vitamin-k-semiquinone-radical and Cardiomyopathies

Patients rarely consult physicians before developing coagulopathy or bleeding in most reported cases of superwarfarin intoxication. A 57-year-old woman ingested red-dyed pellets of anticoagulant rodenticide containing difethialone and warfarin as well as tablets of nitrazepam. Although she presented to the hospital in a comatose state, notable pink-colored excreta hinted at the consumption of anticoagulant rodenticide, which led to the early diagnosis of superwarfarin intoxication. Supplementation of large doses of intravenous and oral vitamin K successfully prevented coagulopathy and bleeding. On the other hand, temporary and reversible myocardial suppression was extremely severe, and required the introduction of percutaneous cardiopulmonary support.

Topics: 4-Hydroxycoumarins; Anticoagulants; Cardiomyopathies; Coloring Agents; Female; Humans; Intra-Aortic Balloon Pumping; Middle Aged; Nitrazepam; Rodenticides; Vitamin K; Warfarin

Vascular calcification in humans is associated with an increased cardiovascular risk. Carboxylated matrix Gla protein (cMGP) inhibits vascular calcification. Vitamin K is an essential cofactor for the activation of uncarboxylated matrix Gla protein (ucMGP). It has been suggested that patients on long-term treatment with vitamin K antagonists develop aortic valve calcifications because of lower levels of circulating MGP. We therefore hypothesized that arterial calcification and a low vitamin K status are associated with ucMGP. To that aim, we measured arterial calcium scores, the osteocalcin ratio (OCR), as a proxy for vitamin K status, and ucMGP.. In 36 hypertensive patients, we determined the Agatston score with computer tomography scans of the abdominal aorta, carotid and coronary arteries. The total calcium score was calculated as the sum of the separate Z-scores.. The total calcium Z-score was significantly correlated to age (r = 0.683, P < 0.001), smoking (r = 0.372, P = 0.026), total cholesterol (r = 0.353, P = 0.034), LDL cholesterol (r = 0.490, P = 0.003), triglycerides (r = 0.506, P = 0.002), fasting glucose (r = 0.454, P = 0.005), systolic blood pressure (r = 0.363, P = 0.029) and pulse pressure (r = 0.685, P < 0.001). In multivariate regression analyses, OCR and total calcium score were significantly associated with ucMGP.. We found a positive association of total arterial calcium score and a high OCR (reflecting low vitamin K status) with ucMGP serum levels. This warrants further studies to explore the pathophysiological background of this phenomenon.

Topics: Adult; Aged; Aged, 80 and over; Calcinosis; Calcium; Calcium-Binding Proteins; Cardiomyopathies; Extracellular Matrix Proteins; Female; Humans; Hypertension; Male; Matrix Gla Protein; Middle Aged; Osteocalcin; Tomography, X-Ray Computed; Vitamin K

Topics: Animals; Blood Coagulation; Cardiomyopathies; Diagnostic Errors; Hemorrhage; Mice; Reverse Transcriptase Inhibitors; Vitamin K; Vitamin K Deficiency

Dietary dosing of the non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125, under development for treatment of HIV-1, resulted in a syndrome in male mice in a previous experiment that was termed hemorrhagic cardiomyopathy. In literature, this syndrome, which was described in rodent species only, was linked to vitamin K deficiency. Two mechanistic studies were conducted, one with dietary administration and a second with gavage. The syndrome was reproduced in only 1 male mouse after continuous dietary dosing, and TMC125 was demonstrated to affect coagulation parameters (prothrombin time [PT], activated partial thromboplastin time [APTT], clotting factors II, VII and XI), particularly in males. This was counteracted by vitamin K supplementation, supporting the hypothesis that the effects were mediated via a vitamin K deficiency. It is therefore concluded that the observed cardiac changes were not caused by a direct cardiotoxic effect but occurred after a state of disabled clotting ability with subsequent effects on mouse cardiac muscle. Therefore, clotting times can be used as adequate safety biomarkers in clinical trials. To date, no changes have been observed at therapeutic doses of TMC125, following human monitoring of PT and APTT. One other NNRTI, Efavirenz (Sustiva), has been reported to cause prolongation of coagulation times in rats and monkeys.

Topics: Administration, Oral; Animals; Area Under Curve; Blood Coagulation; Cardiomyopathies; Diet; Female; Heart; Hemorrhagic Disorders; Male; Mice; Nitriles; Partial Thromboplastin Time; Prothrombin Time; Pyridazines; Pyrimidines; Reverse Transcriptase Inhibitors; Troponin T; Vitamin K; Vitamin K Deficiency

Twelve patient cell lines with biochemically proven complex I deficiency were compared for clinical presentation and outcome, together with their sensitivity to galactose and menadione toxicity. Each patient had elevated lactate to pyruvate ratios demonstrable in fibroblast cultures. Each patient also had decreased rotenone-sensitive NADH-cytochrome c reductase (complexes I and III) with normal succinate cytochrome c reductase (complexes II and III) and cytochrome oxidase (complex IV) activity in cultured skin fibroblasts, indicating a deficient NADH-coenzyme Q reductase (complex I) activity. The patients fell into five categories: severe neonatal lactic acidosis; Leigh disease; cardiomyopathy and cataracts; hepatopathy and tubulopathy; and mild symptoms with lactic acidaemia. Cell lines from 4 out of the 12 patients were susceptible to both galactose and menadione toxicity and 3 of these also displayed low levels of ATP synthesis in digitonin-permeabilized skin fibroblasts from a number of substrates. This study highlights the heterogeneity of complex I deficiency at the clinical and biochemical level.

Topics: Acidosis, Lactic; Adenosine Triphosphate; Cardiomyopathies; Cataract; Cell Line; Child; Child, Preschool; Fibroblasts; Galactose; Hepatomegaly; Humans; Infant; Infant, Newborn; Kidney Diseases; Leigh Disease; NAD(P)H Dehydrogenase (Quinone); Phenotype; Vitamin K

The cause of a fatal condition characterized by hemorrhagic cardiomyopathy, hemothorax, and coagulation defects in hysterectomy-derived male mice was investigated. Microscopic heart alterations included multifocal hemorrhage and necrosis with variable degrees of acute inflammation and fibroplasia that were most severe in the region of the atrioventricular junction. A spontaneous outbreak was arrested by increasing menadione Na-bisulfite (vitamin K) in the feed to 20 ppm. The complete syndrome including hemorrhagic cardiomyopathy was readily reproduced in germ-free male mice given a vitamin K-free diet, and in conventional male and female mice given Warfarin in the diet. We concluded that the cause of this condition was vitamin K deficiency.

Topics: Animals; Blood Coagulation Disorders; Cardiomyopathies; Female; Hemorrhagic Disorders; Hemothorax; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred CBA; Myocardium; Vitamin K; Vitamin K Deficiency; Warfarin

The incisive detection of bioenergetic insufficiency in an organ of known workload by P MRS is noninvasive and nondestructive, and in some cases the portion of the organ involved can be determined, particularly if both PCr and ATP are depleted. The fractional loss of ATP and hence the relative volumes of viable and "metabolically dead" tissue are thereby evaluated. In addition, the value of P MRS in following a therapy complements its value in diagnosis as this has been demonstrated in cases followed over 6 months to three years. The fact that deficiencies of the enzymes and substrates of oxidative metabolism can be detected by P MRS affords a global overview of energy metabolism that can be a key to rapid diagnosis. The distinction of the enzyme and/or substrate deficiency, while not directly indicated by steady state P MRS, can be identified by use of the "Crossover Theorem" and its impact upon blood and tissue levels of substrates (including oxygen). In the case of neonatal systemic hypoxia, there is no doubt about which of the equations applies, and similarly in metabolic disease, a glutaric acid urea is a direct consequence of the crossover response of metabolism and signifies that an enzyme deficiency may be involved. Furthermore, the clinical danger of a high Pi/PCr value is clarified by our observations, both from the animal models and from the theory, the high clues; i.e. 2 and over, suggest work stresses near the capability of oxidative metabolism and imminent failure of the negative feedback afforded by metabolic regulation, particularly ADP control of oxidative metabolism. This control is lost because of the fall of phosphocreatine to the point where creatine kinase is no longer in equilibrium, leading to the loss of ATP and its conversion to large amounts of ADP and its breakdown products. ATP then stimulates glycolysis and results in a massive lactic acidosis. At the same time, the low thermodynamic capability of glycolytic metabolism is unable to prevent irreversible ion disequilibration, water movements, edema, and eventually rupture of the cell membrane. The pathway of resynthesis of ATP is then tortuous, particularly as AMP is deaminated and adenosine is converted eventually to hypoxanthine. Thus, NMR reports that metabolic control is operating in the region where homeostasis of biochemical parameters is feasible. It further reports regions where the metabolic control is susceptible to failure and most aggressive clinical care is require

Topics: Adenosine Triphosphate; Animals; Ascorbic Acid; Cardiomyopathies; Electric Organ; Electrophorus; Humans; Hypoxia; Infant, Newborn; Kinetics; Magnetic Resonance Spectroscopy; Metabolic Diseases; Mitochondria; Muscular Dystrophies; Phosphates; Vitamin K