Subclinical atherosclerosis and brain health in midlife: Rationale and design of the PESA-Brain study.

RATIONALE: Cognitive decline and dementia have been reportedly linked to atherosclerosis, the main cause of cardiovascular disease. Cohort studies identifying early brain alterations associated with subclinical atherosclerosis are warranted to understand the potential of prevention strategies before cerebral damage becomes symptomatic and irreversible. METHODS & DESIGN: The Progression of Early Subclinical Atherosclerosis (PESA) study is a longitudinal observational cohort study that recruited 4,184 asymptomatic middle-aged individuals (40-54 years) in 2010 in Madrid (Spain) to thoroughly characterize subclinical atherosclerosis development over time. In this framework, the PESA-Brain study has been designed to identify early structural, functional and vascular brain changes associated with midlife atherosclerosis and cardiovascular risk factors. The PESA-Brain study targets 1,000 participants at the 10-year follow-up PESA visit and consists of thorough neuropsychological testing, advanced multimodal neuroimaging, and quantification of blood-based neuropathological biomarkers. PRIMARY HYPOTHESIS: We hypothesize that, in middle-age, the presence of cardiovascular risk factors and a high burden of subclinical atherosclerosis will be associated with structural, functional and vascular brain alterations, greater amyloid burden and subtle cognitive impairment. We further hypothesize that the link between subclinical atherosclerosis and poor brain health in midlife will be mediated by cerebrovascular pathology and intracranial atherosclerosis. ENROLLMENT DATES: The PESA-Brain study started in October 2020 and is estimated to be completed by December 2024. CONCLUSION: This study is in a unique position to unveil novel relationships between cardiovascular and brain alterations in the health-to-disease transition, which may have important implications for interventional and therapeutic approaches. CLINICALTRIALS: gov identifier: NCT01410318.

Metabolic changes contribute to maladaptive right ventricular hypertrophy in pulmonary hypertension beyond pressure overload: an integrative imaging and omics investigation.

Right ventricular (RV) failure remains the strongest determinant of survival in pulmonary hypertension (PH). We aimed to identify relevant mechanisms, beyond pressure overload, associated with maladaptive RV hypertrophy in PH. To separate the effect of pressure overload from other potential mechanisms, we developed in pigs two experimental models of PH (M1, by pulmonary vein banding and M2, by aorto-pulmonary shunting) and compared them with a model of pure pressure overload (M3, pulmonary artery banding) and a sham-operated group. Animals were assessed at 1 and 8 months by right heart catheterization, cardiac magnetic resonance and blood sampling, and myocardial tissue was analyzed. Plasma unbiased proteomic and metabolomic data were compared among groups and integrated by an interaction network analysis. A total of 33 pigs completed follow-up (M1, n = 8; M2, n = 6; M3, n = 10; and M0, n = 9). M1 and M2 animals developed PH and reduced RV systolic function, whereas animals in M3 showed increased RV systolic pressure but maintained normal function. Significant plasma arginine and histidine deficiency and complement system activation were observed in both PH models (M1&M2), with additional alterations to taurine and purine pathways in M2. Changes in lipid metabolism were very remarkable, particularly the elevation of free fatty acids in M2. In the integrative analysis, arginine-histidine-purines deficiency, complement activation, and fatty acid accumulation were significantly associated with maladaptive RV hypertrophy. Our study integrating imaging and omics in large-animal experimental models demonstrates that, beyond pressure overload, metabolic alterations play a relevant role in RV dysfunction in PH.

Adolescent Reference Values for MR-Derived Biventricular Strain Obtained Using Feature-Tracking and Myocardial Tagging.

BACKGROUND: Myocardial strain is a promising marker for the detection of early left or right ventricular (LV or RV) dysfunction in pediatric populations. The reference standard for MR strain measurement is myocardial tagging (MT); however, MT has limited clinical utility because the additional acquisitions needed are time-consuming. In contrast, MR-feature tracking (FT) allows strain quantification from routinely acquired cine sequences. Studies providing reference values obtained with both FT and MT for adolescents are lacking. PURPOSE: To use MR-FT and MT to define sex-specific LV and RV strain reference values for adolescents. STUDY TYPE: Cross-sectional, prospective. POPULATION: One hundred twenty-three adolescents aged 15-18 years (52% girls) without known cardiovascular disease. FIELD STRENGTH/SEQUENCE: Balanced steady-state free-precession sequence for FT analysis and a spatial modulation of magnetization hybrid TFE-EPI sequence for MT acquisitions at 3.0-T. ASSESSMENT: Segment Medviso software was used to obtain longitudinal (LS) and circumferential (CS) strain for both ventricles, and radial strain (RS) for LV. STATISTICAL TESTS: The Student t-test was used for between-sex comparisons of continuous variables. Sex-specific percentiles were calculated using the weighted average method. Intraobserver and interobserver agreement was assessed in 30 randomly selected studies using intraclass correlation coefficients (ICC). A P-value <0.05 was considered statistically significant. RESULTS: FT-derived LVLS and LVCS were significantly higher in girls than in boys (-19.8% vs. -17.8% and -22.2% vs. -21.0%, respectively), as they were with MT (LVLS: -18.1% vs. -16.8%; LVCS: -20.8% vs. -19.7%). FT-LVRS was higher in girls than in boys (44.8% vs. 35.1%), while MT-LVRS was the opposite (18.6% vs. 22.7%). FT-RVLS was higher in girls (-23.4% vs. -21.3%), but there were no between-sex differences in MT-derived RVLS or RVCS. ICC values for intraobserver agreement were ≥0.89, whereas for interobserver agreement were <0.80 for MT-LVRS and ≥0.80 for all remaining parameters. DATA CONCLUSION: This study provides sex-specific reference biventricular strain values obtained with MR-MT and MR-FT for adolescents aged 15-18 years. MR-FT may be a valid method for obtaining strain values in pediatric populations. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 3.

Novel systematic processing of cardiac magnetic resonance imaging identifies target regions associated with infarct-related ventricular tachycardia.

AIMS: 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. METHODS AND RESULTS: 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%). CONCLUSION: Systematic imaging processing of LGE-CMR sequences using several SI cut-off ranges may improve and standardize procedure planning to identify VT isthmus sites.

Time-encoded ASL reveals lower cerebral blood flow in the early AD continuum.

INTRODUCTION: Cerebral blood flow (CBF) is reduced in cognitively impaired (CI) Alzheimer's disease (AD) patients. We checked the sensitivity of time-encoded arterial spin labeling (te-ASL) in measuring CBF alterations in individuals with positive AD biomarkers and associations with relevant biomarkers in cognitively unimpaired (CU) individuals. METHODS: We compared te-ASL with single-postlabel delay (PLD) ASL in measuring CBF in 59 adults across the AD continuum, classified as CU amyloid beta (Aß) negative (-), CU Aß positive (+), and CI Aß+. We sought associations of CBF with biomarkers of AD, cerebrovascular disease, synaptic dysfunction, neurodegeneration, and cognition in CU participants. RESULTS: te-ASL was more sensitive at detecting CBF reduction in the CU Aß+ and CI Aß+ groups. In CU participants, lower CBF was associated with altered biomarkers of Aß, tau, synaptic dysfunction, and neurodegeneration. DISCUSSION: CBF reduction occurs early in the AD continuum. te-ASL is more sensitive than single-PLD ASL at detecting CBF changes in AD. HIGHLIGHTS: Lower CBF can be detected in CU subjects in the early AD continuum. te-ASL is more sensitive than single-PLD ASL at detecting CBF alterations in AD. CBF is linked to biomarkers of AD, synaptic dysfunction, and neurodegeneration.

Bone marrow activation in response to metabolic syndrome and early atherosclerosis.

AIMS: Experimental studies suggest that increased bone marrow (BM) activity is involved in the association between cardiovascular risk factors and inflammation in atherosclerosis. However, human data to support this association are sparse. The purpose was to study the association between cardiovascular risk factors, BM activation, and subclinical atherosclerosis. METHODS AND RESULTS: Whole body vascular 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI) was performed in 745 apparently healthy individuals [median age 50.5 (46.8-53.6) years, 83.8% men] from the Progression of Early Subclinical Atherosclerosis (PESA) study. Bone marrow activation (defined as BM 18F-FDG uptake above the median maximal standardized uptake value) was assessed in the lumbar vertebrae (L3-L4). Systemic inflammation was indexed from circulating biomarkers. Early atherosclerosis was evaluated by arterial metabolic activity by 18F-FDG uptake in five vascular territories. Late atherosclerosis was evaluated by fully formed plaques on MRI. Subjects with BM activation were more frequently men (87.6 vs. 80.0%, P = 0.005) and more frequently had metabolic syndrome (MetS) (22.2 vs. 6.7%, P < 0.001). Bone marrow activation was significantly associated with all MetS components. Bone marrow activation was also associated with increased haematopoiesis-characterized by significantly elevated leucocyte (mainly neutrophil and monocytes) and erythrocyte counts-and with markers of systemic inflammation including high-sensitivity C-reactive protein, ferritin, fibrinogen, P-selectin, and vascular cell adhesion molecule-1. The associations between BM activation and MetS (and its components) and increased erythropoiesis were maintained in the subgroup of participants with no systemic inflammation. Bone marrow activation was significantly associated with high arterial metabolic activity (18F-FDG uptake). The co-occurrence of BM activation and arterial 18F-FDG uptake was associated with more advanced atherosclerosis (i.e. plaque presence and burden). CONCLUSION: In apparently healthy individuals, BM 18F-FDG uptake is associated with MetS and its components, even in the absence of systemic inflammation, and with elevated counts of circulating leucocytes. Bone marrow activation is associated with early atherosclerosis, characterized by high arterial metabolic activity. Bone marrow activation appears to be an early phenomenon in atherosclerosis development.[Progression of Early Subclinical Atherosclerosis (PESA); NCT01410318].

Intravenous metoprolol during ongoing STEMI ameliorates markers of ischemic injury: a METOCARD-CNIC trial electrocardiographic study.

Besides its protective effect against neutrophil-mediated injury at reperfusion, intravenous (IV) metoprolol was recently shown to reduce the progression of ischemic injury in a pig model of ST-segment elevation myocardial infarction (STEMI). Here, we tested the hypothesis that IV metoprolol administration in humans with ongoing STEMI blunts the time­dependent progression of ischemic injury assessed by serial electrocardiogram (ECG) evaluations before reperfusion. The METOCARD-CNIC trial randomized 270 anterior STEMI patients to IV metoprolol or control before reperfusion by percutaneous coronary intervention (PCI). In 139 patients (69 IV metoprolol, 70 controls), two ECGs were available (ECG-1 before randomization, ECG-2 pre-PCI). Between-group ECG differences were analyzed using univariate and multivariate regression models. No significant between-group differences were observed on ECG-1. On ECG-2, patients who received IV metoprolol had a narrower QRS than those in the control group (84 ms vs. 90 ms, p = 0.029), a lower prevalence of QRS distortion (10% vs. 26%, p = 0.017), and a lower sum of anterior and total ST-segment elevation (10.1 mm vs. 13.6 mm, p = 0.014 and 10.4 mm vs. 14.0 mm, p = 0.015, respectively). Adjusted analysis revealed similar results. Significant associations were observed between ECG-2 variables and cardiac magnetic resonance imaging measurements (extent of myocardial edema, infarct size, microvascular obstruction, and left-ventricular ejection fraction) after STEMI. In summary, IV metoprolol administration before reperfusion ameliorates ECG markers of myocardial ischemia in anterior STEMI patients. These data confirm that IV metoprolol is able to reduce ischemic injury and highlight the ability of ECG analysis to provide relevant real-time information on the effect of cardioprotective therapies before reperfusion.

Influence of the arterial input sampling location on the diagnostic accuracy of cardiovascular magnetic resonance stress myocardial perfusion quantification.

BACKGROUND: Quantification of myocardial blood flow (MBF) and myocardial perfusion reserve (MPR) by cardiovascular magnetic resonance (CMR) perfusion requires sampling of the arterial input function (AIF). While variation in the AIF sampling location is known to impact quantification by CMR and positron emission tomography (PET) perfusion, there is no evidence to support the use of a specific location based on their diagnostic accuracy in the detection of coronary artery disease (CAD). This study aimed to evaluate the accuracy of stress MBF and MPR for different AIF sampling locations for the detection of abnormal myocardial perfusion with expert visual assessment as the reference. METHODS: Twenty-five patients with suspected or known CAD underwent vasodilator stress-rest perfusion with a dual-sequence technique at 3T. A low-resolution slice was acquired in 3-chamber view to allow AIF sampling at five different locations: left atrium (LA), basal left ventricle (bLV), mid left ventricle (mLV), apical left ventricle (aLV) and aortic root (AoR). MBF and MPR were estimated at the segmental level using Fermi function-constrained deconvolution. Segments were scored as having normal or abnormal perfusion by visual assessment and the diagnostic accuracy of stress MBF and MPR for each location was evaluated using receiver operating characteristic curve analysis. RESULTS: In both normal (300 out of 400, 75 %) and abnormal segments, rest MBF, stress MBF and MPR were significantly different across AIF sampling locations (p < 0.001). Stress MBF for the AoR (normal: 2.42 (2.15-2.84) mL/g/min; abnormal: 1.71 (1.28-1.98) mL/g/min) had the highest diagnostic accuracy (sensitivity 80 %, specificity 85 %, area under the curve 0.90; p < 0.001 versus stress MBF for all other locations including bLV: normal: 2.78 (2.39-3.14) mL/g/min; abnormal: 2.22 (1.83-2.48) mL/g/min; sensitivity 91 %, specificity 63 %, area under the curve 0.81) and performed better than MPR for the LV locations (p < 0.01). MPR for the AoR (normal: 2.43 (1.95-3.14); abnormal: 1.58 (1.34-1.90)) was not superior to MPR for the bLV (normal: 2.59 (2.04-3.20); abnormal: 1.69 (1.36-2.14); p = 0.717). CONCLUSIONS: The AIF sampling location has a significant impact on MBF and MPR estimates by CMR perfusion, with AoR-based stress MBF comparing favorably to that for the current clinical reference bLV.

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.

Translational large animal model of hibernating myocardium: characterization by serial multimodal imaging.

Nonrevascularizable coronary artery disease is a frequent cause of hibernating myocardium leading to heart failure (HF). Currently, there is a paucity of therapeutic options for patients with this condition. There is a lack of animal models resembling clinical features of hibernating myocardium. Here we present a large animal model of hibernating myocardium characterized by serial multimodality imaging. Yucatan minipigs underwent a surgical casein ameroid implant around the proximal left anterior descending coronary artery (LAD), resulting in a progressive obstruction of the vessel. Pigs underwent serial multimodality imaging including invasive coronary angiography, cardiac magnetic resonance (CMR), and hybrid 18F-Fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT). A total of 43 pigs were operated on and were followed for 120 ± 37 days with monthly multimodality imaging. 24 pigs (56%) died during the follow-up. Severe LAD luminal stenosis was documented in all survivors. In the group of 19 long-term survivors, 17 (90%) developed left ventricular systolic dysfunction [median LVEF of 35% (IQR 32.5-40.5%)]. In 17/17, at-risk territory was viable on CMR and 14 showed an increased glucose uptake in the at-risk myocardium on 18FDG-PET/CT. The present pig model resembles most of the human hibernated myocardium characteristics and associated heart failure (systolic dysfunction, viable myocardium, and metabolic switch to glucose). This human-like model might be used to test novel interventions for nonrevascularizable coronary artery disease and ischemia heart failure as a previous stage to clinical trials.

Higher-order diffusion MRI characterization of mesorectal lymph nodes in rectal cancer.

PURPOSE: Mesorectal lymph node staging plays an important role in treatment decision making. Here, we explore the benefit of higher-order diffusion MRI models accounting for non-Gaussian diffusion effects to classify mesorectal lymph nodes both 1) ex vivo at ultrahigh field correlated with histology and 2) in vivo in a clinical scanner upon patient staging. METHODS: The preclinical investigation included 54 mesorectal lymph nodes, which were scanned at 16.4 T with an extensive diffusion MRI acquisition. Eight diffusion models were compared in terms of goodness of fit, lymph node classification ability, and histology correlation. In the clinical part of this study, 10 rectal cancer patients were scanned with diffusion MRI at 1.5 T, and 72 lymph nodes were analyzed with Apparent Diffusion Coefficient (ADC), Intravoxel Incoherent Motion (IVIM), Kurtosis, and IVIM-Kurtosis. RESULTS: Compartment models including restricted and anisotropic diffusion improved the preclinical data fit, as well as the lymph node classification, compared to standard ADC. The comparison with histology revealed only moderate correlations, and the highest values were observed between diffusion anisotropy metrics and cell area fraction. In the clinical study, the diffusivity from IVIM-Kurtosis was the only metric showing significant differences between benign (0.80 ± 0.30 µm2 /ms) and malignant (1.02 ± 0.41 µm2 /ms, P = .03) nodes. IVIM-Kurtosis also yielded the largest area under the receiver operating characteristic curve (0.73) and significantly improved the node differentiation when added to the standard visual analysis by experts based on T2 -weighted imaging. CONCLUSION: Higher-order diffusion MRI models perform better than standard ADC and may be of added value for mesorectal lymph node classification in rectal cancer patients.

Left ventricular functional recovery of infarcted and remote myocardium after ST-segment elevation myocardial infarction (METOCARD-CNIC randomized clinical trial substudy).

BACKGROUND: We aimed to evaluate the effect of early intravenous metoprolol treatment, microvascular obstruction (MVO), intramyocardial hemorrhage (IMH) and adverse left ventricular (LV) remodeling on the evolution of infarct and remote zone circumferential strain after acute anterior ST-segment elevation myocardial infarction (STEMI) with feature-tracking cardiovascular magnetic resonance (CMR). METHODS: A total of 191 patients with acute anterior STEMI enrolled in the METOCARD-CNIC randomized clinical trial were evaluated. LV infarct zone and remote zone circumferential strain were measured with feature-tracking CMR at 1 week and 6 months after STEMI. RESULTS: In the overall population, the infarct zone circumferential strain significantly improved from 1 week to 6 months after STEMI (- 8.6 ± 9.0% to - 14.5 ± 8.0%; P < 0.001), while no changes in the remote zone strain were observed (- 19.5 ± 5.9% to - 19.2 ± 3.9%; P = 0.466). Patients who received early intravenous metoprolol had significantly more preserved infarct zone circumferential strain compared to the controls at 1 week (P = 0.038) and at 6 months (P = 0.033) after STEMI, while no differences in remote zone strain were observed. The infarct zone circumferential strain was significantly impaired in patients with MVO and IMH compared to those without (P < 0.001 at 1 week and 6 months), however it improved between both time points regardless of the presence of MVO or IMH (P < 0.001). In patients who developed adverse LV remodeling (defined as ≥ 20% increase in LV end-diastolic volume) remote zone circumferential strain worsened between 1 week and 6 months after STEMI (P = 0.036), while in the absence of adverse LV remodeling no significant changes in remote zone strain were observed. CONCLUSIONS: Regional LV circumferential strain with feature-tracking CMR allowed comprehensive evaluation of the sequelae of an acute STEMI treated with primary percutaneous coronary intervention and demonstrated long-lasting cardioprotective effects of early intravenous metoprolol. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01311700. Registered 8 March 2011 - Retrospectively registered.

Single breath-hold saturation recovery 3D cardiac T1 mapping via compressed SENSE at 3T.

OBJECTIVES: To propose and validate a novel imaging sequence that uses a single breath-hold whole-heart 3D T1 saturation recovery compressed SENSE rapid acquisition (SACORA) at 3T. METHODS: The proposed sequence combines flexible saturation time sampling, compressed SENSE, and sharing of saturation pulses between two readouts acquired at different RR intervals. The sequence was compared with a 3D saturation recovery single-shot acquisition (SASHA) implementation with phantom and in vivo experiments (pre and post contrast; 7 pigs) and was validated against the reference inversion recovery spin echo (IR-SE) sequence in phantom experiments. RESULTS: Phantom experiments showed that the T1 maps acquired by 3D SACORA and 3D SASHA agree well with IR-SE. In vivo experiments showed that the pre-contrast and post-contrast T1 maps acquired by 3D SACORA are comparable to the corresponding 3D SASHA maps, despite the shorter acquisition time (15s vs. 188s, for a heart rate of 60 bpm). Mean septal pre-contrast T1 was 1453 ± 44 ms with 3D SACORA and 1460 ± 60 ms with 3D SASHA. Mean septal post-contrast T1 was 824 ± 66 ms and 824 ± 60 ms. CONCLUSION: 3D SACORA acquires 3D T1 maps in 15 heart beats (heart rate, 60 bpm) at 3T. In addition to its short acquisition time, the sequence achieves good T1 estimation precision and accuracy.

Effect of pulmonary artery denervation in postcapillary pulmonary hypertension: results of a randomized controlled translational study.

There is scarce evidence for pulmonary artery denervation (PADN) as a potential treatment for chronic postcapillary pulmonary hypertension (PH). We aimed to perform a proof-of-concept of PADN in a translational model of chronic PH. Nineteen pigs with chronic postcapillary PH (secondary to pulmonary vein banding) were randomized to surgical-PADN (using bipolar radiofrequency clamps) or sham procedure. Additionally, 6 healthy animals underwent percutaneous-PADN to compare the pulmonary artery (PA) lesion generated with both approaches. In the surgical-PADN arm, hemodynamic evaluation and cardiac magnetic resonance (CMR) were performed at baseline and at 2 and 3-month follow-up. Histological assessment was carried out at the completion of the protocol. Eighteen pigs (6 following surgical-PADN, 6 sham and 6 percutaneous-PADN) completed the protocol. A complete transmural PA lesion was demonstrated using surgical clamps, whereas only focal damage to adventitial fibers was observed after percutaneous-PADN. In the surgical-PADN arm, the hemodynamic profile did not significantly differ between groups neither at baseline [mean pulmonary artery pressure (mPAP) median values of 32.0 vs. 27.5 mmHg, P = 0.394 and indexed pulmonary vascular resistance (iPVR) 5.9 vs. 4.7 WU m2, P = 0.394 for PADN/sham groups, respectively] nor at any follow-up (mPAP of 35.0 vs. 35.0 mmHg, P = 0.236 and iPVR of 8.3 vs. 6.7 WU m2, P = 0.477 at third month in PADN/sham groups, respectively). Surgical-PADN was not associated with any benefit in RV anatomy or function on CMR/histology. In a large-animal model of chronic postcapillary PH, transmural PADN with surgical clamps was associated with a neutral pulmonary hemodynamic effect.

Effect of Ischemia Duration and Protective Interventions on the Temporal Dynamics of Tissue Composition After Myocardial Infarction.

RATIONALE: The impact of cardioprotective strategies and ischemia duration on postischemia/reperfusion (I/R) myocardial tissue composition (edema, myocardium at risk, infarct size, salvage, intramyocardial hemorrhage, and microvascular obstruction) is not well understood. OBJECTIVE: To study the effect of ischemia duration and protective interventions on the temporal dynamics of myocardial tissue composition in a translational animal model of I/R by the use of state-of-the-art imaging technology. METHODS AND RESULTS: Four 5-pig groups underwent different I/R protocols: 40-minute I/R (prolonged ischemia, controls), 20-minute I/R (short-duration ischemia), prolonged ischemia preceded by preconditioning, or prolonged ischemia followed by postconditioning. Serial cardiac magnetic resonance (CMR)-based tissue characterization was done in all pigs at baseline and at 120 minutes, day 1, day 4, and day 7 after I/R. Reference myocardium at risk was assessed by multidetector computed tomography during the index coronary occlusion. After the final CMR, hearts were excised and processed for water content quantification and histology. Five additional healthy pigs were euthanized after baseline CMR as reference. Edema formation followed a bimodal pattern in all 40-minute I/R pigs, regardless of cardioprotective strategy and the degree of intramyocardial hemorrhage or microvascular obstruction. The hyperacute edematous wave was ameliorated only in pigs showing cardioprotection (ie, those undergoing short-duration ischemia or preconditioning). In all groups, CMR-measured edema was barely detectable at 24 hours postreperfusion. The deferred healing-related edematous wave was blunted or absent in pigs undergoing preconditioning or short-duration ischemia, respectively. CMR-measured infarct size declined progressively after reperfusion in all groups. CMR-measured myocardial salvage, and the extent of intramyocardial hemorrhage and microvascular obstruction varied dramatically according to CMR timing, ischemia duration, and cardioprotective strategy. CONCLUSIONS: Cardioprotective therapies, duration of index ischemia, and the interplay between these greatly influence temporal dynamics and extent of tissue composition changes after I/R. Consequently, imaging techniques and protocols for assessing edema, myocardium at risk, infarct size, salvage, intramyocardial hemorrhage, and microvascular obstruction should be standardized accordingly.

Three-dimensional cardiac fibre disorganization as a novel parameter for ventricular arrhythmia stratification after myocardial infarction.

AIMS: Myocardial infarction (MI) alters cardiac fibre organization with unknown consequences on ventricular arrhythmia. We used diffusion tensor imaging (DTI) of three-dimensional (3D) cardiac fibres and scar reconstructions to identify the main parameters associated with ventricular arrhythmia inducibility and ventricular tachycardia (VT) features after MI. METHODS AND RESULTS: Twelve pigs with established MI and three controls underwent invasive electrophysiological characterization of ventricular arrhythmia inducibility and VT features. Animal-specific 3D scar and myocardial fibre distribution were obtained from ex vivo high-resolution contrast-enhanced T1 mapping and DTI sequences. Diffusion tensor imaging-derived parameters significantly different between healthy and scarring myocardium, scar volumes, and left ventricular ejection fraction (LVEF) were included for arrhythmia risk stratification and correlation analyses with VT features. Ventricular fibrillation (VF) was the only inducible arrhythmia in 4 out of 12 infarcted pigs and all controls. Ventricular tachycardia was also inducible in the remaining eight pigs during programmed ventricular stimulation. A DTI-based 3D fibre disorganization index (FDI) showed higher disorganization within dense scar regions of VF-only inducible pigs compared with VT inducible animals (FDI: 0.36; 0.36-0.37 vs. 0.32; 0.26-0.33, respectively, P = 0.0485). Ventricular fibrillation induction required lower programmed stimulation aggressiveness in VF-only inducible pigs than VT inducible and control animals. Neither LVEF nor scar volumes differentiated between VF and VT inducible animals. Re-entrant VT circuits were localized within areas of highly disorganized fibres. Moreover, the FDI within heterogeneous scar regions was associated with the median VT cycle length per animal (R2 = 0.5320). CONCLUSION: The amount of scar-related cardiac fibre disorganization in DTI sequences is a promising approach for ventricular arrhythmia stratification after MI.

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.

Dynamic Edematous Response of the Human Heart to Myocardial Infarction: Implications for Assessing Myocardial Area at Risk and Salvage.

BACKGROUND: Clinical protocols aimed to characterize the post-myocardial infarction (MI) heart by cardiac magnetic resonance (CMR) need to be standardized to take account of dynamic biological phenomena evolving early after the index ischemic event. Here, we evaluated the time course of edema reaction in patients with ST-segment-elevation MI by CMR and assessed its implications for myocardium-at-risk (MaR) quantification both in patients and in a large-animal model. METHODS: A total of 16 patients with anterior ST-segment-elevation MI successfully treated by primary angioplasty and 16 matched controls were prospectively recruited. In total, 94 clinical CMR examinations were performed: patients with ST-segment-elevation MI were serially scanned (within the first 3 hours after reperfusion and at 1, 4, 7, and 40 days), and controls were scanned only once. T2 relaxation time in the myocardium (T2 mapping) and the extent of edema on T2-weighted short-tau triple inversion-recovery (ie, CMR-MaR) were evaluated at all time points. In the experimental study, 20 pigs underwent 40-minute ischemia/reperfusion followed by serial CMR examinations at 120 minutes and 1, 4, and 7 days after reperfusion. Reference MaR was assessed by contrast-multidetector computed tomography during the index coronary occlusion. Generalized linear mixed models were used to take account of repeated measurements. RESULTS: In humans, T2 relaxation time in the ischemic myocardium declines significantly from early after reperfusion to 24 hours, and then increases up to day 4, reaching a plateau from which it decreases from day 7. Consequently, edema extent measured by T2-weighted short-tau triple inversion-recovery (CMR-MaR) varied with the timing of the CMR examination. These findings were confirmed in the experimental model by showing that only CMR-MaR values for day 4 and day 7 postreperfusion, coinciding with the deferred edema wave, were similar to values measured by reference contrast-multidetector computed tomography. CONCLUSIONS: Post-MI edema in patients follows a bimodal pattern that affects CMR estimates of MaR. Dynamic changes in post-ST-segment-elevation MI edema highlight the need for standardization of CMR timing to retrospectively delineate MaR and quantify myocardial salvage. According to the present clinical and experimental data, a time window between days 4 and 7 post-MI seems a good compromise solution for standardization. Further studies are needed to study the effect of other factors on these variables.

A new dimensional-reducing variable obtained from original inflammatory scores is highly associated to morbidity after curative surgery for colorectal cancer.

PURPOSE: Several scores have been developed to define the inflammatory status of oncological patients. We suspect they share iterative information. Our hypothesis is that we may summarise their information into one or two new variables which will be independent. This will help us to predict, more accurately, which patients are at an increased risk of suffering postoperative complications after curative surgery for CRC. METHODS: Observational prospective study with those patients undergoing curative surgery for CRC between September 2015 and February 2017. We analysed the influence of inflammatory scores (PNI, GPS, NLR, PLR) on postoperative morbidity (overall and severe complications, anastomotic leakage and reoperation). RESULTS: Finally, 168 patients were analysed. We checked these four original scores are interrelated among them. Using a complex and innovative statistical method, we created two new independent variables (resultant A and resultant B) which resume the information coming from them. One of these two new variables (resultant A) was statistically associated to overall complications (OR, 2.239; 95% CI, 1.541-3.253; p = 0.0001), severe complications (OR, 1.773; 95% CI, 1.129-2.785; p = 0.013), anastomotic leakage (OR, 3.208; 95% CI, 1.416-7.268; p = 0.005) and reoperation (OR, 2.349; 95% CI, 1.281-4.305; p = 0.006). CONCLUSIONS: We evinced the four original scores we used share redundant information. We created two new independent new variables which resume their information. In our sample of patients, one of these variables turned out to be a great predictive factor for the four complications we analysed.