Risk Stratification and Efficacy of Spironolactone in Patients with Heart Failure with Preserved Ejection Fraction: Secondary Analysis of the TOPCAT Randomized Clinical Trial.

PURPOSE: We aimed to develop a simple risk score for patients with HFpEF and assessed the efficacy of spironolactone across baseline risk. METHODS: We developed risk stratification scheme for cardiovascular death in placebo arm of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial (TOPCAT). We screened candidate risk indicators and determined strong risk predictors using COX regression. The absolute risk reduction (ARR) in cardiovascular death with spironolactone was evaluated across baseline risk groups. COX regressions were performed to assess the hazard ratios (HRs) of spironolactone therapy for cardiovascular death and drug discontinuation in each risk category. RESULTS: A simple risk score scheme was constructed based on five risk indicators weighted by estimates from the model, including age, diastolic blood pressure, renal dysfunction, white blood cell, and left ventricular ejection fraction. The risk score scheme showed good discrimination in placebo cohort (C index=0.70). ARR with spironolactone therapy was observed only in patients at very high risk (7.9%). Spironolactone therapy significantly reduced the risk of cardiovascular death in the very high-risk group (HR: 0.57; 95%CI, 0.39-0.84; P =0.005 and P for interaction 0.03) but showed similar risk of drug discontinuation across risk categories (P for interaction=0.928). CONCLUSION: This simple risk score stratifies patients with HFpEF by their baseline risk of cardiovascular death. Patients at very high risk derive great benefits from spironolactone therapy. This easy-to-use risk score provides a practical tool that can facilitate risk stratification and tailoring therapy for those who benefit most from spironolactone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00094302.

Six-Year Change in QT Interval Duration and Risk of Incident Heart Failure　- A Secondary Analysis of the Atherosclerosis Risk in Communities Study.

BACKGROUND: Few studies have investigated the association between temporal change in QT interval and incident heart failure (HF). The aim of this study is to examine this association in the Atherosclerosis Risk in Communities (ARIC) study.Methods and Results:A secondary analysis was performed for the ARIC study. Overall, 10,274 participants (age 60.0±5.7 years, 45.7% male and 19.5% black) who obtained a 12-lead electrocardiography (ECG) at both Visit 1 (1987-1989) and Visit 3 (1993-1995) in the ARIC study were included. QT interval duration was corrected by using Bazett's formula (QTc). The change in corrected QT interval duration (∆QTc) was calculated by subtracting QTc at Visit 3 from Visit 1. The main outcome measure was incident HF. Multivariable Cox regression models were used to assess the association between ∆QTc and incident HF. During a median follow up of 19.5 years, 1,833 cases (17.8%) of incident HF occurred. ∆QTc was positively associated with incident HF (HR: 1.06, 95% CI 1.03, 1.08, per 10 ms increase, P<0.001; HR 1.22, 95% CI 1.08, 1.36, T3 vs. T1, P=0.002), after adjusting for traditional cardiovascular risk factor, QTc and QRS duration. CONCLUSIONS: Temporal increases in QTc are independently associated with increased risk of HF.

Behavioral Factors Mediating the Impact of Educational Attainment on Incident Heart Failure　- A Mediation Analysis.

BACKGROUND: To examine the association of low educational attainment with incident heart failure (HF) and explore potential behavioral mediators of the causal pathway.Methods and Results:A total of 12,109 participants in the Atherosclerosis Risk in Communities Study (ARIC) were included. Educational attainment was measured at baseline, and the risk of HF across educational attainment groups was assessed by Cox proportional hazards models. Using mediation analysis, we evaluated the mediating role of behavioral factors in the causal pathway between educational attainment and HF. During a median follow-up of 25.1 years, 2,407 cases (19.9%) of HF occurred. Educational attainment showed an inverse association with HF risk (hazard ratio (HR), 1.41; 95% confidence interval (CI), 1,26-1.57 for low educational attainment; HR, 1.13; 95% CI, 1.02-1.25 for medium educational attainment). In the mediation analysis, the association between educational attainment and HF was partially mediated by income, waist-to-hip ratio, current smoking, body mass index, current drinking, sports and physical activity, which explained 24.3%, 20.2%, 13.8%, 10.1%, 7.7%, 7.3% and 4.5%, respectively, of the relationship. In total, all mediators contributed 56.3% of the total effect. CONCLUSIONS: Low educational attainment was associated with increased risk for HF. Income, obesity and current smoking mediated a great proportion of the total effect of educational attainment on HF. Our results provide underlying insights for the development of targeted public health interventions to reduce educational disparities on HF incidence.

Impact of RAAS Blockers on Contrast-Induced Nephropathy in Patients With Renal Insufficiency: A Meta-Analysis.

The effect of renin-angiotensin-aldosterone system (RAAS) blockers [angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers] on Contrast-induced nephropathy (CIN) is unclear in patients with renal insufficiency. Thus, we conduct a meta-analysis to evaluate the association between the administration of RAAS blockers and CIN in patients with renal insufficiency. We searched PubMed, EMBASE, and Cochrane Library for relevant studies published before September 2019. The primary outcome was the incidence of CIN, and the secondary outcome was the changes in serum creatinine (SCr) from baseline to postprocedure (ΔSCr). Pooled odds ratio (OR) or weighted mean difference (WMD) with their 95% confidence interval (CIs) for the CIN incidence, ΔSCr were used to calculate original data. A total of 8 studies were included in the meta-analysis. Compared with controls, ACEI/angiotensin receptor blocker increased the risk of CIN (OR = 1.61, 95% CI 1.14-2.28, I = 30%; P = 0.007), whereas this association was not significant in Chinese patients (OR = 1.07, 95% CI 0.65-1.77, I = 19%, P = 0.79). The total weighted mean differences of the ΔSCr were 0.06 mg/dL (95% CI: 0.01-0.11, I = 82%; P = 0.03). Administration of RAAS blockers in patients with renal insufficiency was associated with a significantly higher incidence of CIN, whereas it did not show a significant effect on Chinese patients.

Influence of genetic polymorphisms in cytochrome P450 oxidoreductase on the variability in stable warfarin maintenance dose in Han Chinese.

PURPOSE: The aim of this study was to investigate whether any of the single-nucleotide polymorphisms (SNPs) in the POR gene were significantly associated with CYP activity and expression, and could contribute to the total variability in stable warfarin maintenance doses in Han Chinese. METHODS: A total of 408 patients treated at the First Affiliated Hospital of Sun Yat-Sen University were eligible for the study and had attained a stable warfarin maintenance dose at the start of the investigation. Demographics, warfarin maintenance doses, and concomitant medications were documented. Genomic DNA was extracted from peripheral blood samples and genotyped for ten SNPs (CYP 2C9*2 and *3, CYP4F2 rs2108622, VKORC1 -1639C>T, and potential POR genes of rs10239977, rs3815455, rs41301394, rs56256515, rs1057868, and rs2286823) using the Sequenom MassARRAY genotyping system. RESULTS: A predictive model of warfarin maintenance dose was established and indicated that age, gender, body surface area, aspirin use, CYP2C9*3, CYP4F2 rs2108622, VKORC1 -1639C>T, and POR*37 831-35C>T accounted for 42.4 % of dose variance in patients undergoing anticoagulant treatment. The contribution of POR*37 831-35C>T to warfarin dose variation was only 3.9 %. CONCLUSIONS: For the first time, the SNP POR*37 831-35C>T was confirmed as a minor but statistically significant factor associated with interindividual variation in warfarin maintenance dose in Han Chinese. The POR*37 gene polymorphism should be considered in future algorithms for faster and more reliable achievement of stable warfarin maintenance doses.

Risk of thromboembolic events in atrial fibrillation with chronic kidney disease.

BACKGROUND AND PURPOSE: Chronic kidney disease may increase the risk for ischemic stroke or systemic embolism in patients with nonvalular atrial fibrillation (AF). We conducted a meta-analysis to summarize all published studies to investigate the link between chronic kidney disease and risk of thromboembolic events in AF. METHODS: We performed a literature search using MEDLINE (source PubMed, 1966 to July, 2014) and EMBASE (1980 to July 2014) with no restrictions. Pooled effect estimates were obtained by using random-effects meta-analysis. RESULTS: Eighteen studies involving 538 479 patients and 41 719 incident thromboembolic events were identified. From the pooled analysis, AF patients with estimated glomerular filtration rate <60 mL/min compared with those with estimated glomerular filtration rate ≥60 mL/min experienced a significantly increased risk for developing thromboembolic events (relative risk, 1.62 [95% confidence interval, 1.40-1.87; P<0.001]). The annual rate of thromboembolic events increased by 0.41% (95% confidence interval, 0.17%-0.65%) for a 10 mL/min decrease in renal function. Addition of renal impairment to CHADS2 slightly improved the stroke risk stratification. CONCLUSIONS: Impaired renal function is an independent predictor of stroke or systemic embolism in patients with nonvalvular AF. Consideration of renal function may improve stroke risk stratification in patients with AF.

Long-Term Visit-to-Visit Mean Arterial Pressure Variability and the Risk of Heart Failure and All-Cause Mortality.

Background: Systolic or diastolic blood pressure (BP) variability is associated with an increased risk of cardiovascular events. We assessed whether BP variability measured by mean arterial pressure (MAP) was associated with increased risk of heart failure (HF) and death in individuals with or without hypertension. Methods: We evaluated 9,305 Atherosclerosis Risk in Communities (ARIC) study participants with or without hypertension and calculated BP variability based on MAP values from visit 1 to 4 [expressed as standard deviation (SD), average real variability (ARV), coefficient of variation (CV), and variability independent of the mean (VIM)]. Multivariate-adjusted Cox regression model and restricted cubic spline curve were used to evaluate the associations of MAP variability with all-cause mortality and HF. Results: During a median follow-up of 16.8 years, 1,511 had an HF event and 2,903 died. Individuals in the highest quartile of VIM were both associated with a 21% higher risk of all-cause mortality [hazard ratio (HR), 1.21; 95% CI, 1.09-1.35] and HF (HR, 1.21; 95% CI, 1.04-1.39) compared with the lowest quartile of VIM. Cubic spline curves reveal that the risk of deaths and HF increased with MAP variability when it reached a higher level. Results were similar in individuals with normotension (all-cause mortality: HR, 1.30; 95% CI, 1.09-1.55; HF, HR, 1.49; 95% CI, 1.12-1.98). Conclusions: In individuals with or without hypertension, greater visit-to-visit MAP variability was associated with a higher risk of all-cause mortality and HF, indicating that the BP variability assessed by MAP might be a potential risk factor for HF and death.

Short-chain fatty acids combined with intronic DNA methylation of HIF3A: Potential predictors for diabetic cardiomyopathy.

BACKGROUND: Hyperglycemia can induce the heart to enter an oxygen-restricted environment, which results in diabetic cardiomyopathy (DCM). Microbiota-derived short-chain fatty acids (SCFAs) affect O2 consumption and play crucial roles in modulating metabolic and cardiovascular health. The epigenetic regulation of the hypoxia-inducible factor 3A (HIF3A) gene is implicated in oxidative metabolism in the pathogenesis of diabetes. Identifying the associations between plasma SCFA levels and intronic DNA methylation of HIF3A may reveal useful predictors or provide insights into the disease processes of DCM. METHODS: In this cross-sectional study, we analyzed plasma SCFA levels, HIF3A expression, and CpG methylation of HIF3A intron 1 in peripheral blood from patients with type 2 diabetes presenting with (n = 92) and without (n = 105) cardiomyopathy. RESULTS: Plasma butyric acid levels and HIF3A mRNA expression in peripheral blood were decreased in DCM patients, whereas 3 CpGs in HIF3A intron 1 (CpG 6, CpG 7 and CpG 11) were highly methylated in DCM patients. Interestingly, butyric acid levels positively correlated with HIF3A levels, while a negative association was identified between butyric acid levels and the methylation rates of HIF3A intron 1 at CpG 6. Butyric acid levels also correlated with several clinical/echocardiographic factors in DCM patients. Additionally, the combination of plasma butyric acid levels and HIF3A intron 1 methylation at CpG 6 discriminated DCM patients from type2 diabetes mellitus (T2DM) patients. CONCLUSIONS: The novel associations between plasma butyric acid levels and HIF3A intron 1 methylation at CpG 6 may highlight an underlying mechanism by which the "microbial-myocardial" axis and host-microbe interactions may participate in the pathogenesis of DCM.

Intensity of Glycemic Exposure in Early Adulthood and Target Organ Damage in Middle Age: The CARDIA Study.

AIM: To determine whether long-term intensity of glycemic exposure (IGE) during young adulthood is associated with multiple target organs function at midlife independent of single fasting glucose (FG) measurement. METHODS: We included 2,859 participants, aged 18-30 years at Y0, in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. IGE was calculated as the sum of (average FG of two consecutive examinations × years between the examinations) over 25 years. Target organs function was indicated by cardiac structure, left ventricular (LV) systolic function, LV diastolic function, coronary artery calcium (CAC), and urine albumin-to-creatinine ratio (UACR) at Y25. We evaluated the associations between IGE with target organs function using linear regression models and estimated the associations between IGE with numbers of organs involved (0, 1, or ≥ 2 organs) using multinomial logistic regression models. RESULTS: A 1-SD increment of IGE was significantly associated with worse target organs function after multivariable adjustment: left ventricular mass (ß [SE], 5.468 [1.175]); global longitudinal strain (ß [SE], 0.161 [0.071]); E/e' ratio (ß[SE], 0.192 [0.071]); CAC score (ß [SE], 27.948 [6.116]); and log UACR (ß [SE], 0.076 [0.010]). Besides, IGE was independently associated with having ≥ 2 organs involved in both overall population (OR [95% CI], 1.48 [1.23, 1.41], P < 0.001) and subgroups stratified by diabetes at Y25. CONCLUSION: Higher intensity of glycemic exposure during young adulthood was independently associated with subclinical alterations of target organs function at midlife. Our findings highlight the importance of early screening and management of IGE in youth.

Klotho attenuated Doxorubicin-induced cardiomyopathy by alleviating Dynamin-related protein 1 - mediated mitochondrial dysfunction.

Doxorubicin (Dox)-induced cardiotoxicity could lead to dilated cardiomyopathy and heart failure. Our previous study reported the protective effects of Klotho against hyperglycemia-induced cardiomyopathy. We investigated whether Klotho alleviated Dox-induced cardiotoxicity. Neonatal rat ventricular cardiomyocytes and H9c2 cells were incubated with 5 µM Dox for 24 h with or without Klotho (0.1 µg/mL). Dox-induced cardiotoxicity model was approached in C57BL/6 mice. Cardiac function and serum enzyme activity, apoptosis and mitochondrial dysfunction were measured. We found that pretreatment with Klotho significantly reduced Dox-induced apoptosis in cardiomyocytes. In Dox-treated mice, Klotho also suppressed cardiac cell death and improved cardiac function. Moreover, the expression of Dynamin-related protein 1 (Drp1) was increased after Dox-treatment both in vitro and in vivo, which was related to apoptosis in cardiomyocytes. In vitro experiments, Drp1 ser 616 phosphorylation post-Dox stimulation could be significantly attenuated by Klotho or Drp1 specific inhibitor Mdivi-1. Overexpression of Drp1 in cardiomyocytes increased Dox-induced heart injury which could also be attenuated by Klotho. This study demonstrated that Klotho alleviated Dox-induced cardiotoxicity by reducing apoptosis and mitochondrial fission through down-regulating Drp1 expression. Our findings highlighted new targets for the therapy of Dox-induced cardiomyopathy.

Association between calf girth and peripheral artery disease in the Atherosclerosis Risk in Communities Study.

BACKGROUND: The pathogenesis of peripheral artery disease (PAD) is associated with impaired calf muscle. We sought to investigate the association between gender-specific calf girth and the prevalence of PAD among participants from a community-based cohort study. METHODS: A total 13,808 participants in the Atherosclerosis Risk in Communities (ARIC) study without prior PAD were included in the final analysis. Calf girth was measured at baseline (1985-1987). A hospital diagnosis with an ICD-9 code defined incident PAD during follow up. Cox regression analysis adjusted for demographic variables and other covariates was used to estimate hazard ratios (HR) and 95% confidence interval (CI) for the association between calf girth and PAD. RESULTS: After a medium follow-up of 25.2 years, the overall prevalence of PAD in our study was 5.2% (721/13,808), 335 patients were women and 386 were men. The adjusted HR for PAD with calf girth as continuous variables was 0.99 (95% CI 0.95-1.04) in females and 0.93 (95% CI 0.88-0.99) in males, respectively. Moreover, interaction for gender was statistically significant between calf girth and PAD in overall population (p=0.001). CONCLUSIONS: Our findings revealed a linear association of calf girth with the prevalence of PAD among male participants in ARIC.

NLRP3 inflammasome-mediated pyroptosis contributes to the pathogenesis of non-ischemic dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is one of the most common causes of heart failure, and the underlying mechanism remains largely elusive. Here we investigated whether NLRP3 inflammasome-mediated pyroptosis contributes to non-ischemic DCM and dissected the underlying mechanism. We found that hyper activated NLRP3 inflammasome with pyroptotic cell death of cardiomyocytes were presented in the myocardial tissues of DCM patients, which were negatively correlated with cardiac function. Doxorubicin (Dox)-induced DCM characterization disclosed that NLRP3 inflammasome activation and pyroptosis occurred in Dox-treated heart tissues, but were very marginal in either NLRP3-/- or caspase-1-/- mice. Mechanistically, Dox enhanced expressions of NOX1 and NOX4 and induced mitochondrial fission through dynamin-related protein 1 (Drp1) activation, leading to NLRP3 inflammasome-mediated pyroptosis in cardiomyocytes via caspase-1-dependent manner. Conversely, both inhibitions of NOX1 and NOX4 and Drp1 suppressed Dox-induced NLPR3 inflammasome activation and pyroptosis. The alterations of NOX1 and NOX4 expression, Drp1 phosphorylation and mitochondrial fission were validated in DCM patients and mice. Importantly, Dox-induced Drp1-mediated mitochondrial fission and the consequent NLRP3 inflammasome activation and pyroptosis were reversed by NOX1 and NOX4 inhibition in mice. This study demonstrates for the first time that cardiomyocyte pyroptosis triggered by NLRP3 inflammasome activation via caspase-1 causally contributes to myocardial dysfunction progression and DCM pathogenesis.

Long-term tracking of fasting blood glucose variability and peripheral artery disease in people without diabetes.

INTRODUCTION: Long-term changes of fasting blood glucose (FBG) in relation to lower-extremity peripheral artery disease (lower-extremity PAD) in people without diabetes has barely been reported. Our study aimed to investigate the association between FBG variability and the incidence of lower-extremity PAD in people without diabetes. RESEARCH DESIGN AND METHODS: We included 7699 participants without prior lower-extremity PAD and diabetes from the Atherosclerosis Risk in Communities study in the final analysis. At least two measurements of FBG were required during follow-up. Variability of FBG was identified using SD, coefficient of variation (CV), variability independent of the mean (VIM) and average real variability. Lower-extremity PAD was defined as an ankle brachial index <0.9, or hospitalization with a lower-extremity PAD diagnosis. Cox regression model was used to calculate HR for incidence of lower-extremity PAD and FBG variability. RESULTS: During a median follow-up of 19.5 years, 504 (6.5 %) lower-extremity PAD events were observed, 54.4% (n=274) were male, and 17.5% (n=88) were African-American. FBG variability was positively associated with incident lower-extremity PAD, with a linear relationship. HRs for CV and VIM were 1.015 (95% CI: 1.001 to 1.03; p=0.023), and 1.032 (95% CI: 1.004 to 1.06; p=0.022) for lower-extremity PAD, respectively. Participants in the lowest quartile of CV were at lower lower-extremity PAD risk compared with the highest ones (HR: 1.499, 95% CI: 1.16 to 1.938; p=0.002). CONCLUSIONS: Higher FBG variability was independently associated with increased prevalence of lower-extremity PAD in people without diabetes. TRIAL REGISTRATION NUMBER: NCT00005131.

Effectiveness of blood pressure-lowering treatment by the levels of baseline Framingham risk score: A post hoc analysis of the Systolic Blood Pressure Intervention Trial (SPRINT).

This was a post hoc analysis of Systolic Blood Pressure Intervention Trial (SPRINT), aimed to investigate whether intensive blood pressure treatment has differential therapeutic outcomes on patients with different baseline Framingham risk score (FRS). The 9298 SPRINT participants were categorized into low-risk (baseline FRS < 10%), intermediate-risk (FRS = 10%-20%), or high-risk (FRS > 20%) arms. The primary outcome was a composite of myocardial infarction, acute coronary syndrome not resulting in myocardial infarction, stroke, acute decompensated heart failure, or death from cardiovascular causes. Serious adverse events were defined as hypotension, syncope, and bradycardia. Multiple Cox regression was used to calculate hazard ratios for study outcomes with intensive compared with standard SBP treatment between these three groups. After a median follow-up time of 3.26 years, the primary outcome hazard ratio (HR) for intensive versus standard treatment was 0.73 (95% CI: 0.61-0.88, P = .0044) in the high-risk arm. And, for all-cause mortality, the hazard ratio with intensive SBP treatment was 1.58 (95% CI: 0.55-1.06), 0.9 (95% CI: 0.26-9.50), and 0.53 (95% CI: 0.34-0.82) in three arms (all P values for interaction > 0.05). Effects of intensive versus standard SBP control on serious adverse events were similar among patients with different FRS. Our results suggested that regardless of the FRS level, the intensive blood pressure control was beneficial.

Influence of baseline systolic blood pressure on the relationship between intensive blood pressure control and cardiovascular outcomes in the Systolic Blood Pressure Intervention Trial (SPRINT).

OBJECTIVE: To determine whether the effects of intensive (< 120 mmHg) compared with standard (< 140 mmHg) systolic blood pressure (SBP) treatments are different among those with different baseline SBP. METHODS: De-identified SPRINT database was used for this post hoc analysis. SPRINT participants were categorized by baseline SBP status, defined as high-SBP (≥ 140 mmHg) group versus the low-SBP (< 140 mmHg) group. The primary outcome was a composite of myocardial infarction, acute coronary syndrome not resulting in myocardial infarction, stroke, acute decompensated heart failure, or death from cardiovascular causes. Treatment-related adverse events including hypotension, syncope, and bradycardia were also evaluated. Cox regression was used to calculate hazard ratios for study outcomes with intensive compared with standard SBP treatment between these two groups. RESULTS: Among 9361 participants randomized (age 67.9 ± 9.4 years; 35.5% female), 4964 and 4397 had baseline low SBP (< 140 mmHg) and high SBP (≥ 140 mmHg), respectively. After a median follow-up of 3.26 years, the hazard ratio for the primary outcome was 0.65 (95% CI 0.50, 0.83) and 0.84 (95% CI 0.66, 1.06) among those in the low-SBP group and high-SBP group, respectively (P value for interaction 0.15). For treatment-related adverse events, the hazard ratio with intensive SBP treatment was 2.03 (95% CI 1.44, 2.85) for the low-SBP group and 1.80 (95% CI 1.32, 2.47) for the high-SBP group (P value for interaction 0.28). CONCLUSIONS: Hypertensive patients with low baseline SBP may benefit from intensive SBP lowering, whereas benefits were inconclusive among those with high baseline SBP.

Lipid management for coronary heart disease patients: an appraisal of updated international guidelines applying Appraisal of Guidelines for Research and Evaluation II-clinical practice guideline appraisal for lipid management in coronary heart disease.

BACKGROUND: Clinical practice guidelines (CPGs) provide many recommendations for hyperlipidemia management, but some of them are still debatable. METHODS: We applied the six-domain Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument to evaluate the quality of guidelines with lipid management recommendations for coronary heart disease (CHD), including dyslipidemia and CHD guidelines published from 2009 to 2019. Meanwhile, we synthesized and compared major recommendations and present the consistency and controversy in current dyslipidemia management. RESULTS: Among 19 guidelines included, ten guidelines ("strongly recommended" with AGREE scores 61-94%) performed better than the other nine (38-65% as "recommended with some modification") For blood lipid tests, most CHD guidelines simply required fasting sample while dyslipidemia guidelines preferred non-fasting sample except in high triglycerides state. Most guidelines consistently chose low-density lipoprotein cholesterol (LDL-C) as the primary lipid-lowering target (LLT), while non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B were mainly selected as secondary LLTs. The specific goals of LDL-C lowering were either to lower than 70 mg/dL or with at least 50% reduction. All guidelines recommended high intensity or maximally tolerable doses of statins, while ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were recommended as second-line therapy. CONCLUSIONS: The general quality of guidelines for lipid management is satisfactory. Consensus has been reached on the specific goal of lipid reduction and the intensity of statins therapy. Further research is needed to validate the application of non-fasting sample and non-HDL-C target, as well as the efficacy and safety of ezetimibe and PCSK9 inhibitors.

Visit-to-Visit Fasting Glucose Variability in Young Adulthood and Hippocampal Integrity and Volume at Midlife.

OBJECTIVE: To determine whether visit-to-visit fasting glucose (VVFG) variability in young adulthood is associated with midlife hippocampal integrity and volume. RESEARCH DESIGN AND METHODS: Multivariable-adjusted linear regression models were used to estimate the association between VVFG variability and brain MRI variables in 543 CARDIA study participants. VVFG variability was defined by the SD of FG (SDFG), the coefficient of variation of the mean FG (CVFG), and the average real variability (ARVFG) over 25 years of follow-up. Hippocampal integrity fractional anisotropy (FA) and tissue volume standardized to intracranial volume were measured by 3T MRI at year 25. RESULTS: After multivariable adjustment, higher FG variability (1-SD increase) was associated with lower hippocampal FA (SDFG -0.015 [95% CI -0.026, -0.004]; CVFG -0.009 [95% CI -0.018, -0.001]; ARVFG -0.011 [95% CI -0.019, -0.002]) and lower hippocampal volume (SDFG -0.012 [95% CI -0.023, -0.001]). CONCLUSIONS: Higher VVFG variability in young adulthood is associated with lower midlife hippocampal integrity and volume, suggesting its value in predicting risk for hippocampal structural damage.

Phenomapping of subgroups in hypertensive patients using unsupervised data-driven cluster analysis: An exploratory study of the SPRINT trial.

BACKGROUND: Hypertensive patients are highly heterogeneous in cardiovascular prognosis and treatment responses. A better classification system with phenomapping of clinical features would be of greater value to identify patients at higher risk of developing cardiovascular outcomes and direct individual decision-making for antihypertensive treatment. METHODS: An unsupervised, data-driven cluster analysis was performed for all baseline variables related to cardiovascular outcomes and treatment responses in subjects from the Systolic Blood Pressure Intervention Trial (SPRINT), in order to identify distinct subgroups with maximal within-group similarities and between-group differences. Cox regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for cardiovascular outcomes and compare the effect of intensive antihypertensive treatment in different clusters. RESULTS: Four replicable clusters of patients were identified: cluster 1 (index hypertensives); cluster 2 (chronic kidney disease hypertensives); cluster 3 (obese hypertensives) and cluster 4 (extra risky hypertensives). In terms of prognosis, individuals in cluster 4 had the highest risk of developing primary outcomes. In terms of treatment responses, intensive antihypertensive treatment was shown to be beneficial only in cluster 4 (HR 0.73, 95% CI 0.55-0.98) and cluster 1 (HR 0.54, 95% CI 0.37-0.79) and was associated with an increased risk of severe adverse effects in cluster 2 (HR 1.18, 95% CI 1.05-1.32). CONCLUSION: Using a data-driven approach, SPRINT subjects can be stratified into four phenotypically distinct subgroups with different profiles on cardiovascular prognoses and responses to intensive antihypertensive treatment. Of note, these results should be taken as hypothesis generating that warrant further validation in future prospective studies.

Serum magnesium and the prevalence of peripheral artery disease: The Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND AND AIMS: Peripheral arterial disease (PAD) is a clinical manifestation of extracoronary atherosclerosis. Many risk factors are involved in the process of PAD, but the association between serum magnesium (Mg) and PAD is not clear. Our study aimed to investigate whether serum Mg is associated with PAD incidence. METHODS: A total of 13,826 participants (aged 40-64 years) in the Atherosclerosis Risk in Communities (ARIC) study (1987-1989) without prior PAD were included in the final analysis. Serum Mg levels were measured at visits 1 and 2. PAD was defined as an ankle brachial index less than 0.9, or hospitalization with a PAD diagnosis. Cox regression was used to calculate hazard ratios (HRs) for incidence of PAD and serum Mg. RESULTS: During a median follow-up of 24.4 years, 1364 (48.4% female) PAD events were observed. After multiple adjustment, participants in the lowest (≤1.4 mEq/L) category of serum Mg compared with the highest (≥1.8 mEq/L) ones were at higher PAD risk (HR: 1.3; 95% confidence interval (CI): 1.06-1.58) (p value = 0.004). The HRs for PAD in 1.5, 1.6 and 1.7 mEq/L of serum Mg were 1.29 (95% CI: 1.08-1.54), 1.05 (95% CI: 0.89-1.24), and 1.0 (95% CI: 0.85-1.18), respectively. CONCLUSIONS: Low serum Mg was independently associated with an increased prevalence of PAD in the large population-based study; further studies are needed to confirm our findings.

Low-Carbohydrate Diets and Risk of Incident Atrial Fibrillation: A Prospective Cohort Study.

Background The influences of low-carbohydrate diets in cardiovascular disease are controversial. Few studies have examined the relationship of carbohydrate intake and risk of incident atrial fibrillation ( AF ). We aimed to evaluate the association between carbohydrate intake and the risk of incident AF in the ARIC (Atherosclerosis Risk in Communities) Study. Methods and Results We included 13 385 participants (age, 54.2±5.8 years; 45.1% men and 74.7% white) who completed a dietary questionnaire at baseline (1987-1989) in the ARIC Study. The primary outcome was incident AF , which was identified by ECG performed during study examinations, hospital discharge codes, and death certificates. We used multivariable Cox hazard regression models to assess the association between carbohydrate intake and incident AF . We further explored the effects of specific food source (animal versus plant based) used to replace carbohydrate intake in the low-carbohydrate intake setting. During a median follow-up of 22.4 years, 1808 cases (13.5%) of AF occurred. The hazard ratio for incident AF associated with a 1- SD (9.4%) increase in carbohydrate intake as a percentage of energy intake was 0.82 (95% CI , 0.72-0.94), after adjustment for traditional AF risk factors and other diets factors. Results were similar when individuals were categorized by carbohydrate intake quartiles (hazard ratio, 0.64; 95% CI , 0.49-0.84; comparing extreme quartiles). No association was found between the type of protein or fat used to replace the carbohydrate and risk of incident AF . Conclusions Low-carbohydrate diets were associated with increased risk of incident AF , regardless of the type of protein or fat used to replace the carbohydrate.