Using Multiparametric Cardiac Magnetic Resonance to Phenotype and Differentiate Biopsy-Proven Chronic from Healed Myocarditis and Dilated Cardiomyopathy.

(1) Objectives: To discriminate biopsy-proven myocarditis (chronic vs. healed myocarditis) and to differentiate from dilated cardiomyopathy (DCM) using cardiac magnetic resonance (CMR). (2) Methods: A total of 259 consecutive patients (age 51 ± 15 years; 28% female) who underwent both endomyocardial biopsy (EMB) and CMR in the years 2008−2021 were evaluated. According to right-ventricular EMB results, patients were divided into either chronic (n = 130, 50%) or healed lymphocytic myocarditis (n = 60, 23%) or DCM (n = 69, 27%). The CMR protocol included functional, strain, and late gadolinium enhancement (LGE) imaging, T2w imaging, and T2 mapping. (3) Results: Left-ventricular ejection fraction (LV-EF) was higher, and the indexed end-diastolic volume (EDV) was lower in myocarditis patients (chronic: 42%, median 96 mL/m²; healed: 49%, 86 mL/m²) compared to the DCM patients (31%, 120 mL/m²), p < 0.0001. Strain analysis demonstrated lower contractility in DCM patients vs. myocarditis patients, p < 0.0001. Myocarditis patients demonstrated a higher LGE prevalence (68% chronic; 59% healed) than the DCM patients (45%), p = 0.01. Chronic myocarditis patients showed a higher myocardial edema prevalence and ratio (59%, median 1.3) than healed myocarditis (23%, 1.3) and DCM patients (13%, 1.0), p < 0.0001. T2 mapping revealed elevated values more frequently in chronic (90%) than in healed (21%) myocarditis and DCM (23%), p < 0.0001. T2 mapping yielded an AUC of 0.89 (sensitivity 90%, specificity 76%) in the discrimination of chronic from healed myocarditis and an AUC of 0.92 (sensitivity 86%, specificity 91%) in the discrimination of chronic myocarditis from DCM, both p < 0.0001. (4) Conclusions: Multiparametric CMR imaging, including functional parameters, LGE and T2 mapping, may allow differentiation of chronic from healed myocarditis and DCM and therefore help to optimize patient management in this clinical setting.

Hybrid Cardiac Magnetic Resonance/Fluorodeoxyglucose Positron Emission Tomography to Differentiate Active From Chronic Cardiac Sarcoidosis.

OBJECTIVES: The purpose of this study was to investigate the diagnostic value of simultaneous hybrid cardiac magnetic resonance (CMR) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) for detection and differentiation of active (aCS) from chronic (cCS) cardiac sarcoidosis. BACKGROUND: Late gadolinium enhancement (LGE) CMR and FDG-PET are both established imaging techniques for the detection of CS. However, there are limited data regarding the value of a comprehensive simultaneous hybrid CMR/FDG-PET imaging approach that includes CMR mapping techniques. METHODS: Forty-three patients with biopsy-proven extracardiac sarcoidosis (median age: 48 years, interquartile range: 37-57 years, 65% male) were prospectively enrolled for evaluation of suspected CS. After dietary preparation for suppression of myocardial glucose metabolism, patients were evaluated on a 3-T hybrid PET/MR scanner. The CMR protocol included T1 and T2 mapping, myocardial function, and LGE imaging. We assumed aCS if PET and CMR (ie, LGE or T1/T2 mapping) were both positive (PET+/CMR+), cCS if PET was negative but CMR was positive (PET-/CMR+), and no CS if patients were CMR negative regardless of PET findings. RESULTS: Among the 43 patients, myocardial glucose uptake was suppressed successfully in 36 (84%). Hybrid CMR/FDG-PET revealed aCS in 13 patients (36%), cCS in 5 (14%), and no CS in 18 (50%). LGE was present in 14 patients (39%); T1 mapping was abnormal in 10 (27%) and T2 mapping abnormal in 2 (6%). CS was diagnosed based on abnormal T1 mapping in 4 out of 18 CS patients (22%) who were LGE negative. PET FDG uptake was present in 17 (47%) patients. CONCLUSIONS: Comprehensive simultaneous hybrid CMR/FDG-PET imaging is useful for the detection of CS and provides additional value for identifying active disease. Our results may have implications for enhanced diagnosis as well as improved identification of patients with aCS in whom anti-inflammatory therapy may be most beneficial.

Protective role of Gremlin-1 in myocardial function.

BACKGROUND: Gremlin-1 is a cystine knot protein and is expressed in organs developing fibrosis. Transient ischaemia leads to myocardial fibrosis, a major determinant of impaired myocardial function. MATERIALS AND METHODS: Expression of Gremlin-1 was investigated in infarcted myocardium by real-time PCR, Western blot analysis, histological and immunohistochemistry staining. We further elaborated the colocalization of Gremlin-1 and TGF-ß proteins by confocal microscopy and co-immunoprecipitation experiments. The interaction between Gremlin-1 and TGF-ß was analysed by photon correlation spectroscopy. Gremlin-1 modulation of the TGF-ß-dependent collagen I synthesis in fibroblasts was investigated using ELISA and immunohistochemistry experiments. The effect of prolonged administration of recombinant Gremlin-1 on myocardial function following ischaemia/reperfusion was accessed by echocardiography and immunohistochemistry. RESULTS: Gremlin-1 is expressed in myocardial tissue and infiltrating cells after transient myocardial ischaemia (P < .05). Gremlin-1 colocalizes with the pro-fibrotic cytokine transforming growth factor-ß (TGF-ß) expressed in fibroblasts and inflammatory cell infiltrates (P < .05). Gremlin-1 reduces TGF-ß-induced collagen production of myocardial fibroblasts by approximately 20% (P < .05). We found that Gremlin-1 binds with high affinity to TGF-ß (KD  = 54 nmol/L) as evidenced by photon correlation spectroscopy and co-immunoprecipitation. intravenous administration of m Gremlin-1-Fc, but not of equivalent amount of Fc control, significantly reduced infarct size by approximately 20%. In the m Gremlin-1-Fc group, infarct area was reduced by up to 30% in comparison with mice treated with Fc control (I/LV: 4.8 ± 1.2% vs 6.0 ± 1.2% P < .05; I/AaR: 15.2 ± 1.5% vs 21.1 ± 5%, P < .05). CONCLUSIONS: The present data disclose Gremlin-1 as an antagonist of TGF-ß and presume a role for Gremlin-1/TGF-ß interaction in myocardial remodelling following myocardial ischaemia.

Predictors of Mortality in Patients With Biopsy-Proven Viral Myocarditis: 10-Year Outcome Data.

Background There is scarce data about the long-term mortality as well as the prognostic value of cardiovascular magnetic resonance and late gadolinium enhancement (LGE) in patients with biopsy-proven viral myocarditis. We sought to investigate: (1) mortality and (2) prognostic value of LGEcardiovascular magnetic resonance (location, pattern, extent, and distribution) in a >10-year follow-up in patients with biopsy-proven myocarditis. Methods and Results Two-hundred three consecutive patients with biopsy-proven viral myocarditis and cardiovascular magnetic resonance were enrolled; 183 patients were eligible for standardized follow-up. The median follow-up was 10.1 years. End points were all-cause death, cardiac death, and sudden cardiac death (SCD). We found substantial long-term mortality in patients with biopsy-proven myocarditis (39.3% all cause, 27.3% cardiac, and 10.9% SCD); 101 patients (55.2%) demonstrated LGE. The presence of LGE was associated with a more than a doubled risk of death (hazard ratio [HR], 2.40; 95% CI], 1.30-4.43), escalating to a HR of 3.00 (95% CI, 1.41-6.42) for cardiac death, and a HR of 14.79 (95% CI, 1.95-112.00) for SCD; all P≤0.009. Specifically, midwall, (antero-) septal LGE, and extent of LGE were highly associated with death, all P<0.001. Septal LGE was the best independent predictor for SCD (HR, 4.59; 95% CI, 1.38-15.24; P=0.01). Conclusions In patients with biopsy-proven viral myocarditis, the presence of midwall LGE in the (antero-) septal segments is associated with a higher rate of mortality (including SCD) compared with absent LGE or other LGE patterns, underlining the prognostic benefit of a distinct LGE analysis in these patients.

Periprocedural platelet inhibition with cangrelor in P2Y12-inhibitor naïve patients with acute coronary syndromes - A matched-control pharmacodynamic comparison in real-world patients.

BACKGROUND: Effective inhibition of platelet aggregation during PCI in high risk patients with ACS is of utmost importance. The new intravenous short acting P2Y12-receptor inhibitor cangrelor is available for use in PCI-treated patients. We aimed to study platelet inhibition during treatment with cangrelor and transition phase with oral P2Y12-receptor inhibitors in patients with acute coronary syndromes (ACS). METHODS: Cangrelor was administered during PCI to 21 P2Y12-inhibitor naïve patients with ACS. Patients received a loading dose of ticagrelor at the time of procedure or prasugrel 30min before end of the cangrelor infusion. Platelet inhibition was measured by multiple electrode aggregometry (MEA) and thromboelastography (TEG), before and after PCI, immediately and 2h after stopping the infusion. Platelet inhibition after PCI was compared to a matched cohort of patients treated with oral P2Y12-inibitors only. RESULTS: There was a significant reduction of platelet reactivity measured by MEA-ADP from 46.7U to 17.9U and by TEG MA ADP from 43.1mm to 22.0mm before infusion and after PCI respectively (p<0.001). There was also sustained platelet inhibition after stopping of cangrelor infusion and 2h later. Significant higher platelet inhibition was observed at the end of PCI in comparison to control cohort without cangrelor (MEA 17.9U vs. 54.2U, p=0.001). CONCLUSION: We demonstrate significantly improved platelet inhibition during PCI in ACS patients treated with cangrelor in comparison to early treatment with potent oral P2Y12-inhibitors. Cangrelor should be considered for periprocedural treatment of high risk patients with acute coronary syndrome.

Cyclophilin A predicts clinical outcome in patients with congestive heart failure undergoing endomyocardial biopsy.

AIMS: Cyclophilin A (CyPA) represents a ubiquitous intracellular protein, which is secreted by inflammatory and by dying/necrotic cells. The aim of this study was to evaluate the prognostic relevance of CyPA expression in endomyocardial biopsies of consecutive patients with congestive heart failure. METHODS AND RESULTS: A total of 227 unselected patients (age 53.9 ± 15 years) with congestive heart failure undergoing endomyocardial biopsy for diagnostic reasons were enrolled. Biopsies were analysed using established histopathological and immunohistological criteria together with CyPA staining. Virus genome was studied by polymerase chain reaction. CyPA was significantly enhanced in patients with inflammatory cardiomyopathy (n = 127) as compared with patients with non-inflammatory cardiomyopathy (n = 100, P < 0.0001). During a mean follow-up of 16.3 months, 60 patients (26.4%) reached the primary endpoint, a composite of all-cause death, heart transplantation, malignant arrhythmia, and heart failure-related rehospitalization. Of all clinical (ejection fraction, New York Heart Association functional class), laboratory (brain natriuretic peptide), and immunohistological parameters (CyPA, extracellular matrix metalloproteinase inducer, CD68, CD3, major hisocompatibility complex II, and virus genome) tested, only CyPA was identified as an independent predictor for the composite endpoint [hazard ratio (HR) 2.4; 95% confidence interval (CI) 1.2-5.2; P = 0.019] as well as for all-cause death and heart transplantation alone (HR 4.7; 95% CI 1.1-19.8; P = 0.036). Subgroup analysis revealed CyPA as a predictor in patients with non-inflammatory cardiomyopathy for the composite endpoint (HR 3.0; 95% CI 1.3-6.6; P = 0.007) as well as all-cause death or heart transplantation alone (HR 6.4; 95% CI 1.4-28.1; P = 0.014). CONCLUSIONS: CyPA is an independent predictor of clinical outcome in patients with congestive heart failure undergoing endomyocardial biopsy.

Macrophage migration inhibitory factor is enhanced in acute coronary syndromes and is associated with the inflammatory response.

BACKGROUND: Chronic inflammation promotes atherosclerosis in cardiovascular disease and is a major prognostic factor for patients undergoing percutaneous coronary intervention (PCI). Macrophage migration inhibitory factor (MIF) is involved in the progress of atherosclerosis and plaque destabilization and plays a pivotal role in the development of acute coronary syndromes (ACS). Little is known to date about the clinical impact of MIF in patients with symptomatic coronary artery disease (CAD). METHODS AND RESULTS: In a pilot study, 286 patients with symptomatic CAD (n = 119 ACS, n = 167 stable CAD) undergoing PCI were consecutively evaluated. 25 healthy volunteers served as control. Expression of MIF was consecutively measured in patients at the time of PCI. Baseline levels of interleukin 6 (IL-6), "regulated upon activation, normal T-cell expressed, and secreted" (RANTES) and monocyte chemoattractant protein-1 (MCP-1) were measured by Bio-Plex Cytokine assay. C-reactive protein (CRP) was determined by Immunoassay. Patients with ACS showed higher plasma levels of MIF compared to patients with stable CAD and control subjects (median 2.85 ng/mL, interquartile range (IQR) 3.52 versus median 1.22 ng/mL, IQR 2.99, versus median 0.1, IQR 0.09, p<0.001). Increased MIF levels were associated with CRP and IL-6 levels and correlated with troponin I (TnI) release (spearman rank coefficient: 0.31, p<0.001). Patients with ACS due to plaque rupture showed significantly higher plasma levels of MIF than patients with flow limiting stenotic lesions (p = 0.002). CONCLUSION: To our knowledge this is the first study, demonstrating enhanced expression of MIF in ACS. It is associated with established inflammatory markers, correlates with the extent of cardiac necrosis marker release after PCI and is significantly increased in ACS patients with "culprit" lesions. Further attempts should be undertaken to characterize the role of MIF for risk assessment in the setting of ACS.