Mendelian randomization studies on atherosclerotic cardiovascular disease: evidence and limitations

Epidemiological research has revealed a galaxy of biomarkers, such as genes, molecules or traits, which are associated with increased risk of atherosclerotic cardiovascular diseases(ASCVD). However, the etiological basis remains poorly characterized.Mendelian randomization(MR) involves the use of observational genetic data to ascertain the roles of disease-associated risk factors and, in particular, differentiate those reflecting the presence or severity of a disease from those contributing causally to a disease. Over the past decade, MR has evolved into a fruitful approach to clarifying the causal relation of a biomarker with ASCVD and to verifying potential therapeutic targets for ASCVD. In this review, we selected high-quality MR studies on ASCVD, examined the causal relationship of a series of biomarkers with ASCVD, and elucidated the role of MR in validating biomarkers as a therapeutic target by comparing the results from MR studies and randomized clinical trials(RCTs) for the treatment of ASCVD. The good agreement between the results derived by MR and RCTs suggests that MR could be performed as a screening process before novel drug development. However, when designing and interpreting a MR study, the assumptions and limitations inherent in this approach should be taken into account. Novel methodological developments, such as sensitivity analysis, will help to strengthen the validity of MR studies.     

Lifestyle intervention to prevent diabetes: intensive and cost effective

PURPOSE OF REVIEW: Type 2 diabetes is a major cause of morbidity and mortality, and despite treatment advances appears to be increasing in incidence. Since individuals at risk for the disease are usually identifiable in the prediabetic phase of impaired glucose tolerance, early intervention might prevent diabetes and hence its complications from developing. Obesity and sedentary living are powerful determinants of diabetes, and thus lifestyle change is a logical approach to prevention of this disease. Recent clinical trials have now tested the effectiveness of this intervention and form the basis for this review. RECENT FINDINGS: Three clinical trials have demonstrated that, compared with usual care, lifestyle intervention significantly reduced progression rates to diabetes in prediabetic individuals. Each trial incorporated individualization and repeated long-term contacts with facilitators, in which dietary and physical activity goal setting and behavior modification were central themes. Progression to diabetes was reduced in the Da Qing study by approximately 40%, in the Finnish Diabetes Prevention Study by 58% and in the Diabetes Prevention Program by 58%. The Diabetes Prevention Program included a cost-benefit unit that estimated the per capita costs of the lifestyle intervention to exceed that of the usual care group by Dollars 3540, which translated to a cost of Dollars 15,700 per case of diabetes prevented. Lifetime cost-utility analysis demonstrated an overall cost of Dollars 1100 per quality-adjusted life year. SUMMARY: These findings make the case for translation of research findings to healthcare systems. Although there is more to be learned about effective strategies in clinical practice, it seems clear that the intervention needs to incorporate individualization and long-term interaction with trained facilitators.     

Biomarkers for cardiovascular disease: challenges and future directions

The accurate diagnosis and prevention of cardiovascular disease (CVD) is an important public health goal. Although clinical characteristics such as age and gender are well-established risk factors for CVD, such features are not sufficient to identify all patients at risk. Cardiovascular biomarkers have the potential to augment clinical risk stratification by aiding in screening, diagnosis and assessment of prognosis. However, most current biomarkers have only modest predictive value, and there is a need to identify additional biomarkers from new biological pathways. The availability of platforms for profiling DNA, RNA, proteins and metabolites in clinical specimens has facilitated the 'unbiased' search for new biomarkers, which can now be tested in a clinical setting. This review highlights recent developments in the field of cardiovascular biomarkers and describes the use of new technologies for the identification of biomarkers.     

Ideal cardiovascular health and incidence of atherosclerotic cardiovascular disease among Chinese adults: the China-PAR project

Existing evidence on the relationship between cardiovascular health(CVH) metrics and cardiovascular disease(CVD) was primarily derived from western populations. We aimed to evaluate the benefits of ideal CVH metrics on preventing incident atherosclerotic CVD(ASCVD) in Chinese population. This study was conducted among 93,987 adults from the China-PAR project(Prediction for ASCVD Risk in China) who were followed up until 2015. Cox proportional hazard regression models were used to estimate the hazard ratios(HRs) and their corresponding 95% confidence intervals(CIs) of CVH metrics for the risk of ASCVD, including coronary heart disease(CHD), stroke and ASCVD death. We further estimated the population-attributable risk percentage(PAR%) of these metrics in relation to each outcome. We observed gradient inverse associations between the number of ideal CVH metrics and ASCVD incidence. Compared with participants having ≤2 ideal CVH metrics, the multivariable-adjusted HRs(95% CIs) of ASCVD for those with 3, 4, 5, 6 and 7 ideal CVH metrics were 0.83(0.74–0.93), 0.66(0.59–0.74), 0.55(0.48–0.61), 0.44(0.38–0.50) and 0.24(0.18–0.31), respectively(P for trend 0.0001). Approximately 62.1% of total ASCVD, 38.7% of CHD, 66.4% of stroke, and 60.5% of ASCVD death were attributable to not achieving all the seven ideal CVH metrics. After adjusting effects of ideal health factors, having four ideal health behaviors could independently bring adults health benefits in preventing 17.4% of ASCVD, 18.0% of CHD, 16.7% of stroke, and 10.1% of ASCVD death. Among all the seven CVH metrics, to keep with ideal blood pressure(BP) implied the largest public health gains against various ASCVD events(PAR% between 33.0% and 47.2%), while ideal diet was the metric most difficult to be achieved in the long term. Our study indicates that the more ideal CVH metrics adults have, the less ASCVD burden there is in China. Special efforts of health education and behavior modification should be made on keeping ideal BP and dietary habits in general Chinese population to prevent the epidemic of ASCVD.     

Clinical trials of gene therapy for atherosclerotic cardiovascular disease

PURPOSE OF REVIEW: To provide an update on clinical trials of gene therapy for atherosclerotic cardiovascular disease published since 1 August 2001 and summarize the general advantages and potential problems of gene transfer in these disorders. RECENT FINDINGS: There are two major areas in which gene therapy has entered clinical trials. The first is angiogenesis for coronary and peripheral arterial disease. Two relatively small placebo-controlled trials for coronary disease were reported, one using intramyocardial plasmid VEGF-2 gene, the other using intracoronary adenoviral FGF-4 gene. The VEGF-2 study in no-option patients showed reduced angina, and significant improvement in perfusion and function, whereas the FGF-4 study in less severely affected patients showed promising results in some subsets. In peripheral artery disease two phase 1 studies of adenoviral NV1FGF and VEGF showed some objective improvement in pain, ulcer size and ankle:brachial index in one study and endothelial function in the other. Both adenoviral and plasmid VEGF gene transfer at angioplasty increased vascularity in a phase 2 double-blind study. The other major area is the prevention of graft disease and restenosis using antisense oligodeoxynucleotides. E2F decoy led to a significant reduction in venous graft complications after ex-vivo transfection at the time of coronary bypass surgery, whereas the c-Myc oligodeoxynucleotide was ineffective in preventing in-stent coronary restenosis. SUMMARY: There are more reviews of gene therapy for atherosclerosis in the literature than publications with original data or trials, but in the past year the imbalance is being redressed, with some promising results from controlled studies.     

The molecular role of mast cells in atherosclerotic cardiovascular disease

Human atherosclerosis has many characteristics of an inflammatory disorder. Recent data suggest that mast cells might be important in the pathogenesis of atherosclerotic disease. By secretion of pro-inflammatory cytokines, mast cells can assist in the recruitment of monocytes and lymphocytes into vascular tissue, thereby propagating the inflammatory response. Mast cell enzymes might activate pro-metalloproteinases, thereby destabilizing atheromatous plaques. Mast cells can facilitate foam cell formation by promoting cholesterol accumulation. However, mast cell tryptase could slow thrombus formation at sites of plaque rupture by interfering with coagulation. Therefore, mast cells can modulate coronary artery disease by both facilitatory and inhibitory pathways.     

Cardiovascular disease in patients with COVID-19:evidence from cardiovascular pathology to treatment

The coronavirus disease-2019(COVID-19)caused by the novel coronavirus severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)has rapidly developed into a gl...     

Aggressive lipid management for cardiovascular prevention: evidence from clinical trials

Epidemiologic evidence shows that elevated serum cholesterol, specifically low-density lipoprotein cholesterol (LDL-C), increases the risk of coronary heart disease (CHD). Moreover, large-scale intervention trials demonstrate that treatment with HMG-CoA reductase inhibitors (statins), the most effective drug class for lowering LDL-C, significantly reduces the risk of CHD events. Unfortunately, only a moderate percentage of hypercholesterolemic patients are achieving LDL-C targets specified by the National Cholesterol Education Program (NCEP), in part because clinicians are not effectively titrating medications as needed to achieve LDL-C goals. Recent evidence suggests that more aggressive LDL-C lowering may provide greater clinical benefit, even in individuals with moderately elevated serum cholesterol levels. Furthermore, recent studies suggest that statins have cardioprotective effects in many high-risk individuals, including those with baseline LDL-C <100 mg/dl. High-density lipoprotein cholesterol (HDL-C) was recognized by the NCEP-Adult Treatment Panel II (ATP II) as a negative risk factor for CHD. The NCEP-ATP III guidelines have also reaffirmed the importance of HDL-C by increasing the low HDL-C designation from <35 to <40 mg/dl as a major risk factor for CHD. Similarly, triglyceride control will play a larger role in dyslipidemia management. As more clinicians effectively treat adverse lipid and lipoprotein cardiovascular risk factors, patients will likely benefit from reductions in cardiovascular events.     

Bacterial disease management: challenges,experience, innovation and future prospects

Plant diseases caused by bacterial pathogens place major constraints on crop production and cause significant annual losses on a global scale. The attainment of consistent effective management of these diseases can be extremely difficult, and management potential is often affected by grower reliance on highly disease‐susceptible cultivars because of consumer preferences, and by environmental conditions favouring pathogen development. New and emerging bacterial disease problems (e.g. zebra chip of potato) and established problems in new geographical regions (e.g. bacterial canker of kiwifruit in New Zealand) grab the headlines, but the list of bacterial disease problems with few effective management options is long. The ever‐increasing global human population requires the continued stable production of a safe food supply with greater yields because of the shrinking areas of arable land. One major facet in the maintenance of the sustainability of crop production systems with predictable yields involves the identification and deployment of sustainable disease management solutions for bacterial diseases. In addition, the identification of novel management tactics has also come to the fore because of the increasing evolution of resistance to existing bactericides. A number of central research foci, involving basic research to identify critical pathogen targets for control, novel methodologies and methods of delivery, are emerging that will provide a strong basis for bacterial disease management into the future.

• Near‐term solutions are desperately needed. Are there replacement materials for existing bactericides that can provide effective disease management under field conditions?
• Experience should inform the future. With prior knowledge of bactericide resistance issues evolving in pathogens, how will this affect the deployment of newer compounds and biological controls?
• Knowledge is critical. A comprehensive understanding of bacterial pathosystems is required to not only identify optimal targets in the pathogens, but also optimal seasonal timings for deployment.
• Host resistance to effectors must be exploited, carefully and correctly. Are there other candidate genes that could be targeted in transgenic approaches? How can new technologies (CRISPR, TALEN, etc.) be most effectively used to add sustainable disease resistance to existing commercially desirable plant cultivars?
• We need an insider's perspective on the management of systemic pathogens. In addition to host resistance or reduced sensitivity, are there other methods that can be used to target these pathogen groups?
• Biological systems are variable. Can biological control strategies be improved for bacterial disease management and be made more predictable in function?

The answers to the research foci outlined above are not all available, as will become apparent in this article, but we are heading in the right direction. In this article, we summarize the contributions from past experiences in bacterial disease management, and also describe how advances in bacterial genetics, genomics and host–pathogen interactions are informing novel strategies in virulence inhibition and in host resistance. We also outline potential innovations that could be exploited as the pressures to maximize a safe and productive food supply continue to become more numerous and more complex.     

New evidence in the management of cardiovascular risk: the place of heart rate

This session was chaired by M. Boehm (Homburg, Germany) and K.M. Fox (London, UK) and supported by an unrestricted educational grant from Servier.     

Association of lecithin-cholesterol acyltransferase activity and low-density lipoprotein heterogeneity with atherosclerotic cardiovascular disease risk: a longitudinal pilot study

Background

Lecithin-cholesterol acyltransferase (LCAT) is believed to be involved in reverse cholesterol transport, which is known to play a key role in suppression of atherosclerosis. However, recent investigations have demonstrated that higher LCAT activity, measured in terms of the serum cholesterol esterification rate by an endogenous substrate method, is associated with increased formation of triglyceride (TG)-rich lipoproteins (TRLs), leading to a decrease in the low-density lipoprotein (LDL) particle size. The purpose of this hospital-based longitudinal study was to clarify the causal relationship between changes in the LCAT activity and changes in the LDL-particle size.

Methods

The subjects were a total of 335 patients, derived from our previous study cohort, with one or more risk factors for atherosclerotic cardiovascular disease (ASCVD). For this study, we measured the LDL-particle size (relative LDL migration [LDL-Rm value]) by polyacrylamide gel electrophoresis in the subjects, along with the changes in the LCAT activity, at the end of a follow-up period of at least 1 year.

Results

The results revealed that the absolute change (Δ) in the LDL-particle size increased significantly as the quartile of Δ LCAT activity increased (p =?0.01). A multi-logistic regression adjusted-analysis revealed that Δ LCAT activity in the fourth quartile as compared to that in the first quartile was independently predictive of an increased LDL-particle size (odds ratio [95% confidence interval]: 2.03 [1.02/4.04], p =?0.04). Moreover, the ? LCAT activity was also positively correlated with ? TRL-related markers (i.e., TG, remnant particle-like cholesterol [RLP-C], apolipoprotein B, apolipoprotein C-2, and apolipoprotein C-3).

Conclusions

The results lend support to the hypothesis that increased LCAT activity may be associated with increased formation of TRLs, leading to a reduction in the LDL-particle size in patients at a high risk for ASCVD. To reduce the risk of ASCVD, it may be important to focus not only on the quantitative changes in the serum LDL-cholesterol levels, but also on the LCAT activity.

Trial registration

UMIN (https://upload.umin.ac.jp/cgi-bin/ctr/ctr_reg_list.cgi) Study ID: UMIN000033228 retrospectively registered 2 July 2018.

     

Childhood adversities and psychosis: evidence,challenges, implications

There is a substantial body of research reporting evidence of associations between various forms of childhood adversity and psychosis, across the spectrum from experiences to disorder. This has been extended, more recently, to include studies of cumulative effects, of interactions with other factors, of specific effects, and of putative biological and psychological mechanisms. In this paper we evaluate this research and highlight the remaining methodological issues and gaps that temper, but do not dismiss, conclusions about the causal role of childhood adversity. We also consider the emerging work on cumulative, synergistic, and specific effects and on mechanisms; and discuss the broader implications of this line of research for our understanding of psychosis. We conclude that the current balance of evidence is that childhood adversities – particularly exposure to multiple adversities involving hostility and threat – do, in some people, contribute to the onset of psychotic experiences and psychotic disorders.     

Gout. Hyperuricemia and cardiovascular disease: how strong is the evidence for a causal link?

An association between high levels of serum urate and cardiovascular disease has been proposed for many decades. However, it was only recently that compelling basic science data, small clinical trials, and epidemiological studies have provided support to the idea of a true causal effect. In this review we present recently published data that study the association between hyperuricemia and selected cardiovascular diseases, with a final conclusion about the possibility of this association being causal.