Cardiotoxicity, defined mainly as left ventricle (LV) dysfunction, is a significant side effect of anthracyclines (ANT) therapy. The need for an early simple marker to identify patients at risk is crucial. A high neutrophil‐to‐lymphocyte ratio (NLR) has been associated with poor prognosis in cancer patients; however, its role as a predictor for cardiotoxicity development is unknown.Evaluating whether elevated NLR, during ANT exposure, plays a predictive role in the development of cardiotoxicity as defined by LV global longitudinal strain (LV GLS) relative reduction (≥10%).p = .009). NLR ≥ 2.58 at T2 increases the risk for LV GLS reduction by fourfold , with each increase of 1‐point NLR adding an additional 15% risk .Data were prospectively collected as part of the Israel Cardio‐Oncology Registry. A total of 74 female patients with breast cancer, scheduled for ANT therapy were included. NLR levels were assessed at baseline (T1) and during ANT therapy (T2). All patients underwent serial echocardiography at baseline (T1) and after the completion of ANT therapy (T3). NLR ≥ 2.58 at T2 was found to be the optimal predictive cutoff for LV GLS deterioration. A relative LV GLS reduction ≥10% was significantly more common among patients with high NLR (50% vs. 20%, Our study provides novel data that high NLR levels, during ANT exposure, have an independent association with the development of LV dysfunction. Routine surveillance of NLR may be an effective means of risk‐stratifying. Included in the cohort were female patients diagnosed with breast cancer and scheduled for doxorubicin therapy with a cumulative dose of doxorubicin ≥180 mg/m2. All patients performed at least two echocardiography evaluations; at baseline, before doxorubicin exposure (T1), and at the end of doxorubicin therapy (T3). The majority of the patients performed additional echocardiography evaluation following the third ANT cycle (T2). Blood samples, including NLR, were taken at baseline (T1) and during doxorubicin exposure (T2), in close proximity to the echocardiography exam (T2). Exclusion criteria included age below 18, male gender, reduced baseline LV function (LV ejection fraction [LVEF] < 53%), a history of cardiac disease , past ANT therapy, dexrazoxane (cardioxane) therapy and no documentation of NLR values or LV GLS assessment.The study population is part of the Israel Cardio‐Oncology Registry (ICOR) —a prospective registry enrolling patients evaluated in the cardio‐oncology clinic at the Tel Aviv Sourasky Medical Center. All patients signed informed consent at the first clinic visit. The registry was approved by the local ethics Tel Aviv Sourasky committee (Identifier: 0228‐16‐TLV) and is registered on 2.22 + IV cyclophosphamide 600 mg/m2 every 2‐3 weeks for 4 cycles), following in most cases, IV paclitaxel 80 mg/m2 every week for 12 cycles. Patients presenting with a positive humanized anti‐human epidermal growth factor receptor 2 (HER2) were treated with IV trastuzumab  8 mg/kg loading dose/6 mg maintenance and then IV pertuzumab  840 mg loading dose/420 mg maintenance. The number of cycles for trastuzumab and pertuzumab was determined by the treating physician.A complete baseline medical history, cardiac risk factors, medical treatment, and blood tests were noted in all patients from the electronic medical charts. All patients were treated with an AC protocol , and during doxorubicin exposure (T2), before echocardiography follow‐up at the end of doxorubicin therapy (T3). The study population was stratified into two groups based on NLR values, according to the optimal predictive cutoff for LV GLS deterioration at T3, determined by a receiver operator characteristic (ROC) curve . Routine LV echocardiographic parameters included LV diameters and LVEF.2.4χ2 test was used to evaluate the association between these variables. The distribution of continuous variables was assessed using the Kolmogorov–Smirnov test. Normally distributed continuous variables were described as mean and standard deviation, these variables were compared using the independent samples t‐test. Non‐normally distributed continuous variables were expressed as the median and interquartile range (IQR), Mann–Whitney U test was used for comparison. Changes in continuous laboratory variables over time were assessed with paired‐samples t‐test if normally distributed and Wilcoxon signed‐rank test if not normally distributed. ROC curve analysis was performed to identify cutoff points of NLR  for the prediction of future LV GLS reduction. Areas under the curves (AUC) were calculated as measures of the accuracy of the test. The influence of NLR on the risk for LV GLS reduction was evaluated using multivariate binary logistic regression. Variables included were those showing a significant predictive value in univariate analysis (hypertension[HTN]), and variables with a known effect on LV GLS . Adjusted odds ratio (OR) with a 95% confidence interval (CI) was reported for all variables. A two‐tailed p < .05 was considered significant for all analyses. All analyses were performed with the IBM SPSS 23.0 software (SPSS Inc.).Categorical variables were expressed as frequency and percentages. 33.1From July 2016 to March 2021, 143 patients were identified; of which, 74 met the inclusion criteria. Excluded were 23 patients due to lack of documentation of NLR values, 45 patients due to lack of LV GLS measurements before or following the completion of doxorubicin therapy, and 1 due to male gender.3.2p = .24) and binary logistic regression . Sixteen (22%) patients were treated with trastuzumab, 14 (19%) with pertuzumab, and 16 (22%) patients had undergone chest radiations. All therapies were initiated following the completion of ANT therapy. Patients with low NLR values were more likely to have HTN  without significant differences in other clinical and therapeutic aspects, as stated in Table All patients were female with a mean age of 50 ± 12 years. None of the patients had a history of coronary artery disease. Cardiac risk factors were not frequent and ranged from 7% to 22% , while absolute neutrophil counts did not differ significantly between both blood samples  . Serum creatinine levels were similar between both groups at both time points.The median time elapsed from the first doxorubicin treatment to NLR evaluation at T2 was 44 (IQR: 28–64) days, which in the majority of the patients was following the third cycle of ANT with a cumulative dose of ≥180 mg/m3.5p = .31), LV GLS (p = .58), tricuspid annular plane systolic excursion (p = .62), or diastolic dysfunction ≥ Grade 2 (p = .16).As displayed in Table p = .02, respectively; Table p = .009, respectively).The mean relative LV GLS reduction from T1 to T3 differed significantly between patients with NLR at T2 ≥ 2.58 and patients with NLR < 2.58 . In a second model, each 1‐point rise in NLR value was associated with an additional 15% increased risk for LV GLS deterioration . Besides NLR, only treatment with trastuzumab independently predicted LV GLS deterioration. Neither absolute neutrophil count alone  nor absolute lymphocyte count alone  predicted LV GLS reduction in the same multivariate regression model.As presented in Table R2 values of 0.23 and 0.25, respectively. Hosmer–Lemeshow test was nonsignificant for both models .Models 1 and 2 resulted in Nagelkerke 4We evaluated, for the first time to our knowledge, the association between elevated NLR values and the development of cardiotoxicity among patients with breast cancer. We found that NLR ≥ 2.58, during ANT exposure (T2), was associated with a fourfold increased risk for developing significant LV GLS deterioration, with incremental increases of 1‐point NLR adding an additional 15% risk.The use of NLR measurements as a surrogate marker of poor outcomes is gaining popularity, both in the field of cancer and CVD. Past studies have shown that high baseline NLR values are associated with poor overall survival in different types of cancer, including breast cancer.Our findings are consistent with recent papers, showing a statistically significant increase in NLR values over time in patients who developed immune checkpoint inhibitors‐associated myocarditis,In our study, the optimal NLR predictive cutoff value for LV dysfunction was found to be ≥2.58, in concordance with past studies of breast cancer patients that have used an NLR cutoff value of 3 as predictive for overall survival.With a growing need for improved risk stratification of patients at risk for the development of cardiotoxicity, the search for an early, easily accessible marker is necessary. Surveillance with serial LVEF measurements is advised for patients treated with ANT; however, LVEF reduction is usually evident only after significant, oftentimes irreversible, myocardial damage has occurred.Our study has several limitations. First, it is a single‐center study, however, its strength is the prospective nature that enrolls a homogenous population and contains uniformity of all echocardiography exams performed by the same vendor, technician, and interpreting physician. Second, we acknowledge that the relatively small number of patients reduces the statistical power of our results, and larger trials are needed. Third, the relatively short period of follow‐up did not allow us to evaluate the association or predictability between high NLR values and the development of LVEF reduction, cardiac morbidity, and all‐cause mortality.5In summary, our study provides novel data that high NLR, during ANT exposure, has an independent association with the development of LV GLS deterioration, a parameter of LV dysfunction. Routine surveillance of NLR values may be an effective and rapid means of risk‐stratifying and predicting early systolic dysfunction among patients with breast cancer following ANT therapy.The authors declare no conflict of interest.


Physical activity contributes to changes in cardiac morphology, which are known as “athlete’s heart”. Therefore, these modifications can be characterized using different imaging modalities such as echocardiography, including Doppler  and speckle-tracking, along with cardiac magnetic resonance, and cardiac computed tomography.Echocardiography is the most common method for assessing cardiac structure and function in athletes due to its availability, repeatability, versatility, and low cost. It allows the measurement of parameters like left ventricular wall thickness, cavity dimensions, and mass.Left ventricular myocardial strain can be measured by tissue Doppler (using the pulse wave Doppler principle) or speckle tracking echocardiography , which provide information on the deformation of the myocardium.Cardiac magnetic resonance provides a comprehensive evaluation of cardiac morphology and function with superior accuracy compared to echocardiography. With the addition of contrast agents, myocardial state can be characterized. Thus, it is particularly effective in differentiating an athlete’s heart from pathological conditions, however, is less accessible and more expensive compared to other techniques.Coronary computed tomography is used to assess coronary artery anatomy and identify anomalies or diseases, but its use is limited due to radiation exposure and cost, making it less suitable for young athletes.A novel approach, hemodynamic forces analysis, uses feature tracking to quantify intraventricular pressure gradients responsible for blood flow. Hemodynamic forces analysis has the potential for studying blood flow within the heart and assessing cardiac function.In conclusion, each diagnostic technique has its own advantages and limitations for assessing cardiac adaptations in athletes. Examining and comparing the cardiac adaptations resulting from physical activity with the structural cardiac changes identified through different diagnostic modalities is a pivotal focus in the field of sports medicine.The online version contains supplementary material available at 10.1186/s12947-023-00319-3. Athletic training induces cardiac adaptations, including morphologic changes of the left ventricle (LV) . The speCurrently, there is a lack of clarity regarding the most effective strategies to emphasize the critical characteristics of the athlete’s heart despite the availability of numerous diagnostic techniques . TherefoDue to its extensive availability, easy repeatability, versatility, and low cost, echocardiography is undoubtedly the most common method for a comprehensive assessment of cardiac structure and function in athletes and for assessing the effect of training on an athlete’s heart , 7. Accop < 0.001). Combined endurance- and strength-trained athletes have the highest values of LV diastolic dimension (56.2 mm) compared to endurance (53.7 mm) and strength (52.1 mm) trained athletes. As a consequence, the mean relative wall thickness of endurance-trained athletes was significantly lower than that of strength-trained athletes .The advent of echocardiography has allowed us to assess objectively the changes of the cardiac structures in response to different types of exercise , and staA study by Kreso et al. provided useful information on the different echocardiographic characteristics between an athlete’s heart and HCM . Referenp < 0.01) due to greater end-diastolic interventricular septal, LV posterior wall, and LV basal diameter. However, when indexing to body surface area, LV mass did not differ between sexes. Septal and posterior wall thickness were associated with age for both men  and women , which may explain the finding of a strong positive correlation between age and LV mass index for both groups .Cardiac sex and age differences are present among master athletes. A study by Wooten et al.  demonstrCertain ethnic variations in LV remodeling exist among highly-trained athletes of African/Afro-Caribbean (black) and Caucasian (white) descent. Black athletes exhibit a more significant extent of LVH compared to their white counterparts when examined using 2D echocardiography. Consequently, applying conclusions drawn from studies on white athletes may lead to inaccurate diagnosis of HCM in black athletes and up to disqualification from competitive sport in black athletes with LVH ≥ 15 mm . In addiLastly, direct transthoracic examination of the coronary arteries in adults is possible  and may As for the right ventricle, the evaluation of its size and function is difficult because the conventional 2D methods are not precise enough. This is mainly due to the right ventricular complex anatomy that does not resemble any familiar geometric shape .In addition to the undeniable advantages of this method, there are also limitations, such as variability between observers in measurements of the interventricular septum or the LV posterior wall thickness . This isOver the past few decades, there have been significant advancements in ultrasound technology, leading to the evolution of echocardiography from basic M-mode imaging to more advanced techniques such as 3-dimensional (3D) anatomical imaging . The useWith all the advantages and disadvantages mentioned above, echocardiography is expected to continue being the first-line imaging modality for assessing the heart of athletes .Flow pulsed wave Doppler echocardiography allows imaging of high-quality signals that provide blood velocity measurements . Based oDistinguishing between left and right ventricular hypertrophy and pathological conditionsPredicting cardiac performance during physical exerciseEvaluating the interaction between the two ventriclesAnalysing myocardial adaptations to various training protocolsIdentifying specific genotypes associated with cardiomyopathies at an early stage .Doppler myocardial imaging measures the velocity of myocardial walls, which allows the characterization of each ventricular myocardial segment by placing the sample volume at the center of the cardiac wall. Although standard 2D echocardiography is a unique tool in evaluating cardiac adaptations to physical exercise, recent data  indicateMoreover, a study  aimed atTherefore, the combination of standard 2D echocardiography and DMI may be a suitable approach for accurately evaluating both physiological and pathological LVH in a noninvasive and easily repeatable manner . Nonethe. LV global longitudinal strain (GLS) obtained by STE is the most used parameter in clinical practice, and is not significantly different between athletes and healthy controls. Therefore, a reduction in longitudinal strain in athletes has to be considered as a subclinical sign of LV contractile dysfunction and should raise the suspicion of myocardial disease, particularly in the presence of doubtful LV hypertrophy or dilatation : the main direction of HDFs over a selected period, using a polar coordinate system. φ ranges from 0°, when the HDFs are directed in an infero-lateral direction, to 360°, after a complete circular turn .The following parameters can be calculated in systole, diastole, and over the entire cardiac cycle:Current data on adaptations of the heart to physical activity in athletes is limited and needs to provide a comprehensive view. To overcome this limitation, HDFs could be used as an alternative to standard methods. Moreover, the feature of HDFs is that computation can be performed from speckle tracking in B-mode echocardiography or feature tracking in cine CMR , making An illustrative example of calculating HDFs from CMR using a feature tracking approach is given in video format with legends in the “Athlete’s heart” refers to specific adaptive changes in the heart that occur as a result of physical activity and contains increased mass, cavity dimensions, and wall thickness with at least normal systolic and diastolic function. Diagnostic techniques such as 2D echocardiography, incorporating Doppler and STE, along with modalities like CMR and CCT, are employed to identify and characterize such modifications. Consequently, each of these methods aids in distinguishing between physiological cardiac adaptations and pathological changes, particularly in situations where uncertainty arises regarding structural cardiac disease.Not applicable.The authors declare no competing interests.Additional file 1. Slice selection. Slices  are visually assessed on CMR images shown on the right side panel to choose the most appropriate one for border tracing. Red dots correspond to border tracing and were calculated in this case on two cardiac frames by the software (the remaining frames will be completed by launching the automatic contouring option). For easiness of slice selection on pre-strain analysis page, the observer deletes red dots and leaves only on the slice selected (slice #7) as already traced borders.Additional file 2. Frame selection. Frames  are visually assessed on the selected slice by observing myocardial contraction/relaxation on CMR images shown on the right side panel to choose those corresponding to end of diastole and end of systole. The observer follows movements of the myocardium and of the mitral valve leaflets throughout the cardiac cycle to identify the end of systole and end of diastole. Once the appropriate frames are identified (in this case the frames #11 and #30), the observer marks them with LV end-systolic and LV end-diastolic frames, respectively.Additional file 3. Border tracing. After slice and frame selection, automatic contouring is performed. In this case, the observer selects both the endo- and epicardial borders to be traced . When the contouring is finished by the software, the observer visually verifies that all the borders on the selected slice are traced correctly before launching the strain analysis. In the strain analysis results, cine illustration of LV contraction/relaxation shows the direction and the amplitude of the endocardium . There are two graphs on the strain analysis page. The upper one presents curves of endocardial global longitudinal (red), circumferential (pink) and radial (green) strain with % average of strain over time at the end of systole. Note that longitudinal and circumferential strain have negative values, while radial strain has positive value. The lower graph shows two curves, where red corresponds to volume (ml average) over time (ms) and blue – to volume change over time change. Minimal LV blood volume at the end of systole corresponds to the lowest point on the curve, while maximal volume – to the highest. Below the graphs, there are two “bull’s eye” diagrams demonstrating systolic myocardial strain percent in longitudinal (red) and transverse (blue) direction with appropriate color assignment to different segments. The cardiac apex is positioned in the centrum of diagrams.Additional file 4. Valve diameter measurement and HDFs analysis. The valve diameter is measured by placing arrows at the annular plane of the valve between internal contours when the leaflets are open: for the mitral valve using two views , for the aortic valve – only one view (3-chamber). Once the arrow placement is complete, the software automatically calculates the valve area in the designated box on the right side of the screen. When measurements of both valves are finished, the software readily presents the results of HDFs analysis. The graph on the top represents the Apex-to-Base  and the Lateral-to-Septal  HDFs. The polar histogram on the bottom represents the amplitude and the direction of the HDFs (red triangles). In this case, A-B HDFs are 23.03%, L-S HDFs are 4.02%, and the angle is 71°.


Quantitative extracellular volume fraction (ECV) mapping with MRI is commonly used to investigate in vivo diffuse myocardial fibrosis. This study aimed to validate ECV measurements against ex vivo histology of myocardial tissue samples from patients with aortic valve stenosis or hypertrophic cardiomyopathy.1 maps and post-contrast T1 maps after gadobutrol administration, from which hematocrit-corrected ECV maps were estimated. Intra-operatively obtained myocardial tissue samples from the same patients were stained with picrosirius red for quantitative histology of myocardial interstitial fibrosis. Correlations between in vivo ECV and ex vivo myocardial collagen content were evaluated with regression analyses.Sixteen patients underwent MRI examination at 3 T to acquire native Tn = 16, r = 0.70; p = 0.003) with myocardial collagen content. Myocardial native T1 values (1206 ± 36 ms) did not correlate with septal ECV  or with myocardial collagen content .Septal ECV was 30.3% ± 4.6% and correlated strongly (We compared myocardial ECV mapping at 3 T against ex vivo histology of myocardial collagen content, adding evidence to the notion that ECV mapping is a surrogate marker for in vivo diffuse myocardial fibrosis. Quantifications were averaged over the ROIs to yield mean native and post-contrast T1 values and ECV per subject.The quantitative evaluation of the MOLLI image series was performed with QMap 2.2  according to consensus recommendations . Per seris views , conservMyocardial tissue samples from the left ventricular septum were embedded in paraffin, sectioned at 3-µm slices, and stained all at once with picrosirius red to detect myocardial collagen. Stained sections were digitized with a IntelliSite Ultra Fast Scanner 1.6  at 40 × magnification. From these digitized slides, six non-overlapping digital images were grabbed for each specimen. Endocardial and perivascular areas were avoided or excluded from the analyses. Images were loaded into ImageJ , and minimum and maximum signal intensities for picrosirius red-stained collagen were estimated by drawing ROIs in areas of interstitial fibrosis. The resultant signal intensity bandwidth was used to isolate picrosirius red-stained surfaces in all images Fig. . A simil1 and ECV and histological quantifications of the myocardial collagen content were conducted using MATLAB . Specifically, a relative equal weighting of the errors between the linear fit and the in vivo MR measurements and ex vivo histological assays was assumed. The covariance matrices for the slope and intercept parameters were determined as described previously [p < 0.05.Data are presented as mean ± standard deviation (SD). Regression analyses between myocardial native Teviously , and usen = 8 with aortic valve stenosis, n = 8 with obstructive HCM; male/female, 11/5; age, 65.9 ± 8.6 years; body mass index, 26.8 ± 5.2 kg/m2) who completed the MR examination prior to surgery were collected intra-operatively, allowing a direct comparison of quantitative in vivo MRI readouts against ex vivo histology in 16 cases.Out of the 26 recruited patients, three patients experienced shortness-of-breath, dizziness or claustrophobia during MR examination, in which cases the session was aborted before the acquisition of quantitative MRI data. No contrast agent could be administered to three patients due to the unavailability of a qualified research nurse. Myocardial tissue samples were not collected for these cases. Biopsies were unavailable for one patient undergoing aortic valve replacement due to insufficient access to the septum during surgery. An insufficient amount of tissue was obtained in another three patients, which prevented histological evaluation. Thus, myocardial tissue samples of 16 patients . Left ventricular blood native T1 was 1839 ± 98 ms, and R1,blood native correlated strongly . Myocardial collagen content, expressed as the percentage of picrosirius red-stained surface area, was 5.8 ± 2.3%, and was similar for aortic valve stenosis and HCM patients . Notably, myocardial native T1 values did not correlate with septal ECV  did not correlate with myocardial collagen content  and experimental  variatisurrogate evaluation of diffuse myocardial fibrosis. Here, we established a good agreement between in vivo MRI measurements and ex vivo tissue collagen content in a direct comparison in patients with severe aortic valve stenosis and obstructive HCM. Although other work has demonstrated similar results in other diseases such as myocarditis [1, transiently increases directly after marathon running in trained athletes [n = 20, r = 0.66; p = 0.001), but importantly, not with fibrosis alone [Quantitative ECV mapping remains a carditis , dilatedcarditis , 20, andcarditis , cautionathletes , which iis alone . Those sWe report a stronger correlation between ECV and myocardial collagen content in aortic valve stenosis than in obstructive HCM, which is strikingly similar to what was previously found in such patients at 1.5 T . MyocardIn conclusion, we have provided a direct comparison of myocardial ECV mapping at 3 T in patients with severe aortic valve stenosis and HCM against ex vivo quantitative histological assays of myocardial collagen content. Such validations contribute further evidence to the notion that MRI-measured ECV at 3 T is a surrogate marker for in vivo diffuse myocardial fibrosis. Yet, this approach may not hold in conditions or diseases where mechanisms other than myocardial collagen deposition leads to an expansion of the interstitial volume.


Left ventricular (LV) diastolic function (DF) may play an important role in predicting fluid responsiveness. However, few studies assessed the role of diastolic function in predicting fluid responsiveness. The aim of this pilot study was to assess whether parameters of right and left diastolic function assessed with transesophageal echocardiography, including the mitral E/e′ ratio, is associated with fluid responsiveness among patients undergoing elective bypass graft surgery. We also sought to compare other methods of fluid responsiveness assessment, including echocardiographic and hemodynamic parameters, pulse pressure variation, and stroke volume variation (SVV) .P = 0.85). SVV was the only independent variable to predict an increase in cardiac index by multivariate analysis ).We prospectively studied seventy patients undergoing coronary artery bypass grafting (CABG) monitored with a radial arterial catheter, transesophageal echocardiography (TEE), and a pulmonary artery catheter (for cardiac output measurements), before and after the administration of 500 mL of crystalloid over 10 min after the anesthetic induction. Thirteen patients were excluded . Fluid responsiveness was defined as an increase in cardiac index of ≥ 15%. There were 21 responders (36.8%) and 36 non-responders (63.2%). No difference in baseline pulsed wave Doppler echocardiographic measurements of any components of the mitral, tricuspid, and pulmonary and hepatic venous flows were found between responders and non-responders. There was no difference in MV tissue Doppler measurements between responders and non-responders, including E/e′ ratio (8.7 ± 4.1 vs. 8.5 ± 2.8 in responders vs. non-responders, In this pilot study, we found that no parameters of right and left ventricular diastolic function were associated with fluid responsiveness in patients undergoing CABG. SVV was the most useful parameter to predict fluid responsiveness.ClinicalTrials.gov, NCT 02714244. Registered 21 March 2016—retrospectively registered. Fluid responsiveness after volume expansion is better predicted by dynamic parameters compared to static parameters –3. AmongThe Frank-Starling curve illustrates fluid responsiveness, which depends on preload but also on systolic and diastolic ventricular function, venous compliance, and ventricular compliance , 8. HoweThe aim of this pilot study was to assess whether parameters of right and left diastolic function, including the mitral E/e′ ratio, is associated with fluid responsiveness among patients undergoing elective bypass graft surgery. We also sought to compare other methods of fluid responsiveness assessment, including echocardiographic and hemodynamic parameters, PPV, and stroke volume variation (SVV).n = 5), initial CVP ≥ 15 mmHg (n = 1), arrhythmia (n = 1), and scheduling conflict (n = 6). There were 50 men and 7 women included in the study. There was no difference in the demographic variables between the responders and non-responders (Table P = 0.3212).Seventy patients undergoing CABG were enrolled in this study. Thirteen patients were excluded from the analysis, for a total of 57 patients. The reasons for exclusion were initial PCWP ≥ 18 mmHg (P = 0.0076). No difference were found between responders and non-responders in baseline two-dimensional echocardiographic measurements of the right and left ventricle, except for left ventricular end-diastolic area (LVEDA) . No difference in baseline pulsed wave Doppler echocardiographic measurements of any components of the mitral, tricuspid, and pulmonary and hepatic venous flows were found between responders and non-responders. There was no difference in MV tissue Doppler measurements between responders and non-responders, including E/e′ ratio .Baseline hemodynamic data, two-dimensional, pulsed wave, and tissue Doppler echocardiographic data after fluid bolus are shown for the responders and non-responders Table . No diffP value < 0.20 in univariate analysis are shown in Table P = 0.0208).Univariate logistic regressions models were used to assess for the influence of baseline hemodynamic parameters, two-dimensional, pulsed wave, and tissue Doppler echocardiographic measurements to predict fluid responsiveness. Only parameters with a The performance of baseline hemodynamic and echocardiographic data to predict fluid responsiveness was evaluated by constructing ROC curves Table . Area unP < 0.05) in right atrial diameter, right ventricular end diastolic area, and left ventricular end diastolic area, without changes in right or left end systolic area and in right or left ventricular ejection fraction. There was also an increase in RV dP/dT and RV end diastolic pressure . A non-statistically significant interaction term (P = 0.7544) for the left ventricular E/e′ ratio of the mitral valve annulus was observed after fluid challenge, meaning that the two groups have the same evolution of this parameter in time ).The change in right ventricular (RV) echocardiographic parameters, change in RV diastolic pressure over time (dP/dT), and RV end-diastolic pressure, from baseline to post fluid infusion are shown in Table In this pilot study, we observed that predictor of fluid responsiveness was unrelated to left ventricular diastolic function parameters. Although left ventricular diastolic function may play a role in fluid responsiveness, our observations do not support the hypothesis that the evaluation of left ventricular diastolic function parameters is relevant in the prediction of fluid responsiveness. Indeed, there was neither difference in the E/e′ ratio of the mitral valve between responders and non-responders nor there was any difference in Doppler measurements of mitral valve inflow, pulmonary venous flow (PVF), and tissue Doppler components of MV annulus velocities. We also observed a lack of difference for Doppler measurements of tricuspid valve inflow, and hepatic venous flow (HVF) between responders and non-responders. The lack of difference in RV dP/dT of the diastolic filling and RV end-diastolic pressure between responders and non-responders are not in favor for a predominant role of RV diastolic function to predict preload responsiveness. Taken together, assessment of multiple parameters of biventricular diastolic function, including the E/e′ ratio of the mitral valve, does not increase our ability to predict fluid responsiveness in this population of patients undergoing CABG.As confirmed by other investigators, the absolute values of CVP and PCWP (static parameters) were not useful in predicting FR in these patients . In contThere are very few studies evaluating the role of diastolic function to predict fluid responsiveness , 10. In The hemodynamic response to a fluid loading is related to the Frank-Starling function curve. However, it depends also on the venous return to the heart, which determines if the administered volume is actually getting to the heart during diastole to increase preload . Venous This study has several limitations. First, no prestudy power analysis was performed in this exploratory study. Pilot study like this one serves to identify opportunities to test hypotheses with prospective registration trial with adequate sample size. Second, the results apply to patients undergoing CABG with a closed chest, under general anesthesia and mechanical ventilation, in normal sinus rhythm, preserved right ventricular function, and cannot be generalized to other situations. Third, although more recent guidelines have been published to assess diastolic function , it may In addition, we made the measurements with the legs raised, which adds around 150 mL of volume , to the In conclusion, in this pilot study, assessment of multiple parameters of left and right ventricular diastolic function, including E/e′ ratio of the mitral valve annulus measured by TEE, is not a predictor of fluid responsiveness undergoing CABG. The SVV measured by the Flotrac/Vigileo system was the most useful parameter to predict fluid responsiveness; however, almost half of the patients are in a gray zone for this parameter, which decreases its usefulness to guide fluid therapy. Further studies are needed to confirm the results of this exploratory study.Trials.gov  on March 21, 2016, with the Identifier: NCT02714244. Patients with more than mild valvular heart disease, intracardiac shunts, preoperative arrhythmia (non-sinus rhythm), decompensated heart failure, or pulmonary hypertension , renal insufficiency defined as creatinine clearance of less than 30 mL/min or any contraindications for TEE  were excluded. Central venous pressure (CVP) and pulmonary capillary wedge pressure (PWCP) were assessed before fluid administration and patients with high values (CVP ≥ 15 mmHg or PWCP ≥ 18 mmHg) were excluded because of risk of fluid overload in these patients.After approval by the Montreal Heart Institute Research Ethics and New Technology Development Committee (F1-4651) and with informed consent, 70 patients over 18 years old undergoing elective coronary artery bypass grafting (CABG) surgery between January 2016 and September 2017 were enrolled. No prestudy power analysis was performed. After that period, the department elected to terminate this exploratory study and analyze the data. The study was retrospectively registered at Clinical Premedication, induction, and maintenance of anesthesia were achieved at the discretion of the attending anesthetist with the exception of the requirement for the use of isoflurane inspired concentration of 1%. Lungs were ventilated by intermittent positive-pressure ventilation with a fraction of inspired oxygen of 1.0 by use of an Ohmeda volume-cycled ventilator . A respiratory rate of 8 breaths/min with an inspiratory/expiratory ratio of 1:2 and a tidal volume of 8 mL/kg were kept constant for the entire experiment. No positive end-expiratory pressure was applied. Usual monitoring was installed, including a 5-lead electrocardiogram, pulse oximeter, peripheral venous line, radial arterial line, 15-cm 3-lumen catheter , and fast-response thermodilution pulmonary artery catheter . A FloTrac  sensor was added to the arterial line and was analyzed by the Vigileo monitor . A 5.0-MHz TEE omniplane probe  was inserted by the anesthesiologist after induction of general anesthesia.After the induction of anesthesia, central line insertion and hemodynamic stability, the following parameters were recorded: arterial blood pressure, cardiac output (CO), right ventricular pressure, CVP, pulmonary artery pressure (PAP), PCWP, and respiratory-induced SVV. The CO was assessed with thermodilution technique using three injections of dextrose 5% (10 mL) at room temperature at end expiration. The average of three measurements with less than 10% difference between each was noted. Cardiac output response measured with the Swan-Ganz catheter was considered the gold standard to assess preload responsiveness. FloTrac was used to determine SVV. The PPV was calculated from the arterial line tracing on the monitor .−1Normal diastolic function: e′ ≥ 10 cm·s−1; E/e′ ≤ 8Grade 1 diastolic dysfunction (mild): e′ < 10 cm·s−1; E/e′ = 9-12Grade 2 diastolic dysfunction (moderate): e′ < 10 cm·s−1; E/e′ > 13Grade 3 diastolic dysfunction (severe): e′ < 10 cm·sWe obtained a complete baseline TEE exam, including the evaluation of diastolic function of the right and left ventricle, according to the ASE/SCA Guidelines for performing a comprehensive intraoperative multiplane TEE examination , 29. TheA single National Board of Echocardiography (NBE) board-certified anesthetist obtained the echocardiographic images. If any doubt arose about the interpretation of an echocardiographic measurement or hemodynamic waveform interpretation, the advice of a second anesthetist was obtained.All parameters were measured before chest opening and during hemodynamic stability in a supine position. The first measurement (T1) was carried within the 15 min that preceded a rapid volume infusion of 500 mL of Lactate Ringer® over 10 min. The second measurement (T2) was obtained within a maximum of 5 min after the bolus. Because T2 coincided with the time of asepsis, patients’ legs were raised, causing further increase of venous return. The legs were raised for the duration of the measurements for each patient. Fluid infusion was stopped if the PCWP was ≥ 20 mmHg during the protocol and such patients were excluded from the study. Fluid responsiveness was defined as an increase in cardiac index of more than 15% .t test or Mann-Whitney-Wilcoxon test as appropriate for continuous variables, and chi-square test for categorical variables. The number of responders and non-responders for each grade of diastolic dysfunction  was compared using chi-squared test. Comparison of groups for diastolic function parameters , 2-D and Doppler echocardiographic measurements, and hemodynamic measurements was performed with a Students t test. Then, using univariate logistic regression models, we explored the potential predictors of preload responsiveness among the same echocardiographic, and hemodynamic values. Only parameters with a P value < 0.20 in univariate analysis were included in the stepwise selection procedure of a multivariate logistic regression model. Receiver operating characteristic (ROC) curves were also generated for hemodynamic and echocardiographic parameters. Because the ROC curve methodology does not take into account, the existence of overlap between positive and negative fluid challenges, we also use the gray zone approach. This methodology avoids the binary response proposed by the ROC curves and proposed a low cut-off value that excludes positive fluid challenge in 90% of patients, whereas a high cut-off value predicts positive fluid challenge in 90% of cases [P value < 0.05 was considered statistically significant. All statistical analysis was performed using the SAS version 9.4 software .Continuous variables are summarized using mean ± standard deviation, or median , according to the distribution of the variable, while categorical variables are described using frequencies and percentages. Demographic data were compared between responders and non-responders using Student of cases . Two-way


Right ventricular (RV) function plays a critical role in the pathophysiology and acute prognosis of pulmonary embolism (PE). We analyzed the temporal changes of RV function in the cohort of a prospective multicentre study investigating if an early switch to oral anticoagulation in patients with intermediate-risk PE is effective and safe.Echocardiographic and laboratory examinations were performed at baseline (PE diagnosis), 6 days and 6 months. Echocardiographic parameters were classified into categories representing RV size, RV free wall/tricuspid annulus motion, RV pressure overload and right atrial (RA)/central venous pressure.RV dysfunction based on any abnormal echocardiographic parameter was present in 84% of patients at baseline. RV dilatation was the most frequently abnormal finding (40.6%), followed by increased RA/central venous pressure (34.6%), RV pressure overload (32.1%), and reduced RV free wall/tricuspid annulus motion (20.9%). As early as day 6, RV size remained normal or improved in 260 patients (64.7%), RV free wall/tricuspid annulus motion in 301 (74.9%), RV pressure overload in 297 (73.9%), and RA/central venous pressure in 254 (63.2%). At day 180, the frequencies slightly increased. The median NT-proBNP level decreased from 1448 pg/ml at baseline to 256.5 on day 6 and 127 on day 180.In the majority of patients with acute intermediate-risk PE switched early to a direct oral anticoagulant, echocardiographic parameters of RV function normalised within 6 days and remained normal throughout the first 6 months. Almost one in four patients, however, continued to have evidence of RV dysfunction over the long term.The online version contains supplementary material available at 10.1007/s00392-022-02138-4. Impairment of right ventricular (RV) function resulting from acute RV pressure overload plays a critical role in the pathophysiology and prognosis of pulmonary embolism (PE) , 2. In pAmong survivors of the acute phase of PE, approximately 20% have been reported to present with persistent RV dysfunction at follow-up . In factThe prospective multicentre single-arm Pulmonary Embolism International Trial (PEITHO)-2  investigated if the early switch from parenteral heparin to oral anticoagulation using dabigatran in patients with intermediate-risk PE is effective and safe . The preThe rationale and design of the PEITHO-2 study have been previously described . The maiprospectively classified for the present analysis into four categories or groups, each one corresponding to a key manifestation of RV pressure overload cardiac imaging  were prng Table : (i) RV ng Table .Table 1EThe analysis of echocardiographic data required assessment of each one of the four categories as defined above, both at baseline and during follow-up. The ‘hierarchical’ order applied to define an abnormal status within each category was based on existing evidence and expert consensus on the relative prognostic strength and reproducibility of individual ultrasound parameters , 13. ComStatistical analysis was performed in the intention-to-treat population . CategorA total of 402 patients with intermediate-risk PE  were enrolled in the PEITHO-2 study between January 2016 and July 2019. Patients were followed for 180 days after enrolment. During follow-up, 7 (2%) patients developed recurrent symptomatic VTE or PE-related death, 8 (2%) died from any cause and 11 (3%) had major bleeding .n = 338) of the patients at baseline. RV dilatation was the most frequently abnormal echocardiographic finding , followed by increased RA and central venous pressure , RV pressure overload , and reduced RV free wall and tricuspid annulus motion . The baseline characteristics of the patients with complete as opposed to those without completely available echocardiographic data at 180-day follow-up are shown in Table S2. After the acute phase of PE, the frequency of all markers of RV dysfunction decreased substantially; at 6 months, RV dysfunction had recovered in the vast majority of the patients, with RV enlargement and dilated inferior vena cava being the only findings documented somewhat more frequently, in 8.2% and 16.4% of the patients, respectively (Table S1).Echocardiographic signs of RV dysfunction based on any abnormal parameter were present in 84%  pg/ml at baseline, being almost twice as high (1873 [533–4391] versus 956 [304.3–2468.5] pg/ml) in patients compared to those without RV dilatation; three times as high (2964 [860–5007] versus 1084 [310.3–2662.8] pg/ml) in patients with reduced compared to normal RV free wall and tricuspid annulus motion; more than two-fold increased (2036 [901–4360] versus 955 [303.5–2616] pg/ml) in patients with (versus those without) signs of RV pressure overload; and similarly, also twice as high (1862.5 [700–4537.3] versus 979 [333.8–2664.5] pg/ml) in patients with increased versus normal RA and central venous pressure. Overall, median NT-proBNP levels decreased sharply to 256.5 (94.6–799) pg/ml on day 6, and to 127 (61–280.5) pg/ml on day 180. Nevertheless, the median value of NT-proBNP continued to be relatively high, i.e. 519 (144.8–1463.5) pg/ml in patients with at least one abnormal echocardiographic finding at 6 days; it fell to 148.2 (57.8–405.7) pg/ml in patients with at least one abnormal ultrasound parameter at 6 months.As shown in Table The aim of the present analysis was to examine the temporal pattern of changes in RV function, i.e. complete or partial recovery versus persistence or deterioration of abnormal findings, in patients having suffered acute, intermediate-risk PE. We examined the patient population participating in a prospective multicentre multinational single-arm study. Our main results are the following: (i) RV dilatation was the most frequently (41%) reported abnormal echocardiographic finding at the time of the index PE; (ii) in almost two-thirds of the patients, RV function parameters as assessed by echocardiography had already recovered by day 6, and this improvement was maintained over the 6-month follow-up; however, almost one out of four patients had at least one abnormal echocardiographic finding at 6 months; and (iii) the median levels of NT-proBNP remained elevated in patients with at least one abnormal echocardiographic finding at 6 days but decreased and approached normal values at 6 months even among patients with persisting echocardiographic abnormalities.Our results extend those of previous reports on the temporal changes of RV dimensions and function after acute PE. They may help to improve the level of evidence regarding long-term outcomes since our patient population was included in a prospective management study with standardised initial and chronic (over 6 months) treatment of PE. In an early small observational study dating back to the vitamin K antagonist era, it was reported that RV function normalised in the vast majority of PE patients within the first 5–13 days following treatment initiation . HoweverThe present study adds to our knowledge on the patients’ long-term course after acute intermediate-risk PE in view of contemporary treatment with a direct oral anticoagulant  over the entire 6-month period, and it also proposes a standardised approach to categorising, analysing and reporting echocardiographic follow-up data. In this regard, it must be emphasised that our ‘algorithm’ was not developed as a new prognostic score in acute PE but rather as a guidance for following RV dysfunction with echocardiographic parameters used in everyday clinical practice. We believe that the parameter groups and the steps developed for our analysis may be useful for future studies with serial assessments of RV (dys)function, especially when multiple centres in different countries are involved. Since the assessment of RV function may be crucial for the resumption of daily activities during follow-up after acute PE , an echoAlthough RV function is expected to recover early after acute PE in the majority of the patients, there are cases where RV recovers at a later stage or even fails to recover completely , 20. ThiThe observation that obesity was an independent determinant of persistently compromised RV function in our study is of interest but not totally unexpected. Previous studies have reported that obesity negatively affects the cardiovascular system  and is aStrengths of the present study include: (i) the participation of patients from 42 centres across 9 European countries, covering a broad spectrum of clinical settings in which the follow-up took place; (ii) the prospective follow-up of RV function at 6 days and 6 months after the diagnosis of acute PE; (iii) the prospective categorisation of echocardiographic parameters to permit standardised assessment of RV function and its changes over time, and (iv) the assessment of both echocardiographic and biochemical parameters for the evaluation of RV (dys)function and (presumably right) heart failure at baseline and during follow-up. However, our analysis also has some limitations. Firstly, not all parameters related to RV function were available for all patients at all visits. In addition, an association of the kinetics of echocardiographic RV parameters with the primary clinical endpoint of the study, recurrence of symptomatic or fatal VTE at 6 months, could not be established due to the small absolute number of recurrent events . FinallyIn conclusion, our results indicate that in the majority of patients with acute intermediate-risk PE who were switched early (on the third day) to a direct oral anticoagulant, echocardiographic parameters reflecting RV function normalised within 6 days and remain normal throughout the first 6 months. The levels of NT-proBNP also improved during 6-month follow-up. Almost one in four patients, however, still had at least one abnormal echocardiographic finding suggesting some degree of persisting RV dysfunction and possibly the need for continued follow-up over the long term.Supplementary file1 (DOCX 31 KB)Below is the link to the electronic supplementary material.


Congenital heart disease (CHD) is often associated with chronic right ventricular (RV) volume overload. Real-time magnetic resonance imaging (MRI) enables the analysis of cardiac function during free breathing.To evaluate the influence of respiration in pediatric patients with CHD and chronic RV volume overload.n=6) and controls (n=6) were recruited for cardiac real-time MRI at 1.5 tesla during free breathing. Breathing curves from regions of interest reflecting the position of the diaphragm served for binning images in four different tidal volume classes, each in inspiration and expiration. Tidal volumes were estimated from these curves by data previously obtained by magnetic resonance-compatible spirometry. Ventricular volumes indexed to body surface area and Frank-Starling relationships referenced to the typical tidal volume indexed to body height (TTVi) were compared.RV volume overload patients (P=0.01). The Frank-Starling relationship of the RV provided a significantly reduced slope estimate in RV load patients .Indexed RV end-diastolic volume (RV-EDVi) and indexed RV stroke volume (RV-SVi) increased during inspiration . The increase in RV ejection fraction during inspiration was significantly lower in RV load patients (RV load: + 1.1 ± 2.2%; controls: + 6.1 ± 1.5%; In pediatric patients with CHD and chronic RV volume overload, cardiac real-time MRI during free breathing in combination with respiratory-based binning indicates an impaired Frank-Starling relationship of the RV.Supplementary material is available at 10.1007/s00247-023-05765-9. Congenital heart disease (CHD) is frequently associated with chronic volume overload of the right ventricle (RV) causing right heart failure in the long term  –4. AlthoCompared to conventional cardiac magnetic resonance imaging (MRI), which requires breath-holding and only provides a low temporal resolution, real-time MRI enables the analysis of cardiac function under preserved physiological conditions during free breathing with high sampling rates –18. TherIn addition, the combination of cardiac real-time volumetry during free breathing with respiratory-based binning using magnetic resonance-compatible spirometry provides a unique opportunity to assess the dynamics of heart–lung interactions , even alBreath-holding is a nonphysiological and static condition precluding the analysis of the dynamics of respiratory modification of cardiac function. In contrast, real-time MRI during free breathing provides a physiological situation in which to study the dynamics of heart–lung interactions. Such dynamic measurements have already been shown to be superior to static parameters in other scenarios, e.g., in a mini-fluid challenge for assessing fluid responsiveness .Currently, therapy-related parameters and estimation of prognosis are based on the analysis of cardiac function and dimensions acquired with conventional cardiac MRI under nonphysiological conditions. For example, in pediatric patients with tetralogy of Fallot, preoperative thresholds of RV volumes for surgical pulmonary valve replacement rely on conventional cardiac MRI during breath-holding –9, 23–28To date, no study has examined cardiac function in pediatric patients with RV volume overload under physiological conditions using cardiac MRI. In particular, the Frank-Starling mechanism has not yet been studied in children with chronic RV volume overload.The aim of this study was to investigate the respiratory influence on cardiac function in pediatric patients with CHD and chronic RV volume overload. We hypothesized that the respiratory-induced alterations of preload and the adaptability of the heart to further volume load, i.e. chronic RV volume overload, modifies the Frank-Starling mechanism. We further hypothesized that alteration of the Frank-Starling mechanism in patients with RV volume overload can become an additional meaningful diagnostic parameter to assess ventricular function and to add to the information provided by static parameters.The study is a descriptive, retrospective real-time MRI study of pediatric patients at a tertiary children’s hospital . The parents and/or their legal guardians signed a written declaration of consent. The study was approved by the local ethics committee .2]=weight [kg]0.425 × height [cm]0.725 × 0.007184) was used to calculate the body surface area for indexed data.A total of six pediatric patients Table  with sigThe cardiac MRI measurements were performed on a clinical 1.5-tesla MRI scanner  with an installed 32-channel spine matrix coil (direct connect spine 32) and an 18-channel body coil  in supine position. The MRI protocol began with a standard clinical pediatric CHD protocol including conventional cardiac localizers and retrospectively gated four-chamber and two-chamber cine datasets acquired in end-expiratory breath-holding for planning the short axis stack, phase-contrast imaging of the pulmonary and aortic flow, and additional sequences if clinically indicated . A real-Real-time MRIs were binned based on respiration and ECG-derived RR intervals. Information on respiration was derived from signal intensity (SI) changes related to diaphragmatic movement in regions of interest (ROIs). ROIs were positioned using the free-hand contouring tool in the series viewer module of the commercial evaluation software cvi42 (Release 5.10.1.(1241); Circle Cardiovascular Imaging Inc. Calgary, Canada) . The moving median values and the value of the first derivative thereof were assigned to the individual MRIs. Information on the time after the R wave of the ECG was included in the dicom tags provided by the intrinsic magnetic resonance scanner software . SI curves were individually rescaled to eliminate respiratory outliers reflecting functional residual capacity or inspiratory reserve volume, resulting in at least five respiratory cycles for each slice within the typical tidal volume range , by adapting published open-source packages , and the increase in the end-diastolic volume .All statistical analyses were performed in SPSS . The statistics for calibration curves were calculated using linear or quadratic regression as appropriate.Linear regression was performed to evaluate the correlation between estimated tidal volumes and the corresponding RV and LV volumetry results and to investigate Frank-Starling relationships.t-test for independent samples.Finally, the residuals of all regression analyses were tested for normal distribution using the Kolmogorov–Smirnov and Shapiro–Wilk tests. Normally distributed data, the Frank-Starling slopes and respiratory-related ventricular volumes from RV overload patients and controls were compared using the P<0.05 was considered significant.A level of P<0.01) (Table P>0.05); the respiratory rate was higher (P = 0.04) in patients with chronic RV overload compared to controls . Respiratory binning resulted in a high percentage of filled bins . The results are largely based on end-diastolic and end-systolic phases. The number of unfilled bins in these phases was similar in end-diastole  and end-systole .Images were divided into 13,600 bins . The interval between the ECG phases was similar in both groups  in Table Visual inspection of the midventricular slice readily demonstrated the influence of respiration on ventricular dimensions. At end-diastole, the almost triangular shape of the RV became more convex and rounded with increasing tidal volume, especially during inspiration. The respiratory-related alterations of RV dimensions were more prominent in control no. 7 in Table RV-EDVi, RV-SVi, and RV ejection fraction (RV-EF) per TTVi increased with increasing tidal volume both in RV overload patients and in controls, especially during inspiration Fig. , Table 3In comparison to the controls, the RV overload patients showed a smaller increase in RV-SVi, which was accompanied by a mild increase in RV end-systolic volume (RV-ESVi) Fig. , Table 3Thus, the main difference between the two groups was a reduced increase in the ejection fraction during inspiration in the RV overload group.Linear regression revealed that the respiratory-related changes for RV-EDVi, RV-ESVi, RV-SVi, and RV-EF in RV overload patients and controls were statistically significant during inspiration and expiration Fig. .Fig. 3LeIn addition to the mean RV volumetry values from RV overload and control patients Fig. , Table 3The qualitative view of the LV at different time points during the respiratory cycle demonstrates the influence of respiration on LV dimensions. With increasing lung volume, the shape of the LV changes from round to convex at end-diastole in control patients. In chronic RV overload patients, the LV provides a convex shape at end-expiration that even becomes more convex with increasing tidal volume at end-diastole. For details, see Supplementary Material Respiratory-dependent LV volume changes were less pronounced and similar in RV overload patients and controls Fig. , Table 3During expiration, the respiratory influence on LV-EDVi, LV-SVi, and LV-EF was smaller than during inspiration.Linear regression revealed that the respiratory-related changes for LV-EDVi, LV-ESVi, LV-SVi, and LV-EF in RV overload patients and controls were statistically significant during inspiration and expiration Fig. .2) enabled the analysis of the Frank-Starling relationship. Linear regression revealed a highly significant relationship between SVi and EDVi for RV and the LV during inspiration and expiration    because automatic contouring of the RV requires manual confirmation.Future prospective studies should include a larger number and a more homogenous population of patients. For example, based on previous studies, left-to-right shunt lesions, pulmonary regurgitation after pulmonary stenosis, and repaired tetralogy of Fallot can be expected to behave differently , 53. In Real-time MRI during free breathing in combination with respiratory binning allows the assessment of respiratory-induced effects on ventricular volume and function. First experience in pediatric patients with chronic RV volume overload demonstrates an impairment of the Frank-Starling relationship of the RV that might provide a new parameter to optimize timing of interventions.Supplementary file1 (DOCX 340 KB)Supplementary file2 (MP4 2077 KB)Supplementary file3 (MP4 4596 KB)Supplementary file4 (MP4 4662 KB)Supplementary file5 (DOCX 52.0 KB)Below is the link to the electronic supplementary material.


The digital transformation of our health care system has experienced a clear shift in the last few years due to political, medical, and technical innovations and reorganization. In particular, the cardiovascular field has undergone a significant change, with new broad perspectives in terms of optimized treatment strategies for patients nowadays.After a short historical introduction, this comprehensive literature review aimed to provide a detailed overview of the scientific evidence regarding digitalization in the diagnostics and therapy of cardiovascular diseases (CVDs).We performed an extensive literature search of the PubMed database and included all related articles that were published as of March 2022. Of the 3021 studies identified, 1639 (54.25%) studies were selected for a structured analysis and presentation . In addition to studies on CVDs in general, 829 studies could be assigned to a specific CVD with a diagnostic and therapeutic approach. For data presentation, all 829 publications were grouped into 6 categories of CVDs.Evidence-based innovations in the cardiovascular field cover a wide medical spectrum, starting from the diagnosis of congenital heart diseases or arrhythmias and overoptimized workflows in the emergency care setting of acute myocardial infarction to telemedical care for patients having chronic diseases such as heart failure, coronary artery disease, or hypertension. The use of smartphones and wearables as well as the integration of artificial intelligence provides important tools for location-independent medical care and the prevention of adverse events.Digital transformation has opened up multiple new perspectives in the cardiovascular field, with rapidly expanding scientific evidence. Beyond important improvements in terms of patient care, these innovations are also capable of reducing costs for our health care system. In the next few years, digital transformation will continue to revolutionize the field of cardiovascular medicine and broaden our medical and scientific horizons. Digitization is the conversion of analog information into a digital signal consisting of discrete values. Beyond the obvious advantage of storing data for the future, it also provides the potential for further IT processing. In general, the use of digitization to facilitate and optimize processes is referred to as digitalization. With the introduction of the first universally programmable computer by Konrad Zuse in 1941, a path was initiated that led us to an age at the end of the 20th century since when digital technologies have become omnipresent )) AND ((cardiovascular[Title/Abstract]) OR (heart[Title/Abstract])).” The choice of the above-mentioned search terms was the result of a survey of experienced cardiologists involved in digital cardiology at the University Hospital of Ludwig Maximilian University of Munich, Germany. Our search did not restrict any article types; therefore, review articles and comments were found among the results in addition to original articles. Furthermore, there was no thematic restriction within the cardiovascular field, and all studies up to the cutoff date  were included.The review yielded 3021 studies, all of which were then screened and processed in a structured manner. Within this framework, 1018 (33.77%) of the 3021 studies were excluded because they were not directly related to digital technologies in medicine or because they could not be retrieved. In addition, 361 (11.95%) of the 3021 studies were excluded because they did not focus on CVDs, although they addressed digital technologies. Studies from interdisciplinary research areas such as diabetes mellitus as a major cardiovascular risk factor or dietary behavior as a preventive aspect were also excluded. The final analysis included 1639 studies of which 1273 (77.67%) were original articles and 366 (22.33%) were reviews or comments. In addition to studies on CVDs in general, 829 (50.58%) of the 1639 studies included in the final analysis could be assigned to a specific CVD with a diagnostic or therapeutic approach .Qualitative analysis and structuring of the available sources were performed using ATLAS.ti software . In the process, the so-called “codes” in the form of keywords were assigned to individual studies to reflect their content. The main keywords assigned here refer to the CVD pattern, type of digital application, and data processing methodology used in respective studies. In addition, the studies were separately labeled as dealing with new digital prototypes, thus indicating possible future applications.Results section, a brief introduction to the disease itself and use cases of digital medicine are presented and underlined by the scientific data. For this purpose, the results of the screened studies are summarized. In the Discussion section, possible future projects and perspectives are outlined.Building on the qualitative structuring described in the previous paragraph, content analysis was performed. All the 829 disease-specific publications were grouped by linking them to the following fields of cardiovascular medicine: (1) heart failure, (2) arterial hypertension, (3) coronary artery disease, (4) cardiac arrhythmias, (5) congenital heart diseases, and (6) valvular heart disease . In the For visualization, we chose the evaluation of word frequencies, following established concepts of qualitative reporting -13. As hA total of 829 studies in the field of digital medicine could be assigned to a specific CVD, with subsequent grouping into 6 major categories . All majIn the following sections, individual cardiovascular clinical features are briefly introduced. This is followed by a concise description of the current diagnostics and therapy. On the basis of available evidence, digital health concepts are presented and critically evaluated, and potential future perspectives are highlighted.Heart failure is defined as the inability of the heart to provide sufficient blood flow through the body, that is, cardiac output. This is usually due to reduced cardiac contractility, namely, systolic heart failure. The underlying pathomechanism is mostly lack of oxygen supply due to coronary artery disease . IschemiHeart failure is one of the most important diseases in terms of health economics, and it has affected the lives of about 70 million people worldwide for many years . It is nHeart failureHeartFailurePatientsChronicManagementCareTelemedicineStudyMonitoringHealthHypertensionPressureBloodHypertensionTelemedicineHealthManagementMonitoringPatientsStudyBasedCoronary artery diseaseDiseasePatientsHealthCoronaryHeartBasedCardiovascularTrialTelemedicineChronicArrhythmiasAtrialFibrillationCardiacSmartStudyHeartHealthMonitoringDetectionPatientsCongenital heart diseasesHeartCongenitalDiseaseTelemedicinePediatricFetalRemoteCardiologyDiagnosisHealthValvular heart diseasesHeartSoundTelemedicineAuscultationMonitoringStethoscopeDevelopmentStudyBasedCardiacLiving with a diagnosis of heart failure requires consistent use of prescribed medications over many years. Simultaneously, changes in vital signs, blood values, and cardiac function must be monitored regularly. As it is known that the maximum tolerated dose ensures the longest survival, a fine and regular adjustment of the current therapy is necessary. Furthermore, it is essential to check one’s body weight regularly, as this can indicate water retention in case of decompensated heart failure before more pronounced symptoms such as shortness of breath or a decrease in physical performance occur. Telemedicine offers excellent opportunities to provide urgently needed care, especially in medically underserved areas or, as recently, during the COVID-19 pandemic ,44.Telemonitoring to Improve Heart Failure Outcomes (Tele-HF), Telemedical Interventional Monitoring in Heart Failure (TIM-HF), or Baroreflex Activation Therapy for Heart Failure (BEAT-HF) could not confirm the reduction in hospitalization rates. The authors concluded that patient selection may have a crucial impact on success and that it needs to be critically evaluated in the future [A New Model of Medical Care With Use of Modern Methods of Non-invasive Clinical Assessment and Telemedicine in Patients With Heart Failure (AMULET), showed a reduction in hospitalization rates as well as all-cause mortality (TIM-HF2) and cardiovascular mortality (AMULET) [Studies that investigated telephone and telemedical care systems in an outpatient setting were able to demonstrate a significant reduction in hospitalization rates, whereas a trend toward reduced mortality did not reach statistical significance ,45,46. Le future ,16. Metae future -49. Rece(AMULET) ,18. This(AMULET)   failed to show a clear benefit [Evolution of Management Strategies of Heart Failure Patients With Implantable Defibrillators (EVOLVO) and Influence of Home Monitoring on Mortality and Morbidity in Heart Failure Patients With Impaired Left Ventricular Function (IN-TIME) studies [In patients with special pacemakers for cardiac resynchronization or those with implanted cardiac defibrillators, further data can be collected via remote monitoring systems without direct physician-patient contact. These include physical activity and heart rate profiles, detection of possible arrhythmias, and impedance-guided detection of water balance in the body . Studies benefit ,22,63, a studies ,24. Rega studies ,64 (MultCardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in New York Heart Association Class III Heart Failure Patients (CHAMPION) trial for the CardioMEMS system demonstrated that the pulmonary arterial pressure could be lowered, and cardiac symptoms and hospitalization rates were reduced by using this monitoring device [In addition to these implanted devices with primarily therapeutic intention, there are also purely diagnostic monitoring tools such as loop recorders for the detection of arrhythmias or devices for the real-time measurement of pulmonary arterial pressure as a surrogate for hemodynamics in patients with heart failure . For exag device . A techng device . Possiblg device .Patients with heart failure clearly benefit from adapted fitness programs such as those offered in rehabilitation clinics or special cardiac training groups, despite their limited exercise capacity. Given the increased baseline risk, monitoring vital signs, with subsequent transmission to the attending physician or an intelligent system, offers tremendous opportunities for improved exercise planning. Other tools provide specific exercise recommendations and guidance for patients with heart failure via web platforms or smartphones. These telemedicine fitness offerings, especially those for rehabilitation, have a positive impact on patient compliance and quality of life and are noninferior to on-site programs in their effectiveness -70.Overall, digital technologies have become a major tool in guiding patients with heart failure and offer enormous potential for optimized therapy adjustments while substantially reducing planned and unplanned medical consultations in inpatient and outpatient settings. Although the use of digital technologies is associated with additional costs, numerous studies have shown that these systems perform positively in the overall cost balance and reduce financial burdens for health care systems by 10% to 35% while increasing patient comfort ,72.Arterial hypertension is defined as blood pressure >140 mm Hg systolic or >90 mm Hg diastolic blood pressure as measured in the physician’s office. The estimated prevalence according to the World Health Organization is approximately 1.3 billion people worldwide, whereas more than half of them have not been diagnosed yet .Depending on the severity of hypertension and individual cardiovascular risk factors, the initial treatment strategies for mild forms of hypertension can mainly focus on lifestyle changes. These include reduced stress, regular physical activity, and a healthy diet. If these measures fail, drug therapy is initiated according to the current guideline recommendations. For rare cases in which a secondary form of hypertension is present, the first-line treatment involves managing the underlying causes .Digital medicine finds its application in both diagnostics and therapy of hypertension in 123 studies (including 26 reviews or comments). Keywords in the titles of these studies predominantly describe the remote monitoring of blood pressure by telemedicine systems using wearables .Autonomously performed outpatient blood pressure measurements, which are forwarded to a physician using a digital system, can be important for identifying and treating patients with hypertension. Various factors play a decisive role here: blood pressure measurements should be as uncomplicated and accurate as possible. To this end, various systems that allow measurements via smartphone-connected devices have been validated . AlthougBlood pressure monitoring also plays a crucial role in hospitals. In specialized centers or intensive care settings, blood pressure is automatically recorded at specific intervals and sent to a central monitoring unit. As an alternative to conventional monitoring systems, institutions first started to use cost-effective wearables to monitor selected patients .In addition to the diagnosis of hypertension, therapy planning and management are also of major importance. Especially in primary care, blood pressure therapy is a significant topic, and it is not always easy to identify the best therapy according to current recommendations for the individual patient. The first pioneering study used intelligent decision support systems to optimize guideline-based therapy, which was regarded as helpful by most treating physicians . ContinuSeveral randomized controlled trials have shown inconsistent data on the success of telemedicine interventions for the treatment of arterial hypertension. The type of intervention ranges from simple text messages for educational purposes, over internet platforms and smartphone apps, to detailed telemedical consultations in video conferences with physicians -90. DepeThe high prevalence of hypertension and associated outpatient consultations or hospital admissions suggests that telemedicine systems can save costs. Although there is a tendency for an overall reduction in costs, a conclusion is still missing and needs to be addressed in future studies .Coronary artery disease involves the pathology of the heart vessels (coronaries) that ultimately impairs circulation and thus leads to a potential reduction in the supply of oxygen to the heart muscle as is typically found in myocardial infarction. The causes of the development of coronary heart disease are high blood pressure, elevated blood lipid levels (cholesterol), smoking, diabetes mellitus, and a family history of associated diseases. In industrialized nations, coronary heart disease is the leading cause of death  and ranks among the top 3 worldwide . CurrentThe mainstay of treatment for coronary heart disease is to reduce the risk of CVDs. If these methods fail and the coronary vessel is narrowed to an extent that significantly limits blood flow, it is reopened by percutaneous coronary intervention. For selected patients with the most severe forms of coronary artery disease, bypass surgery must also be considered to ensure coronary perfusion .For these reasons, coronary artery disease has been a major focus in the field of digital medicine, with 110 publications (including 42 reviews or comments) investigating this domain. Thematic focuses that are based on the keywords of the study titles concern both acute and chronic telemedical care of coronary artery disease for primary and secondary prevention .Diagnostic apps offer a broad screening potential and the chance to identify high-risk patients . CardiovEven more important, however, is the role of digital diagnostics through wearable devices and telemedicine in secondary prevention. Patients can use smart technologies to monitor their health status based on vital signs, obtain information about their illness, manage and adjust their digital medication plans, and maintain regular web-based communication with their responsible physicians ,100. At Time is often critical when acute cardiac symptoms occur. Typical ECG changes  that occur in life-threatening myocardial infarction can be detected very quickly. Artificial intelligence algorithms are applied to accelerate and simplify this crucial diagnostic procedure, which can even be performed when no physician is present -110. In Under physiological conditions, cardiac action is triggered by the sinus node. From there, the cardiac action spreads through the atrial tissue to the atrioventricular node, from where it is transmitted to the ventricle. When this system is disturbed or in cases of automaticity, fibrosis, or scarring, cardiac arrhythmias occur, originating in either the atrium or the ventricle.To detect cardiac arrhythmias, an ECG must be recorded whenever possible. If an episode of arrhythmia was not documented, a long-term ECG over 24 to 48 hours can be performed or the patient can be connected to permanent monitoring devices in the inpatient setting. If a cardiac arrhythmia can be confirmed, the therapy depends entirely on the type of arrhythmia. In the context of this review, we have limited ourselves to atrial fibrillation because other forms are rarely covered by studies in the field of digital cardiology.Atrial fibrillation requires anticoagulation therapy to prevent the development of stroke. In addition, a strategy of rate control can be pursued, in which one accepts atrial fibrillation and uses only β-blocker therapy to counteract periods of rapid cardiac action. An alternative therapy goal is the conversion to normal sinus rhythm, the so-called rhythm control strategy. This can be performed by either electrical cardioversion or cardiac ablation (pulmonary vein isolation) .Digital medicine offers far-reaching possibilities for the diagnosis of cardiac arrhythmia. The steady availability of spontaneous ECG recordings through smartwatches and other wearables has significantly facilitated the detection of rare rhythm events or assignment of symptoms to ECG images. A total of 83 publications, including 13 reviews or comments, addressed the applications of digital medicine in cardiac arrhythmias. Keywords from these papers map the monitoring and detection of arrhythmias, especially atrial fibrillation, by wearables as priority topics .The focus of digital applications in relation to cardiac arrhythmias is diagnostics. The current standard for the detection of arrhythmias is long-term ECG recordings or, in selected cases, the implantation of a loop recorder. Typical indications are unexplained syncope, the identification of atrial fibrillation in patients after (cryptogenic) stroke, or arrhythmias of any kind in the phase after an acute myocardial infarction . HoweverPatients with implanted pacemakers or defibrillators require regular follow-up. To reduce costs and increase patient comfort, this can be performed at least partially via remote monitoring . FurtherIn the therapeutic field, the applications of digital medicine for cardiac arrhythmias are still limited. First, there is certainly frequency monitoring in patients with atrial fibrillation . ParticuIn the future, the detection of cardiac arrhythmias using smartwatches and other wearables will become more important. However, when detecting atrial fibrillation via optical sensors (photoplethysmography), as they are used in the Apple Watch, for example, we should always keep in mind that false alarms may occur and demand diagnostic confirmation via ECG recordings . NeverthAlmost 1% of newborns in industrialized countries have congenital heart defects. A basic distinction is made between cyanotic (blue skin in the presence of hypoxia) and acyanotic heart defects. The most common pathologies include defects in the ventricular or atrial septum (acyanotic), tetralogy of Fallot (cyanotic), and patent ductus arteriosus (acyanotic).The most relevant cardiac defects are diagnosed during the prenatal examinations. However, it also happens that individual defects are detected only during birth. The essential examination procedures for the diagnosis of cardiac defects include auscultation of heart murmurs and echocardiography to confirm the diagnosis. Depending on the anatomical characteristics and severity of the defect, most corrections are performed via cardiac surgery or interventional procedures by the treating pediatric cardiologists. The only exception is patent ductus arteriosus, which can usually be closed using targeted drug therapy.Diagnosis of congenital heart defects was the pioneering area of digital medicine in the field of cardiology . InitialTimely diagnosis of congenital heart defects is crucial for the treatment of affected individuals. Therefore, high medical standards and a wealth of experience are of particular importance. Especially in smaller hospitals, in rural areas, or during the COVID-19 pandemic, bottlenecks in care can be compensated for by specialized physicians via telemedicine consultations or using artificial intelligence approaches ,134. AltPatients with congenital heart defects often require special care throughout their life. This is especially true in stressful situations such as surgery and physical activities. Telemedicine has enabled a unique network in outpatient care; affected persons can be closely monitored via wearables in their home environment and always have the option of obtaining further information or consulting a physician directly . InitialHeart valve diseases are defects in the closing or opening functions of at least one of the 4 heart valves. Indicators of potential heart valve defects can be obtained from auscultation using a stethoscope. The definite diagnosis is confirmed by ultrasound examination of the heart, which also allows for severity quantification. Valvular heart diseases are usually treated conservatively until they reach a relevant degree of severity. Therefore, patients with valvular defects need to be evaluated regularly with respect to exercise capacity, vital signs, laboratory parameters, and echocardiography findings to detect possible deterioration over time. Once the relevant severity of the defect is reached, younger patients are usually treated surgically, and older patients are usually treated by an interventional approach in the cardiac catheterization laboratory .Acquired valvular heart diseases play important roles in everyday medical practice. A total of 32 publications, including 4 reviews, investigated digital technologies in this field. Similar to keywords related to congenital heart defects, the keywords focus on telemedical remote diagnostics using echocardiography .Beyond technical innovations in the field of image acquisition and processing, telemedicine remote diagnosis of echocardiography and artificial intelligence algorithms for automated analyses have yielded promising results -148. In The therapeutic applications of digital medicine in valvular heart diseases are limited. Nevertheless, the application of intelligent decision support systems seems to gain increasing clinical importance. In addition to technical data and guideline recommendations, past experience and patient preferences can be incorporated .Digital medicine in diagnostics and therapy for CVDs has experienced considerable upswing, particularly in the last 10 to 15 years. Political measures, such as adapted legislation, and special funding programs have laid a significant foundation for medical digitalization. In addition, there is a growing affinity among the population for innovative technical solutions and a more differentiated view of data protection concerns.Beyond the structural conditions described in the previous paragraph, external circumstances have provided an additional boost to digital medicine. These factors include the shortage of physicians in rural areas and the COVID-19 pandemic during the last 3 years. Finally, the increased use of digital medicine is attributed to the advancing technology with the widespread use of smartphones and other wearables as well as the exchange of information via the internet and video conferences as part of our everyday lives . In the This review provides an overview of all the present digital technologies in the cardiovascular field. This illustrates an enormous increase in knowledge and investigations in recent years with respect to optimized diagnostic and therapeutic strategies . We shouAcute disease patterns such as myocardial infarction or sudden-onset arrhythmias can be documented via wearables and made accessible to remote telemedical diagnostics. With these modern methods, we have the unique opportunity to record short-term health conditions on demand or, as in the case of myocardial infarction, to save important time in the emergency cascade and thus reduce mortality.The second major domain of digital technology in CVDs is related to diagnostics. Currently, it is possible to consult highly specialized medical experts for all types of questions regardless of the location. This was also the origin of digital technology in the cardiovascular field in the 1990s, when congenital heart defects were diagnosed via telemedicine expert consultations including guided echocardiography . These rIn terms of cardiovascular therapy, digital technologies are expected to provide significant changes. Chronic diseases such as heart failure and arterial hypertension and secondary prophylaxis in coronary heart disease have huge health economic importance. Due to their high mortality, regular medical contact is essential for checking vital signs, adjusting medications, and detecting possible deterioration. Telemedicine offers a unique opportunity to replace these visits, at least in part, with digital consultations. Although immediate personal contact is certainly important and lost to some extent by telemedicine, more attention can be paid to the individual patient, travel time is reduced, and more patients can be treated by an individual physician. Detailed data records from wearables can be evaluated in a partially automated manner, highly up-to-date information about one’s own illness can be made available, medication plans can be managed and adjusted digitally, and methods of artificial intelligence can be used to optimize treatment strategies. The transitional phases from inpatient to outpatient care or to rehabilitation therapy can also be decisively supported by digital systems. Patients report not only an improved quality of life but also better performance, although it is possible to register any early recurrences of diseases or other adverse events in a timely manner.Nevertheless, the possible risk of a decline in routine personal visits or the complete avoidance of physician contact may also have negative effects and potentially harm the patient. In an individual case, a human second assessment of the digital diagnostics remains essential and beneficial, especially for evaluating potential erroneous conclusions of digital algorithms.Finally, both the patient and the treating physician must be aware that a considerable amount of sensitive patient data are made available to companies involved in digital medicine. As long as the product is not medically or scientifically approved, protected and sensitive handling of patient data is not guaranteed, as opposed to insurance companies or medical institutions.In terms of evidence-based facts, heart failure is the best-investigated field in digital cardiovascular research. Proper patient selection provided by telemedicine monitoring systems has been shown to cause a slight but significant reduction in hospitalization and mortality ,18. MoreDigitalization in cardiovascular medicine will certainly continue to gain importance in the near future, and it will be crucial to make the best possible use of these technologies. Today, the field of digital cardiovascular medicine has a strong focus on telemedicine technologies, as a lack of interoperability and standardization still limits applications such as automation and intelligent decision support systems, as well as modern medical IT-based research tools. Continual efforts will not only improve patient care but also have significant health economic saving potential for various CVD patterns. It is therefore important not to cling obsessively to old systems but to embrace innovations and actively help to shape them.