Residual cardiovascular risk in CKD: Reevaluating remnant cholesterol and inflammation.

Residual cardiovascular risk: When should we treat it?

Although pharmacological treatments of hypertension and dyslipidaemia are both associated with a reduction in cardiovascular risk, little is known about the degree of cardiovascular risk remaining in treated individuals, by assessing the levels of their risk factors achieved, that is their 'residual cardiovascular risk'. We then used the data from the Prospective Epidemiological Study of Myocardial Infarction (PRIME), which involved 9649 men aged 50-59 years, from France and Northern Ireland with a 10-year follow-up, to test the presence of specific residual cardiovascular risks of coronary heart disease, stroke, total of fatal and non-fatal cardiovascular events and cardiovascular mortality, in patients treated with antihypertensive agents or lipid-lowering agents. In the whole cohort, a total of 796 patients developed a fatal or non-fatal cardiovascular event. Antihypertensive drug use at baseline was significantly associated (RR=1.50, 95% CI: 1.25-1.80) with total cardiovascular event risk, but not lipid-lowering drug use, after adjusting for classic risk factors (age, smoking, total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure and diabetes). Similar results were obtained for coronary heart disease (RR=1.46, 95% CI: 1.18-1.80), stroke (RR=1.75, 95% CI: 1.14-2.70) and cardiovascular death (RR=1.62, 95% CI: 1.02-2.58), but neither for total death (RR=1.15, 95% CI: 0.89-1.48) nor for non-cardiovascular death (RR=1.00, 95% CI: 0.74-1.36). For any cardiovascular end point, residual risks did not globally differ according to the antihypertensive drug class prescribed at baseline. In conclusion, treatment with antihypertensive agents, but not with lipid-lowering agents, was associated with a sizeable residual cardiovascular risk, suggesting that more efficient risk reduction strategies in hypertension should be developed as a priority.

Residual cardiovascular risk can be defined as the residual risk of incident vascular events or progression of established vascular damage persisting in patients treated with current evidence-based recommended care including the risk that established from risk factors, such as dyslipidemia, high blood pressure, and the risk related to emerging or newer risk factors. The concept clearly derives from intervention trials, mainly the statin trials, and there is a lot of debate about the residual risk conferred by other lipid components, in particular low levels of HDL cholesterol and high levels of triglycerides. A meta-analysis of 53 fibrates (16,802 subjects) and 30 niacin trials (4,749 subjects) revealed an average HDL-C increase of 10% with fibrates and 16% with niacin, a triglyceride decrease of 36% with fibrates and 20% with niacin, and a LDL-C decrease of 8% with fibrates and 14% with niacin. These lipid changes resulted in similar overall reductions in major coronary events evidenced by a 25% decrease with fibrates and 27% with niacin. However, recent analyses of the primary and secondary prevention trials like JUPITER, Treating to New Targets (TNT) and PROVE-IT TIMI 22 force to reconsider the issue. In these three trials, HDL-C was useful in the initial risk assessment but when LDL-C was aggressively lowered the residual risk predictive value of HDL-C was markedly attenuated. Also epidemiological studies evaluate the residual risk in treated hypertensives and dyslipidemic subjects within a general population. The PRIME study in Northern Ireland and France and the Progetto CUORE study in Italy, both with a 10-year follow-up were able to test the hypothesis of the residual cardiovascular risk in treated hypertensives, because the proportion of treated dyslipidemic subjects was too low at baseline. In both studies treatment with antihypertensive agents was associated with a sizeable residual cardiovascular risk with the hazard ratio of 1.5-1.7, suggesting that more efficient risk reduction strategies in hypertension should be developed as a priority. In conclusion residual cardiovascular risk should be better studied in cardiovascular epidemiology, refining the methods to evaluate it, to consider measures of exposure to the modifiable risk factors and indicators of treatment (both at pharmacological and lifestyle level) over the time. Repeated measures and cohortal follow-up are needed and also new statistical methods are necessary to evaluate the residual risk to understand how to reduce it.

Joint exposure to multiple air pollutants and residual cardiovascular risk in hypertension.

Every cardiovascular clinical trial that has examined the beneficial effects of lowering LDL cholesterol to prevent cardiovascular events has demonstrated residual cardiovascular risk in the interventional treatment group. Residual risk is the term applied to the cardiovascular events (e.g., myocardial infarction, stroke, and cardiovascular death) that occur in spite of being on “optimal” medical therapy. This term is usually applied to secondary intervention studies, i.e., lipid lowering treatments in subjects who have already had at least one cardiovascular event. Studies that described residual risk have attributed it, at least in part, to the fact that the LDLc has not been lowered sufficiently to stop atherosclerotic plaque formation and rupture into the arterial lumen. However, a recent cardiovascular intervention clinical trial which achieved a very low group median LDLc of 30 mg/dl still demonstrated significant residual risk. Of more importance to reducing residual risk may be addressing the ongoing inflammation in the coronary arteries that results in cellular liberation of cytokines and proteases that attack the atherosclerotic plaque’s fibrous cap. Recent studies have shown that inflammation may act independently of LDL to cause cardiovascular events. This article provides evidence that inflammation is the primary cause of residual risk and will need to be treated as aggressively as LDL lowering if CVD events in the post treatment period are to be significantly reduced. Addressing major risk factors including obesity, diabetes, smoking, hypertension and hyperlipidemia are critical to reducing inflammation. Statins and aspirin are the mainstay medications to reduce ongoing inflammation. However, newer pharmaceuticals may also be required to reduce inflammation to undetectable levels. Targeting inflammation to eradicate residual cardiovascular risk will be the next therapeutic challenge facing primary care physicians.

IntroductionThe objective of this study was twofold: 1) to assess the residual cardiovascular (CV) risk among patients treated with statins according to guidelines and at the recommended dosages; and 2) to assess the difference, if any, in the frequency of CV events when patients were treated with other lipid-lowering agents alongside statins.MethodsA retrospective observational study including one local health unit was conducted. Administrative databases were linked to laboratory test database in order to collect cholesterol values at baseline. Patients were included if they had filled at least one prescription for statins between January 1, 2009 and December 31, 2011; patients’ records were considered for a 12-month time span.ResultsA total of 27,330 patients treated with statins were included (50% male, mean age 68.0±11.5 years). Among them, 770 were treated with statins according to guidelines and at the recommended dosages and had a low density lipoprotein-cholesterol value below the therapeutic target. Nevertheless, the risk of myocardial infarction or stroke remained: incidence rates were 1.3±1.0 per patient per year for moderate CV risk, 4.1±2.6 for high risk, and 12.5±11.0 for very high risk. This incremental risk was confirmed further using the Cox model, by correcting for age, sex, use of antiplatelet and/or antihypertensive therapy, and adherence to treatment. As a second analysis, we compared, after a propensity score matching, patients extracted from the overall sample who were treated with fibrates. Based on the Cox model, patients on fibrates had a risk for myocardial infarction or stroke lower than patients on statins.ConclusionAmong patients treated with statins according to guidelines and at the recommended dosages, a residual CV risk was observed. We concluded that intervention for managing residual CV risk during statin therapy should be implemented.

The treatment of essential hypertension has improved dramatically during the past 50 years. However, even optimally treated hypertensives still have considerable residual cardiovascular risk (see below), and this residual risk exerts a huge impact overall because essential hypertension is such a common disease. With regard to residual risk, an optimally treated hypertensive patient still has a 50% increased risk of a cardiovascular event even after correcting for systolic blood pressure, that is, a treated hypertensive is at 50% greater cardiovascular risk than an untreated normotensive with the same systolic BP.1 When the cardiovascular risk in treated hypertension is broken down further, the increased risk of stroke, coronary disease, and cardiovascular death are 75%, 46%, and 62%, respectively. Many other studies have found the same increased residual cardiovascular risk in treated hypertension.2–7 Intriguingly, the higher the pretreatment cardiovascular risk is the greater the absolute risk reduction when BP is reduced and yet the higher also is the residual risk.8 Whatever the cause of this residual risk in hypertension, we ought to strive to find novel therapeutic strategies against it because this extra residual risk (50%) applies to >50% of all individuals aged ≥60 years in a population (ie, all the hypertensives). In other words, the scale of this problem is such that reducing residual risk, even modestly, could markedly reduce cardiovascular events/mortality overall and, thereby have an enormous impact on a population’s health and healthcare costs. The most obvious strategy that has been attempted to reduce residual risk was to try setting a lower target BP than the current one. However, attempts to do this have been disappointing. The best example of this is the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study.9 We therefore need a better strategy to tackle this problem than …

Background: Even with high-dose statin therapy, residual cardiovascular event risks remain in patients with chronic coronary syndrome (CCS). Thus, future treatment targets need to be elucidated. This study determined the factors associated with residual cardiovascular risk in patients with CCS treated with high-dose statins.Methods and Results: This study was a subanalysis of the REAL-CAD study. This study enrolled 5,540 patients with CCS receiving 4 mg/day pitavastatin and assessed the impacts of 3 representative risk factors (i.e., blood pressure, glucose level, and renal function), alone or in combination, on clinical outcomes. Each risk factor was classified according to its severity. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, and unstable angina requiring emergency hospitalization. After adjusting for the effects of confounders, a significantly worse prognosis was observed in the group with an estimated glomerular filtration rate (eGFR) ≤60 mL/min/1.73 m2 (hazard ratio [HR] 1.36; 95% confidence interval 1.03–1.80; P=0.028). No other factors or combinations were associated with the primary endpoint. An eGFR ≤60 mL/min/1.73 m2 was also associated with cardiac (HR 2.38; P=0.004) and all-cause (HR 1.51; P=0.032) death.Conclusions: Insufficient renal function was associated with a worse prognosis in patients with CCS undergoing high-dose statin therapy, suggesting that renal function is the next target for reducing the risk of residual cardiovascular events.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation Background and Purpose Low-density lipoprotein cholesterol (LDL-C) is among the conventional lipid parameters used to predict risk of cardiovascular disease (CVD). Statins lower blood levels of pro-atherogenic LDL-C, but a residual cardiovascular risk remains in some individuals with therapeutically optimised LDL-C levels. Although the metabolism of LDL-C and other lipoprotein particles is governed by a range of different apolipoproteins, only apolipoproteins A-I and B are measured in clinical assays. Using a more comprehensive apolipoprotein panel in a large epidemiological cohort, this study aimed to determine the association of individual apolipoprotein levels with risk of coronary heart disease (CHD). Methods Bottom-up multiple reaction monitoring–mass spectrometry (MRM–MS) was used in conjunction with stable isotope-labelled peptide standards to quantify plasma levels of 13 apolipoproteins in participants of the Precocious Coronary Artery Disease (PROCARDIS) study (N = 1916; 941 cases of CHD, 975 controls). The relationship between apolipoprotein levels and CHD was assessed after adjusting for established risk factors for CVD and correcting for statin use. Results The strongest positive associations with CHD in the PROCARDIS study were seen for triglyceride-related apolipoproteins C-I (odds ratio [OR] 2.38, 95% confidence interval [CI] 1.63–3.46), C-III (OR 2.95, 95% CI 1.85–4.71) and E (OR 2.35, 95% CI 1.54–3.58), as well as for apolipoprotein (a) (kringle IV type 2 repeat, OR 2.84, 95% CI 2.04–3.95). Comparing these with associations of apolipoproteins with CVD in the Bruneck study (N = 688) revealed consistency across the two cohorts. Robust inverse associations with CHD were observed for apolipoproteins A-IV (OR 0.45, 95% CI 0.31–0.65) and M (OR 0.29, 95% CI 0.19–0.44). Conclusion Analysing two large epidemiological cohorts, Bruneck and PROCARDIS, demonstrated that multiplexed apolipoprotein profiling improves the understanding of cardiovascular risk independent of conventional lipid parameters. Most prominently, triglyceride-related apolipoproteins were shown to positively associate with residual cardiovascular risk. The findings of this study support the need for development and implementation of standardised, MRM–MS-based apolipoprotein profiling assays to guide novel lipid-modifying therapies beyond statins.

BackgroundLow-density lipoprotein cholesterol (LDL-C) has now been the primary target for lipid-lowering therapy in the European and US guidelines for the management of dyslipidemia, with increasing interest in apolipoprotein B (ApoB) as a secondary target. The relationship between ApoB and the severity of acute myocardial infarction as well as residual risk still needs to be further determined. Coronary atherosclerosis occurs as a result of a complex set of factors, and there is a strong relationship between insulin resistance and cardiovascular disease. In contrast, there are limited studies on the relationship between TyG index (triglyceride glucose index), an indicator of insulin resistance, and cardiovascular disease. The purpose of this study was to investigate the value of ApoB and TyG index in assessing the severity of myocardial infarction and predicting prognosis.MethodsThis study included 712 participants with acute myocardial infarction for a 5-year follow-up. Spearman correlation analysis and generalized linear model analysis were used to assess the correlation between ApoB and the severity of coronary atherosclerosis. Risk regression analysis was used to assess the correlation between ApoB and residual risk in patients with acute myocardial infarction, and the C-statistic, net reclassification index (NRI), and integrated discriminant improvement index (IDI) were further calculated to assess the predictive value of ApoB for residual risk after myocardial infarction.ResultsCategorizing apoB, LDL-C, and TyG indices according to tertiles, higher levels of ApoB were significantly associated with the severity of coronary artery stenosis in patients with acute myocardial infarction (P<0.001), whereas no such associations were found for elevated levels of LDL-C and TyG indices (P >0.05). Higher levels of apoB were significantly associated with residual risk of coronary atherosclerotic heart disease after full adjustment for confounders. Higher levels of ApoB were significantly associated with residual risk of coronary atherosclerotic heart disease by binary logistic regression analysis after complete adjustment for confounders. In multivariate variable-adjusted models, the OR and 95% CI for intermediate levels of ApoB (0.85-1.05 g/L) compared with low levels of ApoB (≤0.84 g/L) and residual risk after myocardial infarction was 2.06 (1.11, 3.81) (P<0.05), and for high levels of ApoB (≥1.06 g/L) the OR and 95% CI was 2.60 (1.29, 5.26) (P < 0.05); for each SD increase in ApoB level, the increase in residual risk after myocardial infarction would increase 4.75-fold (P = 0.001). Higher levels of TyG index were not found to be significantly associated with residual risk after myocardial infarction (P > 0.05). The inclusion of LDL-C, ApoB, and TyG indices in the constructed baseline risk model, and ApoB significantly improved the predictive ability of the traditional risk model for residual risk. The ROC curve of the baseline risk model showed an AUC of 0.649; the AUC after adding LDL-C to the model was 0.680 (P=0.05684); the AUC after adding TyG to the model was 0.663 (P=0.1635); and the addition of ApoB to the baseline model increased the AUC substantially to 0.702 (P= 0.00417). Inclusion of ApoB in the baseline risk model improved the prediction of MACE most significantly in the baseline model (net reclassification index [NRI]: 0.3324, P < 0.001; integrated discriminant improvement index [IDI]: 0.0414, P < 0.001); with the inclusion of LDL-C the NRI was 0.3218 (P < 0.001), and IDI was 0.0263 (P < 0.001); NRI after inclusion of TyG index was 0.2169 (P = 0.017); IDI was 0.0082 (P = 0.022).ConclusionsApoB is an independent risk factor for major adverse cardiovascular events (MACE) following myocardial infarction. Elevated ApoB levels are more advantageous than elevated LDL-C levels in assessing the severity of coronary artery stenosis in myocardial infarction patients and predicting residual risk after myocardial infarction. Therefore, in patients with acute myocardial infarction, ApoB can be considered to guide further intensive treatment. However, the TyG index did not demonstrate a significant advantage in predicting cardiovascular residual risk in this study.

Background: CAD is the leading cause of death and disability in US. Cardiac rehabilitation (CR) program is an important secondary-prevention intervention to reduce mortality, cardiovascular (CV) events, &amp; disability. At start of CR program, patients undergo extensive risk assessment to guide risk reduction goals. However, the residual risk at CR completion is not well studied. We sought to investigate the residual modifiable risk factors of patients completing CR Methods: We retrospectively reviewed our center’s data on consecutive patients between October 2012 and November 2013 who were entered into the American Association of Cardiovascular and Pulmonary Rehabilitation (AACVPR) registry and identified those who completed the CR program. We calculated their residual risk using the newly released ACC/AHA’s ‘Pooled Cohort Equations CV Risk Calculator’ (ACC/AHA risk) and Framingham risk (FR) calculator Results: Out of 128 consecutive CR participants, 44 (34%) completed the program. Patient characteristics and risk assessment are summarized in table 1. As per AACVPR risk stratification algorithm, 37 (84%) of patients were intermediate to high risk. Compared to the start, at completion of CR program, there was a significant improvement in 6-minute walk distance (365±107 vs 484± 137, p&lt;0.001), favorable reduction in total cholesterol, LDL-C, non-HDL-C (p&lt;0.001) and metabolic syndrome (p=0.02). At time of completion, calculated 10 year CV risk using ACC/AHA risk calculator was still elevated (14±10%), while 64% of patients had elevated risk≥7.5% (mean 19.3±9%). FR estimation was low (9±4%). The two risk scores showed moderate correlation (Pearson’s r=0.6, p&lt;0.001), but the ACC/AHA risk was significantly higher than the FR estimation (p&lt;0.001). In multivariate linear regression model, waist circumference (WC) at discharge was significant modifiable independent predictor of ASCVD risk, while systolic BP showed a trend towards significance Conclusion: Successful completion of CR program is associated with improvement in CV risk profile. However, the residual CV risk remains elevated at time of CR completion and is driven by WC &amp; systolic BP. Elevated WC from central adiposity is the main residual atherogenic CV risk factor post CR completion. Further research on significant WC reduction during CR is needed

Background Patients with a recent acute coronary syndrome (ACS) remain at high residual cardiovascular risk to which cholesterol, inflammation, and yet-to-be-identified pathways jointly contribute (1). The novel Junctional Protein Associated with Coronary Artery Disease (JCAD) protein drives incident cardiovascular events via pathways, among them fibrinolysis, that act independently from lipid metabolism and inflammation (2). Purpose Whether circulating JCAD provides predictive utility over and above established risk factors among ACS patients at residual lipid risk (RLR), residual inflammatory risk (RIR), or both (RILR), remains unknown. Methods Among patients participating in the multicentre SPUM-ACS study, patients at RLR (on-statin LDL-C ≥70.0 mg/dl), RIR (on-statin hs-CRP ≥2.0 mg/l) or both (RILR; on-statin LDL-C ≥70.0 mg/dl and CRP ≥2.0 mg/l),(1,3) and propensity-score matched (PSM) controls were identified, and the contributions of plasma hs-CRP, LDL-C and JCAD toward recurrent major adverse cardiovascular events (MACE; defined as a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) were studied by fitting uni- and multivariable-adjusted Cox proportional hazard regression models. Results Patients at RLR, RIR, or both (RILR) were at higher MACE risk compared to controls (hazard ratio [HR] per log2 increase, 1.51; 95% confidence interval (CI), 1.05-2.17; HR, 1.78; 95% CI, 1.23-2.58; and HR 1.75; 95% CI, 1.12-2.74; Figure 1). Among those at RLR, MACE risk increased with increasing levels of hs-CRP and JCAD, respectively, in uni- (HR, 1.17; 95% CI, 1.06–1.30; HR, 1.29; 95% CI, 1.03-1.62) and multivariable-adjusted models (adjusted [a]HR, 1.16; 95% CI, 1.03–1.30; aHR, 1.27; 95% CI, 1.01-1.60), whereas no association of LDL-C and future MACE risk was noted. Similarly, among patients at RIR, MACE risk increased by 1.28-fold per log2 increase in plasma JCAD (HR, 1.28; 95% CI, 1.03–1.59), which prevailed in multivariable-adjusted models accounting for potential confounders (aHR, 1.31; 95% CI, 1.04–1.65). In ACS patients at both residual inflammatory and lipid risk, MACE risk associated almost linearly with increasing JCAD levels (HR, 1.45; 95% CI, 1.09–1.92), independently of potential confounders (aHR, 1.47; 95% CI, 1.11–1.97). Meanwhile, no association of LDL-C or hs-CRP with MACE risk was identified among these high-risk patients (Figure 2). Conclusions ACS patients at RIR, RLR, or both are at high ischaemic risk, with JCAD ranking among the top predictors of MACE across the broad spectrum of residual risk. Our data highlight the importance of novel pathways to address residual cardiovascular risk, with JCAD ranking among most promising candidates.

One of the most effective classes of medications for preventing cardiovascular events is 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, more commonly known as statins. Statin therapy has been shown to decrease cardiovascular morbidity and mortality rates in virtually every patient population studied and will likely continue to be a mainstay of cardiovascular risk prevention for years to come. However, close examination of statin clinical trial data reveals that, even though this class of drugs has been highly effective, an unacceptably large number of patients on statins still experience cardiovascular events. For example, in the Scandinavian Simvastatin Survival Study (4S) trial, which studied patients with very high levels of low-density lipoprotein cholesterol (LDL-C and known coronary heart disease (CHD), a significant risk reduction was observed with statin treatment. A greater percentage of patients on placebo (28%) experienced a major cardiovascular event than did patients on statin therapy (19%), and the relative risk of a major cardiovascular event in the statin-treated patients was 0.66.27 On the other hand, those results from 4S also indicate that, over the 5 years of the study, almost 20% of statin-treated patients still had a cardiovascular event. In several major statin trials, significant residual cardiovascular risk remained even after significant reductions in LDL-C had been achieved.27-32 Thus, despite the decrease in cardiovascular events due to statin treatment, two-thirds of the adverse cardiovascular events still occurred, which indicates that both patient lifestyle changes and new pharmacological strategies are necessary to address cardiovascular disease.33 Additional trials have included high-risk patients with CHD or diabetes who were treated with intensive LDL-lowering statin therapy. In 3 of these trials, as shown in Figure 1, lowering LDL-C to approximately 100 mg per dL was compared with more intensive LDL-C lowering to approximately 70 mg per dL to investigate cardiovascular event reduction even in high-risk patient populations.14-16,34 In the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) study, 4,162 patients with acute coronary syndrome (ACS) were treated with either pravastatin 40 mg or atorvastatin 80 mg. Treatment with pravastatin reduced LDL-C to 95 mg per dL, whereas treatment with high-dose atorvastatin reduced LDL-C to 62 mg per dL.14 Clinical events were reduced in the high-dose atorvastatin group versus the pravastatin group; however, over the course of the 2-year trial, 22.4% of the individuals treated with intensive statin therapy (atorvastatin 80 mg) still suffered a major cardiovascular event.14 Similar results have been observed in the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study and the Treating to New Targets (TNT) study. After 4.8 years in the IDEAL study, 12.0% of patients experienced a major cardio vascular event even after intensive LDL-C lowering with 80 mg per day of atorvastatin.16 In the TNT trial, after 4.9 years of follow-up, 8.7% of patients receiving 80 mg per day of atorvastatin still suffered a major cardiovascular event.15 Thus, significant residual cardiovascular risk remains in patients even after intensive statin therapy that achieves LDL-C goals < 100 mg per dL.14-16,34 Patients with diabetes, another high-risk population, show significant cardiovascular risk reduction when treated with statins. A meta-analysis of 14 statin trials by the Cholesterol Treatment Trialists’ Collaborators examined data of major vascular events in patients with diabetes.2 A reduction in LDL-C in individuals with a prior history of CHD and either with or without diabetes was associated with a significant reduction in cardiovascular events. There was a 9% proportional reduction in all-cause mortality per 1 mmol per L (39 mg per dL) reduction in LDL-C in individuals with diabetes (P = 0.02) and a 13% reduction in those without diabetes (P < 0.001). Moreover, there was a significant 21% reduction in major vascular events per 1 mmol per L (39 mg per dL) reduction in LDL-C in people with diabetes (P < 0.001) and those without diabetes (P < 0.001).2 Nonetheless, in patients with diabetes treated with statin therapy, the cardiovascular event rate (i.e., residual cardiovascular risk) remained unacceptably high, and was even higher than the cardiovascular event rate of those patients without diabetes who received placebo.2 It is clear, then, that residual cardiovascular risk remains in all patients treated with statins, and that the residual cardiovascular risk is particularly high in patients with diabetes treated with statins.

Purpose of ReviewThe omega-3 fatty acids (n3-FAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have recently undergone testing for their ability to reduce residual cardiovascular (CV) risk among statin-treated subjects. The outcome trials have yielded highly inconsistent results, perhaps attributable to variations in dosage, formulation, and composition. In particular, CV trials using icosapent ethyl (IPE), a highly purified ethyl ester of EPA, reproducibly reduced CV events and progression of atherosclerosis compared with mixed EPA/DHA treatments. This review summarizes the mechanistic evidence for differences among n3-FAs on the development and manifestations of atherothrombotic disease.Recent FindingsLarge randomized clinical trials with n3-FAs have produced discordant outcomes despite similar patient profiles, doses, and triglyceride (TG)-lowering effects. A large, randomized trial with IPE, a prescription EPA only formulation, showed robust reduction in CV events in statin treated patients in a manner proportional to achieved blood EPA concentrations. Multiple trials using mixed EPA/DHA formulations have not shown such benefits, despite similar TG lowering. These inconsistencies have inspired investigations into mechanistic differences among n3-FAs, as EPA and DHA have distinct membrane interactions, metabolic products, effects on cholesterol efflux, antioxidant properties, and tissue distribution. EPA maintains normal membrane cholesterol distribution, enhances endothelial function, and in combination with statins improves features implicated in plaque stability and reduces lipid content of plaques.SummaryInsights into reductions in residual CV risk have emerged from clinical trials using different formulations of n3-FAs. Among high-risk patients on contemporary care, mixed n3-FA formulations showed no reduction in CV events. The distinct benefits of IPE in multiple trials may arise from pleiotropic actions that correlate with on-treatment EPA levels beyond TG-lowering. These effects include altered platelet function, inflammation, cholesterol distribution, and endothelial dysfunction. Elucidating such mechanisms of vascular protection for EPA may lead to new interventions for atherosclerosis, a disease that continues to expand worldwide.

The presence of residual cardiovascular risk is an important cause of cardiovascular events. Despite the significant advances in our understanding of residual cardiovascular risk, a comprehensive analysis through bibliometrics has not been performed to date. Our objective is to conduct bibliometric studies to analyze and visualize the current research hotspots and trends related to residual cardiovascular risk. This will aid in understanding the future directions of both basic and clinical research in this area. The literature was obtained from the Web of Science Core Collection database. The literature search date was September 28, 2022. Bibliometric indicators were analyzed using CiteSpace, VOSviewer, Bibliometrix (an R package), and Microsoft Excel. A total of 1167 papers were included, and the number of publications is increasing rapidly in recent years. The United States and Harvard Medical School are the leading country and institution, respectively, in the study of residual cardiovascular risk. Ridker PM and Boden WE are outstanding investigators in this field. According to our research results, the New England Journal of Medicine is the most influential journal in the field of residual cardiovascular risk, whereas Atherosclerosis boasts the highest number of publications on this topic. Analysis of keywords and landmark literature identified current research hotspots including complications of residual cardiovascular risk, risk factors, and pharmacological prevention strategies. In recent times, global attention toward residual cardiovascular risk has significantly increased. Current research is focused on comprehensive lipid-lowering, residual inflammation risk, and dual-pathway inhibition strategies. Future efforts should emphasize strengthening international communication and cooperation to promote the comprehensive evaluation and management of residual cardiovascular risk.