Koichiro Niwa

Editorial Introduction to the focused series on “Current Management Aspects in Adult Congenital Heart Disease (ACHD): Part V” Koichiro Niwa, Yskert von Kodolitsch, Öztekin Oto, Harald Kaemmerer

Introduction to the focussed series on “Current Management Aspects in Adult Congenital Heart Disease (ACHD): Part IV” Harald Kaemmerer, Yskert von Kodolitsch, Koichiro Niwa

In adults with congenital heart disease (ACHD), conditions acquired with aging, such as metabolic syndrome, hypertension, diabetes mellitus, and obesity, can negatively influence the original cardiovascular disease. Metabolic syndrome has a higher prevalence in ACHD than in the general population. In contrast, coronary artery disease shows a similar prevalence in adults with acyanotic CHD and the general population, while adults with cyanotic CHD, even after repair, have an even lower incidence of coronary artery disease than the general population/adults with acyanotic CHD. However, even in those with cyanotic CHD, coronary artery disease can develop when they have risk factors such as obesity, dyslipidemia, hypertension, diabetes mellitus, smoking habit, or limited exercise. The prevalence of risk factors for cardiovascular disease is similar between ACHD and the general population, but an increased risk of coronary atherosclerosis has been observed for congenital coronary artery anomalies, dextro-transposition of the great arteries after arterial switch operation, Ross procedure, and coarctation of the aorta. Aortopathy may be an additional risk factor for cardiovascular disease. As ACHD have other abnormalities that may make the heart more vulnerable to both the development of atherosclerosis and adverse cardiovascular sequelae, regular evaluation of their cardiovascular disease risk status is recommended. Metabolic syndrome is more common among ACHD than in the general population, and may therefore increase the future incidence of atherosclerotic coronary artery disease even in ACHD. Thus, ACHD should be screened for metabolic syndrome to eliminate risk factors for atherosclerotic coronary artery disease.

Current diagnosis and management of late complications in adult congenital heart disease

The potential contribution of serum osmolarity in the modulation of blood pressure has not been evaluated. This study was done to examine the relationship between hyperosmolarity and hypertension in a five-year longitudinal design. We enrolled 10,157 normotensive subjects without diabetes who developed hypertension subsequently as determined by annual medical examination in St. Luke’s International Hospital, Tokyo, between 2004 and 2009. High salt intake was defined as >12 g/day by a self-answered questionnaire and hyperosmolarity was defined as >293 mOsm/L serum osmolarity, calculated using serum sodium, fasting blood glucose, and blood urea nitrogen. Statistical analyses included adjustments for age, gender, body mass index, smoking, drinking alcohol, dyslipidemia, hyperuricemia, and chronic kidney disease. In the patients with normal osmolarity, the group with high salt intake had a higher cumulative incidence of hypertension than the group with normal salt intake (8.4% versus 6.7%, p = 0.023). In contrast, in the patients with high osmolarity, the cumulative incidence of hypertension was similar in the group with high salt intake and in the group with normal salt intake (13.1% versus 12.9%, p = 0.84). The patients with hyperosmolarity had a higher incidence of hypertension over five years compared to that of the normal osmolarity group (p < 0.001). After multiple adjustments, elevated osmolarity was an independent risk for developing hypertension (OR (odds ratio), 1.025; 95% CI (confidence interval), 1.006–1.044), regardless of the amount of salt intake. When analyzed in relation to each element of calculated osmolarity, serum sodium and fasting blood glucose were independent risks for developing hypertension. Our results suggest that hyperosmolarity is a risk for developing hypertension regardless of salt intake.

The optimal range of serum uric acid (urate) associated with the lowest risk for developing cardiometabolic diseases is unknown in a generally healthy population. This 5-year cohort study is designed to identify the optimal range of serum urate. The data were collected from 13,070 Japanese between ages 30 and 85 at the baseline (2004) from the Center for Preventive Medicine, St. Luke’s International Hospital, Tokyo. We evaluated the number of subjects (and prevalence) of those free of the following conditions: hypertension, diabetes, dyslipidemia, and chronic kidney disease (CKD) over 5 years for each 1 mg/dL of serum urate stratified by sex. Furthermore, the odds ratios (ORs) for remaining free of these conditions were calculated with multiple adjustments. Except for truly hypouricemic subjects, having lower serum urate was an independent factor for predicting the absence of hypertension, dyslipidemia, and CKD, but not diabetes. The OR of each 1 mg/dL serum urate decrease as a protective factor for hypertension, dyslipidemia, and CKD was 1.153 (95% confidence interval, 1.068–1.245), 1.164 (1.077–1.258), and 1.226 (1.152–1.306) in men; 1.306 (1.169–1.459), 1.121 (1.022–1.230), and 1.424 (1.311–1.547) in women, respectively. Moreover, comparing serum urate of 3–5 mg/dL in men and 2–4 mg/dL in women, hypouricemia could be a higher risk for developing hypertension (OR: 4.532; 0.943–21.78) and CKD (OR: 4.052; 1.181–13.90) in women, but not in men. The optimal serum urate range associated with the lowest development of cardiometabolic diseases was less than 5 mg/dL for men and 2–4 mg/dL for women, respectively.

A bicuspid aortic valve and/or coarctation of the aorta (COA) are often associated with dilatation of the ascending aorta and para-coarctation. Congenital heart diseases (CHD), such as truncus arteriosus, transposition of the great arteries (TGA), tetralogy of Fallot (TOF), hypoplastic left heart syndrome (HLHS), single ventricle with pulmonary stenosis/atresia and the Fontan procedure, are also associated with aortic root dilatation, aneurysm and rarely, dissection, which can be fatal and require aortic valve and root surgery. A significant subset of adults with complex CHD exhibit progressive dilatation of the aortic root even after repair due to aortic medial degeneration. Medial degeneration in the ascending aorta is prevalent among the above CHD. In Marfan syndrome, bicuspid aortic valve and COA, medial degeneration is more extensive and severe than in another complex CHD. Accordingly, the incidence of ascending aortic dilatation, dissection and rupture is higher in the former. This aortic medial degeneration in CHD may either be intrinsic or secondary to the increased volume overload of the aortic root due to right-to-left shunting, or a combination of both. The association of aortic pathophysiological abnormalities, aortic dilatation and aorto-ventricular interaction is clinically referred to as “aortopathy”. The major purpose of medical treatment for aortopathy is to reduce the structural changes within the aortic wall and slow down the progression of aortic dilatation to reduce the risk of cardiovascular events. Several medications have been studied, including β-blockers, angiotensin II type I (AT1) receptor blockers (ARBs) and Ca-antagonists. However, the results, except for Marfan syndrome, are limited. In aortopathy, concomitant aortic valve and aortic root repair/replacement is required. The Bentall operation comprises root replacement with an aortic tube graft and mechanical valve, and has been widely applied. On the other hand, valve-sparing operations have been developed in order to preserve the aortic valve.

Obesity is a risk factor for hypertension, diabetes mellitus (DM), dyslipidemia, and hyperuricemia. Here, we evaluated whether the same body mass index (BMI) for the U.S. population conferred similar metabolic risk in Japan. This was a cross-sectional analysis involving 90,047 Japanese adults (18–85 years) from St. Luke’s International Hospital, Tokyo, Japan and 14,734 adults from National Health and Nutrition Examination Survey (NHANES) collected in the U.S. We compared the prevalence of hypertension, DM, dyslipidemia, and hyperuricemia according to BMI in Japan and the U.S. The prevalence of hypertension, DM, and dyslipidemia were significantly higher in the U.S. than Japan, whereas the prevalence of hyperuricemia did not differ between countries. Higher BMI was an independent risk factor for hypertension, DM, dyslipidemia, and hyperuricemia both in Japan and in the U.S. after adjusting for age, sex, smoking and drinking habits, chronic kidney disease, and other cardiovascular risk factors. The BMI cut-off above which the prevalence of these cardio-metabolic risk factors increased was significantly higher in the U.S. than in Japan (27 vs. 23 kg/m² for hypertension, 29 vs. 23 kg/m² for DM, 26 vs. 22 kg/m² for dyslipidemia, and 27 vs. 23 kg/m² for hyperuricemia). Higher BMI is associated with an increased prevalence of hypertension, DM, dyslipidemia, and hyperuricemia both in Japan and U.S. The BMI cut-off above which the prevalence of cardio-metabolic risk factors increases is significantly lower in Japan than the U.S., suggesting that the same definition of overweight/obesity may not be similarly applicable in both countries.

Marfan syndrome, bicuspid aortic valve, and/or coarctation of the aorta are associated with medial abnormalities of the ascending aortic or para-coarctation aorta. Medial abnormalities in the ascending aorta are prevalent in other type of patients with a variety of CHDs such as single ventricle, persistent truncus arteriosus, transposition of the great arteries, hypoplastic left heart syndrome, and tetralogy of Fallot, encompassing a wide age range and may predispose to dilatation, aneurysm, and rapture necessitating aortic valve and root surgery. These CHDs exhibit ongoing dilatation of the aortic root and reduced aortic elasticity and increased aortic stiffness that may relate to intrinsic properties of the aortic root. These aortic dilatation and increased stiffness can induce aortic aneurysm, rapture of the aorta, and aortic regurgitation, but also provoke left ventricular hypertrophy, reduced coronary artery flow, and left ventricular failure. Therefore, a new clinical entity can be used to call this association of aortic pathophysiological abnormality, aortic dilation, and aorto-left ventricular interaction – “aortopathy”.

It is challenging to evaluate aortopathy in congenital heart disease using conventional investigations such as brachial-ankle pulse wave velocity (baPWV). Therefore, we evaluated the cardio-ankle vascular index (CAVI), a dimension of the ascending aorta and plasma transforming growth factor-β1 (TGF-β1) level, in order to find novel noninvasive parameters of aortopathy in adults with repaired tetralogy of Fallot (TOF). Prospectively, we enrolled 42 consecutive adults with TOF (28 patients with repaired TOF were not on ARB, 8 patients with repaired TOF on ARB, 6 patients with no repair or only palliative repair) and 20 age-matched healthy controls. We measured CAVI, baPWV, plasma TGF-β1 level and a diameter of the ascending aorta using echocardiography. The mean age of repaired TOF without ARB were 31.9 ± 9.1 years. An aortic diameter of the ascending aorta, CAVI, and plasma TGF-β1 level were significantly higher in repaired TOF without ARB than those in controls, whereas baPWV did not differ. On a univariate analysis, CAVI, plasma TGF-β1 level and Rastelli procedure were important factors for an aortic diameter of the ascending aorta (r = 0.56, P < 0.01, r = 0.59, P < 0.01, r = 0.39, P < 0.05, respectively) in this population. There was no significant correlation with age, baPWV, NT-pro brain natriuretic peptide (BNP), repair age, shunt duration, aortic regurgitation or right aortic arch. On the other hand, patients with unrepaired or palliative TOF, who had obvious volume overload, showed no significant correlation with CAVI, baPWV or plasma TGF-β1 level. CAVI and plasma TGF-β1 level, not baPWV, correlate to aortopathy in adults with repaired TOF.