surgery: a double-blind randomised controlled trial.

Background: We hypothesised that a continuous 72-h bilateral parasternal infusion of lidocaine at 2×35 mg h-1 would decrease pain and the inflammatory response after sternotomy for open heart surgery, subsequently improving quality of recovery. Methods: We randomly allocated 45 participants to a 72-h bilateral parasternal infusion of lidocaine or saline commencing after wound closure. The primary outcome was the cumulative patient-controlled analgesia (PCA) morphine consumption at 72 h. Secondary outcomes included total morphine requirement, pain, peak expiratory flow, and serum interleukin-6 concentration. In addition, we used an eHealth platform for a 3-month follow-up of pain, analgesic use, and Quality of Recovery-15 scores. Results: The 72-h PCA morphine requirement was significantly lower in the lidocaine than the saline group (10 mg [inter-quartile range: 5-19 mg] and 28.2 mg [inter-quartile range: 16-42.5 mg], respectively; P=0.014). The total morphine requirement (including morphine administered before the start of PCA) was significantly lower at 24, 48, and 72 h. Pain was well controlled with no difference in pain scores between treatment groups. The peak expiratory flow was lower in the lidocaine group at 72 h. Interleukin-6 concentrations showed no difference at 24, 48, or 72 h. Quality of Recovery-15 scores did not differ between treatment groups at any time during the 3-month follow-up. Conclusions: After sternotomy for open heart surgery, a 72-h bilateral parasternal lidocaine infusion significantly decreased PCA and total morphine requirement. However, neither signs of decreased inflammatory response nor an improvement in recovery was seen. Clinical trial registration: EudraCT number 2018-004672-35.

Predictive machine learning models for ascending aortic dilatation in patients with bicuspid and tricuspid aortic valves undergoing cardiothoracic surgery: a prospective, single-centre and observational study.

OBJECTIVES: The objective of this study was to develop clinical classifiers aiming to identify prevalent ascending aortic dilatation in patients with bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV). DESIGN AND SETTING: A prospective, single-centre and observational cohort. PARTICIPANTS: The study involved 543 BAV and 491 TAV patients with aortic valve disease and/or ascending aortic dilatation, excluding those with coronary artery disease, undergoing cardiothoracic surgery at the Karolinska University Hospital (Sweden). MAIN OUTCOME MEASURES: Predictors of high risk of ascending aortic dilatation (defined as ascending aorta with a diameter above 40 mm) were identified through the application of machine learning algorithms and classic logistic regression models. EXPOSURES: Comprehensive multidimensional data, including valve morphology, clinical information, family history of cardiovascular diseases, prevalent diseases, demographic details, lifestyle factors, and medication. RESULTS: BAV patients, with an average age of 60.4±12.4 years, showed a higher frequency of aortic dilatation (45.3%) compared with TAV patients, who had an average age of 70.4±9.1 years (28.9% dilatation, p <0.001). Aneurysm prediction models for TAV patients exhibited mean area under the receiver-operating-characteristic curve (AUC) values above 0.8, with the absence of aortic stenosis being the primary predictor, followed by diabetes and high-sensitivity C reactive protein. Conversely, prediction models for BAV patients resulted in AUC values between 0.5 and 0.55, indicating low usefulness for predicting aortic dilatation. Classification results remained consistent across all machine learning algorithms and classic logistic regression models. CONCLUSION AND RECOMMENDATION: Cardiovascular risk profiles appear to be more predictive of aortopathy in TAV patients than in patients with BAV. This adds evidence to the fact that BAV-associated and TAV-associated aortopathy involves different pathways to aneurysm formation and highlights the need for specific aneurysm preventions in these patients. Further, our results highlight that machine learning approaches do not outperform classical prediction methods in addressing complex interactions and non-linear relations between variables.

Bleeding in minimally invasive versus conventional aortic valve replacement.

BACKGROUND: Observational studies have shown reduced perioperative bleeding in patients undergoing minimally invasive, compared with full sternotomy, aortic valve replacement. Data from randomized trials are conflicting. METHODS: This was a Swedish single center study where adult patients with aortic stenosis, 100 patients were randomly assigned in a 1:1 ratio to undergo either minimally invasive (ministernotomy) or full sternotomy aortic valve replacement. The primary outcome was severe or massive bleeding defined by the Universal Definition of Perioperative Bleeding in adult cardiac surgery (UDPB). Secondary outcomes included blood product transfusions, chest tube output, re-exploration for bleeding, and several other clinically relevant events. RESULTS: Out of 100 patients, three patients randomized to ministernotomy were intraoperatively converted to full sternotomy (none was bleeding-related). Three patients (6%) in the full sternotomy group and 3 patients (6%) in the ministernotomy group suffered severe or massive postoperative bleeding according to the UDPB definition (p = 1.00). Mean chest tube output during the first 12 postoperative hours was 350 (standard deviation (SD) 220) ml in the full sternotomy group and 270 (SD 190) ml in the ministernotomy group (p = 0.08). 28% of patients in the full sternotomy group and 36% of patients in the ministernotomy group received at least one packed red blood cells transfusion (p = 0.39). Two patients in each group (4%) underwent re-exploration for bleeding. CONCLUSIONS: Minimally invasive aortic valve replacement did not result in less bleeding-related outcomes compared to full sternotomy. CLINICAL TRIAL REGISTRATION: http://www. CLINICALTRIALS: gov . Unique identifier: NCT02272621.

A functional genomic framework to elucidate novel causal non-alcoholic fatty liver disease genes.

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver pathology in western countries, with serious public health consequences. Efforts to identify causal genes for NAFLD have been hampered by the relative paucity of human data from gold-standard magnetic resonance quantification of hepatic fat. To overcome insufficient sample size, genome-wide association studies using NAFLD surrogate phenotypes have been used, but only a small number of loci have been identified to date. In this study, we combined GWAS of NAFLD composite surrogate phenotypes with genetic colocalization studies followed by functional in vitro screens to identify bona fide causal genes for NAFLD. Approach & Results: We used the UK Biobank to explore the associations of our novel NAFLD score, and genetic colocalization to prioritize putative causal genes for in vitro validation. We created a functional genomic framework to study NAFLD genes in vitro using CRISPRi. Our data identify VKORC1, TNKS, LYPLAL1 and GPAM as regulators of lipid accumulation in hepatocytes and suggest the involvement of VKORC1 in the lipid storage related to the development of NAFLD. Conclusions: Complementary genetic and genomic approaches are useful for the identification of NAFLD genes. Our data supports VKORC1 as a bona fide NAFLD gene. We have established a functional genomic framework to study at scale putative novel NAFLD genes from human genetic association studies.