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Background— Data are limited on the presence, distribution, and extent of subclinical atherosclerosis in middle-aged populations. Methods and Results— The PESA (Progression of Early Subclinical Atherosclerosis) study prospectively enrolled 4184 asymptomatic participants 40 to 54 years of age (mean age, 45.8 years; 63% male) to evaluate the systemic extent of atherosclerosis in the carotid, abdominal aortic, and iliofemoral territories by 2-/3-dimensional ultrasound and coronary artery calcification by computed tomography. The extent of subclinical atherosclerosis, defined as presence of plaque or coronary artery calcification ≥1, was classified as focal (1 site affected), intermediate (2–3 sites), or generalized (4–6 sites) after exploration of each vascular site (right/left carotids, aorta, right/left iliofemorals, and coronary arteries). Subclinical atherosclerosis was present in 63% of participants (71% of men, 48% of women). Intermediate and generalized atherosclerosis was identified in 41%. Plaques were most common in the iliofemorals (44%), followed by the carotids (31%) and aorta (25%), whereas coronary artery calcification was present in 18%. Among participants with low Framingham Heart Study (FHS) 10-year risk, subclinical disease was detected in 58%, with intermediate or generalized disease in 36%. When longer-term risk was assessed (30-year FHS), 83% of participants at high risk had atherosclerosis, with 66% classified as intermediate or generalized. Conclusions— Subclinical atherosclerosis was highly prevalent in this middle-aged cohort, with nearly half of the participants classified as having intermediate or generalized disease. Most participants at high FHS risk had subclinical disease; however, extensive atherosclerosis was also present in a substantial number of low-risk individuals, suggesting added value of imaging for diagnosis and prevention. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01410318.

Background: The remodeling process that occurs following an acute myocardial infarction produces changes in the myocardial scar and the surrounding tissue. The spatial evolution of the scar has not been yet characterized using MRI. Purpose: To describe the spatial behavior of myocardial scar on its transmural and lateral dimensions following an acute myocardial infarction. Methods: A total of 220 patients with acutely reperfused anterior STEMI (METOCARD-CNIC trial population) were studied. All the patients underwent cardiac MRI at day 7 and 6 months after presentation. The spatial distribution of the scar was analyzed using short axis late gadolinium enhancement images. Endo and epicardial contours of each LV short axis slice was traced, and each one was divided by 100 cords for analysis (Figure 1A). The lateral extension was defined as the percentage of cords with enhancement in every slice, and the transmural extension as the percentage of enhancement within each cord, nested in the lateral extension (Figure 1B). All slices were weighed according to their relative mass. Data were compared by paired t test. Results: Six months after STEMI, myocardial scar was smaller in both dimensions (Figure 1C). Mean ± SEM lateral scar, as a percentage of cords affected, at 7 days and 6 months were, respectively, 27.9 ± 1.1 and 22.2 ± 1.0 (p < 0.001). Transmurality also decreased significantly, mean percentage at day 7 was 46.8 ± 1.5 and at 6 months 35.4 ± 1.4 (p < 0.001). All these changes were accompanied by an increase in LV end-diastolic volume (171.47 ± 2.5 and 190.61 ± 2.9 (p < 0.001)). Conclusions: The myocardial scar remodeling process following a STEMI includes a reduction in both its transmural and lateral extensions.

Background and purpose: The widely accepted wavefront theory of myocardial necrosis during acute coronary occlusion describes its progression as a wavefront from endo towards epicardium. The lateral affection of the myocardium would be predetermined by the location of the coronary occlusion. At the time this phenomenon was firstly described, advanced imaging technology was not available. Current cardiac magnetic resonance (CMR) is able to accurately characterize the necrosis progression in vivo. Methods: A total of 220 patients with reperfused anterior STEMI (METOCARD-CNIC trial population) were studied. All the patients underwent cine, T2-weighted and late gadolinium enhancement CMR at day 5-7 after STEMI. Endo- and epicardial contours of each LV short axis slice was traced, and each one was divided by 100 cords for analysis. Infarct size was characterized in its 2 dimensions: lateral (defined as the percentage of cords with enhancement in every slice) and transmural extension (percentage of enhancement within each cord, nested in the lateral extension). All slices were weighed according to their relative mass. We compared these parameters between the cardioprotected metoprolol group and the control group. Results: A strong lineal correlation between transmural and lateral infarct extension was observed (r: 0.88, p Conclusions: The transmural and lateral extension of necrosis after myocardial infarction are directly correlated. A proven cardioprotective therapy prevented the necrosis progression in both dimensions. These findings cannot be explained by the classical wavefront theory, suggesting that the necrotic wavefront progresses also in the lateral direction.

Mitral valve prolapse (MVP) is a common disease affecting nearly 1 in 40 individuals. It is the leading surgical indication for mitral valve regurgitation. Despite a clear heritable component, the genetic etiology of non-syndromic MVP has remained elusive. Individuals from a large multigenerational family segregating non-syndromic MVP underwent capture sequencing of a previously linked interval on chromosome 11. We found a novel missense mutation in DCHS1, the human homologue of the Drosophila cell polarity gene dachsous (ds) that segregates with MVP in the family. The familial mutation reduced protein stability in zebrafish and cultured cells. Morpholino knockdown of zebrafish dachsous1b yielded a regurgitant atrioventricular canal defect that could be rescued by wild-type human DCHS1 but not by mRNA with the familial mutation. Adult haploinsufficient Dchs1 mice had anatomic and functional prolapse of thickened, elongated leaflets recapitulating the human MVP phenotype. Dchs1 haploinsufficiency was associated with developmental defects in valve shape, cell migration and patterning during fetal morphogenesis, suggesting cell polarity as a previously unrecognized facet of valve morphogenesis. Studies of downstream changes identified increased MAP kinase activities and α-SMA+ cells (myofibroblasts) in the valves preceding myxomatous degeneration; these suggest potential future directions for blunting disease progression. Additional genetic studies identified a second family with a DCHS1 mutation and a significantly increased burden of novel DCHS1 mutations in sporadic MVP cases Interdisciplinary studies strongly support DCHS1 as the first identified disease-causing gene for non-syndromic MVP and suggest potential mechanisms for modifying disease natural history.

We appreciate the interest of and comments by Drs Argulian and Messerli on our recently published study.1 Defining inclusion and exclusion criteria, along with dose selection of the administered pharmacological therapy, is critical in the early stages of a clinical trial design. The scientific method strongly recommends performing a profound bibliographic research in this regard, and for this purpose, we carefully reviewed previously conducted trials on the use of β-blockers in the setting of ST-segment–elevation acute myocardial infarction, taking note of the strengths and weaknesses of each of them. Thus, for the Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) trial, we randomized anterior myocardial infarctions revascularized by primary angioplasty in

Ischemic mitral regurgitation (IMR) relates to papillary muscle (PM) displacement caused by left ventricular (LV) distortion. We tested the hypothesis that displaced PMs can be repositioned by injection of polyvinyl-alcohol (PVA) polymer, a biologically inert material specially formulated to produce an encapsulated, stable, resilient gel once injected into the myocardium. The aim is to alter the compliance of infarcted myocardium and realign the displaced PMs. Methods : 9 sheep underwent circumflex branch ligation to produce acute IMR. PVA polymer was then injected by echo guidance into the myocardium underlying the infarcted PM. Hemodynamic data, EF, Elastance (Emax), preload-recruitable stroke work (PRSW), relaxation constant tau, and echo data were measured post IMR and post PVA injection. Results : One animal died after coronary ligation and 2 had no IMR; MR was moderate in the remaining 6. PVA injection decreased MR vena contracta from 5±0.4mm to 2±0.7mm (p Conclusions : PVA polymer injection can acutely reverse LV remodeling to reposition displaced PMs and decrease IMR without adverse effects on LV systolic or diastolic function. This new approach (to alter pathologic anatomy) offers an alternative for relieving IMR by correcting PM position, thus relieving tethering that causes IMR.