Co-occurrence of infantile hypertrophic pyloric stenosis and congenital heart defects: a nationwide cohort study.

BACKGROUND: Recent studies suggest that infantile hypertrophic pyloric stenosis (IHPS) and congenital heart defects (CHDs) may share some genetic risk factors, but little is known about the co-occurrence of the two conditions in patients. METHODS: Our study cohort included 2,212,756 persons born in Denmark 1977-2013. We identified patients with IHPS and CHD in the National Patient Register. Using log-linear Poisson regression, we estimated the (incidence) rate ratios (RRs) comparing the rate of IHPS among children with a CHD diagnosis (exposed) and the rate among those without such a diagnosis. RESULTS: Twenty-seven thousand three hundred and fifty-seven children in the cohort were diagnosed with CHD out of whom 85 developed IHPS (RR = 2.62, 95% confidence interval (CI) 2.09-3.22]). The results were similar for those with and without other congenital malformations, for preterm and term deliveries, and for both sexes. There was, however, a significant effect of calendar period (P = .003). In the period 1977-1996, the RR of IHPS given a CHD diagnosis was 1.96 (95% CI 1.41-2.64); in the period 1997-2014, the RR was 3.75 (95% CI 2.74-4.99). CONCLUSION: CHD was associated with an increased risk of IHPS. Further research is needed to delineate molecular-level mechanisms that may affect both conditions.

IDegLira improves patient-reported outcomes while using a simple regimen with fewer injections and dose adjustments compared with basal-bolus therapy.

AIMS: Basal-bolus therapy is associated with greater treatment burden and lower adherence compared with more simplified regimens. This post hoc analysis studied the difference between insulin degludec/liraglutide (IDegLira) and basal-bolus therapy on number of injections, dose adjustments and patient outcomes in the DUAL VII trial. MATERIALS AND METHODS: DUAL VII was a 26-week, open-label trial in which patients with uncontrolled type 2 diabetes who were using metformin and insulin glargine 100 units/mL (20-50 U) were randomized 1:1 to IDegLira (N = 252) or basal-bolus (insulin glargine U100 + insulin aspart ≤4 times/day) (N = 254). This post hoc analysis reports the observed mean number of injections and cumulative dose adjustments during 26 weeks of treatment. Patient-reported outcomes (Treatment-Related Impact Measure - Diabetes [TRIM-D] and Short Form-36 Health Survey version 2 [SF-36v2]) were collected at scheduled visits and change from baseline scores calculated. RESULTS: The clinical benefits (non-inferior HbA1c reductions, weight benefit, less hypoglycaemia) of IDegLira vs basal-bolus therapy were achieved with fewer cumulative dose adjustments (16.6 vs 217.2, respectively) and fewer injections (1 vs ≥3 per day, respectively). Patients treated with IDegLira experienced significant improvements across all TRIM-D domains compared with those undergoing basal-bolus therapy. The SF-36v2 showed improvements in both treatment arms with no significant difference between arms in the physical component summary, but there was a significant improvement in patients treated with IDegLira in the mental component summary (P = .0228). CONCLUSIONS: These findings, combined with the DUAL VII results, suggest that IDegLira, through a more simplified regimen versus basal-bolus therapy, may help improve patient adherence and improve patient outcomes related to diabetes management, treatment burden and mental health, which in turn may assist in the timely achievement of glycaemic control in clinical practice.

Lower rates of cardiovascular events and mortality associated with liraglutide use in patients treated with basal insulin: A DEVOTE subanalysis (DEVOTE 10).

AIM: To compare the associations between concomitant liraglutide use versus no liraglutide use and the risk of major adverse cardiovascular events (MACE) and all-cause mortality among patients receiving basal insulin (either insulin degludec [degludec] or insulin glargine 100 units/mL [glargine U100]) in the Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE). MATERIALS AND METHODS: Patients with type 2 diabetes and high cardiovascular risk were randomized 1:1 to degludec or glargine U100. Hazard ratios for MACE/mortality were calculated using a Cox regression model adjusted for treatment and time-varying liraglutide use at any time during the trial, without interaction. Sensitivity analyses were adjusted for baseline covariates including, but not limited to, age, sex, smoking and prior cardiovascular disease. RESULTS: At baseline, 436/7637 (5.7%) patients were treated with liraglutide; after baseline, 187/7637 (2.4%) started and 210/7637 (2.7%) stopped liraglutide. Mean liraglutide exposure from randomization was 530.2 days. Liraglutide use versus no liraglutide use was associated with significantly lower hazard rates for MACE [0.62 (0.41; 0.92)95%CI ] and all-cause mortality [0.50 (0.29; 0.88)95%CI ]. There was no significant difference in the rate of severe hypoglycaemia with versus without liraglutide use. Multiple sensitivity analyses yielded similar results. CONCLUSIONS: Use of liraglutide was associated with significantly lower risk of MACE and death in patients with type 2 diabetes and high cardiovascular risk using basal insulin.

Insulin degludec/liraglutide (IDegLira) was effective across a range of dysglycaemia and body mass index categories in the DUAL V randomized trial.

This study assessed the efficacy of insulin degludec/liraglutide (IDegLira) vs insulin glargine U100 (IGlar) across categories of baseline glycated haemoglobin (HbA1c; ≤7.5%, >7.5% to ≤8.5% and >8.5%), body mass index (BMI; <30, ≥30 to <35 and ≥35 kg/m2 ) and fasting plasma glucose (FPG; <7.2 and ≥7.2 mmol/L) in patients with type 2 diabetes (T2D) uncontrolled on basal insulin, using post hoc analyses of the DUAL V 26-week trial. With IDegLira, mean HbA1c was reduced across all baseline HbA1c (1.0%-2.5%), FPG (1.5%-1.9%) and BMI categories (1.8%-1.9%), with significantly greater reductions compared with IGlar U100. For all HbA1c, FPG and BMI categories, IDegLira resulted in weight loss and IGlar U100 in weight gain; hypoglycaemia rates were lower for IDegLira vs IGlar U100. More patients achieved HbA1c <7% with IDegLira than IGlar U100 across all HbA1c (59%-87% vs 31%-66%), FPG (71%-74% vs 40%-51%) and BMI categories (71%-73% vs 40%-54%). IDegLira improved glycaemic control and induced weight loss in patients with T2D previously uncontrolled on basal insulin, across the categories of baseline HbA1c, FPG or BMI that were tested.

Risk of Cardiomyopathy in Younger Persons With a Family History of Death from Cardiomyopathy: A Nationwide Family Study in a Cohort of 3.9 Million Persons.

BACKGROUND: Recommendations for presymptomatic screening of relatives of cardiomyopathy patients are based on findings from tertiary centers. Cardiomyopathy inheritance patterns are fairly well understood, but how cardiomyopathy in younger persons (<50 years) aggregates in families at the population level is unclear. In a nationwide cohort, we examined the risk of cardiomyopathy by family history of premature death (<60 years) from cardiomyopathy. METHODS AND RESULTS: By linking Danish national register data, we constructed a cohort of 3.9 million persons born from 1950 to 2008. We ascertained family history of premature (<60 years) death from cardiomyopathy or other conditions, and cohort members were followed from 1977 to 2008 for cardiomyopathy diagnosed at <50 years. We identified 3890 cardiomyopathies in 89 million person-years of follow-up. Using Poisson regression, we estimated incidence rate ratios for cardiomyopathy by family history of premature death. Premature cardiomyopathy deaths in first- and second-degree relatives were associated with 29- and 6-fold increases in the rate of cardiomyopathy, respectively. If the first-degree relative died aged <35 years, the rate of cardiomyopathy increased 100-fold; given ≥2 premature deaths in first-degree relatives, the rate increased more than 400-fold. In contrast, a family history of premature death from other cardiac or noncardiac conditions increased the rate of cardiomyopathy 3-fold at most. CONCLUSIONS: A family history of premature cardiomyopathy death was associated with an increase in risk of cardiomyopathy ranging from 6- to 400-fold, depending on age, kinship, gender and number of affected family members. Our general population-based results support recommendations for presymptomatic screening of relatives of cardiomyopathy patients.

Hypertensive disorders of pregnancy and peripartum cardiomyopathy: A nationwide cohort study.

BACKGROUND: Peripartum cardiomyopathy (PPCM) is a serious cardiac disorder occurring late in pregnancy or early in the postpartum period. We examined associations between hypertensive disorders of pregnancy (HDP: preeclampsia and gestational hypertension) and PPCM, accounting for other pregnancy-related risk factors for PPCM. METHODS: Using nationwide Danish register data, we constructed a cohort of all women with ≥1 live birth or stillbirth in Denmark between 1978 and 2012. Using log-linear binomial regression and generalized estimating equations, we estimated risk ratios (RRs) for PPCM associated with HDP of varying severity. RESULTS: In a cohort of 1,088,063 women with 2,078,822 eligible pregnancies, 126 women developed PPCM (39 in connection with an HDP-complicated pregnancy). The risks of PPCM were significantly higher in women with HDP-complicated pregnancies than in women with normotensive pregnancies (severe preeclampsia, RR 21.2, 95% confidence interval [CI] 12.0-37.4; moderate preeclampsia, RR 10.2, 95% CI 6.18-16.9; gestational hypertension, RR 5.16, 95% CI 2.11-12.6). The RRs for moderate preeclampsia and gestational hypertension were not significantly different from one another (p = 0.18); the RR for severe preeclampsia was significantly different from the RR for moderate preeclampsia and gestational hypertension combined (p = 0.02). CONCLUSIONS: Although 70% of PPCM occurred in women with normotensive pregnancies, HDPs were associated with substantial increases in PPCM risk that depended on HDP severity. The heart's capacity to adapt to a normal pregnancy may be exceeded in some women already susceptible to cardiac insult, contributing to PPCM. HDPs, severe preeclampsia in particular, probably represent an additional cardiac stressor during pregnancy.

Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation.

A family history of atrial fibrillation constitutes a substantial risk of developing the disease, however, the pathogenesis of this complex disease is poorly understood. We perform whole-exome sequencing on 24 families with at least three family members diagnosed with atrial fibrillation (AF) and find that titin-truncating variants (TTNtv) are significantly enriched in these patients (P = 1.76 × 10-6). This finding is replicated in an independent cohort of early-onset lone AF patients (n = 399; odds ratio = 36.8; P = 4.13 × 10-6). A CRISPR/Cas9 modified zebrafish carrying a truncating variant of titin is used to investigate TTNtv effect in atrial development. We observe compromised assembly of the sarcomere in both atria and ventricle, longer PR interval, and heterozygous adult zebrafish have a higher degree of fibrosis in the atria, indicating that TTNtv are important risk factors for AF. This aligns with the early onset of the disease and adds an important dimension to the understanding of the molecular predisposition for AF.

Atypical antipsychotics olanzapine, quetiapine, and risperidone and risk of acute major cardiovascular events in young and middle-aged adults: a nationwide register-based cohort study in Denmark.

BACKGROUND: A number of serious cardiovascular safety concerns related to the use of atypical antipsychotics, compared with no use, have emerged, but nearly all reports are from studies of older patients. We aimed to compare the risk of cardiovascular events between the three most commonly used atypical antipsychotics in young and middle-aged adults. METHODS: We conducted a nationwide register-based cohort study in Denmark, 1997-2011, including adults aged 18-64 years, who started treatment with oral or intramuscular olanzapine (n = 15,774), oral quetiapine (n = 18,717), and oral or intramuscular risperidone (n = 14,134). The primary outcome was any major cardiovascular event (composite of cardiovascular mortality, acute coronary syndrome, or ischemic stroke) within 1 year following treatment initiation. Cox regression was used to estimate hazard ratios (HRs) while on current antipsychotic monotherapy in the outpatient setting, adjusting for an outcome-specific disease risk score. RESULTS: The crude rate of any major cardiovascular event was 5.3 per 1,000 person-years among olanzapine users, 3.4 in quetiapine users, and 5.2 in risperidone users. Compared with risperidone, the risk of any major cardiovascular event was not significantly different in olanzapine users (HR 0.90, 95 % confidence interval [CI] 0.53-1.52) and quetiapine users (HR 0.79, 95 % CI 0.45-1.39). The absolute risk difference per 1,000 person-years on treatment was -0.5 (95 % CI -2.4 to 2.7) events for olanzapine and -1.1 (95 % CI -2.9 to 2.0) events for quetiapine. CONCLUSIONS: Among young and middle-aged outpatients, the risk of acute major cardiovascular events was similar with use of olanzapine, quetiapine, and risperidone. Although moderate relative differences cannot be ruled out, any differences are small in absolute terms.

Familial aggregation of lone atrial fibrillation in young persons.

OBJECTIVES: This study investigated whether an individual's risk of developing lone atrial fibrillation (AF) before age 60 years is associated with lone AF in relatives. BACKGROUND: Genetic factors may play a role in the development of lone AF. METHODS: Using Danish national registers, a cohort was established of ~4 million persons born between 1950 and 2008, and those with a family history of lone AF (AF without preceding cardiovascular/endocrine diagnoses) were identified. Individuals were followed up until the first diagnosis of lone AF. Poisson regression was used to estimate incidence rate ratios (IRRs). RESULTS: In ~92 million person-years of follow-up, 9,507 persons were identified as having lone AF. The IRRs for lone AF given an affected first- or second-degree relative were 3.48 (95% confidence interval [CI]: 3.08 to 3.93) and 1.64 (95% CI: 1.04 to 2.59), respectively. IRRs were higher for men than for women but were not associated with the affected relative's sex. IRR for lone AF was 6.24 (95% CI: 2.59 to 15.0), given at least 2 first-degree relatives affected with lone AF. The IRR for lone AF in persons aged <40 years given a first-degree relative affected at age <40 years was 5.42 (95% CI: 3.80 to 7.72), and 8.53 (95% CI: 3.82 to 19.0) in persons age <30 years given a first-degree relative affected at age <30 years. CONCLUSIONS: A family history of lone AF is associated with substantial risk of lone AF, with the strongest risks associated with young age at onset, multiple affected relatives, and in first-degree relatives. These results suggest routine evaluation of the families of at least certain types of patients with lone AF.