X-linked genetic associations in sporadic thoracic aortic dissection.

The male predominance in sporadic thoracic aortic aneurysm and dissection (TAD) suggests that the X chromosome contributes to TAD, but this has not been tested. We investigated whether X-linked variation-common (minor allele frequency [MAF] ≥0.01) and rare (MAF <0.01)-was associated with sporadic TAD in three cohorts of European descent (Discovery: 364 cases, 874 controls; Replication: 516 cases, 440,131 controls, and ARIC [Atherosclerosis Risk in Communities study]: 753 cases, 2247 controls). For analysis of common variants, we applied a sex-stratified logistic regression model followed by a meta-analysis of sex-specific odds ratios. Furthermore, we conducted a meta-analysis of overlapping common variants between the Discovery and Replication cohorts. For analysis of rare variants, we used a sex-stratified optimized sequence kernel association test model. Common variants results showed no statistically significant findings in the Discovery cohort. An intergenic common variant near SPANXN1 was statistically significant in the Replication cohort (p = 1.81 × 10-8). The highest signal from the meta-analysis of the Discovery and Replication cohorts was a ZNF182 intronic common variant (p = 3.5 × 10-6). In rare variants results, RTL9 reached statistical significance (p = 5.15 × 10-5). Although most of our results were statistically insignificant, our analysis is the most comprehensive X-chromosome association analysis of sporadic TAD to date.

Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects.

The 22q11.2 deletion syndrome (22q11.2DS) results from non-allelic homologous recombination between low-copy repeats termed LCR22. About 60%-70% of individuals with the typical 3 megabase (Mb) deletion from LCR22A-D have congenital heart disease, mostly of the conotruncal type (CTD), whereas others have normal cardiac anatomy. In this study, we tested whether variants in the hemizygous LCR22A-D region are associated with risk for CTDs on the basis of the sequence of the 22q11.2 region from 1,053 22q11.2DS individuals. We found a significant association (FDR p < 0.05) of the CTD subset with 62 common variants in a single linkage disequilibrium (LD) block in a 350 kb interval harboring CRKL. A total of 45 of the 62 variants were associated with increased risk for CTDs (odds ratio [OR) ranges: 1.64-4.75). Associations of four variants were replicated in a meta-analysis of three genome-wide association studies of CTDs in affected individuals without 22q11.2DS. One of the replicated variants, rs178252, is located in an open chromatin region and resides in the double-elite enhancer, GH22J020947, that is predicted to regulate CRKL (CRK-like proto-oncogene, cytoplasmic adaptor) expression. Approximately 23% of patients with nested LCR22C-D deletions have CTDs, and inactivation of Crkl in mice causes CTDs, thus implicating this gene as a modifier. Rs178252 and rs6004160 are expression quantitative trait loci (eQTLs) of CRKL. Furthermore, set-based tests identified an enhancer that is predicted to target CRKL and is significantly associated with CTD risk (GH22J020946, sequence kernal association test (SKAT) p = 7.21 × 10-5) in the 22q11.2DS cohort. These findings suggest that variance in CTD penetrance in the 22q11.2DS population can be explained in part by variants affecting CRKL expression.

Neighborhood-level Socioeconomic Position During Early Pregnancy and Risk of Gastroschisis.

BACKGROUND: Neighborhood-level socioeconomic position has been shown to influence birth outcomes, including selected birth defects. This study examines the un derstudied association between neighborhood-level socioeconomic position during early pregnancy and the risk of gastroschisis, an abdominal birth defect of increasing prevalence. METHODS: We conducted a case-control study of 1,269 gastroschisis cases and 10,217 controls using data from the National Birth Defects Prevention Study (1997-2011). To characterize neighborhood-level socioeconomic position, we conducted a principal component analysis to construct two indices-Neighborhood Deprivation Index (NDI) and Neighborhood Socioeconomic Position Index (nSEPI). We created neighborhood-level indices using census socioeconomic indicators corresponding to census tracts associated with addresses where mothers lived the longest during the periconceptional period. We used generalized estimating equations to estimate odds ratios (ORs) and 95% confidence intervals (CIs), with multiple imputations for missing data and adjustment for maternal race-ethnicity, household income, education, birth year, and duration of residence. RESULTS: Mothers residing in moderate (NDI Tertile 2 aOR = 1.23; 95% CI = 1.03, 1.48 and nSEPI Tertile 2 aOR = 1.24; 95% CI = 1.04, 1.49) or low socioeconomic neighborhoods (NDI Tertile 3 aOR = 1.28; 95% CI = 1.05, 1.55 and nSEPI Tertile 3 aOR = 1.32, 95% CI = 1.09, 1.61) were more likely to deliver an infant with gastroschisis compared with mothers residing in high socioeconomic neighborhoods. CONCLUSIONS: Our findings suggest that lower neighborhood-level socioeconomic position during early pregnancy is associated with elevated odds of gastroschisis. Additional epidemiologic studies may aid in confirming this finding and evaluating potential mechanisms linking neighborhood-level socioeconomic factors and gastroschisis.

Are individual-level risk factors for gastroschisis modified by neighborhood-level socioeconomic factors?

BACKGROUND: Two strong risk factors for gastroschisis are young maternal age (<20 years) and low/normal pre-pregnancy body mass index (BMI), yet the reasons remain unknown. We explored whether neighborhood-level socioeconomic position (nSEP) during pregnancy modified these associations. METHODS: We analyzed data from 1269 gastroschisis cases and 10,217 controls in the National Birth Defects Prevention Study (1997-2011). To characterize nSEP, we applied the neighborhood deprivation index and used generalized estimating equations to calculate odds ratios and relative excess risk due to interaction. RESULTS: Elevated odds of gastroschisis were consistently associated with young maternal age and low/normal BMI, regardless of nSEP. High-deprivation neighborhoods modified the association with young maternal age. Infants of young mothers in high-deprivation areas had lower odds of gastroschisis (adjusted odds ratio [aOR]: 3.1, 95% confidence interval [CI]: 2.6, 3.8) than young mothers in low-deprivation areas (aOR: 6.6; 95% CI: 4.6, 9.4). Mothers of low/normal BMI had approximately twice the odds of having an infant with gastroschisis compared to mothers with overweight/obese BMI, regardless of nSEP (aOR range: 1.5-2.3). CONCLUSION: Our findings suggest nSEP modified the association between gastroschisis and maternal age, but not BMI. Further research could clarify whether the modification is due to unidentified biologic and/or non-biologic factors.

Stroke and mortality rates after off-pump vs. pump-assisted/no-clamp coronary artery bypass grafting.

BACKGROUND: Ascending aorta manipulation during on-pump coronary artery bypass grafting (CABG) surgery can release embolic matter and may cause stroke. Strategies for lowering the stroke rate associated with coronary artery bypass grafting surgery include off-pump surgery without cardiopulmonary bypass and pump-assisted surgery with minimal aortic manipulation (i.e., without aortic cross-clamping). We examined whether one approach is superior to the other in reducing stroke and perioperative mortality rates. METHODS: We reviewed consecutive elective, urgent, and emergency off-pump/no-bypass and pump-assisted/no-clamp coronary artery bypass grafting procedures performed by a single surgeon at our institution from June 2011 through October 2017. RESULTS: Of 570 patients analyzed, 395 (69.3%) underwent off-pump/no-bypass surgery, 43 (7.5%) underwent pump-assisted/no-clamp surgery, and 132 (23.2%) transitioned mid-procedure from off-pump/no-bypass to pump-assisted/no-clamp surgery. Patients who were >70 years old, were female, or had diabetes, cardiomegaly, or a history of myocardial infarction or congestive heart failure were more likely to undergo pump-assisted/no-clamp surgery or the combined technique. None of the pump-assisted/no-clamp patients had a stroke, versus 0.3% of the off-pump/no-bypass patients and 0.8% of the combination patients. Stroke and in-hospital mortality rates did not differ by technique. CONCLUSIONS: A hybrid strategy incorporating off-pump, pump-assisted, and combined off-pump/pump-assisted techniques achieved very low stroke rates in patients undergoing coronary revascularization. Perioperative mortality was similar for all three techniques. Avoiding aortic clamping may be crucial for decreasing CABG-related stroke rates. Off-pump/no-bypass surgery had no significant advantage over the pump-assisted/no-clamp or combined techniques in reducing the stroke rate after coronary artery bypass grafting surgery.

Maternal effect genes as risk factors for congenital heart defects.

Maternal effect genes (MEGs) encode factors (e.g., RNA) in the oocyte that control embryonic development prior to activation of the embryonic genome. Over 80 mammalian MEGs have been identified, including several that have been associated with phenotypes in humans. Maternal variation in MEGs is associated with a range of adverse outcomes, which, in humans, include hydatidiform moles, zygotic cleavage failure, and offspring with multi-locus imprinting disorders. In addition, data from both animal models and humans suggest that the MEGs may be associated with structural birth defects such as congenital heart defects (CHDs). To further investigate the association between MEGs and CHDs, we conducted gene-level and gene-set analyses of known mammalian MEGs (n = 82) and two common groups of CHDs: conotruncal heart defects and left ventricular outflow tract defects. We identified 14 candidate CHD-related MEGs. These 14 MEGs include three (CDC20, KHDC3L, and TRIP13) of the 11 known human MEGs, as well as one (DNMT3A) of the eight MEGs that have been associated with structural birth defects in animal models. Our analyses add to the growing evidence that MEGs are associated with structural birth defects, in particular CHDs. Given the large proportion of individuals with structural birth defects for whom etiology of their condition is unknown, further investigations of MEGs as potential risk factors for structural birth defects are strongly warranted.

The influence of preoperative dialysis on survival after continuous-flow left ventricular assist device implantation.

OBJECTIVES: Dialysis is considered a contraindication to continuous-flow left ventricular assist device (CF-LVAD) implantation. We evaluated clinical outcomes and survival in carefully selected, low-risk patients with renal failure who required dialysis before CF-LVAD implantation. METHODS: We extracted medical record data of patients who underwent CF-LVAD placement at our centre between 1 January 2006 and 31 August 2017, with 2 clinical scenarios: those who required long-term (>14 days) dialysis and those who required short-term (≤14 days) dialysis immediately before implantation. Demographic, clinical and intraoperative characteristics and survival outcomes were assessed. RESULTS: Of 621 patients who underwent CF-LVAD implantation during the study period, 31 underwent dialysis beforehand. Of these, 17 required long-term dialysis (13 haemodialysis, 4 peritoneal dialysis), and 14 underwent short-term haemodialysis. Compared with the long-term dialysis patients, the short-term dialysis patients were more likely to be Interagency Registry for Mechanically Assisted Circulatory Support profile 1-2 (92.9% vs 70.6%; P < 0.001), to have needed preoperative mechanical circulatory support (78.6% vs 70.6%; P < 0.01) and to have higher in-hospital mortality (85.7% vs 29.4%; P = 0.01). Patients stable on long-term dialysis had acceptable overall survival and markedly better 6-month and 1-year survival than those with short-term dialysis before implantation (64.7% vs 14.3% and 58.8% vs 7.1%, respectively; P < 0.001). CONCLUSIONS: Carefully selected patients who are stable on long-term dialysis have acceptable survival rates after CF-LVAD implantation. Patients with acute renal failure had much poorer outcomes than those with chronic end-stage renal disease.

Genome-Wide Association Studies of Conotruncal Heart Defects with Normally Related Great Vessels in the United States.

Conotruncal defects with normally related great vessels (CTD-NRGVs) occur in both patients with and without 22q11.2 deletion syndrome (22q11.2DS), but it is unclear to what extent the genetically complex etiologies of these heart defects may overlap across these two groups, potentially involving variation within and/or outside of the 22q11.2 region. To explore this potential overlap, we conducted genome-wide SNP-level, gene-level, and gene set analyses using common variants, separately in each of five cohorts, including two with 22q11.2DS (N = 1472 total cases) and three without 22q11.2DS (N = 935 total cases). Results from the SNP-level analyses were combined in meta-analyses, and summary statistics from these analyses were also used in gene and gene set analyses. Across all these analyses, no association was significant after correction for multiple comparisons. However, several SNPs, genes, and gene sets with suggestive evidence of association were identified. For common inherited variants, we did not identify strong evidence for shared genomic mechanisms for CTD-NRGVs across individuals with and without 22q11.2 deletions. Nevertheless, several of our top gene-level and gene set results have been linked to cardiogenesis and may represent candidates for future work.

Common Variation in Cytoskeletal Genes is Associated with Conotruncal Heart Defects.

There is strong evidence for a genetic contribution to non-syndromic congenital heart defects (CHDs). However, exome- and genome-wide studies conducted at the variant and gene-level have identified few genome-wide significant CHD-related genes. Gene-set analyses are a useful complement to such studies and candidate gene-set analyses of rare variants have provided insight into the genetics of CHDs. However, similar analyses have not been conducted using data on common genetic variants. Consequently, we conducted common variant analyses of 15 CHD candidate gene-sets, using data from two common types of CHDs: conotruncal heart defects (1431 cases) and left ventricular outflow tract defects (509 cases). After Bonferroni correction for evaluation of multiple gene-sets, the cytoskeletal gene-set was significantly associated with conotruncal heart defects (ßS = 0.09; 95% confidence interval (CI) 0.03-0.15). This association was stronger when analyses were restricted to the sub-set of cytoskeletal genes that have been observed to harbor rare damaging genotypes in at least two CHD cases (ßS = 0.32, 95% CI 0.08-0.56). These findings add to the evidence linking cytoskeletal genes to CHDs and suggest that, for cytoskeletal genes, common variation may contribute to the risk of CHDs.

Maternal Hypertension-Related Genotypes and Congenital Heart Defects.

BACKGROUND: Maternal hypertension has been associated with congenital heart defect occurrence in several studies. We assessed whether maternal genotypes associated with this condition were also associated with congenital heart defect occurrence. METHODS: We used data from the National Birth Defects Prevention Study to identify non-Hispanic white (NHW) and Hispanic women with (cases) and without (controls) a pregnancy in which a select simple, isolated heart defect was present between 1999 and 2011. We genotyped 29 hypertension-related single nucleotide polymorphisms (SNPs). We conducted logistic regression analyses separately by race/ethnicity to assess the relationship between the presence of any congenital heart defect and each SNP and an overall blood pressure genetic risk score (GRS). All analyses were then repeated to assess 4 separate congenital heart defect subtypes. RESULTS: Four hypertension-related variants were associated with congenital heart defects among NHW women (N = 1,568 with affected pregnancies). For example, 1 intronic variant in ARHGAP2, rs633185, was associated with conotruncal defects (odds ratio [OR]: 1.3, 95% confidence interval [CI]: 1.1-1.6). Additionally, 2 variants were associated with congenital heart defects among Hispanic women (N = 489 with affected pregnancies). The GRS had a significant association with septal defects (OR: 2.1, 95% CI: 1.2-3.5) among NHW women. CONCLUSIONS: We replicated a previously reported association between rs633185 and conotruncal defects. Although additional hypertension-related SNPs were also associated with congenital heart defects, more work is needed to better understand the relationship between genetic risk for maternal hypertension and congenital heart defects occurrence.

Ten-Year Survival With a Continuous-Flow Left Ventricular Assist Device and Aortic Valve Closure.

We report the long-term survival of a 46-year-old man supported with a HeartMate II continuous-flow left ventricular assist device after complex repair of a bicuspid aortic valve, anomalous left main coronary artery, and dilated aorta. He has been maintained on an anticoagulation regimen of warfarin and low-dose aspirin without problems for 10 years, during which he has worked continuously and productively. Device flow has been kept at 10,000 rpm. Possible contributors to this long-term success include proper alignment of the device inflow cannula, pericardial patch closure of the left ventricular outflow tract, and, notably, the remarkable freedom from mechanical failure of the continuous-flow left ventricular assist device. Whether the higher flow rate produced by the pericardial patch closure contributes to pump longevity is unknown and merits further investigation.

Heterotopic Cardiac Transplantation: Long-term Results and Fate of the Native Heart.

BACKGROUND: The long-term results of heterotopic cardiac transplantation have not been well defined. Patient survival rates and the fate of the native heart remain unclear. METHODS: This study is a retrospective review of all 46 heterotopic cardiac transplantations performed at a single institution, the Texas Heart Institute in Houston, Texas, between 1982 and 2017. Four patients who underwent heterotopic transplantation as an emergency procedure for cardiogenic shock were excluded. Three of the procedures were repeat transplantations in patients who had previously undergone heterotopic transplantation; the 3 repeat transplantations were excluded, but the original procedures were not. Follow-up was 100% complete for mortality and 77% complete (30 of 39 patients) for assessment of preoperative indication for surgery and postoperative cardiac function. RESULTS: For the 39 patients, the 1-year, 5-year, and 10-year survival rates were 69%, 36%, and 21%, respectively. One patient remains alive 25 years after the transplantation procedure. The most frequent indication for heterotopic transplantation was pulmonary vascular resistance greater than 4 Wood units (n = 11), followed by weight greater than 112.5 kg (n = 7). In most patients, native heart left ventricular ejection fraction stabilized over time to between 10% and 30%. Sinus rhythm was preserved in 87% (26 of 30) of native hearts at long-term follow-up. CONCLUSIONS: Heterotopic cardiac transplantation is an acceptable procedure that should be considered for obese patients (especially those heavier than 112.5 kg) and patients with elevated pulmonary vascular resistance (especially those with pulmonary vascular resistance >4.0 Wood units). After heterotopic transplantation, native cardiac function appears to stabilize, and there is potential for native heart recovery.

Rare deleterious variants of NOTCH1, GATA4, SMAD6, and ROBO4 are enriched in BAV with early onset complications but not in BAV with heritable thoracic aortic disease.

BACKGROUND: Bicuspid aortic valve (BAV) is the most common cardiovascular malformation in adults, with a prevalence of 0.5%-2%. The prevalence of BAV in cohorts who were ascertained due to thoracic aortic aneurysms or acute aortic dissections (TAD) is as high as 20%. However, the contribution of causal BAV genes to TAD is not known. Therefore, we evaluated rare deleterious variants of GATA4, NOTCH1, SMAD6, or ROBO4 in patients with BAV who presented with TAD. METHODS: Our cohort consisted of 487 probands with Heritable Thoracic Aortic Aneurysms or Dissections (HTAD, 12% BAV, 29% female) and 63 probands with Early onset complications of Bicuspid Aortic Valve disease (EBAV, 63% TAD, 34% female). After whole exome sequencing, we functionally annotated GATA4, NOTCH1, SMAD6, and ROBO4 variants and compared the prevalence of rare variants in these genes to controls without HTAD. RESULTS: We identified 11 rare deleterious variants of GATA4, SMAD6, or ROBO4 in 12 (18%) EBAV cases. The burden of rare SMAD6 and GATA4 variants was significantly enriched in EBAV but not in HTAD cases, even among HTAD cases with BAV (p < .003). CONCLUSION: Rare variants of NOTCH1, ROBO4, SMAD6, or GATA4 do not significantly contribute to BAV in cohorts with HTAD. We conclude that BAV patients who present with HTAD are a genetically distinct subgroup with implications for genetic testing and prognosis.