Rationale and design of the BA-SCAD (Beta-blockers and Antiplatelet agents in patients with Spontaneous Coronary Artery Dissection) randomized clinical trial.

INTRODUCTION Y OBJECTIVES: Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome. Most patients are empirically treated with beta-blockers and antiplatelet drugs. The Beta-blockers and Antiplatelet agents in patients with Spontaneous Coronary Artery Dissection (BA-SCAD) is an academic, pragmatic, prospective, randomized, open-label, blinded-endpoint clinical trial, performed under the auspices of the Spanish Society of Cardiology, to assess the efficacy of pharmacological therapy in patients with SCAD. METHODS: Using a 2 x 2 factorial design, 600 patients will be randomized (1:1/1:1) to: a) beta-blockers (yes/no) and b) "short" (1 month) vs "prolonged" (12 months) antiplatelet therapy. Only patients with preserved left ventricular ejection fraction will be randomized to beta-blockers (yes/no) because patients with reduced left ventricular ejection fraction will receive beta-blockers according to current guidelines. Similarly, only conservatively managed patients (ie, no coronary intervention) will be randomized to the antiplatelet stratum, as patients requiring coronary interventions will receive 1-year dual antiplatelet therapy. The primary efficacy endpoint includes a composite of death, myocardial infarction, stroke, coronary revascularization, recurrent SCAD, and unplanned hospitalization for acute coronary syndrome or heart failure at 1 year. The primary safety endpoint will be bleeding. All patients will be clinically followed up yearly. A comprehensive set of additional substudies (clinical, imaging, revascularization, biomarkers, inflammatory, immunologic, pharmacogenetics, and genetic) will be conducted to ensure a holistic view of this unique and challenging clinical entity. CONCLUSIONS: The results of the BA-SCAD randomized clinical trial will advance our knowledge in the treatment of patients with SCAD. The study was registered at ClinicalTrials.gov (Identifier: NCT04850417).

Metoprolol blunts the time-dependent progression of infarct size.

Early metoprolol administration protects against myocardial ischemia-reperfusion injury, but its effect on infarct size progression (ischemic injury) is unknown. Eight groups of pigs (total n = 122) underwent coronary artery occlusion of varying duration (20, 25, 30, 35, 40, 45, 50, or 60 min) followed by reperfusion. In each group, pigs were randomized to i.v. metoprolol (0.75 mg/kg) or vehicle (saline) 20 min after ischemia onset. The primary outcome measure was infarct size (IS) on day7 cardiac magnetic resonance (CMR) normalized to area at risk (AAR, measured by perfusion computed tomography [CT] during ischemia). Metoprolol treatment reduced overall mortality (10% vs 26%, p = 0.03) and the incidence and number of primary ventricular fibrillations during infarct induction. In controls, IS after 20-min ischemia was ≈ 5% of the area AAR. Thereafter, IS progressed exponentially, occupying almost all the AAR after 35 min of ischemia. Metoprolol injection significantly reduced the slope of IS progression (p = 0.004 for final IS). Head-to-head comparison (metoprolol treated vs vehicle treated) showed statistically significant reductions in IS at 30, 35, 40, and 50-min reperfusion. At 60-min reperfusion, IS was 100% of AAR in both groups. Despite more prolonged ischemia, metoprolol-treated pigs reperfused at 50 min had smaller infarcts than control pigs undergoing ischemia for 40 or 45 min and similar-sized infarcts to those undergoing 35-min ischemia. Day-45 LVEF was higher in metoprolol-treated vs vehicle-treated pigs (41.6% vs 36.5%, p = 0.008). In summary, metoprolol administration early during ischemia attenuates IS progression and reduces the incidence of primary ventricular fibrillation. These data identify metoprolol as an intervention ideally suited to the treatment of STEMI patients identified early in the course of infarction and requiring long transport times before primary angioplasty.

Definition of a cell surface signature for human cardiac progenitor cells after comprehensive comparative transcriptomic and proteomic characterization.

Adult cardiac progenitor/stem cells (CPC/CSC) are multipotent resident populations involved in cardiac homeostasis and heart repair. Assisted by complementary RNAseq analysis, we defined the fraction of the CPC proteome associable with specific functions by comparison with human bone marrow mesenchymal stem cells (MSC), the reference population for cell therapy, and human dermal fibroblasts (HDF), as a distant reference. Label-free proteomic analysis identified 526 proteins expressed differentially in CPC. iTRAQ analysis confirmed differential expression of a substantial proportion of those proteins in CPC relative to MSC, and systems biology analysis defined a clear overrepresentation of several categories related to enhanced angiogenic potential. The CPC plasma membrane compartment comprised 1,595 proteins, including a minimal signature of 167 proteins preferentially or exclusively expressed by CPC. CDH5 (VE-cadherin),  OX2G (OX-2 membrane glycoprotein; CD200), GPR4 (G protein-coupled receptor 4), CACNG7 (calcium voltage-gated channel auxiliary subunit gamma 7) and F11R (F11 receptor; junctional adhesion molecule A; JAM-A; CD321) were selected for validation. Their differential expression was confirmed both in expanded CPC batches and in early stages of isolation, particularly when compared against cardiac fibroblasts. Among them, GPR4 demonstrated the highest discrimination capacity between all cell lineages analyzed.

In vivo ratiometric optical mapping enables high-resolution cardiac electrophysiology in pig models.

AIMS: Cardiac optical mapping is the gold standard for measuring complex electrophysiology in ex vivo heart preparations. However, new methods for optical mapping in vivo have been elusive. We aimed at developing and validating an experimental method for performing in vivo cardiac optical mapping in pig models. METHODS AND RESULTS: First, we characterized ex vivo the excitation-ratiometric properties during pacing and ventricular fibrillation (VF) of two near-infrared voltage-sensitive dyes (di-4-ANBDQBS/di-4-ANEQ(F)PTEA) optimized for imaging blood-perfused tissue (n = 7). Then, optical-fibre recordings in Langendorff-perfused hearts demonstrated that ratiometry permits the recording of optical action potentials (APs) with minimal motion artefacts during contraction (n = 7). Ratiometric optical mapping ex vivo also showed that optical AP duration (APD) and conduction velocity (CV) measurements can be accurately obtained to test drug effects. Secondly, we developed a percutaneous dye-loading protocol in vivo to perform high-resolution ratiometric optical mapping of VF dynamics (motion minimal) using a high-speed camera system positioned above the epicardial surface of the exposed heart (n = 11). During pacing (motion substantial) we recorded ratiometric optical signals and activation via a 2D fibre array in contact with the epicardial surface (n = 7). Optical APs in vivo under general anaesthesia showed significantly faster CV [120 (63-138) cm/s vs. 51 (41-64) cm/s; P = 0.032] and a statistical trend to longer APD90 [242 (217-254) ms vs. 192 (182-233) ms; P = 0.095] compared with ex vivo measurements in the contracting heart. The average rate of signal-to-noise ratio (SNR) decay of di-4-ANEQ(F)PTEA in vivo was 0.0671 ± 0.0090 min-1. However, reloading with di-4-ANEQ(F)PTEA fully recovered the initial SNR. Finally, toxicity studies (n = 12) showed that coronary dye injection did not generate systemic nor cardiac damage, although di-4-ANBDQBS injection induced transient hypotension, which was not observed with di-4-ANEQ(F)PTEA. CONCLUSIONS: In vivo optical mapping using voltage ratiometry of near-infrared dyes enables high-resolution cardiac electrophysiology in translational pig models.

Implications of bipolar voltage mapping and magnetic resonance imaging resolution in biventricular scar characterization after myocardial infarction.

AIMS: We aimed to study the differences in biventricular scar characterization using bipolar voltage mapping compared with state-of-the-art in vivo delayed gadolinium-enhanced cardiac magnetic resonance (LGE-CMR) imaging and ex vivo T1 mapping. METHODS AND RESULTS: Ten pigs with established myocardial infarction (MI) underwent in vivo scar characterization using LGE-CMR imaging and high-density voltage mapping of both ventricles using a 3.5-mm tip catheter. Ex vivo post-contrast T1 mapping provided a high-resolution reference. Voltage maps were registered onto the left and right ventricular (LV and RV) endocardium, and epicardium of CMR-based geometries to compare voltage-derived scars with surface-projected 3D scars. Voltage-derived scar tissue of the LV endocardium and the epicardium resembled surface projections of 3D in vivo and ex vivo CMR-derived scars using 1-mm of surface projection distance. The thinner wall of the RV was especially sensitive to lower resolution in vivo LGE-CMR images, in which differences between normalized low bipolar voltage areas and CMR-derived scar areas did not decrease below a median of 8.84% [interquartile range (IQR) (3.58, 12.70%)]. Overall, voltage-derived scars and surface scar projections from in vivo LGE-CMR sequences showed larger normalized scar areas than high-resolution ex vivo images [12.87% (4.59, 27.15%), 18.51% (11.25, 24.61%), and 9.30% (3.84, 19.59%), respectively], despite having used optimized surface projection distances. Importantly, 43.02% (36.54, 48.72%) of voltage-derived scar areas from the LV endocardium were classified as non-enhanced healthy myocardium using ex vivo CMR imaging. CONCLUSION: In vivo LGE-CMR sequences and high-density voltage mapping using a conventional linear catheter fail to provide accurate characterization of post-MI scar, limiting the specificity of voltage-based strategies and imaging-guided procedures.

Nutritional preconditioning by marine omega-3 fatty acids in patients with ST-segment elevation myocardial infarction: A METOCARD-CNIC trial substudy.

BACKGROUND: Marine omega-3 eicosapentaenoic acid (EPA) is readily incorporated into cardiomyocyte membranes, partially displacing the omega-6 arachidonic acid (AA). Whereas AA is a substrate for pro-inflammatory eicosanoids, the release of EPA from cell membranes generates anti-inflammatory lipid mediators, contributing to the infarct-limiting effect observed experimental models. Clinical data are lacking. METHODS: In this observational study conducted in 100 patients with a reperfused anterior ST-elevation myocardial infarction (STEMI), at hospital admission we quantified by gas-chromatography the red blood cell proportions of AA, EPA, and the AA:EPA ratio, a valid surrogate for cardiomyocyte membrane content. Patients underwent cardiac magnetic resonance imaging in the acute phase (one week post-STEMI), and at long-term (6 months) follow-up. Infarct size (delayed gadolinium enhancement) and cardiac function (left ventricular ejection fraction [LVEF]) were correlated with exposures of interest by multivariate regression analysis. RESULTS: AA:EPA ratio directly related to acute infarct size (coefficient [95% CI]: 6.19 [1.68 to 10.69], P = 0.008) and inversely to long-term LVEF (coefficient [95% CI]: − 4.02 [− 7.15 to − 0.89], P = 0.012). EPA inversely related to acute infarct size (coefficient [95% CI]: − 6.58; [− 11.46 to − 1.70]; P = 0.009), while a direct association with LVEF at follow-up (coefficient [95% CI]: 3.67 [0.25 to 7.08]; P = 0.036) was observed. CONCLUSIONS: A low AA:EPA ratio in red blood cells at the time of STEMI is associated with smaller acute infarct size and preserved long-term ventricular function. Our results are consistent with prior work in experimental models and add to the notion of omega-3 fatty acids as a healthy fat. TRIAL REGISTRATION: http://www.clinicaltrials.gov/NCT01311700

Design and rationale of a multicentre, randomised, double-blind, placebo-controlled clinical trial to evaluate the effect of vitamin D on ventricular remodelling in patients with anterior myocardial infarction: the VITamin D in Acute Myocardial Infarction (VITDAMI) trial.

INTRODUCTION: Decreased plasma vitamin D (VD) levels are linked to cardiovascular damage. However, clinical trials have not demonstrated a benefit of VD supplements on left ventricular (LV) remodelling. Anterior ST-elevation acute myocardial infarction (STEMI) is the best human model to study the effect of treatments on LV remodelling. We present a proof-of-concept study that aims to investigate whether VD improves LV remodelling in patients with anterior STEMI. METHODS AND ANALYSIS: The VITamin D in Acute Myocardial Infarction (VITDAMI) trial is a multicentre, randomised, double-blind, placebo-controlled trial. 144 patients with anterior STEMI will be assigned to receive calcifediol 0.266 mg capsules (Hidroferol SGC)/15 days or placebo on a 2:1 basis during 12 months. PRIMARY OBJECTIVE: to evaluate the effect of calcifediol on LV remodelling defined as an increase in LV end-diastolic volume ≥10% (MRI). SECONDARY OBJECTIVES: change in LV end-diastolic and end-systolic volumes, ejection fraction, LV mass, diastolic function, sphericity index and size of fibrotic area; endothelial function; plasma levels of aminoterminal fragment of B-type natriuretic peptide, galectin-3 and monocyte chemoattractant protein-1; levels of calcidiol (VD metabolite) and other components of mineral metabolism (fibroblast growth factor-23 (FGF-23), the soluble form of its receptor klotho, parathormone and phosphate). Differences in the effect of VD will be investigated according to the plasma levels of FGF-23 and klotho. Treatment safety and tolerability will be assessed. This is the first study to evaluate the effect of VD on cardiac remodelling in patients with STEMI. ETHICS AND DISSEMINATION: This trial has been approved by the corresponding Institutional Review Board (IRB) and National Competent Authority (Agencia Española de Medicamentos y Productos Sanitarios (AEMPS)). It will be conducted in accordance with good clinical practice (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use - Good Clinical Practice (ICH-GCP)) requirements, ethical principles of the Declaration of Helsinki and national laws. The results will be submitted to indexed medical journals and national and international meetings. TRIAL REGISTRATION NUMBER: NCT02548364; Pre-results.