Javier Sánchez-González

Background: Plasma levels of haptoglobin and IgA2 (immunoglobulin A2) have recently been associated with subclinical atherosclerosis in European cohorts. We sought to validate these findings in an American population and to determine whether these biomarkers predict all‐cause mortality or major cardiovascular adverse events beyond traditional risk scales (Framingham Risk Score) or vascular imaging. Methods: We analyzed 5328 asymptomatic US adults (mean age 69 years, 56.9% women) from the BioImage study (A Clinical Study of Burden of Atherosclerotic Disease in an At‐Risk Population; NCT00738725). Subjects underwent carotid plaque burden assessment by ultrasound, coronary artery calcium by computed tomography, and baseline plasma haptoglobin and IgA2 levels measurement by immunoturbidimetry. The end point was a composite of major cardiovascular adverse events and all‐cause death during follow‐up. Results: Haptoglobin and IgA2 correlated significantly with carotid plaque burden and coronary artery calcium, independent of Framingham Risk Score. After a median follow‐up of 4.6 years, 466 participants (8.8%) experienced the composite outcome. Haptoglobin and IgA2 independently predicted the outcome, and associations remained significant after further adjustment for carotid plaque burden or coronary artery calcium. Similar results were observed for predictive capacity of high‐sensitivity C‐reactive protein. Individuals with high levels of all biomarkers (above the median) had a 2‐fold higher event rate compared with those with low levels. Combined biomarker assessment, albeit modestly, significantly improved risk prediction beyond Framingham Risk Score and imaging. Conclusions: Haptoglobin and IgA2 predict the composite outcome of major cardiovascular adverse events and all‐cause death, independently to Framingham Risk Score, in asymptomatic American adults. Their measurement, alone or in combination with imaging, may enhance cardiovascular risk stratification in primary prevention.

Purpose: First‐pass perfusion cardiovascular MR (FPP‐CMR) enables the non‐invasive diagnosis of microcirculation and coronary artery disease. In free‐breathing FPP‐CMR, motion correction is usually performed in the image domain, requiring an initial reconstruction. This fact hinders its use in model‐based and deep learning reconstructions, which present remarkable performance in obtaining high‐quality images from highly accelerated acquisitions. We address this challenge by estimating and correcting respiratory motion in free‐breathing FPP‐CMR directly in k ‐space. Methods: We propose K‐CC‐MoCo, an inter‐frame rigid motion correction approach formulated exclusively in k ‐space that handles dynamic contrast through a specifically targeted design of the normalized cross‐correlation (CC) objective function to deal with the dynamic contrast. In addition, an ROI‐based coil‐compression approach was employed to focus the optimization on the heart region. The proposed method was compared to state‐of‐the‐art image‐based registration using a digital phantom and real free‐breathing acquisitions with different accelerations. Results: The proposed k ‐space‐based method is approximately 2× faster and can correct respiratory motion even at high acceleration factors (up to 50×), where the image‐based method fails due to severe undersampling artifacts. Notably, after K‐CC‐MoCo, the time‐averaged images are visibly less blurred. Quantitative metrics (SSIM, etc.) support this conclusion. Conclusion: K‐CC‐MoCo outperforms image‐based correction in free‐breathing FPP‐CMR acquisitions accelerated up to 50×. Respiratory motion is estimated and corrected in k ‐space, enabling its use for model‐based and/or deep learning reconstructions from highly accelerated scans.

Background and Aims: Hypertension and valvular heart disease, both associated with left ventricular (LV) pressure overload, increase the risk of anthracycline cardiotoxicity. While epidemiologically established, the underlying mechanisms remain unclear, precluding identification of therapeutic targets. Methods: Two-month-old Yucatan pigs (males and females) underwent aortic banding to induce LV pressure overload or no operation. After 4 months, animals received a low-risk cumulative dose of doxorubicin (5 weekly 1 mg/kg intravenous injections) or vehicle, generating four groups: (i) healthy controls (no LV overload, no doxorubicin), (ii) Dox (doxorubicin, no LV overload), (iii) Banding (B: LV overload, no doxorubicin), and (iv) B + Dox (LV overload plus doxorubicin). Cardiac function, structure, and metabolism were assessed over 8 months by cardiac magnetic resonance, magnetic resonance spectroscopy, and hybrid positron emission tomography/computed tomography. At study end, proteomics and mitochondrial structure and function were analysed. Complementary in vivo and ex vivo studies examined the mechanistic role of energetic imbalance. Results: LV overload increased LV mass (P < .0001) and ejection fraction (P = .0081), with compensatory metabolic changes (drop in phosphocreatine (P = .022)). Low-risk Dox alone altered myocardial metabolism (increased glucose uptake, P = .014) but preserved cardiac function. In pigs with pre-existing LV pressure overload, doxorubicin increased mortality (P < .0001 vs all other groups), reduced left ventricular ejection fraction (LVEF) (P < .0001), increased fibrosis, and impaired mitochondrial respiration (P = .032). In HL-1 cardiomyocytes, reducing energy demand with mavacamten rescued cell viability under combined doxorubicin and hypertrophic stress. Conclusions: LV pressure overload increases myocardial susceptibility to anthracycline cardiotoxicity by inducing a high-energy-demand state. Anthracycline treatment, even at a low-risk dose, disrupts compensatory mechanisms in the pressure-overloaded heart, rapidly leading to cardiac dysfunction and heart failure. Preventive strategies targeting this metabolic vulnerability are urgently needed for patients with extant LV pressure overload (e.g. hypertension or valvular heart disease) who are undergoing anthracycline therapy.

Background: Noninvasive techniques for diagnosing combined postcapillary pulmonary hypertension (CpcPH) are unavailable. Objective: To assess the diagnostic performance of cardiac magnetic resonance (CMR)-based four-dimensional (4D)-flow analysis in identifying CpcPH. Methods: Prospective observational study of heart failure (HF) patients with suspected pulmonary hypertension (PH) who underwent simultaneous CMR and right heart catheterization. The 4D-flow biomarkers were calculated using an automatic pipeline. A predictive model including 4D-flow biomarkers associated with CpcPH with a p-value < 0.20 was built to determine the diagnostic performance of 4D-flow analysis to identify CpcPH. Results: A total of 46 HF patients (55.4 ± 14 years, 63% male) with confirmed PH (19 [41%] isolated postcapillary PH [IpcPH], 27 [59%] CpcPH) were included. No differences were found in baseline characteristics, echocardiography, or CMR anatomical and functional parameters, except for a higher Doppler-estimated systolic pulmonary pressure and larger pulmonary artery in CpcPH patients. The 4D-flow CMR analysis was performed in 31 patients (67%). The maximal peak velocity (67.1 [62.2–77.5] cm/s—IpcPH vs. 58.2 [45.8–66.0] cm/s—CpcPH; p = 0.021) and maximal helicity (339.9 [290.0–391.8]) cm/s²—IpcPH vs. 226.0 (173.5–343.7) cm/s²—CpcPH; p = 0.026) were significantly lower in patients with CpcPH. A maximal multivariable model including sex, maximal average, and peak velocities, Reynolds number, flow rate, and helicity showed fair diagnostic performance (area under the curve: 0.768 [95%-CI: 0.572–0.963]; sensitivity: 100%; specificity: 55%). Conclusions: In HF patients with PH, 4D-flow-derived maximal peak velocity and maximal helicity were significantly lower in CpcPH patients. A multiparametric model including maximal 4D-flow-derived biomarkers showed good diagnostic performance for identifying CpcPH.

Background: Electrophysiological characterization of ventricular tachycardia (VT) isthmus sites is complex and time‐consuming. We aimed at developing and validating a global mapping strategy during programmed ventricular stimulation (PVS) to reveal the underlying electrophysiological properties of the infarct‐related substrate and to enable identification of highly heterogeneous activation sites associated with protected VT isthmus sites. Methods and Results: Experimental study that included 22 pigs with established myocardial infarction undergoing in vivo characterization of the anatomical and functional myocardial substrate associated with potential arrhythmogenicity. High‐density sequential activation maps during ventricular pacing and VT were compared with single‐beat maps using a 64‐pole basket catheter positioned in the left ventricle. Further analyses were performed using a novel local activation time‐dispersion score to identify regional activation time heterogeneities on both baseline drive pacing and each of the extrastimuli of the PVS protocol. Basket catheter splines covered a median of 81.2% of the endocardial surface of the left ventricle. Basket‐catheter‐derived single‐beat activation maps (N=16) during pacing showed a linear relationship with high‐density sequential activation maps. Induction of ventricular arrhythmias was associated with higher local activation time‐dispersion score values on single‐beat global maps during PVS (N=6, 46 arrhythmia induction attempts). Single‐beat‐derived local activation time‐dispersion score maps during successive coupled extrastimuli of the PVS showed a progressive increase in the predictive performance to identify monomorphic VT isthmus sites within the scar region (area under the curve = 0.779 in S2, area under the curve = 0.859 in S4; N=7). Conclusions: Sixty‐four‐pole‐derived single‐beat local activation time‐dispersion score global maps during PVS identify infarct‐related endocardial regions with highly heterogeneous activation times that are associated with protected VT isthmus sites.

There is lack of agreement on late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) imaging processing for guiding ventricular tachycardia (VT) ablation. We aim at developing and validating a systematic processing approach on LGE-CMR images to identify VT corridors that contain critical VT isthmus sites. This is a translational study including 18 pigs with established myocardial infarction and inducible VT undergoing in vivo characterization of the anatomical and functional myocardial substrate associated with VT maintenance. Clinical validation was conducted in a multicentre series of 33 patients with ischaemic cardiomyopathy undergoing VT ablation. Three-dimensional LGE-CMR images were processed using systematic scanning of 15 signal intensity (SI) cut-off ranges to obtain surface visualization of all potential VT corridors. Analysis and comparisons of imaging and electrophysiological data were performed in individuals with full electrophysiological characterization of the isthmus sites of at least one VT morphology. In both the experimental pig model and patients undergoing VT ablation, all the electrophysiologically defined isthmus sites (n = 11 and n = 19, respectively) showed overlapping regions with CMR-based potential VT corridors. Such imaging-based VT corridors were less specific than electrophysiologically guided ablation lesions at critical isthmus sites. However, an optimized strategy using the 7 most relevant SI cut-off ranges among patients showed an increase in specificity compared to using 15 SI cut-off ranges (70 vs. 62%, respectively), without diminishing the capability to detect VT isthmus sites (sensitivity 100%). Systematic imaging processing of LGE-CMR sequences using several SI cut-off ranges may improve and standardize procedure planning to identify VT isthmus sites.

Background: Pseudo continuous arterial spin labelling (pcASL) is an MRI technique to quantify cerebral blood flow (CBF). Time encoded ASL (te‐ASL) is a multiple time‐point pcASL variant that by acquiring several post‐label delays (PLD) to have more accurate CBF estimation allowing to measure arterial‐transit time (ATT). The aim of this study was to assess the performance of te‐ASL in detecting CBF and ATT changes in the Alzheimer’s disease (AD) continuum.Method: The sample consisted of 59 subjects: 25 healthy controls (HC), 17 cognitively unimpaired individuals with positive cerebrospinal fluid (CSF) biomarkers (Ab4219pg/mL; Elecsys® ‐Roche Diagnostics) (preAD) and 17 patients with clinical diagnosis of AD (Ab42/p‐Tau₁₈₁ ratio oxford_asl toolbox in FSL. CBF and ATT maps were spatially normalized to the MNI, smoothed (12mm FWHM) and intensity normalized to the cerebellar gray matter. To detect patterns of lower CBF, voxel‐wise one way 3‐group ANOVA and post‐hoc paired t‐tests were performed using age and sex as confounders (SPM12; statistical threshold: p100 voxels (∼0.33cm³) in all analyses). We compared results with those obtained using a single PLD by computing CBF from the last PLD (perfusion block, nominal PLD time of 2000ms) of the te‐ASL schema.Result: Table 1 displays the descriptive statistics of the sample. Figure 1 shows that, with te‐ASL, AD patients displayed lower CBF (yellow) in extensive bilateral pareto‐temporal, cingulate and occipital areas. Preclinical AD participants showed an overlapping pattern (green), albeit reduced in extension. When using pcASL, the detected pattern of lower CBF in the AD group was less extended and did not overlap with that of the PreAD groups. No ATT differences were found associated to AD.Conclusion: te‐ASL was more sensitive to detect CBF differences across the AD continuum than single PLD ASL. The pattern of lower CBF in the AD group covered expected areas, and that in the preclinical AD group partially overlapped.

Background: MRI multi‐echo sequences can be used to compute quantitative R2 maps (1/T2). This pilot study aimed to determine whether R2 maps might offer relevant information on GM changes in AD continuum.Method: The sample consisted of 60 subjects: 20 healthy controls (HC), 20 cognitively unimpaired individuals with CSF Aβ_42/40181 ratio 3, TR = 2000ms, 32 echoes, TE: successive multiples of 9.3ms). R2 maps were obtained through linear regression of the logarithm of multi‐echo images. GM and R2 maps were spatially normalized to the MNI and smoothed (8mm FWHM). Voxel‐wise one‐way 3‐group ANOVA and post‐hoc paired t‐tests were performed on modulated GM (GMv) and R2 maps using age and sex as confounders and applying a common GM mask (SPM12, statistical threshold: p100 voxels (∼0.33cm³) in all analyses).Result: Table 1 displays the descriptive statistics of the sample. Figure 1 shows the results from post‐hoc two‐sample t‐tests between HC and AD for GMv and R2 maps. GMv decrements were mostly located in temporal and parietal regions, as expected. Differences in R2 maps covered those regions but also others such anterior cingulate. No differences were found between HC and preAD neither in R2 maps nor in GMv.Conclusion: Results might indicate that changes in R2 are not only reflecting atrophy but other undetermined tissular changes. Further research is warranted to further determine the mechanisms underlying R2 maps changes and the potential usefulness of R2 maps in AD characterization and diagnosis.

Background: Biochemical changes, which may precede morphological changes, could be of great relevance in profiling preclinical AD. We aimed to investigate metabolic changes using magnetic resonance spectroscopy (MRS) in three AD‐relevant regions: right hippocampus, right angular gyrus, and right precuneus, focusing on myoinositol due to its role in glial activity (osmoregulation‐neuroinflammation).Method: Three hundred sixty‐six participants from the ALFA+ cohort underwent three single‐voxel MRS (PRESS sequence, TR = 2000ms; TE = 100ms chosen to invert myoinositol peak for more precise quantitation; volume of interest (VOI): 20×20×20mm³ [25×20×16mm³ for hippocampus]). Figure 1 shows VOI location and MRS samples. Concentrations of N‐acetyl‐containing compounds (NAA) that is a neuronal marker, total creatine (Cr) related to brain energy, myoinositol (mI), choline‐containing compounds (Cho) related to cell proliferation, and glutamate/glutamine were calculated with LCModel in arbitrary units (using water reference) with the default settings and basis set adapted to the acquisition conditions. Concentrations were corrected for VOI CSF content. Remaining VOI gray matter percentage was used as a confounder in all analyses, jointly with age, sex, and APOE‐e4 status (carrier/non‐carrier). We investigated the correlation of MRS metabolite concentrations with CSF concentrations of Aβ42/40 and ptau‐181 as biomarkers for AD (Elecsys®; Roche Diagnostics). For completeness, we also checked the dependency of MRS metabolites on age. MRS not meeting QA criteria were discarded (Cramer‐Rao lower bounds >20 for any of the metabolites or imprecise VOI location). The statistical threshold was set to p181 levels in the angular gyrus. NAA was negatively associated with age on cortical regions, as well as Cr on the angular gyrus. Table 2 summarizes the main results.Conclusion: MRS allowed determination of differential metabolite changes in AD‐related regions in preclinical AD. Further research is warranted to better characterize the nature of these metabolic changes and determine their impact on longitudinal outcomes of these participants.