High-risk Atherosclerotic Patients Research Articles

The Influence of Non-High-Density Lipoprotein Cholesterol on the Efficacy of Genotype-Guided Dual Antiplatelet Therapy in Preventing Stroke Recurrence.

Non-high-density lipoprotein cholesterol (non-HDL-C), which represents the total cholesterol content of all pro-atherogenic lipoproteins, has recently been included as a new target for lipid-lowering therapy in high-risk atherosclerotic patients in multiple guidelines. Herein, we aimed to explore the relationship between non-HDL-C level and the efficacy and safety of ticagrelor-aspirin versus clopidogrel-aspirin in preventing stroke recurrence. This study comprised a post hoc analysis of the CHANCE-2 (Ticagrelor or Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events II) trial, from which 5,901 patients with complete data on non-HDL-C were included and categorized by median non-HDL-C levels, using a cutoff of 3.5 mmol/L. The primary efficacy and safety outcomes were recurrent stroke and severe or moderate bleeding within 90 days. Ticagrelor-aspirin significantly reduced the risk of recurrent stroke in patients with low non-HDL-C (71 [4.8%] vs. 119 [7.7%]; adjusted hazard ratio [HR] 0.54; 95% confidence interval [CI], 0.40-0.74), but not in those with high non-HDL-C (107 [7.3%] vs. 108 [7.6%]; adjusted HR, 0.88; 95% CI, 0.67-1.16), compared with clopidogrel-aspirin (P for interaction=0.010). When analyzed as a continuous variable, the benefit of ticagrelor-aspirin for recurrent stroke decreased as non-HDL-C levels increased. No significant differences in the treatment assignments across the non-HDL-C groups were observed in terms of the rate of severe or moderate bleeding (5 [0.3%] vs. 8 [0.5%] in the low non-HDL-C group; 4 [0.3%] vs. 2 [0.1%] in the high non-HDL-C group; P for interaction=0.425). CHANCE-2 participants with low non-HDL-C levels received more clinical benefit from ticagrelor-aspirin versus clopidogrel-aspirin compared to those with high non-HDL-C, following minor ischemic stroke or transient ischemic attack.

Modeling the Five-Element Windkessel Model with Simultaneous Utilization of Blood Viscoelastic Properties for FFR Achievement: A Proof-of-Concept Study

Coronary artery diseases (CADs) are a leading cause of death worldwide. Accurate numerical simulations of coronary blood flow, especially in high-risk atherosclerotic patients, have been a major challenge for clinical applications. This study pioneers a novel approach combining the physiologically accurate five-element Windkessel and sPTT models to enhance the accuracy of the hemodynamics and the fractional flow reserve (FFR) parameter. User-defined functions (UDFs) of the outlet pressure boundary condition (Windkessel model) and the viscoelastic characteristics of blood (sPTT model) were developed and dynamically loaded with ANSYS® 2023 software. In a proof-of-concept study, a patient’s left coronary artery with 40% stenosis was provided by the hospital for further analysis. The numerical FFR value obtained in the present work skews only 0.37% from the invasive measurement in the hospital. This highlights the important roles of both blood viscoelasticity and the five-element Windkessel model in hemodynamic simulations. This proof-of-concept of the FFR numerical calculation tool provides a promising comprehensive assessment of atherosclerosis in a fast, accurate, more affordable, and fully non-invasive manner. After validation with more patient cases in the future, this tool could be employed in hospitals and offer a more accurate and individualized approach for the diagnosis and treatment of CAD.

Management of High-Risk Atherosclerotic Patients by Statins May Be Supported by Logistic Model of Intima-Media Thickening.

While the use of statins in treating patients with atherosclerosis is an undisputed success, the questions regarding an optimal starting time for treatment and its strength remain open. We proposed in our earlier paper published in Int. J. Mol. Sci. (2019, 20) that the growth of intima-media thickness of the carotid artery follows an S-shape (i.e., logistic) curve. In our subsequent paper in PLoS ONE (2020, 15), we incorporated this feature into a logistic control-theoretic model of atherosclerosis progression and showed that some combinations of patient age and intima-media thickness are better suited than others to start treatment. In this study, we perform a new and comprehensive calibration of our logistic model using a recent clinical database. This allows us to propose a procedure for inferring an optimal age to start statin treatment for a particular group of patients. We argue that a decrease in the slope of the IMT logistic growth curve, induced by statin treatment, is most efficient where the curve is at its steepest, whereby the efficiency means lowering the future IMT levels. Using the procedure on an aggregate group of severely sick men, 38 years of age is observed to correlate with the steepest point of the logistic curve, and, thus, it is the preferred time to start statin treatment. We believe that detecting the logistic curve’s steepest fragment and commencing statin administration on that fragment are courses of action that agree with clinician intuition and may support decision-making processes.

Aberrantly Methylated-Differentially Expressed Genes Identify Novel Atherosclerosis Risk Subtypes.

Increasing evidence has indicated that modulation of epigenetic mechanisms, especially methylation and long-non-coding RNA (lncRNA) regulation, plays a pivotal role in the process of atherosclerosis; however, few studies focused on revealing the epigenetic-related subgroups during atherosclerotic progression using unsupervised clustering analysis. Hence, we aimed to identify the epigenetics-related differentially expressed genes associated with atherosclerosis subtypes and characterize their clinical utility in atherosclerosis. Eighty samples with expression data (GSE40231) and 49 samples with methylation data (GSE46394) from a large artery plaque were downloaded from the GEO database, and aberrantly methylated–differentially expressed (AMDE) genes were identified based on the relationship between methylation and expression. Furthermore, we conducted weighted correlation network analysis (WGCNA) and co-expression analysis to identify the core AMDE genes strongly involved in atherosclerosis. K-means clustering was used to characterize two subtypes of atherosclerosis in GSE40231, and then 29 samples were recognized as validation dataset (GSE28829). In a blood sample cohort (GSE90074), chi-square test and logistic analysis were performed to explore the clinical implication of the K-means clusters. Furthermore, significance analysis of microarrays and prediction analysis of microarrays (PAM) were applied to identify the signature AMDE genes. Moreover, the classification performance of signature AMDE gene-based classifier from PAM was validated in another blood sample cohort (GSE34822). A total of 1,569 AMDE mRNAs and eight AMDE long non-coding RNAs (lncRNAs) were identified by differential analysis. Through the WGCNA and co-expression analysis, 32 AMDE mRNAs and seven AMDE lncRNAs were identified as the core genes involved in atherosclerosis development. Functional analysis revealed that AMDE genes were strongly related to inflammation and axon guidance. In the clinical analysis, the atherosclerotic subtypes were associated with the severity of coronary artery disease and risk of adverse events. Eight genes, including PARP15, SERGEF, PDGFD, MRPL45, UBR1, STAU1, WIZ, and LSM4, were selected as the signature AMDE genes that most significantly differentiated between atherosclerotic subtypes. Ultimately, the area under the curve of signature AMDE gene-based classifier for atherosclerotic subtypes was 0.858 and 0.812 in GSE90074 and GSE34822, respectively. This study identified the AMDE genes (lncRNAs and mRNAs) that could be implemented in clinical clustering to recognize high-risk atherosclerotic patients.

Eicosapentaenoic acid levels predict prognosis of peripheral artery disease caused by aortoiliac artery lesions

Background and aimEicosapentaenoic acid (EPA) has been reported to improve clinical outcome of high-risk atherosclerotic patients. We investigated whether endogenous EPA values predict prognosis of peripheral artery disease (PAD) patients. Methods and resultsThis retrospective study included 166 consecutive patients who had received endovascular therapy (EVT) for PAD caused by aortoiliac artery lesions. Patients were divided into 2 groups using median preoperative EPA value (57 μg/ml): LOW EPA (n = 83) and HIGH EPA (n = 83). We compared differences between the 2 groups in prevalence of major adverse limb events (MALE) which included target lesion revascularization (TLR), non-TLR, and major amputation, and major adverse events (MAE) which included MALE and all cause death. At a median follow-up period of 20 months, MALE had occurred in 24 LOW EPA patients (28.9%) and in 12 HIGH EPA patients (14.5%) (p = 0.04), and MAE had occurred in 41 LOW EPA patients (49.4%) and in 21 HIGH EPA patients (25.3%) (p < 0.01). Kaplan–Meier analysis showed prevalence of MALE and MAE was significantly higher in LOW EPA than in HIGH EPA (long-rank test χ2 = 8.5, p < 0.01, log-rank test χ2 = 13.2, p < 0.01, respectively). Multivariate Cox regression revealed preoperative EPA value < 57 μg/ml was an independent predictor for MALE (hazard ratio [HR]: 2.70; 95% CI: 1.35 to 5.4; p < 0.01) and MAE (HR: 2.86; 95% CI: 1.67 to 4.91; p < 0.01). ConclusionsEndogenous EPA value seems to be associated with risk of MALE and MAE after EVT in patients with PAD caused by aortoiliac artery lesions.

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors, Reality or Dream in Managing Patients with Cardiovascular Disease

Statins have been a major keystone in the management of patients with atherosclerotic cardiovascular disease. The benefits of inhibiting HMG CoA reductase, via statins, were translated into reduction in LDL-c with proportionate decrease in cardiovascular events in response to the magnitude of LDL-c reduction. Despite major advances in pharmacological treatments, including the use of high-dose statins, there are urgent need to further reduce future cardiovascular risk. This is in particularly important since 1 out of 5 high-risk atherosclerotic patients who achieve low LDL-c return with a second cardiovascular event within five years. Although this residual risk post-statin is largely heterogeneous, lowering LDL-c beyond 'normal' or guidelines-recommended level using novel therapies has resulted in further reduction in cardiovascular events. The current review will discuss the use of PCSK9 inhibitors in patients with atherosclerotic disease. PCSK9 inhibitors are a new class of lipid-lowering drugs that are either fully human monoclonal antibodies (evolocumab and alirocumab) or humanised monoclonal antibodies (bococizumab) that effectively reduce LDL-c to unprecedented level. By blocking circulating PCSK9, these drugs would preserve LDL receptors and prevent them from cellular degradation. This process promotes recycling of LDL receptors back to hepatocytes surface, leading into further reduction of LDL-c. Combining PCSK9 inhibitors with statin have led into lower LDL-c, reduction in plaque volume and more importantly reduction in future cardiovascular events. These drugs are very promising, nonetheless, the unselective approach of applying these monoclonal antibodies may not prove to be cost-effective and potentially exposing some patients to unnecessary side effects.

Blockade of the Renin-Angiotensin System in Hypertensive Patients with Atherosclerotic Renal Artery Stenosis

Renin angiotensin system (RAS) blockers are generally considered as contraindicated when an atheromatous renal artery stenosis (ARAS) is diagnosed. The main reason is the fear of inducing renal ischemia and, hence, accelerating renal fibrosis and the progression towards end stage renal disease, albeit RAS blocker have been shown to be highly effective in controlling blood pressure. Part of the solution came by the development of the revascularization. There is now growing evidence showing no superiority of angioplasty over medical treatment on cardiovascular events and mortality, renal function and blood pressure control. Hence, RAS blockers resurfaced based on their proven beneficial effects on blood pressure control and cardiovascular prevention in high risk atherosclerotic patients. Thus, RAS blockers belong today to the standard treatment of hypertensive patients with ARAS. However they were not systematically prescribed in trials focusing on ARAS. The ongoing CORAL trial will give us further information on the place of this class of antihypertensive drugs in patients with ARAS.

Costs and Consequences of Clopidogrel versus Aspirin for Secondary Prevention of Ischaemic Events in (High-Risk) Atherosclerotic Patients in Sweden

Antiplatelet therapy plays a central role in the prevention of atherothrombotic events. Both acetylsalicylic acid (aspirin) and clopidogrel have been shown to reduce the risk of recurrent cardiovascular events in various subgroups of patients with vascular disease. To estimate the cost effectiveness of clopidogrel versus aspirin in Sweden for the prevention of atherothrombotic events based on CAPRIE trial data. The focus of this study is on two high-risk subpopulations: (i) patients with pre-existing symptomatic atherosclerotic disease; and (ii) patients with polyvascular disease. A Markov model combining clinical, epidemiological and cost data was used to assess the economic value of clopidogrel compared with aspirin during a patient's lifetime. A societal perspective was used, with costs stated in Swedish kronor (SEK), year 2007 values. For the first 2 years, the clinical input for the model was based on the relevant subpopulations in the CAPRIE trial. Thereafter, transition probabilities were extrapolated, taking account of increased risks related to age and to a history of events. Cost effectiveness of 2 years of therapy is presented as cost per life-year gained (LYG) and as cost per QALY. Univariate and multivariate sensitivity analyses were performed to investigate robustness of results. For patients resembling the total CAPRIE population, who were treated with clopidogrel, the expected cost per LYG was SEK217,806 and the cost per QALY was estimated at SEK169,154. For the high-risk CAPRIE subpopulations, costs per QALY were lowest for patients with pre-existing symptomatic atherosclerotic disease (SEK38,153). Using a 'willingness-to-pay' perspective indicated that treatment with clopidogrel instead of aspirin in high-risk patients is associated with a high probability for cost effectiveness; 81% using a threshold of SEK100,000 per QALY and 98% using a threshold of SEK500,000 per QALY. Overall, the results appeared to be robust over the sensitivity analyses performed. When considering the cost-effectiveness categorization as proposed by the Swedish National Board of Health and Welfare, clopidogrel appears to be associated with costs per QALY that range from intermediate in the total CAPRIE population to low in high-risk atherosclerotic patients.