Kenneth DeSart

Fate of patients with spinal cord ischemia complicating thoracic endovascular aortic repair

OBJECTIVE Spinal cord ischemia (SCI) is a potentially devastating complication of thoracic endovascular aortic repair (TEVAR) that can result in varying degrees of short-term and permanent disability. This study was undertaken to describe the clinical outcomes, long-term functional impact, and influence on survival of SCI after TEVAR. METHODS A retrospective review of all TEVAR patients at the University of Florida from 2000 to 2011 was performed to identify individuals experiencing SCI, defined by any new lower extremity neurologic deficit not attributable to another cause. SCI was dichotomized into immediate or delayed onset, with immediate onset defined as SCI noted upon awakening from anesthesia, and delayed characterized as a period of normal function, followed by development of neurologic injury. Ambulatory status was determined using database query, record review, and phone interviews with patients and/or family. Mortality was estimated using life-table analysis. RESULTS A total of 607 TEVARs were performed for various indications, with 57 patients (9.4%) noted to have postoperative SCI (4.3% permanent). SCI patients were more likely to be older (63.9 ± 15.6 vs 70.5 ± 11.2 years; P = .002) and have a number of comorbidities, including chronic obstructive pulmonary disease, hypertension, dyslipidemia, and cerebrovascular disease (P < .0001). At some point in their care, a cerebrospinal fluid drain was placed in 54 patients (95%), with 54% placed postoperatively. In-hospital mortality was 8.8% for the entire cohort (SCI vs no SCI; P = .45). SCI developed immediately in 12 patients, delayed onset in 40, and indeterminate in five patients due to indiscriminate timing from postoperative sedation. Three patients (25%) with immediate SCI had measurable functional improvement (FI), whereas 28 (70%) of the delayed-onset patients experienced some degree of neurologic recovery (P = .04). Of the 34 patients with complete data available, 26 (76%) reported quantifiable FI, but only 13 (38%) experienced return to their preoperative baseline. Estimated mean (± standard error) survival for patients with and without SCI was 37.2 ± 4.5 and 71.6 ± 3.9 months (P < .0006), respectively. Patients with FI had a mean survival of 53.9 ± 5.9 months compared with 9.6 ± 3.6 months for those without improvement (P < .0001). Survival and return of neurologic function were not significantly different when patients with preoperative and postoperative cerebrospinal fluid drains were compared. CONCLUSIONS The minority of patients experience complete return to baseline function after SCI with TEVAR, and outcomes in patients without early functional recovery are particularly dismal. Patients experiencing delayed SCI are more likely to have FI and may anticipate similar life-expectancy with neurologic recovery compared with patients without SCI. Timing of drain placement does not appear to have an impact on postdischarge FI or long-term mortality.

Smooth muscle cell-specific Tgfbr1 deficiency promotes aortic aneurysm formation by stimulating multiple signaling events

Transforming growth factor (TGF)-β signaling disorder has emerged as a common molecular signature for aortic aneurysm development. The timing of postnatal maturation plays a key role in dictating the biological outcome of TGF-β signaling disorders in the aortic wall. In this study, we investigated the impact of deficiency of TGFβ receptors on the structural homeostasis of mature aortas. We used an inducible Cre-loxP system driven by a Myh11 promoter to delete Tgfbr1, Tgfbr2, or both in smooth muscle cells (SMCs) of adult mice. TGFBR1 deficiency resulted in rapid and severe aneurysmal degeneration, with 100% penetrance of ascending thoracic aortas, whereas TGFBR2 deletion only caused mild aortic pathology with low (26%) lesion prevalence. Removal of TGFBR2 attenuated the aortic pathology caused by TGFBR1 deletion and correlated with a reduction of early ERK phosphorylation. In addition, the production of angiotensin (Ang)-converting enzyme was upregulated in TGFBR1 deficient aortas at the early stage of aneurysmal degeneration. Inhibition of ERK phosphorylation or blockade of AngII type I receptor AT1R prevented aneurysmal degeneration of TGFBR1 deficient aortas. In conclusion, loss of SMC-Tgfbr1 triggers multiple deleterious pathways, including abnormal TGFBR2, ERK, and AngII/AT1R signals that disrupt aortic wall homeostasis to cause aortic aneurysm formation.

Hypertension overrides the protective effect of female hormones on the development of aortic aneurysm secondary to Alk5 deficiency via ERK activation

The prevalence of aortic aneurysm is five times higher in men than women among the general population. Similar sexual dimorphism also exists in syndromic aortic aneurysms triggered by TGF-β signaling disorders. To understand the responsible mechanisms, we developed an animal model where inducible deletion of the type I TGF-β receptor, Alk5, specifically in smooth muscle cells (Alk5iko) causes spontaneous aortic aneurysm formation. This model recapitulated an extreme scenario of the dimorphism in aortic aneurysm development between genders. In a comparative experiment, all Alk5iko males (n=42) developed aortic aneurysms and 26% of them died prematurely from aortic rupture. In contrast, the Alk5iko females (n=14) presented only a subclinical phenotype characteristic of scarcely scattered elastin breaks. Removal of male hormones via orchiectomy (n=7) resulted in only minimal influence on aortic pathology. However, reduction of female hormones via ovariectomy (n=15) increased the phenotypic penetrance from zero to 53%. Finally, an elevation of systolic blood pressure by 30 points unmasked the subclinical phenotype of Alk5iko females (n=17) to 59%. This exaggerated phenotypic penetrance was coupled with an early intensification of ERK signaling, a molecular signature that correlated to 100% phenotypic penetrance in normotensive Alk5iko males. In conclusion, aortic aneurysm induced by Alk5iko exhibits dimorphic incidence between genders with females less susceptible to aortic disease. This sexual dimorphism is partially the result from the protective effects of female hormones. Hypertension, a known risk factor for aortic aneurysm, is able to break the female sex protective effects through mechanisms associated with enhanced ERK activity.

The correlation between computed tomography and duplex evaluation of autogenous vein bypass grafts and their relationship to failure.

OBJECTIVE Duplex ultrasound (DUS) imaging for vein bypass graft (VBG) surveillance is confounded by technical and physiologic factors that reduce the sensitivity for detecting impending graft failure. In contrast, three-dimensional computed tomography angiography (CTA) offers high-fidelity anatomic characterization of VBGs, but its utility in detecting at risk grafts is unknown. The current study analyzed the correlation between DUS and CTA for detection of vein graft stenosis and evaluated the relationship of the observed abnormalities to VBG failure. METHODS Consecutive lower extremity VBG patients underwent surveillance with concurrent DUS imaging and CTA at 1 week and at 1, 6, and 12 months postoperatively. A standardized algorithm was used for CT reconstruction and extraction of the lumen geometries at 1-mm intervals. At each interval, CT-derived cross-sectional areas were coregistered and correlated to DUS peak systolic velocities (PSVs) within six predesignated anatomic zones and then analyzed for outcome association. Vein graft failure was defined as pathologic change within a given anatomic zone resulting in thrombosis, amputation, or reintervention within the 6-month period after the observed time point. RESULTS The study recruited 54 patients, and 10 (18%) experienced failure ≤18 months of implantation. The expected inverse relationship between cross-sectional area and PSV was only weakly correlated (Spearman rank coefficient = -0.19). Moderate elevations in the PSV ratio (PSVr; 2-3.5) were frequently transient, with 14 of 18 grafts (78%) demonstrating ratio reduction on subsequent imaging. A PSVr ≥3.5 was associated with a 67% failure rate. CT stenosis <50% was highly correlated with success (0 failures); however, high-grade (>80%) CT stenosis was more likely to succeed than to fail (25%). Significant discordance between CT and DUS was found in 18 patients. Although 14 of these patients had CT stenosis >70% with a PSVr <3.5, subsequent failure occurred in only two. Conversely, graft failure occurred in three of four patients with CT stenosis <70% but PSVr >3.5. Focused analysis of these patients using computational fluid dynamic modeling demonstrated that vein side branches, local tortuosity, regional diameter variations, and venovenostomies were the drivers of these discrepancies. CONCLUSIONS This analysis demonstrated that a PSVr ≥3.5 is strongly correlated with VBG failure, whereas the natural history of moderately elevated PSVr (2-3.5) is largely clinically benign. Although minimum stenosis on the CT scan was highly predictive of success, high-grade CT stenosis was infrequently associated with failure. The interaction of anatomic features with the local flow dynamics was identified as the primary confounder for a direct correlation between CT and DUS imaging.

Time and flow-dependent changes in the p27kip1 gene network drive maladaptive vascular remodeling

OBJECTIVE Although clinical studies have identified that a single nucleotide polymorphism in the p27(kip1) gene is associated with success or failure after vein bypass grafting, the underlying mechanisms for this difference are not well defined. Using a high-throughput approach in a flow-dependent vein graft model, we explored the differences in p27(kip1)-related genes that drive the enhanced hyperplastic response under low-flow conditions. METHODS Bilateral rabbit carotid artery interposition grafts with jugular vein were placed with a unilateral distal outflow branch ligation to create differential flow states. Grafts were harvested at 2 hours and at 1, 3, 7, 14, and 28 days after implantation, measured for neointimal area, and assayed for cell proliferation. Whole-vessel messenger RNA was isolated and analyzed using an Affymetrix (Santa Clara, Calif) gene array platform. Ingenuity Pathway Analysis (Ingenuity, Redwood City, Calif) was used to identify the gene networks surrounding p27(kip1). This gene set was then analyzed for temporal expression changes after graft placement and for differential expression in the alternate flow conditions. RESULTS Outflow branch ligation resulted in an eightfold difference in mean flow rates throughout the 28-day perfusion period (P < .001). Flow reduction led to a robust hyperplastic response, resulting in a significant increase in intimal area by 7 days (0.13 ± 0.04 mm(2) vs 0.014 ± 0.006 mm(2); P < .005) and progressive growth to 28 days (1.37 ± 0.05 mm(2) vs 0.39 ± 0.06 mm(2); P < .001). At 7 days, low-flow grafts demonstrated a burst of actively dividing intimal cells (36.4 ± 9.4 cells/mm(2) vs 11.5 ± 1.9 cells/mm(2); P = .04). Sixty-five unique genes within the microarray were identified as components of the p27(kip1) network. At a false discovery rate of 0.05, 26 genes demonstrated significant temporal changes, and two dominant patterns of expression were identified. Class comparison analysis identified differential expression of 11 genes at 2 hours and seven genes and 14 days between the high-flow and low-flow grafts (P < .05). At 2 hours, oncostatin M and cadherin 1 were the most differentially expressed. Cadherin 1 and protein kinase B exhibited the greatest differential expression at 14 days. CONCLUSIONS Alterations in flow and shear stress result in divergent patterns of vein graft remodeling. Associated with the dramatic increase in neointimal expansion observed in low-flow vs high-flow grafts is a subset of differentially expressed p27(kip1)-associated genes that correlate with critical stages in the adaptive response. These represent potential biologic targets whose activity may be altered to augment maladaptive vascular remodeling.

Hyperacute Monocyte Gene Response Patterns Are Associated With Lower Extremity Vein Bypass Graft Failure

Background: Despite being the definitive treatment for lower extremity peripheral arterial disease, vein bypass grafts fail in half of all cases. Early repair mechanisms after implantation, governed largely by the immune environment, contribute significantly to long-term outcomes. The current study investigates the early response patterns of circulating monocytes as a determinant of graft outcome. Methods: In 48 patients undergoing infrainguinal vein bypass grafting, the transcriptomes of circulating monocytes were analyzed preoperatively and at 1, 7, and 28 days post-operation. Results: Dynamic clustering algorithms identified 50 independent gene response patterns. Three clusters (64 genes) were differentially expressed, with a hyperacute response pattern defining those patients with failed versus patent grafts 12 months post-operation. A second independent data set, comprised of 96 patients subjected to major trauma, confirmed the value of these 64 genes in predicting an uncomplicated versus complicated recovery. Causal network analysis identified 8 upstream elements that regulate these mediator genes, and Bayesian analysis with a priori knowledge of the biological interactions was integrated to create a functional network describing the relationships among the regulatory elements and downstream mediator genes. Linear models predicted the removal of either STAT3 (signal transducer and activator of transcription 3) or MYD88 (myeloid differentiation primary response 88) to shift mediator gene expression levels toward those seen in successful grafts. Conclusions: A novel combination of dynamic gene clustering, linear models, and Bayesian network analysis has identified a core set of regulatory genes whose manipulations could migrate vein grafts toward a more favorable remodeling phenotype.