In the Netherlands, approximately 250,000 people are living with heart failure. About one-third of them have comorbid diabetes mellitus type 2. Until recently, the effects of antidiabetic agents on heart failure were largely unknown. This changed after an observed increased risk of heart failure and ischaemic heart disease associated with thiazolidinediones that prompted the requirement for cardiovascular outcome trials for new glucose-lowering drugs. In the past decade, three new classes of antidiabetic agents have become available  inhibitors). Although the first two classes demonstrated no beneficial effects on heart failure compared to placebo in patients with diabetes mellitus type 2, SGLT2 inhibitors significantly and consistently lowered the risk of incident and worsening heart failure. Two recent trials indicated that these favourable effects were also present in non-diabetic patients with heart failure with reduced ejection fraction, resulting in significantly lower risks of hospitalisation for heart failure and presumably also cardiovascular and all-cause mortality. SGLT2 inhibitors have been shown to be benefit on top of recommended heart failure therapy including sacubitril/valsartan and may also prove beneficial for heart failure with preserved ejection fraction. In this review, we discuss the effects of antidiabetic agents on heart failure. Doses of diuretics may have to be adjusted in patients who are prone to hypovolaemia.In patients using sulfonylurea derivates or insulin, consultation with an endocrinologist is recommended before prescribing SGLT2 inhibitors due to an increased risk of hypoglycaemia and euglycaemic ketoacidosis.It is important to communicate the prescription of SGLT2 inhibitors to the general practitioner because most patients with diabetes mellitus type 2 in the Netherlands are treated by a family doctor.Many cardiovascular outcome trials on antidiabetic agents have included Dutch patients due to multinational collaboration involving Dutch institutions.Several Dutch institutions also participated in the multinational DAPA-HF and EMPEROR-Reduced trials that for the first time investigated the effects of sodium-glucose cotransporter‑2 (SGLT2) inhibitors on heart failure with reduced ejection fraction in non-diabetic patients.A dedicated multi-institutional study from the Netherlands was first to investigate the effects of SGLT2 inhibitors in patients with acute decompensated heart failure.Dutch researchers were also involved in basic and translational studies on mechanisms underlying the beneficial effects of SGLT2 inhibitors on heart failure risk.In the Netherlands, approximately 250,000 people are living with heart failure . The terDiabetes mellitus type 2 is a frequent cause and comorbidity in patients with heart failure, affecting approximately one-third of the patient population . Heart fUntil recently, the effects of antidiabetic agents on heart failure were largely unknown. This changed after an observed increased risk of incident and worsening heart failure, as well as ischaemic heart disease associated with thiazolidinediones that prompted the requirement for cardiovascular outcome trials for new glucose-lowering drugs in 2008 . In cardIn this review, we discuss the effects of antidiabetic agents on heart failure with a focus on new glucose-lowering drug classes.For this narrative review, we searched PubMed for articles on heart failure and antidiabetic agents published up to December 2020. We used ‘heart failure’, ‘diabetes mellitus type 2’, ‘metformin’, ‘sulfonylurea derivates’, ‘insulin’, ‘thiazolidinediones’, ‘dipeptidyl peptidase‑4 inhibitors’, ‘glucagon-like peptide‑1 receptor agonists’ and ‘sodium-glucose cotransporter‑2 inhibitors’ as search terms. We focused on meta-analyses, review articles and randomised controlled trials but did not exclude other studies. We checked the reference lists of selected articles for additional relevant works. We restricted our search to articles written in English or Dutch.Metformin is a biguanide that is postulated to potentiate insulin sensitivity by inhibition of mitochondrial enzymes and is generally the first-line medical treatment for diabetes mellitus type 2 . It is wThe effects of metformin on heart failure were investigated in a meta-analysis by Crowley et al. that pooled data from 35,410 diabetic patients with heart failure from 11 observational studies [A more recent meta-analysis by Halabi et al. that specifically investigated all-cause mortality in diabetic patients with heart failure did stratify results according to HFrEF and HFpEF . In thisSulfonylurea derivates lower glucose by stimulating endogenous insulin production and consequently predispose to hypoglycaemia and weight gain . CurrentIn contrast to the neutral outcome of the UKPDS, another study demonstrated an increased risk of heart failure associated with sulfonylurea derivates. This recent retrospective population-based cohort study by Xu et al. included 15,752 patients with diabetes mellitus type 2 from the Yinzhou district in China and observed a significantly increased risk of hospitalisation for heart failure in patients treated with sulfonylurea derivate monotherapy compared to acarbose monotherapy  (HR 1.61 95% CI 1.14–2.27)) [–2.27) [1Exogenous insulin may cause oedema by increasing sodium reabsorption in the distal tubule of the kidney . This maAlthough ORIGIN indicated that insulin is safe regarding the risk of incident heart failure, an observational study called CHARM  demonstrated a significantly increased risk of all-cause mortality (HR 1.25 (95% CI 1.03–1.51)), as well as a significantly increased risk of a composite outcome of cardiovascular death and hospitalisation for heart failure (HR 2.03 (95% CI 1.80–2.29)) associated with insulin in patients with established heart failure . While CThiazolidinediones are agonists of the nuclear peroxisome proliferator-activated receptor-gamma that increase insulin sensitivity. Fluid retention is a major side effect and may significantly increase the risk of incident and worsening heart failure . This isDPP4 inhibitors impair the degradation of the gut hormones glucagon-like peptide‑1 and gastric inhibitory polypeptide. Thereby they mimic the incretin effect. The incretin effect is characterised by increased insulin production after oral relative to intravenous glucose challenge and is responsible for more than half of the meal-related insulin secretion in healthy individuals . IncretiOne of the cardiovascular outcome trials on DPP4 inhibitors that was also included in the meta-analysis by Sinha and Ghosal, SAVOR-TIMI 53 , demonstrated a significantly increased risk of hospitalisation for heart failure associated with saxagliptin compared to placebo (HR 1.27 (95% CI 1.07–1.51)) . A post P = 0.55) were comparable between patients treated with vildagliptin and placebo [Because the cardiovascular outcome trials on DPP4 inhibitors included a relatively low number of patients with heart failure, the VIVIDD (Vildagliptin in Ventricular Dysfunction Diabetes) trial was conducted . VIVIDD  placebo .These data indicate that the increased risk of heart failure hospitalisation is likely specific to saxagliptin and not a class effect of DPP4 inhibitors. Variation in substrate selectivity between different DPP4 inhibitors has been postulated as the underlying mechanism of variance in heart failure risk associated with various agents .GLP1R agonists also mimic the incretin effect. In addition to their glucose-lowering potential, they stimulate weight loss and result in lower blood pressure due to afterload reduction and natriuresis . To dateP < 0.05) [Two small trials specifically investigated the GLP1R agonist liraglutide in patients with HFrEF , 37. Bot < 0.05) .SGLT2 inhibitors are antidiabetic agents that lower blood glucose by inducing glycosuria. To date, four cardiovascular outcome trials have evaluated SGLT2 inhibitors in patients with diabetes mellitus type 2  Program , however, did compare a composite outcome of hospitalisation for heart failure and cardiovascular death according to heart failure subtype . AlthougThe beneficial effects of SGLT2 inhibitors on heart failure in patients with diabetes mellitus type 2 prompted the inception of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and EMPEROR-Reduced  trials , 46. TheEMPEROR-Reduced included 1856 diabetic and 1874 non-diabetic patients with HFrEF (NYHA class II to IV). After 1.3 years of follow-up, a composite outcome of hospitalisation for heart failure and cardiovascular death was significantly less common in patients treated with empagliflozin relative to placebo (HR 0.75 (95% CI 0.65–0.86)). Results were comparable between diabetic and non-diabetic patients, as well as between patients treated with or without sacubitril/valsartan .Although both DAPA-HF and EMPEROR-Reduced demonstrated a significant reduction in a composite outcome of cardiovascular death and hospitalisation for heart failure associated with SGLT2 inhibitors, after separation of these events, cardiovascular mortality was only significantly lowered in DAPA-HF , 46. Thep < 0.05) [The aforementioned beneficial findings of SGLT2 inhibitors in HFrEF were corroborated in patients with acute decompensated heart failure in the Dutch multicentre trial EMPA-RESPONSE-AHF  and the multinational SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure) trial , 49. EMP < 0.05) . SOLOIST2 [SGLT‑2 inhibitors have also been shown to decrease the risk of worsening kidney function in both diabetic and non-diabetic patients with chronic kidney disease , 51. Thi2 . A post 2 .Common side effects of SGLT2 inhibitors include genital infections and volume depletion. Rarely, euglycaemic ketoacidosis may develop. Patients using sulfonylurea derivates or insulin are more prone to this latter complication and may also develop hypoglycaemia. One study (i.e. the CANVAS Program) reported a higher risk of amputation . HoweverIndications for prescribing SGLT2 inhibitors and points of concern in patients with HFrEF are shown in Box The data above indicate that SGLT2 inhibitors have beneficial cardiorenal effects. The rapidity of onset of these effects suggests a working mechanism independent of glycaemic control. Although the exact working mechanisms of SGLT2 inhibitors are unknown, osmotic diuresis due to glycosuria and concomitant natriuresis seem to be pivotal  guidelines for the diagnosis and treatment of acute and chronic heart failure, pharmacotherapy with angiotensin-converting-enzyme inhibitors, beta-blockers and mineralocorticoid receptor antagonists is recommended for patients with HFrEF; for patients with HFpEF, diuretics are recommended for congestion. Antidiabetic agents have no important role .Based on our review Fig. , Box 2 aUntil recently, the effects of antidiabetic agents on heart failure were largely unknown. This changed after an observed increased risk of heart failure and ischaemic heart disease associated with thiazolidinediones that prompted the requirement for cardiovascular outcome trials for new glucose-lowering drugs. Subsequently, three classes of antidiabetic agents became available . Of these drug classes, only SGLT2 inhibitors significantly and consistently lower the risk of heart failure in patients with diabetes mellitus type 2. Recent trials demonstrated that SGLT2 inhibitors also protect against worsening heart failure in non-diabetic patients with HFrEF. We believe that current evidence is strong enough to recommend SGLT2 inhibitors in both diabetic and non-diabetic patients with HFrEF. Due to the recent approval of dapagliflozin for the treatment of HFrEF in Europe, SGLT2 inhibitors are likely to be reimbursed by health insurance agencies in the near future. Ongoing studies, including EMPEROR-Preserved and DELIVER  will hopefully replicate the promising findings of SGLT2 inhibition in diabetic and non-diabetic patients with HFpEF.


To evaluate the feasibility and accuracy of diagnosing acute heart failure (HF) with CT pulmonary angiography (CTPA) in emergency department patients.n = 100) and test cohort (n = 50). Three independent, blinded readers measured the attenuation in the right ventricle (RV) and left ventricle (LV) on axial images. The ratio (HUratio) and difference (HUdiff) between RV and LV attenuation were calculated. Diagnosis of acute HF was made on the basis of clinical, laboratory, and echocardiography data. Optimal thresholds, sensitivity, and specificity were calculated using the area under the curve (AUC) from receiver operating characteristics analysis.In this retrospective single-center study, we evaluated 150 emergency department patients (mean age 65 ± 17 years) undergoing CTPA with a fixed scan (100 kVp) and contrast media protocol  who had no pulmonary embolism (PE). Patients were subdivided into training cohort  and HUdiff . In the training cohort, HUratio  and HUdiff  showed a very good performance to diagnose HF. Optimal cutoff values were 1.42 for HUratio  and 113 for HUdiff . Applying these thresholds to the test cohort yielded a sensitivity of 89% and 89% and a specificity of 69% and 63% for HUratio and HUdiff, respectively.Fifty-nine of the 150 patients (40%) were diagnosed with acute HF. Attenuation measurements showed an almost perfect interobserver agreement . NT-pro BNP exhibited moderate correlations with HUratio and HUdiff have a high sensitivity for diagnosing acute HF.In emergency department patients undergoing CTPA and showing no PE, both HU• Heart failure is a common differential diagnosis in patients undergoing CT pulmonary angiography.• In emergency department patients undergoing CT pulmonary angiography and showing no pulmonary embolism, attenuation differences of the left and right ventricle have a high sensitivity for diagnosing acute heart failure. Acute heart failure (HF) is a complex and heterogeneous syndrome being associated with high rates of morbidity and mortality, with reported 1-year mortality rates reaching 10 to 30 % . HF is cPulmonary embolism is another life-threatening condition and the third leading cause of cardiovascular-related death  with an Computed tomography pulmonary angiography (CTPA), owing to its high sensitivity and specificity as well as wide availability, represents the imaging modality of choice for the diagnosis or exclusion of pulmonary embolism , 11, 12.The purpose of our study was to evaluate the feasibility and accuracy of diagnosing HF using attenuation measurements in the right and left ventricles (RV and LV) in patients with negative CTPA for pulmonary embolism. Our hypothesis was that a high contrast attenuation in the right heart on CTPA examinations may indicate acute HF owing to the reduced cardiac function.This single-center, retrospective study was approved by the local ethics committee; written consent requirement was waived. The investigation conformed with the principles outlined in the Declaration of Helsinki.n = 21, 11%). Sixteen of the remaining 169 patients (9%) had to be excluded as no echocardiography was available in the emergency department or during subsequent hospitalization despite increased NT-pro BNP values. Two patients (1%) were excluded because the region of interest (ROI) for bolus tracking was erroneously positioned in the ascending aorta, and one patient (1%) was excluded because the scan delay was manually increased by the technician.Our radiology information system was searched for patients undergoing CTPA with the identical scan and contrast media protocol in our emergency department between November 2019 and June 2020, yielding a total of 218 patients. Patients with suspicion of or with diagnosis of COVID-19 infection were excluded. Twenty-eight of the 218 patients (13%) had pulmonary embolism and were thus excluded from the study. Lack of availability of brain natriuretic peptide (NT-pro BNP) measurements on emergency department admission for the diagnosis of HF , and categorical data is given as count and percentage.t-test or one-way analysis of variance, where appropriate. Pearson’s correlation was applied to assess correlations of continuous variables. Due to the right-skewed distribution of NT-pro BNP, correlations were calculated with log-transformed NT-pro BNP values.Interreader agreement between the two readers in the training cohort was assessed by calculating the intraclass correlation coefficient for consistency (ICC). Parametric continuous values were compared using Student’s J statistic (J = sensitivity + specificity − 1) was applied to derive optimal thresholds to diagnose HF. Furthermore, thresholds with a high sensitivity (≥ 95%) and specificity (≥ 95%) were derived from the AUC. Using a binary logistic regression analysis, we calculated the odds ratios for the optimal thresholds of HUdiff and HUratio to diagnosis HF with age and sex as covariates.The area under the curve (AUC) of receiver operating characteristics (ROC) analysis was calculated for attenuation and diameter measurements. Youden’s p-value below 0.05 was regarded as indicative of statistical significance. All analyses were performed using commercially available software .A two-sided Baseline characteristics of the entire study cohort, the training cohort, and the test cohort are presented as Table ratio was 1.89 ± 1.17 and mean HUdiff was 151 ± 132 HU.We found an almost perfect interobserver agreement of attenuation measurements between the two readers . Bland-Altman plots showed narrow limits of interobserver agreement for LV  and RV , respectively  and HUdiff  between sexes. Weak though significant correlations were found between age and HUratio  and HUdiff  in the overall cohort; however, these findings were not significant for patients without HF (p > 0.05 for both). There were significant correlations between NT-pro BNP and HUratio  and HUdiff .There were no significant differences for HUMean diameters of the LV, RV, and LA were 40.5 ± 8.5 mm, 39.1 ± 7.8mm, and 35.3 ± 8.1mm, respectively.ratio (1.33 ± 0.34) and HUdiff (83 ± 79 HU) were significantly lower in patients without HF compared to patients with HF . Subdivision of HF patients into patients with preserved and reduced ejection fraction showed that HFratio and HFdiff were significantly higher in patients with HFrEF  compared to HFpEF patients  and patients without HF  and HUdiff  showed a very good performance to diagnose HF  and 113 for HUdiff . The odds ratio for a HUratio of 1.42 to detect HF was 27.8 (95%CI: 7.2–106.7). The odds ratio for a HUdiff of 113 was 27.3 (95%CI: 7.2–103.9) to detect HF. Cutoff values for HUratio and HUdiff providing ≥ 95% sensitivity and specificity are shown in Table Optimum cutoff values to detect HF were 1.42 for HUratio was 1.65 ± 0.91 and the mean HUdiff was 131 ± 130 HU.In the test cohort, the mean attenuation in the LV and RV was 262 ± 71 HU and 393 ± 121 HU, respectively. The mean HUratio and 113 HU for HUdiff) yielded a sensitivity of 89% and 89% and specificity of 63% and 69%, respectively, for the diagnosis of HF based on attenuation measurements in the RV and LV (Table ratio of 1.42 to detect HF was 18.2 (95%CI: 3.2–103.5). The odds ratio for a HUdiff of 113 was 17.6 (95%CI: 3.0–102.7) to detect HF.Applying the thresholds established in the training cohort  and in those with preserved left ventricular function (HFpEF), as opposed to patients showing normal cardiac function. Both these parameters showed a very good diagnostic performance to diagnose HF  on CTPA. The sensitivity of both parameters when using optimal thresholds was high (89–92%) and highly reproducible in different patient (training and test) cohorts. Furthermore, both difference and ratio of RV and LV attenuation showed a moderate correlation with NT-pro BNP levels supporting the value of both parameters in identifying patients with acute HF. In comparison diameter measurements of the LV, RV, and LA as well as ratios of diameter measurements showed lower diagnostic performances to diagnose HF. For these parameters, LA diameter had the highest AUC, which is compatible with previous studies .Importantly, measurements of the RV and LV attenuation on axial CT images with calculation of either the ratio or difference in attenuation represents a fast and simple approach for the assessment of HF in patients undergoing CTPA, which is supported by the almost perfect interobserver agreement between readers. Thus, we introduce an easy-to-apply technique for suggesting HF in emergency department patients negative for PE in CTPA with a very good sensitivity. Introducing this technique to the emergency work-up may help accelerating the early detection and treatment of HF with the aim to resolve the patients’ symptoms.The following study limitations must be acknowledged. First, this retrospective study included only CTPA studies performed in the emergency department of a single institution and with a limited sample size. Furthermore, we did not perform a sample size calculation for our study. Future studies with larger patient cohorts  are required to further validate the difference and ratio of attenuation in the RV and LV in such patients, which holds particularly true for the thresholds reported herein. Second, hemodynamic parameters and CT were not recorded simultaneously. Although time intervals between CT and echocardiography were short, this might have influenced our results. Third, while the CT scan and contrast media protocol were kept constant, issues regarding the contrast media application such as a potential obstruction of the venous access route with subsequent lowering of contrast media flow rates, differences in breath-holding, or contrast media extravasation may have influenced the attenuation. Furthermore, the actual numbers of LV and RV attenuation are most probably influenced by the contrast media and/or CT scanning protocol. Whether our approach is also applicable to different techniques with a more individualized scan initiation such as the test-bolus method or using a patient-specific post-trigger delay  must be In patients undergoing CTPA in whom CT shows no pulmonary embolism, the difference and ratio of RV and LV attenuation represent a fast and simple approach to suggest acute HF as a differential diagnosis with a very good diagnostic performance. The excellent sensitivity of the two parameters when using optimal thresholds may allow for the early diagnosis of acute HF and for a prompt initiation of appropriate therapy of this highly prevalent and life-threatening disease.


To demonstrate that quantitative multicomponent T2 relaxation can be more sensitive than conventional FLAIR imaging for detecting cerebral tissue abnormalities.Six patients affected by lower-grade non-enhancing gliomas underwent T2 relaxation and FLAIR imaging before a radiation treatment by proton therapy (PT) and were examined at follow-up. The T2 decay signal obtained by a thirty-two-echo sequence was decomposed into three main components, attributing to each component a different T2 range: water trapped in the lipid bilayer membrane of myelin, intra/extracellular water and cerebrospinal fluid. The T2 quantitative map of the intra/extracellular water was compared with FLAIR images.Before PT, in five patients a mismatch was observed between the intra/extracellular water T2 map and FLAIR images, with peri-tumoral areas of high T2 that typically extended outside the area of abnormal FLAIR hyper-intensity. Such mismatch regions evolved into two different types of patterns. The first type, observed in three patients, was a reduced extension of the abnormal regions on T2 map with respect to FLAIR images (T2 decrease pattern). The second type, observed in two patients, was the appearance of new areas of abnormal hyper-intensity on FLAIR images matching the anomalous T2 map extension (FLAIR increase pattern), that was considered as asymptomatic radiation induced damage.Our preliminarily results suggest that quantitative T2 mapping of the intra/extracellular water component was more sensitive than conventional FLAIR imaging to subtle cerebral tissue abnormalities, deserving to be further investigated in future clinical studies. Previous studies have used T2 relaxometry to investigate brain water , as the T2 relaxometry is at the basis of myelin water imaging (MWI) for the quantification of myelin component –5. Well-In a prospective study that enrolled patients who received proton irradiation to the CNS, we investigated the potential of multicomponent T2 relaxometry in radiation oncology. Herein, we describe the method for acquisition and analysis of multicomponent T2 relaxometry and the first data obtained on a sample of six lower grade glioma patients. The data accidentally showed that decomposing T2 can be more sensitive than conventional FLAIR imaging for detecting subtle tissue alterations in the peri-tumoral region.Patients were recruited from an ongoing institutional review board approved study on the application of MWI in radiotherapy. Written informed consent was obtained for all participants. Six patients affected by lower grade glioma WHO grades II–III were selected. All the lesions had no or marginal enhancement on post-contrast imaging. Patients characteristics, dose prescriptions and time between surgery and treatment are listed in 2, acquisition matrix = 128 × 126 reconstructed to 256x256, 18 contiguous slices 5mm thickness reconstructed to 36 slices 2.5 mm thickness. MWI scans were acquired before PT (pre-PT), at the end of PT (end-PT) and in some cases (see Results section) at follow-up. All the patient underwent diagnostic MRI examination before PT and at follow-up, including conventional 3D FLAIR, which was acquired also at the end of PT. FLAIR parameters were TE = 95 ms, TR = 6,000 ms, inversion time = 1,740 ms, contiguous slice thickness = 1.2 mm and pixel size = 0.5 × 0.5 mm2 for patient #1 and TE = 150 ms, TR = 4,800 ms, inversion time = 1,660 ms, contiguous slice thickness = 1.15 mm and pixel size = 1.0 × 1.0 mm2 for the other patients.Images were acquired with a 1.5T MR scanner . A 16-channel head coil was utilized, routinely used for brain examinations. MWI was obtained using a multicomponent T2 relaxation technique by a 3D GraSE  multi-ecFor all patients, MWI and FLAIR pre-PT images were acquired at the beginning of the PT treatment and MWI and FLAIR end-PT images were acquired within one month after treatment. Follow-up diagnostic MR examinations were acquired more than three months after treatment for patients #1–5 and around fifty days after treatment for patient # 6. MWI was also acquired at follow-up for patients #2 and #3 (see below results).®, The MathWorks.inc, Natick, MA, USA) and by MERA  and end-PT.On both pre-PT and end-PT data, the volume of hyper-intense IEw T2 inside the CTV was automatically segmented by selecting the voxels with T2 higher than a threshold value. This threshold value was chosen on pre-PT data by the normalized distribution of T2 values, at the intersection between the T2 distribution of the voxels inside the GTV and the T2 distribution obtained on the voxels outside the same GTV. The same threshold value was applied to segment end-PT IEw T2 maps.A quantitative comparison was performed on both pre- and end-PT between the segmented volumes on T2 maps and the corresponding volumes on FLAIR imaging.The evolution of the lesion and of the surrounding tissue was visually assessed at pre-PT, at end-PT and at follow-up on the acquired IEw T2 maps and on conventional multi-parameter MRI.Finally, a quantitative analysis was performed on an identified region of interest (ROI), assessing the corresponding T2 distribution of the ROI at different time points.Quantitative volume analysis is reported in Qualitative visual analysis confirmed that for all the patients except patient #4 a spatial mismatch was observed before PT between the IEw T2 quantitative map and FLAIR images, with an area of high T2 that typically extended outside the area identified by abnormal FLAIR hyper-intensity. Only marginal differences were observed in patient #4, with no clear mismatch (not shown). At end-PT, the observed mismatch tends to decrease, by two different evolution patterns.A reduced extension of the exceeding mismatch region (T2 decrease pattern) was observed for two patients, respectively #1 and #5 shown in Figure 1For three patients  new areas of abnormal hyper-intensity on FLAIR images were observed in the mismatch regions identified before PT . Images showing the mismatch on patient #3 and #6 are reported in –A ROI analysis was performed to investigate the characteristics of the T2 distribution that enabled the IEw T2 map to visualize abnormalities not evident with FLAIR imaging Figure 4Visual inspection of IEw T2 maps put into evidence a very small decrease in the contralateral healthy tissue after therapy see 3. TheseFinally, it was more difficult to clearly identify tissue alterations in the other maps  and much better spatial resolution.Moreover, conventional T2-FLAIR sequence provides the information of both T2 relaxation and proton density of the IEw component, but this study only focused on the T2 relaxation of the IEw component. Indeed, the obtained proton fraction maps were not particularly informative as the subtle alterations, clearly visible on the T2 map, were not visible in the proton fraction map (data not shown). An additional map could be obtained by multiplication of T2 relaxation and the corresponding proton fraction of the IEw. However, this last map does not seem to add too much and it would miss the quantitative information available in the corresponding T2 map.Since our sampling of the T2 decay curve stopped at a TE of 320 ms, the analysis of longer T2 components was inaccurate. Besides that, using discrete tissue models with a fixed number of components may work quite well in defined systems, such as normal white matter, but for tissue alterations it might be inappropriate, if the model is incorrect. In a previous study , T2 compFurther and deeper investigations are required to properly assess the specificity of the alteration additionally detected by IEw T2 mapping. MWI is not a well-established widespread used technique and it has to be considered as an experimental method still under development. Visual inspection of IEw T2 maps showed in some cases a diffuse but very small decrease outside the region that received full treatment dose. The ROI analysis demonstrated that these changes in the healthy tissue were negligible compared to the greater changes occurring in the mismatch regions.The regions characterized by a mismatch between FLAIR and IEw T2 followed two different evolution patterns at follow-up. In the FLAIR increase pattern, tissue alteration might be ascribed to predisposition to tissue damage, which was finally diagnosed as asymptomatic radiation induced damage. Due to initial disease, these areas could have been more sensitive to the radiation insult and might be predictive of the corresponding sequelae.The T2 decrease seems more difficult to be specified, as the observed mismatch might be due to evolving post-surgical sequelae or oedema but tumor infiltration cannot be excluded a priori. Lower grade gliomas are heterogeneous neoplasms with infiltrative behaviour along white matter tracts and surgical treatment poses special challenge for the neurosurgeon since, due to their diffusely infiltrative growth pattern, intraoperative identification of the exact tumor border is frequently not possible with certainty . Lower gIn conclusion, the contrast obtained in FLAIR imaging is based on the attenuation of the myelin water, due to long echo-times, and of fluid by inversion recovery. A similar attenuation was expected in T2 relaxation when considering only the intra/extracellular water component, thus T2 mapping of the intra/extracellular component can be considered as equivalent to a quantitative FLAIR. In our preliminarily study, T2 mapping of the intra/extracellular component in lower grade gliomas showed a mismatch with FLAIR imaging, with areas of high T2 that typically extended outside the area identified by abnormal FLAIR hyper-intensity. Such mismatch was due to an increased sensitivity of quantitative T2 mapping to detect subtle cerebral tissue abnormalities and deserves to be further investigated in future clinical studies.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by ethics committee for clinical research of Azienda Provinciale per i Servizi Sanitari . The patients/participants provided their written informed consent to participate in this study.PF and PB contributed to conception and design of the study. PB performed MRI acquisitions and data analysis. PF supported data analysis and data interpretation. UR supported radiological data interpretation. DA, DS, and MA provided patients for the study and supported clinical data interpretation. PF wrote the first draft of the manuscript. PB and UR wrote sections of the manuscript. All authors contributed to the article and approved the submitted version.PB was supported by a grant founded by the Fondazione CARITRO—via Calepina 1, 38122 Trento, Italy.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.


We evaluated the influence of image reconstruction parameters on these measurements.Computed tomography (CT) allows reproducible assessment of left ventricular (LV) function, left ventricular outflow tract area , 0.6-mm-slice thickness, 512 × 512 matrix) and eight reconstructions with modified slice thickness (1–8 mm), number of cardiac phases , matrix size (256×256) and an iterative reconstruction (IR) algorithm were obtained. LV parameters (ejection fraction (EF), stroke volume (SV), end-diastolic (EDV), end-systolic volumes (ESV)), LVOTarea and AVA, were only minimal between standard reconstructions and those with modified matrix size, IR algorithm and ≤2 mm slice thickness, while reconstructions with 8-mm slice thickness significantly overestimated SV (p < 0.001) and EDV (p = 0.016). AVA planimetry in reconstructions with ≥5 mm slice thickness was not feasible in 56% of patients. A decrease in the number of reconstructed phases (10 or 5) underestimated EF, SV, EDV, LVOTarea and AVA and overestimated ESV.Differences in LV parameters, LVOTarea and AVA assessment. However, a reduced number of reconstructions per cardiac cycle may significantly influence measurements.Modifications of reconstruction parameters (except a slice thickness ≤2 mm) have only a marginal effect on LV, LVOTarea and AVA also in modern CT scanners.Substantial modifications in number of reconstructions per cardiac cycle significantly affect the assessment of LV function, LVOT CMR is considered the gold-standard for LV assessment but is a costly and time-consuming examination with limited access.Assessment of left ventricular (LV) parameters, left ventricular outflow tract area  algorithm on the assessment of LV parameters, LVOTEighty patients who underwent contrast-enhanced cardiac CT for standard transcatheter aortic valve replacement work-up between December 2016 and April 2017 were screened for enrollment. After excluding patients with regional wall motion abnormalities and/or LV aneurysm based on prior echocardiography (31 patients) or an artificial aortic valve (four patients), the final cohort counted 45 patients. Covariates, including cardiac history and risk factors, were taken from the patient data records.−1), followed by a 50-ml flush consisting of 80% saline and 20% contrast agent using a dual-head power injector. Patients were not administered additional oral or intravenous beta-blockers for the scan according to our standard TAVI CT protocol.A third-generation dual-source CT scanner  with spiral acquisition and retrospectively ECG-gated image reconstruction was applied. Tube voltage and current were set at 100 kV/500 mAs in patients with 60–100 kg and weight-adapted in patients below or above this weight range. Contrast agent transit time was measured using test bolus technique. CT angiography was performed with 60-ml contrast agent (5 ml sAll datasets were reconstructed with a medium sharp convolution kernel (‘Bv40’). For the standard reconstruction, a filtered back-projection algorithm with 0.6-mm-slice thickness, 0.4-mm increment, 20 cardiac phases  and a 512 × 512 matrix was applied. Additional data sets were reconstructed with modifications in slice thickness , number of cardiac phases [10  and 5 ], matrix size (256 × 256) and an iterative reconstruction (IR) algorithm , but otherwise identical parameters to the standard reconstruction.15 The selected phases of end-diastole and end-systole were recorded as percent R-R-interval values for each dataset.Post-processing was performed using Syngo.via cardiac function module . The reader was blinded to the reconstruction information. Datasets were visually assessed for diagnostic image quality using the 5-point Likert scale . Image quality parameters included homogeneity of contrast distribution and contrast between LV cavity and myocardium to allow automated segmentation. Automated tracing of the endocardial borders was visually verified by the reader and manually corrected, if necessary . Papillaarea and AVA, a multiplanar image display mode was used with reference images in oblique coronal and sagittal planes along the LVOT. Measurements of the AVA were performed in a double-oblique transverse plane across the aortic valve at the level where the orifice was smallest and of the LVOT just below the aortic valve plane, as previously described.11,16 Determination of the anatomic AVA was then performed by manual planimetry at the systolic phase with the widest valve opening by tracing the orifice along the edges of the cusps. LVOTarea was assessed in the same phase of the cardiac cycle. High intra- and/or interobserver variability for this approach has been demonstrated in prior studies.11,16For assessment of the LVOT® SPSS® statistics, version 19 for Windows). Continuous variables were expressed as mean ± SD or median, categorical variables as frequencies and percentage, unless otherwise specified. Correlation was assessed using Pearson’s test. Statistical significance between the standard reconstruction and the modified reconstructions was assessed using the paired t-test for normally distributed data or the paired Wilcoxon test for non-normally distributed data. The 95% limits of agreement were defined using Bland-Altman analysis. p < 0.05 was considered to be statistically significant.Statistical analysis was performed using SPSS software . There was no significant difference in LV parameters when the matrix size was decreased from 512 × 512 to 256 × 256. The use of IR algorithm level 2 compared to standard reconstruction with filtered-back-projection resulted in a minor, but statistically significant underestimation in EF, SV and EDV, whereas the ESV was not significantly changed. A similar effect was observed for an increased slice thickness of 1 mm with a minor, but statistically significant underestimation in EF and SV. A stronger increase in slice thickness resulted in a higher scattering of the LV parameters compared to the standard reconstruction. Here, 8-mm slice thickness reconstruction resulted in a statistically significant overestimation of SV (p = 0.015) and EDV (p = 0.016) compared to the standard reconstruction. In contrast, reducing the number of reconstructed phases of the cardiac cycle from 20 to 10 and 5 resulted in a statistically significant overestimation in ESV (both p < 0.001) and an underestimation in EF, SV and EDV  compared to the standard reconstruction. The mean end-systolic phase was 38±5% for the standard reconstruction and showed a statistically significant difference only for the modified reconstruction reduced to five phases of the cardiac cycle .On standard reconstructed data sets, mean EF was 69±12%, SV 87.6 ± 21.9 ml, EDV 129.5 ± 31.1 ml and ESV 41.9 ± 21.8 ml . PearsonWhen comparing patients with sinus rhythm to those with atrial fibrillation, a minor underestimation in EF, SV and EDV for IR algorithm level two compared to standard reconstruction with filtered-back-projection was observed in patients with sinus rhythm but not in atrial fibrillation . OtherwiSupplementary Table 2.Click here for additional data file.area was 482 ± 90 mm² . There was no significant difference in LVOTarea for reconstructions with a modified matrix size, IR and slice thickness compared to the standard reconstruction. A statistically significant underestimation for LVOTarea was only seen in reconstructions with 10 and 5 phases of the cardiac cycle (both p < 0.001). The heart rhythm  did not have any significant effect on LVOT measurement between standard and modified reconstructions.In the standard reconstructed data set, the mean LVOT± 90 mm² . In recor = 0.88, p < 0.001). There was no significant difference in AVA for reconstructions with modified matrix size, IR and 1- and 2-mm slice thickness compared to the standard reconstruction. A statistically significant underestimation for AVA was only seen in reconstructions with 10 and 5 phases of the cardiac cycle (both p < 0.001). The mean phase of the cardiac cycle for AVA determination was 14±4% in the standard reconstruction. Except for the modified reconstruction with five phases , there was no significant difference in the mean phase of AVA measurement for the other modified reconstructions compared to the standard reconstruction. The heart rhythm  did not have any significant effect on AVA measurement between standard and modified reconstructions.In the standard reconstructed data set, the mean AVA was 0.91 ± 0.21 cm² . In recoarea and perimeter and AVA and overestimation in ESV compared to the standard reconstruction. There was a minor difference for reconstructions with an applied IR algorithm and 1-mm slice thickness. Overall, an increase in slice thickness showed a higher scattering of the measurements.The present study systematically investigated the influence of reconstruction parameters on the assessment of left ventricular function, LVOT and aortic valve area. To our knowledge, this study provides the most comprehensive investigation in terms of the variety of assessed reconstruction parameters including slice thickness, number of phases of the cardiac cycle, matrix size and IR algorithm. Our study revealed that reconstructions with a decrease in the number of phases of the cardiac cycle resulted in a statistically significant underestimation in EF, SV, EDV, LVOTarea and AVA in patients with poor image windows and contraindications for echocardiography and CMR. A high temporal and spatial resolution are crucial for exact LV assessment, LVOTarea and AVA. Several factors affect CT spatial resolution including, for example, pixel size, field of view, slice thickness, detector size, reconstruction algorithm and also patient-dependent factors like motion.17 Temporal resolution, on the other side, can be influenced by, for example, gantry rotation time, acquisition mode, type of image reconstruction and pitch.17 Whereas CT offers an excellent spatial resolution, the temporal resolution is only moderate compared to echocardiography and CMR. One could assume that the more precise and detailed the CT reconstruction parameters are chosen, the more accurate the assessment should be. On the other hand, the more detailed the reconstruction is, the longer it takes for image reconstruction, data post-processing and LV parameter analysis and also the larger the amount of data storage. There are only few studies evaluating the influence on modified CT reconstruction parameters on LV function.12–14 Ko et al12 found no significant difference in LV function assessment between 20- and 10-phase reconstructions. Suzuki et al13 reported an underestimation of EF when only three instead of six systolic cardiac phases were considered. Both studies were performed with 16- or 64-slice CT scanners which achieve a substantially lower temporal resolution than current dual source CT systems. Although a high temporal resolution is crucial for the selection of the exact end-diastolic and -systolic phase and thereby for calculating accurate LV parameters. To capture the correct end-systolic phase, a temporal resolution of ~50 ms is required as demonstrated for other image modalities. 64-slice scanners offer only a temporal resolution between 125 and 250 ms, whereas dual source CT offers a temporal resolution of up to 66 ms.18 Furthermore, the variability of temporal resolution according to the heart rate has been shown to limit a reliable evaluation of LV function in CT scanners with 64 slices or less.12 In contrast, dual source CT provides high diagnostic image quality over a wide range of heart rates with a heart rate-independent temporal resolution.19 For a dual-source CT-based approach, we found a statistically significant underestimation in EF, SV and EDV and overestimation in ESV when reducing the number of reconstructed phases from 20 to 10 and even more for a reduction to five phases. We assume that this observed difference was due to a more precise selection of the correct end-systolic phase in data sets with more approximate reconstructions.CT offers a reliable alternative for assessment of LV parameters, LVOT13 reported no significant difference in EF calculated from end-systolic images with 1, 2 and 3 mm slice thickness. Vural et al14 demonstrated no significant difference in EDV calculated from 1- and 2-mm-reconstructions but reported minor but statistically significant differences between reconstructions in EF and ESV. In our present study, we also observed very minor, but statistically significant differences for EF and SV between 0.6 and 1 mm slice thickness which we do not see as clinically relevant. Further increases in slice thickness , although, showed a larger scattering of the measurements which is most-likely due to the decrease in spatial resolution and, thereby, a more inaccurate distinction between endocardial tissue and ventricular lumen. In reconstructions with 8-mm slice thickness, SV and EDV were statistically significantly overestimated.Slice thickness determines the through-plane (or z-axis) spatial resolution. The larger the slice thickness, the lower the resolution. Suzuki et al20 Pixel size is inversely related to in-plane spatial resolution. A reduction of the matrix size from 512 × 512 to 256 × 256 results in an increase in pixel size and, thereby, in a reduction in in-plane spatial resolution. We observed no significant difference in LV parameters derived from a conventional 512 × 512 compared to a 256 × 256 matrix.The matrix size determines the axial pixel size which is the ratio of field of view to image matrix.21 Advances in computer processing power have made IR algorithms clinically feasible, resulting in reconstructed data with reduced image noise within an acceptable time.22 IR has been shown to potentially alter spatial resolution and image texture.21 Here, we used an IR strength level 2 out of 5. When comparing IR images with filtered-back-projection and otherwise non-modified reconstruction parameters, there was a minor, but statically significant underestimation in EF, SV and EDV, which will be most likely due to a smoothing of the image.Filtered-back-projection is based on several assumptions that simplify CT geometry as a compromise between reconstruction speed and image noise.16 demonstrated that the LVOT area is slightly larger with a more circular shape in systole than in diastole. In the present study, we found a small but significant underestimation in LVOT area for 10 and 20% reconstruction steps compared to the standard reconstruction, which is likely caused by the restriction in the optimal systolic phase available for assessment. Reconstructions with a slice thickness of 8 mm are not suitable for LVOT assessment due to an inaccurate outline. An increase of up to 5 mm, a reduction in matrix size or use of IR showed no statistically significant difference in LVOTarea.CT-based assessment of the LVOT has been shown to be superior to 2D echocardiography given its oval rather than circular shape. Reliable measurements of the LVOT are crucial for aortic valve stenosis and LVOT obstruction assessment. Halpern et al11 We noticed a statistically significant underestimation in AVA when only 10 or 5 phases of the cardiac cycle were reconstructed compared to standard reconstructed data. This is most likely due to the limited choice of phases to select the optimal systolic AVA. Whereas in standard reconstructed data the mean phase of the cardiac cycle for AVA determination was 13.8±4.2%, the AVA planimetry was performed at 20% of the cardiac cycle in all patients when the phases of the cardiac cycle were reduced to 5. With an increase of ≥5 mm slice thickness, AVA could not be longer accurately distinguished from the valve leaflets in more than half of the patients. A minor increase of up to 2 mm, a reduction in matrix size or use of IR showed no statistically significant difference in AVA.To our knowledge, this study is the first to assess the influence of modified reconstruction parameters on CT-based assessment of aortic valve area. Prior studies have shown that planimetric AVA measurements on multidector-CT allow accurate grading of aortic valve stenosis severity.5 Although we observed a small but significant difference in parameters if a 10% interval of the cardiac cycle compared 5% interval was used. The recommended parameters are standard for modern CT scanner generations. However, with the increased use of cardiac CT in daily routine, some hospital may use also earlier scanner generations and our current study points out the limitations in LV and AVA assessment if less accurate reconstruction parameters are applied.Finally, the important question arises of the clinical relevance of the described findings. We believe that the reported minor differences for modified reconstructions with an increase in slice thickness ≤2 mm, a 256 × 256 matrix size and IR algorithm do not influence the clinical decision-making. However, if the slice thickness is increased ≥5 mm or the number of cardiac phases reduced, this may have a clinical relevance. Current recommendations for CT imaging in the context of transcatheter aortic valve implantation recommend reconstructions with <1 mm slice thickness,≤10% intervals of the cardiac cycle, a 512 × 512 matrix and filtered back projection or iterative reconstruction.6–8 To minimize confounders in the present study, assessment was not performed in patients with regional wall abnormalities and/or aneurysm of the left ventricle, as these patients were excluded. Accordingly, the mean ejection fraction was high compared to a real-life TAVI cohort. The number of patients included for analysis was only modest. We did not perform a dedicated inter- and intrareader analysis as a high accuracy for automated LV assessment by CT and a high intra- and/or interobserver variability for LVOTarea and AVA assessment has been demonstrated in earlier studies.11,15,16We did not apply a gold standard like echocardiography or CMR for comparison but used the standard CT reconstruction applied in the latest-generation of dual source CT scanner. This was considered sufficient as agreement of LV function assessed by cardiac CT with echocardiography or CMR has been extensively investigated in earlier studies.area and AVA. A marked reduction in the number of reconstructions per cardiac cycle as well as a substantial increase in slice thickness compared to standard reconstruction settings significantly affect the assessment of LV parameters, LVOTarea and AVA.Cardiac CT is a robust method to determine LV function, LVOT


However, ventricular activation patterns during intrinsic conduction and responses to right ventricular (RV) and left ventricular (LV) pacing vary among different patients. Thus optimizing electrical resynchronization may need individualization according to the interaction between patient substrate and paced effects.•Automatic device-based algorithms are appealing solutions for optimization. However, a one-size-fits-all algorithm may not deliver optimal resynchronization in all patients. For example, simply using LV pacing may not resolve large transseptal delays that account for delayed LV activation in left bundle branch block.•Recent reports indicate that biventricular pacing at individualized atrioventricular intervals is more likely to deliver best electrical resynchronization. This promotes synergy among intrinsic right bundle branch conduction and RV and LV paced wavefronts. This is conceptualized to promote confluent LV activation. This case using electrocardiographic imaging visually depicts this resynchronization scheme of “triple fusion.”•ClinicalTrials.gov Identifier: NCT04100148).Currently enrolling randomized trials are testing advantages of electrocardiographic-guided CRT optimization with a device-based algorithm designed to deliver triple fusion therapy  delivery. Current recommendations emphasize careful candidate selection and left ventricle (LV) lead delivery but do not extend to postimplant optimization in the absence of convincing benefit. However, optimizing electrical resynchronization depends on the interaction between patient substrate and paced effects and may need individualization. Recent data indicate that “Triple Fusion” optimizes CRT delivery.A 72-year-old woman with hypertension, diabetes, and recurrent heart failure found to have nonischemic cardiomyopathy, left bundle branch block (LBBB) (QRSd 180 ms), and persistent LV dysfunction (LV ejection fraction 20%) despite guideline-directed medical therapy received CRT with a posterolateral LV position. Thus the patient met best selection criteria  and implant technique.,Electrocardiographic imaging (ECGI) study was undertaken 1 day post-implant . The metThe ventricular activation underlying LBBB is shown in LV pacing is the therapeutic element of CRT. However, LV epicardial stimulation elicits wavefronts that propagate slowly even in normal myocardium . These vary significantly among patients with LBBB and heart failure and are unrelated to LV activation delay during intrinsic conduction (“qLV”).creates intra-LV electrical dyssynchrony.LV paced effects require coordination with intrinsic RBB conduction (“LV-only fusion pacing”) and/or RV pacing (biventricular pacing) to promote biventricular resynchronization. This underlies optimization methods. LV pacing alone timed to fuse with intrinsic RBB conduction promises LV preexcitation while avoiding RV paced electrical delays.Recent reports indicate that biventricular fusion pacing is more likely to deliver better electrical resynchronization than LV-only fusion pacing.This is the first visual depiction of “triple fusion”—that is, effects of intrinsic RBB conduction combining with RV and LV paced wavefronts to promote best biventricular resynchronization.ClinicalTrials.gov Identifier: NCT04100148).This single case report does not reflect the variability in ventricular activation patterns that occur during intrinsic conduction and in response to LV and RV pacing among different patients.This patient was committed to simultaneous biventricular pacing  to deliver triple fusion. LV function rectified (LV ejection fraction 40% at 1 year and 60% at 18 months post-implant) and has remained stable for 10 years.Patient individualized optimization offers opportunity to improve both biventricular and intra-LV synchrony during CRT.


Myocardial ischemia is known to suppress fatty acid metabolism and favor glucose metabolism. However, changes in myocardial metabolism after coronary revascularization are not fully elucidated.123I-BMIPP SPECT in both the short-term (6.4 ± 4.7 months) and mid-term (29.9 ± 7.2 months) after isolated coronary artery bypass grafting. Tracer uptake was graded using a 17-segment, 5-point scoring model. Serial changes in SRS (summed rest score), SDS (summed difference score), the BMIPP score , and the mismatch score (BMIPP score–SRS) were evaluated. In addition, persistent perfusion–metabolism mismatch (PM) was defined as mismatch score minus SDS of 3 or more during the mid-term postoperative period. The clinical parameters associated with PM were examined.Thirty-eight patients with coronary artery disease were retrospectively enrolled. These patients had undergone stress perfusion single photon emission computed tomography (SPECT) and P = 0.117). The extent of ischemic myocardium (SDS), the BMIPP score and the mismatch score, which reflects perfusion–metabolism mismatch, were significantly improved . Remarkably, perfusion–metabolism mismatch persisted in 13 patients (34%) even in the mid-term postoperative period. eGFR and SYNTAX score were independent predictors of persistent perfusion–metabolic mismatch in multivariable analysis . The mismatch score both in the short- and mid-term significantly correlated with SYNTAX score .From short- to mid-term postoperative period, the extent of infarcted myocardium (SRS) did not change significantly (7.8 ± 8.0 to 7.1 ± 7.0, Fatty acid metabolism disturbance improved from short- to mid-term postoperative period in patients with successful reperfusion by coronary artery bypass grafting. However, in patients with severe atherosclerosis, impaired fatty acid metabolism was sustained until the mid-term postoperative period, even though ischemia had resolved.The online version contains supplementary material available at 10.1007/s12149-021-01696-3. In the follow-up of patients after coronary artery bypass grafting (CABG), evaluation of graft patency by coronary angiography and cardiac function by echocardiography is considered conventional management. However, evaluation of myocardial metabolic function in relation to myocardial perfusion may be more important after revascularization for ischemic myocardium than graft angiography. Myocardial energy metabolism changes in response to stressors such as ischemia and pressure overload .It is also known to change significantly during the progression of heart failure . Therefo123I-BMIPP (β-methyl-iodophenyl pentadecanoic acid). The combination of 123I-BMIPP SPECT and myocardial perfusion imaging (MPI) can, therefore, evaluate the relationship between myocardial fatty acid metabolism and perfusion. In chronic hypoperfused myocardium, discordant BMIPP uptake less than perfusion is often observed, which is called perfusion–metabolism mismatch. Previous clinical studies have reported perfusion–metabolism mismatch where recovery of 123I-BMIPP uptake was delayed at early phase after resolution of ischemia [Myocardial fatty acid metabolism can be visualized using single photon emission computed tomography (SPECT) with ischemia . BMIPP iischemia .123I-BMIPP SPECT / stress MPI in the short- and mid-term postoperative periods.However, serial change in myocardial energy metabolism after coronary revascularization is still not fully understood. A previous study reported impaired fatty acid metabolism in the early phase after revascularization by percutaneous coronary intervention (PCI) . The pre99mTc-tetrofosmin and 123I-BMIPP SPECT to evaluate myocardial perfusion and metabolism in the short-term after CABG. Forty-one patients, who underwent stress perfusion SPECT and 123I-BMIPP SPECT in both the short-term (1–17 months) and mid-term (22–47 months) postoperative periods were retrospectively enrolled. One patient who required revascularization between short- and mid-term postoperative periods was excluded. Two patients with new ischemia (SDS increased ≥ 3 from short- to mid-term postoperative period) were excluded. The study protocol was approved by the Ethics Committee of Nippon Medical School Hospital (No. 28-06-592), and all patients gave informed consent. This study followed the principles outlined in the Declaration of Helsinki.One hundred and fifty-three consecutive patients with coronary artery disease (CAD) who underwent isolated CABG at Nippon Medical School Hospital, Tokyo, Japan between December 2014 and January 2018 were assessed for this study. At our institution, myocardial SPECT is performed for routine follow-up after CABG in patients who have given consent. Among 153 patients, 74 patients underwent stress perfusion SPECT using Baseline demographic and clinical characteristics of the study population are summarized in Table The short-term postoperative period was 6.4 ± 4.7 months, and the mid-term postoperative period was 29.9 ± 7.2 months. The average interval between the short- and mid-term postoperative periods was 23.5 ± 4.8 months. All patients took oral antiplatelet agents postoperatively..Operations were performed by a single surgeon (YI). Our institutional policy for coronary artery bypass grafting aimed to achieve complete myocardial revascularization with an off-pump technique. We bypassed all significantly diseased coronary vessels (at least 50% diameter reduction) larger than 1 mm in diameter. As a general policy, the left internal thoracic artery (LITA) was used as a conduit for the left anterior descending artery (LAD). For patients younger than 70 years of age, total arterial revascularization utilizing the internal thoracic, radial and right gastroepiploic arteries was adopted whenever feasible. For patients over 70 years of age, saphenous vein grafts (SVG) were mainly used for reconstruction of the left circumflex and/or right coronary artery territories. All arterial grafts were harvested in a skeletonized fashion using an ultrasonic scalpel . Saphenous vein grafts were harvested using an open technique with fine scissors99mTc-tetrofosmin  was injected at rest, followed by stress imaging with an injection of 740 MBq. Gated single photon emission computed tomography (SPECT) datasets were acquired with a Cadmium–Zinc–Telluride gamma camera  with a multi-pinhole collimator and 19 stationary detectors. Scan time was 5 min for stress imaging and 10 min for rest imaging in the supine position. All SPECT datasets were reconstructed on a dedicated workstation  using a commercially available dedicated software package  with an iterative algorithm based on integrated collimator geometry modeling, using maximum likelihood iterative reconstruction to obtain perfusion images in standard axes as previously reported [All patients underwent a 1-day ECG-gated rest/stress protocol with pharmacological stress induced by adenosine (0.144 mg/kg/min for 5 min). Patients were instructed to withhold food and beverage, including caffeine, for 24 h before the procedure. A dose of 296 MBq of 123I-BMIPP (Nihon Medi-Physics Co Ltd), and scanned 20 min later for 10 min in the same manner as for 99mTc-TF SPECT imaging [99mTc-TF and 123I-BMIPP SPECT imaging was within 7 days.After at least 6 h of fasting, patients were injected intravenously with 148 MBq of All patients underwent two-dimensional transthoracic echocardiography at rest before CABG. Pre-operative LVEF was computed by the modified Simpson’s method or Teichholz method (no LV asynergy cases). Post-operative LVEF was obtained by gated SPECT data at rest in all patients in early- and mid-term periods after CABG.99mTc-TF SPECT images  with reference to the results of analysis of polar maps, which were used to assess regional perfusion, wall motion, and thickening to improve differentiation between perfusion abnormalities and attenuation artifacts. The visual semi-quantitative scoring was performed by 2 experts with reference to the normal database [123I-BMIPP SPECT images, we calculate the total defect score for each image as the total defect scores (BMIPP score). The mismatch score, which represents perfusion–metabolism mismatch, was calculated using the following formula: BMIPP score–SRS.Stress MPI and BMIPP SPECT images were judged by two experienced observers (Radiologist YF and TK). The myocardium was divided into segments using a 17-segment model. Segmental tracer uptakes were semi-quantitatively categorized using a 5-point grading system . Reversible and fixed defects were identified using database . Summed database . For 123Patient follow-up was performed by hospital records or telephone contact. The patients were followed up for cardiac death and nonfatal cardiac events including myocardial infarction (MI), unstable angina pectoris (AP), and hospitalization for heart failure. Heart failure requiring hospitalization was identified by dyspnea and radiographic evidence of pulmonary edema. The follow-up period was defined as the time from the mid-term postoperative period until September 2020. The mean follow-up period was 22 ± 6 months on average.U test. Changes from baseline were evaluated by Wilcoxon matched-pairs signed ranks test. Univariable and multivariable logistic regression models were utilized to analyze the relationship between perfusion–metabolism mismatch and predictive factors. Explanatory variables with a univariable probability value < 0.2 were considered for inclusion in the multivariable model with the forward selection method. Pearson’s product moment correlation coefficient was performed to determine the correlation. The statistically significant level was defined as P < 0.05.Data were statically analyzed using IBM SPSS 23.0 software . Numerical results are expressed as mean ± SD. Categorical data were compared between two groups using Fisher’s exact probability test and differences between continuous variables were evaluated with Mann–Whitney 123I-BMIPP SPECT parameters between the short- and the mid-term postoperative periods is shown in Fig. P = 0.117; Fig. P = 0.010; Fig. P < 0.001; Fig. P < 0.001; Fig. The time course of stress MPI and Although perfusion–metabolism mismatch generally improved after resolution of ischemia Fig. , it did r = 0.189, P = 0.256, Online Resource 1a). Similarly, change in the SDS score (ΔSDS) score did not correlate with change in the mismatch score . Therefore, there was no correlation between improvement in ischemia and improvement in perfusion–metabolism mismatch.Improvement in SDS score (%) did not correlate with improvement in the mismatch score (%) . Also, fewer patients were taking postoperative ACEI (angiotensin converting enzyme inhibitor) /ARB (angiotensin II receptor blocker) and Statins in Group PM  compared with Group non-PM . More patients were taking postoperative diuretics in Group PM (63%) compared with Group non-PM .Unusually, there were some cases of remained perfusion–metabolism mismatch during the mid-term postoperative period despite the resolution of ischemia Fig. . PersistP = 0.010 and OR = 1.126, 95% CI 1.011–1.254, P = 0.031, respectively).In univariable analysis Table , eGFR anr = 0.400, P = 0.013; and r = 0.472, P = 0.003; Fig. The mismatch score both in the short- and mid-term postoperative periods correlated moderately with the SYNTAX score (P = 0.051). In Group PM, change in LVEF (ΔLVEF) from preoperative to short-term postoperative period tended to be larger . More patients had a ≥ 10% increase in LVEF in Group PM (46%) compared with Group non-PM . There was no significant difference in LVEDVI and changes in LVEDVI (ΔLVEDVI) between the two groups in the short and mid-term postoperative periods. Two patients in Group PM were readmitted to the hospital during follow-up due to heart failure (Table Comparison of change in LVEF and LVEDVI (left ventricular end-diastolic volume index) between the groups is shown in Table This is the first study to evaluate the serial alteration of myocardial fatty acid metabolism in relation to myocardial perfusion in patients after CABG. The present results demonstrated that perfusion–metabolism mismatch improved from the short- to the mid-term after CABG in the whole patient population. However, there was no association between improvement of perfusion–metabolism mismatch and improvement of ischemia from the short- to the mid-term. In addition, perfusion–metabolism mismatch persisted in the mid-term postoperative period in approximately 30% of patients, excluding the effects of ischemia. The results suggest that persistent decrease in BMIPP uptake after CABG does not necessarily mean ischemic myocardial damage. The present study revealed that a certain number of patients with severe atherosclerosis preoperatively have prolonged postoperative fatty acid metabolism impairment even after successful revascularization.Previous studies showed improved perfusion–metabolism mismatch within 2–3 months after percutaneous coronary intervention (PCI) . The pre123I-BMIPP SPECT and stress MPI enabled us to evaluate the time course of perfusion–metabolism mismatch excluding the effect of ischemia. Multivariable analysis identified eGFR  and SYNTAX score  as predictors of persistent perfusion–metabolism mismatch.The combination of 2 [2 [Chronic kidney disease (CKD) is an independent risk factor for cardiovascular events. eGFR showed a significant negative correlation with lipid volume in coronary plaques in patients with eGFR > 30 mL/min/1.73m2 , and art2 [2 . Previou2 [2 , 19. TheAnother predictor, the SYNTAX score, is a comprehensive angiographic scoring system that quantitatively assesses CAD severity based on the type of lesion and correlates well with myocardial ischemia as assessed by stress MPI . Higher The visual assessment of myocardial perfusion imaging is a relative evaluation that assumes that the highest accumulation area is normal. Progression of microvascular dysfunction decreases myocardial blood flow at maximal hyperemia and consequently coronary flow reserve making it difficult to contrast stenotic and normal areas on visual assessment during stress . In the Impaired BMIPP uptake is related to a high probability of cardiac events in CAD patients . LikewisSuppression of fatty acid metabolism in the failing heart may have a protective effect . IncreasThe present study has a few limitations. The study population was relatively small. Myocardial perfusion and metabolism were measured by SPECT. Ideally, they should be evaluated with myocardial perfusion positron emission tomography (PET) with quantitative analysis and other metabolic ligands; however, its clinical use is quite limited at this time. Unlike FDG-PET, BMIPP SPECT is less affected by blood substrates , and has the advantage that it can be evaluated both in cases with diabetes or dyslipidemia and in noncomplicated cases. Also, coronary angiography was not performed after CABG; thus, graft patency was not evaluated. In addition, LVEF was measured by echocardiography before CABG. However, postoperative LVEF was obtained from gated SPECT and a previous study reported a good correlation between gated SPECT and echocardiography for LVEF measurement . Left veIn conclusion, perfusion–metabolism mismatch improved from the short- to mid-term postoperative periods in patients with successful reperfusion by CABG. However, in patients with severe coronary arteriosclerosis, impaired fatty acid metabolism was sustained until the mid-term postoperative period, even though ischemia had resolved.Supplementary file1 (DOCX 64 KB)Below is the link to the electronic supplementary material.


Before anthracyclines, LVEF (69.4 ± 3.6%) and RVEF (55.6 ± 9%) were normal. The median follow-up after anthracyclines was 399 days (IQR 310–517). The RVEF reached its nadir (46.3 ± 6.8%) after 9-months (P < 0.001). RV mass-index and RV CM decreased to 13 ± 2.8 g/m2 and 8.13 ± 2 g/m2, respectively, at 16-months after anthracyclines. The RV ECV expanded from 0.26 ± 0.07 by 0.14 (53%) to 0.40 ± 0.1 (P < 0.001). The RV ECV expansion correlated with a decrease in RV mass-index  and the increase in CK-MB. An RV ESV index at baseline above its median predicted an increased risk of LV dysfunction post-anthracyclines. In BC patients treated with anthracyclines, RV atrophy, systolic dysfunction, and a parallel increase of diffuse interstitial fibrosis indicate a cardiotoxic response on a similar scale as previously seen in the systemic left ventricle.There are limited data on the effects of anthracyclines on right ventricular (RV) structure, function, and tissue characteristics. The goal of this study was to investigate the effects of anthracyclines on the RV using cardiac magnetic resonance (CMR). This was a post-hoc analysis of a prospective study of 27 breast cancer (BC) patients (51.8 ± 8.9 years) using CMR prior, and up to 3-times after anthracyclines (240 mg/m Multiple prior studies5 have provided an in-depth characterization of the changes of left ventricular (LV) and aortic vascular function in patients treated with anthracyclines. Among broad groups of patients with HF, the presence and the extent of right ventricular (RV) dysfunction is a key determinant of outcomes8, but there are limited data on the effect of anthracyclines on the RV10. In patients treated with anthracyclines, studies using CMR imaging have demonstrated a decline in RV systolic function in adult survivors of childhood cancer12 and in breast cancer patients15. However, one of the key strengths of CMR is the ability to apply tissue characterization techniques to improve our understanding of the pathophysiological changes in response to injury. There are a paucity of studies applying such tissue characterization techniques to better understand the effects of anthracyclines on the RV. This is in contrast to several published studies on LV tissue remodeling after anthracyclines5; additionally, several studies17 have suggested that the RV may be more vulnerable to injury from anthracyclines, and early RV dysfunction may predict anthracycline-induced cardiotoxicity. We were specifically interested in understanding the effects of anthracyclines on the RV fibrosis, as measured by calculation of the extracellular volume (ECV), and on cardiomyocyte mass. Such data would improve the current understanding of pre-clinical RV abnormalities induced by anthracycline therapy in BC patients, and are hypothesis generating for future prospective studies of the long-term effects of anthracycline induced cardiotoxicity.Anthracyclines are a standard primary therapy for several malignancies. However, the use of anthracyclines is associated with cardiac injury, adverse cardiac remodeling, and cardiac dysfunction leading to clinical heart failure (HF) and death2 in 27 consecutively recruited female patients with BC enrolled between 2012 and 2015. We previously described2 the effects of anthracyclines in this study on the LV. Patients were eligible for enrollment if they had a BC diagnosis and were scheduled to receive adjuvant anthracycline-based therapy . Exclusion criteria were any contraindications to CMR, chronic kidney disease (GFR < 40 ml/min2), previous myocardial infarction, clinical diagnosis of HF, moderate or severe valvular disease or any other significant cardiac disease. Detailed clinical and medical history, standard anthropometric data, and laboratory evaluation were performed alongside CMR exams. Our local Institutional Review Board approved the study  da Faculdade de Ciências Médicas da UNICAMP; Rua: Tessália Vieira de Camargo, 126; Distrito de Barão Geraldo, Campinas—SP, Brazil, CEP: 13083-887; https://www.prp.unicamp.br/pt-br/contato-2; Phone/Fax: + 55 19 3521.8936). All participants provided written informed consent prior to study enrollment and patients completed the study protocol without suffering adverse events. All methods were carried out in accordance with relevant guidelines and regulations.This is a post-hoc analysis of a previously published clinical study applying CMR to characterize the cardiotoxicity with anthracyclines 2. Time ranges for study visits and CMR exams varied mainly due to patient scheduling and retention issues. Thus, for the longitudinal analysis, we categorized the follow-up times into quartile ranges. In the three patients with HER-2 + breast cancer, trastuzumab was delayed for non-study related reasons and was not administrated until after the last CMR exam.Participants underwent clinical assessment and CMR imaging before and up to three times consecutively after anthracycline treatment  were obtained at baseline after 12 h of fasting. CK, CK-MB  and high-sensitive troponin T (cTnT)  were obtained at baseline, before each anthracycline cycle, and before each CMR visit.6-element phased-array surface-coil. The CMR protocol comprised electrocardiographically gated cine imaging with steady-state free precession  for LV and RV volumes/function, and imaging of late gadolinium enhancement (LGE) for scar assessment as previously described18. A breath-hold Look-Locker spoiled gradient-echo cine technique19 was used for T1 measurements in a single mid-ventricular slice with a temporal resolution of 80 ms for pre-contrast T1 and 55 ms post-contrast 20. The Look-Locker sequence used an adiabatic inversion pulse, which by its very nature is relatively insensitive to the B1 amplitude of the radio-frequency pulses and results in excellent inversion profiles. At least 5 T1 datasets were acquired in each patient.Patients were imaged on a 3 T CMR scanner  with a www.lkeb.nl) to measure biventricular mass, volumes and function21. The RV and LV walls were contoured on the Look-Locker images and divided into 4 and 6 segments, respectively. Ventricular volumes and mass were indexed by body-surface area. For the RV ECV, only the free wall from the superior to the inferior RV-to-LV insertions points was considered. T1s were determined for each myocardial segment and the LV blood pool by nonlinear least squares fitting to an analytic expression for the inversion recovery and correction for the effects of radiofrequency pulses applied using the method originally developed by Deichman and Haase22. The myocardial partition coefficient for gadolinium contrast (λGd) was determined by myocardial sector by linear least-squares fitting of pre and post-contrast R1’s in tissue against R1’s in blood. ECV was estimated as λGd multiplied by (1-Hct), where Hct represents the patient’s blood hematocrit at the time of the CMR examination23. We also estimated the LV and RV cardiomyocyte mass (CM) from the product of (1-ECV) and total LV and RV mass, respectively.The CMR images were analyzed with the MASS CMR software . Data are presented as means ± standard deviation, or median with inter-quartile range (IQR), if not normally distributed. Linear mixed effects (LME) regression models (R-package lme4) were used to analyze longitudinal changes of LV and RV volumes indices, EF and ECV in each patient. Measurement variables which did not appear to have a linear dependence on follow-up time (as continuous variable) were analyzed with generalized additive models with mixed effects (GAM), using a cubic-regression spline to represent time24, a random intercept per patient, and an autoregressive model (AR) for errors to account for the correlation of successive measurements within each patient (R-package mgcv). Variables were log-transformed as needed when a quantile–quantile plot indicated significant deviation from a normal distribution. The occurrence of LV systolic dysfunction after anthracycline therapy was stratified by the median RVEF or RV ESV index at baseline. Bivariate correlation of independent measurements was assessed with Pearson’s method, or alternatively with Spearman’s method if indicated. Repeated measures correlation was computed to determine the overall within-individual relationship among paired measures assessed at multiple time points25. Intra and inter-observer variability of the RV ECV was performed at patient and segmental levels in a randomly selected subset of studies (n = 10), using inter-class correlation (ICC)26. The subset of studies was re-analyzed blinded to any clinical information by the main reader (TFS) and by another reader (ORCF), both fully trained in CMR and with prior experience in T1 mapping analysis.Statistical analysis was performed using R  and RV mass index (18.2 ± 4 g/m2)28. The mean RVEF at baseline was 55.6 ± 9%, consistent with values reported for healthy normal29 of similar age.Baseline characteristics of our study population are shown in Table 2, the LVEF and LV mass-index decreased from baseline, reaching 53.8 ± 8.4% at  and 36 ± 6 g/m2 at  after chemotherapy respectively  and covered a time span from 79 to 700 days. Measurements for RV and LV volumes, wall mass and systolic function are summarized in Fig. 0–517 and2 at baseline to 25.2 ± 10 ml/m2 at . This increase in the RV end-systolic volume occurred with a parallel decline in the RVEF from 55.6 ± 9% to a minimum of 46.3 ± 6.8% at . Both the LV and RV cardiomyocyte mass (CM), derived from the product of (1-ECV) and wall mass indices, decreased after chemotherapy, reaching 23.2 ± 4.3 g/m2 for the LV and 8.3 ± 1.93 g/m2 for the RV, respectively, at .Paralleling the longitudinal expansion of ECV in the LV Fig. A, the RV2, the cTnT and CK-MB fraction levels increased from 4.6 ± 1.4 pg/ml and 13.6 ± 6.1 IU/L (baseline) to 21.3 ± 14.4 pg/ml and 19.8 ± 11.7 IU/L at . The change of RV ECV between baseline and the final follow-up CMR study was associated with the simultaneously measured change of CK-MB serum level, as shown in Fig. P < 0.001 for interaction of follow-up time and log-transformed CK-MB level), as illustrated in Fig. Results for the serum biomarkers cTnT and CK-MB are displayed in the online supplement . The inter-class correlation (ICC) of RV ECV at segmental and patient levels were performed for inter-observed and intra observer variability analysis. The ICC coefficient for the inter-observer comparison at the segmental level was 0.795 (CI 0.678–0.873) and at the patient level was 0.784 (CI 0.373–0.94). The ICC for intra-observer comparison of the RV ECV at segmental level was 0.82 (CI 0.717–0.888) and at patient level was 0.927 (CI 0.473–0.953).P = 0.011) and a higher RV ESVi . Patients with an RV ESVi above its median at baseline, had an overall lower LVEF at multiple time points after anthracyclines (P < 0.001), though at baseline LVEF was > 60% in all patients .After anthracycline therapy, 15 (58%) patients showed signs of LV systolic dysfunction  on one of the follow-up CMR examinations, i.e. these patients met criteria for LV cardiotoxicity, namely a > 10% reduction in LVEF from baseline to < 55%, in the absence of heart failure symptoms. Patients with LV systolic dysfunction at follow-up had a lower RVEF at baseline . The ECV is a well-validated imaging marker of myocardial fibrosis in the LV and increased following anthracycline therapy; however, has not been used previously to study cardiotoxicity in the RV. The simultaneous increase of ECV and a reduction in total RV wall mass both contributed to a reduction of RV CM, suggesting CM atrophy and/or diffuse CM necrosis. Furthermore, subclinical differences in RV systolic EF and end-systolic volumes at baseline predicted LV systolic dysfunction after anthracyclines. These findings are consistent with recent reports that the RV may be at least as vulnerable to injury from anthracyclines as the LV, and early RV dysfunction may predict anthracycline-induced cardiotoxicity34. Nevertheless, there are limited data on the effect of anthracyclines on the RV. In the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS), 27% of patients presented with chemotherapy-induced cardiomyopathy and these patients had significant and severe reduction of RVEF35. Only a few CMR studies have characterized the occurrence of RV dysfunction after anthracyclines with or without antagonism of human epidermal growth factor receptor 2 (HER2)15. Groover et al. noted, in cohort of 56 BC patients treated with anthracycline and/or trastuzumab, a significant decrease in RVEF at 4 months, which persisted to 12 months13. Nakano and colleagues, studying exclusively HER positive BC patients, reported changes on the RV circumferential strain, which decreased 6-months after the initiation of trastuzumab14. More recently, Barthur et al. also investigated HER positive BC patients before, and serially after chemotherapy , and showed adverse effects on RV structure and function that tended to recover after 18 months15. Recently Zhao et al.36, reported in a cohort with large B-cell lymphoma, treated with anthracycline-based chemotherapy, that the RVEF decreased significantly from 54.0 ± 2.8% to 49.8 ± 2.4% (P < 0.001), a change of a similar magnitude as in the present study.A decline in RV systolic function is a robust prognostic marker for adverse outcomes in a variety of clinical scenarios36. Since the lower normal limit of RVEF has been defined as 51% for women28, our findings highlight that even moderated exposure to anthracycline may cause a meaningful decline in RV function. Furthermore, an above-median RV ESV index and a below-median RVEF at baseline were both independently associated with a higher risk of LV cardiotoxicity after anthracyclines (> 10% decline of LV EF and LV EF < 55%). RV dysfunction may even represent an early warning sign of cardiotoxicity following anthracycline therapy. A previous study by Planek et al. of lymphoma patients16 with an average follow-up period of 6-months found that anthracycline therapy was associated with subclinical RV dysfunction, but not LV dysfunction, at a cumulative dose ≥ 200 mg/m2. In the present study LV systolic dysfunction was at a nadir around ~ 300 days allowing a more comprehensive evaluation of full impact of anthracyclines on ventricular function than in the study by Planek et al. A novel finding from this study is that the RV ESVi at baseline is associated with the risk of LV systolic dysfunction after anthracycline therapy, suggesting that RV ESVi baseline status could help in risk stratification for patients undergoing anthracycline therapy.Although criteria for RV cardiotoxicity are not well-defined or agreed upon, it has been proposed that significant reductions of RVEF below the lower limit of normal for the imaging method should be considered15. Experimental models of mice treated with doxorubicin demonstrate that histopathologic modifications in ventricular tissues are analogous, but the degree by which each ventricle is affected may differ, particularly in relation to the level of oxidative stress present37. Our group38, and others39, have also demonstrated that anthracycline-based chemotherapy markedly reduces LV mass, and that this portends a worse prognosis. The mechanisms involved in the decrease in LV mass are thought to be related to cardiomyocyte death and atrophy2. It is reasonable to hypothesize that cardiomyocyte death and atrophy play a similar putative role in the RV loss of mass.We observed a relatively weak correlation between the longitudinal changes of EF in the LV and RV. In prior work, RV remodeling and dysfunction was noted at 4–6 months after therapy implementation and lasted until 12-months reflecting or not LV changes in function4 have demonstrated the usefulness of CMR T1 mapping in characterizing myocardial tissue remodeling of the LV in patients undergoing cancer therapy, but there are no analogous data for the RV. T1 mapping in the RV is technically more challenging. Nevertheless, studies in patients have demonstrated the value of CMR T1 mapping for detecting diffuse fibrosis in the RV. We note here that the RV ECV at baseline in our study (0.26 ± 0.07) is almost identical to the RV ECV reported for control groups in two independent studies of pulmonary hypertension 41). There are limited data from experimental studies on longitudinal RV ECV changes following anthracycline therapy. In a rabbit model42, the ECV increased at both superior and inferior RV insertion regions from 0.28 ± 0.013 and 0.29 ± 0.02, to 0.39 ± 0.01 and 0.41 ± 0.01, respectively, 16 weeks after treatment with doxorubicin (1 mg/kg injections twice a week). The T1-based ECV estimates at the RV insertion regions correlated well with the collagen volume fraction 42.Several groups43. Other biomarkers of interest, such as NT-proBNP, were not initially planned and were not available. There was a negative correlation between RVEF and CK-MB, and it appears plausible that a similar relationship could be expected between RV EF and hs-cTnT, but which was nevertheless not observed. We note here that CK levels, including of the CK-MB heterodimer, have been reported to be lower44 in breast cancer patients, and more so with more advanced cancer stage, which may result in a larger longer-term effect of anthracyclines on CK-MB levels compared to hs-cTnT. Finally, it is important to acknowledge that the current findings have to be interpreted in the context of a hypothesis generating post-hoc study which requires further, larger and dedicated investigations to confirm the clinical usefulness of RV tissues characterization by CMR T1 mapping following anthracyclines.We have investigated a relatively small uniform cohort of BC patients; consequently, current results may not be applicable to patients with a different malignancy clinical profile. As all recruited patients remained asymptomatic during the entire study, exploratory investigation of the associations of RVEF and RV ECV with symptoms after anthracycline therapy was not feasible. In addition, we highlight that we used a Look-Locker technique for T1 measurements rather than the modified Look-Locker imaging (MOLLI), as this sequence was not available at the time of the study. A generalization or comparison of our results obtained with the Look-Locker gradient echo T1-mapping method, to other more commonly used T1 mapping methods, may not apply. It should nevertheless be noted that MOLLI and Look-Locker T1 measurements showed good agreementBreast cancer patients undergoing anthracycline-therapy experienced significant adverse myocardial remodeling in both ventricles, which are reflected in meaningful reductions in function and mass. Similar to the LV, the RV extracellular volume increased and RV cardiomyocyte mass decreased after anthracycline therapy, expanding the current understanding of RV dysfunction induced in this setting.Supplementary Tables.