Incidence of right ventricular (RV) failure in septic shock patients is not well known, and tricuspid annular plane systolic excursion (TAPSE) could be of limited value. We report the incidence of RV failure in patients with septic shock, its potential impact on the response to fluids, as well as TAPSE values.Ancillary study of the HEMOPRED prospective multicenter study includes patients under mechanical ventilation with circulatory failure.This is a multicenter intensive care unit studyTwo hundred and eighty-two patients with septic shock were analyzed. Patients were classified in three groups based on central venous pressure (CVP) and RV size . In group 1, patients had no RV dilatation (RV/LVEDA < 0.6). In group 2, patients had RV dilatation (RV/LVEDA ≥ 0.6) with a CVP < 8 mmHg (no venous congestion). RV failure was defined in group 3 by RV dilatation and a CVP ≥ 8 mmHg. Pulse pressure variation (PPV) was systematically recorded.None.In total, 41% of patients were in group 1, 17% in group 2 and 42% in group 3. A correlation between RV size and CVP was only observed in group 3. Higher RV size was associated with a lower response to passive leg raising for a given PPV. A large overlap of TAPSE values was observed between the 3 groups. 63.5% of patients with RV failure had a normal TAPSE.RV failure, defined by critical care echocardiography (RV dilatation) and a surrogate of venous congestion (CVP ≥ 8 mmHg), was frequently observed in septic shock patients and negatively associated with response to a fluid challenge despite significant PPV. TAPSE was unable to discriminate patients with or without RV failure. Over the last decade, a few studies have highlighted the crucial role of right ventricular (RV) function in hemodynamic and respiratory diseases in critical care , 2. HoweFluid management in septic shock is crucial for prognosis, as fluid overload and high CVP are associated with a worse outcome . It has In a large series of patients with septic shock, our goals were then to report the distribution of RV size and CVP, to determine the incidence of RV failure and its impact on fluid responsiveness.Declaration of Helsinki. HemoPred was approved by the Ethics Committee of Limoges (no 85-2012-09). Among the 540 studied patients, 295 were admitted for septic shock, which was not characterized by the Sepsis-3 definition as the HemoPred study was designed before its publication. Diagnosis was based on a suspected infection responsible for sustained hypotension despite adequate fluid loading that required vasopressors, with associated clinical signs of tissue hypoperfusion  that were confirmed by laboratory values . One hundred and fifty-two patients met the lactate criteria as well as another hypoperfusion sign, while 115 did not meet the lactate criteria and 6 only met the lactate criteria.We did a post hoc analysis of the multicenter observational and prospective HemoPred study in which 540 ventilated patients admitted between 2012 and 2014 were included in five French ICUs  for circulatory failure. Transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) were systematically performed within the first 24 h of ICU admission . The invThe initial clinical data collected included socio-demographic data, biometric parameters, comorbidities, vital parameters  and etiology of sepsis. The Sequential Organ Failure Assessment Score (SOFA) and Simplified Acute Physiology Score SAPS2 were recorded.CVP was obtained by measuring the pressure at the end of a central catheter located at the level of the intrathoracic superior vena cava (SVC) at its entry into the right atrium. Bladder pressure was used as a surrogate of intra-abdominal pressure (IAP) (available in 260/282—92.2% patients), and PPV was calculated from the data obtained from the radial or femoral arterial catheter. Arterial blood gas analysis was performed concomitantly with CCE, and serum lactate level was reported. Acute respiratory distress syndrome (ARDS) was defined using the Berlin definition . Plateau2 + CVP , CCE was performed with continuous ECG and mechanical ventilation monitoring. An end-expiratory beat was defined as the last beat occurring before mechanical lung inflation. Among all variables prospectively recorded in the HemoPred cohort, we especially analyzed tricuspid annular plane systolic excursion (TAPSE), RV size, systolic pulmonary artery pressure (SPAP) and cardiac index (CI). TAPSE was measured at end-expiration with the M-mode study in an apical 4-chamber view as recommended . RV size2 + CVP .Passive leg raising (PLR), as technically validated , was perThe main outcome of the study was to evaluate the incidence of RV failure in septic shock patients.The secondary outcomes included: 1) the relationship between RV failure and fluid responsiveness and 2) the performance of TAPSE in discriminating patients with and without RV failure.Continuous variables were reported as medians, and categorical data were expressed as numbers and percentages. Continuous variables were compared using a Mann–Whitney test or a Kruskal–Wallis test. Categorical data were compared using a Chi-square test or an exact Fisher test when necessary.Three groups of patients were compared according to RV size and CVP, a good surrogate of venous congestion. Cutoff values of 0.6 for RV/LV EDA  and of 8p values are provided. The paired Wilcoxon test was used to compare variations of CVP before and after PLR across the three groups. All the analyses were performed using R (R version 3.4.3 (2017-11-30)—"Kite-Eating Tree" Copyright (C) 2017 The R Foundation for Statistical Computing). A p value < 0.05 was considered significant.Correlation between TAPSE and RV/LV end-diastolic area was evaluated using Spearman’s correlation test. Rho and p = 0.805), − 0.102 (p = 0.493) and 0.241 (p = 0.008) in groups 1, 2 and 3, respectively).Among the 295 patients admitted for septic shock, 13 could not be classified according to RV/LV ratio  and CVP   was observed between TAPSE and RV size  when defined by the association of RV dilatation (RV/LV EDA ≥ 0.6) with systemic congestion (CVP ≥ 8 mmHg). RV size modified the response to a reversible fluid challenge (PLR), as higher RV dilatation was associated with less likelihood of fluid responsiveness for a given PPV. TAPSE was also not accurate enough to detect RV failure since overlap was observed between the 3 groups and around 60% of patients with RV failure had normal values.The current definition is only physiologically based and has no clear cutoff values for RV size and CVP –5, CVP bSeptic cardiomyopathy affects the right ventricle . In a smOur results draw the physician’s attention to the fact that PPV is not systematically associated with fluid responsiveness but also with RV failure that is an obvious situation with no benefit of fluid expansion. A significant PPV was less likely to predict a positive response to PLR in the case of RV dilatation, and this effect was more pronounced when the dilatation increased. Based on our results, we can only report that patients with RV failure, as defined in our study, will respond to fluids in only 30% of cases and so that the risk of giving useless and even harmful fluids is high. To decide to give fluids, physicians have then to suspect a potential high clinical benefit of a positive response. In patients with RV/LV > 0.6 but CVP < 8, we could more clearly suggest that fluids may unmask RV failure, as said by the reviewer, and then that fluid expansion, if considered, has to be done with caution (low volume to test the system) and by monitoring CVP and RV size . This would highlight the need of a repeated hemodynamic evaluation using echocardiography to evaluate RV size when PPV are significant, combined with CVP monitoring which may diagnose congestion, part of RV failure. We demonstrated that RV failure was frequently observed in septic shock patients and echo is the best and easiest way to figure it out. However, our observations with their clinical applications require further validation before to be recommended in daily systematic routine.Our study has some limitations. First, this is a post hoc analysis of the HemoPred study, which was not specifically designed for such a goal. However, HemoPred was a multicenter study with a very low number of missing values. Second, Beurton et al. suggested than PLR could be of limited accuracy in predicting fluid responsiveness when IAP is above 12 mmHg . If so, We report in a large population of ventilated septic shock patients that when RV failure is defined using critical care echocardiography (RV/LV EDA ≥ 0.6) and a surrogate of venous congestion (CVP ≥ 8 mmHg), it was frequently observed (42%) with a negative effect on the response to a fluid challenge even in the case of significant PPV. TAPSE was unable to differentiate between patients with or without RV failure. Future studies should validate our results and our definition of RV failure in a larger population in order to improve hemodynamic management in these critically ill patients.Additional file 1. Electronic supplementary material.


Cardiovascular implantable electronic device (CIED) has helped with advanced technological improvement in the cardiac field and has been a long-term alternative to medical management. There are different forms of CIEDs such as pacemakers, implantable cardioverter-defibrillators, and cardiac resynchronization therapy. These devices are efficient in establishing near-normal hemodynamics and circulation that ultimately aid physicians to improve the quality of life for their patients. However, there are risk factors that can result in postoperative complications, including infection, lead and pulse generator complications, heart complications, medication-related complications, and psychosocial complications. To ensure optimal outcome of CIED placement, preprocedural measures need to be in place such as matching the right candidate and using appropriate devices. This review aims to highlight the surgical techniques for CIEDs, the associated postoperative complications, and long-term health effects. Over the last several decades we have seen technological advancements within the medical community and the cardiology field is no exception. As cardiac issues such as heart failure rise in America, leading to numerous challenges within the clinical setting, device therapy has been an excellent long-term alternative to normal medical management. Arrhythmias affect over 14.4 million Americans leading to over 400,000 deaths yearly [Heart failure can predispose patients to various ventricular arrhythmias from ventricular tachycardia, ventricular fibrillation, or sudden cardiac death. Cardiac implantable electronic devices (CIEDs) are efficient in establishing near-normal hemodynamics and circulation . AlthougThere are different forms of CIED, however, the main three are pacemakers for bradyarrhythmias, implantable cardioverter-defibrillators (ICDs), and cardiac resynchronization therapy (CRT) . CRT canCurrent peer-reviewed literature was studied to give a literature overview on the surgical techniques for CIED, its complications, and long-term health effects. Articles published in the English language, without geographic limitations, between the years of 1989 and 2020 were retrieved from databases including the American Heart Association, European Heart Journal, ScienceDirect, and PubMed. Only free articles were selected. The search excluded predatory publishers and predatory journals.Studies that were included in the review were those on cardiac surgical techniques . The search methodology was as follows: First, the word “cardiac implantable electronic devices” was searched for and the articles were narrowed down by going into the advanced search and typing AND “post-op complications,” “long-term health outcomes.” Second, articles were sorted out relevance. Third, the reference list of identified articles was analyzed to create a list of 33 articles that were included in the review.Surgical techniquesA wide array of surgical techniques are utilized by surgeons when implanting CIEDs under various conditions whether under local or general anesthesia.Pacemaker ImplantationFor patients with cardiac issues such as sinus node dysfunction or tachyarrhythmias, to name a few, a permanent pacemaker implantation is indicated. Pacemakers detect abnormal cardiac impulses via wire-tipped electrodes and the computer generates electrical impulses transduced to the contracting myocardium to pace the heart .Implantation of the pacemaker is normally performed in a cardiac catheterization or electrophysiology lab under local anesthesia. Patients are given antibiotic prophylaxis with first-generation cephalosporin cefazolin similar to other routine surgical procedures. A transvenous percutaneous approach is utilized to gain access to the cephalic vein, as well as to the left or right subclavian vein via the middle inner third of the clavicle and first rib.After the subclavian vein is successfully punctured, a subcutaneous pocket is created where the pacemaker is implanted in the infraclavicular area. Subsequently, using fluoroscopy, the clinicians feed the pacemaker’s wire leads with a guide wire to enter the superior vena cava or the right atrium. The leads are successfully fed into the right atrium and sutured into the atrial wall utilizing non-absorbed sutures. Chest X-rays are taken in anterior-posterior and posterior-anterior positions to confirm the leads and the pacemaker implant are securely in place.Subcutaneous Implantable Cardiac Defibrillators (S-ICDs)S-ICDs are another form of CIED, the implantation technique used is primarily focused on creating pockets between muscle or fascia layers. Submuscular pocket implantations indicate for the defibrillator to be placed under the serratus anterior muscle (SAM). An incision is initially made in the inframammary crease using a “blunt dissection” technique, and the submuscular pocket is created for the CIED/S-ICD . The surSubfascial pocket implantation calls for the CIED/S-ICD to be placed under the fascia using the same blunt dissection technique, as described above. The fascia is dissected from the SAM which is more superficial and less demanding than the subcutaneous methods which requires a more intrusive approach. The subfascial technique introduced an alternative to the subcutaneous method by allowing minimal postoperative pain, with the same cosmetic advantage as the prior technique . PostsurCardiac Resynchronization TherapyCRT is employed to restore automaticity and synchronize the atrial-intraventricular contractions in patients with severe CHF and widened QRS complex ,4. ImplaResearchers noted numerous concerns on the technical and, in particular, the anatomical aspects of the techniques used. The variations in venous anatomy among patients presented implantation complications of the left ventricular pacing lead. Difficulties that were noted included but are not limited to accessing the coronary sinus or the placement of the LV pacing lead in the lateral ventricular wall and voiding phrenic nerve stimulation ,4.We noticed in certain patients with technical difficulties or anatomical variations, different techniques were preferred. Surgical epicardial LV lead implantation was the ideal technique for optimal cardiac resynchronization, in particular, with patients who have transmural myocardial scarring .Postoperative complicationsIdeally, with the advancement of therapy , patients with comorbidities  are expected to live longer. The increase in the likelihood of developing cardiovascular morbidities with increasing age is directly proportional to that of its therapeutic indication  and associated complications. Although CIEDs are generally lifesaving, it is often associated with psychosocial effects, lead and pulse generator complications, heart malfunction , and death. The most vulnerable group are pacemaker-dependent patients ,7.Most studies show a CIED-related complication risk of 5-6%. In a prospective study, a cohort of 114,484 aged 65 years or above with a median follow-up of 2.7 years showed a hospitalization or reoperation rate of 6.1%. Moreover, patients with postoperative complications onset within three months had the highest mortality rate at one and three years .InfectionsStaphylococcus aureus, S. epidermidis, and Enterococci species) and allergic reactions (recurrent infections). Suspicion of CIED infections usually results in device and blood culture, transesophageal echocardiogram, positron emission tomography, and computed tomography [Mostly, CIED implantations are undertaken in an operating room under optimal sterile conditions. Infections have been associated with the skin microbiota  with low virulence and are associated with device erosion towards the superficial subcutaneous tissue, patients with minimal subcutaneous tissue, and those that underwent significant weight loss [Chronic infections, however, may have a late onset . Typically, these infections involve microbiota organisms , artifact oversensing (24%), and lead fractures (24%). Recurrent CIED-related problem rates of 20% at five years have been reported .Dislodgment and malfunction of the CIED pulse generator can occur in the event of malrotation in the pocket. The presenting symptoms usually include bradyarrhythmias  due to lead restraints and higher bradycardia pacing threshold effects. In some cases, CIED malpositioning could be fatal due to failure in detecting and fixing arrhythmia. Precautionary measures aimed at appropriate suturing of the device to the pectoralis fascia in a fitting pocket and educating patients on the effects of mechanical pulling reduce the chances of malrotation ,23.Device hardware failures are an uncommon yet potential complication that could lead to death. Studies have shown the incidence of such an event ranging 0.01-0.1%. Intrinsic hardware failures  and extrinsic hardware failures  are associated with hardware failures . CurrentHeart ComplicationsCIED-related arrhythmias are a potential complication often arising from inappropriate shocks. Paradoxically, CIEDs could trigger arrhythmias when attempting to attenuate supraventricular tachycardias (SVT) or any arrhythmia besides ventricular tachyarrhythmias. The most common SVT associated with inappropriate shocks is atrial fibrillation. Lead malfunction and enhanced sensing are other causes of inappropriate shocks. Studies have shown that novel dual chamber CIEDs and device programming tailored towards inappropriate shock prevention are paramount to reducing inappropriate shocks. Phantom shocks are another associated complication with CIED implantation. Phantom shocks should be suspected when device interrogation proves otherwise ,28.Damage to the endocardial architecture is a potential CIED-related complication sometimes fatal in the event of heart failure. Tricuspid regurgitation can result from the mechanical impedance of the leads or damage to the tricuspid valve. The incidence rate of developing is 10-20%, and about half of those patients end up with heart failure .Psychosocial ComplicationsAppropriate shocks have been associated with psychosocial complications. Studies have shown about a 50% occurence of CIED-related psychosocial effects . Psychosocial complications are associated with anticipation of shock distress and lifestyle changes . In a study of 119 CIED recipients, the majority tolerated the shocks (72%), some feared the shocks (23%), and some would rather be CIED-free (5%) ,30.Studies have shown that individual and group and cognitive and behavioral therapies have shown success in reducing the psychological effects of CIED-related complications. Measures to reduce the frequency of shocks in recurring cases should be undertaken to minimize the psychosocial burden the device has on patients ,31-33.CIEDs have had rapid advancements in the last 70 years. Starting with a bulky external table top pacemaker that successfully provided treatment for heart block to the microprocessor-driven pacemakers that can monitor arrhythmias, bradycardic and tachycardic pacing, provide resynchronization for heart failure, and defibrillation.S. aureus or S. epidermidis using chlorhexidine skin washing, and prophylactic antibiotic therapy. Following the operation, anticoagulation medications, appropriate wound management, early reintervention in case of lead displacement or suspected infection, and routine follow-up care are all factors to reduce adverse effects.All surgeries, especially CIED implantation, carry risks, including infection, lead and pulse generator complications, tricuspid regurgitation, arrhythmias, medication complications, and psychosocial complications. There are preprocedural measures that can be taken to ensure an optimal outcome in CIED placement. Most important is matching the right candidates and appropriate CIED device taking into consideration body habitus, preexisting health conditions, and comorbidities. Other considerations include experienced surgeon and medical staff, number of leads on CIED device, possible decolonization of Cardiac muscle cells have an innate ability to conduct electrical impulses and begin beating even when a collection of cells are grown in a petri dish. However, when the heart is beating abnormally causing symptoms in the patient such as syncope or thromboemboli, CIEDs offer a chance for the patient to live a normal life.


Patients with LVEF < 50% had significantly higher values of TM% . Multivariable analysis showed that female gender and neutral pattern of hypertrophy were directly associated with TM%, while dynamic obstruction, maximal wall thickness and LVEF% were inversely associated with TM%. There was no association between TM% with arterial hypertension, physical activity, or symptoms. Atrial fibrillation and severity of hypertrophy were the only variables associated with cardiovascular death. Multivariable analysis failed to demonstrate any correlation between TM% and arrhythmias. Conclusions: Approximately 25% of myocardium appears non-compacted and can automatically be measured in HCM series. Proportion of non-compacted myocardium is increased in female, non-obstructives, and in those with lower contractility. The amount of trabeculation might help to identify HCM patients prone to systolic heart failure.Aims: Hypertrophic cardiomyopathy (HCM) is often accompanied by increased trabeculated myocardium (TM)—which clinical relevance is unknown. We aim to measure the left ventricular (LV) mass and proportion of trabeculation in an HCM population and to analyze its clinical implication. Methods and Results: We evaluated 211 patients with HCM  with cardiac magnetic resonance (CMR) studies. LV trabecular and compacted mass were measured using dedicated software for automatic delineation of borders. Mean compacted myocardium (CM) was 160.0 ± 62.0 g and trabecular myocardium (TM) 55.5 ± 18.7 g. The percentage of trabeculated myocardium (TM%) was 26.7% ± 6.4%. Females had significantly increased TM% compared to males (29.7 ± 7.2 vs. 25.6 ± 5.8,  Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disease characterized by clinical and prognostic heterogeneity ,2,3,4. TLeft ventricular non-compaction (LVNC) is defined by an increase of trabeculations in the left ventricular endo-myocardium. Adult appearance of trabeculated myocardium may mainly be a consequence of an arrest in the embryologic process of compaction. Some authors have suggested that myocardial trabeculations can be acquired  in response to an increase in cardiac load ,9.This entity was increasingly recognized with the development of high definition cardiac imaging. Although LVNC can be in isolation, an increase in hypertrabeculation often accompanies other genetic cardiomyopthies . DespiteThe clinical relevance of the presence of hypertrabeculation in HCM is unknown. We aim to measure the left ventricular mass and proportion of trabeculation in a population of HCM patients. Patients recruited from an Inherited Cardiomyopathy Clinic—meeting international HCM criteria with an available good quality CMR study—were included. The first CMR of each patient was used for the study. Clinical and outcome data prospectively collected in a database was available for analysis. Patients were prospectively included, cardiac imaging and examinations were performed prospectively; symptoms, history of hypertension (HTN), regular physical exercise and arrhythmic events prior to the first evaluation were also recorded. HTN was defined following European Society of Hypertension and European Society of Cardiology recommendation . Echocardiographic variables included: pattern of left ventricular hypertrophy (LVH) ; maximalAll patients were offered a 24 h ECG-Holter and exercise test in order to complete sudden death (SD) risk stratification. Non-sustained ventricular tachycardia (NSVT) was assessed. Arrhythmic events and complications during follow up were also recorded. In the cohort, there were three resuscitated cardiac arrests (CA) and six appropriate implantable cardioverter defibrillator (ICD) discharges, which were computed as SD equivalent for survival estimates. Mean follow-up was 49.1 ± 37.1 months . All subjects gave their informed consent for inclusion before they participated in the study. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of Clinical Research from Universitary Hospital Virgen de la Arrixaca (218/C/2015).Magnetic resonance studies were performed in two hospitals with different scanners: SIGNA HDxt 1,5T: General Electric Systems, USA, post-processing software Advantage Workstation, AWA.3-08 and Achieva CV, Philips Medical Systems, Netherlands, (Philips Software workspace 2.6.3.2). A dedicated software tool for the automatic quantification and exact hyper-trabeculation degree of LVNC based on automatic delineation of the epicardial and endocardial borders of the LV and trabecular recesses was used  see Sup Figure .Performance of the software was reviewed visually by one imaging cardiologist expert in order to rule out significant deviations. Additionally, delineation of the borders of 10 randomly selected cases was subjectively scored by two skilled cardiologists. The score went from 1 to 5, from large disagreement (1) to exact match (5). A total of 73 CMR slices were evaluated: 65 slices were scored with a five by the two and the remaining eight slices were classified with a four at least by one of the cardiology experts. The weighted kappa statistic showed an agreement between the two observers of 96.6% (kappa 0.76).t-test, Anova and Pearson were used for comparison between groups where appropriate. Variables with p < 0.10 in univariate were included in the multivariate analysis. Additionally, those considered relevant to adjust the model were also included. Variables with redundant information or colinearity were excluded. Linear logistic regression was used for association between study variables (TM and TM%) and clinical variables. Kaplan Meier estimates and Cox regression analysis were used for survival analysis. p-values < 0.05 were considered statistically significant.Statistical analysis was performed using SPSS statistical software . Chi square, The study population comprised 211 HCM patients .Baseline clinical characteristics of patients included in the study regarding the quartile of trabeculation, are summarized in Mean maximal LVH was 18.8 ± 5.1mm. 103 (50.2%) of patients with asymmetric LVH, and 64 (30.5%) demonstrated obstruction .p < 0.0001). Indexed CM remained increased in males compared to females while TM mass was similar in males and females (Despite both trabeculated (TM) and compacted myocardial (CM) mass were increased in males compared to females, females had significantly higher TM%  and in 23 patients who performed versus 181 who did not engage in intense physical activity . There was no association between age and TM%. TM% was similar in 87 HTN versus 124 non-HTN patients with HCM  (p = 0.002).Correlation between TM% and main variables from CMR are illustrated in  0.0001) B. Patienp < 0.0001 and 24.9 ± 27.6% vs. 27.6 ± 6.3%, p < 0.0001, for CM and TM%, respectively). Neutral pattern had an increased TM% , while septal reverse and apical pattern of hypertrophy had significantly less TM% . There was no correlation between left atrium diameter and TM%. Patients with obstruction had increased CM mass (and indexed CM mass) but reduced TM% compared to non-obstructives  (p = 0.02). No correlation was found between end-diastolic and end-systolic LV volumes from CMR and TM% C. An inv = 0.02) D. Patienp < 0.0001), higher TM  but lower TM% , compared to the 90 (45.9%) with no LGE.Late gadolinium enhancement (LGE) was associated with CM, TM and TM% (including indexed parameters). Of the patients, 106 (54.1%) with positive LGE had significantly higher CM mass .TM% was not related with symptoms. Patients with dyspnea (NYHA III-IV) or syncope had similar TM and TM%. There was no difference in TM% in patients with or without AF. There were only 6 (2.8%) patients with sustained ventricular tachycardia who had a significantly lower TM% . 26 (12.3%) patients who subsequently underwent ICD implantation seemed to have also lower TM%  (Nine (4.3%) patients who required pacemaker implantation had significantly lower TM%  .p = 0.03). Eleven (5.2%) patients who developed a stroke had lower TM% than those who did not  patients had at least one major event over a mean 49.1 ± 37.1 months of follow-up: three patients died suddenly, one had a resuscitated cardiac arrest and four had appropriate ICD therapies. There was one heart failure death, one stroke related death, one procedure related death, and one heart transplant. p = 0.02) and TM mass  but similar TM% . TM% was not associated with the combined major outcome. The eight patients with SD  had significantly higher CM  were not associated with TM% in a model with demographic, main morphological variables and symptoms. AF and NSVT on Holter was neither associated with TM%.On multivariable analysis TM% was not associated with cardiovascular (CV) death or equivalent. MWT and AF were the only two variables associated with CV death. In the presence of CM mass calculated from CMR, MWT lost his value in the prediction of CV death. In this model, AF remained significantly associated (and a trend of TM%) .Severity of wall thickness, measured as MWT or CM mass were the strongest predictors of CV death and SD. This is the first study to systematically quantify LV trabeculation in an HCM population. The main finding from our study was that a clinical profile of patients with HCM with increased trabeculations may exist. Some of the features were predominant female gender, and non-obstructive forms with systolic impairment. There was no association between TM with age, ventricular volumes, or LGE. Higher degree of trabeculation in HCM was associated with LVEF below 50% which might precede development of systolic heart failure . Degree Jacquier et al.  manuallyThe percentage of trabeculated myocardium showed in this large series of HCM (26.7 ± 6.4%) patients demonstrate a clear increase from that observed in controls, which suggests that LVNC or hypertrabeculation is part of the clinical phenotype of HCM. In an earlier paper from our group using the same software, a cutoff of 27% MT showed to have a good accuracy for differentiation of LVNC .In contrast to the fractal analysis recently published by Captur et al. , based oTrabeculation in its different forms, including deep crypts and clefts has been suggested to be a pre-diagnostic  feature in carriers of HCM associated mutations . While oIn contrast with an early paper of a dilated cardiomyopathy series , which sTo finalize, we want to highlight the need of a quantification of trabeculation in order to define the limits between normality and abnormality and to establish the role of non-compaction in various cardiac conditions. Our software has demonstrated to be useful not only for automatic quantification of TM but also for CM. In this regard, in our study, CM mass measured by the software was the strongest predictor of the outcome above the traditional maximal wall thickness taken from echocardiography. The latter supports the use of global assessment of left ventricular CM and TM mass to replace focal measurements of wall thickness in risk algorithms.Differences in the characteristics of our series regarding distribution of the pattern of hypertrophy, value of LVH mass, proportion of obstruction or percentage of LGE might be due to the age of the cohort, which is relatively young (mean 44 years old), the inclusion of a ~34% of relatives (as compared to probands) or the relatively high percentage of patients diagnosed through family screening (25%) or incidentally (28%). Further studies are warranted to verify our findings.Despite the number of individuals being relatively large, only a few patients developed CV events. Survival analysis is then limited, and results should be taken carefully. Patients with devices were ruled out from CMR and some high-risk patients were excluded. Repeated CMR studies were not available and changes over follow-up in CM and TM could not be explored. Genetic information was available in 88/140 (62.9%) of the probands included in the cohort. Genetic testing yield was 43/88 (48.9%). Further analysis of the association between genetic results and morphologic and clinical findings was not performed due to the incompleteness of the genetic information.A significant proportion (~25%) of myocardium appears non-compacted and can be automatically measured in HCM series. There is a clinical profile of patients with HCM with increased trabeculations. Proportion of non-compacted myocardium is increased in female, non-obstructives, and in those with lower contractility. The amount of trabeculation might help to identify HCM patients prone to systolic heart failure. Amount of trabeculation does not seem to associate with arrhythmias.


Background: Cardiac function can be influenced by liver cirrhosis and should be thoroughly evaluated before liver transplantation. We investigated left ventricular (LV) and, for the first time, left atrial (LA) strain and strain rate in end-stage liver cirrhosis patients of different etiologies. Methods: This retrospective, cross-sectional study evaluated left heart function in 80 cirrhosis patients and 30 controls using standardized echocardiographic techniques and speckle tracking technology (STE) analysis. Serum markers of liver function were used for correlation analysis. Results: While conventional parameters demonstrated no alteration in systolic function, speckle tracking analysis showed a significant increase in LV longitudinal strain throughout all cardiac layers, with significant correlation to model of end-stage liver disease (MELD) score. LA reservoir and conduit strain as well as LA strain rate in all phases were significantly reduced in end-stage liver disease (ESLD) patients compared to control. STE for the evaluation of LA phasic function seemed to be more sensitive than volumetric methods. Kaplan-Meier curves showed a trend towards reduced post-transplant survival in patients with a reduced LA reservoir and conduit strain. Conclusion: STE analysis detected increased LV and decreased LA deformation in cirrhosis patients, thus proving to be highly sensitive to cardiac changes and useful for more precise cardiac evaluation. Cirrhotic cardiomyopathy (CCM) is cardiac dysfunction in patients with end-stage liver disease in the absence of prior heart disease ,2,3. MilHowever, acute stress conditions, such as infection, transjugular intrahepatic portosystemic shunt (TIPS) procedure, or liver transplantation (LTx), can lead to extreme forms of CCM with overt heart failure in patients with end-stage liver disease (ESLD) ,5. TransTwo-dimensional speckle tracking echocardiography (2D-STE) is a new technique to assess cardiac function, with major focus on the left ventricle (LV) in the clinical setting. It uses grayscale digital images with speckle patterns obtained from sonographic procedures such as TTE and analyzes the relative displacement of individual speckles on a frame-to-frame basis to quantify myocardial deformation, also referred to as “strain” ,5,8,9. STo date, STE has only been validated for LV assessment . HoweverThe present retrospective study aims to evaluate left ventricular and atrial myocardial deformation in patients waiting for liver transplantation using speckle tracking technology. The novel aspect of this study is the detailed evaluation of left atrial strain and strain rate in patients with end-stage liver disease.From an archive of 290 LTxs performed in the Charité Campus Virchow center from 2013 until 2016, 80 ELSD patients with normal LVEF were considered for echocardiographic speckle-tracking analysis. Patients with a history of coronary disease, heart failure, congenital heart disease, atrial fibrillation, or moderate-to-severe valvular disease were excluded from the study. Thirty patients matched for age and sex, without liver disease, served as the control group.Anthropometric measures (height and weight) were recorded for subjects and used to calculate body mass index (BMI) and body surface area (BSA). Laboratory analysis, including liver enzymes aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), alkaline phosphatase (AP), and gamma-glutamyltransferase (γGT); prothrombin time as the international normalized ratio (INR); total serum bilirubin; and creatinine, was performed on blood samples from all subjects on the day of echocardiography ± 10 days, except for one patient, whose lab results were taken 33 days before. We calculated the model for end-stage liver disease (MELD) score according to conventional formula using creatinine, bilirubin, and the INR. Values less than 1.0 were set to 1.0 for the purposes of calculation. The study was approved by the local ethics committee (#EA4/065/19). TTE examinations were performed in the abovementioned timeframe by specialized cardiologists using Vivid 7 Ultrasound . Echopac 201 software  was used to store TTE images and provided necessary tools for analysis and 2D STE. Standard echocardiographic images were recorded in parasternal short and long axes and apical two, three, and four chamber views using 2D echography. These were used to evaluate LV and LA dimensions and function utilizing established and endorsed techniques . The collected values permitted further calculations of relative wall thickness (RWT), LV mass (LVM) and mass index (LVMI), and LA volume index (LAVI). Additionally, LA phasic emptying volumes were calculated for the reservoir (TotEV), conduit (PassEV), and contractile (ActEV) phases. All values were then indexed  according to Andrew et al. . LV ejecFurthermore, a pulse-waved (PW) doppler was used during TTE exams, allowing assessment of LV diastolic function through quantification of transmitral inflow velocities during early (E) and late (A) diastole and deceleration time (DT) . The E/ASTE was performed using three consecutive cycles. Total region of interest (ROI) was manually traced for the software to recognize individual regions automatically. If the system did not identify all regions or tracking was visually inadequate, manual adjustments were made to ROI . We accet-test were applied when appropriate. The Kruskal-Wallis test was used to compare GLS for different etiologies of cirrhosis. Spearman’s correlation coefficient (r) was used to analyze any existing relationship between clinical, STE, and LA phasic function parameters in patients. Survival functions (Kaplan-Meier estimator) were computed to show differences in mortality for ESLD patients according to LA strain. Finally, we assessed predictors for mortality using Cox regression analysis.Statistical analysis was performed with IBM SPSS Version 25  for Windows. All variables were checked for normal distribution graphically and using the Kolmogorov-Smirnov test. Consequently, the Mann-Whitney U or p < 0.05. Results are shown as average mean ± standard deviation and are accepted as statistically significant when n = 30  were recruited for this study. Controls had undergone TTE procedures as evaluation for potential organ or tissue donations or as regular checkup. Eighty ESLD patients  and a control group of p < 0.001). The basic demographic and clinical parameters are summarized in Patients suffered cirrhosis due to various etiologies. These included alcoholism (31.25%), hepatitis C (12.5%), autoimmune (10%), Non-Alcoholic Steatohepatitis (NASH 10%), Primary Sclerosing Cholangitis , idiopathic (8.75%), and others . Due to the retrospective nature of this study, severity of disease was not classified using the Child-Pugh score. At the time of this retrospective study, all patients had undergone LTx at our transplantation center. Up until finalizing data collection (Nov. 2020) 65 patients were still alive, 13 had died, and the status of 2 patients was unknown, as no recent update nor death records were registered. Of the deceased, an average time of survival of 20 months was calculated.p = 0.274), respectively. End-diastolic and end-systolic volumes (EDV and ESV) were also unaltered.ESLD patients presented increased left ventricular mass (LVM) and end-diastolic dimension (LVEDD), as well as interventricular septum (IVS) and posterior wall thickness (PW) in comparison to controls. However, no statistically relevant changes were observed in width of aortic sinus, LV end-systolic dimension (LVESD), or RWT. Most importantly, both groups were found within a normal range concerning LVEF, with healthy controls and ESLD patients averaging at 60.90 ± 4.70% and 60.00 ± 5.17% (p < 0.005). Mitral inflow velocities , deceleration time (DT), and peak mitral annular velocity parameters  were collected for patients and controls when appropriate echocardiographic images were available for evaluation. DT and the calculated E/A ratio, relevant for diagnosis of diastolic dysfunction, showed no difference between the two groups and were within normal ranges (DT < 140 ms and E/A > 0.8) according to ASE/EACVI Guidelines and Standards . E´ valup < 0.001). Mid-myocardial and endo- and epi-cardial layers similarly showed significantly higher values, suggesting increased transmural movement, as illustrated in As seen in GLS analysis subdivided into different cirrhosis etiologies showed no significant difference between the groups . Of notep < 0.001 for all three values. Consequently, all calculated values for LAVI reached similar significance when comparing patients to controls. Volumetric echocardiographic results are not reported for each patient and control due to ECG quality  or missing BMI in one patient, thus limiting the available data points. Nonetheless, elevated LA volumes were recorded at the end of ventricular systole , beginning of p-wave, and end of ventricular diastole  in ESLD patients, reaching statistical relevance with All LA phasic volumetric values showed a consistent significant increase for patients. However, this change was not seen when values were indexed, as only the LA passive emptying fraction  reached statistical significance, while LA total and active emptying fractions  showed no difference between the two groups . p = 0.002 and p < 0.001, respectively. LA contractile strain was unaltered. A significant decrease in strain rate was observed in ESLD patients for all atrial phases. Speckle tracking analysis is exemplarily depicted in Speckle tracking analysis was preformed likewise for all three atrial phases and demonstrated reduced LA strain in reservoir and conduit phasic functions with When applying the criteria proposed by the CCC , 27.5% op < 0.01. This indicates that higher laboratory markers are associated with increased GLS (more negative) values. Hence, correlations between the endo-, epi- and mid-myocardial GLS and MELD are comprehensible since MELD score is based upon previously mentioned laboratory markers. GLS of individual myocardial layers correlated with MELD to a similar extend, with epicardial reaching r = −0.379, mid-myocardial r = −0.360, and endocardial r = −0.346.Correlation analyses are summarized in In addition, correlation analysis of LA parameters with laboratory markers and MELD were computed. The results show that LA strain and strain rate tend to correlate comparatively consistently with liver enzymes ALAT and ASAT, creatinine and the INR when compared with LA phasic volumetric parameters.p = 0.123) and conduit (p = 0.286) strain demonstrated a trend towards patients with pathological values being at higher risk of mortality after LTx (p = 0.434). Similarly, Cox regression analysis identified none of the tested variables as predictors of mortality: LA reservoir (p = 0.099), conduit strain (p = 0.236), contractile strain (p = 0.432), GLS (p = 0.993), MELD (p = 0.797), and BMI (p = 0.921).Kaplan-Meier curves were computed for LA reservoir, conduit, and contractile strain. While none reached statistical significance, it should be noted that reservoir , thus trending towards concentric hypertrophy [The deformation of cardiac fibers throughout all layers illustrates the increased myocardial stress in the context of a hyperdynamic circulatory syndrome, which has long been described in cirrhotic patients and is attributed to the heart’s response to splanchnic arterial vasodilation and decreased systemic vascular resistance ,8,21,22.ertrophy .Based on the accumulating evidence that GLS is a useful value for the assessment of systolic function, the recently updated criteria for the diagnosis of CCM by the CCC included the evaluation of GLS  in addition to LVEF  .DD has been described as an early marker for CCM  and can STE analysis of the left atrium has been proposed as an alternative approach for LV filling pressure and diastolic function assessment, as it displays the physiology of left atrial function which closely follows LV dynamics ,29. RemoIn the current recommendations for the diagnosis of CCM by the CCC, the evaluation of LA strain was included to further evaluate patients with indeterminate diastolic function . In thisThis study demonstrates that STE analysis of LA deformation exposes minor cardiac dysfunction in ESLD patients more accurately than conventional measurements and should be further evaluated during cardiac evaluation. To gain more insight, more studies on this subject including the evaluation of outcome parameters are needed.The most prominent limitation of this study is its retrospective nature. This limited the amount of obtained laboratory data and cardiac imaging.In consideration of previously reported potential changes in GLS post LTx by Kim et al. , the lacIn brief, this study demonstrates that strain analysis of the left ventricle and atrium is a useful tool to detect subtle changes in left ventricular systolic and diastolic function in patients with end-stage liver disease. Using 2D-STE, we were able to demonstrate increased LV GLS and an impairment of LA atrial strain and strain rate in cirrhotic patients.


Fulminant myocarditis (FM) is characterized by a rapid progressive decline in cardiac function and a high mortality rate. Since the first report of FM patients in the 1980s, several clinical trials and research studies have been published increasing our knowledge regarding FM. Currently, the diagnosis of FM depends on various techniques including electrocardiography, echocardiography, endomyocardial biopsy, and cardiac magnetic resonance. The development of mechanical circulation support (MCS) devices and progress in our understanding of the pathophysiological mechanisms underlying FM, treatment regimens have evolved from simple symptomatic treatment to a life support-based comprehensive treatment approach. The core mechanism underlying the development of FM is the occurrence of an inflammatory cytokine storm. This review provides a comprehensive account of the current understanding of FM pathophysiology and knowledge regarding its etiology, pathophysiology, treatments, and outcomes.  Once FM is suspected or diagnosed, use of modern life support devices is highly recommended to prevent loss of life.5 Recent improvements in FM treatments have resulted in decreased mortality rates from over 50%6 to <5%8 in distinct clinical centers, however, detailed knowledge of the pathogenesis remains limited. The aim of this review is to present an integrated account of the latest knowledge about FM, to improve disease understanding and to provide advice to physicians regarding its treatment and possible outcomes.Fulminant myocarditis (FM) is an uncommon but severe cardiac inflammatory disease that can be fatal.FM is a clinical diagnosis where prodromal symptoms, such as fatigue, cough, dyspnea, and chest pain often show no distinguishable difference from the common cold. An important feature of FM is its rapid clinical progress, which can quickly lead to hemodynamic dysfunction and circulation instability. This is presented as a sharp drop of blood pressure that cannot be maintained properly by vasoactive drugs and requires mechanical circulation support (MCS) devices. It is common for multiple organ failure to be observed in FM patients. As several reports about FM indicate, deterioration and collapse of the circulatory system can occur as rapidly as 2 days to 2 weeks from the onset of precursor symptoms, highlighting the importance of early and differential diagnosis of FM to ensure early treatment application.4 Physical examinations may reveal signs of heart failure, including decreased blood pressure, accelerated heartbeat, and markedly decreased heart sounds, usually with gallop rhythm, with or without tachypnea. Routine blood tests may reveal elevated neutrophils or lymphocytes, indicating the presence of infection. Viral serological assays should be considered but importantly negative results do not necessarily rule out possible viral infection.9 ECG tracings demonstrating arrhythmias or tachycardia with sinus rhythm can demonstrate left bundle branch block (LBBB), reduced QRS wave amplitude, ventricular premature beat, and ventricular tachycardia suggestive of severe progression.10 Considering the results of echocardiography can vary according to the state of the FM patient’s heart function, repeated and close monitoring is recommended. Markers of myocardium injury, such as cardiac enzymes and troponin I or T, as well as NT-ProBNP provide insight into damage and cardiac dysfunction but both acute coronary disease and FM can have elevated biomarkers. As such, in order to differentiate FM from acute coronary disease, emergency angiography should be considered.When a suspected patient is admitted, routine tests including physical examinations, blood chemistry, 12-lead electrocardiogram (ECG), and emergency echocardiography should be conducted.11 It is worthy to investigate the value of GLS in FM in the future, but it is not easy to perform in the acute phase because of the critical conditions of patients.When a patient presents symptoms of hemodynamic compromise, it is very important to monitor the hemodynamic status with an electric blood pressure recorder or in-vessel blood pressure monitor and echocardiography. Compared to CMR, echocardiography is an easier approach in common hospital settings limiting operational complexity. In addition, the development of the global longitudinal strain (GLS) techniques, allows better assessment of heart function and provides an index for prognosis as observed in immune checkpoint inhibitor-related myocarditis.12 which manifest in clinical features observed in FM. In fact, certain types of viral nucleic acids can be detected directly in endomyocardial biopsy (EMB) samples and serum by real-time polymerase chain reaction (PCR) or in situ hybridization (ISH),13 such as parvovirus B19 (PVB19), coxsackievirus B3 (CVB3), and cytomegalovirus (CMV).2 Although uncommon, some viruses that usually infect non-cardiac organs, like human immunodeficiency virus (HIV),14 can also induce FM. Importantly, due to the limited sensitivity of detection assays, it is possible to get false-negative results of a viral infection. A multicenter study revealed that only 38% of myocarditis patients can find viral genome in their EMB samples.15 PCR or PCR-based detection techniques show the best performance, reaching sensitivity levels in the range of 50–90%,16 and an ability to detect multiple viruses in clinical samples.17 In contrast, serological tests and ISH of EMB samples show poorer sensitivity.9 A study reported a poor correlation between PCR and serological results, with only 4% of serological evidence of viral infection being determined by EMB.9 However, PCR-based detection techniques are limited in scope to predicted or suspected viruses due to the need for specific primers for amplification. Recent advances with next-generation sequencing (NGS) has provided clinicians with an ability to obtain unbiased results of possible pathogens of infectious myocarditis.19 Interestingly, several uncommon viruses including Epstein Barr virus (41%), human pegivirus (4%), human endogenous retrovirus K (100%), and anellovirus (56%) were found indicating the complexity of the viral constitution in FM. Apart from viruses, bacteria including Chlamydia pneumoniae, Mycobacterium tuberculosis,12Neisseria meningitidis20 or protozoan such as Plasmodium falciparum, Toxoplasma gondii12 or Giardia lamblia21 have all been reported to trigger FM. Hence, special attention should be paid to infected patients with rapid deterioration of cardiac function.While the exact etiology of FM remains largely unknown, our current understanding indicates three main factors contribute to its development. The first factor suggests an infection caused by various pathogens, especially viruses,22 rheumatism,23 scleroderma24, and Sjogren’s syndrome25 have all been reported to induce FM. By expressing PD-L1 on myocardium, the heart is considered to be well-protected from cardiac-specific T cells, which mostly recognize the α-myosin heavy chain peptide.26 However, a disturbance of the balance of immune homeostasis by autoimmune diseases may enable self-antigens to be exposed to the immune system and mistakenly activate myocardium cytotoxic T cells. This may partially explain the effects of glucocorticoids in treating autoimmune disease-induced FM.27 Since the key pathological process of autoimmune disease-induced FM is self-antigen such as alpha or beta-MHC exposure to the immune system, it is convincing that disturbances of the immune system caused by autoimmune diseases lead to the formation of auto-cytotoxic immune cells, CD3+/CD8+ T cell predominantly, as well as macrophages, targeting the myocardium, eventually leading to FM.28The second factor contributing to FM development is autoimmune disease. The systemic lupus erythematosus (SLE),29 are toxic to cardiomyocytes,31 which is exemplified by increased incidences in check-point inhibitor-related FM.32 Although check-point inhibitors have brought revolutionary advances to the treatment of late-stage malignant cancers they induce the formation of auto-cytotoxic immune cells. These cells subsequently attack the myocardium, resulting in the accumulation of CD3+CD8+ T cells, macrophages, and neutrophils in the heart.34 The prevalence rate of cardiac side effects of checkpoint inhibitors is common, which can reach 25% or more.35 Although the prevalence rate of FM from checkpoint inhibitors is <1% and is much lower than other targets, its fatality rate is as high as 40~70%.37 Therefore, it is important to pay attention to patients receiving chemotherapy who display cardiac function deterioration, as this may be a sign of FM.The third factor contributing to FM development is drug toxicity. Many drugs, especially chemotherapy drugs and certain natural derivatives,39To date, there are three major classes of etiological factors in FM known Table . However1 The pathological classifications of FM are still under the framework of the Dallas Criteria, according to which FM is classified as lymphocyte myocarditis, eosinophilic myocarditis and giant cell myocarditis  staining can directly reveal the pathological phenotype but immunohistochemistry (IHC) can be applied for further identification.5 IHC analysis will distinguish between morphological changes that are due to the sampling process and the actual morphological shapes of infiltrated immune cells.43 Moreover, IHC using cell type-specific markers can make accurate classifications and help distinguish the sub-types of infiltrated cells, such as the different T lymphocyte subtypes , macrophage (CD68+), and B lymphocyte (CD20+). Transmission electron microscope (TEM) can provide myocardium ultrastructure information and possibly identify viral particles,44 but technical limitations slow result acquisition and is not used as a routine test.It is recommended to obtain a minimum of four or five samples to limit sampling error45 as well about its etiology and treatment guidance. For example, data demonstrating lymphocyte infiltration often implies infection, usually by a virus.10 While evidence of eosinophil infiltration indicates an allergy, a parasite infection46 or a drug reaction with eosinophilia and systemic symptoms syndrome (DRESS syndrome).47 And the formation of giant cells is often related to autoimmune disease or sarcoidosis.49 Both eosinophils and massive lymphocytes can be observed in parasite-induced FM.50The importance of the pathological classification of FM goes beyond simply providing a pathological diagnosis. A pathological classification will provide information about disease prognosis52 However, the application of glucocorticoids in the treatment of lymphocyte FM remains debatable, notably, disease caused by viral infections. Evidence against the use of glucocorticoids in the treatment of lymphocyte FM reflects concern the virus infection may worsen and spread due to glucocorticoid-induced immunosuppression.5 While others have shown glucocorticoid use could reduce virus titer by stimulating interferon secretion.53 Thus, highlighting the importance in considering the complexity of FM pathogenesis and its exact etiology as different clinical approaches must be carefully determined based on a comprehensive analysis of clinical history, lab auxiliary test results and EMB pathological diagnosis.Important information garnered from pathological assessments can provide guidance toward therapeutic decisions. For example, immediate immunosuppressive treatment with glucocorticoids and subsequent tapering to low maintenance dose may be initiated based on evidence of giant cell FM, cardiac sarcoidosis, and eosinophil myocarditis resulting in better outcomes.The lack of comprehensive and systemic knowledge regarding the pathophysiological mechanisms underlying FM has limited therapeutic treatment regimens hindering effective interventions at different disease stages. Although significant progress has been made in our understanding persistent efforts are still required to elucidate the complete pathophysiological mechanisms involved.54 According to most reports, the majority of infiltrated cells are T lymphocytes, macrophages, and rarely B lymphocytes. Detection of CD3+CD4+ Treg lymphocytes or CD3+CD8+ cytotoxic T lymphocytes55 is commonly observed in EMB samples, which is consistent with the IHC results obtained from FM patients at our center, demonstrating massive lymphocyte infiltration  are reported to produce different immune responses triggered by the same stimulus, which suggests genetic variants might be related to different sensitivities to FM.40While the complete etiology of FM remains unknown, a dysregulated immune response has a critical role in the development of FM. Adverse effects caused by infectious pathogens can overstimulate the immune response contributing to the rapid disease progression. Evidence from EMB samples demonstrate numerous infiltrating immune cells in the necrotic myocardium.ion Fig. . Other i58In our center, we have analyzed the serum of 4 FM patients to assess their cytokine profile. The data demonstrated marked alterations in the cytokine profile and concentrations in FM patients compared to healthy controls Fig. . The maj59 bacteria,60 spirochete61, and fungi62  . Detection of myocardial contraction abnormalities observed during the development of FM is routinely performed by echocardiography Fig. 72 or carMR) Fig. .73 Hallm74 These effects provide insight into two common manifestations observed in FM. First, a rapid reduction in cardiac pump function and cardiogenic shock, represented by significant ventricular hypokinesia. And second, deteriorated heart function, as determined by decreased ejection fraction (EF%) or GLS. Depending upon the timing and therapeutic approach, dysfunctional hearts can return to normal or just slightly below the normal heart function range after appropriate treatments.75 Since myocardial cells are terminally differentiated and cannot be replaced once damaged, the normalization of heart function is probably due to a contraction improvement of each myocardial cell. Interestingly, a cytokine storm might cause myocardial stunning and decreased cardiac function without marked cell death, which could be reversed in a relatively short time once the stressor is removed.75Cytokine storms disturb immune homeostasis and will directly influence the myocardium. It was reported pro-inflammatory cytokines, like IL-1 and tumor necrosis factor-alpha (TNF-α), have a negative ionotropic effect and directly decrease myocardial contraction strength and velocity.76 and reshape the metabolic status of the heart.78 An et al.79 used a LPS-stimulated ex vivo myocarditis model to demonstrate the secretion of TNFα and phosphorylation of NF-κB correlated with the depressed left ventricular contractile ability and H2O2 production in cardiac mitochondria. Accumulation of damaged or dysfunctional mitochondria will markedly disrupt energy supply, increase ROS production and activate innate immune responses, which ultimately lead to loss of cardiomyocytes and decreased heart function.80Regular myocardium contraction is dependent upon mitochondrial function to produce energy. However, adverse consequences of a severe cytokine storm produced during FM can directly inhibit mitochondrial function81 and the extracellular matrix (ECM).82 Degradation of sarcomeric proteins like troponin and dystrophin will directly damage the normal structure of the sarcomere and fracture the myocardial filament. Breakdown of the myofilament results in an inability to transduce the contraction strength of the heart diminishing its ability to efficiently pump enough blood into the circulation. While the degradation of collagen fibers found in the ECM will stiffen the heart and reduce its elasticity further worsening the ability to contract.83Pathogens can directly target the myocardium inducing damage by releasing enzymes such as proteases or collagenases that target sarcomeric proteins84 necrosis, pyroptosis,86 and necroptosis87 resulting in decreased viability. Whether a cause or effect, activation of different cell death pathways are proposed to be involved in the pathogenesis of FM, even myocardium necrosis has been observed in EMB samples.88 Importantly, loss of terminally differentiated cardiomyocytes will significantly reduce the heart’s contraction ability. In addition, the increased cell death in the myocardium will further trigger inflammatory responses and exposure of self-antigens worsening the condition. This may subsequently lead to auto-immune cardiomyopathy,89 which is recognized as a poor prognosis factor in FM.90At the cellular level, pathogens have been demonstrated to activate different cell death pathways including apoptosis,91 Excitation-contraction coupling can transform the electric signal to a physical contraction by manipulating intercellular calcium signaling. Any disturbance in this process may result in development of an arrhythmia.Maintaining coordination of electric transduction and synchronicity of the heart beat is of great importance for hemodynamic stability. However, arrhythmias are very common in FM and indicate a bad prognosis.92 High concentrations of TNF-α decrease calcium transients and attenuate cardiomyocyte contraction.93 IL-1 can activate ryanodine receptor (RyR) and release calcium from the sarcoplasmic reticulum, which causes intracellular calcium overload and deteriorates the excitation-contraction coupling process.94 Together, these changes will contribute to the development of arrhythmias.Unfortunately, the cytokine storm in FM interferes with normal calcium signaling. TNF-α and other pro-inflammatory cytokines can activate calcium/calmodulin-dependent protein kinase alpha (CaMKα) and the following NF-κB pro-inflammation pathway.95 Although rare, refractory arrhythmias are a characteristic of cardiac sarcoidosis, which contributes to its poor prognosis.40 Sarcoidosis may be complicated by cardiac fibrosis, which provides a structural basis for reentry of the electrical signal.96 Another common feature of FM is early repolarization (ERP), which may be a predictor of ventricular tachyarrhythmias. However, a recent study showed ERP was not associated with a worse prognosis and could not predict the development of lethal ventricular tachyarrhythmias.97Dysregulation of the calcium signaling pathways in cardiomyocytes and the infiltration of immune cells, like lymphocytes, during sarcoidosis is an important factor in the development of arrhythmias. Evidence from endomyocardial electroanatomic mapping studies indicate focal sites with massive lymphocyte infiltration have lower potential. Hence, it may be easier for the physician to obtain positive EMB samples under the guidance of endomyocardial electroanatomic mapping.98Indeed, it is important to precisely assess the electrical properties of the myocardium, especially where and when arrhythmia might occur. Arrhythmias are easy to detect with continuous ECG monitoring were atrial fibrillation (AF), tachycardia, and refractory ventricular fibrillation can be observed in FM. Therapeutic treatment options are recommended to follow current guidelines to treat arrhythmias. Implantation of temporary pacemakers or cardiac defibrillator (ICD) have demonstrated success and may be considered whenever necessary.72 disturbances of the immune system, remnant inflammation and changes in autoimmune tolerance influence prognosis and affect cardiac remodeling. We have found at 1-year follow-ups of FM patients, over 20% develop heart failure, arrhythmia or enlarged heart compared to ~10% of acute myocarditis  rapid onset of symptoms of severe heart failure (quick deterioration of EF% or newly occurrence of transduction block) within 2 weeks; (2) prodromal symptoms of upper respiratory or gastrointestinal viral infections; (3) rapid development of hemodynamic compromise requiring large doses of inotropic drugs, like dopamine, dobutamine, and even MCS devices; (4) CMR- or EMB-proven myocarditis (discussed below); and, (5) exclusion of other cardiac diseases, especially acute ischemia cardiomyopathy or coronary artery disease.101 Importantly, it is critical to differentiate between FM and acute coronary artery disease as the treatment regimens are completely different. Once a previous healthy individual or a non-cardiac disease patient shows rapid heart failure, it is very important to consider the possibility of FM.The diagnosis of FM is largely based on the clinical symptoms observed in patients rather than a pathological or pathophysiological diagnosis.101 In Europe, about 20–50% of FM patients undergo EMB,41 whereas a registry of FM patients in the USA demonstrated an EMB rate of <5%.102 Although performing EMB requires tertiary clinical centers with specialized equipment and personnel limiting patient assessment, it is strongly recommended to perform EMB as soon as possible. With the application of modern molecular biological techniques, such as RT-PCR, ISH or NGS,18 EMB samples can provide key information about FM. The safety of EMB can be guaranteed by an experienced operator and the incidence of adverse effects were reported to be <2.5%.42 The majority of complications are not lethal, including tricuspid regurgitation, transient right bundle branch block, and transient arrhythmia. Life-threatening complications include ventricular perforation and related cardiac tamponade.41 Another concern about EMB is that the inflammatory infiltration of the heart may not be uniform, so EMB might give false-negative results. It has been reported that by getting 4–5 or even more EMB samples, the sampling error and false-negative results could be reduced.EMB is considered the golden standard for diagnosis and helps the pathological classification of FM. While not every patient undergoes EMB, recent data indicate the rate of EMB use to diagnose FM has increased.103 The most commonly used contrast enhancement agents are gadolinium-derived. Early gadolinium enhancement is a sign of hyperemia and capillary leak, while late gadolinium enhancement (LGE) is a sign of necrosis and fibrosis.73 When using CMR to diagnose myocarditis, Lake Louise Criteria are the most widely accepted criteria to follow for the final diagnosis.73 According to a recent study, the LGE pattern of FM was significantly different from that of non-fulminant myocarditis (NFM)  Fig. , which c72 while NFM data mimic AMI and display segmental impairment of myocardium strain.105 This feature of FM may also provide information to differentiate FM from NFM.Although CMR is capable of providing physicians with detailed information about pathological morphological changes and heart function, its most important shortcoming is the requirement of special equipment and a time-consuming scanning process, which limits its application in emergency and clinical centers that are not capable of performing CMR because of emergency conditions of patients and its requirement for heart rate control. In contrast, emergency echocardiography is able to provide information about heart function and cardiac contraction status  quickly and is suggested as a first-line assessment. We have found in FM that strains among different layers of the myocardium were diffusedly impaired,106 Because of these unspecific prodromal manifestations of FM, it is important to make a careful differential diagnosis in order to avoid inappropriate treatments. Apart from acute myocardial infarction, FM should also be differentially diagnosed from Tako-Tsubo cardiomyopathy, pneumothorax and even acalculous cholecystitis.107Signs and symptoms like fever, palpitation, sore throat, syncope and arrhythmia could be common but unspecific prodromal signs of FM.110 Recently, FM patients in our center were successfully treated with the “life support-based comprehensive treatment regimen”,4 which significantly reduced FM mortality from ~50% to <5% and shortened the hospitalization period to <2 weeks. Similar beneficial effects have been demonstrated in other centers in China8 using this therapeutic approach.FM presents as a rapidly progressing severe condition where patients respond poorly to conventional vasoactive drug therapies as well to standard heart failure, refractory heart failure, and cardiogenic shock treatments. However, improvements in MCS devices has resulted in better therapeutic success in treating FM patients from being <20% to 40–70%.How did the treatment regimen evolve from being a simple drug therapy to comprehensive treatment regimen? What are the differences among these regimens? It there any possibility of further improvement?111 The only remarkable symptoms were a quick deterioration of heart function and severe heart failure. Hence, it was very reasonable to use standard heart failure therapy to treat FM owing to limited interference strategies. Positive inotropic drugs or vasoactive drugs were the first line of drugs administered to enhance heart pump function and act against the decreased blood pressure. However, high in-hospital mortality indeed announces a failure in simple drug therapy.112Due to limited circulation support and monitoring devices, FM was very hard to distinguish from common myocarditis during this period.115 Additional approaches included administration of glucocorticoids and IVIG to suppress the immune response.112 However, the effects of these immunosuppressive agents remain debatable. For example, results from ‘The Myocarditis Treatment Trial’ failed to support immunosuppressive therapy as a routine treatment for myocarditis and suggested long-term mortality of immunosuppressive therapy was high.115 In this clinical trial, the mean change in LVEF were not significantly different between the immunosuppressive group and control group , and the mortality rates of the two group were also not significantly different throughout the follow-up . Numerous limitations of the study included reliance on the ‘Dallas Criteria’ to distinguish biopsy samples with an EMB rate of only 10%, an inadequate sampling amount, enrollment of patients with EF% <45%, which indicated poor recovery from previous treatment, and insufficient dosage of immunosuppressive agents.116 Taken together, standard heart failure treatment aiming to improve cardiac pump function or immunosuppressive treatment, targeting infiltrating immune cells, showed little effects in FM, which set barriers for patients.Results from pathological findings identified massive immune cells, like lymphocytes, infiltrating myocardium, leading to the utilization of immunosuppressive agents such as cyclosporine, azathioprine and tacrolimus.The development of extracorporeal circulation devices to allow the pump function of the heart to be temporarily replaced by a mechanical device contributed to rapid advancements in cardiac surgery. These new technologies led to further development of different, compatible, and convenient MCS devices that could be rapidly applied to cardiology treatments, including FM, markedly improving outcomes.The predominant physiological change observed in FM patients is hemodynamic instability, which causes a sharp decrease in blood pressure, low infusion of important organs and finally shock. Although there are several different kinds of MCS devices currently in use, the principle of MCS is to provide the patient with the indispensable circulation support to avoid shock.117 Thus, IABP can lower LV afterload and increase the blood flow to the brain and kidneys. However, due to the limited size of the balloon and less power of the pump, IABP can only provide about 15% of extra circulation support compared with the total circulation demand. In our practice, it is good enough for most FM patients and if not enough, additional mechanical support tool, such as extracorporeal membrane oxygenation (ECMO) should be added.Intra-aortic balloon pump (IABP) is the most commercially available MCS device being used in treatment, where a balloon synchronously inflates and deflates with a systolic and diastolic heart rhythm.101 While the venous to venous (VV) mode is used to support pulmonary circulation and provide oxygenation to venous blood when acute respiratory dysfunction syndrome (ARDS) presents.118 VA-ECMO can effectively lower the preload of the heart by 40–60%119 and, therefore, is increasingly being utilized for treating FM. In our clinical observation in more than 100 FM patients, about 75% received only IABP and for the remaining patients ECMO was added over IABP, and thus the circulation was maintained well.8ECMO is another useful MCS device to provide more powerful circulation support. The flow of ECMO can be adjusted from 0.5 L/min to 4.5 L/min, which can meet the basic demand of the body circulation. ECMO has two different working modes. The venous to arterial (VA) mode is designed to support body circulation and organ infusion due to refractory heart failure.121 However, limitations in an ability to reach high flow rates and limited commercial availability restrict the wider application of Impella. In a recent study, comparing the in-hospital mortality rate and major bleeding between Impella and IABP among acute myocardial infarction patients with cardiogenic shock, use of Impella was associated with a higher in-hospital mortality and major bleeding rates.123 In contrast, evidence also suggested a trend of improved outcomes in Impella supported patients.124 Together, this suggests a need for caution when considering the usage of Impella for FM patients. Other approaches employed to treat FM involve Ventricular Assistance Devices (VAD), including Left-VAD (LVAD), Right-VAD (RVAD), and Bi-VAD.127 In addition, an artificial heart has also been reported to be applied to assist circulation and bridge FM patients to heart transplantation.Several other devices have been developed such as Impella, which is a small pump sent into the LV to drain blood and decrease load.128While MCS devices have provided much-improved assistance in the treatment of FM and help lower the mortality rate, there remain limitations as they do not entirely provide the circulation support of natural hemodynamics. For example, the VA mode of an ECMO pump provides oxygenated blood directly into the descending aorta from the femoral artery in the opposite direction of the natural blood flow potentially causing endothelium injury due to turbulence and increased LV afterload. Long-term usage may lead to thrombosis, abnormalities of coagulation and infection of ECMO loops. Impella mimics the natural blood flow direction but due to its limited flow capability and high cost, there is limited usage outside Europe. Due to the underlying risk of life-threatening thrombosis or hemolysis, MCS devices are usually applied as the bridge to recovery or further heart transplantation.6 However, it is important to recognize the benefit of successful co-therapies using proper drugs with MCS devices. Indeed, a majority of clinical cases where MCS were applied successfully to FM patients also showed usage of inotropic drugs like dopamine and dobutamine. It should be noted the success rate of MCS could only reach 40–70%, in a few reports it could reach higher than 80%.108 Considering the residual mortality, we further speculate about the other processes in FM except for “pump failure”.Advancements in FM treatments following the development of MCS devices have resulted in increased survival rates.129 Upregulated cytokines or chemokines are the natural reaction against infection but a huge disturbance of immune homeostasis can lead to organ damage. Pro-inflammatory cytokines like IL-1, IL-6, CD-40, and TNF-α, as well as and anti- inflammatory cytokines including sTNFR and IL-10, are elevated in the serum of FM patients.130 These changes observed in immune responses have been be replicated in FM animal models.132Our increased knowledge about the underlying pathophysiology of FM, revealed it is a severe disease characterized by acute heart failure and the occurrence of a serious inflammatory response. An investigation into the etiology of FM demonstrates disturbances in the immune system, overstimulation, and disrupted cytokines and chemokines profiles, is critical.131 We have determined the plasma cytokine profiles of FM patients and found that over 30 cytokines were upregulated and over 10 cytokines were downregulated, referred to as a “cytokine storm”  and IVIG but not cytotoxic agents, such as cyclosporine or azathioprine  but IVIG prevented death when administrated either before or after the onset in C57 mice (model for myocarditis) or A/J mice (model for FM). The application of glucocorticoids remains debatable and the best timing for administration of glucocorticoids remains unknown. It was reported in an animal model of acute viral myocarditis the different timepoints of glucocorticoid administration results in the different mortality rate of mice.135 It should be noted that although the early application of glucocorticoid was mainly aimed at controlling the cytokine storm rather than suppressing the overall immune response, there is a concern it will lead to enhanced viral spread. Previous recommendations suggest immunosuppressive therapy be considered only whenever the virus load is negative in myocarditis.136 Evidence indicates the administration of glucocorticoids can significantly improve the prognosis of patients with EMB proven lymphocytic myocarditis, in either virus-positive or virus-negative individuals.137 Hence, there remains a debate about the effectiveness of glucocorticoids in FM. It is still recommended that the application of corticoid must be with caution at the stage of viremia. However, at the critical stage with critical illness, the major pathophysiology is the cytokine storm rather than the viremia, and according to our data, the majority of patients had already experienced the onset of a cytokine storm on admission and urgently required immunomodulation therapy. Too much caution regarding the possibility of enhancing virus spreading by glucocorticoid may delay live-saving treatment. Experimental studies suggest the application of glucocorticoid to A/J mice infected with CVB3 lowered the viral titer in heart tissue.8 Clinical evidence also indicated that the application of glucocorticoid in virus pneumonia and recent COVID-19 is safe and effective.138 Therefore, it can be proposed application of immunomodulatory therapies aim to restore the homeostasis of the immune system . The flow chart illustrates the process followed when treating FM patients according to the “life support-based comprehensive treatment regimen” , and the long-term follow-up (7 years) showed 47.7% of FM patient mortality rate compared with 10.4% of non-FM patients, respectively, (p < 0.0001)  myocarditis.8 Together, the low EMB rate and restricted MCS device choice contributed to differential and misleading pathological diagnosis and potentially a wrong prognosis.Numerous differences in how each study was designed to provide some insight into the opposing results in these reports. In the first study, McCarthy’s group enrolled patients from 1984 to 1997 and among the 147 enrolled patients only 15 met the criteria of FM; while Ammirati enrolled 165 EMB-proved FM patients and 55 non-FM patients from 2001 to 2018 resulting in a more powered study. The EMB percentage of FM in McCarthy’s study remained below 5% along the whole enrollment for the study and non-FM decreased from about 20% to <5%. Importantly, the time period between administration and EMB was shorter in Ammirati’s study than McCarthy’s, which means persistent lymphocyte infiltrate after the acute phase of FM. And MCS devices in McCarthy’s study were LVAD, without IABP or ECMO, which might be due to the conditions at that time. In the recent study, IABP, ECMO, and Impella were all considered when stable hemodynamics cannot be sustained.8 Results demonstrated the “life support-based comprehensive treatment regimen” could significantly lower the mortality rate from 46.6 to 3.7% of all enrolled patients, and from 42.1 to 2.6% of propensity-matched patients. These data provide evidence supporting the comprehensive approach in the treatment of FM and reflect experiences from multiple clinical centers in China.8 It has been considered “of great value and can help clinical workers treat and save more lives successfully from FM”.146In contrast, in our multi-center observational study, we compared the in-hospital mortality of 169 FM patients. Of them, 81 patients were treated with the “life support-based comprehensive treatment regimen” while the other 88 patients were treated with the traditional therapy defined as “carrying out stepped regimen of conventional medicines for heart failure and cardiogenic shock”, e.g. vasopressor and positive inotropic drugs, no MCS devices, no immunomodulation therapy or delayed the application of MCS until the circulation of FM patients collapsed; MCS devices, e.g. IABP, were only successively applied if pharmacological therapy could not maintain circulation stability.147 We propose this is the key to a successful treatment of FM. However, there are some differences between the two regimens. In our regimen, we do not recommend the use of inotropic drugs like dopamine or dobutamine, at least, not as dominant treatment, but MCS devices to maintain circulation and suggest a different application rate of glucocorticoids (100% vs. 24%), IVIG (100% vs. 34%) and neuraminidase inhibitor (100% vs. 0%). In addition, we did not recommend use of cytotoxic drugs like cyclosporine and azathioprine to suppress the immune system. Moreover, our 1-year follow-up results  FM in A/J mice. However, a viral infection, although it is the most frequent etiology, is not the only etiology of FM restricting the translational interpretation. Moreover, multiple different types of viruses, besides CVB3, can induce FM. In addition, it is technically difficult and expensive to routinely monitor hemodynamics and utilize MCS in mice.149 and have been excellently reviewed elsewhere.150 Although there are different pathological classifications of FM, whether there is a common immune response or key cytokine(s) is still worthy of investigation. Furthermore, target therapy to special cytokine(s) may be promising approach.Although the fundamental pathophysiological mechanisms underlying FM are far from thoroughly revealed, the disturbance of the immune system plays an important role in the development and progress of FM. The evolution of treatment regimens provide evidence emphasizing the importance of addressing the immune response in treating FM. Unfortunately, there is a lack of experimental models and evidence for determining whether the pathogens directly initiate the cardiac immune response or if the injured myocardium and subsequently released contents induce the immune response. The involvement of a cytokine storm has been confirmed in various clinical studies and animal models. The disrupted cytokine response is potentially an important therapeutic target. The established treatment regimens still rely on global immunomodulation or immunosuppression, like that induced by IVIG or steroid use, instead of relying on precise target interference. Recently, evidence for therapy targeting precise cytokines has been reported113 It is believed the chronic immune response has a major role in the adverse progression of FM. The presence of anti-cardiac antibodies such as anti-MHC can be detected in the serum of these patients, and is associated with decreased left ventricular ejection fraction (LVEF).151 The strategy to prevent this process and which kind of immune cells take part in this process need to be determined.The long-term outcome of FM has an important impact and requires special attention. We and other researchers have observed cardiac outcomes in a considerable proportion of surviving FM patients often progress to dilated cardiomyopathy (DCM) with decreased EF.8 This breakthrough in therapy for FM treatment is easily adapted in the clinic and “has the potential to save the lives of many young, otherwise healthy individuals”.152If we look back to the history of FM, we can find treatment regimens have evolved from drug therapy, only targeting the pump function of the heart, to a current “life support-based comprehensive treatment” regimen, which emphasizes the combination of MCS devices with modulation of the immune system. The success of the approach has led to a reduction in the mortality to <5%.However, the mechanisms underlying FM are still not fully revealed and the best treatment regimen for recovering patients remains to be elucidated. During the acute phase of FM, the future investigation should be focused on the combined management of circulation stability and immunomodulation, which can sustain the basal circulation of the FM patient as well as lower the immune disturbance. New MCS devices capable of providing more natural hemodynamic circulation support may be needed or the ones available may need to be upgraded. Clinical trials should be performed to develop agents or antibodies targeting the elevated cytokines and achieving a precise interference of elevated cytokines. For discharged patients, the long-term cardiac remodeling process is a key issue to be focused on. The true long-term prognosis of FM patients still needs to be determined in future follow-up studies, and the treatment regimen for these patients should be determined by clinical trials.