Cardiovascular research
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Cardiovascular research · Dec 2007
Case ReportsA novel C-terminal truncation SCN5A mutation from a patient with sick sinus syndrome, conduction disorder and ventricular tachycardia.
Individual mutations in the SCN5A-encoding cardiac sodium channel alpha-subunit cause single cardiac arrhythmia disorders, but a few cause multiple distinct disorders. Here we report a family harboring an SCN5A mutation (L1821fs/10) causing a truncation of the C-terminus with a marked and complex biophysical phenotype and a corresponding variable and complex clinical phenotype with variable penetrance. ⋯ The L1821fs/10 mutation causes the most severe disruption of SCN5A structure for a naturally occurring mutation that still produces current. It has a marked loss-of-function and unique phenotype of SSS, CCD and VT with incomplete penetrance.
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Cardiovascular research · Oct 2007
Silencing of caspase-8 and caspase-3 by RNA interference prevents vascular endothelial cell injury in mice with endotoxic shock.
Septic shock and sequential multiple organ failure remain the cause of death in septic patients. Vascular endothelial cell apoptosis may play a role in the pathogenesis of the septic syndrome. Caspase-8 is presumed to be the apex of the death receptor-mediated apoptosis pathway, whereas caspase-3 belongs to the "effector" protease in the apoptosis cascade. Synthetic small interfering RNAs (siRNAs) specifically suppress gene expression by RNA interference. Therefore, we evaluated the therapeutic efficacy of caspase-8/caspase-3 siRNAs in a murine model of polymicrobial endotoxic shock. ⋯ Gene silencing of caspase-8 and caspase-3 with siRNAs provided profound protection against polymicrobial endotoxic shock. The prevention of vascular endothelial cell apoptosis appears to be, at least in part, responsible for their beneficial effects in endotoxic shock.
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Cardiovascular research · Apr 2007
Deletion of the sphingosine kinase-1 gene influences cell fate during hypoxia and glucose deprivation in adult mouse cardiomyocytes.
Activation of sphingosine kinase (SphK), which has two known isoforms, is responsible for the synthesis of sphingosine 1-phosphate (S1P), a cell survival factor. We tested the following hypotheses: 1] cardiac myocytes null for the SphK1 gene are more vulnerable to the stress of hypoxia+glucose deprivation; 2] the monoganglioside GM-1, which activates SphK via protein kinase C epsilon, is ineffective in SphK1-null myocytes; 3] S1P generated by SphK activation requires cellular export to be cardioprotective. ⋯ As the effect of GM-1 is blocked both at the receptor and the G-protein (Gi) levels, we conclude that S1P generated by GM-1 treatment must be exported from the cell and acts in a paracrine or autocrine manner to couple with its cognate receptor.
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Cardiovascular research · Mar 2007
Comparative StudyRelationship between oxidative stress, lipid peroxidation, and ultrastructural damage in patients with coronary artery disease undergoing cardioplegic arrest/reperfusion.
In animal models, formation of oxidants during postischemic reperfusion may exert deleterious effects ("oxidative stress"). Cardioplegic arrest/reperfusion during cardiac surgery might similarly induce oxidative stress. However, the phenomenon has not been precisely characterized in patients, and therefore the role of antioxidant therapy at cardiac surgery is a matter of debate. Thus, we wanted to ascertain whether the relationship between oxidant formation and development of myocardial injury also translates to the situation of patients subjected to cardioplegic arrest. ⋯ Careful investigation reveals that while oxidant production does occur during cardiac surgery in patients with chronic ischemic heart disease, cardiac oxidative stress may not progress through membrane damage and irreversible injury.
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Cardiovascular research · Feb 2007
Comparative StudyThe endothelial glycocalyx affords compatibility of Starling's principle and high cardiac interstitial albumin levels.
To test the role of an oncotic pressure gradient across the endothelial glycocalyx with respect to extravasation of fluid and colloids and development of tissue edema in a whole organ setting. ⋯ We propose a low-filtration model for the coronary system with different barrier properties in arteriolar/capillary and venular sections. Arteriolar/capillary: very little fluid and colloid extravasation due to the endothelial surface layer formed by the glycocalyx and albumin plus the endothelial strand barrier; venular: little net extravsation of fluid and colloids despite large pores, because of low hydrostatic and oncotic pressure differences between intra- and extravascular spaces. The latter sites provide physiological access of large solutes (colloids) to the tissue.