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.