Background: Psychosocial stress has been associated with the development and progression of atherosclerotic cardiovascular disease (CVD). Previously, we reported subtle differences in global longitudinal strain in somatically healthy women with a psychiatric diagnosis of borderline personality disorder (BPD). This study aimed to investigate the impact of BPD on segmental myocardial wall motion using speckle tracking echocardiography (STE) analysis. Methods: A total of 100 women aged between 18 and 38 years were included in this study. Fifty patients meeting the diagnostic criteria for BPD were recruited from the Department of Psychiatry  and compared with fifty age-matched healthy control subjects without previous cardiac disease. Laboratory tests and STE were performed with segmental wall motion analysis. Results: The BPD group had a higher prevalence of risk factors for CVD, with smoking and obesity being predominant, when compared with the control group. Other cardiovascular parameters such as blood pressure, glucose, and cholesterol levels were also elevated, even though not to pathological values. Moreover, in the STE analysis, the BPD group consistently exhibited decreased deformation in nine myocardial wall regions compared with the control group, along with a shift toward higher values in the distribution of peak pathological segments. Additionally, significantly higher values of free thyroxine concentration and thyroid’s secretory capacity were observed in the BPD group, despite falling within the (high-) normal range. Conclusions: BPD is associated with chronic stress, classical risk factors, and myocardial wall motion abnormalities. Further exploration is warranted to investigate the relationship between high-normal thyroid metabolism, these risk factors, and myocardial function in BPD patients. Long-term follow-up studies would be valuable in confirming the potential for predicting adverse events. Beyond traditional risk factors, psychosocial stress has been found to be associated with the development and progression of atherosclerotic cardiovascular disease (CVD) . Not onlIn a recent study, we found small variations in global longitudinal strain (GLS) among physically healthy women diagnosed with borderline personality disorder (BPD) . FurtherBPD is the most common personality disorder in the general population, with a prevalence rate of approximately 3% and a typical onset in adolescence or early adulthood ,12. BPD Prior research has indicated that individuals diagnosed with BPD exhibit elevated prevalence rates of cardiovascular risk factors, such as hypertension, diabetes mellitus, and obesity ,15. ConsWhile emotional stress has been shown to trigger characteristic patterns of segmental myocardial contractility decline in Takotsubo syndrome (TTS) , it remaA detailed description of the study population can be found elsewhere . In summIn order to obtain images for two-dimensional speckle tracking echocardiography (STE), transthoracic echocardiography was performed on all participants following the recommendations of the EACVI/ASE/Industry Task Force on standardization of deformation imaging . The exaFor semiautomated two-dimensional speckle tracking analysis, each recording was processed with dedicated acoustic tracking software .All measurements were conducted in accordance with the guidelines for two-dimensional speckle tracking provided by the European Association of Cardiovascular Imaging (EACVI) and the American Society of Echocardiography (ASE)/Industry Task Force , under tDue to its representation of myocardial shortening in comparison with the baseline length, global longitudinal strain (GLS) of the left ventricle is reported as a negative value. When analyzing speckle tracking data, especially for categorizing GLS within a reference value range, only studies that established their standard values using the General Electric (GE) device manufacturer were considered. This approach was taken due to potential variations among providers and software. According to the American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI), a GLS value less negative than −20% is indicative of regional functional irregularities in the myocardium. Reference values for global and segmental longitudinal strain were obtained from the HUNT study .A single serum tube and one EDTA tube of blood were obtained from each participant to undergo laboratory analysis. The following parameters were analyzed using a fully automated chemiluminescence-based system : Cholesterol, HDL cholesterol, LDL cholesterol, glycosylated hemoglobin (HbA1c), thyrotropin (TSH), free thyroxine (FT4), free triiodothyronine (FT3), and C-reactive protein (CRP). Intra-assay coefficients of variation (CV) for all parameters ranged between 2.0% and 5.0%, while inter-assay coefficients of variation (CV) ranged between 3.0% and 7.5%.To evaluate the respective contributions of the pituitary and thyroid glands to variations in hormone concentrations, Jostel’s TSH index (JTI), thyroid’s secretory capacity (SPINA-GT), and the sum activity of peripheral deiodinases (SPINA-GD) were calculated based on steady-state concentrations of TSH, thyroid hormones, and constants for plasma protein binding and kinetics, respectively. These calculations were performed according to recent recommendations for thyroid trial design ,24.p < 0.05 was selected for all tests. Data are presented as median (interquartile range (IQR)) for continuous variables with a non-normal distribution and as frequency (%) for categorical variables. Mean ± SEM is presented for continuous variables with a normal distribution. Normal distribution was assessed using the Kolmogorov test. Comparisons of categorical variables were conducted with the Pearson chi-square test, and continuous variables were analyzed with Student’s t-test and the Mann–Whitney U test.All analyses were performed using IBM SPSS Statistics for Windows, version 26  and R for macOS version 4.2.3 with the packages MASS, ellipse, and SPINA, and a significance level of Overall, the BPD group had consistently lower values in the echocardiographic measurements and showed significant changes in nine regions compared with the control group. In addition, we compared each region of the 18 segments of the left ventricle for each subject with the normal values reported according to the HUNT study . If any This is the first prospective study to assess wall motion abnormalities in patients with BPD. We detected a significant reduction in myocardial wall motion in patients with BPD compared with healthy controls. BPD is characterized by a history of childhood trauma and chronic stress in young female adults with a higher risk for coronary heart disease (CHD) ,17. In oSubtly reduced myocardial wall motion is often detected in CHD, in other specific cardiomyopathies, or during chemotherapy ,28. ThesThe hypothesis that psychological stress may contribute to altered myocardial wall motion warrants consideration. On the one hand, stress levels are measurably increased in BPD patients . On the In a previous study, we identified a stress-induced type of TTS that mainly affected apical patterns of the myocardium and was characterized by an adapted thyroid metabolism via the hypothalamic–pituitary–thyroid axis . TemplinWhether high-normal thyroid metabolism can be attributed to these risk factors needs to be clarified in further studies. Such a relationship is suggested, however, by a positive association between physiological dysregulation and certain biomarkers of thyroid homeostasis . RegardiPsychiatrists often collaborate with cardiologists regarding QTc-prolonging drugs and ECG abnormalities. Our findings suggest that monitoring cardiac function in psychiatric patients exposed to psychological stress could serve as an additional tool for identifying patients at risk, although further long-term investigations are necessary to assess the precise significance of a latent myocardial wall motion abnormality detected through speckle tracking echocardiography.The significant reduction in BNP levels in the predominantly obese BPD group is most likely derived from the known paradox of low BNP levels in obesity. This phenomenon has not been fully elucidated yet .The present study has several limitations. Echocardiography is an operator-dependent diagnostic tool and may be challenging at times, even in experienced hands. Pathological values have been observed even in supposedly mentally healthy subjects, such as the control group. However, all patients in our study were young women, mainly with slim figures in the control group, which may have contributed to the feasibility of echocardiography due to their constitution. We had to exclude eight patients from the BPD group and one patient from the control group due to inadequate echocardiogram image quality. Nonetheless, poor image quality is a prevalent issue in echocardiography, crucial for correct and reproducible speckle tracking analysis . FurtherIn summary, individuals with BPD often experience persistent stress and exhibit classical risk factors associated with myocardial wall motion abnormalities. Further research is needed to determine the extent to which these findings can provide prognostic insights. Conducting long-term follow-up studies could be of interest and may help validate the potential for predicting adverse events.Clinical implication section: Speckle tracking echocardiography (STE) may have the potential for identifying latent myocardial wall motion irregularities in individuals with BPD, especially those under mental stress. Analyzing cardiac function using STE in psychiatric patients experiencing elevated mental stress levels could complement traditional parameters and aid in the identification of at-risk patients.


Cancer and cardiovascular diseases (CVD) often share common risk factors, and patients with CVD who develop cancer are at high risk of experiencing major adverse cardiovascular events. Additionally, cancer treatment can induce short- and long-term adverse cardiovascular events. Given the improvement in oncological patients’ prognosis, the burden in this vulnerable population is slowly shifting towards increased cardiovascular mortality. Consequently, the field of cardio-oncology is steadily expanding, prompting the need for new markers to stratify and monitor the cardiovascular risk in oncological patients before, during, and after the completion of treatment. Advanced non-invasive cardiac imaging has raised great interest in the early detection of CVD and cardiotoxicity in oncological patients. Nuclear medicine has long been a pivotal exam to robustly assess and monitor the cardiac function of patients undergoing potentially cardiotoxic chemotherapies. In addition, recent radiotracers have shown great interest in the early detection of cancer-treatment-related cardiotoxicity. In this review, we summarize the current and emerging nuclear cardiology tools that can help identify cardiotoxicity and assess the cardiovascular risk in patients undergoing cancer treatments and discuss the specific role of nuclear cardiology alongside other non-invasive imaging techniques.  Vice versa, cardiovascular risk factors (CVRFs) increase cancer risk.7 Additionally, cancer treatments induce short- and long-term cardiotoxicity.9 The prognostic improvement of oncological patients is slowly shifting their burden from cancer to cardiovascular mortality.10 Hence, cardio-oncology is a steadily expanding field, as evidenced by the recent publication of the first European Society of Cardiology (ESC) cardio-oncology guidelines,11 prompting the need for cardiovascular risk stratification markers in oncological patients.13 Despite being challenged by echocardiography and cardiac magnetic resonance (CMR),14 nuclear imaging remains a contemporary modality in patients receiving cardiotoxic therapies.Cancer and cardiovascular diseases (CVD), leading mortality causes in high-income countries,16 this review will not cover this topic.In this article, we briefly summarize the central mechanisms responsible for cancer-treatment-induced cardiotoxicity, review the main established and emergent nuclear cardiology tools useful in cancer settings, and discuss the role of nuclear medicine alongside echocardiography and CMR. Although also beneficial for managing cardiac tumours,17 sharing identical pathophysiological pathways18 .CVD and cancer are two sides of the same coin,19 all of which concomitantly increase cancer risk.20 By promoting inflammation and oxidative stress, diabetes favours a pro-oncogenic environment.21 Similarly, epidemiological data suggest a correlation between hypertension and dyslipidaemia on the one hand and cancer genesis on the other.22 Smoking promotes atherosclerosis and cancer,24 and a plethoric adipose tissue triggers oncogenic inflammatory molecules.25Typical CVRFs include age, diabetes, hypertension, smoking, dyslipidaemia, and overweight,26 For instance, specific age-related somatic mutations, labelled clonal haematopoiesis of indeterminate potential (CHIP), increase the risk of haematological malignancy27 and CVD.28 Other genes involved in drug delivery and metabolism modulate the risk of cancer-therapy-induced cardiotoxicity,26 either by increasing it, such as ATP-binding cassette transporters ABCB4 and ABCC, or by decreasing it, for example, ATP-binding transporters (ABCB1) and solute carriers (SLC28A3).26Intrinsic factors also predispose to CVD and cancer.18 (Table 1). Cancer-treatment-related cardiac dysfunction (CTRCD), i.e. left ventricular (LV) dysfunction induced by cancer treatment, is the most common cardiotoxicity type.8 Two types of CTRCD are distinguished.30 Type I CTRCD, classically caused by anthracyclines, induces direct cumulative, dose-related, and usually irreversible cardiomyocyte damage. Type II CTRCD, traditionally induced by trastuzumab,29 is a reversible and dose-independent myocardial dysfunction without structural alterations. Cancer treatment can also induce coronary artery disease (CAD), notably vasospasm and arterial thrombosis.32 Likewise, chest radiotherapy favours atherosclerosis and fibrosis via inflammatory cascades in the coronary vessels.33Cancer-treatment-induced cardiotoxicity is a critical contributor to CVD35 including myocarditis.36Lately, the introduction of immune checkpoint inhibitors (ICI) to the cancer armamentarium was accompanied by increasing reports of immune-related adverse events (IRAEs),13 This assessment includes a baseline evaluation of LV ejection fraction (LVEF) to guide the cancer treatment choice and the need for cardioprotective therapies.13 However, LVEF alone can prove insufficient, since an LVEF drop is often a late-stage manifestation of cardiac damage.38 Global longitudinal strain (GLS) assessment using echocardiography or CMR is a more sensitive marker of cardiac dysfunction and is, therefore, recommended.14 Nonetheless, GLS is limited by scarce reproducibility,39 prompting the need for alternative tools.The European Society for Medical Oncology guidelines highlight the need for an early screening of CVRFs and close cardiovascular monitoring of cancer patients.41 Although challenged by CMR,42 nuclear cardiology provides critical information for diagnosing, monitoring, and risk-stratifying cancer patients45 (Table 2). In the following part, we will review how nuclear cardiology can detect cardiac complications in oncological patients and discuss its role alongside echocardiography and CMR.Nuclear medicine imaging and particularly multigated acquisition (MUGA) scintigraphy have historically been at the frontline of LV monitoring in oncological patients.14 While only echocardiography and CMR can estimate GLS,46 MUGA robustly determines LVEF.48 In MUGA, cardiac volumes are derived from heart-centred images of the patient’s own radiolabelled erythrocytes49 and are therefore not influenced by geometric assumptions about the myocardial wall.50 Three types of MUGA are distinguished: (i) first-pass MUGA, (ii) planar equilibrium radionuclide angiography (ERNA), and (iii) single-photon emission computed tomography (SPECT) ERNA. In practice, first-pass MUGA is limited to specific indications [right ventricular ejection fraction (RVEF) and shunt assessment51], and only ERNA is used to assess CTRCD. Planar ERNA is acquired when the radiotracer has reached equilibrium and allows measuring LVEF52 , not RVEF, because of the superposition of heart structures. However, ERNA can also be performed with three-dimensional (3D) gated SPECT, which enables the delineation of both LVEF and RVEF.56 Overall, MUGA displays a high inter- and intra-observer reproducibility for LVEF measurement,57 which is crucial for serial follow-up during anticancer treatment.58 MUGA also helps select patients who can safely tolerate higher cumulative anthracycline doses, i.e. asymptomatic patients with LVEF > 40% and a drop in LVEF < 10%,41 significantly reducing heart failure occurrence.59 Although in good agreement,60 LVEF tends to be higher with SPECT than with planar ERNA,61 which needs to be taken into consideration for monitoring.14 Similarly, in breast cancer patients, MUGA gives slightly lower LVEF values than CMR.62 As such, when using MUGA, for an LVEF threshold of 50%, this difference could result in 35% more patients being diagnosed with CTRCD than with CMR.62 Hence, given that LV volumes tend to shrink and LVEF to increase after menopause,63 CTRCD thresholds might need to be adapted in women.64 Regarding surveillance, the European and American nuclear medicine societies recently issued an expert consensus for monitoring LVEF by ERNA for patients receiving anthracyclines,65 which has been summarized in Figure 3.The ESC defines CTRCD as (i) a ≥10% LVEF decrease from baseline to below 50%, (ii) with a GLS drop of ≥15% from baseline, confirmed by a 2–3-week repeat study, in the context of cancer treatment.65 which in case of serial follow-up increases theoretically  cancer risk.68 Cadmium-zinc-telluride (CZT)-based cameras, which detectors are more sensitive than conventional sodium iodide (NaI) ones, enable a two- to three-fold reduction in injected activity without altering image quality,70 hence decreasing the radiation burden. CZT-derived LVEF highly correlates with the one obtained from planar NaI detectors.71 CZT-based SPECT ERNA is also in high agreement with CMR for RVEF.72 Interestingly, LVEF can be obtained from fluor-18-radiolabelled fluorodeoxyglucose positron emission tomography (18F-FDG PET) gated first-pass acquisitions, showing excellent concordance with planar ERNA.73 Given that 18F-FDG PET is the mainstay for cancer staging, this elegant approach allows simultaneously measuring LVEF with no additional radiation exposure. However, first-pass cardiac 18F-FDG acquisitions result in a prolonged acquisition time (5 min), reducing the available scanning time for other patients.A major drawback of MUGA is radiation exposure. Indeed, MUGA requires the injection of 555–1110 MBq (7–15 MBq/kg in children) of radiotracers,Figure 4). Transthoracic echocardiography (TTE) is the frontline risk stratification exam, owing to its wide availability, harmfulness, ability to assess morphology , function, and GLS. Whenever available, 3D echocardiography is preferred over 2D, given its higher reproducibility for LVEF and GLS assessment.76 GLS detects early signs of systolic dysfunction before any LVEF drop, with a change in GLS ≥ 15% predicting the risk of CTRCD.46 Importantly, a GLS-based cardioprotective strategy reduces the rate of CTRCD in patients undergoing anthracycline.77 Nonetheless, echography strain measurements lack inter-device standardization, which limits their routine use.78 In case of reduced acoustic window or low image quality, CMR is recommended as a second-line technique.75 CMR is considered the reference exam to calculate cardiac volumes and function and can detect even minor LVEF impairments and volume changes.75 The latter is particularly important in patients undergoing anticancer treatments, in whom CTRCD can manifest as an isolated LV end-diastolic volume reduction.79 Moreover, CMR accurately determines RVEF, which can be asymptomatically reduced in cancer survivors.80 Besides volumes and strain assessment, CMR is a promising tool for the early detection of cancer-treatment-related myocardial oedema and fibrosis via T1/T2 mapping and extracellular volume (ECV) measurement.81 Increased T1/T2 relaxation times hold promise to predict subsequent CTRCD,81 although there is a significant overlap between mapping parameters of patients who develop CTRCD and those who do not.82In practice, MUGA has long been supplanted by the more readily available and non-irradiating echocardiography and CMR , as its increase could indicate an LVEF decline85 and, therefore, trigger LVEF assessment.14In summary, the 2022 ESC Guidelines on cardio-oncology only recommend MUGA as a third-line technique to assess LVEF, i.e. if TTE and CMR are unavailable or in case of CMR contraindication.86 Additionally, cancer treatments themselves (particularly chest radiotherapy) induce endothelial injuries, favouring vasospasm and thrombosis.87–89 Hence, screening for ischaemic heart diseases (IHD) is recommended in patients with intermediate-to-high pre-test likelihood46 undergoing heart-damaging cancer therapy,8 especially anthracyclines and chest radiotherapy.91 Such screening can be done with SPECT myocardial perfusion imaging (MPI), a mainstay in this indication.92Cancer is a prothrombotic condition associated with enhanced platelet reactivity and circulating procoagulant products, which increase the atherosclerotic burden.93 or later, up to 20 years after treatment completion.94 Most perfusion abnormalities develop in the apical territory,95 indicating left anterior descending artery damage.97 Accordingly, myocardial perfusion impairment is more prevalent in left-sided than right-sided chest cancer,98 a risk that linearly correlates with cardiac exposure volume.99 In patients with left-sided breast cancer, an irradiated cardiac volume of >5% is associated with significantly higher rates of perfusion abnormalities than with lower volumes.100 Interestingly, in cancer patients, SPECT-detected myocardial ischaemia does not correlate well with underlying obstructive CAD,97 highlighting the importance of coronary microvascular dysfunction (CMVD) and coronary spasm in this population.103SPECT myocardial perfusion abnormalities can appear either during radiotherapy13N-ammonia (13N-NH3), 82Rubidium (82Rb), and 15O-water (15O-H2O) radiotracers.104 PET MPI allows for measuring myocardial blood flow (MBF) and coronary flow reserve (CFR), which are central to CMVD diagnosis.105 In patients undergoing chest radiotherapy, PET MPI shows an inverse correlation between the mean radiation dose to the heart and CMVD.107 Moreover, MBF could have prognostic value, with low CFR values being associated with an increased cumulative incidence of MACE in breast cancer patients.108PET MPI is the reference non-invasive modality to diagnose CMVD, using 109 CACS = 0 in asymptomatic patients is associated with a very low prevalence of severe coronary stenosis and high-risk plaque features.110 Conversely, an Agatston score of >400 is predictive of MACE, even for normal MPI.111 CACS can easily be yielded from the low-dose CT of PET/CT and SPECT/CT cameras, showing high agreement with the one obtained from standard non-enhanced scans.114 Since 18F-FDG PET/CT is part of routine oncological work-up, cardiovascular risk stratification with CACS could simultaneously be performed without additional radiation or cost.115Another prognostic parameter is the coronary artery calcium score (CACS). CACS is obtained from a non-enhanced CT and quantifies the degree of coronary artery calcification, expressed with the Agatston score.117 . However, contrary to MUGA, MPI indirectly estimates cardiac volumes based on myocardial wall motion. In case of infarction, the necrotic segment is devoid of signal, leading to overestimating LV volumes.118 Another limitation of SPECT MPI is its inability to assess RVEF. Although more accurate,121 CZT cameras give lower values than conventional SPECT cameras,122 stressing the importance of performing serial follow-up using the same modality.Beyond myocardial perfusion, nuclear MPI can also estimate LVEF14 Although the recent European guidelines on cardio-oncology do not give strict recommendations on which modality to prefer in which setting,11 echocardiography and CMR remain the frontline techniques in this setting.14 Overall, three scenarios can be distinguished: baseline screening, follow-up during treatment, and end-of-treatment surveillance14 .Nuclear MPI is only one of the tools available for myocardial ischaemia screening alongside stress echocardiography, and CMR. Additionally, contrast-enhanced coronary computed tomography angiography (CCTA) is an alternate tool which provides information on coronary plaque burden and coronary stenosis assessment.14 CACS assessment is an easy and minimally invasive way of characterizing the baseline CAD risk. If CACS = 0, the risk of dying from CAD within 5 years of cancer diagnosis remains below the mortality risk from cancer itself; conversely, if CACS > 300, the 5-year CAD mortality risk exceeds the cancer mortality risk,123 prompting more aggressive management.14 As abovementioned, CACS can be extracted from 18F-FDG PET’s low-dose CT without additional scanning time, cost, or radiation.115 As the mainstay baseline staging exam of most cancer types, 18F-FDG-PET-based CACS appears as a reasonable option for baseline CAD risk assessment. Advanced explorations should be preferred in patients with a higher baseline CAD risk. In nononcological settings, non-enhanced CT and CCTA are the first-line exam for detecting coronary calcifications and coronary stenosis in patients with low-to-intermediate CAD risk.92 Given the increased CAD risk in oncological patients, detection of coronary stenosis using CCTA can be discussed in symptomatic patients with no CAD history.14 However, this comes at the expense of increased radiation exposure.124 Stress echocardiography is indicated in patients with intermediate-to-high CAD probability undergoing ischaemia-inducing chemotherapies, such as fluorouracil, bevacizumab, sorafenib, and sunitinib.125 In addition to ischaemia, stress echocardiography could unveil patients at risk of developing CTRCD,127 a 5-unit fall in LV contractile reserve during dobutamine echocardiography predicting the subsequent LVEF drop.128 Myocardial perfusion CMR imaging using pharmacological stress is also an option, but its use for systematic screening is conflicted by its relatively low availability.14 SPECT MPI is a well-validated and widely accessible modality that additionally provides CACS in case of hybrid SPECT/CT.113Baseline screening should always be considered in the oncological population, given their increased CAD risk.During treatment, there is no clear recommendation as to which modality to prioritize and the exploration frequency, which will depend on the clinical presentation and the available modalities.14 particularly in patients with known CAD, whose plaque progression can be accelerated by anticancer treatment, and in young patients treated with chest radiotherapy, i.e. at risk of perivascular fibrosis.90 Radiotherapy can also induce valve leaflet calcification, which can be assessed by CT.90 A limitation of CCTA is for the routine detection of microvascular dysfunction, although dynamic CT MPI is promising in this regard.132 Conversely, CMR detects both segmental ischaemia and CMVD,133 with the advantage over nuclear MPI of being devoid of radiation exposure. Still, CMR assessment of MBF remains in the research realm,134 and PET MPI is the reference exam for CMVD,104 displaying higher accuracy, reproducibility, and prognostic value than CMR.136 This favours PET in patients at risk of CMVD, particularly women with breast cancer137 and patients who underwent chest radiotherapy.138After treatment completion, CCTA is an option for CAD identification,139 Some cancer cells express immune-checkpoint-binding ligands and can thus trick and inhibit T-lymphocytes. ICI block the receptor–ligand bond, allowing T-cells to recognize and attack cancer cells.139 The downfall of lifting T-cell inhibition is that this may unleash IRAEs.140 Cardiovascular IRAEs occur with an incidence ranging from 1.14 to 5%140 and include notably myocarditis, pericarditis, vasculitis, and Takotsubo cardiomyopathy.142The last years have witnessed the development of immunotherapy, a new class of anticancer treatment that leverages the immune system to harness cancer progression. The primarily used class of immunotherapy is ICI. Immune checkpoints are T-lymphocyte-expressed receptors that recognize ligands at the surface of normal cells. The receptor–ligand binding inhibits the T-cell, preventing it from targeting normal cells.143 and the prolonged interval between drug administration and symptom onset.140 While CMR is the reference exam,144 PET can also orient the diagnosis. Due to its availability and high uptake in inflammatory cells, 18F-FDG is a natural candidate in this indication,145 classically displaying focal or diffuse patchy myocardial 18F-FDG uptake with no vascular systematization146 . Despite a good spatial agreement between 18F-FDG uptake and T2 hyperintensity/late gadolinium enhancement (LGE), the diagnostic accuracy of 18F-FDG PET/CT in myocarditis is low.148 Several factors might explain this, such as an inadequate high-fat/low-carbohydrate diet, the initiation of immunosuppressive treatment, and the delay between myocarditis onset and image acquisition. Acquisition timing is indeed critical, with a small series showing a 100% sensitivity when 18F-FDG PET was performed within 14 days of disease onset vs. 20% when performed later.146 In 2019, Bonaca et al.147 proposed a definition of ICI-related myocarditis that includes 18F-FDG PET, with myocarditis deemed as possible in any ‘scenario meeting criteria for possible myocarditis  with 18F-FDG PET showing patchy cardiac 18F-FDG uptake without another explanation’.Diagnosing ICI-related myocarditis is challenging because of the various presentations149 The lower albeit variable150 physiologic myocardial uptake of SSTR radiotracers reduces the risk of false positives. In a small population of nine patients, gallium-68-radiolabelled DOTA0-D-Phe1-Tyr3-octreotide (68Ga-DOTATOC) PET/CT had a 100% sensitivity to diagnose ICI-related myocarditis, despite the initiation of steroid and immunosuppressive therapy.151 Recently, a 68Ga-radiolabelled tracer targeting fibroblast activation protein inhibitors (68Ga-FAPI) was introduced in oncological diseases.153 In three patients fulfilling the Bonaca et al.147 criteria for definite ICI-related myocarditis, focal myocardial uptake of 68Ga-FAPI identified cardiac remodelling territories.154 Similarly, the upregulation of translocator protein-18 kDa (TSPO) and chemokine receptors types 4 and 12 in inflammatory cells suggests a role for radiolabelled TSPO and 68Ga-pentixafor in myocarditis,156 although dedicated studies still need to be performed. Along the same line, radiotracers targeting the C-X-C motif chemokine receptor 4 overexpressed by leucocytes represent an exciting approach to diagnosing myocardial inflammation.157 Finally, novel inflammation radiotracers targeting CD4 and CD8 cells, zirconium-89-radiolabelled desferrioxamine-CD4 (89Zr-DFO-CD4) and 89Zr-DFO-CD8a, are under investigation and hold the potential to image myocarditis.158 Their high specificity could prove particularly useful in ICI-related myocarditis. Indeed, the reference treatment for myocarditis is steroids, which alleviate the antitumour effect of ICI.159 Therefore, establishing the diagnosis with certainty might reduce unnecessary immunosuppressive therapies or withholding ICI.Other promising radiotracers target somatostatin receptors (SSTRs) overexpressed at the surface of vascular macrophages.11 . Echocardiography’s primary role is to rule out non-inflammatory cardiac diseases and serve as a reference exam for LVEF monitoring.160 Serial echocardiography could also be discussed in patients at high risk of myocarditis, i.e. patients undergoing a combination of ICI, ICI with another cardiotoxic regimen, or in case of pre-existing CVD.14 The mainstay examination for diagnosing myocarditis remains CMR, using the Lake Louise criteria,161 updated in 2018 with the implementation of mapping techniques.160 The Lake Louise criteria consist of a triad combining oedema (as assessed by T2-weighted acquisitions), hyperaemia [reflected by early gadolinium enhancement (EGE)], and necrosis (set by LGE). The presence of ≥2 out of 3 criteria in a suggestive context establishes the diagnosis of myocarditis with high sensitivity and specificity.144 Mapping techniques improve intra- and inter-observer diagnostic confidence, the specificity for detecting active inflamamtion and edema, and improve the detection of milder forms of myocarditis.160 Additionally, reduced GLS and global circumferential strain could help risk-stratify patients with ICI myocarditis, the magnitude of strain reduction being predictive of MACE.162 Nonetheless, the updated Lake Louise criteria might not be as performant in ICI myocarditis. Indeed, recent data show the sensitivity of CMR to be lower in the latter, possibly because of reduced LGE in the early phase.164 Detecting LGE is particularly challenging in borderline forms of myocarditis,165 which display less necrotic insult and patchy distribution. Such patients might benefit from 18F-FDG PET, given the increased 18F-FDG uptake in myocarditis areas devoid of LGE, which could also guide potential myocardial biopsies.148 However, no dedicated study has assessed the diagnostic performance of 18F-FDG PET in this specific subgroup. 18F-FDG PET could also help distinguish chronic myocarditis from the scarred non-inflammatory myocardium, i.e. healed myocarditis.166 Indeed, LGE and strain do not clearly differentiate between chronic and healed myocarditis,168 whereas 18F-FDG uptake decreases in the latter,166 a feature that could help monitor treatment response to immunosuppressive therapy.169 Given their complementary diagnostic values, studies have evaluated the value of hybrid 18F-FDG PET/CMR in myocardial inflammatory diseases,171 showing an incremental detection of cases with hybrid PET/CMR over single modalities alone.172In practice, however, the guidelines recommend echocardiography and CMR as first-line examinations in suspected ICI-associated myocarditis and recommend cardiac PET only if CMR is non-available or contraindicated8 .Numerous efforts aim at detecting early-stage cardiac impairment, i.e. when anticancer treatment is still modifiable or cardioprotective measures can be introduced175 which MUGA can assess. MUGA-derived diastolic function parameters include the peak filling rate, time-to-peak filling rate, and first third filling fraction178 that deteriorate before treatment-induced systolic dysfunction.179 However, the inter- and intra-observer reproducibility of ERNA-based diastolic function is moderate,57 questioning its utility in the early detection of CTRCD. CZT-based MUGA is promising, providing a highly reproducible assessment of diastolic function in cancer patients.180 Still, MUGA is not routinely used to assess diastolic function, which can easily be obtained from echocardiography.78 However, echocardiography is strongly operator-dependent, hampering its interest in surveillance.74 CMR can also assess diastolic function based on LV mass and hypertrophy, LA size and function, mitral inflow and pulmonary venous velocity profiles, as well as myocardial deformation imaging with strain. Additionally, T1 mapping and ECV can be used.181 CMR presents the advantage over echocardiography of highly reproducible and accurate volume measurements without geometrical or flat profile assumptions.181 CMR’s downsides are its restricted availability and the length of sequence acquisitions and image post-processing, limiting its routine use.181Diastolic dysfunction is a potential early marker of LV dysfunction,123I-MIBG) reflects the uptake, storage, and release of norepinephrine in the synaptic cleft,182 hence allowing cardiac sympathetic innervation imaging.183 The main parameter is the heart-to-mediastinum ratio (HMR),185 i.e. the ratio between cardiac 123I-MIBG uptake and a mediastinal reference region of interest. A diminished HMR indicates cardiac sympathetic denervation, either functional (downregulation of post-synaptic β-adrenergic receptors) or due to direct damage .Iodine-123 metaiodobenzylguanidine , an analogue of L-dihydroxyphenylalanine (L-DOPA) routinely used to investigate neuroendocrine tumours.193 Another norepinephrine analogue is carbon-11-radiolabelled hydroxyephedrine (11C-HED),194 in which the need for on-site production limits clinical use. To date, however, no study has specifically studied these radiotracers to diagnose CTRCD.PET radiotracers can also assess cardiac sympathetic activity,195 Under physiologic conditions, free fatty acids (FFAs) and glucose represent the primary cardiac energy sources.196 Myocardial glucose consumption can be imaged with 18F-FDG and FFA uptake with beta-methyl-iodine-123 phenylpentadecanoic acid (BMIPP).197 In the fasting phase, FFAs are abundantly available to the heart,196 rendering BMIPP more advantageous for assessing cardiac metabolism than 18F-FDG.198 Nonetheless, BMIPP is only routinely used in Japan,199 and one study reported BMIPP uptake reduction in patients receiving taxanes.200 Conversely, 18F-FDG PET is largely available and part of the routine oncological assessment. In patients treated with doxorubicin, an increased LV 18F-FDG uptake from baseline to end-of-treatment PET is associated with a subsequent LVEF drop85 and MACE.201 Moreover, increased RV 18F-FDG uptake predicts a higher cardiotoxicity risk.202 Similarly, in chest radiotherapy patients, focal cardiac 18F-FDG uptake is associated with myocardial damage,205 a study pointing towards a relation between the radiotherapy dose and the intensity of 18F-FDG uptake.206 Focal 18F-FDG cardiac uptake in cancer patients correlates highly with perfusion abnormalities on SPECT MPI,207 giving potential mechanistic insights for the subsequent cardiotoxicity. Still, a significant drawback of 18F-FDG PET is the high variability of cardiac uptake with diet and insulinaemia,208 which could be reduced by prolonged fasting.209 Additionally, 18F-FDG myocardial uptake increases in the ischaemic myocardium, which, although limiting the specificity of 18F-FDG patterns, could identify ischaemia onset.210Cardiac metabolism is a balance between various fuels, depending on the substrate’s bloodstream availability, dietary conditions, and underlying myocardial conditions.11C) radiotracers can be used to image myocardial metabolism. 11C-acetate is taken up by cardiomyocytes and converted to acetyl-CoA, a substrate for energy production via the tricarboxylic acid cycle.211 The rate of 11C-acetate uptake is a marker of myocardial oxidative metabolism.212 In a pre-clinical model of mice undergoing treatment by tyrosine kinase inhibitors, the myocardium showed a decrease in 11C-acetate uptake concomitantly to an increase in 18F-FDG uptake.213 The short half-life of 11C (∼20 min), although interesting from a radiation exposure perspective, is the main factor limiting its routine use, as 11C requires an on-site cyclotron.211Alternatively, carbon-11 -1H-1,2,3-triazol-4-yl)methoxy)phenyl)-5-methyl-5,6-dihydrophenanthridine-3,8-diamine (18F-DHMT). In a pre-clinical rodent model of anthracycline-induced cardiotoxicity, 18F-DHMT evidenced an increased myocardial ROS production before any LV drop.214 Another ROS-targeting radiotracer is 18F-3-(3-fluoropropyl)-2-phenyl-2,3-dihydrobenzo[d]thiazole (18F-FPBT), in which myocardial uptake is also increased in rats receiving anthracycline.215 Deregulation of cardiomyocyte homeostasis by chemotherapy can manifest as mitochondrial membrane dysfunction, which can be explored with 18F(4-fluorophenyl)triphenylphosphonium (18F-FTPP+). In a swine model receiving intracoronary infusions of anthracycline, 18F-FTPP+ showed a partial mitochondrial depolarization in myocardial areas distal to the infused vessel.216 Recently, a radiotracer targeting TSPO, a translocator protein expressed in mitochondrial-activated microglia, has been validated in a model of myocardial infarction.217 This pre-clinical study showed that an early myocardial uptake of 18F-radiolabelled TSPO on PET predicted the subsequent LVEF reduction.The bottleneck of all cellular energy pathways is the mitochondrial production of ATP. Several chemotherapies affect ATP production and lead to cell death, generally by increasing reactive oxygen species (ROS) production.218 Technetium-99m (99mTc)-radiolabelled annexin V is a phosphatidylserine ligand that detects apoptotic cardiomyocytes.219 In rats receiving doxorubicin, 99mTc-radiolabelled annexin V evidenced drug-induced toxicity in a dose-dependent manner before any functional impairment on echography.220 Recently, PET apoptosis radiotracers have also been developed.221 In a mouse model of experimentally induced anthracycline cardiotoxicity, 18F-CP18, a substrate of the caspase 3 enzyme present in apoptotic cells,222 evidenced apoptosis before any LVEF drop.223 Another target is myosin, externalized by necrotic cells after membrane rupture. Preliminary clinical studies showed that increased myocardial uptake of an indium-111 (111In)-radiolabelled antimyosin antibody preceded LVEF modifications in patients receiving anthracycline.225A hallmark apoptosis feature is the exposition of phosphatidylserine at the cellular surface.226 Although echocardiography and CMR can detect cardiac fibrosis, even at an early stage with mapping techniques,228 fibrosis still indicates myocardial damage. Therefore, detecting the onset of fibrotic replacement could help initiate cardiac treatments at an early and reversible stage.227 Fibroblast activation protein (FAP) is a transmembrane protease with enhanced expression in activated fibroblasts.229 Recently, pre-clinical findings evidenced intense 68Ga-FAPI myocardial uptake in areas of activated fibroblasts, conversely to no uptake in areas of advanced fibrosis.232 Similar incidental cases of 68Ga-FAPI cardiac uptake have been reported in cancer patients, unveiling myocardial ischaemia.233 This suggests that 68Ga-FAPI PET, likely to be used for cancer staging, could help simultaneously detect early stages of myocardial fibrosis. Moreover, 68Ga-FAPI myocardial uptake could pre-date any LVEF decrease, suggesting a potential role in cardiotoxicity prediction.234 Similarly, an 18F-radiolabelled FAPI tracer (18F-AlF-NOTA-FAPI-04) detects radiation-induced myocardial ischaemia before LVEF decreases, comforting the potential role of FAPI radiotracers for the early identification of cardiac damage.235The cardiomyocyte loss induced by anticancer treatments is accompanied by myocardial fibroblast activation, leading to fibrotic ventricular remodelling, a condition of increased risk for heart failure.237 could be augmented by non-invasive imaging. For example, myocardial 18F-FDG uptake obtained from routine staging 18F-FDG PET can help stratify the cardiovascular risk with no additional cost or radiation burden.207 Cardiovascular risk stratification could also benefit from hybrid PET/CMR by combining CMR mapping techniques with the prognostic value of myocardial 18F-FDG uptake to predict the MACE risk.239One next step is to stratify the cardiotoxicity risk before treatment initiation. Predictive scores based on CVRFs and biological markers241 In 2619 cancer-free patients explored with SPECT MPI, a machine learning analysis combined with clinical data outperformed human analysis for MACE prediction.242 Moreover, the higher reproducibility of machine learning could improve diagnostic confidence in uncertain myocarditis patterns, such as patchy 18F-FDG myocardial uptake. AI also improves the characterization of several types of malignant masses,245 which might benefit cardiac tumour characterization.Artificial intelligence (AI) is a potential game changer in cardio-oncology.246 As a metabolic tool targeting specific pathophysiological pathways, nuclear imaging will most certainly play a central role in precision cardio-oncology.246 In addition to mapping cardiotoxicity, these probes might play a theranostic role, as with SSTR radiotracers, which help select patients in whom peptide receptor radionuclide therapy is indicated.247 An unsuccessful attempt in this sense has been made with 111In-labelled trastuzumab scintigraphy to predict cardiotoxicity from trastuzumab.248 Yet, the theranostic field is still in its infancy, and the wideness of metabolic targets assessable with nuclear radiotracers renders this goal within reach.In the era of precision medicine, where similar phenotypes arise from different genomic, metabolomic, and proteomic profiles, it will be crucial to tailoring the diagnosis to the tumour’s ‘-omic signature’.18F-FDG and MPI tracers, could benefit this population with no additional cost or radiation exposure. Consequently, in the expanding field of cardio-oncology, nuclear medicine remains a central player that will most certainly remain at the forefront of the diagnostic armamentarium alongside cross-sectional imaging.The progress in anticancer treatment is progressively turning cancer into a chronic condition. Consequently, the new challenge in this population is slowly shifting towards tackling other mortality causes, particularly CVD. Nuclear imaging allows for diagnosing various cardiac complications of anticancer therapies, even at an early stage, is useful for disease monitoring, and is a promising tool for the risk stratification of patients receiving cardiotoxic treatments. In addition, nuclear imaging has the unique ability to target specific metabolic links in the cardiotoxicity cascade for either diagnosis or treatment. Leveraging radiotracers already used routinely in patients with cancer, such as


However, there was no correlation with ΔT1 or ΔT2 with MPR, respectively (p > 0.05 for both). Native T1 and native T2 correlate with myocardial perfusion during adenosine stress, reflecting the coronary circulation in patients during long-term follow-up of severe Covid-19. Neither ΔT1 nor ΔT2 can be used to assess MPR in patients with severe Covid-19.Severe Covid-19 may cause a cascade of cardiovascular complications beyond viral pneumonia. The severe inflammation may affect the microcirculation which can be assessed by cardiovascular magnetic resonance (CMR) imaging using quantitative perfusion mapping and calculation of myocardial perfusion reserve (MPR). Furthermore, native T1 and T2 mapping have previously been shown to identify changes in myocardial perfusion by the change in native T1 and T2 during adenosine stress. However, the relationship between native T1, native T2, ΔT1 and ΔT2 with myocardial perfusion and MPR during long-term follow-up in severe Covid-19 is currently unknown. Therefore, patients with severe Covid-19  underwent 1.5 T CMR median 292 days following discharge. Quantitative myocardial perfusion (ml/min/g), and native T1 and T2 maps were acquired during adenosine stress, and rest, respectively. Both native T1 (R However, there is increasing evidence linking Covid-19 with cardiovascular disease (CVD)2. Covid-19 infection may induce endothelial dysfunction, microvascular inflammation and thrombosis via angiotensin converting enzyme 2 and secondary autoimmune responses, causing coronary microvascular dysfunction (CMD), which might serve as a mechanism for long-term CVD post-Covid-193. Myocardial perfusion during rest and pharmacological stress can be used to calculate the myocardial perfusion reserve (MPR) to assess the coronary circulation4, which can be performed with quantitative cardiovascular magnetic resonance (CMR) myocardial perfusion maps with an excellent agreement with positron emission tomography (PET)6.The novel betacoronavirus SARS Coronavirus 2 has resulted in a global pandemic of coronavirus disease 2019 (Covid-19)7. Both native T1 and T2 maps have been shown to identify acute myocardial inflammation causing edema and chronic pathologies with expanded interstitium where free water can distribute, and can be used for a range of myocardial pathologies8. Both native myocardial T1 and T2 depend on myocardial blood T1 and T2, which constitute a basis for T1 and T2 mapping to capture change in myocardial perfusion during stress without contrast agents10. Theoretically, the relative change in native T1 and T2, also called T1- and T2-reactivity (ΔT1 and ΔT2) (%), should portray the same physiology as MPR11. However, the relationship between native T1, native T2, ΔT1 and ΔT2 with myocardial perfusion and MPR during long-term follow-up in severe Covid-19 is currently unknown. Therefore, the aim of this study was to elucidate the relationships of the parameters native T1, native T2, ΔT1 and ΔT2 with quantitative myocardial perfusion and MPR during long-term follow-up in severe Covid-19 using CMR.Quantitative parametric pixelbased mapping by CMR has been developed to image both the longitudinal relaxation time constant (T1) and transverse relaxation time constant (T2)Patients hospitalized at Karolinska University Hospital, Stockholm, due to severe Covid-19 , were included from the project ”Follow-up of patients with severe Covid-19 pneumonia” (UppCov), aiming to characterize the long-term consequences of severe Covid-19 pneumonia in a comprehensible fashion. The patients underwent CMR at 1.5 T during long-term follow-up, between November 2020 and September 2021. Patients were eligible to be included in UppCov if discharged from the hospital at the intensive care unit and/or hospital wards for severe Covid-19, defined as respiratory failure with a higher demand of ventilatory support and oxygen (at least 5 l/min of oxygen flow rate).Exclusion criteria for this CMR substudy included risk factors such as diabetes mellitus, myocardial infarction, aortic stenosis (AS), uncontrolled severe hypertension, atrial fibrillation and previous stroke. Patients that had undergone percutaneous coronary intervention and/or coronary artery bypass grafting or valvular surgery, or had contraindications for adenosine including chronic obstructive pulmonary disease and asthma or other standard safety contraindications such as renal failure or pacemaker were also excluded. Ethical approval was granted for all study procedures and all subjects provided written informed consent.2, slice thickness 8.0 mm, echo time (TE)/repetition time (TR) 1.19 ms/37.05 ms, matrix size = 256 × 144 and field of view (FOV) 360 × 270 mm2.CMR was performed at 1.5 T . The image acquisition protocol is summarized in Fig. 5, both during adenosine stress  and at rest, following administration of an intravenous bolus of contrast agent . Perfusion maps were generated using the Gadgetron inline perfusion mapping software, freely available as an executeable12, computed based on a bistributed tissue exchange model13 that estimates arterial delay, perfusion, myocardial blood volme, permeability surface area and interstitial volume in resonable agreement with T1-based estimates of ECV12. Adenosine and contrast were administered in separate cannulas. Typical imaging parameters were: flip angle 50°, slice thickness 8.0 mm, TE/TR 1.04 ms/2.5 ms, bandwidth 1085 Hz/pixel, FOV 360 × 270 mm2 and saturation delay/trigger delay (TD) 105/40 ms.Three short-axis slices  were acquired using first-pass perfusion imaging rendering myocardial quantitative perfusion (ml/min/g) maps2, slice thickness 8.0 mm, imaging duration 167 ms, TE/TR 1.12 ms/2.7 ms, matrix size = 256 × 144 and FOV 360 × 270 mm2. Five ECV-maps at rest were generated from native T1-maps and post-contrast T1-maps and calibrated by the hematocrit15.Five short-axis native T1 maps were obtained during rest using an ECG-gated modified look-locker inversion 3 s) recovery prototype sequence. One midventricular short axis T1-map was acquired during adenosine stress. Typical imaging parameters included single shot SSFP in end-diastole, flip angle 35 degrees, pixel size 1.4 × 1.9 mm2, slice thickness 8.0 mm, acquisition window 700 ms, TD 483 ms and matrix size = 144 × 256.Five short-axis native T2 maps were acquired before adenosine stress, and one midventricular short axis T2-map during adenosine stress. T2-mapping was performed using a T2-prepared sequence. Typical imaging parameters included TE/TR 1.06 ms/2.49 ms, FA 70 degrees, pixel size 1.8 × 1.8 mm16  by carefully delineating the endo- and epicardial borders of the LV in the short-axis images, Fig. Cine images, quantitative perfusion maps, ECV-maps, T1- and T2-maps were analyzed with the software SegmentStatistical analysis was performed using Microsoft Excel version 16  and IBM SPSS Statistics . All data was assessed for normality using the Kolmogorov–Smirnov test. Continuous data was expressed as median and IQR and categorical data was presented as numbers and percentages. Quantification of myocardial perfusion, ECV, native T1 and T2 was performed in each slice, and global values per subject were acquired by averaging the values from all short-axis slices in each subject. MPR was calculated as the ratio of stress to rest myocardial perfusion (ml/min/g). ∆T1 (%), and ∆T2 (%) were calculated as (stress-rest)/rest × 100 (%) for native T1 and T2, respectively. The individual relationships at rest and stress between parameters of myocardial perfusion, MPR and parameters of native T1, native T2, ∆T1 and ∆T2, were assessed by linear regression. By combining rest and stress values in the same data set to maintain aggregated data for T1, T2 and myocardial perfusion, the relations between these pooled parameters were investigated. Inter- and intra-observer agreement was calculated for myocardial rest perfusion, MPR, rest native T1, rest native T2, ∆T1 and ∆T2, and presented as intra-class correlation coefficient (ICC). The significance level in all statistical analyses was defined as p < 0.05.All study procedures were carried out in accordance with relevant guidelines and regulations as per the Declaration of Helsinki and Good Clinical Practice for involving human participants. The study was approved by the Swedish Ethical Review Authority, Dnr 2020-04329 and all patients provided written informed consent.In total, 3 patients did not undergo adenosine stress CMR and were therefore excluded from the analysis. The remaining patients (n = 37) underwent adenosine-stress CMR scan 292 [207–367] days after discharge. All images were assessed with regards to image quality, and no patients were excluded due to poor image quality. Due to operator dependency, 1 patient did not obtain T2 maps and 1 patient did not obtain T2 maps at stress and were consequently excluded from analysis of native T2. Minimal (< 1 segment) late gadolinium enhancement (LGE) was found in 4 patients, and these patients were included in the analysis due to the limited extent of scarring. Baseline characteristics, including previous medical history, are presented in Table 2 = 0.35, p < 0.001) and native T2 , respectively, Fig. 2 = 0.20, p < 0.01), but did not correlate with myocardial rest perfusion. Native T1 at stress correlated moderately with myocardial stress perfusion , but not with myocardial rest perfusion. Native T2 displayed no correlation with myocardial rest nor stress perfusion.In the analysis of pooled rest and stress data, myocardial perfusion correlated with both native T1 PET myocardial perfusion in patients with suspected CAD, and showed a moderate correlation between rest and stress measurements of native T1 and myocardial perfusion19. In normal physiology this correlation is stronger10, which is supported by the findings of the current study. A strong relationship between native T1 and myocardial perfusion was also found in healthy subjects undergoing regadenosone stress22. Myocardial stress perfusion is the net result of perfusion and increase of myocardial blood volume across the entire coronary vasculature which may explain the relationship between native stress T1 and myocardial stress perfusion in all three studies. However, there was no correlation between myocardial rest perfusion and native T1 at rest in patients with suspected CAD19, reproduced by the results of the current study, in contrast to normal physiology10. Potential contributing factors to the difference between patients and healthy volunteers besides age and distributions of sex23, include choice of native T1 mapping sequence, physiology in the presence of pathology, sample size and differences in contrast agents25.The use of native T1 during adenosine stress to capture the intravascular compartment of myocardial perfusion was first illustrated by Mahmod et al. in a mechanistic study of patients with AS with a blunted ΔT1 that normalized following intervention10. Unlike native T1, individual T2 rest and T2 stress did not have a significant correlation with myocardial rest or stress perfusion in neither the present study nor in normal physiology10. More studies on native T2 during stress is needed to further understand the mechanisms behind non-contrast imaging for diagnostic use.Native T2 also correlated with myocardial perfusion, as previously shown in normal physiology20. However, this has not been reproduced in the current study, or in patients with CAD19, and AS18. The present study found no correlation between MPR and ΔT1, as previously reported20, while Everaars et al. found a weak correlation19. Furthermore, there was no correlation between ΔT2 and MPR in the current study, suggesting that non-contrast techniques cannot capture the MPR. It could be hypothesized that ΔT1 or ΔT2 do not reflect the same physiology as MPR. Native T1 and T2 increase with free water content, which may have an intracellular or extracellular origin, including the intravascular and interstitial compartments18. It is still unclear if the change in native T1 and T2 during stress is primarily dependent upon the changes in myocardial blood volume, ECV or myocardial perfusion. While myocardial perfusion is closely linked to myocardial blood volume and ECV, their intrinsic relationships have not been completely elucidated. Furthermore, native mapping may not be able to differentiate between myocardial blood volume and myocardial perfusion, and there may be a need for a contrast agent to separate the contributions of myocardial perfusion and the myocardial blood volume and ECV10. However, the correlation between pooled rest and stress values of myocardial perfusion and native T1, and native T2, respectively indicate that the underlying physiology behind the parameters are closely related.Native T1 during stress has previously been shown to moderately correlate with MPR in diabetic patients26. It has previously been shown that ∆T1 are mediated through both endothelial and non-endothelial dependent mechanism, while adenosine perfusion and MPR are solely mediated through non-endothelial dependent mechanism27. Given that PACS patients more often are affected by postural ortostatic tachycardia syndrome (POTS) together with the observed differences in adenosine and regadenosone response with regards to vasodilator response this might explain the differences in results between the two studies. Further research into the response in ∆T1 and ∆T2 between adenosine and regadensone with regards to endothelial and non-endothelial dependent mechanisms are needed both in covid-19 but also other diseases.In Table The correlation between pooled native T1, T2 and myocardial perfusion, shows that native T1 and T2 mapping indeed can be used to capture changes in myocardial perfusion during stress without the need of contrast agent. Standardization of native T1 mapping protocols remains important to mitigate cofounders such as age and sex. This study is to the best of our knowledge the first to investigate the relation between native T2 and myocardial perfusion in the presence of pathology and present the correlation between ΔT2 and MPR. While there is potential in non-contrast methods during stress for assessing the microcirculation, given that there is no correlation with MPR the diagnostic potential may be limited. Further research is needed in different patient groups, and with different native T1 mapping protocols.28.In this prospective cohort study of previously healthy 37 patients from a single center was included, which is likely reflected in the structurally normal hearts of the study population. Only one native T1 and native T2 map, respectively, were acquired during stress, however there was no differences in significant correlations between one vs five slices at rest (data not shown). Furthermore, one slice at stress does not cover the entire ventricle, why it would be interesting to perform full coverage native mapping in the future. Another limitation is the heart rate dependency associated with native mapping techniques, where Shortened MOLLI and MOLLI 5 s(3 s)3 s (used in this this study) are two different techniques to mitigate heart rate dependecy compared to other MOLLI sequencesNative T1 and native T2 correlate with myocardial perfusion during adenosine stress, reflecting the coronary circulation in patients during long-term follow-up of severe Covid-19. Neither ΔT1 nor ΔT2 can be used to assess MPR in patients with severe Covid-19.


Childhood cancer survivors have an increased lifetime risk of cardiac problems due to the cardiotoxic effects of cancer treatments. While most research has focused on the left side of the heart, little is known about the effects of these treatments on the right-side chambers. We used cardiac ultrasound to examine the right ventricle in 90 long-term survivors of childhood leukemia and a control group of 58 healthy siblings. Our findings showed that a noticeable number of survivors had subtle alterations in the pump function of the right ventricle, especially when measured using a novel parameter called a free-wall strain. Alterations in free-wall strain were more common in the survivors who were obese or smoked. This study underscores the importance of incorporating right ventricular strain assessment into routine cardiac surveillance and promoting healthy lifestyle habits among survivors.p = 0.004) and RVFWS . Modifiable cardiovascular risk factors such as obesity (p = 0.022) and smoking (p = 0.028) were independently associated with reduced RVFWS. In conclusion, RV systolic function impairment was frequent in long-term survivors of childhood leukemia, underscoring the importance of RV assessment, including RVFWS, in the cardiac surveillance of these patients.There are limited data regarding right ventricle (RV) impairment in long-term survivors of childhood acute lymphoblastic leukemia (CLS). The aim of this study was to assess RV function in these patients using echocardiographic conventional measurements and automated RV strain. Echocardiographic recordings of 90 CLS and 58 healthy siblings from the CTOXALL cohort were analyzed. For group comparisons, inverse probability weighting was used to reduce confounding. The CLS group  underwent an echocardiographic evaluation 18 (11–26) years after the diagnosis. RV systolic dysfunction was found in 16.7% of CLS individuals using RV free-wall strain (RVFWS) compared to 2.2 to 4.4% with conventional measurements. RV systolic function measurements were lower in the CLS than in the control group: TAPSE (23.3 ± 4.0 vs. 25.2 ± 3.4,  Acute lymphoblastic leukemia (ALL) is the most prevalent type of cancer in the pediatric population. Over the past few decades, anthracycline-based therapies have significantly improved survival rates in these patients . HoweverThe main mechanism involved in the pathogenesis of anthracycline-related cardiomyocyte injury is the inhibition of topoisomerase 2β, leading to mitochondrial dysfunction, increased reactive oxygen species production, and apoptosis. Other proposed mechanisms are reduced ATP generation, direct damage to the mitochondria, the lipid peroxidation of cell membranes, and changes in calcium and iron homeostasis ,4,5.Most echocardiographic surveillance studies have focused on left ventricle evaluation ,7, with The aim of this study was to assess RV function in a cohort of long-term CLS through the quantification of automated RVS and conventional parameters.This ancillary study is integrated into the framework of the CTOXALL study, a cross-sectional study that recruited a cohort of long-term childhood cancer survivors who had been diagnosed with ALL between 1985 and 2015 at Reina Sofía Hospital . The primary objective of the CTOXALL study was to investigate the long-term prevalence of cardiotoxicity in CLS. Previously, we have reported a high prevalence of left ventricular systolic and diastolic abnormalities in this cohort of patients ,12. The The research protocol for the CTOXALL study received approval from the local clinical research ethics committee in accordance with institutional and good clinical practice guidelines. Written informed consent was obtained from all participants, as well as from the parents or legal guardians of minors involved.Participants underwent evaluation between May 2019 and January 2022. Eligible participants were survivors diagnosed with ALL before the age of 18 and had received the last anthracycline dose at least 3 years before their inclusion in this study. An individual with a congenital heart disease was excluded. A comparison group consisting of healthy siblings of the survivors who were willing to participate was also recruited.2), which were computed using previously described conversion factors: 0.6× daunorubicin dose, 0.8× epirubicin dose, and 10.5× mitoxantrone .,16.15,16To evaluate the intraobserver and interobserver variability in RVFWS, TAPSE, and FAC measurements, the analysis of 20 randomly selected studies was repeated by the same investigator who performed the analysis and another investigator.t-test or the Mann–Whitney U test for continuous variables, as appropriate.Descriptive data are presented as the count (percentage) for categorical variables and, according to the distribution, as the mean ± standard deviation or median and interquartile range (25th–75th percentiles) for continuous variables. Normal distribution was assessed via the Shapiro–Wilk test and QQ plots. Between-group comparisons of descriptive data were performed via the chi-square test or the Fisher exact test for categorical variables and the Student Between-group comparisons of echocardiographic measurements were performed using linear regression models. The inverse probability of treatment weighting (IPW) was used to address confounding . Propensp < 0.100 in the univariable models.Multivariable linear regression analyses were conducted to determine significant predictors for TAPSE, FAC, and RVFWS in the CLS. Covariates included sex, age, age at diagnosis, time since diagnosis, heart rate, systolic and diastolic blood pressure, hypertension, hypercholesterolemia, diabetes mellitus, obesity, smoking, sedentarism, cumulative anthracycline dose, radiotherapy, and HSCT. The models were tested for collinearity and were built using backward stepwise elimination, initially including clinically relevant variables and those with a y-axis) against their mean (y-axis) for each subject. The limit of agreement was computed as the mean difference ± 1.96 standard deviations [Intraobserver and interobserver variability were assessed through intraclass correlation coefficients and the Bland–Altman method, plotting the differences of 2 measurements  and R software .p = 0.018). Sedentarism was prevalent in both groups , as was obesity . Smoking was more common in the CLS group .For the present study, all 148 participants from the original CTOXLAL study were analyzed: 90 CLS and a control group comprising 58 healthy siblings. The CLS had a mean age at inclusion of 24.6 ± 9.7, and 34 (37.8%) were female. The median age at diagnosis was 4 (3–8) years, and the median time elapsed from diagnosis to recruitment was 18 (11–26) years. All the survivors were exposed to anthracyclines, but only three (3.3%) received radiotherapy. Treatment details are shown in p = 0.005), especially in those with left ventricular systolic dysfunction (n = 11)  or subclinical left ventricular systolic dysfunction (n = 24) . Detailed prevalence rates for each parameter are presented in The prevalence of right ventricular systolic dysfunction in CLS was relatively low, ranging from 2.2 to 4.4%, and did not significantly differ from the rates observed in the control group when considering conventional right ventricular systolic parameters . However, the prevalence of subclinical right ventricular systolic dysfunction, as determined using the RVFWS, was significantly higher in the CLS cohort .On average, the CLS group exhibited lower values for the majority of right ventricular systolic function measurements, including TAPSE, RVFWS, and RV4CS. Conversely, FAC and S’DTI were comparable to the control group. The peak systolic RV-RA gradient was slightly higher in the CLS group. Of note, average right ventricular systolic function parameters were within the normal range in both groups. Right ventricular systolic function echocardiographic parameters, along with additional echocardiographic measurements, are summarized in p = 0.01) and age at examination .The results of univariable and multivariable linear regression models for TAPSE are presented in p = 0.41). In the multivariable model, which included other clinically relevant variables, this association was not significant (p = 0.74).Univariable and multivariable linear regression models for FAC are shown in p = 0.02) and smoking  were independently associated with RVFWS.Univariable and multivariable linear regression models for RVFWS are presented in The variability analysis revealed a high level of agreement in the measured RV systolic function parameters, with particular robustness observed in RVFWS. The intraclass correlation coefficients for intraobserver agreement were 0.95 (95% CI: 0.89 to 0.98) for RVFWS, 0.89 (95% CI: 0.74 to 0.96) for TAPSE, and 0.85 (95% CI: 0.66 to 0.94) for FAC. For interobserver agreement, the intraclass correlation coefficients values were 0.90 (95% CI: 0.77 to 0.96) for RVFWS, 0.85 (95% CI: 0.67 to 0.94) for TAPSE, and 0.81 (95% CI: 0.58 to 0.92) for FAC. Bland–Altman plots  were conIn this study, we evaluated RV function in a cohort of long-term survivors of childhood ALL using conventional echocardiographic measurements and RVS. The main findings were as follows: (1) the prevalence of RVSD was notably higher when assessed with RVS compared to conventional parameters; (2) most RV systolic parameters showed significant reductions compared to the control group; (3) modifiable cardiovascular risk factors were frequent and inversely associated with RVS.While historically overlooked, there has recently been a renewed interest in the study of the RV and its significance in cardiovascular disease . In the 2, and 24% of them were exposed to radiotherapy, which appears to exert a particularly cardiotoxic effect on the RV due to its anterior anatomical position [2 (80–419 mg/m2), and 11% received radiotherapy. Interestingly, no myocardial fibrosis, as assessed via late gadolinium enhancement, was detected. Although CMR was not available in our study, RVFWS has been previously demonstrated to be strongly correlated with CMR-based RV function [In the present study, we found a relatively low prevalence of RVSD using conventional 2D echocardiographic parameters, ranging from 2.2 to 4.4%. Nevertheless, when RV function was assessed with RVFWS, the prevalence of RVSD increased to 16.7%. In line with our findings, previous studies have reported a prevalence of RVSD that varied between 6 and 28%, depending on the diagnostic tool, the cut-off values, and the characteristics of the study sample, especially those related to treatment exposure . Massey et al. found a prevalence of RVSD of 13.6% in a cohort of survivors of HSCT treated in their youth (17.6 ± 9.5 years at HSCT) . The preposition . In addiposition . The medfunction ,28.The CLS group presented lower values for the majority of right ventricular systolic function parameters, including TAPSE, RVFWS, and RV4CS, even after adjusting for potential confounders by means of IPW models. These findings are similar to those reported in other previously detailed cohorts of long-term survivors that included a control group ,24. ConsIn long-term childhood cancer survivors, the presence of modifiable cardiovascular risk factors is frequent and can significantly potentiate the risk of cardiovascular disease associated with cardiotoxic therapies . The reaThe current study has several limitations. Firstly, RV was not evaluated with CMR to complement our findings with tissue characterization. Secondly, the cross-sectional design prevents us from identifying the exact moment of the RVSD onset. Thirdly, the conformation of the control group with healthy siblings resulted in sex and smoking habit differences between the two groups. Smoking was not included in the PS model because it was only present in one participant in the control group. However, sex was well balanced in the weighted population, while the inclusion of siblings as controls may have helped to reduce unmeasured confounding related to demographic, sociocultural, environmental, and genetic factors. Lastly, echocardiographic measurements were not analyzed by a core laboratory team.In this cohort of long-term ALL survivors, right ventricular subclinical dysfunction was present in one out of every six patients. When compared to healthy siblings, most RV systolic parameters showed reductions. Notably, obesity and smoking were associated with greater reductions in RVFWS in the survivors.


Pediatric liver transplantation is an important modality for treating biliary atresia. The overall survival rate of pediatric liver transplantation has significantly improved. The incidence of perioperative cardiac events was evaluated, and risk factors were also investigated in adult patients undergoing liver transplantation in previous studies. To the best of our knowledge, this is the first case of a cardiac event during a pediatric living-donor liver transplantation.Our report describes the management of cardiac events during a liver transplantation in a 7-month-old girl. The ST segment began to increase to 3.0 mm immediately after reperfusion, with peak ST-segment elevation reaching 13.2 mm after 45 min. The procedure ended uneventfully after continuous symptomatic and etiological treatment. It was considered to be the occurrence of an acute air embolism complication during the procedure based on the electrocardiograph and biomarkers. An echocardiogram during follow-up showed a patent foramen ovale with a left-to-right shunt tract width of 2.7 mm.Pediatric liver transplantation has become a state-of-the-art treatment for children with end-stage liver disease and can improve the quality of life to some extent. These children may be complicated with congenital heart disease, which increases the risk of surgery. Application of echocardiogram, close monitoring, and appropriate management may reduce the incidence of perioperative cardiac events. Pediatric liver transplantation is an important modality for treating biliary atresia. Living-donor liver transplantation has been widely performed to solve the problem of donor shortage . The oveA 9.3-kg 7-month-old girl with congenital biliary atresia presented for living-donor liver transplantation. At 6 months of age, she developed hepatic dysfunction and was treated with symptomatic therapy. Her preoperative hemoglobin (Hb) was 77 g/L, albumin was 30.7 g/L, total bilirubin was 430.4 μmol/L, and prothrombin time was 17.3 s, with no electrocardiograph (ECG) abnormality or prominent heart murmur. Her preoperative blood pressure was 90/50 mmHg and the heart rate was 130 bpm.2) 154 mmHg, Hb 5.5 g/L, and potassium 2.6 mmol/L during intermittent positive-pressure ventilation with a fraction of inspired oxygen 0.6. The patient received 20% human serum albumin 50 ml and red blood cells 1U. Vital signs were stable at 25 min of the hepatic-free stage, and arterial blood gas values 20 min after portal occlusion were pH 7.310, base excess −6.8 mmol/L, Hb 8.8 g/L, and potassium 3.4 mmol/L, while core body temperature was maintained at 37°C. She received 5% sodium bicarbonate 30 ml.On arrival in the operating room, ECG leads and a pulse oximeter were placed and continuously monitored. General anesthesia was induced by inhalation of sevoflurane 8% (vol) with transvenous midazolam 1 mg, sufentanyl 5 μg, and rocuronium 10 mg, followed by intubation with an endotracheal tube. Subsequently, a 24G left radial arterial catheter was inserted for continuous invasive arterial blood pressure (IABP) monitoring. A 4F double-lumen intravenous catheter was placed in the right internal jugular vein for continuous central venous pressure (CVP) monitoring. Anesthesia was maintained with expiratory sevoflurane 2% (vol), sufentanyl 10 μg/h, and rocuronium 5 mg/h. Arterial blood gas values after intubation were pH 7.300, arterial oxygen pressure  in II, III, and Augmented Voltage Foot (EKG lead) (aVF) leads, and ST-segment depression in I and Augmented Voltage Left Arm (EKG lead) (aVL) leads, consistent with subendocardial and inferior subepicardial myocardial injuries . ArteriaThe procedure was completed 3 h after reperfusion, with consistently stable vital signs. A full-lead ECG was monitored immediately after admission to the transplantation intensive care unit, showing slight ST-segment elevation in II, III, and aVF leads . MarkersThis report describes a rare acute air embolism complication during a liver transplantation procedure in a young infant. The procedure ended uneventfully after continuous symptomatic and etiological treatment.Among pediatric patients undergoing liver transplantation, those with familial hypercholesterolemia associated with severe atherosclerosis in childhood lead to death from myocardial infarction before the age of 20 years . An infaAn acute air embolism complication during the procedure was diagnosed based on the electrocardiograph and biomarkers in this case. Accurate upper reference limits for defining myocardial injury using high-sensitivity cTnl were provided based on established normative data from a representative pediatric sample among participants of 1–18 years of age in the 1999–2004 National Health and Nutrition Examination Survey, and 6 ng/L as the normative upper reference limit was recommended in female children . The peaRecent guidelines for acute coronary syndrome recommend administration of nitroglycerin . Timely


Hypoplastic left heart syndrome is a rare critical congenital heart defect constituting a prevalence of 1/3,500 to 1/12,500 live births in which there is obstructions to the blood flow within the left heart. Here we present a case of a full-term 38 weeks male baby with a birth weight of 3.5 kg, and no obvious physical deformity referred to our centre at 22 hours of life for respiratory distress and cyanosis. At 23 hours of life, he was diagnosed with hypoplastic left heart syndrome and kept on Prostaglandin E1 infusion till the 12th day of life. The baby had a large ventricular septal defect and atrial septal defect with a severely hypoplastic left ventricle, hypoplastic aortic root, ascending aorta and post-ductal coarctation of the aorta. The diagnosis was reconfirmed by computed tomography cardiac angiography on the 10th day of life with the same cardiac findings suggestive of hypoplastic left heart syndrome. The baby developed respiratory distress with cyanosis at 20 hours of life and was referred to our centre for neonatal intensive care. A lethargic, cyanosed, hypotensive baby was received at 22 hours of life at emergency with pre-ductal saturation of partial pressure of oxygen (SPO2) was 65%. The baby was intubated with initial resuscitation and kept under a mechanical ventilator after shifting to the neonatal intensive care unit (NICU) of KMCTH. Despite under mechanical ventilation, the baby's saturation did not improve and bedside echocardiography was done at 23 hours of life which revealed a hugely dilated right ventricle (RV), dilated right atrium (RA), severely hypoplastic left ventricle (LV), 10 mm membranous ventricular septal defect (VSD) , 5 mm atrial septal defect (ASD) , hypoplastic ascending aorta, small patent ductus arteriosus (PDA) 1.2 mm with post-ductal coarctation , cardiac computerized tomography (CT) angiography was done only on the 10e aorta. .th day of life but, unfortunately, the baby could not survive.The baby was referred to the cardiac surgery centre for the operative procedure on the 126The left-sided heart structures are underdeveloped as a result of the complex aetiology of HLHS. The causes of this defect can be divided into two categories: obstruction of flow into the left ventricle , or obstruction of flow out of the left ventricle (obstruction of the left ventricular outflow tract). Aortic stenosis-related obstruction to left ventricular (LV) outflow during fetal development raises LV afterload and results in LV hypertrophy, which eventually causes LV dilatation and reduced LV contractility. Furthermore, decreased blood flow through the LV hinders the ventricle's growth, resulting in hypoplasia. The neonates with HLHS are reliant on a patent ductus arteriosus (PDA) for blood supply to the coronary arteries and systemic circulation. To keep the ductal patency after birth, prostaglandin E1 (PGE1) must be continuously infused. In contrast to the normal heart's series circulation, these patients are thought to have systemic and pulmonary circulations operating simultaneously.7As this is one of the rare critical congenital heart diseases with severe forms of cardiac malformation, very less case notes have been reported so far. An autopsy case published in Sao Paulo, Brazil highlighted that HLHS is a lethal congenital heart disease and despite the availability of improved management and surgical treatment in developed countries, it is still associated with high mortality, especially in the early neonatal period and before the second stage of reconstruction surgery.8 Similar to this, in our case also, the baby had a hypoplastic left ventricle, hypoplastic aortic arch and ascending aorta along with large VSD and ASD.The HLHS, which is characterized anatomically by an insufficiently sized left ventricle to support the systemic circulation and varying degrees of valvular obstructions, involves a spectrum of blood flow obstructions inside the left heart. The main problems mentioned include hypoplasia of the aortic arch and ascending aorta, as well as atresia or stenosis of the mitral and aortic valves. Additionally, an ascending aorta diameter of less than 3 mm is substantially related to aortic coarctation.As HLHS is one of the critical mixed-flow congenital heart diseases with various cardiac malformations, it is very much difficult to save these types of babies, particularly in low-middle-income countries like Nepal where neonatal cardiac surgical infrastructure is suboptimal.