Integrative Multiomics in the Lung Reveals a Protective Role of Asporin in Pulmonary Arterial Hypertension.

BACKGROUND: Integrative multiomics can elucidate pulmonary arterial hypertension (PAH) pathobiology, but procuring human PAH lung samples is rare. METHODS: We leveraged transcriptomic profiling and deep phenotyping of the largest multicenter PAH lung biobank to date (96 disease and 52 control) by integration with clinicopathologic data, genome-wide association studies, Bayesian regulatory networks, single-cell transcriptomics, and pharmacotranscriptomics. RESULTS: We identified 2 potentially protective gene network modules associated with vascular cells, and we validated ASPN, coding for asporin, as a key hub gene that is upregulated as a compensatory response to counteract PAH. We found that asporin is upregulated in lungs and plasma of multiple independent PAH cohorts and correlates with reduced PAH severity. We show that asporin inhibits proliferation and transforming growth factor-ß/phosphorylated SMAD2/3 signaling in pulmonary artery smooth muscle cells from PAH lungs. We demonstrate in Sugen-hypoxia rats that ASPN knockdown exacerbated PAH and recombinant asporin attenuated PAH. CONCLUSIONS: Our integrative systems biology approach to dissect the PAH lung transcriptome uncovered asporin as a novel protective target with therapeutic potential in PAH.

Dissecting the lung transcriptome of pulmonary fibrosis-associated pulmonary hypertension.

Integrative multiomics can help elucidate the pathophysiology of pulmonary fibrosis (PF)-associated pulmonary hypertension (PH) (PF-PH). Weighted gene coexpression network analysis (WGCNA) was performed on a transcriptomic dataset of explanted lung tissue from 116 patients with PF. Patients were stratified by pulmonary vascular resistance (PVR), and differential gene expression analysis was conducted. Gene modules were correlated with hemodynamics at the time of transplantation and tested for enrichment in the lung transcriptomics signature of an independent pulmonary arterial hypertension (PAH) cohort. We found 1,250 differentially expressed genes between high and low PVR groups. WGCNA identified that black and yellowgreen modules negatively correlated with PVR, whereas the tan and darkgrey modules are positively correlated with PVR in PF-PH. In addition, the tan module showed the strongest enrichment for an independent PAH gene signature, suggesting shared gene expression patterns between PAH and PF-PH. Pharmacotranscriptomic analysis using the Connectivity Map implicated the tan and darkgrey modules as potentially pathogenic in PF-PH, given their combined module signature demonstrated a high negative connectivity score for treprostinil, a medication used in the treatment of PF-PH, and a high positive connectivity score for bone morphogenetic protein (BMP) loss of function. Pathway enrichment analysis revealed that inflammatory pathways and oxidative phosphorylation were downregulated, whereas epithelial-mesenchymal transition was upregulated in modules associated with increased PVR. Our integrative systems biology approach to the lung transcriptome of PF with and without PH identified several PH-associated coexpression modules and gene targets with shared molecular features with PAH warranting further investigation to uncover potential new therapies for PF-PH.NEW & NOTEWORTHY An integrative systems biology approach that included transcriptomic analysis of explanted lung tissue from patients with pulmonary fibrosis (PF) with and without pulmonary hypertension (PH) undergoing lung transplantation, combined with hemodynamic correlation and pharmacotranscriptomics, identified modules of genes associated with pulmonary vascular disease severity. Comparison with an independent pulmonary arterial hypertension (PAH) dataset identified shared gene expression patterns between PAH and PF-PH.

Natural history and management of Kommerell's diverticulum in a single tertiary referral center.

OBJECTIVE: The Kommerell diverticulum (KD) is an extremely rare developmental abnormality of the aorta related to an aberrant subclavian artery (ASCA). The objective of our study was to review the natural history of KD and ASCA using our single-center experience in diagnosing and managing KD and ASCA. METHODS: A retrospective review of the Yale radiological database from January 1999 to December 2016 was performed. Only patients with KD/ASCA and a computed tomography (CT) scan of the chest were selected for review. The primary goal was to examine the natural history of KD and ASCA and the secondary goals were to review the management and outcomes of those patients treated for KD and ASCA. RESULTS: There were 75 patients with KD/ASCA identified, with a mean age of 63 ± 19 years; 49 were female (65%). On CT scans, left- and right-sided aortas were present in 47 (63%) and 28 (37%) patients. A right ASCA or a left ASCA were present in 47 (63%) and 28 (37%) patients. Six patients were symptomatic on presentation. Symptoms included dysphagia, chest or back pain, and emboli to the fingers. The mean KD diameter was 21.8 ± 6.0 mm and the distance to the opposite aortic wall (DAW) was 48.3 ± 10.8 mm. Sixty-six patients were followed for a mean of 31.7 ± 32.5 months. One patient ruptured without repair. Nine patients underwent operative intervention, including eight open and one endovascular repair. Complications from operative intervention included ischemic stroke with hemorrhagic transformation, deep vein thrombosis and pneumonia. The mean growth rate for KD and DAW was 1.45 ± 0.39 mm/year and 2.29 ± 0.47 mm/year, respectively. On multivariable regression analysis, hypertension was a predictor of growth of DAW (P = .03). CONCLUSIONS: KD is uncommon and shows a female predominance. The diverticulum grows, albeit slowly (KD and DAW growth rates of 1.45 ± 0.39 mm/year and 2.29 ± 0.47 mm/year). Most patients are asymptomatic, but dysphagia, chest/back pain, and distal emboli may occur. Rupture is rare. Symptomatic patients should be operated. Asymptomatic patients can be followed with serial CT scans.

Natural history and management of splanchnic artery aneurysms in a single tertiary referral center.

OBJECTIVE: Splanchnic artery aneurysms (SAAs) are rare, and little is known about their natural history and management. We reviewed our single-center experience in managing this population of patients. METHODS: A retrospective review of the Yale radiologic database from January 1999 to December 2016 was performed. Only patients with an SAA and a computed tomography scan of the abdomen were selected for review. Demographics of the patients, aneurysm characteristics, management, postoperative complications, and follow-up data were collected. Our primary outcomes included aneurysm growth rate and risk of rupture in those patients managed nonoperatively and morbidity and mortality of those SAA patients who underwent operative intervention. RESULTS: There were 122 patients with 138 SAAs identified; 77 were male (62%), with a mean age of 66 years (range, 25-94 years). On computed tomography, 56 (45%) had previously diagnosed or concomitant aneurysms elsewhere. Of the patients managed nonoperatively, 101 patients (79%) had 108 SAAs; in the operative intervention group, 25 (21%) patients had 30 SAAs. The mean overall vessel diameter was 1.76 ± 0.83 cm. The diameter of observed and operatively repaired SAAs was 1.58 ± 0.56 cm and 2.41 ± 1.23 cm, respectively (P = .00001). Mean follow-up was 50 ± 42 months for nonoperative management without any adverse events related to SAA, including 10 patients with SAA >2.0 cm. The mean observed growth rate for SAA was 0.064 ± 0.18 cm/y. All symptomatic patients who presented with severe abdominal pain (n = 11 [44%]) underwent operative intervention. Five patients presented with a ruptured SAA (3.6%; range, 2.3-5.0 cm); all of them except one underwent operative intervention. Other indications for repair included large size in seven, rapid growth in two, other open abdominal surgical procedures in two, multiple aneurysms in one, and desire to pursue fertility treatment in one. Operative repair included 14 (56%) endovascular embolizations and 11 (44%) open abdominal operations. After endovascular embolization, two patients underwent abdominal operation for hemorrhage and splenectomy. Open repairs included bypasses in six, splenectomy in two, resection in two, and plication in one. Two patients had postoperative acute kidney injury that resolved and one died of multisystem organ failure. One bypass occluded without sequelae. On multivariable regression analysis, female sex (P = .02) was associated with faster growth rate, and a history of smoking (P = .04) was associated with slower growth rate. CONCLUSIONS: It seems reasonable to observe asymptomatic patients with an SAA <2.0 cm because of the slow growth rate (0.064 ± 0.18 cm/y) and benign behavior. When intervention is needed, both open and endovascular options should be considered.

Natural history and management of renal artery aneurysms in a single tertiary referral center.

OBJECTIVE: Although renal artery aneurysms (RAAs) are uncommon, several large reports have been published indicating their benign natural history. The objective of our study was to review our single-center experience managing this disease entity. METHODS: A retrospective review of the Yale radiologic database from January 1999 to December 2016 was performed. Only patients with RAA and a computed tomography scan of the abdomen were selected for review. Demographics of the patients, aneurysm characteristics, management, postoperative complications, and follow-up data were collected. RESULTS: There were 241 patients with 259 RAAs identified, with a mean age of 69 years (range, 35-100 years); 147 were female (61%). On computed tomography, aneurysms were solitary and right sided in 224 (86%) and 159 (61%), respectively; 64 (27%) patients had aneurysms elsewhere. The breakdown of RAAs by location was as follows: renal bifurcation in 84 (32%), renal pelvis in 77 (30%), distal renal artery in 58 (22%), mid renal artery in 34 (13%), and proximal renal artery in 6 (2%). Five patients had symptoms that were attributed to the RAA and underwent operative repair; all others were observed without an operation. Symptoms in the operative repair group included flank pain in four and uncontrolled hypertension in one. The mean overall diameter of the RAAs was 1.22 ± 0.49 cm. The diameter of operatively repaired and observed RAAs was 1.84 ± 0.55 cm and 1.21 ± 0.48 cm, respectively (P = .002). Operative repair included four coil embolizations and one open resection. There were no renal function changes in any of these patients after operation and no other complications. Mean follow-up was 41 ± 35 months for patients in the group that was observed; 18 of these RAAs were >2 cm, and none ruptured. On multivariable regression analysis, female sex (P = .0001), smoking history (P = .00007), left-sided RAA (P = .03), and main renal artery location (P = .03) were inversely related to growth, whereas a history of hypertension was directly related to growth rate (P = .01). The mean growth rate for RAAs was 0.017 ± 0.052 cm/y. CONCLUSIONS: RAAs tend to have a benign natural history. Although previous reports have not identified any factors that contribute to RAA growth, we observed that RAA location, sex, smoking history, and hypertension may have an impact on growth rates. No ruptures were observed. Operative repair at our institution was rare, with no morbidity or mortality. Observation of RAAs over time seems feasible in the asymptomatic patient with a small RAA.

Natural history of aneurysmal aortic arch branch vessels in a single tertiary referral center.

OBJECTIVE: Little is known about the natural history and management of aneurysmal aortic arch branch vessels (AABVs). The objectives of this study were to assess the natural history of aneurysmal AABVs and to examine the outcomes of operative intervention. METHODS: A retrospective review of the Yale radiologic database from 1999 to 2016 was performed. Only those patients with an aneurysmal AABV and a computed tomography scan were selected for review. Patients' demographics, aneurysm characteristics, management, and follow-up information were collected. RESULTS: There were 105 patients with 147 aneurysmal AABVs; 76 were male (72%), with a mean age of 70 years (range, 17-93 years). We identified 63 innominate, 50 left subclavian, 30 right subclavian, and 4 common carotid artery aneurysms. On computed tomography, 65 (62%) had aortic aneurysms and six (6%) had suffered an aortic dissection. Most were asymptomatic (104 [99%]); one had chest pain and an enlarging swollen mass. Twelve (11%) patients underwent operative repair (OR) for 12 aneurysmal AABVs because of symptoms, growth, or concomitant aortic operations; 93 (89%) were observed in the no operative repair (NOR) group with cross-sectional imaging. The overall mean vessel diameter was 2.08 ± 0.68 cm. The mean diameters in the OR and NOR groups were 3.32 ± 1.24 cm and 1.97 ± 0.46 cm, respectively (P = .002). OR included nine bypasses with resection, two stent grafts, and one resection without reconstruction. Two patients developed postoperative hemorrhage requiring re-exploration, one patient developed stent thrombosis, and one patient required pseudoaneurysm repair 20 years after index operation. Mean follow-up was 52 ± 51 months for the NOR group, with no ruptures or emboli. The growth rate was 0.04 ± 0.10 cm/y. On multivariable regression analysis, a descending aortic aneurysm (P = .041) and a left subclavian artery aneurysm (P = .016) were associated with higher growth rates, whereas height was associated with a lower growth rate (P = .001). CONCLUSIONS: Aneurysmal AABVs tend to have a benign natural history with slow growth rates and low rates of complications, including rupture and embolization. We recommend expectant observational management for small, incidentally detected aneurysms.

Immature reticulocyte fraction: A novel biomarker of hemodynamic severity in pulmonary arterial hypertension.

Various erythropoietic abnormalities are highly prevalent among patients with pulmonary arterial hypertension (PAH) and associated with worse disease severity. Given the poorly understood yet important roles of dysregulated erythropoiesis and iron metabolism in PAH, we sought to further characterize the hematologic and iron profiles in PAH and their relationship to PAH severity. We recruited 67 patients with PAH and 13 healthy controls. Hemodynamics attained within 1 year of blood sample collection were available for 36 patients. Multiple hematologic, iron, and inflammatory parameters were evaluated for their association with hemodynamics. The subset with hemodynamic data consisted of 29 females (81%). The most common etiologies were idiopathic PAH (47%) and connective tissue disease-related PAH (33%). 19 (53%) had functional class 3 or 4 symptomatology, and 12 (33%) were on triple pulmonary vasodilator therapy. Immature reticulocyte fraction (IRF) had significant positive correlations with mean pulmonary artery (PA) pressure (mPAP) (0.59, p < 0.001), pulmonary vascular resistance (0.52, p = 0.001), and right atrial pressure (0.46, p = 0.005), and significant negative correlations with cardiac index (-0.43, p = 0.009), PA compliance (PAC) (-0.60, p < 0.001), stroke volume index (SVI) (-0.57, p < 0.001), and mixed venous oxygen saturation (-0.51, p = 0.003). IRF correlated with markers of iron deficiency (ID) and erythropoiesis. On multivariable linear regression, IRF was associated with elevated mPAP and reduced SVI and PAC independent of EPO levels, transferrin saturation, and soluble transferrin receptor levels. We identified IRF as a novel and potent biomarker of PAH hemodynamic severity, possibly related to its associations with erythropoiesis, ID, and tissue hypoxia.

Atrial Arrhythmias in Patients With Pulmonary Hypertension.

TOPIC IMPORTANCE: Atrial arrhythmias (AA) are common in patients with pulmonary hypertension (PH) and contribute to morbidity and mortality. Given the growing PH population, understanding the pathophysiology, clinical impact, and management of AA in PH is important. REVIEW FINDINGS: AA occurs in PH with a 5-year incidence of 10% to 25%. AA confers a higher morbidity and mortality, and restoration of normal sinus rhythm improves survival and functionality. AA is thought to develop because of structural alterations of the right atrium caused by changes to the right ventricle (RV) due to elevated pulmonary artery pressures. AA can subsequently worsen RV function. Current guidelines do not provide comprehensive recommendations for the management of AA in PH. Robust evidence to favor a specific treatment approach is lacking. Although the role of medical rate or rhythm control, and the use of cardioversion and ablation, can be inferred from other populations, evidence is lacking in the PH population. Much remains to be determined regarding the optimal management strategy. We present here our institutional approach and discuss areas for future research. SUMMARY: This review highlights the epidemiology and pathophysiology of AA in patients with PH, describes the relationship between AA and RV dysfunction, and discusses current management practices. We outline our institutional approach and offer directions for future investigation.

Application of the very high risk criterion and evaluation of cholesterol guideline adherence in acute myocardial infarction patients at an urban academic medical center.

Objective: The 2018 AHA/ACC cholesterol guidelines recommend considering non-statin agents among very high-risk (VHR) patients with LDL-C ≥ 70 mg/dL after maximizing statin therapy. We aimed to evaluate the prevalence of VHR status in acute myocardial infarction (AMI) patients at hospital discharge and the adherence to guideline-directed cholesterol therapy (GDCT) within one-year follow-up post-AMI. Methods: We performed a retrospective analysis of patients who suffered a type 1 AMI between October 2015 and March 2019, and then were followed at our institution for 1 year after hospital discharge. We calculated the percentage of patients at VHR and among those with follow up lipid panels, we determined the proportion able to achieve GDCT. Results: The mean age of the 331 AMI patients was 61.0 (SD 11.9) years and 33.6% were women. Overall, 268 (81.0%) patients were categorized as having VHR at discharge. Among patients at VHR, a lipid panel was rechecked in 153 individuals (57.1%) within 1 year of discharge, with the median time to lipid recheck being 22.4 weeks (interquartile range: 10.9-40.7 weeks). Among those with a lipid panel re-check, 100 (65.4%) of patients achieved GDCT. Conclusions: Approximately 4 out of 5 AMI patients were considered VHR per the 2018 AHA/ACC guidelines, only about half had follow up lipid panels in the year following AMI, and about two-thirds of those with follow up lipid panels achieved GDCT.

Utility of non-HDL-C and apoB targets in the context of new more aggressive lipid guidelines.

OBJECTIVE: Major guidelines recommend the use of secondary targets, such as non-HDL-C and apoB, to further reduce cardiovascular risk. We aimed to evaluate the proportion at which newer, more aggressive secondary lipid targets are exceeded in patients with LDL-C < 70 mg/dL estimated by Friedewald (LDLf-C) and Martin/Hopkins equations (LDLm-C). METHODS: We analyzed patients from the Very Large Database of Lipids with fasting lipids and estimated LDL-C <70 mg/dL by the Friedewald equation and Martin/Hopkins algorithm. Patients were categorized into three groups: LDL-C <40, 40-54 and 55-69 mg/dL. We calculated the proportion of patients with non-HDL-C and apoB above high-risk targets (non-HDL-C ≥ 100 and apoB ≥ 80mg/dL) for those with LDL-C 55-69 mg/dL and very high-risk targets (non-HDL-C ≥ 85 and apoB ≥ 65mg/dL) for those with LDL-C < 40 mg/dL and 40-54 mg/dL. RESULTS: In patients with LDLf-C < 40 mg/dL, ~8 and ~4% did not meet high-risk secondary targets and ~21 and 25% did not meet very high-risk secondary targets for non-HDL-C and apoB, respectively. However, in patients with LDLm-C < 40 mg/dL <1% did not meet high-risk targets, while only 3% did not meet the very-high risk secondary target for apoB and none exceeded the very-high risk secondary target for non-HDL-C. Among individuals with LDL-C< 40 mg/dL, there were increasing proportions of individuals not meeting the very high-risk secondary apoB target at greater triglyceride levels, reaching up to ~19% using LDLm-C compared to ~60% using LDLf-C when triglyceride levels were 200-399 mg/dL. There were higher proportions of individuals not meeting high and very-high risk targets as triglyceride levels increased among those with LDL-C 40-54 and 55-69 mg/dL. CONCLUSION: In a large, US cross-sectional sample of individuals with LDL-C < 70 mg/dL, secondary non-HDL-C and apoB targets overall provide modest utility. However, attainment of very high-risk cutpoints for non-HDL-C and apoB is not achieved in a significant fraction of patients with triglycerides 200-399 mg/dL, even when using a more accurate calculation of LDL-C.

Importance of the triglyceride level in identifying patients with a Type III Hyperlipoproteinemia phenotype using the ApoB algorithm.

BACKGROUND: Hyperlipoproteinemia Type III (HLP3), also known as dysbetalipoproteinemia, is defined by cholesterol and triglyceride (TG) enriched remnant lipoprotein particles (RLP). The gold standard for diagnosis requires demonstration of high remnant lipoprotein particle cholesterol (RLP-C) by serum ultracentrifugation (UC), which is not readily available in daily practice. The apoB algorithm can identify HLP3 using total cholesterol (TC), plasma triglyceride (TG), and apoB. However, the optimal TG cutoff is unknown. OBJECTIVE: We analyzed apoB algorithm defined HLP3 at different TG levels to optimize the TG cutoff for the algorithm. METHODS: 128,485 UC lipid profiles in the Very Large Database of Lipids (VLDbL) were analyzed. RLP-C was assessed at TG ≥ 133 mg/dL, ≥175 mg/dL, ≥200 mg/dL, and ≥ 250 mg/dL. Sensitivity (Sn), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV), and prevalence adjusted and bias-adjusted kappa (PABAK) were calculated against UC Criterion (VLDL-C/TG ≥ 0.25) for HLP3. RESULTS: The median age (IQR) was 57 years (46-68). 45% were men, 20.1% had diabetes, and 25.5% had hypertension. The median RLP-C level for the TG cutoffs (mg/dL) of ≥ 133, ≥ 175, ≥ 200, and ≥ 250 were 34, 43, 50, and 62 mg/dL, respectively, compared to 67 mg/dL in UC defined HLP3. TG ≥ 133 mg/dL yielded optimal results (Sn 29.5%, Sp 98.5%, PABAK 0.96, PPV 13.6%, NPV 99.4%). CONCLUSION: TG ≥ 133 mg/dL allows for high sensitivity in screening for HLP3. Higher TG cutoffs may identify more severe HLP3 phenotypes, but with a large loss in sensitivity for HLP3.

More accurate LDL-C calculation: Externally validated, guideline endorsed.

Low density lipoprotein-cholesterol (LDL-C) serves as the primary target of therapy for preventing atherosclerotic cardiovascular disease (ASCVD). Recently released European and American guidelines on lipid management recommend attaining very low LDL-C levels (<1.8 mmol/L or even lower) in high and very-high risk patients. Therefore, utilizing an accurate means for determining LDL-C, especially at such low values, is of paramount importance to inform the best clinical decisions and use of effective therapies. This review compares the different methods of determining LDL-C, including the various forms of direct measurement and most commonly used calculations. This review discusses the evidence behind these methods in different populations of patients and in the fasting versus non-fasting state. The Martin/Hopkins method is the preferred method for determining LDL-C as it is the most accurate and widely applicable method. It is especially useful in patients with low LDL-C levels < 1.8 mmol/L (<70 mg/dL) and high triglyceride levels between 1.7 and 4.5 mmol/L (150-399 mg/dL), and is reliable in the non-fasting state.

Human aortic aneurysm genomic dictionary: is it possible?

Thoracic aortic aneurysm (TAA), a typically silent but frequently lethal disease, is strongly influenced by underlying genetics. Approximately 30 genes have been associated with syndromic and non-syndromic familial thoracic aortic aneurysm and dissection (TAAD) to date. An estimated 30% of patients with non-syndromic familial TAAD, which is typically inherited in an autosomal dominant manner, have a mutation in one of these genes. The underlying genetic mutation helps predict patients' clinical presentation, risk of aortic dissection at small aortic sizes (< 5.0 cm), and risk of other cardiovascular disease. As a result, a TAAD genomic dictionary based on these genes is necessary to provide optimal patient care, but is not on its own sufficient as this disease is typically inherited with reduced penetrance and has widely variable expressivity. Next-generation sequencing has been and will continue to be critical for identifying novel genes and variants associated with TAAD as well as genotype-phenotype correlations that will allow for management to be targeted to not only the underlying gene harboring the pathogenic variant but also the specific mutation identified. The aortic dictionary, to which a clinician can turn to obtain information on clinical consequences of a specific genetic variants, is not only possible, but has been substantially written already. As additional entries to the dictionary are made, truly personalized, genetically based, aneurysm care can be delivered.

Thoracic aortic aneurysm: unlocking the "silent killer" secrets.

Thoracic aortic aneurysm (TAA) is an increasingly recognized condition that is often diagnosed incidentally. This review discusses ten of the most relevant epidemiological and clinical secrets of this disease; (1) the difference in pathogenesis between ascending and descending TAAs. TAAs at these two sites act as different diseases, which is related to the different embryologic origins of the ascending and descending aorta. (2) The familial pattern and genetics of thoracic aneurysms. Syndromic TAAs only explain 5% of the pattern of inheritance. (3) The effect of female sex on TAA growth and outcome. Females have been found to have worse outcomes compared to males. (4) Guilt by Association. TAAs are associated with abdominal aortic aneurysms, intracranial aneurysms, bicuspid aortic valve, and inflammatory disorders. (5) Natural history of TAAs. Important findings have been made regarding the expansion rate (in relation to familial pattern, location and size), and also regarding the risk of rupture or dissection. (6) The aortic size paradox. Size only is not a sufficient predictor of risk of dissection. (7) Biomarker void. Although many serum biomarkers have been studied, imaging remains the only reliable method for diagnosis and follow-up. (8) Indications for repair. Decisions are made depending on symptoms, location, size, and familial patterns. (9) Types of repair. Both open and endovascular repair options are available for certain TAAs. (10) Medical treatment. The efficacy of prescribing beta blockers, angiotensin converting enzyme inhibitors or angiotensin receptor blockers remains dubious.

Simple renal cysts and bovine aortic arch: markers for aortic disease.

Objective: This study aimed to assess the prevalence of thoracic aortic disease (TAD) and abdominal aortic aneurysms (AAA) among patients with simple renal cyst (SRC) and bovine aortic arch (BAA). Methods: Through a retrospective search for patients who underwent both chest and abdominal CT imaging at our institution from 2012 to 2016, we identified patients with SRC and BAA and propensity score matched them to those without these features by age, gender and presence of hypertension, hyperlipidaemia, diabetes and chronic kidney disease. Results: Of a total of 35 498 patients, 6366 were found to have SRC. Compared with the matched population without SRC, individuals with SRC were significantly more likely to have TAD (10.1% vs 3.9%), ascending aortic aneurysm (8.0% vs 3.2%), descending aortic aneurysm (3.3% vs 0.9%), type A aortic dissection (0.6% vs 0.2%), type B aortic dissection (1.1% vs 0.3%) and AAA (7.9% vs 3.3%). The 920 patients identified with BAA were significantly more likely to have TAD (21.8% vs 4.5%), ascending aortic aneurysm (18.4% vs 3.2%), descending aortic aneurysm (6.5% vs 2.0%), type A aortic dissection (1.4% vs 0.4%) and type B aortic dissection (2.4% vs 0.7%) than the matched population without BAA. SRC and BAA were found to be significantly associated with the presence of TAD (OR=2.57 and 7.69, respectively) and AAA (OR=2.81 and 2.56, respectively) on multivariable analysis. Conclusions: This study establishes a substantial increased prevalence of aortic disease among patients with SRC and BAA. SRC and BAA should be considered markers for aortic aneurysm development.

Genes Associated with Thoracic Aortic Aneurysm and Dissection: 2019 Update and Clinical Implications.

Thoracic aortic aneurysm is a typically silent disease characterized by a lethal natural history. Since the discovery of the familial nature of thoracic aortic aneurysm and dissection (TAAD) almost 2 decades ago, our understanding of the genetics of this disorder has undergone a transformative amplification. To date, at least 37 TAAD-causing genes have been identified and an estimated 30% of the patients with familial nonsyndromic TAAD harbor a pathogenic mutation in one of these genes. In this review, we present our yearly update summarizing the genes associated with TAAD and the ensuing clinical implications for surgical intervention. Molecular genetics will continue to bolster this burgeoning catalog of culprit genes, enabling the provision of personalized aortic care.

Decision-making algorithm for ascending aortic aneurysm: Effectiveness in clinical application?

OBJECTIVE: The risk of rupture and dissection in ascending thoracic aortic aneurysms increases as the aortic diameter exceeds 5 cm. This study evaluates the clinical effectiveness of a specific algorithm based on size and symptoms for preemptive surgery to prevent complications. METHODS: A total of 781 patients with nondissecting ascending thoracic aortic aneurysms who presented electively for evaluation to our institution from 2011 to 2017 were triaged to surgery (n = 607, 77%) or medical observation (n = 181, 24%) based on a specific algorithm: surgery for large (>5 cm) or symptomatic aneurysms. A total of 309 of 781 patients did not undergo surgery. Of these, 128 (16%) had been triaged to prompt repair but did not undergo surgery for a variety of reasons ("surgery noncompliant and overwhelming comorbidities" group). Another 181 patients (24%) were triaged to medical management ("medical" group). RESULTS: In the "surgery noncompliant and overwhelming comorbidities" versus the "medical" group, mean aortic diameters were 5 ± 0.5 cm versus 4.45 ± 0.4 cm and aortic events (rupture/dissection) occurred in 17 patients (13.3%) versus 3 patients (1.7%), respectively (P < .001). Later elective surgeries (representing late compliance in the "surgery noncompliant and overwhelming comorbidities group" or onset of growth or symptoms in the "medical" group) were conducted in 21 patients (16.4%) versus 15 patients (8.3%) (P = .04), respectively. Death ensued in 20 patients (15.6%) versus 6 patients (3.3%) (P < .001), respectively. In the "surgery noncompliant and overwhelming comorbidities" group, 7 of 20 patients died of definite aortic causes compared with none in the "medical" group. CONCLUSIONS: Patients with ascending thoracic aortic aneurysms who did not follow surgical recommendations experienced substantially worse outcomes compared with medically triaged candidates. The specific algorithm based on size and symptoms functioned effectively in the clinical setting, correctly identifying both at-risk and safe patients.

A systematic review on management of nutcracker syndrome.

OBJECTIVE: Although nutcracker syndrome (NS) is rare, patients presenting with symptoms or signs and anatomic compression of the left renal vein (LRV) can be considered for intervention. Open, laparoscopic, and endovascular techniques have been developed to decrease the venous outflow obstruction of the LRV. The paucity of data regarding the management of this uncommon disease process poses a challenge for adequate recommendations of the best treatment modality. Herein, we aim to present a systematic review for the management of NS. METHODS: We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement standards to systematically search the electronic databases of MEDLINE from October 1982 to July 2017 for articles about the management of NS. Included were studies in English, Spanish, and German in all age groups. RESULTS: The literature search provided 249 references. After abstract and full review screening for inclusion, 17 references were analyzed. Eight (47%) described the open surgical approach. The LRV transposition was the most commonly reported technique, followed by renal autotransplantation. Seven (41.11%) described the endovascular technique of stent implantation, and two (11.7%) described the minimally invasive laparoscopic extravascular stent implantation. CONCLUSIONS: NS is a rare entity. Multiple techniques have been developed for the treatment of this condition. However, the rarity of this syndrome, the paucity of data, and the short-term follow-up of the existing evidence are the disadvantages that prevent recommendations for the best treatment strategy. Up to now, open surgical intervention, specifically LRV transposition, has been considered by some experts the mainstay for treatment of NS. The endovascular approach is gaining strength as more evidence has become available. However, the long-term patency and durability of this approach remain to be elucidated. Therefore, careful selection of patients is necessary in recommending this technique.

Genes Associated with Thoracic Aortic Aneurysm and Dissection: 2018 Update and Clinical Implications.

Thoracic aortic aneurysms, with an estimated prevalence in the general population of 1%, are potentially lethal, via rupture or dissection. Over the prior two decades, there has been an exponential increase in our understanding of the genetics of thoracic aortic aneurysm and/or dissection (TAAD). To date, 30 genes have been shown to be associated with the development of TAAD and ∼30% of individuals with nonsyndromic familial TAAD have a pathogenic mutation in one of these genes. This review represents the authors' yearly update summarizing the genes associated with TAAD, including implications for the surgical treatment of TAAD. Molecular genetics will continue to revolutionize the approach to patients afflicted with this devastating disease, permitting the application of genetically personalized aortic care.