Publications by authors named "Leticia Fernandez-Friera"

90 Publications

Mitral valve prolapse morphofunctional features by cardiovascular magnetic resonance: more than just a valvular disease.

J Cardiovasc Magn Reson 2021 Oct 11;23(1):107. Epub 2021 Oct 11.

Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.

Introduction: Mitral valve (MV) prolapse (MVP) is a primary valvular abnormality. We hypothesized that additionally there are concomitant abnormalities of the left ventricle (LV) and MV apparatus in this entity even in the absence of significant mitral regurgitation (MR).

Objective: To characterize MV and LV anatomic and functional features in MVP with preserved LV ejection fraction, with and without significant MR, using cardiovascular magnetic resonance (CMR).

Methods: Consecutive MVP patients (n = 80, mean 52 years, 37% males) with preserved LV ejection fraction, and 44 controls (46 years, 52% males) by CMR were included, as well as 13 additional patients with "borderline" MVP. From cine images we quantified LV volumes, MV and LV anatomic measurements (including angle between diastolic and systolic annular planes, annular displacement, and basal inferolateral hypertrophy) and, using feature tracking, longitudinal and circumferential peak systolic strains.

Results: Significant MR was found in 46 (56%) MVP patients. Compared with controls, MVP patients had LV enlargement, basal inferolateral hypertrophy, higher posterior annular excursion, and reduced shortening of the papillary muscles. LV basal strains were significantly increased, particularly in several basal segments. These differences remained significant in patients without significant MR, and many persisted in "borderline" MVP.

Conclusions: In patients with MVP and preserved LV ejection fraction there is LV dilatation, basal inferolateral hypertrophy, exaggerated posterior annular displacement and increased basal deformation, even in the absence of significant MR or overt MVP. These findings suggest that MVP is a disease not only of the MV but also of the adjacent myocardium.
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http://dx.doi.org/10.1186/s12968-021-00800-wDOI Listing
October 2021

Subclinical Liver Disease Is Associated with Subclinical Atherosclerosis in Psoriasis: Results from Two Observational Studies.

J Invest Dermatol 2021 Jul 19. Epub 2021 Jul 19.

National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA. Electronic address:

Psoriasis is associated with a higher risk of liver diseases. We investigated the impact of hepatic steatosis (European cohort) and hepatic inflammation (United States cohort) on subclinical atherosclerosis. In the European cohort (n = 76 psoriasis participants and 76 controls), nonalcoholic fatty liver disease, assessed by the sonographic hepatorenal index, was more prevalent in psoriasis than in controls (61% vs. 45%; P = 0.04). Participants with psoriasis with nonalcoholic fatty liver disease had a higher prevalence of subclinical atherosclerosis (ultrasonographic presence of plaque in femoral or carotid arteries) than participants with psoriasis without nonalcoholic fatty liver disease (61% vs. 23%; P = 0.006) and controls with nonalcoholic fatty liver disease (61% vs. 32%; P < 0.05). Sonographic hepatorenal index was a determinant of subclinical atherosclerosis in psoriasis (OR = 3.5; P = 0.01). In the United States cohort (n = 162 participants with psoriasis who underwent positron emission tomography and coronary computed tomography angiography), those with high hepatic 2-[fluorine-18]fluoro-2-deoxy-D-glucose uptake had higher noncalcified (1.3 [0.49 mm] vs. 1.0 [0.40 mm]), fibrofatty (0.23 [0.15 mm] vs. 0.11 [0.087 mm]), and lipid-rich necrotic core (4.3 [2.3 mm] vs. 3.0 [1.7 mm]) coronary burden (all P < 0.001). Hepatic 2-[fluorine-18]fluoro-2-deoxy-D-glucose uptake associated with noncalcified (β = 0.28; P < 0.001), fibrofatty (β = 0.49; P < 0.001), and lipid-rich necrotic core (β = 0.28; P = 0.003) burden. These results show the downstream cardiovascular effects of subclinical liver disease in psoriasis.
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http://dx.doi.org/10.1016/j.jid.2021.05.034DOI Listing
July 2021

Progression of Early Subclinical Atherosclerosis (PESA) Study: JACC Focus Seminar 7/8.

J Am Coll Cardiol 2021 Jul;78(2):156-179

Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address:

Atherosclerosis starts early in life and progresses silently for decades. Considering atherosclerosis as a "systemic disease" invites the use of noninvasive methodologies to detect disease in various regions before symptoms appear. The PESA-(Progression of Early Subclinical Atherosclerosis) CNIC-SANTANDER study is an ongoing prospective cohort study examining imaging, biological, and behavioral parameters associated with the presence and progression of early subclinical atherosclerosis. Between 2010 and 2014, PESA enrolled 4,184 asymptomatic middle-aged participants who undergo serial 3-yearly follow-up examinations including clinical interviews, lifestyle questionnaires, sampling, and noninvasive imaging assessment of multiterritorial subclinical atherosclerosis (carotids, iliofemorals, aorta, and coronaries). PESA tracks the trajectories of atherosclerosis and associated disorders from early stages to the transition to symptomatic phases. A joint venture between the CNIC and the Santander Bank, PESA is expected to run until at least 2029, and its significant contributions to date are presented in this review paper.
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http://dx.doi.org/10.1016/j.jacc.2021.05.011DOI Listing
July 2021

Triglycerides and Residual Atherosclerotic Risk.

J Am Coll Cardiol 2021 Jun;77(24):3031-3041

National Center for Cardiovascular Research (CNIC), Madrid, Spain; Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address:

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).
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http://dx.doi.org/10.1016/j.jacc.2021.04.059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215641PMC
June 2021

Glycated Hemoglobin and Subclinical Atherosclerosis in People Without Diabetes.

J Am Coll Cardiol 2021 Jun;77(22):2777-2791

Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain; Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jacc.2021.03.335DOI Listing
June 2021

A Novel Circulating MicroRNA for the Detection of Acute Myocarditis.

N Engl J Med 2021 05;384(21):2014-2027

From the Vascular Pathophysiology Area (R.B.-D., R.S.-D., A.M.-M., M. Relaño, R.J.-A., B.L.-P., K.T., D.A.P.-F., V.F., F.S.-M., P.M.) and the Myocardial Pathophysiology Area (L.A.-H., M. Ricote, H.B., L.F.-F., B.I.), Centro Nacional de Investigaciones Cardiovasculares (CNIC), the Department of Immunology (H.F., F.S.-M.), the Department of Cardiology (L.J.J.-B., M.M.G.-G., F.A.), the Department of Dermatology (E.D.), and the Department of Rheumatology (I.G.-A.), Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Fundación Jiménez Díaz (M.L.M.-M., B.I.), the Cardiology Department, Hospital Universitario 12 de Octubre, and Instituto de Investigación Sanitaria Hospital 12 de Octubre (G.M., R.M.-A., H.B.), the Department of Immunology, Hospital Ramón y Cajal (L.M.V.-G.), HM Hospitales-Centro Integral de Enfermedades Cardiovasculares (L.F.-F.), and CIBER de Enfermedades Cardiovasculares (R.S.-D., H.F., L.J.J.-B., F.A., D.A.P.-F., B.I., F.S.-M., P.M.), Madrid, Hospital Universitario Central de Asturias, Oviedo (A.M.-L.), and the Cardiology Department, Hospital Universitario Virgen de la Arrixaca, Murcia (D.A.P.-F.) - all in Spain; the Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, FL (K.A.B., D.F.); the Cardiovascular Division and Corrigan Minehan Heart Center, Massachusetts General Hospital, and Harvard Medical School, Boston (A.M.S.-G., S.A.M., N.E.I., J.L.J., S.D.); Kanntonsspital St. Gallen Klinik für Anesthesiologie und Intensivmedizin, St. Gallen, Switzerland (J.K.); Cardiology (S.I., A.B., A.L.P.C.) and the Cardiovascular Pathology Unit (C.B.), the Department of Cardiac, Thoracic, Vascular Sciences and Public Health, the Department of Laboratory Medicine (M.P., M.S.), and the Department of Medicine, Hematology and Clinical Immunology (R.M.), University of Padua, Padua, Italy; Charite Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin (B.H.); Imperial College and Royal Brompton and Harefield Hospital, London (T.F.L.); and the Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York (V.F.).

Background: The diagnosis of acute myocarditis typically requires either endomyocardial biopsy (which is invasive) or cardiovascular magnetic resonance imaging (which is not universally available). Additional approaches to diagnosis are desirable. We sought to identify a novel microRNA for the diagnosis of acute myocarditis.

Methods: To identify a microRNA specific for myocarditis, we performed microRNA microarray analyses and quantitative polymerase-chain-reaction (qPCR) assays in sorted CD4+ T cells and type 17 helper T (Th17) cells after inducing experimental autoimmune myocarditis or myocardial infarction in mice. We also performed qPCR in samples from coxsackievirus-induced myocarditis in mice. We then identified the human homologue for this microRNA and compared its expression in plasma obtained from patients with acute myocarditis with the expression in various controls.

Results: We confirmed that Th17 cells, which are characterized by the production of interleukin-17, are a characteristic feature of myocardial injury in the acute phase of myocarditis. The microRNA mmu-miR-721 was synthesized by Th17 cells and was present in the plasma of mice with acute autoimmune or viral myocarditis but not in those with acute myocardial infarction. The human homologue, designated hsa-miR-Chr8:96, was identified in four independent cohorts of patients with myocarditis. The area under the receiver-operating-characteristic curve for this novel microRNA for distinguishing patients with acute myocarditis from those with myocardial infarction was 0.927 (95% confidence interval, 0.879 to 0.975). The microRNA retained its diagnostic value in models after adjustment for age, sex, ejection fraction, and serum troponin level.

Conclusions: After identifying a novel microRNA in mice and humans with myocarditis, we found that the human homologue (hsa-miR-Chr8:96) could be used to distinguish patients with myocarditis from those with myocardial infarction. (Funded by the Spanish Ministry of Science and Innovation and others.).
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http://dx.doi.org/10.1056/NEJMoa2003608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258773PMC
May 2021

Clinical Validation of a 3-Dimensional Ultrafast Cardiac Magnetic Resonance Protocol Including Single Breath-Hold 3-Dimensional Sequences.

JACC Cardiovasc Imaging 2021 Sep 14;14(9):1742-1754. Epub 2021 Apr 14.

Clinical Science, Philips Healthcare Iberia, Madrid, Spain. Electronic address:

Objectives: This study sought to clinically validate a novel 3-dimensional (3D) ultrafast cardiac magnetic resonance (CMR) protocol including cine (anatomy and function) and late gadolinium enhancement (LGE), each in a single breath-hold.

Background: CMR is the reference tool for cardiac imaging but is time-consuming.

Methods: A protocol comprising isotropic 3D cine (Enhanced sensitivity encoding [SENSE] by Static Outer volume Subtraction [ESSOS]) and isotropic 3D LGE sequences was compared with a standard cine+LGE protocol in a prospective study of 107 patients (age 58 ± 11 years; 24% female). Left ventricular (LV) mass, volumes, and LV and right ventricular (RV) ejection fraction (LVEF, RVEF) were assessed by 3D ESSOS and 2D cine CMR. LGE (% LV) was assessed using 3D and 2D sequences.

Results: Three-dimensional and LGE acquisitions lasted 24 and 22 s, respectively. Three-dimensional and LGE images were of good quality and allowed quantification in all cases. Mean LVEF by 3D and 2D CMR were 51 ± 12% and 52 ± 12%, respectively, with excellent intermethod agreement (intraclass correlation coefficient [ICC]: 0.96; 95% confidence interval [CI]: 0.94 to 0.97) and insignificant bias. Mean RVEF 3D and 2D CMR were 60.4 ± 5.4% and 59.7 ± 5.2%, respectively, with acceptable intermethod agreement (ICC: 0.73; 95% CI: 0.63 to 0.81) and insignificant bias. Both 2D and 3D LGE showed excellent agreement, and intraobserver and interobserver agreement were excellent for 3D LGE.

Conclusions: ESSOS single breath-hold 3D CMR allows accurate assessment of heart anatomy and function. Combining ESSOS with 3D LGE allows complete cardiac examination in <1 min of acquisition time. This protocol expands the indication for CMR, reduces costs, and increases patient comfort.
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http://dx.doi.org/10.1016/j.jcmg.2021.02.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421247PMC
September 2021

Carotid Plaque Burden by 3-Dimensional Vascular Ultrasound as a Risk Marker for Patients with Metabolic Syndrome.

J Cardiovasc Transl Res 2021 Mar 25. Epub 2021 Mar 25.

Facultad de Medicina, Universidad CEU-San Pablo, CEU Universities, Madrid, Spain.

Our aim was to analyse the associations between carotid plaque burden (CPB), cardiovascular risk factors (CVRF), and surrogate markers of CV risk in subjects with metabolic syndrome (MetS). We consecutively included 75 asymptomatic outpatients with MetS components, <60 years old and non-smokers. We determined the presence of CVRF, left ventricular hypertrophy (LVH), carotid intima-media thickness (cIMT), albumin-creatinine ratio (ACR), coronary artery calcium score (CACS) and CPB by 3-dimensional vascular ultrasound (3DVUS) for comparison. A total of 50 (67%) subjects had MetS defined by harmonized criteria. A CPB >0 mm and a CACS >0 AU were the risk biomarkers most frequently observed (72% and 77%, respectively), followed by LVH (40%). CPB and CACS revealed association with cardiovascular risk (r = 0.308; p = 0.032 and r = 0.601 p < 0.01, respectively), and CPB also showed association with the burden of CVRF (r = 0.349; p = 0.014). CPB by 3DVUS was a prevalent CV risk marker, directly associated with CVRF and cardiovascular risk in MetS subjects.
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http://dx.doi.org/10.1007/s12265-021-10121-zDOI Listing
March 2021

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

J Am Coll Cardiol 2021 02;77(7):888-898

Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address:

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 F-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) (β = -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 (β = -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.
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http://dx.doi.org/10.1016/j.jacc.2020.12.027DOI Listing
February 2021

Identification of a peripheral blood gene signature predicting aortic valve calcification.

Physiol Genomics 2020 12 12;52(12):563-574. Epub 2020 Oct 12.

Intercellular Signaling in Cardiovascular Development and Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.

Calcific aortic valve disease (CAVD) is a significant cause of illness and death worldwide. Identification of early predictive markers could help optimize patient management. RNA-sequencing was carried out on human fetal aortic valves at gestational , , and and on a case-control study with adult noncalcified and calcified bicuspid and tricuspid aortic valves. In dimension reduction and clustering analyses, diseased valves tended to cluster with fetal valves at rather than normal adult valves, suggesting that part of the disease program might be due to reiterated developmental processes. The analysis of groups of coregulated genes revealed predominant immune-metabolic signatures, including innate and adaptive immune responses involving lymphocyte T-cell metabolic adaptation. Cytokine and chemokine signaling, cell migration, and proliferation were all increased in CAVD, whereas oxidative phosphorylation and protein translation were decreased. Discrete immune-metabolic gene signatures were present at fetal stages and increased in adult controls, suggesting that these processes intensify throughout life and heighten in disease. Cellular stress response and neurodegeneration gene signatures were aberrantly expressed in CAVD, pointing to a mechanistic link between chronic inflammation and biological aging. Comparison of the valve RNA-sequencing data set with a case-control study of whole blood transcriptomes from asymptomatic individuals with early aortic valve calcification identified a highly predictive gene signature of CAVD and of moderate aortic valve calcification in overtly healthy individuals. These data deepen and broaden our understanding of the molecular basis of CAVD and identify a peripheral blood gene signature for the early detection of aortic valve calcification.
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http://dx.doi.org/10.1152/physiolgenomics.00034.2020DOI Listing
December 2020

Association Between Left Ventricular Noncompaction and Vigorous Physical Activity.

J Am Coll Cardiol 2020 10;76(15):1723-1733

Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain; Icahn School of Medicine at Mount Sinai, New York, New York.

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.
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http://dx.doi.org/10.1016/j.jacc.2020.08.030DOI Listing
October 2020

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

J Am Coll Cardiol 2020 10;76(14):1674-1685

Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; CIBER de enfermedades CardioVasculares (CIBERCV), Spain. Electronic address:

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).
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http://dx.doi.org/10.1016/j.jacc.2020.08.017DOI Listing
October 2020

Additional value of hybrid PET/MR imaging versus MR or PET performed separately to assess cardiovascular disease.

Rev Esp Cardiol (Engl Ed) 2021 Apr 20;74(4):303-311. Epub 2020 Sep 20.

Unidad de Imagen Cardiaca, Departamento de Cardiología, HM Hospitales-Centro Integral de Enfermedades Cardiovasculares HM CIEC, Madrid, Spain; Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Departamento de Medicina, Universidad CEU San Pablo, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain. Electronic address:

Introduction And Objectives: Hybrid positron emission tomography (PET) and magnetic resonance (MR) imaging is an emerging technology in the diagnosis of cardiovascular disease; however, there have been no reports of its use in the national clinical setting. Our objective was to evaluate the additional value of integrated PET/MR systems compared with MR and PET performed separately in this setting.

Methods: We prospectively included 49 patients, 30 to assess myocardial viability (coronary group) and 19 to assess inflammatory, infectious, and tumoral diseases (noncoronary heart disease group). All patients underwent cardiac F-fluorodeoxyglucose PET/MR. PET/MR studies included attenuation correction sequences, followed by simultaneous cardiac PET and cardiac MR acquisition, with protocols adapted to the clinical indication (cine, tissue characterization and/or late enhancement imaging).

Results: Most (87.8%) PET/MR studies were initially interpretable. Use of PET/MR improved diagnosis vs PET or MR performed separately in 42.1% of coronary cases and 88.9% of noncoronary cases. PET/MR enabled reclassification of 87.5% of coronary cases initially classified as showing inconclusive results on MR or PET and 70% of noncoronary cases.

Conclusions: In our series, multimodality PET/MR technology provided additional diagnostic value in some patients with cardiovascular disease compared with MR and PET performed separately, especially in cases of noncoronary heart disease and in those with inconclusive results on MR or PET. In our experience, the main benefits of PET/MR include the possibility of simultaneous acquisition, the in vivo integration of anatomical/functional/metabolic aspects, and the interaction of different experts in imaging modalities.
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http://dx.doi.org/10.1016/j.rec.2020.06.034DOI Listing
April 2021

Association Between Body Size Phenotypes and Subclinical Atherosclerosis.

J Clin Endocrinol Metab 2020 12;105(12)

U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts.

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.
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http://dx.doi.org/10.1210/clinem/dgaa620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521861PMC
December 2020

Coexistence of transmural and lateral wavefront progression of myocardial infarction in the human heart.

Rev Esp Cardiol (Engl Ed) 2021 Oct 24;74(10):870-877. Epub 2020 Aug 24.

Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, CIBERCV, Madrid, Spain; Servicio de Cardiología, IIS-Fundación Jiménez Díaz, Madrid, Spain. Electronic address:

Introduction And Objectives: According to the wavefront phenomenon described in the late 1970s, myocardial infarction triggered by acute coronary occlusion progresses with increasing duration of ischemia as a transmural wavefront from the subendocardium toward the subepicardium. However, whether wavefront progression of necrosis also occurs laterally has been disputed. We aimed to assess the transmural and lateral spread of myocardial damage after acute myocardial infarction in humans and to evaluate the impact of metoprolol on these.

Methods: We assessed myocardial infarction in the transmural and lateral dimensions in a cohort of 220 acute ST-segment elevation myocardial infarction (STEMI) patients from the METOCARD-CNIC trial (Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction). The patients underwent cardiac magnetic resonance imaging at 5 to 7 days and 6 months post-STEMI.

Results: On day 5 to 7 post-STEMI cardiac magnetic resonance, there was a strong linear correlation between the transmural and lateral extent of infarction (delayed gadolinium enhancement) (r=-0.88; P<.001). Six months after STEMI, myocardial scarring (delayed gadolinium enhancement) was significantly less extensive in the transmural and lateral dimensions, suggesting that infarct resorption occurs in both. Furthermore, progression in both directions occurred both in patients receiving metoprolol and control patients, implying that myocardial salvage occurs both in the transmural and the lateral direction.

Conclusions: Our findings challenge the assumption that irreversible injury does not spread laterally. A "circumferential" or multidirectional wavefront would imply that cardioprotective therapies might produce meaningful salvage at lateral borders of the infarct. This trial was registered at ClinicalTrial.gov (Identifier: NCT01311700).
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http://dx.doi.org/10.1016/j.rec.2020.07.007DOI Listing
October 2021

Effect of sildenafil on right ventricular performance in an experimental large-animal model of postcapillary pulmonary hypertension.

Transl Res 2021 02 22;228:64-75. Epub 2020 Aug 22.

IDIBAPS, Hospital Clínic, Barcelona, Spain; Departament of Medicine, Universitat de Barcelona, Barcelona, Spain; Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain. Electronic address:

Right ventricle (RV) dysfunction is a main determinant of morbidity and mortality in postcapillary pulmonary hypertension (PH). However, currently there are not available therapies. Since reduced nitric oxide (NO) availability and cyclic guanylate monophosphate (cGMP) levels are central in this disease, therapies targeting the NO pathway might have a beneficial effect on RV performance. In this regard, sildenafil has shown contradictory results. Our objective was to evaluate the effect of sildenafil on RV performance in an experimental pig model of postcapillary PH induced by a fixed banding of the venous pulmonary confluent. Animals were evaluated by right heart catheterization and cardiac magnetic resonance before randomization and after 8 weeks on sildenafil (n = 8) or placebo (n = 8), and myocardial tissues were analyzed with histology and molecular biology. At the end of the study, animals receiving sildenafil showed better RV performance as compared with those on placebo (improvement in RV ejection fraction of 7.3% ± 5.8% versus -0.6% ± 5.0%, P= 0.021) associated with less apoptotic cells and gene expression related with reduced oxidative stress and increased anti-inflammatory activity in the myocardium. No differences were observed in pulmonary hemodynamics. In conclusion, in a translational large animal model of chronic postcapillary PH, sildenafil improved RV systolic function independently of afterload. Further research with pharmacological approaches able to manipulate the NO-cGMP axis are needed to confirm this potential cardioprotective effect.
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http://dx.doi.org/10.1016/j.trsl.2020.08.006DOI Listing
February 2021

Heart murmur with unusual diagnosis.

Heart 2020 09;106(17):1301-1367

Unidad de Imagen Cardiaca, Hospital Universitario HM Montepríncipe-CIEC/Hospital Universitario HM Puerta del Sur, Madrid, Spain

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http://dx.doi.org/10.1136/heartjnl-2020-316736DOI Listing
September 2020

Coronary arterial segmental stenosis quantified by MDCT: correlation with quantitative coronary analyses by invasive angiography.

Rev Esp Cardiol (Engl Ed) 2020 12 18;73(12):1068-1070. Epub 2020 Jul 18.

Unidad de Imagen Cardiaca, Hospital Universitario HM Montepríncipe-CIEC, HM Hospitales, Madrid, Spain; Servicio de Cardiología, Hospital Universitario HM Montepríncipe-CIEC, HM Hospitales, Madrid, Spain; Universidad CEU San Pablo, Madrid, Spain; Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; CIBER de enfermedades CardioVasculares (CIBERCV), Madrid, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.rec.2020.04.029DOI Listing
December 2020

Design of the β3-Adrenergic Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure Trial.

JACC Basic Transl Sci 2020 Apr 11;5(4):317-327. Epub 2020 Mar 11.

Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.

Combined pre-and post-capillary hypertension (CpcPH) is a relatively common complication of heart failure (HF) associated with a poor prognosis. Currently, there is no specific therapy approved for this entity. Recently, treatment with beta-3 adrenergic receptor (β3AR) agonists was able to improve pulmonary hemodynamics and right ventricular (RV) performance in a translational, large animal model of chronic PH. The authors present the design of a phase II randomized clinical trial that tests the benefits of mirabegron (a clinically available β3AR agonist) in patients with CpcPH due to HF. The effect of β3AR treatment will be evaluated on pulmonary hemodynamics, as well as clinical, biochemical, and advanced cardiac imaging parameters. (Beta3 Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure [SPHERE-HF]; NCT02775539).
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http://dx.doi.org/10.1016/j.jacbts.2020.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188870PMC
April 2020

Short-Term Progression of Multiterritorial Subclinical Atherosclerosis.

J Am Coll Cardiol 2020 04;75(14):1617-1627

Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; The Zena and Michael A. Wiener Cardiovascular Institute/Marie-Josée and Henry R. Kravis Center for Cardiovascular Health, Mount Sinai School of Medicine, New York, New York. Electronic address:

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 mm [IQR: -32.2 to 57.6 mm] 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).
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http://dx.doi.org/10.1016/j.jacc.2020.02.026DOI Listing
April 2020

Diagnostic and Prognostic Value of Coronary Computed Tomography Angiography in Patients with Severe Calcification.

J Cardiovasc Transl Res 2021 02 1;14(1):131-139. Epub 2020 Apr 1.

Unidad de Imagen Cardiaca, Departamento de Cardiología, HM Hospitales-Centro Integral de Enfermedades Cardiovasculares HM CIEC, Madrid, Spain.

Our aim was to analyze its diagnostic and prognostic value in patients with high coronary calcium score (CCS). A total of 113 patients with CCS > 400 were included. Significant coronary artery disease (CAD) was defined as stenosis ≥ 50%. Invasive coronary angiography and major cardiovascular events were recorded. The CCS and heart rate during the acquisition were significantly lower in the diagnostic coronary computed tomography angiography (CCTA) group. The cut-off value of CCS to establish the diagnostic utility of CCTA was 878. The rate of cardiovascular events was 9.3%. The positive predictive value of CCTA to detect significant CAD was 73.5% and the negative predictive value for predicting cardiovascular events was 96%. In patients with high CCS, CCTA is useful to evaluate CAD, especially when the CCS is lower or equal to 878; moreover, the prognostic value of CCTA is better in patients where significant CAD has been ruled out.
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http://dx.doi.org/10.1007/s12265-020-09977-4DOI Listing
February 2021

Effects of Colchicine on Atherosclerotic Plaque Stabilization: a Multimodality Imaging Study in an Animal Model.

J Cardiovasc Transl Res 2021 02 5;14(1):150-160. Epub 2020 Mar 5.

Centro Nacional de Investigaciones Cardiovasculares (CNIC), Calle de Melchor Fernández Almagro, 3, 28029, Madrid, Spain.

Colchicine demonstrated clinical benefits in the treatment of stable coronary artery disease. Our aim was to evaluate the effects of colchicine on atherosclerotic plaque stabilization. Atherosclerosis was induced in the abdominal aorta of 20 rabbits with high-cholesterol diet and balloon endothelial denudation. Rabbits were randomized to receive either colchicine or placebo. All animals underwent MRI, F-FDG PET/CT, optical coherence tomography (OCT), and histology. Similar progression of atherosclerotic burden was observed in the two groups as relative increase of normalized wall index (NWI). Maximum F-FDG standardized uptake value (meanSUVmax) decreased after colchicine treatment, while it increased in the placebo group with a trend toward significance. Animals with higher levels of cholesterol showed significant differences in favor to colchicine group, both as NWI at the end of the protocol and as relative increase in meanSUVmax. Colchicine may stabilize atherosclerotic plaque by reducing inflammatory activity and plaque burden, without altering macrophage infiltration or plaque typology.
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http://dx.doi.org/10.1007/s12265-020-09974-7DOI Listing
February 2021

Soluble ICAM 1 and VCAM 1 Blood Levels Alert on Subclinical Atherosclerosis in Non Smokers with Asymptomatic Metabolic Syndrome.

Arch Med Res 2019 02 31;50(2):20-28. Epub 2019 May 31.

George Washington Univ School of Medicine and Health Sciences, Washington DC, USA.

Background: Metabolic syndrome (MetS) is a heterogeneous clinical entity associated with insulin resistance, low-grade proinflammatory balance and impaired endothelial function, accelerating atherosclerosis. Atherosclerotic lesions worsen with age, smoking and co-morbidities, making it difficult to accurately diagnose the cardiovascular disease (CVD) risk.

Aim: We investigate the association between subclinical atherosclerosis and the presence of blood parameters related to adipocyte and vascular endothelial cell dysfunction, in non-smokers with MetS, under 60 and without previous CVD events.

Methods: Seventy-eight asymptomatic individuals (average 46.5 years, 69% male; 59 MetS and 19 controls) were studied prospectively. Subclinical CVD was defined by the presence of carotid plaque and/or carotid intima-media thickness (CIMT) > 0.9 in 2/3D ultrasound-studies, left ventricular hypertrophy (LVH) or high coronary calcium score (CCS). Multiplex immunoassay by Luminex xMAP was performed to measure plasma levels of adipokines and endothelial cell-derived molecules.

Results: Compared with controls, MetS patients had higher prevalence of carotid plaque (25 vs. 0%, p = 0.01), CIMT>0.9 (73 vs. 26%, p = 0.001) and higher CCS (69 vs. 5, p = 0.01), which were associated with a remarkable decrease in plasma Omentin levels and increase in sICAM-1, sVCAM-1 and PAI-1 (p <0.05). There was a statistically significant association between CIMT and sICAM-1 (OR: 14.57, 95% CI: 2.56-82.73, p <0.001), sVCAM-1 (OR:7.33, 95% CI: 1,58-33.96, p = 0.007) and PAI-1 (OR:7.80, 95% CI: 1.04-22.10, p = 0.036) in patients with carotid plaque and/or CIMT>0.9. Positive correlation between plaque volume and sICAM-1 levels was also detected (r = 0.40, p = 0.045).

Conclusions: We demonstrated that the increase of sICAM-1, sVCAM-1 and PAI-1, together with decrease of omentin-1 led to a proinflammatory imbalance pointing to the presence of subclinical atherosclerosis, and improving CVD risk stratification in non-smoking patients at early stage MetS beyond traditional scores.
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http://dx.doi.org/10.1016/j.arcmed.2019.05.003DOI Listing
February 2019

Does Socioeconomic Status Influence the Risk of Subclinical Atherosclerosis?: A Mediation Model.

J Am Coll Cardiol 2019 07;74(4):526-535

Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address:

Background: Socioeconomic status (SES)-education, income level, and occupation-is associated with cardiovascular risk.

Objectives: This study aimed to investigate the association between SES and subclinical atherosclerosis and the potential mechanisms involved.

Methods: SES, lifestyle habits (smoking, dietary patterns, physical activity, and hours of sleep), traditional risk factors, and subclinical atherosclerosis extent were prospectively assessed in 4,025 individuals aged 40 to 54 years without known cardiovascular disease enrolled in the PESA (Progression of Early Subclinical Atherosclerosis) study. After factors associated with atherosclerosis were identified, a multiple mediation model was created to quantify the effect of SES on subclinical atherosclerosis as explained by lifestyle behaviors.

Results: Although education level was significantly associated with the presence of atherosclerosis, no differences were found according to income level in this population. Participants with lower education presented with a higher risk of generalized atherosclerosis than those with higher education (odds ratio: 1.46; 95% confidence interval: 1.15 to 1.85; p = 0.002). Lifestyle behaviors associated with both education level and atherosclerosis extent were: smoking status, number of cigarettes/day, and dietary pattern, which explained 70.5% of the effect of SES on atherosclerosis. Of these, tobacco habit (smoking status 35% and number of cigarettes/day 32%) accounted for most of the explained differences between groups, whereas dietary pattern did not remain a significant mediator in the multiple mediation model.

Conclusions: Despite the relative economic homogeneity of the cohort, lower education level is associated with increased subclinical atherosclerosis, mainly mediated by the higher and more frequent tobacco consumption. Smoking cessation programs are still needed, particularly in populations with lower education level.
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http://dx.doi.org/10.1016/j.jacc.2019.05.042DOI Listing
July 2019

Genome-Wide Association Study-Driven Gene-Set Analyses, Genetic, and Functional Follow-Up Suggest GLIS1 as a Susceptibility Gene for Mitral Valve Prolapse.

Circ Genom Precis Med 2019 05;12(5):e002497

INSERM, UMR970, Paris Cardiovascular Research Center, France (M.Y., A.G., S.K., A.A.H., X.J., N.B.-N.).

Background Mitral valve prolapse (MVP) is a common heart valve disease, the most frequent indication for valve repair or replacement. MVP is characterized by excess extracellular matrix secretion and cellular disorganization, which leads to bulky valves that are unable to coapt correctly during ventricular systole resulting in mitral regurgitation, and it is associated with sudden cardiac death. Here we aim to characterize globally the biological mechanisms underlying genetic susceptibility to MVP to better characterize its triggering mechanisms. Methods We applied i-GSEA4GWAS and DEPICT, two pathway enrichment tools to MVP genome-wide association studies. We followed-up the association with MVP in an independent dataset of cases and controls. This research was conducted using the UK Biobank Resource. Immunohistochemistry staining for Glis1 (GLIS family zinc finger 1) was conducted in developing heart of mice. Knockdown of Glis1 using morpholinos was performed in zebrafish animals 72 hours postfertilization. Results We show that genes at risk loci are involved in biological functions relevant to actin filament organization, cytoskeleton biology, and cardiac development. The enrichment for positive regulation of transcription, cell proliferation, and migration motivated the follow-up of GLIS1, a transcription factor from the Krüppel-like zinc finger family. In combination with previously available data, we now report a genome-wide significant association with MVP (odds ratio, 1.20; P=4.36×10), indicating that Glis1 is expressed during embryonic development predominantly in nuclei of endothelial and interstitial cells of mitral valves in mouse. We also show that Glis1 knockdown causes atrioventricular regurgitation in developing hearts in zebrafish. Conclusions Our findings define globally molecular and cellular mechanisms underlying common genetic susceptibility to MVP and implicate established and unprecedented mechanisms. Through the GLIS1 association and function, we point at regulatory functions during cardiac development as common mechanisms to mitral valve degeneration.
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http://dx.doi.org/10.1161/CIRCGEN.119.002497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532425PMC
May 2019

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

J Am Coll Cardiol 2019 04;73(12):1371-1382

Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Icahn School of Medicine at Mount Sinai, New York, New York.

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 F-fluorodeoxyglucose (F-FDG) positron emission tomography/magnetic resonance imaging (PET/MRI).

Methods: Carotid, aortic, and ilio-femoral F-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 F-FDG uptake) and plaques with or without inflammation (coincident F-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). F-FDG arterial uptakes and plaques significantly increased with cardiovascular risk factors (p < 0.01). Coincident F-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 F-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 F-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).
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http://dx.doi.org/10.1016/j.jacc.2018.12.075DOI Listing
April 2019

Association of Sleep Duration and Quality With Subclinical Atherosclerosis.

J Am Coll Cardiol 2019 01;73(2):134-144

Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; IMDEA Food Institute, CEI UAM + CSIC, Madrid, Spain; U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts. Electronic address:

Background: Sleep duration and quality have been associated with increased cardiovascular risk. However, large studies linking objectively measured sleep and subclinical atherosclerosis assessed in multiple vascular sites are lacking.

Objectives: The purpose of this study was to evaluate the association of actigraphy-measured sleep parameters with subclinical atherosclerosis in an asymptomatic middle-aged population, and investigate interactions among sleep, conventional risk factors, psychosocial factors, dietary habits, and inflammation.

Methods: Seven-day actigraphic recording was performed in 3,974 participants (age 45.8 ± 4.3 years; 62.6% men) from the PESA (Progression of Early Subclinical Atherosclerosis) study. Four groups were defined: very short sleep duration <6 h, short sleep duration 6 to 7 h, reference sleep duration 7 to 8 h, and long sleep duration >8 h. Sleep fragmentation index was defined as the sum of the movement index and fragmentation index. Carotid and femoral 3-dimensional vascular ultrasound and cardiac computed tomography were performed to quantify noncoronary atherosclerosis and coronary calcification.

Results: When adjusted for conventional risk factors, very short sleep duration was independently associated with a higher atherosclerotic burden with 3-dimensional vascular ultrasound compared to the reference group (odds ratio: 1.27; 95% confidence interval: 1.06 to 1.52; p = 0.008). Participants within the highest quintile of sleep fragmentation presented a higher prevalence of multiple affected noncoronary territories (odds ratio: 1.34; 95% confidence interval: 1.09 to 1.64; p = 0.006). No differences were observed regarding coronary artery calcification score in the different sleep groups.

Conclusions: Lower sleeping times and fragmented sleep are independently associated with an increased risk of subclinical multiterritory atherosclerosis. These results highlight the importance of healthy sleep habits for the prevention of cardiovascular disease.
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http://dx.doi.org/10.1016/j.jacc.2018.10.060DOI Listing
January 2019

A 52-year-old woman with ventricular tachycardia.

Heart 2018 12 4;104(24):2025-2043. Epub 2018 Sep 4.

HM Hospitales-Centro Integral de Enfermedades Cardiovasculares HM-CIEC, Madrid, Spain.

Clinical Introduction: A 52-year-old woman with shortness of breath and palpitations was referred to a cardiologist. A 24-hour Holter demonstrated high density (37%) of ventricular premature beats (VPBs) and long runs of non-sustained (eventually sustained) monomorphic ventricular tachycardia (VT) with the same morphology as several VPBs detected in a 12-lead ECG (figure 1A). A transthoracic echocardiogram was performed, and the patient's evaluation was completed with a functional and gadolinium-enhanced cardiovascular MR (CMR) study (figure 1B,C) to assess structural heart disease. In a follow-up visit, an electrophysiological study (EPS) was performed to identify the origin of VPBs and VT (figure 1D).heartjnl;104/24/2025/F1F1F1Figure 1(A) A 12-lead ECG. (B) Cine CMR-SSFP (steady-state-free-precession) sequence on a three-chamber view. (C) Inversion-recovery gradient echo CMR pulse sequence for delayed enhancement assessment. (D) Three-dimensional electroanatomic voltage mapping of the left ventricular cavity (cranial left anterior oblique view). CMR, cardiovascular MR.

Question: What is the most likely cause of VPBs and VT?Idiopathic VT in the absence of structural heart disease.Bileaflet mitral valve prolapse (MVP).Dilated cardiomyopathy.Left ventricular non-compaction cardiomyopathy.Ischaemic cardiomyopathy.
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http://dx.doi.org/10.1136/heartjnl-2018-313347DOI Listing
December 2018

Mechanistic insights of the left ventricle structure and fibrosis in the arrhythmogenic mitral valve prolapse.

Glob Cardiol Sci Pract 2018 Mar 14;2018(1). Epub 2018 Mar 14.

Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.

Mitral valve prolapse (MVP) is a common and benign condition. However, some anatomic forms have been recently associated with life-threatening ventricular arrhythmias and sudden cardiac death. Imaging MVP holds the promise of individualized MVP risk assessment. Noninvasive imaging techniques available today are playing an increasingly important role in the diagnosis, prognosis and monitoring of MVP. In this article, we will review the current evidence on arrhythmogenic MVP, with special focus on the utility of echocardiography and CMR for identifying benign and "malignant" forms of MVP. The clinical relevance of this manuscript lies in the value of imaging technology to improve MVP risk prediction, including those arrhythmic-MVP cases with a higher risk of sudden cardiac death.
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http://dx.doi.org/10.21542/gcsp.2018.4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857061PMC
March 2018

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

J Am Coll Cardiol 2017 Dec;70(24):2979-2991

Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain; Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address:

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).
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http://dx.doi.org/10.1016/j.jacc.2017.10.024DOI Listing
December 2017
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