Mattis Flyvholm Ranthe

Familial Aggregation of Lone Atrial Fibrillation in Young Persons

OBJECTIVES This study investigated whether an individuals 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 relatives 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.

Risk of cardiovascular disease in family members of young sudden cardiac death victims

AIMS Descriptive and genetic studies suggest that relatives of sudden cardiac death (SCD) victims have an increased risk of several cardiovascular diseases (CVDs). Given the severe consequences of undiagnosed CVD and the availability of effective treatment, the potential for prevention in this group is enormous if they do have an increased CVD risk. This nationwide prospective population-based cohort study described the risk of CVDs in relatives of young SCD victims, compared with the general population. METHODS AND RESULTS All SCD victims aged 1-35 years in Denmark, 2000-2006, were identified (n = 470), along with their first- and second-degree relatives (n = 3073). We compared the incidence of CVD in those relatives with that in the background population using standardized incidence ratios (SIRs). The observed number of CVDs over 11 years of follow-up was 292, compared with 219 expected based on national rates [SIR 1.33, 95% confidence interval (CI) 1.19-1.50]. Risks varied significantly with age; the SIR for those <35 years was 3.53 (95% CI 2.65-4.69), compared with SIRs of 1.59 (95% CI 1.35-1.89) and 0.91 (95% CI 0.75-1.10) for those aged 35-60 years or >60 years, respectively (P(homogeneity) < 0.0001). For first-degree relatives <35 years, SIRs for ischaemic heart disease, cardiomyopathy, and ventricular arrhythmia were 5.99 (95% CI 1.95-0.13.98), 17.91 (95% CI 4.88-45.87), and 19.15 (95% CI 7.70-39.45), respectively. CONCLUSION CVDs co-aggregated significantly with SCD in families, with young first-degree relatives at greatest risk. Results clearly indicate that family members of young SCD victims should be offered comprehensive and systematic screening, with focus on the youngest relatives.

Family history of premature death and risk of early onset cardiovascular disease.

OBJECTIVES The purpose of this study was to examine the effect of a family history of premature death, cardiovascular death in particular, on the risk of early cardiovascular disease. BACKGROUND Studies suggest that fatal cardiovascular events and less severe cardiovascular diseases may co-occur in families. Consequently, a family history of premature death may indicate a familial cardiac frailty that predisposes to early cardiovascular disease. METHODS We ascertained family history of premature death (age <60 years) in all individuals born in Denmark from 1950 to 2008 and followed this cohort for early cardiovascular disease (age <50 years). Using Poisson regression, we estimated incidence rate ratios (IRRs) reflecting the effect of premature death in the family on early cardiovascular disease risk. RESULTS Among 3,985,301 persons followed up for 89,294,258 person-years, 129,825, 31,172, and 5,214 were diagnosed with any early cardiovascular disease, ischemic heart disease, and ventricular arrhythmia, respectively. IRRs for these conditions given a history of premature cardiovascular death in first-degree relatives were 1.72 (95% confidence interval [CI]: 1.68 to 1.77), 2.21 (95% CI: 2.11 to 2.31), and 1.94 (95% CI: 1.70 to 2.20), respectively. With ≥2 cardiovascular deaths in a family, corresponding IRRs were 3.30 (95% CI: 2.77 to 3.94), 5.00 (95% CI: 3.87 to 6.45), and 6.18 (95% CI: 3.32 to 11.50). The IRR for any early cardiovascular disease given a family history of premature noncardiovascular death was significantly lower, 1.12 (95% CI: 1.10 to 1.14) (p(cardiac vs. noncardiac) < 0.0001). CONCLUSIONS Family history of premature cardiovascular death was consistently and significantly associated with a risk of early cardiovascular disease, suggesting an inherited cardiac vulnerability. These results should be kept in mind when assessing cardiovascular disease risk in persons with a family history of premature cardiovascular death.

Pregnancy loss and later risk of atherosclerotic disease.

Background— Pregnancy losses and atherosclerotic disease may be etiologically linked through underlying pathology. We examined whether miscarriage and stillbirth increase later risk of myocardial infarction, cerebral infarction, and renovascular hypertension. Methods and Results— Among women pregnant at least once between 1977 and 2008, we identified a cohort of women with miscarriages, stillbirths, or live singleton births. These women were followed from the end of pregnancy for incident myocardial infarction, cerebral infarction, and renovascular hypertension. Using Poisson regression, we estimated incidence rate ratios for each of the outcomes by history of miscarriage and stillbirth. Among 1 031 279 women followed for >15 928 900 person-years, we identified 27 98 myocardial infarctions, 40 53 cerebral infarctions, and 1269 instances of renovascular hypertension. Women with stillbirths had 2.69 (95% confidence interval, 2.06–3.50), 1.74 (1.32–2.28), and 2.42 (1.59–3.69) times the rates of myocardial infarction, cerebral infarction, and renovascular hypertension, respectively, as women with no stillbirths. Compared with women with no miscarriages, women with miscarriages had 1.13 (1.03–1.24), 1.16 (1.07–1.25), and 1.20 (1.05–1.38) times the rates of these same outcomes, respectively; these associations were dose dependent, with each additional miscarriage increasing the rates of myocardial and cerebral infarction and renovascular hypertension by 9% (3% to 16%), 13% (7% to 19%), and 19% (9% to 30%), respectively. Associations were strongest in younger women (<35 years). Conclusions— Pregnancy losses were associated with subsequent risks of myocardial infarction, cerebral infarction, and renovascular hypertension, consistent with either shared etiology or the initiation of pathological processes by a pregnancy loss leading to atherosclerosis.

Cardiac involvement in myotonic dystrophy: a nationwide cohort study

AIMS To quantify the association between myotonic dystrophy (DM) and cardiac disease in a nationwide cohort. METHODS AND RESULTS We identified a nationwide cohort of 1146 DM patients (period 1977-2011) using the National Patient Registry (NPR) and a subcohort of 485 patients who had undergone genetic testing for DM1. Information on incident cardiac diseases was obtained from the NPR. We estimated standardized incidence ratios (SIRs) of cardiac disease compared with the background population, overall and according to selected diagnostic subgroups (cardiomyopathy, heart failure, conduction disorders, arrhythmias, and device implantation). In the DM cohort, SIR for any cardiac disease was 3.42 [95% confidence interval (CI) 3.01-3.86]; for a cardiac disease belonging to the selected subgroups 6.91 (95% CI: 5.93-8.01) and for other cardiac disease 2.59 (95% CI: 2.03-3.25). For a cardiac disease belonging to the selected subgroups, the risk was particularly high in the first year after DM diagnosis [SIR 15.4 (95% CI: 10.9-21.3)] but remained significantly elevated in subsequent years [SIR 6.07 (95% CI: 5.11-7.16]). The risk was higher in young cohort members [e.g. 20-39 years: SIR 18.1 (95% CI: 12.3-25.8)] compared with older [e.g. 60-79 years: SIR 3.99 (95% CI: 2.98-5.23)] but remained significantly increased in all age categories. Results were similar in separate analyses of the genetically confirmed DM1 patients. CONCLUSION Myotonic dystrophy is strongly associated with cardiac disease. The risk is pronounced in the young and remains elevated throughout life, stressing the importance of lifelong cardiac follow-up from time of DM diagnosis.

A detailed family history of myocardial infarction and risk of myocardial infarction--a nationwide cohort study.

Background Family history of myocardial infarction (MI) is an independent risk factor for MI. Several genetic variants are associated with increased risk of MI and family history of MI in a first-degree relative doubles MI risk. However, although family history of MI is not a simple dichotomous risk factor, the impact of specific, detailed family histories has not received much attention, despite its high clinical relevance. We examined risk of MI by MIs in first- and second-degree relatives and by number and age of affected relatives. Methods and Findings Using Danish national registers, we established a nationwide cohort of persons born between 1930 and 1992 with identifiable first- or second-degree relatives. Incident MIs in both cohort members and relatives aged ≥20 years were identified. We calculated incidence rate ratios (IRRs) for MI by family history of MI, by Poisson regression. In 4.4 million persons followed for 104 million person-years, we identified 128,384 incident MIs. IRRs with 95% confidence intervals [CIs] for MI by history of MI in 1, 2 or ≥3 first-degree relatives were 1.46 (1.42-1.49), 2.38 (2.22-2.56) and 3.58 (2.66-4.81), respectively. Corresponding estimates for second-degree relatives were 1.17 (1.05-1.30), 1.87 (1.46-2.38) and 2.18 (1.09-4.36). A history of MI in combinations of first- and second-degree relatives increased risks 1.8- to 7-fold in middle-aged persons (36 to 55 years). Estimates were robust to adjustment for diabetes, hypertension, dyslipidemia and use of cardiovascular medications. Conclusion A detailed family history, particularly number of affected first- and second-degree relatives, contributes meaningfully to risk assessment, especially in middle-aged persons. Future studies should test for potential improvement of risk algorithm prediction using detailed family histories.

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.

Association between pregnancy losses in women and risk of atherosclerotic disease in their relatives: a nationwide cohort study

AIMS A common underlying mechanism with a genetic component could link pregnancy losses with vascular disease. We examined whether pregnancy losses (miscarriages and stillbirths) and atherosclerotic outcomes co-aggregated in families. METHODS AND RESULTS Using Danish registers, we identified women with pregnancies in 1977-2008, and their parents (>1 million) and brothers (>435 000). We followed parents for incident ischaemic heart disease (IHD), myocardial infarction (MI), and cerebrovascular infarction (CVI), and brothers for a broader combined atherosclerotic endpoint. Using Cox regression, we estimated hazard ratios (HRs) for each outcome by history of pregnancy loss in daughters/sisters. Overall, parents whose daughters had 1, 2, and ≥3 miscarriages had 1.01 [95% confidence interval (CI) 0.99-1.04], 1.07 (95% CI 1.02-1.11), and 1.10 (95% CI 1.02-1.19) times the rate of MI, respectively, as parents whose daughters had no miscarriages. For parents with ≥3 daughters, the HRs were 1.12 (95% CI 1.02-1.24), 1.29 (95% CI 1.13-1.48), and 1.33 (95% CI 1.12-1.57). Effect magnitudes did not differ for fathers and mothers. We observed similar patterns for IHD and CVI (parents) and the atherosclerotic endpoint (brothers). Parents whose daughters had stillbirths had 1.14 (95% CI 1.05-1.24) and 1.07 (95% CI 0.96-1.18) times the rates of MI and CVI, respectively, as parents whose daughters had no stillbirths. CONCLUSION Certain pregnancy losses and atherosclerotic diseases in both heart and brain may have a common aetiologic mechanism. Women in families with atherosclerotic disease may be predisposed to pregnancy loss; conversely, pregnancy losses in first-degree relatives may have implications for atherosclerotic disease risk.

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.Common genetic variants in structural proteins contribute to risk of atrial fibrillation (AF). Here, using whole-exome sequencing, the authors identify rare truncating variants in TTN that associate with familial and early-onset AF and show defects in cardiac sarcomere assembly in ttn.2-mutant zebrafish.