Prediabetes is associated with increased cardiac events in patients with cancer who are prescribed anthracyclines.

BACKGROUND: Prediabetes, which is a precedent of overt diabetes, is a known risk factor for adverse cardiovascular outcomes. Its impact on adverse cardiovascular outcomes in patients with cancer who are prescribed anthracycline-containing chemotherapy (ACT) is uncertain. The objective of this study was to evaluate the association of prediabetes with cardiovascular events in patients with cancer who are prescribed ACT. METHODS: The authors identified patients with cancer who received ACT from 2000 to 2019 from Clinical Data Analysis Reporting System of Hong Kong. Patients were divided into diabetes, prediabetes, and normoglycemia groups based on their baseline glycemic profile. The Primary outcome, a major adverse cardiovascular event (MACE), was the composite event of hospitalization for heart failure and cardiovascular death. RESULTS: Among 12,649 patients at baseline, 3997 had prediabetes, and 5622 had diabetes. Over median follow-up of 8.7 years, the incidence of MACE was 211 (7.0%) in the normoglycemia group, 358 (9.0%) in the prediabetes group, and 728 (12.9%) in the diabetes group. Compared with normoglycemia, prediabetes (adjusted hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.01-1.43) and diabetes (adjusted HR, 1.46; 95% CI, 1.24-1.70) were associated with an increased risk of MACE. In the prediabetes group, 475 patients (18%) progressed to overt diabetes and exhibited a greater risk of MACE (adjusted HR, 1.76; 95% CI, 1.31-2.36) compared with patients who remained prediabetic. CONCLUSIONS: In patients with cancer who received ACT, those who had prediabetes at baseline and those who progressed to diabetes at follow-up had an increased risk of MACE. The optimization of cardiovascular risk factor management, including prediabetes, should be considered in patients with cancer who are treated before and during ACT to reduce cardiovascular risk. PLAIN LANGUAGE SUMMARY: Patients with cancer who have preexisting diabetes have a higher risk of cardiovascular events, and prediabetes is often overlooked. In this study of 12,649 patients with cancer identified in the Clinical Data Analysis Reporting System of Hong Kong who were receiving treatment with anthracycline drugs, prediabetes was correlated with increased deaths from cardiovascular disease and/or hospitalizations for heart failure. Patients who progressed from prediabetes to diabetes within 2 years had an increased risk of combined hospitalization for heart failure and death from cardiovascular disease. These findings indicate the importance of paying greater attention to cardiovascular risk factors, including how prediabetes is managed, in patients who have cancer and are receiving chemotherapy with anthracyclines, emphasizing the need for surveillance, follow-up strategies, and consideration of prediabetes management in cancer care.

Assessing the safety of lipid-modifying medications among Chinese adolescents: a drug-target Mendelian randomization study.

BACKGROUND: With increasing hypercholesterolemia prevalence in East Asian adolescents, pharmacologic interventions (e.g., HMGCR inhibitors (statins) and PCSK9 inhibitors) may have to be considered although their longer-term safety in the general adolescent population is unclear. This study aims to investigate the longer-term safety of HMGCR inhibitors and PCSK9 inhibitors among East Asian adolescents using genetics. METHODS: A drug-target Mendelian randomization study leveraging the Global Lipid Genetics Consortium (East Asian, n = 146,492) and individual-level data from Chinese participants in the Biobank clinical follow-up of Hong Kong's "Children of 1997" birth cohort (n = 3443, aged ~ 17.6 years). Safety outcomes (n = 100) included anthropometric and hematological traits, renal, liver, lung function, and other nuclear magnetic resonance metabolomics. Positive control outcomes were cholesterol markers from the "Children of 1997" birth cohort and coronary artery disease from Biobank Japan. RESULTS: Genetic inhibition of HMGCR and PCSK9 were associated with reduction in cholesterol-related NMR metabolomics, e.g., apolipoprotein B (HMGCR: beta [95% CI], - 1.06 [- 1.52 to - 0.60]; PCSK9: - 0.93 [- 1.56 to - 0.31]) and had the expected effect on the positive control outcomes. After correcting for multiple comparisons (p-value < 0.006), genetic inhibition of HMGCR was associated with lower linoleic acid - 0.79 [- 1.25 to - 0.35]. Genetic inhibition of PCSK9 was not associated with the safety outcomes assessed. CONCLUSIONS: Statins and PCSK9 inhibitors in East Asian adolescents appeared to be safe based on the outcomes concerned. Larger studies were warranted to verify these findings. This study serves as a proof of principle study to inform the medication safety among adolescents via genetics.

Overall and Sex-Specific Effect of Berberine on Glycemic and Insulin-Related Traits: a Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Berberine is widely available as a nutraceutical supplement for improving glucose metabolism. Berberine affects sex hormones, raising the possibility that its effects on glycemic traits and insulin sensitivity have sex disparity which has been overlooked. OBJECTIVE: To assess the overall and sex-specific effects of berberine on glycemic- and insulin-related traits. METHODS: We identified randomized trials of berberine versus placebo from Medline, Embase, CNKI, clinical trial registries and previous systematic reviews. Mean differences were estimated using inverse-variance weighting with random effects models. Subgroup analyses were conducted by sex, diabetes diagnosis, trial duration, berberine dose and ethnicity. RESULTS: We identified 20 eligible studies (n = 1761). Berberine lowered fasting glucose (-0.52 mmol/L, 95% CI -0.72 to -0.33; 18 studies, n = 1522), HbA1c (-4.48 mmol/mol, 95% CI -6.53 to -2.44, 7 studies, n = 756), fasting insulin (-2.36 mU/L, 95% CI -3.64 to -1.08, 11 studies, n = 966), HOMA-IR (-0.85, 95% CI -1.16 to -0.53,12 studies, n = 1065), and 2-h postprandial glucose (-1.81 mmol/L, 95% CI -2.37 to -1.24, 4 studies, n = 501). Effects on fasting glucose and HOMA-IR showed potential differences by sex, with larger reductions in women than in men. Comparing 4 studies conducted in women to one study conducted in men, the mean difference was -0.21 mmol/L (95% CI -0.41 to -0.00) for fasting glucose and -0.97 (95% CI -1.84 to -0.10) for HOMA-IR. We also found larger reductions in fasting glucose in participants with diabetes and in Asians. CONCLUSION: Berberine is effective in improving glucose metabolism and may result in larger effects on fasting glucose in women, in people with diabetes and in Asians, but subgroup comparisons remain to be replicated given the limited number of studies. Berberine can be considered as a complementary intervention in individuals who may benefit from modest improvements in glucose metabolism and who prefer taking a nutraceutical. STUDY REGISTRATION: PROSPERO (CRD42022345172).

Chronic kidney disease begets heart failure and vice versa: temporal associations between heart failure events in relation to incident chronic kidney disease in type 2 diabetes.

AIM: To investigate the interplay of incident chronic kidney disease (CKD) and/or heart failure (HF) and their associations with prognosis in a large, population-based cohort with type 2 diabetes (T2DM). METHODS: Patients aged ≥18 years with new-onset T2DM, without renal disease or HF at baseline, were identified from the territory-wide Clinical Data Analysis Reporting System between 2000 and 2015. Patients were followed up until December 31, 2020 for incident CKD and/or HF and all-cause mortality. RESULTS: Among 102 488 patients (median age 66 years, 45.7% women, median follow-up 7.5 years), new-onset CKD occurred in 14 798 patients (14.4%), in whom 21.7% had HF. In contrast, among 9258 patients (9.0%) with new-onset HF, 34.6% had CKD. The median time from baseline to incident CKD or HF (4.4 vs. 4.1 years) did not differ. However, the median (interquartile range) time until incident HF after CKD diagnosis was 1.7 (0.5-3.6) years and was 1.2 (0.2-3.4) years for incident CKD after HF diagnosis (P < 0.001). The crude incidence of CKD was higher than that of HF: 17.6 (95% confidence interval [CI] 17.3-17.9) vs. 10.6 (95% CI 10.4-10.9)/1000 person-years, respectively, but incident HF was associated with a higher adjusted-mortality than incident CKD. The presence of either condition (vs. CKD/HF-free status) was associated with a three-fold hazard of death, whereas concomitant HF and CKD conferred a six to seven-fold adjusted hazard of mortality. CONCLUSION: Cardiorenal complications are common and are associated with high mortality risk among patients with new-onset T2DM. Close surveillance of these dual complications is crucial to reduce the burden of disease.

Multi-Omics Signatures Link to Ticagrelor Effects on Vascular Function in Patients With Acute Coronary Syndrome.

BACKGROUND: Long-term antiplatelet agents including the potent P2Y12 antagonist ticagrelor are indicated in patients with a previous history of acute coronary syndrome. We sought to compare the effect of ticagrelor with that of aspirin monotherapy on vascular endothelial function in patients with prior acute coronary syndrome. METHODS: This was a prospective, single center, parallel group, investigator-blinded randomized controlled trial. We randomized 200 patients on long-term aspirin monotherapy with prior acute coronary syndrome in a 1:1 fashion to receive ticagrelor 60 mg BD (n=100) or aspirin 100 mg OD (n=100). The primary end point was change from baseline in brachial artery flow-mediated dilation at 12 weeks. Secondary end points were changes to platelet activation marker (CD41_62p) and endothelial progenitor cell (CD34/133) count measured by flow cytometry, plasma level of adenosine, IL-6 (interleukin-6) and EGF (epidermal growth factor), and multi-omics profiling at 12 weeks. RESULTS: After 12 weeks, brachial flow-mediated dilation was significantly increased in the ticagrelor group compared with the aspirin group (ticagrelor: 3.48±3.48% versus aspirin: -1.26±2.85%, treatment effect 4.73 [95% CI, 3.85-5.62], P<0.001). Nevertheless ticagrelor treatment for 12 weeks had no significant effect on platelet activation markers, circulating endothelial progenitor cell count or plasma level of adenosine, IL-6, and EGF (all P>0.05). Multi-omics pathway assessment revealed that changes in the metabolism and biosynthesis of amino acids (cysteine and methionine metabolism; phenylalanine, tyrosine, and tryptophan biosynthesis) and phospholipids (glycerophosphoethanolamines and glycerophosphoserines) were associated with improved brachial artery flow-mediated dilation in the ticagrelor group. CONCLUSIONS: In patients with prior acute coronary syndrome, ticagrelor 60 mg BD monotherapy significantly improved brachial flow-mediated dilation compared with aspirin monotherapy and was associated with significant changes in metabolomic and lipidomic signatures. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03881943.

Mendelian Randomization Focused Analysis of Vitamin D on the Secondary Prevention of Ischemic Stroke.

BACKGROUND AND PURPOSE: Experimental studies showed vitamin D (Vit-D) could promote vascular regeneration and repair. Prior randomized studies had focused mainly on primary prevention. Whether Vit-D protects against ischemic stroke and myocardial infarction recurrence among subjects with prior ischemic insults was unknown. Here, we dissected through Mendelian randomization any effect of Vit-D on the secondary prevention of recurrent ischemic stroke and myocardial infarction. METHODS: Based on a genetic risk score for Vit-D constructed from a derivation cohort sample (n=5331, 45% Vit-D deficient, 89% genotyped) via high-throughput exome-chip screening of 12 prior genome-wide association study-identified genetic variants of Vit-D mechanistic pathways (rs2060793, rs4588, and rs7041; F statistic, 73; P<0.001), we performed a focused analysis on prospective recurrence of myocardial infarction (MI) and ischemic stroke in an independent subsample with established ischemic disease (n=441, all with prior first ischemic event; follow-up duration, 41.6±14.3 years) under a 2-sample, individual-data, prospective Mendelian randomization approach. RESULTS: In the ischemic disease subsample, 11.1% (n=49/441) had developed recurrent ischemic stroke or MI and 13.3% (n=58/441) had developed recurrent or de novo ischemic stroke/MI. Kaplan-Meier analyses showed that genetic risk score predicted improved event-free survival from recurrent ischemic stroke or MI (log-rank, 13.0; P=0.001). Cox regression revealed that genetic risk score independently predicted reduced risk of recurrent ischemic stroke or MI combined (hazards ratio, 0.62 [95% CI, 0.48-0.81]; P<0.001), after adjusted for potential confounders. Mendelian randomization supported that Vit-D is causally protective against the primary end points of recurrent ischemic stroke or MI (Wald estimate: odds ratio, 0.55 [95% CI, 0.35-0.81]) and any recurrent or de novo ischemic stroke/MI (odds ratio, 0.64 [95% CI, 0.42-0.91]) and recurrent MI alone (odds ratio, 0.52 [95% CI, 0.30-0.81]). CONCLUSIONS: Genetically predicted lowering in Vit-D level is causal for the recurrence of ischemic vascular events in persons with prior ischemic stroke or MI.

Predictive value of visit-to-visit blood pressure variability for cardiovascular events in patients with coronary artery disease with and without diabetes mellitus.

BACKGROUND: High blood pressure is a major risk factor for cardiovascular disease. Visit-to-visit blood pressure variability (BPV) has recently been shown to predict cardiovascular outcomes. We investigated the predictive value of BPV for major adverse cardiovascular events (MACE) among patients with coronary artery disease (CAD), with and without type 2 diabetes mellitus (T2DM). METHODS: Patients with stable CAD were enrolled and monitored for new MACE. Visit-to-visit BPV was defined as the coefficient of variation (CV) of systolic and diastolic BP across clinic visits. Multivariable logistic regression analysis was performed to evaluate the association of BPV with MACE. Area under the receiver operating characteristic curve (AUC) was used to assess its predictive ability. RESULTS: Among 1140 Chinese patients with stable CAD, 192 (17%) experienced a new MACE. In multivariable analyses, the risk of MACE was significantly associated with CV of systolic BP (odds ratio [OR] for highest versus lowest quartile, 3.30; 95% CI 1.97-5.54), and diastolic BP (OR for highest versus lowest quartile, 2.39; 95% CI 1.39-4.11), after adjustment for variables of the risk factor model (age, gender, T2DM, hypertension, antihypertensive agents, number of BP measurements) and mean BP. The risk factor model had an AUC of 0.70 for prediction of MACE. Adding systolic/diastolic CV into the risk factor model with mean BP significantly increased the AUC to 0.73/0.72 (P = 0.002/0.007). In subgroup analyses, higher CV of systolic BP remained significantly associated with an increased risk for MACE in patients with and without T2DM, whereas the association of CV of diastolic BP with MACE was observed only in those without T2DM. CONCLUSIONS: Visit-to-visit variability of systolic BP and of diastolic BP was an independent predictor of new MACE and provided incremental prognostic value beyond mean BP and conventional risk factors in patients with stable CAD. The association of BPV in CAD patients without T2DM with subsequent risk for MACE was stronger than in those with T2DM.

Dietary fiber intake from fresh and preserved food and risk of nasopharyngeal carcinoma: observational evidence from a Chinese population.

BACKGROUND: The role of dietary fiber intake on risk of nasopharyngeal carcinoma (NPC) remains unclear. We examined the associations of dietary fiber intake on the risk of NPC adjusting for a comprehensive list of potential confounders. METHODS: Using data from a multicenter case-control study, we included 815 histologically confirmed NPC incident cases and 1502 controls in Hong Kong, China recruited in 2014-2017. Odds ratios (ORs) of NPC (cases vs controls) for dietary fiber intake from different sources at different life periods (age 13-18, age 19-30, and 10 years before recruitment) were evaluated using unconditional logistic regression, adjusting for sex, age, socioeconomic status, smoking and drinking status, occupational hazards, family history of cancer, salted fish, and total energy intake in Model 1, Epstein-Barr virus viral capsid antigen serological status in Model 2, and duration of sun exposure and circulating 25-hydroxyvitamin D in Model 3. RESULTS: Higher intake of total dietary fiber 10 years before recruitment was significantly associated with decreased NPC risk, with demonstrable dose-response relationship (P-values for trend = 0.001, 0.020 and 0.024 in Models 1-3, respectively). The adjusted ORs (95% CI) in the highest versus the lowest quartile were 0.51 (0.38-0.69) in Model 1, 0.48 (0.33-0.69) in Model 2, and 0.48 (0.33-0.70) in Model 3. However, the association was less clear after adjustment of other potential confounders (e.g. EBV) in the two younger periods (age of 13-18 and 19-30 years). Risks of NPC were significantly lower for dietary fiber intake from fresh vegetables and fruits and soybean products over all three periods, with dose-response relationships observed in all Models (P-values for trend for age 13-18, age 19-30 and 10 years before recruitment were, respectively, 0.002, 0.009 and 0.001 for Model1; 0.020, 0.031 and 0.003 for Model 2; and 0.022, 0.037 and 0.004 for Model 3). No clear association of NPC risk with dietary fiber intake from preserved vegetables, fruits and condiments was observed. CONCLUSION: Our study has shown the protective role of dietary fiber from fresh food items in NPC risk, but no association for total dietary fiber intake was observed, probably because total intake also included intake of preserved food. Further studies with detailed dietary information and in prospective settings are needed to confirm this finding, and to explore the possible underlying biological mechanisms.

Single-chamber leadless pacemaker for atrial synchronous or ventricular pacing.

Leadless pacing is a major breakthrough in the management of bradyarrhythmia. Results of initial clinical trials that have demonstrated a significant reduction in acute and long-term pacing-related complications have been confirmed by real-world experience in a broader spectrum of patients. Nonetheless current use of a leadless pacemaker is hampered by its limited atrial sensing and pacing capability, as well as battery life-span and retrievability. We review the current clinical outcome data, indications and contraindications, implantation and retrieval techniques, synchronous ventricular pacing, and other clinical considerations. We also provide an overview of the latest advancements in leadless pacing technology including device-to-device communication and energy harvesting technology.

Osteogenic circulating endothelial progenitor cells are linked to electrocardiographic conduction abnormalities in rheumatic patients.

BACKGROUND: Osteogenic circulating endothelial progenitor cells (EPC) play a pathogenic role in cardiovascular system degeneration through promulgating vasculature calcification, but its role in conduction disorders as part of the cardiovascular degenerative continuum remained unknown. AIM: To investigate the role of osteocalcin (OCN)-expressing circulating EPCs in cardiac conduction disorders in the unique clinical sample of rheumatoid arthritis (RA) susceptible to both abnormal bone metabolism and cardiac conduction disorders. METHODS: We performed flow cytometry studies in 134 consecutive asymptomatic patients with rheumatoid arthritis to derive osteogenic circulating OCN-positive (OCN+) CD34+KDR+ vs. CD34+CD133+KDR+ conventional EPC. Study endpoint was the prespecified combined endpoint of electrocardiographic conduction abnormalities. RESULTS: Total prevalence of cardiac conduction abnormality was 9% (n = 12). All patients except one had normal sinus rhythm. One patient had atrial fibrillation. No patient had advanced atrioventricular (AV) block. Prevalence of first-degree heart block (>200 ms), widened QRS duration (>120 ms) and right bundle branch block were 6.7%, 2.1%, and 2.2% respectively. Circulating osteogenic OCN+ CD34+ KDR+ EPCs were significantly higher among patients with cardiac conduction abnormalities (p = 0.039). Elevated OCN+ CD34+ KDR+ EPCs> 75th percentile was associated with higher prevalence of cardiac conduction abnormalities (58.3% vs. 20.02%, p = 0.003). Adjusted for potential confounders, elevated OCN+ CD34+ KDR+ EPCs> 75th percentile remained independently associated with increased risk of cardiac conduction abnormalities (OR = 4.4 [95%CI 1.2-16.4], p = 0.028). No significant relation was found between conventional EPCs CD34+CD133+KDR+ and conduction abnormalities (p = 0.36). CONCLUSIONS: Elevated osteogenic OCN+ CD34+ KDR+ EPCs are independently associated with the presence of electrocardiographic conduction abnormalities in patients with rheumatoid arthritis, unveiling a potential novel pathophysiological mechanism.

Genetically deprived vitamin D exposure predisposes to atrial fibrillation.

AIMS: Low vitamin D level is associated with atrial fibrillation (AF) and may be implicated in its pathogenesis. METHODS AND RESULTS: We studied single nucleotide polymorphisms (SNPs) of vitamin D mechanistic pathways and serum 25-hydroxyvitamin D [25(OH)D] levels in an age- and gender-matched case-control study (controls without AF: mean age 68.6 ± 8.7 years, female 25%; n = 1019; with AF: mean age 69.7 ± 9.5 years, female 30%; n = 156) recruited from a Chinese clinical cohort of patients with stable coronary artery disease. Twelve SNPs involved in the vitamin D mechanistic pathways were studied [biosynthetic: rs4646536, rs10877012, rs3829251, rs1790349; activation: rs2060793, rs1993116; vitamin D-binding protein (VBP)/group-specific component (GC): rs4588, rs7041, rs2282679, rs1155563; and vitamin D receptor: rs1544410, rs10735810]. A genetic risk score (GRS) (0-8) was constructed from SNPs associated with serum 25(OH)D as a proxy to lifelong vitamin D-deficient state. All 4 SNPs involved in the VBP/GC were significantly associated with serum 25(OH)D (rs4588, P < 0.001; rs2282679, P < 0.001; rs7041, P = 0.011; rs1155563, P < 0.001; all other SNPs, P > 0.05). Vitamin D GRS (points 0-8) generated from these 4 SNPs was independently predictive of serum 25(OH)D [B = 0.54, 95% confidence interval (CI) 0.30-0.79; P < 0.001]. Genetically deprived vitamin D status as denoted by a low GRS (0-3) independently predicted an increased risk of AF, compared to a high GRS (4-8) (odds ratio = 1.848, 95% CI 1.217-2.805; P = 0.004). CONCLUSION: Genetically deprived vitamin D exposure predisposes to increased AF among patients with coronary artery disease. Whether VBP/GC may alter the risk of AF via alternative mechanisms warrants further studies.

PR interval prolongation in coronary patients or risk equivalent: excess risk of ischemic stroke and vascular pathophysiological insights.

BACKGROUND: Whether PR prolongation independently predicts new-onset ischemic events of myocardial infarction and stroke was unclear. Underlying pathophysiological mechanisms of PR prolongation leading to adverse cardiovascular events were poorly understood. We investigated the role of PR prolongation in pathophysiologically-related adverse cardiovascular events and underlying mechanisms. METHODS: We prospectively investigated 597 high-risk cardiovascular outpatients (mean age 66 ± 11 yrs.; male 67%; coronary disease 55%, stroke 22%, diabetes 52%) for new-onset ischemic stroke, myocardial infarction (MI), congestive heart failure (CHF), and cardiovascular death. Vascular phenotype was determined by carotid intima-media thickness (IMT). RESULTS: PR prolongation >200 ms was present in 79 patients (13%) at baseline. PR prolongation >200 ms was associated with significantly higher mean carotid IMT (1.05 ± 0.37 mm vs 0.94 ± 0.28 mm, P = 0.010). After mean study period of 63 ± 11 months, increased PR interval significantly predicted new-onset ischemic stroke (P = 0.006), CHF (P = 0.040), cardiovascular death (P < 0.001), and combined cardiovascular endpoints (P < 0.001) at cut-off >200 ms. Using multivariable Cox regression, PR prolongation >200 ms independently predicted new-onset ischemic stroke (HR 8.6, 95% CI: 1.9-37.8, P = 0.005), cardiovascular death (HR 14.1, 95% CI: 3.8-51.4, P < 0.001) and combined cardiovascular endpoints (HR 2.4, 95% CI: 1.30-4.43, P = 0.005). PR interval predicts new-onset MI at the exploratory cut-off >162 ms (C-statistic 0.70, P = 0.001; HR: 8.0, 95% CI: 1.65-38.85, P = 0.010). CONCLUSIONS: PR prolongation strongly predicts new-onset ischemic stroke, MI, cardiovascular death, and combined cardiovascular endpoint including CHF in coronary patients or risk equivalent. Adverse vascular function may implicate an intermediate pathophysiological phenotype or mediating mechanism.

Serum 25-Hydroxyvitamin D Was Not Associated with Influenza Virus Infection in Children and Adults in Hong Kong, 2009-2010.

BACKGROUND: Some studies have hypothesized that vitamin D may have a role to play in protection against influenza virus infections and illnesses, and that seasonal fluctuation in serum 25-hydroxyvitamin D [25(OH)D] may affect seasonal patterns of influenza virus infections. OBJECTIVE: We aimed to investigate whether serum 25(OH)D concentrations were associated with the incidence of influenza virus infections and illnesses in children and adults in Hong Kong. METHODS: In 2009-2010, 3030 children and adults of all ages from 796 households in Hong Kong were followed up to identify acute respiratory illnesses. Sera from 2694 participants were collected at baseline and after ∼1 mo, 6 mo, and 12 mo. Influenza virus infections were confirmed by reverse transcriptase-polymerase chain reaction performed on nasal and throat swab samples collected during illness episodes. Serologic evidence of influenza virus infection was measured by hemagglutination inhibition assays in unvaccinated participants. The serum 25(OH)D concentrations were measured after collection of all specimens. Each individual's baseline serum 25(OH)D concentration on 1 January 2010 was predicted by a random-effects linear regression model. RESULTS: We found that, in children and adults who had not received a seasonal influenza vaccine, baseline serum 25(OH)D concentrations (<50 nmol/L compared with ≥50 nmol/L) were not statistically significantly associated with serologic evidence of influenza A(H1N1)pdm09 (RR, 1.18; 95% CI: 0.85, 1.65) or seasonal influenza virus infections [including A(H3N2) and B virus] (RR, 1.13; 95% CI: 0.86, 1.49). In all participants, baseline serum 25(OH)D concentrations were not statistically significantly associated with polymerase chain reaction-confirmed influenza virus infection (RR, 1.15; 95% CI: 0.73, 1.83) and influenza-like illness (RR, 1.18; 95% CI: 0.98, 1.43). CONCLUSIONS: These findings indicate that lower serum vitamin D concentrations may not contribute to the seasonality of influenza and are not associated with an increased risk of influenza virus infections in persons of all ages in Hong Kong.

Determinants of serum 25-hydroxyvitamin D in Hong Kong.

Vitamin D plays an important role in skeletal health throughout life. Some studies have hypothesised that vitamin D may reduce the risk of other diseases. Our study aimed to estimate age-specific and sex-specific serum 25-hydroxyvitamin D (25(OH)D) status and to identify the determinants of serum 25(OH)D status in Hong Kong, a subtropical city in southern China. In 2009-2010, households in Hong Kong were followed up to identify acute respiratory illnesses, and sera from 2694 subjects were collected in three to four different study phases to permit measurement of 25(OH)D levels at different times of the year. A questionnaire survey on diet and lifestyle was conducted among children, with simultaneous serum collection in April and May 2010. The mean of serum 25(OH)D levels in age groups ranged from 39 to 63 nmol/l throughout the year with the mean values in all age groups in spring below 50 nmol/l. Children aged 6-17 years, and girls and women had significantly lower serum 25(OH)D levels than adults, and boys and men, respectively (all P< 0.001). We estimated that serum 25(OH)D levels in Hong Kong followed a lagged pattern relative to climatic season by 5 weeks with lowest observed levels in early spring (March). For children aged 6-17 years, reporting a suntan, having at least 1 servings of fish/week and having at least 1 serving of eggs/week were independently associated with higher serum 25(OH)D levels. Adequate sunlight exposure and increased intake of dietary vitamin D could improve vitamin D status, especially for children and females in the winter and spring.

Subclinical atrial fibrillation and stroke: insights from continuous monitoring by implanted cardiac electronic devices.

Nearly one out of five strokes is associated with atrial fibrillation (AF). Atrial fibrillation is often intermittent and asymptomatic. Detection of AF after cryptogenic stroke will likely change therapy from antiplatelet to oral anticoagulation agents for secondary stroke prevention. A critical step is to convert 'covert' AF into electrocardiogram documented AF. External rhythm recording devices have registered a high incidence of AF to occur after a cryptogenic stroke, but are limited by short duration of continuous recordings. Invasive cardiac monitoring using insertable leadless cardiac monitors are sensitive means to identify subclinical AF (SCAF) after cryptogenic stroke, and AF has been reported to occur in 8.9% of these patients by 6 months in one study. It will be more attractive to identify SCAF before a stroke occurs. Recent series in pacemaker and implantable cardioverter-defibrillator (ICD) recipients showed that short episodes of SCAF increased stroke risk, with odds ratio ∼2.2-3.1 compared with those without SCAF recorded. However, temporal sequence of recorded SCAF and stroke occurrence was uncertain, and the overall stroke risk was lower compared with patients with clinical AF at similar risk scores. This article reviews the incidence and clinical role of using implanted devices to detect SCAF and discusses the implication of SCAF so detected in primary and secondary stroke prevention.

Predictive value of high-sensitivity troponin-I for future adverse cardiovascular outcome in stable patients with type 2 diabetes mellitus.

INTRODUCTION: High-sensitivity cardiac troponin I(hs-TnI) and T levels(hs-TnT) are sensitive biomarkers of cardiomyocyte turnover or necrosis. Prior studies of the predictive role of hs-TnT in type 2 diabetes mellitus(T2DM) patients have yielded conflicting results. This study aimed to determine whether hs-TnI, which is detectable in a higher proportion of normal subjects than hsTnT, is associated with a major adverse cardiovascular event(MACE) in T2DM patients. METHODS AND RESULTS: We compared hs-TnI level in stored serum samples from 276 consecutive patients (mean age 65 ± 10 years; 57% male) with T2DM with that of 115 age-and sex-matched controls. All T2DM patients were prospectively followed up for at least 4 years for incidence of MACE including heart failure(HF), myocardial infarction(MI) and cardiovascular mortality. At baseline, 274(99%) patients with T2DM had detectable hs-TnI, and 57(21%) had elevated hs-TnI (male: 8.5 ng/L, female: 7.6 ng/L, above the 99th percentile in healthy controls). A total of 43 MACE occurred: HF(n = 18), MI(n = 11) and cardiovascular mortality(n = 14). Kaplan-Meier analysis showed that an elevated hs-TnI was associated with MACE, HF, MI and cardiovascular mortality. Although multivariate analysis revealed that an elevated hs-TnI independently predicted MACE, it had limited sensitivity(62.7%) and positive predictive value(38.5%). Contrary to this, a normal hs-TnI level had an excellent negative predictive value(92.2%) for future MACE in patients with T2DM. CONCLUSION: The present study demonstrates that elevated hs-TnI in patients with T2DM is associated with increased MACE, HF, MI and cardiovascular mortality. Importantly, a normal hs-TnI level has an excellent negative predictive value for future adverse cardiovascular events during long-term follow-up.

Worsened arterial stiffness in high-risk cardiovascular patients with high habitual carbohydrate intake: a cross-sectional vascular function study.

BACKGROUND: Previous studies suggested that high dietary carbohydrate intake is associated with increased cardiovascular risk through raised triglyceride and decreased high-density lipoprotein-cholesterol levels. However, the relation between carbohydrate intake and arterial stiffness has not been established. The purpose of this study was to examine this relation among high-risk cardiovascular patients. METHODS: We studied the relation between dietary macronutrient intake and arterial stiffness in 364 patients with documented cardiovascular diseases or risk equivalent (coronary artery diseases 62%, ischemic stroke 13%, diabetes mellitus 55%) and in 93 age-and-sex matched control subjects. Dietary macronutrient intake was assessed using a validated food-frequency questionnaire (FFQ) for Chinese. Heart-ankle pulse wave velocity (PWV) was measured non-invasively with a Vascular Profiling System (VP2000, Colin Corp. USA). A dietary pattern with ≥60% total energy intake derived from carbohydrates was defined as a high-carbohydrate diet according to the Dietary Reference Intakes (DRI) for Chinese. RESULTS: Subjects who consumed a high-carbohydrate diet had significantly higher mean PWV than those who did not consume a high-carbohydrate diet (P = 0.039). After adjustment for potential confounders, high-carbohydrate diet was associated with significantly increased PWV [B = 73.50 (10.81 to 136.19), P = 0.022]. However, there was no significant association between high-carbohydrate diet and PWV in controls (P = 0.634). CONCLUSIONS: High-carbohydrate diet is associated with increased arterial stiffness in patients with established cardiovascular disease or risk equivalent.

Shared genetic architecture between periodontal disease and type 2 diabetes: a large scale genome-wide cross-trait analysis.

PURPOSE: To investigate the relationship between abnormal glucose metabolism, type 2 diabetes (T2D), and periodontal disease (PER) independent of Body Mass Index (BMI), we employed a genome-wide cross-trait approach to clarify the association. METHODS: Our study utilized the most extensive genome-wide association studies conducted for populations of European ancestry, including PER, T2D, fasting glucose, fasting insulin, 2-hour glucose after an oral glucose challenge, HOMA-ß, HOMA-IR (unadjusted or adjusted for BMI) and HbA1c. RESULTS: With this approach, we were able to identify pleiotropic loci, establish expression-trait associations, and quantify global and local genetic correlations. There was a significant positive global genetic correlation between T2D (rg = 0.261, p = 2.65 × 10-13), HbA1c (rg = 0.182, p = 4.14 × 10-6) and PER, as well as for T2D independent of BMI (rg = 0.158, p = 2.34 × 10-6). A significant local genetic correlation was also observed between PER and glycemic traits or T2D. We also identified 62 independent pleiotropic loci that impact both PER and glycemic traits, including T2D. Nine significant pathways were identified between the shared genes between T2D, glycemic traits and PER. Genetically liability of HOMA-ßadjBMI was causally associated with the risk of PER. CONCLUSION: Our research has revealed a genetic link between T2D, glycemic traits, and PER that is influenced by biological pleiotropy. Notably, some of these links are not related to BMI. Our research highlights an underlying link between patients with T2D and PER, regardless of their BMI.

Treatment with trimetazidine dihydrochloride and lung cancer survival: Implications on metabolic re-programming.

BACKGROUND: Metabolic re-wiring with preferential fatty acid oxidation has been observed in lung cancer cells. Whether the use of trimetazidine, an anti-anginal agent that inhibits fatty acid oxidation, alters clinical outcomes in ischemic heart disease (IHD) patients with lung cancers is unknown. METHODS: We carried out this territory-wide, retrospective cohort study of 279,894 IHD patients prescribed with trimetazidine or long-acting oral nitrates in Hong Kong (population coverage of 7.5 millions, January 1999 - December 2020). A total of 6561 patients with pre-existing or de novo lung cancers were identified. Clinical outcomes of all-cause mortality were longitudinally compared between lung cancer patients who received trimetazidine (n = 547) versus non-users (control, n = 6014). RESULTS: Over 902.9 ± 1410.6 days, lower incidence of deaths occurred in the trimetazidine group (79.0 %, n = 432/547) compared to controls (90.5 %, n = 5442/6014, P < 0.001). Kaplan-Meier analyses showed that trimetazidine use was associated with significantly higher survival from all-cause mortality in IHD patients (trimetazidine: mean survival = 1840.6 [95 %CI 1596.0-2085.3], versus control: 1056.7 [95 %CI 1011.3-1102.0] days, Log Rank = 69.4, P < 0.001). Cox regression showed that trimetazidine use was significantly associated with reduced risk of all-cause mortality in crude (HR = 0.60 [95 %CI: 0.53 to 0.68], P < 0.001) and multivariable models (HR = 0.65 [95 % CI: 0.57 to 0.74], P < 0.001). Pre-specified analyses amongst patients with pre-existing lung cancers yielded similar findings (HR = 0.49 [95 %CI: 0.35 to 0.67], P < 0.001). Survival benefits related to trimetazidine use was predominantly restricted to non-cardiovascular mortality (P < 0.001). CONCLUSIONS: Trimetazidine use is associated with higher overall survival in IHD patients with lung cancers, particularly from non-cardiovascular death. These findings need to be confirmed by randomized controlled trials.

Aromatase Inhibitor Therapy Increases the Risk of New-Onset Atrial Fibrillation in Patients With Breast Cancer.

Background: Previous studies suggest that aromatase inhibitors (AIs) increase the risk of adverse cardiovascular events and cardiac arrhythmias in patients with breast cancer, but it is unclear whether AIs also increase the risk of new-onset atrial fibrillation (AF). Objectives: The purpose of this study was to investigate whether the use of AIs was associated with an increased risk of new-onset AF in patients with breast cancer. Methods: We performed a retrospective analysis involving 5,707 patients with breast cancer (mean age 63.9 ± 11.2 years and 99.9% women) who received adjunctive hormone therapy with an AI (AI group, n = 4,878) or tamoxifen (tamoxifen group, n = 829) in Hong Kong between January 1, 1999, and December 31, 2020. After propensity score matching, there were 1,658 and 829 patients with balanced characteristics in the AI group and tamoxifen group, respectively. Results: After 8,863 patient-years of follow-up, patients who were prescribed AI had a trend toward more new-onset arrhythmias compared with those prescribed tamoxifen (0.62 vs 0.30 per 100 patient-years; crude HR: 2.05; P = 0.053). The difference in arrhythmic risk was mainly driven by a higher incidence rate of new-onset AF in the AI group (0.59 vs 0.27 per 100 patient-years; crude HR: 2.18; P = 0.046). The use of AIs was confirmed to be an independent risk factor for new-onset AF on multivariate analysis (adjusted HR: 2.75; P = 0.01). Conclusions: Among breast cancer patients prescribed adjunctive hormonal therapy, AI was associated with an increased risk of new-onset AF. Regular surveillance for new-onset AF should be considered in breast cancer patients treated with an AI.