Cardiomyopathy in First-Degree Relatives of Patients Presenting With Acute Myocarditis: Prevalence and Prognostic Significance.

BACKGROUND: Acute myocarditis has been genetically linked to dilated cardiomyopathy (DCM), but the clinical significance remains uncertain. We investigated the prevalence and long-term prognosis of DCM and heart failure (HF) among unselected patients hospitalized with acute myocarditis and their first-degree relatives compared with an age- and sex-matched cohort. METHODS: This was an observational study utilizing the Danish nationwide registries, where all patients with a first-time myocarditis diagnosis from 1995 to 2018 were identified and matched (on birth year and sex) with 10 controls from the general population. RESULTS: Totally 3176 patients with acute myocarditis and 31 760 controls were included (median age, 49.8 [Q1-Q3, 32.5-70.2] years; 35.6% female). At baseline, patients with myocarditis had a higher prevalence of DCM (7 [0.2%] versus 8 [0.0%]) and HF (336 [10.6%] versus 695 [2.2%]) than controls; P<0.0001 for both. Patients with myocarditis more often had siblings with DCM (12 [0.4%] versus 17 [0.05%]) or HF (36 [1.1%] versus 89 [0.3%]); P<0.0001, odds ratios 7.09 (3.38-14.85) and 2.92 (1.25-6.80), respectively, whereas parental DCM and HF did not differ among patients with myocarditis and controls. Patients with myocarditis had greater 20-year incidence of DCM, HF, and all-cause mortality (0.5% [0.3%-0.9%], 15% [13%-17%], and 47% [44%-50%]) compared with controls (0.06% [0.03%-0.11%], 6.8% [6.4%-7.3%], and 34% [33%-35%]; P<0.0001). Having a first-degree relative with DCM or HF was associated with increased long-term mortality among the patients with myocarditis (hazard ratio, 1.40 [1.11-1.77]) but not among the controls (hazard ratio, 0.90 [0.81-1.01]; Pdifference=0.0008). CONCLUSIONS: Acute myocarditis aggregates with DCM within families, where it carries a worsened prognosis. A differential association between parents and siblings (with sibling preponderance) could suggest that additional environmental factors are important for myocarditis development even in predisposed individuals.

Incidence rates of dilated cardiomyopathy in adult first-degree relatives versus matched controls.

Background: The incidence rates and importance of traditional risk factors in dilated cardiomyopathy among first-degree relatives are unknown. Methods and Results: We identified all probands with dilated cardiomyopathy (n = 13,714, mean age at diagnosis 63 years) from the Danish nationwide registries between 1994 and 2017. Incidence rates among first-degree relatives (n = 29,671, mean age 38 years) and for up to 10 age- and sex-matched controls were calculated. Totally 233 (0.8%) first-degree relatives and 285 (0.1%) controls developed dilated cardiomyopathy during a median follow-up of 8.2 (Q1-Q3 4.4-13.3) years. Incidence rates (per 100,000 person-years) were 86.4 (95% confidence interval 73.9-101.0) and 111.1 (79.4-128.7) for first-degree relatives aged < 50 and ≥ 50 years, respectively, versus 7.5 (6.4-8.9) and 19.7 (16.8-23.2) for controls. Atrial fibrillation, diabetes, ischemic heart disease, and hypertension were associated with increased risks of developing dilated cardiomyopathy both in first-degree relatives and controls. Population attributable fractions for the 4 risk factors were 27.7% for first-degree relatives and 37.3% for controls aged < 50 years, and 46.4% versus 58.4% for first-degree relatives and controls among people aged ≥ 50 years, respectively. Conclusions: The absolute incidence rates of dilated cardiomyopathy in first-degree relatives to patients with dilated cardiomyopathy were low, but significantly higher than in matched controls and elevated by the presence of additional risk factors, especially atrial fibrillation. Additional investigations are warranted to assess whether aggressive treatment of risk factors translates into a reduction of dilated cardiomyopathy in first-degree relatives.

Time trends in incidence, comorbidity, and mortality of ischemic stroke in Denmark (1996-2016).

OBJECTIVE: To examine whether the incidence, comorbidity, and mortality of first-time ischemic stroke changed in Denmark between 1996 and 2016 overall and according to age and sex using a nationwide cohort design. METHODS: In this cohort study, 224,617 individuals ≥18 years of age admitted with first-time ischemic stroke between 1996 and 2016 were identified through Danish nationwide registries. We calculated annual age-standardized incidence rates and absolute 30-day and 1-year mortality risks. Furthermore, we calculated annual incidence rate ratios using Poisson regression, odds ratios for 30-day mortality using logistic regression, and hazard ratios for 1-year mortality using Cox regression. RESULTS: The overall age-standardized incidence rates of ischemic stroke per 1,000 person-years increased from 1996 (2.70 [95% confidence interval [CI] 2.65-2.76]) to 2002 (3.25 [95% CI 3.20-3.31]) and then gradually decreased to below the initial level until 2016 (1.99 [95% CI 1.95-2.02]). Men had higher incidence rates than women in all age groups except 18 to 34 and ≥85 years. Absolute mortality risk decreased between 1996 and 2016 (30-day mortality from 17.1% to 7.6% and 1-year mortality from 30.9% to 17.3%). Women between 55 and 64 and ≥85 years of age had higher mortality than men. Similar trends were observed for all analyses after multivariable adjustment. The prevalence of atrial fibrillation, hypertension, diabetes mellitus, and use of lipid-lowering medication increased during the study period. CONCLUSIONS: The age-standardized incidence of first-time hospitalization for ischemic stroke increased from 1996 to 2002 and then gradually decreased to below the initial level until 2016. Absolute 30-day and 1-year mortality risks decreased between 1996 and 2016. These findings correspond to increased stroke prevention awareness and introduction of new treatments during the study period.

Add-on therapy in metformin-treated patients with type 2 diabetes at moderate cardiovascular risk: a nationwide study.

BACKGROUND: In randomised clinical trials, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 (SGLT-2) inhibitors reduced cardiovascular events in patients with type 2 diabetes (T2D) at high cardiovascular risk, as compared to standard care. However, data comparing these agents in patients with T2D who are at moderate risk is sparse. METHODS: From Danish national registries, we included patients with T2D previously on metformin monotherapy, who started an additional glucose-lowering agent [GLP-1 RA, SGLT-2 inhibitor, dipeptidyl peptidase-4 (DPP-4) inhibitor, sulfonylurea (SU), or insulin] in the period 2010-2016. Patients with a history of cardiovascular events [heart failure (HF), myocardial infarction (MI) or stroke] were excluded. Patients were followed for up to 2 years. Cause-specific adjusted Cox regression models were used to compare the risk of hospitalisation for HF, a composite endpoint of major adverse cardiovascular events (MACE) (MI, stroke or cardiovascular death), and all-cause mortality for each add-on therapy. Patients who initiated DPP-4 inhibitors were used as reference. RESULTS: The study included 46,986 T2D patients with a median age of 61 years and of which 59% were male. The median duration of metformin monotherapy prior to study inclusion was 5.3 years. Add-on therapy was distributed as follows: 13,148 (28%) GLP-1 RAs, 2343 (5%) SGLT-2 inhibitors, 15,426 (33%) DPP-4 inhibitors, 8917 (19%) SUs, and 7152 (15%) insulin. During follow-up, 623 (1.3%, range 0.8-2.1%) patients were hospitalised for HF-hazard ratios (HR) were 1.11 (95% CI 0.89-1.39) for GLP-1 RA, 0.84 (0.52-1.36) for SGLT-2 inhibitors, 0.98 (0.77-1.26) for SU and 1.54 (1.25-1.91) for insulin. The composite MACE endpoint occurred in 1196 (2.5%, range 1.5-3.6%) patients, yielding HRs of 0.82 (0.69-0.97) for GLP-1 RAs, 0.79 (0.56-1.12) for SGLT-2 inhibitors, 1.22 (1.03-1.49) for SU and 1.23 (1.07-1.47) for insulin. 1865 (3.9%, range 1.9-9.0%) died from any cause during follow-up. HRs for all-cause mortality were 0.91 (0.78-1.05) for GLP-1 RAs, 0.79 (0.58-1.07) for SGLT-2 inhibitors, 1.13 (0.99-1.31) for SU and 2.33 (2.08-2.61) for insulin. CONCLUSION: In a nationwide cohort of metformin-treated T2D patients and no history of cardiovascular events, the addition of either GLP-1 RA or SGLT-2 inhibitor to metformin treatment was associated with a similar risk of hospitalisation for HF and death, and a lower risk of MACE for GLP-1 RA when compared with add-on DPP-4 inhibitors. By contrast, initiation of treatment with SU and insulin were associated with a higher risk of MACE. Additionally, insulin was associated with an increased risk of all-cause mortality and hospitalisation for HF.

Age-specific trends in incidence and survival of out-of-hospital cardiac arrest from presumed cardiac cause in Denmark 2002-2014.

BACKGROUND: The general cardiovascular health has improved throughout the last few decades for middle-aged and older individuals, but the incidence of several cardiovascular diseases is reported to increase in younger people. We aimed to assess the age-specific incidence and mortality rates associated with out-of-hospital-cardiac-arrest (OHCA) between 2002 and 2014. METHODS: We used the Danish Cardiac Arrest Register to identify patients with OHCA of presumed cardiac etiology. We calculated the annual incidence rates (IR) and 30-day mortality rates (MR) in 7 age groups (18-34 years, 35-44 years, 45-54 years, 55-64 years, 65-74 years, 75-84 years and ≥85 years, and ≤50 vs. >50 years). RESULTS: Between 2002 and 2014, IR of OHCA decreased in individuals aged 65-74 and 75-84 years (158.08 to 111.2 and 237.5 to 217.09 per 100,000 person-years) and increased in the oldest from 201.01 to 325.4 pr. 100.000 person-years. In 18-34-years incidence of OHCA increased from 1.7 to 2.6 per 100.000 person-years. When stratifying into age ≤50 vs. >50 years, the IR deviated in those >50 years (from 117.8 in 2002 to 91 in 2008 to 117.4 in 2014100,000 person-years). The prevalence of acute myocardial infarction and heart failure prior to OHCA increased in the younger patient group in contrast to the older segment (AMI: ≤50 years: 10% to 16%, vs. >50 years: 25% to 23%, heart failure: ≤50 years 6% to 14%, vs. >50 years: 21% to 24%). CONCLUSION: Over the last decades, incidence rates of OHCA decreased in individuals aged 65-84, but increased in individuals older than 85. An increase was also observed in younger individuals, potentially indicating a need for better cardiovascular disease prevention in younger adults.

Prevalence of heart failure and other risk factors among first-degree relatives of women with peripartum cardiomyopathy.

OBJECTIVES: Peripartum cardiomyopathy (PPCM) is a rare disease carrying a risk of death and chronic heart failure.It is unknown if women with PPCM have a family history of heart failure. We investigated the prevalence of heart failure and hypertension in first-degree relatives to women with PPCM. METHODS: A cohort of 61 women with PPCM was identified through the nationwide Danish registers from 2005 to 2014, and each individual diagnosis of PPCM was validated through review of patient records. We excluded 13 women due to lack of data on relatives. In a case-control design, the 48 remaining women were matched (on age, year of childbirth, parity and number of siblings) to 477 birth-giving Danish women without heart failure. We obtained information on first-degree relatives (parents and siblings) through the National Danish Registers. RESULTS: The cohort of 48 women with PPCM had a mean age of 31 years (SD 6). The prevalence of heart failure in any first-degree relative was higher in women with PPCM, compared with controls (23% vs 10%, p=0.011). A first-degree relative with any cardiovascular diagnosis was not more frequent in women with PPCM versus controls (77% vs 70%, p=0.280), but for siblings only, any cardiovascular diagnosis was more frequent in siblings to women with PPCM (29% vs 16%, p=0.026). CONCLUSION: Having a first-degree relative with heart failure was significantly more frequent in a cohort of validated PPCM cases than in controls, supporting the notion of shared aetiology between PPCM and other forms of heart failure.