Endovascular Treatment of Ruptured or Symptomatic Thoracoabdominal and Pararenal Aortic Aneurysms Using Octopus Endograft Technique: Mid-Term Clinical Outcomes.

OBJECTIVE: To evaluate the effectiveness and safety of using off-the-shelf "Octopus" technique to treat ruptured or symptomatic thoracoabdominal aortic aneurysm (TAAA) and pararenal abdominal aortic aneurysm (PRAAA). METHODS AND RESULTS: All cases who underwent "Octopus" technique from May 2016 to May 2019 at our center were retrospectively analyzed. A total of 10 cases (8 males) were included. The mean age was 54.5±14.2 years (range: 31-80 years). Eight cases presented as aneurysm rupture or impending rupture accepted emergency repair. Technical success, defined by placement of all endografts as planned, was achieved in all cases. A total of 30 target visceral branches were successfully cannulated, 9 celiac arteries were covered intentionally. Intraoperative endoleak was observed in 6 patients, all of them were gutter leak. During hospital stay, there was no death, no side branch occlusion or spinal cord ischemia. Median follow-up was 30 months (range: 12-50 months). One patient died of lung cancer at 14-month follow-up. There was no secondary endoleak. The primary endoleak were found spontaneously resolved in 3 cases at 7 days, 3-month, and 1-year imaging. One persistent endoleak totally resolved after sealing of gutter spaces at 4-month follow-up. The other 2 persistent endoleak decreased during follow-up, which are still under observation. The branch patency rate was 90.3% (28/31). All the 3 occluded branches were renal arteries. Branch occlusion occurred in 2 cases at 1-month follow-up and 1 case at 2-year follow-up, but renal insufficiency was not observed in these cases. Obvious aneurysm sac shrinkage (≥5 mm) was observed in all cases. The aneurysm size shrunk from 7.6±1.9 to 5.5±1.4 cm. No spinal cord ischemia occurred during follow-up. CONCLUSION: Treatment of ruptured TAAA and PRAAA with "Octopus" technique is feasible and safe for high surgical risk patients in the absence of fenestrated and branched devices. The long-term clinical outcomes needed to be investigated.

Comparative Analysis of Patch Angioplasty Versus Selective Primary Closure during Carotid Endarterectomy Performed at a Single Vascular Center in China.

BACKGROUND: One of the ongoing debates about carotid endarterectomy (CEA) is the closure technique of arterial wall in the operation. Current guidelines recommend routine patch closure (PAC); this recommendation is based on the evidence reported 10-20 years ago. Therefore, the exact role of PAC and primary closure (PRC) remains uncertain. The objectives of this study were to compare the perioperative and long-term outcomes of patients who underwent CEA with different closure techniques. METHODS: From January 2013 and December 2018, one senior vascular surgeon performed CEA for 126 patients in the First Affiliated Hospital, Sun Yat-sen University. The closure technique (PAC or PRC) was determined on the characteristics (diameter and level) of carotid arteries. Patient demographics and clinical data were retrospectively collected by two research fellows by reviewing the hospital medical records and relevant radiologic studies, as were carotid duplex reports, indications, intraoperative data, closure technique, and perioperative complications. Data of long-term outcomes were gathered by reviewing outpatient clinic visits and associated supplementary examinations. RESULTS: PRC was performed in 78 operations (61.9%), and PAC was performed in 48 operations (38.1%). There were no statistical differences in demographic and clinical data between the two groups. Carotid clamp time (P < 0.001) and operating time (P < 0.001) were significantly longer when performing PAC (P < 0.001), and intraoperative blood loss was significantly more when performing PAC than that of PRC (P < 0.001). The postoperative outcome and the follow-up results showed that there was no significant difference in the short-term and middle-term overall survival rate and restenosis-free survival rate between the two groups. CONCLUSIONS: There are no differences in postoperative and middle-term outcomes between PAC and selective PRC, whereas PRC technique can save operation time and shorten the intraoperative carotid clamp time. PRC can be safely applied in patients with a greater than 5 mm internal carotid artery (ICA).

Mir-22-3p Inhibits Arterial Smooth Muscle Cell Proliferation and Migration and Neointimal Hyperplasia by Targeting HMGB1 in Arteriosclerosis Obliterans.

BACKGROUND: Aberrant vascular smooth muscle cell (VSMC) proliferation and migration contribute to the development of vascular pathologies, such as atherosclerosis and post-angioplasty restenosis. The aim of this study was to determine whether miR-22-3p plays a role in regulating human artery vascular smooth muscle cell (HASMC) function and neointima formation. METHODS: Quantitative real-time PCR (qRT-PCR) and fluorescence in situ hybridization (FISH) were used to detect miR-22-3p expression in human arteries. Cell Counting Kit-8 (CCK-8) and EdU assays were performed to assess cell proliferation, and transwell and wound closure assays were performed to assess cell migration. Moreover, luciferase reporter assays were performed to identify the target genes of miR-22-3p. Finally, a rat carotid artery balloon-injury model was used to determine the role of miR-22-3p in neointima formation. RESULTS: MiR-22-3p expression was downregulated in arteriosclerosis obliterans (ASO) arteries compared with normal arteries, as well as in platelet-derived growth factor-BB (PDGF-BB)-stimulated HASMCs compared with control cells. MiR-22-3p overexpression had anti-proliferative and anti-migratory effects and dual-luciferase assay showed that high mobility group box-1 (HMGB1) is a direct target of miR-22-3p in HASMCs. Furthermore, miR-22-3p expression was negatively correlated with HMGB1 expression in ASO tissue specimens. Finally, LV-miR-22-3p-mediated miR-22-3p upregulation significantly suppressed neointimal hyperplasia specifically by reducing HMGB1 expression in vivo. CONCLUSIONS: Our results indicate that miR-22-3p is a key molecule in regulating HASMC proliferation and migration by targeting HMGB1 and that miR-22-3p and HMGB1 may be therapeutic targets in the treatment of human ASO.

Autophagy Portends the Level of Cardiac Hypertrophy in Experimental Hypertensive Swine Model.

BACKGROUND: Left ventricular (LV) hypertrophy (LVH) plays an important role in hypertensive heart disease, and may be accompanied by myocardial autophagy. However, the pattern of autophagy during evolution of LVH is unclear. We hypothesized that autophagy activation indicates advancing cardiac LVH with tissue remodeling. METHODS: Ten domestic pigs with a 10-week unilateral renovascular hypertension (HTN) were classified as mild or moderate HTN (n = 5 each group) based on the degree of renal artery stenosis (above or below 75%). Seven normal pigs served as controls. Left ventricular remodeling, function, and microvascular density were assessed using multi-detector- and micro-computed tomography and histology. Markers of myocardial autophagic and endoplasmic reticulum (ER) stress-related unfolded protein response (UPR), apoptosis, and fibrosis were examined ex vivo. RESULTS: Both HTN groups had increased myocyte cross-sectional area, but it was greater in moderate HTN, accompanied by elevated LV muscle-mass. Moderate, but not mild HTN, also showed impaired microvascular density and impaired myocardial perfusion. Autophagy mediators were unaltered in mild HTN but UPR markers were increased, while in moderate HTN they were all upregulated, whereas UPR markers were suppressed. Myocardial apoptosis and fibrosis were also greater in moderate HTN. Autophagic proteins were correlated with LVH and fibrosis. CONCLUSIONS: Autophagic activity is stimulated during the exacerbation of LVH, following a transient early increase in ER stress, and may be involved in the progression of cardiac remodeling in renovascular hypertensive heart disease.

Cardiac metabolic alterations in hypertensive obese pigs.

Obesity and hypertension are major risk factors for cardiovascular diseases, and their growing coexistence accounts for an increase in adverse cardiac events, but the mechanisms are yet to be determined. We hypothesized that obesity exacerbates mitochondrial dysregulation imposed by hypertension and augments left ventricular dysfunction. Obesity-prone Ossabaw pigs were randomized to lean (standard diet) and obese (high-fat diet), without (Lean-sham and Obese-sham) or with renovascular hypertension (Lean-hypertension and Obese-hypertension), induced after 12 weeks of diet (n=7 each). Cardiac function, myocardial perfusion and oxygenation, and microvascular remodeling were assessed 4 weeks later. Mitochondrial biogenesis signals and structural proteins, respiratory chain complex activities, and mitochondrial self-degradation were examined, as was fibrosis. Obesity alone exerted no apparent effect on mitochondrial dynamics, but aggravated in hypertensive hearts the reduction of mitochondrial proteins, deoxyribonucleic acid content, and respiratory chain complex IV subunits activity, and amplified mitochondrial self-degradation. Synergistic interaction of obesity with hypertension also exacerbated myocardial fibrosis and left ventricular diastolic dysfunction. Mitochondrial content, respiratory chain complex IV subunits activity, and mitophagy were correlated with myocardial fibrosis. These findings suggest that obesity aggravates in renovascular hypertension cardiac mitochondrial aberrations. Mitochondrial function may regulate the progression of cardiac injury and functional deterioration in hypertension concomitant with obesity.

Valsartan regulates myocardial autophagy and mitochondrial turnover in experimental hypertension.

Renovascular hypertension alters cardiac structure and function. Autophagy is activated during left ventricular hypertrophy and linked to adverse cardiac function. The angiotensin II receptor blocker, valsartan, lowers blood pressure and is cardioprotective, but whether it modulates autophagy in the myocardium is unclear. We hypothesized that valsartan would alleviate autophagy and improve left ventricular myocardial mitochondrial turnover in swine renovascular hypertension. Domestic pigs were randomized to control, unilateral renovascular hypertension, and renovascular hypertension treated with valsartan (320 mg/d) or conventional triple therapy (reserpine+hydralazine+hydrochlorothiazide) for 4 weeks after 6 weeks of renovascular hypertension (n=7 each group). Left ventricular remodeling, function, and myocardial oxygenation and microcirculation were assessed by multidetector computer tomography, blood oxygen level-dependent MRI, and microcomputer tomography. Myocardial autophagy, markers for mitochondrial degradation and biogenesis, and mitochondrial respiratory-chain proteins were examined ex vivo. Renovascular hypertension induced left ventricular hypertrophy and myocardial hypoxia, enhanced cellular autophagy and mitochondrial degradation, and suppressed mitochondrial biogenesis. Valsartan and triple therapy similarly decreased blood pressure, but valsartan solely alleviated left ventricular hypertrophy, ameliorated myocardial autophagy and mitophagy, and increased mitochondrial biogenesis. In contrast, triple therapy only slightly attenuated autophagy and preserved mitochondrial proteins, but elicited no improvement in mitophagy. These data suggest a novel potential role of valsartan in modulating myocardial autophagy and mitochondrial turnover in renovascular hypertension-induced hypertensive heart disease, which may possibly bolster cardiac repair via a blood pressure-independent manner.

Obesity-metabolic derangement exacerbates cardiomyocyte loss distal to moderate coronary artery stenosis in pigs without affecting global cardiac function.

Obesity associated with metabolic derangements (ObM) worsens the prognosis of patients with coronary artery stenosis (CAS), but the underlying cardiac pathophysiologic mechanisms remain elusive. We tested the hypothesis that ObM exacerbates cardiomyocyte loss distal to moderate CAS. Obesity-prone pigs were randomized to four groups (n = 6 each): lean-sham, ObM-sham, lean-CAS, and ObM-CAS. Lean and ObM pigs were maintained on a 12-wk standard or atherogenic diet, respectively, and left circumflex CAS was then induced by placing local-irritant coils. Cardiac structure, function, and myocardial oxygenation were assessed 4 wk later by computed-tomography and blood oxygenation level dependent (BOLD) MRI, the microcirculation with micro-computed-tomography, and injury mechanisms by immunoblotting and histology. ObM pigs showed obesity, dyslipidemia, and insulin resistance. The degree of CAS (range, 50-70%) was similar in lean and ObM pigs, and resting myocardial perfusion and global cardiac function remained unchanged. Increased angiogenesis distal to the moderate CAS observed in lean was attenuated in ObM pigs, which also showed microvascular dysfunction and increased inflammation (M1-macrophages, TNF-α expression), oxidative stress (gp91), hypoxia (BOLD-MRI), and fibrosis (Sirius-red and trichrome). Furthermore, lean-CAS showed increased myocardial autophagy, which was blunted in ObM pigs (downregulated expression of unc-51-like kinase-1 and autophagy-related gene-12; P < 0.05 vs. lean CAS) and associated with marked apoptosis. The interaction diet xstenosis synergistically inhibited angiogenic, autophagic, and fibrogenic activities. ObM exacerbates structural and functional myocardial injury distal to moderate CAS with preserved myocardial perfusion, possibly due to impaired cardiomyocyte turnover.

Obesity-metabolic derangement preserves hemodynamics but promotes intrarenal adiposity and macrophage infiltration in swine renovascular disease.

Obesity-metabolic disorders (ObM) often accompany renal artery stenosis (RAS). We hypothesized that the coexistence of ObM and RAS magnifies inflammation and microvascular remodeling in the stenotic kidney (STK) and aggravates renal scarring. Twenty-eight obesity-prone Ossabaw pigs were studied after 16 wk of a high-fat/high-fructose diet or standard chow including ObM-sham, ObM-RAS, Lean-RAS, or Lean-sham (normal control) groups. Single-kidney renal blood flow (RBF) and glomerular filtration rate (GFR) were assessed by multidetector computed tomography (CT), renal oxygenation and tubular transport capability by blood-oxygen-level-dependent MRI, and microcirculation by micro-CT for vessel density, and Western blotting for protein expressions of angiogenic factors (VEGF/FLK-1). Renal vein and inferior vena cava levels of inflammatory cytokines were measured to evaluate systemic and kidney inflammation. Macrophage (MØ) infiltration and subpopulations, fat deposition in the kidney, and inflammation in perirenal and abdominal fat were also examined. GFR and RBF were decreased in Lean-STK but relatively preserved in ObM-STK. However, ObM-STK showed impaired tubular transport function, suppressed microcirculation, and stimulated glomerulosclerosis. ObM diet interacted with RAS to blunt angiogenesis in the STK, facilitated the release of inflammatory cytokines, and led to greater oxidative stress than Lean-STK. The ObM diet also induced fat deposition in the kidney and infiltration of proinflammatory M1-MØ, as also in perirenal and abdominal fat. Coexistence of ObM and RAS amplifies renal inflammation, aggravates microvascular remodeling, and accelerates glomerulosclerosis. Increased adiposity and MØ-accentuated inflammation induced by an ObM diet may contribute to structural injury in the post-STK kidney.

Angiotensin receptor blockade has protective effects on the poststenotic porcine kidney.

Angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ARBs) may induce an acute decrease of glomerular filtration rate (GFR) in the stenotic kidney in renal artery stenosis, but most patients tolerate these drugs well. We hypothesized that angiotensin-converting enzyme inhibitors/ARBs stabilize stenotic kidney function during prolonged treatment by conferring protective effects. We tested this in control domestic pigs and pigs with renal artery stenosis untreated or treated with Valsartan, or triple therapy (seven pigs in each group) for 4 weeks starting 6 weeks after stenosis induction. Renal function, oxygenation, tubular function, and microcirculation were assessed by multi-detector computed tomography (CT), blood oxygen level-dependent magnetic-resonance imaging, and micro-CT. Valsartan and triple therapy decreased blood pressure similarly; however, Valsartan did not change the GFR of the stenotic kidney compared with renal artery stenosis and was similar to triple therapy. Both Valsartan and triple therapy stimulated microvascular density and improved tubular function. Valsartan also caused a greater increase of angiogenic factors and a decrease in oxidative stress, which were related to higher cortical perfusion and tubular response than triple therapy. Thus, Valsartan did not decrease stenotic kidney GFR, but improved cortical perfusion and microcirculation. These beneficial effects may partly offset the hemodynamic GFR reduction in renal artery stenosis and preserve kidney function.

Differentially expressed microRNAs at different stages of atherosclerosis in ApoE-deficient mice.

BACKGROUND: Atherosclerosis is the primary cause of cardiovascular disease, carotid artery disease, and peripheral vascular disease. However, it is hard to obtain human arterial tissue at different stages of atherosclerosis for a systematic study. The ApoE-deficient (ApoE(-/-)) mice predictably develop spontaneous atherosclerotic plaques with numerous features similar to the human lesions and contain nearly the entire spectrum of lesions observed during atherogenesis in humans. MicroRNA expression profiles at different stages of atherosclerosis in ApoE-deficient mice were screened to find out the differentially expressed microRNAs. METHODS: ApoE-deficient mice were euthanized at 4, 8, and 20 weeks of age and divided into three groups according to the three time points, including groups A4 (fed a Western-type diet for 0 week), A8 (fed a Western-type diet for 4 weeks), and A20 (fed a Western-type diet for 16 weeks). Atherosclerotic lesions were analyzed. Fifteen aortas were collected and combined into three pools (five aortas in one pool) in each group. MicroRNA microarray analysis was replicated thrice in each group. The threshold of fold change ≥ 2.0 was used to screen up or down-regulated microRNAs. Differentially expressed microRNAs were subsequently verified with quantitative real-time polymerase chain reaction. Those increasingly up or down-regulated microRNAs during the progression of atherosclerosis were selected. RESULTS: Atherosclerotic lesions first appeared in the aortic arch in group A8. Severe atherosclerotic lesions were observed in group A20. In group A8, seven MicroRNAs were up-regulated while two were down-regulated. In group A20, 15 microRNAs were up-regulated while two were down-regulated. miR-34a-5p and miR-497-5p were increasingly up-regulated, while miR-434-3p was progressively down-regulated when atherosclerosis progressed. CONCLUSIONS: In this study, we described that microRNAs are differentially expressed at different stages of atherosclerosis in ApoE-deficient mice. Those increasingly up or down-regulated microRNAs during the progression of atherosclerosis may play an important role in the pathogenesis of atherosclerosis and provide us opportunities for investigating atherosclerosis from early to advanced stages.

The in vivo performance of small-caliber nanofibrous polyurethane vascular grafts.

BACKGROUND: In a previous in vitro study, we confirmed that small-caliber nanofibrous polyurethane (PU) vascular grafts have favorable mechanical properties and biocompatibility. In the present study, we examined the in vivo biocompatibility and stability of these grafts. METHODS: Forty-eight adult male beagle dogs were randomly divided into two groups receiving, respectively, polyurethane (PU) or polytetrafluoroethylene (PTFE) grafts (n = 24 animals / group). Each group was studied at 4, 8, 12, and 24 weeks after graft implantation. Blood flow was analyzed by color Doppler ultrasound and computed tomography angiography. Patency rates were judged by animal survival rates. Coverage with endothelial and smooth muscle cells was characterized by hematoxylin-eosin and immunohistological staining, and scanning electron microscopy (SEM). RESULTS: Patency rates were significantly higher in the PU group (p = 0.02 vs. PTFE group). During the first 8 weeks, endothelial cells gradually formed a continuous layer on the internal surface of PU grafts, whereas coverage of PTFE graft by endothelial cells was inhomogeneous. After 12 weeks, neointimal thickness remained constant in the PU group, while PTFE group showed neointimal hyperplasia. At 24 weeks, some anastomotic sites of PTFE grafts became stenotic (p = 0.013 vs. PU group). Immunohistological staining revealed a continuous coverage by endothelial cells and an orderly arrangement of smooth muscle cells on PU grafts. Further, SEM showed smooth internal surfaces in PU grafts without thrombus or obvious neointimal hyperplasia. CONCLUSIONS: Small-caliber nanofibrous PU vascular grafts facilitate the endothelialization process, prevent excessive neointimal hyperplasia, and improve patency rates.

Impaired myocardial autophagy linked to energy metabolism disorders.

Autophagy represents an evolutionarily conserved catabolic mechanism that promotes cell survival by releasing energy substrates via degradation of cellular constituents and by eliminating defective organelles under conditions of stress, such as starvation and hypoxia. The link between enhanced autophagy and nutrient deprivation has been well established. For example, chronic myocardial ischemia, a condition of insufficient oxygen and nutrition, activates autophagy to degrade and recycle damaged cellular structures, thereby ameliorating cardiomyocyte injury.

Transition from obesity to metabolic syndrome is associated with altered myocardial autophagy and apoptosis.

OBJECTIVE: Transition from obesity to metabolic-syndrome (MetS) promotes cardiovascular diseases, but the underlying cardiac pathophysiological mechanisms are incompletely understood. We tested the hypothesis that development of insulin resistance and MetS is associated with impaired myocardial cellular turnover. METHODS AND RESULTS: MetS-prone Ossabaw pigs were randomized to 10 weeks of standard chow (lean) or to 10 (obese) or 14 (MetS) weeks of atherogenic diet (n=6 each). Cardiac structure, function, and myocardial oxygenation were assessed by multidetector computed-tomography and Blood Oxygen Level-Dependent-MRI, the microcirculation with microcomputed-tomography, and injury mechanisms by immunoblotting and histology. Both obese and MetS showed obesity and dyslipidemia, whereas only MetS showed insulin resistance. Cardiac output and myocardial perfusion increased only in MetS, yet Blood Oxygen Level-Dependent-MRI showed hypoxia. Inflammation, oxidative stress, mitochondrial dysfunction, and fibrosis also increased in both obese and MetS, but more pronouncedly in MetS. Furthermore, autophagy in MetS was decreased and accompanied by marked apoptosis. CONCLUSIONS: Development of insulin resistance characterizing a transition from obesity to MetS is associated with progressive changes of myocardial autophagy, apoptosis, inflammation, mitochondrial dysfunction, and fibrosis. Restoring myocardial cellular turnover may represent a novel therapeutic target for preserving myocardial structure and function in obesity and MetS.

[Endovascular repair of abdominal aortic aneurysm: a clinical report of 81 cases].

OBJECTIVE: To evaluate the efficacy and safety of endovascular aneurysm repair (EVAR) for abdominal aortic aneurysm (AAA), and to compare the prognosis between patients of different ages. METHODS: The hospitalization and follow-up data of 81 AAA patients treated by EVAR from May 2005 to May 2011 were retrospectively analyzed. All the patients were divided into advanced age group (age ≥ 75 years, 24 cases) and relatively young group (age < 75 years, 57 cases). General conditions, comorbidity, procedure, in-hospital complications, and follow-up were compared between these two groups. RESULTS: All covered stents were successfully deployed, a technical success rate of 91.4% (74/81) was achieved. There was no intraoperative death. In-hospital mortality was 1.2% (1/81). The follow-up rate was 91.4% (74/81), with a mean follow-up of 47.5 months. Twelve deaths were recorded during follow-up, 1, 2, 3, 4, and 5-year survival rates were 98.6%, 92.2%, 80.8%, 58.7%, and 44.1%, respectively. When compared with relatively young group, the advanced age group had a lower rate of abdominal pain as the major symptom, but a higher rates of renal diseases and coronary artery diseases. Furthermore, the advanced age group had a longer stay in intensive care unit and higher morbidity of endoleaks, and also tended to have increased rates of pulmonary infection and access site hematoma, while the other parameters were similar between the two groups. CONCLUSIONS: EVAR of AAA is less invasive, safe, and effective during short to mid-tern follow-up. The patients of advanced age suffer from higher rates of some complications, thus careful perioperative preparation and intensive monitor are mandatory for preventing or treating potential complications and improving prognosis for these patients.

[Role of Rac1 activation in platelet derived growth factor-BB induced proliferation and migration in rat aortic smooth muscle cells].

OBJECTIVE: To explore the impact of Rac1 activation on the proliferation and migration under the stimulation of PDGF-BB (platelet derived growth factor-BB). METHODS: The inhibitory effects of Rac1 inhibitor (NSC23766) and Rac1siRNA on the proliferation and migration of vascular smooth muscle cell under the stimulation of PDGF-BB were measured by CCK8 assay and Transwell chamber. The time characteristics of Rac1 activity and pi-JNK expression under the stimulation of PDGF-BB was detected by GST pulldown assay and Western blot. And the inhibitory effects of NSC23766 and Rac1siRNA on the Rac1 activation and pi-JNK expression were also measured. RESULTS: Migration and proliferation of vascular smooth muscle cell increased significantly after the stimulation of PDGF-BB (50 µg/L). Migration and proliferation was inhibited significantly after a pretreatment of Rac1siRNA and various concentrations of NSC23766 (25, 50, 100 µg/L). After the stimulation of PDGF-BB, the expression of pi-JNK and Rac1 activity increased over time. Rac1-GTP peaked at 5 minutes and pi-JNK at 15 minute. The expressions of pi-JNK at 15 minutes and Rac1-GTP at 5 minutes were inhibited significantly by Rac1siRNA and NSC23766 in a concentration-dependent manner. CONCLUSION: JNK phosphorylation is controlled by Rac1 activation. And Rac1 activation play a pivotal role in the migration and proliferation of aortic smooth muscle cell under the stimulation of PDGF-BB.