We have evaluated cardiac function and fibrosis in infarcted male Wistar rats treated with MitoQ (50 mg/kg/day) or vehicle for 4 weeks. A cohort of patients admitted with a first episode of acute MI were also analyzed with cardiac magnetic resonance and T1 mapping during admission and at a 12-month follow-up. Infarcted animals presented cardiac hypertrophy and a reduction in the left ventricular ejection fraction (LVEF) and E- and A-waves (E/A) ratio when compared to controls. Myocardial infarction (MI) rats also showed cardiac fibrosis and endoplasmic reticulum (ER) stress activation. Binding immunoglobulin protein (BiP) levels, a marker of ER stress, were correlated with collagen I levels. MitoQ reduced oxidative stress and prevented all these changes without affecting the infarct size. The LVEF and E/A ratio in patients with MI were 57.6 ± 7.9% and 0.96 ± 0.34, respectively. No major changes in cardiac function, extracellular volume fraction (ECV), or LV mass were observed at follow-up. Interestingly, the myeloperoxidase (MPO) levels were associated with the ECV in basal conditions. BiP staining and collagen content were also higher in cardiac samples from autopsies of patients who had suffered an MI than in those who had died from other causes. These results show the interactions between mitochondrial oxidative stress and ER stress, which can result in the development of diffuse fibrosis in the context of MI. Cardiomyocyte necrosis, granulation tissue formation, inflammation, and scar maturation are important events in the healing process after myocardial infarction (MI) . The losMultiple mechanisms have been proposed as potential players in cardiac remodeling in the context of MI, including oxidative stress. MI triggers excessive reactive oxygen species (ROS) production, especially in response to the reperfusion that is produced in subcellular organelles such as the sarcolemma, endoplasmic reticulum (ER), and especially mitochondria through the electron transport chain . This ox2+ buffering and protein synthesis, folding, and processing, among others [The ER is a dynamic cellular organelle with different functions, including Cag others ,10. In ag others . Howeverg others . Both thn = 20 rats), as previously described [n = 20 rats) was included as a reference group (CT). Both groups of animals received the mitochondrial antioxidant MitoQ  in the drinking water for 4 weeks after surgery. The dose of MitoQ was based on previous data [MI was induced by ligation of the left anterior descendent (LAD) coronary artery in 12-week-old male Wistar rats /(2.4 + EDD), and the LV systolic chamber function was determined from the LV endocardial FS. The FS was calculated in percentage according to the formula: (EDD−EDS)/EDD. The diastolic function was assessed by the early and late transmitral peak diastolic flow velocity (E and A waves), and the ratio between E-waves and A-waves (E/A) was calculated. The images were processed with the Echopack software v. 201 .Cardiac function was evaluated by transthoracic echocardiography with a Vivid-I  connected to a 12 MHz transducer. Then, 2D-guided M-mode recordings were made from short-axis views at the level of the papillary muscles to measure the left ventricular (LV) chamber end-diastolic dimensions, interventricular septum, and posterior wall thickness. The mean measurements from several consecutive beats were used for the data analysis. The end-diastolic diameter (EDD) and end-systolic diameter (EDS) were used to calculate the left ventricular ejection fraction (LVEF) and the fractional shortening (FS). The LVEF was calculated in percentage according to the Teicholz formula: (EDDThe LV mass and infarct size were defined by magnetic resonance imaging (MRI). Both the LV mass and myocardial deformation parameters such as the radial strain and circumferential strain were analyzed in basal, medial, and apical short axis slices from steady state free precession images using a 17-segment model. The MRI study was performed with a Biospec BMT 47/40 spectrometer  located at the NMR Center of the Universidad Complutense of Madrid that was equipped with a 12 cm gradient system and connected to a 1025 SAM monitoring and a gating system , as is previously described [Cardiac tissue samples were dehydrated, embedded in paraffin, and cut in 4 μm thick sections. The sections were stained with picrosirius red in order to detect collagen fibers. The area of cardiac interstitial fibrosis was identified as the ratio of interstitial fibrosis or collagen deposition to the total tissue area after excluding the vessel area from the region of interest. For each sample, 10 to 15 fields were analyzed with a 40× objective under transmitted light microscopy . The cross-sectional area was measured in myocytes along the left ventricle  with visible nuclei, and intact cellular membranes were chosen for the determination of the cross-sectional area in hematoxylin and eosin staining sections with a 40× objective under transmitted light microscopy (Leica DM 2000) in three different sections. A quantitative analysis were performed using an analysis system .2−) levels, cardiac sections (14 µm) were incubated with dye dihydroethidium  for 30 min at 37 °C. DHE is oxidized by superoxide and exhibits red fluorescence. The oxidation products become highly fluorescent upon binding to nucleic acids. The fluorescent signals were viewed using a fluorescent laser scanning microscope . The quantitative analysis of O2− production was performed using an image analyzer . Three sections per animal were quantified and averaged for each experimental condition. The mean fluorescence densities in the target region were analyzed. The results are expressed as n-fold increases over the values of the control group in arbitrary units.For the detection of total superoxide anion  with the Trans-Blot Turbo Transfer System. Membranes were probed with primary antibodies for activating transcription factor 4 , activating transcription factor 6 alpha, , binding immunoglobulin protein , calpain 1 , calreticulin , CCAAT-enhancer-binding protein homologous protein , collagen I , connective tissue growth factor , cyclophilin F , mitofusin 1 , transforming growth factor β , and glyceraldehyde 3-phosphate dehydrogenase  as a loading control. The signals were detected using the ECL system . Several proteins were analyzed in the same membrane after a stripping procedure . The results are expressed as n-fold increases over the values of the control group in arbitrary densitometric units.A cohort of 44 patients admitted to a tertiary care center  with a first episode of acute MI were studied. MI was defined by “The Third Universal Definition of Myocardial Infarction” : an incrTransthoracic echocardiographic (TTE) images were acquired according to the cavity quantification guidelines of the American Society of Echocardiography and the European Society of Cardiovascular Imaging . ConventThe LVEF was calculated from the quantification of the LVEDV and LVESV obtained in the apical 4C and apical 2C planes using the following formula: LVEF = (LVEDV – LVESV)/LVEDV. Diastolic function was assessed according to the current guideline recommendations as well. Diastolic function was assessed by the early and late transmitral peak diastolic flow velocity (E and A waves), and the ratio between the E-waves and A-waves (E/A) was calculated. The images were processed with the Echopack software v.201.T1- and T2-weighted sequences were included in the study to detect late gadolinium enhancement (LGE) and edema. Quantitative T1 mapping was performed with modified look-locker inversion-recovery (MOLLI) sequences for the identification and quantification of the extracellular volume in the affected territory and in the territory remote to the infarct ,17. The Circulating MPO and BiP levels were measured by sensitive enzyme immunoassays  following the instructions of the manufacturers.n = 14) from the Hospital Clínico San Carlos biobank. Patients that had died from another cause were used as controls (n = 14). Immunostaining was detected using a rabbit polyclonal antibody  in 4 μm heart sections in samples fixed in buffered formaldehyde and paraffin-embedded using an automated method (Dako Autostainer). After counterstaining with hematoxylin, slides were dehydrated in ascending concentrations of ethanol and mounted. An external negative control was included. A blinded staining evaluation was performed by an experienced pathologist who did not have access to the clinicopathological data. For each sample, 25 fields were analyzed with a 20× objective under a transmitted light microscope . The area of BiP staining was identified as the ratio of staining to the total tissue area after excluding either the necrotic or vessel areas from the region of interest. The quantitative analysis was performed using an analysis system . This study was approved by the Medical Ethics Review Committee of Hospital Clínico San Carlos (21/168-E).BiP immunohistochemical staining was measured in LV myocardial tissue obtained from patients who had suffered MI . The quantitative analysis was performed using an analysis system .t-test test or a Mann–Whitney test as the parametric and non-parametric tests, respectively. Specific differences between more groups were analyzed using Kruskall–Wallis tests followed by Dunn’s test for variables with non-normal distributions. For variables with normal distributions, a one-way analysis of variance was used followed by a Newman–Keuls test. Either Pearson or Spearman correlation analyses were used to examine the associations among different variables according to whether they were normally distributed. A value of p < 0.05 was used as the cut-off value for defining statistical significance. The data analysis was performed using the statistical programs GraphPad Prism 8  and SPSS version 25.0 .Continuous variables are expressed as means ± standard deviation (SD). Categorical variables are expressed in absolute values and percentages. The differences between categorical variables were analyzed using the chi-square test. The normality of distributions was verified by means of the Kolmogorov–Smirnov test. In the case of continuous variables, differences between two groups were analyzed by either an unpaired Student’s Body weight and blood pressure were similar in all groups . HoweverMI produced an oxidant environment characterized by an increase in superoxide anion levels A,B that p = 0.0022) and ameliorated with MitoQ  or collagen I . Complementary analyses of different pathways involved in ER stress activation revealed , PWT (p < 0.0002), and EDD (p = 0.0458)  of patients had associated comorbidities, with the most frequent being overweight or obesity (78%), hypertension (36.6%), dyslipidemia (36.7%), and diabetes mellitus (22.0%). Drug treatment for hypertension included angiotensin converting enzyme (ACE) inhibitors or angiotensin II type 1 receptor antagonists, whereas all dyslipidemic patients were on statins. After the MI, 80% of patients were on beta-blockers, 87.5% were on ACE inhibitors or angiotensin II type 1 receptor antagonists, and 100% were on statins and antiplatelet therapy. All patients underwent a primary percutaneous intervention during admission, and a culprit lesion was treated in all cases with drug-eluting stents. The anterior descending coronary artery was responsible in 61% of cases. The echocardiography findings of patients are shown in  0.0458)  at 12 mop = 0.0006). Interestingly, a marker of oxidative stress, myeloperoxidase (MPO), was increased after the 12-month follow-up (p = 0.0014). It is noteworthy that patients with BMI > 25 had higher levels of MPO at follow-up  and significantly lower LVEF relative to patients with BMI < 25 kg/m2 . In addition, MPO levels were associated with myocardial ECV in basal conditions , showing the possible relevance of oxidative stress to ECM production. Circulating BiP levels were not detected in either the basal conditions or in the 12-month follow-up.No changes were found in the follow-up in either the myocardial ECV or LV mass , althougp = 0.4302). There were no significant differences between the two groups in terms of age . In the group of infarcted patients, five of the patients (35.7%) died in the 48 h after MI, three of the patients (21.4%) died in the week after of the ischemic event, and 42.8% of the patients (six of the patients) survived more than 2 weeks after the MI. The main cause of death in the control group was cancer in 50% of the patients. In addition, 31.4% died of non-ischemic cardiovascular disease, three of them (31.4%) died of pulmonary disease, one died of pancreatitis, one died of appendicitis, and one died of drowning.Taking into consideration that circulating BiP levels were undetected in patients, we analyzed BiP staining in cardiac sections from autopsies obtained from the Hospital Clínico San Carlos biobank. Most patients were male , indicating the possible role of ER stress in the development of cardiac fibrosis.Our study shows that the administration of the mitochondrial antioxidant MitoQ prevents the development of cardiac fibrosis and the increase in collagen I, TGF-β, and CTGF synthesis in rats with MI. In addition, circulating MPO levels, a marker of oxidative stress, were associated with levels of myocardial ECV, a surrogate marker of interstitial fibrosis, in patients that had suffered their first MI. This suggests a role of oxidative stress in the remodeling triggered by myocardial ischemia. The reduction in fibrosis in infarcted rats treated with MitoQ was accompanied by a reduction in the ER stress activation, and these beneficial effects of the mitochondrial antioxidant were reflected by an improvement in systolic and diastolic function in MI rats. Moreover, higher levels of myocardial collagen content were accompanied by the overexpression of BiP in cardiac tissues from autopsies of patients that suffered an MI compared with those who had died from different causes, supporting the participation of ER stress in the development of cardiac fibrosis in the context of myocardial ischemia. Thus, mitochondrial oxidative stress emerges as one of the factors involved in the cardiovascular remodeling associated with myocardial ischemia through the activation of ER stress.Myocardial fibrosis is a common feature shared by different insults, including myocardial ischemia, which facilitates the development of heart failure by causing contractile dysfunction and arrhythmogenicity . DiffereElevated levels of MPO are predictors of coronary artery disease  and the 2+ overload and oxidative stress [In response to ischemia, the myocardium generates ROS, especially after reperfusion  with care stress . The Mite stress . MitoQ we stress . All theExcessive ROS production shifts their regulatory role to a deleterious one. This involves the activation of different mediators, such as TGF-β , which p2+-binding ER chaperones that is upregulated in response to ER stress in the heart [Our data also showed an overexpression of ATF4 and CHOP down-stream of the PERK pathway in the hearts of infarcted animals, which was reduced in MitoQ-treated animals. ATF4 promotes the expression of CHOP , which che heart . It has he heart . This cahe heart . In addihe heart ,51.2+ dependent protease present in the cytosol and mitochondria, which contributes to protein processing and degradation. Its expression is enhanced under pathological conditions associate with Ca2+ overload, including MI, thereby contributing to cardiac injury [Our data show that MitoQ was unable to normalize calpain 1 levels, a Cac injury ,53 durinc injury . Calpainc injury . Its ovec injury ,53.In summary, we have demonstrated that the cardiac functional alterations, remodeling, and fibrosis observed after MI were accompanied by oxidative stress and ER stress activation in rats. The inhibition of mitochondrial oxidative stress with MitoQ prevented all these alterations. In the clinical context, we have found an association between ECV and the plasma levels of a marker of oxidative stress, MPO. Moreover, an association between markers of ER stress and fibrosis was found in sections of infarcted hearts from patients. All these data suggest that ER stress activation can mediate, at least in part, the role of oxidative stress in the remodeling that occurs after MI by facilitating the development of diffuse cardiac fibrosis.Some limitations of the present study deserve to be briefly mentioned. We were unable to measure circulating BiP levels in patients that suffered their first MI. Therefore, the lack of evaluation of the possible association with myocardial fibrosis and cardiac function as well as how they follow-up one year later represents a limitation of our study. However, the samples obtained from autopsies demonstrated that cardiac BiP levels were higher in patients that had suffered an MI than those who had not. Moreover, the BiP levels were associated with myocardial fibrosis, supporting the role of ER stress in the development of myocardial fibrosis in the context of MI. Although we measured radial and circumferential strain in the experimental study, the lack of data regarding longitudinal strain (due to the lack of specific images) represents a limitation of the study since these data could help to have more comprehensive information about cardiac mechanics and function.


COVID-19 infection is a systemic disease with various cardiovascular symptoms and complications. Cardiac MRI with late gadolinium enhancement is the modality of choice for the assessment of myocardial involvement. T1 and T2 mapping can increase diagnostic accuracy and improve further management. Our study aimed to evaluate the different aspects of myocardial damage in cases of COVID-19 infection using cardiac MRI.This descriptive retrospective study included 86 cases, with a history of COVID-19 infection confirmed by positive RT-PCR, who met the inclusion criteria. Patients had progressive chest pain or dyspnoea with a suspected underlying cardiac cause, either by an abnormal electrocardiogram or elevated troponin levels. Cardiac MRI was performed with late contrast-enhanced (LGE) imaging, followed by T1 and T2 mapping.Twenty-four patients have elevated hsTnT with a median hsTnT value of 133 ng/L (IQR: 102 to 159 ng/L); normal value < 14 ng/L. Other sixty-two patients showed elevated hsTnI with a median hsTnI value of 1637 ng/L (IQR: 1340 to 2540 ng/L); normal value < 40 ng/L. CMR showed 52 patients with acute myocarditis, 23 with Takotsubo cardiomyopathy, and 11 with myocardial infarction. Invasive coronary angiography was performed only in selected patients.Different COVID-19-related cardiac injuries may cause similar clinical symptoms. Cardiac MRI is the modality of choice to differentiate between the different types of myocardial injury such as Takotsubo cardiomyopathy and infection-related cardiomyopathy or even acute coronary syndrome secondary to vasculitis or oxygen-demand mismatch.It is essential to detect early COVID-related cardiac injury using different cardiac biomarkers and cardiac imaging, as it has a significant impact on patient management and outcome.• Cardiac MRI is the modality of choice to differentiate between the different aspects of COVID-related myocardial injury.•  Coronavirus 2019 (COVID-19) was declared a global pandemic by the World Health Organization on March 11, 2020. COVID-19 infection is a multi-systemic disease with various manifestations on the different organs and tissue due to the direct effect of the virus or inflammatory mediators especially the interleukin-6 (IL-6) . The mecMyocarditis is an inflammatory process of the cardiac muscle, characterized by inflammatory infiltrates, interstitial edema, and myocardial injury with no evidence of obstructive coronary artery disease . Some acTakotsubo cardiomyopathy (TCM) is a significant disease entity that differs from acute myocardial infarction. It is presented by transient hypokinesia of the left ventricular (LV) apex and is associated with emotional or physical stress, more often in elderly females. Wall motion abnormality of the LV apex is generally transient and resolves within a few days to several weeks. The prognosis was initially thought to be benign, but subsequent studies have demonstrated that short-term and long-term mortality was higher than expected. Although the pathophysiology of TCM is not clearly understood, coronary spasm, catecholamine toxicity, and myocarditis might contribute to its pathogenesis . The incGenerally, the clinical presentation of myocarditis varies from mild symptoms, such as fatigue and dyspnoea, to a fulminant course with heart failure and cardiogenic shock . ImagingT1 and T2 mapping techniques have been explored in pursuit of more quantitative and objective markers of inflammation in myocarditis to increase diagnostic accuracy. Their values are being recognized as not only robust biomarkers for the diagnosis of cardiomyopathies but also predictive factors for treatment monitoring and prognosis , 16.Our study aimed to characterize the different aspects of myocardial injury in patients with COVID-19 infection using cardiac biomarkers and cardiac imaging with special emphasis on cardiac MRI as the modality of choice to differentiate between the different aspects of COVID-related myocardial injury.n = 22) as diabetes, hypertension, dyslipidemia, and smoking, no available PCR for COVID-19 (n = 5), previous conventional coronary angiography including catheter balloon or percutaneous coronary intervention (PCI) (n = 8), one due to severe renal disease (eGFR < 30 mL/min/1.73 m2), and one due to contrast sensitivity.This descriptive retrospective study included 123 patients examined between 1 March 2020 and 1 June 2021, referred to our institute for cardiac MRI. The inclusion criteria were a history of COVID-19 infection confirmed by PCR, progressive chest pain or dyspnea for 4–10 days, with a suspected underlying cardiac cause as revealed by one or more cardiac investigations, including echocardiography, troponin level, and ECG changes within 14 days from the onset of the symptoms. The exclusion criteria were one or more cardiovascular risk factors .Three cardiologists with at least 10 years of experience participated in this study. Each was responsible for one aspect of the cardiac evaluation to avoid interobserver bias. The first cardiologist was responsible for the clinical history, physical examination, and assessment of the laboratory findings. The second was responsible for performing echocardiography and interpreting the ECG findings. The third performed conventional coronary angiography in selected patients with either combined echocardiography and ECG abnormalities and/or signs of ischemic insult in cardiac MRI. All collected data were discussed by the three cardiologists for further management.All cases underwent echocardiography examination as the first line of imaging to detect any abnormal cardiac findings with particular emphasis on regional wall motion abnormality, calculation of the LV function, and detection of other cardiac pathology. ECG was performed for all patients to detect any abnormality.These were performed for all 86 patients to detect any myocardial involvement as they are specific markers for myocardial injury.The conventional CMR examination and additional T1 and T2 mapping were performed within seven days of troponin rise and the onset of cardiac symptoms (median of 4 days [IQR: 3 to 5 days]) using a 1.5-Tesla scanner .Patient position: The patients were asked to lie on the MRI table in the supine position. The ECG electrodes were placed after cleaning the skin, and the patient was monitored for heart rate and blood pressure.A multi-phase array coil (16 channels) required for parallel imaging was used. The examination was both ECG and respiratory gating.Image acquisition was initiated with localiser images in three orthogonal planes. Black-blood fast spin echo (FSE) sequences were taken in axial and coronal views. The white blood pool (GRE) sequences with true FISP were taken in the vertical long axis (VLA), short-axis (SA), and four-chamber (4 CH) views. T2-weighted-STIR images using a triple-IR black-blood turbo-spin echo pulse sequence were taken in the SA and 4 CH views. This procedure was followed by late gadolinium enhancement using a contrast-enhanced-inversion recovery sequence after 10 min from contrast injection ). Imaging of the left ventricle was performed from base to apex, and the acquisition was performed in SA and 4 CH views. Cine and LGE images were acquired during end-expiration breath-hold. Finally, modified Look-Locker inversion recovery pulse sequence (MOLLI) for T1 and T2 mapping data were acquired in basal, mid-ventricular, and apical short-axis planes before and 15 min post-contrast media injection, immediately after performing the late gadolinium enhancement . Single-Cardiac MRI image analysis:Multiple parameters were measured: End-diastolic and end-systolic left ventricle volumes, ejection fraction, stroke volume, and left ventricle mass for assessment of the ventricular function.Anatomical variants or pathologies within the cardiac chambers were assessed .Wall motion of the left ventricle was assessed at each myocardial segment: normal, hypokinetic, akinetic, or dyskinetic.Any myocardial edema on T2-weighted-STIR images were detected using the T2 signal intensity (SI) ratio by dividing the SI of the myocardium by the SI of skeletal muscle in the same slice. A hypointense core within a high SI area was included in the edematous volume. We selected the anterior chest muscles, including the major and minor pectoral muscles, as a reference range for SI of skeletal muscle.Any late gadolinium enhancement was detected throughout the 17 heart segments based on the 17-segment model recommended by the AHA.Pixel-wise illustration of the absolute T1 relaxation times on a map was performed, and color-coded maps were obtained. The ROI was then placed over the 17 heart segments in both pre- and post-contrast images according to the AHA. Six basal segments, six mid-ventricular segments, four apical segments, and cardiac apex in addition to the blood were used to obtain the pre- and the post-contrast T1 and T2 values in each of these segments.The diagnosis of acute myocarditis was based on updated 2018 Lake Louise criteria and CMR findings, including T1 and T2 myocardial markers.This was performed on 14 patients with combined echocardiographic and ECG abnormalities and/or signs of ischemic insults in cardiac MRI to detect the presence of any obstructive coronary artery disease  who presented with a history of progressive chest pain  and dyspnoea  with recent symptoms of COVID-19 pneumonia, confirmed by positive PCR.Our study included 86 patients  showed elevated cardiac troponin I (hsTn I) with a median hsTn I value of 1637 ng/L (IQR: 1340 to 2540 ng/L); normal value < 40 ng/L. None of the patients showed simultaneously elevated cardiac troponin (hsTn) T and troponin (hsTn) I.Twenty-four patients showed elevated cardiac troponin (hsTn), with a median hsTn T value of 133 ng/L (IQR: 102 to 159 ng/L); normal value < 14 ng/L. The other patients  with Takotsubo-like imaging features: Cine images revealed normal left ventricle end-diastolic volume (median 69 mL/m2 (IQR: 62 to 78 mL/m2); normal value < 90 mL/m2). The images showed ballooning of the cardiac apex, with severe depression of systolic function (ejection fraction < 40%) and no LGE. The T2-weighted-STIR images showed myocardial edema, which was generally diffuse and transmural, involving mainly the regions with RWMA. A T2 SI ratio  greater than or equal to 1.9 was considered diagnostic of myocardial edema. T1 and T2 mapping values were elevated, with a median of 1165 ms (IQR: 1131to 2101 ms); normal value < 1045 ms for T1 mapping and a median of 66 ms (IQR: 59 to 69 ms); normal value < 50 ms for T2 mapping. Both T1 and T2 mapping showed an increasing gradient from the base to the apex. This pattern suggests that myocardial inflammation is global but affects the apical segments predominantly. All these patients were diagnosed with Takotsubo cardiomyopathy and experienced complete recovery of the LV function within 4–6 weeks on follow-up echocardiography examination  with myocarditis-like imaging features:The 2018 Lake Louise criteria were applied for the diagnosis of myocarditis. The two main 2018 Lake Louise criteria are T1-based and T2-based. The T1-based criterion was positive if there was an increase in native T1 relaxation times, an increase in extracellular volume (ECV), or a positive LGE. The T2-based criterion is positive in cases of increased T2 relaxation times, regional high T2 signal intensities on T2-weighted images, or an increased global T2 SI ratio ) and increased native-T1 value (median 1172 ms [IQR: 1170 to 1174 ms])  Fig. .The MRI findings revealed cardiac injury in one of three patterns: (i) Takotsubo-like, (ii) myocarditis-like, and (iii) ischemic-like.Invasive coronary angiography was performed for 14 patients with electrocardiography abnormalities or a pattern of myocardial ischemia on cardiac MRI to detect the presence of obstructive coronary artery disease. Three patients had a normal conventional coronary angiogram, while 11 with akinetic apex and transmural LGE on CMR had attenuated distal LAD confirming the presence of an ischemic insult.No pericardial effusion or abnormal pericardial thickening was detected in the 86 patients.Follow-up occurred after 4 weeks, focusing on the clinical presentation (chest pain and dyspnoea), high-sensitivity troponin level, echocardiography, and ECG changes. Seventy-five patients diagnosed with myocarditis-like and Takotsubo-like findings were discharged with the resolution of chest pain and near-total improvement of the dyspnoea. There was normalization of the ECG changes and cardiac markers and improvement of the LV function as revealed by echocardiography. The 11 patients who presented with associated ischemic changes still had dyspnoea that showed no significant improvement. Chest pain almost disappeared with regression of the ECG changes and high-sensitivity troponin level. Echocardiography still showed increased LV end-diastolic volume and severe affection of systolic function (ejection fraction < 40%).The previous SARS epidemics and the ongoing COVID-19 pandemic have produced multiple theories regarding cardiac damage. One of these is a systemic inflammatory response involving the release of high levels of cytokines that result in damage to the vascular endothelium and cardiac myocytes . AnotherCOVID-19 infection may trigger new cardiac pathologies or exacerbate underlying cardiovascular diseases due to the associated inflammatory process. There was a small number of cases have been reported with AMCovS showing an absence of or very minimal LGE. Thus, may suggest an indirect mechanism causing myocardial inflammation with an absence of myocardial scarring .Antonio Esposito et al (2020) reported the first series of patients with AMCovS, including 10 patients with clinical suspicion of myocarditis referred for CMR examination. The CMR revealed acute myocarditis in eight patients and Takotsubo cardiomyopathy in two. There was diffuse myocardial edema in T2-weighted-STIR images and no appreciable LGE, suggesting an indirect mechanism causing myocardial inflammation .The present study included 86 patients who presented with a history of progressive chest pain or dyspnoea, with suspected underlying cardiac cause. The patients had recent symptoms of COVID-19 pneumonia confirmed by positive PCR. All patients performed electro-echocardiography and troponin level assay. Conventional CMR examinations and additional T1 and T2 mapping were performed within seven days of troponin rise and the onset of cardiac symptoms to detect and characterise any myocardial injury.We were able to explain the proposed mechanisms of cardiac injury through one of three disorders: Takotsubo cardiomyopathy, myocarditis-like acute cardiac syndrome, and ischemia due to vasculitis or other oxygen supply-demand mismatch.Takotsubo cardiomyopathy is non-ischemic cardiomyopathy, more often seen in postmenopausal elderly women and characterized by the ballooning of the cardiac apex. Its clinical manifestations are similar to those of acute coronary syndrome; however, Takotsubo cardiomyopathy is usually preceded by emotional stress and has spontaneous recovery , 28. In Myocarditis is a non-ischemic inflammatory disease of the myocardium that can be triggered by variable events, including viral infection and toxins. Cardiac MRI is the modality of choice for the diagnosis of myocarditis, with typical findings of focal or diffuse myocardial edema and myocardial damage, including the presence of late gadolinium enhancement –32. In oThe third group with ischemic-like imaging features showed increased LV end-diastolic volume and severe affection of systolic function. There was apical edema on T2-weighted STIR and transmural LGE of the cardiac apex keeping with myocardial scarring, in contrast to Takotsubo cardiomyopathy. Furthermore, there were increased native T1 and T2 values. There was also attenuated distal LAD by invasive coronary angiography, confirming the presence of an ischemic insult.All patients in the study had elevated cardiac troponin levels. The high sensitivity and specificity of cardiac troponin levels significantly impact early diagnosis and risk stratification in patients presenting with chest pain. Detection of cardiac troponin is not pathognomonic for acute coronary syndrome but rather suggests myocardial injury of any cause and may be found in non-coronary artery-related conditions . One of It was observed that patients with severe COVID-19 pneumonia can develop cutaneous vasculitis-like lesions and systemic arterial and venous thromboemboli. Kawasaki-like disease has been reported in the context of acute severe myocarditis, without overt coronary vasculitis or aneurysmal formation. There are few reported cases of demonstrable coronary vasculitis with a Kawasaki-like disease phenotype , 35. In Cardiac MRI plays a vital role in the characterization of the different aspects of myocardial injury post-COVID-19 infection and thus adds to the treatment of cardiovascular injury associated with SARS-CoV-2 infection. COVID patients with a known history of pre-existing cardiovascular disease should be closely monitored for any symptoms and signs of cardiovascular dysfunction. The American College of Cardiology (ACC) recently indicated that elderly patients may need plaque stabilizers . When an acute myocardial injury occurs, medication to improve myocardial energy metabolism can significantly protect and improve cardiac function. Thrombolysis is preferred for patients with non-ST-elevation myocardial infarction (NSTEMI) or ST-elevation myocardial infarction (STEMI) without relevant contraindications. Emergency PCI may be performed in patients with acute STEMI with hemodynamic instability and patients with life-threatening NSTEMI –40.Some key points emerge from this review of myocardial injury. A high clinical suspicion should be maintained for COVID-19-associated cardiac injury for early detection of any myocardial insult using different cardiac biomarkers and cardiac imaging. Our review highlights the many proposed mechanisms of myocardial damage secondary to COVID-19 infection, but more research is required to determine whether the damage is due to direct myocardial injury by the virus, inflammatory mediated process, vasculitis, or any other mechanism.The study design was retrospective. Multi-center contributions and data from other countries will be valuable in better assessing rare but severe complications of COVID-19 pneumonia. Endo-myocardial biopsy, which is the golden standard for myocarditis, was not performed due to its invasive nature.The diagnosis of myocardial injury using clinical and imaging criteria is challenging due to its highly heterogeneous manifestations. Cardiac MRI is considered the modality of choice to differentiate between the different aspects of myocardial injury such as Takotsubo cardiomyopathy and myocarditis-like acute cardiac syndrome. Moreover, the spectrum of cardiac involvement can be extended to include acute coronary syndrome secondary to vasculitis or oxygen-demand mismatch. Early and correct diagnosis has a significant impact on the patient outcome and further management.


Many studies published in other countries have identified certain perceived benefits of and barriers to physical activity among patients with coronary heart disease. Nevertheless, there is no data about the issue relating to Jordanian patients with coronary heart disease.This study aimed to describe the prevalence of levels of physical activity, the benefits of and barriers to physical activity as perceived by Jordanian patients with coronary heart disease, and the relationship between physical activity and perceived benefits of and barriers to physical activity. In addition, it focused on examining the influence of selected sociodemographic and health characteristics on physical activity and the perceived benefits of and barriers to physical activity.A cross-sectional design was performed on a sample of 400 patients with coronary heart disease. They were given a list of perceived benefits of and barriers to physical activity and asked to what extent they disagreed or agreed with each.Jordanian patients with coronary heart disease perceived various benefits of and barriers to physical activity. Most of these benefits were physiologically related . The most substantial barriers to physical activity as perceived by the patients were “feeling anxiety,” “not enough time,” “lack of interest,” “bad weather,” and “feeling of being uncomfortable.” Sociodemographic and health characteristics that significantly influenced perceived barriers to physical activity were age, gender, health perception, chest pain frequency, education, job, caring responsibilities, ability to travel alone, smoking, and previous and current physical activity behavior.This study demonstrates that patients with coronary heart disease have perceived physiological benefits of physical activity and have perceived motivational, physical health, and environmental barriers to physical activity, which is significant in developing intervention strategies that aim to maximize patients' participation in physical activity and overcome barriers to physical activity. Physical activity is essential in preventing and treating coronary heart disease (CHD) –3. The sAlthough the significant benefits of PA are well-known in the treatment of CHD, the vast majority of patients with CHD do not achieve PA following recommendations, even when they engage in a structured PA program or cardiac rehabilitation program . The perThe contributing factors of low performance and adherence to PA that have been consistently reported in the literature include individual characteristics, such as motivation and self-efficacy. Perceived barriers to PA, such as time and access, and characteristics of PA behavior, such as PA type, intensity, and duration . In addiThe health promotion model (HPM) identifies perceived benefits of and barriers to action as influencing factors for health-promoting behavior, such as participation in PA. In this model, health-promoting behavior is the desired outcome , 24. TheThe significant aspect of the success of programs and interventions that aim to promote PA in patients with CHD is the recognition of factors that limit participation in these programs . InformaThis study aimed to describe the prevalence of PA levels in patients with CHD and the benefits of and barriers to PA as perceived by Jordanian patients with CH and describe the relationship between perceived benefits of and barriers to PA and the participation of these patients in PA. Furthermore, it aimed to describe the influence of selected sociodemographic and health characteristics on perceived benefits of and barriers to PA and the participation of PA.First, approval from the Institutional Review Board at King Abdullah University Hospital (KAUH) and Jordan University Hospital administration to interview the patients was secured. Then, the researcher reviewed patients' files who visited the cardiac clinic between 1 July 2019 and 1 October 2019. Those who met the inclusion criteria were identified and invited to participate in the study. A structured interview technique to collect the required data was used.The sample size was 400 patients with CHD, determined based on the prevalence of PA among CHD in the previous study by determining 40% at a 95% CI, 5% margin of error and adding 37 patients considering dropouts among participants . Two uniThe participants were administered the International Physical Activity Questionnaire (IPAQ), which assesses physical activity status. The instrument asks questions about the performance of 30 min of moderate-intensity activity 5 days per week (150 min per week) or a combination of walking and moderate-intensity activities amounting to a minimum of at least 600 METs-minutes/week. The IPAQ is a reliable and valid tool for assessing PA .Since there are no clinical tools for the reliable evaluation of perceived benefits of and barriers to PA among patients with CHD, the researcher developed a scale consisting of two lists of perceived benefits of and barriers to PA based on the literature. The first list contains 22 items that reflect PA's physical, psychological, and social benefits. The second list contains 41 items that reflect PA's physical, psychological, social, and environmental barriers. The response for each item was on a 6-point Likert scale ranging from (1) strongly disagree to (6) strongly agree. In addition, two open-ended questions asked participants' opinions about additional benefits of and barriers to PA. Items of perceived benefits and barriers demonstrated a high level of internal consistency; Cronbach's alpha was calculated: 0.87 for perceived benefits of PA and 0.92 for perceived barriers to PA. Also, test-retest reliability for the total instrument was 0.89 for the Exercise Benefits Scale and 0.77 for the Exercise Barriers Scale.To evaluate the clarity and understandability of the perceived benefits of and barriers to PA, the researcher interviewed ten patients with CHD in the cardiac clinics of both hospitals before starting data collection using structured interviews. The patients were six males and four females. In total, seven patients were diagnosed with MI, and three patients with angina. Results showed that all participants reported that all items were clear, understandable, and at the level of the patient's comprehension.t-test, chi-square test, and Fisher's exact test were used to examine differences in perceived benefits of and barriers to PA and individual and health characteristics concerning PA behavior that was measured on a continuous and dichotomous level. A one-way analysis of variance was used to compare the means of two or more independent groups.Descriptive statistical analysis was used to describe the sample. The Pearson correlation was used to describe the relationship between the benefits of and barriers to PA and the continuously measured sociodemographic and health characteristics. The same test was used to describe the relationship between individual and health characteristics, and PA was measured continuously. In addition, the The participants were 400 patients with CHD between 36 and 70 years old, with two-thirds being male. There were no significant differences between the two groups ,2.According to the International Physical Activity Questionnaire (IPAQ), 24% of the patients are classified as physically active. According to IPAQ, participants were recognized as physically active when they met the PA guidelines of 30 min of moderate-intensity activity 5 days/week (150 min/week) or engaged in a combination of walking and moderate-intensity activities for a minimum of at least 600 METs-min/week.It was found that male respondents and laborers were significantly more engaged in PA than females and office workers. Also, there was a statistically significant difference between physically active and non-physically active participants regarding physical activity advice, chest pain frequency, and perception of health. Patients with weak PA advice perceive their health as poor and have more chest pain frequency. They also have low PA levels. However, other factors such as marital status and smoking showed no statistically significant relationship with PA engagement , 4.There was a significant difference between physically active and non-physically active participants regarding PA's psychological and social benefits. Physically active patients perceive these benefits more than non-physically active patients. However, no significant difference between the two groups of patients was detected as regards the physical benefits of PA, such as “preventing overweight,” “decreasing the risk of coronary artery disease,” and “decreasing triglycerides.” Improving knowledge about the physiological benefits of PA is an essential element that should be included in the PA programs provided to patients with CHD.While regarding perceived barriers items about performing PA, physically active and non-physically active participants were significantly different regarding most of the perceived barriers to PA. Physically active patients exhibited fewer physical, psychological, social, and environmental barriers to the perception of PA than non-physically active participants.M = 5.81, SD = 0.53) “improves body muscle's flexibility” , “improves strength” , “prevents overweight” , “decreases risk of CHD” , “decreases triglycerides” , and “improves cardiovascular fitness”   .M = 4.53, SD = 1.81), “not enough time” , “feeling of being too lazy” , “busy at work” , “lack of interest” , “bad weather” , “don't like to do PA alone” , “not frequently seeing others perform PA” , “feeling of being uncomfortable” , and “PA causes shortness of breath”  (The biggest barriers to PA as perceived by the patients were as follows: “feeling with anxiety” ( = 1.82) .Job type significantly influenced the perceived benefits of “decreasing triglycerides” and “giving enjoyment.” Laborer workers perceived this PA benefits more than office workers. Physically active participants perceived all physiological benefits more than non-physically active participants.This study demonstrated the importance of sociodemographic and health characteristics of patients with CHD in influencing their perception of barriers to PA, including (1) health perception, (2) chest pain, (3) the ability to travel alone, (4) education, (5) age, (6) gender, (7) caring responsibilities, (8) job status, (9) current PA behavior, (10) smoking, and (1) PA advice. Health perception had a significant negative relationship with the barriers “feeling with anxiety” and “PA causes shortness of breath”. Patients with poor health were more likely to perceive “feeling with anxiety” and “PA causes shortness of breath” as solid barriers to PA. Chest pain frequency had a significant positive relationship with “feeling uncomfortable” barriers and “PA causes shortness of breath.” Participants who reported more chest pain frequency were more likely to perceive “feeling uncomfortable” and “PA causes shortness of breath” as solid barriers to PA. Age is negatively related to “busy at work” and “not enough time” barriers. Young participants were more likely to perceive “busy at work” and “not enough time” as solid barriers to PA. No significant relationships with other barriers were found.Females, illiterate, patients who could not travel alone, smokers, and non-regular physically active perceived “feeling uncomfortable” and “not enough time” as barriers to PA more than their counterparts. Illiterates and individuals who are unable to travel alone perceived “feeling anxiety” as a barrier to PA more than educated individuals who were able to travel alone. Illiterate and non-regular physically active perceived “PA causes shortness of breath” as a barrier to PA more than educated and regular physically active. Individuals who had caring responsibilities perceived being busy at work as a barrier to PA more than those who were not employed and did not have caring responsibilities. Office workers perceived bad weather as a barrier to PA more than laborers workers. PA advice had a significant negative relationship with barriers such as “not enough time,” “feeling of being uncomfortable,” “lack of advice,” and “feeling too boring.”Although physical activity is widely reported as a principal factor in improving health, it is viewed as a significant challenge for patients with CHD worldwide. This study found that patients were mainly physically inactive (76%). Perceived benefits of and barriers to PA are vital elements influencing PA participation in this study. The physically active patients perceive more benefits of and fewer barriers to PA than non-physically participants. However, no study documented the perceived benefits of and barriers to PA in Jordan among patients with CHD.All participants in this study reported substantial perceived benefits of PA that were mainly physiological benefits rather than psychosocial benefits, which may be related to the influence of media components that focus on the physiological benefits of PA. Therefore, patients may have more information about the physiological benefits of PA than the psychological benefits of PA. However, physically active patients perceived the physiological and psychosocial benefits of PA more than those who were not regularly physically active. In addition, it may be related that most participants (76%) were not regularly physically active to experience PA's physiological and psychosocial benefits. The role of healthcare providers in reinforcing the knowledge about the impact of physical and psychosocial benefits of PA is a crucial step to be considered in PA programs.A predominance of perceived psychosocial barriers to PA was observed were “anxiety,” “lack of interest,” “feeling of being too lazy,” “do not like to do PA alone,” and “not frequently seeing others doing PA.” These barriers were also identified in Myers and Roth's studies . AnxietyNot enough time was reported in the present study. As such, the need for positive reinforcement and reassurance from healthcare providers who advocate physical activity in CHD is considered necessary to overcome this barrier. The time barrier reflects that individuals are busy at work, which is also perceived as a barrier to PA. It reflects no motivation to do PA because time barriers and busyness at work excuse more than the cause of not participating in PA, which is congruent with the findings of other studies, which showed that time was the most significant barrier perceived by cardiac patients. It is the most prevalent self-reported reason for dropout from supervised clinical and community PA programs , 32. MotThis study demonstrated that most patients with CHD (74%) are non-physically active. The challenge of participation in PA was linked to perceived benefits and barriers to PA. The patients in this study perceived various physiological and psychosocial benefits of PA. Also, Jordanian patients with CHD perceived different physical and psychosocial barriers to PA. In addition, it was found that the sociodemographic and health characteristics of the patients with CHD influenced their participation in PA and their perception of PA benefits and barriers to PA. The factors such as age, gender, health perception, chest pain frequency, education, job, PA advice, caring responsibilities, ability to travel alone, smoking, and current PA behavior were considered. It seems that different groups with samples perceived different barriers to PA. The findings of this study suggest that it may be valuable to replicate this study using a more significant and heterogeneous randomly selected sample to increase the generalization of the findings. The findings also suggest investigating barriers to PA as perceived by different groups of people  to identify their specific perceived barriers to PA and investigate selected interventions that are appropriate to decrease barriers to PA among patients with CHD. Also, the findings of this study indicate the need for an influential role for nurses and other health team members who provide care to patients with CHD in Jordanian hospitals and clinics. This role should consider the benefits of and barriers to PA and the influence of sociodemographic and health characteristics on perceived barriers to PA in their interventions to motivate the patients to participate in regular PA.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by the Institutional Review Board at King Abdullah University Hospital (KAUH) and Jordan University Hospital Administration. The patients/participants provided their written informed consent to participate in this study.EA planned the research, carried out the data collection, analyzed the data, and wrote the manuscript. FB reviewed the paper for publication. All authors contributed to the article and approved the submitted version.


Background and Objectives: Pulmonary embolism (PE) has a major burden of morbidity and mortality, consequently the need for a prompt risk stratification for these subjects is crucial. In order to evaluate the risk management and final disposition of patients with PE in the Emergency Department (ED), we conducted a study that was divided in two phases: Phase I retrospective study (RS), Phase II prospective study (PS). Materials and Methods: In Phase I, 291 patients were enrolled while in Phase II, 83 subjects were evaluated. In both study phases, the enrolled subjects were analyzed for final disposition in ED using PESI score, right ventricle (RV) imaging, and high-sensitive cardiac troponin I (hs-cTnI) data. The RS patients were divided into low risk and high risk according to the sPESI score, while PS patients were grouped in low, intermediate, and high risk classes according to PESI score. In both study phases, all the studied patients were further divided into negative (hs-cTnI−) or positive (hs-cTnI+) groups according to hs-cTnI levels within normal or above cutoff values, respectively. For all enrolled subjects, CT pulmonary angiography was analyzed to assess the RV/LV diameter and volume ratio as an indicator of RV involvement. Results: In both RS and PS phases, hs-cTnI+ group showed a higher PESI score. Nevertheless, a significant percentage of hs-cTnI+ patients resulted to be in the low-risk PESI class. Patients with a positive RV/LV ratio were more likely to have a hs-cTnI+ (p < 0.01), while among those with a negative ratio, 24 to 32% showed as hs-cTnI+. In the hs-cTnI+ group from both study phases, patients were more likely to be admitted in an ICU . Conclusions: In conclusion, in patients with PE in the ED compared PESI score alone, the combination of hs-cTnI and PESI seems to be of greater utility in improving risk stratification and final disposition decision-making. Venous thromboembolism (VTE), the pathophysiological entity that includes deep venous thrombosis (DVT) and pulmonary embolism (PE), represents the third most frequent acute cardiovascular disease after acute coronary syndrome and stroke, with an annual incidence between 39 and 115 cases in 100,000 inhabitants .Retrospective study, Phase I: from January 2017 to January 2019, we retrospectively analyzed 291 patients. The patient’s characteristics of the retrospective phase are summarized in According to sPESI class, 28% of the Phase I cohort resulted in the low risk class (sPESI < 1). A history of cancer was present in 21% of cases, cardiovascular disease in 17% of cases, and a history of COPD in 9% of cases. High levels of hs-cTnI were present in 49% of cases at ED admission and the mean hs-cTnI was 187 ± 45 ng/L. A total of five patients died during the study period, all with positive values of troponin and all within the ED.p < 0.001). The mean RV diameter was significantly higher in the hs-cTnI+ group, together with significantly lower values of LV diameters, compared to the hs-cTnI− group (p < 0.001).A significant statistical difference was found between hs-cTnI+ and hs-cTnI− groups and the RV/LV diameter ratio. A total of 54% of patients in the hs-cTnI− group had a positive ratio versus 82% of the hs-cTnI+ group , intermediate risk (25%), and high risk (35%).In these 83 studied subjects at ED admission, the mean values of hs-cTnI were 88.8 ± 20.4 ng·LIn the prospective cohort, a previous history of cancer was present in 28% of cases, while in 15% and 17% of cases there was a history of cardiac diseases and COPD, respectively. Hypotension at ED arrival (SBP< 100 mmHg) was present in 6% of the cases. p < 0.0002). Grouping patients according with PESI risk class, the mean values of hs-cTnI were: 26 ± 8 ng·L−1, 49 ± 18 ng·L−1, and 178 ± 48 ng·L−1 , respectively, for the low, intermediate, and high risk groups. Compared to hs-cTnI− subjects, the hs-cTnI+ group showed a significantly higher values of PESI score . Considering together the hs-cTnI+ patients, 18% were in the low PESI risk class and overall 38% of hs-cTnI+ patients resulted in the low or intermediate PESI risk groups. Low PESI risk class patients who were in the hs-cTnI+ group had a RR 4.4 (IC 2.1–9.5) to be admitted to an intermediate or high intensive care unit. At CTPA evaluation, the hs-cTnI+ group showed significantly higher values of ratio RV/LV (Tabel 4), and frequency of RV involvement, i.e., positive RV/LV diameter.It should be noted that 32% of patients with a negative RV/LV diameter ratio were in the hs-cTnI+ group. Patients in the hs-cTnI+ group were more likely to be admitted in a higher intensity care ward  than hs-cTnI− patients B with anA total of three patients died in ED before hospital admission. They were 95, 60, and 74 years old. The causes of death were cardiogenic shock for two patients and refractory respiratory failure for the other one. All the three of them showed an increase of hs-cTnI over the upper limit at admission (hs-cTnI+ group). One of them was in the intermediate PESI risk group and two in the high PESI risk groupThis study was conducted in two phases. The first was retrospective and a second one that was prospective, in subjects with symptomatic, acute pulmonary embolism in ED, and focused on optimizing patient’s risk stratification and management. Our results have shown that in all patients from the two study phases, a positive relationship between the PESI or sPESI risk class and the levels of hs-cTnI was found. Nevertheless, the percentage of patients that were classified in the low PESI or sPESI risk class presented elevated hs-cTnI levels in >20% of cases, therefore, the use of PESI score alone seems to not be adequate in detecting the presence of myocardial injury and so in the risk assessment process. The PESI score is influenced by age and its calculation relies on 11 different variables, so it is difficult to use in clinical practice and it wasn’t able to detect the presence of myocardial injury also in precedent studies ,16.The presence of myocardial injury, detected through an increase of hs-cTnI levels, has a clinical role in high-risk patients in predicting short-term death and adverse outcome events . It alsoAs such, it seems crucial to use a score that is able to properly classify the patients with a higher risk and detect the presence of myocardial injury at the same time ,27, a taThe presence of myocardial stress or injury can be detected by some biomarkers by natriuretic peptides (BNP and NT-proBNP) or using troponin I and T (particularly a high-sensitivity assays) or even a new marker of damage, heart-type fatty acid-binding protein (HFABP) . As alreTroponin assessment, per se, already has already been shown to be a strong prognostic factor  in PE paFurthermore, although several studies have evaluated the prognostic value of cardiac troponins  in acute PE ,18,27,28In this preliminary study, the presence of hs-cTnI upper to the normal range at ED arrival seems to be more sensitive in detecting the presence of myocardial injury and be able to select a more complex patient which needs a higher intensity of care, as shown in In PE, RV dysfunction is primarily defined by RV pressure overload and it can be assessed using imaging tests, both echocardiography or CTPA.2, CTPA can be used to stratify the patient risk regarding some parameters of RV involvement which involves also: left ventricle (LV) volume and diameter, right atrium (RA) and left atrium (LA) volume, a study of the inferior vena cava (IVC), i.e., RV/LV diameter ratio, RV/LV volume ratio, RA/LA volume ratio, contrast reflux into the IVC; these imaging methods have the same value of echocardiographic parameters assessed for the same purpose, but they are not routinely used in ED. According to clinical guidelinesMoreover, imaging methods are recommended to be part of the first steps in stratifying patients’ risk, instead troponin is facultative in intermediate and low risk patients. In our pilot study, CTPA parameters of RV involvement correlated with hs-cTnI rise but almost one third of patients who did not show significant changes in CTPA had a significant increase in hs-cTnI. CTPA parameters focus on a single cause that can lead to clinical worsening of these patients, the hemodynamic impairment of RV. It is likely that in these patients, myocardial injury is not simply a consequence of the RV hemodynamic impairment but also linked to other mechanisms such as: hypoxia, catecholamines release, changes in coronary perfusion, stress protein release or other underlying stressors. Therefore, hs-cTnI may be a more reliable and direct marker of myocardial damage and it may represent an independent predictor.The study has some limitations. First, it is a single-center trial and the sample of patients that were enrolled is too small to delineate definitive conclusions and needs to be enlarged in order to better understand the relationship between hs-cTnI and PESI score and possibly their combined role in the prognostic stratification process. Lastly, we did not use a direct 30-day follow-up to confirm the poorer prognosis of hs-cTnI+ patients, we used instead an indirect method that was given by the setting of care that was needed by the patients in order to assess the severity of the patients. Here, an intrinsic bias could exist, even if the decision of admission and the intensity of care needed was not formally driven by the levels of hs-cTnI.In subjects with PE presenting to ED compared to PESI score alone, combining hs-cTnI circulating levels and PESI score seems to be of greater utility in improving patient’s risk stratification and consequent decision-making. In these subjects, hs-cTnI plus PESI score assessment seems to be particularly suitable for more accurate final disposition, i.e., home discharge or admission to a more intensive care unit, because it is easy to obtain, fast in response, and highly reproducible.Further studies with a larger number of patients and longer follow-up are needed in order to establish the correct timing in detecting the amount of myocardial injury that is mirrored by hs-cTnI levels in parallel with RV dysfunction detected by echocardiography or CTPA, coupling together cardiomyocyte cell death detection with RV dysfunction.


Right ventricular (RV) involvement in left ventricular (LV) non-compaction (LVNC) remains unknown. We aimed to describe the RV volumetric, functional, and strain characteristics and clinical features of patients with LVNC phenotype and good LV ejection fraction (EF) using cardiac magnetic resonance to characterize RV trabeculation in LVNC and to study the relationships of RV and LV trabeculation with RV volume and function. This retrospective study included 100 Caucasian patients with LVNC phenotype and good LV-EF and 100 age- and sex-matched healthy controls. Patients were further divided into two subgroups according to RV indexed trabecular mass . We measured the LV and RV volumetric, functional, and TMi values using threshold-based postprocessing software and the RV and LV strain values using feature tracking and collected the patients' LVNC-related clinical features. Patients had higher RV volumes, lower RV-EF, and worse RV strain values than controls. A total of 22% of patients had RV-TMi values above the reference range; furthermore, RV-HT patients had higher RV and LV volumes, lower RV- and LV-EF, and worse RV strain values than RV-NT patients. We identified a strong positive correlation between RV- and LV-TMi and between RV-TMi and RV volumes and a significant inverse relationship of both RV- and LV-TMi with RV function. The prevalence of LVNC-related clinical features was similar in the RV-HT and RV-NT groups. These results suggest that some patients with LVNC phenotype might have RV non-compaction with subclinical RV dysfunction and without more severe clinical features. Left ventricular non-compaction (LVNC) has become a well-known clinical entity, and the amount of research on this topic is increasing. Nevertheless, right ventricular (RV) involvement in LVNC remains a controversial issue with little available data. Compared with those of the left ventricle (LV), the unique shape of the RV and its physiologically greater quantity of endocardial trabeculae make it difficult to evaluate RV hypertrabeculation. Despite the lack of established diagnostic criteria, case reports suggest the existence of isolated RV non-compaction –3. The nOur study aimed to describe the RV volumetric, functional and feature-tracking strain parameters of patients with LVNC phenotype and good LV-EF and compare them to those of a healthy control group using cardiac magnetic resonance (CMR); to characterize RV trabeculation in patients with LVNC phenotype; and to describe the relationships of RV and LV trabeculation with RV volume and function. Furthermore, we studied the connection between clinical features and the extent of RV trabeculation in patients with LVNC phenotype.n = 22) subgroup, and those who were within the reference range were assigned to the LVNC phenotype with normal RV trabeculation  subgroup  g/m2, and 50–66 years = 14.3 ± 2.8 g/m2 . Th. Thn = 2Age- and sex-matched healthy volunteers who were free of known cardiovascular or other systemic diseases and who did not take medication were selected from our database as the control group. The average sports activity for both the patients and controls was <6 h/week . All proCMR examinations were performed on a 1.5 T MRI machine . Balanced steady-state free precession cine images were obtained in 2-, 3-, and 4-chamber long-axis views and breath-hold short-axis views from base to apex with full coverage of the LV and RV before the administration of contrast agent . The scan parameters were as follows: repetition time, 2.7 ms; echo time, 1.3 ms; flip angle, 60°; spatial resolution, 1.5 × 1.5 mm; temporal resolution, 25 frames per cardiac cycle; slice thickness, 8 mm without interslice gap; and field of view, 350 mm on average adapted to body size.Segmentation analysis was performed with Medis Suite QMass version 3.0 software . Automatic tracing with manual correction of the LV and RV endo- and epicardial contours was performed by one observer as described previously . Inter-aThe QStrain module of Medis Suite version 3.0 was used for the feature-tracking strain analysis . To assess subendocardial strain, the endocardial contours were drawn in end-diastole and end-systole in the 2-, 3-, and 4-chamber long-axis and short-axis views of the LV and in the 4-chamber view of the RV, including endocardial trabeculation. The LV global longitudinal strain (LV-GLS), LV global circumferential strain (LV-GCS), RV-GLS, RV free-wall strain (RV-FWS), and RV septal strain (RV-SS) were measured.t-test or the Mann–Whitney test was used to compare the studied groups. Differences in normally distributed, variables with equal variance between the control and patient subgroups were analyzed with one-way analysis of variance (ANOVA) and Tukey's post-hoc test, while the Welch test and Games-Howell post-hoc test were used for variables with unequal variance; all other data were compared with the Kruskal–Wallis test with Bonferroni correction for multiple comparisons. Pearson's or Spearman's correlation was performed to describe the linear relationship between the parameters. The chi-squared test was used to compare discrete data. A p-value < 0.05 was considered indicative of statistical significance. IBM SPSS Statistics  was used for calculations.Continuous parameters are described as the mean and standard deviation (SD), and discrete parameters are expressed as percentages. The intra-and interobserver agreement of the two observers was tested using the intraclass correlation coefficient (ICC). Distribution normality was assessed with the Shapiro–Wilk test. An unpaired Student's The baseline LV characteristics of the studied patients with the LVNC phenotype and the control subjects were compared . PatientThe comparison of the RV parameters yielded similar results: the RV-EDVi, RV-ESVi, RV-SVi, and RV-TMi values were significantly larger, and the RV-GLS and RV-SS values were significantly lower in the patient group, while the RV-EF, RV-CMi, and RV-FWS values were similar between the groups. Sixty-nine patients received contrast agent, but none demonstrated late gadolinium enhancement. Wall motion abnormalities were not visible in either the LV or RV in any patients.n = 15, mean age: 36.8 ± 3.8 years), while those whose RV-TMi values were within the normal reference range formed the RV-NT subgroup . None of the healthy control participants exceeded the upper normal limit for RV-TMi. We found significant differences between the two subgroups and the control group: the LV-ESVi, LV-TMi, RV-ESVi, RV-TMi, and RV-CMi values were significantly larger in the RV-HT group than in the RV-NT and control groups, the LV-EF, RV-GLS, and RV-SS values were significantly lower in the RV-HT group than in the RV-NT and control groups, and RV-EF values were significantly lower in the RV-HT group than in the RV-NT group  and without any clinical features (n = 32). The LV-CMi and RV-ESVi values were significantly lower in the patient with at least one clinical feature subgroup. However, all of the other measured RV and LV parameters were comparable between the groups  of the Ministry for Innovation and Technology in Hungary within the framework of the Therapeutic Development and Bioimaging Programs of Semmelweis University; by the Development of Scientific Workshops of Medical, Health Sciences and Pharmaceutical Education (Project identification number: EFOP-3.6.3-VEKOP-16-2017-00009); and by the Ministry of Innovation and Technology NRDI Office within the framework of the Artificial Intelligence National Laboratory Program. Project no. NVKP_16-1–2016-0017  has been implemented with the support provided by the National Research, Development, and Innovation Fund of Hungary, financed under the NVKP_16 funding scheme.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Left ventricular (LV) unloading via the percutaneous micro-axial Impella pump is increasingly used in patients with anterior ST-segment elevation myocardial infarction (STEMI) and overt cardiogenic shock. In this context, the evolution of cardiac function and dimensions beyond hospital discharge remains uncertain. We aimed to characterize echocardiographic changes over time in patients with acute anterior STEMI treated with an Impella device.From an ongoing prospective registry, consecutive patients with acute anterior STEMI managed with an Impella device were extracted. Transthoracic echocardiography was performed at index hospitalization and at first outpatient follow-up. Predictors of response, defined as a ≥ 10% absolute increase in left ventricular ejection fraction (LVEF) at follow-up, were sought.P < 0.0001), whereas LV dimensions, diastolic parameters, and measures of right ventricular dimension and function remained stable. Overall, 28 patients had a ≥ 10% absolute increase in LVEF at follow-up. Baseline creatinine was the only significant predictor of response at univariate analysis.A total of 66 patients  with anterior STEMI were treated with an Impella device in the first 24 hours of hospitalization, from 2014 to 2022. In-hospital mortality was 24%. Major bleeding and vascular complications requiring surgery occurred in 24% and 11% of patients, respectively. At baseline, mean LVEF was 34% ±12%. At follow-up, survivors showed a significant increase in LVEF (Among patients with anterior STEMI requiring mechanical hemodynamic support with an Impella device, the majority of survivors showed a sustained increase in LV function, without evidence of adverse remodelling. This signal warrants further investigation in dedicated trials.  Patients presenting with non-anterior STEMI localization, as well as subacute STEMI , and those receiving another type of MCS, were excluded. All patients were treated according to current STEMI guidelines—thus, they received a coronary angiography and a primary percutaneous coronary intervention (PCI) to the culprit vessel.The catheter-based, Impella 2.5 and CP continuous microaxial flow pumps can be implanted fully percutaneously, generally through the femoral artery.As part of our clinical routine, we obtained a contrast angiogram in an ipsilateral projection to assess puncture height and anatomic suitability of the iliac and femoral arteries prior to Impella device insertion. Ultrasound guidance was used, whenever possible. All patients were anticoagulated with unfractionated heparin to achieve an activated clotting time > 250 seconds during PCI. Finally, the Impella devices were inserted over a stiff 0.018-inch guide wire, advanced under fluoroscopy, and positioned in a retrograde fashion across the aortic valve.The timing of Impella device insertion generally followed 2 principles, as follows: (i) implanting the device and establishing LV unloading prior to PCI, and ensuring continuous support during and after PCI. This approach is preferred for patients presenting with established and profound cardiogenic shock. (ii) Implanting the device after primary PCI, a strategy generally pursued in patients showing growing inotrope-dependency, deteriorating hemodynamics, and/ or signs of multiorgan dysfunction secondary to advancing cardiogenic shock, which worsens following revascularization. In all patients, the decision for Impella device removal was made after interdisciplinary evaluation by the interventional cardiologists and critical care physicians, based on the following 3 main criteria: (i) hemodynamic support no longer needed after appropriate weaning; (ii) escalation of support ; and (iii) withdrawal of therapy and/or patient death.Transthoracic echocardiography (TTE) was performed at index hospitalization (baseline) and at outpatient follow-up. Baseline echocardiography followed the standard protocol in our centre and was performed by a board cardiologist in either the intensive care unit  or our echocardiography laboratory . If more than one TTE was performed during hospitalization, only the first one after STEMI diagnosis was taken into consideration for the analysis. Follow-up echocardiograms were performed either in our outpatient clinic or by external cardiologists. All echocardiograms were reviewed offline using a dedicated software package  by an independent physician certified in TTE by the European Association of Cardiovascular Imaging, and echocardiographic measures were performed according to this institution’s guidelines.t test or the Wilcoxon signed-rank test, depending on distribution. Categorical variables were compared using Fisher’s exact test. In patients who survived and had echocardiographic follow-up within the first months after discharge, we compared baseline and first follow-up echocardiographic data. According to previous literature, which showed a left ventricular ejection fraction (LVEF) absolute increase ≥ 10% after MI being prognostically significant,P values l< 0.05 were considered statistically significant. JMP Pro  was used for data quality assessment, statistical analysis, and graphical representation.Variables are presented as mean ± standard deviation or median (1st-3rd quartile), depending on their distribution. Normality of distribution was assessed using the Shapiro-Wilk test and a Q-Q plot. Categorical variables are presented as number (percentage). Continuous variables were compared using the Student Overall, 66 consecutive patients with the prespecified inclusion criteria were included. Those patients had been treated between December 2014 and February 2022. The patient inclusion flowchart is shown in The baseline characteristics are displayed in In-hospital management is summarized in We observed 7 major vascular complications requiring vascular surgery, and a fairly high rate of major bleeding, most of which was access-related bleeding. The narratives relating to patients facing in-hospital death are shown in Echocardiography at baseline was performed in the first days after hospital admission (median 1.0 days [range: 0.4-4.5]). Overall, the LVEF was reduced (mean 34% ± 12%), whereas the left ventricular end-diastolic diameter, E/e’, and parameters of right ventricular dimension and function were within normal ranges.P < 0.0001; P = 0.001; The echocardiographic follow-up was performed at a median of 110 days (IQR: 77-163) after Impella device treatment. Follow-up echocardiography was unavailable in 3 patients, whereas 2 patients received a LVAD or heart transplantation. Compared to baseline, LVEF at follow-up showed a significant increase, to 48% ± 13%  were identified as being responders , whereas 17 patients (38%) were identified as being nonresponders . Of thesThe performed univariate analyses showed that a low baseline creatinine level was the only significant predictor of response .Table 5CAnterior STEMI is commonly complicated by hemodynamic deterioration and cardiogenic shock, which in turn carry a high mortality risk.•At long-term echocardiographic follow-up after anterior STEMI treated with the Impella device, most patients who survived the index event showed an improvement of LV function and stable parameters of ventricular dilation, diastolic function, and right ventricular function and dimension. Of note, 62% showed a prognostically significant ≥ 10% absolute increase of LVEF.•Baseline creatinine level was the only significant predictor of response at univariate analysis.•Compared to a median expected mortality of 50% at 6 months by means of the Global Registry of Acute Coronary Events-acute coronary syndrome (GRACE-ACS) score,In this context, our analysis highlights the following points:,,In the contemporary era, in which STEMI is treated with primary PCI and optimal pharmacotherapy, almost one-half of patients demonstrate LV post-infarct remodelling.With respect to infarct localization, anterior localization seems to be associated with a greater extent of microvascular obstruction and a larger infarct size, which results in a higher incidence of heart failure and adverse events .Guideline-based medical therapy (GDMT) for heart failure can mitigate adverse negative remodelling by reducing afterload, sympathetic drive, and fibrosis. Nevertheless, in our analysis, GDMT with or without sodium-glucose cotransporter 2 inhibitors was not a significant predictor of LVEF increase at univariate analysis, a result that is expected as the study was underpowered in sample size and length of follow-up time to anticipate this effect.Whether LV unloading prevents adverse cardiac remodelling, or additionally enhances cardiac recovery, in patients presenting with acute MI complicated by cardiogenic shock remains unclear and certainly needs to be determined in further studies. To put our results into perspective, we summarized the data from earlier pivotal studies, which analyzed LV recovery following acute MI, as highlighted in The Impella device has been hypothesized to have beneficial effects, via its counteracting of the detrimental impact of high wall stress and microvascular dysfunction following an anterior STEMI.,Reducing LV volume and LV end-diastolic pressure by mechanical unloading reduces myocardial oxygen demand, activates cardioprotective signaling cascades that mitigate myocardial damage after reperfusion, and may also promote myocardial recovery, which ultimately leads to a reduced infarct size.Methods section, the timing of Impella device insertion in our cohort followed mainly 2 approaches, depending on case-by-case clinical decision-making. Nevertheless, early evidence from animal models and observational trials seems to favour Impella device implantation before revascularization, which may maximize the potential benefit of LV unloading.9,,STEMI-Door-to-Unload (STEMI-DTU) trial is now ongoing to assess the safety and effectiveness of LV unloading with an Impella CP device for 30 minutes before PCI in patients with acute anterior STEMI (NCT03947619).As stated in the Our study provides real-world insight regarding the hypothesis that LV unloading could potentially counteract the impact of negative remodelling post-infarct, even in the long-term, irrespective of when LV unloading occurs, and facilitate subsequent LV recovery. Further studies are needed to better understand the mechanisms and utility of the Impella device in these processes.,Right ventricular (RV) dysfunction after MI has a detrimental impact on prognosis.Our findings must be interpreted in the context of the following limitations. First, this is an observational single-centre study, which may limit its generalizability, and its results show association, not causation. Second, the analyzed echocardiograms were obtained in most cases as part of a routine clinical assessment and according to our local protocol. Due to clinical circumstances and/or limited availability of echocardiography staff, we encountered some variability in the timing of baseline and follow-up echocardiograms. As a result, the number of responders could have been underestimated due to a partial recovery before the first echocardiogram. Third, the limited number of patients in our cohort may have been insufficient to show statistical significance in some endpoints. Fourth, the absence of a control cohort of patients with anterior STEMI who were not treated with an Impella device or were implanted with other MCS devices limits the inferences that can be made about the impact of an Impella device alone, compared to usual care, on the endpoints. However, this issue is beyond the scope of our study. Moreover, selecting a control cohort that consisted of patients without any device support or who were implanted with other means of MCS would have introduced an uncontrolled bias, particularly as Impella implantation in patients who presented with anterior STEMI was made on a case-by-case basis by the treating invasive cardiologist.The present study highlights a positive trend in cardiac remodelling and function during the follow-up period of patients with acute anterior STEMI who received Impella device support on top of standard therapies including primary PCI. Eventually, the results from ongoing randomized trials are needed to determine whether hemodynamic support and LV unloading with Impella devices prevents adverse cardiac remodelling and the new onset of heart failure following acute anterior STEMI.


Paranoia is a frequent and highly distressing experience in psychosis. Models of paranoia suggest limbic circuit pathology. Here, we tested whether resting-state functional connectivity (rs-fc) in the limbic circuit was altered in schizophrenia patients with current paranoia. We collected MRI scans in 165 subjects including 89 patients with schizophrenia spectrum disorders  and 76 healthy controls. Paranoia was assessed using a Positive And Negative Syndrome Scale composite score. We tested rs-fc between bilateral nucleus accumbens, hippocampus, amygdala and orbitofrontal cortex between groups and as a function of paranoia severity. Patients with paranoia had increased connectivity between hippocampus and amygdala compared to patients without paranoia. Likewise, paranoia severity was linked to increased connectivity between hippocampus and amygdala. Furthermore, paranoia was associated with increased connectivity between orbitofrontal and medial prefrontal cortex. In addition, patients with paranoia had increased functional connectivity within the frontal hubs of the default mode network compared to healthy controls. These results demonstrate that current paranoia is linked to aberrant connectivity within the core limbic circuit and prefrontal cortex reflecting amplified threat processing and impaired emotion regulation. Future studies will need to explore the association between limbic hyperactivity, paranoid ideation and perceived stress.The online version contains supplementary material available at 10.1007/s00406-021-01337-w. Most people have a sense of security, i.e. feel generally safe in their social environment –3. The pWhile researchers are beginning to unravel the cognitive and emotional factors of delusion formation across different diagnoses, a neurobiological model of paranoia is still missing. Paranoia is associated with negative self-beliefs, anxiety, and depression  and inclIn people at clinical high risk for psychosis, persecutory delusions were associated with increased functional connectivity from amygdala to the visual cortex . But eviSeveral studies have explored the broader link between resting-state functional connectivity (rs-fc) and delusions generating complex and sometimes conflicting results. In schizophrenia, positive symptom severity, particularly of delusions and hallucinations was associated with rs-fc from thalamus to the middle temporal gyrus . LikewisWhile rs-fc from the amygdala to various brain regions declines with age in typical neurodevelopment, in youth with psychosis this development was deteriorated, leading to increased connectivity between amygdala and striatum, thalamus, ventrolateral prefrontal cortex and occipital cortex . These fIn sum, while perfusion MRI studies suggest increased resting-state neural activity in the amygdala in patients with paranoia, we have currently little understanding of the functional connectivity within the limbic structures in patients with current paranoia. Particularly, the connectivity between amygdala, hippocampus, nucleus accumbens or orbitofrontal cortex requires elucidation.Here, we aimed at exploring associations between aberrant neural activity at rest in the limbic system and current paranoia severity in subjects with schizophrenia. We hypothesized that patients with current paranoia would demonstrate increased functional connectivity at rest between key components of the limbic system when compared to patients without paranoia. In addition, we expect that connectivity within the limbic system was increased as a function of paranoia severity. Therefore, we tested these associations in both categorical and dimensional measures of paranoia.The current study included 89 patients with schizophrenia spectrum disorders according to DSM-5 criteria  and 76 healthy controls (Table n = 27), olanzapine (n = 21), clozapine (n = 11), haloperidol (n = 10), quietiapine (n = 6), amisulpride (n = 5), chlorpromazine (n = 2), lurasidone (n = 2)). Due to the large variability in the medication type, we calculated the mean olanzapine equivalents (OL eq.) according to Leucht . Accordingly, the data sets from the two scanners were merged and the scanner type was used as a covariate of non-interest in the following analyses.No significant differences were observed in the rs-fc between two scanners acquisition neither in healthy subjects nor in patients . [Healthy subjects: no significant difference between the two scanners: F = 2.55, pqFDR = 0.049). The post-hoc t-tests revealed an increase of the rs-fc between the hippocampus and the amygdala in the paranoia group compared to the non-paranoia group , we performed an additional exploratory analysis comparing only patients with and without paranoia using age, education, scanner type, medication dosage, and ICV as covariates of non-interest. We found an increase of the rs-fc in paranoia patients compared to patients without paranoia between the right OFC and the left BA 39 and between the left OFC and the left BA 47 Table , Part B.F = 7.10, pqFDR = 0.0016). The post hoc t tests revealed that an increase in paranoia is associated with increased rs-fc between bilateral hippocampus and bilateral amygdala .As no significant differences were observed in the rs-fc of the selected ROIs, we performed an additional analysis at the whole-brain level. A whole-brain ICA was used to compare rs-fc between patients with schizophrenia and healthy controls. We identified a reduced functional connectivity in patients compared to controls in the DMN and dorsal attention network (DAN) (Supplement 4B). Likewise, whole-brain ICA of rs-fc indicated multiple DMN alterations in patients with paranoia vs. healthy controls: reduction in the posterior cingulate, but increases in bilateral medial and dorsolateral prefrontal cortex, left angular gyrus, and left middle temporal gyrus (Supplement 4C).Here, we tested rs-fc within the limbic system in schizophrenia patients with current paranoia. Probing rs-fc between bilateral amygdala, hippocampus, nucleus accumbens, and OFC, we found increased rs-fc between hippocampus and amygdala in patients with paranoia compared to patients without paranoia. This increase in rs-fc between bilateral hippocampus and amygdala was also linked to the severity of paranoia. In additional seed-to-voxel analyses, we found the left OFC to be connected to right BA47 in patients with paranoia. Finally, patients with paranoia had increased functional connectivity in prefrontal areas of the DMN when compared to healthy controls. Group differences in rs-fc were corroborated by regression analyses with dimensional assessments of paranoia.The experience of paranoia is very unpleasant and stressful . PatientThreat processing engages ventral hippocampus, amygdala, and orbitofrontal cortex in fMRI tasks in healthy subjects –44. ExpoIncreased rs-fc between components of the subcortical amygdala pathway  in paranoia suggests that this pathway is particularly amplified in paranoia, which might be critical to experience stress upon threat. This over-excitation could result from chronic neural alterations in the pathway, as suggested by converging animal models and neuroimaging studies. Indeed, rodent models of schizophrenia consider the ventral hippocampus to be particularly vulnerable to threat induced stress, which is probably due to the distinct maturational profile of fast-spiking parvalbumin interneurons (PIV) –50. If tOutside the core limbic circuit, paranoia was also associated with increased rs-fc within the orbital and medial prefrontal cortex (OMPFC including the OFC and BA 47) and between the OFC and the parietal cortex . In general, the OMPFC constitutes a substantial portion of the cerebral cortex in primates. Although its function is not yet fully understood, studies in both non-human primates and humans suggest a role in decision-making and guidance of emotional and reward‐related behaviours . FurtherThe experience of paranoia may trigger safety behaviors, such as avoidance, which has been linked to Ncl. accumbens function , 45, 61.Aberrant rs-fc in the DMN has become a frequent finding in schizophrenia. However, the direction of change and the DMN associations with schizophrenia symptoms remain subject of debate , 63. DMNIn a broader context, specific behaviors in schizophrenia are linked to patterns of brain alterations including grey matter reductions, increased resting-state neural activity as well as increased structural and functional connectivity within the key networks. In fact, in schizophrenia patients with psychomotor inhibition, we found reduced grey matter volume and increased resting-state perfusion in the supplementary motor area across samples, who in turn demonstrated increased rs-fc and structural connectivity with other motor areas of the brain –75. The The most pronounced differences were noted between patients with and without paranoia. In the ROI-to-ROI or ROI-to-voxel analyses we failed to find differences between patients and controls, while we found differences at the network level (e.g. DMN). This pattern of findings argues for enormous biological variance between patients with schizophrenia that is even exceeding the differences between patients and controls, which is in line with larger analyses of structural brain changes in schizophrenia . TherefoThe findings of the current study should be interpreted in light of some limitations. First, data of three studies in psychosis were pooled for this analysis. These data were acquired with two different 3 T Siemens scanners at Bern University. The differences in the acquisition parameters between the two scanners are mostly observed on the rs-fMRI sequences. The two sequences presented a different type of acquisition (single vs multiband), TR, volume numbers and voxel sizes. Even if some of these differences are corrected after preprocessing and first-level analysis, one could argue that the difference in acquisition might lead to a difference in the observed functional connectivity. However, in this study, the rs-fMRI analysis accounted for the acquisition differences between scanners, and the results remained unchanged after correction. Moreover, the group comparisons between the two scanners demonstrated no significant difference. One additional way to unambiguously check the inter-scanner reliability would be to perform the analyses separately for each acquisition type. However, due to the strong variability in the paranoiac symptoms and severity, large sample sizes are needed to catch the whole picture. In future studies, a more homogenous design and imaging acquisition parameters would be needed to confirm the present results. Second, despite the similarities between the three studies, specific rating scales for the assessment of paranoia have not been consistently applied. Specific scales on paranoia, either expert-rated or self-report are likely to be more sensitive in assessing paranoia severity than the PANSS score . Third, The current study investigated rs-fc in patients with paranoia. Increased connectivity between hippocampus and amygdala as well as alterations in the DMN in patients with paranoia argue for dysfunctional threat processing in these patients. Instead of indicating a general phenomenon, these alterations in functional connectivity are specific to schizophrenia patients experiencing paranoia.Supplementary file1 (DOCX 7561 kb)Below is the link to the electronic supplementary material.