Cardiovascular Risk Reduction Research Articles

NOVEL AGENTS IN THE MANAGEMENT OF DIABETES AND RISK OF WORSENING DIABETIC RETINOPATHY.

Novel therapies for diabetes have potent effects on glycemic control, obesity, and cardiovascular risk reduction, but some, including the popular drug semaglutide, have also been implicated in worsening of diabetic retinopathy (DR). Given the ubiquity of these new agents, understanding the risks to vision is important. Here, we review the data for several newly available agents in terms of systemic efficacy and retinal safety. Literature review. Novel antihyperglycemic treatments include incretin mimetics and enhancers, sodium-glucose cotransporter inhibitors, long-acting insulins, and insulin delivery systems. All improve glycemic control, and some have been shown to reduce major cardiovascular outcomes. In a pivotal trial, semaglutide was associated with approximately 75% increased risk of DR worsening. The novel long-acting insulin icodec, formulated for once weekly dosing, showed increased risk of DR worsening over a once daily insulin. No other recent antihyperglycemic agent was associated with DR worsening, although following the semaglutide trials, nearly all studies excluded patients with preexisting DR. Cases of DR worsening were rare in all instances. Dedicated safety studies for semaglutide in DR are currently underway. For most patients being considered for treatment with a novel antihyperglycemic agent, benefits on systemic metabolic and cardiovascular health are very likely to outweigh potential retinal harms. Although the true risks of the new agents on DR are unclear because their safety data come from secondary end points, the most vulnerable patients are those with preexisting high-risk DR, poor baseline glycemic control, and using insulin.

Effects of Extracted Pulse Proteins on Lipid Targets for Cardiovascular Risk Reduction: Systematic Review and Meta-Analysis of Randomized Controlled Trials

Effects of Extracted Pulse Proteins on Lipid Targets for Cardiovascular Risk Reduction: Systematic Review and Meta-Analysis of Randomized Controlled Trials

Adherence to the 2019 ESC/EAS guidelines for dyslipidaemia management in a large rheumatoid arthritis cohort: Data from the CORDIS Study Group of the Italian Society of Rheumatology

Background/aimLipid-lowering therapy prescription is low in rheumatoid arthritis (RA) patients, often not achieving lipid threshold target despite treatment. However, evidence derives from small, monocentric cohorts. We assessed adherence to lipid-lowering treatment for primary cardiovascular (CV) prevention in a RA cohort according to international guidelines. MethodsA cross-sectional analysis of an Italian RA cohort was performed. Disease-related features and traditional CV risk factors were collected. The 10-year CV risk was estimated by Systematic COronary Risk Evaluation 2 (SCORE-2) algorithm. The primary preventive dyslipidaemia strategy was assessed according to 2019 European Society of Cardiology/European Atherosclerosis Society guidelines. Results1.133 RA patients (78.2% female, aged 60.6±10.2 years) free from CV events were included. According to SCORE-2, 42.9% of patients were at moderate risk (1–5-%), 33.3% at high risk (5–10%) and 23.7% at very high risk (>10%). In the whole cohort, 12.9% of patients with <5%, 23.6% with 5–10% and 32.3% with >10% risk were on statin, respectively (p<0.001). According to 2019 ESC/EAS guidelines, 51.5% of patients had LDL-c at target. Among patients with LDL-c not at target, 76% were not on lipid-lowering treatment. At multivariate analysis, patients with higher CV risk had significantly lower probability of LDL-c at target. ConclusionIn a wide Italian RA cohort, more than 50% of patients had high or very high CV risk. In these, lipid-lowering treatment prescription is suboptimal leading to not achievement of LDL-c target. Physicians should improve lipid screening and primary prevention therapy to reduce CV risk and improve CV comorbidity in RA patients.

Cardiovascular effects of obstructive sleep apnoea and effects of continuous positive airway pressure therapy: evidence from different study models

INTRODUCTIONCardiovascular consequences of obstructive sleep apnoea (OSA) and the effects of continuous positive airway pressure (CPAP) therapy on blood pressure, endothelial dysfunction, and MACE (major adverse cardiovascular events) have been studied over decades using different study designs. However, clinical findings from different study models on cardiovascular outcomes are sometimes contradictory.METHODSA literature search was conducted in PubMed for randomised controlled trials, meta-analyses, population-based epidemiological studies and OSA cohort studies up to September 2023 investigating the cardiovascular effect of OSA and CPAP in adults with OSA on the following cardiovascular endpoints: blood pressure, arterial hypertension, endothelial function, and MACE (myocardial infarction, stroke, transient ischemic attack, cardiovascular death). The level of evidence for these outcomes was discussed on the basis of different study models.RESULTS AND CONCLUSIONSThere is high-level evidence of a causal relationship between OSA and arterial hypertension and endothelial dysfunction, as well as on higher MACE incidence among subgroups of patients with untreated OSA. The cardiovascular effects of OSA depend on the severity of OSA, symptoms, phenotype, and comorbidities. The blood pressure-lowering effect of CPAP is mainly observed in uncontrolled and treatment-resistant hypertension. The MACE risk reduction in OSA depends on good long-term CPAP adherence. Younger, sleepy patients with more severe OSA, higher hypoxaemic burden and without overt cardiovascular end-organ disease may particularly benefit from CPAP treatment in terms of cardiovascular risk reduction. Randomised controlled trials of CPAP or other effective OSA treatments in primary cardiovascular prevention and in patients at highest risk are lacking.

Remnant cholesterol lowering in cardiovascular disease risk reduction in statin trials: meta-regression analyses

Abstract Background Remnant cholesterol is a causal risk factor for cardiovascular disease. Purpose We tested the hypothesis that remnant cholesterol reduction explains part of the cardiovascular disease risk reduction in statin trials. Methods We included statin trials with &amp;gt;1,000 participants and available data on lipid levels. Baseline and follow-up low-density lipoprotein (LDL) and remnant cholesterol levels were extracted. LDL and remnant cholesterol reductions were differences between intervention and reference groups at year one. Risk ratios for any statin use and per 1 mmol/L (39 mg/dL) LDL and remnant cholesterol reductions were estimated using meta-regressions. Results We included 29 statin trials with 191,202 participants and 26,639 major cardiovascular events. On an absolute scale when LDL cholesterol was reduced 1 mmol/L (39 mg/dL), remnant cholesterol was reduced 0.17 mmol/L (7 mg/dL) (Figure 1). On a relative scale when LDL cholesterol was reduced 20%, remnant cholesterol was reduced 12%. The risk ratio for statin use versus reference was 0.82 (95% confidence interval: 0.81-0.84) for major cardiovascular events (Figure 2). Risk ratios per 1 mmol/L (39 mg/dL) reductions were 0.82 (0.80-0.83) for LDL cholesterol and 0.37 (0.33-0.41) for remnant cholesterol for major cardiovascular events. Corresponding risk ratios for 1 mmol/L (39 mg/dL) LDL and remnant cholesterol reductions were 0.78 (0.75-0.80) and 0.30 (0.25-0.35) for coronary events, 0.86 (0.82 -0.90) and 0.48 (0.38-0.61) for stroke, and 0.93 (0.91-0.95) and 0.71 (0.62-0.80) for any death, respectively. Conclusions Remnant cholesterol lowering likely explain part of the cardiovascular disease risk reduction in statin trials. Figure 1. Remnant cholesterol reduction as a function of LDL cholesterol reduction. Regressions were calculated using inverse-variance weighted unadjusted linear regressions. LDL = low-density lipoprotein. LDL-C = LDL cholesterol. R-C = Remnant cholesterol. ∆ = change from baseline to 1 year follow-up. Figure 2. RR for MACE for statin use and cholesterol reductions. Risk ratios were calculated using fixed and random effects inverse-variance weighted meta-regressions. CI = confidence interval. LDL = low-density lipoprotein. LDL-C = LDL cholesterol. MACE = major cardiovascular events. R-C = remnant cholesterol. RR = risk ratio.Figure 1Figure 2

Social vulnerability and disparities in incidence of diagnosed diabetes in the united states, 2004 to 2019

Abstract Introduction Vulnerable populations experience a higher burden of cardiovascular disease.(1) However, the incidence of cardiovascular risk factors, such as diabetes, within these populations, is incompletely characterized. Recently, the United States Centers for Disease Control and Prevention (US CDC) developed the Social Vulnerability Index (SVI) to categorize counties that may be vulnerable to worse health outcomes. The SVI is composed of 4 themes: socioeconomic status (Theme 1), household composition &amp; disability (Theme 2), minority status &amp; language (Theme 3), and housing type &amp; transportation (Theme 4).(2) We sought to evaluate the association of the 4 SVI themes with county incidence of diagnosed diabetes. Method We used CDC data (2004-2019; reported for 94% of US counties), on county incidence of diagnosed diabetes. The SVI themes were scored from 0 to 1 (low to high vulnerability) based on national percentile ranking. We used weighted least squares regression with restricted cubic splines to model the relationship between SVI themes and incidence of diagnosed diabetes (median data 2004−2019), adjusting for median age, sex ratio, state, percent uninsured, food environment index, healthcare providers, and rurality.(3) The partial effects of SVI themes and diabetes incidence were reported as F-statistics (P-values) and diabetes incidence rate ratios (IRR [95% confidence interval]), which were plotted for all values compared with the 50th percentile (SVI 0.5). For each theme, we also present the IRR for a 0.5-point increase when moving over the lower (SVI score 0.5 vs. 0.0) and the upper (1.0 vs. 0.5) half of the SVI score distribution. Results The 4 SVI theme rank scores were significantly associated with diabetes incidence (all, P&amp;lt;.001). However, Theme 1 and 2 scores showed stronger associations with IRR than Theme 3 and 4 (Figure). For Theme 1, SVI score 0.5 vs. 0.0 was associated with a 15% higher incidence (IRR 1.15 [1.13–1.18]) and score 1.0 vs. 0.5 was associated with a 13% higher incidence (IRR 1.13 [1.11–1.16]). For Theme 2, SVI score 0.5 vs. 0.0 was associated with a 16% higher incidence (IRR 1.16 [1.14–1.18]), but there was no difference between rates for SVI score 1.0 vs. 0.5 (IRR 1.01 [0.99–1.03]). For Theme 3, there was no difference between SVI score 0.5 vs. 0.0 (IRR 0.98 [0.96–1.00]), but rates were 8% lower for SVI score 1.0 vs. 0.5 (IRR 0.92 [0.90–0.94]). For Theme 4, SVI score 0.5 vs. 0.0 was associated with a 3% lower incidence (IRR 0.97 [0.96–0.99]) and score 1.0 vs. 0.5 was associated with a 2% higher incidence (IRR 1.02 [1.01–1.04]). Conclusion In US counties, the strength and directionality of the association between SVI themes and diabetes incidence differed by theme and level of SVI scores. These themes, particularly socioeconomic status and household composition &amp; disability may be leveraged to identify high-risk counties for primary prevention of diabetes, with implications for reduction in cardiovascular risk.

Heterogeneous effect of sodium-glucose cotransporter 2 inhibitors on cardiovascular events among people with type 2 diabetes: an application of machine learning to target trial emulation

Abstract Background Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are widely used to reduce cardiovascular risk in patients with type 2 diabetes. However, certain patient subgroups, including younger individuals or those with lower body mass index (BMI), have been underrepresented in previous randomized clinical trials. Therefore, the consistency of the effectiveness of SGLT2i has not been thoroughly investigated. Purpose This research aims to investigate the individual benefit of SGLT2i on cardiovascular risk reduction across the diverse patient population with type 2 diabetes Methods We investigated the effectiveness of SGLT2i versus active comparators (dipeptidyl peptidase 4 inhibitors [DPP4i]) using a target trial emulation framework, prevalent new-user design, and a nationwide insurer-based database covering more than 30 million working-age citizens in Japan. Participants were identified using data from April 2015 to March 2022 and were followed until March 2023. The primary endpoint was the composite of all-cause death, myocardial infarction, stroke, or heart failure. We then applied the machine learning causal forest algorithm to the emulated trial cohort to predict the individualized benefit of SGLT2i in reducing cardiovascular outcomes. After describing the characteristics of patients with predicted benefits above the median (high-benefit group) and those with predicted benefits below the median (low-benefit group), we compared the long-term survival outcomes between the high-benefit group and the low-benefit group using adjusted Cox proportional hazard models. Results The study included 274,886 participants (SGLT2i, n=137,443; DPP4i, n=137,443) with a mean age of 55.7 years, 17.3% (n=47,517) female, and a mean BMI of 27.3kg/m2. Over a median follow-up of 36 months, 3.6% (n=9,896) experienced the primary outcome. SGLT2i were associated with a reduced incidence of the primary endpoint in the entire cohort (hazard ratio [HR] = 0.94 [95% confidence interval (95%CI): 0.90–0.97]). The causal forest model showed that the effects of SGLT2i were heterogeneous across individuals. Patients in the low-benefit group were characterized by older age, female gender, lower BMI, lower blood pressure, worse kidney function, and milder diabetes status than those in the high-benefit group. While we found the preventive effect of SGLT2i on long-term cardiovascular outcomes in the high-benefit group (HR [95%CI] = 0.86 [0.82–0.90]), the effect was not observed in the low-benefit group (HR [95%CI] = 1.05 [1.00–1.11]; p-for-interaction &amp;lt; 0.001). Conclusion By applying a machine-learning causal forest to a target trial emulation cohort in the general population, we found heterogeneity in the effect of SGLT2i on cardiovascular outcomes, and identified characteristics of patients who are less likely to benefit from SGLT2i. The findings suggest personalized treatment strategies for cardiovascular risk reduction in patients with type 2 diabetes.Graphical summary

Red cell distribution width as a predictor of cardiovascular events in high-risk patients with statin intolerance: post-hoc analysis of the CLEAR Outcomes trial

Abstract Background Despite optimal lipid-lowering therapy there is up to 70% residual risk of recurrent atherosclerotic cardiovascular disease (ASCVD) events, motivating further testing of alternative risk factors and disease pathways. Red cell distribution width (RDW) is a simple and reproducible marker of heterogeneity of cell size in the peripheral blood. High RDW is associated with an increased risk of ASCVD and death, independent of established risk factors. Recent data suggest no significant impact of PCSK9 inhibitors on hsCRP or RDW. In CLEAR Outcomes, baseline hsCRP predicted risk for future cardiovascular (CV) events and death more strongly than elevated LDL-C. It has been shown that bempedoic acid (BA) reduces hsCRP, but its effects on RDW are unknown. Purpose To analyze the effect of BA on a 4-component composite of incident myocardial infarction, stroke, coronary revascularization, or cardiovascular death (MACE-4) and for CV death by baseline RDW, and to confirm the association of increased RDW with elevated risk of MACE. Methods A total of 13,970 individuals with statin intolerance, with or at high risk for ASCVD, were randomized in the multinational CLEAR Outcomes trial with a median follow up of 3.4 years. Compared to placebo, BA reduced mean LDL-C by 21% and median hsCRP by 22% at 6 months. Quartiles of increasing baseline RDW were assessed as predictors of future adverse events after adjustment for traditional risk factors, hsCRP, and randomized treatment assignment. Results Compared to placebo, BA reduced mean RDW by 0.28% at 6 months and 0.13% at 36 months (p&amp;lt;0.0001). There was a weak positive correlation between hsCRP and RDW at baseline (Figure 1). In the placebo group, higher baseline RDW was associated with an increase in the likelihood of MACE-4 and CV death, and the hazard ratios (HR) associated with a 1% increase in RDW after adjusting for covariates and hsCRP were 1.06 (95% CI 1.02-1.11) and 1.22 (1.15-1.29), respectively. When grouped by quartiles of baseline RDW, compared with a reference group with lowest RDW (&amp;lt;13.7%), there was a notable increase in the risk of MACE-4 and CV death among the higher quartiles in the placebo group (Table 1). Those in the 4th quartile demonstrated a 3-fold increase in the risk of CV death (HR, 3.03, 2.00-4.60). The adjusted HRs (95% CI) for BA vs placebo for MACE-4 were generally lower in individuals with elevated baseline RDW than in those in the first quartile [Q1: RDW≤13.7%; 0.96 (0.79-1.17), Q2: RDW 13.7%-14.4%; 0.81 (0.67-0.97), Q3: RDW 14.4%-15.2%; 0.90 (0.75-1.09), and Q4: RDW&amp;gt;15.2%; 0.84 (0.7-1.01)]. Conclusions In a large randomized controlled clinical trial setting, we confirmed an association between elevated RDW and MACE-4. Compared with placebo, BA demonstrated efficacy in reducing CV risk in patients with moderately increased RDW.Figure 1.Correlation of hsCRP and RDWTable 1.Risk of Outcome by RDW Quartile

The impact of daily step count with mobile health apps on clinical outcomes among general population

Abstract Background/Introduction Numerous studies have investigated the correlation between daily step count and the reduction of all-cause mortality and cardiovascular events. However, the optimal daily step count for the general population remains controversial. Purpose This study aims to assess cardiovascular risk based on individual step counts using a large cohort that includes step count data from mHealth Apps (Kencom), health checkups databases, and Japanese insurance claims databases. Methods We analyzed data from 85,204 users registered with Kencom between January 2016 and September 2021. The mean step count during one year before and after baseline data collection was used to define each individual's step count. We divided participants into low (N=45,539) and high (N=39,665) step count groups based on their mean step counts. Additionally, we categorized users into five groups based on their step counts (&amp;lt;4000; 4000-5999; 6000-7999; 8000-9999; and ≥10000) to evaluate cardiovascular events. The primary outcome was the occurrence of cardiovascular events, including myocardial infarction, stroke, angina pectoris, heart failure, and atrial fibrillation, as classified by the International Classification of Diseases and Related Health Problems, 10th Revision (ICD-10). The cumulative incidence was estimated over 5 years. Results The high step count group was generally younger and predominantly male. No significant differences in cardiovascular risk factors such as hypertension, dyslipidemia, diabetes mellitus, and current smoking status were found between the two groups. Stratifying baseline characteristics by step count revealed significant differences among the five groups, with the exception of sex. The cumulative incidence of cardiovascular events was significantly lower in the high step count group compared to the low step count group (6.5% vs. 7.5%, log-rank P=0.005, Figure 1). After adjusting for confounding factors, the risk reduction of the high step count group remained significant (HR: 0.92, 95% CI: 0.87-0.98, P=0.005). Among the five step count groups, the incidence of primary outcome significantly differed, with only Group 5 (≥10000 steps) showing a significant reduction in the risk of cardiovascular events compared to Group 1 (&amp;lt;4000 steps) after adjustment (HR: 0.87, 95% CI: 0.77-0.99, P=0.03). Subgroup analyses based on sex indicated that the risk reduction was significant in males in Group 5 but not in females. Conclusion The risk of cardiovascular events was higher in the low step count group compared to the high step count group. After adjusting for confounders, only the highest step count group (≥10,000 steps/day) showed a significant reduction in cardiovascular event risk compared to the lowest step count group.

Adherence to anti-hypertensive therapy with perindopril-based single-pill versus free-pill combinations: a 10-year real-world analysis in Italy

Abstract Background/Introduction Despite the growing availability of blood pressure-lowering drugs, hypertension remains poorly controlled and a significant mortality cause worldwide. The silent course of the disease, suboptimal adherence, and complexity of therapeutic schedules are important factors in reducing the effectiveness of anti-hypertensive treatments at the population level. With the purpose of simplifying patients’ medication self-management, guidelines have strongly endorsed the use of anti-hypertensive therapy with single-pill combinations (SPCs). Perindopril (PER)-based SPCs, including both two- and three-drug combinations, have been available since 2008. Purpose We explored treatment adherence over 10 years in patients receiving PER-based regimens (SPC or free-pill combination) in Italy. Methods A retrospective real-world analysis was conducted on administrative databases covering 6.7 million Italian health-assisted residents. Among adults with hospitalization discharge diagnosis or exemption code for hypertension between 2010 and 2021, those with PER-based prescriptions were identified, considering combinations with amlodipine (AML) and/or indapamide (IND), either as SPC or free-pill or mixed (SPC+separate pill). The index-date (ID) was that of the first prescription of a PER-based regimen throughout the inclusion period. All patients with at least 12 months of available data before and after the ID were included. A cross-sectional analysis evaluated the yearly adherence for the period 2012-2021, calculating the proportion of days covered (PDC) by drug prescriptions on 1-year follow-up (PDC≥80% indicated high-adherence). Results Over 2012-2021, of 121,397 patients on a PER-based therapy, those treated with SPC ranged from 87% (during 2012) to 94.4% (during 2021), while free-pill and SPC+separate pill cohorts represented, respectively, 10.6-3.5% and 2.4-2.1% of all hypertensive patients. Over the decade, the proportion of adherent patients in SPC users was markedly higher than in free-pill and SPC+separate pill cohorts (Fig. 1). The sudden reduction of adherent patients during 2018-2019 was possibly due to a temporary shortage of PER/AML/IND as SPC in Italy from Nov-2018 to Mar-2019. Multivariate analysis showed that over 2012-2021 decade, free-pill and SPC+separate pill regimens resulted in significantly lower adherence (more than 80% reduction) than SPC formulation, while male gender and older age were predictive of better adherence (Table 1). Conclusions These findings from real clinical practice in Italy highlighted a growing attitude from clinicians to prescribe more manageable anti-hypertensive schemes based on SPC formulations, in line with current guidelines. The higher proportion of adherent patients among the users of PER-based SPCs corroborates the importance of alleviating pill burden, that is a key component in blood pressure control, and so in the reduction of hypertensive complications and cardiovascular risk.

A Review of Lifestyle Interventions in Weight Loss Programs for Community-Based Psychiatric Patients

Abstract Background Psychiatric patients face aggravated physical health issues and reduced life expectancy, primarily due to premature cardiovascular diseases. The intricate relationship between lifestyle factors, illness, and psychotropic medications contributes to this phenomenon. The focus of this research is to evaluate weight management interventions for individuals with Severe Mental Disorders through a comprehensive scoping review, focusing on diverse study designs, outcomes, and their clinical implications. Methods 20 studies were analyzed to understand the effectiveness of interventions and characteristics, such as duration, delivery, and professional involvement. Assessment criteria included weight modifications, BMI changes, and metabolic measures like blood pressure and lipid profiles. Results The total number of participants included in the 20 studies evaluated was 3886. All trials included individuals of all genders. The studies included patients with a weighted mean age of 44.37 (SD = 4.72) and a mean BMI of 34.7 kg/m2 (SD = 3.56). Varied interventions, mostly conducted in the US, showed promising weight reduction and cardiovascular risk management results among psychiatric patients. However, disparate methods used in the studies hindered the evaluation of outcomes. The studies which yielded more interesting results included Gaughran F. et al, 2017 who showed improvements in HDL cholesterol and metabolic indicators, (HR 0.085; 95% CI:0.007-0.16), and Bartels S. et al, 2015 who reported that 51% of participants achieved clinically significant reduction in overall cardiovascular risk. Conclusions Although interventions displayed potential benefits for beneficiaries, the lack of standardized protocols and non-uniform endpoints poses challenges in effectively addressing weight-related concerns in psychiatric patients. Clear guidelines and standardized assessments are necessary to implement psychiatric patients’ weight management interventions. Key messages • The health issues and reduced life expectancy of psychiatric patients is a major health burden. The mean BMI of 34.7 kg/m2, indicating a prevalence of Obese individuals needs to be addressed. • Psychotropic medications are associated with increase in weight. More effort in increasing awareness and including mandatory nutritional educational classes when prescribing these drugs is needed.

Direct IL-6 inhibition prevents arterial thrombosis by reducing collagen-mediated platelets activation

Abstract Introduction Interleukin 6 (IL-6) has a pivotal role in atherothrombosis. Yet, targeting IL-6 to prevent atherothrombotic events still requires validation of efficacy and safety. The recent phase 2 RESCUE trial reported that direct inhibition of IL-6 ligand by the monoclonal antibody (mAb) Ziltivekimab is safe in patients with elevated cardiovascular risk. Purpose This project investigated the effects of direct IL-6 inhibition on arterial thrombosis, and assessed the underlying cellular mechanisms. Methods Three month old C56Bl/6 male mice received very-low dose LPS i.p. for 4 weeks. During the last week they were randomized to receive in addition either anti-mouse IL-6 mAb 200 μg i.p. every other day or IgG1 isotype control. Then thrombosis of left common carotid artery (LCCA) was induced by laser injury under anesthesia. Platelets of treated mice were isolated and stimulated with either adenosine di-phosphate (ADP), collagen-related peptide (CRP) or thrombin receptor activating peptide (TRAP). Platelets activation was measured by flow-cytometry, as expression of P-selectin and JON/A.The effect of direct IL-6 inhibition was confirmed in patients with stable coronary artery disease (sCAD) by ex-vivo incubation of isolated platelets with either anti-human IL-6 mAb 1.5 μg/mL or IgG1 isotype control. Platelet activation was measured by flow-cytometry, as expression of P-selectin. Results Mice treated with anti-IL6 antibody displayed a significantly longer time-to-occlusion after the LCCA (Figure 1), without any significant difference in coagulation parameters. After stimulation with CRP, platelets were significantly activated in control mice, but not in mice treated with anti-IL6 mAb. Similarly, activation of isolated platelets from patients with sCAD was significantly reduced (Figure 2) by the ex-vivo treatment with anti-IL6 mAb. Conclusion The direct inhibition of IL-6 reduces platelets reactivity to collagen, thereby blunting arterial thrombosis upon endothelial damage. These results provide a potential mechanism to explain the reduction of cardiovascular risk associated to direct IL-6 inhibition. Conclusion The direct inhibition of IL-6 reduces platelets reactivity to collagen, thereby blunting arterial thrombosis upon endothelial damage. These results provide a potential mechanism to explain the reduction of cardiovascular risk associated to direct IL-6 inhibition.Figure 1Figure 2

Beneficial effects of hydroxychloroquine on blood lipids and glycated haemoglobin: A randomised interventional study in patients with rheumatoid arthritis and systemic lupus erythematosus.

Hydroxychloroquine (HCQ) exerts a large reduction of cardiovascular risk in patients with inflammatory diseases, but the mechanisms are not fully known. The aim of this study was to study potential mechanisms for this. This interventional study (EudraCT 2014-005418-45) in 30 patients (23 with rheumatoid arthritis, 7 with systemic lupus erythematosus) investigates the effects of HCQ on cardiovascular risk factors and arterial stiffness in patients with inflammatory disease. Blood lipids, blood pressure, blood glucose, glycated haemoglobin (HbA1c) and arterial stiffness was assessed at initiation, after four weeks of treatment and after eight weeks of treatment with 200 mg HCQ daily. After four weeks of treatment with HCQ, total cholesterol had decreased from 5.4 mmol/L to 5.1 mmol/L (p<0.001), low-density lipoproteins from 3,0 mmol/L to 2.7 mmol/L (p<0.001) and apolipoprotein B from 0.96 g/L to 0.90 g/L (p<0.01). Those levels remained unchanged after eight weeks of treatment with HCQ. Levels of triglycerides, high-density lipoproteins and apolipoprotein A1 remained unchanged during the study. HbA1c decreased in most patients, especially in patients with high levels at start of HCQ, but increased HbA1c was seen in patients with low levels at start of treatment with HCQ. No significant effect was seen on blood pressure or any measure of arterial stiffness. This study does not identify the mechanisms of cardiovascular risk reduction from HCQ. Arterial stiffness is not affected by HCQ. The impact of HCQ on HbA1c and blood lipids is rapid, but of modest magnitude, and these effects do not fully explain the reduced risk of cardiovascular disease seen in observational studies. The mechanisms of cardiovascular risk reduction from HCQ are yet not completely known.

Circulating Amyloid beta 1-40 is independently associated with statin treatment and LDL cholesterol reduction: a prospective cohort study

Abstract Background Accumulating evidence suggests that circulating amyloid beta 1-40 (Aβ40), a pro-inflammatory and pro-atherogenic peptide, is associated with atherosclerotic cardiovascular disease (ASCVD), providing incremental prognostic value and risk stratification refinement in primary and secondary prevention settings. Existing evidence supports conflicting off-target effects of statins on plasma Aβ40. We aim to explore the impact of cardiovascular risk reduction through statin therapy on Aβ40 plasma levels in subjects with dyslipidemia and with/without ASCVD. Methods In this prospective study, patients with dyslipidemia who visited for the first time our lipid clinic for risk stratification and treatment plan assessment (n=146) were consecutively recruited. Αβ40 was measured in plasma samples by enzyme-linked immunosorbent assay at baseline and after a mean follow-up of 5.2 and 15 months. Patients in whom statin treatment was initiated or intensified in terms of dose or regimen (n= 68) were compared against patients not treated with statins or with unchanged statin intensity (n = 78). Statin intensity treatment was defined based on the European Society of Cardiology (ESC) guidelines. Results Increased Aβ40 plasma levels at baseline were associated with ASCVD presence, decreased glomerular filtration rate (GFR), and history of heart failure (p&amp;lt;0.05 for all). An increase in Aβ40 circulating levels between baseline and follow-up 1 was observed in patients in whom statin treatment was initiated or intensified (p=0.041). However, in patients not treated with statins or treated with unchanged statin intensity, an increase in Aβ40 circulating levels was observed between follow-up 1 and follow-up 2 (p=0.05, Figure 1A). These changes in Aβ40 were significantly different between the two groups during the short follow-up period (β=0.226, p for interaction =0.025) independently from age and changes in GFR, systolic blood pressure, and LDL-C. Additionally, patients who achieved a reduction in low-density lipoprotein cholesterol (LDL-C) ≥ 50% in follow-up 2 have unchanged Aβ40 levels during the long follow-up period, while an increase in Aβ40 was observed in the rest population (p=0.012, Figure 1B). These changes were significantly different between the two LDL-C groups independently of statin treatment and changes in high sensitive C-reactive protein (hs-CRP) (β= -0.231, p for interaction=0.035). Conclusion In a dyslipidemic population, statin initiation or intensification and LDL-C decrease showed a short-term increase and a long-term return to initial levels, respectively, in circulating Aβ40 levels. From a mechanistic point of view, our findings suggest that statins have an impact on Aβ40, possibly through an LDL-C-dependent and a non-LDL-C-dependent pathway. Further studies are needed to evaluate the utility of circulating Aβ40 as a novel biomarker in ASCVD risk reduction assessment.

Moderate-intensity statin combined with ezetimibe versus high-intensity statin monotherapy for secondary cardiovascular risk reduction: a systematic review and meta-analysis

Abstract Introduction Intensive lowering of LDL cholesterol levels is recommended for patients with atherosclerotic cardiovascular disease (ASCVD) [1]. Statins are the first-line therapy for secondary prevention [1]. Recent studies such as the RACING trial suggest that the combination of moderate-intensity statins and ezetimibe (MIS+EZE) may achieve a greater LDL cholesterol reduction and a lower adverse event rate than high-intensity statins alone (HIS) [2]. Purpose The aim of this systematic review and meta-analysis is to assess cardiovascular outcomes and clinical safety of MIS+EZE versus HIS in patients with ASCVD. Methods We searched PubMed, Cochrane and Embase for studies that compared MIS+EZE to HIS in patients with ASCVD and included studies reporting cardiovascular mortality, all cause mortality, non-fatal stroke, non-fatal myocardial infarction, unstable angina, coronary revascularization, heart failure, and LDL-C ≤ 70mg/dL. Studies with the same statin dose in both treatment groups and studies with overlapping populations were excluded. Treatment effects for binary endpoints were compared using pooled risk-ratios (RR) with 95% confidence intervals. Results Out of 6238 studies, we included 6 RCTs and 2 retrospective cohort studies with 40,236 patients of whom 10,254 were treated with MIS+EZE (25,5%). Mean follow-up ranged from 90 days to 3 years. Cardiovascular mortality (RR 0.83; CI95% 0.73-0.94; p=0.003), all-cause mortality (RR 0.90; CI95% 0.82-0.98; p=0.02) and non-fatal stroke (RR 0.83; CI95% 0.73-0.93; p=0.002) were significantly lower in patients treated with MIS+EZE compared to those treated with HIS. A significantly higher proportion of patients in the MIS+EZE group reached an LDL-C ≤ 70mg/dL (RR 1.26; CI95% 1.19-1.34; p&amp;lt;0.00001). No statistically significant difference was found for non-fatal myocardial infarction (RR 0.87; CI95% 0.64-1.17; p=0.36), coronary revascularization (RR 1.03; CI95% 0.78-1.35; p=0.83), heart failure (RR 0.95; CI95% 0.86-1.06; p=0.38) and unstable angina (RR 1.52; CI95% 0.62-3.75; p=0.36). A RCT sub-analysis was feasible for cardiovascular mortality and showed no statistically significant difference between the two groups (RR 1.01; CI95% 0.42-2.42; p=0.98). Regarding safety endpoints, the risk of adverse events (RR 0.84; CI95% 0.74-0.95; p=0.004) and the risk of muscle-related adverse events (RR 0.67; CI95% 0.49-0.92; p=0.01) were significantly lower in MIS+EZE group. The significant reduction in muscle-related adverse events was maintained in the RCT sub-analysis (RR 0.61; CI95% 0.41-0.91; p=0.02). There was no difference between groups in the risk of liver-related adverse events (RR 0.63; CI95% 0.29-1.41; p=0.26) or new-onset malignancy (RR 0.99; CI95% 0.87-1.12; p=0.85). Conclusion The combination of moderate-intensity statins and ezetimibe may be considered as an alternative therapeutic strategy to reduce secondary cardiovascular risk with lower rates of drug intolerance.

High prevalence of coronary artery calcium and aortic calcification in adults with repaired coarctation of the aorta and interrupted aortic arch

Abstract Background There is a high rate of late cardiovascular mortality in patients with repaired coarctation of the aorta (CoA) and interrupted aortic arch (IAA). Coronary artery calcium (CAC) is a marker of cardiovascular disease and there is growing evidence for aortic calcification as a predictor. Recent research in the general population suggests any CAC in males &amp;lt;35 years old and females ≤45 years places them at ≥90th percentile. Aims We aimed (1) to determine the prevalence of CAC, thoracic aorta calcification (TAC), and abdominal aorta calcification (AAC) in patients with CoA or IAA repair, and (2) to compare patients to a control group of Tetralogy of Fallot (TOF) patients, a condition with no known increased risk of atherosclerotic cardiovascular disease. Methods Retrospective cohort study of adult survivors of CoA/IAA repair followed up at an adult congenital heart disease (ACHD) clinic. Patients with at least 1 chest, abdomen, or pelvis computerised tomography (CT) scan for any indication were included. The presence/absence of calcification in the coronary arteries or aorta was assessed qualitatively. Patients on antihypertensive and statin therapy were considered hypertensive and hypercholesterolaemic, respectively. Patients were compared to adult survivors of TOF repair with CT scans for any indication (controls). Results Ninety-three CoA/IAA patients (87% CoA/13% IAA, median age at latest follow-up 34 years) had a total of 169 chest and 37 abdomen/pelvis CTs; 82, 93, and 37 patients had at least 1 CT suitable for CAC, TAC, and AAC review, respectively. CAC was present in 22% (18/82), TAC in 33% (31/93), and AAC in 23% (5/22) of CoA/IAA patients. CAC was present in 12% (18/153) and TAC in 11% (18/158) of TOF patients. CoA/IAA patients were more likely to have CAC and TAC than TOF patients (p=0.04 and p&amp;lt;0.0001; respectively) and be younger at the time of diagnosis (CAC p=0.03, TAC p=0.0001) despite TOF patients being older at time of latest CT scan (p=0.0003) (Table 1). Males aged &amp;lt;35 years and females ≤45 years represented 44% (8/18) of CoA/IAA patients with CAC. CoA/IAA patients with CAC were more likely to be hypertensive and hypercholesterolaemic than those without (78% [14/18] vs 48% [31/64], p=0.03; and 28% [5/18] vs 0% [0/64], p&amp;lt;0.0001; respectively) and was similar for TAC (hypertension p=0.005, hypercholesterolaemia p=0.04) but not AAC. After a mean follow-up of 11±7 years from first ACHD clinic, of the 93 patients, 2 patients died, 5 had coronary artery disease (at least mild stenosis on invasive angiography), 3 had a stroke, and 70% (65/93) were considered hypertensive at latest follow-up. Conclusions There is a high prevalence of CAC, aortic calcification, and hypertension in young adults with repaired CoA/IAA. Coronary and thoracic aortic calcification occurs at a younger age compared to controls. Further studies are warranted to assess the impact of aggressive cardiovascular risk reduction in this high-risk group.

Causal association between visceral fat and coronary artery disease: a large-scale mendelian randomization analysis

Abstract Background While increased body mass index (BMI) is an established risk factor, the residual risk associated with visceral fat, remains a concern. We aimed to perform a Mendelian randomization to explore the causal relationship between visceral fat and the risk of coronary artery disease (CAD), aiming to address gaps left by observational studies that may be influenced by confounding factors and reverse causation. Methods Leveraging large-scale genome-wide association study (GWAS) databases, we identified single-nucleotide polymorphisms (SNPs) associated with visceral fat. These genetic instruments were analyzed to infer causal relationships with CAD outcomes, drawing data from the CARDIoGRAMplusC4D consortium for CAD, and additional databases for related cardiovascular conditions. We performed a Two-sample Mendelian Randomization (MR) to test the genetic association between the visceral obesity and Coronary Artery Disease (CAD). Results The analysis encompassed data from a combined cohort exceeding 500,000 participants, revealing a significant causal relationship between increased levels of visceral fat and the risk of CAD. The observed odds ratio (OR) for CAD per standard deviation (SD) increase in visceral fat was [OR, 1.48 ] ([95% CI, 1.33-1.64]; P&amp;lt;0.001), indicating a robust association which remains independent from BMI on mediation analysis. Notably, the study's methodology ensured minimal risk of pleiotropy, reinforcing the validity of the findings. Conclusions This Mendelian randomization study provides compelling evidence of a genetic causal link between visceral fat and coronary artery disease. The findings suggest that beyond BMI, visceral fat represents a significant, independent risk factor for CAD, underscoring the importance of considering comprehensive lipid management in cardiovascular risk reduction strategies. Further research is warranted to explore potential mechanisms and therapeutic targets associated with visceral fat in the context of cardiovascular disease.

All-cause, cancer and cardiovascular mortality among South Asians living in the UK: Follow-up of the London Life Sciences Population (LOLIPOP) cohort

Abstract Background Although South Asians are the largest ethnic minority group in the UK, and the largest ethnic group worldwide, few studies have investigated patterns of mortality in South Asians. Methods We investigated 16,391 South Asian and 6,970 European men and women living in the UK, and participating in the London Life Sciences Prospective Population study. Participants were recruited in 2002-2008, and survival determined to 2019. We examined relationships of clinical, anthropometric, and lifestyle risk factors to mortality outcomes. Findings: Compared to Europeans, South Asians had higher prevalence of diabetes, cardiovascular disease, and hypertension, higher waist-hip ratio, fasting glucose, insulin and triglycerides, but lower smoking rates and HDL cholesterol (all P&amp;lt;0.001). Age and sex adjusted all-cause mortality was lower (Hazard Ratio (HR): 0.75 [0.68-0.81], P&amp;lt;0.001), all-cancer mortality was lower (HR 0.50 [0.43-0.58], P&amp;lt;0.001), and coronary heart disease (CHD) mortality was higher (HR 1.29 [1.05-1.60], P&amp;lt;0.01) in South Asians compared to Europeans. Mortality rates were ~50% lower for 9 of the 10 most common cancers in South Asians. After adjusting for risk factors, ethnic differences were attenuated only for CHD mortality. Interpretation: All-cause and cancer mortality are lower, but CHD mortality is higher, in South Asians compared to Europeans. Measured risk factors do not explain lower all-cause and all-cancer mortality, but do account for higher CHD mortality. Our findings provide evidence for population-specific exposures protective against cancers in South Asians, as well as the motivation to further improve cardiovascular risk reduction in this major ethnic group.

High glucose enhanced lipoprotein(a) [Lp(a)] oxidation in a manner inhibited by eicosapentaenoic acid (EPA) in vitro

Abstract Background Elevated lipoprotein(a) (Lp(a)) levels are causally and independently associated with increased cardiovascular (CV) risk. Targeted molecular therapies are in development. Levels of oxidized Lp(a) were more predictive of CV events and endothelial dysfunction in type 2 diabetes than non-oxidized forms. EPA administered as icosapent ethyl (IPE) reduced CV events in statin-treated patients (REDUCE-IT) with diabetes and high CV risk. As a fatty acid with multiple conjugated double bonds, EPA inhibits lipoprotein oxidation by a potent lipid-centric scavenging mechanism. We therefore tested the effects of EPA on oxidation of Lp(a) and non-modified LDL under conditions of high glucose to mimic aspects of hyperglycemia in vivo. Methods Lp(a) was enriched to 41% of total ApoB-containing particles from patients with elevated levels by isopycnic centrifugation. Samples of Lp(a) and non-modified LDL were incubated under high glucose (200 mg/dL) conditions at 37°C for 30 min with EPA (50 µM). Samples were then subjected to copper sulfate-induced oxidation (20 µM) monitored by formation of malondialdehyde (MDA) via a colorimetric assay. Results Lp(a) enriched plasma underwent increased oxidation, peaking at 4 hr by 32-fold compared to baseline (0.37 ± 0.04 vs 12.27 ± 0.61 µM, p&amp;lt;0.001) under conditions of high glucose. Non-modified LDL also underwent oxidation in the presence of high glucose with a distinct rate compared to Lp(a), peaking after 3 h (0.28 ± 0.09 vs 10.91 ± 0.93 µM, p&amp;lt;0.001). EPA significantly inhibited both Lp(a) and LDL oxidation in a time-dependent manner. After peak oxidation was achieved in Lp(a) (4 h) and LDL (3 h), EPA inhibited oxidation by 57% (5.29 ± 0.25 µM, p&amp;lt;0.001) and 81% (2.12 ± 0.09 µM, p&amp;lt;0.001), respectively. Conclusions Under hyperglycemic conditions, EPA inhibited oxidation of Lp(a)-enriched plasma and non-modified LDL in a time-dependent manner. The activity of EPA may arise from its lipophilic properties and highly conjugated structure that scavenges free radicals in lipid-concentrated environments. The potent antioxidant activity of EPA may contribute to reduced CV risk in patients with diabetes and elevated Lp(a).

Nighttime blood pressure reductions after radiofrequency renal denervation through 24 months in patients with uncontrolled hypertension: pooled analysis from the SPYRAL HTN trials

Abstract Introduction Studies have shown that elevated nighttime and early morning systolic blood pressure (SBP) are associated with the highest risk for cardiovascular (CV) events. Radiofrequency renal denervation (RF RDN) is an interventional therapy to reduce BP in patients with uncontrolled hypertension (HTN). Although sustained, durable reductions in office and 24-h ambulatory systolic BP (SBP) after RDN have been observed, whether the therapy produces similar, durable nighttime and early morning SBP reductions requires further evaluation. Objective To assess whether RF RDN significantly reduces nighttime SBP through long-term follow-up, in addition to other times of the day. Methods We pooled data from patients with uncontrolled HTN undergoing RF RDN using the latest-generation Symplicity SpyralTM multi-electrode catheter from the published SPYRAL HTN-OFF and -ON MED clinical trials. Office and 24-h ambulatory SBP were evaluated from baseline through 24 months. We also assessed BP changes during specific, diurnal time ranges including nighttime (1am-6am), early morning (7am-9am), and daytime (9am-9pm). The number of antihypertensive drugs and drug burden (determined by number of classes and prescribed dosage) from urine and plasma drug testing were tabulated from baseline through 24 months. Results Outcomes from 388 patients undergoing RF RDN were pooled for this analysis. Patients were on average 54±10yrs old, 26.8% female, mean BMI was 31.3±6.0, 45.1% with &amp;gt;10yrs diagnosis of hypertension, 7.7% with type 2 diabetes, 9.8% with obstructive sleep apnea, 47.7% with a history of smoking. The baseline nighttime SBP was 139±11mmHg, morning SBP was 154±15mmHg, and daytime SBP was 156±9mmHg. At baseline, 92.5% of patients had nocturnal hypertension (BP ≥120/70 mmHg) and took 1.0±1.2 antihypertensive drugs. 12 months after RF RDN, 30.6% of patients no longer had nocturnal hypertension (p&amp;lt;0.0001). The mean nighttime SBP change at 12 months was -10.8±15.4mmHg, morning changed was -12.8±20.4mmHg, and daytime changed was -12.2±13.6mmHg (Figure). The mean 24-h ambulatory SBP change at 12 months was -11.9±12.4mmHg, and the office SBP change was -17.7±15.4mmHg . Patients took 1.8±1.1 antihypertensive drugs at 12 months. Results from 24 months, not currently available, will also be presented for the first time. Conclusions In this pooled cohort of RDN patients with uncontrolled hypertension, nocturnal hypertension was highly prevalent. Clinically meaningful reductions at 12 months throughout the 24-hr circadian cycle, including at nighttime and early morning SBP, are consistent with the "always on" effect of RDN. Results from 24 months will also be presented for the first time at ESC. As an adjunctive therapy to pharmacotherapy, RDN may help to reduce CV risk by lowering nighttime and morning SBP.