Targeting Vulnerable Plaques in Coronary Artery Disease: Detecting Risk, Preventing Events.

Dyslipidemia

Case presentation: A 38-year-old man underwent angiography 2 weeks after a non–ST-segment myocardial infarction. He was overweight and prehypertensive, with a blood pressure of 134/86 mm Hg. His biochemical parameters included low-density lipoprotein cholesterol (LDL-C) 127 mg/dL, high-density lipoprotein cholesterol (HDL-C) 38 mg/dL, and C-reactive protein (CRP) 3.2 mg/L. Angiography revealed mild disease throughout the coronary arteries and a hazy appearance that involved the proximal left anterior descending coronary artery. Intravascular ultrasound (IVUS) imaging revealed diffuse and extensive atherosclerosis with evidence of plaque rupture at multiple sites (Figure 1). In the presence of no significant luminal stenoses, the patient was treated medically with aspirin and low-dose statin therapy. Figure 1. Illustrative example of coronary angiography of the left anterior descending artery that appears to be free of irregularities, apart from a hazy appearance in the proximal segment. A representative cross-sectional tomographic image obtained by IVUS examination (top right) within the proximal segment (white arrow on angiogram) revealed substantial atheroma within the arterial wall. The bottom right segment illustrates a tomographic image of atheroma containing significant ulceration (5 o’clock) at the site of the gold arrow on the angiogram. The application of IVUS in this case highlights a number of important points with regard to the natural history of atherosclerosis and its modification by use of established medical therapies. The ability to image the entire arterial wall represents a significant advantage over coronary angiography. In the presence of minimal luminal stenoses, IVUS imaging in patients with coronary symptoms typically reveals extensive and diffuse atherosclerosis.1 Application of serial IVUS imaging in prospective clinical trials has enabled a greater understanding of the impact of antiatherosclerotic interventions on patients with established coronary artery disease (CAD). Ultrasonic coronary imaging has revealed essential details about the natural history of atherosclerosis. Atheroma formation begins at a …

Adverse cardiovascular (CV) events have declined in Western countries due at least in part to aggressive risk factor control, including dyslipidemia management. The American and European (Western) dyslipidemia treatment guidelines have contributed significantly to the reduction in atherosclerotic cardiovascular disease (ASCVD) incidence in the respective populations. However, their direct extrapolation to Indian patients does not seem appropriate for the reasons described below. In the US, mean low-density lipoprotein cholesterol (LDL-C) levels have markedly declined over the last 2 decades, correlating with a proportional reduction in CV events. Conversely, poor risk factor control and dyslipidemia management have led to increased CV and coronary artery disease (CAD) mortality rates in India. The population-attributable risk of dyslipidemia is about 50% for myocardial infarction, signifying its major role in CV events. In addition, the pattern of dyslipidemia in Indians differs considerably from that in Western populations, requiring unique strategies for lipid management in Indians and modified treatment targets. The Lipid Association of India (LAI) recognized the need for tailored LDL-C targets for Indians and recommended lower targets compared to Western guidelines. For individuals with established ASCVD or diabetes with additional risk factors, an LDL-C target of <50 mg/dL was recommended, with an optional target of ≤30 mg/dL for individuals at extremely high risk. There are several reasons that necessitate these lower targets. In Indian subjects, CAD develops 10 years earlier than in Western populations and is more malignant. Additionally, Indians experience higher CAD mortality despite having lower basal LDL-C levels, requiring greater LDL-C reduction to achieve a comparable CV event reduction. The Indian Council for Medical Research-India Diabetes study described a high prevalence of dyslipidemia among Indians, characterized by relatively lower LDL-C levels, higher triglyceride levels, and lower high-density lipoprotein cholesterol (HDL-C) levels compared to Western populations. About 30% of Indians have hypertriglyceridemia, aggravating ASCVD risk and complicating dyslipidemia management. The levels of atherogenic triglyceride-rich lipoproteins, including remnant lipoproteins, are increased in hypertriglyceridemia and are predictive of CV events. Hypertriglyceridemia is also associated with higher levels of small, dense LDL particles, which are more atherogenic, and higher levels of apolipoprotein B (Apo B), reflecting a higher burden of circulating atherogenic lipoprotein particles. A high prevalence of low HDL-C, which is often dysfunctional, and elevated lipoprotein(a) [Lp(a)] levels further contribute to the heightened atherogenicity and premature CAD in Indians. Considering the unique characteristics of atherogenic dyslipidemia in Indians, lower LDL-C, non-HDL-C, and Apo B goals compared to Western guidelines are required for effective control of ASCVD risk in Indians. South Asian ancestry is identified as a risk enhancer in the American lipid management guidelines, highlighting the elevated ASCVD risk of Indian and other South Asian individuals, suggesting a need for more aggressive LDL-C lowering in such individuals. Hence, the LDL-C goals recommended by the Western guidelines may be excessively high for Indians and could result in significant residual ASCVD risk attributable to inadequate LDL-C lowering. Further, the results of Mendelian randomization studies have shown that lowering LDL-C by 5-10 mg/dL reduces CV risk by 8-18%. The lower LDL-C targets proposed by LAI can yield these incremental benefits. In conclusion, Western LDL-C targets may not be suitable for Indian subjects, given the earlier presentation of ASCVD at lower LDL-C levels. They may result in greater CV events that could otherwise be prevented with lower LDL-C targets. The atherogenic dyslipidemia in Indian individuals necessitates more aggressive LDL-C and non-HDL-C lowering, as recommended by the LAI, in order to stem the epidemic of ASCVD in India.

The concepts for pathogenesis of atherothrombosis and the determinants of atherosclerotic plaque stability have evolved rapidly. Heretofore, plaques that appear ulcerative, fissured, and/or thrombotic and that are characterized histologically by a central lipid core, inflammatory infiltrate, and cap thinning have been termed “vulnerable.” Vulnerable plaque has been implicated in the development of unstable angina, myocardial infarction, and sudden cardiac death. However, as emphasized by the consensus opinions of Drs Maseri and Fuster1 and Dr Casscells et al2 expressed in the current issue of Circulation , this popular concept is overly simplistic and inadequate to explain the clinical spectrum of atherothrombotic events. For example, plaque inflammation may be present in patients with chronic stable angina and yet absent in some patients who present with an acute coronary syndrome. Plaque rupture may result in stable, mural endoluminal thrombus …

Is There Long-Term Clinical Equipoise Between CABG and PCI for Isolated Left Anterior Descending Artery Disease?

Managing dyslipidemia in the high-risk patient

Background Familial hypercholesterolemia is the elective clinical condition that deserves the maximal personalisation in lipid-lowering therapy, especially in the presence of statin intolerance. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represent a promising approach to lower low-density lipoprotein (LDL) cholesterol. Methods We enrolled 18 patients (mean age 62 ± 8 years, 72% men) affected by heterozygous familial hypercholesterolemia and cardiovascular disease, with a history of statin intolerance assigned to PCSK9 inhibitors. Six patients were also on LDL apheresis. Associated Lp(a)-hyperlipoproteinemia (defined as >60 mg/dl) was observed in two out of 18 subjects. PCSK9 inhibitor injectable monoclonal antibodies were administered, every 2 weeks, on top of patient therapy for 12 ± 4 weeks (evolocumab in 15 subjects, alirocumab in three subjects). Results After 3 months (12 ± 4 weeks) of therapy, a decrease in total cholesterol (-35%), LDL cholesterol (-51%) and Lp(a) levels (-20%) was observed. Five out of 18 patients reached LDL cholesterol levels of <70 mg/dl, seven showed LDL cholesterol values between 71 and 100 mg/dl, and six out of 18 still had LDL cholesterol levels above 100 mg/dl. Among the six patients with LDL cholesterol levels >100 mg/dl, three were already on LDL apheresis before the PCSK9 inhibitor treatment, while three were referred to LDL apheresis treatment. Adverse events were reported in two out of 18 patients on evolocumab: one presented with flu-like syndrome and the other reported episodes of mild difficulty in maintaining concentration. Conclusions PCSK9 inhibitors represent a novel therapeutic tool for patients with familial hypercholesterolemia who are intolerant to statins. However, more data are needed before cleaning up the old therapeutic armamentarium, such as LDL apheresis, which is likely to preserve its valuable role also in the new lipid-lowering era.

The importance of considering alternative or combination strategies for lowering LDL-C

ObjectiveThe current guideline recommends lowering low-density lipoprotein cholesterol (LDL-C) for the primary management of dyslipidemia in patients at high-risk of cardiovascular events. Patients who have achieved LDL-C levels below the recommended targets may still experience cardiovascular events, suggesting additional therapeutic targets beyond LDL-C. The aim of this study was to investigate whether high-density lipoprotein cholesterol (HDL-C) levels had an impact on plaque stabilization in patients with acute coronary syndrome (ACS).MethodsThis study consisted of 90 ACS patients with untreated dyslipidemia. In optical coherence tomography (OCT) analysis, a plaque with fibrous cap thickness ≦160 μm was defined as a high-risk plaque. We registered one high-risk plaque per one patient by baseline OCT imaging, and then administrated high-intensity statin. Based on the follow-up OCT results, patients whose registered plaque was no longer high-risk plaque were classified into a responder group and the remains into a non-responder group.ResultsNo differences were observed in the baseline LDL-C and HDL-C levels between the two groups. Reduction of LDL-C levels (δ LDL-C: −53 ± 21 mg/dL vs. −42 ± 29 mg/dL, p = 0.036) and increase of HDL-C levels (δ HDL-C: 2.5 ± 5.9 mg/dL vs. −0.3 ± 6.7 mg/dL, p = 0.039) were greater in the responder group. On multivariate logistic regression analysis, δ LDL-C levels (OR: 0.956, 95% CI: 0.921–0.993; p = 0.020) and δ HDL-C levels (OR: 1.143; 95% CI: 1.005–1.300, p = 0.041) were independent contributors for plaque stabilization.ConclusionsIncrease of HDL-C levels is associated with plaque stabilization in patients with ACS. HDL-C could be a therapeutic target for residual risk management.

Background Lower low-density lipoprotein cholesterol (LDL-C) is significantly associated with improved prognosis in patients with coronary artery disease (CAD). However, LDL-C reduction does not decrease all-cause mortality among CAD patients when renal function impairs. There are currently no studies examining the association of low baseline LDL-C concentration (&amp;lt;1.8 mmol/L) with mortality among patients with CAD and advanced kidney disease (AKD). We aimed to evaluate prognostic value of low baseline LDL-C level for all-cause death in these patients. Methods In this observational study, 803 CAD patients complicated with AKD (eGFR &amp;lt;30 mL/min/1.73 m 2) were enrolled between January 2008 to December 2018. Patients were divided into two groups (LDL-C &amp;lt;1.8 mmol/L, n=138; LDL-C ≥1.8 mmol/L, n=665). We used Kaplan-Meier methods and Cox regression analyses to assess the association between baseline low LDL-C levels and long-term all-cause mortality. Results Among 803 participants (mean age 67.4 years; 68.5% male), there were 315 incidents of all-cause death during a median follow-up of 2.7 years. Kaplan–Meier analysis showed that low LDL-C levels were associated with worse prognosis. After adjusting for full 24 confounders (e.g., age, diabetes, heart failure, and dialysis, etc.), multivariate Cox regression analysis revealed that lower LDL-C level (&amp;lt;1.8mmol/L) was significantly associated with higher risk of all-cause death (adjusted HR, 1.38; 95% CI, 1.01–1.89). Conclusions Our data demonstrated that among patients with CAD and AKD, a lower baseline LDLC level (&amp;lt;1.8mmol/L) did not present a higher survival rate but was related to a worse prognosis, suggesting a cautiousness of too low LDL-C levels among patients with CAD and AKD. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): This study was supported by the National Natural Science Foundation of China (Grant No. 81670339 and Grant No. 81970311), Cardiovascular Research Foundation Project of the Chinese Medical Doctor Association (SCRFCMDA201216) and Beijing Lisheng Cardiovascular Health Foundation (LHJJ20141751).

BackgroundLower low-density lipoprotein cholesterol (LDL-C) is significantly associated with improved prognosis in patients with coronary artery disease (CAD). However, LDL-C reduction does not decrease all-cause mortality among CAD patients when renal function impairs. The association between low baseline LDL-C (< 1.8 mmol/L) and mortality is unknown among patients with CAD and advanced kidney disease (AKD). The current study aimed to evaluate prognostic value of low baseline LDL-C level for all-cause death in these patients.MethodsIn this observational study, 803 CAD patients complicated with AKD (eGFR < 30 mL/min/1.73 m2) were enrolled between January 2008 to December 2018. Patients were divided into two groups (LDL-C < 1.8 mmol/L, n = 138; LDL-C ≥ 1.8 mmol/L, n = 665). We used Kaplan-Meier methods and Cox regression analyses to assess the association between baseline low LDL-C levels and long-term all-cause mortality.ResultsAmong 803 participants (mean age 67.4 years; 68.5% male), there were 315 incidents of all-cause death during a median follow-up of 2.7 years. Kaplan–Meier analysis showed that low LDL-C levels were associated with worse prognosis. After adjusting for full 24 confounders (e.g., age, diabetes, heart failure, and dialysis, etc.), multivariate Cox regression analysis revealed that lower LDL-C level (< 1.8 mmol/L) was significantly associated with higher risk of all-cause death (adjusted HR, 1.38; 95% CI, 1.01–1.89).ConclusionsOur data demonstrated that among patients with CAD and AKD, a lower baseline LDL-C level (< 1.8 mmol/L) did not present a higher survival rate but was related to a worse prognosis, suggesting a cautiousness of too low LDL-C levels among patients with CAD and AKD.

The randomised clinical trial data, which supports preventing coronary heart disease (CHD) events by lowering low density lipoprotein cholesterol (LDL-C) levels, is substantial, consistent and highly significant. HMG-CoA reductase inhibitors (statins), which are the preferred medications for lowering LDL-C levels, are well tolerated, with greater efficacy than other lipid-altering medications. In 1993, the National Cholesterol Education Program (NCEP) guidelines recommended LDL-C target levels to be achieved with therapy in high-risk individuals. In particular, the LDL-C goal of therapy in patients with CHD was < or = 100 mg/dl (2.6 mmol/L), with no specific guidance as to the lower limit or whether additional clinical benefit could be expected. Because little clinical trial data existed at that time to offer support, and because some epidemiological data raised concern about the potential detriments associated with very low total cholesterol and LDL-C levels, the NCEP Adult Treatment Panel remained appropriately vague on the 'how low should you go' question. In the last few years, several additional clinical trials have provided sufficient efficacy and safety data to re-examine that question. Analyses of on-treatment LDL-C levels and subsequent CHD events from three landmark trials with HMG-CoA reductase inhibitors suggest that progressively lower LDL-C levels are associated with lower CHD events in a curvilinear fashion. The Post Coronary Artery Bypass Graft (Post-CABG) trial and Atorvastatin Versus Revascularisation Trial (AVERT) examined a more intensive versus less intensive drug regimen for LDL-C reduction, and concluded that the more aggressively treated patients had better angiographic and end-point outcomes. Most importantly, there did not appear to be any change in noncardiovascular end-points associated with lower LDL-C levels. In several ongoing clinical trials, patients with CHD have been randomised to receive HMG-CoA reductase inhibitors with targets for LDL-C levels of 100 mg/dl versus 75 mg/dl (1.94 mmol/L). These trials have sufficient patient numbers and power to definitely determine if reducing LDL-C levels to approximately 75 mg/dl can provide an acceptable benefit-to-risk-ratio.

Cholesterol control with statins has been shown to have beneficial effects in coronary artery disease. However, the relationship between initial very low low-density lipoprotein (LDL) cholesterol levels and long-term clinical outcomes in patients with acute myocardial infarction (AMI) remains unclear. A total of 8741 (mean age: 64.6 ± 12.7 years, men) consecutive AMI patients treated with drug-eluting stents were entered into the Korea Acute Myocardial Infarction Registry from November 2011 to December 2015. Patients were divided into six groups according to whether they were taking statins (on-statin group) or not (statin naive group) and depending on their LDL cholesterol level at admission (<70, 70-99, 100-129, 130-159, >160 mg/dl). Clinical outcomes at 24 months in patients with AMI were examined. The incidence of risk factors including hypertension, diabetes, coronary artery disease and heart failure was lower as LDL cholesterol increased, except in the on-statin group. Clinical outcomes, including total mortality at 24 months, showed better outcomes in those with high LDL cholesterol than those with low LDL cholesterol, except in the statin group. In the statin-naïve group, the higher the LDL cholesterol level, the higher the rate of 24-month survival. In a Cox regression model, initial low LDL cholesterol was an independent predictor of mortality at 24 months after adjusting for baseline confounding factors. At admission, a very low LDL cholesterol level (<70 mg/dL) in statin-naïve AMI patients undergoing percutaneous coronary intervention was independently associated with higher mortality at 24 months.

Liver cancer a global public health concern and well known for poor prognosis. The association between low total cholesterol level and liver cancer has been reported. However, the association between low low-density lipoprotein (LDL) cholesterol levels and liver cancer is still unclear. The aim of this study was to examine the relationship between LDL cholesterol level and liver cancer mortality. A total of 16,217 persons (5,551 men and 10,666 women) aged 40-79 years in 1993 were followed until 2008. LDL cholesterol levels were divided into four categories (<80 mg/dl, 80-99 mg/dl, 100-119 mg/dl, and ≥120 mg/dl). Hazard ratio of LDL cholesterol level for liver cancer mortality was calculated using a multivariable Cox proportional hazards model. Covariates were age, sex, alanine transaminase, body mass index, alcohol intake and smoking status, all of which were correlated with LDL cholesterol levels. There were 51 deaths (32 men and 19 women) from liver cancer. Multivariable hazard ratios of liver cancer deaths for LDL cholesterol levels of <80 mg/dl was 4.33 (95% confident interval [CI]: 1.94, 9.68), for LDL cholesterol levels of 80-99 mg/dl was 1.03 (95% CI: 0.42, 2.53), and for LDL cholesterol levels of ≥120 mg/dl was 0.43 (95% CI: 0.20, 0.92) compared with LDL cholesterol levels of 100-199 mg/dl (p for trend<0.01). Therefore, low LDL cholesterol levels are associated with elevated risk of liver cancer mortality. Low LDL cholesterol may be a predictive marker for death due to liver cancer.

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