Photoacoustic (PA) imaging has been widely used in biomedical research and preclinical studies during the past two decades. It has also been explored for nondestructive testing and evaluation (NDT/E) and for industrial applications. This paper describes the basic principles of PA technology for NDT/E and its applications in recent years. PA technology for NDT/E includes the use of a modulated continuous-wave laser and a pulsed laser for PA wave excitation, PA-generated ultrasonic waves, and all-optical PA wave excitation and detection. PA technology for NDT/E has demonstrated broad applications, including the imaging of railway cracks and defects, the imaging of Li metal batteries, the measurements of the porosity and Young’s modulus, the detection of defects and damage in silicon wafers, and a visualization of underdrawings in paintings. Nondestructive testing and evaluation (NDT/E) is the process of testing, examining, or evaluating materials, components, or assemblies for characterization without causing damage to the part or system . The terCurrently, the most frequently used NDT/E techniques include liquid penetrant, magnetic particle, electromagnetic, visual, radiographic, and ultrasonic (US) testing . Liquid 2O3 powder and hemoglobin [Photoacoustic (PA), or optoacoustic, technology-based NDT/E is an alternative to the aforementioned NDT/E techniques and has attracted considerable attention over the years. The technique is based on the PA effect, which was discovered by Alexander Graham Bell in 1880, and indicates the fact that varying light intensity can produce sound waves . The PA moglobin , 7. In 1moglobin , measuremoglobin , and vismoglobin , to namePA imaging is a hybrid imaging modality that visualizes optical absorption contrast through the PA effect , 13, a pLaser ultrasonics is a special approach to PA technology for NDT/E and has achieved success in composite inspections in the industry and on-line hot tube thickness measurements for the metallurgical field , 14. TheThis paper is organized as follows. The background of NDT/E is introduced in p under the condition of thermal confinement in a lossless homogenous medium is governed by the following PA wave equation:H is the heating source, representing the energy deposited in the tissue per unit volume per unit time; c is the speed of sound; β is the isobaric thermal volume expansion coefficient; and Cp denotes the specific heat capacity at a constant pressure. Under the condition of stress confinement, the duration of the laser pulse is much shorter than the time it takes for sound to travel across the heated region. The heating function can be decomposed as H ≈ A(r)δ(t), where A(r) is the energy deposited in the tissue per unit volume and δ(t) is the Dirac delta function. As a result, the initial acoustic pressure p0(r) at position r can be written as follows:p recorded by a detector at location rd can be written as follows:V is a 3D volume element at rs. This equation mathematically represents the spherical Radon transform and suggests that the initial acoustic pressure p0(rs) in a small tissue volume at rs linearly contributes to the recorded acoustic pressure p.The generation and propagation of PA signals A variety of PA technologies have been employed in NDT/E. According to the approaches for PA wave excitation, light-sample interactions, and PA wave detection, the technologies can be categorized into a few types, as detailed in the following.The scheme has been extensively used for NDT/E , 15–25. Compared with a CW laser, the pulsed laser is able to generate short US pulses Fig. b. As shoPA A-line and simple imaging. As shown in Fig. PA computed tomography (PACT). To enhance the spatial resolution, an image reconstruction algorithm can be further employed. A schematic is shown in Fig. PA microscopy (PAM). The spatial resolution can be further boosted using PAM, which can be further categorized into acoustic-resolution PAM (AR-PAM) and optical-resolution PAM (OR-PAM), as shown in Fig. A typical OR-PAM imaging setup is shown in Fig. Apart from the PA waves generated by laser illumination on the sample, PA-generated US waves can also be utilized to interrogate the sample for NDT/E –51. A scOptical US detection is an alternative technique to piezoelectric transducers. Compared with piezoelectric transducers, optical US detection generally has the advantages of a broader bandwidth, higher spatial resolution (tiny active detection area), wider acceptance angle, and immunity to electromagnetic interference . A fiberA summary of the technical specifications of PA technologies used for NDT/E (representative examples) is provided in Table In this subsection, earlier studies on a preliminary investigation into NDT/E on metallic films and plates, as well as their detection of cracks and defects, are first introduced. Several recent applications are then described.The first part can be further categorized into three types: (1) Metallic films and plates. Veith  used a fin situ and operando observations of Li metal batteries during cycling, which provides insight into the fundamental mechanisms of Li dendrite growth. (4) Other . The optical reflection coefficient of the metal mirrors was measured using a PA cell [For the second part, thus far, there have been specific applications reported: (1) Railway defects and cracks. Yan et al.  utilized PA cell . Liu et  PA cell  also utiKarabutov et al.  studied Podymova et al.  demonstrWang et al. , 44 deteBerquez et al.  detectedKozhushko and Hess  used a PA+ and A− in Fig. Podymova and Karabutov  demonstrKim and Netzelmann  employedA summary of the materials and applications of PA technologies for NDT/E is provided in Table Several PA technologies have been employed for NDT/E, such as the use of a modulated CW laser or a pulsed laser to excite PA signals, PA-generated US waves to interrogate samples, and an all-optical scheme to realize non-contact remote sensing. Either the interaction of light and the samples, or the interaction of PA-generated US waves and samples, can be considered in NDT/E. Depending on the materials to be characterized or imaged and their environments, a suitable PA technology for specific NDT/E applications may be chosen. For NDT/E using PA technology, a variety of materials have been studied. Applications range widely in different fields such as the semiconductor industry , mass transport , and the energy industry .PA technology has proven to be effective for NDT/E. PAM possesses a high spatial resolution, particularly OR-PAM, which is useful for visualizing fine structures. Meanwhile, fast and real-time PAM imaging systems can facilitate extended studies. By contrast, PA-generated US waves naturally enable broadband US emissions, opening up new opportunities for NDT/E. With the advancement of PA technologies in different aspects , the challenges previously encountered in NDT/E applications are likely to be overcome, and more NDT/E applications by taking advantage of the advanced PA technologies may become possible.Compared with US imaging used in NDT/E, PA imaging offers three advantages. (1) PA imaging can provide a high spatial resolution using the OR-PAM configuration, which can easily realize a microscale resolution. (2) PA imaging provides information associated with optical absorption contrast, which can be useful for certain applications. (3) Multiple wavelengths for PA wave excitation can be used to perform multispectral PA imaging, which helps identify different materials featuring distinct absorption spectra and optimizing imaging effects.The limitations of PA technology for NDT/E are discussed. (1) A major limitation is the penetration depth of PA technology. For biomedical imaging applications, compared with pure optical microscopy, PA imaging can break the optical diffusion limit (transparent mean free path of approximately 1 mm in the skin) and enable a high US resolution at an imaging depth of up to a few centimeters in biological tissue . HoweverDespite the current limitations, there are potential future directions of PA technology for NDT/E. Future directions include, but are not limited to, combined PA and US imaging for NDT/E, structural health monitoring (SHM), and the microscopy of metal: (1) Because piezoelectric transducers are typically used in PA systems, transducers can also be used for US imaging. Therefore, it is natural and usually seamless to integrate the two imaging modalities. The dual-modality approach is advantageous in providing complementary information, a scalable resolution, and the imaging depth. PA technology will be a good supplement for applications where US imaging has been extensively used, such as studying the formation of cracks. (2) SHM detects damage and the performance of mechanical structures  to monitor their safe operation. For example, SHM used for aerospace structures can greatly improve the level of safety and reduce expenses for maintenance and repair. Another example is monitoring railway cracks, as described in


Does an association exist between myocardial injury and systemic release of serum procalcitonin in acute ST-elevation myocardial infarction that is treated with primary percutaneous coronary intervention?In this cohort study of 141 patients with ST-elevation myocardial infarction, there were no significant correlations between concentration of procalcitonin 24 or 48 hours after intervention and myocardial or microvascular injury as assessed by cardiac magnetic resonance imaging.These data highlight the clinical potential of procalcitonin to identify concomitant infection and to guide antibiotic treatments for patients with ST-elevation myocardial infarction; however, randomized trials are needed to evaluate the clinical benefit of a procalcitonin-guided strategy. Myocardial tissue injury due to acute ST-elevation myocardial infarction (STEMI) initiates an inflammatory response that leads to a release of systemic inflammatory biomarkers, including C-reactive protein (CRP) and white blood cells, consequently reducing the usefulness of these routine biomarkers for identifying concomitant infections. The clinical role of procalcitonin (PCT), a promising marker of bacterial infection, to detect concomitant infection in acute STEMI is unknown, mainly because it is unclear whether myocardial injury per se induces systemic PCT release.To investigate the release of serum PCT in the acute setting of STEMI (24 and 48 hours after primary percutaneous coronary intervention) and to elucidate any associations with myocardial injury markers through a comprehensive assessment by cardiac magnetic resonance (CMR) imaging.This prospective cohort study conducted between 2016 and 2018 included 141 consecutive patients with STEMI treated with primary percutaneous coronary intervention. Concentrations of PCT, high-sensitivity CRP (hs-CRP), and high-sensitivity cardiac troponin T (hs-cTnT) and white blood cell counts were measured serially 24 and 48 hours after infarct.Acute STEMI and primary percutaneous coronary intervention.The association of PCT and typical inflammatory marker levels with CMR-determined myocardial damage was assessed. Infarct size, extent of microvascular obstruction, and occurrence of intramyocardial hemorrhage as determined by CMR within the first week following STEMI were also evaluated.r = 0.07; P = .40; at 48 hours: r = 0.13; P = .12) or with microvascular obstruction . Furthermore, PCT levels at 24 hours  and 48 hours  were not significantly associated with the presence of intramyocardial hemorrhage.In total, 141 patients with STEMI (117 men [83%]) having a median age of 56 years  were included. The median PCT concentration was 0.07 μg/L  24 hours after intervention and 0.07 μg/L  48 hours after intervention. Whereas hs-CRP and hs-cTnT levels and white blood cell counts were significantly correlated with CMR markers of myocardial damage at both 24 and 48 hours after intervention, the PCT level showed no significant correlation with infarct size (at 24 hours: In the acute phase after percutaneous coronary intervention for STEMI, circulating PCT levels remained unassociated with the extent of myocardial and microvascular tissue damage as visualized by CMR imaging. This cohort study evaluates whether an association exists between myocardial injury assessed with cardiac magnetic resonance imaging and the release of serum procalcitonin in patients with acute ST-elevation myocardial infarction who are treated with primary percutaneous coronary intervention. In a previous analysis of patients with myocardial infarction, including those with or without STEMI, PCT showed higher accuracy for the diagnosis of coexisting infections than other markers, such as CRP and WBC count.8 In line with this finding, there is evidence that myocardial infarction per se does not induce a significant systemic PCT release.14 By contrast, other earlier studies have shown PCT as an indicator of myocardial damage within the context of infarction.16 Given these controversial data, there is a need for dedicated studies that explicitly evaluate the association between PCT concentrations and infarct severity to improve our understanding of the clinical role of PCT in acute myocardial infarction.However, in the setting of supposed concomitant infections that complicate STEMI, the interpretation of these inflammatory biomarkers are challenging, frequently leading to the misuse of antibiotics in daily clinical practice.17 However, data on the association of PCT with CMR-determined myocardial injury after STEMI are entirely lacking. Therefore, we investigated the association of serum PCT concentration with infarct severity as assessed by comprehensive CMR imaging among patients with acute STEMI who were treated with primary percutaneous coronary intervention.Cardiac magnetic resonance (CMR) imaging enables precise evaluation and quantification of myocardial and microvascular tissue injury and, therefore, represents the current in vivo criterion standard for the assessment of infarct severity after STEMI.STROBE) reporting guideline for cohort studies. The research ethics committee at the Medical University of Innsbruck approved the study, and the investigation was conducted following the Declaration of Helsinki. Before inclusion, all participants gave written informed consent. No participant received compensation or was offered any incentive for participating in this study.In this prospective cohort study, 141 consecutive patients with STEMI who were enrolled in the Magnetic Resonance Imaging In Acute STEMI (MARINA-STEMI) trial were included. The MARINA-STEMI trial is a large prospective cohort study aiming to evaluate the clinical role and prognostic validity of CMR parameters of myocardial tissue injury for patients with STEMI. The present analysis represents a predefined biomarker substudy and included patients enrolled between 2016 and 2018. In total, 150 STEMI patients initially met the inclusion criteria. Of these 150 patients, 4 developed hemodynamic deterioration after inclusion and 5 showed insufficient CMR data . This resulted in a final cohort of 141 stable patients with STEMI having appropriate CMR data. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology . All patients with clinical evidence of infection were also excluded .Inclusion criteria included a first-ever STEMI defined as having symptoms of ischemia and ST-segment elevation of at least 0.1 mV in 2 contiguous extremity leads or at least 0.2 mV in 2 contiguous precordial leads.20 a PCT threshold of 0.25 μg/L defined an increased PCT concentration. Concentrations of hs-cTnT were determined using a validated enzyme immunoassay .21A detailed medical history and comprehensive physical examination (including auscultation of the heart and lungs and measurement of temperature) were taken on admission, as well as once daily during the hospital stay. Chest radiography was conducted for all patients within 24 hours after the intervention. Biochemical measurements of inflammatory markers high-sensitivity cardiac troponin T (hs-cTnT) and creatinine were performed serially on day 1 and day 2 after primary percutaneous coronary intervention. Analyses of PCT and hs-CRP were conducted using the Cobas 8000 Modular Analyzer (Roche Diagnostics). The functional sensitivity of the PCT assay was 0.06 μg/L. Based on previous recommendations for the use of antibiotics in outpatient and emergency department settings,22 In brief, left ventricular dimensions and function were determined on short-axis cine images . The accompanying standard software  was used for postprocessing. For myocardial damage evaluation, late gadolinium enhancement images were acquired 15 minutes after administration of a bolus of contrast agent  using an electrocardiography-triggered phase-sensitive inversion recovery sequence.23 Consistent with previous reports, hyperenhancement was defined by a threshold of 5 SDs higher than the signal intensity of remote myocardium in the opposite left ventricular myocardial segment.25 Infarct size (IS) was presented as a percentage of the entire left ventricular myocardial mass. Microvascular obstruction (MVO) was defined as an area of “hypoenhancement” within the infarcted territory.26 Both the presence and extent  of MVO was ascertained. The presence of intramyocardial hemorrhage (IMH) was evaluated using T2* mapping as described in detail previously.27 The T2* data were not available in 6 patients owing to poor image quality. Experienced observers (C.T. and A.M.), blinded to all clinical data, conducted the CMR measurements and analyses.All CMR examinations were conducted using a 1.5-T Magnetom Avanto scanner (Siemens) 4 days following infarction . The standardized imaging protocol and image postprocessing used by members of our research group was applied.2 test. Associations of continuous variables (biomarkers) with a binary dependent variable (IMH) were assessed by logistic regression analysis. All tests were 2-sided, and P < .05 was defined as significant for all statistical tests.The software SPSS, version 25.0 (IBM), and MedCalc Statistical Software, version 15.8, were used for statistical analyses. Continuous variables are presented as medians with the corresponding IQRs, and categorical variables are expressed as a number with the corresponding percentage. Correlations between continuous variables were assessed using the Spearman ρ test. The correlations of PCT with IS and of PCT with MVO are illustrated using scatter plots . The difIn the present analysis, 141 patients with STEMI  with a total ischemia time of 183 minutes  were included. The baseline demographic and clinical characteristics of the patients, including cardiovascular risk factors, angiographic findings, biochemical markers, and CMR parameters, are provided in 9/L, multiply by 0.001).Median concentrations of PCT were 0.07 μg/L  24 hours after intervention and 0.07 μg/L  at 48 hours. Of 141 patients, at 24 hours, 41 patients (29%) showed a PCT concentration below the functional sensitivity cutoff of 0.06 μg/L. At 48 hours, 47 patients (33%) had PCT concentrations less than 0.06 μg/L. At 24 hours, 42 patients (30%) had a PCT concentration of 0.10 μg/L or higher, and at 48 hours, 30 patients (21%) had a PCT concentration of 0.10 μg/L or higher. A PCT concentration of 0.25 μg/L or higher was detected in 7 patients (5%) at 24 hours and in 3 patients (2%) at 48 hours. The median hs-CRP level increased from 1.63 mg/dL  at 24 hours to 2.88 mg/dL  at 48 hours , whereas the median WBC count decreased from 10 800 cells/μL  to 8800 cells/μL (7700-10 400 cells/μL)  or with MVO . The correlations of PCT levels with IS and with MVO are further illustrated in The correlations of inflammatory markers and hs-cTnT levels with IS and MVO extent are given in P < .001 for all), whereas PCT concentrations were not significantly associated with IS at 24 hours  or at 48 hours .The median IS of the study cohort was 15% . Differences in baseline characteristics between patients with IS less than 15% and patients with IS 15% or higher are presented in P < .001]) and hs-cTnT  and higher WBC counts  were detected. However, PCT concentrations were not significantly different for patients with MVO 0.4% or higher  compared with patients with MVO lower than 0.4% . The concentrations of the biomarkers based on MVO extent are given in the eTable in the With the use of CMR imaging, 81 patients (57%) displayed MVO, and the median MVO was 0.4% . For patients with MVO 0.4% or higher, significantly higher concentrations of hs-CRP , WBC count  and hs-cTnT levels . By contrast, PCT did not differ significantly between patients with or without IMH . The associations of inflammatory biomarkers with IMH as determined by logistic regression analyses are presented in Of 135 patients with T2* data, 44 patients (33%) displayed IMH. Compared with patients without IMH, those with IMH showed significantly higher concentrations of hs-CRP  whereas hs-CRP levels and WBC counts serially measured after STEMI showed significant associations with IS and with MVO, (2) PCT concentrations showed no significant association with the extent of myocardial or microvascular damage; (3) indeed, in contrast to hs-CRP and WBCs, no detectable release of PCT into the circulation was observed in the acute setting of STEMI. These data confirm and extend the knowledge base of previous studies because here we highlight that in stable patients with STEMI, circulating PCT concentrations were unassociated with myocardial tissue injury as directly depicted by multiparametric CMR imaging. Accordingly, there is a potential for PCT to be used as a necrosis-independent clinical biomarker to detect concomitant infection and guide antibiotic therapies for patients with STEMI. However, future studies must be conducted to confirm this hypothesis by including patients with STEMI who also manifest infection.28 However, the commonly used inflammatory biomarkers, including hs-CRP and WBCs, are not only released in the setting of infections but also represent nonspecific markers of inflammation in general.29 Hence, in clinical scenarios of aseptic inflammation, the usefulness of inflammatory biomarkers to identify concomitant infectious diseases is limited. Acute myocardial infarction represents a clinical scenario of systemic inflammatory activation in response to myocardial injury.2 Indeed, several previous studies have shown a significant increase in circulating levels of hs-CRP and WBCs in acute infarctions.6 Furthermore, hs-CRP levels and WBC counts have been correlated with the extent of myocardial and microvascular damage in patients with STEMI,6 which is consistent with the results of the present analyses.Inflammatory markers are of crucial importance for the detection of infectious disease as well as for accurate therapeutic decision-making in everyday clinical practice.9 The BACH trial by Maisel et al,11 which included more than 1600 patients who presented to the emergency department with dyspnea, showed that in the subgroup of patients with acute heart failure, the use of PCT levels was associated with an increase in accuracy for diagnosing coexisting pneumonia and that a PCT-guided strategy may improve antibiotic therapy decision-making. Based on those data, the latest European guidelines recommend PCT assessment for differential diagnosis and the use of antibiotics in acute heart failure.12 However, for patients with acute myocardial infarction, in which ischemic myocardial injury and the associated inflammatory response might influence PCT release and thus bias the validity of PCT to diagnose coexisting infections, the role of PCT remained unclear. Existing literature on this issue is scarce and inconclusive.8 In a study by Vitkon-Barkay et al,8 230 patients with acute myocardial infarction were evaluated by infectious diseases specialists blinded to the PCT results. Their findings indicated that the use of PCT level outperformed the use of the CRP level or WBC count in detecting coexisting infections. Explaining the superior discriminative power of PCT levels over CRP levels and WBC counts, earlier data have suggested that uncomplicated myocardial infarction does not lead to an increase in PCT levels.30 By contrast, other previous reports state that myocardial infarction per se is associated with a significant release of PCT.32 Moreover, PCT was proposed as a sensitive marker of myocardial damage as well as being associated with left ventricular remodeling and worse clinical outcome following infarction.32 Taken together, these limited and controversial previous data cannot clarify the clinical significance of PCT in the setting of acute myocardial infarction. In particular, the fundamental question in this context, namely, whether cardiac damage affects circulating PCT levels, could not be answered by previous studies owing to a lack of suitable methods for adequate assessment and quantification of myocardial injury. The present investigation used comprehensive CMR imaging, which is the in vivo method of choice for the evaluation of myocardial and microvascular injury in acute myocardial infarction,33 to find that circulating PCT concentrations were not associated with the damaged myocardium in acute STEMI. Indeed, neither IS nor extent of MVO showed significant associations with serum PCT levels. In addition, the vast majority (95%) of the included patients with STEMI patients had a PCT concentration lower than 0.25 μg/L, emphasizing that myocardial tissue injury due to acute STEMI by itself is not associated with clinically relevant levels of PCT release. These crucial data suggest that in acute STEMI treated with primary percutaneous coronary intervention, PCT does not act as an unspecific biomarker (such as hs-CRP or WBCs) that is involved in the general inflammatory response reaction following infarction. Consequently, PCT provides great clinical potential to identify coexisting infections and facilitate antibiotic treatment decisions for patients with acute STEMI. This hypothesis warrants prospective evaluation in appropriately designed clinical trials.The precursor molecule of the peptide hormone calcitonin, PCT, has been revealed as a valuable biomarker for the detection of bacterial infections and for the guidance of antibiotic treatments in different patient populations.34 A previous study revealed that in contrast to patients with stable infarction, patients with cardiogenic shock show a clinically relevant increase in PCT concentration despite the absence of infection,14 highlighting that in the clinical context of PCT level interpretation, stable and critically ill cardiac patients need to be differentiated. The mechanisms explaining the systemic PCT release in patients with cardiogenic shock are incompletely understood; however, bacterial endotoxin exposure due to bowel wall congestion, ischemia, or both has been suggested as a possible underlying pathophysiological link.35 This association between PCT and hemodynamic instability may also provide a plausible explanation for the significant increase in PCT levels detected by previous analyses, including unselected patients experiencing acute coronary syndrome.32 Indeed, the study by Kafkas et al32 showed a significant association of PCT with Killip class, however, not with enzymatic infarct severity.We included stable patients with STEMI having Killip class I or II in the present analysis. Accordingly, our findings do not apply to hemodynamically unstable patients with STEMI although they represent only a minority of all patients with STEMI.32 PCT measurements in the present study were performed in that same time range. We, therefore, cannot provide information concerning PCT levels and dynamics in the subacute or chronic phase that follows STEMI.On the basis of prior studies in which a significant PCT level increase was detected in the first 24 to 48 hours after infarction,Finally, because the present study aimed to assess the association between PCT and myocardial damage per se, patients with STEMI and infection were excluded. Hence, the promising clinical role of PCT for patients with STEMI and infection and the usefulness of PCT-guided therapeutic approaches remain to be clarified by future studies.For patients with STEMI treated with percutaneous coronary intervention, hs-CRP levels and WBC counts but not PCT concentrations were associated with the degree of myocardial or microvascular injury as determined by comprehensive CMR imaging. Furthermore, in contrast to hs-CRP level and WBC count, no clinically relevant increase in serum PCT level was detected in the acute setting of STEMI. These data indicated that PCT remained unassociated with the processes of myocardial tissue injury in acute STEMI, suggesting that PCT may be a promising biomarker in detecting, or excluding, concomitant bacterial infection, which can help to guide therapeutic antibiotic decision-making for these patients. Nonetheless, further validation in randomized clinical trials is required.


We sought to investigate the prevalence, functional characteristics, and clinical significance of right ventricular (RV) involvement in patients with hypertrophic cardiomyopathy (HCM). A total of 256 patients with HCM who underwent both cardiac magnetic resonance (CMR) imaging and transthoracic echocardiography within 6 months of each other were retrospectively analysed. RV involvement was defined as an increased RV wall thickness ≥ 7 mm on CMR in the segments of the RV free wall. Primary outcomes were defined as the composite of all-cause death, heart transplantation, and unplanned cardiovascular admission. Thirty-seven (14.4%) patients showed RV involvement. Patients with RV involvement showed a significantly higher left ventricular (LV) maximal wall thickness and left atrial volume index. Multivariate Cox model revealed that RV involvement was independently associated with primary outcomes . In a subgroup analysis of patients with speckle tracking echocardiography (n = 190), those with RV involvement had significantly more impaired RV strain, which was independently associated with primary outcomes. RV involvement in patients with HCM correlated with more advanced LV structure and biventricular dysfunction, suggesting an indicator of severe HCM. RV involvement and impaired RV strain have a prognostic value related to clinical adverse events in patients with HCM. Maximal left ventricular wall thickness, left ventricular outflow tract (LVOT) obstruction, LV apical aneurysm, and late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging are suggested risk factors for sudden cardiac death (SCD) in HCM5 and clinical/subclinical RV dysfunction in patients with HCM7. Although these results suggest that the presence or absence of RV involvement may be important for the current disease status and clinical prognosis in patients with HCM, the prevalence, structural and functional characteristics, and prognostic significance of RV involvement in patients with HCM are still ambiguous. Therefore, the objectives of this study were to identify the prevalence of RV involvement in patients with HCM using CMR imaging and to investigate whether RV involvement and RV dysfunction have prognostic significance in determining clinical outcomes.On the other hand, the right ventricle (RV) relatively has long been neglected, perhaps because RV is not considered a major risk factor for SCD related to HCM, and it is difficult to measure RV thickness accurately by transthoracic echocardiography (TTE). A few studies have recently reported the prevalence and clinical significance of RV involvement using CMR imagingAmong the 256 patients with HCM, 37 14.4%) with RV involvement were identified by CMR. Substantial interobserver agreement was achieved for the evaluation of RV involvement . Baseline characteristics of the study population are presented in Table 4.4% withDuring the follow-up period, there were 33 primary outcomes, including all-cause death (n = 3), heart transplantation n = 1), and unplanned cardiovascular admission n = 29). Two patients had sudden cardiac death, and one patient died from lung cancer. Among the 29 cardiovascular hospitalizations, 10 were admitted for heart failure, 5 had ongoing and recurrent angina, 5 were admitted for atrial tachyarrhythmia, 2 were admitted for ventricular tachyarrhythmia, 4 had a sudden collapse, and 3 had stroke. Table 9. Two pa, and unpIn a subgroup analysis, 190 patients with speckle tracking echocardiography were analysed separately to compare RV mechanical function and its association with RV involvement. Supplementary Table The main findings of the study were as follows: (1) RV involvement in patients with HCM is common (14.4%); (2) patients with RV involvement showed more advanced biventricular dysfunction, suggesting an indicator of severe HCM; (3) RV involvement and impaired RV longitudinal strain in patients with HCM showed prognostic values related to clinical adverse events; and (4) impaired RV GLS and RV free wall LS were more frequently detected in patients with RV involvement than in those without.9, and only a few studies described the prevalence of RV involvement in HCM. In an early study, using transthoracic echocardiography, RV hypertrophy was reported in 44% of patients with HCM10. Studies using CMR demonstrated a prevalence ranging from 1.3 to 30%, depending on the criteria of RV involvement11. Our study showed a prevalence of 14.4%, with the RVMWT ≥ 7 mm on CMR. The varied reported prevalence of RV involvement in HCM is postulated to be a consequence of the different criteria of RV involvement and modalities measured.Many previous studies on RV involvement in HCM were sporadic case reports of severe RV hypertrophy and RV outflow tract obstruction12. LVOT obstruction, diastolic dysfunction, and atrial tachyarrhythmia were considered risk factors related to heart failure14. Consistent with prior studies, our results showed that diastolic dysfunction, AF, unexplained syncope, and reduced LVEF were related to adverse clinical events but LVOT obstruction was not. We assumed that patients with high risk of SCD were managed with optimal medical therapy, ICD implantation, or septal myectomy, which may be responsible for these results. The association between RV involvement and poor prognosis indicated that patients with RV involvement had more advanced HCM and presented with significantly higher LAVI, higher E/e’, lower LVEF, and more impaired LV GLS in this study. LAVI and E/e’ reflect the LV end-diastolic pressure and long-term effects of elevated LV filling pressures; they are well correlated with LV diastolic burden and poor prognosis in patients with HCM17. Moreover, abnormal LV GLS has been shown to occur in HCM and is associated with a worse prognosis, even in patients with a normal LV ejection fraction18. Therefore, it is reasonable to assume that RV involvement is associated with severe systolic and diastolic dysfunction in HCM, which may play a role in determining clinical outcomes.Classically, a family history of HCM-related SCD, unexplained syncope, multiple and repetitive non-sustained ventricular tachycardia, massive LVH, LV apical aneurysm or burn out stage (EF < 50%), and extensive LGE were suggested risk factors for SCD in HCM20. Recently, Wu et al. showed that RV hypertrophy exhibits more reduced RV GLS, supported exercise capacity, and can independently predict exercise intolerance in patients with HCM6. Xiang Li et al. also presented that impaired RV myocardial strain was more obvious in the presence of RVH and LGE in RV21. Our results supported these prior studies and showed both structural abnormality and functional impairment of RV using CMR imaging in a relatively large study population. Patients with RV involvement had more impaired RV mechanical function, and both RV involvement and impaired RV dysfunction were independently associated with clinical outcomes. Therefore, we assumed that RV involvement implies more severe myocardial dysfunction, not only of LV but also of RV.Prior literature regarding RV in HCM has described RV structural features and dysfunction separately. Some studies revealed that the structural feature, RV hypertrophy, is associated with poor clinical outcomes. In addition, RV dysfunction is frequently observed in patients with HCM and is associated with an increased likelihood of adverse clinical eventInterestingly, our study showed a large discrepancy in RV thickness as determined using transthoracic echocardiography and RVMWT on CMR imaging. We assumed this is due to the differing measurement sites and methods. In transthoracic echocardiography, RV thickness was calculated as the diameter of the RV free wall below the tricuspid annulus at a distance approximating the length of the anterior tricuspid leaflet, as recommended in the current guidelines. In contrast, RVMWT on CMR imaging measured the greatest diameter of the segments of the RV free wall, including the basal, mid, and apical levels of the RV free wall, in this study. Considering the methodological difficulty in measuring RV thickness using echocardiography, impaired RV strain is a more meaningful predictor of the structural change in RV and clinically adverse events in patients with HCM.4. Nagata Y. et al. defined RV hypertrophy as RV maximal wall thickness > 5 mm; the average maximal RV thickness was 4.7 ± 2.3 mm in the total patient population and 7.8 ± 1.8 mm in patients with RV hypertrophy in their study. Based on these previous studies, we defined RV involvement as the maximum RV wall thickness of ≥ 7 mm. We presumed that this criterion is reasonable to minimize the possibility of false-positive and false-negative findings of RV involvement. Further large population and prospective studies are required to standardize the diagnostic criteria of RV involvement in HCM. Third, we could not include data of genetic testing for HCM and follow-up CMR due to the retrospective nature of the study. Information regarding genetic mutation and serial change in the RV phenotype orn CMR could provide more concomitant evidence of the mechanism of RV involvement.This study has several limitations. First, the retrospective study design investigated a single-centre registry; thus, there is a possibility of selection bias. Considering LGE was observed in > 90% of patients in our study population, it is suggested that many patients with advanced HCM were selected in this study. Second, the criteria of RV involvement can be deemed arbitrary because standard criteria for RV involvement in HCM were not established. Maron MS. et al. measured RV thickness using automatic software at any site within the RV wall and reported an average RV thickness of 7 ± 2 mm in patients with HCMIn conclusion, RV involvement in patients with HCM is common. Patients with RV involvement showed more severe myocardial dysfunction of the LV and RV, suggesting that it can be considered an indicator of severe HCM. Furthermore, RV involvement and impaired RV longitudinal strain in HCM showed clinical significance related to adverse clinical outcomes.A total of 346 patients who underwent both cardiac magnetic resonance (CMR) imaging and transthoracic echocardiography within 6 months of each other were screened in Yonsei University Cardiovascular Hospital in the Republic of Korea. Patients who had undergone septal myectomy, had combined heart disease leading to RV hypertrophy, or had significant pulmonary hypertension defined as RV systolic pressure (RVSP) > 50 mmHg were excluded. Finally, 256 patients were included for the analysis. The study was approved by the Institutional Review Board of the Yonsei University Health System , and it complied with the ethical principles of the Declaration of Helsinki. The need for informed consent was waived by the local ethics committee of the Yonsei University Health System.2. LV and RV LGE images were acquired 10 min after contrast injection (0.2 mmol/kg of a gadolinium-based contrast media) using a magnitude- and phase-sensitive inversion-recovery-prepared TrueFISP sequence, with the inversion time adjusted to null, thus representing the normal myocardium. Two expert radiologists, blinded to patients’ clinical data, analysed CMR images. All image analyses were performed using semi-automatic segmentation in the software . Additionally, the left and right ventricular volumes and ejection fractions (EFs) were measured from the cine images using semi-automatic segmentation in the software . LV (LVMWT) and RV (RVMWT) maximal wall thickness were measured as the greatest dimension at end-diastole measured manually in short-axis slices. RVMWT was measured in the segments of the RV free wall, as shown in Fig. All patients underwent CMR with a 3-T clinical scanner . Electrocardiogram gated cine images were acquired in the short-axis views using retrospective echocardiography-gated balanced steady-state free precession true fast imaging with steady-state precession (TrueFISP) sequence with the following parameters: repetition time (TR), 3.3 ms; echo time (TE), 1.44 ms; flip angle, 50°, 25 phases; slice thickness, 8 mm; slice gap, 8 mm; acquisition matrix, 216 × 256 pixels; and field of view, 337 × 400 mm23. LVMWT was determined at end-diastole from the parasternal short-axis view. RV wall thickness was measured at end-diastole below the tricuspid annulus at a distance approximating the length of the anterior tricuspid leaflet24. Obstruction of the LV outflow was defined as the peak pressure gradient of the LV outflow tract ≥ 30 mmHg on continuous-wave Doppler echocardiography at rest or by Valsalva manoeuvre. In a subgroup analysis, LV and RV mechanical function were evaluated in 190 patients using speckle tracking echocardiography (STE). LV and RV strain were assessed via STE analysis performed offline using customized software . Three consecutive cardiac cycles were recorded and averaged, and frame rates were set to 60–80 frames per second. LV global longitudinal strain (GLS) was obtained from the average of three standard apical views. RV GLS was defined as the average of the RV free wall and septal segments measured in standard focused RV view or apical four-chamber view using the software designed for LV measurements and adapted for the RV. RV free wall longitudinal strain (LS) was defined as the arithmetical average of three segments  of the RV free wall . A cardiovascular hospitalization was defined as an unplanned cardiovascular event requiring admission for heart failure, angina, atrial or ventricular tachyarrhythmia, sudden collapse, stroke, or myocardial infarction. The clinical events were analysed by two researchers independently, and the occurrence of renal outcomes was decided with the agreement of both researchers.26. All tests were two-sided, and statistical significance was defined as p < 0.05. All statistical analyses were performed with R statistical software .All continuous data are presented as mean ± standard deviation, and categorical data are expressed as numbers and percentages for each group. Interobserver agreement for the presence of RV involvement was calculated using Cohen’s kappa value. The significance of RV involvement on primary outcomes was analysed with multivariate Cox proportional hazard models and Kaplan–Meier curves. Correlation between RVMWT and parameters of LV and RV strain was calculated using Pearson’s correlation method. Diagnostic incremental values of the echocardiographic parameters identifying RV involvement were estimated using receiver operating characteristic (ROC) curves with corresponding areas under the curve (AUC). Comparisons between the AUC were conducted using DeLong's testSupplementary Table 1.


Takotsubo cardiomyopathy (TTC), also known as broken heart syndrome, stress cardiomyopathy (SCM), or apical ballooning syndrome, is a non-ischemic cardiac disease with an initial clinical presentation that is very similar to acute coronary syndrome (ACS). Ventricular arrhythmias (VAs) contribute significantly to an increase in the rates of death in patients with TTC, especially during the acute phase, in which patients with TTC are more susceptible to develop life-threatening arrhythmias (LTA) such as ventricular tachycardia (VT), ventricular fibrillation (VF), torsades de pointes (TdP), and sudden cardiac death (SCD). However, the pathophysiology of TTC and how VA occurs are still a mystery. We aim to review previous literature and discuss the possible mechanisms of VA in TTC patients.VA usually complicates the acute phase of the disease and worsens the long-term prognosis. Alterations of repolarization  indicate a high risk of arrhythmic events . Catecholamine effect on myocardial cells and myocardial edema can create a substrate for the development of VA. Some of the most commonly proposed mechanisms for the development of VA in patients with TTC are coronary vasospasm, myocardial stunning due to catecholamines, re-entry, and triggered activity. Further prospective studies, including a more significant number of patients, are required to understand the disease's pathophysiology better and improve LTA management in patients with TTC. Takotsubo cardiomyopathy (TTC), also known as broken heart syndrome, stress cardiomyopathy (SCM), or apical ballooning syndrome, is a type of non-ischemic cardiac disease characterized by an acute dysfunction of the myocardial tissue primarily affecting the left ventricle. However, the right ventricle can also be affected . TTC recVentricular arrhythmic events associated with TTC come from a very long time. However, clinically relevant information was limited to only a few case reports or small observational studies, resulting in underestimating VA actual burden in patients with TTC . During Long QT syndrome and torsades de pointesECG alterations are one of the TTC hallmarks, and one of the most significant changes is a prolongation of the QT interval, which usually develops in the first two days after the initial symptoms. A QTc greater than 500 ms is a significant risk factor for VA, particularly VF and TdP .Ahn et al.  describeSimilarities exist across all these patients in terms of ECG findings and physical exam. According to the literature, they were predominantly women after menopause, and after a typical stressful factor, either emotional or physical (septoplasty).Ventricular tachycardia, ventricular fibrillation, and other ventricular arrhythmias Cakıcı, Cetin, Polat, and Su Ner described a 67-year-old female with dizziness and palpitations after emotional stress, who presented with episodes of VT on ECG. While QTc was 680 ms , TdP didWatanabe et al. described a 65-year-old man with dyspnea and no recorded stressful factors. ECG showed TdP-type VT, which was terminated by cardio-pulmonary resuscitation without defibrillation. QTc was 693 ms during the episode, and six months after discharge, it returned to the standard value . RotondiWakatsuki, Asano, Mase, Kurata, and Suzuki  reportedTTC tends to occur more frequently in postmenopausal women, especially after a recent stressful episode ,13,16,19Coronary vasospasmTTC usually has an overall long-term good prognosis with recovery in a matter of weeks . HoweverAbnormal repolarizationStreitner et al. studied the relationship between abnormal repolarization and fatal arrhythmias in 73 TTC patients at a medical center and collaborated with previously published cases from other authors. They analyzed the QTc values (corrected for heart rate) and measured T waves to assess repolarization parameters. They concluded that patients with malignant arrhythmias have, in general, lower ejection fraction than the average. They observed that the QTc showed increased values from day one to day three, and patients who developed TdP had slower heart rates . We alsoLife-threatening arrhythmias, J wave, and fragmented QRS in Takotsubo cardiomyopathyMadias et al. reported an 8% association between VA and TTC, and thus, they suggested to include TTC as one cause of acquired LQTS and a more significant risk factor for TdP . ShimizuJesel et al.  studied Common pathophysiological mechanisms of ventricular arrhythmias in Takotsubo cardiomyopathyRe-entry is the most common VA mechanism, especially in the presence of VT . Based oA triggered activity can occur due to microvascular damage provoking repolarization anomalies. Furthermore, early afterdepolarization-induced triggered activity combined with excessive catecholamine activity could explain VT and TdP . These eTakotsubo cardiomyopathy and anorexia nervosa as a substrate for ventricular arrhythmiasNot much information is available about this topic in the literature. Ohwada et al. described the first three cases of an association between anorexia nervosa (AN) and TTC . Only onOur review helped us summarize the most current and most accepted mechanisms that cause VA in patients with TTC Figure  and has LimitationsOne limitation present in this review is that we only included studies from the year 2000 to present and full-text access, possibly missing important information. Another is that we did not conduct a quality assessment.Understanding the pathogenesis of TTC and its complications is a well-known challenge to clinicians around the world. In this context, VAs are present in many patients with TTC, and understanding how these two entities are related is very important. Their development's underlying pathophysiological mechanisms could help identify people at high risk of more severe cardiac events. This review aimed to summarize the most commonly proposed mechanisms provoking VA in patients affected by TTC and the effect on long-term prognosis in these patients. VA usually occurs in the acute phase of the disease and worsens the long-term prognosis of the disease. Depolarization anomalies such as T wave inversion and prolongation of QTc present in the early stage indicate a high risk of progression to severe and deadly arrhythmic events . Catecholamine effect on myocardial cells and myocardial edema can create a substrate for the development of VA. Re-entry is the most common mechanism, but some studies argue it because of the lack of scar tissue in imaging studies. The latter fact points to triggered activity as one of the more accepted and probable theories; however, the exact mechanism remains uncertain.In this review, we summarized all the possible mechanisms leading to VA and raised the awareness of a relationship between TTC and complications like VA. Also, we noticed AN could provide a substrate for the development of VA in patients with TTC, possibly due to a lack of protective effect of estrogen. Information about this topic is limited, and more studies are needed to clarify this relationship. The challenge for future scientists is to conduct more prospective studies and clinical trials assessing electrophysiological parameters in a more significant number of patients to stratify the risk and improve the prevention and management of LTA in TTC.


When a cardiologist is asked to evaluate the cardiac toxic effects of chemotherapy, he/she can use several tools: ECG, echocardiography, coronary angiography, ventriculography, and cardiac MRI. Of all these, the fastest and easiest to use is the ECG, which can provide information on the occurrence of cardiac toxic effects and can show early signs of subclinical cardiac damage. These warning signs are the most desired to be recognized by the cardiologist, because the dose of chemotherapeutics can be adjusted so that the clinical side effects do not occur, or the therapy can be stopped in time, before irreversible side effects. This review addresses the problem of early detection of cardiotoxicity in adult and pediatric cancer treatment, by using simple ECG recordings. In the last twenty years, the survival and life expectancy of adults and children with cancer have risen significantly, mainly due to the new chemotherapy. However, chemotherapeutic agents have secondary and adverse effects, some of them dreadful. Their early recognition can prevent the development of associated sometimes fatal pathologies. Monitoring the cardiac side effects of chemotherapy is feasible generally using echocardiography, radionuclide ventriculography, dosing cardiac biomarkers  such as By the effect of direct damage to the myocardial cell with the release of natriuretic peptides BNP, NT-proBNP, and troponin, with the development of ischemic or nonischemic dilated cardiomyopathy, increased left ventricular filling pressures, and subsequently left atrial and fibrillationCoronary spasm with the induction of myocardial ischemia or a direct effect of the chemotherapeutic on coronary vascularization with secondary ischemia, with or without myocardial necrosis and arrhythmogenesis by the formation of abnormal reentry circuits or abnormal depolarizationsAction at the level of ion channels with impaired ventricular depolarization or repolarization, prolongation of the QT interval, and induction of polymorphic ventricular tachycardia (torsade de pointes)Direct action on the conduction system: sinus node, atrioventricular node, His, left or right branch, respectively, and Purkinje networkThere are several mechanisms by which chemotherapy can become proarrhythmogenic :By the One of the most common side effects of chemotherapy that can be detected on the ECG in 12 leads is sinus bradycardia. Taxanes and angiogenesis inhibitors  can cause sinus bradycardia, most likely through a direct action on the sinus node. Nevertheless, taxanes can have effects at other levels of the atrioventricular conduction system. Thus, paclitaxel can affect the infrahisian conduction system (after the bifurcation of the His) and lead to the appearance of the right or left branch block. If the lesion is located at the suprahisan level, atrioventricular blocks of varying degrees, from 1 to 3, may occur. The conduction disorders generally occur within 4 hours of initiating the paclitaxel infusion and disappear after stopping the chemotherapeutic, usually within the first 48 hours . The mecAnother mechanism promoting cardiac arrhythmias is through myocardial ischemia  or even Anthracyclines cause atrial and ventricular arrhythmias by inducing structural cardiomyopathy associated with decreased left ventricular systolic function with altered ejection fraction. This decrease in ejection fraction leads to increased left ventricular end-diastolic pressure and increased left intra-atrial pressure and favours atrial arrhythmias such as extrasystoles, atrial tachycardia, or atrial fibrillation. On the other hand, the marked decrease of the ejection fraction may favour ventricular arrhythmias: premature ventricular contractions, ventricular tachycardia, and ventricular fibrillation.5-Fluorouracil validates its arrhythmogenic effects through coronary vasospasm and the myocardial ischemia it induces. Like 5-FU, interleukin-2 promotes arrhythmias by inducing vasospasm with consequent prolonged myocardial ischemia or myocardial inflammation (myocarditis) .2) [Anthracyclines are currently used to treat leukemias, lymphomas, breast cancer, and solid pediatric tumors. Generation I anthracyclines (daunorubicin and doxorubicin) have as a side effect the irreversible development of nonischemic dilated cardiomyopathy, and their effects are cumulated with increasing doses and duration of use (an incidence of 5-8% is observed at a cumulative dose of 450 mg/m2) .p < 0.05) [A study by Kilickap's team that involved Holter EKG monitoring for 48 hours of patients immediately after doxorubicin infusion showed a paroxysmal atrial fibrillation rate of 10.3% . However < 0.05) .p < 0.05) compared to the group without dexrazoxane [A study analyzing the effects of epirubicin on QTc interval dispersion  showed an increase in this parameter in all patients included in the research. When dexrazoxane was administered in addition to epirubicin, the dispersion of the QT interval decreased statistically (razoxane .p < 0.001), dilated left atrium over 33 cc/m2 (risk ratio: 2 (95% CI 1.3-3.1), p < 0.001), left ventricular systolic dysfunction (p < 0.001), and even cardiac amyloidosis  [p < 0.001) and also one year after the intervention . Practically, the existence of arrhythmias in post-stem cell transplant patients has been an independent predictor of mortality with a greater risk for death within a year of transplant ) [Alkylating agents are frequently used before stem or bone marrow transplantation. Several factors increase the risk of developing this melphalan-induced arrhythmia, including advanced age  3.2-7.6),  = 0.08) , 20. Bes 0.001)) .Busulfan is another chemotherapeutic belonging to the alkylating agent class. The incidence of developing atrial fibrillation was up to 6.4% when used in combination with cyclophosphamide .In conclusion, during treatment with alkylating agents, patients should be monitored for atrial fibrillation with melphalan and busulfan and also for the development of structural abnormalities that may be responsible for ventricular arrhythmias with cyclophosphamide and ifosfamide.An analysis that included over 8000 patients treated with trastuzumab reported an incidence of atrial fibrillation of 1.2% after trastuzumab use (95% CI 0.56-2.68) . On the The use of trastuzumab with paclitaxel after an anthracycline and cyclophosphamide induction regimen resulted in symptomatic heart failure in 4% of patients enrolled in the study (95% CI 0.5-13.2), and in 21% of them, a decrease in LVEF below 50% was noticed (95% CI 11.1-34.7) .Another study that evaluated the safety of administration of trastuzumab in the elderly found that of the 22 patients, only 2 had a 10% asymptomatic decrease in LVEF .p < 0.001) [More extensive studies of approximately 45,000 women with a mean age of 76.2 years showed that the 3-year incidence of cardiomyopathy or heart failure of any grade was 32.1% in the trastuzumab-only group and 41.9% in patients who also received anthracyclines compared with no adjuvant therapy  .Trastuzumab-emtansine (T-DM1), a combination used in the second line of treatment after trastuzumab, did not cause any significant cardiovascular events (including symptomatic heart failure) in the 153 patients evaluated in Krop et al.'s study .Lapatinib is a safer product than trastuzumab in that it rarely induces left ventricular dysfunction and arrhythmias .These products do not induce structural abnormalities of the myocardium but may prolong the QT interval and induce ventricular arrhythmias such as torsade de pointes.p < 0.001). It should be remembered that the risk of arrhythmia is proportional to the dose and time of treatment [Leukemia journal, the rate of occurrence of atrial fibrillation/flutter as an adverse event was reported at 4.9% [NEJM, showed similar incidences of atrial fibrillation of 6%. In 25% of the patients, it was necessary to stop the treatment, but for the rest, no intervention was needed [Ibrutinib is a Bruton tyrosine kinase inhibitor used in B-line haematological malignancies such as chronic lymphocytic leukemia and mantle cell lymphoma. A study conducted by Yun et al., published in 2017, shows an incidence of atrial fibrillation/flutter of 8.18% in patients treated with ibrutinib compared to placebo  [Cancer patients who are treated with antiarrhythmic medication for heart disease are at risk of developing drug interactions with the possibility of prolonging the QT interval. Class IA (quinidine and procainamide) and class III antiarrhythmics  prolong the QT interval by their particular mechanism of action on ion channels. On the other hand, antiemetic drugs such as ondansetron and droperidol also prolong the QT interval. Among analgesics, methadone, an opioid derivative, also prolongs the QT interval  . Commonl< 0.001) .Arsenic trioxide is known to prolong the QT interval, which is why therapy should be stopped if the interval is prolonged >500 ms. When the interval decreases to 460 ms, the treatment can be resumed. Shen et al. , Niu et Nilotinib was associated with 5 to 15 ms QT prolongation, but this prolongation was not associated with polymorphic ventricular tachycardia . On the Vorinostat has been incriminated in the prolongation of the QT interval complicated with polymorphic ventricular tachycardia in a case report published by Lynch et al. . It is ip < 0.001) and QTc dispersion  after epirubicin-based chemotherapy in non-Hodgkin lymphoma patients). Also, in the study of Nousiainen et al. [p = 0.039). Five patients (18%) developed QT dispersion exceeding 50 ms. At the same time, Liu et al. [Even though the most common side effect of anthracyclines is structural impairment of the left ventricle with decreased LV ejection fraction, to a lesser extent, anthracyclines may alter the QT interval. In the study of Galetta et al. , epirubin et al. , QTc disu et al.  showed iAs in adults, chemotherapy can have cardiac toxicity in children. But children have 2 particularities: First, their heart is constantly developing, and the structure that has been affected by chemotherapy will increase with the growth of the child's heart, so in the following years, the injured structure will become larger . Second,2. Furthermore, prolonged QT interval > 480 ms was found in approximately 14% of children. Another study by Steinherz and Steinherz [Up to 25% of children who are treated with anthracyclines may have electrocardiogram changes . These cteinherz  on 100 cteinherz  found 5%teinherz  can alsoMassin et al.  studied In a study by Mulrooney et al. , 2715 chNewer studies are trying to determine whether lower chemotherapy doses that do not induce ECG changes still remain effective for the suppression of neoplastic disease. Researchers are trying to verify if lower doses that do not cause an excessive increase in QT interval > 480 ms or that produce only benign atrial or ventricular premature beats are still effective in controlling the child's neoplastic disease. The results of the studies would further benefit children, as toxic effects might affect a developing, immature heart.Oncological treatment requires a good collaboration between the oncologist and the cardiologist. Even if new drugs increase the life expectancy of cancer patients, death may be due to a therapeutic dosing error, due to proarrhythmic side effects, or due to impaired left ventricular ejection fraction. For these reasons, some oncology clinics have hired a cardiologist who can monitor the evolution of heart function during chemotherapy by ECG, Holter ECG, and echocardiography. The cardiologist must know the limits that are acceptable for subclinical cardiac toxicity such as a mild but reasonably prolonged QT interval below 480 ms, the presence of benign arrhythmias such as atrial or ventricular premature beats, the presence of insignificant ST segment and T-wave changes, and changes in the heart axis. All of these ECG insignificant changes should not stop the child or adult from receiving a potentially life-saving therapy. When the oncology-cardiologist is not available, close collaboration with a cardiology clinic or outpatient cardiac clinic with experienced physicians in monitoring toxic effects of chemotherapy is required.


Hydrocephalus is a common neurosurgical pathology associated with high patient morbidity and systemwide healthcare costs. A significant portion of these costs are related to the failure of ventricular shunting systems. Despite decades of research and technological development, the rate of shunt failure and revision has not significantly improved. The Reflow™ Ventricular System  is a recent technological development with the potential to prolong the shunt lifespan. This system introduces a noninvasive means of flushing a shunt proximally with a controlled, repeatable pulse of cerebral spinal fluid (CSF) and of creating a new ventricular opening for occluded shunts. In this multicenter case series, we present the early clinical experiences with this device and discuss its potential. Hydrocephalus is a common neurosurgical pathology, with a disproportionate degree of associated morbidity and resource utilization. Nearly 400,000 new cases of pediatric hydrocephalus are estimated annually worldwide , and aduThese patients impose a heavy burden on healthcare systems. United States (US) hospitals discharge approximately 69,000 patients annually with a primary diagnosis of hydrocephalus, of which half undergo placement of a new shunt . A revieThese costs represent a significant economic burden, which is disproportionate to the disease incidence. A cross-sectional review of Healthcare Cost and Utilization Project Kids' Inpatient Databases showed that in 2003, hydrocephalus accounted for 0.6% of all pediatric hospital admissions but 3.1% of all pediatric hospital charges . BecauseOne recent technological development that has the potential for an impact on these economic and patient outcome statistics is the Reflow™ Ventricular System . This system introduces two novel functions to a ventricular shunt, allowing controlled retrograde flushing into the proximal catheter, as well as a “relief membrane” that can create a new intraventricular opening in a shunt with obstructed inlet holes. In this paper, we report the first experiences with this device and discuss preliminary evidence of its potential utility.This is a multicenter case series review of the first 25 consecutive patients in which the Reflow™ system has been employed at four US pediatric hospitals. Twenty-five patients were implanted with the Reflow™ device between May 2018 and November 2019. Operations were performed at Children’s Hospital of Orange County (CHOC), Boston Children’s Hospital (BCH), Medical University of South Carolina (MUSC), and Cincinnati Children’s Hospital and Medical (CCHM).Inclusion criteria involved a diagnosis of shunt-dependent hydrocephalus in both pediatric and adult patients with either a history of frequent shunt failure or clinical factors indicating a high risk of shunt obstruction, including recent infection, hemorrhage, high cerebrospinal fluid (CSF) protein counts, or chronically collapsed ventricles. Patients with active infection underwent appropriate antibiotic management with external ventricular drainage prior to the placement of the VP shunt. Infants were excluded from this study due to the possibility of skin erosion in this population given the prominent profile of the device.Baseline patient characteristics were collected, including age, sex, and etiology of hydrocephalus. Information such as preoperative CSF profile and protein count, as well as radiographic characterization of ventricular systems was not uniformly available among the participating sites. Outcomes were assessed based on clinical data including presentation with concern for shunt failure, use of the flushing system, as well as any complications that may be attributed to the device.The Reflow™ systemThe Reflow™ system introduces two new components to a traditional shunt system: a retrograde flushing device and a “relief-membrane” on the proximal catheter that can open in the setting of occlusion. This system has undergone rigorous preclinical testing and received US Food and Drug Administration (FDA) clearance. It received CE marking for the treatment of hydrocephalus in 2017.The Reflow™ flusher is a single component consisting of a flushing valve and a flushing dome. It does not itself regulate CSF flow but is designed to be connected in series with all standard shunt valves. During passive flow, fluid from the ventricular catheter flows without restriction through the passive flow channel of the flusher. During flushing, the passive channel is manually occluded to create a temporary one-way flow into the ventricular catheter. After a controlled and limited pulse of fluid is sent from the flusher and the dome is released, the flush dome refills with CSF from the ventricular catheter and resumes free-flowing through the passive flow channel Figure . This inThe second novel introduction in this system is the “relief membrane” on the proximal catheter. This is a membrane-bound side port on the catheter located just above the intraventricular inlet holes Figure , which wTable Seven individual patients presented during our observation period with symptoms concerning for shunt malfunction. Three of these improved with flushing of their reflow devices, avoiding additional invasive workups such as shunt taps or operative revisions. One was a six-year-old with spina bifida who returned with profound irritability 10 days after the placement of a new shunt with a Reflow™ system. The Reflow™ dome was pumped once by the physician and after a few hours of observation, the symptoms resolved. Another was a 16-year-old with congenital hydrocephalus with a history of frequent shunt failure who presented with symptoms of shunt failure that improved after being pumped once.The third was an 18-year-old with obstructive hydrocephalus treated with the Reflow™ system who presented with headache. The shunt was interrogated with the Shunt Check system. This system, based on the concept of thermal dilution to assess relative changes in temperature of skin overlying shunt tubing distal to an icepack compared to surrounding skin, uses a change in temperature of 0.2 degrees Celsius as a cut-off to confirm flow . On initFive operative revisions were performed in four patients during this period. One patient was seen to have debris in the proximal catheter on initial revision and was presumed to be a failure due to proximal obstruction. A second Reflow device was, therefore, placed, however, his symptoms did not improve and additional workup determined intra-abdominal adhesions causing elevated intra-abdominal pressure to be responsible. He improved after a second revision with a different terminal site. Another patient was seen to have debris in the proximal catheter and improved after operative revision, indicating a proximal obstruction that did not respond to flushing. Other causes for revision included distal tubing disconnection due to trauma and one case of surgical site infection.Of all patients presenting with symptoms of shunt failure, three out of seven (43%) improved with flushing. Of the four patients ultimately concluded to have a proximal obstruction, either evidenced by a revision or presumed due to symptomatic improvement, three out of four (75%) improved with flushing. Of note, however, none of these cases have a definitive demonstration of the resolution of ventriculomegaly with pre and post-flushing imaging.Mechanical failure of ventricular shunts has been recognized as a significant problem since their introduction in the 1950s, and despite technological advances, there has not been a significant decrease in the rate of shunt failure since that time . FailureThe Reflow™ Ventricular System  is a recent development in shunt technology with the potential to prolong shunt lifespan and decrease revision rate. The Reflow™ flusher offers the unique ability to non-invasively flush a shunt proximally into the ventricle. In the setting of shunt malfunction, this introduces a mechanism to clear the proximal shunt and the inlet holes of debris, which may be contributing to obstruction. Theoretically, patients with factors associated with higher rates of shunt failure, such as trauma, infection, and hemorrhage, which cause elevated CSF protein , or slitIn this series, we present our experiences with the first clinical applications of this technology. We have seen that this system, which is designed to be connected in series with any commercially available shunt valve, does not impair the normal functioning of these valves. While it is possible that the added tortuosity of the flusher may theoretically increase system resistance to CSF flow, we did not see evidence that this had a clinically significant effect. Several of our patients did require shunt revision, however, in all cases, this was due to complications unrelated to the device itself. We did see one case of shunt malfunction ultimately attributable to proximal shunt obstruction, which did not respond to proximal flushing.While we have yet to see a definitive demonstration of shunt rescue by means of flushing open inlet holes or opening of the “rescue membrane,” the three cases discussed are suggestive of the reestablishment of CSF flow through the shunt. These patients all presented with symptoms of shunt failure, which resolved after flushing of their shunts, preventing the need for additional evaluation methods or shunt revision. The demonstration of improvement in shunt flow as measured by thermodilution in one of these patients is the strongest evidence for shunt rescue at this time. The ShuntCheck® System , which measures differential temperature changes in the skin overlying a cooled shunt catheter compared to passive heat conduction in the surrounding skin, has been shown to be a sensitive and specific measure of CSF flow .There are multiple limitations that prevent definitive conclusions from this work. We have yet to see definitive proof of the flushing system and “rescue membrane” salvaging an obstructed shunt, as this would entail imaging of ventriculomegaly, which resolved after flushing. Additionally, this case series is small in sample size and poorly powered, which limits statistical analysis. The follow-up period is also quite short, and long-term outcomes remain to be evaluated. It remains unknown how long a salvaged shunt may remain viable if the primary problem is a continual buildup of debris, which may then obstruct the newly created opening. While no obstruction of the loop through the reflow flushing device was seen here, it is a theoretical possibility that this increased surface area and tortuosity of this CSF pathway may increase the risk of protein buildup and obstruction at this site, and long-term follow-up will be needed to evaluate this.After half a century of slow progress in the treatment for hydrocephalus, reduction in shunt failure remains the foremost goal of research endeavors. The newly introduced Reflow™ Ventricular System has the theoretical potential to prolong shunt lifespan and decrease the rate of shunt revision, thereby reducing patient morbidity and system-wide healthcare costs. In this initial series, we have demonstrated the use of this device in clinical practice. We present preliminary evidence of the potential of the flushing mechanism to non-invasively salvage proximally obstructed shunt catheters. Many questions remained to be answered, and long-term assessment and clinical studies of these patients will be necessary to show what potential impact this new system may have on the comprehensive management of hydrocephalus.


In clinical practice, combined heart and liver dysfunctions coexist in the setting of the main heart and liver diseases because of complex cardiohepatic interactions. It is becoming increasingly crucial to identify these interactions between heart and liver in order to ensure an effective management of patients with heart or liver disease to provide an improvement in overall prognosis and therapy. In this review, we aim to summarize the cross-talk between heart and liver in the setting of the main pathologic conditions affecting these organs. Accordingly, we present the clinical manifestation, biochemical profiles, and histological findings of cardiogenic ischemic hepatitis and congestive hepatopathy due to acute and chronic heart failure, respectively. In addition, we discuss the main features of cardiac dysfunction in the setting of liver cirrhosis, nonalcoholic fatty liver disease, and those following liver transplantation. For many years, a mutual interaction between the heart and the liver has been established. Avicenna first pointed out the interactive effects between these two organs in his famous book titled as “Canon” (The Law). This interaction was described as dominance of the “heart warmth” over “liver coldness and wetness” and the dominance of “liver dryness” over “heart wetness”. According to traditional medicine, each organ is composed of four temperaments where the “wetness” and “dryness” are considered as a spectrum of “tissue moistures”,while “warmth” and “coldness” may be regarded as the basic metabolism of the organ. In normal condition, the heart’s temperament is “warm” and “dry” and the liver temperament is “warm” and “wet”. According to Avicenna, the presence of imbalancebetween the temperaments of human body describes the state of illness or organ disorder .Both heart and liver diseases are regarded as a seriousburden on health system and a leading cause of deterioration of quality of life and shortened life expectancy. In this review, we discuss the complex cardiohepatic interactions in the setting of the main heart and liver diseases.This review seeks to highlight how acute and chronic heart failure may lead to cardiogenic ischemic hepatitis and chronic congestive hepatopathy, respectively. In addition, this paper provides an overview on how chronic liver diseases including hepatic cirrhosis, nonalcoholic fatty liver disease (NAFLD), and conditions following liver transplantation (LT) may impair the cardiac performance and induce electrophysiological abnormalities in the absence of other cardiac disease. In each section, we discuss briefly the likely mechanisms underlying this association, clinical presentations, and diagnostic approaches.Congestive hepatopathy or chronic passive hepatic congestion refers to the congestion of liver parenchyma induced by impaired hepatic venous outflow secondary to a right-sided cardiac failure a.The underlying pathophysiological mechanisms include increased hepatic vein pressures, decreased hepatic blood flow, and decreased arterial oxygen saturation ,3. Main Congestive hepatopathy is usually subclinical. When symptomatic, patients may present with early satiety, malaise, mild jaundice, or intermittent right upper quadrant pain secondary to dilatation of the liver capsule. Physical examination is typically dominated by signs of cardiac failure including jugular vein distension, hepatojugular reflux, and peripheral edema. Spider angiomata, splenomegaly, and varices are rarely present ,7. The pPrimary laboratory finding in congestive hepatopathy is represented by mild hyperbilirubinemia, with a predominantly unconjugated fraction . ElevatiMild hypoalbuminemia and ascites may be present in patients with congestive hepatopathy. In these patients, the state of inadequate nutrition and hemodilution due to heart failure contributes substantially to the aggravation of hypoalbuminemia .Morphologically, congestive hepatopathy is associated with characteristic changes within the liver parenchyma ,13,14. ETreatment of congestive hepatopathy consists mainly of treating the underlying cardiac disease and improvement of cardiac output. Diuretics represent the main stay of pharmacological therapy. Unless contraindicated, angiotensin-converting enzyme (ACE) inhibitors and beta blockers are indicated in symptomatic congestive heart failure. A surgical approach may be indicated in the case of constrictive pericarditis, severe valvular heart disease, and ischemic cardiomyopathy ,18. For Cardiogenic ischemic hepatitis, known also as acute cardiogenic liver injury, is a clinical and histological syndrome characterized by a rapid and transient rise in serum transaminase levels due to acute fall in cardiac output leading to the reduction of hepatic blood flow  Figure b.Cardiogenic ischemic hepatitis has been estimated to emerge in 20–30% of patients with acute heart failure . The patAn acute cardiogenic liver injury is usually related to an acute coronary event, cardiac arrhythmia, or transient severe hypotension . FindingIn another report of patients with clinical and biochemical evidence of acute liver injury admitted to the coronary intensive care unit, the presence of acute liver injury has been shown to be associated with a decrease in hepatic blood flow and passive hepatic venous congestion . AdditioAcute cardiogenic hepatitis is usually asymptomatic. However, clinical signs may appear after a latency period of 2–24 h. Most commonly, patients exhibit symptoms resembling acute viral hepatitis such as weakness, apathy, and, in a minority of cases, mental confusion, flapping tremor, oliguria, jaundice, and hepatic coma ,27.The diagnostic approach of cardiogenic ischemic hepatitis is usually based on clinical presentation and laboratory finding. Non-invasive imaging as abdominal ultrasound can be supportive by showing signs liver congestion as dilation of the suprahepatic veins and inferior vena cava . PulmonaThe typical pattern in laboratory tests consists of rapid, transient rises in serum aminotransferase  and lactate dehydrogenase levels (LDH) with peak levels reaching between 10 and 20 times the upper limit of normal ,29.The ratio of serum ALT to lactate LDH less than 1.5 early in the course of liver injury is characteristic of cardiogenic injury . After cThe main histologic feature of acute cardiogenic ischemic hepatitis is characterized by hepatic necrosis around the central hepatic veins zone 3), a condition known as centrilobular necrosis. This zone has the poorest oxygen delivery, and will be most affected during a low hepatic blood flow , a condi.The management of cardiogenic ischemic hepatitis focuses on identifying and removing the precipitating cause. This may include medications with hypotensive or negative inotropic effects and other medications that likely may induce impairment of renal function.When needed, administration of oxygen and positive inotropic agents may help to restore an adequate organ perfusion .Cirrhotic cardiomyopathy (CCM) was first described in the late 1960s, although for many years, it was mistakenly presumed to result from a latent alcoholic cardiomyopathy . CCM repIn hepatic cirrhosis, portal hypertension results in splanchnic arterial vasodilation due to the release of potential liver-derived vasodilators factors such as carbon monoxide, nitric oxide, and prostacycline ,39. ThisPatients with liver cirrhosis present an impaired ventricular ejection of fraction under physical stress compared with non-cirrhotic subjects. This is mainly related to inadequate heart rate response and decreased myocardial contractility under exercise ,44.Alterations in β-adrenergic receptor function at the membrane of cardiac muscle cells have beenshown to be involved in the myocardial hyporesponsiveness of cirrhotic patients. It is well accepted that the long-term exposure of cardiomyocytes to high levels of noradrenalin usually present in cirrhosis due to enhanced sympathetic tone results in internalization, sequestration, and down regulation of β-adrenergic receptors on plasma membrane ,46.Experimental findings from animal models suggested that nitric oxide (NO) could play a negative inotropic effect in heart of cirrhotic rats . The actIn this context, arachidonoylethanolamide (AEA) or anandamide and 2-arachidonoylglycerol (2-AG) are the most widely studied endocannabinoids, exerting their effects via G protein-coupled cannabinoid receptors (CBRs). The activation of cannabinoid receptor type 1 (CB-1) has been shown to decrease the contractile response to β-adrenergic agonists. This cardiac adrenergic responsiveness was restored by blockage of CB-1 receptor . In addiAbnormalities of diastolic dysfunction are considered an early manifestation of CCM, and frequently precede the systolic dysfunction. Left ventricular diastolic dysfunction is characterized by a decrease in the rate and degree of left ventricular relaxation, together with presence elevated end-diastolic filling pressures . Unlike Liver cirrhosis was associated with changes in expression of collagen isoforms in ventricular heart tissue has been shown to be involved to correlate with diastolic dysfunction in cirrhosis. Ventricular cardiac tissue derived from cirrhotic rats showed an increased collagen type 1 content compared with sham animals, which subsequently contributes significantly to diastolic dysfunction by increasing the passive cardiac stiffness .A prolonged QT interval represents a common electrocardiographic finding in patients with cirrhosis and served as predictor of the increased risk of ventricular arrhythmia and/or sudden death . QT prolChronotropic incompetence is another consistent finding in CCM, and refers to the inability of the heart to increase adequately its rate to match the metabolic demands. Cardiovascular autonomic dysfunction has been suggested to play a role in enhancing chronotropic incompetence in patients with CCM .Considering the subclinical picture of CCM in the majority of patients, the diagnostic approach involves a combination of laboratory, clinical, electrocardiographic, and imaging evaluations. Electrocardiographic assessments may be helpful to identify cirrhotic patients with prolongations of QT interval and arrhythmias. Echocardiographic evaluation of the left ventricular systolic function usually shows a reduction of ventricular ejection of fraction at rest or under stress in response to catecholamine stimulation in the case of subtle systolic dysfunction. Diastolic impairment in CCM manifests mainly by reduced early (E) ventricular filling capacity and increased atrial (A) filling (E/A<1.0), in addition to prolongation of deceleration time (>200 ms) and isovolumetric relaxation time (ITVR > 80ms) .Biomarkers for cardiac dysfunction  might be elevated in early stages of CCM and usually reflect the severity of liver disease .CCM complicates several therapeutic approaches used in cirrhosis and heart failure. Although beta blockers are contraindicated in decompensated cirrhosis with ascites, these drugs have been shown to normalize the prolonged QT interval and might reduce the hyperdynamic load . ACE inhCardiovascular events and mainly heart failure represent a primary source of morbidity and mortality following LT. Heart failure may have an early-onset (within 30 days after transplantation) or in other cases may occur late (>30 days). In the postoperative period, heart failure may reach an overall incidence of 3.3% and may be associated with a mortality risk of 45%  Figure d.The cardiovascular stress due to surgery is considered a main contributor of early heart failure in liver transplanted patients. Takotsubo cardiomyopathy (TTC) or stress-induced cardiomyopathy represents a main cause of acute heart failure in the absence of coronary artery disease . TTC’s cSeveral pathophysiological mechanisms have been suggested to be involved in TTC. The exposure of myocardium to large concentrations of circulating catecholamines during LT makes the heart susceptible to adverse events including multivessel epicardial vasospasm . In addiIntraoperative triggers for TTC during liver transplantation surgery include cardiovascular stress, such uncontrolled bleeding, massive transfusions, and administration of high rates of vasoactive agents .Stress-induced cardiomyopathy is still an underestimated cause of acute heart failure in liver transplanted patients. Beside the exclusion of coronary disease, the diagnostic approach should involve the combination of clinical aspects to electrocardiographic and echocardiographic findings. Multiple studies have evaluated the risk factors for late cardiac events following LT. The severity of liver disease as quantified by Model of End Stage Liver Disease (MELD) score has been shown to be associated with adverse cardiac events following LT . This waIn addition to older age and male sex, several components of the metabolic syndrome factors including hypertension, hyperglycemia, dyslipidemia, and visceral obesity have been shown to be predictive for heart failure following LT ,78.In thHemodynamically stable patients are often treated with diuretics, ACE inhibitors, and beta blockers. Treatment with calcium channel blockers and fluid resuscitation is usually indicated for patients with severe left ventricular outflow tract obstruction and hemodynamic compromise. Inotropic agents can be administered only in absence of moderate or severe left ventricular outflow tract obstruction. In presence of TTC with thromboembolism, anticoagulation should be continued for at least three months .NAFLD encompasses a pathological condition characterized by ectopic deposition of adipose tissue in the liver, in the absence of secondary causes for hepatic fat accumulation, such as excessive alcohol intake, steatogenic drugs, and hereditary disorders . This te2) and in 85% of patients with morbid obesity (BMI = 40–59 kg/m2)  = 30–39.9 kg/m9 kg/m2) . There i9 kg/m2) . Accordi9 kg/m2) .The most common cardiac complications associated with NAFLD include coronary artery disease, and structural myocardial alterations in addition to cardiac arrhythmias. An increasing number of studies have addressed a link between coronary heart disease and NAFLD independently of traditional cardiovascular risk factors . PatientMoreover, the coronary microvascular and endothelial function assessed by the measurement of coronary flow reserve (CFR) has been shown to be impaired in patients with NAFLD compared with healthy subjects .Moreover, subjects with NAFLD have been shown to have common features of left ventricular diastolic dysfunction, which represents a key contributor to the development of heart failure . SimilarCardiac rhythm disturbances are also linked to NAFLD, probably due to an induction of cardiac autonomic dysfunction. Several arrhythmias are found in association with NAFLD such as atrial fibrillation, QT prolongation, and ventricular arrhythmias, which can predispose these patients to sudden cardiac death .The precise mechanisms linking NAFLD with cardiac complications are poorly understood. However, several pathophysiological mechanisms have been postulated to be involved such as insulin resistance, visceral adiposity, subclinical inflammation, dyslipidemia, and oxidative stress e 96]..96].NAFLD patients tend to present whole-body as well as hepatic insulin resistance, inducing disturbances in the transport of free fatty acids, thus leading to visceral and ectopic fat accumulation. Due to the increased lipogenesis, the lipid profile in these subjects consists in increased levels of triglyceride, low-density lipoprotein cholesterol (LDL-C), and very low-density lipoprotein cholesterol (VLDL-C), which are consequently linked to increased cardiovascular risks ,98.NAFLD is considered a chronic subclinical inflammatory condition through secreting proinflammatory cytokines and chemokines by both hepatocytes and by non-parenchymal cells such as stellate cells and Kupffer cells . SeveralIn addition to the role of abdominal obesity, which usually occurs in NAFLD, ectopic fat accumulation in other districts  leads to adipocytes dysfunction with consequent imbalance of pro- and anti-inflammatory cytokinesoriginating from adipose tissue termed adipokines ,102. In Oxidative stress appears to play a key role in promoting the progression from simple steatosis to NASH and increasing the cardiometabolic risk in NAFLD patients . It arisA high production of prothrombotic factors, mainly factors VII, IX, XI and XII, has been shown to be linked to NAFLD  and therIn recent years, novel hepatic tissue-specific molecules known as hepatokines have been described to determine cardiovascular effects. Fibroblast growth factor 21 (FGF-21) is a peptide predominantly produced and secreted by the liver and correlates with hepatic fat content and the severity of NAFLD . ElevateGiven the rapidly growing global burden of NAFLD and limitations of performing liver biopsy due to interobserver variability and procedure-related morbidity and mortality, recent recommendations suggested several noninvasive markers of fibrosis and steatosis . The NAFThe main clinical recommendations for the management of NAFLD include lifestyle modifications through a combination of physical activity, smoking cessation, appropriate dietary changes, and gradual weight loss. This approach has demonstrated to be an effective tool to improve the cardiovascular risk profile in NAFLD patients.Moreover, current guidelines recommend careful clinical screening and treatment for associated cardiometabolic risk factors including obesity, diabetes mellitus, dyslipidemia, and hypertension in all individuals with NAFLD. Bariatric surgery represents a recommended choice for morbidly obese individualsif lifestyle modifications and pharmacological approach have not yielded long-term success. It provides cardiovascular benefits in terms of reducing overall mortality by improving hepatic inflammation, metabolic syndrome components, and cardiac morphology ,117.Increasing evidence suggests that the heart synthesizes and secretes proteins referred to as cardiokines, which are involved in the inter-cellular and inter-organ communication . More thIt has been reported that cardiokinesnot only have local involvement in the stress response and damage repair, but also mediate several regulatory effects on extra-cardiac tissues . In the NOD-like receptor protein 3 (NLRP3) inflammasomeis the most widely studied inflammasome in myocardial tissue. It consists of a multi-protein signaling platform that acts as an intracellular innate immune sensor and its activation induces the transcription, maturation, and release of proinflammatory cytokines, in particular IL-1β and IL-18. In heart failure, three main triggers contribute to the activation of NLRP3 inflammasome components: adenosine triphosphate (ATP), mitochondrial DNA (mtDNA), and reactive oxygen species (ROS) . DespiteOlson’s group reported that the heart controls systemic energy metabolism, fat mass, and body weight via the heart specific microRNA-208a (miR-208a) and Mediator complex subunit 13 (MED13) signaling in rodent cardiomyocytes . MiR-208The co-existence of bidirectional communication was also confirmed in patients with heart failure . ImpaireIn this review paper, we highlight how acute and chronic heart failure may lead to acute hepatic injury and chronic congestive hepatopathy, clinical conditions that are often accompanied by specific clinical and laboratory manifestations. On the other hand, subjects with liver diseases, mainly hepatic cirrhosis and NAFLD, or those undergoing LT can develop heart systolic and diastolic dysfunctions in addition to electrophysiological cardiac abnormalities. In this regard, a better knowledge of the cardiohepatic interactions constitutes a key issuefor the management of cardiac and hepatic dysfunctions.Although still challenging, especially in multi-morbid patients, the early recognition of clinical signs and symptoms of simultaneous heart and liver injury has led to important benefits in terms of reduction of morbidity and mortality. This requires the involvement of a multidisciplinary approach to patients in order to manage the patients at early disease stages. Future research will unravel the molecular mechanisms implicated in the cardiohepatic interactions to further improve the diagnosis and therapy of these disturbances.