Polygenic Scoring for Detection of Ascending Thoracic Aortic Dilation.

BACKGROUND: Ascending thoracic aortic dilation is a complex heritable trait that involves modifiable and nonmodifiable risk factors. Polygenic scores (PGS) are increasingly used to assess risk for complex diseases. The degree to which a PGS can improve aortic diameter prediction in diverse populations is unknown. Presently, we tested whether adding a PGS to clinical prediction algorithms improves performance in a diverse biobank. METHODS: The analytic cohort comprised 6235 Penn Medicine Biobank participants with available echocardiography and clinical data linked to genome-wide genotype data. Linear regression models were used to integrate PGS weights derived from a genome-wide association study of thoracic aortic diameter performed in the UK Biobank and were compared with the performance of the previously published aorta optimized regression for thoracic aneurysm (AORTA) score. RESULTS: Cohort participants had a median age of 61 years (IQR, 53-70) and a mean ascending aortic diameter of 3.36 cm (SD, 0.49). Fifty-five percent were male, and 33% were genetically similar to African reference population. Compared with the AORTA score, which explained 30.6% (95% CI, 29.9%-31.4%) of the variance in aortic diameter, AORTA score+UK Biobank-derived PGS explained 33.1%, (95% CI, 32.3%-33.8%), the reweighted AORTA score explained 32.5% (95% CI, 31.8%-33.2%), and the reweighted AORTA score+UK Biobank-derived PGS explained 34.9% (95% CI, 34.2%-35.6%). When stratified by population, models including the UK Biobank-derived PGS consistently improved upon the clinical AORTA score among individuals genetically similar to European reference population but conferred minimal improvement among individuals genetically similar to African reference population. Comparable performance disparities were observed in models developed to discriminate cases/noncases of thoracic aortic dilation (≥4.0 cm). CONCLUSIONS: We demonstrated that inclusion of a UK Biobank-derived PGS to the AORTA score confers a clinically meaningful improvement in model performance only among individuals genetically similar to European reference population and may exacerbate existing health care disparities.

Population Performance and Individual Agreement of Coronary Artery Disease Polygenic Risk Scores.

Importance: Polygenic risk scores (PRSs) for coronary artery disease (CAD) are a growing clinical and commercial reality. Whether existing scores provide similar individual-level assessments of disease liability is a critical consideration for clinical implementation that remains uncharacterized. Objective: Characterize the reliability of CAD PRSs that perform equivalently at the population level at predicting individual-level risk. Design: Cross-sectional Study. Setting: All of Us Research Program (AOU), Penn Medicine Biobank (PMBB), and UCLA ATLAS Precision Health Biobank. Participants: Volunteers of diverse genetic backgrounds enrolled in AOU, PMBB, and UCLA with available electronic health record and genotyping data. Exposures: Polygenic risk for CAD from previously published PRSs and new PRSs developed separately from the testing cohorts. Main Outcomes and Measures: Sets of CAD PRSs that perform population prediction equivalently were identified by comparing calibration and discrimination (Brier score and AUROC) of generalized linear models of prevalent CAD using Bayesian analysis of variance. Among equivalently performing scores, individual-level agreement between risk estimates was tested with intraclass correlation (ICC) and Light's Kappa, measures of inter-rater reliability. Results: 50 PRSs were calculated for 171,095 AOU participants. When included in a model of prevalent CAD, 48 scores had practically equivalent Brier scores and AUROCs (region of practical equivalence = 0.02). Across these scores, 84% of participants had at least one score in both the top and bottom risk quintile. Continuous agreement of individual risk predictions from the 48 scores was poor, with an ICC of 0.351 (95% CI; 0.349, 0.352). Agreement between two statistically equivalent scores was moderate, with an ICC of 0.649 (95% CI; 0.646, 0.652). Light's Kappa, used to evaluate consistency of assignment to high-risk thresholds, did not exceed 0.56 (interpreted as 'fair') across statistically and practically equivalent scores. Repeating the analysis among 41,193 PMBB and 50,748 UCLA participants yielded different sets of statistically and practically equivalent scores which also lacked strong individual agreement. Conclusions and Relevance: Across three diverse biobanks, CAD PRSs that performed equivalently at the population level produced unreliable individual risk estimates. Approaches to clinical implementation of CAD PRSs must consider the potential for discordant individual risk estimates from otherwise indistinguishable scores.

Performance of the open-first repair strategy in type A aortic dissection with mesenteric malperfusion syndrome eligible for delayed repair.

OBJECTIVE: For patients with type A aortic dissection complicated by mesenteric malperfusion syndrome, some centers advocate a nontraditional approach based on up-front endovascular intervention and delayed open repair. However, the efficacy of this strategy cannot be understood without first understanding outcomes of the traditional open-first strategy in the same select patient population eligible for delayed repair, applying modern techniques of hybrid aortic surgery. METHODS: Patients with acute type A aortic dissection and mesenteric malperfusion syndrome were queried from a single institution. Those presenting with aortic rupture, tamponade, or cardiogenic shock (ineligible for delayed repair) were excluded. Patients were managed with immediate open aortic repair. Short-term and long-term outcomes are reported. RESULTS: A total of 1228 patients were treated for acute type A dissection in the study period, of whom 77 were included in the mesenteric malperfusion syndrome cohort. In-hospital mortality was 29% compared with 39% in an identically selected mesenteric malperfusion syndrome population undergoing delayed repair reported previously. Among patients with mesenteric malperfusion syndrome, 32% underwent additional procedures addressing distal malperfusion in a hybrid operating room during or after open repair. Concomitant proximal malperfusion (coronary, cerebral, or upper extremity) was common in the mesenteric malperfusion syndrome cohort, present in 35% of cases. Although early mortality was greater in the mesenteric malperfusion syndrome cohort compared with all acute type A dissections, 10-year survival among those discharged alive was similar (65% vs 59%, P = .18). CONCLUSIONS: The traditional open-first repair strategy performs equal to or better than the delayed repair strategy for patients with mesenteric malperfusion syndrome eligible for delayed repair.

Differential Effects of HDAC6 Inhibition Versus Knockout During Hepatic Ischemia-Reperfusion Injury Highlight Importance of HDAC6 C-terminal Zinc-finger Ubiquitin-binding Domain.

BACKGROUND: Ischemia-reperfusion injury (IRI) causes significant morbidity in liver transplantation among other medical conditions. IRI following liver transplantation contributes to poor outcomes and early graft loss. Histone/protein deacetylases (HDACs) regulate diverse cellular processes, play a role in mediating tissue responses to IRI, and may represent a novel therapeutic target in preventing IRI in liver transplantation. METHODS: Using a previously described standardized model of murine liver warm IRI, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were assessed at 24 and 48 h after reperfusion to determine the effect of different HDAC inhibitors. RESULTS: Broad HDAC inhibition with trichostatin-A (TSA) was protective against hepatocellular damage ( P  < 0.01 for AST and P  < 0.05 for ALT). Although HDAC class I inhibition with MS-275 provided statistically insignificant benefit, tubastatin-A (TubA), an HDAC6 inhibitor with additional activity against HDAC10, provided significant protection against liver IRI ( P  < 0.01 for AST and P  < 0.001 for ALT). Surprisingly genetic deletion of HDAC6 or -10 did not replicate the protective effects of HDAC6 inhibition with TubA, whereas treatment with an HDAC6 BUZ-domain inhibitor, LakZnFD, eliminated the protective effect of TubA treatment in liver ischemia ( P  < 0.01 for AST and P  < 0.01 for ALT). CONCLUSIONS: Our findings suggest TubA, a class IIb HDAC inhibitor, can mitigate hepatic IRI in a manner distinct from previously described class I HDAC inhibition and requires the HDAC6 BUZ-domain activity. Our data corroborate previous findings that HDAC targets for therapeutic intervention of IRI may be tissue-specific, and identify HDAC6 inhibition as a possible target in the treatment of liver IRI.

Titin-Truncating variants Predispose to Dilated Cardiomyopathy in Diverse Populations.

Importance: The effect of high percentage spliced in (hiPSI) TTN truncating variants (TTNtvs) on risk of dilated cardiomyopathy (DCM) has historically been studied among population subgroups defined by genetic similarity to European reference populations. This has raised questions about the effect of TTNtvs in diverse populations, especially among individuals genetically similar to African reference populations. Objective: To determine the effect of TTNtvs on risk of DCM in diverse population as measured by genetic distance (GD) in principal component (PC) space. Design: Cohort study. Setting: Penn Medicine Biobank (PMBB) is a large, diverse biobank. Participants: Participants were recruited from across the Penn Medicine healthcare system and volunteered to have their electronic health records linked to biospecimen data including DNA which has undergone whole exome sequencing. Main Outcomes and Measures: Risk of DCM among individuals carrying a hiPSI TTNtv. Results: Carrying a hiPSI TTNtv was associated with DCM among PMBB participants across a range of GD deciles from the 1000G European centroid; the effect estimates ranged from odds ratio (OR) = 3.29 (95% confidence interval [CI] 1.26 to 8.56) to OR = 9.39 (95% CI 3.82 to 23.13). When individuals were assigned to population subgroups based on genetic similarity to the 1000G reference populations, hiPSI TTNtvs conferred significant risk of DCM among those genetically similar to the 1000G European reference population (OR = 7.55, 95% CI 4.99 to 11.42, P<0.001) and individuals genetically similar to the 1000G African reference population (OR 3.50, 95% CI 1.48 to 8.24, P=0.004). Conclusions and Relevance: TTNtvs are associated with increased risk of DCM among a diverse cohort. There is no significant difference in effect of TTNtvs on DCM risk across deciles of GD from the 1000G European centroid, suggesting genetic background should not be considered when screening individuals for titin-related DCM.

Placement of Temporary Left Ventricular Assist Device Using Monitored Anesthesia Care and Regional Anesthesia.

Patients with advanced cardiogenic shock requiring mechanical circulatory support are uniquely susceptible to clinical deterioration. Limiting physiologic perturbations via avoidance of general anesthesia and endotracheal intubation by awake Impella 5.5 placement is safe and may represent a novel strategy in mechanical circulatory support initiation among patients in cardiogenic shock. (Level of Difficulty: Intermediate.).

Relationships between body fat distribution and metabolic syndrome traits and outcomes: A mendelian randomization study.

BACKGROUND: Obesity is a complex, multifactorial disease associated with substantial morbidity and mortality worldwide. Although it is frequently assessed using BMI, many epidemiological studies have shown links between body fat distribution and obesity-related outcomes. This study examined the relationships between body fat distribution and metabolic syndrome traits using Mendelian Randomization (MR). METHODS/FINDINGS: Genetic variants associated with visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (ASAT), and gluteofemoral adipose tissue (GFAT), as well as their relative ratios, were identified from a genome wide association study (GWAS) performed with the United Kingdom BioBank. GWAS summary statistics for traits and outcomes related to metabolic syndrome were obtained from the IEU Open GWAS Project. Two-sample MR and BMI-controlled multivariable MR (MVMR) were performed to examine relationships between each body fat measure and ratio with the outcomes. Increases in absolute GFAT were associated with a protective cardiometabolic profile, including lower low density lipoprotein cholesterol (ß: -0.19, [95% CI: -0.28, -0.10], p < 0.001), higher high density lipoprotein cholesterol (ß: 0.23, [95% CI: 0.03, 0.43], p = 0.025), lower triglycerides (ß: -0.28, [95% CI: -0.45, -0.10], p = 0.0021), and decreased systolic (ß: -1.65, [95% CI: -2.69, -0.61], p = 0.0019) and diastolic blood pressures (ß: -0.95, [95% CI: -1.65, -0.25], p = 0.0075). These relationships were largely maintained in BMI-controlled MVMR analyses. Decreases in relative GFAT were linked with a worse cardiometabolic profile, with higher levels of detrimental lipids and increases in systolic and diastolic blood pressures. CONCLUSION: A MR analysis of ASAT, GFAT, and VAT depots and their relative ratios with metabolic syndrome related traits and outcomes revealed that increased absolute and relative GFAT were associated with a favorable cardiometabolic profile independently of BMI. These associations highlight the importance of body fat distribution in obesity and more precise means to categorize obesity beyond BMI.

Using a polygenic score to account for genomic risk factors in a model to detect individuals with dilated ascending thoracic aortas.

Background: Ascending thoracic aortic dilation is a complex trait that involves modifiable and non-modifiable risk factors and can lead to thoracic aortic aneurysm and dissection. Clinical risk factors have been shown to predict ascending thoracic aortic diameter. Polygenic scores (PGS) are increasingly used to assess clinical risk for multifactorial diseases. The degree to which a PGS can improve aortic diameter prediction is not known. In this study we tested the extent to which the addition of a PGS to clinical prediction algorithms improves the prediction of aortic diameter. Methods: The patient cohort comprised 6,790 Penn Medicine Biobank (PMBB) participants with available echocardiography and clinical data linked to genome-wide genotype data. Linear regression models were used to integrate PGS weights derived from a large genome wide association study of thoracic aortic diameter in the UK biobank and were compared to the performance of the standard and a reweighted variation of the recently published AORTA Score. Results: Cohort participants were 56% male, had a median age of 61 years (IQR 52-70) with a mean ascending aortic diameter of 3.4 cm (SD 0.5). Compared to the AORTA Score which explained 28.4% (95% CI 28.1% to 29.2%) of the variance in aortic diameter, AORTA Score + PGS explained 28.8%, (95% CI 28.1% to 29.6%), the reweighted AORTA score explained 30.4% (95% CI 29.6% to 31.2%), and the reweighted AORTA Score + PGS explained 31.0% (95% CI 30.2% to 31.8%). The addition of a PGS to either the AORTA Score or the reweighted AORTA Score improved model sensitivity for the identifying individuals with a thoracic aortic diameter ≥ 4 cm. The respective areas under the receiver operator characteristic curve for the AORTA Score + PGS (0.771, 95% CI 0.756 to 0.787) and reweighted AORTA Score + PGS (0.785, 95% CI 0.770 to 0.800) were greater than the standard AORTA Score (0.767, 95% CI 0.751 to 0.783) and reweighted AORTA Score (0.780 95% CI 0.765 to 0.795). Conclusions: We demonstrated that inclusion of a PGS to the AORTA Score results in a small but clinically meaningful performance enhancement. Further investigation is necessary to determine if combining genetic and clinical risk prediction improves outcomes for thoracic aortic disease.

Common- and rare-variant genetic architecture of heart failure across the allele frequency spectrum.

Heart failure (HF) is a complex trait, influenced by environmental and genetic factors, that affects over 30 million individuals worldwide. Historically, the genetics of HF have been studied in Mendelian forms of disease, where rare genetic variants have been linked to familial cardiomyopathies. More recently, genome-wide association studies (GWAS) have successfully identified common genetic variants associated with risk of HF. However, the relative importance of genetic variants across the allele-frequency spectrum remains incompletely characterized. Here, we report the results of common- and rare-variant association studies of all-cause heart failure, applying recently developed methods to quantify the heritability of HF attributable to different classes of genetic variation. We combine GWAS data across multiple populations including 207,346 individuals with HF and 2,151,210 without, identifying 176 risk loci at genome-wide significance (p < 5×10-8). Signals at newly identified common-variant loci include coding variants in Mendelian cardiomyopathy genes (MYBPC3, BAG3), as well as regulators of lipoprotein (LPL) and glucose metabolism (GIPR, GLP1R), and are enriched in cardiac, muscle, nerve, and vascular tissues, as well as myocyte and adipocyte cell types. Gene burden studies across three biobanks (PMBB, UKB, AOU) including 27,208 individuals with HF and 349,126 without uncover exome-wide significant (p < 3.15×10-6) associations for HF and rare predicted loss-of-function (pLoF) variants in TTN, MYBPC3, FLNC, and BAG3. Total burden heritability of rare coding variants (2.2%, 95% CI 0.99-3.5%) is highly concentrated in a small set of Mendelian cardiomyopathy genes, and is lower than heritability attributable to common variants (4.3%, 95% CI 3.9-4.7%) which is more diffusely spread throughout the genome. Finally, we demonstrate that common-variant background, in the form of a polygenic risk score (PRS), significantly modifies the risk of HF among carriers of pathogenic truncating variants in the Mendelian cardiomyopathy gene TTN. These findings suggest a significant polygenic component to HF exists that is not captured by current clinical genetic testing.