Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries.

RATIONALE: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. OBJECTIVE: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. METHODS AND RESULTS: We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10-10, OR=0.69 per C allele). SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10-5). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A, which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. CONCLUSIONS: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A. Genomic and functional data support a causal role of WNT5A at the locus.

Noninvasive identification of left-sided heart failure in a population suspected of pulmonary arterial hypertension.

Exclusion of pulmonary hypertension secondary to left-sided heart disease (left heart failure (LHF)) is pivotal in the diagnosis of pulmonary arterial hypertension (PAH). In case of doubt, invasive measurements are recommended. The aim of the present study was to investigate whether it is possible to diagnose LHF using noninvasive parameters in a population suspected of PAH.300 PAH and 80 LHF patients attended our pulmonary hypertension clinic before August 2010, and were used to build the predictive model. 79 PAH and 55 LHF patients attended our clinic from August 2010, and were used for prospective validation.A medical history of left heart disease, S deflection in V1 plus R deflection in V6 in millimetres on ECG, and left atrial dilation or left valvular heart disease that is worse than mild on echocardiography were independent predictors of LHF. The derived risk score system showed good predictive characteristics: R(2)=0.66 and area under the curve 0.93. In patients with a risk score ≥72, there is 100% certainty that the cause of pulmonary hypertension is LHF. Using this risk score system, the number of right heart catheterisations in LHF may be reduced by 20%.In a population referred under suspicion of PAH, a predictive model incorporating medical history, ECG and echocardiography data can diagnose LHF noninvasively in a substantial percentage of cases.

Clinical Course of TGA After Arterial Switch Operation in the Current Era.

Background: The number of patients with an arterial switch operation (ASO) for transposition of the great arteries (TGA) is steadily growing; limited information is available regarding the clinical course in the current era. Objectives: The purpose was to describe clinical outcome late after ASO in a national cohort, including survival, rates of (re-)interventions, and clinical events. Methods: A total of 1,061 TGA-ASO patients (median age 10.7 years [IQR: 2.0-18.2 years]) from a nationwide prospective registry with a median follow-up of 8.0 years (IQR: 5.4-8.8 years) were included. Using an analysis with age as the primary time scale, cumulative incidence of survival, (re)interventions, and clinical events were determined. Results: At the age of 35 years, late survival was 93% (95% CI: 88%-98%). The cumulative re-intervention rate at the right ventricular outflow tract and pulmonary branches was 36% (95% CI: 31%-41%). Other cumulative re-intervention rates at 35 years were on the left ventricular outflow tract (neo-aortic root and valve) 16% (95% CI: 10%-22%), aortic arch 9% (95% CI: 5%-13%), and coronary arteries 3% (95% CI: 1%-6%). Furthermore, 11% (95% CI: 6%-16%) of the patients required electrophysiological interventions. Clinical events, including heart failure, endocarditis, and myocardial infarction occurred in 8% (95% CI: 5%-11%). Independent risk factors for any (re-)intervention were TGA morphological subtype (Taussig-Bing double outlet right ventricle [HR: 4.9, 95% CI: 2.9-8.1]) and previous pulmonary artery banding (HR: 1.6, 95% CI: 1.0-2.2). Conclusions: TGA-ASO patients have an excellent survival. However, their clinical course is characterized by an ongoing need for (re-)interventions, especially on the right ventricular outflow tract and the left ventricular outflow tract indicating a strict lifelong surveillance, also in adulthood.

Outcomes of the modified Yacoub aortocoronary flap technique for 'non-separable' single sinus coronary arteries with intramural course in the neonatal arterial switch operation.

OBJECTIVES: Coronary transfer remains the most crucial part of the arterial switch operation (ASO); yet, certain coronary anatomies prohibit the use of button or trap-door transfer techniques. In the rare setting of 'non-separable' single sinus coronary arteries with intramural course, the modified Yacoub aortocoronary flap technique is a viable option. The aim of this study is to describe this operative technique and review its early- and mid-term outcomes. METHODS: This retrospective analysis included all cases with 'non-separable' single sinus coronary arteries with intramural course where the modified Yacoub aortocoronary flap technique served as a bail-out option. RESULTS: Of 516 patients who underwent ASO at our institution between January 1977 and April 2022, 14 underwent the modified Yacoub aortocoronary flap technique. The median age at ASO was 10 (interquartile range 7-19) days. Hospital mortality occurred in 3 patients (21.4%), all being related to coronary complications. All hospital survivors were still alive at a median of 9.1 (interquartile range 4.2-18.3) years after the ASO. None of them developed complaints of ischaemia, ventricular arrhythmias, ventricular dysfunction or exercise intolerance. Surveillance computed tomography angiography showed stable aortocoronary relationships free from stenosis, compression and kinking. No reoperations for coronary artery problems and/or neoaortic valve or root problems were needed. CONCLUSIONS: Although close monitoring of early coronary events seems crucial to prevent perioperative mortality, the modified Yacoub aortocoronary flap technique may serve as a viable bail-out option in patients with 'non-separable' single sinus coronary anatomy with intramural course, with excellent results among hospital survivors.

Common genetic variants improve risk stratification after the atrial switch operation for transposition of the great arteries.

BACKGROUND: Clinical factors are used to estimate late complication risk in adults after atrial switch operation (AtrSO) for transposition of the great arteries (TGA), but heterogeneity in clinical course remains. We studied whether common genetic variants are associated with outcome and add value to a clinical risk score in TGA-AtrSO patients. METHODS AND RESULTS: This multicenter study followed 133 TGA-AtrSO patients (aged 28 [IQR 24-35] years) for 13 (IQR 9-16) years and examined the association of genome-wide single-nucleotide polymorphisms (SNPs) with a composite endpoint of symptomatic ventricular arrhythmia, heart failure hospitalization, ventricular assist device implantation, heart transplantation, or mortality. Thirty-two patients (24%) reached the endpoint. The genome-wide association study yielded one genome-wide significant (p < 1 × 10-8) locus and 18 suggestive loci (p < 1 × 10-5). A genetic risk score constructed on the basis of independent SNPs with p < 1 × 10-5 was associated with outcome after correction for the clinical risk score (HR = 1.26/point increase [95%CI 1.17-1.35]). Risk stratification improved with a combined risk score (clinical score + genetic score) compared to the clinical score alone (p = 2 × 10-16, C-statistic 0.95 vs 0.85). In 51 patients with a clinical intermediate (5-20%) 5-year risk of events, the combined score reclassified 32 patients to low (<5%) and 5 to high (>20%) risk. Stratified by the combined score, observed 5-year event-free survival was 100%, 79% and 31% for low, intermediate, and high-risk patients, respectively. CONCLUSIONS: Common genetic variants may explain some variation in the clinical course in TGA-AtrSO and improve risk stratification over clinical factors alone, especially in patients at intermediate clinical risk. These findings support the hypothesis that including genetic variants in risk assessment may be beneficial.

Medication in adults after atrial switch for transposition of the great arteries: clinical practice and recommendations.

AIMS: Heart failure is the main threat to long-term health in adults with transposition of the great arteries (TGA) corrected by an atrial switch operation (AtrSO). Current guidelines refrain from recommending heart failure medication in TGA-AtrSO, as there is insufficient data to support the hypothesis that it is beneficial. Medication is therefore prescribed based on personal judgements. We aimed to evaluate medication use in TGA-AtrSO patients and examine the association of use of renin-angiotensin-aldosterone system (RAAS) inhibitors and ß-blockers with long-term survival. METHODS AND RESULTS: We identified 150 TGA-AtrSO patients [median age 30 years (interquartile range 25-35), 63% male] included in the CONCOR registry from five tertiary medical centres with subsequent linkage to the Dutch Dispensed Drug Register for the years 2006-2014. Use of RAAS inhibitors, ß-blockers, and diuretics increased with age, from, respectively, 21% [95% confidence interval (CI) 14-40], 12% (95% CI 7-21), and 3% (95% CI 2-7) at age 25, to 49% (95% CI 38-60), 51% (95% CI 38-63), and 41% (95% CI 29-54) at age 45. Time-varying Cox marginal structural models that adjusted for confounding medication showed a lower mortality risk with use of RAAS inhibitors and ß-blockers in symptomatic patients [hazard ratio (HR) = 0.13 (95% CI 0.03-0.73); P = 0.020 and HR = 0.12 (95% CI 0.02-0.17); P = 0.019, respectively]. However, in the overall cohort, no benefit of RAAS inhibitors and ß-blockers was seen [HR = 0.93 (95% CI 0.24-3.63); P = 0.92 and HR = 0.98 (0.23-4.17); P = 0.98, respectively]. CONCLUSION: The use of heart failure medication is high in TGA-AtrSO patients, although evidence of its benefit is limited. This study showed lower risk of mortality with use of RAAS inhibitors and ß-blockers in symptomatic patients only. These findings can direct future guidelines, supporting use of RAAS inhibitors and ß-blockers in symptomatic, but not asymptomatic patients.

Long-term outcome after the arterial switch operation: 43 years of experience.

OBJECTIVES: The objective of this study was to assess our 43-year experience with arterial switch operation (ASO) for transposition of the great arteries (TGA) by analysing cardiac outcome measures (hospital and late mortality, reoperations and catheter interventions, significant coronary artery obstruction) and to identify risk factors for reoperation and catheter interventions. METHODS: A total of 490 patients who underwent ASO for TGA from 1977 to 2020 were included in this retrospective, single-centre study. Data on reoperation and catheter intervention of hospital survivors were estimated by the Kaplan-Meier method and compared using a long-rank test. Risk factors for reoperation and/or catheter intervention were assessed by multivariate Cox regression analysis. RESULTS: Hospital mortality occurred in 43 patients (8.8%), late death in 12 patients (2.9%) and 43 patients were lost to follow-up. Median follow-up time of 413 hospital survivors was 15.6 (interquartile range 7.0-22.4) years. Reoperations were performed in 83 patients (117 reoperations). Neoaortic valve regurgitation with root dilatation was the second most common indication for reoperation (15/83 patients, 18.1%) after right ventricular outflow tract obstruction (50/83 patients, 60.2%). Risk factors for any reoperation on multivariable analysis were: TGA morphological subtype [TGA with ventricular septal defect: hazard ratio (HR) = 1.99, 95% confidence interval (CI) 1.18-3.36; P = 0.010 and Taussig-Bing: HR = 2.17, 95% CI 1.02-4.64; P = 0.045], aortic arch repair associated with ASO (HR = 3.03, 95% CI 1.62-5.69; P = 0.001) and a non-usual coronary artery anatomy (HR = 2.41, 95% CI 1.45-4.00; P = 0.001). One hundred and one catheter interventions were performed in 54 patients, usually for relief of supravalvular pulmonary stenosis (44/54 patients, 81.5%) or arch obstruction (10/54 patients, 18.5%). Main risk factor for catheter intervention on multivariable analysis was aortic arch repair associated with ASO (HR = 2.95, 95% CI 1.37-6.36; P = 0.006). Significant coronary artery stenosis was relatively uncommon (9/413 patients, 2.2%) but may be underrepresented. CONCLUSIONS: Patients after ASO typically have good long-term clinical outcomes but reoperations and interventions remain necessary in some patients. Neoaortic valve regurgitation with root dilatation is the second most common indication for reoperation after right ventricular outflow tract obstruction and an increasing need for neoaortic valve and root redo surgery in future is to be expected.

The Prevalence of Cardiac Diseases in a Contemporary Large Cohort of Dutch Elderly Ankylosing Spondylitis Patients-The CARDAS Study.

OBJECTIVES: The aim of the present study was to determine the prevalence of specific cardiac manifestations, i.e., conduction disorders, valvular disease and diastolic left ventricular (LV) dysfunction, in a large cross-sectional controlled cohort of elderly ankylosing spondylitis (AS) patients. METHODS: This cross-sectional study assessed the prevalence of valvular disease, conduction disorders and LV dysfunction in 193 randomly selected AS patients compared with 74 osteoarthritis (OA) controls aged 50-75 years. Patients underwent conventional and tissue Doppler echocardiography in combination with clinical and laboratory assessments. Multivariate regression analyses were performed to compare the odds of mitral valve regurgitation (MVR) and aortic valve regurgitation (AVR) between AS patients and OA controls. RESULTS: The prevalence of diastolic dysfunction was trivial and comparable in AS patients compared to controls (respectively, 4% and 3%) and had no further clinical relevance. In addition, the prevalence of conduction disturbances was similar in both groups, with little clinical relevance, respectively 23% vs. 24%. The prevalence of AVR was significantly higher in AS patients compared to the controls, respectively 23% (9% trace, 12% mild, 1% moderate, 1% severe, 1% prosthesis) vs. 11%, p = 0.04. After correcting for age, sex and CV risk factors, AS patients had an odds ratio of 4.5 (95% CI 1.1-13.6) for AVR compared to the controls. In contrast, the prevalence values of MVR were similar and mostly not clinically relevant in AS patients and controls, respectively 36% and 32% and p = 0.46. CONCLUSION: The prevalence of diastolic LV dysfunction and conduction disorders was mostly not clinically relevant, and similar in AS patients and controls. However, AS patients had an up to five times increased odds to develop AVR compared to controls. Therefore, echocardiographic screening of elderly (50-75 years) AS patients should be considered.

Clinical Course Long After Atrial Switch: A Novel Risk Score for Major Clinical Events.

Background Patients with transposition of the great arteries corrected by an atrial switch operation experience major clinical events during adulthood, mainly heart failure (HF) and arrhythmias, but data on the emerging risks remain scarce. We assessed the risk for events during the clinical course in adulthood, and provided a novel risk score for event-free survival. Methods and Results This multicenter study observed 167 patients with transposition of the great arteries corrected by an atrial switch operation (61% Mustard procedure; age, 28 [interquartile range, 24-36] years) for 13 (interquartile range, 9-16) years, during which 16 (10%) patients died, 33 (20%) had HF events, defined as HF hospitalizations, heart transplantation, ventricular assist device implantation, or HF-related death, and 15 (9%) had symptomatic ventricular arrhythmias. Five-year risk of mortality, first HF event, and first ventricular arrhythmia increased from 1% each at age 25 years, to 6% (95% CI, 4%-9%), 23% (95% CI, 17%-28%), and 5% (95% CI, 2%-8%), respectively, at age 50 years. Predictors for event-free survival were examined to construct a prediction model using bootstrapping techniques. A prediction model combining age >30 years, prior ventricular arrhythmia, age >1 year at repair, moderate or greater right ventricular dysfunction, severe tricuspid regurgitation, and mild or greater left ventricular dysfunction discriminated well between patients at low (<5%), intermediate (5%-20%), and high (>20%) 5-year risk (optimism-corrected C-statistic, 0.86 [95% CI, 0.82-0.90]). Observed 5- and 10-year event-free survival rates in low-risk patients were 100% and 97%, respectively, compared with only 31% and 8%, respectively, in high-risk patients. Conclusions The clinical course of patients undergoing atrial switch increasingly consists of major clinical events, especially HF. A novel risk score stratifying patients as low, intermediate, and high risk for event-free survival provides information on absolute individual risks, which may support decisions for pharmacological and interventional management.

Echocardiographic determinants of the clinical condition in patients with a systemic right ventricle.

BACKGROUND: Ventricular systolic and diastolic function, as measured by echocardiography, are diminished in patients with a systemic right ventricle (RV). As the clinical implications of these finding remained unknown, we aimed to identify echocardiographic parameters of systolic and diastolic ventricular function that are independent determinants of the clinical condition in these patients. METHODS: Forty-six adult patients (61% male; mean age 33 [range 18-69] years) with a systemic RV underwent echocardiography to assess qualitative and quantitative systolic and diastolic function of the systemic RV and the subpulmonary left ventricle (LV). Uni- and multivariate linear regression analyses were performed to identify independent echocardiographic determinants for NYHA class, maximal exercise capacity (V'O(2peak)) and NT-proBNP levels. RESULTS: We found qualitative assessment of RV and LV function to be significantly associated with NYHA class (RV: ß= 0.26; P = 0.05 and LV: ß= 0.82; P < 0.01), V'O(2peak) (RV: ß=-10.4; P < 0.05 and LV: ß=-18.4; P < 0.05) and NT-proBNP levels (RV: ß= 0.58; P < 0.01 and LV: ß= 1.40; P < 0.001). Tricuspid annulus plane systolic excursion (TAPSE) was significantly associated with NYHA class (ß=-0.92; P = 0.001), V'O(2peak) (ß= 18.5; P = 0.05), and serum NT-proBNP levels (ß=-1.00; P < 0.05). Associations between quantitative parameters of systolic subpulmonary LV function and clinical parameters were less distinct. We found no associations between RV and LV diastolic function and clinical parameters. CONCLUSIONS: Qualitative function of the systemic RV and the subpulmonary LV, and TAPSE, are determinants of clinical condition in patients with a systemic RV. These patients' clinical condition could not be determined by echocardiographically measured diastolic RV function, and systolic and diastolic LV function.

The Effect of Anti-TNF Therapy on Cardiac Function in Rheumatoid Arthritis: An Observational Study.

Congestive heart failure (CHF) is the second most prevalent cause of death in rheumatoid arthritis (RA). The systemic inflammatory state in RA patients is deemed responsible for this finding. Anti-inflammatory treatment with anti-tumor necrosis factor (anti-TNF) therapy decreases CV risk and subsequently might improve the cardiac function by lowering the overall inflammatory state. This study investigated the effect of anti-TNF on the cardiac function in RA patients. Fifty one RA patients were included, of which thirty three completed follow-up. Included patients were >18 years, had moderate-high disease activity and no history of cardiac disease. Patients were assessed at baseline and after six months of anti-TNF treatment. Patients underwent conventional Speckle tracking and tissue Doppler echocardiography in combination with clinical and laboratory assessments at baseline and follow-up. The left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) showed no changes during follow-up, LVEF 63% (±9) to 62% (±8) p = 0.097 and GLS -20 (±4) to -20 (±3) p = 0.79, respectively. Furthermore, E/e' nor E/A changed significantly between baseline and follow-up, respectively 8 (7-9) and 8 (7-9) p = 0.17 and 1.1 (±0.4) and 1.1 (±0.4) p = 0.94. Follow-up NT-proBNP decreased with 23%, from 89 ng/L (47-142) to 69 ng/L (42-155), p = 0.10. Regression analysis revealed no association between change in inflammatory variables and cardiac function. Echocardiography showed no effect of anti-TNF treatment on the cardiac function in RA patients with low prevalence of cardiac dysfunction. Moreover, NT-proBNP decreased, possibly indicating (subtle) improvement of the cardiac function.

Risk of coronary artery disease in adults with congenital heart disease: A comparison with the general population.

BACKGROUND: Coronary artery disease (CAD) will increasingly determine outcome in the aging adult congenital heart disease (CHD) population. We aimed to determine sex-specific incidence of CAD in adult CHD patients throughout adulthood, compared to the general population. METHODS AND RESULTS: We followed 11,723 adult CHD patients (median age 33 years; 49% male; 57% mild, 34% moderate, 9% severe CHD) from the Dutch CONCOR registry, and two age-sex-matched persons per patient from the general population for first CAD event in national registers (period 2002-2012). Incidence rates were estimated using smoothed hazard functions. CAD risk during follow-up, stratified by CHD severity, was compared using proportional subdistribution hazards regression. In ACHD patients, 103 CAD events (43 women) occurred over 60,456 person-years. Rates per 1000person-years increased from 0.3(95% confidence interval: 0.1-0.6) at age 20 to 5.8(3.7-8.9) at 70 years in female, and from 0.5(0.3-1.0) to 7.8(5.1-11.8) in male patients. Compared to the general population, relative risk was 12.0(2.5-56.3) in women and 4.6(1.7-12.1) in men aged 20 years. Relative risk declined with age, remaining significant up to age ~65 years in women and ~50 years in men. In patients with mild, moderate and severe CHD, CAD risk was 1.3(0.9-1.9), 1.6(1.0-2.5) and 2.9(1.3-6.9) times increased compared to the general population, respectively. CONCLUSIONS: We found increased CAD risk in adult CHD patients, with greater relative risk at younger age, in women and those with more severe CHD. These results underline the importance of screening for and treatment of CAD risk factors in these patients.

Doppler gradients, valve area and ventricular function in pregnant women with aortic or pulmonary valve disease: Left versus right.

OBJECTIVE: Little is known about the course of echocardiographic parameters used for the evaluation of valvular heart disease (VHD) during pregnancy, hampering interpretation of possible changes (physiological vs. pathophysiological). Therefore we studied the course of these parameters and ventricular function in pregnant women with aortic and pulmonary VHD. METHODS: The cohort comprised 66 pregnant women enrolled in the prospective ZAHARA studies or evaluated by an identical protocol who had pulmonary VHD or aortic VHD (stenosis/prosthetic valve). The control group comprised 46 healthy pregnant women. Echocardiography was performed preconception, during pregnancy and 1 year postpartum. Peak gradient, mean gradient, aortic valve area (AVA)/effective orifice area (EOA), left ventricular ejection fraction (LVEF) and right ventricular function (RVF; TAPSE) were assessed. RESULTS: Peak and mean gradients increased during pregnancy compared to preconception in women with aortic VHD and controls (p < 0.0125), but not in women with pulmonary VHD. AVA/EOA remained unchanged. Preconception and postpartum gradients were comparable in all groups. Mean LVEF was normal in pregnant women with VHD and controls. Mean TAPSE was lower (p < 0.001) in women with pulmonary VHD compared to women with aortic VHD and controls (<20 mm vs. ≥23 mm; p < 0.001). In women with pulmonary VHD a decrease of TAPSE was observed during pregnancy (p = 0.005). CONCLUSION: Physiological changes during pregnancy lead to increased Doppler gradients in women with aortic VHD. This increase was not found in women with pulmonary VHD, probably caused by impaired RVF. Therefore, evaluation of RVF during pregnancy might be important to prevent underestimation of the degree of stenosis.

The Natural and Unnatural History of Congenital Aortic Arch Abnormalities Evaluated in an Adult Survival Cohort.

BACKGROUND: This study describes the different types of congenital vascular rings according to their anatomy, symptoms, and age at clinical onset and reports the surgical outcomes. METHODS: A retrospective observational database study was conducted, reviewing the medical charts of 69 adult survivors with a history of a vascular ring, identified from the Dutch Congenital Cor vitia database. RESULTS: Median age at presentation was 8.5 years (0-53.0 years). Thirty patients (43.5%) had a "left aortic arch with aberrant right subclavian artery," 21 patients (30.4%) a "double aortic arch," and 16 patients (23.2%) a "right aortic arch with aberrant left subclavian artery." The main symptomatology at presentation comprised respiratory symptoms (82.9%). Almost three-quarters of patients were also diagnosed with asthma/bronchial hyperreactivity. Patients with a double aortic arch had more symptoms than patients with a left aortic arch with aberrant right subclavian artery and right aortic arch with aberrant left subclavian artery (P < 0.001), requiring surgery most often (P < 0.001). In patients with childhood onset of symptoms, preoperative spirometry (ie, peak expiratory flows) was more often abnormal as compared with adult patients (P = 0.007). Surgery was performed in 42.0% of all patients at a median age of 17 years (0-63.0 years). Twenty-four (92.3%) of the operated patients showed improvement or complete relief of symptoms shortly after surgery. Of 26 asymptomatic nonoperated patients, 3 patients (11.5%) eventually developed symptoms. CONCLUSIONS: The low incidence of vascular rings, their anatomic heterogeneity, and a wide range of common symptoms often lead to misdiagnosis. Clinical awareness is warranted as a large subset of patients could benefit from surgery, even at an adult age.

High burden of drug therapy in adult congenital heart disease: polypharmacy as marker of morbidity and mortality.

AIMS: To assess medication use in adult congenital heart disease (ACHD) patients compared to the age- and sex-matched general population, identify patterns of pharmacotherapy, and analyse associations between pharmacotherapy and adverse outcomes in ACHD. METHODS AND RESULTS: Data of 14 138 ACHD patients from the CONCOR registry [35 (24-48) years, 49% male] and age- and sex-matched referents (1:10 ratio) were extracted from the Dutch Dispensed Drug Register for the years 2006-14. Adult congenital heart disease patients had more cardiovascular and non-cardiovascular drugs than referents (median 3 vs. 1, P < 0.001). Polypharmacy, defined as ≥5 dispensed drug types yearly, was present in 30% of ACHD and 15% of referents {odds ratio [OR] = 2.47 [95% confidence interval (CI) 2.39-2.54]}. Polypharmacy was independently associated with female sex [OR = 1.92 (95% CI 1.88-1.96)], older age [for men: OR = 2.3/10 years (95% CI 2.2-2.4) and for women: OR = 1.6/10 years (95% CI 1.5-1.6); Pinteraction < 0.001], and ACHD severity [mild: OR = 2.51 (95% CI 2.40-2.61), moderate: OR = 3.22 (95% CI 3.06-3.40), severe: OR = 4.87 (95% CI 4.41-5.38)]. Cluster analysis identified three subgroups with distinct medication patterns; a low medication use group (8-year cumulative survival: 98%), and a cardiovascular and comorbidity group with lower survival (92% and 95%, respectively). Cox regression revealed a strong association between polypharmacy and mortality [hazard ratio (HR) = 3.94 (95% CI 3.22-4.81)], corrected for age, sex, and defect severity. Polypharmacy also increased the risk of hospitalization for adverse drug events [HR = 4.58 (95% CI 2.04-10.29)]. CONCLUSION: Both cardiovascular and non-cardiovascular medication use is high in ACHD with twice as much polypharmacy compared with the matched general population. Patients with polypharmacy had a four-fold increased risk of mortality and adverse drug events. Recognition of distinct medication patterns can help identify patients at highest risk. Drug regimens need repeating evaluation to assess the appropriateness of all prescriptions. More high-quality studies are needed to improve ACHD care with more evidence-based pharmacotherapy.

Progression of aortic root dilatation and aortic valve regurgitation after the arterial switch operation.

OBJECTIVE: To study neo-aortic growth and the evolution of neo-aortic valve regurgitation (AR) in patients with transposition of the great arteries (TGA) after arterial switch operation (ASO) from newborn to adulthood and to identify patients at risk. METHODS: Neo-aortic dimensions (annulus/root/sinotubular junction) and neo-aortic valve regurgitation were assessed serially in 345 patients with TGA who underwent ASO between 1977 and 2015. Linear mixed-effect models were used to assess increase of neo-aortic dimensions over time and to identify risk factors for dilatation. Risk factor analysis for AR by using time-dependent Cox regression models. RESULTS: After a rapid increase in the first year after ASO and proportional growth in childhood, neo-aortic dimensions continue to increase in adulthood without stabilisation. Annual diameter increase in adulthood was 0.39±0.06, 0.63±0.09 and 0.54±0.11 mm for, respectively, neo-aortic annulus, root and sinotubular junction, all significantly exceeding normal growth. AR continues to develop over time: freedom from AR ≥moderate during the first 25 years post-ASO was 69%. Risk factors for root dilatation were complex TGA anatomy (TGA-ventricular septal defect (VSD), double outlet right ventricle with subpulmonary VSD) and male gender. Risk factors for AR ≥moderate were: complex TGA anatomy and neo-aortic growth. Per millimetre increase in aortic root dimension, there was a 9% increase in the hazard of AR ≥moderate. Bicuspid pulmonary valve did not relate to the presence of root dilatation or AR. CONCLUSION: After ASO, neo-aortic dilatation proceeds beyond childhood and is associated with an increase in AR incidence over time. Careful follow-up of the neo-aortic valve and root function is mandatory, especially in males and in patients with complex TGA anatomy.

Factors associated with coronary artery disease and stroke in adults with congenital heart disease.

OBJECTIVE: To determine factors associated with coronary artery disease (CAD) and ischaemic stroke in ageing adult congenital heart disease (ACHD) patients. METHODS: We performed a multicentre case-control study, using data from the national CONgenital CORvitia (CONCOR) registry to identify ACHD patients within five participating centres. Patients with CAD were matched (1:2 ratio) with ACHD patients without CAD on age, CHD defect group and gender. Patients with ischaemic stroke (or transient ischaemic attack) were matched similarly. Medical charts were reviewed and a standardised questionnaire was used to determine presence of risk factors. RESULTS: Of 6904 ACHD patients, a total of 55 cases with CAD (80% male, mean age 55.1±12.4 years) and 56 cases with stroke (46% male, mean age 46.9±15.2) were included and matched with control patients. In multivariable logistic regression analysis, traditional atherosclerotic risk factors (hypertension (OR 2.45; 95% CI 1.15 to 5.23), hypercholesterolaemia (OR 3.99; 95% CI 1.62 to 9.83) and smoking (OR 2.25; 95% CI 1.09 to 4.66)) were associated with CAD. In contrast, these risk factors were not associated with ischaemic stroke. In multivariable analysis, stroke was associated with previous shunt operations (OR 4.20; 95% CI 1.36 to 12.9), residual/unclosed septal defects (OR 2.38; 95% CI 1.03 to 5.51) and left-sided mechanical valves (OR 2.67; 95% CI 1.09 to 6.50). CONCLUSIONS: Traditional atherosclerotic risk factors were associated with CAD in ACHD patients. In contrast, ischaemic stroke was related to factors (previous shunts, septal defects, mechanical valves) suggesting a cardioembolic aetiology. These findings may inform surveillance and prevention strategies.

Assessment of aortic stiffness in patients with ankylosing spondylitis using cardiovascular magnetic resonance.

To evaluate aortic stiffness in patients with ankylosing spondylitis (AS) using cardiovascular magnetic resonance (CMR) and to assess its association with AS characteristics and left ventricular (LV) remodeling. In this prospective study, 14 consecutive AS patients were each matched to two controls without cardiovascular symptoms or known cardiovascular disease who underwent CMR imaging for the assessment of aortic arch pulse wave velocity (PWV) at 1.5 Tesla. To enhance comparability of the samples, matching was done with replacement resulting in 20 unique controls. Only AS patients with abnormal findings on screening echocardiography were included in this exploratory study. Cine CMR was used to assess LV geometry and systolic function, and late gadolinium enhancement was performed to determine the presence of myocardial hyperenhancement (i.e., fibrosis). Aortic arch PWV was significantly higher in the AS group compared with the control group (median 9.7 m/s, interquartile range [IQR] 7.1 to 11.8 vs. 6.1 m/s, IQR 4.6 to 7.6 m/s; p < 0.001). PWV was positively associated with functional disability as measured by BASFI (R: 0.62; p = 0.018). Three patients (21%) with a non-ischemic pattern of hyperenhancement showed increased PWV (11.7, 12.3, and 16.5 m/s) as compared to the 11 patients without hyperenhancement (9.0 m/s, IQR 6.6 to 10.5 m/s; p = 0.022). PWV was inversely associated with LV ejection fraction (R: - 0.63; p = 0.015), but was not found to be statistically correlated to LV volumes or mass. Aortic arch PWV was increased in our cohort of patients with AS. Higher PWV in the aortic arch was associated with functional disability, the presence of non-ischemic hyperenhancement, and reduced LV systolic function.

Insights into cardiac involvement in ankylosing spondylitis from cardiovascular magnetic resonance.

OBJECTIVE: To evaluate cardiac involvement in patients with ankylosing spondylitis using cardiac magnetic resonance (CMR). METHODS: Patients with ankylosing spondylitis without cardiovascular symptoms or known cardiovascular disease were screened by transthoracic echocardiography (TTE) for participation in this exploratory CMR study. We prospectively enrolled 15 ankylosing spondylitis patients with an abnormal TTE for further tissue characterisation using late gadolinium enhancement (LGE) and T1 mapping. T1 mapping was used to calculate myocardial extracellular volume (ECV). Disease activity was assessed by C reactive protein (CRP) and erythrocyte sedimentation rate (ESR) measurements. RESULTS: In the total of 15 included patients, 14 had a complete CMR exam (mean age 62 years, 93% male and mean disease duration 21 years). Left ventricular (LV) diastolic dysfunction was the most common finding on TTE (79%), followed by aortic root dilatation (14%), right ventricular (RV) dilatation (7%) and RV dysfunction (7%). CMR revealed focal hyperenhancement in three patients (21%), all with a particular pattern of enhancement. LV dysfunction, as defined by a LV ejection fraction below 55%, was observed in five patients (36%). Myocardial ECV was correlated with the CRP concentration (R=0.78, p<0.01) and ESR level (RS=0.73, p<0.01). CONCLUSIONS: In patients with ankylosing spondylitis, CMR with cine imaging and LGE identified global LV dysfunction and focal areas of hyperenhancement. Myocardial ECV, quantified by CMR T1 mapping, was associated with the degree of disease activity. These results may suggest the presence of cardiac involvement in ankylosing spondylitis and may show the potential of ECV as a marker for disease monitoring.