HIV infection and lipids.

PURPOSE OF REVIEW: We comment on the role of dyslipidaemia in cardiovascular disease (CVD) in HIV-infected patients. We have discussed various risk factors, including traditional CVD risk factors, HIV-related risk factors and antiretroviral therapy (ART)-induced dyslipidaemia. RECENT FINDINGS: HIV-infected individuals are prone to lipid and lipoprotein abnormalities as a result of the infection itself and the effect of ART. The older drugs used for the treatment of HIV were associated with an increased risk of these abnormalities. New therapies used to treat HIV are lipid friendly. Calculating CVD risk in the HIV population is complex due to the infection itself and the ART-related factors. The advancement in ART has helped to increase the life expectancy of HIV patients. As a result, a growing number of patients die of non-HIV related complications such as CVD, hepatic and renal disease. Outcome studies with intervention for dyslipidaemia in HIV are underway. SUMMARY: The implications of the above findings suggest that all patients with HIV should undergo a CVD risk assessment before starting ART. Appropriate lipid-friendly ART regimen should be initiated along with intervention for associated CVD risk factors (e.g. lipids, hypertension and smoking).

South Asians: why are they at a higher risk for cardiovascular disease?

PURPOSE OF REVIEW: We comment on the high prevalence of cardiovascular disease (CVD) in South Asians (SA). The effect of various risk factors, for example biochemical, genetic, lifestyle, socioeconomic factors and psychosocial stress on CVD risk is discussed. RECENT FINDINGS: 'Prediabetes' is common in SA, but its relationship with coronary artery disease (CAD) is not significant unlike for the white population. At the same time, 'prediabetes' in SA is associated with an increased risk for cerebrovascular disease (CeVD). The differentiating factor could be the high lipids in Europeans and their relationship to CAD. Likewise, higher diastolic blood pressure in SA may explain the risk of CeVD. Small, dense, low-density lipoprotein (LDL), low high-density lipoprotein-cholesterol (HDL-C) concentration and high triglycerides may contribute to atherosclerosis. Thrombotic factors such as increased levels of plasminogen activator inhibitor, fibrinogen, lipoprotein (a) and homocysteine have been shown to be associated with increased CVD. Impaired cerebrovascular autoregulation and sympathovagal activity, increased arterial stiffness and endothelial dysfunction may increase CVD risk further. In addition, environmental and dietary factors may exaggerate the unfavourable cardiovascular profile through genetic factors. SUMMARY: The implications of the findings suggest comprehensive screening of SA for CVD. Cultural differences should be considered while designing prevention strategies specifically targeting barriers for uptake of preventive service.

Whole exome sequencing of familial hypercholesterolaemia patients negative for LDLR/APOB/PCSK9 mutations.

BACKGROUND: Familial hypercholesterolaemia (FH) is an autosomal dominant disease of lipid metabolism, which leads to early coronary heart disease. Mutations in LDLR, APOB and PCSK9 can be detected in 80% of definite FH (DFH) patients. This study aimed to identify novel FH-causing genetic variants in patients with no detectable mutation. METHODS AND RESULTS: Exomes of 125 unrelated DFH patients were sequenced, as part of the UK10K project. First, analysis of known FH genes identified 23 LDLR and two APOB mutations, and patients with explained causes of FH were excluded from further analysis. Second, common and rare variants in genes associated with low-density lipoprotein cholesterol (LDL-C) levels in genome-wide association study (GWAS) meta-analysis were examined. There was no clear rare variant association in LDL-C GWAS hits; however, there were 29 patients with a high LDL-C SNP score suggestive of polygenic hypercholesterolaemia. Finally, a gene-based burden test for an excess of rare (frequency <0.005) or novel variants in cases versus 1926 controls was performed, with variants with an unlikely functional effect (intronic, synonymous) filtered out. CONCLUSIONS: No major novel locus for FH was detected, with no gene having a functional variant in more than three patients; however, an excess of novel variants was found in 18 genes, of which the strongest candidates included CH25H and INSIG2 (p<4.3×10(-4) and p<3.7×10(-3), respectively). This suggests that the genetic cause of FH in these unexplained cases is likely to be very heterogeneous, which complicates the diagnostic and novel gene discovery process.

Familial hypercholesterolaemia.

PURPOSE OF REVIEW: Familial hypercholesterolaemia is associated with lifelong elevated cholesterol levels and is an important cause of premature coronary heart disease (CHD). This condition is often underdiagnosed and undertreated. Awareness of this condition is poor among nonlipid specialists. Treatment of elevated cholesterol levels with statins reduces the risk for CHD. The review will increase the awareness of this condition among nonspecialists. RECENT FINDINGS: Recently, several guidelines have been produced by different countries, but a unified approach to this global problem is addressed through a recent guideline facilitated by the Familial Hypercholesterolaemia Foundation. Although the widespread use of statins has been successful in reducing the risk for CHD in familial hypercholesterolaemia, there have been difficulties in getting to targets, especially in those with established vascular disease. New therapies such as mipomersen, a second-generation antisense oligonucleotide, microsomal triglyceride transfer protein inhibitors that decrease the synthesis of apolipoprotein B-containing lipoproteins and proprotein convertase subtilisin/kexin type 9 inhibitors hold promise in reducing cholesterol levels in those patients in whom low density lipoprotein cholesterol (LDL-C) reduction is required beyond the use of statins, especially in those with severe heterozygous familial hypercholesterolaemia or homozygous familial hypercholesterolaemia. SUMMARY: Increased awareness and wider availability of guidance to treat familial hypercholesterolaemia will improve management of familial hypercholesterolaemia. New therapies, if they become available after appropriate outcome studies, will reduce LDL-C levels in both homozygous familial hypercholesterolaemia and severe heterozygous familial hypercholesterolaemia, thus reducing the risk for premature CHD.

Lipid Association of India 2023 update on cardiovascular risk assessment and lipid management in Indian patients: Consensus statement IV.

OBJECTIVE: In 2016, the Lipid Association of India (LAI) developed a cardiovascular risk assessment algorithm and defined low-density lipoprotein cholesterol (LDL-C) goals for prevention of atherosclerotic cardiovascular disease (ASCVD) in Indians. The recent refinements in the role of various risk factors and subclinical atherosclerosis in prediction of ASCVD risk necessitated updating the risk algorithm and treatment goals. METHODS: The LAI core committee held twenty-one meetings and webinars from June 2022 to July 2023 with experts across India and critically reviewed the latest evidence regarding the strategies for ASCVD risk prediction and the benefits and modalities for intensive lipid lowering. Based on the expert consensus and extensive review of published data, consensus statement IV was commissioned. RESULTS: The young age of onset and a more aggressive nature of ASCVD in Indians necessitates emphasis on lifetime ASCVD risk instead of the conventional 10-year risk. It also demands early institution of aggressive preventive measures to protect the young population prior to development of ASCVD events. Wide availability and low cost of statins in India enable implementation of effective LDL-C-lowering therapy in individuals at high risk of ASCVD. Subjects with any evidence of subclinical atherosclerosis are likely to benefit the most from early aggressive interventions. CONCLUSIONS: This document presents the updated risk stratification and treatment algorithm and describes the rationale for each modification. The intent of these updated recommendations is to modernize management of dyslipidemia in Indian patients with the goal of reducing the epidemic of ASCVD among Indians in Asia and worldwide.

Cardiovascular risk assessment of South Asian populations in religious and community settings: a qualitative study.

BACKGROUND: Cardiovascular disease (CVD) is a leading cause of mortality, and South Asian groups experience worse outcomes than the general population in the UK. Regular screening for CVD risk factors is recommended, but we do not know the best settings in which to deliver this for ethnically diverse populations. Health promotion in religious and community settings may reduce inequalities in access to cardiovascular preventative health care. OBJECTIVES: To use stakeholders' and attendees' experiences to explore the feasibility and potential impact of cardiovascular risk assessment targeting South Asian groups at religious and community venues and how health checks in these settings might compare with general practice assessments. METHOD: Qualitative semi-structured interviews were used. The settings were two Hindu temples, one mosque and one Bangladeshi community centre in central and north-west London. Twenty-four participants (12 stakeholders and 12 attendees) were purposively selected for interview. Interviews were recorded and transcribed verbatim. Themes from the data were generated using thematic framework analysis. RESULTS: All attendees reported positive experiences of the assessments. All reported making lifestyle changes after the check, particularly to diet and exercise. Barriers to lifestyle change, e.g. resistance to change from family members, were identified. Advantages of implementing assessments in religious and community settings compared with general practice included accessibility and community encouragement. Disadvantages included reduced privacy, organizational difficulties and lack of follow-up care. CONCLUSION: Cardiovascular risk assessment in religious and community settings has the potential to trigger lifestyle change in younger participants. These venues should be considered for future health promotional activities.

Management of Dyslipidaemia for the Prevention of Stroke: Clinical Practice Recommendations from the Lipid Association of India.

Stroke is the second most common cause of death worldwide. The rates of stroke are increasing in less affluent countries predominantly because of a high prevalence of modifiable risk factors. The Lipid Association of India (LAI) has provided a risk stratification algorithm for patients with ischaemic stroke and recommended low density lipoprotein cholesterol (LDL-C) goals for those in very high risk group and extreme risk group (category A) of <50 mg/dl (1.3 mmol/l) while the LDL-C goal for extreme risk group (category B) is ≤30 mg/dl (0.8 mmol/l). High intensity statins are the first-line lipid lowering therapy. Nonstatin therapy like ezetimibe and proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors may be added as an adjunct to statins in patients who do not achieve LDL-C goals with statins alone. In acute ischaemic stroke, high intensity statin therapy improves neurological and functional outcomes regardless of thrombolytic therapy. Although conflicting data exist regarding increased risk of intracerebral haemorrhage (ICH) with statin use, the overall benefit risk ratio favors long-term statin therapy necessitating detailed discussion with the patient. Patients who have statins withdrawn while being on prior statin therapy at the time of acute ischaemic stroke have worse functional outcomes and increased mortality. LAI recommends that statins be continued in such patients. In patients presenting with ICH, statins should not be started in the acute phase but should be continued in patients who are already taking statins. ICH patients, once stable, need risk stratification for atherosclerotic cardiovascular disease (ASCVD).

Fibrinogen, lipoprotein (a), albumin and bilirubin (F-L-A-B) levels and cardiovascular risk calculated using the Framingham equation.

OBJECTIVES: To determine the correlation between cardiovascular risk calculated using the Framingham equation and the circulating levels of 4 'emerging'predictors of vascular events: fibrinogen (Fib), lipoprotein (a) (Lp(a)), albumin (Alb) and bilirubin (Bil) (F-L-A-B). PATIENTS AND METHODS: A retrospective survey was carried out using patients referred to a specialist university-based clinic. A total of 376 patients with primary dyslipidaemia (209 men), without overt vascular disease, had their cardiovascular risk estimated using the Framingham equation. RESULTS: Among the men, smokers (n=45) were significantly younger (p =0.014) than non-smokers (n=164). Smokers when compared with non-smokers had significantly higher median Fib levels (3.84 (1.15-5.87) vs. 3.08 (1.44-5.47) g/l; p<0.0001) and lower median Bil levels (8 (3-17) vs. 10 (1-28) micromol/l; p=0.016). When non-smoker men without clinically evident vascular disease were considered, there was a significant positive Fib and negative Alb correlation with calculated risk, whether the family history was considered or not. Moreover in smokers, the only significant correlation was a negative one between Bil and cardiovascular disease risk. Lp(a) correlated with risk for stroke in women non-smokers whether the family history was considered or not, while Alb correlated with risk for stroke in women non-smokers without family history. CONCLUSION: Fib, Lp(a), Alb and Bil (F-L-A-B) may be predictors of vascular events in high-risk populations. Prospective studies should evaluate whether the F-L-A-B markers are useful in the assessment of cardiovascular risk load. Such an advantage would make treatment more cost effective by improving patient targeting. The F-L-A-B markers could eventually become targets for new drugs.

The relationship between circulating fibrinogen and lipoprotein (a) levels in patients with primary dyslipidemia.

The correlation between 2 predictors of vascular events, plasma fibrinogen and serum lipoprotein (a), was evaluated in patients referred to a specialist clinic because of primary hyperlipidemia. A significant correlation existed between fibrinogen and lipoprotein (a) in nonsmokers but not in smokers. Plasma fibrinogen concentration correlated positively and significantly with serum lipoprotein (a) levels in men nonsmokers without cardiovascular disease and in women nonsmokers with cardiovascular disease. Nonsmoker women without cardiovascular disease had significantly higher plasma fibrinogen (3.63 g/L versus 3.07 g/L, P < .0001) than the corresponding men. Nonsmoker women with and without cardiovascular disease had significantly higher lipoprotein (a) levels than the corresponding groups of men (0.36 versus 0.18 g/L; P = .0015 and 0.40 versus 0.26 g/L; P = .008), respectively. The relationship between fibrinogen and lipoprotein (a) levels alters markedly depending on the population selected. This relationship is influenced by gender, the presence of cardiovascular disease and smoking status.

Evaluation of the point of care Afinion AS100 analyser in a community setting.

Background A 'one stop shop' model for multifactorial risk factor management in a culturally sensitive environment may improve cardiovascular disease and diabetes prevention. A full biochemical profile for cardiovascular disease risk assessment includes a lipid profile, glucose, glycated haemoglobin and urine albumin creatinine ratio measurements. This may require the use of more than one point of care testing instrument. Methods Individuals who attended a community cardiovascular disease risk screening or an audit programme of the diabetic care pathway in the community were sampled. Bland-Altman and Deming regression plots were used to assess agreement between methods for total cholesterol, high-density lipoprotein cholesterol, triglycerides, glycated haemoglobin and urine albumin creatinine ratio. Results There was good agreement between the Afinion AS100 analyser, Cholestech LDX and the laboratory methods for total cholesterol, high-density lipoprotein cholesterol and triglycerides ( n = 232). The Afinion AS100 agreed well with the laboratory method for glycated haemoglobin ( n = 255) and urine albumin creatinine ratio ( n = 176). There was statistically significant bias ( p = 0.03 to <0.0001) for several measurements. However, these were judged not to be clinically relevant. Specifically for the total cholesterol and high-density lipoprotein cholesterol values, we obtained good agreement (weighted kappa: 0.91 and 0.94 for the Afinion AS100 vs. Cholestech LDX and Afinion AS100 vs. laboratory method, respectively) for cardiovascular disease risk calculation using QRISK2. Conclusions Point of care testing can support a 'one stop shop' approach by providing rapid, reliable results. The Afinion AS100 analyser provides a multi-analyte platform and compares well with laboratory-based methods and another well-established point of care testing analyser.

All for Statins and Statins for All; An Update.

Statins exert beneficial effects on cardiovascular [CV] outcomes as well as on inflammation and oxidative stress. The widespread use of statins for both primary and secondary CV disease prevention is based on the evidence from large randomized controlled trials. The benefits of statin treatment outweigh any harm in high risk patients. In this narrative review, we provide an update on several aspects of statin treatment based on the most recent evidence in this field.

Molecular analysis of the LDLR gene in coronary artery disease patients from the Indian population.

BACKGROUND: Cardiovascular disease is a leading cause of mortality in Indian population. Mutations in LDLR, APOB and PCSK9 genes may lead to Familial Hypercholesterolemia, an autosomal dominant disorder which in turn leads to cardiovascular diseases. The primary objective of this study is to analyze these genes in CAD patients of Indian population. METHODS: A total of 30 patients were selected out of 300 CAD patients based on UK-Simon Broome criteria from South India. The gDNA was isolated by organic extraction method and the exons and exon-intron boundaries of LDLR gene, APOB (exon 26) and PCSK9 (exon 7) were screened by PCR-high resolution melt analysis. The amplicons showing shift in melting pattern were sequenced to find out the variation. RESULTS: This study reports three novel variations, an intronic deletion c.694+8_694+18del in intron 4, a synonymous variation c.966 C>T [p. (N322=)] in exon 7 and a deletion insertion c.1399_1340delinsTA [p. (T467Y)] in exon 10, two recurrent variations c.862G>A [p. (E288K)] in exon 6 and a splice site variation c.1845+2T>C in exon-intron junction of exon 12 in LDLR gene and PCSK9 gene had c.1180+17C>T change in intron 7. However there are no pathogenic variations in APOB and PCSK9 genes in Indian population. In silico analysis predicted all the variations as pathogenic except the synonymous variation. CONCLUSION: This report adds five new variations to the spectrum of LDLR variations in Indian population. This study also suggests that UK Simon Broom criteria can be followed to categorize FH patients in Indian population.