Contribution of Gene Regulatory Networks to Heritability of Coronary Artery Disease

BackgroundGenetic variants currently known to affect coronary artery disease (CAD) risk explain less than one-quarter of disease heritability. The heritability contribution of gene regulatory networks (GRNs) in CAD, which are modulated by both genetic and environmental factors, is unknown.ObjectivesThis study sought to determine the heritability contributions of single nucleotide polymorphisms affecting gene expression (eSNPs) in GRNs causally linked to CAD.MethodsSeven vascular and metabolic tissues collected in 2 independent genetics-of-gene-expression studies of patients with CAD were used to identify eSNPs and to infer coexpression networks. To construct GRNs with causal relations to CAD, the prior information of eSNPs in the coexpression networks was used in a Bayesian algorithm. Narrow-sense CAD heritability conferred by the GRNs was calculated from individual-level genotype data from 9 European genome-wide association studies (GWAS) (13,612 cases, 13,758 control cases).ResultsThe authors identified and replicated 28 independent GRNs active in CAD. The genetic variation in these networks contributed to 10.0% of CAD heritability beyond the 22% attributable to risk loci identified by GWAS. GRNs in the atherosclerotic arterial wall (n = 7) and subcutaneous or visceral abdominal fat (n = 9) were most strongly implicated, jointly explaining 8.2% of CAD heritability. In all, these 28 GRNs (each contributing to >0.2% of CAD heritability) comprised 24 to 841 genes, whereof 1 to 28 genes had strong regulatory effects (key disease drivers) and harbored many relevant functions previously associated with CAD. The gene activity in these 28 GRNs also displayed strong associations with genetic and phenotypic cardiometabolic disease variations both in humans and mice, indicative of their pivotal roles as mediators of gene–environmental interactions in CAD.ConclusionsGRNs capture a major portion of genetic variance and contribute to heritability beyond that of genetic loci currently known to affect CAD risk. These networks provide a framework to identify novel risk genes/pathways and study molecular interactions within and across disease-relevant tissues leading to CAD.     

Genetic prediction of age at menarche,age at natural menopause and type 2 diabetes: A Mendelian randomization study

Background and aimsThe relationship between reproductive factors and type 2 diabetes (T2D) is controversial; therefore, we explored the causal relationship of age at menarche (AAM), age at natural menopause (ANM), with the risk of T2D and glycemic traits using two-sample Mendelian randomization.Methods and resultsWe used publicly available data at the summary level of genome-wide association studies, where AAM (N = 329,345), ANM (N = 69,360), T2D (N = 464,389). The inverse variance weighting (IVW) method was employed as the primary method. To demonstrate the robustness of the results, we also conducted various sensitivity analysis methods including the MR-Egger regression, the weighted median (WM) and the MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test. After excluding IVs associated with confounders, we found a causal association between later AAM and reduced risk of T2D (OR 0.81 [95% CI 0.75, 0.87]; P = 2.20 × 10⁻⁸), lower levels of FI (β −0.04 [95% CI -0.06, −0.01]; P = 2.19 × 10⁻³), FPG (β −0.03 [95% CI -0.05, −0.007]; P = 9.67 × 10⁻⁵) and HOMA-IR (β −0.04 [95% CI -0.06, −0.01]; P = 4,95 × 10⁻³). As for ANM, we only found a causal effect with HOMA-IR (β −0.01 [95% CI -0.02, −0.005]; P = 1.77 × 10⁻³), but not with T2D.ConclusionsOur MR study showed a causal relationship between later AAM and lower risk of developing T2D, lower FI, FPG and HOMA-IR levels. This may provide new insights into the prevention of T2D in women.     

Association of NT-ProBNP,Blood Pressure,and Cardiovascular Events: The ARIC Study

BackgroundAlthough intensive blood pressure reduction has cardiovascular benefits, the absolute benefit is greater in those at higher cardiovascular disease (CVD) risk.ObjectivesThis study examined whether N-terminal pro–B-type natriuretic peptide (NT-proBNP) helps identify subjects at higher risk for CVD events across systolic blood pressure (SBP), diastolic blood pressure (DBP), or pulse pressure (PP) categories.MethodsParticipants from the ARIC (Atherosclerosis Risk In Communities) study visit 4 (1996 to 98) were grouped according to SBP, DBP, or PP categories and further stratified by NT-proBNP categories. Cox regression models were used to estimate hazard ratios for incident CVD (coronary heart disease, ischemic stroke, or heart failure hospitalization) and mortality across combined NT-proBNP and/or BP categories, adjusting for CVD risk factors.ResultsThere were 9,309 participants (age: 62.6 ± 5.6 years; 58.3% women) with 2,416 CVD events over a median follow-up of 16.7 years. Within each SBP, DBP, or PP category, a higher category of NT-proBNP (100 to <300 or 300 pg/ml, compared with NT-proBNP <100 pg/ml) was associated with a graded increased risk for CVD events and mortality. Participants with SBP 130 to 139 mm Hg but NT-proBNP ≥300 pg/ml had a hazards ratio of 3.4 for CVD (95% confidence interval: 2.44 to 4.77) compared with a NT-proBNP of <100 pg/ml and SBP of 140 to 149 mm Hg.ConclusionsElevated NT-proBNP is independently associated with CVD and mortality across SBP, DBP, and PP categories and helps identify subjects at the highest risk. Participants with stage 1 hypertension but elevated NT-proBNP had greater cardiovascular risk compared with those with stage 2 SBP but lower NT-proBNP. Future studies are needed to evaluate use of biomarker-based strategies for CVD risk assessment to assist with initiation or intensification of BP treatment.     

Association of exposure to Chinese famine in early life with the incidence of hypertension in adulthood: A 22-year cohort study

Background and aimsUndernutrition in early life may have a lifelong effect on adult health. The conclusions on the association of exposure to famine with the risk of hypertension were inconsistent. The aim of this study was to examine the association of exposure to the Chinese famine with incident hypertension.Methods and resultsData were obtained from the China Health and Nutrition Survey. All included participants were divided into five birth cohorts: no exposure, born in or after 1962 (N = 2 088); fetal exposure, between 1959 and 1961 (N = 880); early childhood exposure, between 1956 and 1958 (N = 1 214); mid-childhood exposure, between 1953 and 1955 (N = 1 287); and late childhood exposure, between 1949 and 1952 (N = 1 445). Hypertension was defined as SBP/DBP ≥140/90 mmHg, use of hypertensive medications, or a self-reported diagnosis. A total of 6 914 participants were included. The exposure to famine decreased the incidence of hypertension (P = 0.0018, 0.0001, <0.0001, and <0.0001; HR: 0.715, 0.686, 0.622, and 0.527, respectively) in males. Similarly, the exposure to famine might also decrease incident hypertension in the rural areas (P = 0.0013, <0.0001, <0.0001, and <0.0001; HR: 0.735, 0.706, 0.679, and 0.539, respectively). There were interaction effects between famine severity and exposure to famine in early (P = 0.024) and late childhood (P = 0.009).ConclusionExposure to the Chinese famine decreased the incidence of hypertension, especially in males and in the rural areas. Furthermore, the exposure postponed the age at the onset of hypertension.     

Causal associations of body mass index and waist-to-hip ratio with cardiometabolic traits among Chinese children: A Mendelian randomization study

Background and aimsBody mass index (BMI) and waist-to-hip ratio (WHR) have been reported to be causally associated with cardiometabolic diseases in adults in European populations. However, this causality was less explored in East Asian populations and in children. Our study aimed to explore and compare the causal associations of general obesity (measured by BMI) and central obesity (measured by WHR) with cardiometabolic traits.Methods and resultsWe performed a Mendelian randomization (MR) analysis in 2030 unrelated children from two independent case–control studies in Beijing, China. BMI-associated single nucleotide polymorphisms (SNPs) and WHR-SNPs identified by previous genome-wide association studies were used as genetic instruments to examine the casual associations of BMI and WHR with cardiometabolic traits, including glycemic traits, blood lipids, and blood pressure. Each 1-SD increase in BMI and WHR were significantly associated with 0.111 mmol/L and 0.110 mmol/L increase in log-transformed fasting insulin (FINS), 0.049 and 0.060 increase in log-transformed HOMA-β, 0.112 and 0.108 increase in log-transformed HOMA-IR, 0.009 mmol/L and 0.015 mmol/L increase in log-transformed triglyceride, and 15.527 mmHg and 7.277 mmHg increase in systolic blood pressure, respectively (all P < 0.05). The receiver operating characteristic curves showed that WHR had a stronger effect on FINS, HOMA-β, HOMA-IR, and triglyceride than BMI (all P < 0.05).ConclusionsUsing the MR method, we found that the genetic predisposition to higher BMI or WHR was associated with altered cardiometabolic traits in Chinese children. When compared with general obesity, central obesity might have stronger effects on glycemic traits and blood lipids among children.     

Diastolic Blood Pressure and Heart Rate Are Independently Associated With Mortality in Chronic Aortic Regurgitation

BackgroundThe prognostic significance of diastolic blood pressure (DBP) and resting heart rate (RHR) in patients with hemodynamically significant aortic regurgitation (AR) is unknown.ObjectivesThis study sought to investigate the association of DBP and RHR with all-cause mortality in patients with AR.MethodsConsecutive patients with ≥ moderate to severe AR were retrospectively identified from 2006 to 2017. The association between all-cause mortality and routinely measured DBP and RHR was examined.ResultsOf 820 patients (age 59 ± 17 years; 82% men) followed for 5.5 ± 3.5 years, 104 died under medical management, and 400 underwent aortic valve surgery (AVS). Age, symptoms, left ventricular ejection fraction (LVEF), LV end-systolic diameter-index (LVESDi), DBP, and RHR were univariable predictors of all-cause mortality (all p ≤ 0.002). When adjusted for demographics, comorbidities, and surgical triggers (symptoms, LVEF, and LVESDi), baseline DBP (adjusted-hazard ratio [HR]: 0.79 [95% confidence interval: 0.66 to 0.94] per 10 mm Hg increase, p = 0.009) and baseline RHR (adjusted HR: 1.23 [95% confidence interval: 1.03 to 1.45] per 10 beat per min [bpm] increase, p = 0.01) were independently associated with all-cause mortality. These associations persisted after adjustment for presence of hypertension, medications, time-dependent AVS, and using average DBP and RHR (all p ≤ 0.02). Compared with the general population, patients with AR exhibited excess mortality (relative risk of death >1), which rose steeply in inverse proportion (p nonlinearity = 0.002) to DBP starting at 70 mm Hg and peaking at 55 mm Hg and in direct proportion to RHR starting at 60 bpm.ConclusionsIn patients with chronic hemodynamically significant AR, routinely measured DBP and RHR demonstrate a robust association with all-cause death, independent of demographics, comorbidities, guideline-based surgical triggers, presence of hypertension, and use of medications. Therefore, DBP and RHR should be integrated into comprehensive clinical decision-making for these patients.     

Causal relationship between serum uric acid and abnormal blood pressure based on the panel model study: A 5-year cohort study

Background and aimsTo investigate the relationship between elevated serum uric acid (SUA) levels and blood pressure (BP).Methods and resultsBased on the Beijing Health Management Cohort, 5276 health examination people were enrolled. Cross-lagged model was used to explore the relationship between SUA levels and blood pressure. The results showed: (1) increased SUA and increased systolic blood pressure (SBP): ① The path coefficients from baseline SUA to follow-up SBP were statistically significant in both the general population (β = 0.034, P < 0.05) and men (β = 0.048, P < 0.05). The path coefficients from baseline SBP to follow-up SUA were not statistically significant in either the general population (β = 0.010, P > 0.05) or men (β = 0.011, P > 0.05). ② The path coefficients from baseline SUA to follow-up SBP and from baseline SBP to follow-up SUA were not statistically significant in women with BMI ≥ 25 kg/m² and BMI < 25 kg/m². (2) Increased SUA and diastolic blood pressure (DBP): ① There was no statistical significance between the path coefficients from baseline DBP to follow-up SUA and the path coefficients from baseline SUA to follow-up DBP. ② In men and women, BMI ≥ 25 kg/m² and BMI < 25 kg/m², the path coefficients from baseline DBP to follow-up SUA and from baseline SUA to follow-up DBP were not statistically significant.ConclusionsSUA can increase blood pressure in the general male population; no reverse time sequence relationship was found. The temporal relationships between SUA levels and SBP abnormalities were different in the sex and BMI subgroups. No bidirectional causal temporal relationship was found between SUA elevation and DBP abnormality.     

T1 Mapping and Extracellular Volume Fraction in Dilated Cardiomyopathy: A Prognosis Study

ObjectivesThe aim of this study is to examine the prognostic value of T1 mapping and the extracellular volume (ECV) fraction in patients with dilated cardiomyopathy (DCM).BackgroundPatients with DCM with functional left ventricular remodeling have poorer prognoses. Noninvasive assessment of myocardial fibrosis using T1 mapping and the ECV fraction may improve risk stratification of patients with DCM; however, this has not yet been systematically evaluated.MethodsA total of 659 consecutive patients with DCM (498 men; 45 ± 15 years) who underwent cardiac magnetic resonance with T1 mapping and late gadolinium enhancement (LGE) imaging with a 1.5-T magnetic resonance scanner were enrolled in this study. Primary endpoints were cardiac-related death and heart transplantation. Secondary endpoints were hospitalization for heart failure, ventricular arrhythmias, and implantable cardioverter-defibrillator or cardiac resynchronization therapy implantation. Survival estimates were calculated by Kaplan-Meier curves with the log-rank test.ResultsDuring a mean follow-up of 66.3 ± 20.9 months, 122 and 205 patients with DCM reached the primary and secondary endpoints, respectively. The presence of LGE had an association with both of the primary and secondary endpoints observed in the patients with DCM (both P < 0.001). The maximum native T1 (HR: 1.04; 95% CI: 1.02-1.09) and maximum ECV fraction (HR: 1.14; 95% CI: 1.08-1.21) had associations with the primary endpoints in the patients with positive LGE (both P < 0.001), whereas the mean native T1 (HR: 1.13; 95% CI: 1.10-1.36) and mean ECV fraction (HR: 1.32; 95% CI: 1.12-1.53) had the best associations in the patients with negative LGE (all P < 0.001).ConclusionsT1 mapping and the ECV fraction had prognostic value in patients with DCM and were particularly important in patients with DCM without LGE. Using a combination of T1 mapping, ECV fraction, and LGE provided optimal risk stratification for patients with DCM.     

Contribution of metabolic risk factors and lifestyle behaviors to cardiovascular disease: A mendelian randomization study

Background and aimsEtiologic associations between some modifiable factors (metabolic risk factors and lifestyle behaviors) and cardiovascular disease (CVD) remain unclear. To identify targets for CVD prevention, we evaluated the causal associations of these factors with coronary artery disease (CAD) and ischemic stroke using a two-sample Mendelian randomization (MR) method.Methods and resultsPreviously published genome-wide association studies (GWASs) for blood pressure (BP), glucose, lipids, overweight, smoking, alcohol intake, sedentariness, and education were used to identify instruments for 15 modifiable factors. We extracted effects of the genetic variants used as instruments for the exposures on coronary artery disease (CAD) and ischemic stroke from large GWASs (N = 60 801 cases/123 504 controls for CAD and N = 40 585 cases/406 111 controls for ischemic stroke). Genetically predicted hypertension (CAD: OR, 5.19 [95% CI, 4.21–6.41]; ischemic stroke: OR, 4.92 [4.12–5.86]), systolic BP (CAD: OR, 1.03 [1.03–1.04]; ischemic stroke: OR, 1.03 [1.03–1.03]), diastolic BP (CAD: OR, 1.05 [1.05–1.06]; ischemic stroke: OR, 1.05 [1.04–1.05]), type 2 diabetes (CAD: OR, 1.11 [1.08–1.15]; ischemic stroke: OR, 1.07 [1.04-1.10]), smoking initiation (CAD: OR, 1.26 [1.18–1.35]; ischemic stroke: OR, 1.24 [1.16–1.33]), educational attainment (CAD: OR, 0.62 [0.58–0.66]; ischemic stroke: OR, 0.68 [0.63–0.72]), low-density lipoprotein cholesterol (CAD: OR, 1.55 [1.41–1.71]), high-density lipoprotein cholesterol (CAD: OR, 0.82 [0.74–0.91]), triglycerides (CAD: OR, 1.29 [1.14–1.45]), body mass index (CAD: OR, 1.25 [1.19–1.32]), and alcohol dependence (OR, 1.04 [1.03–1.06]) were causally related to CVD.ConclusionThis systematic MR study identified 11 modifiable factors as causal risk factors for CVD, indicating that these factors are important targets for preventing CVD.     

Coronary Flow Assessment Using 3-Dimensional Ultrafast Ultrasound Localization Microscopy

BackgroundDirect assessment of the coronary microcirculation has long been hampered by the limited spatial and temporal resolutions of cardiac imaging modalities.ObjectivesThe purpose of this study was to demonstrate 3-dimensional (3D) coronary ultrasound localization microscopy (CorULM) of the whole heart beyond the acoustic diffraction limit (<20 μm resolution) at ultrafast frame rate (>1000 images/s).MethodsCorULM was performed in isolated beating rat hearts (N = 6) with ultrasound contrast agents (Sonovue, Bracco), using an ultrasonic matrix transducer connected to a high channel–count ultrafast electronics. We assessed the 3D coronary microvascular anatomy, flow velocity, and flow rate of beating hearts under normal conditions, during vasodilator adenosine infusion, and during coronary occlusion. The coronary vasculature was compared with micro-computed tomography performed on the fixed heart. In vivo transthoracic CorULM was eventually assessed on anaesthetized rats (N = 3).ResultsCorULM enables the 3D visualization of the coronary vasculature in beating hearts at a scale down to microvascular structures (<20 μm resolution). Absolute flow velocity estimates range from 10 mm/s in tiny arterioles up to more than 300 mm/s in large arteries. Fitting to a power law, the flow rate–radius relationship provides an exponent of 2.61 (r² = 0.96; P < 0.001), which is consistent with theoretical predictions and experimental validations of scaling laws in vascular trees. A 2-fold increase of the microvascular coronary flow rate is found in response to adenosine, which is in good agreement with the overall perfusion flow rate measured in the aorta (control measurement) that increased from 8.80 ± 1.03 mL/min to 16.54 ± 2.35 mL/min (P < 0.001). The feasibility of CorULM was demonstrated in vivo for N = 3 rats.ConclusionsCorULM provides unprecedented insights into the anatomy and function of coronary arteries at the microvasculature level in beating hearts. This new technology is highly translational and has the potential to become a major tool for the clinical investigation of the coronary microcirculation.     

No association between alcohol consumption and risk of atrial fibrillation: A two-sample Mendelian randomization study

Background and aimsAlthough many observational studies have suggested that alcohol intake was associated with incident atrial fibrillation (AF), controversy remains. This study aimed to examine the causal association of alcohol intake with the risk of AF.Methods and resultsTwo-sample Mendelian randomization (MR) analysis was performed to estimate the causal effects of alcohol consumption, alcohol dependence, or alcohol use disorder identification test (AUDIT) scores on AF. Summary data on single nucleotide polymorphisms (SNPs) associated with AF were obtained from a genome-wide association study (GWAS) with up to 1,030,836 participants. The fixed- and random-effect inverse-variance weighted (IVW) methods were used to calculate the overall causal effects. MR analysis revealed nonsignificant association of genetically predicted alcohol consumption with risk of AF using fixed- and random-effect IVW approaches (odds ratio (OR) [95% confidence interval (CI)] = 1.004 [0.796–1.266], P = 0.975; OR [95% CI] = 1.004 [0.766–1.315], P = 0.979). Genetically predicted alcohol dependence was also not causally associated with AF in the fixed- and random-effect IVW analyses (OR [95% CI] = 1.012 [0.978–1.048], P = 0.490; OR [95% CI] = 1.012 [0.991–1.034], P = 0.260). There was no significantly causal association between AUDIT and AF in the fixed- and random-effect IVW analyses (OR [95% CI] = 0.889 [0.433–1.822], P = 0.748; OR [95% CI] = 0.889 [0.309–2.555], P = 0.827). Sensitivity analyses indicated no evidence of pleiotropy and heterogeneity in statistical models.ConclusionsThis MR study did not find evidence of a causal association between alcohol intake and AF.     

Role of Exercise Treadmill Testing in the Assessment of Coronary Microvascular Disease

ObjectivesThe authors aimed to study the sensitivity and specificity of exercise treadmill testing (ETT) in the diagnosis of coronary microvascular disease (CMD), as well as the prognostic implications of ETT results in patients with CMD.BackgroundETT is validated to evaluate for flow-limiting coronary artery disease (CAD), however, little is known about its use for evaluating CMD.MethodsWe retrospectively studied 249 consecutive patients between 2006 and 2016 who underwent ETT and positron emission tomography within 12 months. Patients with obstructive CAD or left ventricular systolic dysfunction were excluded. CMD was defined as a coronary flow reserve <2. Patients were followed for the occurrence of a first major adverse event (composite of death or hospitalization for myocardial infarction or heart failure).ResultsThe sensitivity and specificity of a positive ETT to detect CMD were 34.7% (95% CI: 25.4%-45.0%) and 64.9% (95% CI: 56.7%-72.5%), respectively. The specificity of a positive ETT to detect CMD increased to 86.8% (95% CI: 80.3%-91.7%) when only classifying studies with ischemic electrocardiogram changes that lasted at least 1 minute into recovery as positive, although at a cost of lower sensitivity (15.3%; 95% CI: 8.8%-24.0%). Over a median follow-up of 6.9 years (IQR: 5.1-8.2 years), 30 (12.1%) patients met the composite endpoint, including 13 (13.3%) with CMD (n = 98). In patients with CMD, ETT result was not associated with the composite endpoint (P = 0.076).ConclusionsOur data suggest limited sensitivity of ETT to detect CMD. However, a positive ETT with ischemic changes that persist at least 1 minute into recovery in the absence of obstructive CAD should raise suspicion for the presence of CMD given a high specificity. Further study is needed with larger patient sample sizes to assess the association between ETT results and outcomes in patients with CMD.     

Association of adherence to the dietary approach to stop hypertension and Mediterranean diets with blood pressure in a non-hypertensive population: Results from Isfahan Salt Study (ISS)

Background and aimsHypertension is among the major risk factors for cardiovascular events in the Iranian population. This cross-sectional study was designed to examine the association of adherence to the dietary approaches to stop hypertension (DASH) and Mediterranean (MED) dietary patterns with the distribution of blood pressure and pre-hypertension prevalence.Methods and resultsThis cross-sectional study was carried out in 1363 non-hypertensive adults. Adherence to the DASH and MED diets was calculated using a semi-quantitative food frequency questionnaire (FFQ). Hypertension was measured by the standard method. Multiple logistic regression was applied to obtain the odds ratio of pre-hypertension in the tertiles of MED and DASH dietary patterns. Compared to the lowest, participants with the highest adherence to the DASH dietary pattern had significantly lower systolic blood pressure (SBP) (111.3 ± 11.8 vs. 112.8 ± 12.5; P = 0.010) and diastolic blood pressure (DBP) (70.7 ± 9.2 vs. 71.8 ± 9.8; 0.042). There was no significant difference in the mean SBP and DBP among the participants across tertiles of MED or diet adherence. Higher scores of the DASH and MED diets were inversely associated with lower SBP after adjustment for all potential confounders (OR = ?0.04, 95% CI = ?0.29, ?0.01, P = 0.039) and (OR = ?0.04, 95% CI = ?0.72, ?0.02, P = 0.044), respectively. Also, DASH and MED dietary patterns was associated with reduced OR of pre-hypertension occurrence by 13% (OR: 0.87; 95% CI: 0.70–0.98; P for trend = 0.042) and 16% ([OR: 0.84; 95% CI: 0.69–0.97; P trend = 0.035), respectively.ConclusionAdherence to the DASH and MED diets was inversely associated with the odds for pre-hypertension and SBP.     

Association between nut consumption and prostate cancer risk in adults: A systematic review and dose-response meta-analysis of observational studies

AimsData on the association between nut consumption and prostate cancer risk are conflicting. Therefore, this systematic review and dose-response meta-analysis aimed to summarize available findings from observational studies on the associations of nut intake with risk of total, advanced, non-advanced, and fatal prostate cancers.Data synthesisWe searched the online databases of PubMed, Scopus, and Web of Science as well as Google Scholar using appropriate keywords to identify eligible articles up to September 2022. In total, 11 articles with a total sample size of 287,786 participants and 32,213 cases of prostate cancer were included in the current systematic review and meta-analysis. By comparing the highest and lowest intake of total nuts, pooled relative risks (RRs) and 95% confidence intervals (95% CIs) for total, advanced, non-advanced, and fatal prostate cancers were 0.94 (95% CI: 0.85–1.04, P = 0.22), 1.10 (95% CI: 0.98–1.24, P = 0.12), 0.97 (95% CI: 0.85–1.11, P = 0.69), 0.97 (95% CI: 0.79–1.18, P = 0.73), respectively, which indicated non-significant inverse associations for total, non-advanced, and fatal prostate cancers and a non-significant positive association for advanced prostate cancer. In the dose-response analyses, we found no evidence of a linear or non-linear association between total nut intake and prostate cancer risk. Data on other types of nuts, including walnut, tree nuts, peanut, and peanut butter, were not sufficient for performing a meta-analysis.ConclusionWe found no significant association between nut intake and risk of total, advanced, non-advanced, and fatal prostate cancer. Further studies are required to confirm our findings.Prospero registration codeCRD42022347094.Ethical approvalNot required.     

Association of Sex,Reduced Myocardial Flow Reserve,and Long-Term Mortality Across Spectrum of Atherosclerotic Disease

BackgroundCoronary vasomotor dysfunction (defined by reduced myocardial blood flow reserve [MBFR]) is associated with high cardiac risk in both men and women in absence of significant coexisting epicardial disease. Whether there is a sex-specific difference in prognostic value of reduced MBFR in patients with a greater burden of coexisting epicardial atherosclerotic disease is not well understood.ObjectivesThe purpose of this study was to examine the association of sex, MBFR, and mortality in consecutive patients with suspected or known coronary artery disease undergoing positron emission tomography myocardial perfusion imaging.MethodsUnique consecutive patients undergoing rubidium (Rb)-82 rest/stress positron emission tomography myocardial perfusion imaging from 2010-2016 were followed for a median of 3.2 years. Multivariable Cox models were built to describe the interaction of sex and MBFR on all-cause and cardiac death for the overall population and stratified by extent of calcified atherosclerosis (none: coronary artery calcium score = 0, subclinical: coronary artery calcium >0, clinical: prior myocardial infarction/percutaneous coronary intervention) and abnormal perfusion (no significant obstructive disease: summed stress score = 0, 1%-9.9%, and ≥10%) at baseline.ResultsAmong 12,594 patients, 52.8% were women. Compared with men, women had a lower prevalence of known coronary artery disease (16.5% vs 29.5%; P < 0.001) and were less likely to undergo revascularization after myocardial perfusion imaging (4.9% vs 9.7%; P < 0.001), but were more likely to have a reduced MBFR of <2 (56.2% vs 50.6%; P < 0.001). There were 1,699 (13.5%) all-cause and 490 (3.9%) cardiac deaths. In fully adjusted Cox models, reduced MBFR was independently associated with higher risk of death (HR per 0.1-U decrease: 1.09 [95% CI: 1.08-1.10]; P < 0.001), but female sex was not (HR: 0.95 [95% CI: 0.85-1.05]; P = 0.27). There was no significant interaction between sex and MBFR on death (P = 0.22) and cardiac death (P = 0.35) overall or in subgroups of patients with clinical, subclinical, and no atherosclerosis or across categories of perfusion abnormality at baseline.ConclusionsThe association between reduced MBFR and higher risk of all-cause and cardiac death did not differ by sex, regardless of extent of coexisting atherosclerosis or perfusion abnormality.     

Comparison of the associations between appendicular lean mass adjustment methods and cardiometabolic factors

Background and aimsTo compare the cross-sectional and longitudinal associations between appendicular lean mass (ALM) and cardiometabolic risk factors according to body-size adjustment methods and the contributions of genetic and/or environmental factors to the correlations between those traits.Methods and resultsRegression coefficients per sex-specific 1 standard deviation in bodyweight (wt), body mass index (BMI), or height-squared (ht²) adjusted ALM (assessed using a dual-energy X-ray absorptiometer (DXA) and a bioelectrical impedance analyzer (BIA) at baseline)/changes in these indices (assessed using BIA) were compared in terms of their associations with blood pressure (BP), lipid profiles, and insulin resistance profiles in 2655 participants for cross-sectional analysis and 332 participants for longitudinal analysis (follow-up time, 32.2 ± 7.9 months). A bivariate genetic analysis of the genetic/environmental cross-trait correlations was conducted to determine their cross-sectional relationships. After adjusting for sociodemographic factors, health behaviors, and BMI in the analysis for ALM/ht², ALM/wt and ALM/BMI had favorable associations with all cardiometabolic risk factors, while ALM/ht² had favorable associations with some risk factors. In longitudinal associations, changes in ALM/wt and ALM/BMI had inverse associations with increments of lipid profiles, insulin, and homeostasis model assessment of insulin resistance (HOMA), while change in ALM/ht² did not have associations with increments of cardiometabolic risk factors. ALM/ht² had genetic correlations with seven of nine risk factors; ALM/wt and ALM/BMI had correlations with three and one risk factors, respectively.ConclusionALM/wt and ALM/BMI are better indicators for cardiometabolic risk factors; genetic factors may contribute more to the correlations between ALM/ht² and those traits.     

Statins and risk of venous thromboembolic diseases: A two-sample mendelian randomization study

Background and aimsIn observational studies, statins have been suggested to have protective effects on venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE). To this aim, we performed a two-sample mendelian randomization (MR) analysis to determine whether these associations were causal.Methods and resultsData on the single nucleotide polymorphisms (SNPs) related to statin medication were obtained from the FinnGen study, and data for VTE, PE and DVT of lower extremities (LEDVT) were from the UK Biobank study, respectively. Inverse variance weighted (IVW) method was used as the principal analysis of MR, and sensitivity analysis was performed to detect horizontal pleiotropy and heterogeneity. MR estimates showed an inverse causal association between statin medication and the risk of VTE (odds ratio [OR]: 0.999, 95% CI: 0.998–1.000, P = 0.004), PE (OR: 0.999, 95% CI: 0.999–1.000, P = 0.011) and LEDVT (OR: 0.999, 95% CI: 0.999–1.000, P = 0.008).ConclusionOur findings provide direct evidence that statins might decrease the risk of VTE, PE and LEDVT in agreement with observational studies. The specific mechanism of statin therapy for venous thromboembolism needs to be further studied.     

Coronary Microvascular Dysfunction Assessed by Pressure Wire and CMR After STEMI Predicts Long-Term Outcomes

ObjectivesThis study sought to evaluate the long-term prognostic implications of coronary microvascular dysfunction (CMD) when assessed with both cardiovascular magnetic resonance (CMR) and index of microcirculatory resistance (IMR) in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI).BackgroundPost-ischemic CMD can be assessed using the pressure-wire based IMR and/or by the presence of microvascular obstruction (MVO) on CMR.MethodsA total of 198 patients with STEMI underwent IMR and MVO assessment. Patients were classified as follows: Group 1, no significant CMD (low IMR [≤40 U] and no MVO); Group 2, CMD with either high IMR (>40 U) or MVO; Group 3, CMD with both IMR >40 U and MVO. The primary endpoint was the composite of all-cause mortality, diagnosis of new heart failure, cardiac arrest, sustained ventricular tachycardia/fibrillation, and cardioverter defibrillator implantation.ResultsCMD with both high IMR and MVO was present in 23.7% of the cases (Group 3) and CMD with either high IMR or MVO was observed in 40.9% of cases (Group 2). At a median follow-up of 40.1 months, the primary endpoint occurred in 34 (17%) cases. At 1 year of follow-up, Group 3 (hazard ratio [HR]: 12.6; 95% confidence interval [CI]: 1.6 to 100.6; p = 0.017) but not Group 2 (HR: 7.2; 95% CI: 0.9 to 57.9; p = 0.062) had worse clinical outcomes compared with those with no significant CMD in Group 1. However, in the long-term, patients in Group 2 (HR: 4.2; 95% CI: 1.4 to 12.5; p = 0.009) and those in Group 3 (HR: 5.2; 95% CI: 1.7 to 16.2; p = 0.004) showed similar adverse outcomes, mainly driven by the occurrence of heart failure.ConclusionsPost-ischemic CMD predicts a more than 4-fold increase in long-term risk of adverse outcomes, mainly driven by the occurrence of heart failure. Defining CMD by either invasive IMR >40 U or by CMR-assessed MVO showed similar risk of adverse outcomes.     

Prognostic Implications of Left Atrial Stiffness Index in Heart Failure Patients With Preserved Ejection Fraction

BackgroundThe left atrium (LA) plays an important role in the pathophysiology and disease progression of heart failure with preserved ejection fraction (HFpEF).ObjectivesThis study sought to assess the prognostic potential of LA stiffness index in patients who have HFpEF.MethodsThis study retrospectively screened patients with elevated left ventricular end-diastolic pressure (≥16 mm Hg) and preserved ejection fraction (≥50%) between January 1, 2004, and December 31, 2019. All patients underwent left heart catheterization to measure left ventricular end-diastolic pressure. Among these, 307 patients who had suitable image quality for left peak atrial longitudinal strain (PALS) measurement were analyzed. The study population was classified into low LA stiffness (n = 178, early diastolic transmitral inflow velocity/mitral annulus early diastolic velocity [E/e′]/PALS ≤0.26) and high LA stiffness (n = 129, E/e′/PALS >0.26) according to the best LA stiffness index (E/e′/PALS) cutoff value. The primary outcome was a composite of mortality or hospitalization caused by heart failure during follow-up.ResultsLA stiffness index showed good correlations with E/e′ (r = 0.737; P < 0.001), LA volume index (r = 0.529; P < 0.001), right ventricular systolic pressure (r = 0.404; P < 0.001), and log N-terminal pro–B-type natriuretic peptide (r = 0.540; P < 0.001). LA stiffness index demonstrated better predictive performance than echocardiographic diastolic parameters did (P < 0.001). Patients with low LA stiffness had better clinical outcomes than those with high LA stiffness during a median follow-up of 6 years did (P < 0.001). In multivariable analysis, LA stiffness index was independently associated with increased risk of the composite endpoint of death or heart failure hospitalization (HR: 1.59 [95% CI: 1.01-2.51]; P = 0.044).ConclusionsIncreased LA stiffness was associated with increased risk for all-cause mortality and hospitalization caused by heart failure in patients who have HFpEF, and its prognostic role was more pronounced than that of indexes of left ventricular filling pressure.