Correction Of Hypertriglyceridemia Research Articles

Correction of hypertriglyceridemia in order to reduce the residual risk in atherosclerosis-related diseases. Expert Council Opinion

In opinion the Expert council provides management tactics for patients with hypertriglyceridemia (HTG). It is demonstrated that HTG is a common condition in overweight patients and is an important component of residual risk. HTG creates additional conditions for the progression of atherosclerosis, so the level of triglycerides (TG) is recommended to be measured in patients with a high, very high and extremely high risk level. An indication for the appointment of drugs that reduce the concentration of TG is its level of more than 2,3 mmol/L. Statins are the agents of choice to reduce the risk of cardiovascular disease in high-risk patients with hypercholesterolemia and HTG. Fenofibrate is used to correct HTG, and in case of intolerance to it or when the target level of TG is not reached, omega-3 ethers of polyunsaturated fatty acids in a dose of 2-4 g/day are recommended. In patients with HTG with a TG level >5,6 mmol/L, fenofibrate is the agent of choice.

Correction of Hypertriglyceridemia as the Way to Reduce Residual Risk in Diseases Caused by Atherosclerosis. Conclusion of the Advisory Board of the Russian Society of Cardiology, the Russian Scientific Medical Society of Therapists, the Eurasian Association of Therapists, the Russian National Atherosclerosis Society, the Russian Association of Endocrinologists, and the National League of Cardiologic Genetics

Tactics for the management of patients with hypertriglyceridemia (HTG) is provided in the conclusion of the Advisory Board. It is demonstrated that HTG is quite prevalent in patients with excessive body weight and is an important component of residual risk. HTG creates additional conditions for the progression of atherosclerosis, and thus it is recommended to test triglyceride in patients with high, very high and extremely high cardiovascular risk. The indication for the pharmacological treatment to reduce the triglycerides concentration is their level more than 2.3 mmol/l. Statins are drugs of choice aimed to decrease the cardiovascular risk in patients with hypercholesterinemia and HTG. Fenofibrate is used to correct HTG; in case of its intolerance or if the triglyceride target level is not reached, ethyl esters of omega-3 polyunsaturated fatty acid can be used in the dosage of 2-4 g daily. In patients with triglyceride level higher than 5.6 mmol/l, fenofibrate is the main option of treatment.

40. Correction of Dyslipidemia in Murine and Feline Models of Lipoprotein Lipase Deficiency by Intramuscular Administration of AAV1-LPLS447X

Lipoprotein lipase (LPL) deficiency is characterized by excessive plasma triglyceride levels (TG), resulting in visibly milky plasma and severe clinical symptoms including life-threatening pancreatitis. There is no treatment for this inherited metabolic disease. We therefore proposed to test LPL gene therapy, expressing the human LPL variant S447X in muscle. This naturally-occurring variant is associated with a beneficial lipid profile in man, and improved disease correction over wild type LPL following adenoviral transfer to LPL deficient (LPL−/−) mice. To realize long-term correction of hypertriglyceridemia, adeno-associated virus serotype 1 (AAV1) was used to instill stable expression of LPLS447X in muscle. IM administration of 8×1011–8×1012 gc/kg AAV1-LPLS447X in LPL−/− mice was sufficient to reduce plasma TG levels (by up to 98%, from 99 to 1.8 mmol/L). These beneficial effects were observed within 1 week post-transfer, and lasted for >1 year. Importantly, only a fraction of LPL activity ( 98% reduction of plasma TG within 1 week. After 3 weeks, antibodies against human LPL were detected in plasma, and TG levels returned to pre-treatment levels. In accordance, LPL expression was greatly reduced. In contrast to LPL−/− mice that have low residual levels of LPL activity and protein, LPL−/− cats have no detectable LPL protein mass. Therefore, administration of LPLS447X to LPL−/− cats likely provoked an immune response that abrogated treatment efficacy. CONCLUSION: AAV1-mediated delivery of LPLS447X to muscle provides immediate correction of hypertriglyceridemia in two different animal models of LPL deficiency.

Correction of hypertriglyceridemia with low high-density lipoprotein cholesterol by the novel compound NO-1886, a lipoprotein lipase-promoting agent, in STZ-induced diabetic rats

Correction of hypertriglyceridemia with low high-density lipoprotein cholesterol by the novel compound NO-1886, a lipoprotein lipase-promoting agent, in STZ-induced diabetic rats

Correction of Hypertriglyceridemia with Low High-Density Lipoprotein Cholesterol by the Novel Compound NO-1886, a Lipoprotein Lipase-Promoting Agent, in STZ-Induced Diabetic Rats

We have previously reported that the novel compound NO-1886 increased lipoprotein lipase (LPL) activity, with resulting elevation of high-density lipoprotein (HDL) cholesterol in normal rats (J Clin Invest 92:411-417, 1993). The aim of this study was to ascertain whether the compound has the same action in diabetes, because hypertriglyceridemia with low HDL cholesterol is an extremely common concomitant condition in diabetes. Streptozotocin-induced diabetic rats showed marked elevation of plasma triglyceride and reduction of HDL cholesterol. Both single and repeated administration of NO-1886 increased postheparin plasma LPL activity, with resulting reduction of plasma triglyceride and elevation of HDL cholesterol. Repeated administration increased the amount of LPL mRNA in adipose tissue and myocardium. The compound had no effects on plasma glucose and insulin levels. Our study indicates that the compound is potentially beneficial for the treatment of hypertriglyceridemia with low HDL cholesterol in diabetes.

Neuropathy associated with hyperlipidemia.

We describe six patients with painful polyneuropathy associated with hyperlipidemia. Each had mild, slowly progressive neuropathy characterized by pain in feet, without proximal extension or involvement of hands. Weakness and autonomic symptoms and signs were absent. Three patients had normal tendon reflexes; three others had decreased ankle reflexes. Serum cholesterol levels were moderately increased; serum triglyceride levels were exceedingly high. In one patient, symptoms resolved with correction of hypertriglyceridemia. No other cause of peripheral neuropathy was found. Marked increases in serum triglycerides may cause painful small-fiber neuropathy.

Mechanism of plasma cholesteryl ester transfer in hypertriglyceridemia.

Plasma net cholesteryl ester (CE) transfer and optimum cholesteryl ester transfer protein (CETP) activity were determined in primary hypertriglyceridemic (n = 11) and normolipidemic (n = 15) individuals. The hypertriglyceridemic group demonstrated threefold greater net CE transfer leading to enhanced accumulation of CE in VLDL. This increased net transfer was not accompanied by a change in CETP activity. In normolipidemia, but not in hypertriglyceridemia, net CE transfer correlated with VLDL triglyceride (r = 0.92, P less than 0.001). In contrast, net CE transfer in hypertriglyceridemia, but not in normolipidemia, correlated with CETP activity (r = 0.73, P less than 0.01). Correction of hypertriglyceridemia with bezafibrate reduced net CE transfer towards normal and restored the correlation with VLDL triglyceride (r = 0.90, P less than 0.005) while suppressing the correlation with CETP activity. That net CE transfer depends on VLDL concentration was confirmed by an increase of net CE transfer in normolipidemic plasma supplemented with purified VLDL. Supplementation of purified CETP to normolipidemic plasma did not stimulate net CE transfer. In contrast, net CE transfer was enhanced by addition of CETP to both plasma supplemented with VLDL and hypertriglyceridemic plasma. Thus, in normal subjects, VLDL concentration determines the rate of net CE transfer. CETP becomes rate limiting as VLDL concentration increases, i.e., in hypertriglyceridemia.