Restoration of coronary blood flow after a heart attack can cause reperfusion injury potentially leading to impaired cardiac function, adverse tissue remodeling and heart failure. Iron is an essential biometal that may have a pathologic role in this process. There is a clinical need for a precise noninvasive method to detect iron for risk stratification of patients and therapy evaluation. Here, we report that magnetic susceptibility imaging in a large animal model shows an infarct paramagnetic shift associated with duration of coronary artery occlusion and the presence of iron. Iron validation techniques used include histology, immunohistochemistry, spectrometry and spectroscopy. Further mRNA analysis shows upregulation of ferritin and heme oxygenase. While conventional imaging corroborates the findings of iron deposition, magnetic susceptibility imaging has improved sensitivity to iron and mitigates confounding factors such as edema and fibrosis. Myocardial infarction patients receiving reperfusion therapy show magnetic susceptibility changes associated with hypokinetic myocardial wall motion and microvascular obstruction, demonstrating potential for clinical translation. Restoration of coronary blood flow after a heart attack may lead to reperfusion injury and pathologic iron deposition. Here, the authors perform magnetic susceptibility imaging showing its association with iron in a large animal model of myocardial infarction during wound healing, and showing feasibility in acute myocardial infarction patients undergoing percutaneous coronary intervention. While reperfusion remains the most effective strategy for reducing infarct size and substantially improves myocardial salvage, reperfusion injury may be independently associated with adverse left ventricular (LV) remodeling, increased risk of fatal arrhythmias and hospitalization for heart failure11.Reperfusion injury is a complication of vascular reperfusion therapy for acute myocardial infarction and is estimated to occur in up to 60% of patients14. Imaging could be used to evaluate the effectiveness or the dose optimization of adjunctive therapies for reperfusion such as periprocedural glycoprotein IIb/IIIa inhibitor15, iron chelation therapy16, and β1-adrenergic receptor antagonists17.These findings highlight the need for noninvasive imaging techniques, specific to the molecular components of reperfusion injury, to identify patients at high risk for adverse LV remodeling and heart failure. High-risk patients could be treated more aggressively, while allowing low-risk patients to be seen less frequently for follow up, improving cost effectiveness. Patients could be enrolled in studies of emerging preventative approaches such as stem cell and biomaterial therapy18, specifically the production of reactive oxygen species, and subsequent DNA damage. Magnetic resonance imaging (MRI) provides a noninvasive approach to map myocardial iron. It applies a strong magnetic field (~3 T) that induces an additional magnetic field (~µT) that depends on the tissue magnetic susceptibility distribution and its orientation with respect to the applied field19. Quantitative susceptibility mapping (QSM) is a technique that quantifies the magnetic susceptibility using the induced field and is measured directly using the MRI signal phase. Biometals such as iron perturb the MRI magnetic field and can be detected using this technique.While iron is an essential biometal in many normal metabolic reactions involving cardiac function, it also has a pathologic role in reperfusion injury20, however, no prior studies have investigated the relationship between magnetic susceptibility and myocardial tissue iron content with myocardial infarction in animal models or patients. Magnetic susceptibility might be a specific imaging biomarker of myocardial hemorrhage, unlike conventional MRI relaxation time contrast or mapping, which is also affected in part by inflammation and fibrosis.To investigate the role of iron in reperfusion injury, we associated QSM with coronary occlusion duration in a large animal model and in patients with successful reperfusion after ST-elevation myocardial infarction (STEMI). The feasibility of this approach was recently shown in healthy subjects1H T2* relaxation times and LGE) and correlated to infarct size and cardiac function. We also sought to determine the evolution of iron and magnetic susceptibility during wound healing. Finally, we studied patients following reperfusion for STEMI to determine the feasibility of mapping reperfusion injury using QSM.The purpose of this study was to measure the magnetic susceptibility of myocardial infarction and determine its association with infarct tissue iron. We hypothesized that reperfusion injury in myocardial infarctions show a paramagnetic shift of magnetic susceptibility caused by elevated tissue iron content, which was independently determined by histology and inductively coupled plasma optical emission spectrometry (ICP-OES), electron paramagnetic resonance (EPR) spectroscopy, and RNA analysis of markers for iron metabolism. To test this hypothesis, we performed a cross-sectional study in a large animal model of reperfusion injury myocardial infarction and investigated the effect of occlusion time on tissue iron and magnetic susceptibility. QSM was compared with conventional MRI tissue characterization methods , 90 min (n = 5), 180 min (n = 5) and permanent occlusion (n = 4) at 1 week after infarction. After mapping the affected territory  or circumflex coronary artery branchesP = 0.05), greater microvascular obstruction (MVO) (P = 0.05) and increased infarct transmurality (P = 0.02), as detailed in Supplementary Fig. At 1 week after occlusion, cine MRI showed that all animals had comparable end-diastolic and end-systolic volumes (EDV and ESV), ejection fraction (EF), and left ventricle (LV) mass  and permanent (P = 0.025) infarct groups  and colorimetric assay of total and Fe2+ iron revealed the same trend  and desferrioxamine-chelatable labile iron from EPR (P = 3e−4)  and remote myocardium (n = 20) tissue samples. Ferritin is a scavenger of intracellular labile iron, arresting its redox activity. Ferritin light chain (FLC) expression significantly increased in the infarct  and ferritin heavy chain (FTH1) expression was not significantly modified in infarct compared to remote area in any of the conditions studied  was significantly decreased in the infarct region  , which transports iron into the labile iron pool, was significantly decreased in the infarct region   transcription is activated in response to increased intake of heme proteins, and its expression was significantly increased  . Iron was significantly increased in the infarct region as shown by total iron measurements from ICP-OES (−4) Fig. . To confied Fig. . The exp35) Fig. . Divalen02) Fig. . Heme oxP = 7e−4) and 180 min (P = 0.003) of coronary artery occlusion compared with isointense regions .To investigate the relationship between magnetic susceptibility and conventional MRI biomarkers in ischemic myocardium, we compared LGE MRI, T2*-weighted images (T2*w), T2* maps, phase images, and susceptibility maps in Fig. ons Fig. . As expeons Fig. . In contT2* and R2*.Receiver operating characteristic (ROC) curves were computed for each predictor variable  with binary response variable as infarct equal to 1 and remote myocardium equal to 0  and at 1 week (n = 15) and 8 weeks (n = 8) after infarction. Cardiac structural and functional data were obtained using cine and LGE MRI, and show changes in wall thickening (WT), end-systolic wall thickness, and wall motion (WM) between remote and infarct regions and between controls, 1 week and 8 week post-infarction groups (Supplementary Table n = 11) and 8 weeks (n = 8) post-infarction. LGE, T2*-weighted and QSM images from one animal imaged serially at 1 and 8 weeks post-infarction are displayed in Fig. χ = 0.055 ± 0.039 ppm) compared with the remote myocardium (Δχ = −0.011 ± 0.020 ppm) (P = 2e−4)   and total iron concentration . There was a significant association between MVO versus magnetic susceptibility  and a significant association between total iron concentration and ex vivo tissue magnetic susceptibility   Fig. . This wa01) Fig. . By 8 weHistology Fig.  showed tThe large animal model preclinical findings demonstrated the potential for clinical translation and formed the basis of an observational, cross-sectional MRI study in humans. Seven STEMI patients , LAD artery (n = 3), and left circumflex artery (n = 1). All patients (n = 3) with TIMI grade 0/1 prior to revascularization had myocardial hemorrhage while three of four patients with TIMI grade 2/3 did not have hemorrhage. After intervention, all patients had successful reperfusion with TIMI grade 3 flow. Infarct size and regions of MVO tended to be larger in patients with hemorrhage  compared with those without . The magnetic susceptibility of the infarct in the hemorrhage group  was significantly elevated compared with the remote myocardium in all patients . The duration from symptom onset to reperfusion was 303.7 min in the no hemorrhage group and 695.5 min in the hemorrhage group ) resembling the physiology seen with permanent occlusion infarcts.T2* relaxation time on T2* maps. The reason for the discrepancy between T2* compared with total iron and magnetic susceptibility measurements is not yet fully clear and may be caused by technical factors such as field strength24 and voxel size25 or an incomplete understanding of the physical mechanisms underlying T2* contrast in their relation to infarct pathophysiology. There was only a moderate association between transverse relaxation rate (R2* = 1/T2* [ms−1]) and iron , but this improved when excluding the 45 min and permanent infarct groups  44 to hemorrhage, edema, and fibrosis are currently active areas of investigation. T2 and T2* MRI typically appear hypointense with hemorrhage, but the spatial correspondence of T2 and T2* may not overlap and the relative contributions of hemorrhagic injury, edema, and fibrosis to the MR signal are unknown. T2 and T2* are increased in edema and fibrosis35, but appear to decrease in hemorrhagic infarction. T2* is affected by imperfections in the MRI static magnetic field, background field heterogeneity at the lung-myocardium interface, signal fluctuations due to cardiac and respiratory motion, and fluctuations of the MR signal due to the intravascular blood oxygen level-dependent effect and venous oxygen saturation. Moreover, the effect of hemorrhagic tissue iron on the MR signal phase is nonlocal, affecting adjacent nonhemorrhagic tissues, and the presence and spatial extent of hemorrhage may be underestimated or overestimated and confounded by other tissue changes.In comparing QSM to conventional gadolinium and relaxation time contrasts, there were several interesting findings. All animals with permanent infarcts and 90 and 180 min reperfused infarcts had hypointense regions within the hyperintense infarct on LGE MRI, which indicates more severe infarctions and MVO. In the permanent infarct group, all animals showed MVO without hypointense regions on T2*. In reperfused animals at 90 and 180 min, T2*-weighted and T2* maps of reperfused infarcts had hypointense regions attributed to hemorrhage. However, the sensitivity, specificity and spatial distribution of conventional MRI contrasts and mapping techniques such as T11. In an additional 30 patients who underwent serial imaging, MVO and hemorrhage showed a distinct time course post-infarction. Myocardial iron appears to be retained in some patients for months after the acute event and 13–15 patients had evidence of residual iron deposition using T2* imaging at 5 months after infarction even in the absence of MVO46. We found that all animals that underwent permanent coronary occlusion showed significant MVO, yet the spatial distribution of iron deposition as observed on T2* or QSM did not match MVO on LGE  and ferritin and hemosiderin are superparamagnetic (many unpaired electrons). The ionization state, Fe2+ or Fe3+, as well as the molecular form of protein-bound iron, is expected to affect QSM.For extracellular iron, immunostaining of hemoglobin showed that leftover hemoglobin from hemorrhage is present at 1 week (90 and 180 min infarcts) and declines by 8 weeks after reperfusion injury, indicating a clearance of hemoglobin during wound healing. Permanent infarct groups showed similar positive hemoglobin, with less concentrated areas of positive staining at 1 week post-infarction. The darker IHC staining contrast may reflect extracellular or uptake of hemoglobin from past hemorrhage. Hemoglobin may be an important source of magnetic susceptibility and iron content of the tissue, especially in the 90 and 180 min infarct groups. Significantly increased n = 3) 3 days after reperfusion and found magnetic susceptibility changes were detected in both animals and humans  to limit cardiac and respiratory motion across the cardiac slice direction. Free-breathing cardiac-gated GRE acquisitions using respiration gating may have the potential to further improve image quality49.There are several challenges to accurately estimate of myocardial magnetic susceptibility in humans. There are errors caused by cardiac motion, respiratory motion, blood flow, and imperfections in local tissue field estimation. These cause artifacts in the magnetic susceptibility images and hinder accurate estimation. A combination of ECG gating, apnea and magnetic field gradient flow compensation helped mitigate the adverse effects of cardiac motion, respiratory motion, and blood flow, respectively. A major source of artifacts was the presence of large significant background magnetic field gradients at the myocardium–lung interface. While these artifacts were readily identified in both patients and animals, it is necessary to develop methods that limit these effects across the heart muscle. We addressed these issues of background field heterogeneity and motion in animals by embedding the whole heart tissue explants in a susceptibility-matched fluid. In addition, we showed the feasibility to perform cardiac susceptibility mapping and detect regions of altered magnetic susceptibility in patients, spatially corresponding to the areas of infarction on LGE MRI. There may be differences between the 1 week timepoint in animals compared with the subacute (3 day) period in humans that limit extrapolation of the findings. We investigated QSM in swine , 90 min (n = 15), and 180 min (n = 5) after initiation of occlusion or permanent occlusion (n = 4) without reperfusion. Swine had a terminal study 1 week post-infarction. Three additional groups were studied at 3 days (n = 3) and 8 weeks (n = 8) after a 90 or 180 min occlusion followed by reperfusion and a separate set of controls without myocardial infarction (n = 5). The experimental model was chosen to emulate human post-PCI ischemia reperfusion injury and remodeling post-infarction.All swine underwent occlusion of the LAD or circumflex coronary artery branches and were partitioned into groups: reperfusion occurred at 45 min  were studied according to the protocols approved by the Institutional Animal Care and Use Committee of University of Pennsylvania . During all procedures, sedation was induced with 25–30 mg/kg ketamine intramuscularly, endotracheal intubation was performed, and the animal was maintained with a mixture of isoflurane 0.5–5% and oxygen was kept at 6 L during procedure; tidal volume was manipulated based on arterial blood gas readings, generally maintained at 10–20 mL/kg . Anesthesia and animal temperature were monitored during surgical and imaging procedures to maintain a constant physiologic state. Arterial access was obtained at the carotid or femoral artery for measurement of intraventricular pressure . Venous access was obtained at the internal jugular veins for administration of medication. After each procedure, the animal was weaned from anesthesia and transported to the recovery room. Upon completion of the terminal MRI study, the animal was returned to the operating room for euthanasia and cardiac tissue harvest.Yorkshire swine (n = 4) or LAD artery (n = 34) to induce an infarction of ~20–30% of the LV size22. Swine underwent open chest surgery (n = 17) or balloon catheter ligation (n = 16). For open chest surgery, the dimensions of the infarction were determined by visible color changes at the epicardium  with 40 mT/m gradients and 18 channel RF receiver arrays. Intraventricular pressure was interfaced to physiological monitoring software and filtered to facilitate dual respiratory and cardiac gating . All 2D images were acquired in the short axis during apnea and 3D with dual cardiac and respiratory gating. Apnea was achieved by temporarily disabling the animal ventilator.2, spatial resolution = 1.3 × 1.3 mm2, slice thickness = 6 mm, number of slices = 18–20, flip angle = 12°, bandwidth = 399 Hz/pixel, parallel imaging acceleration factor = 2, NEX = 1 and 3–4 slices with 60 cardiac phases per slice were acquired during a breath hold of 20 s followed by a 1 min break between each breath hold. The animals received a 0.1 mmol/kg intravenous injection of gadolinium contrast for LGE imaging . Imaging was performed 10 min after injection of contrast agent using a inversion time (TI) scout sequence to determine the optimal TI to null normal myocardial tissue signal. LGE MRI was obtained using a cardiac and respiratory gated 3D multishot phase-sensitive inversion recovery (PSIR) bSSFP sequence with a TR = 443 ms, TE = 2.42 ms, FOV = 35 × 219 cm2, voxel size = 1.4 × 1.4 × 4 mm3, number of slices = 26, flip angle = 20°, bandwidth = 244 Hz/pixel, parallel imaging acceleration factor = 2, NEX = 2, and total acquisition time ranged from 7 to 9 min. Respiratory and cardiac-gated 2D T2*-weighted single-echo gradient-echo images were obtained using TR = 160 ms, TE = 10 ms, FOV = 24.0 × 17.3 cm2, spatial resolution = 0.9 × 0.9 mm2, slice thickness = 4 mm, number of slices = 10–15, flip angle = 13°, bandwidth = 260 Hz/pixel, parallel imaging acceleration factor = 2, NEX = 12, and each slice was acquired during a breath hold of 60 s followed by a 3 min break between each breath hold.In vivo retrospective, short axis, multi-slice cine MRI was performed with a TR = 41 ms, TE = 2.84 ms, FOV = 34 × 20 cm1H magnetic susceptibility-matched fluid (Fomblin), and T2*-weighted multiecho gradient-echo images of whole heart specimens were obtained using TR = 42 ms, 5 TEs = 3.3–16.1 with ΔTE = 3.2 ms, FOV = 23 × 23 cm2, voxel size = 0.9 × 0.9 × 0.9 mm3, flip angle = 16°, bandwidth = 610 Hz/pixel, NEX = 1, and total acquisition time was 30 min.Ex vivo imaging at 3 days, 1 week and 8 weeks post-infarction, animals were euthanized, their hearts were excised and bathed in non-n = 7, age = 61 ± 9 years, 1 female, 6 male) enrolled in this study had ST-elevation acute myocardial infarctions and were treated by primary PCI. The trial was conducted in accordance with the Declaration of Helsinki and the Guidelines for Good Clinical Practice. The trial protocol was approved by the Institutional Review Board of the University of Pennsylvania . The full trial protocol can be accessed through ClinicalTrials.gov with trial registration number, NCT03531151. Patients were recruited and imaged at the Penn Presbyterian Medical Center during the time period of March to June 2018. Eligibility criteria included: (1) between the ages of 18 and 80, (2) must be able to read and understand English and sign the informed consent form, (3) elevated and delayed peak creatine kinase-MB and troponin I (cTnI) and troponin T (cTnT) in blood serum, (4) no contraindications to MRI such as claustrophobia, (5) adequate renal function, as determined by glomerular filtration rate > 30 mL/min, (6) no presence of cardiac pacemaker or implanted cardioverter defibrillator, (7) were not pregnant, (8) did not have a personal or family history of hypertrophic cardiomyopathy, (9) did not have a history of seizure disorder. The indications for PCI were based on ECG criteria showing 1 mm ST elevation in precordial leads or 0.5 mm ST elevation in limb leads in at least 2 contiguous leads. A minority of patients received thrombolytic therapy. The indications for PCI in these cases were as follows: (1) lack of resolution of ECG changes, as determined by >50% resolution of ST elevation from maximum elevation, (2) significant resolution of chest pain, as assessed by verbal confirmation with the patients, and (3) hemodynamic instability, as determined by noninvasive blood pressure measurement, heart rate changes on ECG and clear lungs.Patients  with 40 mT/m gradients and 48 channel RF receiver arrays. ECGs were obtained during MRI and used for gating using a wireless ECG monitor. All 2D images were acquired in the short axis during breath-holding and 3D with dual cardiac and respiratory gating. All patients were in a head first supine position.2, spatial resolution = 2.1 × 2.1 mm2, slice thickness = 8 mm, number of slices = 10–15, flip angle = 55°, bandwidth = 930 Hz/pixel, parallel imaging acceleration factor = 2, NEX = 1 and 3–4 slices with 30 cardiac phases per slice were acquired during breath hold of 10 s followed by a 45 s break between each breath hold. LGE imaging was performed 10 min after intravenous injection of 0.15 mmol/kg gadolinium contrast . Imaging was performed 10 min after injection of contrast agent using an TI scout sequence to determine the TI to null myocardial tissue signal. LGE MRI was obtained using a 3D multishot PSIR turboflash sequence with navigator respiratory gating with TR = 882 ms, TE = 1.1 ms, FOV = 24 × 32 cm2, voxel size = 2 × 2 × 8 mm3, number of slices = 12–15, flip angle = 40°, bandwidth = 1080 Hz/pixel, NEX = 1, and total acquisition time ranged from 5 to 6 min. Breath held cardiac-gated 2D T2*-weighted single-echo gradient-echo images were obtained using TR = 192 ms, TE = 15 ms, FOV = 23 × 30 cm2, spatial resolution = 1.6 × 1.6 mm2, slice thickness = 3 mm, number of slices = 10–15, flip angle = 25°, bandwidth = 400 Hz/pixel, parallel imaging acceleration factor = 2, NEX = 1, each slice was acquired during breath hold of 12–18 s followed by a 1 min break between each breath hold. All patients were in the MRI for a maximum duration of 1 h to acquire all protocol sequences.Retrospective, short axis, cardiac-gated, breath held, multi-slice cine MRI was performed with a TR = 33.4 ms, TE = 1.09 ms, FOV = 30 × 40 cm50. Ex vivo infarct ROI measurements  on T2*-weighted images. The ROIs for healthy myocardium (isointense), infarct (hypointense), and infarct (hyperintense) were obtained by segmenting the T2*-weighted images acquired at the last echo (TE = 16.1 ms) using thresholding active contour segmentation nts Fig.  and 11 ints Fig.  includedA is the amplitude at TE = 0. The T2* GRE magnitude images had signal decay across five TEs. The two parameters (A and T2*) were estimated using least-squares minimization and error maps were computed to validate the accuracy of the fit.T2* mapping was performed in Matlab-R2017B  using a two-parameter model χ) is a material property that determines how effectively it is magnetized in an applied magnetic field. Δχ represents the magnetic susceptibility difference from water . In the forward model, the relationship between Δχ and the measured local tissue magnetic field (Φ) is FΦ = DFΔχ, where F is the discrete Fourier transform operator and 51. The estimation of the local Δχ is inherently ill-posed due to the presence of zeros in the Fourier domain representation of the dipole kernel52. Hence, estimation of the susceptibility map using a direct inversion of the dipole kernel leads to artifacts. A common approach for removing the artifacts from the reconstructed susceptibility maps is the use of Bayesian regularization, which consists of a combination of least-squares data fidelity term and a data regularizing term, leveraging sparsity of the image in a suitable transformation domain to remove artifacts. Tikhonov and the total variation (TV)53 constraints are well known data regularizers that penalize the gradient of the image to enforce a piece-wise-constant/smooth model54. Here, the morphology enabled dipole inversion technique57 was used to reconstruct the magnetic susceptibility using an unconstrained formulation:1 is the L1 norm, || ||2 is the L2 norm, M is an edge map estimated from the magnitude image, G is a spatial gradient operator, W is an estimate of the signal-to-noise ratio at each voxel from the magnitude images, and λ is a Lagrangian weight, balancing data fidelity and TV-based data regularization. The cost functional in Eq. , EDV, ESV, EF cardiac output, WT, WM, and wall thickness at end systole. Epi- and endocardial contours were drawn manually at ED and ES using standard techniques .Infarct volume and transmurality were assessed using full width at half maximum (FWHM) thresholding with visible enhancement on LGE MRI . After defining the infarct region with FWHM, MVO regions were defined as a hypointense core within a hyperintense region on LGE and were manually segmented. Infarct volume included hyperintense regions in LGE, selected based on FWHM and hypointense MVO regions that were manually segmented.2 samples from short-axis cardiac slices. Similarly, from each swine cardiac specimen, at least four samples of viable myocardium were isolated from the tissue opposite of the infarct region. Contiguous tissue samples were collected for both histology, ICP-OES iron measurements, EPR spectroscopy, and gene expression analysis.The excised heart from each animal was sliced (2 mm thickness) using a 330 M 13″ Prosciutto Meat Slicer . Infarct regions were sectioned into 2 × 2 cmn = 2–10) from each of the infarct and remote regions from every animal. These sections were stained with H&E for cell viability, Masson Trichrome for fibrosis, and Prussian Blue for iron and sections were digitally imaged at ×40 magnifications and viewed with Aperio ImageScope [v12.3.2.8013]  software. Color adjustment of Prussian blue digital images was performed . IHC was done using the Dako Envision+ Peroxidase Based System . Hemoglobin, MHC class II antigen-presenting cells and newly recruited macrophages were detected using a Hemoglobin Beta antibody , Cathepsin-S antibody (GeneTex: GTX114350) and a MAC-387 antibody (Abcam: ab22506), respectively. Tissue fiducial markers, RV insertion, papillary muscle shape, length of the LV, and distance to the apex were used to correlate MR images with histology.For histology, 5 μm sections were obtained from representative samples  was measured using ICP-OES. Stored samples were thawed from −80 °C, blotted, weighed, and placed in individual borosilicate glass centrifuge tubes  with PTFE-lined caps . Sample weights ranged from 50 to 300 mg. Seventy-five microliter of nitric acid  and 225 μL of hydrochloric acid  were added to the samples. The samples were then placed in a water bath overnight at a temperature of 50 °C. The digested samples were cooled down to room temperature, diluted with ultrapure water to a volume of 6 mL, and then filtered through 0.2 μm Nalgene syringe-filters  and the filtrates were collected in individual 15 mL metal-free polypropylene tubes . A set of standards with concentrations ranging from 0 to 100 ppm was prepared using a 1000 ppm iron stock solution .All samples were analyzed using a Genesis ICP-OES . Sample selection occurred automatically via an ASX-260 autosampler ; sample introduction occurred via peristaltic pump at a rate of 1.5 mL/min through a modified Lichte nebulizer with a cyclonic spray chamber. Data was acquired using the dedicated SmartAnalyzer Vision software. Fe content measured within each sample at wavelength 259.9 nm was averaged between three duplicates and expressed as mg of Fe per L of sample by using the weight of the tissue sample and volume dilution the concentration was calculated to be mg of Fe per g of tissue.n = 327) total iron concentration measurements were analyzed, at 1 week post-infarction: remote (n = 141) tissue samples, 45 min (n = 24), 90 min (n = 32), 180 min (n = 37), permanent (n = 50) infarct tissue samples, at 8 weeks post-infarction: remote (n = 20) tissue samples and 90 min (n = 23) infarct tissue samples.ICP-OES was performed on multiple contiguous tissue samples of viable myocardium and infarct regions; measurements were averaged from each region within 90, 45, 180 min, and permanent ligation animal models. In all (60. Frozen samples (30–90 mg) were weighed and homogenized in 500 μL of sterile saline with a TissueRuptor (Thermo-Fisher). Aliquots were saved for colorimetric iron measurements (Sigma MAK025). Decreasing concentrations of a stock solution of 10 mM FeSO4 in 0.2 mM HCl (100–12.5 μM) were diluted in saline to be used as standards. Two hundred microliter of each homogenate and FeSO4 standards were treated for 16 h with 200 µL of 10 mM desferrioxamine (Sigma). Desferrioxamine oxidizes Fe2+ to Fe3+, hence the desferrioxamine-bound iron detected by EPR corresponds to both original Fe3+ in the homogenate and Fe2+ converted into Fe3+. For EPR measurements, samples, standards and saline as blank (80 μL) were placed in 1/8″ teflon tubes (Cole-Parmer) and frozen in liquid nitrogen (77 K). EPR spectra of samples, standards, and saline in liquid N2 were recorded using a Bruker EMX spectrometer under the following conditions: microwave frequency 9.47 GHz; power, 20 mW; modulation amplitude, 1.0 mT. EPR signal was measured at g ~4.3 to estimate desferrioxamine-iron concentration. Fe content measured within each sample was averaged between at least two duplicates and expressed as mg per g of tissue. EPR was performed on multiple contiguous tissue samples of viable myocardium and infarct regions. Representative measurements from each infarct group were averaged together, in all remote (n = 25) and infarct (n = 43) tissue samples were analyzed. The EPR technique is not without error in tissue, as the isolation may mobilize or dilute catalytic iron. All tissue was processed under the same conditions, making any mobilization, or dilution of labile iron during the isolation process comparable in all samples. However, it is possible that the actual concentration (mg/g) of labile iron in the original tissue differs from the values of our results.EPR spectroscopy was performed with a modified method based on the study by Yegorov et al.n = 20, infarct, n = 24) using the RNeasy mini kit (Qiagen) and a TissueRuptor (Thermo). Total RNA concentration and purity were measured on a Denovix spectrophotometer (Denovix). cDNA synthesis was performed using 100 ng of RNA with Maxima H Minus First Strand Kit (Thermo Scientific). Real-time PCR for quantification of mRNA was performed on a Piko Real 96 (Thermo Scientific) by using an SYBR-Green protocol. The results were expressed as fold changes in expression when compared with the average of remote samples from all time points using the cycle threshold 2(ΔΔCT) method with GAPDH and HPRT as reference genes. Primers producing a PCR product smaller than 200 bp were designed using NIH Primer Blast with spanning an exon-exon junction when possible. The corresponding sequences were as follows: porcine GAPDH forward, 5′-ccctgcgctctctgctc-3′; porcine GAPDH reverse, 5′-gccagagttaaaagcagccc-3′; porcine HPRT forward, 5′-agccccagcgtcgtgatta-3′; porcine HPRT reverse, 5′-acatctcgagcaagccgttc-3′; porcine FLC forward, 5′-ctcatggctggtcggcaata-3′; porcine FLC reverse 5′-tgtttggacggaacagaccc-3′; porcine FTH1 forward, 5′-ttgggtctgcagcttcatca-3′; porcine FTH1 reverse, 5′-gccagaactaccaccaggac-3′; porcine DMT1 forward, 5′-ccaggatctagggcatgtgg-3′; porcine DMT1 reverse, 5′-actggtggcttcttcagtcag-3′; porcine ACO1 forward, 5′-accattgccaacatgtgtcc-3′, porcine ACO1 reverse, 5′-agtctgggtcttgagaggagt-3′, porcine HO1 forward, 5′-gtaccgctcccgaatgaaca-3′, and porcine HO1 reverse, 5′-tggtccttagtgtcctgggt-3′.Total mRNA was isolated from frozen samples  with Tukey’s HSD post-hoc multiple comparisons test or a nonparametric Kruskal–Wallis test when appropriate. Comparisons between multiple groups and two factors were performed using a two-way ANOVA with Tukey’s HSD post-hoc multiple comparisons test. ROC curves were computed for each predictor variable with binary response variable as infarct equal to 1 and remote myocardium equal to 0. The data were fit to a logistic regression model. AUC and Youden’s index were computed. Sensitivity and specificity were measured at the optimal operating point. Linear regression was performed to determine if there was a significant correlation between two measures and the P value was generated by testing whether the β coefficient was zero using a Wald test. The results were found to be significant for P < 0.05. *P < 0.05, and **P < 0.001.Statistics were performed in Matlab-R2017B  and R-3.6.3 (Vienna Austria). The descriptive results are reported as mean ± SD or interquartile range. Comparisons between two groups were performed using a two-tailed two-sample Further information on research design is available in the Supplementary InformationPeer Review FileReporting Summary


The right ventricle (RV) often fails when functioning as the systemic ventricle, but the cause is not understood. We tested the hypothesis that myofiber organization is abnormal in the failing systemic right ventricle.We used diffusion-weighted cardiovascular magnetic resonance imaging to examine 3 failing hearts explanted from young patients with a systemic RV and one structurally normal heart with postnatally acquired RV hypertrophy for comparison. Diffusion compartment imaging was computed to separate the free diffusive component representing free water from an anisotropic component characterizing the orientation and diffusion characteristics of myofibers. The orientation of each anisotropic compartment was displayed in glyph format and used for qualitative description of myofibers and for construction of tractograms. The helix angle was calculated across the ventricular walls in 5 locations and displayed graphically. Scalar parameters  were compared among specimens.The hypertrophied systemic RV has an inner layer, comprising about 2/3 of the wall, composed of hypertrophied trabeculae and an epicardial layer of circumferential myofibers. Myofibers within smaller trabeculae are aligned and organized with parallel fibers while larger, composite bundles show marked disarray, largely between component trabeculae. We observed a narrow range of helix angles in the outer, compact part of the wall consistent with aligned, approximately circumferential fibers. However, there was marked variation of helix angle in the inner, trabecular part of the wall consistent with marked variation in fiber orientation. The apical whorl was disrupted or incomplete and we observed myocardial whorls or vortices at other locations. Fractional anisotropy was lower in abnormal hearts while mean diffusivity was more variable, being higher in 2 but lower in 1 heart, compared to the structurally normal heart.Myofiber organization is abnormal in the failing systemic RV and might be an important substrate for heart failure and arrhythmia. It is unclear if myofiber disorganization is due to hemodynamic factors, developmental problems, or both. The myocardium is a highly anisotropic tissue, with myocytes (long axis approximately 10 times the transverse axis) organized into parallel bundles. The organization of myofibers appears to be important for heart function and electrical conduction. Early studies of myofiber organization were performed using histological sections . More rePathological states, including some genetic cardiomyopathies as well as myocardial infarction, have been shown to be associated with abnormal tissue structure as indicated by abnormal MD and FA values as well as disarray of myofibers seen in tractograms , 7. We hIn this work, we tested our hypothesis that myofiber architecture is abnormal in the systemic RV of explanted, failing hearts using ex vivo DW CMR.The explanted hearts from 3 patients with a systemic RV and from 1 patient with a structurally normal heart with acquired RV hypertrophy were examined. The families gave consent for the hearts to be used for research and the protocol was approved by the institutional review board (IRB) (IRBP00016280).The explanted hearts were fixed  under 10 cm of water distending pressure and immersed in Galden®  for imaging. Each heart was packaged in a sealed, close-fitting bag to minimize the distance between the CMR coil and the sample. Care was taken to remove microscopic air bubbles to reduce B1 field inhomogeneity so that susceptibility geometric and intensity distortion were minimized.All imaging was performed on a 3 T CMR system  with a pulsed gradient spin echo sequence and single shot echo planar imaging (EPI) readout pulse sequence. We have used the posterior part of the 64-channel head coil at the bottom of the sample and a 7 cm loop coil at the top of the sample to increase signal and coverage. Eddy current distortion was minimized by utilizing a twice-refocused spin echo sequence . Scan paWe characterized the tissue microstructure using diffusion compartment imaging (DCI)  estimatewww.benoitscherrer.com/MisterI/) and for construction of tractograms (FiberNavigator) [The orientation of each anisotropic compartment was displayed in glyph format and used for qualitative description of myofibers  .The helix angle was computed across the ventricular wall in 5 evenly spaced locations using MisterI software. The long axis of the ventricle was constructed as a line from the center of the AV valve to the apex of the ventricle Fig. . A shortDCI allows characterization of diffusion scalar parameters such as FA and MD that are specific to each compartment, therefore referred to as compartment FA (cFA) and compartment MD (cMD). cFA and cMD values were computed at each voxel and average values were derived for each specimen as a whole and for each of their walls .Blocks of ventricular myocardium were removed after imaging, sectioned, mounted and stained, photographed, and stored digitally for comparison with diffusion data. The heart specimen was imaged with computed tomography following removal of tissue samples and a 3D reconstruction created (MisterI). The diffusion images were then overlaid on the 3D image to localize the sites for comparison with histology.The quantitative statistical analysis was carried out using Stata . We used 1-way ANOVA to test the significance of differences in global means among the 4 hearts. We then used a Mann-Whitney U test (non-parametric) for pairwise comparisons of the global means of the 3 systemic RV hearts with the RVH ‘normal’ heart and for pairwise comparisons of the 2 free walls of the univentricular hearts.Patient 1 is a 14-year-old boy with mitral atresia/aortic atresia (MA/AA) who underwent Norwood palliation as a neonate, a bi-directional Glenn anastomosis at 10 months of age and fenestrated lateral tunnel Fontan operation at 3 years of age. The fenestration was closed (device closure) at 6 years of age. By 12 years he had developed increasing exercise intolerance, edema and ascites. Echocardiography showed moderate to marked global RV systolic dysfunction and mild-moderate tricuspid regurgitation  and elevated RV filling pressure (18 mmHg) with pulmonary vein desaturation (88–92%). Symptoms progressed and he underwent orthotopic heart transplantation at age 14 years.Additional file 1Patient 2 is a 5-year-old girl with DIRV and double-outlet RV (DORV) who underwent balloon septostomy and pulmonary valve dilation as a neonate because of cyanosis. At 6 months of age she underwent bi-directional Glenn anastomosis and atrial septectomy. At 2.5 years she underwent fenestrated lateral tunnel Fontan operation, with device closure of the fenestration 6 weeks later. By 5 years she had developed increased fatigue and abdominal pain with exercise. An echocardiogram showed severely depressed global RV systolic function with minimal left AV valve regurgitation , mean pressure in the Fontan circuit of 10–11 mmHg, wedge and RV filling pressure of 6 mmHg, and no coronary obstruction. She became increasingly symptomatic with limited activity, abdominal pain, and failure to gain weight. She underwent orthotopic heart transplantation at 5 years of age.Additional file 2Patient 3 is a 19-year-old man with congenitally physiologically corrected transposition of the great arteries (C-TGA), atrio-ventricular and ventriculo-arterial discordance, who underwent closure of a ventricular septal defect at 3 months of age. By age 10 years he had begun to have reduced stamina. Echocardiography showed moderately decreased RV systolic function which progressed to severe global dysfunction by age 16 years , markedly elevated RV filling pressure (33 mmHg), pulmonary artery hypertension (1/2 systemic), and elevated systemic venous pressure (12 mmHg). Heart failure progressed leading to inpatient treatment with inotropic support and heart transplantation at age 19 years.Additional file 3For comparison, a heart with postnatally acquired RVH was obtained at autopsy from a 1-year old boy who died from idiopathic pulmonary vein stenosis Fig. d.The systemic RV is markedly hypertrophied and often bizarrely shaped , in which loss of fiber orientation, fibrosis and disarray lead to a reduction of FA , 22. DifThe only previous report of diffusion imaging in a systemic RV of which we are aware was in a living adult patient with transposition of the great arteries and an atrial switch operation . Helix aFirst, our study is based on a very small number of cases. This reflects the limited availability of such hearts for study and is only an initial exploration of these abnormal hearts. Second, although the resolution of our DW CMR exams was higher than most reported studies in human hearts, each glyph or fiber tract represents hundreds or thousands of myofibers. Consequently, our data reflect the orientation of aggregate myocardial diffusion streamlines and not individual myofibers. Given the organization of the myocardium in these hearts into trabeculae, the flow streams that we describe appear to reflect the level of myocardial organization likely to be important for ventricular function. Third, we had no control over the phase of the cardiac cycle in which the heart arrested. We fixed the hearts mildly distended to standardize the conditions as much as possible. Finally, the heart with RV hypertrophy and no structural heart defect was from a significantly younger child than the other hearts. However, it represents the effects of postnatal hypertrophy on myofiber organization.Our work shows for the first time that the failing systemic RV in congenital heart disease is abnormally structured and, although it is not clear yet whether these alterations are genetically or hemodynamically determined, they could be the substrate for heart failure and arrhythmias affecting these patients.


The author has undertaken multiple echocardiographic studies during his academic career; most of these were published in peer-reviewed journals. These studies include an evaluation of the role of echocardiography in the estimation of left-to-right shunt in isolated ventricular septal defects, an examination of the utility of contrast echocardiography in the diagnosis of anomalous connection of the right superior vena cava to the left atrium, a description of pitfalls in M-mode echocardiographic assessment of the aortic root in left ventricular hypoplasia syndromes, reviews of echocardiographic evaluation of left ventricular function, study of the role of contrast echocardiography in the evaluation of hypoxemia following open heart surgery, a quantification of left ventricular muscle mass by m-mode echocardiography in children, an examination of race and sex related differences in echocardiographic measurements in children, study of cardiac size and function in patients with sickle cell disease, an examination of afterload reduction in the management of primary myocardial disease, study of the utility of echo-Doppler studies in the evaluation of the results of balloon pulmonary valvuloplasty, study of the usefulness of Doppler in the prediction of pressure gradients in valvar pulmonary stenosis, a review of Doppler echocardiography in noninvasive diagnoses of heart disease, echo-Doppler studies of the evaluation of the results of balloon angioplasty of aortic coarctation, study of the value of Doppler in the prediction of pressure gradients across coarctation of the aorta, and a characterization of foramen ovale and transatrial Doppler velocity patterns in the normal fetus. When the author was named as Interim Director of Pediatric Echocardiography Laboratory at Children’s Memorial Hermann Hospital/University of Texas-Houston Medical School, Houston, Texas in 2006, some of the staff critiqued this appointment, as the author was considered to be an interventionist pediatric cardiologist. The author responded to this critique by sending them a list of the his echo publications ,31,32,33At the time of the author’s fellowship training in 1969/1970 at Stanford University Medical Center, Palo Alto, California, there were only two echocardiography recording machines in the United States: one was at University of Indiana, Indianapolis, Indiana and the other at Stanford University. The author was exposed to echocardiography to evaluate mitral valve motion and pericardial effusion on M-mode tracings. During subsequent fellowship training at Case-Western Reserve University and the University of California at Los Angeles, the echo machines had not yet arrived at the respective institutions. By 1972, when the author joined the Faculty at the Medical College of Georgia, Augusta, Georgia, there were indeed echocardiography facilities at that institution. Shortly thereafter, Dr. Wesley Covitz  joined our faculty at Georgia and provided the author with additional understanding of the principles and practice of M-mode echocardiography, thereby adding to the author’s knowledge base. This resulted in the author’s active participation in echocardiography research at that time ,4,5. Twop < 0.01) than those of control subjects , we compared the cardiac catheterization data with echocardiographic values (echo performed within 24 h of cardiac catheterization) in 35 babies; 35 children with normal hearts by physical examination and ECG were used as controls ) in the modified Bernoulli equation. Duration-related measures of Doppler flow signal distal to the coarctation site, namely, acceleration time (AT) and antegrade flow time (AFT)  , were al2) peak instantaneous and catheterization-measured peak-to-peak gradients resulted in a correlation coefficient of 0.757. (22 − V12]) in the modified Bernoulli equation (r = 0.763). A comparison of the catheterization data with antegrade flow time (r = 0.82) and antegrade flow time fraction (r = 0.737) showed marginal, if any, improvement in the correlation coefficients  following balloon angioplasty of native aortic coarctation; this was similar to reduction in peak-to-peak pressure gradients by catheterization. A discussion of possible reasons for the lack of correlation between Doppler and catheter gradients included peak-to-peak vs. peak instantaneous gradients and possible collateral vessel flow in aortic coarctation. It was concluded that (i) the magnitude and duration related Doppler velocity recordings are helpful in estimating coarctation gradients, and (ii) Doppler is useful in demonstrating the relief of obstruction by balloon angioplasty [It was further noted that the Doppler flow velocity magnitude and calculated gradients improved  in fetal circulation, the size of and shunt velocity patterns across the FO in the fetus had not been thoroughly investigated as of the mid-/late-1980s. Therefore, we endeavored to define the normal size of FO and the Doppler velocity patterns across the atrial septum in the normal fetus. Normal human fetal ultrasound studies in 48 consecutive fetuses were examined and the size of FO, foramen flap angle , its motThe maximal FO diameter was similar to the diameter of the Ao at all gestational ages ; there wOur study showed that the size of normal foramen ovale is similar to aortic root diameter, and that the foramen flap angle reaches 30 degrees or greater. Right-to-left flow is as anticipated for fetal circulatory physiology; the left-to-right flow documented in this study was unexpected and may be related instantaneous pressure difference between atria, as previously shown in patients with tricuspid atresia . These fThe author’s contributions to the echocardiography literature from 1991 to the current date will be detailed in Part II of this review.


There are a variety of causes of left ventricular aneurysm, but it is rarely due to a disturbance in intraventricular hemodynamics. To the best of our knowledge, there have been no reports of ventricular aneurysm at the left ventricular apex caused by an abnormal left ventricular muscle bundle.We report two cases of patients with congenital abnormal left ventricular muscle bundles which caused disturbances in intraventricular hemodynamics. This process eventually led to a left ventricular aneurysm at the apex of the heart. In both cases, transthoracic echocardiography (TTE) and cardiac magnetic resonance imaging (CMR) indicated ventricular aneurysm formation at the apex of the left ventricle. There were also abnormal muscular bundles connecting the ventricular septum and the posterior wall of the left ventricle. The only differences between these two cases were the comorbidities and severity of symptoms.Ventricular aneurysm at the apex of the left ventricle is common. However, it is rare for a ventricular aneurysm to form due to intraventricular hemodynamic disturbances caused by an abnormal muscle bundle as opposed to that due to original ventricular wall damage, which is more common. There is currently a lack of relevant studies on the treatment and prognosis of such patients. Whether surgical resection of a ventricular aneurysm leads to a better prognosis remains uncertain. Currently, the common definition of ventricular aneurysm adopted by most clinicians is any large area of left ventricle (LV) akinesia or dyskinesia that reduces the LV ejection fraction. Myocardial infarction (MI) is the most common cause of ventricular aneurysm; other underlying diseases include sarcoidosis, trauma, left coronary artery originating from the pulmonary artery, Chagas disease, or myocarditis . IdiopatA 67-year-old man developed chest tightness and recurrent cerebral infarction. No obvious cause of cerebral infarction was found in the local hospital, so the patient was subsequently referred to our hospital for further evaluation. The patient had no family history of heart disease. A physical examination demonstrated left-downward displacement of the cardiac apex. Subsequently, transthoracic echocardiography (TTE) displayed a slightly enlarged left ventricle (left ventricular end-diastolic diameter was 55 mm) with decreased segmental motion of the ventricular wall and ventricular aneurysm formation at the apex of the left ventricle. Cardiac function was reduced, with a left ventricular ejection fraction (LVEF) of 45%. The left ventricle had several abnormal muscle bands connecting the posterior wall of the left ventricle and the interventricular septum, which separated the left ventricle into two parts. There was a relatively small communication between the main chamber and the aneurysm, with a diameter of 20 mm in diastole, and color Doppler flow imaging (CDFI) showed no obstruction to blood flow in the communication. Doppler detected a velocity of 190 cm/s during systole , coronary angiography (CAG) and cardiac magnetic resonance imaging (CMR) to identify a common etiology. There was no obvious abnormality in the ECG, and CAG showed no obstructive lesions. Even after an extensive investigation, we could not identify any common cause of ventricular aneurysm formation. We repeatedly inquired about the medical history of the patient. He complained of discomfort in the precordium since he was young and underwent TTE in 1989 and 1995. The TTE indicated the existence of a large abnormal muscle bundle that separated the left ventricle into two lumens including a proximal chamber and a distal chamber; however, there was no ventricular aneurysm at that time. The diameter of the communication measured 15 mm in diastole. Different from the present situation, we detected a mean systolic gradient of 35 mmHg and a diastolic gradient of 10 mmHg between the two chambers by continuous wave Doppler. Therefore, we believe that the formation of the apical ventricular aneurysm was related to hemodynamic changes caused by the multiple abnormal bundles in the left ventricle. Subsequent CMR confirmed the existence of the abnormal muscle bundles and the apical ventricular aneurysm with a wall thickness of 4 mm  at a local hospital and received standard medical therapy for CHD . However, subsequent coronary angiography showed no significant stenosis of the coronary arteries. Because coronary spasm and microvascular lesions could not be ruled out, doctors continued to give her routine treatment for CHD. The patient’s symptoms persisted after treatment at the local hospital, and she was subsequently referred to our hospital for treatment. TTE showed a left ventricle diastolic diameter of 64 mm and diffuse hypokinesis, with an LVEF of 34%. It is noteworthy that an apical ventricular aneurysm with a wall thickness of 3 mm had formed. Multiple, developed muscle bundles were found in the left ventricle, which also divided the left ventricle into two distinct chambers. Blood entered the apical aneurysm in diastole and was ejected out of it in systole, as it occurs in the normal LV. The diameter of the communication measured 25 mm in diastole. The flow rate from the main chamber to the apical aneurysm was 150 cm/s. The patient also had no family history of heart disease. Subsequent CMR suggested that the myocardial three-layer structure in the left ventricular apex disappeared with ventricular aneurysm formation  during systole . In addiFurthermore, the symptoms of cardiac insufficiency and systemic emboli in these two patients remind us of the need to consider non-compact cardiomyopathy (NCM), which is of genetic origin. The characteristic features of NCM include a two-layered ventricular wall, comprising a thinner compact epicardial layer and an inner non-compact layer, with prominent trabeculations associated with deep, inter-trabecular recesses. Echocardiography and CMR are effective tools for detection of these morphologic diagnostic criteria .There are currently no reports on treatment for this kind of abnormality. Resection of the abnormal muscle bundle might be helpful to prevent aneurysm formation, but open surgery seems impractical before the aneurysm forms unless severe obstruction exists. Resection of the aneurysm is a reasonable approach for those with symptomatic heart failure or arrythmia. Since the first patient had only mild symptoms of heart failure and exhibited less myocardial necrosis on CMR, we recommended an anticoagulant drug and ACE inhibitor, as well as scheduled follow-up. However, the second case was a younger patient with more severe symptoms of heart failure. Therefore, we recommended surgical resection of the aneurysm, but she declined, as she felt much better after 1 month of medical treatment. Both patients have been discharged and have remained in good condition for the past few months.In summary, given that the morbidity of abnormal ventricular muscle bundle-associated ventricular aneurysm is extremely rare, clear data about the prognosis, risk factors, and treatment of this condition are unavailable. The effectiveness of drugs that attenuate ventricular remodeling needs further research. Surgical treatment, however, is indicated when other cardiovascular abnormalities or left cardiac insufficiency is present. The timing of operation is decided based on the cardiac function of the patient, the risk of ventricular aneurysm rupture and the degree of obstruction between the two chambers. The patient’s need for anticoagulation therapy depends on his presentation. Anticoagulation may be necessary in the event of repeated embolization.


In both groups, mitral A and tissue Doppler E’, A’, and S’ values decreased post-closure, while the E/E’ was higher in Group II than in Group I at both pre-closure and long-term follow-up measurements . The LA size and LV function exhibited recognizable remodeling after transcatheter ASD closure. Because the LV preload elevation  after ASD closure can be pronounced in older patients, caution should be provided more in older patients than in younger patients. Hence, it may be beneficial to close the ASD at an earlier age in adults even after a late diagnosis; a relatively younger age may be more suited for adaptation to the remodeling process to protect the myocardial function. Careful consideration should be given to the previous underloaded left heart after long-term closure.Transcatheter device closure of a secundum atrial septal defect (ASD) is followed by a noticeable change in the left atrium (LA) and left ventricle (LV) over a long-term follow-up. This study aimed to assess the remodeling of the atrial and ventricular myocardium with respect to diastolic function in adult ASD patients. Around 38 asymptomatic patients  diagnosed with ASD during routine health check-up and who underwent ASD device closure with the Amplatzer septal occluder were included in this retrospective study, and their medical records (containing echocardiographic data) were reviewed. The defect size was 21.77 + 6.79 mm, while the balloon measurement of the defect was 24.29 ± 6.64 mm. The patients were divided into two groups, namely, Group I (with 18 patients aged <50 years [mean: 33.06 ± 9.43 years] and Group II (with 20 patients aged ≥50 years [mean: 62.55 ± 7.54 years]). Comparison of echocardiographic data collected before closure and at a follow-up 2 years later revealed significant differences between pre-closure and post-closure states in the left ventricular end-diastolic dimension (40.76 ± 3.28 vs. 43.39 ± 3.52), left ventricular mass (99.64 ± 28.81 vs. 116.57 ± 32.03), and right ventricular pressure (36.88 ± 12.20 vs. 31.81 ± 11.11). Tissue Doppler measurements were significantly decreased 2 years after closure, while the post-closure E/E’ was higher than the pre-closure E/E’ (11.58 ± 4.80 vs. 8.79 + 3.19,  In recent years, an increasing number of cases with atrial septal defect (ASD) have been treated using transcatheter device occlusion. Beneficial for hemodynamic improvement, it is a safe procedure that is associated with lesser complications than conventional surgical procedures ,2. HowevLeft-to-right inter-atrial shunting through the ASD causes right and left heart volume overload , and chaThe purpose of this study was to assess cardiac function including diastolic function after transcatheter atrial septal defect closure in asymptomatic younger and older patients with ASD.Thirty-eight patients  incidentally diagnosed with ASD during routine health check-up, and who were indicated for ASD treatment and underwent ASD closure with the Amplatzer Septal Occluder, were included in this retrospective study. All the patients were asymptomatic. The patients’ medical records, including the echocardiographic data collected before closure and 2 years after closure during a follow-up, were reviewed. The patients were divided into two groups according to their ages: Group I consisted of 18 patients <50 years old (33.06 ± 9.43 years) and Group II consisted of 20 patients ≥50 years old (62.55 ± 7.54 years). The echocardiographic data comprised the LV inflow velocity, early and late mitral inflow velocities with the ratio of early diastole to atrial contraction (E/A), tissue Doppler image (TDI) findings, and all conventional measurements such as the LV and right ventricular (RV) diameters, LV ejection fraction (LVEF), LV mass, and LA volume. The LVEF was calculated using the Teichholz formula, while the mitral inflow pattern was assessed using the peak velocity during E and A, the ratio of E to A, and the E deceleration time. Myocardial velocities were obtained by tissue Doppler measurements (TDI) of the septal E’, septal A’, septal S’, septal E/E’, lateral E’, lateral A’, lateral S,’ and lateral E/E’, then all the TDI values were presented with the average of septal and lateral measurements.The pre- and post-closure data were compared. Furthermore, these data were also compared between the two groups. t tests were used to analyze changes in the continuous variables between baseline and follow-up assessments; accordingly, the pre-closure and post-closure baseline characteristics were compared using a paired t test. Differences between Groups I and II were assessed using an unpaired t test. The Wilcoxon signed-rank test was used to compare variables between the baseline and follow-up assessments. p-values <0.05 were considered statistically significant.All statistical analyses were performed using SPSS version 23.0 for Windows . Data are expressed as means ± SD. Paired This study was approved by the Yonsei University College of Medicine Institutional Review Board and the Research Ethics Committee of Severance Hospital . All research was performed in accordance with the relevant guidelines and regulations. The requirement for written informed consent was waived by the Institutional Review Board owing to the retrospective study design.Thirty-eight patients were indicated for ASD closure. The defect size was 21.77 + 6.79 mm and the balloon measurement was 24.29 ± 6.64 mm, with RV volume overload and without pulmonary hypertension. The post-closure measurements of left ventricular end-diastolic dimension (LVEDD) and the LV mass were greater than their pre-closure measurements. The post-closure RV pressure was lower than the pre-closure RV pressure . LA voluIn Group I, the post-closure measurements of the LVEDD, LV mass, and mass index were higher than their pre-closure measurements. The post-closure RV pressure was lower than the pre-closure RV pressure. The post-closure measurements of TDI E’ and S’ were lower than their pre-closure measurements; however, A’ was higher at post-closure than at pre-closure. The estimated post-closure E/E’ was higher than the pre-closure E/E’  Figure .In Group II, the pre-closure measurements of LVEDD, LV mass, and mass index were higher than their pre-closure measurements. The post-closure RV pressure was lower than the pre-closure RV pressure. The TDI E’ and S’ at post-closure were lower than those at pre-closure; however, the post-closure A’ was higher than the pre-closure A’. The estimated post-closure E/E’ was higher than the pre-closure E/E’  Figure .p = 0.008) (p = 0.008)  (p = 0.005) and II    and II (= 0.008) . Both A’ < 0.02) , also E/= 0.005) . Left-to-right inter-atrial shunting through the ASD causes right and left heart volume overload . Even inIn patients presenting with senile LV dysfunction, left-to-right shunt in ASD could offer another inter-atrial route for LA flow instead of LV filling, and mask the abnormal increase of LA pressure and LV filling pressure . TherefoTo exclude ASD patients with existing diastolic dysfunction, we included asymptomatic patients who believed that they did not have any heart diseases or cardiac dysfunction, and were incidentally diagnosed with ASD at routine health check-up without presenting with arrhythmias, right HF, or pulmonary hypertension. Surprisingly, the size of their ASDs were relatively large, and they presented with RV volume overload; the defect size was 21.77 + 6.79 mm and the balloon measurement was 24.29 ± 6.64 mm, certainly requiring treatment with device occlusion. ASD closure causes a rapid left ventricular (LV) volume overload and a consequent surge in myocardial oxygen consumption, because of the abrupt stoppage of the left-to-right shunt. These important hemodynamic changes are generally tolerated in patients with normal LV function , but mayAs we compared the echocardiographic measurements taken before procedure and 2 years after ASD closure, the LVEDD and LV mass were observed to have increased, while the RV pressure had lowered after closure. With ASD closure, the LV changed from being a long-standing underloaded chamber to a relatively enlarged chamber that was as normal as could be expected, while the RV changed from being a volume-overloaded ventricle with an elevated pressure to a reasonably-sized chamber with a reduced volume. Meanwhile, LA volume and the LA volume index showed the increased measurement after closure, even it was without statistical significance, however, the older age patients showed the variation of re-decreasing LA volume and LA volume index , which mFurthermore, the post-closure increase of E/E’ implied a diastolic function decline with relaxation abnormality in all the patients in younger age and older age group . DiastolPrevious studies that examined changes in relaxation using echocardiographic parameters measured before and after ASD device repair yielded inconsistent results. Hanseus KC et al. reported no significant changes in relaxation 1 or 2 days after ASD closure in both, the pediatric  and wideAs Tomai F et al. reported for the case of ASD related with LV dysfunction, a real-time preprocedural evaluation of the hemodynamic effects with left-to-right shunt elimination may be useful for decision-making . Even thThe most prominent and consistent hemodynamic change after transcatheter ASD closure, and subsequent elimination of the inter-atrial shunt flow with device occlusion, is an increase in the LV preload with a simultaneous decrease in the RV volume. If LV diastolic dysfunction already existed before ASD closure, the LV cannot handle this acute elevation in preload after closure, resulting in a marked escalation of the LV end-diastolic pressure and pulmonary congestion . FurtherTherefore, older patients experience prominent diastolic dysfunction after ASD closure more frequently than younger patients, as demonstrated by our study results. Moreover, even asymptomatic patients exhibited a similar diastolic function change after ASD closure, without presenting with any cardiac function deterioration patterns before diagnosis. We believe that ASD closure in elderly patients with suspected or existing LV or RV dysfunction should be performed only after a meticulous consideration of the hemodynamic benefits and risks of closure ,19. The limitation of this study, due to the retrospective review of the patients from the regular health check-up, did not include blood test, especially brain natriuretic peptide (BNP) data, quality of life data with cardiac function including diastolic assessment long-term prior to ASD closure. Although it is not possible to investigate the functional change and myocardial analysis, all the included patients were asymptomatic without any cardiac disease, such as arrhythmias, right HF, or pulmonary hypertension. Further study will be necessary with the prospective design for the various aspects, not only for the diastolic function, but also with the quality of life with functional class, and other various comorbidities including diabetes, liver or kidney issues, comparing with healthy controls.The LA size and LV function exhibited recognizable remodeling after transcatheter ASD closure. Because the LV preload elevation  after ASD closure can be pronounced in older patients, caution should be provided more in older patients than in younger patients. It may be beneficial to close the ASD at an earlier age in adults even after a late diagnosis; a relatively younger age may be more suited for adaptation to the remodeling process to protect the myocardial function. In addition, vigilant early care would be helpful for the previous underloaded left heart by considering for latent diastolic impairment with the procedure.


Long‐term right ventricular pacing is the only treatment for patients with a complete atrioventricular block (CAVB); however, it frequently triggers ventricular dys‐synchrony with left ventricular (LV) dysfunction. Previous studies showed that an early decline of LV global longitudinal strain (GLS) predicts pacing‐induced LV dysfunction. We aimed to investigate the potential ability of the initial LV strain to predict pacing‐induced cardiomyopathy (PICM) through long‐term follow‐ups.We retrospectively enrolled 80 patients with CAVB with normal LV function who were implanted with dual‐chamber pacemakers between 2008 and 2018. Echocardiographic data and parameters  were analyzed for the pre‐implant (≤6 months) and post‐implant periods. PICM was defined as a ≥10% reduction in the left ventricular ejection fraction (LVEF) resulting in an LVEF of <50% during the post‐implant period. Predictors of PICM were identified using Cox proportional hazard models.P = .016, P = .011, and P = .026, respectively). In the multivariate analysis, pre‐implant LV GLS  was independently associated with the development of PICM.Patients who developed PICM were more likely to exhibit lower baseline LV GLS, as well as wider native and pacing QRS durations, than those who did not develop PICM (A lower baseline LV GLS predicts an increased risk of PICM. Patients with CAVB exhibiting low GLS are at increased risk of PICM. More frequent follow‐up visits are warranted in these patients, who may also require de novo His‐bundle pacing or an upgrade to biventricular pacing. However, this method is less effective than native human pacing, given that it can only produce approximately one quarter of the normal conduction velocity and may induce heterogeneous electrical ventricular activation.Despite this knowledge, predicting PICM remains challenging.22.1We retrospectively reviewed data from 131 patients who received a pacemaker due to a complete atrioventricular block (CAVB) between January 2008 and January 2018. Inclusion criteria were as follows: baseline LVEF ≥ 50%, implantation of a single‐chamber ventricular or dual‐chamber pacemaker (but not of an implantable cardioverter‐defibrillator or biventricular pacemaker), echocardiography ≤6 months before and after pacemaker implantation in our hospital using the same manufacturer's echocardiography machine. Patients with atrial fibrillation, congenital heart disease, more than a moderate degree of valvular heart disease, a history of open‐heart surgery, and a history of myocardial infarction were excluded. Patients were also excluded due to technical issues related to echocardiographic image analysis if the examinations were performed at another hospital, the echocardiographic images could not be analyzed due to low frame rate, there was a poor echo window, or the images were in a non‐DICOM format. PICM was defined as a ≥10% decrease in LVEF, resulting in an LVEF < 50%. Patients with other definite causes of cardiomyopathy including atrial fibrillation on follow‐up ECG, those with high right atrial (RA) episodes, and those with >1% automatic mode switching in the pacemaker program were also excluded. The study protocol was approved by the Institutional Review Board of Eulji University Hospital (IRB No. EMC 2018‐01‐013‐006).2.2Patients underwent echocardiography  with a 3.5‐MHz phased‐array transducer. A total of two consecutive cycles in three parasternal short axis views  and three longitudinal standard apical views  were obtained. The resulting loops were digitally stored and subsequently analyzed offline using EchoPAC workstation 7.1.1 software (GE Vingmed). The LVEF was calculated using the modified Simpson's method. Speckles were tracked frame by frame throughout the LV myocardium over the course of one cardiac cycle, following which the basal, mid, and apical regions of interest were defined. Thereafter, each image was carefully inspected, and the segments that failed to track were manually adjusted. If more than one segment could not be tracked, there was a lack of a full cardiac cycle, or there was significant foreshortening of the left ventricle, then the measurements were considered unreliable, and the patient was excluded from our study. Global radial and circumferential strain values were calculated as the average strain across the parasternal views. GLS was calculated as the average strain across the apical four‐, two‐, and three‐chamber views. Analyses were performed on single, optimal cardiac cycle. All analyses were conducted offline, and the analyzer was blinded to the identities of the patients and other clinical data.2.3To assess inter‐observer variability in measurements of global strain, a subset of 10 randomly selected echocardiographic images (19% of patients) were assessed by two observers (Jung Yeon Chin and Ho‐joong Yoon) who were blinded to each other's results. Four weeks later, these measurements were reviewed by the same investigator, who remained blinded to the previous results. Both inter‐ and intra‐observer variability were expressed in terms of intra‐class correlation coefficients and percent variability.2.4t tests and Pearson's χ2 tests, for which P‐values < .05 were considered statistically significant. The survival curve for PICM was generated using the Kaplan–Meier method. Univariate and multivariate predictors of PICM were analyzed using Cox proportional hazard models. The variables used for the univariate analysis included sex, age (per 1‐year increase), coronary artery disease, hypertension, diabetes, beta‐blocker use, calcium channel blocker use, diuretic use, initial echocardiographic parameters , initial ECG findings (including native and paced QRS duration), and ventricular pacing percentage. Receiver operating characteristic curve analysis was performed to determine the optimal sensitivity and specificity of LV global longitudinal peak systolic strain. Values higher than the cutoff values were considered positive. All data were analyzed using SPSS .Continuous variables are expressed as medians and interquartile ranges, while categorical variables are expressed as percentages. Continuous and categorical variables were compared using Student's 3We initially enrolled 80 patients who received a pacemaker due to a CAVB with normal baseline LVEF values and no atrial fibrillation on initial and follow‐up ECG. We further excluded 28 patients for various reasons: Seven patients were excluded because they did not undergo baseline echocardiography at Daejeon Eulji University Hospital, 15 were excluded due to poor image quality (low frame rate/poor windowing), two were excluded because they did not undergo follow‐up echocardiography, one was excluded due to previous mitral valve replacement, one was excluded due to an atrial septal defect with pulmonary stenosis, and two were excluded due to myocardial infarcts after receiving a pacemaker. Of the 52 remaining patients, 16 (31%) were diagnosed with PICM, while the remaining 36 were not (69%). The mean follow‐up duration among these 52 patients was 5.2 years . However, post‐implantation LVEF values were significantly lower in the PICM group than in the non‐PICM group  and native QRS duration  remained independently associated with the development of PICM , 0.80 , and 0.74  for global longitudinal, radial, and circumferential strain, respectively. Percent variability for global longitudinal, radial, and circumferential strain was 6.2%, 10.0%, and 11.7%, respectively. The intra‐observer variability for global strain was also low, with intra‐class correlation coefficients of 0.93 , 0.94 , and 0.91  for global longitudinal, radial, and circumferential strain, respectively. Similarly, percent variability for each type of strain was 2.2%, 6.4%, and 4.9%, respectively.The inter‐observer variability for global strain was low: Intra‐class correlation coefficients were 0.87  in the current study, pacing QRS duration exhibited significant predictive ability in the univariate analysis only, showing a positive trend in the multivariate analysis. Given that the previous study relied on data from a different population , additional large‐scale multi‐center cohort studies are required to determine whether pacing or native QRS duration can predict PICM occurrence.In accordance with previous findings, our data indicate that PICM may be more common in patients with relatively longer native QRS durations. A previous study reported that a wide native QRS duration was associated with higher rates of death, heart transplantation, and LV device implantation in patients with non‐ischemic cardiomyopathy and ventricular tachycardia.A previous meta‐analysis reported that LV GLS exhibited greater prognostic value for global LV dysfunction than LVEF in patients with HF, acute myocardial infarction, and valvular heart disease.There are three potential explanations for the increased risk of PICM in patients with GLS values <−21%. This value is considered high when compared to a GLS value of >−18%, which has been considered normal. However, a recent meta‐analysis of 2396 individuals with a mean age of 42 years conducted from 2011 to 2018 indicates that the new normal value for GLS is −21% (range: −22.7% to −19.2%). This new range coincides with findings we observed in healthy children, whose mean LV GLS is −20.2%. The discrepancy between our results and the standard normal value may be due to our use of the latest data when analyzing GLS value. Although GLS is dependent on weight, age, and load, variations among equipment vendors may also explain the observed differences in the cutoff values. According to the abovementioned meta‐analysis, the normal range for GLS varied among vendors, with values for Tomtec and General Electric being significantly higher than those for Toshiba, Philips, and Siemens. In our study, data were obtained from a General Electric Echopac device, which may again explain the higher value. Finally, cumulative ventricular pacing percentage (>80%) was higher, while the duration of follow‐up was longer (4.5 years), in our study than in previous studies. This high pacing burden results in more instances of PICM because premature ventricular contractions activate vagal afferents and alter autonomic tone. This finding suggests that patients with supernormal LV GLS values can be protected from PICM.Patients in the PAVD study exhibited low GLS values 1 month after receiving a pacemaker. GLS values at 1 month also predicted pacing‐induced LV dysfunction at 12 months . However, there were no significant differences in baseline GLS between patients with and without LVEF decline (−16.3 vs −17.5). Most patients included in this study had a second‐degree atrioventricular block (82%), rather than a third‐degree block, the latter of which requires more pacing. In the PAVD study, mean cumulative ventricular pacing at 12 months was only 53.5%, whereas it was 80% in our study.4.1Our study is the first to analyze baseline LV strain as a prognostic indicator of PICM. In addition, we utilized recent real‐world data and analyzed LV strain using the same instrument. In contrast to previous studies regarding PICM, we selected patients with CAVB to exclude bias related to the percentage of pacing. Patients with CAVB are mostly pacing‐dependent, whereas the percentage of pacing is diverse among patients with sick sinus syndrome or tachy–bradycardia syndrome. Furthermore, we carefully excluded patients with other causes of cardiomyopathy.4.2Our study was clearly limited by the small number of patients and its single‐center design. Furthermore, inclusion bias may exist because we excluded patients with poor echocardiographic images, patients who did not undergo follow‐up echocardiography, and patients who underwent echocardiography at other hospitals. However, due to the follow‐up policy at our hospital, we are potentially able to identify patients with PICM slightly earlier than other hospitals.5Our study provides evidence that the prognostic value of GLS for predicting adverse cardiac events is superior to that of LVEF. Indeed, our findings indicate the PICM may begin to develop even when LV function is still normal, and that the risk of PICM can be predicted based on baseline GLS. As such, patients with low GLS are at increased risk of developing PICM. These patients warrant closer follow‐up examinations and must be considered for de novo His‐bundle pacing or an upgrade to cardiac resynchronization therapy to avoid LV dys‐synchrony.Dr. Ki‐Woon Kang contributed to the conceptualization to this work and we appreciated it.None declared.


In patients with non-obstructive hypertrophic cardiomyopathy (HCM) and preserved left ventricular (LV) systolic function, diastolic dysfunction is one of the major factors contributing to limited exercise capacity.To assess the usefullness of simple cardiovascular magnetic resonance (CMR) parameters of LV diastolic function at rest and exercise capacity in patients with non-obstructive HCM and preserved LV systolic function.The study included 13 patients who underwent cardiopulmonary exercise testing on treadmill and CMR within 1 month distance. Analyzed parameters of diastolic function included: atrio-ventricular plane descent (AVPD), sphericity index (SI), left ventricular mass index (LVMI), peak filling rate normalized to LV stroke volume index (PFR/LVSVI) and time from the end-systole to PFR normalized to heart rhythm (TPFR).2peak) . Patients with V02peak below median (<30 ml/kg/min) had a significantly lower PFR/LVSVI then patients with higher V02peak [5.12 m2/s, interquartile range (IQR) 4.16–6.82 vs. 7.93 m2/s, IQR 7.49–8.21 respectively, p = 0.035). AVPD, SI, LVMI, TPFR were not related to exercise capacity. There was also no correlation between V02peak and age , LV ejection fraction  or normalized LV volume indices: LVEDVI , LVESVI .There was a significant correlation between PFR/LVSVI at rest and peak oxygen uptake (V0Assessment of LV diastolic function by peak filling rate normalized to stroke volume index with means of CMR at rest in patients with non-obstructive hypertrophic cardiomyopathy and preserved LV systolic function is a usefull predictor of exercise capacity. It can be added to CMR study protocols of HCM patients.


Objective: We sought to investigate the possible association of a wide QRS-T angle on the surface EKG and myocardial fibrosis on contrast-enhanced cardiovascular magnetic (CMR) imaging in patients with hypertrophic cardiomyopathy (HCM).Background: Risk stratification in HCM patients is challenging. Late gadolinium enhancement (LGE) visualizes myocardial fibrosis with unique spatial resolution and is a strong and independent prognosticator in these patients. The QRS-T angle from the surface EKG is a promising prognostic marker in various cardiac pathologies.Methods: 70 patients with HCM obtained a standardized digital 12-lead EKG for the calculation of the QRS-T angle and underwent comprehensive CMR imaging for visualization of fibrosis by LGE. Patients were divided into groups according to the absence or presence of fibrosis on CMR.Results: 43 of 70 patients with HCM showed LGE on CMR following contrast administration. HCM patients with LGE (fibrosis) had wider QRS-T angles as compared to the patient group without LGE . A QRS-T angle of 90 degrees or more was a strong predictor  of HCM with LGE.Conclusion: There is a strong association of a wide QRS-T angle and myocardial fibrosis in patients with HCM. Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease characterized by left ventricular hypertrophy We sought to investigate the association of fibrosis (LGE), the morphologically substrate of life-threatening arrhythmias in HCM, and the QRS-T angle a simple prognostic parameter from routine EKG.We consecutively enrolled patients with known HCM admitted for further risk stratification by CMR to the CV Imaging Section of our Department of Cardiology and Angiology at Elisabeth Hospital Essen Germany. HCM was defined by the presence of left ventricular hypertrophy with an end diastolic septal thickness of 13 mm or more, occurring in the absence of secondary causes such as hypertension, aortic valve stenosis or phenocopy conditions . A standardized 12-lead digital EKG using a Schiller Cardiovit AT 102 plus® was recorded at a speed of 50 mm/s speed with 10mm/mV for the limb and precordial leads. Computerized values of QRS and T-wave axis were automatically given by the Schiller AT 102 plus® software. The frontal QRS-T-angle was calculated as the absolute difference between the frontal QRS- and frontal T-wave axes and expressed as absolute values CMR images were acquired on a 1.5 Tesla MR System  during end-inspiratory breath-holding using a phased-array receiver coil. Three long axis and 6 to 8 contiguous short axis cine images were acquired by using a steady-state free precession  sequence covering the entire left ventricle LV function was analyzed by outlining epicardial and endocardial borders on the short axis cine sequences. Left ventricular volumes and ejection fraction were derived from contour summation. Maximum wall thickness was evaluated in all end-diastolic short axis cine images. The extent of late gadolinium enhancement was assessed on short axis contrast images by planimetry of hyperenhanced pixels with a signal intensity of 2 standard deviation above normal remote myocardium, calculated by summation of disc method and expressed as percent of total left ventricular mass.Figure 2). Differences between groups were analyzed by the two-way ANOVA test. Univariate predictors of the presence of myocardial fibrosis on contrast CMR were analyzed using the chi-square test and expressed as hazard ratio (HR) with 95% confidence interval (CI). Multivariate binary logistic regression was performed to identify independent predictors of myocardial fibrosis on contrast CMR. All variables with an univariate p-value <0.05 were included in the final multivariate model. Results of the binary logistic regression model are presented in the same way as the variables in univariate analysis. The correlation between the QRS-T angle and the extent of fibrosis in CMR (fibrosis in percent of LV mass) was tested by pearsons correlation coefficient. All reported p-values are two-sided and a p-value <0.05 was considered statistically significant. All statistical analyses were performed with IBM SPSS Statistics version 26.0 .Continuous variables are presented as mean ± standard deviation and compared with the two-way ANOVA test. Categorical variables are presented as numbers and percentages and compared with the chi-square test. Mean QRST angle with 95% confidence interval are presented as a Box-Plot-diagram  with HCM were enrolled. Patients were divided into two groups according to the presence (n=43) or absence (n=27) of myocardial fibrosis (LGE) on contrast CMR. Patients with fibrosis had a wider QRS-T angle as compared to patients without fibrosis . 24 of 43 patients in the fibrosis group had a QRS-T angle of 90° or more, whereas only 1 of 27 patients in the non-fibrosis group displayed a pathologic QRS-T angle. For clinical examples, also see Table 1). As the number of risk factors increases, the QRS-T angles increase numerically between groups but missed significance niveau (p=0.881) .There were no differences with regards to age, gender, NYHA class and ejection fraction. Patients with myocardial fibrosis had greater maximum wall thickness . There were no differences in QRS-T angle for each single clinical risk factor  between HCM with and without fibrosis (p<0.001).In a multivariate analysis a QRS-T angle of 90° or more is a strong predictor  of HCM with myocardial fibrosis. There was a moderate correlation between the QRS-T angle on ECG and myocardial fibrosis defined by LGE. With increasing QRS-T angle the extent of myocardial fibrosis increased  and T loop (repolarization) and thus indicates electrical instability. In several cardiovascular patient groups the QRS-T angle has been shown to contribute substantially to risk stratification of SCD Late gadolinium enhancement visualizes HCM with myocardial fibrosis, the border zones of which reflect the morphological substrate for the re-entrant pathways of ventricular tachycardias. Early CMR studies were able to demonstrate a correlation of myocardial fibrosis on contrast CMR and ventricular tachycardia Shi et al. found that in 66 patients with reduced LV function before ICD placement LGE positive patients had a larger QRS-T angle In our study 24 of 25 (96%) patients with QRS-T angle ≥90° had myocardial fibrosis on CMR, whereas 26 of 45 (58%) patients with QRS-T angle <90° did not display fibrosis. Overall, the extent of fibrosis increased with increasing QRS-T angles on ECG. However, several limitations of our study have to be taken into account. Our study is retrospective analysis in a small patient group, no advanced CMR tissue mapping techniques were used and follow-up was not performed.In conclusion, a QRS-T angle of 90 degrees or more is strongly associated with advanced disease as indicated by fibrosis on contrast-enhanced CMR. Our study adds to a growing body of literature about the prognostic potential of the QRS-T angle in various cardiomyopathies. Of course prospective studies in a larger HCM patient population are needed to investigate the prognostic impact of the QRS-T angle in this specific group of patients.