Citations

Abstract Aims Conotruncal anomalies share common embryogenic defects of the outflow tracts and great arteries, which result in a predisposition to aortic aneurysms. The purpose of this study was to describe the prevalence and risk of progressive aortic aneurysms in adults with conotruncal anomalies. Methods and results Retrospective study of adults with conotruncal anomalies that underwent cross-sectional imaging 2003–20. Aneurysm was defined as aortic root/mid-ascending aorta >2.1 mm/m2/>1.9 mm/m2, progressive aneurysm as increase by >2 mm, and severe aneurysm as dimension >50 mm. Of 2261 patients (38 ± 12 years; male 58%), 1167 (52%) had an aortic aneurysm, and 205 (14%) had a severe aortic aneurysm. Mean annual increase in aortic root/mid-ascending aorta was 0.3 ± 0.1 mm/0.2 ± 0.1 mm. The 3-, 5-, and 7-year cumulative incidence of the progressive aortic aneurysm was 4%, 7%, and 9%, respectively. The rate of aneurysm growth decreased with age, with no significant growth after age 40 years. There was an excellent correlation between aortic indices from cross-sectional imaging and echocardiography. Of 950 females, 184 had ≥1 pregnancy, and 81 (44%) of the 184 patients had aortic aneurysm prior to pregnancy. There was no aortic dissection or progression of the aortic aneurysm during pregnancy. Overall, there was no aortic dissection during 7984 patient-years of follow-up. Conclusions Aortic aneurysm was common in patients with conotruncal anomalies. However, the risk of progressive aneurysm or dissection was low. Collectively, these data suggest a benign natural history and perhaps a less frequent need for cross-sectional imaging. Further studies are required to determine the optimal timing for surgical intervention in this population.

Abstract BACKGROUND The purpose of this document is to provide clinicians with guidance, using expert consensus, to help summarize evidence and offer practical recommendations. METHODS Expert Consensus Documents are intended to provide guidance for clinicians in areas in which there are no clinical practice guidelines, especially for new and evolving tests such as arterial stiffness measurements, until any formal guidelines are released. RESULTS This expert consensus document is intended as a source of information for decision-making and to guide clinician–patient discussions in various clinical scenarios. CONCLUSIONS The goal is to help clinicians and patients make a more informed decision together.

AbstractStatistical methods to integrate multiple layers of data, from exposures to intermediate traits to outcome variables, are needed to guide interpretation of complex data sets for which variables are likely contributing in a causal pathway from exposure to outcome. Statistical mediation analysis based on structural equation models provide a general modeling framework, yet they can be difficult to apply to high‐dimensional data and they are not automated to select the best fitting model. To overcome these limitations, we developed novel algorithms and software to simultaneously evaluate multiple exposure variables, multiple intermediate traits, and multiple outcome variables. Our penalized mediation models are computationally efficient and simulations demonstrate that they produce reliable results for large data sets. Application of our methods to a study of vascular disease demonstrates their utility to identify novel direct effects of single‐nucleotide polymorphisms (SNPs) on coronary heart disease and peripheral artery disease, while disentangling the effects of SNPs on the intermediate risk factors including lipids, cigarette smoking, systolic blood pressure, and type 2 diabetes.

Abstract The public health impact of genomic screening can be enhanced by cascade testing. However, cascade testing depends on communication of results to family members. While the barriers and facilitators of family communication have been researched following clinical genetic testing, the factors impacting the dissemination of genomic screening results are unknown. Using the pragmatic Electronic Medical Records and Genomics Network‐3 (eMERGE‐3) study, we explored the reported sharing practices of participants who underwent genomic screening across the United States. Six eMERGE‐3 sites returned genomic screening results for mostly dominant medically actionable disorders and surveyed adult participants regarding communication of results with first‐degree relatives. Across the sites, 279 participants completed a 1‐month and/or 6‐month post‐results survey. By 6 months, only 34% of the 156 respondents shared their results with all first‐degree relatives and 4% did not share with any. Over a third (39%) first‐degree relatives were not notified of the results. Half (53%) of participants who received their results from a genetics provider shared them with all first‐degree relatives compared with 11% of participants who received their results from a non‐genetics provider. The most frequent reasons for sharing were a feeling of obligation (72%) and that the information could help family members make medical decisions (72%). The most common reasons indicated for not sharing were that the family members were too young (38%), or they were not in contact (25%) or not close to them (25%). These data indicate that the professional returning the results may impact sharing patterns, suggesting that there is a need to continue to educate healthcare providers regarding approaches to facilitate sharing of genetic results within families. Finally, these data suggest that interventions to increase sharing may be universally effective regardless of the origin of the genetic result.

Abstract Background The relationship between office vs ambulatory blood pressure (BP) indices is well-studied in patients with idiopathic hypertension, and based on these data, it is known that average 24-hour ambulatory BP is typically lower than office BP. However, emerging data show that office systolic BP (SBP) underestimates arterial afterload in patients with coarctation of aorta (COA), and minimal increase in stroke volume during low intensity exercise results in exaggerated rise in SBP as compared to those with idiopathic hypertension. We hypothesized that COA patients will have higher ambulatory SBP and a higher prevalence of masked hypertension compared to patients with idiopathic hypertension. Methods Case-control study of 118 COA patients and 118 patients with idiopathic hypertension matched by age, sex, body mass index and office SBP. Results Although both groups had similar office SBP (132±17 mmHg) by design, the COA group had paradoxical increases in 24-hour ambulatory SBP (135±14 vs 126±13, p<0.001) and daytime ambulatory SBP (142±16 vs 130±13, p<0.001), and less nocturnal dipping (−3±5 vs −9±4, p<0.001). The COA group also had a higher prevalence of masked hypertension (36 [31%] vs 14 [12%], p<0.001), and worse arterial function indices. Conclusion These findings underscore the potential limitations of relying on office SBP for screening/monitoring of hypertension in COA and potential pitfalls in extrapolating idiopathic hypertension guidelines recommendations to the treatment of COA. It also provides rationale for further studies to determine if pharmacologic BP interventions guided by ambulatory BP data will improve clinical outcomes in the COA population. Funding Acknowledgement Type of funding sources: None.

Abstract Background Left atrial dysfunction (LAD) and left ventricular diastolic dysfunction (LVDD) has been described in patients with coarctation of aorta (COA). However, it is unknown whether LA function and LV diastolic function indices can be used for prognostication in this population. The purpose of this study was to determine whether LAD and LVDD were associated with mortality in adults with COA. We hypothesized that LA and LV diastolic function indices will predict transplant-free survival in COA patients. Methods Retrospective study of COA patients (age ≥18) at Mayo Clinic (2000–2018). LVDD was determined using the 2016 guidelines for LVDD assessment, and LAD was assessed using LA reservoir strain. Results Of 721 patients, LV diastolic function could be determined in 635 (88%), while 86 (12%) were classified as indeterminate diastolic function. Of 635 patients, 414 (65%) had no LVDD, while 146 (23%), 53 (8%), and 22 (4%) had grade I/II/III LVDD respectively. The mean LA reservoir strain was −39±11%, and patients were divided into quartiles: top quartile (reference group), mild LAD, moderate LAD, and severe LAD. Of 635 patients, 49 died and 4 underwent heart transplant. On multivariate analysis, Grade III diastolic dysfunction (but not Grade I and II) was associated with mortality as compared to normal diastolic function. On the other hand, there was an incremental risk of mortality across LA strain quartiles: mild LAD (HR 1.16, 1.04–2.06), moderate LAD (HR 1.75, 1.27–3.58), and severe LAD (HR 3.49, 1.88–7.16). Of the 86 patients with indeterminate diastolic function, LAD was associated with a lower 5-year transplant-free survival as compared to normal LA function (83% vs 91%, p=0.06). Conclusions LAD (but not LVDD) was associated with incremental risk of mortality, and thus can be used for prognostication in all patients including those with indeterminate diastolic function. Although the current study did not identify a consistent relationship between LVDD severity classifications and mortality among COA patients, it does not imply that LVDD is benign. Rather it suggests that the conventional criteria for LVDD severity classifications may not be generalizable to every disease subgroup Funding Acknowledgement Type of funding sources: None.

Abstract Background There are limited data about outcomes after repair of native coarctation of aorta (COA) in adulthood. The purpose of this study was to describe the procedural outcomes, hemodynamic improvement, regression of LV hypertrophy and cardiovascular events in adults undergoing repair of native COA. Methods The primary outcomes were procedural complications, re-interventions, and hemodynamic improvement (residual COA gradient <20 mmHg) after COA repair. The secondary outcomes were improvement in the severity of hypertension, regression of left ventricular mass index (LVMI), and incidence of cardiovascular events (atrial fibrillation, heart failure hospitalization, and cardiovascular death) after COA repair. Clinical and imaging indices were assessed pre-intervention, and at 1-year (Y1) and 3-years (Y3) post-intervention. Results A total of 172 patients (age 38 [27–48]) underwent COA repair (surgical 161; transcatheter 11). There were no procedural deaths, and all patients had residual COA gradient <20 mmHg. One patients that received transcatheter stent therapy required re-dilation of stent at 12 months post-intervention. There as a reduction in the prevalence of patients requiring anti-hypertensive therapy from 73% (pre-intervention) to 59% and 64% at Y1 and Y3 respectively. However, 72% and 69% of the patients still had systolic blood pressure >130 mmHg (stage 1 and 2 hypertension) at Y1 and Y3 respectively. As compared to patients without hypertension at Y1, patients with stage 1 and stage 2 hypertension had less robust LVMI regression (% change in LVMI 12±5% vs 9±6% vs 5±3%, p<0.001). Hypertension (HR 1.16, 1.05–1.27) and LVMI regression (HR 0.86, 0.81–0.90) were independently associated with cardiovascular events. Conclusions Persistent hypertension was common after repair of native COA in adults. Hypertension (including stage 1 hypertension) was associated with suboptimal regression of LVMI and cardiovascular events. These results are concerning, and highlight the importance of early COA diagnosis and repair, and optimal medical therapy for hypertension after COA repair. Funding Acknowledgement Type of funding sources: None.

Abstract Background Certain factors such as left ventricular (LV) geometry and loading conditions affect the validity and reliability of LV ejection fraction (LVEF) as a true measure of LV contractility. LV global longitudinal strain (LVGLS) is less sensitive to these factors, and it has superior prognostic performance in patients with acquired heart disease. The purpose of this study was to determine the clinical implications of using LVGLS (instead of LVEF) as the measure of LV systolic function in adults with Ebstein anomaly given the inherent abnormalities of LV geometry and preload in this population. Methods Retrospective cohort study of 673 adults with Ebstein anomaly (2003–2018). We hypothesized that LVGLS had a stronger correlation with heart failure indices and transplant-free survival compared to LVEF. Results Compared to LVEF, LVGLS had stronger correlations with cardiac index (r=0.46 vs r=0.21, p=0.007), glomerular filtration rate (r=0.57 vs r=0.19, p<0.001), and NT-proBNP (r=−0.64 vs r=−0.41, p=0.01). Of 673 patients, 514 (76%) had normal LV systolic function (LVGLSNormal-LVEFNormal), 87 (13%) had subclinical LV dysfunction (LVGLSLow-LVEFNormal) and 66 (10%) had overt LV dysfunction (LVGLSLow-LVEFLow). Compared to the overt LV dysfunction group, the subclinical LV dysfunction group had similar 10-year transplant-free survival (64% vs 63%, p=0.6), but were less likely to be on heart failure therapy (12% vs 82%, p<0.001). LVGLS (but not LVEF) was the independent predictor of transplant-free survival Conclusions LVGLS provided more robust risk stratification and prognostication than LVEF in patients with Ebstein anomaly, and patients with low LVGLS had reduced transplant-free survival regardless of LVEF. The use of LVGLS (rather than LVEF) as the measure of LV systolic function has important clinical implications with regards to initiation of medical and surgical therapies. Funding Acknowledgement Type of funding sources: None.

Background: Peripheral artery disease (PAD) affects >200 million people worldwide and is associated with high mortality and morbidity. We sought to identify genomic variants associated with PAD overall and in the contexts of diabetes and smoking status. Methods: We identified genetic variants associated with PAD and then meta-analyzed with published summary statistics from the Million Veterans Program and UK Biobank to replicate their findings. Next, we ran stratified genome-wide association analysis in ever smokers, never smokers, individuals with diabetes, and individuals with no history of diabetes and corresponding interaction analyses, to identify variants that modify the risk of PAD by diabetic or smoking status. Results: We identified 5 genome-wide significant ( P association ≤5×10 −8 ) associations with PAD in 449 548 (N cases =12 086) individuals of European ancestry near LPA (lipoprotein [a]), CDKN2BAS1 (CDKN2B antisense RNA 1), SH2B3 (SH2B adaptor protein 3) - PTPN11 (protein tyrosine phosphatase non-receptor type 11), HDAC9 (histone deacetylase 9), and CHRNA3 (cholinergic receptor nicotinic alpha 3 subunit ) loci (which overlapped previously reported associations). Meta-analysis with variants previously associated with PAD showed that 18 of 19 published variants remained genome-wide significant. In individuals with diabetes, rs116405693 at the CCSER1 (coiled-coil serine rich protein 1 ) locus was associated with PAD (odds ratio [95% CI], 1.51 [1.32–1.74], P diabetes =2.5×10 −9 , P interactionwithdiabetes =5.3×10 −7 ). Furthermore, in smokers, rs12910984 at the CHRNA3 locus was associated with PAD (odds ratio [95% CI], 1.15 [1.11–1.19], P smokers =9.3×10 −10 , P interactionwithsmoking =3.9×10 −5 ). Conclusions: Our analyses confirm the published genetic associations with PAD and identify novel variants that may influence susceptibility to PAD in the context of diabetes or smoking status.

Abstract IntroductionCurrently, one of the commonly used methods for disseminating electronic health record (EHR)-based phenotype algorithms is providing a narrative description of the algorithm logic, often accompanied by flowcharts. A challenge with this mode of dissemination is the potential for under-specification in the algorithm definition, which leads to ambiguity and vagueness. MethodsThis study examines incidents of under-specification that occurred during the implementation of 34 narrative phenotyping algorithms in the electronic Medical Record and Genomics (eMERGE) network. We reviewed the online communication history between algorithm developers and implementers within the Phenotype Knowledge Base (PheKB) platform, where questions could be raised and answered regarding the intended implementation of a phenotype algorithm. ResultsWe developed a taxonomy of under-specification categories via an iterative review process between two groups of annotators. Under-specifications that lead to ambiguity and vagueness were consistently found across narrative phenotype algorithms developed by all involved eMERGE sites. Discussion & ConclusionOur findings highlight that under-specification is an impediment to the accuracy and efficiency of the implementation of current narrative phenotyping algorithms, and we propose approaches for mitigating these issues and improved methods for disseminating EHR phenotyping algorithms.