Citations

While elevated blood cholesterol has been associated with an increased risk of colorectal cancer (CRC) in observational studies, causality is uncertain. Here we apply a Mendelian randomisation (MR) analysis to examine the potential causal relationship between lipid traits and CRC risk. We used single nucleotide polymorphisms (SNPs) associated with blood levels of total cholesterol (TC), triglyceride (TG), low‐density lipoprotein (LDL), and high‐density lipoprotein (HDL) as instrumental variables (IV). We calculated MR estimates for each risk factor with CRC using SNP‐CRC associations from 9,254 cases and 18,386 controls. Genetically predicted higher TC was associated with an elevated risk of CRC (odds ratios (OR) per unit SD increase = 1.46, 95% confidence interval [CI]: 1.20–1.79, p = 1.68 × 10−4). The pooled ORs for LDL, HDL, and TG were 1.05 (95% CI: 0.92–1.18, p = 0.49), 0.94 (95% CI: 0.84–1.05, p = 0.27), and 0.98 (95% CI: 0.85–1.12, p = 0.75) respectively. A genetic risk score for 3‐hydoxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR) to mimic the effects of statin therapy was associated with a reduced CRC risk (OR = 0.69, 95% CI: 0.49–0.99, p = 0.046). This study supports a causal relationship between higher levels of TC with CRC risk, and a further rationale for implementing public health strategies to reduce the prevalence of hyperlipidaemia.

Background— Ventricular tachycardia and premature ventricular complexes (PVCs) most frequently occur in the context of structural heart disease. However, the burden of idiopathic ventricular arrhythmias (IVA) in the general population is unknown. Methods and Results— We identified incident cases of IVA between 2005 and 2013 from Olmsted County, Minnesota, using the Rochester Epidemiology Project database. For PVC cohorts, we included those with frequent (defined as ≥100 PVC/24 hours) symptomatic PVCs. We defined IVA-associated cardiomyopathy as a drop in ejection fraction of ≥10% from baseline. Between 2005 and 2013, we identified 614 individuals with incident IVA (229 [37.3%] were male; average age was 52.1±17.2 years). Of these, 177 (28.8%) had idiopathic ventricular tachycardia, 408 (66.5%) had symptomatic PVCs, and 29 (4.7%) had IVA-associated cardiomyopathy. The age- and sex-adjusted incidence rates in 2005 to 2007, 2008 to 2010, and 2011 to 2013 were 44.9 per 100 000 (95% confidence interval [CI], 38.0–51.8), 47.6 per 100 000 (95% CI, 40.8–54.5), and 62.0 per 100 000 (95% CI, 54.4–69.6), respectively. In idiopathic ventricular tachycardia, there was an increase in incidence rate with ages ( P <0.001) but not between sexes ( P =0.12). The age-adjusted incidence of symptomatic PVC was higher in females than in males (46.2 per 100 000 [95% CI, 40.9–51.6] versus 20.5 per 100 000 [95% CI, 16.8–24.3]; P <0.001). The small number of individuals with IVA-associated cardiomyopathy precluded any formal testing. Conclusions— The incidence of IVA is increasing. Furthermore, overall incidence increases with age. Although the rate of idiopathic ventricular tachycardia is similar across sexes, women have a higher incidence of symptomatic PVC.

Background: In patients with heart failure and preserved ejection fraction, little is known about the characteristics of, and outcomes in, those with and without diabetes mellitus. Methods: We examined clinical and echocardiographic characteristics and outcomes in the I-Preserve trial (Irbesartan in Heart Failure With Preserved Ejection Fraction) according to history of diabetes mellitus. Cox regression models were used to estimate hazard ratios for cardiovascular outcomes adjusted for known predictors, including age, sex, natriuretic peptides, and comorbidity. Echocardiographic data were available in 745 patients and were additionally adjusted for in supplementary analyses. Results: Overall, 1134 of 4128 patients (27%) had diabetes mellitus. Compared with those without diabetes mellitus, they were more likely to have a history of myocardial infarction (28% versus 22%), higher body mass index (31 versus 29 kg/m 2 ), worse Minnesota Living With Heart Failure score (48 versus 40), higher median N-terminal pro-B-type natriuretic peptide concentration (403 versus 320 pg/mL; all P <0.01), more signs of congestion, but no significant difference in left ventricular ejection fraction. Patients with diabetes mellitus had a greater left ventricular mass and left atrial area than patients without diabetes mellitus. Doppler E-wave velocity (86 versus 76 cm/s; P <0.0001) and the E/e’ ratio (11.7 versus 10.4; P =0.010) were higher in patients with diabetes mellitus. Over a median follow-up of 4.1 years, cardiovascular death or heart failure hospitalization occurred in 34% of patients with diabetes mellitus versus 22% of those without diabetes mellitus (adjusted hazard ratio, 1.75; 95% confidence interval, 1.49–2.05), and 28% versus 19% of patients with and without diabetes mellitus died (adjusted hazard ratio, 1.59; confidence interval, 1.33–1.91). Conclusions: In heart failure with preserved ejection fraction, patients with diabetes mellitus have more signs of congestion, worse quality of life, higher N-terminal pro-B-type natriuretic peptide levels, and a poorer prognosis. They also display greater structural and functional echocardiographic abnormalities. Further investigation is needed to determine the mediators of the adverse impact of diabetes mellitus on outcomes in heart failure with preserved ejection fraction and whether they are modifiable. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00095238.

BACKGROUNDAlthough previous studies have noted an increased risk of colorectal cancer (CRC) among moderate to heavy alcohol consumers in comparison with nondrinkers, the relation between alcohol consumption and CRC survival remains unclear.METHODSCases of incident invasive CRC diagnosed between 1997 and 2007 were identified via population‐based cancer registries at 4 study sites in the Colon Cancer Family Registry. Study participants completed a risk‐factor questionnaire on prediagnostic behaviors, including wine, beer, and liquor consumption, at the baseline. Prospective follow‐up for survival was conducted for 4966 CRC cases. Cox regression was used to compare nondrinkers with individuals who consumed, on average, 1 or more servings of alcohol per day in the years preceding their CRC diagnosis with respect to overall and disease‐specific survival. Separate analyses by beverage type, stratified by patient and tumor attributes, were also performed. All models were adjusted for the age at diagnosis, sex, study site, year of diagnosis, smoking history, body mass index, and education.RESULTSPrediagnostic beer and liquor consumption was not associated with CRC survival; however, higher levels of wine consumption were modestly associated with a better prognosis overall (CRC‐specific hazard ratio [HR], 0.70, 95% confidence interval [CI], 0.48‐1.03; overall HR, 0.70; 95% CI, 0.53‐0.94). Similar patterns were noted in stratified analyses.CONCLUSIONSThese findings suggest that prediagnostic wine consumption is modestly associated with more favorable survival after CRC. Cancer 2017;123:1035–43. © 2016 American Cancer Society.

Abstract Background: People with germline mutation in one of the DNA mismatch repair (MMR) genes have increased colorectal cancer risk. For these high-risk people, study findings of the relationship between alcohol consumption and colorectal cancer risk have been inconclusive. Methods: 1,925 MMR gene mutations carriers recruited into the Colon Cancer Family Registry who had completed a questionnaire on lifestyle factors were included. Weighted Cox proportional hazard regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between alcohol consumption and colorectal cancer. Results: Colorectal cancer was diagnosed in 769 carriers (40%) at a mean (SD) age of 42.6 (10.3) years. Compared with abstention, ethanol consumption from any alcoholic beverage up to 14 g/day and &gt;28 g/day was associated with increased colorectal cancer risk (HR, 1.50; 95% CI, 1.09–2.07 and 1.69; 95% CI, 1.07–2.65, respectively; Ptrend = 0.05), and colon cancer risk (HR, 1.78; 95% CI, 1.27–2.49 and 1.94; 95% CI, 1.19–3.18, respectively; Ptrend = 0.02). However, there was no clear evidence for an association with rectal cancer risk. Also, there was no evidence for associations between consumption of individual alcoholic beverage types (beer, wine, spirits) and colorectal, colon, or rectal cancer risk. Conclusions: Our data suggest that alcohol consumption, particularly more than 28 g/day of ethanol (∼2 standard drinks of alcohol in the United States), is associated with increased colorectal cancer risk for MMR gene mutation carriers. Impact: Although these data suggested that alcohol consumption in MMR carriers was associated with increased colorectal cancer risk, there was no evidence of a dose-response, and not all types of alcohol consumption were associated with increased risk. Cancer Epidemiol Biomarkers Prev; 26(3); 366–75. ©2016 AACR.

Abstract Background: Although high-risk mutations in identified major susceptibility genes (DNA mismatch repair genes and MUTYH) account for some familial aggregation of colorectal cancer, their population prevalence and the causes of the remaining familial aggregation are not known. Methods: We studied the families of 5,744 colorectal cancer cases (probands) recruited from population cancer registries in the United States, Canada, and Australia and screened probands for mutations in mismatch repair genes and MUTYH. We conducted modified segregation analyses using the cancer history of first-degree relatives, conditional on the proband's age at diagnosis. We estimated the prevalence of mutations in the identified genes, the prevalence of HR for unidentified major gene mutations, and the variance of the residual polygenic component. Results: We estimated that 1 in 279 of the population carry mutations in mismatch repair genes (MLH1 = 1 in 1,946, MSH2 = 1 in 2,841, MSH6 = 1 in 758, PMS2 = 1 in 714), 1 in 45 carry mutations in MUTYH, and 1 in 504 carry mutations associated with an average 31-fold increased risk of colorectal cancer in unidentified major genes. The estimated polygenic variance was reduced by 30% to 50% after allowing for unidentified major genes and decreased from 3.3 for age &lt;40 years to 0.5 for age ≥70 years (equivalent to sibling relative risks of 5.1 to 1.3, respectively). Conclusions: Unidentified major genes might explain one third to one half of the missing heritability of colorectal cancer. Impact: Our findings could aid gene discovery and development of better colorectal cancer risk prediction models. Cancer Epidemiol Biomarkers Prev; 26(3); 404–12. ©2016 AACR.

BackgroundAlthough sudden death (SD) is a rare complication after atrioventricular junction (AVJ) ablation and permanent pacemaker implantation, the risk factors leading to this SD remain unknown. The purpose of this study was to investigate SD and its risk factors after ablate‐and‐pace strategy for rate control in atrial fibrillation (AF) patients during long‐term follow‐up.HypothesisMethodsFrom January 2005 to December 2009, we enrolled into this study 517 AF patients with AVJ ablation and right ventricular pacemaker implantation. Patients were divided into 2 groups, SD and non‐SD. Cox proportional hazards models were used to assess potential risk factors for overall mortality and SD.ResultsDuring a mean follow‐up of 25.8 ± 18.6 months (range, 3 days to 63.8 months), 53 patients died (15 with SD). Cox proportional hazards models showed that the presence of congestive heart failure, New York Heart Association functional class, chronic renal failure, and nonsustained ventricular tachycardia were risk factors that predicted overall mortality. For SD, the presence of dilated cardiomyopathy and mitral stenosis were associated risk factors. SD was exclusively seen in patients who had narrow QRS complex or right bundle branch block prior to AVJ ablation and pacemaker implantation; SD was not seen in any patient with preexisting complete left bundle branch block.ConclusionsDilated cardiomyopathy, mitral stenosis, and baseline QRS morphology should be examined as potential risk factors for SD after AVJ ablation and pacemaker implantation.

The incidence and prevalence of most cardiovascular disorders increase with age, and cardiovascular disease ( CVD ) is the leading cause of death and major disability in adults aged 75 and older. Despite the effect of CVD on quality of life, morbidity, and mortality in older adults, individuals aged 75 and older have been markedly underrepresented in most major cardiovascular trials, and virtually all trials have excluded older adults with complex comorbidities, significant physical or cognitive disabilities, frailty, or residence in nursing homes and assisted living facilities. As a result, current guidelines are unable to provide evidence‐based recommendations for diagnosis and treatment of older adults typical of those encountered in routine clinical practice. The objectives of this scientific statement are to summarize current guideline recommendations as they apply to older adults, identify critical gaps in knowledge that preclude informed evidence‐based decision‐making, and recommend future research to close existing knowledge gaps. To achieve these objectives, a detailed review was conducted of current American College of Cardiology/American Heart Association ( ACC / AHA ) and American Stroke Association ( ASA ) guidelines to identify content and recommendations that explicitly targeted older adults. A pervasive lack of evidence to guide clinical decision‐making in older adults with CVD was found, as well as a paucity of data on the effect of diagnostic and therapeutic interventions on outcomes that are particularly important to older adults, such as quality of life, physical function, and maintenance of independence. Accordingly, there is a critical need for a multitude of large population‐based studies and clinical trials that include a broad spectrum of older adults representative of those seen in clinical practice and that incorporate relevant outcomes important to older adults in the study design. The results of these studies will provide the foundation for future evidence‐based guidelines applicable to older adults and enhance person‐centered care of older individuals with CVD in the United States and around the world.

MicroRNAs (miRNAs) regulate up to one‐third of all protein‐coding genes including genes relevant to cancer. Variants within miRNAs have been reported to be associated with prognosis, survival, response to chemotherapy across cancer types, in vitro parameters of cell growth, and altered risks for development of cancer. Five miRNA variants have been reported to be associated with risk for development of colorectal cancer (CRC). In this study, we evaluated germline genetic variation in 1,123 miRNAs in 899 individuals with CRCs categorized by clinical subtypes and in 204 controls. The role of common miRNA variation in CRC was investigated using single variant and miRNA‐level association tests. Twenty‐nine miRNAs and 30 variants exhibited some marginal association with CRC in at least one subtype of CRC. Previously reported associations were not confirmed (n = 4) or could not be evaluated (n = 1). The variants noted for the CRCs with deficient mismatch repair showed little overlap with the variants noted for CRCs with proficient mismatch repair, consistent with our evolving understanding of the distinct biology underlying these two groups. © 2016 The Authors Genes, Chromosomes & Cancer Published by Wiley Periodicals, Inc.