Atherosclerosis newsletter
Highlighted articles from May issue Vol 392
Newsletter by Editor in Chief Prof Arnold von Eckardstein, and Editorial Office Manager Simona Negrini
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The May issue of Atherosclerosis contains several articles on the importance of imaging biomarkers in the diagnostics, prognostics, and monitoring of atherosclerotic cardiovascular diseases per se and as a reference for the evaluation of circulating biomarkers.
Coronary artery calcium as a marker of healthy and unhealthy aging in adults aged 75 and older: The Atherosclerosis Risk in Communities (ARIC) study
The aging process is marked by cellular senescence via several underlying biological mechanisms, which have also been implicated in the pathogenesis of atherosclerosis. Coronary artery calcium (CAC) is a widely validated marker of atherosclerosis that strongly predicts coronary heart disease events, cardiovascular disease events, and all-cause mortality among middle-aged adults, however, there is limited research exploring implications of CAC among older adults. Obisesan et al. used data from the Atherosclerosis Risk in Communities (ARIC) study to evaluate the association of CAC with domains of healthy and unhealthy aging in adults aged ≥75 years.
2,290 participants aged ≥75 years free of known coronary heart disease who underwent CAC scoring at study visit 7 were included in the study. Cross-sectional association of CAC = 0, 1–999 (reference), and ≥1000 with seven domains of aging: cognitive function, hearing, ankle-brachial index (ABI), pulse-wave velocity (PWV), forced vital capacity (FVC), physical functioning, and grip strength, was examined.
The mean age of study patients was 80.5 ± 4.3 years, 38.6% male, and 77.7% White. 10.3% had CAC = 0 and 19.2% had CAC≥1000. Individuals with CAC = 0 had the lowest while those with CAC≥1000 had the highest proportion with dementia, hearing impairment, low ABI, high PWV, reduced FVC, impaired grip strength, and mean composite abnormal aging score. Participants with CAC = 0 were less likely to have abnormal ABI, high PWV, and reduced FVC. Conversely, participants with CAC≥1000 were more likely to have low ABI, high PWV, impaired physical functioning, and impaired grip strength.
These findings highlight CAC as a simple measure broadly associated with biological aging, with clinical and research implications for estimating the physical and physiological aging trajectory of older individuals.
Subclinical vascular composites predict clinical cardiovascular disease, stroke, and dementia: The Multi-Ethnic Study of Atherosclerosis (MESA)
Cardiovascular risk summarizes important modifiable and non-modifiable risk factors for cardiovascular disease (CVD), which includes coronary heart disease (CHD) and stroke that extend to the risk of dementia, and even dementia-related neuropathology. Hughes et al. used the longitudinal Multi-Ethnic Study of Atherosclerosis (MESA) data to create novel composite factor scores collected at baseline by factor analysis and related these subclinical composite factor scores to incident events of all cause CVD, including CHD and stroke, and dementia, adjusted for conventional clinical risk scores for CVD, stroke, and dementia.
MESA followed 6814 participants (45–84 years of age) from baseline in 2000–2002 to 2018 over 6 clinical examinations and annual follow-up interviews. MESA baseline subclinical CVD procedures included: seated and supineblood pressure, coronary calcium scan, radial artery tonometry, and carotid ultrasound. Baseline subclinical CVD measures were transformed into z-scores before factor analysis to derive composite factor scores. Time to clinical event for all-cause CVD, CHD, stroke and ICD code-based dementia events were modelled using Cox proportional hazards models reported as area under the curve (AUC) with 95% confidence intervals at 10 and 15 years of follow-up. All models included all factor scores together, and adjustment for conventional risk scores for global CVD, stroke, and dementia.
After factor selection, 24 subclinical measures aggregated into four distinct factors representing: blood pressure, atherosclerosis, arteriosclerosis, and cardiac factors. Each factor significantly predicted time to CVD events and dementia at 10 and 15 years independent of each other and conventional risk scores. Subclinical vascular composites of atherosclerosis and arteriosclerosis best predicted time to clinical events of CVD, CHD, stroke, and dementia. These results were consistent across sex and racial and ethnic groups.
Subclinical vascular composites of atherosclerosis and arteriosclerosis may be useful biomarkers to inform the vascular pathways contributing to events of CVD, CHD, stroke, and dementia.
Effects of alirocumab on endothelial function and coronary atherosclerosis in myocardial infarction: A PACMAN-AMI randomized clinical trial substudy
The vascular endothelium plays a key role in the pathogenesis of atherosclerosis and its impairment precedes the development of structural atherosclerotic alterations. Flow-mediated dilation (FMD) allows the evaluation of the systemic vascular endothelial-dependent function and is considered the “gold standard” for non-invasive assessment of endothelial function. The effects of protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors on endothelial function as evaluated with FMD in patients with acute myocardial infarction (AMI) are unknown. Rexhaj et al. aimed to investigate the effects of the PCSK9 inhibitor alirocumab added to high-intensity statin on FMD, and its association with coronary atherosclerosis in non-infarct related arteries using intracoronary intravascular ultrasound (IVUS), near-infrared spectroscopy (NIRS), and optical coherence tomography (OCT).
This was a pre-specified substudy among patients recruited at Bern University Hospital, Switzerland, for the randomized-controlled, double-blind, PCSK9 Antibody Alirocumab on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction (PACMAN-AMI) trial, which compared the effects of biweekly alirocumab 150 mg vs. placebo added to rosuvastatin. Brachial artery FMD was measured at 4 and 52 weeks, and intracoronary imaging at baseline and 52 weeks.
139/173 patients completed the substudy. There was no difference in FMD at 52 weeks in the alirocumab versus placebo group. FMD improved throughout 52 weeks in both groups, similarly. There was a significant association between 4 weeks FMD and baseline plaque burden (IVUS), but not with lipid pool (NIRS), or fibrous cap thickness (OCT). Among patients with AMI, the addition of alirocumab did not result in further improvement of FMD as compared to 52 weeks secondary preventative medical therapy including high-intensity statin therapy. FMD was significantly associated with coronary plaque burden at baseline, but not with lipid pool or fibrous cap thickness.
EMatrix Gla protein and the long-term incidence and progression of coronary artery and aortic calcification in the Multi-Ethnic Study of Atherosclerosis
Matrix Gla protein (MGP) is an inhibitor of calcification that requires carboxylation by vitamin K for activity. The inactive form of MGP, dephosphorylated-uncarboxylated matrix Gla protein (dp-ucMGP), has been associated with increased calcification. However, it is not known whether there is a longitudinal relationship between dephosphorylated-uncarboxylated matrix Gla protein levels and coronary and aortic calcification in large population cohorts. Berlot et al. assessed the combined incidence and progression of CAC, ascending thoracic aortic calcification (ATAC), and descending thoracic aortic calcification (DTAC), over long-term follow-up in a subset with baseline dp-ucMGP levels in the Multi-Ethnic Study of Atherosclerosis (MESA), a diverse cohort of healthy individuals at centers across the United States.
MESA followed participants with serial cardiac computed tomography (CT) measures of vascular calcification. Dp-ucMGP was measured at baseline in a subset of participants who completed baseline and follow-up CTs approximately 10 years later and had available plasma specimens (n = 2663). Linear mixed effects models (LMMs) were used to determine the association of dp-ucMGP with the simultaneous incidence and progression of coronary artery, ascending thoracic aortic, or descending thoracic aortic calcification (CAC, ATAC, DTAC)].
For every one standard deviation increment in dp-ucMGP, CAC increased by 3.44 Agatston units/year (AU/year), ATAC increased by 0.63 AU/year, and DTAC increased by 8.61 AU/year. The association was stronger for DTAC in those ≥65 years and with diabetes.
The authors found a positive association of the inactive form of matrix Gla protein, dp-ucMGP, and long-term incidence/progression of CAC, ATAC, and DTAC. Dephosphorylated-uncarboxylated matrix Gla protein may be a useful biomarker for calcification risk.
Circulating miR-6821-5p levels and coronary calcification in asymptomatic familial hypercholesterolemia patients
Premature atherosclerotic cardiovascular disease (CVD) is a clinic characteristic of familial hypercholesterolemia (FH). The presence of calcium in the coronary arteries seems to predict coronary events in asymptomatic middle-aged FH-patients treated with statins. Coronary calcium score (CCS) is a highly used imaging modality to evidence atherosclerotic plaque burden. microRNAs (miRNAs) are non-coding RNAs that epigenetically regulate gene expression. Escate et al. investigated whether CCS associates with a specific miRNA-signature in FH-patients.
Patients with genetic diagnosis of FH (N = 86) from the nationwide Spanish Familial Hypercholesterolaemia cohort study (SAFEHEART) were assessed by computed tomography angiography imaging and classified depending on the presence of coronary calcification in FH-CCS (+) and FH-CCS (−) groups by the Agatston score. Differential miRNA profiling was performed in two stages: first by Affymetrix microarray technology (high-throughput differential profiling-studies) and second by RT-PCR using TaqMan-technology (analytical RT-qPCR study) in plasma of the two patient groups.
miR-193a-5p, miR-30e-5p and miR-6821-5p levels were significantly higher in FH-CCS (+) compared to FH-CCS (−). miR-6821-5p was the best miRNA to discriminate FH-patients CCS(+), according to receiver operating characteristic (ROC) analysis. High miR-6821-5p levels were associated with older age and high LDL-burden using a ROC-derived cut-off value. However, miR-6821-5p did not correlate with age in either the CCS- or CCS + group. Genes involved in calcification processes were identified by in silico analysis. The relation of cell-calcification and expression levels of miR-6821-5p, bone morphogenetic protein 2 (BMP2)and secreted phosphoprotein 1 (SPP1) was validated experimentally in human vascular smooth muscle cell cultures.
Up-regulated levels of miR-6821-5p are found in the plasma of asymptomatic FH-patients with coronary calcified atherosclerotic plaques, as well as in isolated human vascular smooth muscle cells expressing the pro-calcification genes BMP2 and SPP1. These findings highlight the impact of epigenetic regulation on the development of subclinical atherosclerosis.