Correct staging and grading of patients with clear cell renal cell carcinoma (cRCC) is of clinical relevance for the prediction of operability and for individualized patient management. As partial or radial resection with postoperative tumor grading currently remain the methods of choice for the classification of cRCC, non-invasive preoperative alternatives to differentiate lower grade from higher grade cRCC would be beneficial.This institutional-review-board approved cross-sectional study included twenty-seven patients  with histopathologically confirmed cRCC, graded according to the International Society of Urological Pathology (ISUP). A native, balanced steady-state free precession T2 mapping sequence (TrueFISP) was performed at 1.5 T. Quantitative T2 values were measured with circular 2D ROIs in the solid tumor portion and also in the normal renal parenchyma (cortex and medulla). To estimate the optimal cut-off T2 value for identifying lower grade cRCC, a Receiver Operating Characteristic Curve (ROC) analysis was performed and sensitivity and specificity were calculated. Students’ t-tests were used to evaluate the differences in mean values for continuous variables, while intergroup differences were tested for significance with two-tailed Mann-Whitney-U tests.p < 0.001), with higher T2 values for lower grade cRCC compared to higher grade cRCC. The sensitivity and specificity for the differentiation of lower grade from higher grade tumors were 83.3% (95% CI: 0.59–0.96) and 88.9% (95% CI: 0.52–1.00), respectively, using a threshold value of ≥110 ms. Intraobserver/interobserver agreement for T2 measurements was excellent/substantial.There were significant differences between the T2 values for lower grade (ISUP 1–2) and higher grade (ISUP 3–4) cRCC  contains supplementary material, which is available to authorized users. Globally, renal cell carcinomas (RCC) have significant impact with approximately 65,000 new cases in the United States and 84,000 cases in the European Union each year , 2, withMagnetic resonance imaging (MRI) is a non-invasive imaging modality, not relying on ionizing radiation. T2 weighted MRI sequences allow for visualization of inflammation and edema . While cWhile initially developed in the context of cardiac imaging, e.g. for quantification of myocardial edema as an early predictor of myocardial injury , T2-weigIn the context of brain tumors, it was previously suggested that tumors with higher cellularity showed a corresponding reduction in the extracellular fluid space . While lWe hypothesized, that quantitative T2 mapping could be used to distinguish lower from higher grade cRCC by visualization of differences in tissue composition, e.g. extracellular liquid. This proof-of-concept study therefore investigates the feasibility of a T2 mapping approach to grade cRCC, correlating imaging findings with the corresponding histology.This cross-sectional study was approved by the local Institutional Review board with written consent obtained from all participants prior to examinations. Between January 2017 and October 2018, 42 consecutive patients with suspected RCC, who agreed to participate, had no previous ablations or contraindications to MRI, were referred to our department for abdominal MRI. Out of these, 27 patients with histologically validated cRCC were included in the final analysis. The exclusions were as follows: 3 patients with urothelial carcinomas, 2 patients with oncocytomas, 2 patients with atypical angiomyolipomas, 2 patients without histologic examination (missing data on the reference standard), 4 patients with incorrect acquisition protocols and 2 patients with insufficient image quality due to motion artifacts.Image acquisitions were performed using a 1.5 T clinical MRI scanner  with dedicated 18-channel body and spine matrix coils. Apart from a clinical routine image protocol of the kidneys, the patients received a native, balanced steady-state free precession T2 mapping sequence (T2-prepared single-shot TrueFISP) in coronal plane, which was adjusted to the long axis of the kidney. The routine imaging protocol of the kidney included a coronal/sagittal T2 half Fourier single-shot turbo spin echo sequence (HASTE), a native coronal 3D gradient echo pulse T1-weighted (FLASH) sequence, a T1-FLASH angiography , and a delayed fat saturated 3D T1 VIBE (volumetric interpolated breath-hold examination) sequence. Bolus tracking was used to determine the first pass and 3D FLASH images were obtained in the corticomedullary and nephrogenic phase. The T2-preparation was an iterative Carr-Purcell Malcom-Levitt (MLEV) sequence , 17. T2 T2 maps were automatically calculated on a pixel-by-pixel basis, based on the assumption of mono-exponential signal decay. They were displayed by a customized 12-bit lookup table with a visible colour map, whereby the signal intensity of each pixel reflected its absolute T2 value.PACS workstations  were used for image evaluation/analysis. An evaluation of T2 mapping images was performed independently by two radiologists, who were blinded to the histopathological findings, enabling the assessment of interobserver agreement. One radiologist repeated the measurements after 2 weeks and two further ROI measurements were conducted after 3 months to enable a comprehensive intraobserver assessment. In large tumors with necrosis zones, circular 2D ROIs were placed within the most homogeneous and bright appearing portion of solid tumor area on the basis of visual assessment (in the postcontrast sequences), also in conjunction with T2-weighted images and were set in as large an area as possible. In small tumors without apparent necrosis zones, a circular 2D ROI was drawn around the entire tumor to avoid measurement inaccuracies / World Health Organization (WHO) . Based op-value < 0.05 was considered to indicate a significant difference.All statistical analysis was performed with the statistical software “R” . Variables were averaged across measurements and expressed as mean ± standard deviations in case of normal distribution and with median and interquartile range in absence of normal distribution. Students’ t-tests were used to evaluate the differences in mean values for continuous variables, while intergroup differences were tested for significance using the two-tailed Mann-Whitney-U test. Boxplots were created to show the distribution of the averaged quantitative T2 values among the different grades. To estimate the optimal cut-off T2 value for identifying a lower grade cRCC, a Receiver Operating Characteristic Curve (ROC) analysis was performed with exploratory selection of the optimal cut-off value. Sensitivity and specificity were calculated and based on values averaged over the two observers. Intraobserver and interobserver agreement were calculated using Bland Altman plots with limits of agreement and corresponding confidence intervals, whereby for the intraobserver agreement a graphical method for assessment of more than two readings was used . A p-valThe final study population consisted of 27 patients  with histologically diagnosed cRCC. Figure p = 0.21). The interval between MRI imaging and surgical removal was 25.1 ± 20.7 days.Histologic classification of patients revealed 8 ISUP grade 1 lesions, 10 ISUP grade 2 lesions, 5 ISUP grade 3 lesions, and 4 ISUP grade 4 lesions. The maximum cRCC diameter as determined in T2 HASE images, using the longest tumor diameter in coronal sections, was between 1.4 cm and 17 cm . There was no difference in tumor size between men and women (p < 0.001). We also looked at the distribution of T2 values in the tumor area based on a whole-tumor-approach, using density plots .Average T2 values were 134 ms ± 20 ms for ISUP grade 1, 128 ms ± 21 ms for ISUP grade 2, 108 ms ± 19 ms for ISUP grade 3 and 96 ms ± 6 ms for ISUP grade 4 tumors. For the normal renal cortex and medulla, the average T2 values were 92 ± 16 and 85 ± 16, respectively. There was no significant correlation between values for renal medulla, cortex and the glomerular filtration rate  and a specificity of 88.9% (95% CI: 0.52–1.00)  for cRCC with a Coefficient of Variation (CoV) of 0.03, 0 (95% CI: − 6.74 – 6.74) for the renal cortex with a CoV of 0.03 and 0 (95% CI: − 7.18 – 7.18) for the medullary pyramids with a Coefficient of Variation  was used for the differentiation of lower and higher grade cRCC. Lower grade cRCC  showed significantly higher T2 values compared to higher grade cRCC , supporting the potential of T2 mapping as a noninvasive marker of cRCC grade.While conventional, qualitative T2 weighted imaging is subject to various limitations, such as the use of arbitrary signal intensity scales for T2 values with subsequent test-retest and interobserver variability, T2 mapping offers the potential for a standardized, reproducible assessment of tissue composition and water contents, e.g. facilitating the diagnosis of interstitial edema and extracellular space expansion , 23. It Non-invasive cRCC grading would not only improve preoperative planning options, but also aid in prognosis assessment and prior patient information, for example by informing patients about the best individual therapy options. Furthermore, it may reduce the need for kidney mass biopsies. In addition, it might prevent cases of upstaging after partial nephrectomy in larger tumors, help identify patients who might be eligible for immunotherapy, and, finally, facilitate the selection of patients suitable for less invasive therapies , includiRegarding histology, cRCC consists of cells with clear cytoplasm and necrosis with often occurring cystic degeneration or hemorrhage . Lower gAlthough a considerable difference in the average T2 relaxation times between lower grade and higher grade cRCC was observed in a two-tier-system, there was a significant overlap between the subgroups  with no apparent difference. As a consequence, based on our data, it was not possible to differentiate between ISUP grade 1 and 2 or ISUP grade 3 and 4 tumors. However, the number of patients in the subgroups, especially regarding higher grade tumors, was very small and future studies with larger case numbers might help to assess the feasibility of T2 mapping in a four-tier-grading system, potentially allowing for/leading to T2 mapping value reference ranges with diagnostic utility. On route towards renal T2 mapping as a potential additional biomarker, it will, furthermore, be necessary to validate T2 mapping against accepted reference measurements, such as nuclear medicine evaluations as well as histological findings .In the context of future clinical applications, the use of T2 mapping might be a helpful addition to multiparametric imaging instead of being used exclusively. To this end, a novel T2-mapping-derived parameter could be integrated into a multiparametric MR imaging model. In the context of radiomics, it could also be included as a quantitative imaging feature, be converted into minable data and aid in the building of predictive models. It can be expected, that multiparametric approaches will yield superior diagnostic performance, when compared to single imaging parameters alone. Therefore, in the future, multiparametric approaches may enable reliable, noninvasive grading of cRCC.Regarding practicability, the T2 mapping approach chosen in the present study would be easy to implement in a clinical setting, as no complex mathematical modelling is required and the TrueFISP sequence is already commercially available on some MR scanners. Furthermore, it enables the acquisition of T2 maps during MRI scanning with a short scanning time. TrueFISP has been previously shown to be a robust method for T2 mapping, combining T2-magnetization preparation with steady-state free precession imaging and being sufficiently fast to be acquired in a single breathhold . An advaDue to the relatively long T2 relaxation times of the kidneys, ideally longer T2 preparation times with more than three weightings are used. While a repetition time of 1000 ms allows for time-efficient acquisition within a single breathhold, it does not ensure complete signal recovery. Therefore, the T2 maps in the present study are partly influenced by renal T1 signal and do not correspond to a pure T2 signal. To overcome this limitation in future studies, either the time of repetition can be increased (with a subsequent increase in scan time) or the flip angle can be reduced (with a decrease in SNR). However, within the scope of the present proof, we first aimed to investigate if a cardiac T2 mapping approach would be feasible for kidney imaging at all. Another limitation of this proof-of-concept study is, that it was based on a single-center design, only measuring T2 values at one time point prior to the intervention/surgery and including a small number of patients, especially with regard to higher grade cRCC. The small number of images was also an important limitation for assessment of intraobserver and interobserver agreement. In addition, the exclusion of other subtypes of renal masses brings about the risk of potential selection bias. Also, even though larger areas of necrosis were excluded, smaller necrotic regions may have been included in the ROI measurements and might have affected T2 measurements. Furthermore, the T2 relaxation time of the tumor was only measured in one representative coronal plane, not in the whole tumor. Besides, no automatic motion or alignment correction was applied to correct for misregistrations between the different sequences. Therefore, slight misalignments cannot be completely excluded. Apart from that, even though patients were advised not to thirst and to drink water in the morning before the MRI, this was not explicitly controlled prior to the examination and patients were not instructed to drink a specific amount of water. Therefore, patients may have exhibited certain fluctuations in the hydration status, which could have affected T2 measurements in the renal parenchyma and potentially also in the tumor tissue. Finally, only one scanner from one vendor was used, therefore the results may not be generalizable to other institutions. Further investigations will be required to validate T2 mapping as a tool for cRCC assessment.There was a significant difference in average T2 relaxation times between lower grade and higher grade cRCC, with lower grade cRCC showing significantly longer T2 relaxation times compared to higher grade cRCC. We therefore believe, that this technique holds potential for the future to noninvasively assess cRCC tumor grade in vivo and could provide a helpful addition to multiparametric imaging. However, studies with larger patient cohorts and a broader range of higher grade tumors are required to explore the utility of T2 mapping as a possible primary diagnostic MRI sequence for cRCC grading.Additional file 1:Figure S1. Visualization of circular 2D ROI placement for smaller tumors without and larger tumors with apparent necrosis zones for ISUP grades 1 to 4. ROIs were first placed in a corresponding postcontrast image and then copied to the T2 map. (TIF 8355 kb)Additional file 2:Figure S2. Segmentation of tumors  with creation of image masks (A2 through D2). A3 through D3 show the calculated percentage densities of the absolute T2 values. (TIF 2244 kb)Additional file 3:Figure S3. The upper part of the figure illustrates the percentage density of T2 values for whole-tumor measurements of the four colour-coded ISUP grades (refer to the legend on the upper right side). For each tumor, the T2 maps were segmented and image masks were imported into the open access software ‘R’. The lower part of the figure shows the colour-coded percentage density of T2 values for lower grade tumors (combined ISUP grades 1 and 2) and higher grade tumors (combined ISUP grades 3 and 4). (TIF 773 kb)


We hypothesized that liver relaxation times are not only influenced by liver fibrosis, inflammation and fat, but also by air in liver segments adjacent to the lung – especially in MR imaging at 3T. A total of 161 study participants were recruited, while 6 patients had to be excluded due to claustrophobia or technically uninterpretable MR elastography. Resulting study population consisted of 12 healthy volunteers and 143 patients who prospectively underwent multiparametric MR imaging at 3T. Of those 143 patients, 79 had normal liver stiffness in MR elastography  and normal proton density fat fraction , defined as reference population. T1 relaxation times in these patients were significantly shorter in liver segments adjacent to the lung than in those not adjacent to the lung . In liver segments not adjacent to the lung, T1 allowed to differentiate significantly between the reference population and patients with steatosis and/or fibrosis (p ≤ 0.011), while there was no significant difference of T1 between the reference population and healthy volunteers. In conclusion, we propose to measure T1 relaxation times in liver segments not adjacent to the lung. Otherwise, we recommend taking into account slightly shorter T1 values in liver segments adjacent to the lung.Magnetic resonance (MR) T Most conventional liver MR sequences measure relative signal intensities and therefore allow relative comparison between focal disease and adjacent normal hepatic parenchyma3. However, detection and quantification of diffuse liver disease remains challenging4 but is desirable to avoid invasive and expensive biopsies5.Magnetic resonance (MR) imaging of the liver is a powerful tool in diagnosis of focal liver disease and is frequently used in clinical routine6 and MR elastography8. Another emerging technique is the quantification of T1 relaxation time on parametric maps, which is routinely used in cardiac imaging9, for example in diffuse cardiac fibrosis11 or myocarditis12. Recently, the modified Look-Locker inversion recovery sequence (MOLLI) demonstrated great potential for application in diffuse liver disease14.Currently, existing non-invasive imaging biomarkers for diffuse liver disease include proton density fat fraction (PDFF) calculation1 mapping in clinical routine16. Further, it is known from cardiac imaging that T1 values might be influenced if measured in the ventricle close to the lung, why usually measurements in the septum are preferred17. Therefore, specific anatomical conditions of the liver with adjacent air-containing lungs and potential internal confounders, such as hepatic fat and iron composition, should be considered in hepatic T1 mapping2.However, as known from cardiac applications, reference values should be established for different manufacturers, technical parameters and field strengths before using T1 relaxation time is significantly shorter in liver segments adjacent to the lung than in liver segments not adjacent to the lung due to air-induced susceptibility effects at 3T.We hypothesized that T19.Patient characteristics are shown in Table 1 and in 149/155 participants (96%) for T2*  were measurable in 61–63% of patients and the right caudal segments (V and VI) were measurable in 86–88% of patients.Out of 143 patients and 12 volunteers, resulting in 155 participants, there was at least one segment of good diagnostic image quality in 152/155 participants (98%) for T1 values were significantly lower in the cranial slices than in the caudal slices . This did not count for the comparison between cranial segment II and caudal segment III, where no significant difference between both segments was detected . Values between segments were very comparable on each level, except for segment II, which showed values more comparable with the caudal level segments  and 746 ± 81 ms (segments adjacent to the lung) (Table 1 and p = 0.521 for T2*).Normal T1 relaxation time was significantly longer than in the reference population . These results are illustrated in Fig. In positive patients with steatosis as well as in patients with increased liver stiffness, T2* time was a significant confounder of T1 time (p < 10−15), while PDFF, age and sex  were not  for T1 and 0.91 (95%-CI: 0.78–0.97) for T2*.The ICC values were excellent for both T1 relaxation time is significantly shorter in liver segments adjacent to the lung than in liver segments not adjacent to the lung. We calculated a mean T1 value of 780 ± 83 ms at 3T in liver segments not adjacent to the lung , while T1 was around 30 ms shorter in liver segments adjacent to the lung  in a patient population, without focal (based on CT) or diffuse (based on PDFF and MR elastography) liver disease.This study shows that T1 underestimation. Similar effects are known from myocardial T1 mapping21. In addition, there is a T2-dependency of the MOLLI based T1 mapping sequence due to its bSSFP design, therefore influencing the measured T1 value. Another explanation might be partial volume effects at the liver dome since the slice thickness is 10 mm  were drawn carefully to exclude liver vessels and outer 10 mm of the liver border, to prevent this possible bias as much as possible.This difference may be explained by different reasons. One possibility are susceptibility effects from adjacent air in the lungs. Susceptibility differences between liver and lungs cause off-resonance, which may lead to T mm Fig. , which i1 relaxation time difference between segment II and III was smaller. A potential explanation for this different behaviour might be that segment II is in close anatomical neighborhood to the heart and not to the lungs as the cranial segments VII, VIII and IVb are. We therefore propose to measure T1 relaxation time in liver segments V and VI with excellent inter-reader-reliability, when a representative T1 quantification of the liver is intended. These segments are normally targeted for liver biopsy and may be regarded as representative for the whole liver. However, for a more detailed segmental analysis of T1 relaxation times in the liver shorter normal T1 values in liver segments adjacent to the lung should be taken into account. T2* seems to be more prone to respiratory and pulsation artefacts from the beating heart, which might explain lower image quality in segments of the left liver lobe (adjacent to the heart) and in cranial segments, while image quality in caudal left segment V and VI showed the best image quality. Electrocardiography gating might improve image quality, which was not tested in this study.While differences between cranial and caudal segments in the right liver lobe and segment IVa vs. IVb were comparable, the T1 values of the liver at 3T using the MOLLI technique. Katsube et al. presented a mean value of 836 ± 69 ms in 16 patients with normal liver function. The slightly lower values in our study  may be explained by a smaller population in the study of Katsube et al., as well as the by the fact that Katsube et al. defined the normal population based on normal liver function in laboratory tests, which does not exclude patients with steatosis or early liver fibrosis23. Other published normal T1 values were generated with other mapping techniques, but are nevertheless in a similar range, such as 824 ± 61 ms in 26 healthy volunteers using a spiral GRAPPA-based method24, 825 ± 49 ms in 6 healthy volunteers using an inversion recovery method with refocusing pulses25, and 745 ± 65 ms in 8 healthy volunteers using MR fingerprinting26. Slight differences might be explained by different techniques of assessment and small sample sizes used in the cited studies. This underlines the recommendation, that normative values should be established for the particular site and set-up for different manufacturers, technical parameters and field strengths before using T1 mapping in clinical routine16. In accordance with other published studies, increased T1 time correlated with increased liver stiffness in MR elastography as a non-invasive surrogate for liver fibrosis23. Yoon et al. published T1 values in patients with chronic liver disease (863 ± 81 ms) and Child A liver cirrhosis (879 ± 86 ms)27 in the same range as we present here (849 ± 107 ms for early liver fibrosis and 910 ± 98 ms for significant fibrosis). T1 values calculated with commercially available software solutions using the MOLLI mapping technique have been shown to correlate with the severity of NAFLD/NASH and fibrosis28 and may predict clinical outcome in these patients29. We demonstrated an increased T1 time in patients with steatosis, which is in accordance with other published studies30. This is a paradox, since fat has a much shorter T1 time than water. According to recent publications, off-resonance effects in imaging voxels containing a mixture of fat and water signals may explain this finding32.There are very few published data on normal T1 and T2*. One known confounder inducing T1 shortening is liver iron content33, however patients with iron overload have been excluded in this study. Liver blood distribution and oxygenation levels are might influence T1 and T2* times as well. These effects and possible influences on T1 and T2* need further investigation. In multivariate analysis of reference patients without focal or diffuse liver disease and healthy volunteers, we could not demonstrate a significant age- or sex- dependency of the measured T1 values. However, there was a collinearity between T1 and T2* values. Further research should be performed to show whether T1 is T2* dependent  or whether it is the other way round and T2* is influenced by T1 due to a too short TR in the used T2*-mapping sequence. Also using a multiparametric approach combining T1, T2*, MRE and PDFF might deliver further insights.In addition to fat and fibrosis content as well as susceptibility-effects in liver segments adjacent to the lung, there are several other potential confounders of T1 mapping of the liver. For an accurate non-invasive characterization of diffuse liver disease, a combined analysis of different MR parameters such as T1 mapping, T2* mapping, elastography and PDFF should be performed. Further research will show how a multiparametric combination of those MR imaging biomarkers may help differentiating and quantifying diffuse liver disease.Our study highlights the importance of standardized technical parameters and well-defined normal values when performing T34 and steatosis grades35, as the non-invasive gold standard, and we included negative and positive controls based on these imaging techniques. Another limitation is that we did not obtain full 3D coverage of the liver, as we used commercially available Siemens MOLLI sequences with 2D acquisitions on three transverse slices. Nevertheless, we present a segmental comparison of T1 mapping in a reference population, as well as in negative and positive controls. Newer 3D mapping sequences or MR fingerprinting may offer even more applications for future use.Our study has several limitations. First, we focused on a population without known chronic liver disease. Due to the study design and associated ethical considerations, liver biopsy was not possible. Instead, we used MR elastography and PDFF, which have been shown to correlate very well with biopsy-confirmed fibrosis1 maps in the liver at 3T, we propose to measure T1 relaxation times in liver segments not adjacent to the lung. Otherwise, we recommend taking into account slightly shorter T1 normal values in liver segments adjacent to the lung.When analysing T1 and T2* mapping, proton density fat fraction (PDFF) quantification and MR elastography.This prospective cross-sectional study was approved by the institutional review board  and was conducted in accordance with relevant guidelines and regulations after obtaining written patient informed consent. All participants underwent multiparametric MR imaging at 3T in our institution between 03/2016–06/2017, including TA total of 161 study participants were recruited, while 6 patients had to be excluded due an incomplete MR exam due to claustrophobia or technically uninterpretable MR elastography. Resulting study population consisted of twelve healthy volunteers without a history of liver disease (negative controls) and 143 patients Fig. . The incClinical information and laboratory test results were recorded for the included patients. Clinical parameters included age, gender, body mass index (BMI), history of diabetes or hypertension, daily drug intake, tobacco use and alcohol consumption. Biological parameters included dyslipidemia, platelet count, quick value, total bilirubin levels, gamma-glutamyltranspeptidase (GGT), aspartateaminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, albumin, creatinine and hematocrit.1 of 5% (=40 ms) between the upper and lower liver segments with a significance level of 0.05 and a power of 0.8, a sample size of 72 was needed. A mean T1 time of 800 ms with standard deviation of 85 ms was based on a pilot readout for sample size calculations.To detect a mean difference in T1 mapping, we used an axial-acquired, MOLLI single breath-hold sequence (echo time (TE) of 1.01 ms, data acquisition window of 740 ms, inversion time (TI) 225 ms , flip angle (FA) 35°, 8-mm slice thickness, field-of-view (FOV) 384, matrix 154 × 192 pixels, and scan time of 11 s) with a 3-3-5 design . T2* mapping was performed with a multiecho gradient echo (GRE) single breath-hold sequence . T1 and T2* maps were generated on three single slices in the upper, mid and lower liver. PDFF was calculated using the Dixon method with axial T1-weighted axial vibe images  to differentiate patients with and without liver steatosis. For MR elastography, a pneumatic driver (Resoundant) was placed on the right upper quadrant transmitting shear waves by continuous acoustic vibrations with a frequency of 60 Hz. The liver shear stiffness in kPa in the right upper liver lobe was determined with a gradient echo-based elastography sequence  using the 95% confidence map of stiffness. A shear modulus ≥2.8 kPa was considered to represent early liver fibrosis , while a shear modulus ≥3.5 kPa was defined as significant liver fibrosis (corresponding to histology fibrosis grade ≥F3)37.Patients were examined with a 3T-MR system  in a fasting state (>6 h). For T1 and T2* mapping, 8 polygonal regions of interest (ROI) were drawn in liver segments II-VIII by the radiologist (V.O.) who was blinded to the patient’s clinical history. In liver segments without excellent image quality (e.g. due to motion artefacts) or in segments that were not captured on any of the three acquired slices, no ROI was drawn at this location, and thus no value was assigned to the respective segment. The mean ROI size was 685 ± 203 mm2. Large blood vessels, bile ducts and regions with partial volume, including air or perihepatic fat at the liver border, were excluded . For T38 and GraphPad Prism . Clinical characteristics were compared between groups using the Wilcoxon test for continuous variables or Fisher’s exact test for categorical variables. The p-value for significance was <0.05. T1 and T2* mapping parameters with good quality were then compared between segments using a paired Wilcoxon test. To address intersegmental variability and to identify the best area for reference, the median values of the liver segments adjacent to the lung  and those not adjacent to the lung  were calculated for the reference population and compared with the negative and positive controls using the Wilcoxon test.Analysis was performed with the statistical software package R 1 (segments not adjacent to the lung) as the outcome and sex (dummy-coded), age, PDFF and T2* (segments not adjacent to the lung) as variables. Age and sex were chosen as basic demographic characteristics that might bias the measured T1 in the liver while PDFF and T2* were added as known representatives of liver fat and iron content that might influence T1. Pearson correlation was used to compare MR elastography shear modulus with T1 values. For interrater reliability, T1 and T2* relaxation time was measured in segment VI in 20 randomly selected consecutive patients by a second radiologist (A.H.), who was blinded to the patient’s clinical history and had 7 years of experience in hepatic imaging. The two-way consistency intraclass correlation (ICC) was then calculated and classified as follows: ICC 0.4-0.59 defined as fair; 0.6–0.74 defined as good; and 0.75–1.00 defined as excellent39.To assess possible confounders in the reference population and among healthy volunteers (n = 79 + 12), a multivariate regression model was used with TThis prospective cross-sectional study was approved by the institutional review board (IRB number 282-15) and was conducted after obtaining written patient informed consent.


In-depth understanding of early cardiovascular manifestations in diabetes is high on international research and prevention agendas given that cardiovascular events are the leading cause of death for diabetic patients. Our aim was to review recent developments in the echocardiographic assessment of left ventricular diastolic dysfunction (LVDD) as a telltale pre-clinical disturbance preceding diabetic cardiomyopathy. We analyzed papers in which patients had been comprehensively assessed echocardiographically according to the latest LVDD guidelines (2016), and those affording comparisons with previous, widely used recommendations (2009). We found that the updated algorithm for LVDD is more effective in predicting adverse cardiovascular events in patients with established LVDD, and less specific in grading other patients (labelled “indeterminate”). This may prove instrumental for recruiting “indeterminate” LVDD cases among patients with type 2 diabetes mellitus (T2DM) in future screening programs. As an interesting consideration, the elevated values of the index E/e’ can point to early diastolic impairment, foretelling diabetic cardiomyopathy. Identifying subclinical signs early makes clinical sense, but the complex nature of T2DM calls for further research. Specifically, longitudinal studies on rigorously selected cohorts of diabetic patients are needed to better understand and predict the subtle, slow onset of cardiac manifestations with T2DM as a complicating backdrop. The undisputed bidirectional relationship between type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) acts as a vicious circle, whereby the former heightens the risk of the latter, and the latter is an important complication, comorbidity, and mortality factor in the former ,2. This Type 2 diabetic patients may develop underlying CVD without experiencing or recognizing the telltale signs and symptoms until too late. Subclinical manifestations are therefore difficult to study and report, which makes the real scale of the problem an important question in an otherwise well-understood associated pathology. There is, however, progress: researchers have proposed appropriate terminology as well as the need for early screening tools for confirmed diabetic subjects without cardiovascular symptoms ,5. For iThe most widely known, applied, and reviewed set of recommendations for assessing diastolic function is the guideline for the evaluation of left ventricular diastolic function by means of echocardiography, available since 2009 . In our We started from the online text of the 2016 recommendations and investigated all its PubMed citations by mid-March 2019. There were seventy-four papers in English citing the new guidelines from a range of medical perspectives. The titles and abstracts were screened to select those papers relevant for the diagnosis, classification, and treatment of LVDD. Thirty-one papers were selected based on their use and/or appraisal of the new algorithm, the inclusion of diabetic patients in the studied cohorts, and the implications for clinical practice, etc.Notably, only one study was found in this manner to specifically address LVDD in T2DM subjects . HoweverThe same approach was then repeated for SCOPUS and Science Direct, resulting in 685 citations. These were filtered down to 187 based on the keywords “diastolic dysfunction” and “diabetes mellitus”. The screening of their titles and abstracts led to a further reduction to 62 papers other than those previously indexed on PubMed. Further, the 133 citations available through the Thompson ISI Web of Science search engine were analyzed, with no additional results. Finally, two international research registries did not enlist any relevant studies ,15.Apart from the published studies applying the 2016 algorithm on diabetic patients, we also sought to identify the most comprehensive reviews of prior research using the 2009 guidelines. On SCOPUS, the 2009 recommendations were cited 2054 times by mid-March 2019, of which seven took into account LVDD in diabetes mellitus.Systolic dysfunction associated with left ventricular ejection fraction reduction was proven to be insufficiently indicative of heart failure diagnoses, as symptoms may also occur with mid-range as well as preserved ejection left ventricular fractions (recently redefined as ≥ 50%) . In thisIn addition, taking diastolic dysfunction into account allows for a more accurate prognosis of heart diseases other than endo- or pericardial (where different mechanisms are involved). In a nutshell, this is because diastolic dysfunction betrays the structural deterioration taking place at the level of myocardial cells and matrix. Basically, the myocardial stiffness resulting from collagen damage, interstitial fibrosis, and inflammation delays the relaxation period with negative consequences further down the chain of the diastolic and filling pressure ,18,19,20It is important to identify metabolic and structural changes in the heart as early as possible because, in time, they bring about the progressive impairment of cardiac structure and function leading up to irreversible heart failure HF; . The knoResearch has been fruitful in unraveling the more subtle metabolic and structural mechanisms involved in diabetic cardiomyopathy, but important challenges still remain. For one, since diabetes-related cardiomyopathy was studied mostly in patients with a long history of diabetes, the current definition of cardiomyopathy does not address early, insidious, subclinical pathophysiological alterations. These are now generating substantial scientific interest, but existing datasets do not hold all the necessary information. More prospective studies are needed to take a new understanding of relevant molecular processes and signaling pathways from research on mice to human cohorts. Moreover, it is difficult to single out the individual contributions of hyperglycemia or of hyperinsulinemia (secondary to insulin resistance and specific to type 2 diabetes) from other risk factors such as hypertension, obesity, or coronary heart disease, because most diabetic patients enrolled in clinical trials feature a combination of these comorbidities ,38,39,40When such limitations are resolved, the scientific and clinical community will be in a better position to expand and optimize early diagnostic and therapeutic approaches. At present, various techniques using biomarkers and imagistic assessment methods can detect subclinical manifestations involved in cardiac dysfunction before it reaches more advanced, overt stages. A practical guide comprehensively pooling high-sensitivity, high-specificity approaches together would maximize these opportunities for early subclinical sign detection, prevention, and possibly even reversal in the target population ,32,35,37The mechanisms outlined above help define a restrictive phenotype of cardiomyopathy in diabetes and are also consistent with the imagistic pattern of heart failure with preserved ejection fraction (HFpEF). However, the ejection fraction commonly used to diagnose heart failure is not a reliable indicator of cardiomyopathy in type 2 diabetes because it may still be preserved even if the LVDD has already set in (and is often present in T2DM). More elaborate imagistic measurements are needed in addition to the usual ratio between E and A waves (E/A)  in orderPeak of passive filling (E wave), peak of active filling (A wave), E/A ratio, deceleration time of E wave (EDT) with pulsed Doppler ;Isovolumetric relaxation time (IVRT) , early dTricuspid regurgitation peak velocity TRpV;  with CW S and D wave peak velocity on right superior pulmonary vein flow in pulsed Doppler ;Left atrial size assessed by area or better by left atrium volume (indexed) LAVi; .Transthoracic echocardiography is the preferred approach in assessing heart functions due to its non-invasiveness. According to the 2009 and 2016 guidelines , multiplThe 2016 guideline revised and expanded the one from 2009 with regard to how such parameters may be used to distinguish between different patterns of diastolic function when the left ventricular ejection fraction is normal . In 2019However, these measurements must be correctly assessed, according to the current recommendations, by experienced operators ideally accredited by national societies or the European Society of Cardiology .Since 2016, several researchers reviewed the differences between the two algorithms  and condFor instance, Almeida et al. looked at their 1000 subject dataset retrospectively, in which 114 were confirmed with type 2 diabetes and more than half of were at risk of diabetes. What emerged from the comparison was that the prevalence of diastolic dysfunction was considerably higher using the 2009 algorithm (38.1%), whereas it was almost negligible when assessed with the updated version (1.4%) . In anotMoreover, after monitoring 157 patients, of which 45 were diagnosed with T2DM, over the course of five years, Sanchis et al. found that the 2009 guidelines might overestimate the prevalence of first degree diastolic dysfunction, while the 2016 recommendations facilitated better prediction of cardiovascular events  ,52. The With specific regard to patients graded as “indeterminate”, their clinical and echocardiographic characteristics seem to more closely resemble diastolic dysfunction rather than normal diastolic function. The similarities were found by Shimron et al. in a retrospective analysis of 1674 cases (20% diabetics), and they encompassed an elevated risk ratio for heart failure symptoms in both the “indeterminate” and the diastolic dysfunction groups compared to normal . In our In his 2017 review, Fraser pointed out that seemingly objective and straightforward algorithms were being applied with a degree of variability depending on clinicians’ understanding and experience, creating the risk of over-, under-, and misdiagnosis. With regard to diastolic function, he noticed that the variables included in the latest algorithm accounted for a large number of combinations, leading to the impractical classification of some patients as “indeterminate”. Moreover, while imagistic technology had been perfected to provide high levels of specificity and sensitivity, there was also cognitive overload and bias undermining the effective and consistent interpretation. Consequently, Fraser urged for transdisciplinary collaboration towards automated systematization by pooling databases together and using machine learning to optimize both processes and results .One interesting example of such an undertaking is by Tamas and Nylander who, in 2016, created an automated assessment process and compared its performance to two rounds of manual interpretation of the same data at different times. The inter-rater agreement between manual assessments was less than moderate, and it was poor between automated and manual, which demonstrates substantial variability in how algorithms are applied by clinicians . MoreoveSuch contributions, as well as the challenges of interpretation in clinical practice, have been acknowledged by Nagueh, the lead author of both guidelines. His advice to practitioners and researchers is to include clinical findings, conduct complete measurements, and consider specific pathological conditions when applying the algorithm in order to minimize “indeterminate” classifications . Indeed,With regard to the need and opportunity for preventive screening, until recently, patients with diabetes were not among those for whom such programs were recommended . HoweverAnother perspective that has been considered is the extent to which diabetes per se, versus in association with other factors, can exert an aggravating influence on the diastolic function of the patient. For instance, while an increased body mass index (BMI) (overweight and obesity) was found capable of worsening systolic and diastolic function independently , it seemMoreover, the mean E/e’ ratio was found in several studies to be higher in diabetic patients, including those who do not exhibit overt cardiovascular manifestations . The question is whether or not an elevated E/e’ index is an indication, or even a “hallmark”, of early diastolic alteration in diabetic cardiomyopathy. However, not everyone is convinced of this assertion based on research pointing to modifications occurring possibly even before the onset of diastolic impairment . In our When interpreting echocardiographic data using algorithms for classification of diastolic dysfunction, the demographic profile of patient cohorts may bear relevance. For instance, D’Andrea et al. applied the 2009 and 2016 algorithms to a healthy population of 1168 Caucasians and found statistically significant E/e’ differences in men versus women. In addition, this index appeared to also naturally increase with age  without A similar argument can be made about anthropological characteristics such as height and weight. These are computed into the Body Surface Area (BSA), which is then used to determine the Left Atrial Volume index (LAVi), one parameter included in the assessment of diastolic function. As an example, healthy native Dutch people are generally taller and, consequently, they have higher BSAs. When assessing left atrial parameters and indices in Dutch patients, van Grootel et al. suggest that normative values be adjusted accordingly .Myocardial properties susceptible to diastolic dysfunction can nowadays be investigated non-invasively in a variety of ways. They include mechanical deformation (by speckle tracking), fibrosis and ischemia (by magnetic resonance imaging), autonomic dysfunction (by nuclear imaging), and filling pressure during physical exertion (by exercise stress testing) ,71,72,73There is consensus on both sides of the Atlantic regarding the management of hyperglycemia required in case of already established atherosclerotic cardiovascular disease . HoweverNote should be made that this is a narrative review and that we considered the possibility of including more studies from before 2016, ultimately deciding against it. These would have introduced too much heterogeneity in the underlying conceptual framework of definitions and criteria, as Selmeryd et al. and Bouthoorn et al. had already encountered in their reviews of studies from before the publication of the 2016 LVDD algorithm ,82. SimiAmong the selected papers, some used prediction models based on echocardiographic parameters in combination with biomarkers , which cardiomyocytes produce when subjected to mechanical stress) . While wWe are aware of the current medical interest in the understanding of molecular mechanisms that could lead to new discoveries and theories explaining the onset and development of heart failure with preserved ejection fraction in patients with type 2 diabetes. However, we took note of methodological limitations in this area  and hence our choice was to err on the side of caution .What we have learned with regard to the diagnosis and grading of diastolic function is that the latest, 2016 guideline appears to serve best in identifying the more severe cases. Moreover, the echocardiographic parameters, such as the diastolic index E/e’, were found to be predictors of adverse cardiovascular events. At the same time, while it does not fully cater for the subclinical domain, it does create an opportunity to select the cases classified as “indeterminate” for the purpose of screening for silent CVD and subsequent monitoring.Concurrently, upon reviewing available studies and in relation to other recent reviews, editorials, and commentaries, we have become aware of the challenges of full investigations and accurate interpretations: equipment model and availability, methodological heterogeneity, patient profiling and matching, inter-observer variability, and clinician experience and expertise. Moreover, the underlying demographic and anthropological profile of the population to which the patient belongs may further interfere with interpretation and results, in conjunction with known associated comorbidities. Such difficulties have imprinted a significant degree of heterogeneity onto existing scientific endeavors and outcomes. As guideline improvements are constantly sought, retrospective and comparative studies are useful but limited to those databases affording analyses with updated parameters and formulae.With or without the ‘usual suspects’ in the picture , diabetes can distort diastolic function by itself and contribute to the snowball effect of serious cardiac complications such as heart failure. In the daily clinical practice of managing the wide spectrum of complications related to diabetes, not all clinicians may fully appreciate the significance of detecting diastolic dysfunction early, or lack methodological capacity to do it. Therefore, the widespread screening of diabetic patients, aiming to detect subclinical manifestations as early as possible, makes clinical sense. Current concerns regarding the poor cost efficiency of such programs could be outweighed by more scientific evidence into the long term benefits of early detection and prevention.While researchers have been including patients with T2DM in their cohorts, practitioners could learn more from further studies focusing exclusively on the aforementioned diabetic profile  via robu


Traditional chemotherapeutic agents and newer targeted therapies for cancer have the potential to cause cardiovascular toxicities. These toxicities can result in arrhythmias, heart failure, vascular toxicity, and even death. It is important for oncologists and cardiologists to understand the basic diagnostic and management strategies to employ when these toxicities occur. While anti-neoplastic therapy occasionally must be discontinued in this setting, it can often be maintained with caution and careful monitoring. In the second of this two-part review series, we focus on the management of cardiovascular toxicity from anthracyclines, HER2/ErbB2 inhibitors, immune checkpoint inhibitors, and vascular endothelial growth factor inhibitors. Cardiovascular disease and cancer remain leading causes of mortality in the United States. The co-existence of cardiovascular disease and toxicity that develops as a result of cancer therapy presents a growing challenge for both oncologists and cardiologists. As cancer therapy outcomes continue to improve, this aging population is living long enough to experience adverse effects from therapeutic complications, including electrophysiological abnormalities, vascular toxicity, and heart failure (HF).1. Cardiovascular complications often represent a limiting factor in the therapeutic options for many otherwise treatable and potentially curable malignancies. It is essential that oncologists and cardiologists be aware of the most up-to-date strategies for management in order to optimize the potential for further therapy. In this review, we explore the management of select cardiovascular toxicities from anthracyclines, HER2/ErbB2 inhibitors, immune checkpoint inhibitors, and vascular endothelial growth factor (VEGF) inhibitors.These toxicities and their proposed and established mechanisms were discussed in detail in the first installment of this review2. The risk is dose dependent, with over 25% of patients experiencing clinical HF with cumulative doses of 550 mg/m2 or greater. Subclinical evidence of toxicity is present in 30% of patients, even at cumulative doses of 180 to 240 mg/m24. While clinicians must be aware that higher doses are associated with increased risk, it is also important to recognize that there is no dose at which the risk for cardiac toxicity is zero3.Cardiomyopathy from anthracyclines, initially daunorubicin, was the first described cardiotoxicity5. At a minimum, this includes careful clinical evaluation and assessment of traditional cardiovascular risk factors including the presence of coronary artery disease, diabetes mellitus, hypertension, or smoking. Given the effect on left ventricular systolic function, this should be assessed prior to beginning therapy6. Most commonly, a transthoracic echocardiogram is the screening test of choice. Multigated acquisition radionuclide ventriculography or cardiac magnetic resonance imaging can be used, although these techniques are limited by radiation exposure and cost/availability, respectively. Any evidence of pre-therapy reduced ejection fraction should prompt referral to a cardiologist for evaluation and optimization prior to anthracycline exposure.It is imperative to recognize any pre-existing cardiac dysfunction in patients prior to the initiation of therapy7. Cardiotoxicity in this setting has been defined by a decline in ejection fraction by ≥10% (e.g. from 50% to 40%) or ≥5% in the presence of HF symptoms, although a variety of criteria have been used4. Advanced imaging strategies have been developed to identify early myocardial dysfunction with increased sensitivity and specificity. This includes multiple techniques to characterize myocardial strain, which appears to be very sensitive. A reduction of 10–15% in global longitudinal strain is the most useful parameter to identify the early development of anthracycline-induced cardiomyopathy8. Cardiac biomarkers  are associated with the development of left ventricular dysfunction and symptomatic HF; although their routine use as screening tests is promising, there is not universal agreement on the significance of isolated biomarker elevation8. Prolongation of the QT interval on electrocardiogram has also been shown to be associated with the development of anthracycline-induced ventricular dysfunction9.Once therapy is initiated, monitoring strategies must be individualized to identify early evidence of cardiotoxicity. Echocardiography is often recommended at 3-month intervals with additional imaging mandated by clinical evidence of HF10. A PEGylated liposomal version of doxorubicin has been shown to decrease the circulating concentration of free doxorubicin without decreased effectiveness, although high cost has limited its utility11.Based on the mechanisms discussed in the first part of this review, several therapeutic strategies have been proposed to treat anthracycline-induced cardiotoxicity or to prevent it in high-risk patients. Prevention involves avoidance of anthracyclines when possible, utilization of minimal cumulative doses, and preference for continuous infusion versus bolus dosing12. There was initial evidence that the use of dexrazoxane decreased anti-neoplastic efficacy and although this did not hold up in meta-analysis, the U.S. Food and Drug Administration has approved its use only in patients who have already received at least 300 mg/m2 of doxorubicin for metastatic breast cancer13. In a pediatric population receiving simultaneous etoposide and doxorubicin, there is evidence of an increased risk for secondary malignancies, potentially due to genetic instability14. While this association has not been clearly established, the signal must be taken seriously in this population. Use of dexrazoxane should be considered given its established efficacy and safety exclusive of patients receiving simultaneous etoposide.Dexrazoxane is protective against anthracycline cardiotoxicity by mediating topoisomerase 2β. Its effectiveness has been well established in numerous clinical trials, although two controversies limit its widespread adoption16. The results of the PRADA trial have suggested that treatment with candesartan during anthracycline therapy for early breast cancer provides protection against early decline in left ventricular function17. Newer agents, including sacubitril/valsartan, and advanced therapies for HF should be considered when necessary. Because anthracycline-induced cardiomyopathy is considered irreversible, the development of reduced LV function has been recommended as a contraindication to continuing anthracyclines, although cessation of lifesaving therapy should be considered only as a last resort4.Once clinical HF or imaging evidence of reduced left ventricular systolic function is present, treatment should follow established guidelines for patients with non-ischemic cardiomyopathy. The mainstays of therapy are angiotensin-converting enzyme (ACE) inhibitors and beta-blockers uptitrated to the maximum tolerated doses with diuretics as needed18.The role of these agents and HMG-CoAr inhibitors (statins) for the prevention of anthracycline-induced cardiomyopathy remains unclear though is currently under investigation in the Preventing Anthracycline Cardiovascular Toxicity With Statins (PREVENT) trials, among others. The impact of physical activity has not been conclusively established from clinical studies, although animal models and evidence from other non-ischemic cardiomyopathies suggest it may be beneficial4.Trastuzumab, a monoclonal antibody directed against HER2/ErbB2 receptors, has also been established as a cause of left ventricular dysfunction. This agent is used for the treatment of breast cancers that overexpress HER2/ErbB2 and is known to cause a reversible cardiomyopathy that is otherwise phenotypically similar to anthracycline-induced cardiomyopathy. The symptomatic HF that develops can be severe and life threatening, though it is generally mild and improves with medical management and discontinuation of therapy. Trastuzumab can often be resumed after recovery of ventricular function19. Given the reversibility of trastuzumab-induced left ventricular dysfunction, a more lenient cut-off of ejection fraction <40% to withhold therapy has been proposed. There is considerable evidence that strain is strongly predictive of trastuzumab-associated cardiotoxicity and is even more specific when combined with elevated troponin20. A monitoring regimen of troponin measurement at baseline and every 3 weeks with echocardiography with strain every 3 months has been suggested6. When left ventricular dysfunction or HF does develop, institution of targeted therapy based on the guidelines discussed above is recommended without substantial evidence in this population.Recommendations for pre-therapy screening and imaging studies are generally similar to those discussed above for anthracyclines. Patients at high risk should ideally avoid concurrent treatment with anthracyclines, which results in worse cardiovascular outcomes21. Although the true incidence is unknown, it has been increasingly recognized and reported, especially when combination therapy is used22.By allowing the immune system to upregulate its activity against malignant cells, immune checkpoint inhibitors have proven to be highly effective cancer drugs. Cardiotoxicity, which can include arrhythmias, heart block, and myocarditis, is due to autoimmune activity against normal myocardium25. These regimens come from more established management of other autoimmune toxicities with immune checkpoint inhibitors including hepatitis, pneumonitis, colitis, and endocrinopathies. Therapy may be withheld in the acute setting, but resumption should be considered if ventricular dysfunction resolves.The gold standard of diagnosis remains myocardial biopsy, although the development of heart block, ventricular arrhythmias, left ventricular dysfunction, or clinical HF after the initiation of immune checkpoint inhibitors is generally considered sufficient to initiate treatment. Additional diagnostic studies, especially cardiac magnetic resonance imaging to identify myocarditis, have been suggested. There are no established guidelines and there is very little evidence to guide the management of cardiotoxicity when it occurs. Based on the autoimmune mechanism of toxicity, immunosuppressive agents are recommended. High-dose corticosteroids have been used with some success and when insufficient alternative immunosuppressive regimens have been utilized, including mycophenolate mofetil and tumor necrosis factor-alpha antagonistsThere are no clear guidelines for prevention or monitoring, and a deeper understanding of the pathophysiology is needed before recommendations can be established. Physicians must be alert to this important complication, and further research and establishment of guidelines is mandatory.26. For this reason, early recognition and management are essential.Several malignancies, including renal cell carcinoma and hepatocellular carcinoma, can be treated with VEGF inhibitors. Their use can be limited by both left ventricular dysfunction and, more commonly, hypertension. Although the majority of cardiovascular complications are not fatal, they are associated with significant morbidity and can impact the ability to continue potentially lifesaving therapy28. Hypertension, however, has been reported in nearly half of patients with varying clinical significance depending on the baseline blood pressure and comorbid conditions30. In the most recent meta-analysis of 77 studies, severe hypertension is noted in 7.4% of patients, arterial thromboembolism in 1.8%, myocardial ischemia in 1.7%, and ventricular dysfunction in 2.3%31.Approximately a quarter of patients experience asymptomatic decline in left ventricular function, while symptomatic HF is seen in 4–8%33. Diagnosed based on simple ambulatory blood pressure screenings, hypertension occurring within the first month after treatment initiation is likely to be secondary to therapy. While there are many antihypertensive medications that can be used, ACE inhibitors are considered first line owing to favorable hemodynamic and anti-proteinuric effects and evidence of improved mortality34. When other agents are necessary, attention should be paid to potential drug–drug interactions given the effects of VEGF inhibitors, especially sorafenib, or the cytochrome P450 system. Although hypertension in this setting can have significant consequences, providers should resist unnecessary discontinuation because an increase in blood pressure may be a sign of efficacy of VEGF inhibitor therapy35.Hypertension secondary to kinase modification can be marked and result in significant downstream effects on the cardiovascular system. Even without end organ damage, poorly controlled blood pressure often results in the discontinuation of essential anti-neoplastic therapy27. The mechanism of HF, however, is generally felt to be secondary to hypertension and increased afterload in vulnerable patients. For that reason, the main focus is on the prevention and treatment of severe hypertension36. Other cardiovascular toxicities that have been noted in association with VEGF inhibitors include venous and arterial thrombosis, coronary artery disease, acute coronary syndromes, and conduction abnormalities4. These complications should be managed according to their respective current guidelines with additional consideration for cessation or modification of therapy.Patients with pre-existing left ventricular dysfunction or coronary artery disease must be monitored closely and treated with the same strategies discussed for anthracyclines and HER2/ErbB2 inhibitorsThe field of cardio-oncology has rapidly expanded, but there remains significant room for growth in research and clinical practice. This two-part series highlights only a subset of the agents capable of causing profound cardiovascular toxicities, and many complications of cancer and cancer therapy were not discussed, including pericardial disease, myocardial ischemia, and QT prolongation. Numerous questions are unanswered about the mechanism of toxicities and the optimal screening and management strategies. Given the tremendous complexity of impacted patients, close communication and collaboration between oncologists and cardiologists is mandatory at all stages of therapy. Oncologists must know when to turn to cardiologists for assistance in risk stratification and management of toxicities when they develop. Critically, cardiologists need to recognize that their role is to facilitate the delivery of lifesaving cancer therapy through optimization and management of toxicity.


The characteristics and optimal management of heart failure with a moderately reduced ejection fraction  are still unclear. Advanced cardiac MRI offers information about function, fibrosis and inflammation of the myocardium, and might help to characterize HFmrEF in terms of adverse cardiac remodeling. We, therefore, examined 17 patients with HFpEF, 18 with HFmrEF, 17 with HFrEF and 17 healthy, age-matched controls with cardiac MRI (Phillips 1.5 T). T1 and T2 relaxation time mapping was performed and the extracellular volume (ECV) was calculated. Global circumferential (GCS) and longitudinal strain (GLS) were derived from cine images. GLS (−15.7 ± 2.1) and GCS (−19.9 ± 4.1) were moderately reduced in HFmrEF, resembling systolic dysfunction. Native T1 relaxation times were elevated in HFmrEF (1027 ± 40 ms) and HFrEF (1033 ± 54 ms) compared to healthy controls (972 ± 31 ms) and HFpEF (985 ± 32 ms). T2 relaxation times were elevated in HFmrEF (55.4 ± 3.4 ms) and HFrEF (56.0 ± 6.0 ms) compared to healthy controls (50.6 ± 2.1 ms). Differences in ECV did not reach statistical significance. HFmrEF differs from healthy controls and shares similarities with HFrEF in cardiac MRI parameters of fibrosis and inflammation. Heart failure is a clinical entity with a diverse spectrum of etiologies and phenotypes. Classification systems and diagnostic criteria have been established paralleling better understanding of its pathophysiology. Early on, the significance of the left ventricular ejection fraction (LV-EF) in the classification of heart failure was acknowledged. The European Society of Cardiology recently suggested to define heart failure with moderately reduced ejection fraction  as a distinct category between heart failure with preserved  and reduced  ejection fractions . PatientCardiac magnetic resonance (CMR) imaging is a noninvasive method to assess cardiac function, structure, inflammation, and fibrosis. The development of T1 and T2 relaxation time mapping techniques has greatly improved the ability to detect changes in tissue composition, most notably fibrosis and edema . The comThe purpose of our study was to further characterize HFmrEF patients in terms of advanced CMR imaging markers of adverse cardiac remodeling, with a focus on T2 mapping as a potential biomarker in heart failure.From a contemporary trial, a total of 52 well characterized patients with HFpEF, HFmrEF and HFrEF, along with 17 controls, were included in this analysis  . HFrEF, 3, reconstructed voxel size = 0.5 × 0.5 × 10 mm3, balanced SSFP readout, flip angle = 35°, parallel imaging (SENSE) factor = 2 and effective inversion times between 150 and 3382 ms. T2-mapping was performed before administration of contrast media using a black-blood-prepared, navigator-gated, free-breathing hybrid gradient  and a spin-echo multi-echo sequence (GraSE), as described previously, with the following typical imaging parameters: TR = 1 heartbeat, 9 echoes , FA 90°, parallel imaging (SENSE = 2), EPI factor = 7, black-blood prepulse and breath-hold (scan duration about 14 s). [®, Bayer AG, Leverkusen, Germany). Quantitative modified DIXON-imaging (mDIXON) for late enhancement was performed using a black-blood prepared, T1-weighted, spoiled-gradient, multi-echo sequence with 6 echoes starting 10 min post contrast agent application. Typical imaging parameters were as follows: Acquired voxel size = 2.0 × 2.0 × 8 mm3, reconstructed voxel size = 1.1 × 1.1 × 8 mm3, flip angle = 15° and effective echo time 4.75 ms.All patients were examined with a clinical 1.5 Tesla MRI scanner  equipped with a cardiac, five-element phased array coil. Cine images were acquired using a retrospectively gated cine-CMR in cardiac short-axis, vertical long-axis and horizontal long-axis orientations using a steady-state free precession (SSFP) sequence. Native and 15 min post contrast T1-mapping were performed using a modified Look-Locker (MOLLI) 5s(3s)3s-scheme . Typicalt 14 s).  PatientsImage analysis was performed offline using commercially available software . Late gadolinium enhancement (LGE) was assessed visually from mDIXON images. Segments with LGE were excluded from analysis, resulting in a total of 659 analyzed segments using a 16-segment-model. Mapping parameters were measured using QMap RE version 2.0 . Pre and post-contrast MOLLI images were manually corrected for in-plane-motion. The T1 and T2 relaxation times were calculated using nonlinear fitting with a maximum likelihood estimator (MLE). Extracellular volume (ECV) was calculated from pre and post-contrast T1-maps and the hematocrit, as described previously . Exemplar = 0. For quality of life, Spearman correlation was used. p-values below 0.05 were considered statistically significant.Statistical analysis was performed using SPSS 24  and R 3.5.1  . BaselinSample size calculations were performed for the detection of significant differences in native T1 relaxation time, T2 relaxation time and ECV between groups with a power of 80%. For native T1 relaxation time, previous studies have shown standard deviations between 20 and 50 ms and effect sizes of 30 to 40 ms ,16. For 17 patients with HFpEF, 18 with HFmrEF, 17 with HFrEF and 17 controls were included in the analysis. The baseline data of the patients and controls are given in One patient with HFpEF was excluded from analysis due to extensive artifacts. A boxplot of the measurements by group is given in One patient with HFpEF and one patient with HFmrEF were excluded from analysis due to extensive artifacts. A boxplot of the measurements by group is given in The ECV was calculated for patients with HFpEF, HFmrEF and HFrEF. One patient with HFpEF and one with HFmrEF were excluded from analysis due to extensive artifacts in the T1 mapping sequences, from which ECV would be calculated. A boxplot of the measurements by group is given in Boxplots for the measurements of GCS, GLS and SR (GLS/GCS) are given in Our study is the first to date to examine advanced imaging markers of remodeling in patients with HFmrEF.Differences in ECV did not reach statistical significance. The ECV values in our HFpEF patients were lower than those reported in other studies, ranging from 28.3% to 32.9%  19,20,2,22,23. TNative T1 relaxation times in HFmrEF were closer to HFrEF than HFpEF. A summary of studies examining native T1 relaxation times is given in T2 relaxation times were significantly elevated in HFmrEF and HFrEF compared to healthy controls. Our values for T2 relaxation times in controls were within the published reference range for our mapping sequence . To our The observed increase in both longitudinal and circumferential strain in HFmrEF and HFrEF reflects the reduced ejection fraction. Our strain values for controls and patients with HFpEF were within previously published reference values for cardiac MRI-derived endocardial strain . ImpairmIn our study, GLS and GCS seem to increase at different rates as the LV-EF decreases, so that the ratio of longitudinal to circumferential strain  differs in HFpEF compared to HFmrEF and HFrEF. To our knowledge, no previous study has examined the strain ratio as a cardiac parameter. The significance of this remains to be determined in future studies.One limitation of all parametric mapping studies is the inherent dependence of the measurements on the local setup. Our study does not intend to provide diagnostic criteria but to characterize the heart failure subtypes in relation to each other in terms of pathophysiological targets.p-values were not corrected for multiple testing and should be confirmed in further studies.Another obvious limitation of our study is its small sample size. Consequently, small differences between groups and correlations between parameters may have been missed. Yet, despite the small sample size, we found significant differences between heart failure subgroups and hope to contribute towards the characterization of HFmrEF. Our The groups differed in baseline parameters, such as age, sex, comorbidities, laboratory values and medication use. The differences observed are mostly consistent with previous studies, showing intermediate values in HFmrEF compared to HFpEF and HFrEF for the parameters age, sex and NT-proBNP ,36,37. OThe high number of patients reclassified with MRI-derived LV-EF compared to echocardiography-derived LV-EF diminishes the comparability of our results with trials relying on echocardiography alone. Furthermore, the question arises as to how many HFpEF patients in the general population actually do have a moderate reduction in LV-EF that is missed by echocardiography.Despite the small sample size, our study was able to show significant adverse remodeling beyond systolic functional impairment in patients with HFmrEF that resembles the changes seen in HFrEF.


ST) method, has been used for arterial stiffness assessment and early identification of atherosclerosis. We investigated whether the ascending aortic strain assessed by 2D‐ST echocardiography at rest can predict the presence of coronary artery disease (CAD).Arterial stiffening and atherosclerosis tend to coexist. Strain imaging, using a 2‐dimensional speckle tracking  and radial ascending aortic strain were assessed by 2D‐ST echocardiography. Ninety‐two patients with coronary lumen area stenosis ≥70% were categorized as having significant CAD. Global CAAS was significantly lower in patients with significant CAD  and remained an independent predictor of significant CAD  after multivariate regression. Based on the receiver operating characteristic curve for diagnosing significant CAD, the optimal cut‐off value of global CAAS was ≤9.22% . Global CAAS decreased with increasing severity of CAD and was significantly associated with 3‐vessel disease . Diagnostics for significant CAD were remarkably better for global CAAS combined with exercise treadmill testing than for exercise treadmill testing alone .Two hundred seventy‐one consecutive patients with suspected stable angina pectoris sequentially underwent exercise treadmill testing, 2‐dimensional echocardiography, M‐mode echocardiography, 2D‐CAAS assessed by 2D‐ST echocardiography at rest was able to predict the presence of significant CAD and identify multivessel disease. In addition, global CAAS combined with exercise treadmill testing remarkably improved the diagnostics for significant CAD.Global  This study demonstrated, for the first time, that global circumferential ascending aortic strain (CAAS) obtained by 2‐dimensional speckle tracking echocardiography at rest predicted significant coronary artery disease (CAD) in consecutively enrolled patients with suspected stable angina pectoris.Global CAAS decreased gradually with increasing severity of CAD, as determined by the increasing number of coronary vessels with lumen area stenosis ≥70%, and identified multivessel diseaseGlobal CAAS combined with the exercise treadmill test remarkably improved the diagnostics for significant CAD.Global CAAS analysis based on 2‐dimensional speckle tracking echocardiography is a rapid, robust, and reproducible noninvasive method without contraindications and radiation exposure.Based on the present study, 2‐dimensional speckle tracking global CAAS may be a feasible and accurate tool for clinicians in the screening of patients with significant CAD.Furthermore, global CAAS may become a supplementary index for risk stratification of CAD, given that it is capable of identifying multivessel CAD.Arterial stiffening is one of the earliest detectable manifestations of adverse structural and functional changes within the vessel wall.Two‐dimensional (2D) strain echocardiography was developed to allow a rapid, accurate, angle‐independent determination of regional myocardial deformation.Aorta influences the circulation in a global fashion by serving as a conduit and playing important roles in modulating left ventricular (LV) performance, myocardial perfusion, central hemodynamics, and arterial function throughout the entire cardiovascular system.Chest pain, a potential manifestation of CAD, is a common complaint of patients presenting to cardiology departments.Data, analytical methods, and study materials will be made available to other researchers for purposes of reproducing the results or replicating the procedure. This material can be made available by the first author and the corresponding author on reasonable request.A total of 308 consecutive patients with suspected SAP were enrolled from January 2015 to May 2017. SAP was defined as chest pain or discomfort (angina) suspected to be caused by myocardial ischemia.All patients underwent ETT, 2D echocardiography, M‐mode echocardiography, and 2D‐ST echocardiography before coronary angiography. Coronary angiography was performed regardless of the outcome of echocardiography and ETT. The study was approved by the institutional review board, and all patients provided written informed consent.Symptom‐limited ETT was performed according to the recommended Bruce treadmill protocol.Transthoracic echocardiography was performed using a Vivid E9 ultrasound system with a 3.5‐MHz transducer  after ETT and before coronary angiography. The operator was blinded to the patient history and results of ETT. Before echocardiography, blood pressure was measured at the right brachial artery using an electronic sphygmomanometer  with the patient supine. Standard 2D echocardiographic images were obtained during breathhold when patients were in the left lateral decubitus position. A frame rate of 55 to 75 frames per second was used for 2D speckle tracing analysis.Each echocardiographic measurement was taken from the average of 3 continuous cardiac cycles. Conventional echocardiographic values, including LV dimensions, LV ejection fraction, LV fractional shortening, LV mass index, peak transmitral early velocity, peak atrial diastolic filling, deceleration time, peak longitudinal early diastolic velocity, and peak transmitral early diastolic inflow velocity/peak longitudinal early diastolic velocity ratio, were measured and calculated according to the recommendations of the American Society of Echocardiography.s) was measured at the point of maximal anterior motion of the ascending aorta (systole), and diastolic aortic diameter (Ad) was measured at the q wave on ECG (end diastole) using M‐mode echocardiography. The mean of 5 measurements for diameter in sequential cardiac cycles was used for data analysis. Three elastic indices of aortic stiffness, namely aortic distensibility (D), stiffness index (β), and elastic modulus (Ep), were calculated as D=2(As−Ad)/[Ad(Ps−Pd)], β=ln(Ps/Pd)/[(As−Ad)/Ad], and Ep=(Ps−Pd)/[(As−Ad)/Ad], respectively, where Ps=systolic blood pressure, Pd=diastolic blood pressure, and ln=natural logarithm.Ascending aorta was imaged at 3 cm above the aortic valve from the parasternal long‐axis viewAt the same sampling location of M‐mode echocardiography measurements, a circular plane of the ascending aorta was obtained at 3 cm above the aortic valve from the parasternal short‐axis view. 2D image acquisition was performed at end‐expiratory apnea. Loops of 3 cardiac cycles were stored digitally and analyzed offline using commercial software .Ascending aortic strain was assessed by 2D‐ST echocardiography. In high‐frame‐rate images of ascending aorta, a loop was manually drawn along the inner edge of the aortic wall, and then an additional loop near the outer edge of the aortic wall was automatically generated by the software. Because of the small thickness of the aortic wall, the width of the region of interest was adjusted to the minimum allowed by the software.The software automatically divided the optimal aortic wall image into 6 equally sized color‐coded segments . Quantitative curves with different colors were used to represent the 2D‐ST variables of different segments of aortic wall. Peak values of circumferential strain and radial strain in each segment, which typically appeared near the aortic valvular closure (systole), were identified Figure B and 1C.Study participants were subjected to coronary angiography, which was performed by the percutaneous radial or femoral approach. An experienced operator blinded to the results of the preceding examinations analyzed the angiograms visually. Significant coronary stenosis was defined as ≥70% reduction in the coronary lumen area.t test was used to compare the differences between groups. Categorical variables are expressed as frequencies and percentages and were compared using the chi‐squared test or Fisher's exact test. Multiple step‐wise logistic regression was performed to assess the influence of baseline characteristics, including age, sex, body mass index (BMI), heart rate, hypertension, diabetes mellitus, hypercholesterolemia, smoking, pulse pressure on ascending aortic strain, and stiffness parameters. For the optimal predictors, receiver operating characteristic (ROC) curves were constructed, and the area under the curve (AUC) was calculated. The difference in AUC from ROC curves was evaluated by the Delong method. Subsequently, the optimal cut‐off value of the predictors with the highest sensitivity and specificity was selected using ROC curves. One‐way ANOVA was used to assess whether the aortic strain value changed with increasing severity of CAD, as determined by an increasing number of stenotic coronary vessels. The Student–Newman–Keuls method was used for post‐hoc tests of one‐way ANOVA. A two‐tailed P<0.05 was considered statistically significant. Inter‐ and intraobserver reproducibility for measurement of global CAAS and global RAAS were assessed on recorded images from 30 randomly selected patients with the Bland–Altman method by repeating the entire processes from the initial 2D image acquisition of ascending aorta. Data were analyzed using SPSS  and MedCalc software .Normality of the distribution of continuous variables was confirmed by the Kolmogorov–Smirnov test. Continuous variables are presented as the mean±SD, and the Student Among the 308 consecutively enrolled patients, 37 were excluded because of poor echocardiographic image quality. Of the remaining 271 patients, 92 were categorized as having significant CAD with coronary area stenosis ≥70%, whereas 179 had nonsignificant CAD or no CAD.Baseline characteristics are summarized in Table P<0.001), exercise capacity , maximum heart rate , maximal ST‐deviation , and DTS .In patients with significant CAD, exercise performance was significantly impaired in all parameters, including exercise time . Corrected CAAS was significantly reduced in patients with significant CAD . Statistical difference of the global RAAS, assessed by 2D‐ST echocardiography , was found between patients with and without significant CAD.Table P<0.001) and corrected CAAS  remained independent predictors of significant CAD.Table P<0.001), which determined the diagnostic performance of global CAAS , respectively. In post‐hoc tests, global CAAS of patients without CAD was significantly higher than that of those with 1‐, 2‐, or 3‐VD , global CAAS was 11.54±4.03%, 8.45±2.02%, 6.91±1.54%, and 6.03±2.52%  and corrected CAAS  were significantly associated with 3‐VD. The area under the ROC curve of global CAAS and corrected CAAS for detecting 3‐VD was 0.87  and 0.75 , respectively . Based on the ROC curve of DTS for diagnosing significant CAD, the optimal cut‐off value of DTS was ≤−1.12  global CAAS obtained by 2D‐ST echocardiography had a high feasibility and satisfactory reproducibility; (2) global CAAS at rest predicted significant CAD with high sensitivity (86%) in patients with suspected SAP Tables  and 4;  and 4;  and the optimal cut‐off value of global CAAS was 9.22%. The ability of global CAAS to differentiate significant CAD was remarkable, with 86% of enrolled patients with global CAAS ≤9.22% having significant coronary stenosis confirmed by coronary angiography . The fact that blood pressure and CAAS for calculation of corrected CAAS were measured at different locations imposes limitations on the diagnostic accuracy of corrected CAAS. Additionally, RAAS, based on thinning of the aortic wall, was difficult to measure accurately using 2D‐ST.Our study demonstrated that both global CAAS and corrected CAAS were significantly associated with prevalence of significant coronary stenosis. Although CAD patients were older and had a higher male proportion, BMI, and prevalence of smoking, only global CAAS and corrected CAAS remained independent predictors of significant CAD after adjustment for baseline characteristics in multivariate regression analysis Table . Based ohy Table . AccordiP<0.001; sensitivity, 76%; specificity, 91%; Figure P<0.001; Figure Risk stratification is essential for patients with established coronary atherosclerosis. Our study population consisted of patients with no previous history of heart disease, a relatively low prevalence of cardiovascular risk factors, and normal LVEF determined by echocardiography. Accordingly, overall prevalence of significant CAD was low 34%). In such a low‐risk study population, the fact that global CAAS and corrected CAAS were independent predictors of significant CAD implies that global CAAS and corrected CAAS might be useful for risk stratification of patients with suspected SAP. Our study demonstrated that both global CAAS and corrected CAAS decreased incrementally with increasing severity of CAD, as determined by an increasing number of diseased vessels  was significantly better than that of ETT alone .In the conventional diagnostic procedure for CAD, ETT is a recommended diagnostic examination for patients with suspected SAP induced by coronary artery stenosis, despite its flawed specificity and sensitivity.Based on the ROC curve analysis, the optimal cut‐off values were suggested to be global CAAS ≤9.22% and DTS ≤−1.12, respectively. When combining these 2 optimal cut‐off values, patients without significant CAD only had a 6% possibility of global CAAS ≤9.22% and DTS ≤−1.12, corresponding to a specificity of 94%. Patients with significant CAD had a 9% possibility of global CAAS >9.22% and DTS >−1.12, corresponding to a sensitivity of 91%. On the other hand, if patients had a global CAAS ≤9.22% and DTS ≤−1.12, the risk of having significant CAD was 85%, corresponding to a positive predictive value. If patients had a global CAAS >9.22% and DTS >−1.12, the risk of having significant CAD was only 8%, corresponding to a negative predictive value of 92%. It is encouraging that the diagnostic procedure for significant CAD was remarkably optimized by the combination of 2 noninvasive methods, which are easily applicable to clinical practice.Recently, quantification of LV longitudinal strain using 2D‐ST echocardiography was shown to be a sensitive method for identifying significant CAD.The global CAAS analysis based on 2D‐ST echocardiography is a rapid, robust, and reproducible noninvasive method without contraindications and radiation exposure. Based on the present study, 2D‐ST global CAAS may be a feasible and accurate tool for clinicians in the screening of patients with significant CAD. Furthermore, global CAAS may become a supplementary index for risk stratification of CAD, given that it is capable of identifying multivessel CAD.First, because of the sampling location of ascending aorta, image quality may have been affected by breathing and adjacent structures. Thirty‐seven recruited patients were excluded from the study because the image quality did not reach the standard for accurately tracking and analyzing the vascular image. Second, we used the global CAAS, which was calculated as the mean value of peak CAAS in 6 segments of ascending aorta, to evaluate the changes of elastic properties of ascending aorta. Given the heterogeneity of arterial deformation, it is worth testing whether maximal and/or minimal CAAS are better predictors of coronary stenosis in further investigations. Third, 2D‐ST echocardiography is a semiautomated technology that requires operators to manually draw a line along the inner side of the aortic wall. Thus, this technique is operator dependent, which might limit its wide use in clinical practice. Finally, the consecutive patient enrollment in the study may not have completely precluded selection bias. Further validation and prognostic research are warranted.In this study of suspected stable angina patients, global CAAS assessed by 2D‐ST echocardiography at rest was an independent predictor of significant CAD. Furthermore, global CAAS was related to the severity of CAD and capable of identifying multivessel disease. In addition, global CAAS combined with ETT can remarkably improve the diagnostics for significant CAD.This work was supported by the National Science Fund for Distinguished Young Scholars (81625002); National Natural Science Foundation of China ; Shanghai Outstanding Academic Leaders Program (18XD1402400); Shanghai Municipal Education Commission (20152209 and 20172014); Shanghai Science and Technology Committee (15411963600); Shanghai ShenKang Hospital Development Center (16CR3020A and 16CR3034A); National Key Research and Development Program of China (2016YFC1301203); and Shanghai Jiao Tong University .None.


We present a case of a centenarian patient in whom pre-existing left bundle branch block (LBBB) transiently reverted to normal ventricular conduction during general anesthesia. A 104-year-old woman with a history of hypertension, chronic heart failure, and cognitive impairment was admitted for surgical repair of a femoral neck fracture. The standard 12-lead electrocardiogram (ECG) on admission revealed left axis deviation and complete LBBB with a heart rate (HR) of 60 bpm. Echocardiography indicated left ventricular dyssynchrony with an ejection fraction of 51%. Due to her restless and agitated behavior, general anesthesia was selected for surgery.On arrival in the operating room, the patient’s blood pressure (BP) was 170/110 mmHg and HR was 110 bpm with a regular rhythm. ECG monitoring showed a wide QRS complex (140 ms) with RsrS pattern  at a HR of 50 bpm and BP of 100/60 mmHg (Fig. Intraoperatively, HR, BP, SLBBB is commonly associated with structural heart disease and left ventricular dysfunction and is thought to increase cardiac mortality in patients with congestive heart failure . LBBB caThe choice of anesthesia technique for hip fracture fixation in elderly patients has been discussed . We spec


Chemotherapeutic agents have contributed importantly to the increased survival of patients with cancer. However, with greater survival, their cardiotoxic side effects emerge more often as a source of great concern . AlreadyIn addition to anthracyclines, several other chemotherapeutic agents that were used successfully to treat a wide variety of cancers were found to be toxic for the heart. Potential cardiotoxic side effects of antineoplastic agents include but are not limited to myocardial dysfunction, arrhythmias, ischaemia, myocarditis and pericarditis .Knowledge of these cardiotoxic side effects and the increased survival of patients with cancer has urged cardiologists and oncologists to identify risk factors (e. g. higher cumulative dose), preventive measures (e. g. dexrazoxane), early detection tools and treatment options to reduce the risk of chemotherapy-induced heart failure. This led to a position paper on cancer treatments and cardiovascular toxicity by the European Society of Cardiology in 2016 . This poIn the current issue of the Netherlands Heart Journal, Teske and colleagues give an inspiring overview on the management of oncology patients treated with cardiotoxic chemotherapies at their cardio-oncology outpatient clinic, which stems from a close collaboration between oncologists and cardiologists . In contHowever, as the authors also mention, evidence for their management strategy remains scarce and mainly comes from studies on anthracycline and/or trastuzumab cardiotoxicity and leaves room for discussion. The overview advises echocardiographic surveillance for up to 1 year after chemotherapy cessation in adult patients based on a study by Cardinale et al. showing that development of left ventricular dysfunction beyond 1 year is rare . This coAlso, the ejection fraction (EF) thresholds (EF <45% or >10 point EF decline <53% and NYHA II/IV) used for initiation of heart failure medications are based on two non-randomised trials and require more studies to support or refine these thresholds.Nonetheless, this overview from Teske and colleagues provides a useful framework for the management of patients treated with cardiotoxic chemotherapy and this should serve as an incentive for more research on mechanisms, risk estimation, early detection, prevention and treatment of chemotherapy-related cardiac dysfunction. All of which would greatly benefit from close collaboration between cardiologists and oncologists.