Residual Cardiovascular Disease Risk Research Articles

Early-Onset Hypertension and Sex-Specific Residual Risk for Cardiovascular Disease in Type 2 Diabetes.

To investigate whether the sex disparities in type 2 diabetes-associated cardiovascular disease (CVD) risks may be related to early-onset hypertension that could benefit from intensive blood pressure (BP) control. We analyzed intensive versus standard BP control in relation to incident CVD events in women and men with type 2 diabetes, based on their age of hypertension diagnosis. Among 3,792 adults with type 2 diabetes (49% women), multivariable-adjusted CVD risk was increased per decade earlier age at hypertension diagnosis (hazard ratio 1.11 [1.03-1.21], P = 0.006). Excess risk associated with early-diagnosed hypertension was attenuated in the presence of intensive versus standard antihypertensive therapy in women (P = 0.036) but not men (P = 0.76). Women with type 2 diabetes and early-onset hypertension may represent a higher-risk subpopulation that not only contributes to the female excess in diabetes-related CVD risk but may benefit from intensive BP control.

Associations of the triglyceride-glucose index and remnant cholesterol with coronary artery disease: a retrospective study

BackgroundRemnant cholesterol (RC) represents a low-cost and readily measured lipid index that contributes significantly to residual cardiovascular disease risk. The triglyceride-glucose (TyG) index exhibits a significant correlation with cardiovascular disease occurrence. However, RC and the TyG index have rarely been examined for their potentials in predicting coronary artery disease (CAD). Accordingly, the study was designed to validate the correlations of these two biomarkers with CAD and to compare the forecasted values of these two biomarkers for newly diagnosed CAD.MethodsTotally 570 subjects firstly administered coronary angiography were enrolled, including 431 newly diagnosed CAD cases and 139 individuals without CAD. The individuals were classified into two groups according to CAD diagnosis. RC was derived as total cholesterol content (mmol/L) – (high density lipoprotein cholesterol content + low density lipoprotein cholesterol content; both in mmol/L). The TyG index was determined as ln (fasting triglyceride level [mg/dL] × fasting plasma glucose level [mg/dL])/2.ResultsBaseline feature analysis revealed significant differences in RC and the TyG index between the CAD and non-CAD groups (both P < 0.001). RC and the TyG index were independent risk factors for CAD in accordance with logistic regression analysis (both P < 0.05). Moreover, spearman correlation analysis elucidated CAD had a more remarkable correlation with the TyG index compared with RC (both P < 0.001). Furthermore, according to receiver operating characteristic curve analysis, the TyG index was better than RC in predicting CAD.ConclusionsThe TyG index and RC have significant associations with CAD. Compared with RC, the TyG index possesses a closer correlation with CAD and a higher predictive value for CAD.

A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk.

Despite intensive preventive cardiovascular disease (CVD) efforts, substantial residual CVD risk remains even for individuals receiving all guideline-recommended interventions. Niacin is an essential micronutrient fortified in food staples, but its role in CVD is not well understood. In this study, untargeted metabolomics analysis of fasting plasma from stable cardiac patients in a prospective discovery cohort (n = 1,162 total, n = 422 females) suggested that niacin metabolism was associated with incident major adverse cardiovascular events (MACE). Serum levels of the terminal metabolites of excess niacin, N1-methyl-2-pyridone-5-carboxamide (2PY) and N1-methyl-4-pyridone-3-carboxamide (4PY), were associated with increased 3-year MACE risk in two validation cohorts (US n = 2,331 total, n = 774 females; European n = 832 total, n = 249 females) (adjusted hazard ratio (HR) (95% confidence interval) for 2PY: 1.64 (1.10-2.42) and 2.02 (1.29-3.18), respectively; for 4PY: 1.89 (1.26-2.84) and 1.99 (1.26-3.14), respectively). Phenome-wide association analysis of the genetic variant rs10496731, which was significantly associated with both 2PY and 4PY levels, revealed an association of this variant with levels of soluble vascular adhesion molecule 1 (sVCAM-1). Further meta-analysis confirmed association of rs10496731 with sVCAM-1 (n = 106,000 total, n = 53,075 females, P = 3.6 × 10-18). Moreover, sVCAM-1 levels were significantly correlated with both 2PY and 4PY in a validation cohort (n = 974 total, n = 333 females) (2PY: rho = 0.13, P = 7.7 × 10-5; 4PY: rho = 0.18, P = 1.1 × 10-8). Lastly, treatment with physiological levels of 4PY, but not its structural isomer 2PY, induced expression of VCAM-1 and leukocyte adherence to vascular endothelium in mice. Collectively, these results indicate that the terminal breakdown products of excess niacin, 2PY and 4PY, are both associated with residual CVD risk. They also suggest an inflammation-dependent mechanism underlying the clinical association between 4PY and MACE.

Omega-3 Fatty Acids Reduce Remnant-like Lipoprotein Cholesterol and Improve the Ankle-Brachial Index of Hemodialysis Patients with Dyslipidemia: A Pilot Study.

Background and Objectives: Omega-3 fatty acids have potent lipid-lowering and antiplatelet effects; however, randomized controlled trials have yet to examine the effect of high-dose omega-3 fatty acid administration on peripheral artery disease (PAD) in hemodialysis patients with dyslipidemia. Therefore, this study aimed to evaluate the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on the ankle-brachial index (ABI) and remnant-like lipoprotein cholesterol (RLP-C) levels, which are indicators of PAD severity. Materials and Methods: Thirty-eight participants (mean age: 73.6 ± 12.7 years) were randomly assigned using stratified block randomization to either conventional therapy alone or conventional therapy supplemented with high-dose EPA/DHA (EPA: 1860 mg; DHA: 1500 mg) for a three-month intervention period. Patients in the conventional therapy alone group who opted to continue were provided with a low-dose EPA/DHA regimen (EPA: 930 mg; DHA: 750 mg) for an additional three months. The baseline and 3-month values for RLP-C, an atherogenic lipid parameter, and the ABI were recorded. Results: The results of the 3-month assessments revealed that the mean RLP-C changes were -3.25 ± 3.15 mg/dL and 0.44 ± 2.53 mg/dL in the EPA/DHA and control groups, respectively (p < 0.001), whereas the changes in the mean ABI values were 0.07 ± 0.11 and -0.02 ± 0.09 in the EPA/DHA and control groups, respectively (p = 0.007). In the EPA/DHA group, a significant negative correlation was found between the changes in RLP-C levels and the ABI (r = -0.475, p = 0.04). Additionally, the change in the RLP-C levels independently influenced the change in the ABI in the EPA/DHA group, even after adjusting for age, sex, and statin use (p = 0.042). Conclusions: Add-on EPA/DHA treatment improved the effectiveness of conventional therapy (such as statin treatment) for improving the ABI in hemodialysis patients with dyslipidemia by lowering RLP-C levels. Therefore, clinicians involved in dialysis should focus on RLP-C when considering residual cardiovascular disease risk in hemodialysis patients and should consider screening patients with elevated levels.

Age and the Residual Risk of Cardiovascular Disease following Low Density Lipoprotein-Cholesterol Exposure.

We believe that there is sufficient evidence from basic science, longitudinal cohort studies and randomised controlled trials which validates the low-density lipoprotein cholesterol (LDL-C) or lipid hypothesis. It is important that we can communicate details of the cardiovascular disease (CVD) risk reduction that the average patient could expect depending on the scale of LDL-C decrease following lipid lowering therapy. It is also essential that residual risk (ResR) of CVD be highlighted. To achieve this aim by using existing trial evidence, we developed mathematical models initially for relative risk reduction (RRR) and absolute risk (AR) reduction and then showed that despite optimising LDL-C levels, a considerable degree of ResR remains that is dependent on AR. Age is significantly associated with AR (odds ratio: 1.02, 95% confidence intervals: 1.01-1.04) as was previously demonstrated by analysing the Whickham study cohort using a logistic regression model (age remaining significant even when all the other significant risk factors such as sex, smoking, systolic blood pressure, diabetes and family history were included in the regression model). A discussion of a paper by Ference et al. provided detailed evidence of the relationship between age and AR, based on lifetime LDL-C exposure. Finally, we discussed non-traditional CVD risk factors that may contribute to ResR based on randomised controlled trials investigating drugs improving inflammation, thrombosis, metabolic and endothelial status.

Evaluating the effect of the antiPCSK9 vaccine on systemic inflammation and oxidative stress in CFA-challenged albino mice

Abstract Background Besides effective lipid lowering therapy aimed to reduce LDL-C, one should always look at other risk factors that may essentially increase the risk of residual cardiovascular disease risk, including diabetes, thrombotic factors and inflammation. Purpose To find whether the antiPCSK9 vaccine can affect the serum C-reactive protein (CRP) and oxidative stress during acute systemic inflammation. Methods Male albino mice were randomly divided into three groups, including non-treated mice (the sham group), mice treated with Freund's complete adjuvant (CFA) (the CFA group), and vaccinated mice treated with CFA (the vaccine group). The vaccine group was subcutaneously immunized with the antiPCSK9 formulation, four times in bi-weekly intervals. To induce inflammation, all mice were subjected to the CFA challenge after the vaccination plan. To determine the efficacy of the antiPCSK9 vaccine in albino mice, plasma antiPCSK9 antibody titer, plasma PCSK9 concentration, and PCSK9/LDLR interaction were assayed. The serum level of high-sensitive CRP (hs-CRP) and oxidative stress status were evaluated by a mouse CRP ELISA kit and the pro-oxidant antioxidant balance (PAB) assay, respectively. Results Upon three boosters, the vaccine induced a high-titer IgG antiPCSK9 antibody in albino mice, which was accompanied with a significant reduction in the plasma level of the free PCSK9 (-24.7% and -28.5% compared with the sham and CFA group, respectively), and the inhibition of PCSK9/LDLR interaction (-27.8% and -29.4% compared with the sham and CFA group, respectively). In addition, the serum level of hs-CRP was significantly increased in the vaccine and CFA groups by 225% and 274%, respectively, when compared with the sham group; however, it was non-significantly decreased (-18%) in the vaccine group in comparison with the CFA group (Figure 1A). Moreover, the PAB values indicated that oxidative stress was significantly increased in the CFA group (by 72.7%) and the vaccine group (by 76%) when compared to the sham group; however, there was no significant difference in the PAB values between the vaccine and CFA groups (Figure 1B). Conclusion Our results indicate that, despite inducing the production of the functional antiPCSK9 antibodies, the antiPCSK9 vaccine failed to significantly reduce the serum hs-CRP and oxidative stress induced in the CFA-challenged albino mice. Figure 1. The effect of the antiPCSK9 vaccine on (A) the serum level of hs-CRP in albino mice and (B) the serum PAB in albino mice. The sham group involved non-treated mice, the CFA group involved the CFA-treated mice, and the vaccine group involved mice who after vaccination were treated with the CFA. Pooling of samples was performed to obtain sufficient sample volume for assay, when needed. The PAB values were expressed in an arbitrary HK (Hamidi-Koliakos). Data are expressed as mean ±SD (10 mice per group). Statistical differences at a p-value &amp;lt;0.05 were considered as significant.Figure 1.

High residual cardiovascular risk after lipid-lowering: prime time for Predictive, Preventive, Personalized, Participatory, and Psycho-cognitive medicine.

As time has come to translate trial results into individualized medical diagnosis and therapy, we analyzed how to minimize residual risk of cardiovascular disease (CVD) by reviewing papers on "residual cardiovascular disease risk". During this review process we found 989 papers that started off with residual CVD risk after initiating statin therapy, continued with papers on residual CVD risk after initiating therapy to increase high-density lipoprotein-cholesterol (HDL-C), followed by papers on residual CVD risk after initiating therapy to decrease triglyceride (TG) levels. Later on, papers dealing with elevated levels of lipoprotein remnants and lipoprotein(a) [Lp(a)] reported new risk factors of residual CVD risk. And as new risk factors are being discovered and new therapies are being tested, residual CVD risk will be reduced further. As we move from CVD risk reduction to improvement of patient management, a paradigm shift from a reductionistic approach towards a holistic approach is required. To that purpose, a personalized treatment dependent on the individual's CVD risk factors including lipid profile abnormalities should be configured, along the line of P5 medicine for each individual patient, i.e., with Predictive, Preventive, Personalized, Participatory, and Psycho-cognitive approaches.

Association of remnant cholesterol with hypertension, type 2 diabetes, and their coexistence: the mediating role of inflammation-related indicators

PurposeCholesterol metabolism is a risk factor for cardiovascular disease, and recent studies have shown that cholesterol metabolism poses a residual risk of cardiovascular disease even when conventional lipid risk factors are in the optimal range. The association between remnant cholesterol (RC) and cardiovascular disease has been demonstrated; however, its association with hypertension, type 2 diabetes mellitus (T2DM), and the concomitance of the two diseases requires further study. This study aimed to evaluate the association of RC with hypertension, T2DM, and both in a large sample of the U.S. population, and to further explore the potential mechanisms involved.MethodsThis cross-sectional study used data from the 2005—2018 cycles of the National Health and Nutrition Examination Survey (N = 17,749). Univariable and multivariable logistic regression analyses were performed to explore the relationships of RC with hypertension, T2DM, and both comorbidities. A restricted cubic spline regression model was used to reveal the dose effect. Mediation analyses were performed to explore the potential mediating roles of inflammation-related indicators in these associations.ResultsOf the 17,749 participants included (mean [SD] age: 41.57 [0.23] years; women: 8983 (50.6%), men: 8766 (49.4%)), the prevalence of hypertension, T2DM, and their co-occurrence was 32.6%, 16.1%, and 11.0%, respectively. Higher RC concentrations were associated with an increased risk of hypertension, T2DM, and their co-occurrence (adjusted odds ratios for per unit increase in RC were 1.068, 2.259, and 2.362, and 95% confidence intervals were 1.063–1.073, 1.797–2.838, and 1.834–3.041, respectively), with a linear dose–response relationship. Even when conventional lipids were present at normal levels, positive associations were observed. Inflammation-related indicators (leukocytes, lymphocytes, monocytes, and neutrophils) partially mediated these associations. Among these, leukocytes had the greatest mediating effect (10.8%, 14.5%, and 14.0%, respectively).ConclusionThe results of this study provide evidence that RC is associated with the risk of hypertension, T2DM, and their co-occurrence, possibly mediated by an inflammatory response.

Remnant Cholesterol, a Valuable Biomarker for Assessing Arteriosclerosis and Cardiovascular Risk: A Systematic Review.

Arteriosclerosis, as the foundation for the development of cardiovascular diseases, is influenced by disturbances in lipid metabolism. Extensive research has consistently shown a correlation between conventional lipid parameters, arteriosclerosis, and cardiovascular diseases. Guidelines highlight the importance of targeting low-density lipoprotein cholesterol (LDL-C) for primary and secondary prevention of cardiovascular diseases, with reducing LDL-C remaining the primary lipid-lowering strategy. However, even when LDL-C is lowered to optimal levels, there is a residual risk of cardiovascular disease. Recent findings have brought attention to remnant cholesterol (RC) as a significant factor contributing to this residual risk. The close association between RC, arteriosclerosis, and cardiovascular diseases presents exciting opportunities for lifestyle interventions and medical treatments to control and lower RC levels, offering new targets for preventing and managing related cardiovascular conditions. Our systematic review sheds light on the importance of considering RC as a valuable biomarker in assessing arteriosclerosis and its potential impact on cardiovascular health. By understanding the link between remnant cholesterol and arteriosclerosis, researchers and healthcare professionals can develop targeted interventions to mitigate cardiovascular risks, thus improving public health outcomes and reducing the economic burden associated with cardiovascular diseases.

The analysis of the role of probiotics in preventing and reducing the risk of atherosclerosis - literature review

Atherosclerosis is a chronic inflammatory disease of large and medium-sized arteries underlying cardiovascular disease (CVD), such as myocardial infarction, cerebrovascular stroke and peripheral vascular disease, which is the leading cause of mortality worldwide. It is characterized by deposition of modified lipoproteins, accumulation of immune cells and formation of fibrous tissue in the vessel wall. The disease occurs in vessels throughout the body and affects the function of almost all organs, including the lymphatic system, bone marrow, heart, brain, pancreas, adipose tissue, liver, kidneys and gastrointestinal tract. Many clinical trials of anti-atherosclerotic drugs have not provided satisfactory results, and their use is associated with a significant residual risk of cardiovascular disease and various side effects.Probiotics have recently attracted considerable interest for their potential use to prevent atherosclerosis. This review will discuss the mechanisms of effect and impact of probiotics on atherosclerosis risk factors, as well as the potential use of probiotics in the prevention of atherosclerosis, based on a review of the available literature in the PubMed database from 2019 to 2023 using key words on studies related to this topic.

The relevance of competing risk adjustment in cardiovascular risk prediction models for clinical practice.

Many models developed for predicting the risk of cardiovascular disease (CVD), are adjusted for the competing risk of non-CVD mortality, which has been suggested to reduce potential overestimation of cumulative incidence in populations where the risk of competing events is high. The objective was to evaluate and illustrate the clinical impact of competing risk adjustment when deriving a CVD prediction model in a high-risk population. Individuals with established atherosclerotic CVD were included from the Utrecht Cardiovascular Cohort - Secondary Manifestations of ARTerial disease (UCC-SMART). In 8,355 individuals, followed for median of 8.2 years (IQR 4.2-12.5), two similar prediction models for the estimation of 10-year residual CVD risk were derived: with competing risk adjustment using a Fine and Gray model and without competing risk adjustment using a Cox proportional hazards model. On average, predictions were higher from the Cox model. The Cox model predictions overestimated the cumulative incidence ((predicted-observed ratio 1.14 [95%CI 1.09-1.20), which was most apparent in the highest risk quartiles and in older persons. Discrimination of both models was similar. When determining treatment eligibility on thresholds of predicted risks, more individuals would be treated based on the Cox model predictions. If, for example, individuals with a predicted risk >20% were considered eligible for treatment, 34% of the population would be treated according to the Fine and Gray model predictions and 44% according to the Cox model predictions. Individual predictions from the model unadjusted for competing risks were higher, reflecting the different interpretations of both models. For models aiming to accurately predict absolute risks, especially in high-risk populations, competing risk adjustment must be considered.

Abstract 720: Integration Of Population Genetic And Human Knockout Studies With Smooth Muscle Cell Lineage Tracing In Mouse Models Identifies Novel Targets For Atherosclerosis And Cardiovascular Risk.

Despite lipid-lowering therapies, residual cardiovascular disease risk remains a major unmet clinical need. Large-scale genetic analyses have identified &gt;250 loci for coronary artery disease (CAD) risk. Genes that function in vascular smooth muscle cells (SMC) are causal at several loci, yet the causal genes at most loci remain unknown. Using single cell profiling and SMC lineage tracing in mouse models, we and others have shown that SMC transition through an intermediate state to SMC-derived cells (SDC) with protective or harmful phenotypes for plaque stability. In this study, we integrated SMC lineage tracing in mouse models with ongoing analyses in &gt; 1 million human participants with whole-genome (WGS) and whole-exome sequencing (WES) data, as well as rare variant analysis of human “knockouts” (homozygous for predicted loss-of-function variants) for a novel gene discovery pipeline (Figure 1). Through WES in 76,000 highly consanguineous participants in the Pakistan Genomic Resource (PGR), we assembled the largest global cohort of human KOs. At non-lipid CAD loci from a recent large multi-ethnic meta-analysis (~1.1 million participants), we prioritized genes as potentially causal in SMC/SDC as those that are expressed and regulated in human or mouse arteries and SMC in atherosclerosis progression. Through gene burden testing and analyses of rare predicted loss-of-function (pLoF) and damaging (pDMs) variants in the largest CAD WES/WGS meta-analyses we enriched for causal genes. We restricted to genes with at least 5 pLoF carriers in PGR to facilitate recall studies in Pakistan. Final prioritization incorporated state-of-the-art fine mapping and co-localization analyses as well as biological plausibility. From an initial pool of 1696 genes, our gene discovery pipeline prioritized 15 SMC/SDC genes, and initial recall in PGR identified multiple large pedigrees for mutations in candidate causal genes PDE3A, SERPINH1, HHIPL1, and ZEB2.

Association of Multitrajectories of Lipid Indices With Premature Cardiovascular Disease: A Cohort Study.

Background The multitrajectory model can identify joint longitudinal patterns of different lipids simultaneously, which might help better understand the heterogeneous risk of premature cardiovascular disease (CVD) and facilitate targeted prevention programs. This study aimed to investigate the associations between multitrajectories of lipids with premature CVD. Methods and Results The study enrolled 78 526 participants from the Kailuan study, a prospective cohort study in Tangshan, China. Five distinct multitrajectories of triglyceride, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol over 6-year exposure were identified on the basis of Nagin's criteria, using group-based multitrajectory modeling. During a median follow-up of 6.75 years (507 645.94 person-years), 665 (0.85%) premature CVDs occurred. After adjustment for confounders, the highest risk of premature CVD was observed in group 4 (the highest and increasing triglyceride, optimal and decreasing LDL-C, low and decreasing high-density lipoprotein cholesterol) (hazard ratio [HR], 2.13 [95% CI, 1.36-3.32]), followed by group 5 (high and decreasing triglyceride, optimal and increasing LDL-C, low and decreasing high-density lipoprotein cholesterol) (HR, 2.07 [95% CI, 1.45-2.98]), and group 3 (optimal and increasing triglyceride, borderline high and increasing LDL-C, optimal and decreasing high-density lipoprotein cholesterol) (HR, 1.90 [95% CI, 1.32-2.73]). Conclusions Our results showed that the residual risk of premature CVD caused by increasing triglyceride levels remained high despite the fact that LDL-C levels were optimal or declining over time. These findings emphasized the importance of assessing the joint longitudinal patterns of lipids and undertaking potential interventions on triglyceride lowering to reduce the residual risk of premature CVD, even among individuals with optimal LDL-C levels.

Exosomes in Cardiovascular Disease: From Mechanism to Therapeutic Target.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally. In recent decades, clinical research has made significant advances, resulting in improved survival and recovery rates for patients with CVD. Despite this progress, there is substantial residual CVD risk and an unmet need for better treatment. The complex and multifaceted pathophysiological mechanisms underlying the development of CVD pose a challenge for researchers seeking effective therapeutic interventions. Consequently, exosomes have emerged as a new focus for CVD research because their role as intercellular communicators gives them the potential to act as noninvasive diagnostic biomarkers and therapeutic nanocarriers. In the heart and vasculature, cell types such as cardiomyocytes, endothelial cells, vascular smooth muscle, cardiac fibroblasts, inflammatory cells, and resident stem cells are involved in cardiac homeostasis via the release of exosomes. Exosomes encapsulate cell-type specific miRNAs, and this miRNA content fluctuates in response to the pathophysiological setting of the heart, indicating that the pathways affected by these differentially expressed miRNAs may be targets for new treatments. This review discusses a number of miRNAs and the evidence that supports their clinical relevance in CVD. The latest technologies in applying exosomal vesicles as cargo delivery vehicles for gene therapy, tissue regeneration, and cell repair are described.

Design and methods of an open-label, randomized controlled trial to evaluate the effect of pemafibrate on proteinuria in CKD patients (PROFIT-CKD).

Hypertriglyceridemia is increasingly considered a residual risk of cardiovascular disease in patients with chronic kidney disease (CKD). Pemafibrate-a novel selective peroxisome proliferator-activated receptor alpha modulator and a new treatment for hypertriglyceridemia in CKD patients-is reported to have fewer side effects in CKD patients than other fibrates. Appropriate control of hypertriglyceridemia can be expected to improve renal prognosis. However, data on the renal protective effect of pemafibrate are limited. This study aims to evaluate the effectiveness of pemafibrate on urinary protein excretion in CKD patients. The Pemafibrate, open-label, Randomized cOntrolled study to evaluate the renal protective eFfect In hyperTriglyceridemia patients with Chronic Kidney Disease (PROFIT-CKD) study is an investigator-initiated, multi-center, open-label, parallel-group, randomized controlled trial. Participants are outpatients with hypertriglyceridemia aged 20years and over, who have received the care of a nephrologist or a diabetologist for more than 3months. Inclusion criteria include the following: proteinuria (urine protein/creatinine ratio of ≥ 0.15g/gCr) within three months before allocation, and hypertriglyceridemia (triglycerides ≥ 150mg/dL and < 1,000mg/dL) at allocation. In the treatment group, pemafibrate is added to conventional treatment, while conventional treatment is continued with no additional treatment in the control group. Target patient enrollment is 140 patients. The primary endpoint is the change from baseline in the logarithmic urine protein/creatinine ratio at 12months after study start. This study will provide new findings on the renal protective effect of pemafibrate in CKD patients. This clinical trial was registered at the University Hospital Medical Information Network (UMIN) Center (UMIN-CTR: UMIN000042284).

Residual Atherosclerotic Cardiovascular Disease Risk: Focus on Non-High-Density Lipoprotein Cholesterol.

Cardiovascular disease (CVD) caused by atherosclerosis is the leading cause of death worldwide. The level of low-density lipoprotein cholesterol (LDL-C), considered as the initiator of atherosclerosis, is the most widely used predictor for CVD risk and LDL-C has been the primary target for lipid-lowering therapies. However, residual CVD risk remains high even with very low levels of LDL-C. This residual CVD risk may be due to remnant cholesterol, high triglyceride levels, and low high-density lipoprotein cholesterol (HDL-C). Non-high density lipoprotein cholesterol (non-HDL-C), which is calculated as total cholesterol minus HDL-C (and represents the cholesterol content of all atherogenic apolipoprotein B-containing lipoproteins), has emerged as a better risk predictor for CVD than LDL-C and an alternative target for CVD risk reduction. Major international guidelines recommend evaluating non-HDL-C as part of atherosclerotic CVD risk assessment, especially in people with high triglycerides, diabetes, obesity, or very low LDL-C. A non-HDL-C target of <130 mg/dL (3.4 mmol/L) has been recommended for patients at very high risk, which is 30 mg/dL (0.8 mmol/L) higher than the corresponding LDL-C target goal. Non-HDL-C lowering approaches include reducing LDL-C and triglyceride levels, increasing HDL-C, or targeting multiple risk factors simultaneously. However, despite the growing evidence for the role of non-HDL-C in residual CVD risk, and recommendations for its assessment in major guidelines, non-HDL-C testing is not routinely done in clinical practice. Thus, there is a need for increased awareness of the need for non-HDL-C testing for ascertaining CVD risk and concomitant prevention of CVD.

Atherogenic Lipoproteins for the Statin Residual Cardiovascular Disease Risk

Randomized controlled trials (RCTs) show that decreases in low-density lipoprotein cholesterol (LDL-C) by the use of statins cause a significant reduction in the development of cardiovascular disease (CVD). However, one of our previous studies showed that, among eight RCTs that investigated the effect of statins vs. a placebo on CVD development, 56-79% of patients had residual CVD risk after the trials. In three RCTs that investigated the effect of a high dose vs. a usual dose of statins on CVD development, 78-87% of patients in the high-dose statin arms still had residual CVD risk. The risk of CVD development remains even when statins are used to strongly reduce LDL-C, and this type of risk is now regarded as statin residual CVD risk. Our study shows that elevated triglyceride (TG) levels, reduced high-density lipoprotein cholesterol (HDL-C), and the existence of obesity/insulin resistance and diabetes may be important metabolic factors that determine statin residual CVD risk. Here, we discuss atherogenic lipoproteins that were not investigated in such RCTs, such as lipoprotein (a) (Lp(a)), remnant lipoproteins, malondialdehyde-modified LDL (MDA-LDL), and small-dense LDL (Sd-LDL). Lp(a) is under strong genetic control by apolipoprotein (a), which is an LPA gene locus. Variations in the LPA gene account for 91% of the variability in the plasma concentration of Lp(a). A meta-analysis showed that genetic variations at the LPA locus are associated with CVD events during statin therapy, independent of the extent of LDL lowering, providing support for exploring strategies targeting circulating concentrations of Lp(a) to reduce CVD events in patients receiving statins. Remnant lipoproteins and small-dense LDL are highly associated with high TG levels, low HDL-C, and obesity/insulin resistance. MDA-LDL is a representative form of oxidized LDL and plays important roles in the formation and development of the primary lesions of atherosclerosis. MDA-LDL levels were higher in CVD patients and diabetic patients than in the control subjects. Furthermore, we demonstrated the atherogenic properties of such lipoproteins and their association with CVD as well as therapeutic approaches.

Remnant cholesterol and the risk of cardiovascular disease in type 2 diabetes: a nationwide longitudinal cohort study

BackgroundElevated remnant cholesterol (remnant-C) is considered a risk factor for cardiovascular disease (CVD); however, whether this notion applies to the East Asian population with type 2 diabetes (T2D) has not been established. This study investigated the association between remnant-C concentrations and the risk of CVD in Korean patients with T2D.MethodsBy using the Korean National Health Insurance Service database, 1,956,452 patients with T2D and without atherosclerotic CVD who underwent regular health checks between 2009 and 2012 were included. Cox regression analyses were conducted to assess the association between remnant-C concentrations and incident CVD comprising myocardial infarction (MI) and ischemic stroke.ResultsIn total, 50,120 (2.56%) cases of MI and 73,231 (3.74%) cases of ischemic strokes occurred during a median follow-up of 8.1 years. The adjusted hazard ratios for MI and stroke in the highest remnant-C quartile were 1.281 (95% confidence interval [CIs], 1.249–1.314) for MI and 1.22 (1.195–1.247) for ischemic stroke, compared to those in the lowest quartiles. The results were similar, based on stratified analysis by age, sex, use of statin or fibrate, and levels of other cholesterol. The increased risk of CVD in the highest remnant-C quartile was profound in patients who had a longer T2D duration. A remnant-C concentration ≥ 30 mg/dL differentiated patients who were at a higher risk of CVD, compared to patients with a lower concentrations, regardless of whether LDL-C levels were or were not on target at ≤ 100 mg/dL.ConclusionIn Korean patients with T2D, remnant-C was associated with CVD, independent of the LDL-C level or other conventional CVD risk factors. Our finding confirmed evidence of the causal role of remnant-C on CVD, as a residual risk of CVD, in East Asian patients with T2D.

Probiotics Bring New Hope for Atherosclerosis Prevention and Treatment.

Cardiovascular disease is the leading cause of human mortality and morbidity worldwide. Atherosclerosis (AS) is the underlying pathological responsible in most acute and severe cardiovascular diseases including myocardial infarction and stroke. However, current drugs applied to the treatment of AS are not clinically effective, and there is a large residual risk of cardiovascular disease and multiple side effects. Increasing evidence supports a close relationship between microorganisms and the incidence of AS. Recent data have shown that probiotics can improve multiple key factors involved in the development and progression of AS, including cholesterol metabolism imbalance, endothelial dysfunction, proinflammatory factor production, macrophage polarization, intestinal flora disturbance, and infection with pathogenic microorganisms, and therefore probiotics have attracted great interest as a novel potential “medicine”. This review is aimed at summarizing the effects of probiotics on various influencing factors, and providing valuable insights in the search for early prevention and potential therapeutic strategies for AS.

Lipoprotein Lipase: Is It a Magic Target for the Treatment of Hypertriglyceridemia.

High levels of triglycerides (TG) and triglyceride-rich lipoproteins (TGRLs) confer a residual risk of cardiovascular disease after optimal low-density lipoprotein cholesterol (LDL-C)–lowering therapy. Consensus has been made that LDL-C is a non-arguable primary target for lipid lowering treatment, but the optimization of TGRL for reducing the remnant risk of cardiovascular diseases is urged. Omega-3 fatty acids and fibrates are used to reduce TG levels, but many patients still have high TG and TGRL levels combined with low high-density lipoprotein concentration that need to be ideally treated. Lipoprotein lipase (LPL) is a key regulator for TGs that hydrolyzes TGs to glycerol and free fatty acids in lipoprotein particles for lipid storage and consumption in peripheral organs. A deeper understanding of human genetics has enabled the identification of proteins regulating the LPL activity, which include the apolipoproteins and angiopoietin-like families. Novel therapeutic approach such as antisense oligonucleotides and monoclonal antibodies that regulate TGs have been developed in recent decades. In this article, we focus on the biology of LPL and its modulators and review recent clinical application, including genetic studies and clinical trials of novel therapeutics. Optimization of LPL activity to lower TG levels could eventually reduce incident atherosclerotic cardiovascular disease in conjunction with successful LDL-C reduction.