To discuss the recent developments in structure, function and physiology of lipoprotein lipase (LpL) and the regulators of LpL, which are being targeted for therapy.
Recent studies have revealed the ...long elusive crystal structure of LpL and its interaction with glycosylphosphatidylinositol anchored high-density lipoprotein binding protein 1 (GPIHBP1). New light has been shed on LpL being active as a monomer, which brings into questions previous thinking that LpL inhibitors like angiopoietin-like 4 (ANGPTL4) and stabilizers like LMF1 work on disrupting or maintaining LpL in dimer form. There is increasing pharmaceutical interest in developing targets to block LpL inhibitors like ANGPTL3. Other approaches to reducing circulating triglyceride levels have been using an apoC2 mimetic and reducing apoC3.
Lipolysis of triglyceride-rich lipoproteins by LpL is a central event in lipid metabolism, releasing fatty acids for uptake by tissues and generating low-density lipoprotein and expanding high-density lipoprotein. Recent mechanistic insights into the structure and function of LpL have added to our understanding of triglyceride metabolism. This has also led to heightened interest in targeting its posttranslational regulators, which can be the next generation of lipid-lowering agents used to prevent hypertriglyceridemic pancreatitis and, hopefully, cardiovascular disease.
Abstract
Background
Various patient demographic and clinical characteristics have been associated with poor outcomes for individuals with coronavirus disease 2019 (COVID-19). To describe the ...importance of age and chronic conditions in predicting COVID-19-related outcomes.
Methods
Search strategies were conducted in PubMed/MEDLINE. Daily alerts were created.
Results
A total of 28 studies met our inclusion criteria. Studies varied broadly in sample size (n = 21 to more than 17,000,000). Participants’ mean age ranged from 48 years to 80 years, and the proportion of male participants ranged from 44% to 82%. The most prevalent underlying conditions in patients with COVID-19 were hypertension (range: 15%–69%), diabetes (8%–40%), cardiovascular disease (CVD) (4%–61%), chronic pulmonary disease (1%–33%), and chronic kidney disease (range 1%–48%). These conditions were each associated with an increased in-hospital case fatality rate (CFR) ranging from 1% to 56%. Overall, older adults have a substantially higher case fatality rate (CFR) as compared to younger individuals affected by COVID-19 (42% for those <65 vs 65% > 65 years). Only one study examined the association of chronic conditions and the risk of dying across different age groups; their findings suggested similar trends of increased risk in those < 65 years and those > 65 years as compared to those without these conditions.
Conclusions
There has been a traditional, single-condition approach to consideration of how chronic conditions and advancing age relate to COVID-19 outcomes. A more complete picture of the impact of burden of multimorbidity and advancing patient age is needed.
Despite the decades-old knowledge that diabetes mellitus is a major risk factor for cardiovascular disease, the reasons for this association are only partially understood. While this association is ...true for both type 1 and type 2 diabetes, different pathophysiological processes may be responsible. Lipids and other risk factors are indeed important, whereas the role of glucose is less clear. This lack of clarity stems from clinical trials that do not unambiguously show that intensive glycemic control reduces cardiovascular events. Animal models have provided mechanisms that link diabetes to increased atherosclerosis, and evidence consistent with the importance of factors beyond hyperglycemia has emerged. We review clinical, pathological, and animal studies exploring the pathogenesis of atherosclerosis in humans living with diabetes and in mouse models of diabetes. An increased effort to identify risk factors beyond glucose is now needed to prevent the increased cardiovascular disease risk associated with diabetes.
Diabetes increases cardiovascular disease risk, but the reasons for the association are not fully understood. Here, Eckel et al. review clinical and animal studies that explore the pathogenesis of atherosclerosis in the diabetes context. They discuss the need to identify and understand risk factors beyond glucose in order to prevent increased cardiovascular disease risk in diabetes.
Lipid Use and Misuse by the Heart Schulze, P Christian; Drosatos, Konstantinos; Goldberg, Ira J
Circulation research,
2016-May-27, Volume:
118, Issue:
11
Journal Article
Peer reviewed
Open access
The heart utilizes large amounts of fatty acids as energy providing substrates. The physiological balance of lipid uptake and oxidation prevents accumulation of excess lipids. Several processes that ...affect cardiac function, including ischemia, obesity, diabetes mellitus, sepsis, and most forms of heart failure lead to altered fatty acid oxidation and often also to the accumulation of lipids. There is now mounting evidence associating certain species of these lipids with cardiac lipotoxicity and subsequent myocardial dysfunction. Experimental and clinical data are discussed and paths to reduction of toxic lipids as a means to improve cardiac function are suggested.
Between 40% and 60% of Americans use complementary and alternative medicine to manage medical conditions, prevent disease, and promote health and well-being. Omega-3 polyunsaturated fatty acids ...(omega-3 PUFAs) have been used to treat joint pain associated with several inflammatory conditions. We conducted a meta-analysis of 17 randomized, controlled trials assessing the pain relieving effects of omega-3 PUFAs in patients with rheumatoid arthritis or joint pain secondary to inflammatory bowel disease and dysmenorrhea. Meta-analysis was conducted with Cochrane Review Manager 4.2.8. for six separate outcomes using standardized mean differences (SMDs) as a measure of effect size: (1) patient assessed pain, (2) physician assessed pain, (3) duration of morning stiffness, (4) number of painful and/or tender joints, (5) Ritchie articular index, and (6) nonselective nonsteroidal anti-inflammatory drug consumption. Supplementation with omega-3 PUFAs for 3-4 months reduces patient reported joint pain intensity (SMD: -0.26; 95% CI: -0.49 to -0.03, p=0.03), minutes of morning stiffness (SMD: -0.43; 95% CI: -0.72 to -0.15, p=0.003), number of painful and/or tender joints (SMD: -0.29; 95% CI: -0.48 to -0.10, p=0.003), and NSAID consumption (SMD: -0.40; 95% CI: -0.72 to -0.08, p=0.01). Significant effects were not detected for physician assessed pain (SMD: -0.14; 95% CI: -0.49 to 0.22, p=0.45) or Ritchie articular index (SMD: 0.15; 95% CI: -0.19 to 0.49, p=0.40) at 3-4 months. The results suggest that omega-3 PUFAs are an attractive adjunctive treatment for joint pain associated with rheumatoid arthritis, inflammatory bowel disease, and dysmenorrhea.
Abstract Heart disease was an uncommon cause of death in the US at the beginning of the 20th century. By mid-century it had become the commonest cause. After peaking in the mid-1960s, the number of ...heart disease deaths began a marked decline that has persisted to the present. The increase in heart disease deaths from the early 20th century until the 1960s was due to an increase in the prevalence of coronary atherosclerosis with resultant coronary heart disease, as documented by autopsy studies. This increase was associated with an increase in smoking and dietary changes leading to an increase in serum cholesterol levels. In addition, the ability to diagnose acute myocardial infarction with the aid of the electrocardiogram increased the recognition of coronary heart disease before death. The substantial decrease in coronary heart disease deaths after the mid-1960s is best explained by the decreased incidence, and case fatality rate, of acute myocardial infarction and a decrease in out-of-hospital sudden coronary heart disease deaths. These decreases are very likely explained by a decrease in coronary atherosclerosis due to primary prevention, and a decrease in the progression of nonobstructive coronary atherosclerosis to obstructive coronary heart disease due to efforts of primary and secondary prevention. In addition, more effective treatment of patients hospitalized with acute myocardial infarction has led to a substantial decrease in deaths due to acute myocardial infarction. It is very likely that the 20th century was the only century in which heart disease was the most common cause of death in America.
Abstract Background The clinical epidemiology of venous thromboembolism has changed recently because of advances in identification, prophylaxis, and treatment. We sought to describe secular trends in ...the occurrence of venous thromboembolism among residents of the Worcester, Massachusetts, metropolitan statistical area. Methods Population-based methods were used to monitor trends in event rates of first-time or recurrent venous thromboembolism in 5025 Worcester, Massachusetts, metropolitan statistical area residents who were diagnosed with acute pulmonary embolism or lower-extremity deep vein thrombosis during 9 annual periods between 1985 and 2009. Medical records were reviewed by abstractors and validated by clinicians. Results Age- and sex-adjusted annual event rates for first-time venous thromboembolism increased from 73 (95% confidence interval CI, 64-82) per 100,000 in 1985/1986 to 133 (CI, 122-143) in 2009, primarily because of an increase in pulmonary embolism. The rate of recurrent venous thromboembolism decreased from 39 (CI, 32-45) in 1985/1986 to 19 (CI, 15-23) in 2003, and then increased to 35 (CI, 29-40) in 2009. There was an increasing trend in using noninvasive diagnostic testing, with approximately half of tests being invasive in 1985/1986 and almost all noninvasive by 2009. Conclusions Despite advances in identification, prophylaxis, and treatment between 1985 and 2009, the annual event rate of venous thromboembolism has increased and remains high. Although these increases partially may be due to increased sensitivity of diagnostic methods, especially for pulmonary embolism, they also may imply that current prevention and treatment strategies are less than optimal.
CD36 is a multifunctional immuno-metabolic receptor with many ligands. One of its physiological functions in the heart is the high-affinity uptake of long-chain fatty acids (FAs) from albumin and ...triglyceride rich lipoproteins. CD36 deletion markedly reduces myocardial FA uptake in rodents and humans. The protein is expressed on endothelial cells and cardiomyocytes and at both sites is likely to contribute to FA uptake by the myocardium. CD36 also transduces intracellular signaling events that influence how the FA is utilized and mediate metabolic effects of FA in the heart. CD36 transduced signaling regulates AMPK activation in a way that adjusts oxidation to FA uptake. It also impacts remodeling of myocardial phospholipids and eicosanoid production, effects exerted via influencing intracellular calcium (iCa2+) and the activation of phospholipases. Under excessive FA supply CD36 contributes to lipid accumulation, inflammation and dysfunction. However, it is also important for myocardial repair after injury via its contribution to immune cell clearance of apoptotic cells. This review describes recent progress regarding the multiple actions of CD36 in the heart and highlights those areas requiring future investigation. This article is part of a Special Issue entitled: Heart Lipid Metabolism edited by G.D. Lopaschuk.
•Importance of CD36 for cardiac metabolic flexibility•CD36 maintains AMPK quiescent.•Fatty acid uptake signals to upregulate fatty acid oxidation.•Cytosolic calcium and myocardial phospholipid metabolism•CD36 contributes to inflammation and its resolution in the heart.
Renal fibrosis is the histological manifestation of a progressive, usually irreversible process causing chronic and end-stage kidney disease. We performed genome-wide transcriptome studies of a large ...cohort (n = 95) of normal and fibrotic human kidney tubule samples followed by systems and network analyses and identified inflammation and metabolism as the top dysregulated pathways in the diseased kidneys. In particular, we found that humans and mouse models with tubulointerstitial fibrosis had lower expression of key enzymes and regulators of fatty acid oxidation (FAO) and higher intracellular lipid deposition compared to controls. In vitro experiments indicated that inhibition of FAO in tubule epithelial cells caused ATP depletion, cell death, dedifferentiation and intracellular lipid deposition, phenotypes observed in fibrosis. In contrast, restoring fatty acid metabolism by genetic or pharmacological methods protected mice from tubulointerstitial fibrosis. Our results raise the possibility that correcting the metabolic defect in FAO may be useful for preventing and treating chronic kidney disease.
Despite the success of LDL-lowering drugs in reducing cardiovascular disease (CVD), there remains a large burden of residual disease due in part to persistent dyslipidemia characterized by elevated ...levels of triglyceride-rich lipoproteins (TRLs) and reduced levels of HDL. This form of dyslipidemia is increasing globally as a result of the rising prevalence of obesity and metabolic syndrome. Accumulating evidence suggests that impaired hepatic clearance of cholesterol-rich TRL remnants leads to their accumulation in arteries, promoting foam cell formation and inflammation. Low levels of HDL may associate with reduced cholesterol efflux from foam cells, aggravating atherosclerosis. While fibrates and fish oils reduce TRL, they have not been uniformly successful in reducing CVD, and there is a large unmet need for new approaches to reduce remnants and CVD. Rare genetic variants that lower triglyceride levels via activation of lipolysis and associate with reduced CVD suggest new approaches to treating dyslipidemia. Apolipoprotein C3 (APOC3) and angiopoietin-like 3 (ANGPTL3) have emerged as targets for inhibition by antibody, antisense, or RNAi approaches. Inhibition of either molecule lowers TRL but respectively raises or lowers HDL levels. Large clinical trials of such agents in patients with high CVD risk and elevated levels of TRL will be required to demonstrate efficacy of these approaches.
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