Marker Of Residual Risk Research Articles

Is High-Density Lipoprotein Functionality Useful as a Residual Risk Marker for Familial Hypercholesterolemia?

Is High-Density Lipoprotein Functionality Useful as a Residual Risk Marker for Familial Hypercholesterolemia?

Atherogenic index of plasma predicts coronary artery disease severity and major adverse cardiac events in absence of conventional risk factors.

Various overlapping risk factors lead to coronary artery disease (CAD). The atherogenic index of plasma (AIP) is a marker for CAD severity and progression. However, little is known about its contribution to the residual risk of CAD observed in the absence of all typical risk factors. A prospective cohort study of 366 Indian patients undergoing coronary computed tomography (CT) angiography and diagnosed with stable CAD. Diabetes, hypertension, hypercholesterolemia, smoking, previous CAD, alcohol or lipid-lowering medication intake, renal, liver or thyroid dysfunction were exclusion criteria. Coronary stenosis was graded using the CAD-reporting and data system (CAD-RADS™) system. Lipid profile, HbA1c, uric acid, highly sensitive C-reactive protein (hsCRP) and anthropometric measurements were taken. AIP, triglyceride/high-density lipoprotein cholesterol (HDLc) and total cholesterol (Tc)/HDLc ratios were calculated. Independent predictors of CAD severity and the occurrence of major adverse cardiac events (MACE) during 2.57 (0.52) years of follow-up were identified using logistic regression and Cox proportional hazards regression. Sixty patients experienced a MACE during a cumulative 887.03 person-years. HbA1c, uric acid, hsCRP, Tc/HDLc and AIP were independent predictors of severe coronary lesions (CAD-RADS 4,5) on multivariate analysis with odds ratio 4.52 (2.37-8.61), 1.41 (1.08-1.84), 1.33 (1.09-1.62), 1.76 (1.27-2.44) and 1.29 (1.11-1.50), respectively. Only AIP and Tc/HDLc were independent predictors of MACE with hazard ratios of 1.41 (1.20-1.65) and 1.78 (1.33-2.39) besides patient age and CAD severity. AIP is associated with both the severity of CAD and the occurrence of MACE within 3 years. It could serve as an effective marker of residual risk of CAD in patients devoid of traditional risk factors. Lipid-profile ratios, such as AIP are cost-effective and accessible parameters suitable for low and middle-income settings.

Prognostic impact of lipoprotein (a) on long-term clinical outcomes in diabetic patients on statin treatment after percutaneous coronary intervention

BackgroundSerum levels of lipoprotein (a) [Lp(a)] have been reported as a residual risk marker for adverse events in patients with coronary artery disease (CAD). However, the prognostic impact of Lp(a) on long-term clinical outcomes among diabetic patients on statin therapy after percutaneous coronary intervention (PCI) remains unclear. MethodsThe present investigation was a single-center, observational, retrospective cohort study. Among consecutive patients with CAD who underwent first PCI in our institution from 2000 to 2016, we enrolled diabetic patients on statin treatment. As a result, 927 patients (81% men; mean age, 67 years) were enrolled and divided into 2 groups according to a median Lp(a) level of 19.5 mg/dL. The incidence of major adverse cardiac events (MACE), including all-cause death, non-fatal myocardial infarction (MI), and non-fatal cerebral infarction (CI), was evaluated. ResultNo significant differences were seen in age, sex, smoking habits, hypertension, chronic kidney disease, or body mass index between high and low Lp(a) groups. During follow-up (median, 5.0 years; interquartile range, 1.9–9.7 years), MACE occurred in 90 cases (17.6%), including 40 (7.9%) cardiac deaths, 18 (3.6%) non-fatal MI, and 37 (7.9%) non-fatal CI. Frequency of MACE was significantly higher in the high-Lp(a) group than in the low-Lp(a) group (log-rank test, p = 0.002). Higher Lp(a) level at the time of PCI was significantly associated with higher frequency of MACE, even after adjusting for other covariates, including other lipid profiles (hazard ratio, 1.91; 95% confidence interval, 1.20–3.09; p = 0.006). ConclusionOur results demonstrated that in diabetic patients with CAD on statin treatment, increased Lp(a) levels could offer a good residual lipid risk marker. Assessing Lp(a) levels may be useful for risk stratification of long-term clinical outcomes after PCI, especially in diabetic patients.

Abstract 12577: Markers of Residual Risk in Type 2 Diabetes and Stable Ischemic Heart Disease: Insights From the BARI 2D Trial

Background: In spite of aggressive preventive therapy, patients with type 2 diabetes (T2D) and stable ischemic heart disease (SIHD) remain at high risk for major cardiovascular events and death. Understanding the pathophysiologic determinants of that residual risk could help identify effective preventive therapies. Methods and Results: In this Ancillary Study of the BARI 2D trial, we examined the predictive value of biomarkers from 6 distinct pathophysiologic pathways in 2285 men and women with T2D and SIHD who were followed for a median (IQR) of 5.0 (4.1-6.0) years. The endpoint for this Ancillary Study was a composite of myocardial infarction, stroke, heart failure, or all-cause mortality. The 5-year Kaplan-Meier event rate was 31%. The pathophysiologic processes evaluated included dysglycemia (HbA1c), dyslipidemia (LDL-C), myocardial strain (NT-proBNP), myocardial injury (high-sensitivity cardiac troponin T [hsTnT]), subclinical inflammation (high-sensitivity C-reactive protein [hsCRP]), and nephropathy (presence/absence of macroalbuminuria). In Cox proportional hazards models adjusted for baseline risk factors, angiographic severity of disease, and ejection fraction, each marker except LDL-C was a significant predictor of outcome (Figure) in this population with 74% baseline statin use. After mutual adjustment for all 6 markers and baseline risk factors, the hazard ratio (95% CI) per 1-SD of natural logarithm transformed concentration was largest for NT-proBNP [1.29 (1.17, 1.42)], followed by hsTnT [1.16 (1.07, 1.26)], HbA1c [1.12 (1.03, 1.21)], and hsCRP [1.11 (1.03, 1.20). Macroalbuminuria was not a significant predictor after adjustment for the other markers (Figure). Conclusions: In this high-risk population of patients with type 2 diabetes and stable ischemic heart disease, strategies to target myocardial strain, myocardial injury, and subclinical inflammation may lead to improvements in cardiovascular outcome.

Abstract 18619: All Advanced Lipid Tests are Not Equal: Prospective Analysis of Discordance Between LDL-P, Small Dense LDL (or Subfractions), and HDL-P (or Subfractions) as Determined by NMR, Ion Mobility, and VAP in Treated Patients

Introduction: LDL-P has been shown to be a better predictor of cardiovascular risk than LDL-C (Framingham Offspring, Jupiter, and MESA). HDL-P has been reported as a better predictor than HDL-C (Jupiter and MESA) and small dense LDL measurements have been reported as more predictive of cardiovascular disease progression than LDL-C (HATS). Clinicians rely on these markers to assess residual risk in treated patients. Hypothesis: NMR, ion mobility (IM), and VAP tests will report discordant results for LDL-P, HDL-P (or subfraction), and small dense LDL (or subfraction) in treated patients. Methods: This is a prospective study (#SCIML001 on ClinicalTrials.gov), approved by the Scripps Clinic (#IRB-14-6458). We aimed to determine the discordance between Liposcience NMR, Quest CardioIQ, and Atherotech VAP Plus. 102 patients older than 18 years on therapy for at least 30 days were included. A one-time fasting lab draw was obtained with all 3 lipid tests performed simultaneously on fresh samples. Concordance and discordance analysis was performed with the cut-off between normal and abnormal ranges. Results: Pearson correlations between LDL-P by VAP and NMR, NMR and IM, and VAP and IM were 0.886, 0.785, and 0.762, respectively. All 3 tests were concordant 63% and discordant 37% of the time. IM reported an abnormal LDL-P more commonly (28% of time vs NMR and 20% of the time vs VAP) when using the same cutoff value of 1000 as NMR. When using the cutoff of 1260 for LDL-P for IM, NMR was abnormal 15.6% of the time vs IM and VAP was abnormal 24% of the time vs IM. VAP more frequently reported an abnormal LDL-P vs NMR (27% of the time) and vs IM (32% of the time). VAP small LDL sub-fractions were more commonly reported as abnormal vs NMR and IM (27% and 32% respectively). Ion mobility more consistently reported a lower large HDL-P (48% of the time vs VAP and vs NMR). Conclusions: Correlations between advanced markers of residual risk were low and would give discordant signals on decisions to intensify therapy.

On-Statin Resistin, Leptin, and Risk of Recurrent Coronary Events After Hospitalization for an Acute Coronary Syndrome (from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Study)

Resistin is an adipokine secreted by macrophages and inflammatory cells linked to insulin resistance and inflammation. Leptin is an adipokine regulator of appetite and obesity. Although circulating levels of both have been associated with atherosclerosis, few data have reported their relation to coronary events in the context of statin therapy. This study measured on-statin levels of both resistin and leptin through enzyme-linked immunosorbent assay in a nested case-control cohort (n= 176 cases with coronary death, myocardial infarction, or unstable angina pectoris observed in follow-up matched 1:1 to 176 controls) derived from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 study, a randomized controlled trial of atorvastatin 80mg/day versus pravastatin 40mg/day in patients with a recent acute coronary syndrome. Resistin demonstrated a moderate association with high-sensitivity C-reactive protein (hsCRP; Spearman rho= 0.25, p <0.0001). On-statin resistin levels were linked to recurrent coronary events in conditional logistic regression analysis adjusted for additional risk factors including hsCRP and history of diabetes (tertile 3 vs 1 adjusted odds ratio 2.08; 95% confidence interval [CI] 1.04 to 4.19). An additive risk was noted when patients were stratified by resistin and glycated hemoglobin levels. In contrast, leptin levels were associated with obesity, diabetes, triglycerides, and hsCRP (p <0.001 for each) but demonstrated no association with recurrent coronary events (tertile 3 vs 1 adjusted odds ratio 0.72; 95% CI 0.28 to 1.83). In conclusion, on-statin resistin, but not leptin, is an independent marker of residual risk for recurrent coronary events in patients after hospitalization for an acute coronary syndrome.

ATHEROGENIC LIPOPROTEIN PARTICLE SUBCLASSES AND RESIDUAL CARDIOVASCULAR RISK: AN ANALYSIS OF THE JUPITER TRIAL

Despite potent statin therapy, residual risk of CVD events remains unacceptably high. Atherogenic lipoprotein particles and subclass distribution on statin therapy may identify markers of residual risk. Among 11,984 participants in JUPITER ([NCT00239681][1]; AstraZeneca) with lipoproteins measured

Abstract 14864: Risk Markers for Coronary Plaque Progression and Destabilization Beyond LDL-Cholesterol in Patients with Acute Coronary Syndrome

Introduction and Purpose: In acute coronary syndrome (ACS) patients, it is important to stabilize pan-coronary vulnerable plaques as early as possible in ACS patients, in addition to revascularization of the culprit lesion by percutaneous coronary intervention (PCI). Although statins are effective for regression and stabilization of vulnerable plaques in ACS patients, several patients experience plaque progression and/or destabilization despite aggressive control of low-density lipoprotein (LDL)-cholesterol by statins. Therefore, we should do further efforts to research new risk markers beyond LDL-cholesterol and to intervene in them. Methods and Results: In 57 patients with ACS, who underwent emergent percutaneous coronary intervention (PCI), we performed a virtual histology (VH)-IVUS for a non-culprit lesion, at baseline and at the follow-up time (8-10 months), to assess plaque regression/progression and plaque stabilization/destabilization. At the follow-up time, we measured specific biomarkers. All of the patients received aggressive treatment with statins. Change in the total plaque volume by the gray scale IVUS was correlated positively with derivatives of reactive oxygen metabolites (d-ROMs) level (0.32, P&lt;0.05). Change in the volume of destabilized components, i.e., necrotic core plus fibro-fatty compositions, was correlated negatively with the eicosapentaenoic acid to arachidonic acid (EPA/AA) ratio (R=-0.39, P&lt;0.01) and positively with the levels of interleukin (IL)-8 (R=0.31, P&lt;0.01) and d-ROMs (0.32, P&lt;0.01). Multivariate logistic regression analysis showed that only the d-ROMs level was an independent discriminative biomarker for plaque progression (hazard ratio; 1.018, 95% confidence interval; 1.005-1.032, P&lt;0.01) and plaque destabilization (hazard ratio; 1.022, 95% confidence interval; 1.005-1.038, P&lt;0.01). Conclusions: The d-ROMs would be a powerful biomarker to predict plaque progression and destabilization as the residual risk marker beyond LDL-cholesterol. Intervention to oxidative stress state would be the most important residual target beyond LDL cholesterol lowering for plaque regression and stabilization.

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries

High-Density Lipoprotein Cholesterol, Size, Particle Number, and Residual Vascular Risk After Potent Statin Therapy

Chemically measured high-density lipoprotein cholesterol (HDL-C) may not be the best clinical measure of HDL. Little is known about alternative HDL measures such as HDL size or particle number (HDL-P) as determinants of residual risk after potent statin therapy. In Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), HDL size and HDL-P were measured by nuclear magnetic resonance spectroscopy, and HDL-C and apolipoprotein A-I (apoA-I) were chemically assayed in 10 886 participants without cardiovascular disease (CVD) before and after random allocation to rosuvastatin 20 mg/d or placebo. Levels were examined with first CVD (n=234). HDL-P correlated better with apoA-I (Spearman r=0.69, P<0.0001) than with HDL-C (r=0.55, P<0.0001). Rosuvastatin lowered low-density lipoprotein cholesterol (49%) and raised HDL-C (6.1%), apoA-I (2.1%), HDL-P (3.8%), and HDL size (1.2%); all P<0.0001. Among placebo-allocated individuals, on-treatment HDL-C, apoA-I, and HDL-P had similar inverse associations with CVD (risk factor-adjusted hazard ratio and 95% confidence interval per 1 standard deviation: 0.79 [0.63-0.98], 0.75 [0.62-0.92], and 0.81 [0.67-0.97], respectively). Among rosuvastatin-allocated individuals, on-treatment HDL-P had a statistically significant and somewhat stronger association with CVD (0.73, 0.57-0.93, P=0.01) than HDL-C (0.82, 0.63-1.08, P=0.16) or apoA-I (0.86, 0.67-1.10, P=0.22). Among rosuvastatin-allocated individuals, on-treatment HDL-P remained significant (0.72, 0.53-0.97, P=0.03) after additionally adjusting for HDL-C. In risk factor-adjusted models, HDL size showed no significant association with CVD. In the setting of potent statin therapy, HDL particle number may be a better marker of residual risk than chemically measured HDL-C or apoA-I. This has potential implications for evaluating novel therapies targeting HDL. http://www.clinicaltrials.gov. Unique identifier: NCT00239681.

Relationship between Coronary Artery Disease and Non-HDL-C, and Effect of Highly Purified EPA on the Risk of Coronary Artery Disease in Hypercholesterolemic Patients Treated with Statins: Sub-Analysis of the Japan EPA Lipid Intervention Study (JELIS)

The present study examined the importance of reducing non-high-density lipoprotein cholesterol (non-HDL-C) for the primary prevention of the occurrence of coronary artery disease (CAD) in the JELIS, and the effects of EPA. The patients were distributed into 4 subgroups using the lipid management goal for LDL-C recommended by the Japan Atherosclerosis Society guideline (2007) and the goal for non-HDL-C defined as 30 mg/dL higher than LDL-C: A) achieved both goals; B) achieved the LDL-C but not non-HDL-C goal; C) achieved the non-HDL-C but not LDL-C goal; and D) did not attain either goal. The incidences of CAD in the 4 subgroups were compared, and the effects of eicosapentaenoic acid (EPA) on the risk of CAD in these subgroups were examined. In the non-EPA group, the incidence of CAD in patients who did not achieve the goals for LDL-C or non-HDL-C was higher than in patients who achieved those goals. Patients in subgroups B, C, and D were at higher risk for CAD than those in subgroup A (B, HR 2.31; C, HR 1.90; D, HR 2.47). EPA reduced the risk of CAD by 38% in subgroups B, C, and D (p= 0.007). We reconfirmed non-HDL-C as a predictor of the risk for CAD and a residual risk marker of CAD after LDL-C-lowering therapy. EPA was useful to reduce the occurrence of CAD in patients who did not achieve the goals for LDL-C and/or non-HDL-C.

NT-pro-BNP Identifies Patients with High Risk of Cardiac Events in the First Six Months after Cardiac Resynchronization Therapy

Despite cardiac resynchronization therapy (CRT) patients (pts) with heart failure (HF) remain at high risk for major cardiac events. We aimed to determine markers of residual risk for major cardiac events on pts with HF after CRT. We studied 109 pts with ischemic (ICM) or idiopathic cardiomiopathy, III-IV NYHA class, on optimized medical therapy. CRP level and NT-pro-BNP was measured immediately before CRT. Values are reported in table. During 6 months follow-up we observed mayor cardiac events in 16 pts: 6 deaths for heart failure and 10 VT/VF-events. Pts with events showed significant higher values of NT-pro-BNP. NT-pro-BNP, on the contrary of CRP, identifies, during CRT, pts at high risk of cardiac events. This may have implications for future risk assessment of pts with potential benefit from CRT.