Assessing causal associations of blood counts and biochemical indicators with pulmonary arterial hypertension: a Mendelian randomization study and results from national health and nutrition examination survey 2003-2018.

Background: Blood counts and biochemical markers are among the most common tests performed in hospitals and most readily accepted by patients, and are widely regarded as reliable biomarkers in the literature. The aim of this study was to assess the causal relationship between blood counts, biochemical indicators and pulmonary arterial hypertension (PAH). Methods: A two-sample Mendelian randomization (MR) analysis was performed to assess the causal relationship between blood counts and biochemical indicators with PAH. The genome-wide association study (GWAS) for blood counts and biochemical indicators were obtained from the UK Biobank (UKBB), while the GWAS for PAH were sourced from the FinnGen Biobank. Inverse variance weighting (IVW) was used as the primary analysis method, supplemented by three sensitivity analyses to assess the robustness of the results. And we conducted an observational study using data from National Health and Nutrition Examination Survey (NHANES) 2003-2018 to verify the relationship. Results: The MR analysis primarily using the IVW method revealed genetic variants of platelet count (OR=2.51, 95% CI 1.56-4.22, P<0.001), platelet crit(OR=1.87, 95% CI1.17-7.65, P=0.022), direct bilirubin (DBIL)(OR=1.71, 95%CI 1.18-2.47,P=0.004), insulin-like growth factor (IGF-1)(OR=0.51, 95% CI 0.27-0.96, P=0.038), Lipoprotein A (Lp(a))(OR=0.66, 95% CI 0.45-0.98, P=0.037) and total bilirubin (TBIL)(OR=0.51, 95% CI 0.27-0.96, P=0.038) were significantly associated with PAH. In NHANES, multivariate logistic regression analyses revealed a significant positive correlation between platelet count and volume and the risk of PAH, and a significant negative correlation between total bilirubin and PAH. Conclusion: Our study reveals a causal relationship between blood counts, biochemical indicators and pulmonary arterial hypertension. These findings offer novel insights into the etiology and pathological mechanisms of PAH, and emphasizes the important value of these markers as potential targets for the prevention and treatment of PAH.

The Association of High Lipoprotein(a) Concentration and Risk of Ischaemic Stroke in Atrial Fibrillation Patients.

Background: Lipoprotein(a) [Lp(a)] is a well-established risk factor for ischaemic stroke (IS). It is unclear whether Lp(a) is associated with IS in patients with atrial fibrillation (AF). The aim of this study is to explore the association between the concentration of Lp(a) and the risk of IS in AF patients, hope to find the potential risk factor for the IS in AF patients. Methods: This study is a retrospective cohort study. The screened AF patients between January 2017 and July 2021 were matched at 1:1 by the propensity score matching (PSM) method in the Second Affiliated Hospital of Nanchang University. Associations between Lp(a) and ischaemic stroke were analysed using logistic regression models, stratified analysis and sensitivity analysis. Statistical analyses were conducted using IBM SPSS software. Results: The number of enrolled participates is 2258, which contains 1129 non-AF patients and 1129 AF patients. Among IS patients, the median Lp(a) concentration was higher than that of controls (17.03 vs. 15.36 mg/dL, P = 0.032). The Spearman rank-order correlation coefficients revealed significant positive relationships between IS and Lp(a) (P = 0.032). In addition, a significant increase in IS risk was associated with Lp(a) levels >30.00 mg/dL in unadjusted model [OR:1.263, 95% CI(1.046-1.523), P = 0.015], model 1 [OR:1.284, 95% CI(1.062,1.552), P = 0.010], model 2 [OR: 1.297, 95% CI(1.07,1.573). P = 0.008], and model 3 [OR: 1.290, 95% CI (1.064, 1.562). P = 0.009]. The stratified analysis indicated that this correlation was not affected by female sex [1.484 (1.117, 1.972), P = 0.006], age ≤ 60 [1.864 (1.067-3.254), P=0.029], hypertension [1.359 (1.074, 1.721), P = 0.011], or non-coronary heart disease (CHD) [1.388 (1.108, 1.738), P = 0.004]. Conclusion: High levels of Lp(a) were significantly related to IS in AF patients and may be a potential risk factor in the onset of an IS in AF patients.

Predictors, clinical impact, and management strategies for conduction abnormalities after transcatheter aortic valve replacement: an updated review.

Transcatheter aortic valve replacement (TAVR) has increasingly become a safe, feasible, and widely accepted alternative surgical treatment for patients with severe symptomatic aortic stenosis. However, the incidence of conduction abnormalities associated with TAVR, including left bundle branch block (LBBB) and high-degree atrioventricular block (HAVB), remains high and is often correlated with risk factors such as the severity of valvular calcification, preexisting conditions in patients, and procedural factors. The existing research results on the impact of post-TAVR conduction abnormalities and permanent pacemaker (PPM) requirements on prognosis, including all-cause mortality and rehospitalization, remain contradictory, with varied management strategies for post-TAVR conduction system diseases across different institutions. This review integrates the latest research in the field, offering a comprehensive discussion of the mechanisms, risk factors, consequences, and management of post-TAVR conduction abnormalities. This study provides insights into optimizing patient prognosis and explores the potential of novel strategies, such as conduction system pacing, to minimize the risk of adverse clinical outcomes.

Causal effect of gallstone disease on the risk of coronary heart disease or acute myocardial infarction: a Mendelian randomization study.

Gallstone disease (GSD) is thought to be associated with the risk of coronary heart disease (CHD) or acute myocardial infarction (AMI), which may be due to abnormal cholesterol metabolism. We used multiple Mendelian randomization (MR) methods based on publicly available genome-wide association study data to assess whether this association is genetically causal and to search for loci driving causality. Pooled data for GSD were obtained from FinnGen Biobank and Biobank Japan, while CHD and AMI were obtained as pooled data from the CARDIoGRAMplusC4D consortium. In this MR study, we found a significant negative causal effect of genetic susceptibility to GSD on AMI in the Finnish population, but no causal effect was found on CHD. This causal effect was not confounded by reverse causality and the same findings were obtained in the Japanese population. Furthermore, the negative causal effect of GSD on AMI risk may be driven by the rs4245791-regulated ABCG5/8 protein. In conclusion, the results of this MR study support a negative causal effect of GSD on AMI and suggest that rs4245791 is the causal driver locus of this effect, which provides new ideas and evidence for the prevention and etiologic study of AMI in patients with GSD.

Applications of machine learning in familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is a common hereditary cholesterol metabolic disease that usually leads to an increase in the level of low-density lipoprotein cholesterol in plasma and an increase in the risk of cardiovascular disease. The lack of disease screening and diagnosis often results in FH patients being unable to receive early intervention and treatment, which may mean early occurrence of cardiovascular disease. Thus, more requirements for FH identification and management have been proposed. Recently, machine learning (ML) has made great progress in the field of medicine, including many innovative applications in cardiovascular medicine. In this review, we discussed how ML can be used for FH screening, diagnosis and risk assessment based on different data sources, such as electronic health records, plasma lipid profiles and corneal radian images. In the future, research aimed at developing ML models with better performance and accuracy will continue to overcome the limitations of ML, provide better prediction, diagnosis and management tools for FH, and ultimately achieve the goal of early diagnosis and treatment of FH.

Screening and clinical characteristics analysis of familial hypercholesterolemia in a tertiary public hospital.

Background and aims: Familial hypercholesterolemia (FH) is becoming a global burden. However, it remains underdiagnosed and undertreated worldwide. This study aimed to observe the screening rate of FH patients and department distribution among hospitalized patients using different diagnostic criteria. Methods: A total of 45,410 inpatients with LDL-C ≥3.5 mmol/L between 2008 and 2019 were included from The Second Affiliated Hospital of Nanchang University. Inpatients are diagnosed and divided into groups by Dutch Lipid Clinic Network (DLCN) criteria, Chinese-modified DLCN criteria and Chinese expert consensus (CEC) criteria. Results: There were 172, 1,076 and 115 inpatients included in the DLCN group, Chinese-modified DLCN group and CEC group, respectively (screening rates: 0.38%, 2.37% and 0.25%). These FH patients had a very high risk of atherosclerotic cardiovascular disease (ASCVD) (55.7%-74.4%), especially in the DLCN group and CEC group (70.4%-74.4%). More than half of the patients were in the Department of Cardiology, and other high-risk departments included Neurology, Nephrology, Vascular Surgery, Otolaryngology & Head Neck Surgery and Traditional Chinese Medicine (24.35%-31.51%). Overall, hypertension, coronary heart disease, carotid arteriosclerosis, hepatic cyst, arrhythmia, and nonalcoholic fatty liver disease were common accompanying diseases with FH. Conclusions: It is necessary to establish appropriate diagnostic criteria and more positive treatment strategies for the FH inpatient population. In addition, promoting awareness of FH among doctors from other departments is also necessary. Therefore, developing a comprehensive management strategy for FH disease is very important.

Recent Advances in Gene Therapy for Familial Hypercholesterolemia: An Update Review.

(1) Background: Existing lipid-lowering therapies have difficulty in achieving lipid target levels in patients with familial hypercholesterolemia (FH), especially in the treatment of patients with homozygous familial hypercholesterolemia. (2) Method: All of the literature data containing "Familial hypercholesterolemia" and "Gene Therapy" in PubMed and Clinical Trials from 2018 to 2022 were selected. (3) Results: The rapid development of gene therapy technology in recent years is expected to change the treatment status of FH patients. As emerging gene therapy vectors, the optimized adeno-associated viruses, exosomes, and lipid nanoparticles have demonstrated an improved safety and higher transfection efficiency. Various RNA-targeted therapies are in phase 1-3 clinical trials, such as small interfering RNA-based drugs inclisiran, ARO-ANG3, ARO-APOC3, olpasiran, SLN360, and antisense oligonucleotide-based drugs AZD8233, vupanorsen, volanesorsen, IONIS-APO(a)Rx, etc., all of which have demonstrated excellent lipid-lowering effects. With gene editing technologies, such as CRISPR-Cas 9 and meganuclease, completing animal experiments in mice or cynomolgus monkeys and demonstrating lasting lipid-lowering effects, patients with FH are expected to reach a permanent cure in the future. (4) Conclusion: Gene therapy is being widely used for the lipid-lowering treatment of FH patients and has shown excellent therapeutic promise, but the current delivery efficiency, economic burden, immunogenicity and the precision of gene therapy can be further optimized.

High lipoprotein(a) concentrations are associated with lower type 2 diabetes risk in the Chinese Han population: a large retrospective cohort study.

BACKGROUND: Lipoprotein (a) [Lp(a)] is a proven independent risk factor for coronary heart disease. It is also associated with type 2 diabetes mellitus (T2DM). However, the correlation between Lp(a) and T2DM has not been clearly elucidated. METHODS: This was a retrospective cohort study involving 9248 T2DM patients and 18,496 control individuals (1:2 matched). Patients were randomly selected from among inpatients in the Second Affiliated Hospital of Nanchang University between 2006 and 2017. Clinical characteristics were compared between the two groups. Spearman rank-order correlation coefficients were used to evaluate the strength and direction of monotonic associations of serum Lp(a) with other metabolic risk factors. Binary logistic regression analysis was used to establish the correlation between Lp(a) levels and T2DM risk. RESULTS: The median Lp(a) concentration was lower in T2DM patients than in controls (16.42 vs. 16.88 mg/dL). Based on four quartiles of Lp(a) levels, there was a decrease in T2DM risk from 33.7% (Q1) to 31.96% (Q4) (P for trend < 0.0001). Then, Lp(a) levels > 28.72 mg/dL (Q4) were associated with a significantly lower T2DM risk in the unadjusted model [0.924 (0.861, 0.992), P = 0.030]. Similar results were obtained in adjusted models 1 [Q4, 0.925 (0.862, 0.993), P = 0.031] and 2 [Q4, 0.919 (0.854, 0.990), P = 0.026]. Furthermore, in the stratified analysis, Q4 of Lp(a) was associated with a significantly lower T2DM risk among men [0.813 (0.734, 0.900), P < 0.001] and those age > 60 years [0.819 (0.737, 0.910), P < 0.001]. In contrast, the low-density lipoprotein cholesterol (LDL-C) levels and coronary heart disease (CHD) did not impact these correlations between Lp(a) and diabetes. CONCLUSIONS: There is an inverse association between Lp(a) levels and T2DM risk in the Chinese population. Male patients, especially those aged more than 60 years with Lp(a) > 28.72 mg/dL, are low-risk T2DM individuals, regardless of LDL-C levels and CHD status.