Adrian Mahlmann

S100A1 Deficiency Impairs Postischemic Angiogenesis Via Compromised Proangiogenic Endothelial Cell Function and Nitric Oxide Synthase Regulation

Rationale: Mice lacking the EF-hand Ca2+ sensor S100A1 display endothelial dysfunction because of distorted Ca2+-activated nitric oxide (NO) generation. Objective: To determine the pathophysiological role of S100A1 in endothelial cell (EC) function in experimental ischemic revascularization. Methods and Results: Patients with chronic critical limb ischemia showed almost complete loss of S100A1 expression in hypoxic tissue. Ensuing studies in S100A1 knockout (SKO) mice subjected to femoral artery resection unveiled insufficient perfusion recovery and high rates of autoamputation. Defective in vivo angiogenesis prompted cellular studies in SKO ECs and human ECs, with small interfering RNA–mediated S100A1 knockdown demonstrating impaired in vitro and in vivo proangiogenic properties (proliferation, migration, tube formation) and attenuated vascular endothelial growth factor (VEGF)–stimulated and hypoxia-stimulated endothelial NO synthase (eNOS) activity. Mechanistically, S100A1 deficiency compromised eNOS activity in ECs by interrupted stimulatory S100A1/eNOS interaction and protein kinase C hyperactivation that resulted in inhibitory eNOS phosphorylation and enhanced VEGF receptor-2 degradation with attenuated VEGF signaling. Ischemic SKO tissue recapitulated the same molecular abnormalities with insufficient in vivo NO generation. Unresolved ischemia entailed excessive VEGF accumulation in SKO mice with aggravated VEGF receptor-2 degradation and blunted in vivo signaling through the proangiogenic phosphoinositide-3-kinase/Akt/eNOS cascade. The NO supplementation strategies rescued defective angiogenesis and salvaged limbs in SKO mice after femoral artery resection. Conclusions: Our study shows for the first time downregulation of S100A1 expression in patients with critical limb ischemia and identifies S100A1 as critical for EC function in postnatal ischemic angiogenesis. These findings link its pathological plasticity in critical limb ischemia to impaired neovascularization, prompting further studies to probe the microvascular therapeutic potential of S100A1.

Medical management of abdominal aortic aneurysms

Abdominal aortic aneurysms (AAA) are the most common arterial aneurysms. Endovascular or open surgical aneurysm repair is indicated in patients with large AAA ≥ 5.5 cm in diameter as this prevents aneurysm rupture. The presence even of small AAAs not in need of immediate repair is associated with a very high cardiovascular risk including myocardial infarction, stroke or cardiovascular death. This risk by far exceeds the risk of aneurysm rupture. These patients therefore should be considered as high-risk patients and receive optimal medical treatment and life-style modification of their cardiovascular risk factors to improve their prognosis. In addition, these patients should be followed-up for aneurysm growth and receive medical treatment to decrease aneurym progression and rupture rate. Treatment with statins has been shown to reduce cardiovascular mortality in these patients, and also slows the rate of AAA growth. Use of beta-blockers, ACE inhibitors and AT1-receptor antagonists does not affect AAA growth but may be indicated for comorbidities. Antibiotic therapy with roxithromycin has a small effect on AAA growth, but this effect must be critically weighed against the potential risk of wide-spread use of antibiotics.

Anastomotic leak after surgical repair of type A aortic dissection – prevalence and consequences in midterm follow-up

BACKGROUND This study reports the mid-term prevalence and therapeutic consequences of anastomotic leaks after surgery for Stanford type A aortic dissections. PATIENTS AND METHODS From July 2007 to July 2013, 93 patients survived surgery for acute type A dissections at our center and underwent a standardized follow-up. The pre-, peri-, and postoperative as well as the midterm results were collected prospectively. Follow-up computed tomography (CT) imaging was performed 7 days, 3, and 12 months after surgery, and yearly thereafter, to assess the presence or progression of anastomotic leaks at the aorto-prosthesis anastomotic sites. RESULTS The mean follow-up was 4 years (1534 ± 724 days). Follow-up CT revealed anastomotic leaks in 4 patients (4.3 %). All leaks developed during midterm follow-up and half of them did not increase with time. Two patients required redo surgery for an increase in periaortic extravasation and compression of neighboring structures. Further analysis was not able to reveal independent risk factors for development or deterioration of leaks. CONCLUSIONS Anastomotic leaks after surgery for Stanford Type A aortic dissection can develop in midterm follow-up, even after initially excellent results. Meticulous follow-up is mandatory to detect possible deterioration and a need for redo surgery.

Management of the left subclavian artery during TEVAR – complications and mid-term follow-up

BACKGROUND Numerous conditions that affect the boundary between the aortic arch and descending aorta are treated with thoracic endovascular aortic repair (TEVAR). In 40 % of cases, coverage of the left subclavian artery (LSA) cannot be prevented. Subsequently, neurological complications such as stroke or ischemia of the left upper extremity may develop. However, the actual risk of these complications is subject to considerable controversy. The optimal treatment approach, specifically the question whether primary revascularization of the LSA should be performed in all cases, is unclear. PATIENTS AND METHODS The present retrospective study analyzed the short- and mid-term results of patients treated with TEVAR with complete coverage of the LSA. The postoperative protocol consisted of clinical and noninvasive examinations as well as morphological imaging. Survival, complication, and reintervention rates were recorded. RESULTS A total of 40 patients, undergoing TEVAR with complete coverage of the LSA between January 2010 and December 2014 were analyzed retrospectively. The 30-day survival rate was 95 %, the survival one year after performed TEVAR was 67.5 %. The average follow-up was 1.5 years. After TEVAR procedure with complete coverage of the LSA, only one patient (2.5 %) developed critical ischemia of the left arm immediately after aortic stent implantation, requiring revascularization by transposition of the LSA. Anterior spinal artery syndrome occurred in another patient (2.5 %) immediately following TEVAR. During follow-up examinations, all patients showed a compensated arterial arm status. None of the patients developed new neurological deficits during the follow-up period. CONCLUSIONS The study shows that performing TEVAR without primary revascularization of the LSA was justifiable in our cohort. An important risk factor of developing cerebral ischemia seems to be insufficient collateralization through the circle of Willis.

Microarray analysis for delineating the gene expression in biopsies of gastrocnemius muscle of patients with chronic critical limb ischaemia compared with non-ischaemic controls

BACKGROUND Microarray analysis has been carried out in this pilot study to compare delineated gene expression profiles in the biopsies of skeletal muscle taken from patients with chronic critical limb ischaemia (CLI) and non-ischaemic control subjects. PATIENTS AND METHODS Biopsy of gastrocnemius muscle was obtained from six patients with unreconstructed CLI referred for surgical major amputation. As control, biopsies of six patients undergoing elective knee arthroplasty without evidence of peripheral arterial occlusive disease were taken. The differences in gene expression associated with angiogenic processes in specimens obtained from ischaemic and non-ischaemic skeletal muscle were confirmed by quantitative real-time polymerase chain reaction (PCR) analysis. RESULTS Compared with non-ischaemic skeletal muscle biopsy of chronic-ischaemic skeletal muscle contained 55 significantly up-regulated and 45 down-regulated genes, out of which 64 genes had a known genetic product. Tissue samples of ischaemic muscle were characterized by increased expression of cell survival factors (e. g. tissue factor pathway inhibitor 2) in combination with reduced expression of cell proliferation effectors (e. g. microfibrillar-associated protein 5 and transferrin receptor). The expression of growth factors (e. g. early growth response 3 and chemokine receptor chemokine C-X-C motif ligand 4) which play a central role in arterial and angiogenic processes and anti-angiogenetic factors (e. g. pentraxin 3) were increased in chronic ischaemic skeletal muscle. An increased expression of extracellular matrix proteins (e. g. cysteine-rich angiogenic inducer 61) was also observed. CONCLUSIONS Gene expression profiles in biopsies of gastrocnemius muscle in patients with chronic critical limb ischaemia showed an increase in pro-survival factors, extracellular matrix protein deposition, and impaired proliferation, compared with non-ischaemic controls. Further studies are required to analyse the endogenous repair mechanism.

Warfarin anticoagulation in acute type A aortic dissection survivors (WATAS)

Background Early survivors of acute type A aortic dissection (AAAD) remain at risk for late death and late aortic events. However, the frequency and long-term effects of warfarin anticoagulation on long-term outcome in post-surgical AAAD survivors have not been elucidated. Methods Two tertiary care centers performed a retrospective observational cohort study of warfarin anticoagulation in AAAD in 243 persons with early survival of surgical repair (WATAS). Serial postoperative tomographic imaging was available in 106 persons. Results A total of 88 postoperative AAAD survivors (36%) were on long-term warfarin anticoagulation. The indication for anticoagulation was a mechanical aortic prosthesis in 46 (52%), atrial fibrillation in 33 (38%), stroke in 7 (8%), and pulmonary embolism in 1 (1%). The indication for anticoagulation remained unclear in 1 person (1%). Survival and aortic event free survival were 98.3±0.01 and 98.7±0.01 at 1 year, and 76.4±0.03 and 91.8±0.02 at 5 years, respectively, with no differences irrespective of warfarin anticoagulation. Multivariate Cox regression analysis established higher age (P<0.001), and operation extending into the descending aorta (P=0.030) as independent predictors of late death. Follow-up without tomographic imaging independently predicted increased long-term mortality (P<0.001) and lower rates of documented aortic events (P=0.003). Kaplan-Meyer analysis showed a relationship of aortic diameter growth ≥0.5 cm per year with late death (P=0.041) and with late aortic events (P<0.001). However, rapid aortic growth did not relate to warfarin anticoagulation. Conclusions Warfarin anticoagulation is frequent in postsurgical AAAD and it is administered for vital indications. Warfarin anticoagulation does not relate to late mortality or to late aortic events. Rapid aortic growth predicts late mortality and late aortic events, but warfarin anticoagulation is not associated with aortic growth. Follow-up tomographic imaging is mandatory for long-term survival after surgical repair of AAAD.

Anesthesia management during aortic surgery: Preoperative patient assessment

Patients with aortic diseases have a high rate of cardiac, cerebrovascular, or pulmonary comorbidities. Open surgery or endovascular interventions of the aorta are associated with high perioperative cardiac risk. Simple scoring systems for preoperative risk stratification can be used to identify high-risk patients. In these patients, further diagnostic and therapeutic interventions are required to reduce perioperative morbidity and mortality. In contrast, low-risk patients can be identified, who may proceed to intervention without additional cardiopulmonary diagnostic testing. According to evidence-based recommendations in patients at risk, statin therapy should be initiated and beta blockers should be uptitrated preoperatively. Smoking cessation preoperatively reduces perioperative complications and should be encouraged in all patients.

How to asses and improve cardiopulmonary risk prior to vascular surgery

Patients with peripheral arterial disease have a high rate of cardiac, cerebrovascular, or pulmonary comorbidities. Peripheral arterial surgical interventions are associated with a moderate to high perioperative cardiac risk. Simple clinical scoring systems for preoperative risk stratification can be used to identify high-risk patients. In these patients further diagnostic and therapeutic measures are required to reduce perioperative morbidity and mortality. In contrast, a group of patients can be identifed that do not require additional cardiopulmonary diagnostics and can immediately proceed to the intervention. According to evidence-based recommendations in patients at risk beta blocker should be uptitrated and statin therapy should be initiated preoperatively. Quitting smoking preoperatively also reduces perioperative complications and should be encouraged in all patients.