Modifiable risk factors and risk of myocardial infarction in offspring with parental disease.

AIMS: Children of patients with early-onset myocardial infarction (MI) are at increased risk, but the importance of concordant versus discordant parent-offspring risk factor profiles on MI risk is largely unknown. We quantified the long-term absolute risk of MI according to shared risk factors in adulthood. METHODS: We sampled data on familial predisposed offspring and their parents from the Framingham Heart Study. Early MI was defined as a history of parental MI onset before age 55 in men or 65 in women. Individuals were matched 3:1 with non-predisposed offspring. Cardiovascular risk factors included obesity, smoking, hypertension, high cholesterol, and diabetes. We estimated the absolute 20-year incidence of MI using the Aalen-Johansen estimator. RESULTS: At age 40, the 20-year risk of MI varied by cholesterol level (high cholesterol 25.7% [95% confidence interval 11.2%; 40.2%] vs. non-high cholesterol 3.4% [0.5; 6.4]) among predisposed individuals and this difference was greater than in controls (high cholesterol 9.3% [1.5; 17.0] vs. non-high cholesterol 2.5% [1.1; 3.8]). Similar results were observed for prevalent hypertension (26.7% [10.8; 42.5] vs. 4.0% [0.9; 7.1] in predisposed vs. 10.8% [3.2; 18.3] and 2.1% [0.8; 3.4] in controls). Among offspring without risk factors, parental risk factors carried a residual impact on 20-year MI risk in offspring (0% [0; 11.6] for 0-1 parental risk factors versus 3.3% [0; 9.8] for ≥2 parent risk factors at age 40, versus 2.9% [0; 8.4] and 8.5% [0; 19.8] at age 50 years). CONCLUSION: Children of patients with early-onset MI have low absolute risks of MI in the absence of midlife cardiovascular risk factors, especially if the parent also had a low risk factor burden prior to MI.

Children of patients with early-onset myocardial infarction (MI) are at a higher risk of disease themselves. Cardiovascular risk factor control is important to lower the risk of disease, but little is known about how the offspring's risk differs based on risk factor controls. Using multi-generational data from the Framingham Heart Study, we observed that adult children of people with early-onset MI have low absolute 20-year risk of developing an MI if they do not have any cardiovascular risk factors, especially if the parent also had low risk factor burden prior to MI, suggesting that close surveillance for risk factor development in offspring is warranted. In offspring of parents with early-onset MI who did not have any risk factors, the number of risk factors in the parent seemed to slightly impact the risk of MI. Improved clarity of the interplay between risk factors in parents and offspring can help medical doctors provide accurate guidance in terms of preventing the development of MI. Our findings suggest that in the absence of risk factors, assessment of the parents' risk factors burden may be helpful for further risk stratification.

Depression risk in users of different doses of levonorgestrel intrauterine systems: a nationwide prospective cohort study.

Background: Use of the high-dose levonorgestrel-releasing intrauterine system (LNG-IUS) has been associated with increased risk of incident depression. Evidence is lacking on the influence of use of two recently marketed low-dose LNG-IUS on risk of depression. This study aims to examine associations between use of different doses of LNG-IUS and risk of depression. Methods: We conducted a nationwide prospective cohort study involving all first-time users of an LNG-IUS among all Danish nulliparous women aged 15-34 years with no medical history of depression, major psychiatric diseases, endometriosis, heavy menstrual bleeding, polyp, myoma, dysmenorrhoea, iron supplement use, abortion, and infertility treatment. Findings: A total of 46,565 first-time users of LNG-IUS were followed for 80,516 person-years with 1,531 incident initiations of antidepressant use observed during follow-up. Use of the high-dose LNG-IUS containing 52 mg levonorgestrel was initiated by 9,902 (21%) women, while 20,665 (44%), and 15,998 (34%) initiated use of the low-dose LNG-IUS containing 19·5 mg and 13·5 mg levonorgestrel, respectively.The age-, calendar-time-, and education-standardised incidence rates of first-time depression per 1,000 person-years at full LNG-IUS duration were 30.8 (95% CI 23·6-39·5) for the 52 mg LNG-IUS, 19·8 (95% CI 16·1; 24·0) for the 19·5 mg LNG-IUS, and 17·7 (95% CI 14·4-21·5) for the 13·5 mg LNG-IUS-. Compared to the high-dose 52 mg LNG-IUS, the adjusted number of avoided depressions per 1,000 person-years were 11·0 (95% CI 7·1-14·9) for the 19·5 mg LNG-IUS and 13·1 (95% CI 9·6-16·6) for the 13·5 mg LNG-IUS. The corresponding adjusted rate ratios were 0·77 (95% CI 0·68; 0·88) and 0·85 (95% CI 0·75-0·96). The reduced risk of depression with low-dose LNG-IUS compared to high-dose LNG-IUS was observable throughout duration of use. Interpretation: Use of low-dose LNG-IUS containing 19·5 mg and 13·5 mg levonorgestrel, respectively, were associated with a reduced risk of incident depression compared to use of the high-dose 52 mg LNG-IUS. The study suggests that low-dose LNG-IUS should be preferred over the high-dose LNG-IUS for contraceptive purpose. Funding: Sygeforsikringen "Danmark" grant: 2021-0128.

Integrated omics analysis of coronary artery calcifications and myocardial infarction: the Framingham Heart Study.

Gene function can be described using various measures. We integrated association studies of three types of omics data to provide insights into the pathophysiology of subclinical coronary disease and myocardial infarction (MI). Using multivariable regression models, we associated: (1) single nucleotide polymorphism, (2) DNA methylation, and (3) gene expression with coronary artery calcification (CAC) scores and MI. Among 3106 participants of the Framingham Heart Study, 65 (2.1%) had prevalent MI and 60 (1.9%) had incident MI, median CAC value was 67.8 [IQR 10.8, 274.9], and 1403 (45.2%) had CAC scores > 0 (prevalent CAC). Prevalent CAC was associated with AHRR (linked to smoking) and EXOC3 (affecting platelet function and promoting hemostasis). CAC score was associated with VWA1 (extracellular matrix protein associated with cartilage structure in endomysium). For prevalent MI we identified FYTTD1 (down-regulated in familial hypercholesterolemia) and PINK1 (linked to cardiac tissue homeostasis and ischemia-reperfusion injury). Incident MI was associated with IRX3 (enhancing browning of white adipose tissue) and STXBP3 (controlling trafficking of glucose transporter type 4 to plasma). Using an integrative trans-omics approach, we identified both putatively novel and known candidate genes associated with CAC and MI. Replication of findings is warranted.

National all-cause mortality during the COVID-19 pandemic: a Danish registry-based study.

Denmark implemented early widespread social distancing to reduce pressure on the healthcare system from the coronavirus disease 2019 (COVID-19) pandemic, with the aims to reduce mortality. Unintended consequences might be delays in treatment for other diseases and subsequent mortality. We examined national all-cause mortality comparing weeks 1-27 in 2020 and 2015-2019. This registry-based study used Danish national registry data until 5 July 2020. We examined all-cause mortality rates among all deaths recorded from 2015 to 2020 and among chronic conditions (cardiovascular (cardiac & circulatory), chronic pulmonary, chronic kidney disease, cancer, and diabetes), comparing each week in 2020 to weeks in 2015-2019. In 2020, there were 28,363 deaths in weeks 1-27 (30 December 2019-5 July 2020), the mean deaths in 2015-2019 were 28,630 deaths (standard deviation 784). Compared to previous years, the mortality rate in weeks 3-10 of 2020 was low, peaking in week 14 (17.6 per 100,000 persons in week 9, 19.9 per 100,000 in week 14). Comorbidity prevalence among deceased individuals was similar in 2020 and 2015-2019: 71.1% of all deceased had a prior cardiovascular diagnosis, 30.0% of all deceased had a prior cardiac diagnosis. There were 493 deaths with COVID-19 in weeks 11-27, (59.8% male), and 75.1% had a prior cardiovascular diagnosis. Weekly mortality rates for pre-existing chronic conditions peaked in week 14, and then declined. During the COVID-19 pandemic, due to timely lockdown measures, the mortality rate in Denmark has not increased compared to the mortality rates in the same period during 2015-2019.