Congenital Heart Disease, Type 1 and Type 2 Diabetes Mellitus

Sammanfattning: Worldwide, 1% of all live born children are born with a congenital heart disease (CHD) and currently >95% reach adulthood due to better diagnostics and medical care. At the same time, Diabetes Mellitus (DM), type 1 (T1DM) and type 2 (T2DM), is increasing worldwide. The incidence of the endocrine disease T2DM, which makes up more than 90% of all diabetes increases in particular and is part of the metabolic syndrome. T2DM is due to a decrease in insulin sensitivity and insulin production depending on genetic factors as well as obesity and a sedentary lifestyle. T1DM is an autoimmune disease that can develop due to i.e. genetic factors, exposure to infections and stress-strain leading to an autoimmune response. The incidence of T1DM in patients with CHD is unknown and the incidence of T2DM in patients with CHD is previously not extensively studied. Also, the effect of T1DM and T2DM in the CHD population on mortality is unknown. The aim of this thesis was to in large reliable registers and cohorts investigate the prevalence and incidence of T1DM and T2DM in a CHD population, and how this influences the mortality and morbidity in patients with CHD and T1DM and T2DM. Paper I, a retrospective comparative cohort study, investigated the risk of concurrent CHD in patients with T2DM, regarding T2DM onset, mortality and morbidity compared with patients with T2DM without CHD. The study combined data from the National Diabetes Register (NDR), National Patient Register (NPR) and the Cause of Death Register (CDR). Out of patients with T2DM, 833 patients with CHD were matched with 5 controls without CHD, matched by sex, year of birth and year of entry in to the NDR. CHD patients had significantly lower body mass index (BMI), higher creatinine and were more sedentary as compared to patients with T2DM but without CHD. The overall mortality was 26.2% for CHD patients as compared with 19.9% (P<0.001) for the control group, and five-year mortality rates were 5.2% for patients with CHD and T2DM com- pared to 3.4% (P=0.014) in the controls. In conclusion, CHD and secondary risk factors for cardiovascular disease frequently coexist and the development of T2DM in the adult CHD population is not uncommon with an estimated prevalence of between 4 and 8%. Treatment of conventional cardiovascular risk factors in patients with CHD could be considered important given the relatively high morbidity and high risk for mortality observed in patients with the com- bination of CHD and T2DM. Paper II, a retrospective comparative cohort study investigated the risk of concurrent CHD in patients with T1DM, regarding T1DM onset, mortality and morbidity compared to patients with T1DM without CHD. The study combined data from the National Diabetes Register (NDR), National Patient Register (NPR) and the Cause of Death Register (CDR). Out of patients with T1DM, a total of 104 patients with CHD were matched with 520 controls without CHD, matched by sex, year of birth and year of entry in to the NDR. Patients with CHD and T1DM had an earlier onset of diabetes (13.9 vs. 17.4 years, P<0.001), longer duration of T1DM (22.4 vs. 18.1 years, P<0.001), higher prevalence of retinopathy (64.0 vs. 43.0%, P=0.003), higher creatinine levels (83.5 vs. 74.1 μmol/L, P=0.03) and higher mortality (16 vs. 5%, P=0.002). Patients with CHD and T1DM had a higher rate of co-morbidities, expressed as a higher number of hospitalizations per patient (5.28 vs 3.18 P=0.007) with a discharge diagnosis of CHD, IHD, heart failure (9% vs. 2%, P=0.02), atrial fibrillation, stroke (6% vs. 2%, P=0.048), PCI, CABG, or renal failure, after onset of T1DM compared with controls. In conclusion, from a nationwide register of patients with T1DM, the coexistence of CHD and T1DM was associated with an earlier onset of T1DM, a higher frequency of microvascular complications, co-morbidity, and mortality. In paper III, a retrospective comparative cohort study performed by combining registers (NPR and CDR), the incidence of T1DM and the mortality was analyzed in patients with CHD by birth cohort (1970-1993, 1970-1984 and 1984- 1993). Patients with CHD were matched with population-based controls matched for sex and year of birth without CHD and followed from birth until a maximum of 42 years. Among 21,982 patients with CHD, 221 patients developed T1DM and among 219,816 matched controls 1,553 patients developed T1DM . The hazard ratio (HR) for developing T1DM was 1.50 (95%, CI 1.31-1.73) in patients with CHD compared to the controls. The first birth cohort (1970-1984) had the highest risk for developing T1DM, HR 1.87 (95%, CI 1.56-2.24). After T1DM onset, the mortality risk was 4.21 times higher (95%, CI 2.40-7.37) in patients with CHD and T1DM compared to controls with T1DM without CHD. In conclusion, a nationwide cohort of patients with CHD and controls, the incidence of T1DM onset was 50% higher in patients with CHD, indicating a significant increase in risk among birth cohort 1970-1984. A four-fold increase in mortality among patients with CHD and T1DM was seen compared to controls with only T1DM. In paper IV, a retrospective comparative cohort study combining registers (NPR and CDR) analyzed the incidence of DM and the mortality in patients above 35 years of age with CHD. The CHD population was compared with population-based controls matched for sex and year of birth without CHD, divided by birth cohort, CHD lesion cohort and gender cohort, and followed from birth until a maximum of 87 years of age. Out of patients with CHD who survived until at least 35 years of age without developing DM, 8,4 % had an onset of DM after 35 years of age com- pared to 5.6% of the matched controls. The risk for developing DM was significant increased in patients with CHD compared to the controls and the second birth cohort (1960-1983) had the highest risk for DM. The risk of DM increased with complexity of CHD. After DM onset, mortality was significantly higher in patients with CHD and DM compared to controls with DM without CHD. From a nationwide cohort of patients with CHD and controls, the incidence of developing DM was significant higher in patients with CHD, showing a significant increase in risk also divided by birth cohort and by CHD lesion. The combination of CHD and DM was associated with a significantly increased mortality compared to controls without CHD. In conclusion, this thesis show that the CHD population do have a higher risk of T1DM and T2DM compared with the general population. Whether this is due to environmental risk factors or due to genetics needs to be further studied. Patients with CHD also have a higher mortality and morbidity after onset of DM compared with controls without CHD indicating that the combination of CHD and DM are more lethal than each diagnosis on its own. These findings are of great importance in future preventive and medical care for patients with CHD.