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Background: Although risk factors for atherosclerotic cardiovascular disease (ASCVD) in familial hypercholesterolemia (FH) have been described, models for predicting incident ASCVD have not been reported. Our aim was to use the SAFEHEART registry (Spanish Familial Hypercholesterolemia Cohort Study) to define key risk factors for predicting incident ASCVD in patients with FH. Methods: SAFEHEART is a multicenter, nationwide, long-term prospective cohort study of a molecularly defined population with FH with or without previous ASCVD. Analyses to define risk factors and to build a risk prediction equation were developed, and the risk prediction equation was tested for its ability to discriminate patients who experience incident ASCVD from those who did not over time. Results: We recruited 2404 adult patients with FH who were followed up for a mean of 5.5 years (SD, 3.2 years), during which 12 (0.5%) and 122 (5.1%) suffered fatal and nonfatal incident ASCVD, respectively. Age, male sex, history of previous ASCVD, high blood pressure, increased body mass index, active smoking, and low-density lipoprotein cholesterol and lipoprotein(a) levels were independent predictors of incident ASCVD from which a risk equation with a Harrell C index of 0.85 was derived. The bootstrap resampling (100 randomized samples) of the original set for internal validation showed a degree of overoptimism of 0.003. Individual risk was estimated for each person without an established diagnosis of ASCVD before enrollment in the registry by use of the SAFEHEART risk equation, the modified Framingham risk equation, and the American College of Cardiology/American Heart Association ASCVD Pooled Cohort Risk Equations. The Harrell C index for these models was 0.81, 0.78, and 0.8, respectively, and differences between the SAFEHEART risk equation and the other 2 were significant ( P =0.023 and P =0.045). Conclusions: The risk of incident ASCVD may be estimated in patients with FH with simple clinical predictors. This finding may improve risk stratification and could be used to guide therapy in patients with FH. Clinical Trial Registration: URL: http://clinicaltrials.gov . Unique identifier: NCT02693548.

: Although myocardial ischaemia usually manifests as a consequence of atherosclerosis-dependent obstructive epicardial coronary artery disease, a significant percentage of patients suffer ischaemic events in the absence of epicardial coronary artery obstruction. Experimental and clinical evidence highlight the abnormalities of the coronary microcirculation as a main cause of myocardial ischaemia in patients with ‘normal or near normal’ coronary arteries on angiography. Coronary microvascular disturbances have been associated with early stages of atherosclerosis even prior to any angiographic evidence of epicardial coronary stenosis, as well as to other cardiac pathologies such as myocardial hypertrophy and heart failure. The main objectives of the manuscript are (i) to provide updated evidence in our current understanding of the pathophysiological consequences of microvascular dysfunction in the heart; (ii) to report on the current knowledge on the relevance of cardiovascular risk factors and comorbid conditions for microcirculatory dysfunction; and (iii) to evidence the relevance of the clinical consequences of microvascular dysfunction. Highlighting the clinical importance of coronary microvascular dysfunction will open the field for research and the development of novel strategies for intervention will encourage early detection of subclinical disease and will help in the stratification of cardiovascular risk in agreement with the new concept of precision medicine.

Summary: Plaque rupture followed by thrombosis is the underlying cause of the majority of acute coronary syndromes. Circulating microparticles (cMPs), membrane blebs released into blood by activated cells, have been associated to vascular diseases. Specifically, high levels of platelet-derived microparticles (pMPs) have been found in patients with coronary disease. However, it is unknown whether microparticles have a contributing role to the development of damaged vessel wall-induced arterial thrombi. The aim of this proof of concept study was to investigate whether an increased number of cMPs and pMPs could functionally contribute to blood thrombogenicity on areas of arterial damage. Microparticles were isolated from blood of healthy volunteers and were characterised by flow cytometry. Effects of microparticles on platelet deposition were assessed under controlled flow conditions exposing damaged arterial wall in the Badimon perfusion chamber and collagen type-I in the flat perfusion chamber to human blood. Platelet deposition on damaged arteries was significantly increased in cMP- and pMP-enriched bloods (p<0.05). pMPs also induced increase in platelet (p<0.05) and fibrin (p<0.05) deposition on human atherosclerotic arteries and in platelet adhesion to purified collagen surfaces. pMP-enriched blood induced a dose-dependent shortening of epinephrine/collagen closure time evaluated by PFA-100 (p<0.001), increased lowdose ADP-induced platelet aggregation by LTA (p<0.05), and decreased clotting time by thromboelastography (p<0.01). In conclusion, an increased content of cMPs and pMPs, even in normal blood conditions, enhance platelet deposition and thrombus formation. This study shows for the first time that, beyond biomarkers of cell activation, blood microparticles have functional effects on cardiovascular atherothrombotic disease.