Determinants of Carotid Wall Echolucency in a Cohort of European High Cardiovascular Risk Subjects: A Cross-Sectional Analysis of IMPROVE Baseline Data.

Echolucency, a measure of plaque instability associated with increased cardiovascular risk, can be assessed in both the carotid plaque and the plaque-free common carotid intima-media (IM) complex as a gray-scale median (plaque-GSM and IM-GSM, respectively). The impact of specific vascular risk factors on these two phenotypes remains uncertain, including the nature and extent of their influence. This study aims to seek the determinants of plaque-GSM and IM-GSM. Plaque-GSM and IM-GSM were measured in subjects from the IMPROVE study cohort (aged 54-79, 46% men) recruited in five European countries. Plaque-GSM was measured in subjects who had at least one IMTmax ≥ 1.5 mm (n = 2138), whereas IM-GSM was measured in all subjects included in the study (n = 3188). Multiple regression with internal cross-validation was used to find independent predictors of plaque-GSM and IM-GSM. Plaque-GSM determinants were plaque-size (IMTmax), and diastolic blood pressure. IM-GSM determinants were the thickness of plaque-free common carotid intima-media complex (PF CC-IMTmean), height, systolic blood pressure, waist/hip ratio, treatment with fibrates, mean corpuscular volume, treatment with alpha-2 inhibitors (sartans), educational level, and creatinine. Latitude, and pack-yearscode were determinants of both plaque-GSM and IM-GSM. The overall models explain 12.0% of plaque-GSM variability and 19.7% of IM-GSM variability. A significant correlation (r = 0.51) was found between plaque-GSM and IM-GSM. Our results indicate that IM-GSM is a weighty risk marker alternative to plaque-GSM, offering the advantage of being readily measurable in all subjects, including those in the early phases of atherosclerosis where plaque occurrence is relatively infrequent.

Assessment of New Coronary Features on Quantitative Coronary Angiographic Images With Innovative Unsupervised Artificial Adaptive Systems: A Proof-of-Concept Study.

Background and Purpose: The Active Connection Matrixes (ACMs) are unsupervised artificial adaptive systems able to extract from digital images features of interest (edges, tissue differentiation, etc.) unnoticeable with conventional systems. In this proof-of-concept study, we assessed the potentiality of ACMs to increase measurement precision of morphological structures (e.g., stenosis and lumen diameter) and to grasp morphological features (arterial walls) from quantitative coronary angiography (QCA), unnoticeable on the original images. Methods: Archive images of QCA and intravascular ultrasound (IVUS) of 10 patients (8 men, age 69.1 ± 9.7 years) who underwent both procedures for clinical reasons were retrospectively analyzed. Arterial features derived from "IVUS images," "conventional QCA images," and "ACM-reprocessed QCA images" were measured in 21 coronary segments. Portions of 1-mm length (263 for lumen and 526 for arterial walls) were head-to-head compared to assess quali-quantitative between-methods agreement. Results: When stenosis was calculated on "ACM-reprocessed QCA images," the bias vs. IVUS (gold standard) did not improve, but the correlation coefficient of the QCA-IVUS relationship increased from 0.47 to 0.83. When IVUS-derived lumen diameters were compared with diameters obtained on ACM-reprocessed QCA images, the bias (-0.25 mm) was significantly smaller (p < 0.01) than that observed with original QCA images (0.58 mm). ACMs were also able to extract arterial wall features from QCA. The bias between the measures of arterial walls obtained with IVUS and ACMs, although significant (p < 0.01), was small [0.09 mm, 95% CI (0.03, 0.14)] and the correlation was fairly good (r = 0.63; p < 0.0001). Conclusions: This study provides proof of concept that ACMs increase the measurement precision of coronary lumen diameter and allow extracting from QCA images hidden features that mirror well the arterial walls derived by IVUS.

Relationship between Circulating PCSK9 and Markers of Subclinical Atherosclerosis-The IMPROVE Study.

(1) Background and purpose: circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) is one of the key regulators of cholesterol metabolism. Despite this, its role as a player in atherosclerosis development is still matter of debate. Here, we investigated the relationships between this protein and several markers of subclinical atherosclerosis. (2) Methods: the IMPROVE study enrolled 3703 European subjects (54-79 years; 48% men; with ≥3 vascular risk factors), asymptomatic for cardiovascular diseases. PCSK9 levels were measured by ELISA. B-mode ultrasound was used to measure markers of carotid subclinical atherosclerosis. (3) Results: in the crude analysis, PCSK9 levels were associated with several baseline measures of carotid intima-media thickness (cIMT) (all p < 0.0001); with cIMT change over time (Fastest-IMTmax-progr) (p = 0.01); with inter-adventitia common carotid artery diameter (ICCAD) (p < 0.0001); and with the echolucency (Grey Scale Median; GSM) of both carotid plaque and plaque-free common carotid IMT (both p < 0.0001). However, after adjustment for age, sex, latitude, and pharmacological treatment, all the afore-mentioned correlations were no longer statistically significant. The lack of correlation was also observed after stratification for sex, latitude, and pharmacological treatments. (4) Conclusions: in subjects who are asymptomatic for cardiovascular diseases, PCSK9 plasma levels do not correlate with vascular damage and/or subclinical atherosclerosis of extracranial carotid arteries.

The Association between HDL-C and Subclinical Atherosclerosis Depends on CETP Plasma Concentration: Insights from the IMPROVE Study.

The impact of cholesteryl ester transfer protein (CETP) on atherosclerosis is highly debated. This study aimed to investigate the associations between plasma CETP or CETP genotypes and carotid intima-media thickness (cIMT) and the influence of high-density lipoprotein cholesterol (HDL-C) on these associations. Plasma CETP and HDL-C concentrations were measured in 552 subjects free of any pharmacological treatment from the IMPROVE cohort, which includes 3711 European subjects at high cardiovascular risk. CETP single-nucleotide polymorphisms (SNPs) and cIMT measures (cIMTmax; cIMTmean-max of bifurcations, common and internal carotids; plaque-free common carotid [PF CC]-IMTmean) were available for the full cohort. In drug-free subjects, plasma CETP correlated with HDL-C levels (r = 0.19, p < 0.0001), but not with cIMT variables. When stratified according to HDL-C quartiles, CETP positively correlated with cIMTmax and cIMTmean-max, but not with PF CC-IMTmean, in the top HDL-C quartile only. Positive associations between the CETP concentration and cIMTmax or cIMTmean-max were found in the top HDL-C quartile, whereas HDL-C levels were negatively correlated with cIMTmax and cIMTmean-max when the CETP concentration was below the median (HDL-C × CETP interaction, p = 0.001 and p = 0.003 for cIMTmax and cIMTmean-max, respectively). In the full cohort, three CETP SNPs (rs34760410, rs12920974, rs12708968) were positively associated with cIMTmax. rs12444708 exhibited a significant interaction with HDL-C levels in the prediction of cIMTmax. In conclusion, a significant interplay was found between plasma CETP and/or CETP genotype and HDL-C in the prediction of carotid plaque thickness, as indexed by cIMTmax. This suggests that the association of HDL-C with carotid atherosclerosis is CETP-dependent.

Relationship between Influenza Vaccination Coverage Rate and COVID-19 Outbreak: An Italian Ecological Study.

Background: The lack of specific vaccines or drugs against coronavirus disease 2019 (COVID-19) warrants studies focusing on alternative clinical approaches to reduce the spread of this pandemic disease. In this study, we investigated whether anti-influenza vaccination plays a role in minimizing the diffusion of COVID-19 in the Italian population aged 65 and over. Methods: Four COVID-19 outcomes were used: severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence, hospitalizations for COVID-19 symptoms, admissions to intensive care units for reasons related to SARS-CoV-2, and deaths attributable to COVID-19. Results: At univariate analyses, the influenza vaccination coverage rates correlated negatively with all COVID-19 outcomes (Beta ranging from -134 to -0.61; all p < 0.01). At multivariable analyses, influenza vaccination coverage rates correlated independently with SARS-CoV-2 seroprevalence (Beta (95% C.I.): -130 (-198, -62); p = 0.001), hospitalizations for COVID-19 symptoms (Beta (95% C.I.): -4.16 (-6.27, -2.05); p = 0.001), admission to intensive care units for reasons related to SARS-CoV-2 (Beta (95% C.I.): -0.58 (-1.05, -0.12); p = 0.017), and number of deaths attributable to COVID-19 (Beta (95% C.I.): -3.29 (-5.66, -0.93); p = 0.010). The R2 observed in the unadjusted analysis increased from 82% to 159% for all the considered outcomes after multivariable analyses. Conclusions: In the Italian population, the coverage rate of the influenza vaccination in people aged 65 and over is associated with a reduced spread and a less severe clinical expression of COVID-19. This finding warrants ad hoc studies to investigate the role of influenza vaccination in preventing the spread of COVID-19.

Sex-specific predictors of PCSK9 levels in a European population: The IMPROVE study.

BACKGROUND AND AIMS: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is one of the key regulators of low-density lipoprotein cholesterol plasma levels. Circulating PCSK9, which differs between genders, represents a valid pharmacological target for preventing cardiovascular (CV) events. We aimed to investigate sex-related associations between PCSK9 plasma levels and biochemical and anthropomorphic factors, and familial and personal morbidities, in a large European cohort (n = 3673) of men (47.9%) and women (52.1%). METHODS: Individuals (aged 54-79 years) free of CV diseases were enrolled in seven centers of five European countries: Finland, France, Italy, the Netherlands, and Sweden. PCSK9 plasma levels were measured by ELISA. RESULTS: PCSK9 was higher in women than in men. Multiple linear regression analysis showed that latitude, sex, and treatments with statins and fibrates were the strongest predictors of PCSK9 in the whole group. These variables, together with triglycerides and high-density lipoprotein cholesterol, were also associated with PCSK9 in men or women. Mean corpuscular hemoglobin concentration and pack-years were PCSK9 independent predictors in women, whereas hypercholesterolemia and physical activity were independent predictors in men. The associations between PCSK9 and latitude, uric acid, diabetes, hypercholesterolemia and physical activity were significantly different in men and women (pinteraction <0.05 for all). CONCLUSIONS: Besides confirming the association with lipids in the whole group, our study revealed previously unknown differences in PCSK9 predictors in men and women. These might be taken into account when defining individual risk for CV events and/or for refining PCSK9 lowering treatments.

Traditional Risk Factors are Causally Related to Carotid Intima-Media Thickness Progression: Inferences from Observational Cohort Studies and Interventional Trials.

In the present review, associations between traditional vascular risk factors (VRFs) and carotid intimamedial thickness progression (C-IMTp) as well as the effects of therapies for VRFs control on C-IMTp were appraised to infer causality between each VRF and C-IMTp. Cohort studies indicate that smoking, binge drinking, fatness, diabetes, hypertension and hypercholesterolemia are associated with accelerated C-IMTp. An exception is physical activity, with mixed data. Interventions for the control of obesity, diabetes, hypertension and hypercholesterolemia decelerate C-IMTp. Conversely, scarce information is available regarding the effect of smoking cessation, stop of excessive alcohol intake and management of the metabolic syndrome. Altogether, these data support a causative role of several traditional VRFs on C-IMTp. Shortcomings in study design and/or ultrasonographic protocols may account for most negative studies, which underlines the importance of careful consideration of methodological aspects in investigations using C-IMTp as the outcome.

Data on the association between a simplified Mediterranean diet score and the incidence of combined, cardio and cerebro vascular events.

Data presented in this article are related to the research article entitled "A priori-defined Mediterranean-like dietary pattern predicts cardiovascular events better in north Europe than in Mediterranean countries" [Veglia et al., 2018]. Data contain information about the incidence of cardiovascular events in a high-risk European population (IMPROVE study) [Baldassarre et al., 2010, 2012, 2013]. Combined vascular events, as well as cardio- and cerebro-vascular events were stratified according to a priori-defined simple Mediterranean Diet (MD) score, based on just seven nutritional items (minimal adherence was 0 and maximal adherence was 7).

A priori-defined Mediterranean-like dietary pattern predicts cardiovascular events better in north Europe than in Mediterranean countries.

BACKGROUND: The Mediterranean Diet (MD) is a model of healthy eating contributing to a favorable health status, but its clinical usefulness is still debated. The aim of this study was to relate the adherence to MD with the incidence of cardio/cerebro-vascular events (VEs) in north and south European participants of the IMPROVE study. METHODS: IMPROVE is an observational, longitudinal, prospective cohort study involving 3703 individuals from five European countries (Finland, Sweden, Netherlands, France and Italy). The study end-point was the incidence of the first combined cardio/cerebro-vascular event occurring during 36-months follow-up. At baseline, a dietary questionnaire about the usual intake during the year preceding enrollment was administered. Based on 7 nutritional items, a MD Score was constructed in which minimal adherence was 0 and maximal adherence was 7. RESULTS: Latitude was the strongest determinant of MD score (p < 0.001). VEs occurred in 215 participants. The incidence of VEs was the highest in subjects with MD score 0-1, lower in those with score 2-3 and the lowest in those with score ≥ 4. MD score remained significantly associated with subsequent VEs after adjustment for confounders (hazard ratio for one-point increment of the score = 0.75, p < 0.001) and the association was stronger in northern than in southern countries (p = 0.04 for MD Score × latitude interaction). CONCLUSIONS: The MD adherence score based on a simple dietary questionnaire detects changes of risk of VEs. According to our findings north Europeans appear to benefit most from VE-prevention when their diet is altered to the MD diet.