Emergency revascularization in patients with cardiogenic shock on admission: a report from the SHOCK trial and registry

Aims To determine clinical correlates and optimal treatment strategy in patients with cardiogenic shock (CS) on admission. Methods and results In SHould we emergently revascularize Occluded Coronaries in cardiogenic shocK? (SHOCK) trial and registry patients with left ventricular (LV) dysfunction (n=1053), CS on admission occurred in 26% of directly admitted patients (n=166/627). Time from myocardial infarction to CS was shorter, initial haemodynamic profile poorer, and aggressive treatment less frequent in CS on admission than in delayed CS patients. CS on admission patients constituted a smaller relative proportion (11%) of the transferred (n=48/426) when compared with the directly admitted cohort (P<0.001). In-hospital mortality was higher (75 vs. 56%; P<0.001) with more rapid death (24-h mortality 40 vs. 17%; P<0.001) in CS on admission than in delayed CS patients. Emergency revascularization reduced in-hospital mortality in CS on admission (60 vs. 82%; P=0.001) and in delayed CS patients similarly (46 vs. 62%; P<0.001; interaction P=0.25). After adjustment for clinical differences, CS on admission was an independent predictor of in-hospital mortality (P=0.008). Conclusion CS on admission patients have a worse outcome but benefit equally from emergency revascularization as delayed CS patients, emphasizing the need for rapid and direct access of CS on admission patients to facilities providing this car

Inheritance, Biochemical Abnormalities, and Clinical Features of Feline Mucolipidosis II: The First Animal Model of Human I-Cell Disease

Mucolipidosis II (ML II), also called I-cell disease, is a unique lysosomal storage disease caused by deficient activity of the enzyme N-acetylglucosamine-1-phosphotransferase, which leads to a failure to internalize enzymes into lysosomes. We report on a colony of domestic shorthair cats with ML II that was established from a half-sibling male of an affected cat. Ten male and 9 female kittens out of 89 kittens in 26 litters born to clinically normal parents were affected; this is consistent with an autosomal recessive mode of inheritance. The activities of three lysosomal enzymes from affected kittens, compared to normal adult control cats, were high in serum (11-73 times normal) but low in cultured fibroblasts (9-56% of normal range) that contained inclusion bodies (I-cells), reflecting the unique enzyme defect in ML II. Serum lysosomal enzyme activities of adult obligate carriers were intermediate between normal and affected values. Clinical features in affected kittens were observed from birth and included failure to thrive, behavioral dullness, facial dysmorphia, and ataxia. Radiographic lesions included metaphyseal flaring, radial bowing, joint laxity, and vertebral fusion. In contrast to human ML II, diffuse retinal degeneration leading to blindness by 4 months of age was seen in affected kittens. All clinical signs were progressive and euthanasia or death invariably occurred within the first few days to 7 months of life, often due to upper respiratory disease or cardiac failure. The clinical and radiographic features, lysosomal enzyme activities, and mode of inheritance are homologous with ML II in humans. Feline ML II is currently the only animal model in which to study the pathogenesis of and therapeutic interventions for this unique storage diseas

Evaluation of Adeno-Associated Viral Vectors for Liver-Directed Gene Transfer in Dogs

This study evaluated six adeno-associated viral (AAV) vectors expressing green fluorescent protein (GFP) from the liver-specific thyroid hormone–binding globulin (TBG) promoter made with novel capsids in canine liver-directed gene transfer. Studies in 1.5-month-old dogs, which were administered vector through a peripheral vein, showed that AAV8 capsid vectors had the most favorable performance profiles. Interestingly, the absolute levels of hepatocyte transduction achieved with AAV8 were lower in dogs compared with what had been achieved in mice and nonhuman primates. Additional studies were performed with AAV8 delivered into the hepatic artery in adult dogs, with higher doses of vector used to assess potential dose-limiting toxicities. These studies showed good transduction on day 7 in one dog that apparently was lost by day 28 in another dog through the generation of GFP-specific T cells. Each adult dog was carefully monitored for any hemodynamic changes associated with vector infusion. Both animals demonstrated mild to moderate hypotension and bradycardia, which appeared to be anesthesia-related, making it difficult to evaluate contributions of the vector

Cardiac Gene Transfer of Short Hairpin RNA Directed Against Phospholamban Effectively Knocks Down Gene Expression but Causes Cellular Toxicity in Canines

Derangements in calcium cycling have been described in failing hearts, and preclinical studies have suggested that therapies aimed at correcting this defect can lead to improvements in cardiac function and survival. One strategy to improve calcium cycling would be to inhibit phospholamban (PLB), the negative regulator of SERCA2a that is upregulated in failing hearts. The goal of this study was to evaluate the safety and efficacy of using adeno-associated virus (AAV)-mediated cardiac gene transfer of short hairpin RNA (shRNA) to knock down expression of PLB. Six dogs were treated with self-complementary AAV serotype 6 (scAAV6) expressing shRNA against PLB. Three control dogs were treated with empty AAV6 capsid, and two control dogs were treated with scAAV6 expressing dominant negative PLB. Vector was delivered via a percutaneously inserted cardiac injection catheter. PLB mRNA and protein expression were analyzed in three of six shRNA dogs between days 16 and 26. The other three shRNA dogs and five control dogs were monitored long-term to assess cardiac safety. PLB mRNA was reduced 16-fold, and PLB protein was reduced 5-fold, with treatment. Serum troponin elevation and depressed cardiac function were observed in the shRNA group only at 4 weeks. An enzyme-linked immunospot assay failed to detect any T cells reactive to AAV6 capsid in peripheral blood mononuclear cells, heart, or spleen. Microarray analysis revealed alterations in cardiac expression of several microRNAs with shRNA treatment. AAV6-mediated cardiac gene transfer of shRNA effectively knocks down PLB expression but is associated with severe cardiac toxicity. Toxicity may result from dysregulation of endogenous microRNA pathways

Long-Term Systemic Myostatin Inhibition via Liver-Targeted Gene Transfer in Golden Retriever Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a lethal, X-linked recessive disease affecting 1 in 3,500 newborn boys for which there is no effective treatment or cure. One novel strategy that has therapeutic potential for DMD is inhibition of myostatin, a negative regulator of skeletal muscle mass that may also promote fibrosis. Therefore, our goal in this study was to evaluate systemic myostatin inhibition in the golden retriever model of DMD (GRMD). GRMD canines underwent liver-directed gene transfer of a self-complementary adeno-associated virus type 8 vector designed to express a secreted dominant-negative myostatin peptide (n =4) and were compared with age-matched, untreated GRMD controls (n =3). Dogs were followed with serial magnetic resonance imaging (MRI) for 13 months to assess cross-sectional area and volume of skeletal muscle, then euthanized so that tissue could be harvested for morphological and histological analysis. We found that systemic myostatin inhibition resulted in increased muscle mass in GRMD dogs as assessed by MRI and confirmed at tissue harvest. We also found that hypertrophy of type IIA fibers was largely responsible for the increased muscle mass and that reductions in serum creatine kinase and muscle fibrosis were associated with long-term myostatin inhibition in GRMD. This is the first report describing the effects of long-term, systemic myostatin inhibition in a large-animal model of DMD, and we believe that the simple and effective nature of our liver-directed gene-transfer strategy makes it an ideal candidate for evaluation as a novel therapeutic approach for DMD patients

Percutaneous coronary intervention for cardiogenic shock in the SHOCK trial

AbstractObjectivesWe examined the clinical, angiographic, and procedural characteristics determining survival after percutaneous coronary intervention (PCI) for cardiogenic shock.BackgroundThe SHOCK (SHould we emergently revascularize Occluded coronaries for Cardiogenic shocK?) trial prospectively enrolled patients with shock complicating acute myocardial infarction (MI). Patients were randomized to a strategy of early revascularization or initial medical stabilization.MethodsPatients randomized to early revascularization underwent PCI or bypass surgery on the basis of predefined clinical criteria. Patients randomized to early revascularization who underwent PCI and had angiographic films available for analysis are the subject of this report (n = 82).ResultsThe median time from MI to PCI was 11 h. The majority of patients had occluded culprit arteries (Thrombolysis In Myocardial Infarction [TIMI] grade 0 or 1 flow in 62%) and multivessel disease (81%). One-year mortality in PCI patients was 50%. Mortality was 39% if PCI was successful but 85% if unsuccessful (p < 0.001). Mortality was 38% if TIMI flow grade 3 was achieved, 55% with TIMI grade 2 flow, and 100% with TIMI grade 0 or 1 flow (p < 0.001). Mortality was 67% if severe mitral regurgitation was documented. Independent correlates of mortality were as follows: increasing age (p < 0.001), lower systolic blood pressure (p = 0.009), increasing time from randomization to PCI (p = 0.019), lower post-PCI TIMI flow (0/1 vs. 2/3) (p < 0.001), and multivessel PCI (p = 0.040).ConclusionsRestoration of coronary blood flow is a major predictor of survival in cardiogenic shock. Benefit appears to extend beyond the generally accepted 12-h post-infarction window. Surgery should be considered in shock patients with severe mitral insufficiency or multivessel disease not amenable to relatively complete percutaneous revascularization

Differences in Presentation and Outcomes between Children with Familial Dilated Cardiomyopathy and Children with Idiopathic Dilated Cardiomyopathy: A Report from the Pediatric Cardiomyopathy Registry Study Group

Research comparing the survival of children with familial dilated cardiomyopathy (FDCM) to that of children with idiopathic dilated cardiomyopathy (IDCM) has produced conflicting results

Therapeutic Neonatal Hepatic Gene Therapy in Mucopolysaccharidosis VII Dogs

Dogs with mucopolysaccharidosis VII (MPS VII) were injected intravenously at 2–3 days of age with a retroviral vector (RV) expressing canine β-glucuronidase (cGUSB). Five animals received RV alone, and two dogs received hepatocyte growth factor (HGF) before RV in an attempt to increase transduction efficiency. Transduced hepatocytes expanded clonally during normal liver growth and secreted enzyme with mannose 6-phosphate. Serum GUSB activity was stable for up to 14 months at normal levels for the RV-treated dogs, and for 17 months at 67-fold normal for the HGF/RV-treated dog. GUSB activity in other organs was 1.5–60% of normal at 6 months for two RV-treated dogs, which was likely because of uptake of enzyme from blood by the mannose 6-phosphate receptor. The body weights of untreated MPS VII dogs are 50% of normal at 6 months. MPS VII dogs cannot walk or stand after 6 months, and progressively develop eye and heart disease. RV- and HGF/RV-treated MPS VII dogs achieved 87% and 84% of normal body weight, respectively. Treated animals could run at all times of evaluation for 6–17 months because of improvements in bone and joint abnormalities, and had little or no corneal clouding and no mitral valve thickening. Despite higher GUSB expression, the clinical improvements in the HGF/RV-treated dog were similar to those in the RV-treated animals. This is the first successful application of gene therapy in preventing the clinical manifestations of a lysosomal storage disease in a large animal

Exploring Human/Animal Intersections: Converging Lines of Evidence in Comparative Models of Aging

At a symposium convened on March 8, 2007 by the Institute on Aging at the University of Pennsylvania, researchers from the University’s Schools of Medicine and Veterinary Medicine explored the convergence of aging research emerging from the two schools. Studies in human patients, animal models, and companion animals have revealed different but complementary aspects of the aging process, ranging from fundamental biologic aspects of aging to the treatment of age-related diseases, both experimentally and in clinical practice. Participants concluded that neither animal nor human research alone will provide answers to most questions about the aging process. Instead, an optimal translational research model supports a bidirectional flow of information from animal models to clinical research

Chronic Losartan Administration Reduces Mortality and Preserves Cardiac but Not Skeletal Muscle Function in Dystrophic Mice

Duchenne muscular dystrophy (DMD) is a degenerative disorder affecting skeletal and cardiac muscle for which there is no effective therapy. Angiotension receptor blockade (ARB) has excellent therapeutic potential in DMD based on recent data demonstrating attenuation of skeletal muscle disease progression during 6–9 months of therapy in the mdx mouse model of DMD. Since cardiac-related death is major cause of mortality in DMD, it is important to evaluate the effect of any novel treatment on the heart. Therefore, we evaluated the long-term impact of ARB on both the skeletal muscle and cardiac phenotype of the mdx mouse. Mdx mice received either losartan (0.6 g/L) (n = 8) or standard drinking water (n = 9) for two years, after which echocardiography was performed to assess cardiac function. Skeletal muscle weight, morphology, and function were assessed. Fibrosis was evaluated in the diaphragm and heart by Trichrome stain and by determination of tissue hydroxyproline content. By the study endpoint, 88% of treated mice were alive compared to only 44% of untreated (p = 0.05). No difference in skeletal muscle morphology, function, or fibrosis was noted in losartan-treated animals. Cardiac function was significantly preserved with losartan treatment, with a trend towards reduction in cardiac fibrosis. We saw no impact on the skeletal muscle disease progression, suggesting that other pathways that trigger fibrosis dominate over angiotensin II in skeletal muscle long term, unlike the situation in the heart. Our study suggests that ARB may be an important prophylactic treatment for DMD-associated cardiomyopathy, but will not impact skeletal muscle disease