MADRID, SPAIN — Subclinical atherosclerosis was detectable by ultrasound or cardiac CT in about half of middle-aged adults who were without standard cardiovascular risk factors, including diabetes and high LDL cholesterol by usual definitions, in a prospective observational cohort[1].
Moreover, LDL-C, despite being in a range typically considered normal, was independently correlated with both the presence and extent of atherosclerosis—measured in coronary, limb, carotid, and infrarenal arteries—in the analysis of 1779 participants in the Progression of Early Subclinical Atherosclerosis (PESA) cohort study.
The subcohort, at baseline aged mostly in their 40s or early 50s, represented those of the entire PESA population of >4000 who were free of standard modifiable CV risk factors, including smoking along with hypertension, diabetes, and dyslipidemia according to Adult Treatment Panel (ATP) III definitions.
The relationships between LDL-C and atherosclerosis presence and extent remained significant in a further subset of 740 participants who not only met the criteria for being risk-factor free, they met more discriminating criteria for measures of blood pressure, glycemia, and total cholesterol that put them in the “optimal” ranges.
The correlation of rising LDL-C levels with greater-degree atherosclerosis suggested, for both men and women, that development of vascular disease begins at an LDL-C of about 50 mg/dL to 60 mg/dL, “similar to the level associated with disease regression,” according to a report published in the December 19, 2017 issue of the Journal of the American College of Cardiology with first author Dr Leticia Fernández-Friera (Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain).
That’s also a range of LDL-C achievable with contemporary dyslipidemia agents, notably proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors on top of statins as demonstrated in the FOURIER trial, the authors observe. That trial also saw improved clinical outcomes with the combination treatment.
Odds Ratio (OR) for Atherosclerosis Presence and Extent in Population Initially Free of CV Risk Factorsa
| End points | Atherosclerosis present,b OR (95% CI), P | >1 arterial system involvement, OR (95% CI), P |
|---|---|---|
| Age (per year) | 1.11 (1.08–1.13), <0.001 | 1.14 (1.11–1.16), <0.001 |
| Male | 2.03 (1.66–2.47), <0.001 | 2.20 (1.80–2.69), <0.001 |
| LDL-C (per 10 mg/dL) | 1.14 (1.08–1.19), <0.001 | 1.14 (1.09–1.20), <0.001 |
| HbA1c (per 1%) | 1.77 (1.31–2.40), <0.001 | 1.79 (1.36–2.36), <0.001 |
|
a. CV risk-factor freedom defined as no current smoking, untreated blood pressure 40 mg/dL
b. Presence of atherosclerotic plaques by ultrasound of carotid arteries, infrarenal abdominal aorta, and iliofemoral artery; CAD by calcium scores from CT imaging |
||
The findings highlight that “physiologic” LDL-C levels—that is, those that might be present in people not exposed to diet and lifestyle patterns common to today—are probably <50 mg/dL, senior author Dr Javier Sanz (Centro Nacional de Investigaciones Cardiovasculares Carlos III) told theheart.org | Medscape Cardiology.
“It shows that relatively mild elevations of LDL-C, which we would call ‘normal,’ are probably harmful,” he said. “In advanced industrialized societies, everybody has high cholesterol. We call it normal, but in reality it’s probably already creating atherosclerosis.”
Odds Ratio (OR) for Atherosclerosis Presence and Extent in Population Initially with “Optimal” CV Risk Factorsa
| End points | Atherosclerosis present,b OR (95% CI) P | >1 arterial system involvement, OR (95% CI), P |
|---|---|---|
| Age (per year) | 1.11 (1.06–1.15), <0.001 | 1.13 (1.08–1.17), <0.001 |
| Male | 2.00 (1.45–2.77), <0.001 | 2.13 (1.57–2.91), <0.001 |
| LDL-C (per 10 mg/dL) | 1.16 (1.05–1.28), 0.003 | 1.18 (1.07–1.30), 0.001 |
|
a. CV risk-factor freedom defined as no current smoking, untreated blood pressure 40 mg/dL
b. Presence of atherosclerotic plaques by ultrasound of carotid arteries, infrarenal abdominal aorta, and iliofemoral artery; CAD by calcium scores from CT imaging |
||
The PESA risk-factor-free cohort averaged 45 in age and 50.3% were women. They were evaluated at baseline for carotid, iliofemoral, and abdominal aortic plaques by ultrasound and coronary artery calcification by CT, and for a range of serum biomarkers and lifestyle measures.
Subclinical atherosclerosis, indicated by plaques or coronary calcification, was identified in 49.7% of the group and in more than one arterial system in 30%. The relationships between LDL-C and atherosclerosis presence and extent were seen in all arterial systems, Sanz said.
After the field’s long-time success of statin therapy for primary and secondary prevention, the addition of drugs like ezetimibe and the PCSK9 inhibitors that can push LDL-C to below 50 mg/dL have shaken up traditional views of how contemporary drug therapy should be used for prevention of atherosclerotic cardiovascular disease (ASCVD), according to an editorial accompanying the report[2].
“In this context, the current analysis by Fernández-Friera et al is highly relevant and now raises the question of what the optimal cholesterol level may be in the primordial and primary prevention of ASCVD,” write Dr Vijay Nambi (Baylor College of Medicine, Houston, TX) and Dr Deepak L Bhatt (Brigham and Women’s Hospital, Boston, MA).
They speculate that “arterial imaging at an early age,” perhaps supplemented by biomarker and genetic screening, “would help further refine and personalize risk assessment prior to the establishment of atherosclerosis and/or ASCVD.” But there are no appropriate trials supporting that approach, they add.
Meanwhile, they write, “physicians should consider avoiding the term ‘normal’ and instead inform their patients of their current cholesterol, blood pressure, or blood glucose values and discuss what preventive efforts may be needed given their level of risk.”
PESA was funded in part by Banco de Santander (Madrid). The authors had no relevant financial relationships. Nambi reports holding a provisional patent with Baylor College of Medicine and Roche entitled “Use of biomarkers in prediction of heart failure,” serving as an event adjudicator for Siemens Diagnostics, and serving as a site principal investigator for Merck. Bhatt discloses serving on the advisory board of Medscape Cardiology and Regado Biosciences; receiving honoraria from WebMD; receiving research funding from Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Ironwood, Ischemix, Lilly, Medtronic, Pfizer, Roche, Sanofi, and the Medicines Company; serving as site coinvestigator for Biotronik, Boston Scientific, and St Jude Medical (now Abbott); “and has performed unfunded research for FlowCo, Merck, PLx Pharma, and Takeda.”
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