Introduction: While cardiac tumors are rare, their identification and differentiation has wide clinical implications. Recent cardiac magnetic resonance (CMR) parametric mapping techniques allow for quantitative tissue characterization. Our aim was to examine the range of values encountered in cardiac myxomas in correlation to histological measurements.Methods and Results: Nine patients with histologically proven cardiac myxomas were included. CMR  including parametric mapping was performed in all patients pre-operatively. All data are reported as mean ± standard deviation. Compared to myocardium, cardiac myxomas demonstrated higher native T1 relaxation times , ECV , and T2 relaxation times . Areas with LGE showed higher ECV than areas without , with differences in native T1 relaxation times  and T2 relaxation times  not reaching statistical significance.Conclusions: Parametric CMR showed elevated native T1 and T2 relaxation times and ECV values in cardiac myxomas compared to normal myocardium, reflecting an increased interstitial space and fluid content. This might help in the differentiation of cardiac myxomas from other tumor entities. While cardiac tumors are rare, their identification and differentiation has wide clinical implications. Myxomas represent 25–50% of primary cardiac tumors. They contain variable amounts of stromal and inflammatory cells set in a mucopolysaccharide-rich fibrous matrix . MyxomasThe aim of this study is to examine the range of parametric mapping values of cardiac myxomas and to compare these values with histopathological data.From January 2013 till March 2015, 10 consecutive patients were analyzed. These patients were found to have a mass on trans-thoracic and trans-esophageal echocardiography that was clinically suspected to be a myxoma. Other imaging modalities followed in the preoperative assessment as clinically indicated. CMR was performed for all patients. Patients underwent open heart surgery for removal of the masses and the histopathological examination confirmed the excised cardiac masses to be myxomas in nine cases and fibroma in one, the latter being excluded from further analysis. Case 1 of our study has been previously published as a case report .CA was performed in all patients to exclude coexisting ischemic heart disease. One patient showed the presence of a two-vessel disease. There was no evidence of neovascularization of the tumors on angiography.3, 50 heart phases, TR/TE = 3.2/1.6, flip angle 60°)  and T2- weighted fast spin echo  sequences were performed (3)  with an acceleration factor of 2)  with an acceleration factor of 2. In addition T2 mapping images were taken. An ECG-triggered breath hold GraSE sequence was used  with an acceleration factor of 2 and 12 s breath hold time . A dedicated 32 channel phased-array surface coil was used as receiver. Sequences were acquired during end-expiratory breath-holds with electrocardiographic (ECG) or pulse triggering. A work-up scheme is given in gle 60°) . T1-weigerformed . First prmed (3) . Late gaor of 2) . ECG-trior of 2) . A singlwas used  with 9 eold time .Commercially available MR analysis software was used for the Analysis of T1 and T2 relaxation times and the ECV . ECV was calculated from pre- and post-contrast T1 relaxation times and hematocrit as described previously . HematocThe excised cardiac masses were received in 4% buffered formaldehyde. The macroscopical findings were photo-documented and the mass was bi-halved or serially sectioned across its base attached to atrial myocardium, as appropriate. At least one, preferably full-thickness tissue section of the tumor was submitted for further histopathological evaluation, which had as a minimum to include the base of the excised mass attached to atrial myocardium, and in addition any suspicious features for malignancy as solid areas or areas of bleeding. None of the lesions showed areas of necrosis.The histological evaluation of the atrial masses was performed on 3-micron-thick formalin-fixed paraffin-embedded tissue sections . The fir2, were obtained with a NIKON Eclipse light projection microscope. Areas of interception between atrial myocardium and atrial mass were due to the overtly high number of large caliber muscular vessels, associated perivascular and interstitial fibrosis avoided, as well as areas of bleeding, pseudocyst formation and areas containing Gamna Gandy bodies  throughout the entire lesion. Subsequent image analysis was performed to determine the level of fibrosis, regardless of the staining intensity indicative of the arrangement of the collagen fibers (dark red shades were indicative of established and light red shades were indicative of newly formed fibrosis). The level of interstitial fibrosis was calculated as collagen volume fraction (%) per square millimeter .Quantitative histological analysis was performed using a standardized semiautomatic image analysis software . Images of 12 randomly chosen consecutive high power fields (x200 magnification) of the Sirius red stained tissue sections, equaling 1 mmThe level of mucopolysaccharides was assessed in an analogous manner, with the percentage of blue stained background in 12 randomly chosen fields assessed semi-quantitatively with the above mentioned image analysis software.T-tests for dependent samples were performed to evaluate differences for statistical significance. A two-sided p-value < 0.05 was regarded as statistically significant. A Pearson correlation analysis was performed for MR parameters  vs. histological parameters (fibrosis and mucopolysaccharide volume).Statistical analysis was performed using SPSS for Windows . All parameters are given as mean ± standard deviation and median. Categorical data are summarized as frequencies and percentages. Patient characteristics and clinical presentation are given in 2 and 48 × 35 mm2. Mobility was variable depending on the thickness and length of the stalk connecting the tumor to the left atrium. CMR showed iso-intense signal of the mass in comparison to the myocardium on T1-weighted images and hyper-intense signal on T2-weighted images in all but one case. The masses did not show signal drop out on fat suppression images. First pass perfusion imaging showed evidence of delayed perfusion in one patient. Late gadolinium enhancement was inhomogeneous in cardiac myxomas in all patients. Compared to myocardium, cardiac myxomas demonstrated higher native T1 relaxation times , ECV , and T2 relaxation times  (p = 0.042), with differences in native T1 relaxation times  and T2 relaxation times  not reaching statistical significance.CMR-characteristics of the myxomas are given in = 0.008) –6. AreasAll patients underwent surgery for mass excision. Histopathology confirmed nine masses to be myxomas. Macroscopically they had a smooth surface and gelatinous, variably hemorrhagic cut surface. Histologically, there were hypo-cellular myxoid masses, composed of stellate-shaped cells without significant nuclear atypia accumulating around blood vessels. There was no infiltrative growth pattern into the atrial myocardium. Furthermore, there were no atypical mitoses and immunohistochemistry for calretinin showed a diffuse and strong staining reaction of the myxoma cells. Interstitial bleeding and associated hemosiderin-laden macrophages and calcifications were common features. Semi-quantitatively assessed percentage of fibrosis was variable within and between myxomas ranging from 5 to 65% . The samTo our knowledge, this is the first report to systematically assess T1 and T2 relaxation times in cardiac myxomas. Our study examined parametric CMR-mapping as an addition to standard cardiac tumor imaging protocols for the non-invasive tissue-characterization of myxomas.We found the following:Native T1 and T2 relaxation times and ECV were higher in myxomas compared to the myocardium.Within the myxomas, areas with LGE had higher ECV, T1 and T2 relaxation times than areas without, albeit this did not reach statistical significance for T1 and T2 relaxation times due to the small size of the sub-sample.So far, only case reports of parametric mapping in cardiac myxomas are published with various CMR protocols. Case 1 of our study, showing elevated T1 and T2 relaxation times and ECV in a left atrial myxoma compared to myocardium, has been previously published as a case report . A retroMyxomas are characterized by a mixed tissue composition, consisting mostly of myxoid stroma that may contain cysts and areas of hemorrhage . CompareLate gadolinium enhancement (LGE) is very robust in the identification of focal areas of fibrosis and necrosis. LGE was present in all but one patient with a very small myxoma. LGE was heterogeneous for all cases, indicating the heterogeneous composition of myxomas.3 voxel.Global alterations of the myocardium are more readily diagnosed by ECV measurements, allowing for the detection of subtle myocardial changes . It has The statistically non-significant difference in parametric mapping values between myxoma regions with and without LGE warrants further examination in a larger sample. If confirmed, this would underline the heterogeneous nature of myxomas and might improve further tissue characterization.Mapping of T1 and T2 relaxation times and ECV therefore provides objective, quantitative parameters for the MR-characterization of cardiac myxomas in addition to the visual comparison of unit-less signal intensities on conventional T1 and T2 weighted sequences. While our study does not include other cardiac masses, other studies have provided case reports  11, 12), 1211, 1The main limitation of our study is its small sample size. Nevertheless, it is the largest study of parametric mapping in this rare entity.The high mobility of myxomas makes it difficult to seize them on CMR-images. However, in all of the cases they still could be identified. The current spatial resolution of CMR makes small sized tumors difficult to recognize. The smallest tumor we were able to depict on cine images was 8 × 8 mm in size. More studies are needed to establish a cut-off point for tumor size to be detected my CMR.T1 and T2 mapping are prone to motion artifacts due to the high mobility as well as arrhythmias. Tumors attached to the mitral valve show the least motion and best visualization when the valve is closed. The feasibility of changing the phase of image acquisition from diastole to systole should be studied and accordingly may facilitate T1 and T2 mapping of cardiac myxomas.We demonstrated that native T1 mapping, ECV, and T2 mapping offer an objective and quantitative measurement of tissue alterations seen in conventional T1 and T2 weighted and LGE imaging. We therefore suggest integrating these in the routine evaluation of morphologically suspected cardiac myxomas, adding valuable information.The original contributions presented in the study are included in the article/supplementary materials, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by Ethikkommission der Charité Universitätsmedizin Berlin, Germany. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.PD owned stock of Siemens AG and Bayer AG. BS was an employee of Philips Healthcare. BP had received advisory board and lecture honoraria from Bayer Healthcare, Novartis, Merck Sharp and Dohme, Stealth Peptides, Sanofi, and Servier. KW had received lecture honoraria from Roche. SK was supported by Philips Health Care. The remaining 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.


To evaluate the presence and location of late gadolinium enhancement (LGE), increased T2 signal abnormality, right ventricular involvement and cardiac function by cardiac magnetic resonance (CMR) imaging in patients with suspected cardiac sarcoidosis.46 patients with known extra-cardiac sarcoidosis underwent CMR with T2-weighted, LGE and cine imaging for evaluation of cardiac sarcoidosis. Images were evaluated by 2 expert reviewers in consensus using the 17-segment model of the left ventricle (LV) for presence and location  of LGE, presence of increased T2-signal abnormalities, and regional wall motion abnormalities. In addition, right ventricular (RV) involvement was evaluated.13 of 46 (28%) patients demonstrated evidence of segmental LGE suggestive of cardiac sarcoidosis. In these 13 patients, LGE involvement was noted in 51 of 221 (23%) segments, and was predominantly transmural (35%), followed by midwall (27%), subepicardial (25%) and subendocardial (20%). LGE was most frequently located in the basal segments (36%) compared to mid (23%) and apical (22%) segments, and more commonly involved the septal (37%) followed by the lateral (29%), inferior (23%) and anterior (10%) segments. T2-weighted images were evaluable in 11 of the 13 patients, and 24 of 187 segments (13%) demonstrated evidence of increased T2-signal abnormality and was significantly associated with the LGE segmental involvement (p < 0.005). 4 patients (31%) also demonstrated evidence of RV involvement. There was no significant correlation between presence of LGE or increased T2-signal intensity with regional function.Late gadolinium enhancement and increased T2-signal intensity are common findings in the left ventricle in patients with cardiac sarcoidosis, but not necessarily correlated with overall ventricular size and function. Although not previously reported, similar findings are frequently present in the right ventricle as well.


In human DMD patients, plasma BDNF levels had a positive correlation with left ventricular function, opposite to that seen in rs6265 carriers. There was also a substantial decrease in skeletal muscle function in carriers compared to the Val homozygotes. Surprisingly, the opposite was true when cardiac function of DMD carriers and non-carriers were compared. On the other hand, Val66Met wild-type mice had only subtle functional differences at baseline but significantly decreased cardiomyocyte contractility. Our results indicate that the Val66Met polymorphism alters myocyte contractility, conferring worse skeletal muscle function but better cardiac function in DMD patients. Moreover, these results suggest a mechanism for the relative preservation of cardiac tissues compared to skeletal muscle in DMD patients and underscores the complexity of BDNF signaling in response to mechanical workload.Brain-derived neurotrophic factor (BDNF) is a neuronal growth and survival factor that harbors cardioprotective qualities that may attenuate dilated cardiomyopathy. In ~30% of the population, BDNF has a common, nonsynonymous single nucleotide polymorphism rs6265 , which might be correlated with increased risk of cardiovascular events. We previously showed that BDNF correlates with better cardiac function in Duchenne muscular dystrophy (DMD) patients. However, the effect of the Val66Met polymorphism on cardiac function has not been determined. The goal of the current study was to determine the effects of rs6265 on BDNF biomarker suitability and DMD cardiac functions more generally. We assessed cardiovascular and skeletal muscle function in human DMD patients segregated by polymorphic allele. We also compared echocardiographic, electrophysiologic, and cardiomyocyte contractility in C57/BL-6 wild-type mice with rs6265 polymorphism and in  Brain-derived neurotrophic growth factor (BDNF) is an essential mediator of neuronal growth, differentiation, and survival and plasticity . BDNF isn = 206) but not in otherwise healthy individuals (n = 498), whereas the Met allele was apparently protective compared to the Val/Val genotype in a separate cohort of 5510 patients assessed for severity of coronary artery disease and incidence of clinical cardiovascular disease events carbonyl]phenyl]benzo[b]thiophene-2-carboxamide (ANA-12) ,15, a spThere is controversy over the importance of circulating BDNF and the utility in correlating with cardiovascular function ,16,17,18Despite having higher cardiac levels of BDNF and an increase in LVEF at baseline, Val66Met mice had abnormal cardiomyocyte contractility, which is consistent with gene expression alterations in contractile and calcium handing domains. Thus, this polymorphism appears to predispose cardiac muscle to abnormal contraction, and while there may be compensatory mechanisms under basal conditions, there may be less contractile reserve and a higher risk of developing functional decline under pathological conditions. This finding was consistent with CMR data from DMD patients demonstrating decreased LV mass but increased LVEF and better GCS. While this may at first appear counterintuitive, recent evidence in young adult cancer survivors showed heart failure symptoms correlated with decline in LV mass and not necessarily with LVEF . In DMD n = 27, p = 0.002) in explants from patients with end-stage human heart failure, compared to unused donor healthy heart controls (n = 16)  , perhapsDMD cardiomyopathy is characterized by muscle fibrosis, loss of contractility, and progressive development of DCM. The apparent disparate correlations between plasma BDNF levels and LVEF observed when segregating by polymorphic allele in DMD patients may help to partially explain the controversial effects of BDNF in human disease. Another universal feature of DMD muscle cells is that the absence of dystrophin leads to altered calcium handling through multiple mechanisms . This haThe striking difference seen in skeletal muscle performance in DMD patients segregated by the Val66Met polymorphism was not entirely surprising, given BDNF’s known role as a mitokine and in promoting exercise-induced skeletal muscle regeneration . As DMD For the first time, we have shown that a polymorphism in the BDNF gene leads to functional changes in both mouse models and humans with DCM and in skeletal muscle function in DMD patients. This will allow for further investigation into the mechanisms of altered cardiomyocyte contractility and may provide a novel component of risk assessment in patients with cardiomyopathy or other cardiovascular diseases.Met knock-in allele  mice [tm1RdpTerc/mdx−4CvDmd/BlauJ, Jackson #023535) [This study was carried out in accordance with the National Institutes of Health’s Public Health Service Policy of Humane Care and Use of Laboratory Animals and the Animal Welfare Act. Transgenic BDNFet) mice  were cro#023535) , which d#023535) . Litter #023535) ,15. Transthoracic M-mode echocardiography was performed with a 12-mHz probe  on conscious mice and on mice anesthetized by inhalation of isoflurane (1–1.5%). LV end-systolic interior dimension , LV end diastolic interior dimension , ejection fraction (EF) and fractional shortening (FS) values were obtained by analyzing data using the Vevo 2100 program .ECG leads were recorded with surface electrodes  on anesthetized mice by constant inhalation of isoflurane (1–1.5%). The mean value for each mouse was obtained from four values consisting of four consecutive cardiac cycles using LabChart software . Adult mouse cardiomyocytes were isolated as described previously . For recThe Vanderbilt Institutional Review Board approved this prospective study, and this investigation conforms with the principles outlined in the Declaration of Helsinki . Appropriate consents and assents were obtained as part of study enrollment. Sixty-one DMD subjects were enrolled from the Neuromuscular Cardiology Clinic. Inclusion criteria were: (1) diagnosis of DMD with clinical phenotype and confirmation with either genetic testing or muscle biopsy, (2) blood obtained at time of cardiac MRI (CMR), (3) able to tolerate CMR without sedation or anesthesia. Exclusion criteria were: (1) additional cardiac diagnoses that could affect biomarkers, (2) inadequate volume of blood. Enrolled DMD subjects underwent blood draw, CMR, skeletal muscle strength assessment, and assessment of physical activity levels using accelerometry. BDNF was measured using the Quantikine BDNF enzyme linked immunosorbent assay (ELISA) kit , as previously described . ®, Bayer Healthcare Pharmaceuticals, Wayne, NJ, USA or gadobutrol, Gadovist®, Bayer Healthcare Pharmaceuticals, Wayne, NJ, USA) at a dose of 0.2 mmol/kg. CMR was performed using a 1.5 Tesla Siemens Avanto  and calculations performed as previously described . A peripQuantitative muscle testing (QMT) was performed on DMD subjects using a handheld myometer—an objective, reproducible method for upper and lower extremity strength evaluation in DMD. QMT score was calculated as previously described . QMT wasRNA sequencing (RNA-seq) was performed by Vanderbilt Technologies for Advanced Genomics (VANTAGE) core as previously described , using IGel electrophoresis was performed as previously described  and probAll data are expressed as means ± SEM. Statistical comparisons made between two variables were performed using the Student’s t test. Comparisons between more than two variables were performed using one-way ANOVA with a Tukey’s post hoc test. Human demographic variables were compared using either a Wilcoxon rank-sum (continuous variables) or a chi-square or Fisher’s exact test . Patient data were collected and managed using research electronic data capture (REDCap) at Vanderbilt .This study is limited by the relatively small population of the study cohort of DMD patients. The number of patients could be potentially increased in future studies using multicenter collaborative data collection. CMR analysis was done separately from BDNF analysis in order to minimize potential bias.The rs6265 polymorphism alters cardiomyocyte contractility in mice without overt cardiovascular disease and is augmented in a mouse model of progressive dilated cardiomyopathy; thus, it may represent a novel risk factor for worse outcomes in cardiovascular disease. In patients with Duchenne muscular dystrophy, the rs6265 polymorphism is associated with altered relationship between plasma BDNF levels and LVEF and worse skeletal muscle performance.


Sudden cardiac death in athletes is a relatively rare event, but due to the increasing number of individuals practicing high-performance sports, in absolute terms, it has become an important issue to be addressed. Since etiologies are many and the occurrence is rare, tracing the ideal preparticipation screening program is challenging. So far, as screening tools, a comprehensive clinical evaluation and a simple 12-lead electrocardiogram (ECG) seem to be the most cost-effective strategy. Recent technological advances came to significantly help as second-line investigation tools, especially the cardiac magnetic resonance, which allows for a more detailed ventricular evaluation, cardiac tissue characterization, and eliminates the poor acoustic window problem. This article aims to review all aspects related to sudden cardiac death in athletes, beginning with definitions and epidemiology, passing through etiology and clinical characteristics, then finishing with a discussion about the best ambulatory investigational approach. It is public knowledge that physical activity promotes health because once practiced properly, it brings benefits regardless of age, sex, or ethnicity. Despite this, rare, sudden cardiac death may occur in the exercise context. When it happens to famous athletes, it reaches the journalistic spotlight and tends to cause public clamor since they are public figures and symbols of health. Strategies trying to mitigate it have been developed by the local arrhythmia societies. However, the development and implementation of these guidelines are challenging due to many factors such as the non-unanimous athlete definition, the varying etiology of sudden cardiac death between different ages and the geographic areas, and the difficulty to develop studies in the field due to the low incidence.Sudden cardiac death (SCD) is defined by the 2015 Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death European Society of Cardiology (ESC) Guidelines as an unexpected, non-traumatic death within 1 h of symptoms’ onset in a patient known to have a potentially fatal cardiac condition, or when autopsy finds a cardiac or vascular anomaly as the probable cause, or when no extracardiac causes are found in the post-mortem examination, and therefore an arrhythmic event is the likely cause of death [One who participates in an organized team or individual sport that requires regular competition against others as a central component, places a high premium on excellence and achievement, and requires some form of systematic  training”. On the other hand, ESC defines the same as: “Individuals of young and adult age, either amateur or professional, who are engaged in exercise training on a regular basis and participate in official sports competition. Official sports competition  is defined as an organized team or individual sports event that, placing a high premium on athletic excellence and achievement, is organized and scheduled in the agenda of a recognized Athletic Association”. Despite being clear about the term athlete, both definitions ignore the growing existence of the exerciser: the person that does regular physical exercise, and at times very intense, but never participates in organized competitions. This individual is precisely the most frequently seen in cardiology medical visits and pre-sports training evaluation. Pragmatically, this individual should be evaluated in the same way a competing athlete would be. Although, some authors defend that they may have different cardiovascular risk profiles since an exerciser would be primarily motivated by health improvement, while an athlete would be mainly motivated to win the competition, which can lead to exaggerated training and/or substance abuse, despite the control that has been put in practice by many sports organizations [The definition of an athlete, on the other hand, is not homogeneous between epidemiological studies evaluating cardiac events. Most often, an athlete is defined as a regular exercise practitioner (force or endurance) aiming for participation in competitions. The Bethesda conference, commonly used as a guideline to decide for exercise qualification, defines an athlete as: “izations ,2.In a world where the leading cause of death is ischemic heart disease, exercise practice is a growing tendency. The New York Marathon had, in 2019, 53,627 finishers, an impressive number for a competition with such rigid criteria for participation. The self-reported evaluation of physical activity worldwide published in 2003 had already observed 31.4% of adults declaring to practice vigorous-intensity physical activity at least three times per week [The real incidence of SCD in athletes is very controversial due to the heterogeneity of the available data. Between the studies, neither the athlete definition is unanimous (denominator), nor the SCD event (numerator). Some studies considered only the fatal events, while others also considered persons that were successfully resuscitated or revived.A retrospective forensic study developed in Spain evaluated the epidemiological data of 645 SCD victims, 1 to 35 years old, from 2010 to 2017. In this cohort, 75 (11.6%) of the events were exercise-related. Myocardial disease was diagnosed in 33 patients, arrhythmogenic cardiomyopathy being the leading cause (37%), followed by hypertrophic cardiomyopathy (24%) and myocarditis (15%). Only five had a previous cardiomyopathy diagnosis, and 85% were practicing recreational sports [In Italy, Corrado et al. evaluated a 26-year trend in SCD in athletes (12 to 35 years old), and observed an incidence of 1.9/100,000 person-years [An epidemiological study in high school athletes from Minnesota state, USA, over 12 years found three SCD events, an incidence of 1:500,000 competitive sports participants. Over a 3-year high school career for a student-athlete, the estimated risk was 1:72,500 .In Israel, a study led by Steinvil et al. searched for SCD in athletes in the two main newspapers from 1985 to 2009. Using data from the Israel Sports Authority as the denominator, the calculated incidence of SCD in this context was 2.6/100,000 athlete-years .A study from Sweden evaluated all SCDs in 10- to 35-year-old individuals from 2000–2010, retrieving information from medical records, death certificates, and autopsy data. In the 10-year period, 514 SCDs events were observed, 62 (12%) being considered exercise-related. Of those individuals, 21 were considered athletes and 41 non-athletes. The leading causes were primary arrhythmic heart diseases, followed by hypertrophic cardiomyopathy. Unfortunately, in this study, no denominator was estimated, so it did not provide us an incidence .A study run in the USA evaluated, from 2003 to 2013, a database from the National Collegiate Athletic Association. They observed a total of 79 SCDs, an incidence of 1:53,703 athletes-year. In this study, most commonly, the autopsy was negative for cardiac structural abnormalities, followed by coronary anomalies (11%) and hypertrophic cardiomyopathy (10%). A total of 40 patients had a previous ECG, and 67% of these ECGs had T wave inversion [Evaluating adolescents specifically, a study from 1996 to 2016 screened 11,168 adolescent athletes registered in the English Football Association Cardiac Screening Program (mean age 16 years old). In this group, the SCD incidence was 6.8 per 100,000 person-years [A study from Sweden evaluated all SCD events in 10- to 35-year-old Swedish patients from 2000 to 2010. In this cohort of 514 patients, 12% were exercise-related. In the subgroup of exercise-related, 90% were men. The most frequent etiologies found in autopsy were: sudden arrhythmic death syndrome (24%), hypertrophic cardiomyopathy (16%), and arrhythmogenic cardiomyopathy (13%). The premortal diagnosis was known in 27%; 13% had cardiac symptoms, and 31% had a family history of SCD, heart disease, or familial hypercholesterolemia .In the United States, the RACER Study Group evaluated runners from marathons and half-marathons in the U.S. from January 2000 to May 2010. The incidence of SCD was 0.54/100,000 participants. The incidence in marathons was 3.7 times higher compared to half-marathons and 5.6 times higher in men. From the 59 events, only 31 had medical information to be certain about the cause of death. Hypertrophic cardiomyopathy was not only the leading cause but also the predictor of non-survival of the event .p < 0.01) [Maron et al. studied, over a 10-year period, the causes and clinical profile of 182 athletes registered in national college registries. In this cohort, cardiovascular deaths were 5-fold more common in African-American athletes than in white athletes  .A nested case-crossover study from Albert et al. evaluated the SCD risk during vigorous exercise and 30 min after. A total of 122 SCDs were observed in a cohort of 21,518 male physicians in 12 years of follow-up. Vigorous exercise elevated the risk of SCD by a factor of 14 to 45. In the same context, they observed that the habitus of practicing vigorous exercise was a mitigating factor to the risk of SCD .Again, it is hard to be sure about risk factors for SCD in athletes, but looking at the evidence, despite somewhat heterogeneous, it points that male sex, African-American ethnicity, the presence of structural or electrical heart diseases, and vigorous exercise  are risk factors that should be taken into account. Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease, being found in up to 1 of every 500 individuals, with equal predominance in men and women. The autosomal dominant mutation causes disarray in the cardiac sarcomeres, the most frequently muted genes being the MYH7 and the MYBPC3. The phenotypic presentation of the disease is a hypertrophied left ventricle (LV), predominantly in the septum. The ESC 2014 guidelines consider a LV wall thickness of ≥15 mm as diagnostic criteria, not explained by loading conditions .In a study by Lorenzini et al., in a median follow-up of 6.2 years, the incidence of all-cause mortality in HCM patients was 12.4%. Compared to the general population, the excess mortality was lowered after the year 2000, probably related to the widespread implantable cardiac defibrillator (ICD) implant .HCM is historically known as the main cause of SCD in patients younger than 35 years old. However, it is important to remember that it may not be true for different regions/countries. In the U.S. National Registry of Sudden Death in Athletes, HCM was responsible for 36% of SCD cases . On the The last American College of Cardiology (ACC)/The American Heart Association (AHA) guidelines consider an indication for ICD implant for primary prevention: family history of SCD in first-degree relatives, LV wall thickness of ≥30 mm, and recent unexplained syncope. The ESC guidelines, on the other hand, use the calculated risk as a percentage. In the same context, ICD implantation has a IIb recommendation level when the 5-year risk is ≥4% and a IIa recommendation level if the risk is ≥6% ,20.Despite most of the ICD therapies for ventricular tachycardia (VT) and ventricular fibrillation (VF) happening not in the exercise context, both guidelines advise against participation in high-intensity sports, even for those with ICD already implanted.Arrhythmogenic cardiomyopathy (ACM) is an inherited disease characterized by progressive myocyte loss with fibrofatty tissue replacement, which happens most often in the right ventricle (RV), but can affect the LV or both. In 30–60% of cases, the disease is familial, with the remaining cases having a de novo mutation, the PKP2 being the most frequently mutated gene. This mutation determines desmosome dysfunction, culminating in fibrosis. As part of the same disease spectrum, we also have Naxos disease and Carvajal syndrome . ClinicaIn a registry from Veneto, Italy, ACM was the most common cause of SCD in athletes (24%) .In an autopsy study of 118 athletes from the U.K. who had SCD, ACM was the second identified cause of SCD (14%) .There is no single exam able to provide a conclusive diagnosis of ACM; thus, the diagnosis is made based on major and minor criteria defined by the Revised Task Force Criteria .The arrhythmic risk stratification is based on criteria as sustained VT or VF, RV ejection fraction (RVEF), LV ejection fraction (LVEF), non-neurocardiogenic syncope, and non-sustained VT ,25.In the ACM context, intense and even moderate competitive or recreational sports should be avoided. Different from other conditions, in ACM, sports practice not only conveys arrhythmic risk to that specific moment but also accelerates disease progression. A study evaluating genotype-positive/phenotype-negative patients observed that athletes developed the clinical disease earlier (30 vs. 41 years of age) and were more likely to develop ventricular arrhythmias and heart failure ,27.Congenital long QT syndrome (LQTS) is an inherited cardiac channelopathy related to the prolongation of the QT interval, or even a normal baseline QT interval but an increased sensibility to the effect of QT-prolonging drugs. Different mutations can cause the syndrome. By now, more than 600 types of gene mutations are known, giving name to 17 different autosomal dominant LQTSs. Between them, there are two syndromes with extracardiac findings: Andersen–Tawil syndrome (LQTS-7) and Tymothy syndrome (LQTS-8). There are two autosomal recessive forms, the Jervel and Lange–Nielsen syndrome types 1 and 2, both associated with hearing loss. Despite being numerous and clinically heterogeneous, LQTS-1, LQTS-2, and LQTS-3 are responsible for more than 90% of cases, LQTS-1 being the most frequent [The diagnosis is clinical, and one of the most widespread ways to conduct it is based on a validation score, the Schwartz score. LQTS is estimated to affect one in every 2000 individuals, and if left untreated, the SCD rate would be between 0.33–0.9% per year .The triggering events are different according to the type of LQTS. Schwartz et al. demonstrated that exercise, especially swimming, was the trigger in 62% of cardiac events in LQTS-1, 13% in LQTS-2, and 13% in LQTS-3. Moreover, in LQTS-1, exercise was the trigger in 68% of arrhythmic events. On the other hand, for LQTS-2, loud and sudden auditory stimuli were the main trigger; and in LQTS-3, vagal situations such as sleep .The 2015 ESC Guidelines on Prevention of SCD only restrict vigorous swimming in patients with LQTS-1. Other LQTS types or sports are not mentioned. The 2015 U.S. guidelines do not restrict competitive sports in patients adequately treated and asymptomatic for at least 3 months, with the exception of swimming for LQTS-1 individuals. The same guidelines do not restrict any activities in genotype-positive/phenotype-negative ones, given the proper preventive measures .In a study cohort led by Johnson et al., 353 patients with LQTS clinically or only genotype positive were evaluated. After outpatient evaluation, treatment, and counseling, 130 patients (54% were genotype-positive/phenotype-negative) decided to keep competing in sports, 20 of those with an ICD implanted. During an average follow-up of 5.5 years, only one had a ventricular arrhythmia treated by an ICD shock [Anomalous origin of a coronary artery is a congenital disease with 0.17–1.3% prevalence in the general population. This disease has a wide range of presentations, i.e., it can be simply an independent origin of the anterior descending artery and the circumflex, or even a higher or lower origin in the same cusp. However, only the contralateral origin plays a role as an SCD risk factor. Even when it originates in the contralateral cusp, it may be a benign condition since it may take many routes to reach the contralateral side, but only the interarterial path (between the aorta and pulmonary trunk) has been shown to increase the risk of SCD. The proposed mechanism of SCD is ischemia triggered ventricular arrhythmia once exercise tends to induce expansion of aortic root and pulmonary trunk, and both may compress the passing coronary artery .The clinical presentation, other than SCD as the first manifestation, can include angina, palpitations, syncope, and/or disproportionate dyspnea exercise triggered. It is remarkable that SCD risk tends to decrease with aging; this can be explained by aortic wall stiffening. A suspect case must be evaluated by direct angiography or by coronary tomography. In confirmed cases, presenting aborted SCD or induced ischemia, invasive treatment is indicated, which can be surgical or percutaneous .These anomalies are the second cause of SCD in athletes in the USA and the third in Veneto, Italy ,21. The Myocarditis is myocardial inflammation triggered by external antigens  or autoimmune response. Viruses are the etiology most of the time, the most frequent being the parvovirus B19 .A study using the International Classification of Diseases (9th revision) codes estimated the global prevalence of myocarditis to be approximately 22/100,000 patient-years .The clinical manifestations of myocarditis are heterogeneous, ranging from virtually asymptomatic to severe myocardial destruction yielding cardiogenic shock and arrhythmias. The diagnosis is sometimes challenging, but cardiac magnetic resonance (CMR) has evolved and nowadays is the main tool for the 2018 Lake Louise criteria for myocarditis diagnosis .In athletes’ autopsy studies, myocarditis was present in up to 8%. Despite appearing low in frequency, in some cohorts, it is the third cause of sports-related SCD. The risk of sudden death caused by myocarditis does not appear to correlate with the severity of myocardial inflammation .The 2015 AHA/ACC Eligibility and Disqualification guidelines postulate that the athlete, after acute myocarditis, shall stop the activities and undergo new evaluation of serum markers, Holter, echocardiogram, and exercise ECG after 3 to 6 months. The athlete can resume training if the LV function is in normal range, serum markers are normal, and clinically relevant arrhythmias are absent on Holter. The routine use of CMR in this context is still debated [Atherosclerotic disease is the leading cause of SCD in athletes over 35 years old (>60%). It can also cause SCD in young individuals with severe metabolic disease or familial hyperlipemia. It can cause SCD in the sports context due to plaque rupture and consequent coronary occlusion leading to ischemia and ventricular arrhythmias or vasospasm .In a cohort from Germany, 144 sports-related SCD were evaluated (mean age: 46.8 years old) in 66 patients. The cause of death was clearly defined, and from this group, 34 patients had myocardial infarction as the triggering event .A prospective cohort study led by Marijon et al. evaluated 1247 sudden cardiac arrests, all patients between 35 and 65 years old (mean age 51.1 years old). Of these, 63 (5%) occurred during sports activities, and in 43 (68%), the etiology could be identified. Coronary artery disease was identified as the cause in 84% .In patients with atherosclerotic coronary disease, two main subgroups need to be differentiated: those with a clinically manifested disease  and those with a concealed disease . This division comes from the fact that the risk is much lower for those with a concealed disease. For both groups, the exams necessary for decision making are the maximal stress ECG and any method to evaluate the LV function. For both groups, in those with normal LV function and no inducible ischemia, there is no restriction to exercise, but keeping the optimized pharmacological treatment is strongly advised. If the patient does not fulfill the above criteria, it is advisable to practice only low-intensity activities. In the context of post-infarction and/or post-revascularization, the minimum time of competitive sports restrictions is 3 months .Wolff-Parkinson-White (WPW) accounts for approximately 1% of SCD in athletes, as demonstrated in a long-term registry. However, this is likely to be underestimated due to the lack of ECG screening . DiagnosCommotio cordis (CC) is an arrhythmic cause of sudden death of traumatic origin. It is caused by a blunt chest trauma leading to VF. It needs to be differentiated from cardiac contusion (contusio cordis), a situation in which the trauma causes structural cardiac damage, such as observed in motor vehicle accidents.Most frequently, the affected individuals are young males, which can be explained by the overwhelming predominance of males in the sports in which commotio occurs. Among the sports, baseball is the one with the highest risk for CC. Nearly all CC events are caused by direct baseball strikes to the anterior chest. Other common sports in which CCs occur are hockey and softball, yet it has been described in nearly all sports. In those sports with no solid, hard ball, it can also occur due to impacts with elbows, fists, and helmets. A recently published registry gathered SCD data from soccer matches (2014 to 2018 period). Of the 617 SCDs reported, seven were confirmed to be due to commotio cordis, and another seven were very likely to be as well .The concerns about sports practice in patients with ICD implanted are many. Between them is the fear about a possible failure of the shock to terminate a ventricular arrhythmia given the high adrenergic output intrinsic to vigorous exercise; the other is the possibility of bodily injury due to a syncopal event in the context of a competition; and last, the possibility of ICD system damage due to mechanical stress/trauma. All these concerns motivated the guideline authors to be restrictive in terms of sports practice in this context. Despite this, exercise restriction can have an impact on quality of life, mainly in children and adolescents that practice sports as a way to socialize.The current recommendations provide the athlete with ICD implanted free participation in sports Ia  as long as they are free of device therapy for 3 months. Participation in sports with higher peak static and dynamic components than class Ia may be considered if the athlete is free from ventricular arrhythmias requiring device therapy for more than 3 months. The decision regarding athletic participation should be made considering the likelihood of appropriate and inappropriate shocks and the potential for device-related trauma in high-impact sports .It is critical that downstream testing, which can include cardiac imaging, exercise testing, and electrophysiological evaluation, is delivered and interpreted by physicians  who understand the cardiovascular adaptations to exercise training and resultant physiologic changes in the heart’s structure and function. This is the so-called athlete’s heart.In most athletes, cardiac changes induced by exercise are modest and easily distinguishable from cardiac illnesses. However, in a small subset of athletes, vigorous training can be associated with more profound electrical and structural changes that may overlap with phenotypically mild manifestations of cardiac disease.For example, sports with intense isometric exercise may induce left ventricular hypertrophy with wall thicknesses up to 12 to 14 mm in range, the same as that of mild HCM (gray zone hypertrophy) .A small but significant proportion of endurance athletes will have dilated LV cavities with LV function in the inferior limit, which overlaps with findings of a dilated cardiomyopathy .These physiologic changes in the LV may be accompanied by RV dilatation and reduced systolic function, which could raise concern for ACM in the appropriate context.In these types of cases, it is crucial that an expert team evaluate the patient, including cardiologists familiar with the healthcare of athletes.Since many of the cardiac conditions that cause SCD in athletes may not present warning symptoms, there has been considerable discussion about the role of preparticipation screening tests to evaluate for occult cardiovascular disease. A flowchart of screening and evaluating athletes is shown in As demonstrated above, the incidence and causes of SCD vary widely depending on age, sex, race, country, and type of sport. The value of any screening test is determined by the characteristics of the population. Therefore, it is unlikely that a given single screening program will be effective across all groups.The Sports Cardiology Study Group of the Working Group of Cardiac Rehabilitation and Exercise Physiology and the Working Group of Myocardial and Pericardial Diseases of the European Society of Cardiology recommend systematic preparticipation cardiovascular screening in young competitive athletes at the beginning of their activity, at the age of 12–14 years and at least every 2 years thereafter, to allow timely identification of progression of some diseases .Accordingly, there are major differences in contemporary guidelines for the preparticipation screening of athletes. The American Heart Association (AHA) and American College of Cardiology (ACC) recommend screening that is limited to a targeted medical history and physical exam .The specific 12-element list recommended by the AHA includes questions regarding a personal history of concerning cardiovascular symptoms  and a family history of premature sudden death or disability from heart disease in addition to a focused physical exam. In contrast to the American recommendations, the European Society of Cardiology (ESC) and the International Olympic Committee (IOC) advocate for screening that also includes a resting 12-lead electrocardiogram (ECG) . Thus, tECG-inclusive screening appears to increase the sensitivity of preparticipation screening for identifying cardiovascular disorders that predispose to SCD. Several guidelines and expert consensus statements have been designed to help clinicians interpret ECGs in athletes, with the goal of preserving sensitivity and improving specificity.The interpretation of ECGs in athletes is also complicated by the fact that exercise may be associated with a number of ECG findings that are not pathologic but can be perceived as such, especially by clinicians unaccustomed to interpreting ECGs in athletic individuals. Over time, the refinement in ECG criteria has led to a reduction in the false-positive rate. The last consensus added the borderline ECG concept and provided a more accurate evaluation . The sugThis approach has important implications for the cardiovascular management of athletes, including preparticipation screening, clinical diagnosis, and risk stratification. An Italian study provided the most compelling evidence of the efficacy of ECG screening to save lives by identifying and disqualifying athletes with at-risk heart diseases. The annual incidence of SCD in athletes decreased by 89%, from 3.6 per 100,000 person-years in the prescreening period to 0.4 per 100,000 person-years in the late-screening period in the Veneto region .Many of the causes of syncope can be suspected on the basis of ECG abnormalities at preparticipation screening .In cases of positive findings at any of the first-line examinations, the athlete should be evaluated with other invasive and/or noninvasive tests such as Holter, echocardiogram, exercise stress test, CMR, coronary computed tomography (CCT), invasive angiography, electrophysiological study with electroanatomical mapping, and endomyocardial biopsy (EMB) ,50. In cLong-term ECG monitoring with Holter monitors can be useful in those patients with frequent or reproducible symptoms, such as palpitation or syncope. Athletes with intermittent, infrequent symptoms are best evaluated with a continuous loop monitor. These monitors continuously record a 1 to 3 min segment of surface ECG and, with activation by a button on the device, the tape is frozen, and the previous few minutes of the event are recorded.Exercise testing should be adapted to the specific type of exercise/sport responsible for the arrhythmic events because a conventional exercise test may not replicate the specific clinical situation and the arrhythmogenic mechanism triggered by a given sport modality. An increase in the arrhythmia frequency at the beginning of exercise, disappearance at the peak of exercise, and reappearance during recovery usually suggests a benign behavior for premature ventricular beats. On the other hand, the triggering or worsening of ventricular arrhythmia with the increasing workload may point to an underlying cardiomyopathy or ion channel disease and may predict risk for malignant arrhythmias during sports .In those athletes who are suspected of having an underlying cardiogenic substrate, a careful echocardiographic evaluation is usually the first choice as initial morphological evaluation. Despite the overall suitable diagnostic performance, transthoracic echocardiography (TTE) is typically normal in catecholaminergic ventricular tachycardia, anomalous coronary arteries, Brugada syndrome, and LQTS. TTE findings vary according to the cardiomyopathy. In ACM, they include RV and/or LV enlargement/hypokinesis, RV free wall thinning/dyskinesia, and prominent RV trabeculations, with a hyper-reflective moderator band. In HCM, we may find unexplained increased LV wall thickness (>13–15 mm). To differentiate from physiologic athlete’s hypertrophy, findings such as systolic anterior motion of the mitral valve, LV outflow tract gradient obstruction, and impaired diastolic function must be taken into account. LV remodeling in athletes is associated with normal or enhanced myocardial relaxation, leading to supranormal diastolic function, with findings as transmitral E/A ratio > 2, with typical low A wave velocity (late diastole). The tissue doppler imaging (TDI)-derived early diastolic myocardial velocity (e’) of the basal septal and basal lateral wall is increased, being responsible for a low E/e’ ratio. The RV has larger inflow and outflow dimensions in athletes compared to sedentary controls, with no impairment of the systolic function. Moreover, in highly trained endurance athletes, resting RV global systolic function is measured by fractional area change, and tricuspid annular plane systolic excursion (TAPSE) can be lower .CMR has emerged as an important noninvasive, non-radiating imaging technique, particularly suited to provide detailed cardiac tissue characterization in athletes in the last decade . Other tA recent study from Andreini et al. sought to determine whether CMR was capable of identifying structural heart disease (SHD) in patients with ventricular arrhythmia and normal echocardiography. A total of 946 patients were enrolled . CMR detected SHD in 241 patients (25.5%) and abnormal findings not specific for a definite SHD diagnosis in 187 patients (19.7%). The most frequent cardiomyopathy detected in this cohort was myocarditis. All of them had a previous completely normal echocardiography .Finally, myocardial fibrosis, identified in late gadolinium-enhanced images (LGE) taken 15 min post-contrast-enhanced CMR sequences can identify those patients who are at increased arrhythmic risk. In HCM, LGE is present in about half of the individuals. Myocarditis, in its turn, can be suggested by CMR in athletes through the identification of a number of abnormalities, including: (1) mildly or severely reduced systolic function, with or without regional wall motion abnormalities; (2) patchy or diffuse areas of LGE localized to the mid-myocardial or sub-epicardial layer with a non-coronary artery distribution; and (3) in the acute phase of the disease, areas of increased signal intensity on T2 weighted images due to edema .CCT and coronary catheterization are also useful in the diagnosis of congenital anomalous coronary arteries and necessary in the diagnosis of atherosclerotic coronary disease.In those athletes who are suspected of having an underlying myocardial substrate for arrhythmias due to abnormal second-level examinations, performing an electrophysiological study and electroanatomical mapping can be useful.The new imaging technologies are promising tools to better characterize the arrhythmic substrate. High-density electroanatomical mapping with the assessment of late, fragmented potentials and channels can help to localize the critical isthmus in complex arrhythmias. In addition, the real-time image integration of pre-acquired magnetic resonance and computed tomography information is feasible and accurate to assess epicardial fat and coronary artery, which are important issues during epicardial ablation .The role of EMB in the diagnosis and treatment of adult and pediatric cardiovascular diseases remains controversial, and the practice varies widely even among cardiovascular centers of excellence. A need for EMB exists because specific myocardial disorders that have unique prognoses and treatment are seldom diagnosed by noninvasive testing .In a recent study, Narducci et al. evaluated the role of an extensive diagnostic work-up in apparently healthy young patients with complex ventricular arrhythmias, comparing athletes and non-athletes. A total of 33 patients were enrolled: 18 competitive athletes (56%) and 15 non-athletes (44%). All of them underwent echocardiography and CMR that did not show structural disease. The diagnostic yield of EMB was 50% in athletes and 40% in non-athletes. Among athletes, the final diagnosis was myocarditis in 2, arrhythmogenic ventricular right cardiomyopathy in 1, and focal replacement fibrosis in 1 .In athletes, the presentation of myocarditis is heterogeneous, and establishing the diagnosis is challenging with no current uniform clinical gold standard. The combined information from symptoms, electrocardiography, laboratory testing, echocardiography, cardiac magnetic resonance imaging, and in certain cases, endomyocardial biopsy can help to establish the diagnosis.Sudden cardiac death in the athlete is a relatively rare event, but as sports practice is growing, and its occurrence is a tragedy, in absolute terms, it is a rather relevant issue. The causative disease is not the same through different population profiles. Therefore, the screening strategy must be adapted to the local demand. In general, a comprehensive clinical evaluation associated with ECG is enough for screening in most of the scenarios, and as a strategy, has been shown to reduce events in a classical cohort from Italy. In recent years, technological advances brought valuable tools that can be used in additional investigations such as the CMR and the endomyocardial biopsy.


Early detection of cardiovascular dysfunctions directly caused by acute ischemic stroke (AIS) has become paramount. Researchers now generally agree on the existence of a bidirectional interaction between the brain and the heart. In support of this theory, AIS patients are extremely vulnerable to severe cardiac complications. Sympathetic hyperactivity, hypothalamic–pituitary–adrenal axis, the immune and inflammatory responses, and gut dysbiosis have been identified as the main pathological mechanisms involved in brain–heart axis dysregulation after AIS. Moreover, evidence has confirmed that the main causes of mortality after AIS include heart attack, congestive heart failure, hemodynamic instability, left ventricular systolic dysfunction, diastolic dysfunction, arrhythmias, electrocardiographic anomalies, and cardiac arrest, all of which are more or less associated with poor outcomes and death. Therefore, intensive care unit admission with continuous hemodynamic monitoring has been proposed as the standard of care for AIS patients at high risk for developing cardiovascular complications. Recent trials have also investigated possible therapies to prevent secondary cardiovascular accidents after AIS. Labetalol, nicardipine, and nitroprusside have been recommended for the control of hypertension during AIS, while beta blockers have been suggested both for preventing chronic remodeling and for treating arrhythmias. Additionally, electrolytic imbalances should be considered, and abnormal rhythms must be treated. Nevertheless, therapeutic targets remain challenging, and further investigations might be essential to complete this complex multi-disciplinary puzzle. This review aims to highlight the pathophysiological mechanisms implicated in the interaction between the brain and the heart and their clinical consequences in AIS patients, as well as to provide specific recommendations for cardiovascular management after AIS. Cardiovascular disease is regarded as the main predisposing risk factor for acute ischemic stroke (AIS) . CardiacThe incidence of cardiovascular complications after AIS ranges from 3% for myocardial infarction to > 50% for asymptomatic coronary stenosis . The mosThe main mechanisms involved in the so-called stroke-heart crosstalk include the hypothalamic–pituitary–adrenal axis (HPA) , the immCentral pathways regulating autonomic responses from the brain to the heart involve structures implicated in physiological, pathological, and emotional responses  Fig. 1)1). When FOXO) genes. FOXO genes have been recently identified as a potential new molecular target for cardiac dysfunction and are associated with increased risk of myocardial infarction [FOXO pathway, decrease protein degradation by ubiquitin, thus regulating cardiomyocyte proteostatic equilibrium and cardiac mass maintenance with muscle ring finger-1, a class of proteins that is upregulated in a deficient heart [Sympathetic connections between the central nucleus and the heart are mediated by sympathetic pre-ganglionic neurons in the upper thoracic segment of the spinal cord, synaptic connections in the cervical and upper thoracic ganglia, and sympathetic post-ganglionic neurons . The “fifarction . Noradrent heart . The connt heart  Fig. 3)FOXO) genParasympathetic connections include noradrenergic pre-ganglionic neurons in the medulla oblongata, nucleus ambiguus, vagus nerve, and reticular formation . These nBaroreceptor and chemoreceptor afferent neurons reach the solitary nucleus, and signals are transmitted to cardiac neurons (via glutamatergic neurons), to the caudal ventrolateral medulla (via GABAergic neurons), or to the rostral ventrolateral medulla. After input integration, the central autonomic network re-transmits signals to the heart via the parasympathetic and the sympathetic systems  Fig. 1)1).Adrenocorticotropic hormone activates the adrenal gland to release cortisol, followed by catecholamines, which, by binding β1 adrenoreceptor, modifies intracellular calcium levels, induces oxidative stress, reduces adenosine triphosphate synthesis, and leads to osmotic swelling, which causes myocardial cell death .The immune inflammatory response plays a prominent role immediately after AIS, and is strongly associated with ischemic stroke progression . During l-carnitine into trimethylamine-N-oxide (TMAO). TMAO induces platelet hyperactivity and foam cell formation, alters bile and sterol metabolism, increases nuclear factor kappa-B, and reduces nitric oxide. It also enhances the inflammatory response by acting on dendritic cells, macrophages, and platelets. These mechanisms are responsible for heart failure, cardiac remodeling, myocardial infarction, thrombosis, and atherosclerosis [After a brain insult, up to 50% of AIS patients develop gastrointestinal complications such as dysphagia, gastrointestinal hemorrhage, and intestinal paralysis, which can have a major impact on neurological outcomes and mortality . The gutclerosis . Some clclerosis . Its levclerosis  Identification of risk factors for AIS is complicated by the fact that both cardiac dysfunction and AIS share the same factors. Hypertension may contribute to atherosclerotic disease, which is prominent in the pathophysiology of AIS . MoreoveCardiac issues that may be implicated in AIS include atrial fibrillation, patent foramen ovale, a hypokinetic segment with mural thrombus, infective endocarditis, and hematological disorders  . Based oAtrial fibrillation and flutter cause blood stagnation in the left atrium, thus predisposing to thrombosis and cerebral embolism . ValvulaBoth ischemic and arrhythmic electrocardiographic changes are common after AIS within the first 24 h . AdditioElectrocardiographic changes occur in 60–90% of AIS patients , 11. ComThe primary causative factors of stroke-induced myocardial dysfunction might be autonomic dysregulation and the physiological stress response . StudiesChronic cardiac dysfunctions after AIS are triggered by endothelial inflammation, oxidative stress, and catecholamine release leading to myocardial remodeling. Sympathetic stimulation activates a catecholamine surge, which causes vasoconstriction of the peripheral vessels and of the coronary arteries, followed by acute ischemia. The direct toxic effect of catecholamines on the myocardium and subsequent neurogenic hypertension also contribute to chronic myocardial dysfunction and remodeling .The current understanding of heart disease corroborates that cardiac remodeling is a common consequence of chronic myocardial or arrhythmic dysfunctions . A pre-cCerebral autoregulation plays an essential role in maintaining cerebral blood flow and cerebral perfusion pressure within constant ranges to ensure adequate irrigation of the brain . However2 and CHA2DS2-VASc scores have been validated to identify the risk of AIS [Given the fact that cardiovascular and cerebrovascular diseases share similar risk factors, the Framingham Risk Score and the Pooled Cohort Equations , 32 shouk of AIS .General management of AIS is often complicated because of both possible cardiovascular dysfunction and several medical complications, such as swallowing impairment, neurogenic respiratory failure, stroke-associated pneumonia, gut dysbiosis, systemic inflammation, and need for tracheostomy or mechanical ventilation . The NatCriteria for ICU admission vary significantly across countries and centers. In more severe cases, ICU admission of AIS patients might be essential to ensure invasive neuro- and cardiovascular monitoring and for early detection of any multiorgan complications . ContinuCardiac enzymes may increase after AIS, but generally less than during a primary heart attack . TroponiCatheter ablation has been considered as a more effective alternative than anti-arrhythmic drugs to reverse atrial fibrillation to sinus rhythm . The lefDespite great strides in our understanding of the brain–heart crosstalk after AIS, the roles of sympathetic control, gut dysbiosis, and inflammatory response are still under-investigated. Stroke-heart interactions are now a central theme of interest for researchers, and the causative mechanisms of stroke-related heart dysfunction are attractive new targets for future therapeutic strategies. Further studies are warranted to explore these fascinating theories and mechanisms and to translate pathophysiological knowledge into clinical practice.Additional file 1: Table S1. Incidence and prevalence of all cardiac dysfunctions after ischemic stroke; Table S2. Cardiac dysfunctions after ischemic stroke and their association with outcome; Table S3. Blood pressure control in ischemic stroke and its association with outcome; Table S4. Troponin T as acute biomarker of cardiovascular complications after ischemic stroke.


Previous studies have shown gadoxetate disodium’s potential to represent liver function by its retention in the hepatobiliary phase. Additionally, in cardiac imaging, quantitative characterization of altered parenchyma is established by extracellular volume (ECV) calculation with extracellular contrast agents. Therefore, the purpose of our study was to evaluate whether intracellular accumulation capacity (IAC) of gadoxetate disodium derived from ECV calculation provides added scientific value in terms of liver function compared to the established parameter reduction rate (RR). After local review board approval, 105 patients undergoing standard MR examination with gadoxetate disodium were included. Modified Look-Locker sequences were obtained before and 20 min after contrast agent administration. RR and IAC were calculated and correlated with serum albumin, as a marker of synthetic liver function. Correlation was higher between IAC and albumin, than between RR and albumin. Additionally, capacity of both RR and IAC to distinguish between patients with or without liver cirrhosis was investigated, and differed significantly in their respective means between patients with cirrhosis and those without. We concluded, that the formula to calculate ECV can be transferred to calculate IAC of gadoxetate disodium in hepatocytes, and, thereby, IAC may possibly qualify as an imaging-based parameter to estimate synthetic liver function. While initially, calculations were based on signal intensities, later on, mapping techniques, which are less dependent on the type of the scanner or the sequence and well known from cardiac imaging, were also introduced in liver imaging6. Based on accordingly acquired relaxation times, a reduction rate (RR) was determined, which describes the ratio between enhancement of liver parenchyma after application of gadoxetate disodium and native liver parenchyma7. Still, the reduction rate does not account for the effect blood may have on relaxation time, which may vary due to factors such as the amount of gadolinium contrast injected, post contrast scan times, renal function, hematocrit, and Bo field. Normalizing hepatic T1 in relationship to blood T1 may diminish much of these complexities10.For more than 20 years it has been established, that magnetic resonance imaging (MRI) with gadoxetate disodium has the potential to evaluate hepatic function9, and the approach has been translated to hepatic imaging in the experimental field11. Due to the property of gadoxetate disodium to be taken up by hepatocytes according to the amount of functioning organic-anion-transport proteins (OATP), in the equilibrium phase, extracellular concentrations are very low, whereas intracellularly, the contrast agent is accumulated. Therefore, for gadoxetate disodium, we hypothesized that the intracellular accumulation capacity (IAC) could be calculated according to the established formula for the extracellular space with a minor correction made due to retained contrast agent within the blood and the extracellular space in the hepatobiliary phase11.Cardiac MR imaging has shown the potential of myocardial extracellular volume fraction (ECV) as the percent of tissue composing the extracellular spaceThe purpose of the present exploratory study was to evaluate whether the well-established method to estimate ECV can be transferred to calculation of IAC using the hepatocellular contrast agent gadoxetate disodium, and, if so, whether this method might have advantages over the calculation of the reduction rate.This prospective cohort study was approved by and registered with the local ethics committee . From January 2017 to November 2019, patients referred for MR examination of the liver with gadoxetate disodium were evaluated for study participation. Exclusion criteria were age younger than 18 years, pregnancy, metallic implants or functional devices not eligible for MR examination, claustrophobia, a history of allergic reaction to Gd-EOB-DTPA, and a glomerular filtration rate below 30 ml/min. With written informed consent to participate in the study, 105 patients  were included in the study.All included patients underwent the standard liver MR imaging protocol using the hepatocyte-specific contrast agent gadoxetate disodium , and the study sequences as specified below. All methods were carried out in accordance with the relevant guidelines and regulations.12.MR imaging was performed on a 1.5 T scanner  equipped with a 32-channel body-phased-array coil. The standard liver MR imaging protocol using the hepatocyte specific contrast agent gadoxetate disodium comprises an axial T1-weighted spin echo sequence, an axial fat-saturated T2-weighted turbo spin echo sequence acquired with a 2D navigator for abdominal imaging, an axial T1-weighted dual echo sequence, axial T1 VIBE (volume-interpolated breath-hold) sequences for dynamic imaging before and 15 s, 55 s and 2, 5, 10 and 20 min after contrast agent administration and a coronally orientated T1 VIBE sequence for the hepatobiliary phase at least 20 min after contrast agent administrationApart from the clinical routine image protocol, patients received steady-state precession readout single-shot Modified Look-Locker inversion recovery (MOLLI) sequences in the axial plane before contrast agent administration and throughout the hepatobiliary phase.T1 maps were calculated automatically on a pixel-by-pixel basis, and displayed on a 12-bit lookup table with a visible color-coded map, on which the signal intensity of each of the pixels reflects their absolute T1 value.The imaging parameters for the study sequence are shown in Table All images were analysed using PACS workstations  by a radiologist with 12 years of experience in MR imaging. MOLLI images were assessed by a single reader, blinded to the paraclinical including histopathological findings, if present. Regions of interest of maximal size were placed in the liver parenchyma on native as well as on post-contrast MOLLI images. ROI placement was chosen avoiding larger vessels or focal lesions to avoid partial volume averaging. Additionally, ROIs were placed in the abdominal aorta both on precontrast and postcontrast images.Patients’ electronic medical records were searched for history of liver disease and documented pertinent laboratory data .14:Calculation of the ECV normalized for hematocrit using an extracellular contrast agent was described elsewhereFor hepatocyte specific contrast agents, one may assume a low-level equilibrium between intravascular und extracellular compartment, and a mainly intracellular storage. An illustration can be found in Fig. Therefore, the above-mentioned formula may allow for calculation of IAC, with a minor correction by subtracting the low-level amount of extracellular contrast agent.4:The reduction rate was calculated as described elsewhereAll statistical analyses were performed using SPSS Version 24 . For a test of normality, the Shapiro–Wilk test was applied. Accordingly, t-test and Mann–Whitney-U were applied. Correlation analyses were performed with Spearman’s Rho and Pearson’s correlation coefficient. Data are expressed as means and standard deviation (SD).Hepatic T1 relaxation times varied between 319.67 and 819.00 ms (mean 564.7 ms) for the native sequences, and between 137.67 and 460.00 ms (mean 219.41 ms) for hepatobiliary sequences. The hematocrit varied between 0.238 and 0.492 l/l (mean 564.72 l/l). Albumin values were available in 69 of patients and varied between 20 and 48 g/l (mean 39.89 g/l).15 with a Pearson’s r of 0.697 (p < 0.001)—a visualization of this correlation is given in Fig. IAC showed a mean of 3.33 with a minimum of 0.36 and a maximum of 8.37. Reduction rate varied between 21.19 and 78.09 with a mean of 61.06. Correlation between both measures was strongCirrhosis was present in 20 patients. IAC was 3.38 in non-cirrhotic organs and 2.50 in cirrhotic livers (p = 0.023). Reduction Rate was 65.6 in non-cirrhotic organs and 56.5 in cirrhotic livers (p = 0.002). Figure 15.As a simplified surrogate parameter for liver function, albumin was chosen and correlations with both RR and IAC were computed. Correlation, as expressed by Spearman’s ρ, was higher between IAC and albumin , than between RR and albumin   as a novel imaging marker for liver function on Gd-EOB-DTPA enhanced MR-imaging. IAC can be calculated easily from T1 mapping sequence image data, and it correlates slightly better with serum albumin as a simplified surrogate parameter of liver function than the reduction rate.Our results show a close correlation between values of reduction rate and those of IAC. Equally, predictability of cirrhosis is comparable between both parameters. We thereby conclude, that the approach to calculate ECV using an extracellular contrast agent can be transferred to the intracellular space in hepatic imaging using the hepatocyte-specific contrast agent gadoxetate disodium.16. Calibrating the T1 maps to blood including its hematocrit seemed to be a valuable tool to circumvent at least several of these confounding factors, and led to the description of a new parameter named ECV (extracellular volume)17. Calculation of the percentage of the noncellular tissue volume (ECV) is established in cardiac magnetic resonance imaging and is based on the assumption of an equilibrium between the intravascular, extracellular compartment and the extracellular compartment in organs such as the myocardium or the liver. The myocardial ECV is measured as the percent of tissue comprised of extracellular space, which is a physiologically intuitive unit of measurement and is independent of field strength10.Quantitative measurement of the myocardial tissue T1 time has long been used and is now well established for the assessment of diffuse myocardial fibrosis. Nevertheless, the accuracy of post contrast T1 mapping is sensitive to a lot of confounding factors, such as dose and concentration of the contrast agent, the time delay between contrast agent administration and image acquisition, the wash-out rate, and the hematocrit level, which affects the partition coefficient of the gadolinium contrast agent as gadolinium resides only in plasma and does not enter intact red blood cells18. Therefore, the adaptation of the ECV-formula on IAC includes a minor correction by subtracting the low-level amount of extracellular contrast agent. The thereby calculated IAC can range from close to 0, meaning no relevant intracellular accumulation with a gadoxetate retention similar to blood, to around eight, indicating a high intracellular accumulation capacity due to well-functioning hepatocytes, as Gd-EOB-DTPA uptake into hepatocytes depends on the integrity of the hepatic transport proteins20.As most of the aforementioned confounding factors to myocardial T1 relaxation times also apply to hepatic relaxation times, we assumed, that description of liver function using gadoxetate disodium might also benefit from a calibration to blood including its hematocrit. Whereas extracellular contrast agents show an equilibrium between the extracellular space and the intravascular compartment without relevant intracellular uptake, with gadoxetate disodium, in the hepatobiliary phase, one may assume a mainly intracellular storage and a low-level equilibrium between intravascular und extracellular compartment26. Still, apart from field strength, signal intensities in MRI are also dependent on the manufacturer, the device, and also the sequence used, and, therefore, cannot be easily transferred, and in direct comparison, relaxation time measurements showed higher correlation to scintigraphically evaluated liver function than signal intensity-based measurements21.There are other approaches to quantify liver function using gadoxetate disodium of which most refer to signal intensity measurements and their derived measures liver-to-spleen ratio, liver-to-muscle-ratio, and relative enhancement27. This approach appears to be promising, and a direct comparison to the approach presented here would be desirable. Still, it includes a comparison to another organ, the spleen, thereby possibly introducing new confounding factors.Most recently, another approach using relaxometry was presented by Liu et al., using the hepatocyte enhancement fraction as a surrogate parameter for liver function, which is calculated by the T1 differences before and after the enhancement of liver and spleen using the double compartment model10 and thus might lead to more precise results. This might be of value at an earlier stage of reduced liver function, even though the test is not specific for liver disease: albumin serum levels are also reduced in patients with malnutrition or malabsorption, protein-losing enteropathy, or nephrotic syndrome, but, nevertheless, even though we cannot confidently exclude malnutrition as a confounding factor, according to the accessible medical records, the other typical preconditions for serum albumin alterations were not present in our study population.To further evaluate the diagnostic value of IAC, we correlated it to serum albumin, which is one of the parameters that can be measured in peripheral blood and are used to assess liver synthetic function in clinical practice. Compared to reduction rate, the correlation was higher with IAC, a finding, which might support the assumption, that calibrating the T1 values to blood circumvents a few of the confounding factors limiting reproducibility of T1 valuesYet, in the present collective, prediction of cirrhosis was not improved by IAC compared to reduction rate. Due to the small number of patients with cirrhosis (n = 20) as well as the heterogeneity of its etiology as well as the disease’s stage, we regard these results as preliminary and cannot draw any final conclusion as to IAC’s value in cirrhotic livers.There are some limitations to this investigation that need to be addressed: the study as approved by and registered with the local ethics committee did not include an additional blood sample for scientific reasons. Therefore, possibilities to measure liver function were limited as the only parameter which could be obtained in a relevant part of the patient collective was albumin, present in at least about 65% of patients. In a prospective approach, dedicated liver function tests such as the ICG or also the LIMAx test could have been applied, additionally, more patients with highly decreased liver function should be examined. Additionally, liver imaging was performed mainly for characterization of focal liver lesions—therefore the majority of patients included did not have relevantly impaired liver function. However, advantages of the IAC over the reduction rate are to be expected in patient populations with reduced liver function, therefore further studies are warranted to characterize the benefits of this imaging marker further.The formula to calculate ECV can be transferred to calculate the IAC of hepatocytes using the hepatocyte-specific contrast agent gadoxetate disodium. Additionally, IAC shows a higher correlation to albumin, thus possibly qualifying as a new image-based parameter to estimate synthetic liver function.