Histamine intolerance (HIT) is a common disorder associated with impaired histamine metabolism. Notwithstanding, it is often misdiagnosed as other diseases because of its lack of specific clinical manifestations. HIT did not gain traction until the early 21st century. In this review, we will focus on the latest research and elaborate on the clinical manifestations of HIT, including its manifestations in special populations such as atopic dermatitis (AD) and chronic urticaria (CU), as well as the latest understanding of its etiology and pathogenesis. In addition, we will explore the latest treatment strategies for HIT and the treatment of specific cases. HIT  is a disease that was only discovered and defined in this century . It has Histamine (2-(4-imidazolyl)-ethylamine) is a biogenic amine that is widely present in the human body and can have a wide range of physiological and pathological effects, such as allergy and inflammation, by binding to its specific receptors  ,52,53. IHistamine has many other sources besides cells, such as foods ,56. CommHistamine is metabolized through two main pathways: the cyclopentyl action of histamine-N-methyltransferase (HNMT) and the oxidative deamination of DAO ,40,63,64HIT is a non-immune reaction, which we call a pseudoallergic reaction in the title. It is food intolerance caused by histamine accumulation and ingestion . VariousThe related enzymes that degrade histamine are DAO and HNMT. The DAO gene is located at 7q35 and is about 10 kb in length, and the HNMT gene is located at 2q22.HIT is mainly caused by SNPs in the DAO gene. The expression of this gene leads to changes in protein production, and enzyme activity is lower than normal. The most important SNPs in the DAO gene are rs10156191, rs1049742, rs2268999, and rs104979. SNPs in the promoter region rs2052129) have also been reported to reduce DAO gene expression . Various9 have alProteus in the HIT group increased, and the α diversity decreased significantly. The abundance of bifidobacteria in HC was significantly higher than that in other research groups, while the abundance in the HIT group was the lowest. In patients with HIT, the abundance of the genera Butyricimonas and Hespellia was significantly decreased, and the abundance of Roseburia was significantly increased. Therefore, the changes in Proteus and Bifidobacteriaceae, the decrease in α diversity, and the increase in fecal zonrin levels suggest that patients with HIT have ecological disorders and intestinal-barrier dysfunction.In addition to the impaired degradation of oral histamine due to a lack of DAO, disturbances in the intestinal flora may also lead to increased histamine levels. Some bacteria also seem to synthesize and secrete histamine ,69. MartLactobacillus rhamnosus on mice and found that both host- and microbiota-derived histamine significantly altered the innate immune response to microbes through H2 receptors [The presence of bacteria, yeasts, and molds that form histamine in the GI tract may increase the sensitivity of some people to histamine ingestion. Frei et al. studied the effects of histamine-producing strains of eceptors .HIT may be a comorbidity in most cases. Studies on DAO/HNMT deficiency or increased serum histamine levels are associated with allergic diseases , and the severity of bronchial hyper-responsiveness supports this view ,17,19. IThe causes of histamine overdose are related to the widely used phlegm-reducing agents , antiemetics (metoclopramide), antiarrhythmic drugs , anti-arrhythmic drugs, hypertension drugs (dihydro hydrazine), alcohol, antidepressants (amitriptyline), chloroquine, and clavulanic acid inhibiting the activity of DAO ,24. AfteSauerkraut, fish, smoked meat products, and some kinds of cheeses contain large amounts of histamine, which may contribute to HIT symptoms due to a slight excess of histamine ,25,26,27In summary, HIT is a food intolerance caused by multiple factors. The etiology of HIT is mainly related to genetic polymorphisms of DAO or HNMT, diseases associated with DAO or HNMT deficiency, dysbacteriosis, drugs that inhibit DAO activity, foods that are rich in histamine, foods that inhibit DAO, and foods that promote histamine release .Due to the above causes of histamine accumulation in the body, exogenous or endogenous histamine is involved in various clinical responses of systemic organs by binding to four types of receptors (H1–H4 subtypes) . H1-subtThe skin contains histamine receptors , which cThe GI tract contains almost all of the histamine receptors. As a result, patients with HIT are often accompanied by many GI symptoms, including diffuse stomachache, GI colic, flatulence, diarrhea, and so on . ElevateWhen ingesting foods that are rich in histamine, patients with HIT may have respiratory symptoms such as a runny nose, nasal obstruction and nasal mucosal congestion. Some severe patients even have asthma symptoms .The four types of histamine, H1, H2, H3 and H4, are widely distributed in the human body ,75. The HIT is reported to occur more frequently in some AD patients because of decreased DAO activity and increased histamine concentration ,78. The Histamine is the primary mediator of wheal and angioedema in CU, so HIT is also specific in patients with CU. HIT has also been considered as a cause of or contributing factor to CU. According to relevant reports, symptoms of some CU patients can be erased after a low-histamine diet ,79. MeanFood allergy can also be manifested as abdominal pain, diarrhea, itching, urticaria, angioedema and so on. It can also occur after eating. However, food allergy is caused by an allergic reaction, while HIT is not. In laboratory examination, patients with food allergy may have elevated IgE, while patients with HIT have normal IgE. In addition, the gold standard of food allergy is the oral food-challenge test, while the specificity of the oral histamine-challenge test is not high ,5. Both Clinicians often classify many clinical symptoms of food intolerance as IBS. At present, the diagnostic standard of IBS is the Rome IV criteria . However2 breath test. Therefore, an identification can be made based on the type of food consumed and the serum DAO level. Interestingly, HIT patients also seem to present with disrupted gut flora [The clinical manifestations of HIT are often very similar to intolerance diseases such as sugar (lactose and fructose), protein (gluten), sulfite, or other biogenic amines (such as tyramine), which are often misdiagnosed or missed. The onset of HIT is often associated with the intake of high histamine in foods (such as fish and aged or fermented foods) or beverages (such as red wine) ,56. Moreut flora . This maCD is mainly caused by the degranulation of mast cells and the release of histamine and other inflammatory mediators after the ingestion of gluten . CD is c13 breath test, serological antibody test, and GI endoscopy combined with a GI mucosal histological evaluation and can be cured by the specific antibiotic. Conversely, these treatments have no effect on HIT.HP can lead to changes in the stomach environment that affect the absorption of nutrients, resulting in some GI symptoms. HP infection can often be confirmed by a CThe GI symptoms of EGE are somewhat similar to those of HIT . The detWhen patients with HIT develop urticaria-like rashes, the HIT should be differentiated from other types of urticaria, such as spontaneous urticaria and artificial urticaria. Patients with HIT often have a history of eating foods that are rich in histamine. In laboratory examination, the DAO concentration is decreased in HIT.Histamine is released by mast cells, so the clinical manifestations of histamine overdose caused by systemic mastocytosis are similar to those caused by HIT . HoweverHIT can be inferred or suspected by the aforementioned clinical manifestations. However, it is necessary to consider the patient’s history due to the low specificity and complexity of the HIT clinical manifestations. Moreover, it is also important to consider whether the clinical manifestations are related to eating foods that are rich in histamine or taking drugs that inhibit DAO activity.DAO plays the role of degrading exogenous histamine. As a result, its expression is very important for the diagnosis of HIT. According to relevant tests, the DAO concentration and activity in patients with HIT were significantly lower than those in normal subjects ,35. TherThis test involves an oral 75 mg histamine solution to observe the clinical reaction. The trial may cause dangerous clinical symptoms, so it must be carried out under the supervision of a doctor and in preparation for rescue in the hospital. According to the studies ,5, the dWith 0.9% of physiologic saline solution serving as a negative control, the intact skin is pipetted with 1% (10 mg/mL) histamine solution, and the skin is punctured with a lancet. A wheal ≥ 3 mm within 50 min is considered positive. The experiment of Lukas suggests that the sensitivity of the histamine 50-skin-prick test is 79% , and the specificity is 81.3%  . It can As mentioned above, HIT is related to the lack of intestinal DAO. As a result, intestinal biopsy through a gastroscopy to detect the concentration of intestinal DAO can be a highly sensitive and specific method. According to the research of , HIT is It has been proven that a low-histamine diet and DAO supplement could be the main treatment for HIT, since they can effectively relieve the symptoms of HIT ,42,49. TAccording to recent studies, the detection of histamine and histamine metabolites in urine can also be used as a diagnostic method for HIT . DoctorsThere is a lack of histamine degradation due to the lack of DAO in patients with HIT. Therefore, the elevation of histamine in the blood can be used as one aspect of the diagnosis of HIT. Current methods for detecting histamine include colorimetry, fluorescence, ELISA and chromatography, which are expensive and inconvenient . HistamiHIT is related to the deficiency of histamine degradation by DAO in the intestine. Therefore, the SNPs of these two can be used to estimate the susceptibility of HIT. SNPs are assessed by sampling blood or oral mucosa.All of the above methods of diagnosing HIT need to exclude symptomatic diseases and other concomitant GI disorders, as well as related diseases mentioned in the previous differential diagnosis .H1- and H2-receptor antagonists can be taken after taking a large amount of histamine, but they cannot be used for long-term treatment of HIT . Most anBased on the diagnosis of HIT, a low-histamine diet was developed to treat individual symptoms by reducing the intake of histamine-containing foods . This aiSchnedl et al. conducted a study on 28 HIT patients and instructed them to take DAO capsules before meals for four consecutive weeks. During the oral DAO process, GI, respiratory, cardiovascular and skin symptoms were significantly improved . The EurSevere HIT may have life-threatening reactions, such as hypotension, bronchospasm, shock, etc., presenting a state of anaphylactic shock. Generally, this serious reaction is related to high-dose, high-histamine substances. In this case, first aid is needed . First, Taking vitamin C and vitamin B6 can increase the activity of DAO, which is conducive to the degradation of histamine. Mast-cell stabilizers and pancreatin have a positive effect on HIT, especially for patients with GI symptoms ,40,46,86HIT is a kind of common comprehensive disease in the clinical setting, which is caused by heredity, dysbacteriosis, related diseases, drugs and food. The manifestations of HIT lack specificity. They can occur in the skin, GI tract, the nervous system, and so on. In particular groups, HIT can have a relatively different effect. Therefore, when a doctor encounters a patient with these clinical symptoms, they should consider the possibility of HIT and distinguish it from diseases with similar symptoms. The current detection methods are complex, sometimes expensive, and time consuming. There is a need to find a more convenient and rapid detection method. The existing treatments include a low-histamine diet, antihistamine therapy, DAO supplementation, and some adjuvant therapies. In the case of serious patients, the doctor should treat them in a timely and effective manner according to the methods described above in order to avoid serious consequences caused by improper or untimely treatment. Further studies are needed on the etiology, diagnosis, and treatment of HIT. I believe that we can learn more about HIT in the future.


Post-systolic shortening (PSS) is an important indicator for early identifying myocardial dysfunction. We aimed to investigate the predictive value of PSS assessed with speckle tracking automated functional imaging (AFI) on adverse events in patients with stable coronary artery disease (CAD) and preserved systolic function.A total of 204 consecutive patients clinically diagnosed with stable CAD and left ventricular ejection fraction (LVEF) > 50% were included. Multiple parameters were analyzed with AFI technique. The composite endpoint included all-cause mortality, heart failure, myocardial infarction and stroke.p = 0.005) and per 1 increase in the number of left ventricle walls with PSS  were independent predictors of the endpoint, whereas GLS was not significantly associated with the endpoint after adjustment models. For patients with absolute value of GLS > 15.4%, a significant prognostic superiority was found in PSI compared with GLS .During a median follow-up of 24 months (IQR 19–28 months), 30 patients (14.7%) reached the endpoint. Patients experiencing the endpoint had a lower absolute global longitudinal strain (GLS), a higher post-systolic index (PSI), and more left ventricle walls displaying PSS than patients without events. PSI (hazard ratio, 1.15; 95% CI, 1.04–1.27; PSS is an independent predictor for adverse events in stable CAD patients with preserved systolic function, and the prognostic value may be superior to GLS in patients with normal or mildly reduced GLS.The online version contains supplementary material available at 10.1186/s13244-022-01174-y. GLS and PSS can early identify myocardial dysfunction.PSI and LV walls with PSS can independently predict adverse outcomes.PSS may have a superiority predicting adverse outcomes when GLS was preserved.Coronary artery disease (CAD) remains the leading cause of death in developed and developing countries . Stable Transthoracic echocardiography is the commonly used non-invasive imaging method for the evaluation of CAD, which was shown not only to aid diagnosis but also to provide valuable prognostic information in the clinical setting . CompareIn addition to longitudinal strain, post-systolic shortening (PSS) has recently attracted attention as another marker of myocardial ischemia . PSS is It is reported that PSS may occur in passive dyskinesia and also at a low magnitude in healthy individuals . AccordiDifferent from the traditional manually tracing the myocardium, a novel algorithm of STE, named automatic functional imaging (AFI), can automatically and quickly provide multiple strain parameters, in turn improving workflow and reducing user variability . TherefoWe prospectively studied 297 consecutive patients with clinically diagnosed stable CAD from April 2016 to December 2020. Inclusion criteria were (1) suspected CAD patients had stable intermittent chest pain or exertional dyspnea related to myocardial ischemia according to a comprehensive clinical investigation including location, character, duration and relationship to exertion and other exacerbating or relieving factors. (2) No changes in frequency, duration, precipitating causes or relief for at least two months before admission. All patients underwent transthoracic echocardiography combined with speckle tracking AFI analysis. Critical exclusion criteria were (1) coronary angiography revealed < 50% reduction of the arterial lumen area in any major coronary artery; (2) LVEF ≤ 50%; (3) a history of significant heart failure, acute coronary syndrome within the last year; (4) other heart diseases including cardiomyopathy and significant valvular heart disease, ventricular arrhythmia, atrial fibrillation, left or right bundle branch block or paced rhythm, and other serious non-cardiac diseases; (5) suboptimal image quality and arrhythmia that may influence the analysis of speckle tracking AFI. A total of 204 patients were finally included in this study. Tongji Hospital Ethics Committee approved the study, and informed consent was obtained from all patients before the study.Transthoracic echocardiograms were performed using GE Vivid E95 ultrasound equipment  with an M5Sc transducer (1.7–3.3 MHz) and a high frame rate (70–80 frame/s). LV parasternal long-axis view, short-axis views at basal, midventricular and apical levels, as well as apical 2-, 3- and 4-chamber views were acquired. All echocardiograms were analyzed in accordance with the quantitative method recommended by the American Society of Echocardiography . The intThe commercial speckle tracking AFI software  was used to perform two-dimensional (2D) strain analysis in apical two-, three- and four-chamber views. The AFI software analyses myocardial motion by tracking frame-to-frame speckle changes in 2D images . When neGLS was calculated as the average value of the peak systolic strain in LV 18 myocardial segments . PSI of All patients underwent coronary angiography to confirm the diagnosis with CAD. Coronary angiography was performed by two experienced interventionists using standard technique . StenosiAll participants were followed from July 2016 to August 2021 or the time of the event. The composite endpoint included all-cause mortality, heart failure, myocardial infarction and stroke. If a patient experienced several events, the first occurring event was used in the composite end point. The end points were obtained from our hospital’s Patient Registry and telephone calls. Fifteen patients lost to follow-up were excluded in the final analysis.To define intra- and inter-observer variability, 30 patients were randomly selected and remeasured by two observers blinded to patient data and each other's results. One of the researchers did the analysis once again after two weeks. Intra- and inter-observer reproducibility and variability were calculated by intraclass correlation coefficient (ICC).2 test or Fisher's exact test (as appropriate).All analyses were performed using SPSS version 21.0 statistical analysis software , MedCalc version 15.2.2  and R version 4.1.1 . Normally distributed continuous data are presented as mean ± standard deviation. Non-normally distributed continuous data are presented as median and interquartile range (IQR). Shapiro–Wilk test and q-q plots were used to check continuous values for normality of the data distribution. The differences between two groups were assessed using Student’s t test for normally distributed data and Mann– Whitney U test for non-normally distributed data. The differences among the three groups were analyzed using the one-way analysis of variation (ANOVA) test for normally distributed data with the Bonferroni correction for pairwise comparisons between the data in each group. The Kruskal–Wallis rank-sum test was used for non-normally distributed data in three groups, and the all pairwise method was used for further pairwise comparisons between two groups. Categorical data are presented as percentages and statistically analyzed with the χp value < 0.05 was considered a statistically significant difference.Receiver operator characteristic (ROC) curve analysis was performed to investigate the predictive ability of different indicators for adverse events. From the analysis of the ROC, areas under the curve (AUC) and 95% confidence intervals were obtained. By maximization of Youden's index, the optimal cutoff values with specificity or sensitivity were calculated. Comparison of AUC was performed using the method of DeLong in MedCalc. This cutoff value was used to construct Kaplan–Meier survival curves, and associations between the respective echocardiographic parameters and endpoints were compared by the log-rank test. Cox proportional hazards method was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). For multivariable COX proportional hazards regression analyses, LVEF and variables with significant P value < 0.05 in univariable analyses were included in the multivariable models to detect independent risk factors for predicting adverse events. Restricted cubic spline model was constructed to analyze the relationship between PSI and the hazard ratio of adverse events. A two-way random-effects model was used with absolute agreement-type analysis for intraclass correlation coefficient (ICC). A two-tailed A total of 297 participants diagnosed with stable CAD were examined by conventional echocardiography and STE. Of these participants, 78 were excluded because of exclusion criteria and 15 patients lost to follow-up. A total of 204 patients  were finally evaluated in this study , a higher PSI  and more LV walls with PSS than patients without events. No significant differences were found regarding E/A, E/e′, ventricular wall thickness, left ventricular volumes and LVEF between the two groups (p > 0.05).Patient characteristics stratified by follow-up outcome are summarized in Table p < 0.05) than patients with no PSS. Increasing numbers of LV walls with PSS were related to a higher incidence of adverse events, a lower LVEF, a higher LVESV and a lower GLS, such that participants with no PSS had a mean GLS of − 17.7 ± 2.4%, those with 1–2 wall of PSS had a mean GLS of − 17.4 ± 2.8% and those with ≥ 3 walls of PSS had a mean GLS of −15.2 ± 3.5% (p trend < 0.05). To some extent, these results indicated that patients with ≥ 3 walls of PSS had impaired LV function compared with patients with < 3 walls of PSS. No significant differences were found regarding left ventricular wall thickness, E/e′ across groups.In total, there are 99 (48.5%) patients with no PSS, 62 (30.4%) patients with 1–2 walls of PSS and 43 (21.1%) patients with ≥ 3 walls of PSS. As shown in Table p = 0.003; 0.76 [PSI] vs. 0.54 [E/A], p = 0.002; 0.76 [PSI] vs. 0.53 [E/e′], p = 0.002) was superior to conventional parameters in predicting adverse events. The cutoff value was 10.4% for PSI with a sensitivity of 63.3% and specificity of 81.0%. Similarly, GLS  was also superior to conventional parameters in predicting adverse events. The cutoff value was −15.4% for GLS with a sensitivity of 56.7% and specificity of 77.0%, whereas no significant difference was found between PSI and GLS  , whereas conventional parameters  except E/e′ showed no significant differences in survival time at different levels (log-rank p > 0.05).Kaplan–Meier event-free survival curves are shown in Fig. p = 0.008), hypertension , NYHA functional class III-IV , GLS , PSI  were significantly associated with adverse events, while no significant associations were found in LVEF, E/A and E/e' . Per 1 increase in number of LV walls with PSS, the risk of adverse events increased by 1.69 times . LVEF and all variables with p < 0.05 in univariable Cox regression analysis were included in multivariable Cox regression analysis. Both the number of walls with PSS  and PSI  remained independent predictors, but no remained significant prediction was observed in GLS after adjustment.In univariable Cox regression analysis Table , age . These results indicated that for patients with normal or mildly reduced GLS, the prognostic value of PSS may be superior to GLS. Furthermore, Kaplan–Meier survival curves showed that patients with both GLS and PSI beyond the prognostic cutoff values had significantly higher adverse events risk than patients with only GLS beyond the prognostic cutoff value . For patients with the absolute value of GLS > 15.4%, ≥ 3 walls of PSS showed a higher risk of adverse events than 1–2 walls of PSS  and no walls of PSS  (log-rank p = 0.010)  the novel strain parameters, including GLS, PSS and PSI obtained from the AFI algorithm can early identify myocardial dysfunction and predict adverse events in stable CAD with normal LVEF; (2) PSI and the number of LV walls with PSS are independent predictors of the endpoint; (3) the cutoff of PSI in predicting the adverse events is 10.4% with sensitivity 63.3% and specificity 81.0%; (4) for patients with normal or mildly reduced GLS, the prognostic value of PSS may be superior to GLS.Coronary artery disease (CAD) is a pathological process characterized by atherosclerotic plaque accumulation in the epicardial arteries. The disease can have long, stable periods but can also become unstable at any time, leading to major adverse cardiovascular events such as myocardial infarction (MI), stroke and death . Therefop = 0.024). In Cox regression analysis, both PSS and PSI are independent predictors rather than GLS. It is reported that absolute GLS < 12% represents severe systolic dysfunction and adverse prognosis, and < 15%-16% seems to represent risk in patients with relatively preserved EF  × 100. Fig. S2. Flowchart of study population. CAD: coronary artery disease; LVEF: left ventricular ejection fraction. Fig. S3. Receiver operating characteristic curves of multiple parameters for evaluating adverse events. AUC: area under the curve; E/A: mitral inflow peak early velocity/mitral inflow peak late velocity; E/e': mitral inflow peak early velocity/mitral annular peak early velocity; LVEF: left ventricular ejection fraction; PSI: post-systolic index; GLS: global longitudinal strain.


Takotsubo syndrome (TTS) is an increasingly recognized condition burdened by significant acute and long-term adverse events. The availability of novel techniques expanded the knowledge on TTS and allowed a more accurate risk-stratification, potentially guiding clinical management. The present review aims to summarize the recent advances in TTS prognostic evaluation with a specific focus on novel imaging and genetic markers. Parametric deformation analysis by speckle-tracking echocardiography, as well as tissue characterization by cardiac magnetic resonance imaging T1 and T2 mapping techniques, currently appear the most clinically valuable applications. Notwithstanding, computed tomography and nuclear imaging studies provided limited but promising data. A genetic predisposition to TTS has been hypothesized, though available evidence is still not sufficient. Although a genetic predisposition appears likely, further studies are needed to fully characterize the genetic background of TTS, in order to identify genetic markers that could assist in predicting disease recurrences and help in familial screening. Takotsubo syndrome (TTS) is an acute heart failure (HF) syndrome accounting for ~1-2% of all suspected acute coronary syndromes, it is characterized by transient systolic dysfunction , 4. In rTTS was initially perceived as a benign condition , 7. ThisTo date, multiple studies from several multicenter registries have led to a changing perspective and currently agree on considering TTS a not-entirely benign condition, burdened by both in-hospital and long-term mortality , 9–12. Sp = 0.955) . Stiermaier et al. reported a long-term mortality higher than in patients with ST-elevation AMI . In the = 0.955) . In the = 0.955) . Likewis= 0.955) . Concord= 0.955)  and RETA= 0.955)  registriFinally, the risk of TTS recurrence is low but persistent throughout the clinical history of TTS. This is a potentially life-threatening event, presenting even several years after the first occurrence . In thisOver the years, several studies have investigated the usefulness of diverse tools (particularly imaging) to better define risk stratification in TTS .In the acute phase of TTS, transthoracic echocardiography (TTE) is the cornerstone of risk stratification. Several features can be identified by standard TTE that are associated with a higher risk, including low LV ejection fraction (EF) , 27 and Novel, advanced echocardiographic techniques may provide an accurate and sensitive detection of cardiac abnormalities during both the acute and the “recovery” phase of TTS. Speckle tracking-TTE (ST-TTE) provides parametric quantification of myocardial chambers deformation. In the acute phase of TTS, assessment of LV global longitudinal strain (GLS) by ST-TTE has an important prognostic value, being associated to worse outcomes including in-hospital death and major adverse cardiovascular events . Also RVThe added value of ST-TTE is even more evident after the acute event, as LVEF usually normalize, but functional LV abnormalities might persist . Indeed,Echocardiographic particle imaging velocimetry (E-PIV) is an emerging technique for estimating intracardiac blood flow patterns , 42. To Amongst cardiovascular imaging techniques, cardiac magnetic resonance (CMR) is the diagnostic gold standard for assessing cardiac volumes, function , and tisper se a CMR criteria to exclude TTS diagnosis, taking into account that bystander diseases conditioning the presence of replacement fibrosis might also be present  imaging, especially when strict criteria for identification are used  . Notwith present , includi present . Preform present , where i present ; however present . Focal T present ; in thes present –56.In summary, standard CMR techniques can be extremely useful to establish a TTS diagnosis against other forms of MINOCA, moreover, novel tools are emerging to grant quantitative analysis and more accurate prognostic information.Feature-tracking CMR (FT-CMR) is a novel technique for evaluating cardiac chambers deformation in a similar fashion as ST-TTE does for echocardiography, though basic principles behind the two techniques are quite diverse . LV longRecently developed CMR mapping sequences allow a parametric quantification of interstitial expansion in the myocardium, with signal intensity mainly depending on extra-cellular water (T2 mapping) as well as fibrosis and infiltration (native T1 and ECV). In TTS, marked increase of native T1 and T2 as well as ECV were observed in the acute phase , 61–63 . InteresIn recovered TTS patients, native T1 has been described as persistently elevated when compared to that observed in a matched control group, even more than 1 year after the acute event . This fiCoronary computed tomography (CCT) is a non-invasive morphologic evaluation of the coronary tree, with an expanding role in the evaluation of patients with suspected coronary artery disease. In TTS presenting without ST-elevation at ECG, it can be reliably used in the acute phase to rule-out AMI , 73, alsWhen compared to matched control subjects, TTS patients were found to have increased peri-coronary fat attenuation index (pFAi), a measure associated with coronary artery inflammation . pFAi shSingle photon emission computed tomography (SPECT) with 201-thallium chloride has been used to investigate myocardial perfusion in TTS with conflicting results. Some studies reported a mild reduction of perfusion limited to the dis/akinetic segments in the acute phase, while others reported normal perfusion –80. CardHowever, up today, almost all nuclear imaging studies have been performed mainly for research purposes, while prognostic data are scarce. A recent study in a cohort of 90 TTS patients demonstrated that an extensive defect of 123-I-MIBG scintigraphy uptake appears to be associated with a higher rate of in-hospital complications . PatientBoth nuclear and non-nuclear imaging modalities have been used to investigate the brain-heart axis in TTS. The precise pathophysiological mechanisms of TTS are incompletely understood but there is considerable evidence that sympathetic stimulation is central to its pathogenesis , thus anThe response to stressors is governed by an ensemble of neural structures, such as the limbic system , the ventromedial prefrontal cortex and the brainstem. Recently, increasing interest has been directed toward the involvement of the brain–heart axis in in the pathophysiology of TTS. In 2014, Suzuki et al. first documented brain activation in three patients with TTS examining cerebral blood flow with single photon-emission computed tomography (SPECT). In the acute phase, the researchers observed a marked increase in brain activity in areas linked to abnormal stress-induced sympathetic arousal . Furthermore, brain activation remained to some extent in the chronic phase, after full recovery of cardiac wall motion .Later functional magnetic resonance imaging studies demonstrated structural alterations in the limbic networks of TTS patients during the acute  and chroAll of these studies investigated brain alterations in TTS patients after the acute event.The study by Radfar et al. is the first to assess cerebral activity prior to the onset of TTS. The amygdala activity using [18F] fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDGPET/CT) was measured retrospectively in 104 patients who underwent clinical 18F-FDG-PET/CT imaging, including 41 who subsequently developed TTS and 63 matched controls. Patients with subsequent TTS had higher baseline amygdala activity and, among the patients who developed TTS, those with higher amygdala activity developed TTS about 2 years earlier compared with those with lower level of amygdala activity .These neuroimaging findings demonstrate structural and functional alterations of stress-related brain networks in patients with TTS even before the acute event, suggesting long-lasting psychological stress. Chronically heightened stress-associated neural activity may hypothetically induce an individual to react to subsequent stressors with a more vigorous neurophysiological response, thus increasing TTS risk . ConsequNew neuroimaging techniques could be useful in identifying patients at high risk of TTS recurrence, suggesting a longer follow-up and the implementation of both pharmacological and non-pharmacological behavioral therapy .However, additional randomized prospective trials and new interdisciplinary approaches are required to further investigate the role of the brain-heart axis in the pathogenesis and prognosis of TTS.A relatively larger genome-wide association study reported findings from 96 TTS patients . SeveralIn summary, current data on the genetic features of TTS only suggest a genetic etiology of this pathological condition. However, we are becoming aware that, whereas environmental triggers and concomitant comorbidities are pivotal in TTS development, the genetic heterogeneity and a potential polygenic predisposition may also play a contributory role mainly by determining the dysregulation of the adrenergic system. Larger cohorts are required for a better evaluation of the impact of genetic background on TTS occurrence and prognosis.Despite similar long-term outcomes, the nature of adverse events in AMI and TTS is different. Indeed, TTS is featured by mainly non-cardiovascular mortality , 110–112Genetic investigations, rather than cardiac imaging, may play an important role in risk stratification in the particular setting of the predisposition to TTS recurrence. However, where clinical implementation of genetic testing implies a multidisciplinary approach with genetic counseling and ethical considerations , currentPatients with TTS may benefit from advanced cardiovascular imaging tools offering unique information to assist in short- and mid-term risk stratification, well beyond traditional assessment of left ventricular ejection fraction. Due to the limited robust evidence, genetic evaluation does not currently provide significant advantages in guiding the clinical management. Hopefully, future studies aimed at better characterizing the genetic background of TTS may identify useful markers that could assist in predicting disease recurrences and help in familial screening.LA and LL designed the study. LA, LL, CA, MS, and GT drafted the manuscript. All authors provided relevant comments, revised the draft, and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Restrictive cardiomyopathy (RCM) includes a heterogeneous group of diseases that cause increased myocardial stiffness, leading to impaired ventricular relaxation and severe diastolic dysfunction. Given that it is the least common type of cardiomyopathy, it can be a diagnostic challenge due to its varied pathogenesis, clinical presentation, and diagnostic evaluation. In this review, we provide an overview of different etiologies of RCM and examine the diagnostic and treatment approaches for various types. Systolic function and left ventricular (LV) cavity size is normal or mildly reduced until advanced stages of the disease. RCM can involve left, right, or both ventricles with typically normal to slightly increased ventricular thickness. However, atrial enlargement is common due to increased atrial pressure.3Cardiomyopathy is a disorder in which the heart muscle is structurally and functionally abnormal in the absence of coronary artery disease, hypertension, valvular heart disease, and congenital heart disease sufficient to explain the observed myocardial abnormality. Based on the morphological and functional phenotypes, cardiomyopathy can be subdivided into dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), arrhythmogenic right ventricular cardiomyopathy, and unclassified cardiomyopathy .Table 1).4 To further add to the challenge of classifying cardiomyopathies, infiltrative diseases such as sarcoidosis and hemochromatosis can progress to DCM. Younger patients tend to have genetically inherited forms of RCM, such as storage disorders and hereditary hemochromatosis, whereas older patients tend to present with acquired disorders such as cardiac amyloidosis, secondary iron overload cardiomyopathy, and radiation-induced cardiotoxicity. In endemic areas such as Uganda, Nigeria, and India, endomyocardial fibrosis is more common.RCM has traditionally been subdivided into primary/idiopathic and secondary. Primary/idiopathic RCM can be familial or sporadic, and it is associated with a worse prognosis than secondary RCM. Secondary RCM stems from systemic disorders affecting the heart, such as amyloidosis, sarcoidosis, and iron overload. RCM can also be subdivided based on the histopathologic types, including infiltrative, non-infiltrative, storage disorders, and endomyocardial type , including dyspnea, fatigue, orthopnea, and paroxysmal nocturnal dyspnea that can worsen over months. Exercise intolerance is an early symptom because increased heart rate can lead to significant decline in diastolic ventricular filling and cardiac output. With right ventricular (RV) involvement, lower extremity edema and right upper quadrant pain can be present. Patients can also present with chest pain, syncope, and palpitations. Atrial fibrillation is common in RCM given the atrial enlargement, and thromboembolic complications are common. Examination findings include signs of left-sided HF such as pulmonary edema, third heart sound (S3), and right-sided HF signs such as elevated jugular venous pressure, pedal edema, ascites, and hepatomegaly. On examination of the jugular venous pulsations, prominent x and y descent can be a sign of RCM. With advanced disease, patients can have malnutrition, cardiac cachexia, and hepatic and renal dysfunction. Patients also present with manifestations of their underlying systemic disease process, which can serve as clues in diagnosis.Table 2 provides an overview of the physical exam, laboratory, and imaging findings that point to RCM.RCM should be suspected in patients who have HF of unknown etiology and features of RCM on echocardiography. Physicians should assess for a history of amyloidosis, sarcoidosis, hemochromatosis, storage disorders, prior mediastinal radiation, use of hydroxychloroquine, family history of RCM, and HCM. In patients with signs and symptoms of RCM and increased LV thickness, it is important to assess for long-standing hypertension and HCM. Electrocardiogram can show p-wave abnormalities suggestive of atrial enlargement and nonspecific ST-T wave changes. Atrial fibrillation is the most common rhythm abnormality encountered in these patients. Other nonspecific findings include pseudo-infarct pattern, atrioventricular (AV) block, interventricular conduction delay, and premature atrial complexes. Low voltage or LV hypertrophy can be seen. Figure 1). It is important to note that diastolic dysfunction alone cannot be used to diagnose RCM, as this is commonly present in other forms of HF, including HF with reduced and preserved ejection (Table 3).5Echocardiography is an essential tool in the initial evaluation of patients with RCM. Findings characteristic of RCM include normal or near-normal systolic function and cavity size, biatrial enlargement, and abnormal diastolic function. LV wall thickness is typically normal in non-infiltrative RCM but can be increased in patients with infiltrative and storage diseases. Abnormal diastolic dysfunction is noted on Doppler evaluation , with LVEDP at least 5 mm Hg higher than RVEDP. Right atrial pressure is elevated with a prominent x and y descent, which represent rapid filling in the setting of high-pressure gradient between the right atrium and ventricle. Right ventricular systolic pressure (RVSP) can be > 50 mm Hg, and RVEDP is typically less than one-third of RVSP, resulting in a ratio of RVEDP/RVSP < 0.3. In contrast, with constrictive pericarditis, there is equalization of right and left ventricular EDP, and RVSP is typically < 50 mm Hg. The “dip and plateau” sign refers to the rapid decline in ventricular pressure during early diastole followed by a rapid rise and plateau of ventricular pressure as the stiff ventricle fills; this phenomenon is also present in patients with constrictive pericarditis. Whereas with constrictive pericarditis there is intrathoracic-intracardiac pressure dissociation with respiration, there is no inspiratory discordance in concomitant left and right ventricular pressures in RCM.7Cardiac magnetic resonance imaging (CMR) is a noninvasive gold standard for assessing ventricular volumes, myocardial mass, and regional and global systolic function. CMR also plays a crucial role in the diagnosis of RCM etiologies given its enhanced tissue characterization of various patterns of late gadolinium enhancement (LGE). LGE and post-contrast T1 mapping sequences can be used to calculate extracellular volume, a quantitative marker of myocardial fibrosis. Conventional T2-weighted imaging and T2 mapping enable the detection of myocardial edema and inflammation. T2* relaxation time is used to assess iron overload cardiomyopathy. CMR can also help differentiate constrictive pericarditis from restrictive cardiomyopathy. In certain circumstances, CMR has decreased the need for endomyocardial biopsy.When noninvasive studies have failed, endomyocardial biopsy (EMB) can be helpful in identifying the underlying etiology; furthermore, the histopathologic findings can help identify specific infiltrative and storage disorders such as amyloidosis, hemochromatosis, Fabry’s disease, or idiopathic RCM, which is characterized by myocardial disarray and fibrosis. Risks associated with EMB are rare but include injury to the tricuspid valve apparatus leading to tricuspid regurgitation, RV free wall perforation malignant arrhythmias, or tamponade. Depending on where the biopsies are taken, the involved myocardium may not be sampled appropriately, leading to a false negative biopsy.8 In small studies, guidance with CMR or electroanatomic mapping has improved the sensitivity and specificity of EMB in diagnosing various types of cardiomyopathies and is an important subject for future large-scale trials.9While there is no standard guideline-based medical therapy specific to RCM, treatment is targeted to the underlying disease process. Symptomatic treatment includes diuretics for relieving systemic and pulmonary congestion. Hypovolemia is poorly tolerated in RCM given a decrease in ventricular filling and decreased cardiac output. Although new therapies such as spironolactone, empagliflozin, and sacubitril-valsartan have shown some benefits in HF with preserved ejection fraction (HFpEF), these therapies have not yet been specifically studied in RCM patients. Supraventricular arrhythmias like atrial fibrillation are common and are poorly tolerated; rhythm control over rate control is preferred when feasible. Conduction abnormalities can be seen in infiltrative disease and may indicate pacemaker implantation. Patients with advanced HF should be referred for transplant evaluation early given the rapid progression of disease. Specific treatments for the individual disease are discussed below.10 EMB of patients with idiopathic RCM can show nonspecific degenerative changes such as myocyte hypertrophy, disarray, and interstitial fibrosis, and the extent of the interstitial fibrosis can be mild to severe. The prognosis in children with idiopathic RCM is poor, with a median survival of 1 to 1.4 years, although heart transplant has improved overall survival.11 In a retrospective study of 94 patients with idiopathic RCM with a mean age of 64 years, 5-year survival was 64%; men aged > 70 years, left atrial enlargement > 60 mm, and higher NYHA class were each associated with poor survival.12 The overall prognosis in idiopathic RCM is poor, and early referral to a specialty center for advanced HF therapy is important.The primary form of RCM is noninfiltrative disease, a rare disease that can occur at any age and can be familial or sporadic. Increased sensitivity of muscle filament to calcium and accumulation of desmin and collagen type III is thought to be the pathogenesis of primary RCM. The familial form of idiopathic RCM is usually autosomal dominant with incomplete penetrance. Various mutations in genes encoding troponin I and T, actin, myosin, and desmin have been associated with idiopathic RCM. RCM with hypertrophied LV walls demonstrates microscopic characteristics similar to that of HCM, and these two conditions are thought to be a different phenotypic expression of the same genotype.Table 4 provides an overview of the diverse forms as well as diagnosis and management.Iron overload cardiomyopathy (IOC) can be defined as excess iron deposition in the cardiac tissue, leading to early restrictive cardiomyopathy with diastolic dysfunction and later DCM. Systolic dysfunction can occur as the disease progresses. 13IOC occurs mainly in two different scenarios: patients with hereditary hemochromatosis (HH) who have increased iron absorption, and patients receiving high parenteral iron  or repeated blood transfusions for acquired or inherited anemias .14Primary or HH IOC is an autosomal recessive disorder most commonly caused by HH gene mutation that regulates iron absorption. In HH, there is increased intestinal iron absorption and toxic accumulation in the body, leading to organ dysfunction. While it is the most common genetic disorder in White patients, there is low penetrance and disease manifestation, especially in women.15 Cardiovascular disease is a major cause of death in these patients, so early recognition and treatment is important .16Secondary IOC is more common, and one reason for the increased prevalence is improved survival from better treatment strategies in patients with hereditary anemias and other hematological disorders, but with an increased need for chronic blood transfusions.17 It can also affect the conduction system and lead to AV blocks as well as atrial and ventricular arrhythmias.18 In early stages of IOC, iron accumulation in the myocardium leads to diastolic LV dysfunction from the restrictive pathophysiology, which, if left untreated, leads to LV remodeling and progression to end-stage DCM. In some phenotypes, LV dysfunction leads to pulmonary hypertension, RV dilation, and right HF even in patients with preserved LV ejection fraction (LVEF).19When there is excess iron in circulation, transferrin becomes saturated and non–transferrin-bound toxic iron accumulates in hepatocytes, myocytes, endocrine glands, and other organs. In cardiac tissue, accumulation begins in the epicardium, spreads to the myocardium, and eventually involves the endocardium. This helps explain the preservation of systolic function until very late in the disease course.13Symptoms vary, but patients are usually asymptomatic in the early stages. Exertional dyspnea is the initial presenting symptom from restrictive pathophysiology, and as the disease progresses, patients can present with pulmonary edema, leg swelling, arrhythmias, and conduction abnormalities. A high degree of suspicion and clinical vigilance is required, especially in patients at increased risk, to identify cardiac involvement early in the disease process and prevent irreversible HF.20 Serum ferritin can be elevated in other active inflammation conditions, and although these tests are important screening tools, they are not diagnostic of iron overload.Diagnosis can be challenging in the early stages of IOC. A thorough history, physical examination, electrocardiogram, and chest x-ray should be obtained in all patients with suspected disease, with regular cardiac follow-up and screening. Biomarkers, serum ferritin, and transferrin saturation are the initial clues to identify iron overload. If serum ferritin is > 200 ng/mL in premenopausal women or 300 ng/mL in men and postmenopausal women, or if transferrin saturation is > 45% in men and 55% in women, iron overload should be suspected.21 While echocardiography is a great tool to screen and follow patients, it cannot detect cardiac iron content. CMR-derived T2* relaxation time has emerged as the main noninvasive imaging tool for quantitative assessment of cardiac iron content. T2* valve < 20 ms indicates IOC, and < 10 ms indicates severe iron overload and poor outcomes.22 Endomyocardial biopsy is no longer required routinely to assess patients with IOC; instead, CMR can be used to diagnose and monitor response to treatment.Echocardiography is an important imaging tool used to screen and follow patients with suspected IOC. The early finding includes diastolic dysfunction with pseudonormalization or restrictive filling pattern with or without atrial enlargement. In later stages, left and right cardiac chamber dilation with reduced LVEF is seen, and in some cases RV dilation and pulmonary hypertension, even with preserved ejection fraction; LV hypertrophy is generally not seen.Early diagnosis is critical to prevent and treat iron overload and subsequent myocardial fibrosis. Dietary intervention, phlebotomy, iron chelating agents, and guideline-directed medical therapy for HF are the standard of care. Phlebotomy is used to decrease the iron load in patients with HH, beginning initially one or two times a week until the target ferritin level is achieved, followed by maintenance phlebotomies to keep ferritin at goal.23 A heart transplant with or without liver transplant can be considered in patients with advanced HF, although it has been performed in a limited number of selected patients.24In patients with hypotension, malignancy, or anemia, iron chelating agents are used, including deferiprone, deferasirox, and parenteral deferoxamine. Use of iron chelating agents has been shown to prevent the development of IOC and has also been shown to reduce myocardial iron overload, improve cardiac function, reverse arrhythmias, and improve survival in patients with IOC.GLA gene that encodes alpha-galactosidase A . There is a disruption in glycosphingolipid metabolism due to alpha-Gal A deficiency that results in intralysosomal accumulation of glycosphingolipids in various organs such as the heart, kidney, and nerves. Men are more commonly affected than women, and disease can present during childhood or early adulthood. Cardiac manifestations present later in life, the third decade in men, and can be silent until much later in women. In the classical variant, cardiac manifestations include arrhythmias, valvular abnormalities, and cardiomyopathy; however, the isolated cardiac variant  presents later in life as LV hypertrophy. Echocardiography shows LV wall thickening, and tissue Doppler signals demonstrate reduced systolic and diastolic velocities of the mitral and tricuspid annulus. CMR may show a midmyocardial pattern of late enhancement of the basal inferolateral wall, sparing of subendocardium, and prolonged T2 relaxation time. For diagnosis in men, leukocyte alpha-Gal A activity is measured; however, this can be normal in heterozygous females, so genetic testing is recommended in women. EMB may be necessary in patients with uncertain genetic testing that demonstrates concentric lamellar bodies in the sarcoplasm of myocytes. Other than the standard medical therapy for HF, enzyme replacement therapy with agalsidase beta is the mainstay of treatment.25Anderson-Fabry’s disease is an X-linked recessive lysosomal storage disorder with a mutation in the 26 The etiology of EMF has been debated, and various factors have been suggested, including parasitic infection, malnutrition, protein-poor diet, magnesium deficiency, high vitamin D, serotonin, cassava plant toxicity , eosinophilia, and immunological and genetic influence.27 EMF starts as an acute inflammation of the heart, leading to myocardial edema, eosinophilic infiltration, vasculitis, and fibrosis, collectively known as the active phase. Thromboembolic events are frequent during this phase, with mural thrombi occurring in apical and valvular pockets. Some patients go into fulminant cardiogenic shock, while others have recurrent inflammation that leads to fibrosis and, eventually, the chronic phase.28 In the chronic phase, there is fibrotic obliteration of one or both ventricles, and restrictive physiology, papillary muscle, and chordae tendineae involvement can cause valvular regurgitation. Biventricular involvement is seen in 50% of patients, followed by RV cardiomyopathy, and isolated left-sided disease is rarely seen. Patients present with dyspnea, paroxysmal nocturnal dyspnea, and lower-extremity swelling; when there is predominant right-sided involvement, marked ascites, elevated jugular venous distension, facial edema are common.29 Atrial fibrillation occurs in 30% of cases and predicts poor outcomes, especially in end-stage disease.30Endomyocardial fibrosis (EMF) is an idiopathic disease that causes inflammation and fibrosis of the endomyocardium in one or both ventricles, leading to restrictive ventricular filling. EMF has geographic clustering and is prevalent in tropical countries such as Uganda, Nigeria, and Brazil. EMF has a strong association with poverty and malnutrition and is a disease of the young, with bimodal peaks at ages 10 and 30 years.31 Medical therapy includes symptomatic treatment with diuretics and vasodilators, anticoagulation in patients with atrial fibrillation, and mural thrombus. Finally, management of advanced disease with endomyocardectomy, valve repair or replacement has shown to offer long-term benefits.27Echocardiography is useful in diagnosis. Other than the typical restrictive filling pattern noted on Doppler assessment, characteristic findings include retracted ventricles with obliteration of the apex, endomyocardial thickening, atrial enlargement, and AV valve regurgitation. CMR can be useful in early disease to identify patients with active inflammation who may benefit from steroids; in chronic disease, LGE can demonstrate the extent of fibrosis, which correlates with prognosis and need for surgery.Table 5).32 Eosinophil-mediated endomyocardial damage can be seen on EMB, although the degree of cardiac injury does not correlate with the degree of eosinophilia. Cardiac involvement in HES evolves in three stages: an acute necrotic stage, an intermediate stage with thrombus formation, and a late fibrotic stage characterized by restrictive cardiomyopathy and AV valvular regurgitation depending on involvement of the chordae tendinae.33 In the acute phase, there is myocardial eosinophilic infiltration and degranulation that leads to myocardial necrosis and microabscess formation. At this stage, patients are generally asymptomatic except for those with fulminant eosinophilic myocarditis. Serum troponin elevation can be noted, and echocardiography is generally unremarkable.34 In the second stage, ventricular wall vascular damage leads to von Willebrand factor, tissue factor activation, and thrombus formation along with areas of damaged endocardium.35 Mural thrombus can be present in both ventricles, the ventricular outflow tract, and subvalvular areas. Distal embolization of the thrombus can lead to stroke, limb ischemia, and other thromboembolic consequences. In the third stage, persistent inflammation and necrosis will lead to subendocardial fibrosis and restrictive cardiomyopathy. Involvement of the valvular structures can lead to valvular incompetence from entrapment, rupture of the chordae tendinea, or fusion of the valves to the surface of the endocardium.36 Echocardiography in HES shows endomyocardial thickening/fibrosis, apical thrombus, biatrial enlargement, restrictive filling, and AV valvular regurgitation. CMR can differentiate different stages of the disease and can delineate intracardiac thrombus and the extent of fibrosis .37Previously known as Loeffler’s endocarditis, hypereosinophilic syndromes (HES) are a group of disorders that cause persistent eosinophilia (absolute eosinophil count > 1.5 × 109/L) for longer than a month and cause eosinophil mediated end-organ damage. HES can be primary , secondary , or idiopathic . Anticoagulation is not used prophylactically but is indicated in patients with thromboembolic events. Its use in patients with ventricular thrombus is debated because thrombus formation occurs at the damaged endocardium, and systemic anticoagulation may not suppress thrombosis. Vitamin K antagonists are preferred although there is no consensus on INR goal.32 In the fibrotic stage, some patients may need endomyocardectomy, valve repair, or replacement if there is valvular involvement. Bioprosthetic valves are preferred over mechanical valves due to the risk of thrombosis, even in patients on anticoagulation. Optimal medical management of the underlying disease is paramount as persistent eosinophilia is associated with poor outcomes and rapid valve deterioration. Endomyocardectomy in advanced restrictive cardiomyopathy has been shown to improve 5-year survival compared to medical management alone.39EMB is the gold standard in the diagnosis of eosinophilic cardiomyopathy but is reserved for patients with an unclear diagnosis. Management strategies depend on the underlying condition; in the early stages of disease, high-dose corticosteroids can prevent disease progression to endomyocardial fibrosis. Steroid-sparing or second-line agents such as hydroxyurea, interferon alfa, methotrexate, and IL-5 blocker mepolizumab are other treatment options.40 These medications can cause RCM with or without conduction abnormalities. On echocardiography, there is increased ventricular wall thickness and restrictive filling pattern. Endomyocardial biopsy, which must include samples sent for electron microscopy, shows loss of architecture, curvilinear bodies, lysosomes, myeloid bodies, glycogen granules, and myocyte vacuolation. Drug withdrawal in some cases has shown complete resolution of EMB changes.4Long-term use of chloroquine and hydroxychloroquine has been associated with cardiotoxicity. Risk factors are thought to be old age, female sex, long duration of hydroxychloroquine use (> 10 years), high dosage of the medication, renal dysfunction, and preexisting cardiac disease.41 Radiation causes microvascular endothelial injury and inflammation that eventually leads to myocardial fibrosis, restrictive hemodynamics, and diastolic dysfunction. Systolic dysfunction may also be seen with concomitant use of anthracycline chemotherapy. Patients can be asymptomatic or can have exercise intolerance and symptomatic HF. Echocardiography demonstrates diastolic dysfunction, valvular calcification, and normal or reduced LVEF. Constrictive pericarditis physiology is present in some patients and may overlap with RCM, presenting a diagnostic challenge.42 Prevention by limiting cardiac radiation dose is important, and more novel techniques for treatment planning using rotational and multiple radiation sources, respiratory gating, or deep inspiration breath-hold techniques are now recommended to decrease cardiac radiation exposure.43 The treatment strategy for HF is symptomatic management. Heart transplantation can be considered in patients with advanced HF, although the United Network for Organ Sharing database study demonstrated that 5-year survival was lower than in transplants for other types of RCM, mainly due to higher postoperative mortality. Radiation-induced RCM with the end-stage disease was predominantly in younger females with previous cardiac surgeries.44Mediastinal radiation has been associated with long-term cardiovascular sequelae, and these patients have an increased risk of coronary artery disease, valvular heart disease, congestive HF, arrhythmias, and pericardial disease. Radiation-induced cardiotoxicity typically occurs with a latent period of 10 to 15 years. Patients treated before 40 years of age are at increased risk given their longer period of survival.Restrictive cardiomyopathy usually presents as HFpEF and has distinct echocardiographic and hemodynamic features. Given its varied etiology and clinical presentations, it can be a diagnostic challenge and requires a high degree of suspicion. Evaluation of patients with suspected RCM is guided by their history, presenting features, and clinical suspicion. Management involves treatment of the underlying condition in secondary RCM, symptomatic therapy for systemic and pulmonary congestion, and early initiation of advanced HF therapies when needed.Restrictive cardiomyopathy (RCM) is a spectrum of diseases that increase myocardial stiffness and lead to diastolic dysfunction.RCM can be primary/idiopathic or secondary to systemic disorders.Echocardiographic findings include biatrial enlargement, normal left ventricular cavity size, and systolic function with severe diastolic dysfunction.A high degree of clinical suspicion and disease-specific workup is required for diagnosis.Management includes symptomatic treatment and treatment of underlying systemic disease.


ECV was increased in patients with LGE lesions compared to those without . The presence of LGE lesions was associated with a fivefold increase in the incidence of all-cause mortality , independent of age, sex, New York Heart Association (NYHA) functional class, NT-proBNP, LGE mass and LVEF. Myocardial scarring on CMR is associated with increased mortality in HF patients with LVEF > 40% and may aid in selecting a subpopulation at increased risk.Heart failure (HF) with mid-range or preserved ejection fraction  is a heterogeneous disorder that could benefit from strategies to identify subpopulations at increased risk. We tested the hypothesis that HFmrEF and HFpEF patients with myocardial scars detected with late gadolinium enhancement (LGE) are at increased risk for all-cause mortality. Symptomatic HF patients with left ventricular ejection fraction (LVEF) > 40%, who underwent cardiac magnetic resonance (CMR) imaging were included. The presence of myocardial LGE lesions was visually assessed. T1 mapping was performed to calculate extracellular volume (ECV). Multivariable logistic regression analyses were used to determine associations between clinical characteristics and LGE. Cox regression analyses were used to assess the association between LGE and all-cause mortality. A total of 110 consecutive patients were included  1259 pg/ml). LGE lesions were detected in 37 (34%) patients. Previous myocardial infarction and increased LV mass index were strong and independent predictors for the presence of LGE  2.07–19.31, The online version contains supplementary material available at 10.1007/s00380-021-01910-2. Heart failure (HF) with mid-range or with preserved ejection fraction  > 40%) has a high morbidity and mortality rate and there are currently no evidence-based therapies for this condition –4. The lCardiac magnetic resonance (CMR) imaging offers unique opportunities for tissue characterisation that may assist in the identification of distinct subpopulations of HF with LVEF > 40%. In particular, the ability of CMR to detect focal myocardial scars using late gadolinium enhancement (LGE) imaging is of interest, as myocardial fibrosis is thought to be a pathophysiological hallmark of HF with LVEF > 40% . LGE lesN-terminal prohormone of brain natriuretic peptide (NT-proBNP) was > 125 pg/ml and echocardiography showed evidence of LV diastolic dysfunction, left atrial dilatation and/or LV hypertrophy, according to current European Society of Cardiology criteria  days. CMR measurements are depicted in Table p = 0.02). LVEF on echocardiography and CMR were moderately associated . CMR characteristics for HFpEF and HFmrEF are displayed in Supplementary Table 2.Patients with an LGE lesion were more often male  patients. In patients with LGE lesions, native T1 times and ECV were significantly increased compared to patients without LGE lesions  with LGE lesions are depicted in Table p = 0.001 and 1.68 (1.03–2.73), p = 0.04, respectively). Forced entry of age and sex into the model did not improve the predictive accuracy of the model.Patient- and CMR characteristics with a univariable association  (Table During a median follow-up of 34 months (interquartile range 19–53), 19 (17%) patients died. Of these 19 patients, 11 died due to cardiovascular causes and 8 due to a variety of non-cardiovascular causes such as cancer, and chronic obstructive pulmonary disease. In Fig. In the present study, we sought to determine whether CMR with LGE imaging could aid in the identification of a high-risk subgroup of patients with well-defined HFmrEF and HFpEF. Myocardial scarring was present in one third of patients with HFmrEF and HFpEF. In addition, myocardial scars were associated with left ventricular hypertrophy and a history of myocardial infarction. In patients with myocardial scar, ECV values were significantly increased in the myocardium remote from the LGE lesion. Lastly, the presence of myocardial scar was associated with poor outcome. Together, our findings indicate that CMR with LGE imaging may aid in detecting a subpopulation of high-risk HF patients with LVEF > 40% and its use should, therefore, be considered in the work-up of HF.The identification of high-risk subgroups in HF with LVEF > 40% could be a first step towards better, more tailored treatment of this disease. Our data suggest that the detection of myocardial scar with CMR can help identify such a high-risk subgroup. It is plausible that the difference in survival between patients with- and without an LGE lesion is due to an increase in arrhythmic death. Earlier studies in HFrEF patients showed that the presence of an LGE lesion was associated with ventricular arrhythmic events . HoweverOur data support the findings of a prior study, which reported increased mortality and HF hospitalizations in HFpEF patients with myocardial scar on CMR . HoweverIn our study, LVEF and LV GLS were not associated with LGE or all-cause mortality. This is in line with previous studies, showing that LV systolic function is not independently associated with outcome in patients with HFpEF . LGE volNative T1 and ECV values were significantly increased in the myocardium remote from the LGE lesion, indicating that patients with a focal myocardial scar also display more interstitial myocardial fibrosis. These findings suggest that focal fibrosis is also associated with more general fibrotic heart disease in HF with LVEF > 40% and may reflect a higher burden of heart failure.Our study is exploratory in nature and suffers from general limitations associated with its retrospective nature. In addition, a few specific limitations should be acknowledged. First, because T1/ECV mapping became available in our center during the course of the study, it is only available in 75 out of 110 patients. Second, although our population was meticulously characterised, our sample size is relatively small and our mortality rate was lower than in most HFmrEF/HFpEF trials. The incidence and prognostic significance of LGE may, therefore, be different in the general HFmrEF/HFpEF population. Fourth, we did not include a control group, and we cannot rule out that the association between LGE and mortality also applies to similar subjects without HF.Our study has shown that a considerable amount of HF patients with LVEF > 40% have myocardial scars and these patients are at increased risk. The presence of an LGE lesion may not only aid in follow-up, but the pattern of LGE may also assist in the diagnosis of the underlying cause of HFpEF/HFmrEF. For instance, of the 22 patients in our study with an ischemic LGE scar, 8 (36%) did not have a history of myocardial infarction. These findings suggest that HF was caused by a silent myocardial infarction, and these patients may benefit from anti-ischemic therapy. On the other hand, clinical trials may also profit from selecting HF patients with LGE lesions, as this would result in a study population at increased risk.Myocardial scarring on CMR is associated with increased mortality in HF patients with LVEF > 40% and may aid in selecting a subpopulation of patients at increased risk.Supplementary file1 (DOCX 19 KB)Below is the link to the electronic supplementary material.


A growing number of older adults suffer hip and pelvic fractures leading to hospital admission. They often result in reduced physical activity (PA) and impaired mobility. PA can be objectively measured with body-worn sensors. Usually, global cumulative PA parameters are analysed, such as walking duration, upright-time and number of steps. These traditional parameters mix different domains of PA, such as physical capacity (PC), behaviour and living environment. We examined the change of global cumulative PA measures during rehabilitation and after discharge in patients with hip or pelvic fracture and whether more ‘in-depth’ PA parameters, such as walking interval length, variability of interval length and sit-to-stand transitions and their changes during rehabilitation and 3 months after discharge might better reflect the above mentioned three clinically relevant domains of PA.This study is a secondary data analysis of a randomised controlled trial to improve PA and fall-related self-efficacy in hip or pelvic fracture patients (≥60 years) with concerns about falling. Changes of accelerometer-measured global cumulative and in-depth PA parameters (activPAL3) were analysed in an observational design before and after discharge combining both groups. For comparison, the same analyses were applied to the traditional PC measures gait speed and 5-chair-rise.Seventy-five percent of the 111 study participants were female (mean age: 82.5 (SD = 6.76) years. Daily walking duration, upright time and number of steps as aspects of global PA increased during inpatient rehabilitation as well as afterwards. The in-depth PA parameters showed differing patterns. While the total number of walking bouts increased similarly, the number of longer walking bouts decreased by 50% after discharge. This pattern was also seen for the average walking interval length, which increased by 2.34 s : 0.68; 4.00) during inpatient rehabilitation and decreased afterwards below baseline level ). The traditional PC measures showed similar patterns to the in-depth PA parameters with improvements during rehabilitation, but not at home.Our findings suggest that the in-depth PA parameters add further information to the global cumulative PA parameters. Whereas global cumulative PA parameters improved significantly during inpatient rehabilitation and after discharge, in-depth PA parameters as well as PC did not continuously improve at home. In contrast to global cumulative PA parameters the in-depth parameters seem to reflect contextual factors such as the build environment and aspects of PC, which are traditionally assessed by clinical PC measures. These in combination with digital mobility measures can help clinicians to assess the health status of fragility fracture patients, individually tailor therapy measures and monitor the rehabilitation process. A growing number of older adults suffer hip and pelvic fractures occurring as a result of a low energy trauma . In EuroImproving PA and especially mobility that allow a return to the place of origin must be considered as the core elements and the goals of the rehabilitation process for fracture patients . SufficiTherefore, it makes sense to assess and monitor the PA during rehabilitation and after discharge. This enables clinicians to personalise therapy, give face valid feedback to patients and not the least could allow health care funders to assess cost-effectiveness and cost-utility of different approaches.Body-worn sensors that objectively and continuously collect data on body movements are increasingly being used augmenting self-report measures of patient reported PA. In fragility fracture patients, the few studies using sensor-based measures have analysed global cumulative PA parameters. Number of steps as a surrogate measure of PA has been used as an outcome after hip fracture –16. AnotHowever, such traditional cumulative measures reflect a mix of several PA domains. By PA domains we mean three factors: Physical capacity (PC), such as muscle strength, behavioural aspects and environmental aspects. By behavioural aspects we mean the influence of for example the social environment and intrinsic or extrinsic motivation on PA. By environmental aspects we mean the influence of for example room sizes, ward lengths, accessibility of the housing environment and outdoor environment and number of stairs on PA. Therefore, besides these global cumulative PA parameters, we additionally analysed more ‘in-depth’ PA parameters, such as the pattern of different walking bout intervals, the variability of the walking bouts, the number of sit-to-stand transitions and other features, because we think that they might help to better reflect these mentioned PA domains, such as PC and behavioural or environmental aspects.Therefore, the aim of our analysis was to examine the change of global cumulative PA measures during rehabilitation and after discharge in patients with hip or pelvic fracture and whether more ‘in-depth’ PA parameters, such as walking interval length, variability of interval length and sit-to-stand transitions and their changes during rehabilitation and 3 months after discharge might better reflect the mentioned three clinically relevant domains of PA.The current study is a secondary, explorative data analysis of a randomised controlled trial that aimed to improve PA and fall-related self-efficacy in hip and pelvic fracture patients , 23. ParThe primary analyses did not show statistically significant differences between IG and CG regarding PA outcomes . TherefoAll PA outcomes were measured using an inertial sensor including a tri-axial accelerometer . The device was attached on the midline anterior aspect of the preferred upper thigh and was fully wrapped in waterproof adhesive tape to allow participants to wear the activPAL3 during showering and bathing activities. The commercial manufacture’s software was used to initialise the accelerometer with the default settings  and to process the recorded data (activPAL process and presentation V7.2.32). The algorithm detects postures , counting steps and sit-to-stand transitions. The activities detected can be classified as inactivity  and upright time, such as standing and walking . PA was In the present study, we have followed the analyses previously described by Klenk and colleagues  analysinAs Klenk and colleagues  suggesteHabitual gait speed and 5-chair-rise time  were assAge and sex were ascertained by patient file. Education was asked by interview. Cognitive function was screened by the Short Orientation–Memory–Concentration Test (SOMC) , a test The analyses focused on the progression of global cumulative as well as ‘in-depth’ PA-parameters between times of measurement. Least-square means and mean differences with 95%-confidence intervals were calculated for each point in time. For comparison, the same analyses were applied to the PC measures gait speed and 5-chair-rise, traditionally being used in clinical routine. Statistical analyses were performed using SAS 9.4.The study population comprised 111 individuals. Seventy-five percent of the participants were female, and the mean age was 82.5 years (SD = 6.76 years). Participants’ characteristics are presented in Table Average daily walking duration, average daily number of steps and average daily upright duration increased during inpatient rehabilitation and further until to the follow-up three months after discharge. Walking duration and number of steps had their main gain during geriatric rehabilitation . These parameters levelled off in the home environment . The increase of daily upright duration between T0 and T1 (+ 27%) and between T1 and T2 (+ 33%) were similar , but mainly after discharge with an increase of 64%. The number of walking bouts ≥10 s rose by 111% (from 36 to 76 bouts) in total with equal slopes in both periods. In contrast, the number of longer bouts ≥60 s increased during inpatient rehabilitation by 50% (+ 2) and decreased by the same amount at home. All changes were statistically significant as indicated by the confidence intervals of the mean value differences.The observed pattern for number of walking bouts was also reflected by the daily walking interval length with an increase by 2.34 s : 0.68; 4.00) from 11.9 s to 14.2 s during inpatient rehabilitation. However, the walking interval length decreased after discharge even below the baseline level to 10.0 s . The variability for walking interval lengths ≥10s indicated by the coefficient of variation increased slightly between T0 and T1 by 13% and more pronounced between T1 and T2 by 28%.Median cadence only statistically significantly improved during inpatient rehabilitation by 6.23 steps per minute . The average daily number of sit-to-stand transfers increased during geriatric rehabilitation by 14% (49 to 56 sit-to-stand transfers), but decreased in the home environment below the baseline level (44 sit-to-stand transfers).The PC in-lab measures of gait speed and 5-chair rise time showed a comparable pattern to the in-depth PA parameters with a statistically significant improvement during inpatient rehabilitation and no further progression after discharge.Until now, only a few studies on fragility fracture patients have reported objective sensor-based PA measures. These have mainly analysed global cumulative parameters, such as walking duration, uptime and step counts. In our study we additionally examined further in-depth PA parameters. These parameters showed different patterns and obtain a more detailed picture of mobility during rehabilitation and after discharge, which might better reflect different clinically relevant domains of PA, such as PC. The in-depth PA parameters seem also to have been affected by behavioural and environmental factors.All measured global cumulative PA parameters assessed by an inertial sensor improved statistically significantly and clinically meaningfully during inpatient rehabilitation and after discharge. At home uptime duration  reached more than 4 h a day. Other published studies showed improvements in global cumulative PA parameters such as “daily walking duration”, “daily number of steps” and/or “daily upright time” , 38, 39.The in-depth PA parameters underpin the change of the global cumulative PA parameters after discharge, but give further insights in to the change of PA patterns. The following three findings underline the shift to shorter walking bouts after discharge: the decrease of the mean walking interval length after an initial increase during rehabilitation, the rising number of walking bouts and the decline of longer bouts ≥60 s at home. The profiling shows that after discharge patients are longer on their feet, but interrupt walking activities more often to do other standing activities. This probably reflects the required person-environment fit. The walking bouts of 10 s and more are particularly relevant for longer distance indoor activities such as transfers between rooms at home. In contrast, walking bouts of 60 s and more reflect very long indoor distances like in the inpatient setting  or outdoor activities. The majority of the participants in the study were mostly homebound, which corresponds to the observed decrease of walking bouts of 60 s and more. Somewhat similar observations have been reported by other publications in the field . The incThe current clinical gold standard PC parameters gait speed and chair rise improved by 10–20% during inpatient rehabilitation, but not after discharge. The pattern corresponds to the progress of the in-depth PA parameters median cadence and number of sit-to-stand transfers, which might reflect the same PA domain, namely PC. These in-depth PA parameters could help to continuously monitor PC during rehabilitation and at home. Our results indicate that outpatient rehabilitation measures are lacking in this population. Outpatient programmes such as the Eva-Hip study  show thaOur findings suggest that the in-depth PA parameters add further information to the global cumulative PA measures. Whereas all parameters improved significantly during inpatient rehabilitation, some parameters, which might be mainly related to PC, did not continue to improve after discharge. Furthermore, contextual factors such as the build environment probably have an influence on PA parameters. Therefore, we think that a matrix of in-depth digital mobility parameters can add important information to better describe domains of PA, such as PC, behavioural and environmental factors, and its changes. However, the validity of these in-depth PA parameters has to be proven in future studies.We have to acknowledge certain limitations. First, it has been shown that activPAL and other sensors  may undeWe observed the changes of PA patterns in patients after hip and pelvic fracture during inpatient rehabilitation and transition to home settings. Global cumulative PA parameters, such as walking duration, number of steps and upright duration provide measures of total activity. The in-depth PA parameters add more detailed information about different domains of PA: They seem to reflect the living environment and aspects of PC, which are traditionally assessed by PC measures, such as gait speed or 5-Chair rise time. In combination with these classical clinical outcomes, digital mobility measures can help clinicians to assess the health status of fragility fracture patients, individually tailor therapy measures and monitor the rehabilitation process.


Effective anticancer treatments have dramatically improved the outcome of patients with cancer, but cardiac toxicity reduces their clinical efficacy in a non-negligible percentage of patients. Sacubitril/valsartan is a new paradigm in the treatment of chronic heart failure, with a reduced ejection fraction due to the enhancement of natriuretic peptides' properties when coupled with a blocking effect on the angiotensin II type 1 (AT1) receptors. As with other clinical conditions of heart failure with potentially reversible declines in cardiac function, a wearable cardioverter defibrillator (WCD) is a valid tool for protection against sudden death until recovery occurs. We report a case series of four patients with chemotherapy-related acute cardiac failure with severely reduced cardiac function. They were successfully treated with sacubitril/valsartan while being protected from malignant arrhythmias using a wearable cardioverter defibrillator until the recovery of cardiac function. Sacubitril/valsartan was confirmed to be effective in anthracycline-related cardiac toxicity and the wearable cardioverter defibrillator should be considered as a support tool even in the oncology patient. Improvements in anti-cancer global strategy have resulted in better outcomes for a large part of patients with cancer, with many of them experiencing remission or long-term survival. Cardiovascular disease is the second leading cause of death in cancer survivors, preceded only by the cancer-related mortality itself . SystoliCardiac magnetic resonance (CMR) represents the gold standard in cardiac function assessment and can be used for an early-stage screening of heart damage. Its role in tissue characterization can help eliminate other possible causes of myocardial dysfunction when cardiac toxicity is suspected. For this purpose, T1 and T2 mapping, in addition to late gadolinium enhancement (LGE), are very useful tools . We coll2), and with a regular clinical and echocardiographic follow-up. The patient was hospitalized in November 2019 for acute heart failure with reduced ejection fraction (EF 25%) 1 month after the end of chemotherapy. The event occurred 8 months after the treatment started and 5 months after crossing the threshold dose of 300 mg/m2. The patient started the anthracyclines therapy after a long period of hospitalization due to complications from abdominal surgery and a significant weight loss. No coronary lesions were detectable on coronary angiography. The CMR findings were an increased biventricular size and a severe biventricular dysfunction, with left systolic ejection fraction (LVEF) of 25% and right ventricle (RV) EF of 40%, increased native T1 signal  with a marked increase of extracellular volume (ECV) , but no LGE was found. Laboratory findings showed normal high-sensitive C-reactive protein (hs-CRP) levels and glomerular filtration rate. High-sensitive troponin T (hs-TnT) was elevated at admission time (190 pg/ml), with a slight decline during the in-hospital stay (162 pg/ml). The N-terminal prohormone of natriuretic peptide (NT-proBNP) levels was clearly elevated at baseline , but we observed a reduction during hospitalization to 7,200 pg/ml at discharge. During the follow-up, the NT-proBNP levels continued to decrease to 530 pg/ml within the year. Given the severe LV dysfunction, the patient was discharged with heart failure therapy  and a WCD. At the first follow-up visit 10 days later, ACE-inhibitor was replaced with S/V due to persistent systolic dysfunction. After 3 months, the LVEF increased from 25 to 40% with the reverse remodeling of ventricular size and WCD was discontinued. The patient compliance to WCD was high with a median of 22.4 h/day. No significant arrhythmias were detected. Echocardiography findings were confirmed at 6 months by CMR (LVEF 43% and RVEF 51%), and while the native myocardial T1 signal decreased, it was not yet normal . At the one-year follow-up visit, the LVEF had improved to 45%  plus cyclophosphamide followed by trastuzumab for 1 year, ending in 2007. In September 2020, the patient was hospitalized for acute heart failure, with EF at 30%, and a coronary computed tomography (CT) that documented the absence of coronary artery disease. The patient reported smoking habits and hypertension in her medical history. The Hs-CRP and hs-TnT values and the glomerular filtration rate were all within the normal range, while NT-proBNP levels were elevated at admission , but during hospitalization, they rapidly decreased to 863 pg/ml at discharge and normalized at 3 months follow-up. The CMR showed an LV dilatation with severe impairment of contractile function (LVEF 32%) and a mild RV failure (RVEF 48%); native myocardial T1 signal was increased  while LGE was absent. The patient was discharged with WCD and heart failure therapies including beta-blocker, anti-aldosterone therapy, and S/V that was later replaced by ramipril (2.5 mg/day) due to hypotension. After 3 months, the CMR highlighted a normalized left ventricular size and right ventricular function (RVEF 69%), left ventricle systolic function improvement (LVEF 48%), and a native myocardial T1 signal decreased to 1,000 ms with respect to baseline 1,040 ms with normal ECV (28%). No LGE was detectable, but septal edema was still present in the T2 mapping. The WCD was discontinued due to LVEF recovery . The patient presented with a reduced glomerular filtration rate and elevated hs-CRP levels (42 mg/L). The filtration rate remained unchanged during the in-hospital stay, while hs-CRP decreased to 18 mg/L. A high-sensitive troponin T was elevated at admission time (130 pg/ml) with a trend in reduction (90 pg/ml). The baseline NT-proBNP levels were clearly elevated , with a sharp reduction during hospitalization . A coronary CT  showed diffuse and severe coronary atherosclerosis without obstructive coronary disease. The patient was started on heart failure therapy with beta-blocker and S/V; after 2 weeks from therapy, introductory CMR was performed and has shown the normal biventricular dimensions and right ventricular function (RVEF 60%), left ventricular systolic function improvement (LVEF 45 vs. 25%), interventricular septal and lateral wall abnormal native T1 signal , and an increased ECV (32%) and a mid-wall septal LGE with a non-ischemic pattern. At the one-month follow-up, LVEF had further improved to 48% .2), followed by radiotherapy (dose 50Gy) in 2003. In January 2021, the patient reported dyspnea for mild effort. This patient also reported a history of smoking and hypertension. Chest X-Ray showed a pleural effusion, and the echocardiography documented a dilated left ventricle with severe systolic dysfunction (EF 25%) leading to hospitalization. The admission hs-CRP levels and hs-TnT were slightly elevated but remained in a stable trend during hospitalization. The filtration rate showed a baseline reduction that stayed unchanged during observation. As expected, the NT-proBNP levels were clearly elevated at baseline  but we observed a sharp and fast reduction . No coronary artery disease was found at coronary angiography. CMR confirmed an increased left ventricular size, severe biventricular systolic dysfunction (LVEF 27% and RVEF 29%), and no significant LGE. Heart failure therapy, with beta-blocker and anti-aldosterone therapy plus S/V, was started together with SGLT2 inhibitor empagliflozin for the previously undiagnosed diabetes. The patient was discharged with WCD. At the first follow-up visit 1 month later, LV size was normal, and the ejection fraction improved to 35%. At the three-month follow-up visits, LVEF had improved to 46%, and WCD was discontinued  is the gold standard for ventricular dimension and ejection fraction assessment. All our patients had biventricular dysfunction in the acute phase, but, while LV impairment was clearly detected by echocardiography, RV dysfunction was detected only by CMR. However, EF reduction is just a small part of cardio-toxic damage . Early dThe reference for non-invasive recognition of focal fibrosis areas is LGE, but a limitation of this technique is the low sensitivity for diffuse fibrosis that is more frequent in patients with cardiotoxicity, especially in anthracycline cardiomyopathy . The T1 Implantable cardioverter defibrillators (ICDs) are indicated for the primary prevention of sudden cardiac death (SCD) in patients with reduced LV function . A subset of patients with cancer is at risk for SCD due to a variety of cardiac causes, including chemotherapy-induced cardiomyopathy. The data regarding the risk of arrhythmic death in these patients are very limited, but a study on the use of WCD in patients suffering from anthracycline cardiotoxicity showed a risk of malignant arrhythmia at around 7% in 3 months, which is significantly higher than in the general population with heart failure . An indiChemotherapy-induced acute heart failure could represent a potentially life-threatening side effect of many oncology drugs. Besides representing a clinical emergency, it could also negatively affect long-term patient outcome from an oncological point of view. In fact, a steadily impaired EF could limit the anticancer therapeutic options. Prompt and steady recovery of cardiac function has been a 2-fold relevance. All available therapeutic strategies should be implemented to get this goal. The presented case series highlighted the positive role of the early use of S/V in LVEF recovery in this clinical setting. The WCD should be considered in oncology patients when recovery of cardiac function is expected. A prospective evaluation of a larger size of the S/V effect in an oncology population is needed to confirm its retrospective and positive results.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.Written informed consent was obtained from all participants for their participation in this study.MLC, KC, GS, JDM, AC, FS, and EV: study conception and case description. MLC, KC, GS, AC, GC, NM, CT, and IB: drafting of the manuscript or revising it critically for important intellectual content. All authors: final approval of the manuscript.This study received funding from Zoll  for the open access option only. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.This study received funding from Zoll  for open access option only. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.