Background LGE by CMR is a predictor of adverse cardiovascular outcomes in non-ischemic cardiomyopathy (NICM) patients. However, these findings are limited by single center studies, small sample sizes, and low event rates. We performed a meta-analysis to evaluate the prognostic role of late-gadolinium enhancement by cardiac magnetic resonance (LGE-CMR) imaging in NICM patients. Methods and Results PubMed, Cochrane CENTRAL and EMBASE were searched for studies looking at the prognostic value of LGE-CMR in NICM patients. The primary end-points included all-cause mortality, heart failure hospitalization (HFH), and a composite end point of sudden cardiac death (SCD) or aborted SCD. Pooling of odds ratios (OR) was performed using a random-effect model and annualized event rates (AER) were assessed. Data was included from 9 studies with a total of 1,488 patients and a mean follow-up of 30 months. Patients had a mean age of 52 years, 67% were male and the average LVEF was 37% on CMR. LGE was present in 38% of patients. Patients with LGE had increased overall mortality (OR 3.27, p<0.00001), HFH (OR 2.91, p=0.02), and SCD/aborted SCD (OR 5.32, p<0.00001) when compared with those without LGE. The AERs for mortality were 4.7% for LGE+ subjects vs. 1.7% for LGE- subjects (p=0.01), 5.03% vs. 1.8% for HFH (p=0.002), and 6.0% vs. 1.2% for SCD/aborted SCD (p<0.001). Conclusions LGE in NICM patients is associated with increased risk of all-cause mortality, HFH, and SCD. Detection of LGE by CMR has excellent prognostic characteristics and may help guide risk stratification and management in NICM patients.
Targeting therapeutic gene expression to skeletal muscle following intravenous administration is an attractive strategy for treating peripheral arterial disease (PAD), except that vector access to the ischemic limb could be a limiting factor. Since AAV serotype 9 transduces skeletal muscle at high efficiency following systemic delivery, we employed AAV-9 vectors bearing luciferase or enhanced green fluorescent protein (eGFP) reporter genes to test the hypothesis that increased desialylation of cell surface glycans secondary to hindlimb ischemia (HLI) might help offset the reduction in tissue perfusion that occurs in mouse models of PAD. The utility of the creatine kinase-based (CK6) promoter for restricting gene expression to skeletal muscle was also examined by comparing it to the cytomegalovirus (CMV) promoter after systemic administration following surgically-induced HLI. Despite reduced blood flow to ischemic limbs, CK6 promoter-driven luciferase activities in ischemic gastrocnemius (GA) muscles were ~34-, ~28-, and ~150-fold higher than in fully-perfused contralateral GA, heart, and liver, respectively, 10 days after intravenous administration. Furthermore, luciferase activity from the CK6 promoter in ischemic GA muscles was ~2-fold higher than with CMV, while in the liver CK6-driven activity was ~42-fold lower than with CMV, demonstrating that the specificity of ischemic skeletal muscle transduction can be further improved with muscle-specific promoters. Studies with Evans blue dye and fluorescently-labeled lectins revealed that vascular permeability and desialylation of cell surface glycans were increased in ischemic hindlimbs. Furthermore, AAV9/CK6/Luc vector genome copy numbers were ~6-fold higher in ischemic muscle compared to non-ischemic muscle in the HLI model, whereas this trend was reversed when the same genome was packaged in the AAV-1 capsid (which binds sialylated, as opposed to desialylated glycans), further underscoring the importance of desialylation in the ischemic enhancement of transduction displayed by AAV-9. Taken together, these findings suggest two complementary mechanisms contributing to the preferential transduction of ischemic muscle by AAV-9: increased vascular permeability and desialylation. In conclusion, ischemic muscle is preferentially targeted following systemic administration of AAV-9 in a mouse model of HLI. Unmasking of the primary AAV-9 receptor as a result of ischemia may contribute importantly to this effect.
Atherosclerotic occlusion of vessels outside of the heart is commonly referred to as peripheral arterial disease (PAD). The lower extremity is the most common site of PAD and its development is associated with the same risk factors involved in general atherosclerosis. However, there is emerging evidence that other risk factors may play a key role in the development of PAD. Over the past decade polymorphism in a number of genes has been shown to contribute to the risk of developing PAD. These genes can be classified into proartherosclerosis or proatherothrombosis based on the known gene function. Moreover, they can be categorized as “novel” polymorphism when the function of the genes is not known or when the specific gene within an associated genetic locus is not known. It is intriguing that not only are gene polymorphisms associated with PAD being identified, but more recently studies are now finding gene polymorphisms that may be important in development of this syndrome only in the contest of certain environmental factors such as diabetes. Currently how these gene–environment interactions contribute to the pathogenesis of PAD is poorly understood but will likely play a critical role in future understanding of this complex disease.
Objective Neovascularization is a physiological repair process that is partly dependent on nitric oxide. Extracellular superoxide dismutase (EcSOD) is the major scavenger of superoxide and thus is an important regulator of nitric oxide bioavailability and thus protects against vascular dysfunction. We hypothesized that overexpression of EcSOD in skeletal muscle would improve recovery from hind-limb ischemia. Methods Adeno associated virus (AAV) vectors expressing EcSOD or luciferase (control) from the Cytomegalovirus (CMV) promoter were cross-packaged into AAV9 capsids and injected IM into hind-limb muscles (1×1011 viral genomes(vg)/limb) of 12 wk-old mice. Ischemia was then induced after IM injections. Limb perfusion was serially measured by laser Doppler on days 0, 7 & 14 post-injection and values were expressed as a ratio relative to the non-ischemic limb. EcSOD expression was measured by Western blotting. Capillary density was documented by immunohistochemical staining for platelet endothelial cell adhesion molecule (PECAM). Apoptosis was assessed by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and necrosis was visually evaluated daily. Results EcSOD expression was 2-fold up-regulated in EcSOD treated vs. control ischemic muscles at day 14. Capillary density was 1.9-fold higher in treated (1.65±0.02 capillaries/fiber) vs. control muscle (0.78±0.17 capillaries/fiber, p<0.05). Recovery of perfusion ratio at day 14 post-ischemia was 1.5-fold greater in EcSOD vs. control mice (p<0.05). The percentage of apoptotic nuclei was 1.3 ± 0.4% in EcSOD treated mice as compared to 4.2± 0.2% in controls (p<0.001). Limb necrosis was also significantly lower in EcSOD vs. control mice. Conclusion AAV9-mediated overexpression of EcSOD in skeletal muscle significantly improves recovery from hind-limb ischemia in mice, consistent with improved capillary density and perfusion ratios in treated mice.
We describe a patient with rotational vertebrobasilar ischemia (RVBI) due to vertebral artery (VA) compressive stenoses during neck rotation, complicated by an ostial atherosclerotic stenosis (OAS). Referred for 'near-syncopal spells', inquiry revealed a symptom-complex consistent with vertebrobasilar transient ischemic attacks (TIAs) provoked by head rotation. VA dynamic angiography with imaging via prevertebral subclavian injections in neck-rotated positions while reproducing symptoms, demonstrated two compressive stenoses not present in the neck-neutral position, establishing the diagnosis of RVBI due to CT-demonstrated cervical spondylosis. There was an occluded contralateral VA, isolated posterior circulation, and absent vertebral collateral flow. Disabling symptoms persisted despite using a cervical collar. Surgical decompression of the dynamic stenoses would not address the OAS, was considered high risk, and absence of a suitable donor artery precluded distal VA reconstruction. RVBI resolved with ostial stent placement by improving perfusion pressure across the compressive stenoses. To our knowledge, this is the first report of RVBI in which the affected VA had an obstructive atherosclerotic stenosis in addition to the characteristic rotation-induced dynamic stenoses, and the first report of stent placement in the culprit artery to treat this disorder. Diagnosis depends on recognizing the association of symptoms with positional neck changes and VA dynamic angiography demonstrating the compressive stenosis while reproducing symptoms. This case illustrates the management complexities when there are coexisting abnormalities, emphasizing the need to individualize treatment. RVBI is a potentially correctable cause of TIAs and particularly relevant due to the aging population which has a significant incidence of both degenerative cervical and atherosclerotic cerebrovascular disease.
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