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.

Left and right ventricular strain-volume/area loops: a narrative review of current physiological understanding and potential clinical value.

Traditionally, echocardiography is used for volumetric measurements to aid in assessment of cardiac function. Multiple echocardiographic-based assessment techniques have been developed, such as Doppler ultrasound and deformation imaging (e.g., peak global longitudinal strain (GLS)), which have shown to be clinically relevant. Volumetric changes across the cardiac cycle can be related to deformation, resulting in the Ventricular Strain-Volume/Area Loop. These Loops allow assessment of the dynamic relationship between longitudinal strain change and volumetric change across both systole and diastole. This integrated approach to both systolic and diastolic function assessment may offer additional information in conjunction with traditional, static, measures of cardiac function or structure. The aim of this review is to summarize our current understanding of the Ventricular Strain-Volume/Area Loop, describe how acute and chronic exposure to hemodynamic stimuli alter Loop characteristics, and, finally, to outline the potential clinical value of these Loops in patients with cardiovascular disease. In summary, several studies observed Loop changes in different hemodynamic loading conditions and various (patho)physiological conditions. The diagnostic and prognostic value, and physiological interpretation remain largely unclear and have been addressed only to a limited extent.

Peripheral microvascular function is linked to cardiac involvement on cardiovascular magnetic resonance in systemic sclerosis-related pulmonary arterial hypertension.

AIMS: Systemic sclerosis (SSc) is characterized by vasculopathy, inflammation, and fibrosis, and carries one of the worst prognoses if patients also develop pulmonary arterial hypertension (PAH). Although PAH is a known prognosticator, patients with SSc-PAH demonstrate disproportionately high mortality, presumably due to cardiac involvement. In this cross-sectional study, the relationship between cardiac involvement revealed by cardiovascular magnetic resonance (CMR) and systemic microvascular disease severity measured with nailfold capillaromicroscopy (NCM) in patients with SSc-PAH is evaluated and compared with patients with idiopathic PAH (IPAH). METHODS AND RESULTS: Patients with SSc-PAH and IPAH underwent CMR, echocardiography, and NCM with post-occlusive reactivity hyperaemia (PORH) testing on the same day. CMR imaging included T2 (oedema), native, and post-contrast T1 mapping to measure the extracellular volume fraction (ECV, fibrosis) and adenosine-stress-perfusion imaging measuring the relative myocardial upslope (microvascular coronary perfusion). Measures of peripheral microvascular function were related to CMR indices of oedema, fibrosis, and myocardial perfusion. SSc-PAH patients (n = 20) had higher T2 values and a trend towards a higher ECV, compared with IPAH patients (n = 5), and a lower nailfold capillary density (NCD) and reduced capillary recruitment after PORH. NCD correlated with ECV and T2 (r = -0.443 and -0.464, respectively, P < 0.05 for both) and with markers of diastolic dysfunction on echocardiography. PORH testing, but not NCD, correlated with the relative myocardial upslope (r = 0.421, P < 0.05). CONCLUSION: SSc-PAH patients showed higher markers of cardiac fibrosis and inflammation, compared with IPAH patients. These markers correlated well with peripheral microvascular dysfunction, suggesting that SSc-driven inflammation and vasculopathy concurrently affect peripheral microcirculation and the heart. This may contribute to the disproportionate high mortality in SSc-PAH.

Exercised-based cardiac rehabilitation associates with lower all-cause mortality in patients with primary pulmonary hypertension.

Background: Despite pharmacological therapies to improve outcomes of pulmonary hypertension (PH), poor long-term survival remains. Exercised-based cardiac rehabilitation (ExCR) may be an alternative strategy to improve prognosis. Therefore, using an electronic medical record (EMR) database, the objective of this study was to compare mortality between patients with primary PH with ExCR vs. propensity-matched PH patients without ExCR. Methods: The retrospective analysis was conducted on February 15, 2023 using anonymized data within TriNetX, a global federated health research network. All patients were aged ≥18 years with primary PH recorded in EMRs with at least 1-year follow-up from ExCR. Using logistic regression models, patients with PH with an EMR of ExCR were 1:1 propensity score-matched with PH patients without ExCR for age, sex, race, and comorbidities, and cardiovascular care. Results: In total, 109,736 patients with primary PH met the inclusion criteria for the control group and 784 patients with primary PH met the inclusion criteria for the ExCR cohort. Using the propensity score-matched cohorts, 1-year mortality from ExCR was proportionally lower with 13.6% (n = 101 of 744 patients) in the ExCR cohort compared to 23.3% (n = 174 of 747 patients) in the controls (OR 0.52, 95% CI 0.40-0.68). Conclusion: The present study of 1,514 patients with primary PH suggests that ExCR is associated with 48% lower odds of 1-year mortality, when compared to propensity score-matched patients without ExCR.

Nailfold capillaroscopy and candidate-biomarker levels in systemic sclerosis-associated pulmonary hypertension: A cross-sectional study.

Objectives: Pulmonary hypertension is one of the leading causes of death in systemic sclerosis. Early detection and treatment of pulmonary hypertension in systemic sclerosis is crucial. Nailfold capillaroscopy microscopy, vascular autoantibodies AT1R and ETAR, and several candidate-biomarkers have the potential to serve as noninvasive tools to identify systemic sclerosis patients at risk for developing pulmonary hypertension. Here, we explore the classifying potential of nailfold capillaroscopy microscopy characteristics and serum levels of selected candidate-biomarkers in a sample of systemic sclerosis patients with and without different forms of pulmonary hypertension. Methods: A total of 81 consecutive systemic sclerosis patients were included, 40 with systemic sclerosis pulmonary hypertension and 41 with no pulmonary hypertension. In each group, quantitative and qualitative nailfold capillaroscopy microscopy characteristics, vascular autoantibodies AT1R and ETAR, and serum levels of 24 soluble serum factors were determined. For evaluation of the nailfold capillaroscopy microscopy characteristics, linear regression analysis accounting for age, sex, and diffusing capacity of the lungs for carbon monoxide percentage predicted was used. Autoantibodies and soluble serum factor levels were compared using two-sample t test with equal variances. Results: No statistically significant differences were observed in quantitative or qualitative nailfold capillaroscopy microscopy characteristics, or vascular autoantibody ETAR and AT1R titer between systemic sclerosis-pulmonary hypertension and systemic sclerosis-no pulmonary hypertension. In contrast, several serum levels of soluble factors differed between groups: Endostatin, sVCAM, and VEGFD were increased, and CXCL4, sVEGFR2, and PDGF-AB/BB were decreased in systemic sclerosis-pulmonary hypertension. Random forest classification identified Endostatin and CXCL4 as the most predictive classifiers to distinguish systemic sclerosispulmonary hypertension from systemic sclerosis-no pulmonary hypertension. Conclusion: This study shows the potential for several soluble serum factors to distinguish systemic sclerosis-pulmonary hypertension from systemic sclerosis-no pulmonary hypertension. We found no classifying potential for qualitative or quantitative nailfold capillaroscopy microscopy characteristics, or vascular autoantibodies.

Left ventricular deformation and myocardial fibrosis in pediatric patients with Duchenne muscular dystrophy.

BACKGROUND: Left ventricular (LV) strain and rotation are emerging functional markers for early detection of LV dysfunction and have been associated with the burden of myocardial fibrosis in several disease states. This study examined the association between LV deformation (i.e., LV strain and rotation) and extent and location of LV myocardial fibrosis in pediatric patients with Duchenne muscular dystrophy (DMD). METHODS AND RESULTS: 34 pediatric patients with DMD underwent cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) to assess LV myocardial fibrosis. Offline CMR feature-tracking analysis was used to assess global and segmental longitudinal and circumferential LV strain, and LV rotation. Patients with fibrosis (n = 18, 52.9%) were older than those without fibrosis (14 ± 3 years (yrs) vs 11 ± 2 yrs., p = 0.01). There was no significant difference in LV ejection fraction (LVEF) between subjects with and without fibrosis (54 ± 6% vs 56 ± 4%, p = 0.18). However, lower endocardial global circumferential strain (GCS), but not LV rotation, was associated with presence of fibrosis (adjusted Odds Ratio 1.25 [95% CI 1.01-1.56], p = 0.04). Both GCS and global longitudinal strain correlated with the extent of fibrosis (r = .52, p = 0.03 and r = .75, p < 0.01, respectively). Importantly, segmental strain did not seem to correspond to location of fibrosis. CONCLUSION: A lower global, but not segmental, strain is associated with presence and extent of LV myocardial fibrosis in pediatric DMD patients. Therefore, strain parameters might detect structural myocardial alterations, however currently more research is needed to evaluate its value (e.g., prognostic) in clinical practice.

Association of left ventricular strain-volume loop characteristics with adverse events in patients with heart failure with preserved ejection fraction.

AIMS: Patients with heart failure with preserved ejection fraction (HFpEF) are characterized by impaired diastolic function. Left ventricular (LV) strain-volume loops (SVL) represent the relation between strain and volume during the cardiac cycle and provide insight into systolic and diastolic function characteristics. In this study, we examined the association of SVL parameters and adverse events in HFpEF. METHODS AND RESULTS: In 235 patients diagnosed with HFpEF, LV-SVL were constructed based on echocardiography images. The endpoint was a composite of all-cause mortality and Heart Failure (HF)-related hospitalization, which was extracted from electronic medical records. Cox-regression analysis was used to assess the association of SVL parameters and the composite endpoint, while adjusting for age, sex, and NYHA class. HFpEF patients (72.3% female) were 75.8 ± 6.9 years old, had a BMI of 29.9 ± 5.4 kg/m2, and a left ventricular ejection fraction of 60.3 ± 7.0%. Across 2.9 years (1.8-4.1) of follow-up, 73 Patients (31%) experienced an event. Early diastolic slope was significantly associated with adverse events [second quartile vs. first quartile: adjusted hazards ratio (HR) 0.42 (95%CI 0.20-0.88)] after adjusting for age, sex, and NYHA class. The association between LV peak strain and adverse events disappeared upon correction for potential confounders [adjusted HR 1.02 (95% CI 0.96-1.08)]. CONCLUSION: Early diastolic slope, representing the relationship between changes in LV volume and strain during early diastole, but not other SVL-parameters, was associated with adverse events in patients with HFpEF during 2.9 years of follow-up.

Left ventricular strain-volume loops and diastolic dysfunction in suspected heart failure with preserved ejection fraction.

BACKGROUND: Presence of left ventricular diastolic dysfunction (DD) is key in the pathogenesis of heart failure with preserved ejection fraction (HFpEF). However, non-invasive assessment of diastolic function is complex, cumbersome, and largely based on consensus recommendations. Novel imaging techniques may help detecting DD. Therefore, we compared left ventricular strain-volume loop (SVL) characteristics and diastolic (dys-)function in suspected HFpEF patients. METHOD AND RESULTS: 257 suspected HFpEF patients with sinus rhythm during echocardiography were prospectively included. 211 patients with quality-controlled images and strain and volume analysis were classified according to the 2016 ASE/EACVI recommendations. Patients with indeterminate diastolic function were excluded, resulting in two groups: normal diastolic function (control; n = 65) and DD (n = 91). Patients with DD were older (74.8 ± 6.9 vs. 68.5 ± 9.4 years, p < 0.001), more often female (88% vs 72%, p = 0.021), and more often had a history of atrial fibrillation (42% vs. 23%, p = 0.024) and hypertension (91% vs. 71%, p = 0.001) compared to normal diastolic function. SVL analysis showed a larger uncoupling i.e., a different longitudinal strain contribution to volume change, in DD compared to controls (0.556 ± 1.10% vs. -0.051 ± 1.14%, respectively, P < 0.001). This observation suggests different deformational properties during the cardiac cycle. After adjustment for age, sex, history of atrial fibrillation and hypertension, we found an adjusted odds ratio of 1.68 (95% confidence interval 1.19-2.47) for DD per unit increase in uncoupling (range: -2.95-3.20). CONCLUSION: Uncoupling of the SVL is independently associated with DD. This might provide novel insights in cardiac mechanics and new opportunities to assess diastolic function non-invasively.

Imaging the right atrium in pulmonary hypertension: A systematic review and meta-analysis.

BACKGROUND: Right atrial (RA) imaging has emerged as a promising tool for the evaluation of patients with pulmonary hypertension (PH), albeit without systematic validation. METHODS: PubMed, Web of Science and the Cochrane library were searched for studies investigating the prognostic value of RA imaging assessment in patients with PH from 2000 to June 2021 (PROSPERO Identifier: CRD42020212850). An inverse variance-weighted meta-analysis of univariable hazard ratios (HRs) was performed using a random effects model. RESULTS: Thirty-five studies were included (3,476 patients with PH; 74% female, 86% pulmonary arterial hypertension). Risk of bias was low/moderate (Quality of Prognosis Studies checklist). RA area (HR 1.06; 95% confidence interval [CI] 1.04-1.08), RA indexed area (HR 1.09; 95% CI 1.04-1.14), RA peak longitudinal strain (PLS; HR 0.94; 95% CI 0.91-0.97) and RA total emptying fraction (HR 0.96; 95% CI 0.94-0.98) were significantly associated with combined end-points including death, clinical worsening and/or lung transplantation; RA volume and volume index showed marginal significant associations. RA area (HR 1.06; 95% CI 1.04-1.07), RA indexed area (HR 1.12; 95% CI 1.07-1.17) and RA PLS (HR 0.98; 95% CI 0.97-0.99) showed significant associations with mortality; RA total emptying fraction showed a marginal association. CONCLUSIONS: Imaging-based RA assessment qualifies as a relevant prognostic marker in PH. RA area reliably predicts composite end-points and mortality, which underscores its clinical utility. RA PLS emerged as a promising imaging measure, but is currently limited by the number of studies and different acquisition methods.

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.

Cardiovascular magnetic resonance-derived left ventricular intraventricular pressure gradients among patients with precapillary pulmonary hypertension.

AIMS: Precapillary pulmonary hypertension (pPH) affects left ventricular (LV) function by ventricular interdependence. Since LV ejection fraction (EF) is commonly preserved, LV dysfunction should be assessed with more sensitive techniques. Left atrial (LA) strain and estimation of LV intraventricular pressure gradients (IVPG) may be valuable in detecting subtle changes in LV mechanics; however, the value of these techniques in pPH is unknown. Therefore, the aim of our study is to evaluate LA strain and LV-IVPGs from cardiovascular magnetic resonance (CMR) cines in pPH patients. METHODS AND RESULTS: In this cross-sectional study, 31 pPH patients and 22 healthy volunteers underwent CMR imaging. Feature-tracking LA strain was measured on four- and two-chamber cines. LV-IVPGs (from apex-base) are computed from a formulation using the myocardial movement and velocity of the reconstructed 3D-LV (derived from long-axis cines using feature-tracking). Systolic function, both LV EF and systolic ejection IVPG, was preserved in pPH patients. Compared to healthy volunteers, diastolic function was impaired in pPH patients, depicted by (i) lower LA reservoir (36 ± 7% vs. 26 ± 9%, P < 0.001) and conduit strain (26 ± 6% vs. 15 ± 8%, P < 0.001) and (ii) impaired diastolic suction (-9.1 ± 3.0 vs. ‒6.4 ± 4.4, P = 0.02) and E-wave decelerative IVPG (8.9 ± 2.6 vs. 5.7 ± 3.1, P < 0.001). Additionally, 11 pPH patients (35%) showed reversal of IVPG at systolic-diastolic transition compared to none of the healthy volunteers (P = 0.002). CONCLUSIONS: pPH impacts LV function by altering diastolic function, demonstrated by an impairment of LA phasic function and LV-IVPG analysis. These parameters could therefore potentially be used as early markers for LV functional decline in pPH patients.

Hypertensive response to exercise in adult patients with repaired aortic coarctation.

OBJECTIVE: The clinical and prognostic implications of a hypertensive response to exercise after repair of coarctation of the aorta (CoA) remain controversial. We aimed to determine the prevalence of a hypertensive response to exercise, identify factors associated with peak exercise systolic blood pressure (SBP) and explore the association of peak exercise SBP with resting blood pressure and cardiovascular events during follow-up. METHODS: From the Dutch national CONgenital CORvitia (CONCOR) registry, adults with repaired CoA who underwent exercise stress testing were included. A hypertensive response to exercise was defined as a peak exercise SBP ≥210 mm Hg in men and ≥190 mm Hg in women. Cardiovascular events consisted of coronary artery disease, stroke, aortic complications and cardiovascular death. RESULTS: Of the original cohort of 920 adults with repaired CoA, 675 patients (median age 24 years (range 16-72 years)) underwent exercise stress testing. Of these, 299 patients (44%) had a hypertensive response to exercise. Mean follow-up duration was 10.1 years. Male sex, absence of a bicuspid aortic valve and elevated resting SBP were independently associated with increased peak exercise SBP. Peak exercise SBP was positively predictive of office SBP (ß=0.11, p<0.001) and 24-hour SBP (ß=0.05, p=0.03) at follow-up, despite correction for baseline SBP. During follow-up, 100 patients (15%) developed at least 1 cardiovascular event. Peak exercise SBP was not significantly associated with the occurrence of cardiovascular events (HR 0.994 (95% CI 0.987 to 1.001), p=0.11). CONCLUSIONS: A hypertensive response to exercise was present in nearly half of the patients in this large, prospective cohort of adults with repaired CoA. Risk factors for increased peak exercise SBP were male sex, absence of a bicuspid aortic valve and elevated resting SBP. Increased peak exercise SBP independently predicted hypertension at follow-up. These results support close follow-up of patients with a hypertensive response to exercise to ensure timely diagnosis and treatment of future hypertension.

Type D Personality Associated With Increased Risk for Mortality in Adults With Congenital Heart Disease.

BACKGROUND: Type D personality has been previously shown to increase the risk for mortality in patients with acquired heart disease. OBJECTIVE: We aimed to compare mortality in adult patients with congenital heart disease (CHD) with and without type D. METHODS: Survival was assessed using prospective data from the Dutch national Congenital Corvitia registry for adults with CHD. Patients were randomly selected from the registry and characterized at inclusion in 2009 for the presence of type D using the DS14 questionnaire. RESULTS: One thousand fifty-five patients, with 484 (46%) males, a mean (SD) age of 41 (14) years, 613 (58%) having mild CHD, 348 (33%) having moderate CHD, and 94 (9%) having severe CHD, were included. Type D personality was present in 225 patients (21%). Type D was associated with an increased risk for all-cause mortality independent of age, sex, New York Heart Association class, number of prescribed medications, depression, employment status, and marital status (hazard ratio, 1.94; 95% confidence interval, 1.05-3.57; P = .033). CONCLUSION: Type D personality was associated with an increased risk for all-cause mortality in adult patients with CHD.

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.

Exercise Training Induces Left- but not Right-sided Cardiac Remodelling in Olympic Rowers.

Whilst the athlete's heart has been extensively described, less work has focused on the potential for elite athletes to demonstrate further cardiac remodelling upon an increase in training volume. Moreover, little work explored potential side-specific cardiac remodelling. Therefore, we examined the impact of an increase in training volume across 9-months in elite rowers on left- and right-sided cardiac structure, function and mechanics (i. e. longitudinal, radial and circumferential strain, twist and strain-volume loops). As part of the preparations to the 2012 Olympic Games, twenty-seven elite rowers (26.4±3.7years, 19 male) underwent echocardiography prior to and post (9 months) an increase in training volume (24 to 30-35 h weekly). Training increased left ventricular structure, including wall thickness, diameter, volume, mass and LV twist (all p<0.05). Female rowers demonstrated larger adaptation in left ventricular diameter and mass compared to male rowers (both p<0.05). No changes were observed in other measures of left ventricular function in both sexes (all p>0.05). The 9-month intervention showed no change in right ventricular/atrial structure, function or mechanics (all p>0.05). In conclusion, our data revealed that 9-month increased training volume in elite rowers induced left-sided (but not right-sided) structural remodelling, concomitant with an increase in left ventricular twist, with some changes larger in women.

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.

Cardiovascular Morbidity and Mortality in Adult Patients With Repaired Aortic Coarctation.

Background The long-term burden of cardiovascular disease after repair of coarctation of the aorta (CoA) has not been elucidated. We aimed to determine the incidence of and risk factors for cardiovascular events in adult patients with repaired CoA. Additionally, mortality rates were compared between adults with repaired CoA and the general population. Methods and Results Using the Dutch Congenital Corvitia (CONCOR) registry, patients aged ≥16 years with previous surgical or transcatheter CoA repair from 5 tertiary referral centers were included. Cardiovascular events were recorded, comprising coronary artery disease, stroke/transient ischemic attack, aortic complications, arrhythmias, heart failure hospitalizations, endocarditis, and cardiovascular death. In total, 920 patients (median age, 24 years [range 16-74 years]) were included. After a mean follow-up of 9.3±5.1 years, 191 patients (21%) experienced at least 1 cardiovascular event. A total of 270 cardiovascular events occurred, of which aortic complications and arrhythmias were most frequent. Older age at initial CoA repair (hazard ratio [HR], 1.017; 95% CI, 1.000-1.033 [P=0.048]) and elevated left ventricular mass index (HR, 1.009; 95% CI, 1.005-1.013 [P<0.001]) were independently associated with an increased risk of cardiovascular events. The mortality rate was 3.3 times higher than expected based on an age- and sex-matched cohort from the Dutch general population (standardized mortality ratio, 3.3; 95% CI, 2.3-4.4 [P<0.001]). Conclusions This large, prospective cohort of adults with repaired CoA showed a high burden of cardiovascular events, particularly aortic complications and arrhythmias, during long-term follow-up. Older age at initial CoA repair and elevated left ventricular mass index were independent risk factors for the occurrence of cardiovascular events. Mortality was 3.3-fold higher compared with the general population. These results advocate stringent follow-up after CoA repair and emphasize the need for improved preventive strategies.

Acute exercise-induced changes in cardiac function relates to right ventricular remodeling following 12-wk hypoxic exercise training.

Repeated ventricular exposure to alterations in workload may relate to subsequent cardiac remodeling. We examined whether baseline acute changes in right (RV) and left ventricular (LV) function relate to chronic cardiac adaptation to 12-wk exercise training. Twenty-one healthy individuals performed 12-wk high-intensity endurance running training under hypoxia (fraction of inspired oxygen: 14.5%). Resting transthoracic echocardiography was performed before and after the training program to assess ventricular structure, function, and mechanics (including strain-area/volume loops). In addition, we examined systolic cardiac function during recumbent exercise under hypoxia at baseline (heart rate of 110-120 beats/min, "stress echocardiography"). Fifteen individuals completed training (22.0 ± 2.4 yr, 10 males). Hypoxic exercise training increased RV size, including diameter and area (all P < 0.05). With exception of an increase in RV fractional area change (P = 0.03), RV function did not change post-training (all P > 0.05). Regarding the RV strain-area loop, lower systolic and diastolic slopes were found post-training (P < 0.05). No adaptation in LV structure, function, or mechanics was observed (all P > 0.05). To answer our primary aim, we found that a greater increase in RV fractional area change during baseline stress echocardiography (r = -0.67, P = 0.01) inversely correlated with adaptation in RV basal diameter following 12-wk training. In conclusion, 12-wk high-intensity running hypoxic exercise training induced right-sided structural remodeling, which was, in part, related to baseline increase in RV fractional area change to acute exercise. These data suggest that acute cardiac responses to exercise may relate to subsequent RV remodeling after exercise training in healthy individuals.NEW & NOTEWORTHY During exercise, the right ventricle is exposed to a disproportionally higher wall stress than the left ventricle, which is further exaggerated under hypoxia. In this study, we showed that 12-wk high-intensity running hypoxic exercise training induced right-sided structural remodeling, which was, in part, related to baseline cardiac increase in RV fractional area change to acute exercise. These data suggest that acute RV responses to exercise are related to subsequent right ventricular remodeling in healthy individuals upon hypoxic training.

Patient information portal for congenital aortic and pulmonary valve disease: a stepped-wedge cluster randomised trial.

BACKGROUND: In response to an increased need for patient information in congenital heart disease, we previously developed an online, evidence-based information portal for patients with congenital aortic and pulmonary valve disease. To assess its effectiveness, a stepped-wedge cluster randomised trial was conducted. METHODS: Adult patients and caregivers of paediatric patients with congenital aortic and/or pulmonary valve disease and/or tetralogy of Fallot who visited the outpatient clinic at any of the four participating centres in the Netherlands between 1 March 2016-1 July 2017 were prospectively included. The intervention (information portal) was introduced in the outpatient clinic according to a stepped-wedge randomised design. One month after outpatient clinic visit, each participant completed a questionnaire on disease-specific knowledge, anxiety, depression, mental quality of life, involvement and opinion/attitude concerning patient information and involvement. RESULTS: 343 participants were included (221 control, 122 intervention). Cardiac diagnosis (p=0.873), educational level (p=0.153) and sex (p=0.603) were comparable between the two groups. All outcomes were comparable between groups in the intention-to-treat analyses. However, only 51.6% of subjects in the intervention group (n=63) reported actually visiting the portal. Among these subjects (as-treated), disease-specific knowledge (p=0.041) and mental health (p=0.039) were significantly better than in control subjects, while other baseline and outcome variables were comparable. CONCLUSION: Even after being invited by their cardiologists, only half of the participants actually visited the information portal. Only in those participants that actually visited the portal, knowledge of disease and mental health were significantly better. This underlines the importance of effective implementation of online evidence-based patient information portals in clinical practice.

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.