Paraspinous muscle gene expression profiling following simulated staged endovascular repair of thoracoabdominal aortic aneurysm: exploring potential therapeutic pathways.

OBJECTIVES: Thoracic endovascular techniques for aneurysm repair offer less invasive alternatives to open strategies. Both approaches, however, are associated with the risk for neurological complications. Despite adjuncts to maintain spinal cord perfusion, ischaemia and paraplegia continue to occur during thoracoabdominal aortic aneurysm (TAAA) repair. Staging of such extensive procedures has been proven to decrease the risk for spinal cord injury. Archived biopsy specimens may offer insight into the molecular signature of the reorganization and expansion of the spinal collateral network during staged endovascular interventions in the setting of TAAA. METHODS: Biological replicates of total RNA were isolated from existing paraspinous muscle samples from 22 Yorkshire pigs randomized to 1 of 3 simulated TAAA repair strategies as part of a previous study employing coil embolization of spinal segmental arteries within the thoracic and lumbar spine. Gene expression profiling was performed using the Affymetrix GeneChip Porcine array. RESULTS: Microarray analysis identified 649 differentially expressed porcine genes (≥1.3-fold change, P ≤ 0.05) when comparing paralysed and non-paralysed subjects. Of these, 355 were available for further analysis. When mapped to the human genome, 169 Homo sapiens orthologues were identified. Integrated interpretation of gene expression profiles indicated the significant regulation of transcriptional regulators (such as nuclear factor кB), cytokine (including CXCL12) elements contributing to hypoxia signalling in the cardiovascular system (vascular endothelial growth factor and UBE2) and cytoskeletal elements (like dystrophin (DMD) and matrix metallopeptidase (MMP)). CONCLUSIONS: This study demonstrates the ability of microarray-based platforms to detect the differential expression of genes in paraspinous muscle during staged TAAA repair. Pathway enrichment analysis detected subcellular actors accompanying the neuroprotective effects of staged endovascular coiling. These observations provide new insight into the potential prognostic and therapeutic value of gene expression profiling in monitoring and modulating the arteriolar remodelling in the collateral network.

Hospital Incidence and In-Hospital Mortality of Surgically and Interventionally Treated Aortic Dissections: Secondary Data Analysis of the Nationwide German Diagnosis-Related Group Statistics From 2006 to 2014.

Background Population-based data about the incidence and mortality of patients with aortic dissections ( ADs ) are sparse. Therefore, the hospital incidence and in-hospital mortality of patients undergoing open or endovascular surgery for type A ADs ( TAADs ) and type B ADs ( TBADs ) in Germany were analyzed on a nationwide basis between 2006 and 2014. Methods and Results A secondary data analysis of the nationwide diagnosis-related group statistics, compiled by the German Federal Statistical Office, was performed for patients who were surgically/interventionally treated for AD ( International Classification of Diseases, Tenth Revision, German Modification [ ICD -10- GM] codes I71.00-I71.07; n=20 533). By using specific procedure codes, a distinction between TAAD (n=14 911/72.6%) and TBAD (n=5622/27.4%) could be made. The standardized hospital incidence of surgically/interventionally treated AD was 2.7/100 000 per year, comprising 2.0/100 000 per year for TAAD and 0.7/100 000 per year for TBAD . The in-hospital mortality of TAAD was 19.5%; and of TBAD, 9.3%. Both the incidence and in-hospital mortality increased over the 9-year period. The share of endovascularly treated TBAD increased steadily during the same time interval. A multilevel multivariable analysis revealed that, for TAAD , age and comorbidity were significantly associated with a higher mortality risk. The latter was also true for TBAD . Sex was not significantly associated with mortality. A significant association between higher annual center volume and mortality was found for TAAD , but not for TBAD . Conclusions This is the first report on hospital incidence and mortality for surgically/interventionally treated AD on a nationwide basis. Overall, in Germany, hospital incidence and mortality of TAAD and TBAD increased over time. In addition, TAAD is performed more safely in high-volume centers.

Editor's Choice - Hospital Incidence, Treatment, and In Hospital Mortality Following Open and Endovascular Surgery for Thoraco-abdominal Aortic Aneurysms in Germany from 2005 to 2014: Secondary Data Analysis of the Nationwide German DRG Microdata.

OBJECTIVE: Hospital incidence, treatment modality, and in hospital mortality after surgery are reported for thoraco-abdominal aortic aneurysms (TAAAs) treated by endovascular or open means in Germany from 2005 to 2014. METHODS: Data were extracted from diagnosis related group statistics from the German Federal Statistical Office. All inpatient cases with a diagnosis of ruptured and non-ruptured TAAA (ICD-10 I71.5 and I71.6) and procedure codes for fenestrated or branched endovascular aortic repair (f/bEVAR 5-38a.7x and 5-38a.8x), open aortic repair (OAR 5-384.4), or hybrid procedure (5-384.b/c, 5-38a.a/b/8/80) were included. To adjust for sex, age, medical risk (Elixhauser comorbidity score), type of procedure, and type of admission, a multilevel multivariable regression model with robust error variance was applied. The primary outcome was in hospital mortality; secondary outcomes were organ complications. The relationship between annual hospital volume and outcome was analysed. RESULTS: A total of 2607 cases (406 rTAAA, 2201 nrTAAA) were included. f/bEVAR was performed in 856 cases (32.8%), OAR in 1422 cases (54.5%), and hybrid repair in 354 cases (13.6%). Endovascular repair became more frequent over time (6% in 2005 vs. 76% in 2014 for nrTAAA). Hypertension (75.2%), peripheral artery disease (including abdominal aortic aneurysm, 49.5%), other heart diseases (44.6%), coronary heart disease (30.6%), and renal failure (28.7%) were the most frequently coded comorbidities. The number of hospitals treating TAAAs almost tripled within 9 years. The in hospital mortality was 46.1% for rTAAA and 15.9% for nrTAAA. f/bEVAR (RR 0.35, 0.24-0.51) and high hospital volume (p < .001) were significantly associated with decreased in hospital mortality. Aortic rupture, increasing age, and comorbidity were significantly associated with higher mortality (RR 3.17, 2.45-4.09; 1.52, 1.32-1.76, and 1.05, 1.04-1.06). CONCLUSIONS: Seventy-six percent of all TAAAs were treated endovascularly in 2014 with increasing frequency over a decade. In hospital mortality is lower with endovascular repair and in high volume centres. Aortic rupture, age, and severe comorbidities are associated with worse outcomes.

Increasing Incidence of Thoracic Aortic Aneurysm Repair in Germany in the Endovascular Era: Secondary Data Analysis of the Nationwide German DRG Microdata.

OBJECTIVES: Nationwide population based data on epidemiology and surgical treatment of descending thoracic aortic (DTA) aneurysms are not available for Germany. The aim was to assess the in hospital incidence, and to report outcomes of patients who received surgical treatment. METHODS: Data were acquired by analysing the diagnosis related group (DRG) statistics of the German Federal Statistical Office. All inpatient cases of ruptured (rDTA aneurysm, ICD Code I71.1) or non-ruptured DTA aneurysm (nrDTA aneurysm; I71.2) who received thoracic endovascular (TEVAR; OPS procedure code 5-38a.7/70/8/80) or open aortic repair (OAR; OPS 5-384.3) between 2005 and 2014 were included. To adjust for sex, age, medical risk (Elixhauser comorbidity score), type of procedure, and type of admission, a multilevel multivariable regression model with robust error variance was applied. The primary outcome was in hospital mortality; secondary outcomes were organ complications. A volume outcome analysis was performed. RESULTS: A total of 48,098 cases of DTA aneurysm (5,848, 12.2% rDTA aneurysm) were identified. The average age was 69 ± 12 years. 65.2% were male. Frequent comorbidities were hypertension (74.9%), peripheral artery disease (including abdominal aortic aneurysm, 42.6%), other heart diseases (41.6%), coronary heart disease (26.2%), and renal failure (22.5%). Surgical treatment was received by 4969 patients (10.3%): 4057 TEVAR (81.6%) and 912 OAR (18.4%) procedures. Mortality for rDTA aneurysm was 42.9% (OAR) and 22.3% (TEVAR). It was 10.5% and 3.7% for DTA aneurysm, respectively. Rupture, increasing age, and higher comorbidity score were significantly associated with higher mortality (RR 6.66, 5.33-8.25; 1.28, 1.17-1.40; and 1.06, 1.05-1.08, respectively). Endovascular treatment was associated with lower mortality (RR 0.31, 0.23-0.41). Hospital volume was not significantly associated with in hospital mortality. CONCLUSIONS: Eighty per cent of patients treated surgically for a DTA aneurysm receive endovascular therapy, with low peri-operative mortality in non-ruptured cases. Elective endovascular repair should be considered for individuals at a high risk of rupture who are fit for surgery. Open repair, increased age, and a high comorbidity score are associated with higher mortality.

The incidence of delayed complications in acute type B aortic dissections is underestimated.

OBJECTIVE: Acute type B aortic dissections (TBADs) can have immediate or delayed complications within the first 2 weeks. Because the majority of clinical series retrospectively categorized TBAD, the incidence and outcome of delayed complications in initially uncomplicated TBAD within the first 14 days are not well described. METHODS: We retrospectively analyzed 86 patients (78% male; age, 62.5 ± 13 years) with acute TBAD treated consecutively between January 2004 and May 2016 at a tertiary referral center. All TBADs were confirmed by computed tomography angiography (CTA) on admission, after 2 to 5 days, and after 10 to 14 days. Study end points were the incidence of immediate and delayed complications (aortic rupture, malperfusion, rapid aortic expansion >4 mm, pain or hypertension resistant to medical therapy) and in-hospital mortality. In addition, we looked at CTA-detected morphometric variables (maximum diameters of descending aorta, false lumen [FL], and primary entry tear; number of intimal tears; FL configuration; true lumen collapse; course of the dissection) and their association with delayed complications. Finally, we assessed treatment modalities and clinical outcomes. RESULTS: Of all TBADs, 22 (26%) presented with immediate complications (rupture, n = 11); 64 patients (74%) were initially assessed as having uncomplicated TBAD. Of these 64 patients, 24 (28% of all 86) suffered from delayed complications (malperfusion, n = 10; aortic rupture, n = 3; early expansion >4 mm, n = 8; refractory pain, n = 2; uncontrollable hypertension, n = 1) at a median interval of 7.1 (2-14) days after symptom onset. During the first 14 days, 40 patients (46%) remained uncomplicated. The CTA analysis revealed a significant association of initial thoracic aortic diameter (P = .009), size of the primary entry tear (P = .018), true lumen collapse (P = .019), and partially thrombosed FL (P = .019) with the occurrence of delayed complications within the first 14 days. Of the patients with delayed complications, 87.5% underwent surgery (90% thoracic endovascular aortic repair, 10% peripheral revascularization); 12.5% in this group died following aortic rupture before they received surgical repair. The mortality of patients with delayed complicated TBAD was significantly higher compared with those who remained uncomplicated within the 14-day period (12.5% vs 0%; P = .0221). CONCLUSIONS: Delayed complications in initially uncomplicated acute TBAD are not infrequent. Morphologic variables like maximum diameter of the descending aorta, primary entry tear, true lumen collapse, and partially thrombosed FL were associated with an increased risk of delayed complications in initially uncomplicated TBAD. Future clinical research must verify the predictive role of clinical and morphologic variables in the acute phase, particularly with regard to a possible early surgical treatment to prevent a fatal outcome.

Cathepsin S is associated with degradation of collagen I in abdominal aortic aneurysm.

BACKGROUND: Cathepsins have been described in the pathogenesis of abdominal aortic aneurysm (AAA), their exact role, especially in collagen degradation, is still unclear. The aim of the present study was therefore to analyse relevant cathepsins in human AAA tissue samples in relation to collagen I, III, and their degradation products. MATERIALS AND METHODS: Samples from 37 AAA patients obtained from elective open surgical repair and eight healthy non-aneurysmatic aortas from kidney donors were included. Expression of cathepsins B, D, K, L, S, cystatin C, collagen I and III, their degraded products C-Telopeptide of type 1 and 3 collagen (CTX-I, CTX-III), cellular markers for leukocytes (CD45), T cells (CD3), macrophage scavenger receptor-1 (MSR-1), synthetic, and contractile smooth muscle cells (SMCs) (smoothelin: SMTH, collagen I and III, myosin heavy chain: MHC, embryonic smooth muscle myosin heavy chain: SMemb) were determined at messenger RNA (mRNA) level, using SYBRGreen-based quantitative PCR and at protein level using enzyme-linked immunosorbent assay (ELISA). RESULTS: Expression of cathepsins B, D, L, and S at mRNA level was significantly elevated in AAA compared to control aorta (1.7-fold, p = 0.025; 2.5-fold, p = 0.002; 2.6-fold, p = 0.034; and 7.0-fold, p = 0.003). Expression of cathepsin S correlated significantly with leukocytes and macrophages (ρ = 0.398, p = 0.033 and ρ = 0.422, p = 0.020), synthetic SMCs were significantly associated with cathepsins B, D, and L (ρ = 0.522, p = 0.003; ρ = 0.431, p = 0.015 and ρ = 0.467, p = 0.008). At protein level, cathepsins B and S were elevated in AAA compared to controls (5.4-fold, p = 0.001 and 7.3-fold, p < 0.001). Significant correlations were observed between collagen I, its degraded product, and cathepsin S (r = -0.350, p = 0.034 and r = +0.504, p < 0.001). Expression of cathepsin B was associated with SMCs, expression of cathepsin S with inflammatory cells. CONCLUSIONS: Particularly cathepsin S was associated with the degradation product of collagen I and thus might be involved in the progression of AAA. Furthermore, cathepsin S correlated with inflammatory cells.

Endovascular coil embolization of segmental arteries prevents paraplegia after subsequent thoracoabdominal aneurysm repair: an experimental model.

OBJECTIVES: To test a strategy for minimizing ischemic spinal cord injury after extensive thoracoabdominal aneurysm (TAAA) repair, we occluded a small number of segmental arteries (SAs) endovascularly 1 week before simulated aneurysm repair in an experimental model. METHODS: Thirty juvenile Yorkshire pigs (25.2 ± 1.7 kg) were randomized into 3 groups. All SAs, both intercostal and lumbar, were killed by a combination of surgical ligation of the lumbar SAs and occlusion of intercostal SAs with thoracic endovascular stent grafting. Seven to 10 days before this simulated TAAA replacement, SAs in the lower thoracic/upper lumbar region were occluded using embolization coils: 1.5 ± 0.5 SAs in group 1 (T13/L1), and 4.5 ± 0.5 SAs in group 2 (T11-L3). No SAs were coiled in the controls. Hind limb function was evaluated blindly from daily videotapes using a modified Tarlov score (0 = paraplegia, 9 = full recovery). After death, each segment of spinal cord was graded histologically using the 9-point Kleinman score (0 = normal, 8 = complete necrosis). RESULTS: Hind limb function remained normal after coil embolization. After simulated TAAA repair, paraplegia occurred in 6 of 10 control pigs, but in only 2 of 10 pigs in group 1; no pigs in group 2 had a spinal cord injury. Tarlov scores were significantly better in group 2 (control vs group 1, P = .06; control vs group 2, P = .0002; group 1 vs group 2, P = .05). A dramatic reduction in histologic damage, most prominently in the coiled region, was seen when SAs were embolized before simulated TAAA repair. CONCLUSIONS: Endovascular coiling of 2 to 4 SAs prevented paraplegia in an experimental model of extensive hybrid TAAA repair, and helped protect the spinal cord from ischemic histopathologic injury. A clinical trial in a selected patient population at high risk for postoperative spinal cord injury may be appropriate.

A prospective study of growth and rupture risk of small-to-moderate size ascending aortic aneurysms.

OBJECTIVE: The natural history of small-to-moderate size ascending aortic aneurysms is poorly understood. To follow these patients better, we have developed a method to objectively and reproducibly measure ascending aortic volume on the basis of gated contrast computed tomography scans. METHODS: From 2009 to 2011, 507 patients were referred for management of ascending aortic aneurysms. A total of 232 patients (46%) with small-to-moderate size aneurysms who did not have compelling indications for operation had measurement(s) of ascending aortic and total aortic volume; 166 patients had more than 1 scan, allowing measurement of growth. A total of 66 patients admitted to the emergency department without ascending aortic pathology served as a reference group. RESULTS: None of the patients experienced rupture, dissection, or death; 3 patients ultimately underwent operation. Ascending aortic volume and volume/total aortic volume differed for the surveillance and reference groups: 132.8 ± 39.4 mL versus 78.0 ± 24.5 mL; 38.3% ± 7.4% versus 29.1% ± 3.9%, respectively (both P < .001). Diameters at the sinotubular junction and mid-ascending aortic were 4.1 ± 0.6 cm and 4.4 ± 0.6 cm, respectively, for the surveillance group and 3.0 ± 0.4 cm and 3.2 ± 0.4 cm, respectively, for controls. The increase in ascending aortic volume was 0.95 ± 4.5 mL/year and 0.73% ± 3.7%/year (P = .007 and .012, respectively). Analysis of risk factors for ascending aortic growth revealed only the use of antithrombotic medication as possibly significant. CONCLUSIONS: Computed tomography volume measurements provide an objective method for ascertaining aortic size and monitoring expansion. Patients with small-to-moderate ascending aortic aneurysms who are carefully followed and managed appropriately have slow aneurysm growth and a small risk of rupture or dissection. Annual computed tomography screening may not be indicated, and elective resection-absent other surgical indications-is not necessary. The rupture/dissection risk for even larger aneurysms in carefully followed patients may be lower than currently believed.

Open repair of descending and thoracoabdominal aortic aneurysms and dissections in patients aged younger than 60 years: superior to endovascular repair?

BACKGROUND: The best option for repair of descending thoracic and thoracoabdominal aortic aneurysms (TAAA)-whether open operation or stent grafting-is increasingly a subject of controversy. We examined the results of open surgical repair in patients aged 60 years or younger to assess the value of conventional repair in younger patients. METHODS: From October 2002 to October 2010, 107 of 294 TAAA operations were in patients (75 men [70%]) aged a mean of 48 ± 9 years. Twelve patients (11%) had Marfan syndrome. Operations were elective in 101 (94%); previous aortic operations had been performed in 40 (37%). The most common indication for operation was chronic dissection, in 60 (56%); 5 (4.7%) had acute dissection, and rupture was present in 6 (5.6%). Descending repair was undertaken in 44 (41%), in 32 (73%) as an elephant trunk stage II. Deep hypothermic circulatory arrest was used in 46 (42.9%). Neurologic monitoring and cerebrospinal fluid drainage were routine. Median postoperative follow-up was 4.3 years (range, 2 days to 7.9 years). RESULTS: Overall 30-day mortality was 4.7%. Stroke occurred in 4 patients (3.7%) and paraplegia in 1 (0.9%). The linearized rate for reoperation for TAAA was 0.22/100 patient-years (1 patient in 448.8 patient-years). Survival at 1, 5, and 8 years was 90.5%, 89.4% and 80.5%, respectively. During follow-up, 1 patient with Ehlers-Danlos died of aortic complications at 4.5 years. CONCLUSIONS: Although direct comparison with stent grafting is limited by the diversity of patients and indications in published reports, our results suggest that open repair should be the modality of choice. Early mortality and neurologic complication rates are similar, if not superior, to endovascular repair for descending aortic and TAAAs. Open repair has proven durability and a very low rate of required reintervention, in contrast with endovascular repair.

Imaging of vascular remodeling after simulated thoracoabdominal aneurysm repair.

OBJECTIVE: A better understanding of the response of the spinal cord blood supply to segmental artery (SA) sacrifice should help minimize the risk of paraplegia after both open and endovascular repair of thoracoabdominal aortic (TAA) aneurysms. METHODS: Twelve female juvenile Yorkshire pigs were randomized into 3 groups and perfused with a barium-latex solution. Pigs in group 1 (control) had infusion without previous intervention. Pigs in group 2 were infused 48 hours after ligation of all SAs (T4-L5) and those in group 3 at 120 hours after ligation. Postmortem computed tomographic scanning of the entire pig enabled overall comparisons and measurement of vessel diameters in the spinal cord circulation. RESULTS: We ligated 14.5 ± 0.8 SAs: all filled retrograde to the ligature. Paraplegia occurred in 38% of operated pigs. A significant increase in the mean diameter of the anterior spinal artery (ASA) was evident after SA sacrifice (P < .0001 for 48 hours and 120 hours). The internal thoracic and intercostal arteries also increased in diameter. Quantitative assessment showed an increase in vessel density 48 hours after ligation of SAs, reflected by an obvious increase in small collateral vessels seen on 3-dimensional reconstructions of computed tomographic scans at 120 hours. CONCLUSIONS: Remodeling of the spinal cord blood supply--including dilatation of the ASA and proliferation of small collateral vessels--is evident at 48 and 120 hours after extensive SA sacrifice. It is likely that exploitation of this process will prove valuable in the quest to eliminate paraplegia after TAA aneurysm repair.

Incidence and management of CoreValve dislocation during transcatheter aortic valve implantation.

BACKGROUND: Transcatheter aortic valve implantation is a highly specialized technique offering a new therapeutic option to patients at high risk for conventional surgery. Complications associated with this catheter procedure differ from complications after surgical aortic valve replacement. This is to report incidence, management, and impact on morbidity and mortality of CoreValve dislocation during catheter valve implantation. METHODS AND RESULTS: Between June 2007 and September 2009, the self-expandable CoreValve prosthesis (Medtronic Inc, Minneapolis, Minn) was implanted in 212 patients through a transarterial (femoral or subclavian) access. Patients with severe aortic stenosis who were at high risk for conventional surgery were included. We observed dislocation of the prosthesis during CoreValve implantation in 21 patients. In 16 cases, the CoreValve could be implanted in the correct annular position after retrieving it and reloading the catheter. In 4 patients, the completely deployed prosthesis had to be placed in the ascending or abdominal aorta before implanting a second one. One patient underwent open surgery. Overall 30-day mortality was 11.0%, 21.5% in the dislocation group and 9.9% in patients without dislocation (P=0.024). Coronary ischemia, stroke, and renal failure occurred more frequently in patients with dislocation, whereas pacemaker dependency did not differ significantly between the groups. CONCLUSIONS: CoreValve dislocation during transcatheter aortic valve implantation occurred in 10% of the cases and significantly increases perioperative risk for severe complications or death. It requires individual specific management and can be managed either interventionally or, rarely, results in open surgery.

Predictors for new-onset complete heart block after transcatheter aortic valve implantation.

OBJECTIVES: The aim of this study was to identify risk factors for new-onset atrioventricular (AV) block requiring pacemaker (PM) implantation after transcatheter aortic valve implantation (TAVI). BACKGROUND: High-grade AV block and consecutive PM implantation are frequent complications following TAVI. METHODS: For logistic regression analysis, we included 159 patients (mean age: 81 +/- 6 years, EuroSCORE: 22 +/- 13%) who underwent TAVI (n = 116 transfemoral, n = 4 via subclavian artery, n = 37 transapical, n = 2 transaortic) between June 2007 and January 2009 and who had no previously implanted PM. RESULTS: Thirty-five patients (22%) developed new-onset post-operative AV block with the need of PM implantation. Logistic regression revealed a 2-fold increased risk for new-onset AV block in patients in whom a large valve is implanted in a small annulus (32% pacemaker implantations, odds ratio [OR]: 2.378, p = NS), a 4-fold increased risk with the implantation of the CoreValve (Medtronic, Minneapolis, Minnesota) versus the Edwards Sapien valve (Edwards Lifesciences, Irvine, California) (27% pacemaker implantations, OR: 3.781, p = NS), and a 5-fold increased risk for patients who exhibit an AV block episode instantly during the implantation procedure (49% pacemaker implantations, OR: 4.819, p = 0.001). Pre-existing ECG alterations were not identified as risk factors for AV block after transcatheter aortic valve implantation. CONCLUSIONS: We assume that conduction tissue impairment is provoked by mechanical compression with large prostheses in smaller annuli or in the larger area of the CoreValve covering the outflow tract and may appear instantly during the implantation procedure. Continuous post-operative electrocardiogram monitoring should be performed for at least 3 days in all patients after TAVI procedures and until discharge in patients with increased risk for this complication.