Familial Risks of Heart Failure in Sweden

Sammanfattning: Introduction: Despite major advances, the incidence rate and mortality of heart failure (HF) remains high, with a five-year survival of approximately 50%. At the time of inception of this thesis the familial risks of HF, including the aspects of mortality, were largely underdetermined. This thesis is composed of four papers with the main aims as follows:To determine the risk of hospitalization of HF associated with having affected siblings, and the ages at which this hypothesized risk apply (Paper I). To investigate the heritability (h2) of HF and the risk of HF in adoptees as determined by HF in biological and adoptive parents (Paper II). To determine if HF survival time is associated among affected siblings (Paper III). To investigate if mortality risks are increased in subjects with a sibling affected with HF (Paper IV).Methods All studies were based on Swedish nationwide interlinked registry data including the National Patient Register and the Multi-Generation Register to retrieve information of, e.g. family relationships, hospital discharge diagnoses and, in some instances, also hospital outpatient data. Adjustments were made for common HF comorbidities, age, sex and (with the exception of Paper III) aspects of socioeconomic data. Standardized incidence ratios (SIRs) of HF hospitalization were calculated for individuals with siblings hospitalized with HF compared with those whose siblings were not (Paper I). In a cohort study design using unconditional logistic regression, the odds ratios (ORs) of HF hospitalization were calculated in adoptees as determined by adoptive and biological parental hospitalization for HF, respectively. Heritability was estimated by using the Falconer regression method (Paper II). Using Cox regression, mortality hazard ratios (HRs) after first hospitalization for HF was calculated as determined by the survival of a sibling previously hospitalized first time for HF (Paper III). Mortality HRs were calculated for siblings of individuals who had been diagnosed with HF compared with siblings of individuals unaffected by HF as the reference group (Paper IV).Results: The SIR of HF hospitalization was 1.62 (95% CI 1.54–1.70) for subjects with one affected sibling and 15.46 (12.82–18.50) for subjects with two affected siblings. SIRs were highest among the youngest stratum of subjects under the age of 50 years and decreased with age (Paper I). The adoptee OR for HF hospitalization with an affected biological parent was 1.45 (95% CI, 1.04-2.03), whereas no significant association was found with an affected adoptive parent. Heritability of HF was 26% (SE, 14%) (Paper II).The mortality HR after first HF hospitalization for subjects having a sibling with corresponding survival < 5 years was 2.02 (95% CI, 1.32–3.09) (Paper III). Subjects with a sibling affected with HF had a mortality HR of 1.21 (95% CI 1.18–1.25). This risk remained (HR=1.19, 95% CI 1.15–1.23) also among subjects without HF themselves (Paper IV).Discussion: Family history, in the form of affected siblings or biological parents, is an important risk factor for HF. The moderate heritability level in relation to the magnitude of familial risk motivates further genetic studies. Sibling HF is also a risk factor for death. Familial factors may also be important for the prognosis of patients with HF. These results suggest the value of more studies to investigate the genomics influencing the risk of HF and the associated mortality risk. They also indicate that individuals with such a family history may be at increased risk and that clinical evaluation may be considered in select categories of patients.