👤 Spencer Proctor

Polycystic ovary syndrome (PCOS) is associated with increased cardiometabolic risk in young women of reproductive age. There are limited studies on atherogenic dyslipidemia, inclusive of triglycerides (TG), Apolipoprotein (apo) B-lipoproteins and remnant-cholesterol (C), atherosclerotic cardiovascular disease (ACVD), cardiac function and remodeling in young women with and without PCOS. The aim of this pilot study was to investigate the relationship of atherogenic dyslipidemia and other cardiometabolic risk factors with ACVD, cardiac function-remodeling in high-risk young overweight-obese PCOS women compared to non-PCOS and healthy-weight controls. Women with and without PCOS (non-PCOS control) aged 18 - 45 years who were overweight and obese (>25kg/m PCOS (n=48) and non-PCOS control overweight-obese age-BMI matched groups (n=19) were shown to have significantly higher fasting and non-fasting lipids including TG, remnant-C, total ApoB and ApoB48, compared to healthy-weight non-PCOS controls (n=10). PCOS and non-PCOS control overweight-obese groups had significantly higher SBP, DBP, cIMT and evidence of cardiac dysfunction and remodeling, with reduced Mitral E/A ratio, intraventricular (IV) relaxation time and increased Left ventricle (LV) end diastolic and systolic diameter, LV posterior wall thickness and IV septal thickness, compared to healthy-weight non-PCOS controls. Individuals with PCOS had significantly higher fasting plasma TG and remnant-C compared to the non-PCOS overweight-obese control group. The PCOS group tended to have 25% higher carotid plaque height, although this was not significant, compared to the non-PCOS overweight-obese control group. DBP, HOMA-IR and ApoB predicted 40% of the variability in cIMT and ApoB was shown to predict 14% of the variability in carotid plaque height, independent of age and BMI. A 1mg/ml increase in ApoB was associated with a 0.041mm increase in cIMT and a 0.75mm increase in carotid plaque height in all young women. Our pilot results supports the potential of apoB-dyslipidemia, cIMT, carotid plaque height and left ventricular diastolic dysfunction and remodeling to be used in screening for CVD risk in high-risk populations such as overweight-obese women with and without PCOS. ApoB may be useful to predict atherosclerotic vascular burden and progression of cIMT and carotid plaque, and could be used to develop a female specific algorithm for ACVD risk in high-risk young women with and without PCOS. Show less

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids, fibrous elements, and cellular debris in the blood vessels. The response-to-retention hypothesis, the leading theory on the pathogenesis of this cardiovascular disease, describes the initial event in atherosclerosis as when Apolipoprotein B-containing lipoproteins, including endogenous and dietary-derived lipoproteins, bind to the inner arterial wall, the tunica intima. The subsequent lipoprotein modifications trigger an immune response that promotes atherosclerotic plaque formation. Despite the prevalence of atherosclerosis globally, and its vascular nature, therapies directed to the artery wall are limited. Immunotherapies, most notably monoclonal antibodies (mAbs), are of special interest due to their high specificity, reliability and proven success in a variety of diseases. However, current mAbs for atherosclerosis tend to target disease risk factors, notably inflammation and circulating lipoprotein levels, rather than address the root cause of atherosclerosis. These treatments result in a phenomenon known as residual risk, defined by the occurrence of severe cardiovascular events, including myocardial infarction, during treatment. Per the "response to retention" hypothesis, a plausible strategy for atherosclerosis would be blocking cholesterol retention Show less

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease, which goes along with increased risk for sudden cardiac death (SCD). Despite the knowledge about the different causal genes, the relationship between individual genotypes and phenotypes is incomplete. We retrieved PubMed/Medline literatures on genotype-phenotype associations in patients with HCM and mutations in MYBPC3, MYH7, TNNT2, and TNNI3. Altogether, 51 studies with 7675 HCM patients were included in our meta-analysis. The average frequency of mutations in MYBPC3 (20%) and MYH7 (14%) was higher than TNNT2 and TNNI3 (2% each). The mean age of HCM onset for MYH7 mutation positive patients was the beginning of the fourth decade, significantly earlier than patients without sarcomeric mutations. A high male proportion was observed in TNNT2 (69%), MYBPC3 (62%) and mutation negative group (64%). Cardiac conduction disease, ventricular arrhythmia and heart transplantation (HTx) rate were higher in HCM patients with MYH7 mutations in comparison to MYBPC3 (p < 0.05). Furthermore, SCD was significantly higher in patients with sarcomeric mutations (p < 0.01). A pooled dataset and a comprehensive genotype-phenotype analysis show that the age at disease onset of HCM patients with MYH7 is earlier and leads to a more severe phenotype than in patient without such mutations. Furthermore, patients with sarcomeric mutations are more susceptible to SCD. The present study further supports the clinical interpretation of sarcomeric mutations in HCM patients. Show less

In Akita and OVE26 mice, two genetic models of type 1 diabetes, diabetic nephropathy is characterized by mesangial expansion and loss of podocytes, resulting in glomerulosclerosis and proteinuria, and is associated with increased expression of profibrotic growth factors, proinflammatory cytokines, and increased oxidative stress. We have also found significant increases in renal triglyceride and cholesterol content. The increase in renal triglyceride content is associated with 1) increased expression of sterol regulatory element-binding protein (SREBP)-1c and carbohydrate response element-binding protein (ChREBP), which collectively results in increased fatty acid synthesis, 2) decreased expression of peroxisome proliferator-activated receptor (PPAR)-alpha and -delta, which results in decreased fatty acid oxidation, and 3) decreased expression of farnesoid X receptor (FXR) and small heterodimer partner (SHP). The increase in cholesterol content is associated with 1) increased expression of SREBP-2 and 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, which results in increased cholesterol synthesis, and 2) decreased expression of liver X receptor (LXR)-alpha, LXR-beta, and ATP-binding cassette transporter-1, which results in decreased cholesterol efflux. Our results indicate that in type 1 diabetes, there is altered renal lipid metabolism favoring net accumulation of triglycerides and cholesterol, which are driven by increases in SREBP-1, ChREBP, and SREBP-2 and decreases in FXR, LXR-alpha, and LXR-beta, which may also play a role in the increased expression of profibrotic growth hormones, proinflammatory cytokines, and oxidative stress. Show less