Relationship between moderate-to-vigorous physical activity, abdominal fat and immunometabolic markers in postmenopausal women

AbstractObjectsTo assess the burden of levels of physical activity, non-esterified fatty acids (NEFA), triacylglycerol and abdominal fat on the immunometabolic profile of postmenopausal women.Study designForty-nine postmenopausal women [mean age 59.43 (standard deviation 5.61) years] who did not undertake regular physical exercise participated in this study. Body composition was assessed using dual-energy X-ray absorptiometry, and levels of NEFA, tumour necrosis factor-α, adiponectin, insulin and triacylglycerol were assessed using fasting blood samples. The level of physical activity was assessed using an accelerometer (Actigraph GTX3x), and reported as counts/min, time spent undertaking sedentary activities and time spent undertaking moderate-to-vigorous physical activity (MVPA). The following conditions were considered to be risk factors: (i) sedentary lifestyle (<150min of MVPA per week); (ii) high level (above median) of abdominal fat; and (iii) hypertriacylglycerolaemia (<150mg/dl of triacylglycerol).ResultsIn comparison with active women, sedentary women had higher levels of body fat (%) (p=0.041) and NEFA (p=0.064). Women with higher levels of abdominal fat had impaired insulin resistance (HOMA-IR) (p=0.016) and spent more time undertaking sedentary activities (p=0.043). Moreover, the women with two risk factors or more had high levels of NEFA and HOMA-IR (p<0.05), as well as an eight-fold higher risk of a high level of NEFA, independent of age (p<0.05). No significant relationship was found between levels of physical activity, abdominal fat, tumour necrosis factor-α and adiponectin (p>0.05).ConclusionPostmenopausal women with a combination of hypertriacylglycerolaemia, a high level of abdominal fat and a sedentary lifestyle are more likely to have metabolic disturbances

Low‐Density Lipoprotein Cholesterol Attributable Cardiovascular Disease Risk Is Sex Specific

Background: Epidemiological studies show that women are generally at lower risk for cardiovascular disease than men. Here, we investigated the sex‐specific differential effect of genetically increased low‐density lipoprotein cholesterol (LDL‐C) on cardiovascular disease (CVD) and other lipid‐associated diseases. Methods and Results: This is a 2‐sample Mendelian randomization study that uses individual participant data from 425 043 participants from the UK Biobank, including 229 279 female participants. An 80‐variant LDL‐C weighted genetic score was generated. Linear and logistic regression models with interactions were used to identify differences between sex‐specific LDL‐C effects on lipids, carotid‐intima media thickness, and multiple cardiovascular outcomes such as CVD, ischemic heart disease, peripheral artery disease, heart failure, aortic valve disease, type 2 diabetes, atrial fibrillation, and aortic aneurysm and dissection. After correction for multiple testing, we observed that the genetically increased LDL‐C effect on CVD events was sex specific: per SD genetically increased LDL‐C, female participants had a higher LDL‐C increase but an attenuated CVD risk increase compared with male participants (LDL‐C: female participants 0.71 mmol/L, 95% CI, 0.70–0.72 and male participants 0.57 mmol/L, 95% CI, 0.56–0.59. P for interaction: 5.03×10−60; CVD: female participants: odds ratio [OR], 1.32; 95% CI 1.24–1.40 and male participants: OR, 1.52; 95% CI, 1.46–1.58. P for interaction: 9.88×10−5). We also observed attenuated risks for ischemic heart disease and (nominally for) heart failure in female participants, and genetically increased LDL‐C results in higher risk for aortic valve disease in female participants compared with male participants. Genetically increased LDL‐C was also associated with an attenuated carotid‐intima media thickness increase in female participants. We did not observe other significant attenuations. Sensitivity analyses with an unweighted genetic score and sex‐specific weighted genetic scores showed similar results. Conclusions: We found that genetically increased LDL‐C has a sex‐specific differential effect on the risk for cardiovascular disease, ischemic heart disease, heart failure, and aortic valve stenosis. Our observations provide evidence that LDL‐C might be a less important determinant of CVD in women compared with men, suggesting that male patients might benefit more from LDL‐C targeted therapies for CVD management than female patients and warranting investigations into the sex‐specific relative contribution of risk factors for CVD

Genetically Predicted Neutrophil-to-Lymphocyte Ratio and Coronary Artery Disease: Evidence From Mendelian Randomization.

Inflammation contributes to atherosclerosis and coronary artery disease (CAD). In order to help identify therapeutic targets, it is important to ascertain whether biomarkers associated with CAD risk are causal. In a recent meta-analysis of clinical trials, neutrophil-to lymphocyte ratio (NLR) was associated with increased cardiovascular risk 1 . We investigate a potential causal nature of this relationship by performing Mendelian randomization (MR) analyse

Impact of statin therapy on coronary plaque composition: A systematic review and meta-analysis of virtual histology intravascular ultrasound studies

Background: Virtual histology intravascular ultrasound (VH-IVUS) imaging is an innovative tool for the morphological evaluation of coronary atherosclerosis. Evidence for the effects of statin therapy on VH-IVUS parameters have been inconclusive. Consequently, we performed a systematic review and meta-analysis to investigate the impact of statin therapy on plaque volume and its composition using VH-IVUS. Methods: The search included PubMed, Cochrane Library, Scopus and Embase (through 30 November 2014) to identify prospective studies investigating the effects of statin therapy on plaque volume and its composition using VH-IVUS. Results: We identified nine studies with 16 statin treatment arms and 830 participants. There was a significant effect of statin therapy in reducing plaque volume (standardized mean difference (SMD): -0.137, 95 % confidence interval (CI): -0.255, -0.019; P = 0.023), external elastic membrane volume (SMD: -0.097, 95 % CI: -0.183, -0.011; P = 0.027) but not lumen volume (SMD: -0.025, 95 % CI: -0.110, +0.061; P = 0.574). There was a significant reduction in fibrous plaque volume (SMD: -0.129, 95 % CI: -0.255, -0.003; P = 0.045) and an increase of dense calcium volume (SMD: +0.229, 95 % CI: +0.008, +0.450

Segmental volvulus of the ileum without malrotation in an infant: A case report

AbstractIntestinal volvulus usually occur secondary to malrotation, and primary segmental volvulus has rarely been reported. A 12-month-old female infant presented with a 3-day history of excessive vomiting. An ultrasonography revealed a “whirlpool sign” in the right upper abdomen, suggesting small bowel volvulus with obstruction. Laparotomy revealed a twisted, viable loop of small bowel in the right upper abdomen, and abnormal adhesions were noted between the distal and mid ileum, with resulting mesenteric narrowing. Attempted mesenteric widening by dissection of the peritoneum overlying the adhesions failed, because of abnormal, taut mesenteric vessels. Subsequent resection of the involved segment cured the patient. Recurrent obstructive symptoms in an infant can be an atypical presentation of segmental volvulus, and segmental volvulus should be included in the differential diagnosis of such cases

Association of High-Density Lipoprotein-Cholesterol Versus Apolipoprotein A-I With Risk of Coronary Heart Disease: The European Prospective Investigation Into Cancer-Norfolk Prospective Population Study, the Atherosclerosis Risk in Communities Study, and the Women's Health Study.

BACKGROUND: The contribution of apolipoprotein A-I (apoA-I) to coronary heart disease (CHD) risk stratification over and above high-density lipoprotein cholesterol (HDL-C) is unclear. We studied the associations between plasma levels of HDL-C and apoA-I, either alone or combined, with risk of CHD events and cardiovascular risk factors among apparently healthy men and women. METHODS AND RESULTS: HDL-C and apoA-I levels were measured among 17 661 participants of the EPIC (European Prospective Investigation into Cancer)-Norfolk prospective population study. Hazard ratios for CHD events and distributions of risk factors were calculated by quartiles of HDL-C and apoA-I. Results were validated using data from the ARIC (Atherosclerosis Risk in Communities) and WHS (Women's Health Study) cohorts, comprising 15 494 and 27 552 individuals, respectively. In EPIC-Norfolk, both HDL-C and apoA-I quartiles were strongly and inversely associated with CHD risk. Within HDL-C quartiles, higher apoA-I levels were not associated with lower CHD risk; in fact, CHD risk was higher within some HDL-C quartiles. ApoA-I levels were associated with higher levels of CHD risk factors: higher body mass index, HbA1c, non-HDL-C, triglycerides, apolipoprotein B, systolic blood pressure, and C-reactive protein, within fixed HDL-C quartiles. In contrast, HDL-C levels were consistently inversely associated with overall CHD risk and CHD risk factors within apoA-I quartiles (P<0.001). These findings were validated in the ARIC and WHS cohorts. CONCLUSIONS: Our findings demonstrate that apoA-I levels do not offer predictive information over and above HDL-C. In fact, within some HDL-C quartiles, higher apoA-I levels were associated with higher risk of CHD events, possibly because of the unexpected higher prevalence of cardiovascular risk factors in association with higher apoA-I levels. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00000479

Dissecting the IL-6 pathway in cardiometabolic disease: A Mendelian randomization study on both IL6 and IL6R

Aims: Chronic inflammation is a risk factor for cardiovascular disease (CVD). IL-6 signalling perturbation through IL-6 or IL-6R blockade may have potential benefit on cardiovascular risk. It is unknown whether targeting either IL-6 or IL-6 receptor may result in similar effects on CVD and adverse events. We compared the anticipated effects of targeting IL-6 and IL-6 receptor on cardiometabolic risk and potential side effects. // Methods: We constructed four instruments: two main instruments with genetic variants in the IL6 and IL6R loci weighted for their association with CRP, and two after firstly filtering variants for their association with IL-6 or IL-6R expression. Analyses were performed for coronary artery disease (CAD), ischemic stroke, atrial fibrillation (AF), heart failure, type 2 diabetes (T2D), rheumatoid arthritis (RA), infection endpoints, and quantitative haematological, metabolic and anthropometric parameters. // Results: A 1 mg/L lower CRP by the IL6 instrument was associated with lower CAD (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.77;0.96), AF and T2D risk. A 1 mg/L lower CRP by the IL6R instrument was associated with lower CAD (OR 0.90, 95% CI 0.86;0.95), any stroke and ischemic stroke, AF, RA risk and higher pneumonia risk. The eQTL-filtered results were in concordance with the main results, but with wider confidence intervals. // Conclusions: IL-6 signalling perturbation by either IL6 or IL6R genetic instruments is associated with a similar risk reduction for multiple cardiometabolic diseases, suggesting that both IL-6 and IL-6R are potential therapeutic targets to lower CVD. Moreover, IL-6 rather than IL-6R inhibition might have a more favourable pneumonia risk

A genetic risk score is associated with statin-induced low-density lipoprotein cholesterol lowering

To find new genetic loci associated with statin response, and to investigate the association of a genetic risk score (GRS) with this outcome. In a discovery meta-analysis (five studies, 1991 individuals), we investigated the effects of approximately 50000 single nucleotide polymorphisms on statin response, following up associations with p < 1 × 10(-4) (three independent studies, 5314 individuals). We further assessed the effect of a GRS based on SNPs in ABCG2, LPA and APOE. No new SNPs were found associated with statin response. The GRS was associated with reduced statin response: 0.0394 mmol/l per allele (95% CI: 0.0171-0.0617, p = 5.37 × 10(-4)). The GRS was associated with statin response, but the small effect size (˜2% of the average low-density lipoprotein cholesterol reduction) limits applicabilit

Genetic evidence implicating natriuretic peptide receptor-3 in cardiovascular disease risk : a Mendelian randomization study

AbstractBackground: C-type natriuretic peptide (CNP) is a known target for promoting growth and has been implicated as a therapeutic opportunity for the prevention and treatment of cardiovascular disease (CVD). This study aimed to explore the effect of CNP on CVD risk using the Mendelian randomization (MR) framework.Methods: Instrumental variables mimicking the effects of pharmacological intervention on CNP were identified as uncorrelated genetic variants located in the genes coding for its primary receptors, natriuretic peptide receptors-2 and 3 (NPR2 and NPR3), that associated with height. We performed MR and colocalization analyses to investigate the effects of NPR2 signalling and NPR3 function on CVD outcomes and risk factors. MR estimates were compared to those obtained when considering height variants from throughout the genome.Results: Genetically-proxied reduced NPR3 function was associated with a lower risk of CVD, with odds ratio (OR) 0.74 per standard deviation (SD) higher NPR3-predicted height, and 95% confidence interval (95% CI) 0.64–0.86. This effect was greater in magnitude than observed when considering height variants from throughout the genome. For CVD subtypes, similar MR associations for NPR3-predicted height were observed when considering the outcomes of coronary artery disease (0.75, 95% CI 0.60–0.92), stroke (0.69, 95% CI 0.50–0.95) and heart failure (0.77, 95% CI 0.58–1.02). Consideration of CVD risk factors identified systolic blood pressure (SBP) as a potential mediator of the NPR3-related CVD risk lowering. For stroke, we found that the MR estimate for NPR3 was greater in magnitude than could be explained by a genetically predicted SBP effect alone. Colocalization results largely supported the MR findings, with no evidence of results being driven by effects due to variants in linkage disequilibrium. There was no MR evidence supporting effects of NPR2 on CVD risk, although this null finding could be attributable to fewer genetic variants being identified to instrument this target.Conclusions: This genetic analysis supports the cardioprotective effects of pharmacologically inhibiting NPR3 receptor function, which is only partly mediated by an effect on blood pressure. There was unlikely sufficient statistical power to investigate the cardioprotective effects of NPR2 signalling. Abstract Background: C-type natriuretic peptide (CNP) is a known target for promoting growth and has been implicated as a therapeutic opportunity for the prevention and treatment of cardiovascular disease (CVD). This study aimed to explore the effect of CNP on CVD risk using the Mendelian randomization (MR) framework. Methods: Instrumental variables mimicking the effects of pharmacological intervention on CNP were identified as uncorrelated genetic variants located in the genes coding for its primary receptors, natriuretic peptide receptors-2 and 3 (NPR2 and NPR3), that associated with height. We performed MR and colocalization analyses to investigate the effects of NPR2 signalling and NPR3 function on CVD outcomes and risk factors. MR estimates were compared to those obtained when considering height variants from throughout the genome. Results: Genetically-proxied reduced NPR3 function was associated with a lower risk of CVD, with odds ratio (OR) 0.74 per standard deviation (SD) higher NPR3-predicted height, and 95% confidence interval (95% CI) 0.64–0.86. This effect was greater in magnitude than observed when considering height variants from throughout the genome. For CVD subtypes, similar MR associations for NPR3-predicted height were observed when considering the outcomes of coronary artery disease (0.75, 95% CI 0.60–0.92), stroke (0.69, 95% CI 0.50–0.95) and heart failure (0.77, 95% CI 0.58–1.02). Consideration of CVD risk factors identified systolic blood pressure (SBP) as a potential mediator of the NPR3-related CVD risk lowering. For stroke, we found that the MR estimate for NPR3 was greater in magnitude than could be explained by a genetically predicted SBP effect alone. Colocalization results largely supported the MR findings, with no evidence of results being driven by effects due to variants in linkage disequilibrium. There was no MR evidence supporting effects of NPR2 on CVD risk, although this null finding could be attributable to fewer genetic variants being identified to instrument this target. Conclusions: This genetic analysis supports the cardioprotective effects of pharmacologically inhibiting NPR3 receptor function, which is only partly mediated by an effect on blood pressure. There was unlikely sufficient statistical power to investigate the cardioprotective effects of NPR2 signalling

Global disparities in access to lipid-lowering therapies for patients with homozygous familial hypercholesterolemia – A physician survey

BACKGROUND: Lipid levels and atherosclerotic cardiovascular disease (ASCVD) outcomes have been shown to differ globally in patients with homozygous familial hypercholesterolemia (HoFH), which may be related to availability and accessibility of lipid-lowering therapy (LLT). OBJECTIVE:In the current study, we investigated global disparities in availability and accessibility of LLTs for patients with HoFH. METHODS: Physicians participating in the HoFH International Clinical Collaborators (HICC, NCT04815005) were invited to complete an online survey on registration status, reimbursement, and access to various LLTs. Responses were compared between high-income and non-high-income countries. RESULTS:Responses were received from 87 physicians (64.4% from high-income countries). Physicians from high-income countries reported significantly higher registration rates for proprotein convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9 mAbs) (96.4% vs 51.6%), lomitapide (83.6% vs 9.7%), evinacumab (69.1% vs 0.0%), colesevelam (50.0% vs 3.2%), and lipoprotein-apheresis (96.4% vs 45.2%). Public sector reimbursement was also more common in high-income countries for PCSK9 mAbs (90.9% vs 24.1%), lomitapide (74.5% vs 3.4%), evinacumab (60.0% vs 0.0%), colesevelam (40.0% vs 3.4%), and lipoprotein-apheresis (94.5% vs 37.9%). Access to LLTs was also higher in high-income countries for statins (91.1% vs 61.3%), ezetimibe (87.5% vs 38.7%), PCSK9 mAbs (53.6% vs 6.5%), lomitapide (32.% vs 0.0%), evinacumab (32.1% vs 3.2%), colesevelam (39.3% vs 3.2%), and lipoprotein-apheresis (57.1% vs 3.2%). CONCLUSION: Our results confirm significant global disparities in LLT registration, reimbursement, and access between high-income and non-high-income countries. Improving LLT availability and accessibility, particularly in non-high-income countries, is essential to improve outcomes in patients with HoFH.</p