Association between subclinical atherosclerosis burden and unrecognized myocardial infarction detected by cardiac magnetic resonance in middle-aged adults.

AIMS: Evidence on the association between subclinical atherosclerosis (SA) and cardiovascular (CV) events in low-risk populations is scant. To study the association between SA burden and an ischemic scar (IS), identified by cardiac magnetic resonance (CMR), as a surrogate of CV endpoint, in a low-risk population. METHODS: A cohort of 712 asymptomatic middle-aged individuals from the Progression of Early SA (PESA-CNIC-Santander) study (median age 51 years, 84% male, median SCORE2 3.37) were evaluated on enrollment and at 3-year follow-up with 2D/3D vascular ultrasound (VUS) and coronary artery calcification scoring (CACS). A cardiac magnetic study (CMR) was subsequently performed, and IS defined as the presence of subendocardial or transmural late gadolinium enhancement (LGE). RESULTS: On CMR, 132 (19.1%) participants had positive LGE, and IS was identified in 20 (2.9%) participants. Individuals with IS had significantly higher SCORE2 at baseline and higher CACS and peripheral SA burden (number of plaques by 2DVUS and plaque volume by 3DVUS) at both SA evaluations. High CACS and peripheral SA (number of plaques) burden were independently associated with the presence of IS, after adjusting for SCORE2 (OR for 3rd tertile, 8.31; 95% CI 2.85-24.2; p<0.001; and 2.77; 95% CI, 1.02-7.51; p=0.045, respectively) and provided significant incremental diagnostic value over SCORE2. CONCLUSIONS: In a low-risk middle-aged population, SA burden (CAC and peripheral plaques) was independently associated with a higher prevalence of IS identified by CMR. These findings reinforce the value of SA evaluation to early implement preventive measures.

Apolipoprotein E-ε2 and Resistance to Atherosclerosis in Midlife: The PESA Observational Study.

BACKGROUND: APOE is a known genetic contributor to cardiovascular disease, but the differential role APOE alleles play in subclinical atherosclerosis remains unclear. METHODS: The PESA (Progression of Early Subclinical Atherosclerosis) is an observational cohort study that recruited 4184 middle-aged asymptomatic individuals to be screened for cardiovascular risk and multiterritorial subclinical atherosclerosis. Participants were APOE-genotyped, and omics data were additionally evaluated. RESULTS: In the PESA study, the frequencies for APOE -ε2, -ε3, and -ε4 alleles were 0.060, 0.844, and 0.096, respectively. This study included a subcohort of 3887 participants (45.8±4.3 years of age; 62% males). As expected, APOE-ε4 carriers were at the highest risk for cardiovascular disease and had significantly greater odds of having subclinical atherosclerosis compared with ε3/ε3 carriers, which was mainly explained by their higher levels of low-density lipoprotein (LDL)-cholesterol. In turn, APOE-ε2 carriers were at the lowest risk for cardiovascular disease and had significantly lower odds of having subclinical atherosclerosis in several vascular territories (carotids: 0.62 [95% CI, 0.47-0.81]; P=0.00043; femorals: 0.60 [0.47-0.78]; P=9.96×10-5; coronaries: 0.53 [0.39-0.74]; P=0.00013; and increased PESA score: 0.58 [0.48-0.71]; P=3.16×10-8). This APOE-ε2 atheroprotective effect was mostly independent of the associated lower LDL-cholesterol levels and other cardiovascular risk factors. The protection conferred by the ε2 allele was greater with age (50-54 years: 0.49 [95% CI, 0.32-0.73]; P=0.00045), and normal (<150 mg/dL) levels of triglycerides (0.54 [0.44-0.66]; P=4.70×10-9 versus 0.90 [0.57-1.43]; P=0.67 if ≥150 mg/dL). Omics analysis revealed an enrichment of several canonical pathways associated with anti-inflammatory mechanisms together with the modulation of erythrocyte homeostasis, coagulation, and complement activation in ε2 carriers that might play a relevant role in the ε2's atheroprotective effect. CONCLUSIONS: This work sheds light on the role of APOE in cardiovascular disease development with important therapeutic and prevention implications on cardiovascular health, especially in early midlife. REGISTRATION: URL: https://www.clinicaltrials.gov: NCT01410318.

Early insulin resistance in normoglycemic low-risk individuals is associated with subclinical atherosclerosis.

BACKGROUND: Elevated glycated hemoglobin (HbA1c) is associated with a higher burden of subclinical atherosclerosis (SA). However, the association with SA of earlier insulin resistance markers is poorly understood. The study assessed the association between the homeostatic model assessment of insulin resistance index (HOMA-IR) and SA in addition to the effect of cardiovascular risk factors (CVRFs) in individuals with normal HbA1c. METHODS: A cohort of 3,741 middle-aged individuals from the Progression of Early Subclinical Atherosclerosis (PESA) study with basal HbA1c < 6.0% (< 42 mmol/mol) and no known CV disease underwent extensive imaging (multiterritorial vascular ultrasound and coronary artery calcium score, CACS) to assess the presence, burden, and extent of SA. RESULTS: Individuals with higher HOMA-IR values had higher rates of CVRFs. HOMA-IR showed a direct association with the multiterritorial extent of SA and CACS (p < 0.001) and with global plaque volume measured by 3-dimensional vascular ultrasound (p < 0.001). After adjusting for key CVRFs and HbA1c, HOMA-IR values ≥ 3 were associated with both the multiterritorial extent of SA (odds ratio 1.41; 95%CI: 1.01 to 1.95, p = 0.041) and CACS > 0 (odds ratio 1.74; 95%CI: 1.20 to 2.54, p = 0.004), as compared with the HOMA-IR < 2 (the reference HOMA-IR category). In a stratified analysis, this association remained significant in individuals with a low-to-moderate SCORE2 risk estimate (75.6% of the cohort) but not in high-risk individuals. CONCLUSIONS: The use of HOMA-IR identified low-risk individuals with a higher burden of SA, after adjusting for the effects of key traditional CVRFs and HbA1c. HOMA-IR is a simple measure that could facilitate earlier implementation of primary CV prevention strategies in clinical practice.

Cardiac Insulin Resistance in Subjects With Metabolic Syndrome Traits and Early Subclinical Atherosclerosis.

OBJECTIVE: Experimental evidence suggests that metabolic syndrome (MetS) is associated with changes in cardiac metabolism. Whether this association occurs in humans is unknown. RESEARCH DESIGN AND METHODS: 821 asymptomatic individuals from the Progression of Early Subclinical Atherosclerosis (PESA) study (50.6 [46.9-53.6] years, 83.7% male) underwent two whole-body 18F-fluorodeoxyglucose positron emission tomography-magnetic resonance (18F-FDG PET-MR) 4.8 ± 0.6 years apart. Presence of myocardial 18F-FDG uptake was evaluated qualitatively and quantitatively. No myocardial uptake was grade 0, while positive uptake was classified in grades 1-3 according to target-to-background ratio tertiles. RESULTS: One hundred fifty-six participants (19.0%) showed no myocardial 18F-FDG uptake, and this was significantly associated with higher prevalence of MetS (29.0% vs. 13.9%, P < 0.001), hypertension (29.0% vs. 18.0%, P = 0.002), and diabetes (11.0% vs. 3.2%, P < 0.001), and with higher insulin resistance index (HOMA-IR, 1.64% vs. 1.23%, P < 0.001). Absence of myocardial uptake was associated with higher prevalence of early atherosclerosis (i.e., arterial 18F-FDG uptake, P = 0.004). On follow-up, the associations between myocardial 18F-FDG uptake and risk factors were replicated, and MetS was more frequent in the group without myocardial uptake. The increase in HOMA-IR was associated with a progressive decrease in myocardial uptake (P < 0.001). In 82% of subjects, the categorization according to presence/absence of myocardial 18F-FDG uptake did not change between baseline and follow-up. MetS regression on follow-up was associated with a significant (P < 0.001) increase in myocardial uptake. CONCLUSIONS: Apparently healthy individuals without cardiac 18F-FDG uptake have higher HOMA-IR and higher prevalence of MetS traits, cardiovascular risk factors, and early atherosclerosis. An improvement in cardiometabolic profile is associated with the recovery of myocardial 18F-FDG uptake at follow-up.

Longitudinal interplay between subclinical atherosclerosis, cardiovascular risk factors, and cerebral glucose metabolism in midlife: results from the PESA prospective cohort study.

BACKGROUND: Cardiovascular disease and dementia often coexist at advanced stages. Yet, longitudinal studies examining the interplay between atherosclerosis and its risk factors on brain health in midlife are scarce. We aimed to characterise the longitudinal associations between cerebral glucose metabolism, subclinical atherosclerosis, and cardiovascular risk factors in middle-aged asymptomatic individuals. METHODS: The Progression of Early Subclinical Atherosclerosis (PESA) study is a Spanish longitudinal observational cohort study of 4184 asymptomatic individuals aged 40-54 years (NCT01410318). Participants with subclinical atherosclerosis underwent longitudinal cerebral [18F]fluorodeoxyglucose ([18F]FDG)-PET, and annual percentage change in [18F]FDG uptake was assessed (primary outcome). Cardiovascular risk was quantified with SCORE2 and subclinical atherosclerosis with three-dimensional vascular ultrasound (exposures). Multivariate regression and linear mixed effects models were used to assess associations between outcomes and exposures. Additionally, blood-based biomarkers of neuropathology were quantified and mediation analyses were performed. Secondary analyses were corrected for multiple comparisons using the false discovery rate (FDR) approach. FINDINGS: This longitudinal study included a PESA subcohort of 370 participants (median age at baseline 49·8 years [IQR 46·1-52·2]; 309 [84%] men, 61 [16%] women; median follow-up 4·7 years [IQR 4·2-5·2]). Baseline scans took place between March 6, 2013, and Jan 21, 2015, and follow-up scans between Nov 24, 2017, and Aug 7, 2019. Persistent high risk of cardiovascular disease was associated with an accelerated decline of cortical [18F]FDG uptake compared with low risk (ß=-0·008 [95% CI -0·013 to -0·002]; pFDR=0·040), with plasma neurofilament light chain, a marker of neurodegeneration, mediating this association by 20% (ß=0·198 [0·008 to 0·740]; pFDR=0·050). Moreover, progression of subclinical carotid atherosclerosis was associated with an additional decline in [18F]FDG uptake in Alzheimer's disease brain regions, not explained by cardiovascular risk (ß=-0·269 [95% CI -0·509 to -0·027]; p=0·029). INTERPRETATION: Middle-aged asymptomatic individuals with persistent high risk of cardiovascular disease and subclinical carotid atherosclerosis already present brain metabolic decline, suggesting that maintenance of cardiovascular health during midlife could contribute to reductions in neurodegenerative disease burden later in life. FUNDING: Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III, Santander Bank, Pro-CNIC Foundation, BrightFocus Foundation, BBVA Foundation, "la Caixa" Foundation.

Subclinical atherosclerosis and accelerated epigenetic age mediated by inflammation: a multi-omics study.

AIMS: Epigenetic age is emerging as a personalized and accurate predictor of biological age. The aim of this article is to assess the association of subclinical atherosclerosis with accelerated epigenetic age and to investigate the underlying mechanisms mediating this association. METHODS AND RESULTS: Whole blood methylomics, transcriptomics, and plasma proteomics were obtained for 391 participants of the Progression of Early Subclinical Atherosclerosis study. Epigenetic age was calculated from methylomics data for each participant. Its divergence from chronological age is termed epigenetic age acceleration. Subclinical atherosclerosis burden was estimated by multi-territory 2D/3D vascular ultrasound and by coronary artery calcification. In healthy individuals, the presence, extension, and progression of subclinical atherosclerosis were associated with a significant acceleration of the Grim epigenetic age, a predictor of health and lifespan, regardless of traditional cardiovascular risk factors. Individuals with an accelerated Grim epigenetic age were characterized by an increased systemic inflammation and associated with a score of low-grade, chronic inflammation. Mediation analysis using transcriptomics and proteomics data revealed key pro-inflammatory pathways (IL6, Inflammasome, and IL10) and genes (IL1B, OSM, TLR5, and CD14) mediating the association between subclinical atherosclerosis and epigenetic age acceleration. CONCLUSION: The presence, extension, and progression of subclinical atherosclerosis in middle-aged asymptomatic individuals are associated with an acceleration in the Grim epigenetic age. Mediation analysis using transcriptomics and proteomics data suggests a key role of systemic inflammation in this association, reinforcing the relevance of interventions on inflammation to prevent cardiovascular disease.

Bone marrow activation in response to metabolic syndrome and early atherosclerosis.

AIMS: Experimental studies suggest that increased bone marrow (BM) activity is involved in the association between cardiovascular risk factors and inflammation in atherosclerosis. However, human data to support this association are sparse. The purpose was to study the association between cardiovascular risk factors, BM activation, and subclinical atherosclerosis. METHODS AND RESULTS: Whole body vascular 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI) was performed in 745 apparently healthy individuals [median age 50.5 (46.8-53.6) years, 83.8% men] from the Progression of Early Subclinical Atherosclerosis (PESA) study. Bone marrow activation (defined as BM 18F-FDG uptake above the median maximal standardized uptake value) was assessed in the lumbar vertebrae (L3-L4). Systemic inflammation was indexed from circulating biomarkers. Early atherosclerosis was evaluated by arterial metabolic activity by 18F-FDG uptake in five vascular territories. Late atherosclerosis was evaluated by fully formed plaques on MRI. Subjects with BM activation were more frequently men (87.6 vs. 80.0%, P = 0.005) and more frequently had metabolic syndrome (MetS) (22.2 vs. 6.7%, P < 0.001). Bone marrow activation was significantly associated with all MetS components. Bone marrow activation was also associated with increased haematopoiesis-characterized by significantly elevated leucocyte (mainly neutrophil and monocytes) and erythrocyte counts-and with markers of systemic inflammation including high-sensitivity C-reactive protein, ferritin, fibrinogen, P-selectin, and vascular cell adhesion molecule-1. The associations between BM activation and MetS (and its components) and increased erythropoiesis were maintained in the subgroup of participants with no systemic inflammation. Bone marrow activation was significantly associated with high arterial metabolic activity (18F-FDG uptake). The co-occurrence of BM activation and arterial 18F-FDG uptake was associated with more advanced atherosclerosis (i.e. plaque presence and burden). CONCLUSION: In apparently healthy individuals, BM 18F-FDG uptake is associated with MetS and its components, even in the absence of systemic inflammation, and with elevated counts of circulating leucocytes. Bone marrow activation is associated with early atherosclerosis, characterized by high arterial metabolic activity. Bone marrow activation appears to be an early phenomenon in atherosclerosis development.[Progression of Early Subclinical Atherosclerosis (PESA); NCT01410318].

Triglycerides and Residual Atherosclerotic Risk.

BACKGROUND: Even when low-density lipoprotein-cholesterol (LDL-C) levels are lower than guideline thresholds, a residual risk of atherosclerosis remains. It is unknown whether triglyceride (TG) levels are associated with subclinical atherosclerosis and vascular inflammation regardless of LDL-C. OBJECTIVES: This study sought to assess the association between serum TG levels and early atherosclerosis and vascular inflammation in apparently healthy individuals. METHODS: An observational, longitudinal, and prospective cohort study, including 3,754 middle-aged individuals with low to moderate cardiovascular risk from the PESA (Progression of Early Subclinical Atherosclerosis) study who were consecutively recruited between June 2010 and February 2014, was conducted. Peripheral atherosclerotic plaques were assessed by 2-dimensional vascular ultrasound, and coronary artery calcification (CAC) was assessed by noncontrast computed tomography, whereas vascular inflammation was assessed by fluorine-18 fluorodeoxyglucose uptake on positron emission tomography. RESULTS: Atherosclerotic plaques and CAC were observed in 58.0% and 16.8% of participants, respectively, whereas vascular inflammation was evident in 46.7% of evaluated participants. After multivariate adjustment, TG levels ≥150 mg/dl showed an association with subclinical noncoronary atherosclerosis (odds ratio [OR]: 1.35; 95% confidence interval [CI]: 1.08 to 1.68; p = 0.008). This association was significant for groups with high LDL-C (OR: 1.42; 95% CI: 1.11 to 1.80; p = 0.005) and normal LDL-C (OR: 1.85; 95% CI: 1.08 to 3.18; p = 0.008). No association was found between TG level and CAC score. TG levels ≥150 mg/dl were significantly associated with the presence of arterial inflammation (OR: 2.09; 95% CI: 1.29 to 3.40; p = 0.003). CONCLUSIONS: In individuals with low to moderate cardiovascular risk, hypertriglyceridemia was associated with subclinical atherosclerosis and vascular inflammation, even in participants with normal LDL-C levels. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318).

Glycated Hemoglobin and Subclinical Atherosclerosis in People Without Diabetes.

BACKGROUND: The metabolic injury caused by protein glycation, monitored as the level of glycated hemoglobin (HbA1c), is not represented in most risk scores (i.e., Systematic Coronary Risk Estimation or atherosclerotic cardiovascular disease risk scale). OBJECTIVES: The purpose of this study was to assess the association between HbA1c and the extent of subclinical atherosclerosis (SA) and to better identify individuals at higher risk of extensive SA using HbA1c on top of key cardiovascular risk factors (CVRFs). METHODS: A cohort of 3,973 middle-aged individuals from the PESA (Progression of Early Subclinical Atherosclerosis) study, with no history of cardiovascular disease and with HbA1c in the nondiabetic range, were assessed for the presence and extent of SA by 2-dimensional vascular ultrasound and noncontrast cardiac computed tomography. RESULTS: After adjusting for established CVRFs, HbA1c showed an association with the multiterritorial extent of SA (odds ratio: 1.05, 1.27, 1.27, 1.36, 1.80, 1.87, and 2.47 for HbA1c 4.9% to 5.0%, 5.1% to 5.2%, 5.3% to 5.4%, 5.5% to 5.6%, 5.7% to 5.8%, 5.9% to 6.0%, and 6.1% to 6.4%, respectively; reference HbA1c ≤4.8%; p < 0.001). The association was significant in all pre-diabetes groups and even below the pre-diabetes cut-off (HbA1c 5.5% to 5.6% odds ratio: 1.36 [95% confidence interval: 1.03 to 1.80]; p = 0.033). High HbA1c was associated with an increased risk of SA in low-risk individuals (p < 0.001), but not in moderate-risk individuals (p = 0.335). Relative risk estimations using Systematic Coronary Risk Estimation or atherosclerotic cardiovascular disease predictors confirmed that inclusion of HbA1c modified the risk of multiterritorial SA in most risk categories. CONCLUSIONS: Routine use of HbA1c can identify asymptomatic individuals at higher risk of SA on top of traditional CVRFs. Lifestyle interventions and novel antidiabetic medications might be considered to reduce both HbA1c levels and SA in individuals without diabetes.

Subclinical Atherosclerosis and Brain Metabolism in Middle-Aged Individuals: The PESA Study.

BACKGROUND: Atherosclerosis has been linked to cognitive decline in late life; however, the impact of cardiovascular risk factors (CVRFs) and subclinical atherosclerosis on brain metabolism at earlier stages remains unexplored. OBJECTIVES: This study sought to determine the association between brain metabolism, subclinical atherosclerosis, and CVRFs in middle-aged asymptomatic individuals. METHODS: This study included 547 asymptomatic middle-aged participants (50 ± 4 years, 82% men) from the PESA (Progression of Early Subclinical Atherosclerosis) study with evidence of subclinical atherosclerosis. Participants underwent 18F-fluorodeoxyglucose (FDG)-positron emission tomography. Global brain FDG uptake and voxel-wise analyses were used to evaluate the associations of cerebral metabolism with CVRFs and atherosclerotic plaque burden in carotids and femorals assessed by 3-dimensional vascular ultrasound. RESULTS: Global FDG uptake showed an inverse correlation with 30-year Framingham Risk Score (FRS) (ß = -0.15, p < 0.001). This association was mainly driven by the presence of hypertension (d = 0.36, p < 0.001). Carotid plaque burden was inversely associated with global brain FDG uptake (ß = -0.16, p < 0.001), even after adjusting for 30-year FRS. Voxel-wise approaches revealed that the brain areas most strongly affected by hypometabolism in association with 30-year FRS, hypertension, and carotid plaque burden were parietotemporal regions (angular, supramarginal, and inferior/middle temporal gyri) and the cingulate gyrus. CONCLUSIONS: In asymptomatic middle-aged individuals, cardiovascular risk is associated with brain hypometabolism, with hypertension being the modifiable CVRF showing the strongest association. Subclinical carotid plaque burden is also linked to reduced brain metabolism independently of CVRFs. Cerebral areas showing hypometabolism include those known to be affected in dementia. These data reinforce the need to control CVRFs early in life in order to potentially reduce the brain's midlife vulnerability to future cognitive dysfunction.

Machine Learning Improves Cardiovascular Risk Definition for Young, Asymptomatic Individuals.

BACKGROUND: Clinical practice guidelines recommend assessment of subclinical atherosclerosis using imaging techniques in individuals with intermediate atherosclerotic cardiovascular risk according to standard risk prediction tools. OBJECTIVES: The purpose of this study was to develop a machine-learning model based on routine, quantitative, and easily measured variables to predict the presence and extent of subclinical atherosclerosis (SA) in young, asymptomatic individuals. The risk of having SA estimated by this model could be used to refine risk estimation and optimize the use of imaging for risk assessment. METHODS: The Elastic Net (EN) model was built to predict SA extent, defined by a combined metric of the coronary artery calcification score and 2-dimensional vascular ultrasound. The performance of the model for the prediction of SA extension and progression was compared with traditional risk scores of cardiovascular disease (CVD). An external independent cohort was used for validation. RESULTS: EN-PESA (Progression of Early Subclinical Atherosclerosis) yielded a c-statistic of 0.88 for the prediction of generalized subclinical atherosclerosis. Moreover, EN-PESA was found to be a predictor of 3-year progression independent of the baseline extension of SA. EN-PESA assigned an intermediate to high cardiovascular risk to 40.1% (n = 1,411) of the PESA individuals, a significantly larger number than atherosclerotic CVD (n = 267) and SCORE (Systematic Coronary Risk Evaluation) (n = 507) risk scores. In total, 86.8% of the individuals with an increased risk based on EN-PESA presented signs of SA at baseline or a significant progression of SA over 3 years. CONCLUSIONS: The EN-PESA model uses age, systolic blood pressure, and 10 commonly used blood/urine tests and dietary intake values to identify young, asymptomatic individuals with an increased risk of CVD based on their extension and progression of SA. These individuals are likely to benefit from imaging tests or pharmacological treatment. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318).

Association Between Left Ventricular Noncompaction and Vigorous Physical Activity.

BACKGROUND: Left ventricular (LV) hypertrabeculation fulfilling noncompaction cardiomyopathy criteria has been detected in athletes. However, the association between LV noncompaction (LVNC) phenotype and vigorous physical activity (VPA) in the general population is disputed. OBJECTIVES: The aim of this study was to assess the relationship between LVNC phenotype on cardiac magnetic resonance (CMR) imaging and accelerometer-measured physical activity (PA) in a cohort of middle-aged nonathlete participants in the PESA (Progression of Early Subclinical Atherosclerosis) study. METHODS: In PESA participants (n = 4,184 subjects free of cardiovascular disease), PA was measured by waist-secured accelerometers. CMR was performed in 705 subjects (mean age 48 ± 4 years, 16% women). VPA was recorded as total minutes per week. The study population was divided into 6 groups: no VPA and 5 sex-specific quintiles of VPA rate (Q1 to Q5). The Petersen criterion for LVNC was evaluated in all subjects undergoing CMR. For participants meeting this criterion (noncompacted-to-compacted ratio ≥2.3), 3 more restrictive LVNC criteria were also evaluated (Jacquier, Grothoff, and Stacey). RESULTS: LVNC phenotype prevalence according to the Petersen criterion was significantly higher among participants in the highest VPA quintile (Q5 = 30.5%) than in participants with no VPA (14.2%). The Jacquier and Grothoff criteria were also more frequently fulfilled in participants in the highest VPA quintile (Jacquier Q5 = 27.4% vs. no VPA = 12.8% and Grothoff Q5 = 15.8% vs. no VPA = 7.1%). The prevalence of the systolic Stacey LVNC criterion was low (3.6%) and did not differ significantly between no VPA and Q5. CONCLUSIONS: In a community-based study, VPA was associated with a higher prevalence of CMR-detected LVNC phenotype according to diverse established criteria. The association between VPA and LVNC phenotype was independent of LV volumes. According to these data, vigorous recreational PA should be considered as a possible but not uncommon determinant of LV hypertrabeculation in asymptomatic subjects.

Association Between Body Size Phenotypes and Subclinical Atherosclerosis.

CONTEXT: The underlying relationship between body mass index (BMI), cardiometabolic disorders, and subclinical atherosclerosis is poorly understood. OBJECTIVE: To evaluate the association between body size phenotypes and subclinical atherosclerosis. DESIGN: Cross-sectional. SETTING: Cardiovascular disease-free cohort. PARTICIPANTS: Middle-aged asymptomatic subjects (n = 3909). A total of 6 cardiometabolic body size phenotypes were defined based on the presence of at least 1 cardiometabolic abnormality (blood pressure, fasting blood glucose, triglycerides, low high-density lipoprotein cholesterol, homeostasis model assessment-insulin resistance index, high-sensitivity C-reactive protein) and based on BMI: normal-weight (NW; BMI <25), overweight (OW; BMI = 25.0-29.9) or obese (OB; BMI >30.0). MAIN OUTCOME MEASURES: Subclinical atherosclerosis was evaluated by 2D vascular ultrasonography and noncontrast cardiac computed tomography. RESULTS: For metabolically healthy subjects, the presence of subclinical atherosclerosis increased across BMI categories (49.6%, 58.0%, and 67.7% for NW, OW, and OB, respectively), whereas fewer differences were observed for metabolically unhealthy subjects (61.1%, 69.7%, and 70.5%, respectively). When BMI and cardiometabolic abnormalities were assessed separately, the association of body size phenotypes with the extent of subclinical atherosclerosis was mostly driven by the coexistence of cardiometabolic risk factors: adjusted OR = 1.04 (95% confidence interval [CI], 0.90-1.19) for OW and OR = 1.07 (95% CI, 0.88-1.30) for OB in comparison with NW, whereas there was an increasing association between the extent of subclinical atherosclerosis and the number of cardiometabolic abnormalities: adjusted OR = 1.21 (95% CI, 1.05-1.40), 1.60 (95% CI, 1.33-1.93), 1.92 (95% CI, 1.48-2.50), and 2.27 (95% CI, 1.67-3.09) for 1, 2, 3, and >3, respectively, in comparison with noncardiometabolic abnormalities. CONCLUSIONS: The prevalence of subclinical atherosclerosis varies across body size phenotypes. Pharmacologic and lifestyle interventions might modify their cardiovascular risk by facilitating the transition from one phenotype to another.

Short-Term Progression of Multiterritorial Subclinical Atherosclerosis.

BACKGROUND: Atherosclerosis progression predicts cardiovascular events; however, progression of multiterritorial subclinical atherosclerosis is incompletely understood. OBJECTIVES: This study sought to study short-term progression of atherosclerosis using different noninvasive imaging techniques and their relationship with cardiovascular risk. METHODS: The study included 3,514 PESA (Progression of Early Subclinical Atherosclerosis) study participants (45.7 ± 4.2 years of age; 63% men). Participants underwent 2-dimensional vascular ultrasound (2DVUS) of abdominal aorta, carotid, iliac, and femoral territories to determine a plaque number score; 3DVUS to quantify carotid and femoral plaque volume; and coronary artery calcium score (CACS) at baseline and 2.8 years later. The authors calculated the rate of new disease incidence and changes in disease extent. Logistic regression models were used to evaluate associations of progression rates with baseline cardiovascular risk factors and estimated 10-year risk. RESULTS: Imaging detected short-term (3-year) atherosclerosis progression in 41.5% of participants (26.4% by 2DVUS, 21.3% by 3DVUS, and 11.5% by CACS), particularly in peripheral territories examined by vascular ultrasound. New atherosclerosis onset accounted for approximately one-third of total progression, also more frequently by 2DVUS and 3DVUS (29.1% and 16.6%, respectively), than by CACS (2.9%). Participants with baseline disease by all 3 modalities (n = 432) also showed significant atherosclerosis progression (median: 1 plaque [interquartile range (IQR): -1 to 3 plaques] by 2DVUS; 7.6 mm3 [IQR: -32.2 to 57.6 mm3] by 3DVUS; and 21.6 Agatston units [IQR: 4.8 to 62.6 Agatston units] by CACS). Age, sex, dyslipidemia, hypertension, smoking, and family history of premature cardiovascular disease contributed to progression, with dyslipidemia the strongest modifiable risk factor. Although disease progression correlated with cardiovascular risk, progression was detected in 36.5% of participants categorized as low risk. CONCLUSIONS: With this multimodal and multiterritorial approach, the authors detected short-term progression of early subclinical atherosclerosis in a substantial proportion (41.5%) of apparently healthy middle-aged men and women, more frequently by peripheral 2D/3DVUS than by CACS. Disease progression, as defined in this study, correlated with almost all cardiovascular risk factors and estimated risk. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318).

Inspiratory collapse of the inferior vena cava and the kissing ventricle sign: markers of poor prognosis in emergency gastrointestinal bleeding. / El colapso inspiratorio de la vena cava inferior y la obliteración sistólica (kissing) ventricular izquierda: marcadores de mal pronóstico en la hemorragia gastrointestinal en urgencias.

OBJECTIVES: Gastrointestinal bleeding, one of the main reasons for emergency department visits, is associated with significant mortality, complications, and high health care spending. Studies have shown the usefulness of hemodynamic monitoring by ultrasound of the inferior vena cava (IVC), imaging of systolic obstruction of the left ventricle (the kissing sign), changes in cardiac output, or surrogates for cardiac output such as the left ventricular velocity time integral before and after a passive leg raise. There is currently no evidence for applying this approach to evaluating hypovolemia due to gastrointestinal bleeding. MATERIAL AND METHODS: We prospectively recruited 203 emergency department patients with gastrointestinal bleeding between August 2015 and April 2017; this sample size provided a 95% CI for a proportion of 5%, with a precision of 3% and expected losses of 15%. Recorded data were as follows: medical histories, observations during physical examinations, laboratory results, diagnostic variables, treatment details, clinical course, and ultrasound findings related to hemodynamics. RESULTS: Clinical course was worse in patients with evidence of hypovolemia such as a small (<1 cm) end-expiratory IVC diameter (IVCEE) or the kissing sign. Complications were more prevalent at 24 hours and 30 days, a finding that was not associated with the other clinical or laboratory variables commonly monitored. We also saw that both a small IVCEE and persistent inspiratory collapse of the IVC of more than 50% after a passive leg raise test might prove useful for identifying patients at risk for anemia at 24 hours, allowing time to start preventive measures. CONCLUSION: The analysis of IVCEE, inspiratory collapse of the IVC, or the kissing sign in combination with clinical and laboratory findings can facilitate the use of clinical practice algorithms that can encourage the efficient risk-based assignment of resources and improve prognosis.

OBJETIVO: La hemorragia digestiva (HD) constituye un problema médico con significativa morbimortalidad y elevado consumo de recursos sanitarios, y es uno de los motivos principales de consulta en los servicios de urgencias. Varios estudios han destacado la utilidad de la ecografía clínica en la monitorización hemodinámica, a partir del análisis de la vena cava inferior (VCI), visualizando la obliteración sistólica del ventrículo izquierdo ("kissing del VI") así como cambios en el gasto cardíaco (GC) o marcadores subrogados al GC como la integral velocidad tiempo (IVT) en el tracto de salida del VI, antes y después de la prueba de elevación pasiva de miembros inferiores (EPMI). En la actualidad, no hay evidencia directa relacionada con la aplicabilidad de este enfoque en la hipovolemia por HD. METODO: Entre agosto de 2015 y abril de 2017, se reclutaron prospectivamente 203 pacientes (nivel de confianza del 95%, precisión 3%, proporción 5%, pérdidas estimadas 15%), que consultaron en el servicio de urgencias por HD. Se recogieron los antecedentes médicos, la exploración física, los hallazgos analíticos, variables relacionadas con el diagnóstico, con el tratamiento, con la evolución clínica y variables ecográficas relacionadas con la situación hemodinámica. RESULTADOS: Los pacientes con datos de hipovolemia como un diámetro de VCI espiratorio (CAVAesp) < 1 cm o un "kissing del VI" presentaron peor evolución, con mayor presencia de complicaciones a las 24 horas y 30 días, hallazgo que no se observó con otros parámetros clínicos o analíticos comúnmente empleados. Además se observó que tanto la CAVAesp < 1 cm, como la persistencia del colapso inspiratorio de la VCI (CICAVA) > 50% tras la PLR podrían ser de utilidad para identificar a los pacientes en los que es esperable una anemización a las 24 horas. CONCLUSIONES: El análisis de marcadores ecográficos como la CAVAesp, CIVACA o el "kissing del VI", combinados con variables clínicas y de laboratorio, permitiría implementar algoritmos de actuación más eficientes y asignar mejor los recursos en función del perfil de riesgo, lo cual podría conducir a una mejora en el pronóstico.

El colapso inspiratorio de la vena cava inferior y la obliteración sistólica (kissing) ventricular izquierda: marcadores de mal pronóstico en la hemorragia gastrointestinal en urgencias / Inspiratory collapse of the inferior vena cava and the kissing ventricle sign: markers of poor prognosis in emergency gastrointestinal bleeding

Objetivo: La hemorragia digestiva (HD) constituye un problema médico con significativa morbimortalidad y elevado consumo de recursos sanitarios, y es uno de los motivos principales de consulta en los servicios de urgencias. Varios estudios han destacado la utilidad de la ecografía clínica en la monitorización hemodinámica, a partir del análisis de la vena cava inferior (VCI), visualizando la obliteración sistólica del ventrículo izquierdo ("kissing del VI") así como cambios en el gasto cardíaco (GC) o marcadores subrogados al GC como la integral velocidad tiempo (IVT) en el tracto de salida del VI, antes y después de la prueba de elevación pasiva de miembros inferiores (EPMI). En la actualidad, no hay evidencia directa relacionada con la aplicabilidad de este enfoque en la hipovolemia por HD. Método: Entre agosto de 2015 y abril de 2017, se reclutaron prospectivamente 203 pacientes (nivel de confianza del 95%, precisión 3%, proporción 5%, pérdidas estimadas 15%), que consultaron en el servicio de urgencias por HD. Se recogieron los antecedentes médicos, la exploración física, los hallazgos analíticos, variables relacionadas con el diagnóstico, con el tratamiento, con la evolución clínica y variables ecográficas relacionadas con la situación hemodinámica. Resultados: Los pacientes con datos de hipovolemia como un diámetro de VCI espiratorio (CAVAesp) < 1 cm o un "kissing del VI" presentaron peor evolución, con mayor presencia de complicaciones a las 24 horas y 30 días, hallazgo que no se observó con otros parámetros clínicos o analíticos comúnmente empleados. Además se observó que tanto la CAVAesp < 1 cm, como la persistencia del colapso inspiratorio de la VCI (CICAVA) > 50% tras la PLR podrían ser de utilidad para identificar a los pacientes en los que es esperable una anemización a las 24 horas. Conclusiones: El análisis de marcadores ecográficos como la CAVAesp, CIVACA o el "kissing del VI", combinados con variables clínicas y de laboratorio, permitiría implementar algoritmos de actuación más eficientes y asignar mejor los recursos en función del perfil de riesgo, lo cual podría conducir a una mejora en el pronóstico

Background: Gastrointestinal bleeding, one of the main reasons for emergency department visits, is associated with significant mortality, complications, and high health care spending. Studies have shown the usefulness of hemodynamic monitoring by ultrasound of the inferior vena cava (IVC), imaging of systolic obstruction of the left ventricle (the kissing sign), changes in cardiac output, or surrogates for cardiac output such as the left ventricular velocity time integral before and after a passive leg raise. There is currently no evidence for applying this approach to evaluating hypovolemia due to gastrointestinal bleeding. Methods: We prospectively recruited 203 emergency department patients with gastrointestinal bleeding between August 2015 and April 2017; this sample size provided a 95% CI for a proportion of 5%, with a precision of 3% and expected losses of 15%. Recorded data were as follows: medical histories, observations during physical examinations, laboratory results, diagnostic variables, treatment details, clinical course, and ultrasound findings related to hemodynamics. Results: Clinical course was worse in patients with evidence of hypovolemia such as a small (<1 cm) end-expiratory IVC diameter (IVCEE) or the kissing sign. Complications were more prevalent at 24 hours and 30 days, a finding that was not associated with the other clinical or laboratory variables commonly monitored. We also saw that both a small IVCEE and persistent inspiratory collapse of the IVC of more than 50% after a passive leg raise test might prove useful for identifying patients at risk for anemia at 24 hours, allowing time to start preventive measures. Conclusions: The analysis of IVCEE, inspiratory collapse of the IVC, or the kissing sign in combination with clinical and laboratory findings can facilitate the use of clinical practice algorithms that can encourage the efficient risk-based assignment of resources and improve prognosis

Vascular Inflammation in Subclinical Atherosclerosis Detected by Hybrid PET/MRI.

BACKGROUND: Atherosclerosis is a chronic inflammatory disease, but data on arterial inflammation at early stages is limited. OBJECTIVES: The purpose of this study was to characterize vascular inflammation by hybrid 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/magnetic resonance imaging (PET/MRI). METHODS: Carotid, aortic, and ilio-femoral 18F-FDG PET/MRI was performed in 755 individuals (age 40 to 54 years; 83.7% men) with known plaques detected by 2-/3-dimensional vascular ultrasound and/or coronary calcification in the PESA (Progression of Early Subclinical Atherosclerosis) study. The authors evaluated the presence, distribution, and number of arterial inflammatory foci (increased 18F-FDG uptake) and plaques with or without inflammation (coincident 18F-FDG uptake). RESULTS: Arterial inflammation was present in 48.2% of individuals (24.4% femorals, 19.3% aorta, 15.8% carotids, and 9.3% iliacs) and plaques in 90.1% (73.9% femorals, 55.8% iliacs, and 53.1% carotids). 18F-FDG arterial uptakes and plaques significantly increased with cardiovascular risk factors (p < 0.01). Coincident 18F-FDG uptakes were present in 287 of 2,605 (11%) plaques, and most uptakes were detected in plaque-free arterial segments (459 of 746; 61.5%). Plaque burden, defined by plaque presence, number, and volume, was significantly higher in individuals with arterial inflammation than in those without (p < 0.01). The number of plaques and 18F-FDG uptakes showed a positive albeit weak correlation (r = 0.25; p < 0.001). CONCLUSIONS: Arterial inflammation is highly prevalent in middle-aged individuals with known subclinical atherosclerosis. Large-scale multiterritorial PET/MRI allows characterization of atherosclerosis-related arterial inflammation and demonstrates 18F-FDG uptake in plaque-free arterial segments and, less frequently, within plaques. These findings suggest an arterial inflammatory state at early stages of atherosclerosis. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318).

Rationale and design of the SI! Program for health promotion in elementary students aged 6 to 11 years: A cluster randomized trial.

Unhealthy habits in children are increasing at an alarming rate. The school provides a promising setting for effective preventive strategies to improve children's lifestyle behaviors. The SI! Program is a multilevel multicomponent school-based educational intervention aimed at all stages of compulsory education in Spain. Here, we present the design of the SI! Program for Elementary School cluster-randomized controlled trial, targeting children aged 6 to 11 years. This trial aims to study the impact of different timings and intensities of exposure to SI! Program activities on elementary school children and their immediate environment (parents/caregivers, teachers, and school). The trial includes 1770 children from 48 public elementary schools in Madrid (Spain), together with their parents and teachers. Schools and their children were randomly assigned to the intervention group (the SI! curriculum-based educational program over 3 or 6 academic years) or to the control group (standard curriculum). The primary outcomes are the change from baseline at 3-year and 6-year follow-up in children's scores for knowledge, attitudes, and habits (KAH) and health factors (blood pressure, height, weight, waist circumference, and skinfold thickness). Secondary outcomes include 3-year and 6-year changes from baseline in lifestyle questionnaire scores for parents/caregivers and teachers, and in the school environment questionnaire. The overarching goal of the SI! Program is to provide an effective and sustainable health promotion program for the adoption of healthy behaviors in children. The present trial will address the impact and the optimal timing and duration of this educational intervention in the elementary school setting.

Normal LDL-Cholesterol Levels Are Associated With Subclinical Atherosclerosis in the Absence of Risk Factors.

BACKGROUND: Absence of cardiovascular risk factors (CVRFs) is traditionally considered low risk for atherosclerosis; however, individuals without CVRFs, as currently defined, still have events. OBJECTIVES: This study sought to identify predictors of subclinical atherosclerosis in CVRF-free individuals. METHODS: Participants from the PESA (Progression of Early Subclinical Atherosclerosis) study (n = 4,184) without conventional CVRFs were evaluated (n = 1,779; 45.0 ± 4.1 years, 50.3% women). CVRF freedom was defined as no current smoking and untreated blood pressure <140/90 mm Hg, fasting glucose <126 mg/dl, total cholesterol <240 mg/dl, low-density lipoprotein cholesterol (LDL-C) <160 mg/dl, and high-density lipoprotein cholesterol ≥40 mg/dl. A subgroup with optimal CVRFs (n = 740) was also defined as having blood pressure <120/80 mm Hg, fasting glucose <100 mg/dl, glycosylated hemoglobin <5.7%, and total cholesterol <200 mg/dl. We evaluated ultrasound-detected carotid, iliofemoral, and abdominal aortic plaques; coronary artery calcification; serum biomarkers; and lifestyle. Adjusted odds ratios (with 95% confidence interval) and ordinal logistic regression models were used. RESULTS: Subclinical atherosclerosis (plaque or coronary artery calcification) was present in 49.7% of CVRF-free participants. Together with male sex and age, LDL-C was independently associated with atherosclerosis presence and extent, in both the CVRF-free and CVRF-optimal groups (odds ratio [×10 mg/dl]: 1.14 to 1.18; p < 0.01 for all). Atherosclerosis presence and extent was also associated in the CVRF-free group with glycosylated hemoglobin levels. CONCLUSIONS: Many CVRF-free middle-aged individuals have atherosclerosis. LDL-C, even at levels currently considered normal, is independently associated with the presence and extent of early systemic atherosclerosis in the absence of major CVRFs. These findings support more effective LDL-C lowering for primordial prevention, even in individuals conventionally considered at optimal risk. (Progression of Early Subclinical Atherosclerosis [PESA] Study; NCT01410318).