Eliot A. Brinton is the President of the Utah Lipid Center in Salt Lake City. He is a founding board member of the National Lipid Association and of the American Board of Clinical Lipidology, of which he is also Past-President. He is a fellow of the American Heart Association and of the National Lipid Association, and past chair of the Clinical Lipidology Committee of the AHA. Dr. Brinton is widely published in the field of lipoprotein metabolism, having published original research articles in the New England Journal of Medicine, JAMA, and Circulation. He is Associate Editor of the Journal of Clinical Lipidology and Assistant Editor of the Journal of Obesity, and has served on the editorial boards of the Journal of Clinical Endocrinology and Metabolism and the Journal of Managed Care Pharmacy. Dr. Brinton has served on the faculty of the Rockefeller University, Wake Forest University and the University of Utah. He has won several awards and has held numerous leadership and advisory positions in scientific and governmental organizations and in the pharmaceutical industry.
Statement of the Problem: Homozygous familial hypercholesterolemia (HoFH) is ultra-rare and hard to treat, with high LDL-C and premature major adverse cardiovascular events (MACE). No randomized trials, few real-world studies, and no published lomitapide (LOM) studies address MACE in HoFH, despite LOM being indicated as an adjunct therapy to diet and other lipid-lowering treatments for HoFH. This study presents for the first time MACE rates in LOM-treated patients. Methodology & Theoretical Orientation: Optum claims data (2012-2016, ~25 million covered lives) were combined with LDL-C from Optum and a pharmaceutical patient support program. LDL-C, and rates of MACE and hospitalization were assessed in HoFH patients for 1 year before drug initiation, during LOM treatment, and 1 year after LOM discontinuation (in those who discontinued). Patients were stratified based on LDL-C response to LOM. Findings: 62 patients started LOM and had baseline and follow-up LDL-C. LOM use was associated with LDL-C reductions and a trend to lower hospitalizations and MACE rates. Nearly 2/3 of patients (40 of 62) had a sustained response to LOM (>10% LDL-C reduction for >60 days), of whom 27 later discontinued LOM, with the expected subsequent worsening of outcomes. Conclusion & Significance Consistent with clinical trials, LOM significantly reduces LDL-C in real-world HoFH patients. Although data are limited by the rarity of HoFH, there was clinically meaningful (albeit not statistically significant) decrease in MACE and hospitalization with LOM treatment, and, as expected, there was a trend toward loss of LDL-C and MACE/hospitalization benefits after LOM discontinuation.
Radwa Mohammed is a researcher and teaching staff in the department of pharmacology and toxicology, Faculty of pharmacy, Cairo, Egypt.
Background: 5-fluorouracil (5-FU) is a chemotherapeutic agent widely used in the treatment of different solid tumors, especially colorectal cancer. Its use is associated with rare but potentially serious cardiovascular toxicity. This study aims to investigate molecular mechanisms underlying the cardiovascular toxicity of 5-FU and the potential protective effects of simvastatin. Methods: Adult male albino Wistar rats were randomly divided into four groups (15-20/group). The first group received normal saline (i.p) once weekly for six successive weeks. In the second group rats received 5-FU (50 mg/kg; i.p) once weekly for six successive weeks (cardiotoxic group). Rats of the third group received simvastatin (15 mg/kg/day, p.o.) daily for eight successive weeks. Finally, rats of the forth group received simvastatin daily a week before the first 5-FU injection, then concomitantly for six weeks, and continued alone for another week after the last dose of 5-FU. ECG recording was weekly carried out. Cardiac content of NADPH-oxidase, COX-2, NF-ƙB, p-eNOS and p-AKT in addition to aortic content of endothelin-1 and thromboxane-A2 were assessed by enzyme-linked immunosorbent assay. Protein expression of cardiac caspase-3 and Rho-kinase was evaluated by western blotting. Serum level of NT-proBNP and cardiac TBARS (thiobarbituric acid reactive substances) were also evaluated. Finally, histopathological evaluation of both cardiac and aortic tissues was carried out. Results: 5-FU caused histopathological changes in both myocardial and aortic tissues. Myocardial ischemia and QTc prolongation were confirmed by ECG recording. 5-FU increased myocardial NADPH-oxidase and COX-2 content, leading to increased ROS production. Oxidative stress, inflammation and associated apoptosis in the heart were indicated by elevated TBARS, caspase-3 protein expression and NF-ƙB content. Elevated aortic tissue content of endothelin-1 and thromboxane-A2, the two potent vasoconstrictors was observed. 5-FU significantly increased ROCK protein expression and p-AKT content, and suppressed p-eNOS level. Finally, elevated serum level of NT-proBNP was observed. Simvastatin was able to prevent most of these abnormalities. Conclusion: Direct myocardial injury and ischemia caused by endothelial dysfunction and activation of Rho/ROCK pathway are potential mechanisms of 5-FU cardiovascular toxicity. Inhibition of ROCK activity by simvastatin, a drug with potent antioxidant and pleiotropic properties, mitigates the cardiovascular toxicity of 5-FU.