Anne Lejay

Mitochondria: Mitochondrial participation in ischemia–reperfusion injury in skeletal muscle

Irrespective of the organ involved, restoration of blood flow to ischemic tissue is vital, although reperfusion per se is deleterious. In the setting of vascular surgery, even subtle skeletal muscle ischemia contributes to remote organ injuries and perioperative and long-term morbidities. Reperfusion-induced injury is thought to participate in up to 40% of muscle damage. Recently, the pathophysiology of lower limb ischemia-reperfusion (IR) has been largely improved, acknowledging a key role for mitochondrial dysfunction mainly characterized by impaired mitochondrial oxidative capacity and premature mitochondrial permeability transition pore opening. Increased oxidative stress triggered by an imbalance between reactive oxygen species (ROS) production and clearance, and facilitated by enhanced inflammation, appears to be both followed and instigated by mitochondrial dysfunction. Mitochondria are both actors and target of IR and therapeutic strategies modulating degree of ROS production could enhance protective signals and allow for mitochondrial protection through a mitohormesis mechanism.

Long-Term Outcomes of Direct and Indirect Below-The-Knee Open Revascularization Based on the Angiosome Concept in Diabetic Patients with Critical Limb Ischemia

BACKGROUND We compared long-term outcomes of isolated below-the-knee (BTK) bypass revascularization in diabetic patients presenting with critical limb ischemia (CLI) with and without achieving the bypass on the artery corresponding to the territory of the lesion based on the angiosome concept. MATERIALS We analyzed outcomes of 58 consecutive CLI limbs of 54 diabetic patients presenting with tissue loss who underwent isolated BTK bypasses from 2003 to 2009 for crural occlusive arterial disease. Bypasses were classified into direct and indirect groups based on the angiosome concept, whether feeding artery flow to the site of ischemic tissue loss was achieved or not. We compared median ulcer-healing time, survival, primary patency, and limb salvage rates between both groups by Kaplan-Meier analysis and log-rank test. Independent factors of major amputations were explored by univariate analysis. Variables with P < 0.2 in univariate analysis were submitted to multivariable analysis. RESULTS Median ulcer-healing time was 56 ± 18 days in direct group (n = 36) and 112 ± 45 days in indirect group (n = 22, P = 0.01). There was no difference between both groups in terms of survival or primary patency. Limb salvage rate was significantly higher in direct group than in indirect group: 91% vs. 66% at 1 year, 65% vs. 24% at 3 years, and 58% vs. 18% at 5 years, respectively (P = 0.03). After multivariable Cox proportional analysis, independent factors associated with major amputation were end-stage renal disease (P = 0.030) and C-reactive protein level (P = 0.025). CONCLUSIONS Achieving a direct arterial flow based on angiosome concept in CLI diabetic patients presenting with tissue loss appears to be important for ulcer healing and limb salvage.

Chronology of mitochondrial and cellular events during skeletal muscle ischemia-reperfusion

Peripheral artery disease (PAD) is a common circulatory disorder of the lower limb arteries that reduces functional capacity and quality of life of patients. Despite relatively effective available treatments, PAD is a serious public health issue associated with significant morbidity and mortality. Ischemia-reperfusion (I/R) cycles during PAD are responsible for insufficient oxygen supply, mitochondriopathy, free radical production, and inflammation and lead to events that contribute to myocyte death and remote organ failure. However, the chronology of mitochondrial and cellular events during the ischemic period and at the moment of reperfusion in skeletal muscle fibers has been poorly reviewed. Thus, after a review of the basal myocyte state and normal mitochondrial biology, we discuss the physiopathology of ischemia and reperfusion at the mitochondrial and cellular levels. First we describe the chronology of the deleterious biochemical and mitochondrial mechanisms activated by I/R. Then we discuss skeletal muscle I/R injury in the muscle environment, mitochondrial dynamics, and inflammation. A better understanding of the chronology of the events underlying I/R will allow us to identify key factors in the development of this pathology and point to suitable new therapies. Emerging data on mitochondrial dynamics should help identify new molecular and therapeutic targets and develop protective strategies against PAD.

Muscles susceptibility to ischemia-reperfusion injuries depends on fiber type specific antioxidant level

Muscle injury resulting from ischemia-reperfusion largely aggravates patient prognosis but whether and how muscle phenotype modulates ischemia-reperfusion-induced mitochondrial dysfunction remains to be investigated. We challenged the hypothesis that glycolytic muscles are more prone to ischemia-reperfusion-induced injury than oxidative skeletal muscles. We therefore determined simultaneously the effect of 3 h of ischemia induced by aortic clamping followed by 2 h of reperfusion (IR, n = 11) on both gastrocnemius and soleus muscles, as compared to control animals (C, n = 11). Further, we investigated whether tempol, an antioxidant mimicking superoxide dismutase, might compensate a reduced defense system, likely characterizing glycolytic muscles (IR-Tempol, n = 7). In the glycolytic gastrocnemius muscle, as compared to control, ischemia-reperfusion significantly decreased mitochondrial respiration (−30.28 ± 6.16%, p = 0.003), increased reactive oxygen species production (+79.15 ± 28.72%, p = 0.04), and decreased reduced glutathione (−28.19 ± 6.80%, p = 0.011). Less deleterious effects were observed in the oxidative soleus muscle (−6.44 ± 6.30%, +4.32 ± 16.84%, and −8.07 ± 10.84%, respectively), characterized by enhanced antioxidant defenses (0.63 ± 0.05 in gastrocnemius vs. 1.24 ± 0.08 μmol L−1 g−1 in soleus). Further, when previously treated with tempol, glycolytic muscle was largely protected against the deleterious effects of ischemia-reperfusion. Thus, oxidative skeletal muscles are more protected than glycolytic ones against ischemia-reperfusion, thanks to their antioxidant pool. Such pivotal data support that susceptibility to ischemia-reperfusion-induced injury differs between organs, depending on their metabolic phenotypes. This suggests a need to adapt therapeutic strategies to the specific antioxidant power of the target organ to be protected.

Five Year Outcomes of Surgical Treatment for Popliteal Artery Entrapment Syndrome

OBJECTIVE/BACKGROUND The aim of this study was to evaluate long-term outcomes following surgery for popliteal artery entrapment syndrome. METHODS A retrospective study of all patients that underwent surgery for popliteal artery entrapment syndrome between January 2003 and December 2009 was performed. Patient demographic data, clinical features, imaging modalities, and surgical management were recorded. The primary outcome was 5 year patency. RESULTS Eighteen patients (25 limbs) underwent surgery. The mean age at the time of surgical procedure was 35 (median 35 years; range 15-49). Presentation was bilateral in seven patients (39%). Diagnosis was made using various imaging modalities, including position stress test, Duplex ultrasonography, computed tomography angiography, magnetic resonance imaging and conventional angiography. In four limbs the popliteal artery was compressed and undamaged (16%), and treatment consisted of musculo-tendinous division alone. In 16 limbs the popliteal artery was damaged with lesions limited to the popliteal artery (64%) where treatment consisted of venous interposition. In five limbs lesions extended beyond the popliteal artery (20%) and procedures included one below knee femoro-popliteal bypass, three femoro-posterior tibial bypasses, and one popliteo-posterior tibial bypass. Musculo-tendinous division was associated with vascular reconstruction in 19 limbs (90%). Mean follow up was 82 months (median 81 months, range 60-120). Five year patency was 84%. CONCLUSION Long-term outcomes of surgical procedures performed for popliteal artery entrapment syndrome can be considered satisfactory.

Cryopreservation with dimethyl sulfoxide prevents accurate analysis of skinned skeletal muscle fibers mitochondrial respiration

Impact of cryopreservation protocols on skeletal muscle mitochondrial respiration remains controversial. We showed that oxygen consumption with main mitochondrial substrates in rat skeletal muscles was higher in fresh samples than in cryopreserved samples and that this difference was not fixed but grow significantly with respiration rates with wide fluctuations around the mean difference. Very close results were observed whatever the muscle type and the substrate used. Importantly, the deleterious effects of ischemia-reperfusion observed on fresh samples vanished when cryopreserved samples were studied. These data demonstrate that this technic should probably be performed only extemporaneously.

Poor long-term stability of the Corvita abdominal stentgraft.

INTRODUCTION The endovascular treatment of abdominal aortic aneurysms was introduced in the early 1990s, with different generations of devices using various options for either the stent skeleton or the membrane. REPORT Corvita generated one of these devices using braided stainless steel and a porous spun polycarbonate urethane membrane. DISCUSSION In this report, we describe a case involving Corvita stentgraft explantation for complete aneurysm reperfusion after 13 years, demonstrating major degradation of the polyurethane membrane.

Midterm failure after endovascular treatment of a persistent sciatic artery aneurysm.

Persistent sciatic artery (PSA) is a rare arterial embryologic malformation that tends to present early atherosclerotic degeneration such as aneurysmal formation. Open surgical treatment of PSA aneurysms has been considered as the gold standard but endovascular techniques have been recently proposed in the literature. We report the case of a 65-year-old man, diagnosed with a PSA aneurysm on peripheral thromboembolic complications. We achieved an endovascular repair with a covered stent. Despite an uneventful postoperative course, the covered stent demonstrated fracture and thrombosis 6 months after implantation without any symptoms.

Effects of cyclic nucleotide phosphodiesterases (PDEs) on mitochondrial skeletal muscle functions

Mitochondria play a critical role in skeletal muscle metabolism and function, notably at the level of tissue respiration, which conduct muscle strength as well as muscle survival. Pathological conditions induce mitochondria dysfunctions notably characterized by free oxygen radical production disturbing intracellular signaling. In that way, the second messengers, cyclic AMP and cyclic GMP, control intracellular signaling at the physiological and transcription levels by governing phosphorylation cascades. Both nucleotides are specifically and selectively hydrolyzed in their respective 5′-nucleotide by cyclic nucleotide phosphodiesterases (PDEs), which constitute a multi-genic family differently tissue distributed and subcellularly compartmentalized. These PDEs are presently recognized as therapeutic targets for cardiovascular, pulmonary, and neurologic diseases. However, very few data concerning cyclic nucleotides and PDEs in skeletal muscle, specifically in mitochondria, are reported in the literature. The knowledge of PDE implication in mitochondrial signaling would be helpful for resolving critical mitochondrial dysfunctions in skeletal muscle.

Gender Related Long-Term Differences After Open Infrainguinal Surgery for Critical Limb Ischemia

OBJECTIVE The role of gender on long-term infrainguinal open surgery outcomes still remains uncertain in critical limb ischemia patients. The aim of this study is to evaluate the gender-specific differences in patient characteristics and long-term clinical outcomes in terms of survival, primary patency and limb salvage among patients undergoing infrainguinal open surgery for CLI. MATERIAL AND METHODS All consecutive patients undergoing infrainguinal open surgery for critical limb ischemia between 2003 and 2012 were included. Survival, limb salvage and primary patency rates were assessed. Independent outcome determinants were identified by the Cox proportional hazard ratio using age and gender as adjustment factors. RESULTS 584 patients (269 women and 315 men, mean age 76 and 71 years respectively) underwent 658 infrainguinal open surgery (313 in women and 345 in men). Survival rate at 6 years was lower among women compared to men with 53.5% vs 70.9% (p < 0.001). The same applied to primary patency (35.9% vs 52.4%, p < 0.001) and limb salvage (54.3% vs 81.1%, p < 0.001) at 6 years. Female-gender was an independent factor predicting death (hazard ratio 1.50), thrombosis (hazard ratio 2.37) and limb loss (hazard ratio 7.05) in age and gender-adjusted analysis. CONCLUSION Gender-related disparity in critical limb ischemia open surgical revascularization outcomes still remains.