SARS-CoV-2 spike protein acts as a ß-adrenergic receptor agonist: A potential mechanism for cardiac sequelae of long COVID.

BACKGROUND: Currently, pathophysiological mechanisms of post-acute sequelae of coronavirus disease-19-cardiovascular syndrome (PASC-CVS) remain unknown. METHODS AND RESULTS: Patients with PASC-CVS exhibited significantly higher circulating levels of severe acute respiratory syndrome-coronavirus-2 spike protein S1 than the non-PASC-CVS patients and healthy controls. Moreover, individuals with high plasma spike protein S1 concentrations exhibited elevated heart rates and normalized low frequency, suggesting cardiac ß-adrenergic receptor (ß-AR) hyperactivity. Microscale thermophoresis (MST) assay revealed that the spike protein bound to ß1- and ß2-AR, but not to D1-dopamine receptor. These interactions were blocked by ß1- and ß2-AR blockers. Molecular docking and MST assay of ß-AR mutants revealed that the spike protein interacted with the extracellular loop 2 of both ß-ARs. In cardiomyocytes, spike protein dose-dependently increased the cyclic adenosine monophosphate production with or without epinephrine, indicating its allosteric effects on ß-ARs. CONCLUSION: Severe acute respiratory syndrome-coronavirus-2 spike proteins act as an allosteric ß-AR agonist, leading to cardiac ß-AR hyperactivity, thus contributing to PASC-CVS.

Association between liver fibrosis and thrombotic or bleeding events in acute coronary syndrome patients.

BACKGROUND: The prognostic implication of liver fibrosis in acute coronary syndrome (ACS) patients are scarce. We sought to evaluate whether liver fibrosis scores (LFS) were associated with thrombotic or bleeding events in patients with acute coronary syndrome. METHODS: We included 6386 ACS patients who underwent percutaneous coronary intervention (PCI). This study determined liver fibrosis with aspartate aminotransferase to platelet ratio index (APRI), aspartate aminotransferase to alanine aminotransferase ratio (AST/ALT ratio), Forns score, and nonalcoholic fatty liver disease fibrosis score (NFS). The primary endpoint was major adverse cardiac and cerebrovascular events (MACCE), a composite of all-cause mortality (ACM), myocardial infarction (MI), and ischemic stroke (IS). RESULTS: During the follow-up, 259 (4.06%) MACCE and 190 (2.98%) bleeding events were recorded. As a continuous variable or a categorical variable stratified by the literature-based cutoff, LFS was positively associated with MACCE (p > 0.05) but not with bleeding events. Compared with subjects with low APRI scores, AST/ALT ratio scores, Forns scores, and NFS scores, subjects with high scores had a 1.57- to 3.73-fold increase risk of MACCE after adjustment (all p < 0.05). The positive relationship between LFS and MACCE was consistent in different subgroups. CONCLUSIONS: In ACS patients, increased LFS predicted an elevated risk of thrombotic events but not bleeding. LFS may contribute to thrombotic risk stratification after ACS.

Association of heart rate and diabetes among 0.5 million adults in the China Kadoorie biobank: Results from observational and Mendelian randomization analyses.

BACKGROUND AND AIMS: Observational studies have associated resting heart rate with incident diabetes. Whether the associations are causal remains unclear. We aimed to examine the shape and strength of the associations and assessed the causal relevance of such associations in Chinese adults. METHODS AND RESULTS: The China Kadoorie Biobank enrolled 512,891 adults in China. Cox proportional hazard regression models was conducted to estimate hazard ratios (HRs) for the associations of resting heart rate with type 2 diabetes and total diabetes. Among 92,724 participants, 36 single-nucleotide polymorphisms (SNPs) related to resting heart rate were used to construct genetic risk score. We used Mendelian randomization analyses to make the causal inferences. During a median follow-up of 9 years, 7872 incident type 2 diabetes and 13,349 incident total diabetes were documented. After regression dilution bias adjustment, each 10 bpm higher heart rate was associated with about a 26% higher risk of type 2 diabetes (HR, 1.26 [95% CI, 1.23, 1.29]) and 23% higher risk of total diabetes (HR, 1.23 [95% CI, 1.20, 1.26]). Instrumental variable analyses showed participants at top quintile compared with those at bottom quintile had 30% higher risk for type 2 diabetes (HR, 1.30 [95% CI, 1.17, 1.43]), and 10% higher risk for total diabetes (HR, 1.10 [95% CI, 1.02, 1.20]). CONCLUSIONS: This study provides evidence that resting heart rate is an important risk factor for diabetes risk. The results suggest that novel treatment approaches targeting reduction of high heart rate for incidence of diabetes may be worth further investigation.

Evaluation of a risk index for predicting short-term and long-term outcomes in patients with ST-elevation myocardial infarction.

OBJECTIVE: This study aimed to evaluate the usefulness of the admission risk index (RI) to predict short-term and long-term outcomes in a broad population with ST-elevation myocardial infarction (STEMI) using data from the Chinese Acute Myocardial Infarction Registry. BACKGROUND: The RI was developed as a simple tool to predict risk of death in STEMI patients. The performance in predicting short-term and long-term risk of death in Chinese patients receiving percutaneous coronary intervention and conservative treatment for STEMI remains unclear. METHODS: Age, heart rate (HR), and systolic blood pressure (SBP) were used to calculate RI using (HR×[age/10]2 )/SBP. We used the prediction tool to predict mortality over 12 months. RESULTS: The C-index of the admission RI for predicting in-hospital, 1-, 6-, and 12-months mortality were 0.78, 0.78, 0.78, and 0.77, respectively, compared with 0.75 of the Global Registry in Acute Coronary Events score. Based on the receiver operating characteristic curve analysis, the RI was categorized into quintiles for convenient clinical use, and it revealed a nearly 15-fold gradient of increasing mortality from 2.29 to 32.5% (p < .0001) while RI >34 had the highest mortality. By categorizing into five different risk groups, the short-term and long-term mortality of patients receiving different treatments could be distinguished. CONCLUSIONS: RI based on three routine variables and easily calculated by any medical practitioner is useful for predicting in-hospital and long-term mortality in patients with STEMI at the initial consultation with clinicians.

Coronary Artery Disease: From Mechanism to Clinical Practice.

In most developed countries, coronary artery disease (CAD), mostly caused by atherosclerosis of coronary arteries, is one of the primary causes of death. From 1990s to 2000s, mortality caused by acute MI declined up to 50%. The incidence of CAD is related with age, gender, economic, etc. Atherosclerosis contains some highly correlative processes such as lipid disturbances, thrombosis, inflammation, vascular smooth cell activation, remodeling, platelet activation, endothelial dysfunction, oxidative stress, altered matrix metabolism, and genetic factors. Risk factors of CAD exist among many individuals of the general population, which includes hypertension, lipids and lipoproteins metabolism disturbances, diabetes mellitus, chronic kidney disease, age, genders, lifestyle, cigarette smoking, diet, obesity, and family history. Angina pectoris is caused by myocardial ischemia in the main expression of pain in the chest or adjoining area, which is usually a result of exertion and related to myocardial function disorder. Typical angina pectoris would last for minutes with gradual exacerbation. Rest, sit, or stop walking are the usual preference for patients with angina, and reaching the maximum intensity in seconds is uncommon. Rest or nitroglycerin usage can relieve typical angina pectoris within minutes. So far, a widely accepted angina pectoris severity grading system included CCS (Canadian Cardiovascular Society) classification, Califf score, and Goldman scale. Patients with ST-segment elevated myocardial infarction (STEMI) may have different symptoms and signs of both severe angina pectoris and various complications. The combination of rising usage of sensitive MI biomarkers and precise imaging techniques, including electrocardiograph (ECG), computed tomography, and cardiac magnetic resonance imaging, made the new MI criteria necessary. Complications of acute myocardial infarction include left ventricular dysfunction, cardiogenic shock, structural complications, arrhythmia, recurrent chest discomfort, recurrent ischemia and infarction, pericardial effusion, pericarditis, post-myocardial infarction syndrome, venous thrombosis pulmonary embolism, left ventricular aneurysm, left ventricular thrombus, and arterial embolism.

Effects of levothyroxine in subclinical hypothyroidism and heart failure with reduced ejection fraction: An open-label randomized trial.

We report a randomized, multicenter, open-label trial (ClinicalTrials.gov: NCT03096613) to investigate the clinical benefits of levothyroxine (L-T4) administration in subclinical hypothyroidism (SCH) patients with heart failure with reduced ejection fraction (HFrEF). Overall, 117 patients were enrolled and received L-T4 plus standard HFrEF treatment (experimental group, N = 57) or standard HFrEF therapy alone (control group, N = 60). The change of 6-min walk test distance in the experimental group was significantly higher than that in the control group at 24 weeks (70.08 ± 85.76 m vs. 27.73 ± 82.00 m, mean difference [95% confidence interval (CI)] 46.90 [12.90, 80.90], p < 0.001). Improvements in New York Heart Association (NYHA) classification (p = 0.033) and thyroid function were significant. Adverse event incidence was similar between groups (risk ratio [95% CI]: 0.942 1.053 (0.424, 2.616); p = 0.628). L-T4 addition to HFrEF treatment improved activity tolerance, NYHA class, and thyroid function within 6 months, suggesting its potential for combined therapy in HFrEF patients with SCH. Future double-blind, placebo-controlled trials should be performed to confirm these results.

The application of large language models in medicine: A scoping review.

This study systematically reviewed the application of large language models (LLMs) in medicine, analyzing 550 selected studies from a vast literature search. LLMs like ChatGPT transformed healthcare by enhancing diagnostics, medical writing, education, and project management. They assisted in drafting medical documents, creating training simulations, and streamlining research processes. Despite their growing utility in assisted diagnosis and improving doctor-patient communication, challenges persisted, including limitations in contextual understanding and the risk of over-reliance. The surge in LLM-related research indicated a focus on medical writing, diagnostics, and patient communication, but highlighted the need for careful integration, considering validation, ethical concerns, and the balance with traditional medical practice. Future research directions suggested a focus on multimodal LLMs, deeper algorithmic understanding, and ensuring responsible, effective use in healthcare.

The triglyceride-glucose index as a potential protective factor for hypertrophic obstructive cardiomyopathy without diabetes: evidence from a two-center study.

OBJECTIVE: This study aimed to investigate the relationship between the TyG (Triglyceride-glucose index) and the prognosis of patients with HOCM (hypertrophic obstructive cardiomyopathy) without diabetes. RESEARCH DESIGN AND METHODS: A total of 713 eligible patients with HOCM were enrolled in this study and divided into two groups based on treatment: an invasive treatment group (n = 461) and a non-invasive treatment group (n = 252). The patients in both two groups were then divided into three groups based on their TyG index levels. The primary endpoints of this study were Cardiogenic death during long-term follow-up. Kaplan-Meier analysis was used to study the cumulative survival of different groups. Restricted cubic spline was used to model nonlinear relationships between the TyG index and primary endpoints. Myocardial perfusion imaging/Myocardial metabolic imaging examinations were performed to assess glucose metabolism in the ventricular septum of the HOCM patients. RESULTS: The follow-up time of this study was 41.47 ± 17.63 months. The results showed that patients with higher TyG index levels had better clinical outcomes (HR, 0.215; 95% CI 0.051,0.902; P = 0.036, invasive treatment group; HR, 0.179; 95% CI 0.063,0.508; P = 0.001, non-invasive treatment group). Further analysis showed that glucose metabolism in the ventricular septum was enhanced in HOCM patients. CONCLUSIONS: The findings of this study suggest that the TyG index may serve as a potential protective factor for patients with HOCM without diabetes. The enhanced glucose metabolism in the ventricular septum of HOCM patients may provide a potential explanation for the relationship between the TyG index and HOCM prognosis.

Hypertrophic Obstructive Cardiomyopathy: Comparison of Outcomes After Myectomy or Alcohol Ablation.

Introduction and Objectives: The risk of ventricular arrhythmia and heart failure in patients with hypertrophic obstructive cardiomyopathy (HOCM) is much higher than that in the general population. More and more pieces of evidence showed that HOCM is the leading cause of sudden cardiac death in young people. We reported our experience in a study, comparing surgical myectomy, alcohol septal ablation (ASA), and medical therapy. Methods: The original cohort included 965 consecutive patients with HOCM. The patients were divided into three groups according to treatment strategies: myectomy group (n = 502), ASA group (n = 138), and medical treatment group (n = 325). The median follow-up duration was 42.99 ± 18.32 months, and the primary endpoints were all-cause mortality and heart transplantation. Results: Both in short- and long-term observations, surgical myectomy reduced the left ventricular outflow tract (LVOT) gradients more effectively (7 days, 16.15 ± 12.07 mmHg vs. 42.33 ± 27.76 mmHg, p < 0.05; 1 year, 14.65 ± 13.18 mmHg vs. 41.17 ± 30.76 mmHg, p < 0.05). Among the three groups, the patients in the medical treatment group were at a higher risk of mortality and cardiac transplantation (vs. the myectomy group, p < 0.001 by log-rank test; vs. the alcohol septal ablation group, p = 0.017 by log-rank test), and the myectomy group shows a lower risk of reaching the primary endpoint than the two other groups. In the multivariate Cox regression analysis, previous atrial fibrillation (AF), N terminal pro B type natriuretic peptide (NT-pro-BNP), and surgical myectomy predicted an HOCM prognosis. However, the impact of surgical myectomy on HOCM prognosis seems to be limited to the <56 years group. Conclusions: The patients with medical treatments seemed to suffer from the highest risk of achieving an all-cause mortality and the endpoint of heart transplantation. In the long-term survival and clinical outcome, myectomy seemed better than alcohol septal ablation, especially the younger patients. Due to the less-controllable degree, periprocedural complication frequency after alcohol septal ablation was higher, compared with myectomy. Furthermore, gradients after myectomy are lower at late follow-up. To sum up, when selecting treatment strategies, the patients should be individually evaluated by a multidisciplinary team of cardiologists and surgeons.

Association Between Thyroid Dysfunction and Incidence of Atrial Fibrillation in Patients With Hypertrophic Obstructive Cardiomyopathy.

Objective: To explore the correlation between the incidence of atrial fibrillation (AF) and thyroid dysfunction in patients with hypertrophic obstructive cardiomyopathy (HOCM). Methods: Thyroid function testing in 755 consecutive patients with HOCM were examined at the National Center for Cardiovascular Diseases (China) from October 2009 to December 2013. Patients were divided into four groups according to the TSH levels: TSH<0.55 mIU/L(n=37)、0.55~2.49 mIU/L (n=490)、2.50~9.9 mIU/L (n=211) and >10.00mIU/L(n=17). Results: A total of 107 patients were diagnosed with AF (14%).(1) Compared to HOCM patients without AF,HOCM patients with AF have older age (P<0.001), higher NT-proBNP (P=0.002), higher Cr (P=0.005), larger left atrial diameter(P=0.001), lower FT3 (P=0.046), higher FT4 (P=0.004).(2) In the four groups according to the TSH levels: TSH<0.55 mIU/L, 0.55~2.49mIU/L, 2.50~9.9mIU/L and ≥10.00mIU/L, the incidence of AF was 27.02%(10/37),10.20%(50/490), 19.43%(41/211), and 35.29%(6/17), respectively. Both high and low TSH levels were associated with an increased incidence of AF. After adjusting for the common risk factor (age, NT-proBNP, and so on), stepwise multiple logistic regression analysis revealed that TSH levels were significantly related to AF incidence.Compared to patients with TSH 0.55~2.49 mlU/L, the adjusted odds ratio of AF for TSH<0.55, 2.50~9.99, ≥10.00 mIU/L were 1.481 (95% CI 0.485~4.518,P=0.490), 1.977 (95%CI 1.115~3.506, p=0.02), 4.301 (95%CI 1.059~17.476, P=0.041), respectively. Conclusion: Our results suggested that thyroid dysfunction was associated with an increased risk of AF in patients with HOCM.

Genetically Determined Lifestyle and Cardiometabolic Risk Factors Mediate the Association of Genetically Predicted Age at Menarche With Genetic Predisposition to Myocardial Infarction: A Two-Step, Two-Sample Mendelian Randomization Study.

Background: Observational studies have shown an association between early age at menarche (AAM) and myocardial infarction (MI) with recorded cases. In this Mendelian randomization (MR) study, we used large amounts of summary data from genome-wide association studies (GWASs) to further estimate the association of genetically predicted AAM with genetically predicated risk of MI and investigate to what extent this association is mediated by genetically determined lifestyles, cardiometabolic factors, and estrogen exposure. Methods: A two-step, two-sample MR study was performed by mediation analysis. Genetic variants identified by GWAS meta-analysis of reproductive genetics consortium (n = 182,416) were selected for genetically predicted AAM. Genetic variants identified by the Coronary ARtery DIsease Genome-wide Replication and Meta-analysis plus The Coronary Artery Disease Genetics Consortium (n = 184,305) were selected for genetically predicted risk of MI. Genetic variants from other international GWAS summary data were selected for genetically determined mediators. Results: This MR study showed that increase in genetically predicted AAM was associated with lower risk of genetically predicted MI (odds ratio 0.91, 95% confidence interval 0.84-0.98). Inverse variance weighted (IVW) MR analysis also showed that decrease in genetically predicted AAM was associated with higher genetically predicted alcohol intake frequency, current smoking behavior, higher waist-to-hip ratio, and higher levels of systolic blood pressure (SBP), fasting blood glucose, hemoglobin A1c (HbA1c), and triglycerides (TGs). Furthermore, increase in genetically predicted AAM was associated with genetically predicted longer sleep duration, higher levels of high-density lipoproteins, and older age at which hormone replacement therapy was started. The most essential mediators identified were genetically predicted current smoking behavior and levels of HbA1c, SBP, and TGs, which were estimated to genetically mediate 13.9, 12.2, 10.5, and 9.2%, respectively, with a combined mediation proportion of 37.5% in the association of genetically predicted AAM with genetically predicted increased risk of MI in an MR framework. Conclusion: Our MR analysis showed that increase in genetically predicted AAM was associated with lower genetically predicted risk of MI, which was substantially mediated by genetically determined current smoking behavior and levels of HbA1c, SBP, and TGs. Intervening on the above mediators may reduce the risk of MI.

Conventional and Bidirectional Genetic Evidence on Resting Heart Rate and Cardiometabolic Traits.

CONTEXT: Observational studies have suggested that higher resting heart rate (RHR) may be associated with increased cardiometabolic risk. However, causal associations are not fully understood. OBJECTIVE: We aimed to examine the direction, strength, and causality of the associations of RHR with cardiometabolic traits. METHODS: We assessed the strength of associations between measured RHR and cardiometabolic traits in 506 211 and 372 452 participants from China Kadoorie Biobank (CKB) and UK Biobank (UKB). Mendelian randomization (MR) analyses were used to make causal inferences in 99 228 and 371 508 participants from CKB and UKB, respectively. RESULTS: We identified significant directionally concordant observational associations between RHR and higher total cholesterol, triglycerides (TG), low-density lipoprotein, C-reactive protein (CRP), glucose, body mass index, waist-hip ratio (WHR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) after the Bonferroni correction. MR analyses showed that 10 beat/min higher genetically predicted RHR was trans-ethnically associated with a higher DBP (beta 2.059 [95% CI 1.544, 2.574] mmHg in CKB; 2.037 [1.845, 2.229] mmHg in UKB), higher CRP (0.180 [0.057, 0.303] log mg/L in CKB; 0.154 [0.134, 0.174] log mg/L in UKB), higher TG (0.052 [-0.009, 0.113] log mmol/L in CKB; 0.020 [0.010, 0.030] log mmol/L in UKB) and higher WHR (0.218 [-0.033, 0.469] % in CKB; 0.225 [0.111, 0.339] % in UKB). In the opposite direction, higher genetically predicted SBP, TG, glucose, and WHR, and lower high-density lipoprotein, were associated with elevated RHR. CONCLUSION: Our large-scale analyses provide causal evidence for associations between RHR and cardiometabolic traits, highlighting the importance of monitoring heat rate as a means of alleviating the adverse effects of metabolic disorders.

Assessment of causal direction between thyroid function and cardiometabolic health: a Mendelian randomization study.

BACKGROUND: Growing evidence have demonstrated that thyroid hormones have been involved in the processes of cardiovascular metabolism. However, the causal relationship of thyroid function and cardiometabolic health remains partly unknown. METHODS: The Mendelian randomization (MR) was used to test genetic, potentially causal relationships between instrumental variables and cardiometabolic traits. Genetic variants of free thyroxine (FT4) and thyrotropin (TSH) levels within the reference range were used as instrumental variables. Data for genetic associations with cardiometabolic diseases were acquired from the genome-wide association studies of the FinnGen, CARDIoGRAM and CARDIoGRAMplusC4D, CHARGE, and MEGASTROKE. This study was conducted using summary statistic data from large, previously described cohorts. Association between thyroid function and essential hypertension (EHTN), secondary hypertension (SHTN), hyperlipidemia (HPL), type 2 diabetes mellitus (T2DM), ischemic heart disease (IHD), myocardial infarction (MI), heart failure (HF), pulmonary heart disease (PHD), stroke, and non-rheumatic valve disease (NRVD) were examined. RESULTS: Genetically predicted FT4 levels were associated with SHTN (odds ratio = 0.48; 95% CI = 0.04-0.82,P = 0.027), HPL (odds ratio = 0.67; 95% CI = 0.18-0.88,P = 0.023), T2DM (odds ratio = 0.80; 95% CI = 0.42-0.86,P = 0.005), IHD (odds ratio = 0.85; 95% CI = 0.49-0.98,P = 0.039), NRVD (odds ratio = 0.75; 95% CI = 0.27-0.97,P = 0.039). Additionally, genetically predicted TSH levels were associated with HF (odds ratio = 0.82; 95% CI = 0.68-0.99,P = 0.042), PHD (odds ratio = 0.75; 95% CI = 0.32-0.82,P = 0.006), stroke (odds ratio = 0.95; 95% CI = 0.81-0.97,P = 0.007). However, genetically predicted thyroid function traits were not associated with EHTN and MI. CONCLUSIONS: Our study suggests FT4 and TSH are associated with cardiometabolic diseases, underscoring the importance of the pituitary-thyroid-cardiac axis in cardiometabolic health susceptibility.

Uric acid is associated with cardiac death in patients with hypertrophic obstructive cardiomyopathy.

BACKGROUND: The role of uric acid (UA) in survival of patients with hypertrophic obstructive cardiomyopathy (HOCM) has not been fully evaluated. This study aimed to determine whether UA could be an independent risk factor of cardiac death in patients with HOCM. METHODS: A total of 317 patients with HOCM, who were receiving conservative treatment in Fuwai Hospital from October 2009 to December 2014, all of them completed UA evaluations, were analyzed. Patients were divided into three groups according to the UA levels: Tertile 1 (≤ 318 µmol/L, n = 106), Tertile 2 (319 to 397 µmol/L, n = 105), and Tertile 3 (≥ 398 µmol/L, n = 106). RESULTS: During a median follow-up of 45 months, 29 cardiac deaths (9.1%) occurred, including 6 sudden cardiac deaths and 23 heart failure-related deaths. Cardiac death in Tertile 3 (n = 16, 55.2%) was significantly higher than in Tertile 1 (n = 6, 20.7%) and Tertile 2 (n = 7, 24.1%). In univariate model, UA level (continuous value) showed predictive value of cardiac death [hazard ratio (HR) = 1.006, 95% CI: 1.003-1.009,P = 0.009]. Univariate Cox survival analysis had shown a significant higher property of cardiac death in patients of Tertile 3 when compared with those of Tertile 1, but cardiac death in patients of Tertile 2 did not show significant prognositic value compared with those of Tertile 1 (HR = 3.927, 95% CI: 0.666-23.162,P = 0.131). UA was found to be an independent risk factor (HR = 1.005, 95% CI: 1.001-1.009,P = 0.009) of cardiac death in the multivariate regression analysis after the adjustment for age, body mass index, atrial fibrillation, hemoglobin, creatinine, high-sensitivity C-reactive protein, interventricular septum/left ventricular posterior wall ratio, left ventricular outflow tract and left ventricular ejection fraction. CONCLUSIONS: UA concentration was found to be independently associated with cardiac death in HOCM patients receiving conservative treatment. Randomized trials of UA-lowering agents for HOCM patients are warranted.

CYP2C19 genotype has prognostic value in specific populations following coronary stenting.

BACKGROUND: The prognostic value of the CYP2C19 genotype in post-percutaneous coronary intervention (PCI) patients remains controversial. The recently-published, limited-sample PHARMCLO trial indicates a personalized pharmacogenomic approach may reduce adverse events. This study aimed to determine the prognostic value of CYP2C19 genotypes. METHODS: The original cohort consisted of 10,724 PCI patients in 2013. 756 patients with genotyped CYP2C19 were included in our analysis. The CYP2C19 genotype prognostic value was tested based on different clinical factors. The primary endpoint was major adverse cardio- and cerebro-vascular event (MACCE). RESULTS: MACCE 2-years post-PCI occurred in 19 patients (17.4%) in poor metabolizers (PM, CYP2C19 *2/*2, *2/*3, *3/*3), 43 patients (12.2%) in intermediate metabolizers (IM, CYP2C19 *1/*2 or *1/*3) and 27 patients (9.2%) in extensive metabolizers (EM, CYP2C19 *1/*1). PM was an independent MACCE predictor compared with EM (HR: 1.960, 95% CI: 1.139-3.372), but the difference between IM and PM was not significant (HR: 1.314, 95% CI: 0.843-2.048). Major bleeding (BARC grade ≥3) was not significantly different between the three groups (2.5% vs. 2.1% vs. 0.8%, P=0.133). Subgroup analysis showed that the CYP2C19 genotype prognostic value was present in the following subgroups: male, age >60 years, body mass index (BMI) >24 kg/m2, SYNTAX score >15, current smokers, and patients without chronic kidney disease. CONCLUSIONS: Utilizing CYP2C19 genotype to guide post-PCI antiplatelet therapy might be appropriate in patients with the following characteristics: male, age >60 years, BMI >24 kg/m2, SYNTAX score >15, current smokers, and non-chronic kidney disease (CKD) patients.

Age, creatinine clearance, and ejection fraction (mACEF) score predicts long-term cardiac mortality in patients with hypertrophic obstructive cardiomyopathy treated non-invasively.

OBJECTIVE: Presently, an effective model to predict long-term cardiac mortality in patients with hypertrophic obstructive cardiomyopathy (HOCM) is lacking. Therefore, the objective of this study was to evaluate the predictive value of the modified Age, Creatinine clearance, and Ejection Fraction (mACEF) score for long-term cardiac mortality in patients with HOCM. METHODS: Two hundred and ninety two patients with HOCM treated non-invasively were enrolled in this study, all of whom had intact medical information. RESULTS: Over a median follow-up period of 41.9 months, 28 cardiac deaths occurred. In univariate Cox regression analysis, the mACEF score was associated with long-term cardiac death [hazard ratio (HR)=1.795, 95% confidence interval (CI) 1.518-2.124, p<0.001]. Multiple Cox regression analysis identified the mACEF score as an independent risk factor for long-term cardiac death (adjusted HR=1.372, 95% CI 1.076-1.749, p=0.011). Analysis of the receiver operating characteristic (ROC) for long-term cardiac death showed that the mACEF score had a considerable predictive value (area under ROC 0.844, sensitivity 89.29%, specificity 75.00%) with an optimum cut-off value of 0.96. The study population was divided into high-risk (mACEF score ≥0.96, n=91) and low-risk (mACEF score <0.96, n=201) groups according to the optimum cut-off value. Kaplan-Meier survival analysis was performed and showed a dramatic higher rate of long-term cardiac mortality in the high-risk group than in the low-risk group (27.4% vs. 1.7%, p<0.001 by log-rank test). CONCLUSION: The mACEF score has a considerable predictive value for long-term cardiac mortality in patients with HOCM treated non-invasively. A mACEF score ≥0.96 could be considered as a sign of poor prognosis in patients with HOCM.

Assessment of causal association between thyroid function and lipid metabolism: a Mendelian randomization study.

BACKGROUND: Thyroid dysfunction is associated with cardiovascular diseases. However, the role of thyroid function in lipid metabolism remains partly unknown. The present study aimed to investigate the causal association between thyroid function and serum lipid metabolism via a genetic analysis termed Mendelian randomization (MR). METHODS: The MR approach uses a genetic variant as the instrumental variable in epidemiological studies to mimic a randomized controlled trial. A two-sample MR was performed to assess the causal association, using summary statistics from the Atrial Fibrillation Genetics Consortium (n = 537,409) and the Global Lipids Genetics Consortium (n = 188,577). The clinical measures of thyroid function include thyrotropin (TSH), free triiodothyronine (FT3) and free thyroxine (FT4) levels, FT3:FT4 ratio and concentration of thyroid peroxidase antibodies (TPOAb). The serum lipid metabolism traits include total cholesterol (TC) and triglycerides, high-density lipoprotein, and low-density lipoprotein (LDL) levels. The MR estimate and MR inverse variance-weighted method were used to assess the association between thyroid function and serum lipid metabolism. RESULTS: The results demonstrated that increased TSH levels were significantly associated with higher TC (ß = 0.052, P = 0.002) and LDL (ß = 0.041, P = 0.018) levels. In addition, the FT3:FT4 ratio was significantly associated with TC (ß = 0.240, P = 0.033) and LDL (ß = 0.025, P = 0.027) levels. However, no significant differences were observed between genetically predicted FT4 and TPOAb and serum lipids. CONCLUSION: Taken together, the results of the present study suggest an association between thyroid function and serum lipid metabolism, highlighting the importance of the pituitary-thyroid-cardiac axis in dyslipidemia susceptibility.

Pneumonia hospitalizations and the subsequent risk of incident ischaemic cardiovascular disease in Chinese adults.

BACKGROUND: Acute respiratory infections have been associated with a transient increase in cardiovascular risk. However, whether such an association persists beyond 1 month and the potential modifying effect of cardiovascular risk factors on such an association are less well established. METHODS: The China Kadoorie Biobank enrolled 512 726 participants aged 30-79 years from 10 areas across China during 2004-2008. By the end of 2017, a total of 5444 participants with new-onset ischaemic heart disease (IHD) and 4846 with ischaemic stroke (IS) who also had at least a record of hospitalization for pneumonia during follow-up were included. We used a self-controlled case-series method and calculated the age- and season-adjusted relative incidences (RIs) and 95% confidence intervals (CIs) for ischaemic cardiovascular disease (CVD) after pneumonia. RESULTS: The risk of ischaemic CVD increased during days 1-3 after pneumonia hospitalization, with an RI (95% CI) of 4.24 (2.92-6.15) for IHD and 1.85 (1.02-3.35) for IS. The risk gradually reduced with longer duration since pneumonia hospitalization but remained elevated until days 92-365 for IHD (1.23, 1.12-1.35) and days 29-91 for IS (1.25, 1.05-1.48). Pre-existing cardiovascular risk factors amplified the associations between pneumonia and ischaemic CVD risks, such as chronic obstructive pulmonary disease for both IHD and IS, and diabetes and smoking for IHD (all Pinteraction < 0.05). Besides, the risk of ischaemic CVD was also higher among the participants aged ≥70 years (Pinteraction < 0.001 for IHD and 0.033 for IS). CONCLUSION: Among middle-aged and older Chinese adults, pneumonia hospitalization was associated with both short- and long-term increases in ischaemic CVD risk for ≤1 year.

Efficacy and safety of levothyroxine (L-T4) replacement on the exercise capability in chronic systolic heart failure patients with subclinical hypothyroidism: Study protocol for a multi-center, open label, randomized, parallel group trial (ThyroHeart-CHF).

BACKGROUND: Subclinical hypothyroidism is a common condition in patients with heart failure and is defined as elevated serum thyroid hormone (TSH) with normal circulating free thyroxine (FT4). Evidence on the effect of thyroid hormone treatment is lacking. We designed a randomized controlled trial to compare the efficacy and safety of thyroid hormone supplementation in patients with chronic heart failure complicated with subclinical hypothyroidism. METHODS/DESIGN: Eligible participants were identified from the cardiology units of five study centers based on the following criteria: 18 years or older, systolic heart failure with NewYork Heart Association (NYHA) class II-III, left ventricular ejection fraction ≤ 40%, and subclinical hypothyroidism (TSH > 4.78µIU/ml, < 10 µIU/ml + FT4 level within reference range). Eligible patients will be randomly assigned in a 1:1 manner to receive thyroxine replacement therapy plus standard chronic heart failure (CHF) treatment or only standard CHF therapy. Levothyroxine will be administered at an initial dose of 12.5 µg once daily and will be titrated until TSH is within the normal range. The primary endpoints include the difference in distance of the six-minute walk test between 24 weeks and baseline. The secondary endpoints include differences in plasma NT-proBNP levels and serum lipid profiles, changes in the NYHA classification, cardiovascular death, re-hospitalization, differences in echocardiographic and cardiac magnetic resonance imaging measures, and Minnesota Living With Heart Failure Questionnaire (MLHFQ) results between 24 weeks and baseline. DISCUSSION: ThyroHeart-CHF is designed as a prospective, multi-center, randomized, controlled clinical trial to study the efficacy and safety of thyroid hormone supplementation in patients with chronic heart failure complicated with subclinical hypothyroidism. The study findings will have significant implications for discovering the new therapeutic targets and methods of heart failure. TRAIL REGISTRATION: ClinicalTrials.gov, NCT03096613 . Registered on 30 March 2017.