Iatrogenic QT Abnormalities and Fatal Arrhythmias: Mechanisms and Clinical Significance

Severe and occasionally fatal arrhythmias, commonly presenting as Torsade de Pointes [TdP] have been reported with Class III-antiarrhythmics, but also with non-antiarrhythmic drugs. Most cases result from an action on K+ channels encoded by the HERG gene responsible for the IKr repolarizing current, leading to a long QT and repolarization abnormalities. The hydrophobic central cavity of the HERG-K+ channels, allows a large number of structurally unrelated drugs to bind and cause direct channel inhibition. Some examples are dofetilide, quinidine, sotalol, erythromycin, grepafloxacin, cisapride, dolasetron, thioridazine, haloperidol, droperidol and pimozide. Other drugs achieve channel inhibition indirectly by impairing channel traffic from the endoplasmic reticulum to the cell membrane, decreasing channel membrane density (pentamidine, geldalamicin, arsenic trioxide, digoxin, and probucol). Whereas, ketoconazole, fluoxetine and norfluoxetine induce both direct channel inhibition and impaired channel trafficking. Congenital long QT syndrome, subclinical ion-channel mutations, subjects and relatives of subjects with previous history of drug-induced long QT or TdP, dual drug effects on cardiac repolarization [long QT plus increased QT dispersion], increased transmural dispersion of repolarization and T wave abnormalities, use of high doses, metabolism inhibitors and/or combinations of QT prolonging drugs, hypokalemia, structural cardiac disease, sympathomimetics, bradycardia, women and older age, have been shown to increase the risk for developing drug-induced TdP. Because most of these reactions are preventable, careful evaluation of risk factors and increased knowledge of drugs use associated with repolarization abnormalities is strongly recommended. Future genetic testing and development of practical and simple provocation tests are in route to prevent iatrogenic TdP

Monoamine Release by Compound 48/80 from Nonmast Cell Compartments in Mouse Brain Slices1

ABSTRACT In the present study we investigated the specificity of the releasing effects of compoun

Outcomes of Patients Who Have Do Not Resuscitate Status prior to Being Admitted to an Intensive Care Unit

Admission of patients who have do not resuscitate (DNR) status to an intensive care unit (ICU) is potentially a misallocation of limited resources to patients who may neither need nor want intensive care. Yet, patients who have DNR status are often admitted to the ICU. This is a retrospective review of patients who had a valid DNR status at the time that they were admitted to an ICU in a single hospital over an eighteen-month period. Thirty-five patients met the criteria for inclusion in the study. The primary reasons for admission to the ICU were respiratory distress (54.2%) and sepsis (45.7%). Sixteen (45.7%) of the patients died, compared to a 5.4% mortality rate for all patients admitted to our ICU during this period (p<0.001). APACHE II score was a significant predictor of mortality (18.5 ± 1.3 alive and 23.4 ± 1.4 dead; p=0.038). Of the 19 patients discharged alive, 9 were discharged home, 5 to hospice, and 4 to a post-acute care facility. Conclusions. Patients who have DNR status and are admitted to the ICU have a higher mortality than other ICU patients. Those who survive have a high likelihood of being discharged to hospice or a post-acute care facility. The value of intensive intervention for these patients is not supported by these results. Only a minority of patients were seen by palliative care and chaplain teams, services which the literature supports as valuable for DNR patients. Our study supports the need for less expensive and less intensive but more appropriate resources for patients and families who have chosen DNR status

Alpha-Adducin Polymorphism and Salt-Induced Hypertension

Genes encoding for alpha-adducin, angiotensin converting enzyme and nitric oxide synthase levels have been considered as candidate genes for hypertension (HT). Alpha adducin is a cytoskeletal protein present in the renal tubules and is involved in sodium reabsorption. Point mutations in this protein (Gly460Trp) are associated with HT. Because alpha adducin regulates sodium reabsorption, mutations in the adducin gene may be associated with salt-sensitive forms of HT. In this study, we propose: To develop an assay with the purpose of genotyping the alpha-adducin point mutation. The assay should detect subjects carrying the wild type of alpha adducin (Gly/Gly), as well as those who carry the heterozygous (Gly460Trp) and homozygous (Trp460Trp) mutants. To determine if the presence of alpha-adducin polymorphism is associated with salt sensitive HT. This is the first of a series of studies devoted to evaluate the contribution of candidate genes to the development of salt sensitive hypertension

Glucose Abnormalities in Hispanics: How Long Before Type 2 Diabetes Mellitus?

Objectives. To determine the screening value of fasting plasma glucose and insulin in detecting glucose intolerance and diabetes mellitus (DM) in “healthy” Hispanics. Background. Glucose abnormalities precede development of diabetes mellitus. However, only fasting glucose levels are used in clinical practice, and its diagnostic value varies among ethnicities. Methods. Oral glucose tolerance testing was conducted in 592 Hispanics. A cross-sectional design was employed. Results. GA were found in 34% of subjects, defined as impaired fasting glucose (IFG) (13.3%), IGT (6.9%), combined IFG+IGT (7.8%) and type2-DM (6.5%). FPG of 5.6-6.9mmol/l diagnostic of IFG missed 47.1% of subjects with IGT, and FPG \u3e 7.0mmol/l missed 53.9% of DM. IFG showed a sensitivity of 52.9 % and a specificity of 83% in predicting IGT. The diagnostic yield, expressed by the positive predictive value was poor (36.8%). GA were associated with abdominal obesity, hypertriglyceridemia, hyperinsulinemia, hypertension and metabolic syndrome (MS). Prevalence of MS was greater in DM=IFG+IGT \u3e IGT=IFG \u3e controls. Post-load hyperinsulinemia and hyperglycemia was higher in IGT than in IFG; whereas HOMA-IR was higher in IFG. Insulin secretion was reduced in DM, IFG-IGT and IGT. Conclusion. Diagnosis of GA must include both, fasting and 2-hour post-load glucose levels. Presence of fasting and post-load hyperglycemia-hyperinsulinemia in one individual may explain the increased risk in combined IFG-IGT and in DM. Because of its 19 high prevalence, silent course, and associated increased risk, full-scale screening programs and aggressive management of GA must be implemented

Mechanisms of Hypertension Associated with Obesity

Background. Obesity is extremely common in people with high BP. However, the mechanisms by which BP increases in obese subjects are unknown. Objectives. We are interested in understanding the role of dietary salt and the BP reactivity to dietary salt (salt sensitivity) in the genesis of hypertension associated with obesity. We have recently shown that individuals with the metabolic syndrome are more salt sensitive that those without the syndrome. In addition, we have reported that high salt intake is associated with indices of obesity (BMI, weight and waist circumference). However, not all obese individuals have high BP, nor weight loss lowers BP in all subjects. Methods and Results. Therefore, a prospective study was designed to investigate the role of the salt sensitive (SS) and the salt resistant (SR) phenotypes in determining the degree of BP lowering induced by weight loss. Overweight/obese classified as SS or SR (n=45; BMI:27-35 kg/m2) entered a 1-year program of dietary restriction, aerobic exercise and metformin. Comparable reductions in obesity (8-10%), triglyceride (25%), and fasting insulin concentrations (40%) were observed in SR and SS individuals. In SS subjects the intervention lowered SBP/DBP by 8.8/6.1 mmHg, albuminuria by 63%, and decreased the subject’s SS. Neither BP nor albuminuria was modified in SR by the intervention. However, in obese SS individuals, restricting dietary salt lowered BP to a similar extent to the BP reduction achieved with the one-year intervention (weight loss). Conclusions. Our findings indicate that BP lowering induced by the lifestyle-metformin intervention appears to be determined by the SR/SS phenotype. Correcting adiposity in SS lowers BP because it makes the BP insensitive to dietary salt (corrects the SS phenotype). Therefore, weight loss and correction of metabolic abnormalities lowers BP in obese SS but not in obese SR, suggesting that the SR phenotype protects from obesity-induced increases in BP. These findings suggest that most of the hypertension associated with obesity is determined by dietary salt intake due to the development of a SS phenotype. The mechanisms (genetic or acquired) that determine the SS phenotype are under investigation

Cholesterol-dependent Gene Regulation of Vascular Function

Coronary heart disease is the leading cause of morbidity and mortality worldwide. It has been unequivocally shown that lowering of blood cholesterol levels reduces cardiovascular events and the development of atherosclerosis. In addition of the pathogenic role of blood cholesterol, the endogenous production of cholesterol by vascular cells impacts vascular health. Inhibition of the cholesterol synthetic pathway in vascular cells facilitates the production of vascular-protective substances, while inhibiting the production of substances with vascular-deleterious actions. Conversely, activation of the cholesterol synthetic pathway leads to severe vascular dysfunction. The interactions between changes in cholesterol synthesis in vascular cells and vascular function are poorly understood. The objective of this application is to determine in vascular endothelial and smooth muscle cells which of the genes that code for vascular protective and vascular deleterious substances are sensitive to modulation by changes in cholesterol synthesis. Our central hypothesis is that in addition to high blood cholesterol, a high rate of cholesterol synthesis in vascular cells affects vascular function. We propose that this is achieved through the activation of genes coding for substances with vascular constrictive, growth-promoting and pro-inflammatory activities. Microarrays will be employed to detect up-regulation and/or down-regulation of gene expression induced by treatments that inhibit or stimulate the cholesterol synthetic pathway. Completion of this proposal will help in determining which genes participate in inducing vascular dysfunction when the cholesterol synthetic pathway is activated. Identifying these genes is fundamental to design new therapeutic interventions, and to better comprehend the regulation of vascular function

Vascular Dysregulation During And After Statins Withdrawal: Role Of Small Gtpases

3-hydroxy-3-methylglutaryl-coenzyme-A-reductase inhibitors (statins) are the most effective drugs for lowering serum cholesterol. However, acute discontinuation of statins impair vascular function and increase adverse cardiovascular events. Because of its clinical relevance, the mechanisms underlying the vascular dysfunction associated with statin withdrawal are under active investigation. Vascular protective mechanisms, such as nitric oxide production and endothelial-dependent vasodilation, are impaired after acute statin discontinuation. We have also shown that angiotensin II (AII)-signaling, and the mRNA and protein levels for AT1 receptors (AII primary receptor) are increased after statin withdrawal. Since AII vasoconstrictor, inflammatory and growth promoting effects on the vasculature are well known, our findings suggest that AII may participate in vascular dysfunction following statin discontinuation. Current evidence indicates that by inhibiting mevalonate formation, statins decrease intracellular levels of isoprenoid intermediates, reducing the levels of prenylated membrane-bound (active) rhoA small GTPase. The latter, is known to reduce expression and levels of AT1 receptors. It is thus feasible that the opposite effect may determine the upregulation of AT1-receptors and AIIsignaling observed after statin withdrawal. Consequently, in this proposal, we would like to study the intracellular mechanisms determining the upregulation of AT1 receptors and AIIsignaling observed after statin withdrawal. Experiments will be conducted in vascular smooth muscle cells (VSMC) in the presence of selective inhibitors and stimulators of farnesylation and of geranylgeranylation. Completion of these experiments will allow us to determine the relative role of farnesylation and geranylgeranylation in the upregulation of AII receptors and signaling after statin withdrawal, and to test our hypothesis that the upregulation of AII is due to increased isoprenylation of small GTPases. In summary, the relevance of this research project is to further elucidate the vascular mechanisms by which statins withdrawal may impair cardiovascular functions, and to investigate the role of the cholesterol biosynthetic pathway on vascular function

Stain Modulation of Oncolytic Vesicular Stomatitis Virus

Background and Rationale: Cancer is the second leading cause of death in the United States. Current anticancer treatments have low specificity, affecting cancerous as well as normal cells. New therapeutics approaches, such as the use of viruses with selective killing effects on cancer cells (oncolytic viruses), are worth exploring. Such an approach requires of drugs and/or procedures that would minimize infectivity to normal cells and/or enhance the virus oncolytic potency. Statins, the extensively used cholesterol-lowering drugs (i.e., Lipitor®, Zocor®) have been shown to modulate viral activity and to induce cytoprotection. More importantly, we have recently observed that the statin, simvastatin, at very low concentrations, increased the expression of the oncolytic Vesicular Stomatitis Virus (VSV), which is an attractive candidate for anticancer investigation. Methods: In this study, we propose to expand our research activities by characterizing and comparing the effects of simvastatin on the VSV infectivity, growth and cell-killing (cytopathic actions) in cancer cells (HeLa, uterine cancer) and in UtSM (normal uterine smooth muscle) cells. Cells pretreated with different concentrations of simvastatin and subsequently infected with VSV, will be monitored for cell death and survival rates, viral replication (viral protein levels and viral titers), for cytopathic effects and for antiviral proteins. Significance: Funding will enable us to understand the mechanisms underlying the novel viral-modulatory and cytoprotective properties of statins. Our studies will provide light on the possible role of statins as neoadjuvant and/or as modulator for future VSV oncolytic therapy