ARHGAP18 Protects Against Thoracic Aortic Aneurysm Formation by Mitigating the Synthetic and Proinflammatory Smooth Muscle Cell Phenotype.

RATIONALE: Thoracic aortic aneurysm (TAA) is a potentially lethal condition, which can affect individuals of all ages. TAA may be complicated by the sudden onset of life-threatening dissection or rupture. The underlying mechanisms leading to TAA formation, particularly in the nonsyndromal idiopathic group of patients, are not well understood. Thus, identification of new genes and targets that are involved in TAA pathogenesis are required to help prevent and reverse the disease phenotype. OBJECTIVE: Here we explore the role of ARHGAP18, a novel Rho GAP expressed by smooth muscle cells (SMCs), in the pathogenesis of TAA. METHODS AND RESULTS: Using human and mouse aortic samples, we report that ARHGAP18 levels were significantly reduced in the SMC layer of aortic aneurysms. Arhgap18 global knockout (Arhgap18-/-) mice exhibited a highly synthetic, proteolytic, and proinflammatory smooth muscle phenotype under basal conditions and when challenged with angiotensin II, developed TAA with increased frequency and severity compared with littermate controls. Chromatin immunoprecipitation studies revealed this phenotype is partly associated with strong enrichment of H3K4me3 and depletion of H3K27me3 at the MMP2 and TNF-α promoters in Arhgap18-deficient SMC. We further show that TAA formation in the Arhgap18-/- mice is associated with loss of Akt activation. The abnormal SMC phenotype observed in the Arhgap18-/- mice can be partially rescued by pharmacological treatment with the mTORC1 inhibitor rapamycin, which reduces the synthetic and proinflammatory phenotype of Arhgap18-deficient SMC. CONCLUSION: We have identified ARHGAP18 as a novel protective gene against TAA formation and define an additional target for the future development of treatments to limit TAA pathogenesis.

Use of multi-velocity encoding 4D flow MRI to improve quantification of flow patterns in the aorta.

PURPOSE: To show that the use of a multi-velocity encoding (VENC) 4D-flow approach offers significant improvements in the characterization of complex flow in the aorta. Four-dimensional flow magnetic resonance imaging (MRI) (4D-flow) can be used to measure complex flow patterns and dynamics in the heart and major vessels. The quality of the information derived from these measures is dependent on the accuracy of the vector field, which is limited by the vector-to-noise ratio. MATERIALS AND METHODS: A 4D-flow protocol involving three different VENC values of 150, 60, and 20 cm/s was performed on six control subjects and nine patients with type-B chronic aortic dissection at 3T MRI. Data were processed using a single VENC value (150 cm/s) or using a fused dataset that selected the lowest appropriate VENC for each voxel. Performance was analyzed by measuring spatial vector angular correlation, magnitude correlation, temporal vector conservation, and "real-world" streamline tracing performance. RESULTS: The multi-VENC approach provided a 31% improvement in spatial and 53% improvement in temporal precision of velocity vector measurements during the mid-late diastolic period, where 99% of the flow vectors in the normal aorta are below 20 cm/s. In low-flow conditions this resulted in practical improvements of greater than 50% in pathline tracking and streamline tracing quantified by streamline curvature measurements. CONCLUSION: A multi-VENC 4D-flow approach provides accurate vector data across normal physiological velocities observed in the aorta, dramatically improving outputs such as pathline tracking, streamline estimation, and further advanced analyses.

Long Term Outcomes Following Freestyle Stentless Aortic Bioprosthesis Implantation: An Australian Experience.

BACKGROUND: The Freestyle stentless bioprosthesis (FSB) has been demonstrated to be a durable prosthesis in the aortic position. We present data following Freestyle implantation for up to 10 years post-operatively and compare this with previously published results. METHODS: A retrospective cohort analysis of 237 patients following FSB implantation occurred at five Australian hospitals. Follow-up data included clinical and echocardiographic outcomes. RESULTS: The cohort was 81.4% male with age 63.2±13.0 years and was followed for a mean of 2.4±2.3 years (range 0-10.9 years, total 569 patient-years). The FSB was implanted as a full aortic root replacement in 87.8% patients. The 30-day all cause mortality was 4.2% (2.0% for elective surgery). Cumulative survival at one, five and 10 years was 91.7±1.9%, 82.8±3.8% and 56.5±10.5%, respectively. Freedom from re-intervention at one, five and 10 years was 99.5±0.5%, 91.6±3.7% and 72.3±10.5%, respectively. At latest echocardiographic review (mean 2.3±2.1 years post-operatively), 92.6% had trivial or no aortic regurgitation. Predictors of post-operative mortality included active endocarditis, acute aortic dissection and peripheral vascular disease. CONCLUSIONS: We report acceptable short and long term outcomes following FSB implantation in a cohort of comparatively younger patients with thoracic aortic disease. The durability of this bioprosthesis in the younger population remains to be confirmed.

Clinical utility of magnetic resonance imaging in the follow-up of chronic aortic type B dissection.

Several imaging modalities are utilised in the assessment of disease progression in chronic aortic dissection. We present the case of a 66 year-old male who underwent ascending aorta repair for Stanford type A aortic dissection. On follow-up the persisting dissection of the descending thoracic aorta was observed to regress on magnetic resonance imaging (MRI). MRI has several advantages over computed tomography (CT) scanning and echocardiography in the follow-up phase of this disease.

The freestyle aortic bioprosthesis: a systematic review.

BACKGROUND: The Medtronic Freestyle bioprosthesis (FSB) provides an alternative to other prostheses for both aortic valve and aortic root surgery. This paper is a systematic review of the post-operative outcomes in patients with aortic valve and/or aortic root disease following FSB implantation. METHODS: Electronic databases were searched for primary analysis, prospective randomised studies comparing the FSB with an alternative aortic prosthesis were included. Additionally, case series that included data for at least 100 individual operated patients were used for secondary analysis. RESULTS: Among three identified randomised studies, 199 FSB cases were compared with homografts, and stented and an alternative stentless bioprosthesis. The FSB showed comparable hospital mortality (4.5% vs. 5.3%) and eight-year actuarial survival (80±5.0% versus 77±6.0%) with the homograft (respectively) and comparable reduction in left ventricular mass index relative to other prosthesis types. Over 6000 individual patients were included in the selected 15 case series. Weighted mean operative mortality, neurological event rate and five-year actuarial survival was 5.2%, 5.5% and 77.8%, respectively. CONCLUSION: The FSB performed comparably against alternative prostheses regarding in-hospital mortality, long-term survival and reduction in left ventricular mass index. Included case series demonstrated robust post-operative outcomes in both the short and long term.

Dual inflow, total-arterial, anaortic, off-pump coronary artery bypass grafting: how to do it.

Coronary surgery performed on an arrested heart, using one internal mammary artery and a saphenous vein carries two main potential drawbacks: the known failure rate of vein grafts and the relatively high rate of neurologic injury. To address these concerns, we describe a technique that achieves complete revascularization without manipulating the ascending aorta (anaortic, off-pump) and utilizing total arterial grafts. All patients undergo thorough preoperative investigation, including bilateral carotid, vertebral and subclavian artery Duplex ultrasounds. A pulmonary artery catheter, transoesophageal echocardiography, and point-of-care coagulation testing are used in each case. The left and right internal mammary arteries and non-dominant radial artery are harvested using a fully skeletonised technique. Wide bilateral extrapleural retrothymic tunnels are developed and the pericardium is opened widely to facilitate cardiac positioning. A tandem graft is constructed with the right internal mammary artery (RIMA) in situ and radial artery using an end-to-end anastomosis. This graft is brought into the pericardium and through the transverse sinus in order to graft the lateral and inferior walls with multiple sequential distal anastomoses. The left internal mammary artery (LIMA) in situ is used to graft the anterior wall. Four main cardiac positions (high and low lateral walls, inferior and anterior walls) are obtained using a combination of off-pump stabilizer positioning, alternate tension on pericardial 'heart-strings', table tilting and folded wet sponges. All distal anastomoses are performed using silastic intracoronary shunts and an off-pump myocardial stabilizer. All grafts are checked using transit-flow time measurements. Milrinone is continued overnight and dual antiplatelet therapy is continued for 3 months postoperatively.

Multi-Velocity Encoding Four-Dimensional Flow Magnetic Resonance Imaging in the Assessment of Chronic Aortic Dissection.

BACKGROUND: Chronic descending thoracic aortic dissection (CDTAD) following surgical repair of ascending aortic dissection requires long-term imaging surveillance. We investigated four-dimensional (4D)-flow magnetic resonance imaging (MRI) with a novel multi-velocity encoding (multi-VENC) technique as an emerging clinical method enabling the dynamic quantification of blood volume and velocity throughout the cardiac cycle. METHODS: Patients with CDTAD (n = 10; mean age, 55.1 years; standard deviation (SD) 10.8) and healthy volunteers (n = 9; mean age, 37.1 years; SD 11.4; p < 0.01) underwent 3T MRI, and standard views and 4D-flow data were obtained. Flow measurements were made in selected regions of interest within the ascending and descending thoracic aorta. RESULTS: The overall flow profile at peak systole was reduced in the false lumen (FL) compared with the true lumen (TL) and normal aortas (p < 0.05 for velocity < 0.4 m/s). Peak systolic flow rate per aortic lumen area (mL/s/cm2) was lower in the FL than in the TL (p < 0.05), and both rates were lower than that of control aortas (p < 0.05). Blood flow reversal was higher in the FL than in the TL throughout the descending aorta in CDTAD patients (p < 0.05). A derived pulsatility index was elevated in the TL compared with that in the FL in CDTAD patients. Generated pathline images demonstrated flow patterns in detail, including sites of communication between the true and FL. CONCLUSIONS: 4D-flow MRI revealed FL blood flow and reduced blood flow velocity and flow rate in the TL of CDTAD patients compared with normal aortas of healthy participants. Thus, multi-VENC 4D-flow MRI could serve as an adjunct in the long-term assessment of CDTAD following surgical repair of ascending aortic dissection.

Familial non-syndromal thoracic aortic aneurysms and dissections - Incidence and family screening outcomes.

BACKGROUND: Non-syndromal thoracic aortic aneurysm and dissection (ns-TAAD) is a genetic aortopathy, with uncertain incidence. This study documented the incidence of ns-TAAD and outcomes of family screening over 15years. METHODS: Consecutive series of 2385 patients with aortic disease in prospective registry (2000 to 2014), including 675 undergoing surgery. Diagnosis of ns-TAAD included family history, aortic imaging, tissue pathology and mutation testing. Screening was offered to relatives of ns-TAAD probands, with follow-up for affected individuals. RESULTS: There were 270 ns-TAAD probands (74% males), including 116 (43%) presenting with aortic dissection. Among surgical cases, a diagnosis of ns-TAAD was established for 116 (17%). Age of probands was 50.4±14.1years, with aortic diameter of 51±12mm. Screening of 581 at-risk relatives identified 216 new ns-TAAD cases (detection rate=37%). Among 71 probands with known family history, screening identified 130 new affected relatives and among 53 probands with no family history, screening identified 86 new affected relatives. Mean age of new affected relatives at diagnosis was 44±18years, with aortic diameter of 42±7mm, including 42 with diameter>50mm. Ten-year mortality was similar for probands without dissection (7.7±3.1%) and new affected relatives (11.4±4.0%) but greater for probands surviving initial dissection (27.6±7.8%, p=0.003). CONCLUSIONS: Up to 1 in 6 patients undergoing aortic surgery have features of ns-TAAD, frequently presenting as aortic dissection but at later age than other genetic aortopathies. Family screening identifies affected relatives in up to half of ns-TAAD probands, many of whom already have significant aortic dilatation.

Nonsyndromic Thoracic Aortic Aneurysm and Dissection: Outcomes With Marfan Syndrome Versus Bicuspid Aortic Valve Aneurysm.

BACKGROUND: Genetic aortopathy (GA) underlies thoracic aortic aneurysms (TAA) in younger adults. Comparative survival and predictors of outcomes in nonsyndromic TAA (NS-TAA) are incompletely defined compared to Marfan syndrome (MFS) and bicuspid aortic valve (BAV). OBJECTIVES: The study sought to compare survival and clinical outcomes for individuals with NS-TAA, MFS, and BAV. METHODS: From 1988 to 2014, all patients presenting with GA 16 to 60 years of age were enrolled in a prospective study of clinical outcomes. Risk factors for death and aortic dissection were identified by Cox proportional hazards modeling and a mortality risk score developed. RESULTS: Diagnosis of GA was made for 760 patients (age 36.9 ± 13.6 years, 26.8% female; NS-TAA, n = 311; MFS, n = 221; BAV, n = 228). MFS patients were younger than NS-TAA and BAV. Presentation with aortic dissection was more common for NS-TAA than MFS or BAV. The 687 patients surviving >30 days after presentation were followed for a median of 7 years. Calculated 10-year mortality was 7.8% for NS-TAA, 8.7% for MFS, and 3.5% for BAV (NS-TAA and MFS vs. BAV p <0.05). Factors associated with all-cause mortality were MFS (p = 0.04), age at presentation, and family history of dissection. CONCLUSIONS: Clinical outcomes for MFS and NS-TAA are similar but worse than BAV. Independent predictors of mortality, including family history of aortic dissection and age, can be included in an Aortopathy Mortality Risk Score to predict survival. Management of NS-TAA, including surgical intervention, should be similar to that of MFS.

MRI in Chronic Aortic Dissection: A Systematic Review and Future Directions.

The acute event of thoracic aortic dissection carries with it high mortality and morbidity. Despite optimal initial surgical or medical management strategies, the risk of further complications in the long-term, including aneurysmal dilatation and false lumen (FL) expansion, are not insignificant. Adequate follow-up of such conditions requires dedicated imaging where relevant prognostic indicators are accurately assessed. We perform a systematic review of the literature and report the current evidence for the use of magnetic resonance imaging (MRI) in assessment of chronic aortic dissection. We then make a comparison with traditional imaging modalities including computed tomography and echocardiography. We discuss new ways in which MRI may extend existing aortic assessment, including identification of blood-flow dynamics within the TL and FL using phase-contrast imaging.