In the case of breast cancer (BC), radiotherapy (RT) helps reduce locoregional recurrence and BC-related deaths but can lead to cardiotoxicity, resulting in an increased risk of long-term major cardiovascular events. It is therefore of primary importance to early detect subclinical left ventricular (LV) dysfunction in BC patients after RT and to determine the dose–response relationships between cardiac doses and these events.Within the frame of the MEDIRAD European project (2017–2022), the prospective multicenter EARLY‐HEART study  included chemotherapy naïve BC women aged 40–75 years and treated with lumpectomy and adjuvant RT. Myocardial strain analysis was provided using speckle‐tracking echocardiography performed at baseline and 6 months following RT. A global longitudinal strain (GLS) reduction >15% between baseline and follow-up was defined as a GLS-based subclinical LV dysfunction. Individual patient dose distributions were obtained using multi-atlas-based auto-segmentation of the heart. Dose-volume parameters were studied for the whole heart (WH) and left ventricle (LV).p = 0.01). A significantly increased risk of subclinical LV dysfunction was observed with the increase in the dose received to the WH  and to the LV . Based on ROC analysis, the LV-V5 parameter may be the best predictor of the short-term onset of subclinical LV dysfunction.The sample included 186 BC women . GLS-based subclinical LV dysfunction was observed in 22 patients (14.4%). These patients had significantly higher cardiac exposure regarding WH and LV doses compared to patients without LV dysfunction (for mean WH dose: 2.66 ± 1.75 Gy versus 1.64 ± 0.96 Gy, These results highlighted that all cardiac doses were strongly associated with the occurrence of subclinical LV dysfunction arising 6 months after BC RT. Whether measurements of GLS at baseline and 6 months after RT combined with cardiac doses can early predict efficiently subclinical events occurring 24 months after RT remains to be investigated. Breast cancer (BC) among women represents a public health challenge due to its rising incidence and its life-threatening consequences . PrescriTherefore, early screening for subclinical CV changes following RT could prove beneficial for asymptomatic patients who could nevertheless have subclinical left ventricle (LV) dysfunction. According to the American Society of Echocardiography and the European Association of Cardiovascular Imaging, oncological cardiotoxicity is diagnosed when the left ventricular ejection fraction (LVEF) is reduced by ≥10% points to below 53% after RT . TherefoThe ability of GLS to detect cardiotoxicity early has been little investigated among BC patients treated with RT. Some studies have shown that a statistically significant reduction of the GLS can be detected in BC women from a few weeks to 12 months following RT –17. HoweTherefore, within the frame of the European MEDIRAD project, the multi-center EARLY-HEART cohort study was designed to investigate early cardiac changes arising after BC RT in the largest population ever studied, using three approaches based on echocardiography, cardiac MRI and heart CT, and computed tomography coronary angiography . The preThe guidelines proposed by the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement were applied to the manuscript .http://www.medirad-project.eu/), the multi-center EARLY-HEART study was launched in 2017. This observational study consisted of the prospective follow-up of a cohort of BC patients treated with RT over two time points post-RT . The detailed protocol has already been described elsewhere and registered at ClinicalTrials.gov (identifier NCT03297346)  and blood-circulating biomarkers were assessed at baseline and at 6 months following RT. The current article focuses on the assessment of subclinical dysfunction post‐RT using 2D speckle-tracking echocardiography at the 6-month follow-up.Patients were included from 5 European investigation centers: the Clinique Pasteur  for the Institut de Radioprotection et de Sûreté Nucléaire , the Universitair Medisch Centrum Groningen UMCG; Groningen, Netherlands), the Klinikum Rechts der Isar der Technischen Universität München , the Institut Català d’Oncologia , and the Centro Cardiovascular da Universidade de Lisboa .in situ (DCIS) and treated with adjuvant RT after breast-conserving surgery in one of the 5 investigating centers could be included. In addition, women had to be chemotherapy naïve. Non-inclusion criteria were previous thoracic or mediastinal radiation, previous CV diseases, and current pregnancy and/or lactation. Abnormal cardiac imaging exams after inclusion were considered as dismissal criteria. Specifically for echocardiography, an LVEF <50%, suggesting an alteration of the cardiac function before RT, was set as a dismissal criterion.All women aged 40–75 years with histologically diagnosed unilateral left- or right-sided stage I–III invasive adenocarcinoma of the breast or ductal carcinoma All patients underwent adjuvant radiotherapy following the lumpectomy. According to the center, three-dimensional conformal radiotherapy (3D-CRT), volumetric modulated arc therapy (VMAT), and/or fixed-field intensity-modulated radiotherapy (IMRT) was performed.Different fractionation schedules were used according to patient and center specificities: mainly 25 fractions/50 Gy following a standard protocol or 15 fractions/40.5 Gy following a hypofractionated protocol. A boost dose was delivered to the tumor site in some patients (with a maximum of 14.49 Gy administered). Deep inspiring breath-holding was recommended in some patients with a heart close to the anterior chest wall and in all left-sided patients followed at the UMCG center. The patient treatment was normalized and optimized according to the statement of the International Commission on Radiation Units and Measurements (ICRU) and in compliance with QUANTEC dose constraints , minimum dose , and maximum dose  were studied as well as relative volumes of the WH and LV receiving at least 5 Gy  and 20 Gy , both suggested as good prognostic parameters of cardiac complications  have been recorded. A >15% relative percentage reduction from the initial GLS value was considered a clinically relevant marker of subclinical LV dysfunction as suggested in 2016 by the European Society of Cardiology  or a nonparametric Wilcoxon–Mann–Whitney test in case of skewed distribution. Qualitative variables were reported in absolute (n) and relative (%) frequencies and were compared using χ² or Fisher’s exact tests. Paired Wilcoxon signed-rank tests were applied to assess changes in echocardiography parameters before RT and 6 months post-RT. The impact of baseline characteristics  on the risk of subclinical LV dysfunction was explored using a binary logistic regression yielding odds ratio (OR) and the 95% confidence interval (95% CI). The relationship between dose-volume parameters and subclinical LV dysfunction was also investigated using univariate (crude model) and multivariate (adjusted model) binary logistic regressions. An adjustment was made for age, smoking status, hypertension, total cholesterol level, and hormonal therapy. Obesity and diabetes were not included in the model to avoid the strong correlation with total cholesterol levels. To determine which dose-volume parameter best discriminates between BC patients at risk of subclinical LV dysfunction and those not at risk, areas under the curve were obtained using receiver operating characteristic analysis (AUROC). An AUROC between 0.5 (no discriminative power) and 1 (perfect discriminative power) is essential for clinical testing (All quantitative variables were expressed as mean (µ) ± standard deviation (SD). Group comparisons were carried out using a  testing . The AUR testing . OptimalThe 5 European centers included a total of 258 BC patients. For the present study based on echocardiography parameters, 186 BC patients were analyzed, 72 being excluded due to the absence of paired echocardiography data available . A detailed flowchart is available in The 186 BC women had a mean age of 57.5 ± 7.9 years. Baseline characteristics of the 186 BC patients are described in mean to WH and Dmean to LV dose were 1.76 ± 1.16 Gy and 2.09 ± 1.91 Gy, respectively, with higher dose-volume parameters for left-sided BC than for right-sided BC .The cardiac dose-volume parameters are reported in p-values >0.05). LVEF-based LV dysfunction defined by a ≥10% reduction in LVEF from baseline to <53% after RT was found in 6 patients (3.2% of the sample).Conventional echocardiography parameters at baseline and 6 months post-RT are shown in p-values >0.05) . Among the 6 patients with LVEF-based LV dysfunction, 5 patients (83.3%) had a reduction of GLS >15%.Regarding the strain imaging, by considering GLS and GLS rate as continuous variables, no significant changes were observed between baseline and 6 months post-RT  Table 4.p-values >0.05) with GLS reduction. Parameters of the RT protocol also affected the onset of a subclinical LV dysfunction: the RT protocol  increased the risk by 4.32-fold (95% CI of the OR: 1.33–16.8), irradiation of lymph nodes by 5.55-fold (95% CI of the OR: 1.27–23.0), and a boost by 2.83-fold (95% CI of the OR: 1.09–8.32) .The impact of baseline characteristics on the risk of a reduction of GLS >15% at the 6-month follow-up was analyzed Table 5.Comparisons between dose-volume parameters obtained for the WH and the LV were performed between patients with or without relative reduction of GLS >15%. A significantly higher mean dose was observed in patients with a relative reduction of GLS >15% Figure 25 (%) and V20 (%) (The same observation was made regarding V V20 (%) Figure 2mean, V5, and V20) were significantly associated with a reduction of GLS >15% , except for Dmin and Dmax (after adjustment). For both cardiac structures, the associations remained significant after adjustment for covariates and multiple statistical testing . In the adjusted model, each increase of 1 Gy of Dmean to WH increased the risk of a reduction of GLS >15% by 74% and each increase of 1 Gy of Dmean to LV increased the risk by 46%. Moreover, each additional percent of V5 and V20 increased the risk of subclinical LV dysfunction by 13% and 39% (WH) and by 10% and 20% (LV), respectively. Sensitivity analysis had been undertaken using a reduction of GLS >10% to define a subclinical LV dysfunction . Also, AUROC values of V20  showed a very satisfactory discriminative power. However, the AUROC values of all the dose-volume parameters did not differ between them . Therefore, no dose-volume parameter statistically performed better than another. In addition to the dose–response relationship showing the relevance of heart dose for GLS reduction with a risk gradually increasing with higher doses, we evaluated the optimal cutoff of dose parameters to predict the risk of subclinical LV dysfunction-based ROC analysis. Dmean >2.74 Gy to the WH was the mean dose from which the classification of our patients between the two groups  was the most accurate. Regarding LV, a Dmean >3.1 Gy was established. For V5, the threshold was set at >5.2% (WH) and >8.4% (LV).Designed to early identify cardiotoxicity in BC women treated with RT, the EARLY-HEART study suggested a strong relationship between cardiac absorbed dose and the occurrence of subclinical LV dysfunction at 6 months following RT based on >15% reduction in GLS estimated by echocardiography.The mean value of GLS in the whole population did not significantly decrease from baseline to 6 months post-RT. Other authors previously showed significant GLS changes after BC RT, with a mean reduction of the GLS following RT of 5% in Erven et al., 6% in Walker et al., and 7.9% in Trivedi et al. (follow-up from 3 to 12 months) , 16, 17.GLS damage was further studied as a relative change in each individual and from a clinical perspective . A binar5) to 1.74 [1.20–2.61] (Dmean) for the WH structure and from 1.10 [1.05–1.17] (V5) to 1.46 [1.17–1.87] (Dmean) for the LV structure). The magnitude of the association was consistent with previous studies (or even stronger): OR = 1.37 [1.01–1.86] in Walker et al. and OR = 1.04 [1.01–1.06] in Fourati et al.   and the highest AUROC was 0.815 for V5 (LV). Then, V5, a dose-volume parameter, seemed highly relevant, as previously shown by other studies (5 (LV) was the best predictor of acute coronary events . However, the mean heart dose remains currently the most widely used predictor of cardiotoxicity  or a V5 >5.2% (WH) should not be exceeded to prevent the CV risk. The threshold of 3 Gy for Dmean, previously identified by Erven et al. (mean of 3 Gy to LV). Vigilance must be brought to this specific point, especially in randomized controlled trials where a systemic assessment of radiation‐induced cardiotoxicity should be investigated as a clinical endpoint.The EARLY-HEART study robustly showed a relationship between dose-volume parameters and an increased risk of subclinical LV dysfunction (adjusted ORs ranging from 1.13 [1.05–1.23] (VLS >10%) , 31. Fur studies . Indeed,0 1.05–1. (V5) to 0 1.05–1. (V5) to 4 1.20–2.1 (Dmean)Our study was the first to demonstrate, with sufficient statistical power, a dose-dependent relationship between early cardiotoxicity defined using the stringent and recommended criterion of a reduction of GLS >15% and a wide range of doses absorbed (inclusion of both right- and left-sided BC patients). Its prospective design allowed us to include only BC women without baseline overt CV diseases and chemotherapy and to control CV risk factors, making the results on the observation of an early subclinical LV dysfunction induced by RT more robust.However, our study had some limitations. The interpretation of the present results must be made with knowledge of these. First, our sample of BC women was limited by strict inclusion criteria. Further studies should include a larger representation of BC patients treated with RT only . Likewise, the lower proportion of left-sided BC patients in our EARLY-HEART population compared to other studies could impact the observed change in mean GLS, which was not significant. Moreover, inter-observer  and inter-operator  imprecisions cannot be excluded to explain the absence of a statistically significant decrease in mean GLS in our study even if the good reproducibility of the strain measure using echocardiography was established . Indeed,In the future, it remains to be investigated whether the occurrence of subclinical LV dysfunction observed at RT+6 months is declining, maintaining, or improving in the longer term. The specific interest in echocardiography data imaging from the EARLY‐HEART study will be further studied to determine which specific segments of the longitudinal strain  could be the most affected by dose-volume parameters. Indeed, Tuohinen et al. recently showed that the dose absorbed at the level of the apical region of the anterior wall of the LV was linked to a significantly higher deterioration of the GLS than in other locations . FurtherThe present analysis of BC women from the EARLY-HEART study showed that the cardiac doses absorbed during RT were strongly associated with the occurrence of a subclinical LV dysfunction at 6 months after RT. Therefore, primary and secondary CV health prevention could be beneficial at this early asymptomatic phase to reduce long-term CV complications. These findings already suggest the potential relevance of an early screening of BC patients treated with RT to eventually early implement cardioprotective actions during RT by limiting the dose absorbed by the heart as much as possible.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The study protocol and related amendments received approval from the competent ethics authority of each center involved . The patients/participants provided their written informed consent to participate in this study.Conceptualization: SJ, AC, HL, AE, SS, KB, GF, and EC. Methodology: SJ, HL, GF, and EC. Software: ML. Validation: ML and SJ. Formal analysis, ML and SJ. Investigation: SJ, AC, ML, DS, FG, MF, SS, SC, KB, EM, and UG. Resources: GF and EC. Data curation: ML, EM, UG, SJ, and DS. Writing—original draft preparation: ML and SJ. Editing: all authors. Supervision: EC, GF, and HL. All authors contributed to the article and approved the submitted version.The European Community’s Horizon 2020 Programme supported the EARLY-HEART study conducted in the frame of the MEDIRAD - Implications of Medical Low Dose Radiation Exposure - project spanning from 2017 to 2021 granted by the Euratom Research and Training Programme 2014-2014 under agreement No. 755523.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


This study investigated a patient-specific approach of using cardiac magnetic resonance (CMR) feature tracking for scar detection in a heterogenous patient group with chronic ischemic and non-ischemic heart disease.median), segmental values from GCSmedian percentage plots were correlated with corresponding myocardial segments in late gadolinium enhancement (LGE).CMR exams of 89 patients with concomitant chronic ischemic and non-ischemic heart disease (IHD+) as well as 65 patients with ischemic scars only (IHD) were retrospectively evaluated. In all patients, global (GCS) and segmental circumferential strain (SCS) was derived from native cine images using a dedicated software . After calculation of patient-specific median GCS .Overall GCS ranged between −3.5% to −19.8% and average GCS was lower in IHD+ than in IHD (p <0.05). In IHD, 19% of all myocardial segments were infarcted, in IHD+ 16.6%. Additionally, non-ischemic LGE was present in 6.7% of segments in IHD+. Correlation of GCSmedian percentage plots calculated from native cine images, ischemic scar tissue can be suspected in myocardial segments below the threshold of 40% GCSmedian , even in a heterogenous patient cohort with ischemic and non-ischemic heart disease.In patient-specific GCS Clinica2.2.1This retrospective study had institutional review board and local ethics committee approval and all included patients provided written informed consent. This study analysed patients undergoing CMR exams between September 2017 and January 2020 in our department. From 181 patients with both chronic ischemic and non-ischemic heart disease, 89 patients could be enrolled (“ischemic heart disease+” [IHD+]); 2.22; repetition time/echo time: 3.0/1.5 ms; spatial resolution 1.2 × 1.2 x 8 mm3; number of cardiac phases: 50) were acquired for functional LV assessment. After acquisition of cine images, Gadolinium  was applied for LGE sequences  in short axis orientation and in 2-,3- and 4 chamber view.All CMR exams were conducted on a clinical 1.5T MR . Cine balanced steady-state free precession (bSSFP) images in long-axis geometries  as well as in short axis orientation covering the left ventricle (LV) (field of view: 350 × 350 mm2.32.3.1median) was calculated from the segmental circumferential strain values. Subsequently, percentages of GCSmedian were visualized in an individualized polar plot map  and segmental (SCS) circumferential strain was derived from native cine short axis stacks (anonymized data) using a specific software . LGE was classified as “ischemic LGE”  or “non-ischemic LGE” . In ischemic LGE, segments with infarct transmurality above 50% wall thickness were considered “non-viable” . Every C2.4t-tests or Wilcoxon signed rank tests. To measure interobserver agreement, the intraclass correlation coefficient (ICC) was used; ICC = 0.50- 0.75 was considered moderate, ICC = 0.75- 0.9 was considered good and ICC > 0.9 was considered excellent agreement [median to differentiate infarcted from remote myocardium; optimal cut-off was defined by the Youden’s index. A two-sided p-value < 0.05 indicated statistical significance.Statistical analyses were conducted using commercially available software . Categorical variables were expressed as frequencies or percentages, continuous variables were expressed as means ± standard deviations. Global and segmental circumferential strain values were compared using two-tailed paired greement . Receive3.3.13.1.1In IHD, 210 out of 1105 segments (19%) had ischemic LGE; 194 of 210 infarcted segments (92.4%) were non-viable.3.1.2In IHD+, 251 out of 1513 (16.6%) segments had ischemic LGE with mostly non-viable infarcts . Furthermore, 101 segments (6.7%) showed non-ischemic LGE. In patients with hypertensive heart disease, 3 segments showed midmyocardial LGE antero-/inferoseptal basal and 4 segments showed epicardial LGE at the basal RV junction. In patients with dilatative cardiomyopathy, 15 segments show midmyocardial septal LGE. Midmyocardial fibrosis was also found in 9 patients with hypertrophic cardiomyopathy and 70 segments showed circular/diffuse LGE in amyloidosis patients .3.2Among all patients (IHD and IHD+), individual GCS ranged widely between −3.5% to −19.8%. IHD+ patients had significantly lower average GCS than IHD patients . The lowest GCS was measured in patients with cardiac amyloidosis . Average GCS was higher in women than in men .3.33.3.1In IHD, average SCS was −17.4% (range −11.5 % to −22.8%) in segments without ischemic LGE and −5.9% (range 2.3 % to −7.3 %) for segments with ischemic LGE; inter-reader agreement was very good . In IHD+, average SCS in segments without LGE was −16.6% (range −6.5 % to −19.1%). In myocardial segments with ischemic LGE SCS was −5.4% (range 0.4 % to −9.1 %) and in segments with non-ischemic LGE −11.8% (range −2.4% to −21.3%). Inter-reader agreement was very good .3.3.2median calculated for every patient (IHD and IHD+) revealed a cut-off value of 39.5% below the presence of ischemic LGE in a segment had a sensitivity of 87.5% and specificity of 86.3% , 8 infarcted segments showed values above the proposed threshold of 40% GCSmedian  indicated ischemic scar tissue in a myocardial segment with a sensitivity of 88% and a specificity of 86%. Derived from routinely acquired native cine images, CMR feature tracking displays global and segmental myocardial deformation [median) - which is more robust to outliers than mean GCS - and segmental circumferential strain values, GCSmedian percentage polar plots could be easily generated. Segment-wise correlation of the resulting polar plot values with LGE images revealed that a threshold below 40% GCSmedian can identify the presence of ischemic scar with 88% sensitivity and 82% specificity in a heterogenous patient group with various cardiac conditions. Few infarcted segments showed values above the proposed threshold, most of them in patients with severely reduced GCS (below −7% GCS), e.g. in amyloidosis patients. In fact, identifying ischemic scars in amyloidosis with LGE imaging can be problematic as well due to often extensive diffuse LGE that might cover additional ischemic scars. Also, some viable infarcts caused false negative results with values above the proposed threshold. Viable scars might be difficult to diagnose even in LGE due to similar signal intensities between scar and adjacent myocardium and only subtle wall motion disturbance [median threshold is also applicable for data calculated with other commercially available CMR feature tracking software. Cine images are often performed before contrast application; therefore, the proposed feature tracking method could be easily applied in a prospective clinical setting in patients with known or suspected ischemic heart disease. This method might reduce gadolinium application in future CMR exams and could improve diagnostic power of native CMR exams in patients who decline contrast or have contraindications for gadolinium.This study investigated a patient-specific approach of using CMR feature tracking for native scar detection in a heterogenous population with patients with chronic ischemic as well as non-ischemic heart disease. A threshold below 40% patient-specific median global circumferential strain  indicates chronic scars in myocardial segments with a sensitivity of 88% and a specificity of 86%. Since alternatives for detecting scar tissue from native CMR exams are limited, this patient-specific cine-based method could help to improve diagnostic power of native CMR exams in patients with contraindication to Gadolinium. However, in patients with severely reduced GCS, this method might be not sensitive enough to detect ischemic scars and additional use of tissue characterization techniques should be considered.A threshold below 40% patient-specific median global circumferential strain (GCS


Cardiac allograft vasculopathy (CAV) is an obliterative and diffuse form of vasculopathy affecting almost 50% of patients after 10 years from heart transplant and represents the most common cause of long-term cardiovascular mortality among heart transplant recipients. The gold standard diagnostic technique is still invasive coronary angiography, which however holds potential for complications, especially contrast-related kidney injury and procedure-related vascular lesions. Non-invasive and contrast-sparing imaging techniques have been advocated and investigated over the past decades, in order to identify those that could replace coronary angiography or at least reach comparable accuracy in CAV detection. In addition, they could help the clinician in defining optimal timing for invasive testing. This review attempts to examine the currently available non-invasive imaging techniques that may be used in the follow-up of heart transplant patients, spanning from echocardiography to nuclear imaging, cardiac magnetic resonance and cardiac computed tomography angiography, weighting their advantages and disadvantages. Cardiac allograft vasculopathy (CAV) is an obliterative and diffuse form of vasculopathy that can be considered as a late complication of heart transplant (HTx). It affects almost 50% of patients after 10 years from transplant and represents the most common cause of long-term cardiovascular mortality , vascula0), mild (CAV1), moderate (CAV2) and severe (CAV3), accordingly [Given the denervation of the cardiac allograft, CAV manifestations are often subtle, especially in early stages of disease. Invasive coronary angiography (ICA) still represents the gold standard for the diagnosis, especially when combined to intravascular ultrasound (IVUS) and optical coherence tomography (OCT) . As an eordingly .Table 1RICA is the gold-standard method used to routinely screen HTx patients, even in the absence of left ventricular dysfunction or symptoms. However, despite its demonstrated safety, ICA holds potential for severe complications, including contrast-related kidney injury and procedure-related vascular lesions , with alResting echocardiography provides limited diagnostic accuracy for CAV detection, particularly in mild forms –11. The p < 0.05 and 75% vs 11%, p < 0.05 respectively), although LVEF was found to be preserved in the majority of them [LVEF is often at the upper limit of normal due to either graft denervation and increased levels of circulating catecholamines, and is generally preserved even in advanced forms of CAV, making it unsuitable as an early marker of disease. David et al. showed that patients with severe forms of CAV were characterized by lower values of LVEF and a higher prevalence of grade 2 and 3 diastolic dysfunction as compared with less severe forms of disease  global longitudinal strain (GLS) through both tissue Doppler imaging (TDI) and speckle tracking echocardiography, the latter being more angle-independent. Compared to visually assessed WMAs, wall motion velocity analysis assessed by TDI has been proven to detect earlier ventricular dysfunction , 19–21. 0 vs CAV1), as well as a preserved LVEF even in presence of moderate-to-severe CAV [3 showed a reduced absolute value of LV-GLS and a higher LV longitudinal strain time to peak, highlighting a more severe degree of LV dyssynchrony [LV-GLS is less dependent on heart rate and loading conditions as compared to LVEF and other diastolic indexes , 25. Thevere CAV . Furthervere CAV . In addivere CAV . At lastvere CAV , 31–33. ynchrony .Fig. 3LeIn the general population, exercise should be the preferred stressor when stress echocardiography is performed. Nonetheless, physical exercise might not represent an adequate cardiovascular stressor for the denervated allograft, mostly because of impaired chronotropic response , 35–37. As concerns pharmacological agents, dobutamine stress echocardiography (DSE) represents the preferred choice , 40. UnfThe latest ISHLT guidelines recommend dobutamine or treadmill stress echocardiography in patients who cannot undergo invasive testing (class of recommendation IIaB) . In partThe accuracy of stress echocardiography might improve if combined with other techniques, such as myocardial deformation analysis and the use of contrast agents. For instance, strain analysis can increase DSE sensitivity from 63 to 88% in the detection of CAV 51, repreCardiac computed tomography angiography (CCTA), as most of the below-mentioned techniques, has proved useful in the diagnosis of non-allograft coronary artery disease, with the highest benefit in patients with low-to-intermediate risk of disease .Regarding CAV, many concerns with the feasibility of CCTA have been raised. In particular, denervated hearts usually show elevated heart rates at rest . This poIn 2005, first evidences stated that CCTA may be used as a screening tool in HTx recipients for de novo CAV or as a follow-up strategy . FurtherThe use of multi-slice machines significantly improved the diagnostic accuracy of the technique. In a pilot study on 10 patients using 16-slice CCTA, the detection of inflammatory plaques  well correlated with IVUS-derived virtual histology . 64-slic58Whether CCTA proved overall applicable to CAV, the quantification of coronary artery calcium (CAC) showed heterogeneous results. First evidences stated that the only absence of CAC was not reliable enough to exclude CAV , confirmSeveral parameters from CCTA—as well as their combination—may be useful in the prediction and the identification of early CAV: volume/length ratio of the plaque, wall burden and the proportion of fibrotic/fibro-fatty/calcified/low-attenuation tissue . The sprWhile the role of single-photon emission computed tomography (SPECT) is well established in the diagnosis of non-allograft coronary artery disease, its role in the diagnostic workup of CAV is way less clear. In patients with inadequate acoustic window and contraindication to contrast agents, pharmacological SPECT could represent an alternative imaging technique for CAV detection. Globally, the use of pharmacological stressors is preferred over physical exercise, and gated technique can improve sensitivity . Many tr99mTc-tetrofosmin-gated adenosine stress SPECT was not found to be sensitive in detecting CAV, even when stricter criteria of ≥ 70% stenosis were applied [SPECT has a high NPV, especially when combined with a normal wall motion pattern, but low specificity and sensitivity for milder cases of CAV, wherein LVEF is still preserved. This may be explained by the diffuse, balanced distribution of ischemia in CAV, as it is not territory-related . In thes applied . Some cl applied . This ev99mTc have a high NPV for major events at 12 months [As for what concerns the prognostic value of SPECT, data are more encouraging, as many studies showed that a negative stress SPECT is associated with better outcome. For instance, the presence of wall motion abnormalities together with a positive stress SPECT can predict cardiac events . Manriqu2 months , and thi2 months . Accordi2 months . Large t2 months . In cont2 months .The study of perfusion using positron emission tomography (PET) shows more accuracy as compared with SPECT in the diagnostic workup of non-allograft coronary artery disease . This se13NH3-PET with quantification of MBF provided improved detection of CAV, and valid stratification of severity, representing a strong predictor of major cardiac events [82Rb-dipiridamole PET test demonstrated that the reduction in MBF and the concurrent increase in coronary resistance were highly suggestive of CAV, with > 96% specificity [13NH3 was inversely related to the volume of coronary plaques as estimated by IVUS, also when ICA was negative [The first evidence comes from an outdated study by Allen-Auerbach et al., whom demonstrated that endothelial-independent MBF abnormalities were related to morphological indexes of CAV progression with IVUS . 13NH3-Pc events  Fig. 5)13NH3-PETcificity . Moreovenegative . Despite18fluorodeoxyglucose (FDG)-PET detected vascular inflammation before the onset of alterations on ICA, still using IVUS as gold standard [PET imaging may also allow vascular wall evaluation, as a case report in 2016 demonstrated that standard . This isstandard .82Rb-dipiridamole PET was found to be related to increased rate of major cardiac events, also in the setting of preserved LVEF and normal perfusion [PET still holds prognostic information, according to several studies. Myocardial flow reserve ≤ 1.75 using erfusion . The quaCardiac magnetic resonance (CMR) represents a useful resource in the assessment of both structural and functional changes, providing also information regarding the composition of myocardial tissue. In fact, in patients with insufficient acoustic window, CMR is an alternative to echocardiography to assess cardiac chamber volumes and function as well as to exclude acute cellular rejection. In fact, its role in HTx patients has been more intensively studied with regards to acute cellular rejection, since first studies in CAV showed low sensitivity 8584 Fig85. First eMicrovascular disease can be assessed by stress perfusion CMR, through the estimate of myocardial perfusion reserve (MPR), even though first results were not encouraging in detecting CAV , later oMicrovascular reactivity has also been studied by oxygenation-sensitive CMR with a protocol of 1-min hyperventilation, followed by 30 s of apnea . SignifiAs mentioned above, contrast-enhanced CMR with gadolinium is able to identify portions of myocardium characterized by inflammation, scarring and diffuse fibrosis, which could provide valid help in serial assessment of adverse cardiac remodelling as well as strong prognostic value. Late gadolinium enhancement imaging has been widely proven to be a prognosticator in HTx patients , even thThe identification of CAV, especially with regard to early disease, represents a puzzling challenge for cardiologists. ICA is still the gold standard in the diagnosis of this long-term, survival-limiting disease, but does not show high sensitivity nor is free from complications. Non-invasive and more sensitive techniques are an appealing field but are still quite nebulous. To date, no technique—ICA included—is able to interpret the diffuse and subtle nature of CAV, so that such new techniques are expected to point out early alterations in vessel walls and significative early metabolic alterations for CAV. Echocardiography is a low cost, widely available technique but with limited sensitivity; the use of speckle tracking techniques may improve its diagnostic power. CCTA showed a good accuracy, but results concerning the detection of subtle CAV are controversial; the combination of multiple parameters as well as the development of sophisticated acquisitions may help in the diagnosis of earlier forms. Nuclear imaging, especially PET, will likely help in the management of HTx patients with suspected CAV, with a shift from anatomic to metabolic assessment. Nonetheless, radiation issues still limit its large-scale feasibility. MPR as assessed by CMR is promising, but anatomical vessel definition is scarce; further studies are deemed to state whether the evaluation of the extracellular volume may be an early sign of CAV. Studies regarding the combination of imaging techniques are strongly required, as their complementary nature may increase the overall sensitivity for CAV, thus limiting the need for invasive, periodic follow-ups.


Mechanical circulatory support (MCS) can help to maintain hemodynamic stability, improve cardiac function, reduce cardiac load, and is an important method for the treatment of advanced heart failure. However, traditional MCS systems  are associated with limitations including trauma, a high rate of complications  and require complex care from nurses.We report a case of left heart failure resulting from dilated cardiomyopathy in a 24 years-old man. A catheter was placed through the right jugular vein and a drainage tube was positioned under ultrasound guidance through the superior vena cava, right atrium, atrial septum, to the left atrium, and returned to the axillary artery using an extracorporeal magnetic levitation ventricular assist device (VAD). The patient was successfully supported for 10 days and bridged to heart transplant.via a percutaneous approach. Our findings support the wider use of this strategy for patients awaiting myocardial recovery or who require heart bridging or transplantation.To the best of our knowledge, this is the first report of the use of an extracorporeal magnetic levitation VAD for MCS  In China, common treatments for temporary mechanical circulatory support (MCS) in patients with cardiogenic shock (CS) include intra-aortic balloon pump (IABP) and veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Although the IABP is simple to operate, the results of the SHOCK-II clinical trial showed that IABP had no clear effect on improving survival in patients with CS ; SimilarThe extracorporeal magnetic levitation ventricular assist device (VAD) uses a magnetic levitation rotor that can rotate without friction or wear, with less blood stagnation, turbulence or hemolysis, compared with ECMO and almost no mechanical failure . In our A 24 years-old man  with a history of dilated cardiomyopathy, pulmonary hypertension, severe mitral insufficiency, and moderate tricuspid insufficiency was admitted with a New York Heart Association (NYHA) cardiac function rating of IV and a left ventricular ejection fraction of 20%. He received extensive medical treatment to increase myocardial contractility, reduce pulmonary hypertension and control heart rate. Unfortunately, the patient developed persistent systemic hypoperfusion with CS. He was given temporary left ventricular assist using a magnetic levitation extra-VAD device. Before implantation, ultrasound examination showed left ventricular dilatation (left ventricular end-diastolic diameter 9.5 cm), systolic dysfunction , and pulmonary artery systolic blood pressure of 57 mmHg.To circumvent the difficulties of atrial septal puncture through the jugular vein, puncture through the femoral vein was performed. A guide wire was inserted through the right femoral vein puncture to achieve right heart catheterization under the guidance of ultrasound and digital subtraction angiography (DSA) . The catHemodynamic and hematological parameters were monitored throughout extra-VAD implantation, and indicated good recovery. No hemolysis-related complications occurred , and livCardiogenic shock is a recognized cause of death in patients with heart failure due to low cardiac output resulting in severe hypoperfusion of vital organs, with a short-term mortality rate of more than 50% . MCS canTraditional short-term MCS units such as Impella, TandemHerat, and VA-ECMO use mechanical bearing axial flow pumps. In contrast, the magnetic levitation centrifugal pump increases blood compatibility and reduces the incidence of pump thrombosis, hemolysis, and gastrointestinal bleeding, thereby minimizing blood loss, the need for blood transfusion, and postoperative inflammation , 9. In aIn addition, only CentriMag can offer full circulatory support; the rest of the device such as Impella CP with up to 4.3 L/min, Impella 5.5 with 5.5 L/min  and TandemHeart with 4 L/min can only provide partial support. In life threatening end stage heart failure patient, the support average flow range is from approximately 3.5–6.0 L/min . In thesNo bleeding or thrombotic complications and no hemolysis were observed during the entire course of circulatory support, which is consistent with our previous report . While oIn addition, we modified the conventional method of median sternotomy and re-cannulation to a percutaneous approach. To our knowledge, this is the first time this surgical method has been reported in the literature and suggests that minimally invasive, short-term and mid-term external magnetic levitation artificial heart implantation should be considered for widespread use.Percutaneous left VAD reduces left ventricular volume, wall stress, and myocardial oxygen consumption whilst increasing cardiac output and coronary perfusion to minimize myocardial ischemia and hemodynamic failure in high-risk patients with heart failure. This minimally invasive method greatly reduces patient trauma and avoids the risks associated with complicated thoracotomy .Additionally, the percutaneous approach reduces blood loss and potential coagulation disorders, which simplifies postoperative care . With trvia jugular vein intubation. This model avoids unnecessary surgeries and is associated with fewer complications than existing methodologies. Further clinical data are necessary to evaluate the advantages of this model over traditional MCS strategies.In conclusion, we propose a novel, minimally invasive and easy-to-care mode of extracorporeal ventricular assistance using an extracorporeal magnetic levitation VAD The original contributions presented in this study are included in this article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. The patients/participants provided their written informed consent to participate in this study.PL: data curation, formal analysis, methodology, software, validation, visualization, and writing—original draft. XZ: methodology, investigation, validation, software, and formal analysis. SC and P-LH: methodology, validation, and writing—review and editing. TW and SQ: writing—review and editing. WS and GW: resources and supervision. ND: conceptualization, review and editing, supervision, and funding acquisition. All authors reviewed the manuscript and approved the submitted version.


N = 48), small for gestational age , or large for gestational age ; SGA and LGA defined as birth weight Z-score < − 2 and >  + 2, respectively. We examined the heart using echocardiography, including Doppler and strain imaging, in relation to anthropometrics, body composition, blood pressure, physical activity, and diet. Although groupwise differences in body size decreased during the first year after birth, LGA remained larger at follow-up, with higher lean body mass and BMI, while SGA were smaller. Slight changes in left ventricular diastolic function were present in SGA and LGA, with SGA showing increased mitral diastolic E- and A-wave peak flow velocities, and increased septal E/E′ ratio, and LGA showing larger left atrial volume adjusted for sex and lean body mass. In univariate analyses, lean body mass at follow-up was the strongest predictor of cardiac morphology. We found no groupwise differences at follow-up for ventricular sphericity, cardiac morphology adjusted for lean body mass and sex, or blood pressure, diet, or physical activity. Cardiac morphology is predicted by lean body mass during childhood, even in the setting of abnormal fetal growth. Our results are consistent with a limited effect of fetal programming on cardiac dimensions during childhood. Minor changes in diastolic function are present in both SGA and LGA children, however, the clinical significance of these changes at this stage is likely small.Studies examining the link between abnormal fetal growth and cardiac changes in childhood have presented conflicting results. We studied the effect of abnormal fetal growth on cardiac morphology and function during childhood, while controlling for body size, composition and postnatal factors. We report on the follow-up of 90 children  born appropriate for gestational age (AGA, The online version contains supplementary material available at 10.1007/s00380-022-02064-5. The antenatal milieu affects health in adulthood , and lowConflicting findings on the link between fetal growth and the cardiovascular system in childhood have been presented. SGA and fetal growth restriction (FGR) have been linked to cardiac remodeling in childhood . This reBody surface area (BSA) is commonly used to adjust childhood cardiac dimensions for body size. The association between cardiac structures and BSA is often not linear , and indWe aimed to assess the effect of fetal growth on cardiac morphology, geometry, and function in children born either LGA or SGA with FGR, and to explore associations between cardiovascular morphology, body size and composition, while controlling for postnatal factors, diet and physical activity. We hypothesized cardiovascular morphology to associate with current body size, with LBM being the main predictor.N = 48, SGA N = 23, LGA N = 19], examined between October 2017 and June 2019. Initially, we examined a cohort of 174 newborns born at gestational weeks 31–42 between November 2011 and January 2014 at the Women’s Hospital, Helsinki, Finland. We recruited the children into three groups at birth: SGA, LGA and appropriate for gestational age (AGA). The groups were defined according to weight Z-score for gestational age at birth according to Finnish growth charts [In this study, we report on the follow-up of 90 patients [appropriate for gestational age (AGA) h charts . Inclusih charts , 22. NonZ-scores for birth weight [Z-scores corresponded well to group assignment at birth, with only minor discrepancies, and no reassignment was done between the groups as to maintain compatibility with the newborn stage. Written informed consent was given by the children’s guardians at both baseline and follow-up enrollment. The Helsinki University Hospital Ethics Committee for gynecology and obstetrics, pediatrics and psychiatry approved the research protocol (138/13/03/03/2011 and HUS/2274/2016).New Finnish fetal and childhood growth references were published during the follow-up time, and we generated new h weight , 24. TheZ-scores for height and BMI in relation to age and for weight in relation to height [At the follow-up visit, we measured standard anthropometrics , with thoracic circumference measured using a tape measure at the level of the xiphoid process. BSA was calculated using the Haycock formula . We asseo height . Prior tBlood pressure was measured, following a 1-h rest period, in the upright sitting position from the right arm by a trained technician using appropriately sized cuffs . Means from three consecutive measurements were used in analysis. Parallel measurement coefficients of variance (CV) were 4% for systolic and diastolic blood pressure, and 6% for heart rate.One investigator examined the children with transthoracic echocardiography using a 7-MHz 7S transducer . Another investigator performed the measurements offline  from standard views, according to American Society of Echocardiography recommendations , 27. ArtLeft ventricular mass was attained from parasternal short axis B-mode measurements using Devereux’s formula . We deteWe assessed the systolic function of the ventricles by calculating the ejection fraction and fractional area change of the left and right ventricles respectively, by measuring the mitral and tricuspid annular plane systolic excursion (MAPSE and TAPSE) with M-mode, and through standard myocardial tissue Doppler and speckle tracking strain measurements. We examined diastolic function through standard pulsed wave and tissue Doppler and strain measurements, and by examining left atrial volume as noted above. Echocardiograms were obtained for 88 of the children. Intra- and inter-observer variability (CV) was assessed for morphologic measurements, ranging from 4 to 8% and 5 to 10%, respectively.U, Z-test for proportions). Adjusted means were examined using ANCOVA, with Fisher’s LSD used post hoc. A two-sided P value < 0.05 was determined statistically significant. Significance levels of Mann–Whitney U, Z-test for proportions and Fisher’s LSD were Bonferroni-corrected for two pairwise comparisons, as group differences between AGA and SGA or LGA were examined.We present results as count, mean ± SD, median Q1; Q3 or adjusted mean (SE). Normality was assessed from histograms and using the Shapiro–Wilk test. We used ANOVA, Kruskal–Wallis, and Fisher–Freeman–Hamilton exact tests to compare unadjusted values between groups, with corresponding post hoc tests  for data analysis, and created graphs using GraphPad Prism 9 .Finally, multiple linear regression models with sex, birth weight Significant differences were observed between groups in anthropometry, with the SGA children consistently reporting smaller body size, including height, weight, and LBM, but similar adiposity to AGA Table . The LGAWhen examining children participating and not participating in the follow-up, we found no differences for sex, gestational parameters, birth weight Z-score or distribution of children between the SGA/LGA/AGA groups (results not shown).When comparing unadjusted cardiovascular morphology groupwise, the SGA group showed significantly smaller diameters at the aortic valve and isthmus, smaller diameters at the bases of both ventricles, and smaller right ventricular and atrial areas . LGA showed an increased left atrial volume. No differences in sphericity of either ventricle were observed between groups . No association was observed between cardiovascular morphology and age, or systolic blood pressure and maternal pre-gestational diabetes and left ventricular mass (not shown).In univariate analyses , we observed significant associations between cardiovascular morphology, sex, birth weight, current body size and adiposity. Boys showed larger aortic valve and sinus diameter, left ventricular diastolic diameter, mass and volume, along with right ventricular mid-cavity diameter and diastolic area. LBM was the strongest and most consistent predictor of cardiovascular morphology . Adding BMI to the LBM model did not result in overall improvements in model fit, except for abdominal aorta diameter and right ventricular basal diameter (adjusted R2 0.158 vs 0.142 and 0.165 vs 0.149), with BMI only remaining independently associated with abdominal aorta diameter. As no independent association was observed for the other dimensions, and BMI did not alter the groupwise differences of the abdominal aorta, only models without BMI are reported . Models adjusting groupwise differences for only sex and LBM performed the best, with higher adjusted Red Table . Adjustied Table .Table 3Cp = 0.018). No significant interaction was observed in any of the models between group and current body size.Notably, in ANCOVA models with LBM, sex remained a significant independent predictor only for left ventricular diastolic diameter and right ventricular mid-cavity diameter and diastolic area, while in the models containing BSA or BSA raised to an exponent, sex remained a significant independent predictor for aortic valve and sinus, left ventricular mass and end-diastolic volume, in addition to left ventricular diastolic diameter and right ventricular mid-cavity diameter and diastolic area. When examining differences for BSA and LBM for sex, no difference was found for BSA, while boys had a significantly larger LBM . LBM remained an independent predictor for all measures, except for abdominal aorta dimension. Sex remained an independent predictor of right ventricular mid-cavity diameter and diastolic area and left ventricular diastolic diameter, similar to ANCOVA models.In this study, we examined the role of prenatal growth, current body size and composition, and the influence of a comprehensive set of other potential factors on the morphology and function of the heart during childhood. Despite reporting subtle changes in left ventricular diastolic function, we found no evidence of changes in cardiac morphology or geometry attributable to restricted or excessive fetal growth and body size at birth. Overall, our findings suggest that cardiac morphology during childhood is largely determined by current LBM and sex in the setting of abnormal fetal growth.The effect of altered fetal growth on cardiac geometry during childhood seems to be small. In contrast to our findings, increased sphericity of the ventricles of SGA and FGR fetuses , neonateE/E′ ratio in the SGA group, possibly indicating differences in ventricular filling, these differences were minor. Previous studies report both increased [E/E′ ratios in SGA children during early childhood, while in the neonate stage, we found the E/E′ ratio to be decreased in SGA and increased in LGA [While we found significantly increased diastolic mitral E- and A-wave peak inflow velocities, and an increased septal ncreased  and simincreased  E/E′ ratd in LGA . The incd in LGA . Thus, aWe found that even in the setting of abnormal fetal growth, cardiovascular dimensions in early childhood are largely explained by current body size, LBM and sex. This is supported by our previous findings in children examining left ventricular mass in the presence of maternal obesity and diabetes, which found LBM to be the strongest predictor of left ventricular mass . InteresOur study is mainly limited by the lack of differentiation regarding time-of-onset of FGR. The severity of FGR has previously been found to influence cardiac morphology in fetuses, with early-onset FGR being associated with hypertrophy and late-onset with elongation or increased sphericity of the ventricles in fetuses . FurtherIn this study, we show that cardiac morphology is mainly predicted by current body size and LBM in children with restricted and excessive fetal growth. While subtle changes in diastolic function were observed both in the SGA and LGA children, their clinical significance at this stage is likely small. We found cardiac morphology to overall be appropriate for current body size. This suggests that effect of fetal growth on cardiac morphology in childhood is limited.Supplementary file1 (PDF 432 kb)Below is the link to the electronic supplementary material.


As a new method of left ventricular-arterial coupling (VAC), the non-invasive myocardial work index (MWI) may provide more useful information than the classical methods of arterial elastance/left ventricular (LV) elastance index  over end-systolic elastance [Ea/Ees]). This research aims to investigate if MWI might be better associated with hypertension-mediated organ damage (HMOD) and diastolic dysfunction than Ea/Ees in hypertension.We prospectively enrolled 104 hypertensives and 69 normotensives. All subjects had speckle-tracking echocardiography for myocardial work, conventional echocardiography, and brachial-ankle pulse wave velocity (baPWV) measurements. The global work index (GWI) is a myocardial work component. The correlation between GWI and HMOD, as well as diastolic dysfunction, was analyzed. The receiver operating characteristic (ROC) curve was utilized for evaluating the GWI predicting efficacy.p < 0.001). Higher GWI was a risk factor on its own for increased baPWV, pulse pressure (PP), echocardiographic LV hypertrophy (LVH), and left atrial volume index (LAVI) , taking into account the sex, age, mean arterial pressure (MAP), body mass index (BMI), and antihypertensive therapy. However, no considerable associations were found between Ea/Ees and HMOD parameters and the diastolic dysfunction markers. The GWI area under the ROC curve for increased PP and baPWV, echocardiographic LVH, and increased LAVI were 0.799, 0.770, 0.674, and 0.679, respectively (p < 0.05).The global work index was significantly higher in hypertensives than in normotensives (2,021.69 ± 348.02 vs. 1,757.45 ± 225.86 mmHg%, respectively, The global work index but not traditionally echocardiographic-derived Ea/Ees of VAC is independently related to HMOD and diastolic impairment in hypertensives with preserved LV ejection fraction. The GWI may be a potential marker for evaluating the VAC in hypertension. Ventricular-arterial coupling (VAC) is defined by constant heart and arterial tree interaction, which reflects the global cardiovascular performance and has a pivotal function in the cardiac and aortic mechanics physiology .Traditionally, VAC is most frequently assessed by echocardiography using the effective ratio of effective arterial elastance (Ea) over end-systolic elastance (Ea/Ees) . HoweverAs the concept of VAC is evolving, the myocardial work index (MWI), derived using speckle tracking echocardiography from pressure-LV global longitudinal strain loop, is proposed as a novel VAC non-invasive method . Previou*SBP + 2/3*DBP formula was utilized to compute the MAP. The pulse pressure (PP) was derived by subtracting diastolic pressure from systolic pressure. According to the established protocol, each individual had a comprehensive clinical assessment, such as hypertension history, blood pressure, weight, height, waist, smoking, and alcohol use status, electrocardiograph, and brachial-ankle pulse wave velocity (baPWV). Professional athletes and individuals with documented diabetes mellitus, chronic kidney dysfunction, atrial fibrillation, hyperthyroidism, valvular heart disease, coronary artery disease or its symptoms, secondary hypertension, ankle-brachial pressure index (ABI) of < 1, and primary cardiomyopathies were excluded. This research initially included 191 subjects by excluding 18 individuals with suboptimal echocardiographic images, and finally, 104 hypertensives and 69 normotensives underwent LV myocardial work and strain assessment using the 2D speckle-tracking echocardiography method , following the “Declaration of Helsinki.” On clinicaltrials.gov, the research was registered . All individuals gave consent to participate.2 for men and women, respectively. The Simpson biplane and area-length methods were applied to compute the Left atrial and LV volumes. The E velocity was measured by applying the pulse wave Doppler sample volume at the mitral valve tips. The tissue Doppler imaging (TDI) was used to record the early diastolic septal and lateral annular e'velocities.The Vivid E95, a commercially available system, was utilized in the study. The American Society of Echocardiography instructions were followed in the study recordings and measurements . DopplerThe Ea and Ees were expressed as ESP divided by stroke volume (SV) (ESP/SV) and ESP divided by end-systolic volume, respectively. The ESP equals brachial systolic blood pressure multiplied by 0.90. The Ea/Ees ratio was then simplified to ESV/SV .2  velocity > 2.8 m/s, and left atrial volume index (LAVI) > 34 ml/mp < 0.001).The methodology to analyze myocardial work and LV global longitudinal strain (GLS) was validated in previous publications , 16; briThe baPWV was measured with a commercially available PWV/ABI device (Omron Colin BP-203RPE III). The baPWV measurement was conducted on the same day as echocardiography. For a minimum of 5 min of rest, the individual was first positioned supine in rest, and then around the bilateral upper arms and ankle, four blood pressure cuffs were put before connecting to oscillometric and plethysmographic pressure sensors. At the bilateral brachia and ankles, the devices record the arterial blood pressure, volume pulse form, and phonogram. The distance from the ankle to the right brachium was measured. Automatically, by dividing the transmission distance over the transmission duration, the baPWV was derived. ABI was determined bilaterally by calculating the ankle-SBP to brachium-SBP ratio on both sides. For analysis, the mean baPWV and ABI for both sides were utilized.t-test for normally distributed variables otherwise. The GWI and Ea/Ees correlates were evaluated by Spearman's or Pearson's correlation analysis according to the distribution of the variables. The binary logistic regression was utilized to define the VAC markers and their components  with HMOD indices and LV diastolic dysfunction, such as (1) elevated or normal arterial stiffening ; (2) ecctively) ; (3) imp4 ml/m2) . Sex, agp = 0.577). GWI was considerably higher in hypertensives than in normotensives . In both groups, no considerable correlation was noted between GWI and Ea/Ees.The hypertensive individuals' median age was 50.00 (44.25–56.75) years. These patients have a median SBP of 144.00 (135.00–154.00) mmHg, median DBP of 90.50 (84.25–97.75) mmHg, and MAP of 107.67 (101.33–115.58) mmHg. The median history of hypertension in these patients was 2.00 (1.00–5.00) years. p < 0.001), however, the GWI values were similar in older and younger patients by utilizing the median age (50 years) as a cut-off.Female subjects, as compared to male subjects in hypertensives, had higher GWI values  and with LAVI . No considerable correlation was noted between Ea/Ees index and SBP, MAP, PP, LVMI, baPWV, and LV diastolic function markers except for a significant correlation of the Ea/Ees index with LVEF and GLS .p = 0.004, p < 0.001, p = 0.002, respectively).Hypertension-mediated organ damage indexes in the study included baPWV > 1,400 cm/s, PP ≥ 60 mmHg, and echocardiographic LVH. Increased baPWV, PP, and echocardiographic LVH were detected in 93, 45, and 32, respectively, hypertensive subjects. The distribution of GWI in hypertension subjects according to the cut-off of baPWV, PP, and LVH is shown in p = 0.023), PP ≥ 60 mmHg (p = 0.023) and echocardiographic LVH (p = 0.002). By multivariate analysis and adjusting for the sex, age, MAP, BMI, and antihypertensive therapy, GWI was still an independent risk factor of baPWV > 1,400 cm/s, PP ≥ 60 mmHg, and echocardiographic LVH . However, no considerable correlations were observed between Ea/Ees and baPWV > 1,400 cm/s, PP ≥ 60 mmHg, and echocardiographic LVH.As shown in 2 were detected in 70, 4, and 20, respectively, of hypertensive individuals. There was no patient with TR velocity > 2.8 m/s.Left ventricular diastolic function impaired markers in this study including septal e'velocity < 7 cm/s, average E/e' ratio > 14 and LAVI > 34 ml/mp = 0.006), and this association was retained statistically significant in a multivariate model such as age, sex, MAP, BMI, and antihypertensive therapy (p = 0.031), as revealed in There was also an association of GWI with LAVI in the univariate logistic regression (AUC) to predict increased PP and baPWV, echocardiographic LVH, and increased LAVI was 0.799, 0.770, 0.674, and 0.679, respectively . The cut-off values were 2,110 mmHg% , 1,803 mmHg% , 2,260 mmHg% , and 2,116 mmHg% , respectively, as revealed in The GWI area under the curve (The GWI and Ea/Ees were measured in a population of hypertensive and normotensive controls. The research's primary findings were (1) GWI was considerably elevated, but the Ea/Ees was similar in the hypertensives in comparison with the normotensives; and (2) GWI but not Ea/Ees in hypertensives was linked to HMOD, such as increased baPWV and PP and echocardiographic LVH, and also associated with increased LAVI, after adjusting for sex, age, and MAP.2 were founded to be associated with Ea/Ees ratio in hypertensives.The vessel and heart need to be considered as a unique system; thus, the assessment of cardiovascular performance should incorporate the examination of ventricular properties and the arterial system regulating effects. VAC refers to the heart-pumping action coupled with the arterial system load resistance, which can be easily described as the Ea/Ees ratio, and eventually determined the cardiovascular system performance and efficiency . It was The global work index was calculated as the LV pressure–strain loop area. As a myocardial work component obtained from a non-invasive LV pressure–strain loop by speckle tracking echocardiography, it was considered a novel VAC marker that affects the myocardial oxygen metabolism and cardiovascular function . It has Of note, although both GWI and Ea/Ees were indexes of VAC, no considerable GWI and Ea/Ees correlation was noted in the hypertensive group, as well as in normotensives, probably owing to the different properties of these two methods.There are some limitations of this study. First, not all parameters of asymptomatic HMOD were included as it was an exploratory research that aimed to indicate the GWI fundamental clinical value. Second, this research was based in one location, and the cross-sectional aspect did not conclude real causation between GWI and HMOD, such as arterial stiffness and LVH and increased LAVI. Third, the echocardiographic-derived Ea/Ees limitations in the present study, rather than using the gold standard estimate of Ea/Ees from the invasively obtained pressure–volume curve, might partly account for the significant Ea/Ees with HMOD and diastolic dysfunction association. Fourth, patients' hypertension is usually complicated by diabetes, coronary heart disease, and other conditions, but these factors were excluded in this study in order to exclude the influence of these factors on myocardial work and HMOD. Therefore, the results of this study are not applicable to all patients with hypertension. Moreover, we evaluated the arterial stiffening by baPWV but not by the gold standard methodology of carotid-femoral pulse wave velocity (cfPWV) . NeverthIn summary, in patients with hypertension, the GWI but not the echocardiographic-derived Ea/Ees ratio of VAC is related to HMOD, including arterial stiffening and LVH, and diastolic impairment evaluated by increased LAVI. The GWI may be a new potential marker for the VAC assessment and, finally the early cardiovascular performance in hypertension.geping216022@163.com.The data analyzed in this study is subject to the following licenses/restrictions: The datasets generated and/or analyzed during the current study are not publicly available due to limitations of ethical approval involving the patient data and anonymity but are available from the corresponding author on reasonable request. Requests to access these datasets should be directed to The studies involving human participants were reviewed and approved by First Affiliate Hospital of Chongqing Medical University, Chongqing, China. All individuals gave consent to participate.The research was undertaken by QDu, HT, QDo, KL, and YY. Data analysis was performed by QDu and XC. The manuscript was written by QDu and HT. The study design and the manuscript review were undertaken by QDu, PG, and XC. All authors reviewed the manuscript.This study was supported by Chongqing Science and Technology Commission, key project, (2019 ZLXM003); Chongqing Science and Technology Commission, Youth Project (2018QNXM024).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Aortic stenosis is the most common heart valve disease in the world, and patients that present with symptoms have a high mortality rate. Aortic valve replacement has the objective of promote left ventricular remodeling, reduce symptoms, and increase overall survival. The objective of this study is to evaluate reverse remodeling of the left ventricle in patients with severe and symptomatic aortic stenosis who underwent surgical or percutaneous transcatheter aortic valve replacement.This is a longitudinal, prospective, non-concurrent, non-randomized unicentric study with patients who underwent aortic valve replacement. Echocardiogram was performed before and after replacement procedure to evaluate several remodeling indexes.Of 91 patients, 77 (84.6%) underwent surgical aortic valve replacement, and 14 (15.4%) underwent percutaneous transcatheter aortic valve replacement. Mean age was 68,96±11,98 years, and most patients were male. Remodeling evaluation revealed that patients who decreased left ventricular index mass  and those who reduced the mass/volume ratio  presented with positive left ventricular remodeling. No endpoint difference was found in those with positive remodeling.Regarding the left ventricular remodeling in patients with severe and symptomatic aortic valve stenosis who underwent percutaneous transcatheter or surgical valve replacement, there is a positive increment in remodeling, however it remains in concentric hypertrophic shape. Implication of these findings remains uncertain and to be studied in large dedicated trials with clinical endpoints. As stenosis progresses, there is an increase in the afterload; increased left ventricular (LV) pressure and adaptive hypertrophy to maintain ventricular wall stress can cause an inappropriate hypertrophic response, leading to fibrosis, dilation, and loss of ventricular function and resulting in symptoms, heart failure, arrhythmia, and death-7. Reestablishing the valve function with an increase in the effective orifice area, reduction of transvalvular gradient, and reversal of hypertrophy results in improvements of symptoms and increased survival-5.Aortic stenosis (AS) is the most prevalent heart valve disease in the world, and symptomatic patients have high rates of morbidity and mortality-13. Treatment is usually indicated according to stenosis severity, symptoms, and ejection fraction (EF)-2.The definitive treatment for AS is valve replacement, and the gold standard procedure is surgical aortic valve replacement (SARV), but it has been accompanied, in the last decade, by percutaneous transcatheter aortic valve replacement (TAVR) in low, intermediate, and high-risk surgical cases, with overlapping clinical results in both therapeutic methods,4,14-16. Greatest reduction usually occurs within the first six months, but it persists improving until up to two years after valve replacement, accompanied by reduction in the LV mass/volume ratio, reduction in cavitary volumes, and enhance in diastolic filling and global heart function-7,15-17.Reverse remodeling is a phenomenon that occurs in patients with AS after valve replacement, and it is characterized by enhance in hypertrophy pattern followed by ventricular mass regression and increase in ventricular function, evaluated through echocardiogram or magnetic resonanceThe aim of this study is to perform an echocardiographic evaluation of aortic valve replacement effects in LV remodeling in patients with severe symptomatic AS who underwent SARV or TARV.A longitudinal, prospective, non-concurrent, non-randomized unicentric trial was performed in patients with AS who underwent SAVR or TAVR from January 2014 to December 2018 in a large tertiary cardiology center. Data collection was carried out mostly through review of electronic medical records, with complement of physical records, when necessary, without contact with patients or interference in their treatment, therefore informed consent was dispensed.Research was approved by local institution’s ethics and humans research independent committee through Plataforma Brasil, under protocol nº 3.593.226.2 or indexed valve area ≤ 0.6 cm2/m2, mean aortic valve gradient ≥ 40 mmHg, and maximum jet velocity ≥ 4 m/s; patients with low flow/low gradient AS with aortic valve area ≤ 1 cm2 with LV ejection fraction (LVEF) < 50%, and mean aortic valve gradient ≤ 40 mmHg, but who presented myocardial reserve, were also considered. Symptoms were chest pain, syncope or dyspnea, and functional class ≥ 2 secondary to valvar disease. Patients with pacemakers, cardiac resynchronizers or implantable defibrillators, hypertrophic cardiomyopathy with or without outflow tract obstruction, myocardial infiltrative disease, predominance of aortic regurgitation, presence of infectious endocarditis or metallic or biological prosthesis in the aortic position, major LV dysfunction (EF < 20%), deaths in the perioperative period, and those who did not have echocardiogram data before or after valve replacement were excluded from the present study.Patients > 18 years of age, with severe and symptomatic AS, and submitted to SAVR or percutaneous TAVR were included. Severe AS was defined as a valvar area ≤ 1 cm.Data collection was related to characteristics and clinical evaluation, characteristics of valve replacement procedures, length of hospital stay, and complications that occurred both in the perioperative period and in clinical follow-up. The baseline echocardiogram used was the one performed closest to the valve replacement, no later than six months before the procedure. Follow-up echocardiogram was performed preferably between six and 24 months after the procedure. When the patient had more than one echocardiogram, the examination performed closer to 12 months of valve replacement was chosen for analysis. Echocardiographic data evaluated and collected from both echocardiograms were LV end-diastolic diameter (LVEDD) and diameters of other cavities, thicknesses of septal and posterior walls, LVEF, LV mass index (LVMI), and LV diastolic volume index (LVDVI), after their calculations, and relative wall thickness (RWT) The primary objective of the study was to evaluate the impact of aortic valve replacement on reverse LV remodeling in patients with AS, evaluating LVMI, LVDVI, type of ventricular hypertrophy, mass/volume ratio, RWT, and LVEF before and after the procedure. As secondary objective, the characteristics associated with improvement in the remodeling variables evaluated in the primary outcome were analyzed. Variables were then associated with a defined composite outcome of death by all causes, need for a new pacemaker implantation, valve prosthesis dysfunction, considered stenosis, significant valve insufficiency or paravalvular leak, and need for valve replacement in the follow-up.t-test or the Mann-Whitney U test, when the continuous data did not have a normal distribution, for paired samples. Categorical variables were described as frequencies and percentages and were compared using the chi-squared test or Fisher’s exact test. A multiple regression model was used to evaluate those variables that were associated with the increase in remodeling and the events in the follow-up. Variables that presented a modestly close relationship with P<0.3 were included in the multiple regression model. The significance level used in all evaluations was a two-sided P-value of 0.05. The continuous variables were categorized according to their means, when appropriate for their association.Statistical analysis was performed with the IBM Corp. Released 2013, IBM SPSS Statistics for Windows, version 22.0, Armonk, NY: IBM Corp. program. Continuous variables were expressed as means and a standard deviation and, when necessary, they were compared using the Student’s From January 2014 to December 2018, 260 patients with symptomatic AS underwent valve replacement in our institution. Of these, 169 were excluded because they did not meet inclusion criteria. Aortic valve replacement was combined with other procedures in 23 (25.3%) cases — 15 cases (16.5%) with coronary revascularization. During hospitalization in the postoperative period, 60 (65.9%) patients had an event. The most common events were bleeding and occurrence of atrial fibrillation in 12 (13.1%) and 24 (26.3%) patients, respectively. There were also three (3.2%) cases of acute myocardial infarction, six (6.5%) patients evolved with acute renal injury, six (6.5%) with total atrial-ventricular block, and four (4.3%) with need for a definitive pacemaker implantation. Postoperatively, mean time in intensive care unit (ICU) was 4.56±4.43 days, and mean length of hospital stay after valve replacement was 14.31±13.59 days, including the mean ICU time. Twenty-four (26.4%) patients died in the postoperative period and were not included in the final analysis .Echocardiographic data at baseline and after aortic valve replacement are presented in Seventeen (19%) patients had moderate to important aortic regurgitation associated with stenosis before valve replacement. After the procedure, this number was reduced to three (4%). A reduction in the maximum and mean valve gradients was also observed, in addition to a slight reduction in pulmonary artery systolic pressure (PASP). As not all patients had measurements of PASP and valve gradients on the follow-up echocardiogram, no additional analyses were performed with these variables.Despite the improvement in various remodeling indexes observed after the procedure, ventricular geometry remained similar, with a concentric hypertrophic LV shape, either after SAVR or TAVR .The remodeling indexes, including LVMI, LVDVI, RWT, and mass/volume ratio, were dichotomized according to the difference of their means, and the LVEF was evaluated according to ≥ 10% increase of their values after valve replacement, in order to evaluate factors associated with the improvement of these indexes.vs. 28.1%; P=0.047), patients with reduced LVEF , LVMI values , and LV end-diastolic volume (LVEDV)  higher than the average on baseline echocardiogram. After logistic regression model that also involved age and smoking, the baseline LVMI remained the only variable associated with improvement in LVMI . Only patients with LVDVI ≥ 75 mL/m2cs at baseline echocardiogram presented a significant reduction in LVDVI after valve replacement , as higher the initial LVDVI, greater the regression of the same index was. This association was lost in multivariate analysis (P=0.370).The factors related to the greatest reduction in LVMI were male sex  and a higher RWT at baseline echocardiogram  were associated with its regression. In a multivariate regression model, which included smoking, LVEDV, and LVEF, the RWT of the baseline echocardiogram remained associated with enhanced ventricular remodeling . Three factors were associated with an increase of at least 10% in LVEF after valve replacement, high baseline LVEDV , low baseline RWT , and reduced baseline LVEF . In this evaluation, patients with eccentric hypertrophic pattern had a higher chance of increasing LVEF. This association was lost in multivariate analysis. No variable analyzed was associated with improvement of the mass/volume ratio.Regarding RWT, not presenting a previous myocardial infarction  and the non-increase of at least 10% in LVEF after valve replacement  were the only two factors associated with the events that occurred during the clinical follow-up period. After adjustments in multivariate regression analysis, no association with the events was detected.The mean follow-up time was 2.6±1.6 years, and 12 (13.2%) patients had an event in the composite outcome. The occurrence of perioperative events , observed in patients with or without myocardial fibrosis, but with no difference in LVDVI, LVEF, and systolic volume. In this analysis, the authors indicated a reverse remodeling with reduction of the mass/volume ratio (P=0.001) at the expense of LVMI, but no factor was a predictor of reverse remodeling in multivariate analysis. The reduction of LVMI starts early and seems to persist until at least four years after aortic valve replacement, but its effect on remodeling and final ventricular geometry is still uncertain,16. In 50 high-risk patients, with a mean age of 77 years, with symptomatic AS, Fairbairn et al. also demonstrated a reduction in LVMI and LV systolic volume with both SAVR and TAVR. In this study, only patients submitted to SARV[25] presented a significant reduction in LVDVI  and baseline LV volumes were predictors of reverse remodeling (P<0.001). In our study, the factors associated with increased remodeling after multivariate analysis were LVMI and LVDVI. We found a slight and non-significant increase in LVEF after valve replacement. This increase is observed in several studies and, in general, is important after procedure, particularly in patients with previous reduced LVEF,6,15. Age, gender, presence of fibrosis, and myocardial reserve are usually factors related to the improvement in LVEF, despite none was found in our analysis,4.With barrier elimination and afterload reduction, patients submitted to aortic valve replacement present various degrees of reduction in ventricular mass, with an increase in volumes and improvement of LV diastolic and systolic functions compared patients undergoing SAVR and TAVR at three and 12 months. They found similar reduction in RWT in both groups and a more marked reduction in LVMI in patients undergoing SAVR . Thus, ventricular geometry, with a concentric hypertrophic pattern in both groups before the procedure, changed only in patients undergoing SAVR, moving to a concentric remodeling pattern. This was probably observed by the increase in LVEDV of patients undergoing TAVR due to factors such as aortic regurgitation and the need for pacemaker implantation. Lamb et al. have already demonstrated in the past that early reduction of LVMI is accompanied by reduction of mass/volume ratio improving ventricular remodeling and diastolic filling of those patients. Despite the increase in remodeling rates, our patients remained in a spectrum of LV concentric hypertrophy , Ngo et al.ertrophy , a fact . In an evaluation, with a five-year follow-up, of 1,434 patients who were alive one year after TAVR, Chau et al. demonstrated an average reduction of 14% in LVMI, with reduced mortality and need for further hospitalization. For each 10% reduction of LVMI, there was a reduction of 5% in mortality. The presence of significant LV hypertrophy in one year (39% of patients) was also associated with all-cause mortality . On the other hand, a study with 31,199 patients from 422 centers of the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy (or STS-ACC TVT) Registry, which evaluated patients undergoing TAVR, found no association between concentric or eccentric ventricular hypertrophy when a one-year death, myocardial infarction, stroke, or need for dialysis endpoint was evaluated. Despite some contradictory data, the presence of greater ventricular hypertrophy before valve replacement and a less significant reduction of LVMI seems to be associated with a worse prognosis in these patients, indicating that an earlier intervention according to overall LV characteristics, which goes beyond LVEF, seems to be the way to improve prognosis in this population.We did not demonstrate the impact of different remodeling indexes on patient prognosis. An analysis of 4,280 patients identified that the presence of important LV hypertrophy before valve replacement was associated with an increase of 16% in mortality and 34% in the compound outcome of mortality and the need for new hospitalization at five-year follow-up. Mild or moderate hypertrophy was not associated with outcomesOur study has several limitations. Due to high rates of patient exclusion, accounting for approximately 2/3 of total procedures, most due to the absence of all necessary data, a small sample was submitted to final analysis. Patient-prosthesis mismatch and other valve hemodynamics measures were not performed and analyzed due to lack of echocardiogram data and may have impact on LV remodeling. The heterogeneity of the sample, which included patients undergoing SAVR with mechanical, biological, and TAVR prosthesis, may also have some influence on the results due to the different populations that usually receive each of these devices. The exclusion of patients with death in the perioperative period was necessary to be able to complete the follow-up and to have at least one echocardiographic examination in the follow-up, but this also causes a population of lower risk for future events, leading to a low incidence of outcomes in the medium-term follow-up. Finally, the non-complete return to normal LV geometry, remaining the pattern of concentric hypertrophy in the population mean, may indicate that patients were late submitted to valve replacement with worse remodeling and LV function, consequently.Our study concludes that in patients with severe and symptomatic AS, remodeling indexes including LVMI, LVDVI, RWT, and mass/volume ratio enhance after aortic valve replacement. This is more evident in patients with higher initial mass and volumes, did not result in changes of LV final geometry, and was not associated with reduction in population events in a medium-term follow-up.