Background: While prolonged pro-inflammatory/delayed anti-inflammatory macrophage (MΦ) polarization post-MI promotes adverse cardiac remodeling, the impact of mast cell (MC) polarization on remodeling remains unknown. Timely MΦ infiltration is crucial for beneficial remodeling, but PET/MRI studies in reperfused MI revealed that microvascular obstruction (MVO) impairs early local MΦ influx, delaying “good” inflammation and promoting adverse remodeling. Whether MC degranulation contributes to the formation of MVO, thus delaying “good” inflammation in reperfused MIs is unknown. Purpose: Histamine, a product of MCs, can act as a vasodilator or vasoconstrictor depending on vessel type. Notably, autopsy reports have shown that in the number of degranulated MCs is increased at the site of vasospasm in patients with variant angina, indicating a role for histamine in coronary spasm. In the present study we tested whether loratadine, a commonly used over-the-counter antihistamine and MC stabilizer, attenuates MVO and augments early inflammation in reperfused MIs. Methods: Twelve pigs underwent a closed-chest 90-minute ischemia-reperfusion of the left anterior descending artery and were followed through Day 5-Week 8 with LGE, cine and 18 FDG-PET/MRI. Six pigs (LORA group) were treated with loratadine (10 mg/day PO), while six remained untreated (CTRL group). Remote myocardium FDG uptake was suppressed by 48-hour ketogenic diet, 12-hour fasting, and 2000 U heparin 15 minutes before FDG injection. LGE and PET images were fused to compute target-to-background ratio (TBR) between infarct and remote. Results: Comparing CTRL to LORA at Day 5, there was: (i) no difference in infarct size (IS) (CTRL=26.8±6.8%LV;LORA=20.9±6.2%LV; p=0.08); (ii) a reduction of MVO in LORA (p=0.02)(Fig 1a/b); (iii) an increased TBR in LORA (p=0.04)(Fig 1c); (iv) no difference in end-systolic volume (ESV: p=0.29) and end-diastolic volume (EDV: p=0.22)(Fig 2). Comparing the groups at Week 8, there was: (i) no difference in IS (CTRL=12.8±2.9%LV; LORA=9.5±2.2%LV; p=0.05); (ii) no difference in TBR (p=0.41); (iii) decreased ESV and EDV in LORA (ESV: p=0.03; EDV: p=0.02). Conclusion: Our seemingly paradoxical findings of MC stabilizer-augmented initial inflammatory response and lower subsequent ventricular volumes indicate that fine-tuning of MC degranulation post-MI could be a novel therapeutic strategy for optimized remodeling of reperfused MIs.

Background: Fatty degeneration of infarcted myocardium, also known as lipomatous metaplasia (LM), is a highly prevalent phenomenon linked with high incidence of major adverse cardiovascular events. Notably, the transformation of dense post-myocardial infarction (MI) scar into a compressible and mobile adipose tissue impairs local contraction and electrical conductivity. So far, LM has been reported in both humans and animal models (canine, ovine, rabbit, mouse). In recent study using a canine model, LM was observed in hemorrhagic (HEMO+) but not in nonhemorrhagic (HEMO-) MIs. Residual iron deposits in the HEMO+ MI have been shown to promote prolonged inflammation culminating in LM. However, it remains unknown whether the absence of LM in HEMO- MI is observable across species, and whether HEMO- and HEMO+ MIs indeed exhibit different metabolic phenotypes. Methods: Ten pigs underwent a 90-minute ischemia-reperfusion in the left anterior descending artery, followed by T2*, LGE, cine, and 18 FDG-PET/MRI at Day 5 and Week 12 post-MI. At Day 5, HEMO+ MIs were identified by T2* as hypointense core (≥1 mL) within the MI zone. Remote myocardium FDG uptake was suppressed by 48-hour ketogenic diet, 12-hour fasting, and 2000 U heparin injection 15 minutes before FDG administration. LGE and PET images were fused to compute target-to-background ratio (TBR). At Week 12, hearts were explanted for histological analysis using Masson’s trichrome and Prussian Blue stains. Results: Comparing HEMO+ (n=5) and HEMO- (n=5) groups at Day 5 (Fig 1a), there was: (i) increased infarct size in HEMO+ (HEMO+=25.8±3.5%LV; HEMO-=17.5±3.7%LV; p<0.01); (ii) decreased ejection fraction (EF) in HEMO+ (HEMO+=32.1±3.4%; HEMO-=42.9±7.0%; p=0.01); (iii) decreased infarct:remote TBR in HEMO+ (p=0.04)(Fig 1b). At Week 12, there was: (i) no difference in infarct size (HEMO+=9.6±2.0%LV; HEMO-=7.6±2.7%LV; p=0.12); (ii) reduced EF in HEMO+ (HEMO+=35.6±6.7%; HEMO-=43.4±3.9%; p=0.03); (iii) no difference in infarct:remote TBR (p=0.32)(Fig 1b). Histological analysis revealed individual adipose cells in MI scar in both HEMO+ and iron-deposit-negative HEMO- groups (Fig 1c). Conclusions: By comparing MIs of same chronicity, we provide evidence that LM occurs in both HEMO+ and HEMO- MIs. Furthermore, we demonstrate for the first time that reperfused MIs undergoing LM, regardless of infarct size and hemorrhage, exhibit similar metabolic phenotype, suggesting that LM may be independent from iron-related inflammation.

Purpose: While mast cells (MCs) have been shown to exacerbate damage in hemorrhagic stroke models by amplifying histamine-driven inflammation, disrupting the blood-brain barrier and promoting hemorrhage, their role in reperfused myocardial infarction (MI) remains unclear. It has been long known that reperfusion after prolonged ischemia worsens myocardial injury by inducing inflammation, microvascular obstruction (MVO) and intramyocardial hemorrhage (IMH). This process involves erythrocyte and neutrophil-platelet aggregation, releasing inflammatory mediators that increase vasoconstriction, edema, and intravascular pressure, leading to microvascular rupture and IMH. We hypothesized that MC stabilization reduces MVO and IMH post-reperfusion. Methods: Female farm pigs (n=24; 30-35kg) underwent a 90-minute occlusion of left anterior descending artery followed by reperfusion to induce MVO. Animals were randomized into untreated MI (MI; n=12) and loratadine-treated (LORA; n=12) groups, with the latter receiving oral loratadine (10mg/day) for 5 days; after which infarcts were assessed for IMH and MVO (Figure 1a). Non-infarcted animals of the same initial weight were used as control (CTRL; n=10) group. On Day 5 post-MI, clinical 3T scanner was used to acquire cine, LGE and T2* CMR. Results: At Day 5 post-MI, there was no significant difference in infarct size between untreated MI (25.39±6.78%LV) and LORA (22.41±3.74%LV; p =0.10) groups. End systolic volume (ESV), end diastolic volume (EDV) and peak global longitudinal strain (PLS) were not significantly different between LORA (ESV: 63.84±11.96ml; EDV: 98.52±15.62ml; PLS: -7.36±2.20) and untreated MI (ESV: 60.16±15.56ml, p =0.27; EDV: 98.51±16.24ml, p =0.50; PLS: -7.26±1.92, p =0.46). ESV and EDV in both LORA ( p <0.01) and untreated MI ( p <0.01) were significantly higher compared to CTRL (ESV: 31.36±6.28ml; EDV: 60.11±7.51ml), PLS was significantly decreased in LORA ( p =0.01) and untreated MI ( p =0.01) compared to CTRL (PLS: -10.62±2.65). Notably, LORA showed reduced MVO (3.49±1.31%LV vs. 6.10±1.92%LV, p<0.01) and IMH (1.37±0.58%LV vs. 2.98±1.20%LV, p<0.01) versus untreated MI (Figures 1a-b). Conclusions: Loratadine treatment significantly attenuated MVO and IMH in acute MI post-reperfusion, suggesting its potential as a pharmacological intervention in acute MI. It remains to be determined whether short-term antihistamine administration translates into beneficial cardiac remodelling during the chronic phase.

Purpose: Evidence suggests that mast cells (MCs) become overstimulated during reperfusion after a period of prolonged myocardial ischemia. However, the role of MC degranulation on post-reperfusion hemorrhage formation/resolution is unknown. Notably, recent in vitro studies have shown that, as opposed to resting/unstimulated MCs, activated MCs act as "scavengers" by actively engulfing and clearing damaged/oxidized erythrocytes (oxRBC). To date, however, the interaction of MCs with stagnant blood/oxydized erythrocytes in reperfused infarcted myocardium (MI) remains grossly unexplored. In the present study, we investigated the effects of MC stabilization on post-MI hemorrhage resorption/clearance in a clinically relevant porcine model using longitudinal MRI. Methods: Female farm pigs (n=14; 30-35kg) underwent 90-minute occlusion of the left anterior descending artery followed by reperfusion. At Day 5, MI and intramyocardial hemorrhage (IMH) were confirmed using a clinical 3T MRI scanner (Figure 1a). Pigs with comparable MI, IMH and microvascular obstruction (MVO) sizes were randomized into untreated MI (MI, n=7) and treated (LORA, n=7) groups, with the latter given daily oral loratadine (10mg) until termination. The animals were followed longitudinally through Weeks 4 and 8. Cardiac function was assessed using cine MRI sequences (short-axis, horizontal, and vertical long-axis). MI and MVO were quantified using LGE, while IMH was assessed using T2*-weighted imaging. Results: As seen in Figure 1b, no significant differences were observed in infarct ( p =0.23), MVO ( p =0.21) or IMH ( p =0.11) sizes between the untreated MI and LORA groups at Day 5. Hemorrhage resorption from Day 5 to Week 4 and Week 8 was significantly greater in LORA (Week 4: -89.37%; Week 8: -96.53%) than in untreated MI (Week 4: -73.67%, p <0.05; Week 8: -88.66%, p =0.02). Notably, at Week 8, while both groups demonstrated similar ( p =0.48) reductions in MI scar size, the extent of ventricle volume increase was significantly lower in LORA (ESV: +22.23%; EDV: +25.06%) compared to untreated MI (ESV: +64.55%, p <0.01; EDV: +64.11%, p =0.02) group. Conclusions: MC stabilization accelerates hemorrhage resolution and attenuates adverse remodeling in hemorrhagic MI. However, whether overstimulated MC during myocardial ischemia/reperfusion directly exhibit reduced oxRBC scavenging potential, or it is the MC degranulation that indirectly inhibits hemorrhage resolution, remains to be determined.

Purpose To evaluate a novel continuous-acquisition cardiac MRI method that integrates non-contrast-enhanced and contrast-enhanced imaging within a single 20-minute, free-breathing, non-electrocardiographically (ECG) gated scan. Materials and Methods A three-dimensional (3D) stack-of-stars T2-prepared fast low angle shot (FLASH) pulse sequence, combined with a 3D multitasking reconstruction and multiparametric mapping framework, was developed to jointly reconstruct coregistered precontrast and postcontrast images. A prospective study conducted from September 2021 to February 2022 involved 10 healthy human volunteers (mean age, 37 years ± 21 [SD]; eight male, two female) and four pigs with reperfusion injury. Quantitative and qualitative MRI measurements were verified in a digital phantom and in vivo. Statistical analysis included intraclass correlation coefficient, Bland-Altman analysis, and paired t tests to compare the proposed method against reference methods. Results Multitasking T1 measurements were highly correlated with two-dimensional (2D) inversion recovery spin-echo-T1 (R2 > 0.99) and T2 measurements with 2D spin-echo-T2 (R2 > 0.960) in the phantom study. In vivo, multitasking provided higher myocardial T1 values than did modified Look-Locker inversion recovery (MOLLI) (1383 msec ± 37.8 vs 1217 msec ± 16.3; P < .001) and higher myocardial T2 values than did T2-prep FLASH (43.9 msec ± 1.4 vs 40.0 msec ± 1.6; P < .001). There was no evidence of a difference between multitasking and MOLLI extracellular volume (ECV) values (27.5% ± 1.4 and 27.9% ± 1.8; P = .52). In pigs, the proposed method depicted increased precontrast T1 and ECV in ischemic injury regions, aligning well with reference measurements. Conclusion The novel 3D multitasking method enables a comprehensive, 20-minute, push-button cardiac MRI examination without ECG gating or breath holding, providing cardiac function, T1, T2, ECV, and late gadolinium enhancement measurements. Keywords: Cardiac MRI, Cardiac MRI Multitasking, Continuous-Acquisition Cardiac MRI, All-in-One Cardiac MRI Supplemental material is available for this article. © RSNA, 2025.

Sudden blockage of arteries supplying the heart muscle contributes to millions of heart attacks (myocardial infarction, MI) around the world. Although re-opening these arteries (reperfusion) saves MI patients from immediate death, approximately 50% of these patients go on to develop chronic heart failure (CHF) and die within a 5-year period; however, why some patients accelerate towards CHF while others do not remains unclear. Here we show, using large animal models of reperfused MI, that intramyocardial hemorrhage - the most damaging form of reperfusion injury (evident in nearly 40% of reperfused ST-elevation MI patients) - drives delayed infarct healing and is centrally responsible for continuous fatty degeneration of the infarcted myocardium contributing to adverse remodeling of the heart. Specifically, we show that the fatty degeneration of the hemorrhagic MI zone stems from iron-induced macrophage activation, lipid peroxidation, foam cell formation, ceroid production, foam cell apoptosis and iron recycling. We also demonstrate that timely reduction of iron within the hemorrhagic MI zone reduces fatty infiltration and directs the heart towards favorable remodeling. Collectively, our findings elucidate why some, but not all, MIs are destined to CHF and help define a potential therapeutic strategy to mitigate post-MI CHF independent of MI size.

BACKGROUND:Intramyocardial hemorrhage following reperfusion is strongly associated with major adverse cardiovascular events in myocardial infarction (MI) patients; yet the mechanisms contributing to these outcomes are not well understood. Large animal models have been used to investigate intramyocardial hemorrhage, but they are exorbitantly expensive and difficult to use for mechanistic studies. In contrast, rat models are widely used to investigate mechanistic aspects of cardiovascular physiology, but a rat model that consistently recapitulates the characteristics of an hemorrhagic MI does not exist. To bridge this gap, we investigated the physiological conditions of MI that would create intramyocardial hemorrhage in rats so that a reliable model of hemorrhagic MI would become available for basic research.METHODS & RESULTS:Sprague-Dawley rats underwent either a 90-minute (90-min) ischemia and then reperfusion (I/R) (n = 22) or 30-minute (30-min) I/R (n = 18) of the left anterior descending coronary artery. Sham rats (n = 12) were used as controls. 90-min I/R consistently yielded hemorrhagic MI, while 30-min I/R consistently yielded non-hemorrhagic MI. Twenty-four hours post-reperfusion, ex-vivo late-gadolinium-enhancement (LGE) and T2* cardiac MRI performed on excised hearts from 90-min I/R rats revealed colocalization of iron deposits within the scarred tissue; however, in 30-min I/R rats scar was evident on LGE but no evidence of iron was found on T2* CMR. Histological studies verified tissue damage (H&E) detected on LGE and the presence of iron (Perl's stain) observed on T2*-CMR. At week 4 post-reperfusion, gene and protein expression of proinflammatory markers (TNF-α, IL-1β and MMP-9) were increased in the 90-min I/R group when compared to 30-min I/R groups. Further, transmission electron microscopy performed on 90-min I/R myocardium that were positive for iron on T2* CMR and Perl's stain showed accumulation of granular iron particles within the phagosomes.CONCLUSION:Ischemic time prior to reperfusion is a critical factor in determining whether a MI is hemorrhagic or non-hemorrhagic in rats. Specifically, a period of 90-min of ischemia prior to reperfusion can produce rat models of hemorrhagic MI, while 30-minutes of ischemia prior to reperfusion can ensure that the MIs are non-hemorrhagic. Hemorrhagic MIs in rats result in marked increase in iron deposition, proinflammatory burden and adverse left-ventricular remodeling compared to rats with non-hemorrhagic MIs.

Background: Preclinical studies and pilot patient studies have shown that chronic infarctions can be detected and characterized from cardiac magnetic resonance without gadolinium-based contrast agents using native-T1 maps at 3T. We aimed to investigate the diagnostic capacity of this approach for characterizing chronic myocardial infarctions (MIs) in a multi-center setting. Methods: Patients with a prior MI (n=105) were recruited at 3 different medical centers and were imaged with native-T1 mapping and late gadolinium enhancement (LGE) at 3T. Infarct location, size, and transmurality were determined from native-T1 maps and LGE. Sensitivity, specificity, receiver-operating characteristic metrics, and inter- and intraobserver variabilities were assessed relative to LGE. Results: Across all subjects, T1 of MI territory was 1621±110 ms, and remote territory was 1225±75 ms. Sensitivity, specificity, and area under curve for detecting MI location based on native-T1 mapping relative to LGE were 88%, 92%, and 0.93, respectively. Native-T1 maps were not different for measuring infarct size (native-T1 maps: 12.1±7.5%; LGE: 11.8±7.2%, P =0.82) and were in agreement with LGE ( R 2 =0.92, bias, 0.09±2.6%). Corresponding inter- and intraobserver assessments were also highly correlated (interobserver: R 2 =0.90, bias, 0.18±2.4%; and intraobserver: R 2 =0.91, bias, 0.28±2.1%). Native T1 maps were not different for measuring MI transmurality (native-T1 maps: 49.1±15.8%; LGE: 47.2±19.0%, P =0.56) and showed agreement ( R 2 =0.71; bias, 1.32±10.2%). Corresponding inter- and intraobserver assessments were also in agreement (interobserver: R 2 =0.81, bias, 0.1±9.4%; and intraobserver: R 2 =0.91, bias, 0.28±2.1%, respectively). While the overall accuracy for detecting MI with native-T1 maps at 3T was high, logistic regression analysis showed that MI location was a prominent confounder. Conclusions: Native-T1 mapping can be used to image chronic MI with high degree of accuracy, and as such, it is a viable alternative for scar imaging in patients with chronic MI who are contraindicated for LGE. Technical advancements may be needed to overcome the imaging confounders that currently limit native-T1 mapping from reaching equivalent detection levels as LGE.

Background: Despite advances, blood oxygen level-dependent (BOLD) cardiac MRI for myocardial perfusion is limited by inadequate spatial coverage, imaging speed, multiple breath holds, and imaging artifacts, particularly at 3.0 T. Purpose: To develop and validate a robust, contrast agent-unenhanced, free-breathing three-dimensional (3D) cardiac MRI approach for reliably examining changes in myocardial perfusion between rest and adenosine stress. Materials and Methods: A heart rate-independent, free-breathing 3D T2 mapping technique at 3.0 T that can be completed within the period of adenosine stress (<= 4 minutes) was developed by using computer simulations, ex vivo heart preparations, and dogs. Studies in dogs were performed with and without coronary stenosis and validated with simultaneously acquired nitrogen 13 (N-13) ammonia PET perfusion in a clinical PET/MRI system. The MRI approach was also prospectively evaluated in healthy human volunteers (from January 2017 to September 2017). Myocardial BOLD responses (MBRs) between normal and ischemic myocardium were compared with mixed model analysis. Results: Dogs (n = 10; weight range, 20-25 kg; mongrel dogs) and healthy human volunteers (n = 10; age range, 22-53 years; seven men) were evaluated. In healthy dogs, T2 MRI at adenosine stress was greater than at rest (mean rest vs stress, 38.7 msec +/- 2.5 [standard deviation] vs 45.4 msec +/- 3.3, respectively; MBR, 1.19 +/- 0.08; both, P < .001). At the same conditions, mean rest versus stress PET perfusion was 1.1 mL/mg/min +/- 0.11 versus 2.3 mL/mg/min +/- 0.82, respectively (P < .001); myocardial perfusion reserve (MPR) was 2.4 +/- 0.82 (P < .001). The BOLD response and PET MPR were positively correlated (R = 0.67; P < .001). In dogs with coronary stenosis, perfusion anomalies were detected on the basis of MBR (normal vs ischemic, 1.09 +/- 0.05 vs 1.00 +/- 0.04, respectively; P < .001) and MPR (normal vs ischemic, 2.7 +/- 0.08 vs 1.7 +/- 1.1, respectively; P < .001). Human volunteers showed increased myocardial T2 at stress (rest vs stress, 44.5 msec +/- 2.6 vs 49.0 msec +/- 5.5, respectively; P = .004; MBR, 1.1 msec +/- 8.08). Conclusion: This three-dimensional cardiac blood oxygen level-dependent (BOLD) MRI approach overcame key limitations associated with conventional cardiac BOLD MRI by enabling whole-heart coverage within the standard duration of adenosine infusion, and increased the magnitude and reliability of BOLD contrast, which may be performed without requiring breath holds. (C) RSNA, 2020