Gotowa bibliografia na temat „Cholesterol Physiological effect”

Lipid metabolism has gained cardiological interest only after statins were demonstrated to reduce cardiovascular disease in secondary and primary prevention. Therefore, this chapter first introduces the physiological and atherogenic properties of lipoproteins, before focusing on interventions. Both the efficacy and safety of statins have been proven in numerous randomized clinical trials. Because there is a considerable residual risk in statin-treated patients, additional approaches have been investigated. The focus is now on further reductions in low-density lipoprotein (LDL) cholesterol levels. First, high-intensity statin regimens were shown to reduce residual risk. Subsequently, ezetimibe was demonstrated, for the first time, to have a beneficial effect as a non-statin lipid intervention. More recently, inhibitors of the enzyme PCSK9 have demonstrated a very high efficacy in reducing LDL cholesterol levels. Although the causality of LDL for atherosclerotic cardiovascular disease has been proven in epidemiological studies, including Mendelian randomization studies, as well as interventional trials, adherence to statins and other therapies is far from optimal. In contrast, interventions to increase high-density lipoprotein (HDL) cholesterol levels could not proven to have further benefits when combined with statins.

Lipid metabolism has gained cardiological interest only after statins were demonstrated to reduce cardiovascular disease in secondary and primary prevention. Therefore, this chapter first introduces the physiological and atherogenic properties of lipoproteins, before focusing on interventions. Both the efficacy and safety of statins have been proven in numerous randomized clinical trials. Because there is a considerable residual risk in statin-treated patients, additional approaches have been investigated. The focus is now on further reductions in low-density lipoprotein (LDL) cholesterol levels. First, high-intensity statin regimens were shown to reduce residual risk. Subsequently, ezetimibe was demonstrated, for the first time, to have a beneficial effect as a non-statin lipid intervention. More recently, inhibitors of the enzyme PCSK9 have demonstrated a very high efficacy in reducing LDL cholesterol levels. Although the causality of LDL for atherosclerotic cardiovascular disease has been proven in epidemiological studies, including Mendelian randomization studies, as well as interventional trials, adherence to statins and other therapies is far from optimal. In contrast, interventions to increase high-density lipoprotein (HDL) cholesterol levels could not proven to have further benefits when combined with statins.

High blood cholesterol and high blood triglycerides are causal risk factors for atherosclerotic cardiovascular disease, which remains the leading cause of death in the developed world. Lipid and lipoprotein metabolism—cholesterol, triglycerides, and fat-soluble vitamins are transported with specific proteins in the blood as multimeric complexes called lipoproteins. Lipid and lipoprotein metabolism are effected by three principal physiological processes: (1) intestinal absorption of dietary lipid and transport in the blood of dietary lipid and lipids, principally derived from the liver (as triglyceride-rich lipoproteins) to peripheral tissues for catabolism by skeletal and cardiac muscle or storage in adipose tissue; (2) return of triglyceride-rich lipoprotein remnants to the liver, hepatic synthesis of low-density lipoprotein, and the transport of cholesterol between peripheral tissues and the liver; and (3) reverse cholesterol transport by high-density lipoprotein (HDL) between peripheral tissues and the liver. Dyslipidaemias are disorders of lipoprotein metabolism in which there is elevation of total cholesterol and/or triglycerides, often accompanied by reduced levels of HDL cholesterol. Causes of dyslipidaemia—particular lipid disorders including polygenic hypercholesterolaemia, familial hypercholesterolaemia, combined hypercholesterolaemia and hypertriglyceridaemia, familial combined hyperlipidaemia, familial dysbetalipoproteinaemia (also called type 3 hyperlipoproteinaemia), and severe hypertriglyceridaemia, as well as secondary or aggravating factors. Management of dyslipidaemia—the key questions are: (1) what classes of lipoproteins and lipids are increased or decreased in the patient’s plasma? (2) Does the patient has a primary (genetic) or secondary (acquired) dyslipidaemia (often contributions from both influences)? (3) Is the patient at risk of atherosclerotic cardiovascular disease or acute pancreatitis? (4) What other risk factors (e.g. hypertension or diabetes) are present? (5) What treatments might be used to address these abnormalities?

Physiologically, in the presence of an intracellular deficit of cholesterol, the LDLR synthesis, expression and function increase, thus uptaking and providing cholesterol to the cell. This process is counter-regulated by PCSK9 expression, the protease inducing LDLR proteolysis, thereby limiting its function maintaining a constant cholesterol intracellular concentration. Accordingly, the balance between PCSK9 and LDLR regulates the intracellular concentration of cholesterol and in consequence has impact on circulating LDL-cholesterol. This chapter reviews the brief and amazing recent history with PCSK9 inhibition from basic science to current clinical recommendations for MAbs-PCSK9. In 2003 and 2005, respectively, the pcsk9 gene mutations, determinants of the “gain of function” of PCSK9 and severe hypercholesterolemia, and the pcsk9 gene mutations with “loss of function” of PCSK9, determinants of hypocholesterolemia were described; subsequently, in 2006, the association between the pcsk9 gene mutations and the “loss of function” of PCSK9 with hypocholesterolemia and reduction of up to 88% for the risk of a coronary event in the “mutant” population versus the control population was published. Since evolocumab clinical research program has completed and published their phases I, II and III results including its cardiovascular outcomes trial, this chapter is focused in reviewing the results of evolocumab clinical research program. In 2009, the effect of a “full human” monoclonal antibody vs PCSK9 in mice and non-human primates was first reported; MAb-PCSK9, AMG-145 (evolocumab) produced in cynomolgus monkeys a doubling in the number of LDLR and an average 75% reduction in circulating LDL-cholesterol. In 2012, the first phase I study with evolocumab versus placebo were reported; this program informed very significant reductions in LDLcholesterol in healthy subjects and patients with familial and non-familial hyper cholesterolemia treated without/with statins; tolerability and safety of evolocumab were similar to placebo. With this evidence, the phase II and III investigations with evolocumab initiated; four years later, the OSLER trial allowed us to envisage the following scenario: MAb-PCSK9 evolocumab have a favorable effect on LDLcholesterol, other apo-B100 lipoproteins and overall mortality and myocardial infarction; all the aforementioned with a very favorable safety and tolerability profile. In the same direction, in 2016 was published the GLAGOV trial, wich demonstrates for the first time that the addition of a non-statin therapy -evolocumab- to the optimal treatment with statins is associated with atheroregression; and finally, in 2017, the FOURIER and the EBBINGHAUS trials were presented, wich confirmed that the addition of evolocumab to the optimal treatment with statins is associated with an additional and significant 20% relative risk reduction -26 months of follow-up- for cardiovascular mortality, myocardial infarction and/or ischemic stroke, all without neurocognitive risk. Beyond the currently approved indications by regulatory agencies, considering the high cost of PCSK9 inhibitors and financial restraints within healthcare budgets, for now and before definitive and necessary cost-effectiveness analysis and price optimization are in place, evolocumab is recommended in specific clinical scenarios reviewed in this chapter.

Elastin is a protein in the extracellular matrix that provides critical mechanical properties of elasticity and extensibility to many connective tissues, including arteries. Such properties of elastin allow arteries to accommodate deformations encountered during physiological functions. Elastin is subjected to changes in mechanical properties upon exposure to various chemical environments. Elastin is a hydrophobic protein, which makes it an attractive site for the deposition of hydrophobic ligands such as cholesterol [1]. Cholesterol is a type of lipid that gradually builds up along arterial w

ABSTRACT Background: Kebo rubber leaves (ficus elastica roxb) contain flavonoids, polyphenols, and tannins. Flavonoids in the leaves of ficus elastica roxb such as catechins, isoflavones are polyphenolic antioxidants from plant metabolites. The leaves of ficus elastica roxb are trusted and proven empirically in the community to reduce cholesterol levels in the blood. Mice choose animals because they are considered to have physiological similarities with humans. This study aimed to determine the effect of ethanol extract of ficus elastica roxb leaves on reducing total cholesterol level in male

The increase in the clinical manifestations of coronary artery disease (CAD) since the 1920s cannot be explained solely in terms of atheroma. Another major process such as thrombogenesis must also be involved. Pathological studies show that thrombosis contributes not only to myocardial infarction but to nearly all cases of sudden coronary death as well. Epidemiologically, it is the coagulation system rather than platelet function that has so far been more rewarding in attempting to identify characteristics of the haemostatic system that are associated with the subsequent risk of CAD. In partic