Mothers against decapentaplegic homolog 4 as a proteomic hub in vascular remodeling and residual cardiovascular risk

Residual cardiovascular risk: When should we treat it?

Background: The SMART-REACH model predicts the risk or recurrent cardiovascular events. Objectives: The objectives of this study were: a) to evaluate the residual cardiovascular risk in a secondary prevention population with low-density lipoprotein cholesterol (LDL-C) levels above the recommended goal, using a simulation model; and b) to determine the impact of optimizing lipid-lowering therapies in terms of residual cardiovascular risk reduction. Methods: We conducted a cross-sectional, descriptive and multicenter study. Patients with a history of cardiovascular disease and LDL-C ≥ 55 mg/dL were consecutively included. The 10-year and lifetime risk of recurrent events (myocardial infarction, stroke, or vascular death) were estimated using the SMART-REACH model. By means of a simulation, lipid-lowering treatment was optimized for each patient [using statins, ezetimibe and/or proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i)], with estimation of LDL-C reduction, checking if lipid-lowering goal was achieved and calculating the reduction in cardiovascular risk and the corresponding number needed to treat (NNT). Results: The cohort was made up of 187 patients; mean age was 67.9 ± 9.3 years and 72.7% were men. The calculated 10-year and lifetime residual risks were 37.1 ± 14.7% and 60.3 ± 10.7%, respectively. Overall, treatment was optimized with a single pharmaco logical strategy with statins, ezetimibe or PCSK9i inhibitor in 38.5%, 11.5% and 5.5% of the population, respectively. Optimization based on two treatments was performed in 27.5% (statins + ezetimibe), 7.7% (statins + PCSK9i) and 1.1% (ezetimibe + PCSK9i ) of the cases. In 15 patients, treatment was optimized when the three drugs (statins + ezetimibe + PCSK9i) were considered. Overall, 53.9% and 62.9% of the actions implemented to optimize treatment showed a 10-year or lifetime NNT < 30 to prevent an event, respectively. Conclusion: In this study, patients with a history of cardiovascular disease who do not reach LDL-C goal showed significant residual cardiovascular risk. The simulation model showed a significant margin for optimizing treatment, with a marked reduction in residual cardiovascular risk. Keywords: Residual cardiovascular risk - Cholesterol LDL - Hydroxymethylglutaryl-CoA reductase inhibitors - Ezetimibe - PCSK9 inhibitors. How to cite this article Masson W, Barbagelata L. Masson G, Lynch S, Huerin M, Siniawski D. Impact of Optimizing Lipid-Lowering Therapy on Residual Cardiovascular Risk. Rev Argent Cardiol 2023;91:309-16. http://dx.doi.org/10.7775/rac.v91.i5.20666

Protein Kinase G-I Deficiency Induces Pulmonary Hypertension through Rho A/Rho Kinase Activation

A significant proportion of patients continue to experience cardiovascular (CV) events despite achieving recommended low-density lipoprotein cholesterol (LDL-C) targets, a phenomenon referred to as residual CV risk. Clinical evidence from large outcome trials highlights the impact of residual risk on cardiovascular disease (CVD) burden, underscoring the need for therapeutic strategies beyond LDL-C lowering. Residual CV risk arises from diverse mechanisms, including persistent atherogenic dyslipidaemia [elevated triglyceride-rich lipoproteins (TRL), high triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C) levels and increased apolipoprotein B (ApoB), Lipoprotein(a) (Lp[a]) and non-HDL-C], chronic inflammation, metabolic disorders and a prothrombotic state. These abnormalities continue to drive atherosclerotic progression in optimally treated patients, underscoring that managing residual CV risk requires a multifaceted approach. Lifestyle and dietary interventions remain foundational, targeting weight reduction, smoking cessation or adoption of a Mediterranean diet. Pharmacological options include statins (as first-line therapy), or the use of ezetimibe, or bempedoic acid since they both have complementary effects to LDL-C lowering. Emerging therapies, including proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein C-III (ApoC3) and angiopoietin-like 3 (ANGPTL3) inhibitors, demonstrate potential efficacy in favourably modulating lipid profiles and targeting specific components of atherogenic dyslipidaemia (AD). Combination therapies tailored to individual lipid profiles show promise to reduce residual CV risk. The following review aims to provide a comprehensive overview of the latest evidence on the factors driving residual CV risk and the therapeutic interventions available to treat atherogenic dyslipidaemia beyond LDL-C reduction.

To study the effect of bempedoic acid on markers of inflammation and lipoprotein (a) to help determine if the drug would be useful to treat patients with elevated cardiovascular risks and residual cardiovascular risk despite optimal low-density lipoprotein cholesterol (LDL-C) levels. Bempedoic acid is found to cause significant reduction in LDL-C and high-sensitivity C-reactive protein (hs-CRP) in various randomized clinical trials. Multiple meta-analyses have also found that bempedoic acid therapy leads to reduction in non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC) and apolipoprotein B (ApoB) levels. However, it has minimal effect on lipoprotein (a) (Lp(a)) level. Bempedoic acid is a new lipid-lowering agent that inhibits enzyme ATP-citrate lyase in the cholesterol biosynthesis pathway. Major risk of cardiovascular events and its associated morbidity and mortality are proportional to LDL-C and inflammatory markers levels. It was found that bempedoic acid significantly lowers LDL-C, hs-CRP and other inflammatory markers levels. This drug could potentially be used in patients with elevated cardiovascular risk, in patients with residual cardiovascular risk despite attaining LDL-C goal and in statin intolerant patients.

Opening a New Lipid “Apo-thecary”: Incorporating Apolipoproteins as Potential Risk Factors and Treatment Targets to Reduce Cardiovascular Risk

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.

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.

The role of Epicardial Adipose Tissue (EAT) has evolved in the latest years from a passive energy repository to a dynamic contributor in cardiovascular health. This case discusses the role of EAT in residual cardiovascular risk and the potential benefits of GLP-1 receptor agonist liraglutide in mitigating its effects. We describe the case of a 62-year-old male patient, obese, hypertensive, and with a history of ischemic heart disease, was admitted to the emergency room complaining palpitations and shortness of breath. The ECG showed atrial fibrillation with rapid ventricular response with evidence of a new-onset left bundle branch block. The echocardiogram revealed heart-rate dependent regional dyskinesias, while both echocardiogram and CT scan evidenced the presence of EAT. Intrastent restenosis in the left anterior descending artery was found and treated with percutaneous revascularization. The patient was initiated on liraglutide to address residual cardiovascular risk. Follow-up showed reduced Low-Density Lipoprotein Cholesterol (LDL-c) and High-Sensitivity C-Reactive Protein (hs-CRP) levels, as well as decreased EAT thickness and Body Mass Index (BMI). EAT’s contribution to residual cardiovascular risk underscores the need for targeted interventions and treatments. Glucagon-Like Peptide-1 Receptor Agonists (GLP-1-RA) like liraglutide offer promise in addressing this risk, representing a potential venue for therapeutic exploration.

Current guidelines target low-density lipoprotein cholesterol (LDL-C) concentrations to reduce atherosclerotic cardiovascular disease (ASCVD) risk, and yet clinical trials demonstrate persistent residual ASCVD risk despite aggressive LDL-C lowering. Non-LDL-C lipid parameters, most notably triglycerides, triglyceride-rich lipoproteins (TGRLs), and lipoprotein(a), and C-reactive protein as a measure of inflammation are increasingly recognized as associated with residual risk after LDL-C lowering. Eicosapentaenoic acid in statin-treated patients with high triglycerides reduced both triglycerides and ASCVD events. Reducing TGRLs is believed to have beneficial effects on inflammation and atherosclerosis. High lipoprotein(a) concentrations increase ASCVD risk even in individuals with LDL-C < 70 mg/dL. Although statins do not generally lower lipoprotein(a), proprotein convertase subtilisin/kexin type 9 inhibitors reduce lipoprotein(a) and cardiovascular outcomes, and newer approaches are in development. Persistent increases in C-reactive protein after intensive lipid therapy have been consistently associated with increased risk for ASCVD events. We review the evidence that biochemical assays to measure TGRLs, lipoprotein(a), and C-reactive protein are associated with residual risk in patients treated to low concentrations of LDL-C. Growing evidence supports a causal role for TGRLs, lipoprotein(a), and inflammation in ASCVD; novel therapies that target TGRLs, lipoprotein(a), and inflammation are in development to reduce residual ASCVD risk.

Identifying alternative contributors to the residual risk of atherosclerotic cardiovascular disease (ASCVD) beyond LDL cholesterol (LDL-C) levels is crucial. We investigated the relative impact of triglycerides (TGs) and high-sensitivity C-reactive protein (hs-CRP) on outcomes in statin-treated patients with well-controlled LDL-C undergoing percutaneous coronary intervention (PCI) for established ASCVD. We included 9446 statin-treated patients with LDL-C < 70 mg/dL undergoing PCI between 2012 and 2022, stratified into four groups: (i) no residual risk (TG <150 mg/dL + hs-CRP <2 mg/L); (ii) residual TG risk (TG ≥150 mg/dL + hs-CRP <2 mg/L); (iii) residual inflammatory risk (TG <150 mg/dL + hs-CRP ≥2 mg/L); and (iv) residual TG and inflammatory risk (TG ≥150 mg/dL + hs-CRP ≥2 mg/L). The primary endpoint was major adverse cardiovascular events (MACE) at 1 year, consisting of all-cause mortality, myocardial infarction, or stroke. Cox regression analysis was performed, using the no residual risk group as a reference. Of the total population, 5339 (56.5%) had no residual risk, 555 (5.9%) presented residual TG risk, 3009 (31.9%) had residual inflammatory risk, and 543 (5.7%) exhibited residual combined risk. After multivariable adjustment, patients with residual inflammatory or combined risk showed a significantly higher hazard of MACE, mainly driven by all-cause mortality. No significant difference was observed between patients with residual TG risk and those with no residual risk. In statin-treated patients with well-controlled LDL-C undergoing PCI, residual inflammatory risk-alone or in combination with residual TG risk-was associated with a higher incidence of MACE, highlighting the need for targeted preventive strategies beyond LDL-C lowering.

Background: Among patients with coronary artery disease, residual inflammatory risk assessed by high-sensitivity C-reactive protein (hsCRP) is at least as strong a predictor of future cardiovascular events as is residual risk assessed by low-density lipoprotein cholesterol (LDL-C). Objectives: To evaluate the relationships between relative importance of hsCRP and LDL-C as determinants of clinical outcomes among patients who underwent percutaneous coronary intervention (PCI) for in-stent restenosis (ISR) lesions. Methods: Between January 2017 and December 2018, a total of 2079 patients who underwent PCI for ISR were consecutively enrolled. The primary outcome was the rate of major adverse cardiac events (MACE), defined as a composite endpoint of all-cause death, spontaneous myocardial infarction (MI), or repeat revascularization. Quartiles of increasing hsCRP and LDL-C were assessed as predictors of clinical outcomes after adjustment for covariates. Patients were then categorized as four predefined residual risk groups according to hsCRP (≥2 mg/L vs. &lt;2mg/L) and LDL-C levels (≥70mg/dL vs. &lt;70mg/dL). Results: During a median follow-up of 36 months, 436 MACEs occurred. Baseline hsCRP was significantly associated with MACE (highest versus lowest quartile; adjusted hazard ratio [aHR], 1.90 [95% CI, 1.39-2.59]; P&lt;0.001). By contrast, the baseline LDL-C quartile was not associated with MACE (highest versus lowest quartile; aHR, 0.93 [95% CI, 0.71- 1.22]; P=0.59). Compared with patients without residual risk (hsCRP &lt;2 mg/L and LDL-C &lt;70 mg/dL), participants with both residual inflammatory and LDL-C risk (hsCRP ≥2 mg/L and LDL-C ≥70 mg/dL) (aHR, 1.39 [95% CI, 1.06-1.83]; P=0.02) and those with residual inflammatory risk only (hsCRP ≥2 mg/L and LDL-C &lt;70 mg/dL) (aHR, 1.34 [95% CI, 1.01-1.72]; P=0.04) had significantly higher risks of MACE. Conclusions: In the current cohort of patients after ISR PCI, inflammation assessed by hsCRP predicted higher risk of adverse clinical outcomes, whereas the level of LDL-C was not associated with prognosis.

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

Background Elevated concentrations of low-density lipoprotein cholesterol (LDL-c) and low grade vascular inflammation, commonly quantified using high-sensitivity C-reactive protein (hsCRP), have been demonstrated to be causal in the development of atherosclerotic disease. Whilst recent large-scale trials have investigated the relative impact of LDL-c and inflammation on cardiovascular outcomes, there is a scarcity of data in real-world patients undergoing percutaneous coronary intervention (PCI). Purpose To investigate the relative drivers of residual risk in patients with established statin treatment undergoing PCI in a contemporary large-scale cohort. Methods From January 2012 to February 2020 patients undergoing PCI at a tertiary center were included for current analysis. Patients were categorized into 4 subgroups according to different combinations of LDL-c and hsCRP concentrations at baseline: no residual cholesterol or inflammatory risk (LDL-c &amp;lt;70 mg/dL + hsCRP &amp;lt;2 mg/L), residual cholesterol risk (LDL-c ≥70 mg/dL + hsCRP &amp;lt;2 mg/L), residual inflammatory risk (LDL-c &amp;lt;70 mg/dL + hsCRP ≥2 mg/L), and combined residual cholesterol and inflammatory risk (LDL-c ≥70 mg/dL + hsCRP ≥2 mg/L). Individuals who presented with acute myocardial infarction, neoplastic disease and hsCRP concentrations &amp;gt;10 mg/l were excluded. The outcome of interest was major adverse cardiac events (MACE - composite of all-cause mortality, myocardial infarction, or stroke). A univariable cox regression model was calculated. Results Overall, 10,845 patients were included. In total, 3,210 patients displayed neither cholesterol nor inflammatory risk and 3,059 individuals had elevated cholesterol risk only. In 1,839 patients an inflammatory risk was noted, whilst 2,737 patients presented with combined cholesterol and inflammatory risk. Kaplan-Meier curves for 1-year follow-up are displayed in Figure 1. Patients with residual inflammatory risk had the highest event rate of the composite endpoint (5.2%), followed by patients with combined residual risk (3.5%), individuals with residual cholesterol risk (2.3%) and persons with neither cholesterol nor inflammatory risk (2.4%; p&amp;lt;0.0001 for log rank test across all groups). An association with MACE was solely documented for patients with residual inflammatory risk (HR: 2.09, 95% CI: 1.52 - 2.88; p&amp;lt;.001), and also borderline significant for combined cholesterol and inflammatory risk (HR: 1.41, 95% CI: 1.03 - 1.95; p=0.034), whilst this was not the case for patients with elevated cholesterol risk only (see Figure 2). Conclusion In a contemporary real-world cohort of statin treated patients undergoing PCI, inflammation irrespective of LDL-c concentrations was the driver for adverse cardiovascular outcomes. This data might be helpful to further define target populations for both intensified lipid-lowering as well as anti-inflammatory treatment approaches.

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.