Our study aimed to compare the difference of LV mass regression and remodeling in regard of conduction disturbances (CD) following transcatheter aortic valve replacement (TAVR). A prospective analysis of 152 consecutive TAVR patients was performed. 53 patients (34.9%) had CD following TAVR, including 30 (19.7%) permanent pacemaker implantation and 23 (15.2%) new left bundle branch block. In 123 patients with 1-year follow-up, significant improvement of LV ejection fraction (LVEF)  and reduced LV end-systolic volume (LVESV)  was found in non-CD group (N = 85), but not in CD group (N = 38). Both groups had significant decrease in LV mass index . In 46 patients with 3-year follow-up, only non-CD patients (N = 28) had statistically significant decrease in LV mass index . Our study showed the improvement of LV systolic function, reduced LVESV and LV mass regression at 1 year could be observed in patients without CD after TAVR. Sustained LV mass regression within 3-year was found only in patients without CD. Unfortunately, the incidence of conduction disturbances requiring permanent pacemaker (PM) implantation, and new-onset left bundle-branch block (LBBB) have not changed significantly, with reports even suggesting an increased risk after the introduction of newer generation transcatheter valves (THV)7. Both LBBB and PM implantation were known to be associated with left ventricular (LV) dyssynchrony and ventricular remodeling, and then result in impairment of LV function in long term follow-up10. It is mandatory to know the long-term effect of TAVR-induced conduction disturbance (CD) to LV function and geometry, because TAVR is set to expand to younger age and low surgical risk population.With the improvements in technology and the advent of minimalist approach, the rate of periprocedural complications during transcatheter aortic valve replacement (TAVR) has decreased over time17. The aim of this study was to compare the difference of LV function, remodeling and mass regression between the patients with and without CD following TAVR.New onset of CD has been associated with a decreased recovery of LV ejection fraction (LVEF) and a less favorable LV remodeling 6 to 12 months after TAVR, but few data exists regarding the impact to LV mass regression and remodeling170 consecutive patients  with severe symptomatic aortic stenosis (AS), with extreme or high surgical risks, underwent TAVR in National Taiwan University Hospital from September 2010 to November 2017. Of them, a total of 18 patients were excluded for the following reasons: peri-procedural death (n = 2), previous PM implantation (n = 7), missing data in electrocardiogram and echocardiogram (n = 4), lost follow-up within 1 year (n = 3), THV explant 6 months after TAVR due to infected endocarditis (n = 1), and TAVR for failed surgical prosthesis (n = 1). A total of 152 patients were finally included.18.All patients had sign informed consent at our clinic, and all the clinical information were collected according the protocol of Asian TAVR registry (NCT02308150) which was also proved by the local institutional review board of National Taiwan University Hospital. The evaluation and management of above patients were carried out in accordance with current guideline of valvular heart disease19, and 4 mm in Sapien XT, Lotus, or Portico20.The TAVR was performed by a heart team composed of interventional cardiologists, cardiac surgeons, echocardiographer, and anesthesiologist. The pre-TAVR evaluation included transthoracic echocardiography and computed tomography (CT). The area and perimeter of the aortic valve annulus were analyzed through CT scan for selection of optimal valve size. The patients were implanted with CoreValve/Evolute R  , Sapien XT  , Lotus   or Portico   respectively. The depth of implantation was assessed by the angiography with angle vertical to the alignment of valve prosthesis, and was determined by the distance between the bottom of metallic frame and lowest annulus. The definitions of low implantation are: 6 mm below annular plane in CoreValve/Evolute R21. New-onset LBBB was defined as any new LBBB occurring during the hospitalization period after the TAVR procedure that persisted at hospital discharge. PM implantation was indicated if third-degree or advanced second-degree atrioventricular block was found at any anatomic level that was not expected to resolve after the intervention and for sinus node dysfunction with documented symptomatic bradycardia, in agreement with the American Heart Association/ American College of Cardiology Foundation/Heart Rhythm Society guidelines for device-based therapy of cardiac rhythm abnormalities19. The indication of PM implantation in the presence of LBBB with PR prolongation (> 200 ms) not expected to normalize was at the discretion of the physician. The selection of a single-chamber or dual-chamber pacemaker was left to the implanter. The definition of new CD was either documentation of a new-onset LBBB or the new need of PM before discharge.Electrocardiographic records were obtained from all patients at baseline, immediately after the procedure, and daily until hospital discharge. The diagnosis of intraventricular conduction abnormalities was based on American Heart Association/American College of Cardiology Foundation/Heart Rhythm Society recommendations for the standardization and interpretation of the electrocardiogramTransthoracic echocardiography examinations were performed at baseline, at 1 and 6-month, and annually during follow-up. Echocardiographic parameters included LV end-systolic dimension (LVESd) and volume (LVESV), LV end-diastolic dimension (LVEDd) and volume (LVEDV), septal wall thickness at end diastole (SWTd) and posterior wall thickness at end diastole (PWTd), LV ejection fraction (LVEF), aortic valve area (AVA), trans-aortic valve peak and mean pressure gradient were measured. The LVEDV and LVEF were measured by the biplane Simpson’s method from apical views. The AVA was estimated by the 2-dimensional Doppler method using the continuity equation. The LV mass was calculated by the formula as shown below:3 − (LVEDd)3]} + 0.6 g.LV mass = 0.8 × {1.04  and 14 patients did not receive 12-month echocardiographic evaluation [7 13.2%) in CD group and 7 (7.1%) in non-CD group]. A total of 123 patients completed 12 month echocardiographic evaluation, with 38 patients (30.9%) having new CD after TAVR and 85 (69.1%) without. At baseline, there were no statistical differences in any echocardiographic parameters between patients with and without new CD after TAVR  required more than 99% of ventricular pacing. 2 patients had less than 1% ventricular pacing, and another 2 patients had 43%, 22% ventricular pacing respectively.2) reduction , SWTd (mm) reduction  and LVEDd (mm) reduction  were observed only in non-CD group, with also a trend toward reduced LVEDV (ml)  and decreased LVESV (ml) . Figure 77 patients have received TAVR procedure for 3 years [32 41.6%) in CD group and 45 (58.4%) in non-CD group]; among these patients, 24 patients died [10  in CD group and 14  in non-CD group] and 7 patients did not receive echocardiographic evaluation [4  in CD group and 3  in non-CD group]. A total 46 patients completed 3 year echocardiographic evaluation, 18 patients (39.1%) with new CD after TAVR and 28 (60.9%) without. Baseline LVEF (%) before TAVR was better in CD group ,with significantly smaller LVESd (mm)  and LVESV (ml)  . They found that the changes both in LVESd and LVEDd were significantly different between these two groups. However, the impact of new CD on LV mass regression and remodeling, were less well described. The main findings of this study are: (1) clinical risk factors of new onset CD after TAVR are male sex and low THV implantation. (2) At 1-year, significant LV mass regression could be observed both in CD and non-CD group, but more pronounced in non-CD group. LVEF improvement as well as LVESd and LVESV reduction could only be found in the non-CD group. (3) At 3-year, sustained LV mass regression and a trend toward reduced LVEDV and LVESV could only be observed in the non-CD group. The results not only remind the operators to avoid low implantation during procedure, but also urge the device manufactures to make every effort to prevent new CD, especially as TAVR is now being extended to a younger and lower risk population.It was already known that new CD after TAVR had negative effect on LV function recovery23. In addition, the asynchronous ventricular activation leads to redistribution of circumferential shortening and myocardial blood flow, and then results in myocardial hypoperfusion in the absence of flow-limiting coronary artery disease26. The detrimental effects on LV geometry and function have been considered as one of possible mechanisms to explain why poorer functional status was observed in the population with post-TAVR LBBB, which has been illustrated in several studies27. The hypothesis is also congruent with observations that in chronic right ventricular pacing, heart failure hospitalization occurs more frequently in patients with depressed systolic function than in patients with normal systolic function28.Several clinical and experimental studies have established the potential adverse effects of long term LBBB and right ventricular (RV) pacing on LV function. Early activation of RV may lead to a decrease in cardiac output as well as intraventricular and interventricular dyssynchrony, thus resulting in LV systolic dysfunction and remodeling29 using cardiac magnetic resonance, evaluated 24 patients with new LBBB following TAVR, matched with 24 patients with a narrow post-procedure QRS. Similar to our findings, significant improvement of LVEDV as well as reduced indexed LVESV at 6-months were seen only in narrow QRS group but not in the post-TAVR LBBB group. The authors concluded that TAVR-induced LBBB is associated with less favorable cardiac reverse remodeling at medium term follow up. However, these results were limited by its small case numbers and short follow-up period to provide longer term evidence of the adverse impact of new CD on cardiac reverse remodeling.Dobson et al.31. Interestingly though, the LV mass regression was more pronounced in non-CD group (CD vs non-CD group: 8% vs 18%) despite similar post-TAVR AVA in both groups. Less LV mass regression in CD group may result from the slight increase in LVEDd and LVEDV at 1 year, in contrast to the slight reduction of LVEDd and LVEDV in non-CD group. The effect of LV dimension and volume change to mass regression became more pronounced at 3-year follow-up. In non-CD group, sustained LV mass regression was observed along with sustained LVEDd and LVEDV reduction. The stationary (or slightly increasing) LVEDd and LVEDV in CD group, on the contrary, offset the wall thickness reduction and resulted in less LV mass regression. Our results may also provide explanation to the more pronounced LV mass regression observed in surgical aortic valve replacement compared with TAVR in prior randomized study30, as the incidence of CD was higher in TAVR group using self-expanding prosthesis.The difference of LV mass regression in long term follow-up between the patients with and without CD could be considered as a consequence of different geometric change after TAVR. In the first year after TAVR, the LV mass regression mostly resulted from the decrease of LV wall thickness in response to increased AVA and LV unloading, which could be demonstrated by our findings and previous study32, and of intrinsic atrioventricular conduction increased from 25.9% at 7 days to 59.3% at 30 days19. Future larger study with longer term follow-up on the clinical outcome and detailed analysis of the PM recordings is mandatory. Furthermore, the patients who died within the interval of 1 year to 3 years follow-up might have experienced less LV mass regression and poorer LVEF improvement. Thus, the potential of a competitive risk bias could not be excluded.The main limitation of the present study was its small sample size, especially case numbers completing 3-year follow-up. Selection bias might exist, and it is mandatory to prove the hypothesis in a larger population. Second, the clinical significance of reverse LV remodeling following TAVR remains to be established. Third, the pacing percentage and the rate of pacemaker dependence among the patients receiving PM were not fully investigated. According to previous literature, overall pacemaker dependence after TAVR varied from 27 to 68%We concluded that in patients with severe AS receiving TAVR, the improvement of LV systolic function associated with decrease of LVESV at 1 year could be observed in non-CD group. Significant LV mass regression could be found in both groups at 1 year, but more pronounced in non-CD group. In limited patients completing 3-year echocardiographic follow-up, sustained LV mass regression and a trend toward reduced LVEDV and LVESV were observed in patients without post-TAVR CD.


Background: Pulmonary arterial wave reflection provides novel information about pulmonary artery hemodynamics in pulmonary hypertension (PH). PH is common in dogs with myxomatous mitral valve disease (MMVD), though research examining the relationship between pulmonary arterial wave reflection and MMVD with PH is lacking.Hypothesis/Objective: This study investigated conventional echocardiographic parameters and pulmonary artery wave reflection parameters before and after mitral valvuloplasty in canine patients with PH due to MMVD. The parameters were backward pressure (Pb), forward pressure (Pf), and the reflection coefficient calculated as the ratio of peak Pb to peak Pf (RC).Animals: The study subjects were 10 client-owned dogs receiving mitral valvuloplasty for MMVD with PH.Methods: Conventional echocardiographic parameters and pulmonary artery wave reflection parameters were measured before and after mitral valvuloplasty. The relationships between pulmonary artery wave reflection parameters and echocardiographic parameters, estimation of pulmonary artery systolic pressure, and right atrium pressure (RAP) gained by catheter in mitral valvuloplasty were also investigated. Post-operative echocardiography and the measurement of pulmonary arterial wave reflection were performed 2 weeks after mitral valvuloplasty.Results: The parameters of normalized left ventricular internal diameter at end-diastole (LVIDDN), E velocity, and the estimation of pulmonary artery systolic pressure were significantly reduced post-operatively compared with baseline measurements (p < 0.05). Post-operative Pb decreased significantly compared with pre-operative measurements  as did RC . A statistically significant positive correlation existed between wave reflection parameters and RAP, an estimation of pulmonary artery systolic pressure.Conclusions: Results demonstrate that mitral valvuloplasty can be used to treat secondary PH caused by MMVD, resulting in the improvement of post-operative echocardiographic and wave reflection parameters and a decrease in the right afterload. In some patients, some degree of vascular admittance mismatch persisted, despite the improvement of left atrial pressure. This may be indicative of residual pulmonary arterial disease, which may continue to adversely affect interactions between the right ventricle and the vasculature. Myxomatous mitral valve degeneration (MMVD) is the most common heart disease in dogs, with severe MMVD causing congestive heart failure, resulting in death within a year , 2. MediThis study evaluated the change in pulmonary artery wave reflection before and after MVP in canine patients with PH due to MMVD. In addition, we investigated the relationship between the pulmonary artery wave reflection and cases with residual post-operative PH by measuring pulmonary artery wave reflection before and after MVP in patients with PH due to MMVD.The study was carried out at a private clinic  between August 2019 and April 2021. The subjects were 10 client-owned dogs receiving MVP exclusively for MMVD with suspected PH due to left heart disease. Permission for this study was granted by SHIRAISHI Animal Hospital Animal Care and Use Committee (protocol number R2-062). Before subject enrollment, written, informed client consent was obtained. All cases were classified with American College of Veterinary Internal Medicine (ACVIM) stage C or D, as determined through comprehensive evaluation including medical history and records, physical examination, hematology, serum biochemistry, diagnostic electrocardiography, radiography, and echocardiography. MVP with cardiopulmonary bypass was performed in all cases.The definitive diagnosis of PH requires right heart catheterization (RHC). However, given RHC is difficult to apply in small animals. Therefore, PH were suspected if a maximal TR velocity of ≥3.4 m/s was observed, based on ACVIM consensus, and if the dogs presented with PH-related clinical signs. PH was also suspected if a maximal TR velocity of ≥2.9 m/s was observed via Doppler echocardiographic assessment, or if other echocardiographic findings suggestive of PH were found in dogs with PH-related clinical signs. Other echocardiographic findings were defined as the flattening of the interventricular septum, especially systolic flattening, pulmonary artery enlargement, or systolic notching of the Doppler RV outflow profile . ClinicaThe main causes of precapillary  were excluded using blood examination, ultrasonogram, thorax radiography as much as possible without hemodynamic examination by catheter.Conventional echocardiographic parameters and pulmonary artery wave reflection parameters were measured before and after MVP. The relationships between pulmonary artery wave reflection parameters and echocardiographic parameters, right atrium pressure (RAP) gained by catheter, and pulmonary artery systolic pressure gained by echo-Doppler were also investigated. Echocardiography and measurement of pulmonary artery wave reflection were performed 2 weeks after MVP.Pulmonary artery wave reflection can be obtained by simultaneously measuring pulmonary artery pressure and flow velocity. Previous research, however, reported that wave reflection as measured by Doppler echocardiography correlated with wave reflection measured by catheter, indicating that wave reflection can also be measured in this manner. The pulmonary artery wave reflection was calculated by measuring the TR flow and RVOT using Doppler echocardiography by the same method as in the previous paper . The met3), and c is the wave speed. Pressure attributed to forward-traveling  and backward-traveling  waves can be separated using Equations (2) and (3). Backward-traveling waves indicate pulmonary artery wave reflection.where dP is the temporal change in P, dU is the temporal change in U, ρ is the blood density  could be calculated using only the instantaneous pressure gradient of TR. In contrast, the U waveform was obtained by measuring flow at the right ventricular RV outflow tract (RVOT), using pulsed-wave Doppler. The calculations were performed throughout the ejection period. Wave separation analysis is performed on the pulse pressure and flow velocity waveforms by synchronizing waveforms of TR flow and RVOT flow using electrocardiogram. This analysis resulted in the determination of three wave reflection indices: Pb, Pf, and the reflection coefficient (RC), which was calculated as peak Pb/peak Pf. These waveforms were smoothened using a Savitzky–Golay filter and then ensemble-averaged over three cardiac cycles with reference to the R wave on the electrocardiogram. The calculations were performed using an in-house program code, written in MATLAB .TM 300 with a sector probe of five MHz . Analysis of pulmonary artery wave reflection was also performed by same echocardiography machine. Three consecutive heartbeats were recorded at the end of the expiratory phase. To evaluate structural and functional changes during the course of reverse remodeling of the left atrium and the left ventricle, combined conventional echocardiography protocol including Two-dimensional, M-mode, Doppler blood flow, and tissue Doppler imaging techniques from the right and left parasternal long- and short-axes views were carried out  was estimated by applying the simplified Bernoulli equation to a continuous-wave Doppler tracing of TR flow and adding a term of right atrial pressure as below.The RAP was measured at the time of MVP invasively.Atropine , fentanyl , and midazolam hydrochloride , were administered pre-operatively. Anesthesia was induced with propofol 1%  and maintained with 1–2 vol% of isoflurane  in 100% oxygen.The patient was placed in right lateral recumbency. The right femoral artery and vein were cannulated for measurement of atrial pressure (RAP). After patients were heparinized at a dose of 400 U/kg, the left carotid artery and jugular vein were cannulated for cardiopulmonary bypass (CPB). activated clotting time was used for determining the anticoagulant effect of heparin. Cardiac arrest was achieved by aortic clamping followed by the administration of cardioplegia from an aortic root cannula. MVP was performed as previously described. In brief, the left atrium was approached through a fifth intercostal thoracotomy and left auricle incision. The MVP is consisted of artificial chordae tendineae reconstruction and mitral annuloplasty, using expanded polytetrafluoroethylene. After the closure of the left atrium, the aorta was unclamped and sinus rhythm was restored. Patients were weaned from CPB after conducting modified ultrafiltration and confirming the stability of the hemodynamic system. A constant-rate infusion of protamine 4 mg/kg was administered for 30 min through the cephalic vein. The activated clotting time was measured after the end of the protamine infusion. After confirming that the protamine was antagonized, the chest was closed according to the standard method, and the crotch and cervical arteries and veins were anastomosed to finish the operation.p < 0.05. The normal distribution of the data was evaluated using a Kolmogorov–Smirnov test. The assumption of homogeneity of variances was determined by Bartlett's test. For normally distributed parameters, differences between groups were analyzed using a paired t-test. For non-parametric statistics, differences between groups were analyzed using a Wilcoxon matched-pairs signed-rank test. Spearman's correlation coefficients and multivariate linear regression analysis were used to assess the relationship between the pulmonary artery wave reflection parameters and echocardiographic parameters, and the hemodynamic parameters gained by catheter. Statistical analyses were performed using GraphPad Prism 8.0 .Continuous data are expressed as the mean ± standard deviation (SD). Categorical data are expressed as a number and percentage. The level of significance was set to n = 1), Chihuahua (n = 4), Maltese (n = 1), miniature dachshund (n = 1), mixed-breed (n = 2), Shiba Inu (n = 1). In accordance with the ACVIM classifications scheme, seven and three dogs were diagnosed with stage C and D ACVIM, respectively. When first diagnosed, 30% of patients had syncope, 20% of patients had ascites and/or pleural effusion. In addition, 20% of PH cases presented with septal flattening, and 30% had a notch in the pulmonary artery waveform at the initial visit. Before surgery, pimobendan and a diuretic drug had been prescribed in all dogs and sildenafil had been prescribed in only one dog. All canine subjects were discharged post-operatively within 2 weeks and in medication affecting hemodynamics  were discontinued. However, after hospitalization, two cases were prescribed sildenafil 0.5 mg/kg BID  due to presenting symptoms and echocardiography findings associated with PH. Two dogs with persistent PH after MVP presented with the flattening of the interventricular septum, however, TR was mild (TR velocity 3.0 m/s in both PH patient).A total of 10 dogs were the subject of this study, aged 9.6 ± 2.3 years old (range 7−14 years), and with a bodyweight of 4.6 ± 2.1 kg (range 2.4−10 kg). Breeds were Cavalier King Charles spaniel (p < 0.05) post-operatively: LVIDd, LVIDDN, LA/Ao, FS, E velocity, E′ sep, E′ lat, A′ lat, RVOT, and TR velocity. Echocardiography revealed a reduction in the left-sided chamber size and stable mild mitral regurgitation after MVP in all dogs .r = 0.5, p = 0.22; Pf vs. Estimated sPAP, r = 0.58, p = 0.08; RC vs. Estimated sPAP, r = 0.2, p = 0.58). On the other hands, there was a statistically significant positive correlation between 676 Pb, RC, and RAP, Estimated sPAP . RAP and Estimated sPAP measured during surgery were 11 ± 2.8 mmHg and 69.5 ± 18.73 mmHg. No significant correlation was identified between pulmonary artery wave reflection parameters and other echocardiographic parameters , respectively. RC demonstrated significant effect on RAP and Estimated sPAP . Pb and RC did not significantly affect other parameters.Result of linear regression analysis of the parameters of pulmonary artery wave reflection, hemodynamic parameters are shown in This study investigated both conventional echocardiographic parameters and pulmonary artery wave reflection parameters before and after MVP in patients with PH due to MMVD. Results indicated pulmonary artery wave reflection was closely related to PH that persisted despite treatment.In recent years, cardiac surgery techniques in the small animal field have made great strides and MVP has contributed significantly to lowering left atrial pressure by improving mitral regurgitation caused by MMVD –37. ReduPulmonary artery wave reflection occurs when the forward flow out of the right ventricle is reflected by the pulmonary arterial tree, generating a backward wave. Pulmonary artery wave reflection can be detected by measuring pulmonary artery flow and pressure simultaneously using wave intensity analysis. In particular, wave reflection is enhanced when the energy transmission property changes between the proximal and distal vasculature due to vascular remodeling, arteriosclerosis, or thrombus , 24, 40.In eight out of 10 cases, the post-operative Pb and RC decreased significantly compared with pre-operative measurements. This was attributed to the decrease in pulmonary arterial pressure and the pulmonary vascular resistance, through improving the pulmonary vein pressure by MVP. However, the Pb and RC of two cases in which pulmonary hypertension remained after MVP had higher Pb and RC than the other eight cases, suggesting that the wave reflection did not improve. It could be that the two cases may have already progressed to reactive post-capillary-PH, due to remodeling of the pulmonary artery. Therefore, we suggest that pulmonary hypertension remained and the wave reflection was a high value, despite the pulmonary vein pressure decreasing after MVP. Two dogs with persistent PH after MVP presented with flattened interventricular septum despite mild TR flow velocity (TR velocity 3.0 m/s in both PH patient). Although the measurement of estimated pulmonary artery systolic pressure using TR is often used as a screening tool for the diagnosis and severity of PH, the accuracy of this method has been questioned because it is affected by right ventricular dysfunction and technical errors , 44. ThuSu et al. previously demonstrated that in patients with chronic thromboembolic pulmonary hypertension, both a large wave reflection and symptoms related to PH remained and were not improved despite pulmonary endarterectomy being performed . DespiteIn conclusion, both before and after MVP in PH patients with left heart failure, high wave reflection was observed. The magnitude of wave reflection diminished in almost all patients after MVP. From the results, we conclude that MVP is one of the treatment methods for secondary PH due to MMVD. Through this method post-operative echocardiographic and wave reflection parameters can improve and the right afterload can be reduced. In some patients, however, despite improving the left atrial pressure due to left heart failure after MVP, some degree of vascular admittance mismatch persisted. This may be indicative of residual pulmonary arterial disease, which may continue to adversely affect interactions between the right ventricle and the vasculature.In this study, the number of PH due to MMVD cases was small; therefore, additional studies should be performed. PH may not have been accurately evaluated, given pulmonary vascular resistance and pulmonary artery wedge pressure—the gold standards for evaluating the hemodynamic assessment of PH—were not measured using a catheter. The value of the pulmonary artery wave reflection may differ from that measured by a catheter since the measurement method is by non-invasive Doppler echocardiography. In this non-invasive method using echocardiography, since pressure and flow velocity profile are gained at different timing, pulmonary arterial wave reflection may be affected by situation of examined dogs (exciting level) and respiration timing. In clinical cases, measuring the pulmonary artery wave reflection in cases that do not exhibit TR can be difficult, as can the evaluation of wave reflection in cases that present with severe arrhythmia. Right ventricular function  wasn't measured in this study. However, we think the indicator of right ventricular function cannot be evaluated correctly after surgery. After MVP, heart function decreases temporarily due to invasive open-heart surgery. In addition, cardiac contractility decreases ostensibly due to reducing the volume loading by improved mitral regurgitation. Therefore, relationship between pulmonary arterial wave reflection and right ventricular function are unclear. In the future, it is necessary to investigate the relationship between wave reflection and the right ventricular function.The scale of this study was small and that limits being able to affirm that the technique has been validated completely. More animal research and subsequent research in humans are necessary to clinically apply this novel indicator.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The animal study was reviewed and approved by Shiraishi Animal Hospital Animal Care and Use Committee (protocol number R2-062). Written informed consent was obtained from the owners for the participation of their animals in this study.TY and KM designed the study and prepared original draft. KS acquired and analyzed the data. LH interpreted the results and critically reviewed the results. RT and TU edited the manuscript and approved the final version of the manuscript. All authors contributed to the article and approved the submitted version.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.


Background: Late enhanced cardiac magnetic resonance (CMR) images of the left ventricular myocardium contain an enormous amount of information that could provide prognostic value beyond that of late gadolinium enhancements (LGEs). With computational postprocessing and analysis, the heterogeneities and variations of myocardial signal intensities can be interpreted and measured as texture features. This study aimed to evaluate the value of texture features extracted from late enhanced CMR images of the myocardium to predict adverse outcomes in patients with dilated cardiomyopathy (DCM) and severe systolic dysfunction.Methods: This single-center study retrospectively enrolled patients with DCM with severely reduced left ventricular ejection fractions (LVEFs < 35%). Texture features were extracted from enhanced late scanning images, and the presence and extent of LGEs were also measured. Patients were followed-up for clinical endpoints composed of all-cause deaths and cardiac transplantation. Cox proportional hazard regression and Kaplan–Meier analyses were used to evaluate the prognostic value of texture features and conventional CMR parameters with event-free survival.Results: A total of 114 patients  with severely impaired systolic function  were followed-up for a median of 504.5 days. Twenty-nine patients experienced endpoint events, 12 died, and 17 underwent cardiac transplantations. Three texture features from a gray-level co-occurrence matrix (GLCM)  showed good prognostic value for adverse events when analyzed using univariable Cox hazard ratio regression . When each of the three features was analyzed using a multivariable Cox regression model that included the clinical parameter (systolic blood pressure) and LGE extent, they were found to be independently associated with adverse outcomes.Conclusion: Texture features related LGE heterogeneities and variations  are novel markers for risk stratification toward adverse events in DCM patients with severe systolic dysfunction. Idiopathic dilated cardiomyopathy (DCM) is one of the most common non-ischemic cardiomyopathies, which is associated with a poor prognosis due to sudden cardiac death and heart failure (HF) , 2. LeftTexture analysis is a quantitative imaging-processing method, which can detect subtle pixel formation features that cannot be observed by direct visual inspection , 13. FolA retrospective study was conducted at a local institute on patients enrolled between June 2014 and April 2020 through searching the Picture Archiving and Communication Systems and medical records. Our study was conformed to the principles outlined in the Declaration of Helsinki and was approved by the local ethics committee. Due to the retrospective nature of the study, written informed consent from patients was waived by the local ethical committee.Patients referred to contrast-enhanced CMR examination for evaluation of cardiomyopathic etiologies at the local institute were retrospectively reviewed. By reviewing medical records, those who had been previously diagnosed with DCM and with LVEF < 35% were finally included. The diagnosis of DCM was made according to the criteria of the WHO/International Society and Federation of Cardiology . Exclusi2, matrix 256 × 256, slice thickness 8 mm, slice gap 1.6 mm, temporal resolution < 45 ms, number of calculated cardiac phases 25. LGE images were acquired 10–15 min  after cumulative intravenous administration of 0.2 mmol/kg (median amount 13.0 mmol) of gadopentetate dimeglumine  or gadobutrol , with the same positions used for cine-CMR imaging. After selecting an inversion time for optimal normal myocardium nulling with an inversion time scout sequence, a phase-sensitive inversion recovery technique was used to acquire LGE images with the following parameters: field of view, 400 × 360 mm2; matrix, 256 × 256; slice thickness, 8 mm; slice gap, 1.6 mm.Cardiac magnetic resonance was performed at 1.5 or 3.0 T MR scanners  with 12-channel surface-phased array coils. The standard acquisition protocol included steady-state free-precession cine-sequences in 3 long-axis views and continuous short-axis views, covering the entire LV and late enhancement sequences after administrating the gadolinium contrast agent. Typical imaging parameters for cine imaging were as follows: field of view 415 × 340 mmThe conventional analysis was performed offline using dedicated commercially available software  following standardized recommendations by researchers blinded to clinical data. Conventional parameters derived from cine images included EF of bilateral ventricles, end-systolic and end-diastolic volumes of bilateral ventricles indexed to body surface area, and LV mass index. The presence and extent, and LGE distributions were evaluated by two senior operators with a consensus. An LGE was defined as an area with a signal intensity >6 standard deviations above the mean normal myocardial signal intensity derived in a remote location using the same short-axis slice. After drawing the contours of the epi- and endomyocardium, the extent of LGE was calculated as the percentage volume of enhanced myocardium accounting for the whole left ventricular myocardium. The LGE distribution was classified into different patterns, including septal, free-wall, or as involving both septal and free-wall.In late enhanced scanning, the LV myocardium was segmented and extracted in continuous short-axis views according to the contours drawn in the conventional analysis process. The process of texture feature extraction was achieved with a radiomic python toolbox named pyradiomics . The orivia telephone in October 2020 by researchers blinded to the clinical information. The endpoint was defined as the composite of all-cause death and heart transplantation. The duration of follow-up was calculated from the baseline CMR study date to the occurrence of endpoint event or last contact with the patient. Baseline clinical information for each patient was retrieved from medical records.All patients were followed-up Continuous variables were expressed as medians and interquartile ranges (IQRs). Categorical data were described as frequencies and percentages. For assessment-extracted texture features robustness, inter-/intraclass correlation (ICC) was analyzed based on different myocardial segmentation groups. The Spearman correlation coefficient with cluster analysis was performed to divide the texture features into different groups. Then, multivariate Cox proportional hazard regression analysis with backward stepwise selection was performed in each group to identify the non-redundancy representative features. This process was implemented again on all identified features to determine a non-redundant set of prognostic indicators.t-test, Wilcoxon–Mann–Whitney test, χ2 test, or Fisher's exact test were used to compare the differences between patients with and without endpoint events. Kaplan–Meier (K–M) curves and log-rank tests were used to analyze the association between baseline variables and cardiac events. For continuous variables, median values were chosen for transforming into categorical data. Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CIs) were used to assess the association between baseline variables and endpoint events in both univariate and multivariable analyses. The prognostic abilities of constituted models were assessed by calculating the concordance probability (C index). A two-sided value of p < 0.05 was considered statistically significant. All analyses were performed using SPSS software .Student's A total of 114 patients were included after multiple selection processes . The medp = 0.873). However, the RVEF value was higher in patients with adverse outcomes. Indexed parameters of ventricular volume and LV mass showed no differences between the groups. The presence of LGEs was prevalent in the study cohort (83.3%), and there was no significant difference between the events group and those without cardiac events. In addition, the locations of LGE on LV myocardium did not show a significant difference between the groups. However, the extent of LGE areas, accounting for the entire LV myocardium, was much more significant in patients who experienced adverse events .Baseline CMR parameters of both the groups are shown and compared in A total of 58 texture features with good reproducibility, defined as ICCs higher than 0.7, w included in the final analysis. There were six first-order statistical features, 18 GLCM features, 11 GLRLM features, 10 GLSZM features, 10 GLDM features, and 3 NGTDM features. They were divided into 10 different groups by cluster analysis; all pairs of features within each group had Spearman correlation coefficients >0.4. According to the prognostic value of the texture features of adverse outcome, the backward stepwise Cox method was used to select robust texture features among each group. A total of 20 texture features was chosen from 10 different groups. To further minimize the number of meaningful features and find out more robust markers, backward Cox analysis was implemented again between these candidate features, and three features  were finally selected. Their basic characteristics are described in p < 0.05 for all, The baseline clinical variables, conventional CMR parameters, and texture features derived from late enhanced images were analyzed to evaluate the association with adverse outcomes . Among tp < 0.05 for all three features, Considering that a limited number of patients experienced endpoint events, and after assessing collinearity and evaluating clinical interpretability, systolic blood pressure (SBP) and LGE extents were included in multivariable Cox regression analysis with selected texture features. When incorporated into the multivariable Cox regression model, each texture feature was identified as a significant independent predictor of adverse events  and 3.0 T (n = 48) scanners  and between patients administrated with Magnevist (n = 67) and Gadovist (n = 47) . The median time interval between contrast administration and image acquisition was 12.40 min, and there was no significant difference between the patients group . The median amount of contrast agent used for whole cohort was 13 mmol and there was no significant difference between the patients group . However, further studies are required to identify factors that influence the values of these texture features. Besides, though with fixed slice thickness and gap, the minimal variation in slice number between patients caused by the length of LV might also affect the texture values. Finally, as the final three texture features were selected through a statistical process, the true meaning of the selected texture features needs further investigation by correlating these features with histological results in patients with DCM.As for the imaging acquirement, images from scanners with different static field strengths (1.5 and 3.0 T) and contrast agents were analyzed together with a normalization process before feature extraction in our study. Additionally, the minimal differences during late enhanced image acquisitions that affect the texture features, such as delay time after contrast injection and inversion time selection are unknown. In our study, we compared the texture features between patients examined with different scanners and patients who received different contrast agents. We found that the three important texture features  that are closely related to survival outcome showed no differences between the patient groups. Specifically, there is no significant differences between patients when performed on 1.5T  are novel markers associated with adverse outcome in DCM patients with severely reduced systolic function. They demonstrate a promising ability to predict adverse events beyond conventional LGE parameters in patients with severe DCM.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethics Committee of Tongji Medical College of Huazhong University of Science and Technology. Written informed consent from patients was waived by the ethical committee due to retrospective nature of the study.CZ and JW contributed to the conception of the study. SS, CW, and ZH analyzed and interpreted the clinical data and imaging data and they were major contributors in writing the manuscript. QP helped perform the analysis with constructive discussions. XZ and TZ contributed greatly in writing and editing the manuscript. All authors read and approved the final manuscript.This study was funded by the National Natural Science Foundation of China (Grant No. 81701653).XZ is employed by Siemens Healthineers and TZ was employed by Philips Healthcare. The remaining 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.


Two-dimensional speckle-tracking echocardiography represents an advanced imaging technique that allows the analysis of global and regional myocardial function, cardiac rotation and synchronicity using deformation imaging. It has gained growing importance over the last decade, especially in human medicine as a method of evaluating myocardial function. This review aims to give an overview of the current understanding of this technique and its clinical applicability in the field of veterinary medicine with a focus on early detection of left ventricular dysfunction in dogs.Two-dimensional speckle-tracking echocardiography (2D–STE) is an advanced echocardiographic technique based on deformation imaging that allows comprehensive evaluation of the myocardial function. Clinical application of 2D–STE holds great potential for its ability to provide valuable information on both global and regional myocardial function and to quantify cardiac rotation and synchronicity, which are not readily possible with the conventional echocardiography. It has gained growing importance over the past decade, especially in human medicine, and its application includes assessment of myocardial function, detection of subclinical myocardial dysfunction and serving as a prognostic indicator. This review illustrates the fundamental concepts of deformation analysis and gives an overview of the current understanding and its clinical application of this technique in veterinary medicine, with a focus on early detection of left ventricular (LV) dysfunction in dogs.  Standard echocardiography is a widely used non-invasive method for evaluating myocardial function. In veterinary medicine, left ventricular (LV) fractional shortening (FS) is the most commonly used echocardiographic measurement of systolic function, readily obtained from LV chamber dimensions ,2. HowevThe 2D–STE technique is advanced echocardiography that assesses myocardial function by quantifying myocardial deformation. It is based on the formation of “speckles”  generated by interactions between myocardial tissue and ultrasound beams in standard gray scale two-dimensional (2D) echocardiographic images ,4. TrackL is the instantaneous length, and L0 is the initial length . Add. Add4]. Longitudinal strain is evaluated in apical 2-, 3-, 4-chamber views, and it represents myocardial deformation along the longitudinal axis a. In humLongitudinal fibers of the myocardium consist mainly of sub-endocardial fibers and most significantly contribute to the longitudinal myocardial function ,14,15. TRadial and circumferential strains are evaluated in parasternal short axis views at the level of basal, papillary muscles and apex b,c. LikeMyocardial contractility occurs in radial and circumferential directions, and radial and circumferential strains have been shown to be sensitive indicators of myocardial contractility in dogs . It mustCombining the two opposing movements at the apex and the base results in the twisting of the heart during systole and untwisting during early diastole along the long axis ,11. The LV dyssynchrony, defined as an uncoordinated contraction of LV, has detrimental effects on regional myocardial perfusion, metabolism and electrophysiology, and leads to compromised global LV systolic function and energy insufficiency . In humap < 0.001, respectively); nevertheless, the circumferential strain had better correspondence with a smaller bias .,33.32,33Chetboul et al. was the first to provide data on strain analysis in awake dogs . Radial p = 0.01; r = 0.56, p < 0.001, respectively), whereas, a study with controlled HR using right-atrial pacing showed no significant changes with increased HR .,44.40,44DCM is the most common myocardial disease in dogs, characterized by progressive chamber dilation and impaired myocardial contractility ,53,54,55Ro et al. reported serial changes of N-terminal pro-brain natriuretic peptide (NT–proBNP) and 2D–STE with disease progression observed in a Golden Retriever diagnosed with DCM and sub-aortic stenosis (SAS)  16]. Co. Co16]. PDA is the most common congenital heart defect in dogs, resulting from the failure of the ductus arteriosus to close, a normal fetal structure that shunts blood from the pulmonary artery to the aorta by bypassing the nonfunctional lung and normally closes soon after birth . After bSubsequently, Spalla et al. evaluated changes associated with the surgical closure of the PDA  48]. Du. Du48]. p = 0.001), without affecting the epicardial longitudinal or the radial strains [SIRS is a clinical syndrome of infectious or non-infectious origin causing secondary multiple-organ dysfunction or death due to the excess release of cytokines. Cardiac dysfunction in SIRS has been demonstrated by an increase in cardiac biomarkers, such as NT–proBNP, cardiac muscle troponin T (cTnT) and lactate in dogs ,58. Alth strains . The sub strains ,15. Cons strains . HAC is an endocrinological disorder characterized by the chronic elevation of glucocorticoid in the blood. Systemic hypertension, LV hypertrophy and myocardial fibrosis are commonly recognized cardiovascular changes in humans and dogs with HAC ,61. In v−1 made possible the distinction between dogs with severe PVE and non-surviving dogs with 100% sensitivity and specificity [−1 at the mid-septal epicardial segment may indicate a grave prognosis [PVE, caused by the infection of canine parvovirus (CPV-2), is presented as acute hemorrhagic gastroenteritis with high fatality in young dogs ,63. CPV-cificity . Such rerognosis . In human medicine, the importance of 2D–STE analysis in evaluating myocardial function has been recognized, and a consensus document has been published by the EACVI and ASE to standardize deformation analysis . Moreove2D–STE analysis has gained increasing significance in human medicine over the past decade, and it is also becoming a promising tool for evaluating myocardial function in veterinary medicine. There is growing evidence that superior deformation parameters can serve as an indicator of myocardial function compared to conventional parameters for early diagnosis of myocardial dysfunction and as a possible prognostic indicator in both human and veterinary medicine. Additional information provided by the analysis of rotation, synchronicity and bull’s-eye maps by the 2D–STE analysis allow more comprehensive and accurate evaluation of myocardial function. There is no doubt that further development will allow deformation analysis to mature and play an important role in routine clinical use, with better diagnostic accuracy and reliability for dogs.


Background: The substrate for ventricular tachycardia (VT) in patients with structural heart disease is usually complex and often requires extensive ablation. As a result, the incidence of major procedure-related complications has been reported to be higher when compared to patients without structural heart disease. In this study, we present a rare complication after extensive substrate modification of scar-related VT.Case: A 65-year-old man with ischemic cardiomyopathy was referred to the electrophysiology laboratory for radiofrequency ablation of VT following repetitive implantable cardioverter defibrillator shocks within a short period. As with hemodynamic intolerance of induced VT, an approach involving extensive endocardial substrate modification to reduce the arrhythmogenicity of the scars was adopted. After the procedure, the heart function of the patient deteriorated significantly. The postprocedural ECG showed a bizarre, extremely wide surface QRS complex (360 ms), termed as homologous ventricular separation. The pronounced dyssynchrony of the ventricle was corrected by an upgrade to cardiac resynchronization therapy with defibrillation (CRT-D). As a result, the symptoms of the patient improved significantly. The width of the intrinsic QRS complex was not recovered during an 18-month follow-up.Conclusion: Homologous ventricular separation is a rare arrhythmia, manifested as two separated QRS waves. This case report demonstrates, for the first time, that homologous ventricular separation may occur after extensive substrate modification of scar-related VT. CRT-D can correct the dyssynchronous ventricle caused by homologous ventricular separation. For patients with structural heart disease, catheter ablation is indicated as adjunctive treatment when recurrent ventricular tachycardia (VT) leads to repetitive implantable cardioverter defibrillator (ICD) therapies within a short time. Catheter ablation of VT has been shown to improve VT-free survival at long-term follow-up in the setting of ischemic cardiomyopathy . AlthougA 65-year-old man with ischemic cardiomyopathy was referred to the electrophysiology laboratory for radiofrequency (RF) ablation of VT following repetitive ICD shocks, even after appropriate antiarrhythmic therapy . A baselUpon close examination of the limb leads, we found a bizarre, extremely wide surface QRS complex (360 ms), which was composed of two independent QRS complexes separated by an isoelectric baseline. The first QRS complex in this sequence, highlighted in This evaluation led to the recommendation of an upgrade to cardiac resynchronization therapy with defibrillation (CRT-D). Due to the deterioration of heart function, even after appropriate heart failure therapy, the patient consented to the upgrade. The procedure was successfully performed with extracorporeal membrane oxygenation support . The intCardiac resynchronization therapy with defibrillation has demonstrated improved outcomes in selected patients with heart failure. The therapeutic benefit of CRT-D is achieved by the mechanical correction of the dyssynchronous left ventricle. Therefore, the greater the intraventricular dyssynchrony, which manifested as a widened surface QRS complex, the greater the benefit of CRT-D . To imprThere are two strategies for the ablation of scar-related VT: (1) standard strategy: selective targeting the critical isthmus that supports the development and maintenance of VT  and 2) substrate modification: extensive substrate modification to reduce the arrhythmogenicity of scarring without any specific arrhythmia targeting. In a meta-analysis, Briceno et al. found that complete substrate modification results in a lower risk of long-term ventricular arrhythmia recurrence and all-cause mortality than standard ablation and incomplete substrate modification (3). In addition, the complication rate of substrate modification-related was approximately 7% including complete atrioventricular block, acute hemodynamic decompensation, puncture hematoma, cardiac tamponade, stroke/transient ischemic attack, phrenic nerve palsy, transient ST-segment elevation, and death  substrat. To dateThe original contributions presented in this study are included in the article. Further inquiries can be directed to the corresponding author.Written informed consent was obtained from the participant for the publication of this case report .XYX, MY, YXS, QL, CYJ, and FSM: contribute to conceptualization. XYX, YXS, QL, and MY: were involved in data collection, validation, and formal analysis. XYX: wrote the manuscript. All authors reviewed and approved the final manuscript for publication.This study was supported in part by the Natural Science Foundation of Ningbo 2017A610200 and 2014A610270 for open access publication fees.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.


Background: Right ventricular (RV) function predicts survival in numerous cardiac conditions, including left heart disease. The reference standard for non-invasive assessment of RV function is cardiac magnetic resonance imaging (CMR). The aim of this study was to investigate the association between pre-procedural CMR-derived RV functional parameters and mortality in patients undergoing transcatheter aortic valve implantation (TAVI).Methods: Patients scheduled for TAVI were recruited to undergo pre-procedural CMR. Volumetric function and global longitudinal and circumferential strain (GLS and GCS) of the RV and left ventricle (LV) were measured. The association with the primary endpoint  was analyzed with Cox regression.Results: Of 133 patients undergoing CMR, 113 patients were included in the analysis. Mean age was 81.8 ± 5.8 years, and 65% were female. Median follow-up was 3.9 [IQR 2.3–4.7] years. All-cause and cardiovascular mortality was 14 and 12% at 1 year, and 28 and 20% at 3 years, respectively. One-year all-cause mortality was significantly predicted by RV GLS , RV ejection fraction , RV end-diastolic volume index , and RV end-systolic volume index . In receiver operating characteristic (ROC) analysis for 1-year all-cause mortality, the area under the curve was 0.705 (RV GLS) and 0.673 (RV EF). Associations decreased in strength at longer follow-up. None of the LV parameters was associated with mortality.Conclusions: RV function predicts intermediate-term mortality in TAVI patients while LV parameters were not associated with outcomes. Inclusion of easily obtainable RV GLS may improve future risk scores. Transcatheter aortic valve implantation (TAVI) is a minimally invasive treatment for patients suffering from severe aortic stenosis and is now available for more than a decade. Since then, procedure numbers are steadily increasing and are expected to rise further . While iUntil recently, the right ventricle (RV) has not received much attention in this respect. However, emerging evidence shows that the RV plays a key role in many cardiac conditions, including primary left heart disease . A prognDue to the complex shape of the RV, standard echocardiography relies on tricuspid annular systolic excursion, fractional area change, or more recently strain as surrogates for RV function. Unlike echocardiography, cardiac magnetic resonance imaging (CMR) not only is capable of myocardial tissue characterization but also allows for more accurate measurement of cardiac chamber volumes. Measures of myocardial deformation derived from CMR feature tracking predict cardiovascular events . CMR is This study aims to elucidate the association between pre-procedural RV functional parameters derived from CMR and mortality in patients undergoing TAVI.In this single-center cohort study, patients with severe aortic stenosis scheduled for TAVI at the Division of Cardiology, Medical University of Graz were prospectively recruited to undergo pre-procedural CMR between May 2011 and March 2015, in the absence of CMR contraindications . Patients who underwent a successful transfemoral TAVI procedure with a CoreValve (Medtronic) prosthesis were included in the study. Cases with a CMR image quality insufficient to allow reliable analysis were excluded.The primary endpoint was all-cause mortality  at 1 yea3 for long axes and 1.4 × 2.2 × 8 mm3 for short-axis views. To compensate for breathing artifacts, threefold averaging was used. Using dedicated software , right and left ventricular (LV) end-diastolic and end-systolic volumes  were determined from a short-axis stack according to recommendations . Steady-state free precession cine sequences with retrospective electrocardiographic gating were acquired during free breathing in two-, three-, and four-chamber views and a stack of gapless slices in short-axis view to cover the entire left and right ventricle. Typical protocol parameters were: echo time 1.2 ms; measured temporal resolution 37–51 ms reconstructed to 30 phases; resolution 1.4 × 1.7–2.0 × 6 mmndations  and indep value of <0.05 was considered statistically significant.Statistical analysis was performed using SPSS Statistics 25.0.0.1 (IBM). Parameters are presented as mean ± standard deviation, median [interquartile range] or percentage (absolute numbers). The primary endpoint was 1-year all-cause mortality; associations with mortality were analyzed in uni- and multivariate Cox regression models. To ensure acceptable proportional hazards in Cox regression, follow-up was truncated at 1 year. For Kaplan–Meier plots, variables were dichotomized at their median. Receiver operating characteristic (ROC) analysis was performed for 1-year all-cause mortality. Area under the curve was compared with the DeLong method using the package pROC in R 3.5.1 . A n = 10) and an enlarged LV in 32.7% (n = 37) (n = 32) and 32.7% (n = 37), respectively. Detailed baseline characteristics are presented in During the study period, a total of 296 patients underwent TAVI at our institution; of those, 133 patients had pre-procedural CMR (at a median of 2 [1–4] days before the procedure). Exclusion criteria were met by 20 patients, leaving 113 patients qualifying for analysis . The coh(n = 37) . RV and n = 16) and 28% (n = 32), and cardiovascular mortality was 12% (n = 13) and 20% (n = 23) at 1 and 3 years, respectively. Significant differences in RV EF, RV GLS, RV ESV, and RV EDV index were found between those who survived after 1 year and those who did not .On analysis of the secondary endpoints , RV EF aWe also assessed RV to pulmonary artery coupling using the ratio of RV GLS/invasive mean pulmonary artery pressure (mPAP), which was not significantly associated with mortality . Interesp = 0.003; RV EF vs. LV EF: ΔAUC = 0.145, p = 0.035). The difference in the area under the curve was not significant for comparisons of RV GLS with RV EF , STS score , or NT-proBNP .Additional ROC analyses for 1-year all-cause mortality  illustraOur data illustrate that RV functional parameters, especially RV GLS and RV EF, associate with intermediate-term outcomes in patients undergoing TAVI. Intriguingly, this association was much stronger than in corresponding LV parameters, which did not predict outcomes in our cohort.When assessing the RV, the main advantage of CMR is its unique ability to accurately measure volumes, a task that is not easily achieved by echocardiography. Our study shows that both volumetric parameters (such as EF and EDV), as well as measures of RV myocardial contraction (RV GLS), predict mortality after TAVI. These associations were independent from multiparametric clinical risk scores. In contrast to the LV, longitudinal contraction pre-dominates RV function. Thus, GLS reflects RV function better than GCS, which was not associated with outcomes. Compared to volumetric parameters, RV GLS is easy to measure and, importantly, it can also be assessed by widely available echocardiography if acoustic windows permit. In line with our results, RV function assessed by echocardiography is also associated with mortality in patients with severe aortic stenosis , 24 and Importantly, LV function, which is usually central in clinical assessment, did not predict mortality in our cohort. Consistent with our findings, other studies showed that LV EF predicted outcomes only in the subgroup of low gradient aortic stenosis , 27. In When assessing the prognostic value of pulmonary hypertension, we found that the mortality prediction of mPAP became only evident at longer follow-up. To further investigate the interdependency with the pulmonary vasculature, we related RV function assessed by CMR RV GLS to RV afterload using invasively measured mPAP and thereby assessed RV to pulmonary artery coupling. This approach was similarly applied before in other collectives but with estimating rather than directly measuring pulmonary artery pressures and relying on echocardiographic TAPSE , 34. PatWhen analyzing the survival curves of the full available follow-up, long-term follow-up for more than 3 to 4 years increasingly attenuated survival prediction. This observation is likely explained by the age distribution of TAVI patients where non-procedure-related mortality is high and dominates after a few years.This is the first study to comprehensively analyze the RV with gold standard CMR in patients undergoing TAVI including long-term follow-up and invasive hemodynamic assessment. This was accomplished in a reasonably sized cohort, although larger numbers might have allowed more extensive analyses with higher power for the detection of weaker associations. Our cohort reflects a typical TAVI cohort and mostly consisted of patients with high gradient aortic stenosis; thus, findings may be different in patients suffering from low gradient aortic stenosis where LV function may discriminate outcome better. The use of CMR (excluding patients with pacemakers and severely reduced kidney function) and the non-consecutive nature of our cohort may induce a certain selection bias in the study cohort.RV function predicts intermediate-term mortality after TAVI while LV-derived parameters do not. In particular, RV GLS is a promising parameter to stratify outcomes after TAVI, as the echocardiographic equivalent measures of longitudinal contraction (GLS and TAPSE) can be easily obtained and included in future prospectively validated clinical risk scores, which may help to improve patient selection.The raw data supporting the conclusions of this article will be made available by the authors on request, without undue reservation.The study involving human participants was reviewed and approved by the Ethics committee of the Medical University of Graz, Graz, Austria. The patients provided their written informed consent to participate in this study.JS and PR conceptualized and designed the study. JS organized and collected data, performed statistical analyses and drafted the manuscript. CK analyzed cardiac magnetic resonance images. DZ and DH collected clinical and outcome data. UR acquired cardiac magnetic resonance images and wrote sections of the manuscript. JB recruited patients. PR, DZ, UR, GT, JB, AZ, MF, and AS revised the manuscript critically for important intellectual content. JS, JB, and PR supervised the study. All authors read and approved the submitted version.GT received consultancy fees and unrestricted research support from Abbott, Medtronic, Biotronic and Boston Scientific, not related to this work. The remaining 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.


Widely established compared to myocardial perfusion imaging, cardiac autonomous nervous system (CANS) assessment by radiopharmaceutical means is of potential use especially to arrhythmogenic diseases not correlated with anatomic or functional alterations revealed by classical imaging techniques. Molecular imaging of both pre- and postsynaptic functions of the autonomous nervous system is currently feasible, since single photon emission tomography (SPECT) and positron emission tomography (PET) have the ability to reveal the insights of molecular pathophysiology depicting both sympathetic and parasympathetic imbalance in discrete heart pathologies. This review provides not only a brief presentation of radiopharmaceuticals used for non-invasive CANS imaging in the case of ventricular arrhythmias, but also a current update on ventricular tachycardias, cardiomyopathies, Brugada and Long QT syndrome literature. Both radiopharmaceuticals depict cardiac sympathetic activity by mimicking the neuronal transport and storage process of norepinephrine. A radiotracer’s success is dependent upon its behavioral similarities to the endogenous neurotransmitter.The autonomous nervous system provides cardiac dynamic control during the entire life. A multilevel neural network is responsible for control of chronotropy, lusitropy, dromotropy, and inotropy function. Ventricular arrhythmogenesis is commonly attributed to impaired autonomic innervation and pre/postsynaptic imbalance . NuclearN-[11C]- methylquinuclidinyl benzilate ([11C]-MQNB) has been the tracer with the highest affinity towards muscarinic acetylcholine receptors and is considered the best representative of radiopharmaceuticals assessing the parasympathetic arm of the cardiac autonomous nervous system [The parasympathetic arm of the heart nervous system primarily uses acetylcholine (ACh) and alternatively peptides as the physiological neurotransmitters. s system .18F] dopamine and [11C] epinephrine, the substrate analogues such as [123I]-MIBG, [11C]-mHED and [11C]-phenylephrine and uptake-1 inhibitors such as [11C]-methylreboxetine -MIBG  breakdown -EPI  and it is proven to be cost effective. As a result, several attempts for designing 18F labelled traces for imaging the sympathetic nervous system have been made.Despite the advantages that carbon-11 radiopharmaceuticals such as HED have, their short half-life, of 20 min, limit the flexibility on their transportation, leading to the necessity of on-site cyclotron productions. As a result, both the designing of new radiotracers and the price of the existing radiopharmaceuticals are affected. On the other hand, fluorine-18 has a longer half-life of 110 min which is considered ideal for the design and development of new radiotracers, and can be dispatched from a central production site to several smaller facilities for administration. The aforementioned model of a central production site has been established for the production and use of 18F]-LMI1195 .[-LMI1195  is so fa6F-DA can be used for imaging the function of cardiac sympathetic innervation. It exhibits almost identical properties to an endogenous dopamine neurotransmitter with respect to uptake and release kinetics and metabolism . Dopamin18F]-4F-MHPG (18F]-fluoro-4-hydroxy-phenelthylguadinine ([18F]-3F-PHPG) was produced and investigated. [-4F-MHPG  was desi123I]-MIBG uptake often decreases in patients with cardiomyopathies, revealing alterations in the adrenergic innervation in the heart of these patients -MIBG) at the left ventricular myocardial walls, while the perfusion was preserved in patients with idiopathic DCM. Despite the small number of patients who had been examined, Maeno et al. laid down the foundations for the identification of patients with DCM at risk for the development of VT [123I]-MIBG uptake and washout index and LV function, perfusion and histopathologic abnormalities in patients with DCM. Yakamado et al. investigated changes in myocardial [123I]-MIBG concentrations in patients with DCM, by comparing myocardial uptake ratio (MUR) both for MIBG and 201Tl. They found that the washout of [123I]-MIBG, was significantly increased in DCM compared to the control group, reflecting the severity of the disease in these patients. The association between cardiac sympathetic innervation and function, LV function and perfusion in cardiomyopathy was investigated by Zhao et al., concluding that quantifying MIBG washout may prove myocardial functional impairment [123I]-MIBG). They showed that patients suffering from DCM, and appearing with high [123I]-MIBG uptake during early imaging, are highly possible to improve by beta-blocker medication, suggesting that this method could be appropriate for evaluating DCM severity, usefulness and right dosage of beta-blocker therapy, and prognosis -MQNB). Moreover, PET has been proved to play a role in evaluating the association of occult inflammation in DCM and ventricular arrhythmias. Approximately 50% of patients referring to the UCLA Cardiac Arrhythmia Center from 1/2012 to 1/2015, suffering from cardiomyopathy of unknown origin and ventricular arrhythmias (VA) demonstrated on FDG PET persistent focal myocardial inflammation -MIBG scintigraphy, [99mTc]-MIBI SPECT at rest, and echocardiography in 11 patients with HCM in order to assess the relationship between sympathetic nervous function and left ventricular perfusion and function. Similarly, they found positive relationship of [123I]-MIBG washout rate with septum thickness. Moreover, they showed a positive relationship between MIBG clearance and left ventricular outflow tract gradient and negative one with left atrial fractional shortening. Their results showed close correlation of the myocardial sympathetic activity to cardiac anatomy (such as degree of hypertrophy) as well as diastolic function in patients suffering from HCM [123I]-MIBG scintigraphy and ECG at rest and after biventricular cardiac catheterization at rest and during exercise. They concluded that in patients with non-obstructive HCM, LV functional reserve in response to exercise can be non-invasively evaluated at rest using [123I]-MIBG myocardial scintigraphy -ammonia (13NH3) PET scanning.6-[18F]-fluorodopamine (18F-FDA) served as the sympathetic neuronal imaging agent in 8 patients with HCM and 15 healthy controls. Their results stated that myocardial [13NH3]-imaging was similar in hypertrophied and non-hypertrophied myocardium in both HCM patients and in normal volunteers. The 18F/13N ratio was inferior in hypertrophied than in non-hypertrophied HCM regions, as well as in the septum of normal volunteers. These results proved that in HCM there is decreased neuronal uptake of catecholamines in hypertrophied but not in non-hypertrophied myocardium. By enhancing norepinephrine delivery to adrenoceptors for a given amount of sympathetic nerve traffic, decreased neuronal uptake could explain major clinical features of HCM such as arrhythmias -MIBG scintigraphy in ARVC patients and no morphological or functional left ventricular abnormalities allows detection of adrenergic dysinnervation of the left ventricle. Twenty-two of the 25 patients that they enrolled showed reduced uptake of MIBG, while [201Tl] SPECT was normal in 16 patients. The remaining 9 patients showed areas of slight hypoperfusion not correlated with the reduced MIBG uptake [123I]-MIBG uptake. To the best of our knowledge this study group is the only one to employ state-of-the-art functional SPECT/CT hybrid imaging to evaluate right and left ventricle uptake separately. They found a significant reduction [123I] MIBG uptake at the area of the right ventricular wall in ARVC patients compared to their reference group (with idiopathic ventricular fibrillation), such that the right ventricle/mediastinum ratio (RV/M) confirmed diagnosis of ARVC with a high sensitivity and specificity [Originally Lerch et al. showed that using [G uptake . A year G uptake . Other pG uptake . In theicificity .11C]-HED to assess presynaptic norepinephrine reuptake, with [11C]CGP-12177 to assess postsynaptic beta-adrenergic receptor density, and with [15O]H2O for quantification of myocardial blood flow. They found a significant reduction of myocardial beta-adrenergic receptor density in patients with ARVC in comparison with age-matched control subjects. That was attributed to secondary downregulation of β-adrenergic receptors, due to locally increased synaptic norepinephrine levels. This may be the result of either an increased sympathetic tone or because of impaired presynaptic catecholamine reuptake -MIBG uptake can be expressed, by the heart-to-mediastinum ratio (H/M), that has independent and incremental prognostic value, being able to identify high risk ICM patients. However, the long-term prognostic value of MIBG uptake in patient with ischemic versus idiopathic cardiomyopathy remains unclear [123I]-MIBG and [99mTc]-Tetrofosmin SPECT/CT imaging during an anger recall mental stress task and dual isotope imaging was repeated approximately 1 week later during rest. They found that the hemodynamic response to mental stress was similar in both groups. Anger recall significantly decreased the MIBG H/M in ICM patients , but not in normal subjects, which is indicative of the pathophysiological mechanisms causing arrhythmia in ICM under certain trigger -mHED), perfusion ([13N]-ammonia) and viability (18-FDG). Myocardial sympathetic denervation quantified by [11C]-mHED PET was able to identify ICM patients at high risk of SCA. The total volume of denervated myocardium was the main risk factor of SCA and was independent of other imaging parameters like hibernating myocardium or Left Ventricular Injection Fraction (LVEF). These results indicate that being able to quantify the extent of cardiac sympathetic denervation may help significantly in the identification of ICM patients who will benefit the most from a primary prevention ICD implantation -mHED and PET imaging, they examined the presynaptic reuptake of norepinephrinein 8 patients with idiopathic RVO-VT and in a total of 29 control patients of the same age range. Additionally, [15O]-H2O was used to quantify the myocardial blood flow and [11C]CGP 12177 to measure the postsynaptic beta-adrenoceptor density. It was proven that both beta-adrenoceptor density and myocardial catecholamine reuptake were significantly decreased in patients with idiopathic RVO-VT, suggesting that in patients with RVO-VT, downregulation of myocardial beta-adrenoceptor occurs in conjunction to an increase in of local synaptic catecholamines, due to impaired catecholamine reuptake -MIBG uptake. On the other hand nobody from the control group had these characteristics  MIBG SPECT by Paul et al. The study group performed MIBG scans in 20 patients (as well as in a control group of 10). The follow-up time was 7.2+/−1.5 years (range 4.9–10.5 years). During follow-up, 18 episodes of VF/fast polymorphic ventricular tachycardias appeared in 4 IVF patients with abnormal MIBG uptake, while only 2 episodes of monomorphic ventricular tachycardia occurred in a single IVF patient with normal MIBG uptake. Their study revealed that future episodes of life-threatening ventricular tachyarrhythmias were more likely to occur in patients with IVF and impaired sympathetic innervation MIBG in part of the inferior wall, the apex and anterior wall of the left ventricle as well as an increased wash out in the inferior wall -MIBG uptake in 8 (47%) of 17 patients but in none of the control patients. Quantitative analysis showed segmentally decreased uptake in the inferior and septal left ventricular wall in patients with BS compared with control subjects. However, no correlation was found between MIBG uptake and the clinical characteristics of the study patients -HED to quantify myocardial pre- and postsynaptic sympathetic function and the nonselective β-blocker [11C]-CGP, by Kies et al. reported that norepinephrine recycling, as assessed by PET- [11C]-HED scintigraphy, was increased in patients with BS compared to the control- group, while postsynaptic β-adrenoceptor density, was found to be of the same levels in patients and control subjects, further supporting the hypothesis of an autonomic dysfunction in BS HED and PET in genotyped LQTS patients. [15O] H2O and [11C]HED PET studies were carried out in 11 patients (5 symptomatic) and 8 controls. Controls and patients showed similar sectorial perfusion, while most LQTS patients showed a localized and decreased pattern of [11C]HED retention. The larger number of heterogeneous sectors in symptomatic patients suggests that sympathetic function could play an amplifier role for severity of the disease [Mazzadi et al. evaluated sympathetic nervous system using [ disease .123I]-MIBG remains the most widely studied and used SPECT tracer, able to distinguish between normal hearts and hearts where the autonomic nervous system is disarranged, like in cardiomyopathies or in arrhythmogenic syndromes. Increased and homogenous cardiac uptake appears to have high negative predictive value for severe cardiac events, i.e., death and arrhythmias, and could be crucial in decision making. Future studies revealing robust associations between cardiac autonomous innervation disorders and ventricular arrhythmias are needed and could provide novel insights in selecting patients who are suitable candidates for device implantation, such as an ICD (implantable cardioverter defibrillator), CRT (cardiac resynchronization therapy), LVAD (left ventricular assist device), or cardiac transplantation. Cardiac autonomic research remains an evolving area due to its crucial role in a group of life-threatening arrhythmias, while imaging can specify the severity of the disease and contribute as a therapeutic and prognostic tool. Radiotracer analogs of norepinephrine have been investigated extensively during the past 30 years and remain in widespread clinical use. [Cardiac autonomic using SPECT and PET is able today to extract vital information, visualizing and quantifying the underlying molecular aspects of cardiac disease, providing a perspective that other cardiac non-invasive methods cannot.


Cardiotoxicity is a serious side effect of doxorubicin in cancer patients due to the risk of development of heart failure. Early detection of doxorubicin-induced cardiomyopa-thy (DXR-ICM) has become a major objective to reduce heart failure in cancer patients. Echocar-diography is the gold standard method to diagnose cardiac diseases when cardiac dysfunction is prominent; however, it still cannot predict or early diagnose heart failure before functional de-cline. The intraventricular blood flow is characterized by intraventricular pressure gradients (IVPG) that created due to the suction of blood by the ventricles. Currently, advanced imaging techniques allow non-invasive assessment of IVPG from color M-mode echocardiography (CMME) after image processing for the clinical setting. Studies revealed that IVPG indices are promising for the early diagnosis of cardiac dysfunction. In this study, we aimed to investigate the usefulness of IVPG to detect cardiac function changes after DXR administration in dogs. p < 0.05). Mid-to-apical IVPG was also reduced in Post2 compared with the baseline (0.29 ± 0.13 vs. 0.51 ± 0.11). Meanwhile, the fraction shortening, ejection fraction, and longitudinal strain revealed no change between groups. Total and mid-IVPG were significantly correlated with Emax  but only mid-IVPG was a predictor for Emax . In conclusion, this study revealed that impairment of contractility was the initial changes observed with DXR-ICM in dogs and only IVPG could noninvasively detect subclinical alterations in cardiac function. Color M-mode echocardiography-derived IVPG could be a potential marker for the early detection of doxorubicin cardiomyopathy.Early detection of doxorubicin (DXR)-induced cardiomyopathy (DXR-ICM) is crucial to improve cancer patient outcomes and survival. In recent years, the intraventricular pressure gradient (IVPG) has been a breakthrough as a sensitive index to assess cardiac function. This study aimed to evaluate the usefulness of IVPG for the early detection of chemotherapy-related cardiac dysfunction. For this purpose, six dogs underwent conventional, speckle tracking, and color M-mode echocardiography concomitantly with pressure-and-volume analysis by conductance catheter. The cardiac function measurements were assessed before DXR administration , at the end of treatment protocol (Post), and at 1.5 years follow-up (Post2). The result showed a significant reduction in the left ventricular end-systolic pressure-volume , total-IVPG , and mid-IVPG , respectively in Post2 and Post compared with the baseline ( Despite the effectiveness of DXR in chemotherapy, the increased likelihood of cardiotoxic activity of the drug, which determines the patient’s survival, becomes a management challenge for oncologists. Studies have revealed that DXR affects cardiac function in a cumulative and dose-dependent manner in humans and dogs ,2. Aftertoxicity . RegardlThe ejection fraction (EF) in human medicine and fractional shortening (FS) in veterinary practice are widely used indices in echocardiographic examination to evaluate cardiac function . HoweverAlthough most attention has been paid to systolic function in the diagnosis of DXR-ICM, several reports have suggested that diastolic dysfunction precedes systolic failure in both human and canine patients ,8,9. RecRecently, the evaluation of diastolic and systolic IVPG has shown promising results in the evaluation of heart functions and showed agreeable feasibility and reproducibility in humans . The cli2) via the cephalic vein at three weeks intervals [2. Echocardiography and catheter measurements were performed at three-time intervals: before DXR administration (Pre), after completing the treatment at 4.5 months (Post), and 1.5 years post-treatment (Post2). This study was conducted under strict anesthetic doses and stable hemodynamic conditions for all dogs across the study to exclude the effect of anesthesia on the obtained measurements.Six adult female beagle dogs  weighing between 8–10 kg , 2 to 3 years old, were used in this study. All dogs were physically fit based on the medical examination and routine hemato-biochemical profile. Special attention was paid to the cardiac function, and the dogs were free from any cardiac abnormalities upon auscultation of the heart, electrocardiography, and echocardiography. All dogs were administered six consecutive doses of DXR , and ampicillin-sodium  in addition to buprenorphine  to provide an analgesic effect. Anesthesia was induced by propofol  and then maintained by isoflurane  after tracheal intubation. All dogs were administered lactated Ringer’s solution . The respiratory rate was controlled by an anesthesia machine (positive pressure ventilation). Expiratory CO2 was controlled at 35–45 mmHg. The dogs were pre-medicated with atropine , meloxicam  was inserted into the LV through the sheath being guided by fluoroscopy. The analysis of real-time pressure-and-volume loop data was conducted using the Micro-Tip Pressure-Volume Ultra Foundation System , PowerLab hardware , and LabChart Pro software . LV end-diastolic pressure and Tau were calculated from 10 consecutive pressure-and-volume loops. Tau was measured according to the method of Weiss et al. . The valThe echocardiographic assessment was performed using a Prosound F75 with a sector probe of 5 MHz . All dogs were placed in lateral recumbency, and the echocardiography was performed after confirming stable hemodynamics and equable conditions for 10 min after catheterization. Three heartbeats were recorded at the end of the expiratory phase. The LV inner diameter at end-diastole (LVIDd), EF, and FS were calculated in the short-axis view at the papillary muscle level through M-mode . The LV For two-dimensional speckle tracking echocardiography (2DSTE), motion images from the left parasternal long-axis view were obtained with the frame rates of 70–110 frames/s and saved for further off-line analysis using the special software  to measure the global longitudinal strain (GLS) and the early diastolic strain rate (EDSR). Both basal- and apical-level images of the right parasternal short-axis view were used to obtain the LV twist. The intraventricular pressure gradient (IVPG) was calculated from the image obtained from the CMME of the left parasternal longitudinal apical four-chamber view. The machine was set to sweep speed of 300 mm/s and color baseline-shift of 64 to increase the Nyquist limit for proper tracing of the CMME. The IVPG was calculated using in-house code written in MATLAB , as showed in The LV was divided into three equal parts. The basal part was defined as the region comprising one-third from the mitral valve to the apex. The middle part was defined as the mid part, and the remaining part was defined as the apical part. Besides, a two-thirds segment of LV length on the apex side was adopted as mid to apical-IVPG . IVPG anp values < 0.05 were considered statistically significant. After an assessment of the differences in the Pre, Post, and Post2 results using one-way repeated-measures ANOVA, Tukey’s honestly significant difference post hoc test was used to compare variables between the Pre, Post, and Post2 results. Pearson’s correlation coefficients were used to assess the relationship between Emax and conventional, 2DSTE, and the IVPG variables. Multivariate linear regression analysis was performed to determine the independent variables that correlated with Emax. The stepwise method was used for the selection of variables.All statistical analyses were performed using R software . Data were reported as mean ± SD. For all statistics, p < 0.01, 0.001), respectively. The Emax was reduced with time course after medication and also found to be significantly lower in Post2-stage than Post .p > 0.05). There was no significant change in 2DSTE indices either.The conventional and two-dimensional speckle tracking echocardiographic indices are summarized in p < 0.05, 0.01; respectively). Similarly, mid-IVPG was significantly decreased in the Post and Post2-stages compared with Pre-stage . Besides, there was a significant reduction in mid to apical-IVPG in the Post2-stage compared with Pre-stage . In contrast, basal- and apical-IVPGs were relatively constant throughout the experimental time intervals.p < 0.05, both). Meanwhile, no significant correlation between Emax and basal-, apical-, and mid to apical-IVPGs were observed. The multivariate analysis determined that only mid-IVPG was a predictor of Emax , as shown in There was no correlation between Emax and conventional, and 2DSTE indices. On the other hand, as observed in Side effects of chemotherapy are an endless challenge that has attracted comparative oncologists to use dogs as models to evaluate the pros and cons of therapeutic strategies ,29. CardIn this study, EF and FS did not show a statistically significant decline throughout the experiment in comparison to the reference values (39.63 ± 6.26 and 70.9 ± 6.0), respectively , and couThe current study revealed that the deterioration of systolic function precedes the impairment of diastolic function in DXR-ICM. Only Emax obtained by invasive catheter was able to detect impairment in left ventricular contractility. On the other hand, Tau “LV diastolic time constant”, the most widely used index for ventricular relaxation, showed no obvious change during the study period.Several reports have suggested that diastolic dysfunction precedes systolic failure. This is contrary to recent studies suggesting that diastolic indices may be the earliest predictors of DXR-ICM ,30. HereData of the currently used indices of contractility are controversial. GLS, which focuses on LV contractility in the long axis direction, was reported as a sensitive indicator even when EF was preserved , but itsDuring the early diastolic period, the LV works as an effective pump, actively drawing blood from the left atrium into the LV apex, without any elevation of left atrial pressure. This suction force created by the pressure gradient from the left atrium to the LV apex is a major determinant of adequate filling in the early diastole during normal cardiac function ,45,46. TAttention has been paid to the evaluation of diastolic function based on the prior decline of diastolic function. The quantitative evaluation of therapeutic effects and the progression of HF is complicated. The 2016 American Society of Echocardiography and European Association of Cardiovascular Imaging guidelines for diastolic function assessment have recommended an evaluation that combines multiple indices instead of a single index because of their dependency on age and preload . AlthougAlthough there are some limitations in IVPG assessment, including the inter-system variability, IVPG is expected to be superior to GLS because it provides a higher frame rate to illustrate the heart with good feasibility and reproducibility . In thisThe time lag between Post and Post2 was relatively long because of the unrepeatability and unacceptability of invasive catheterization. The study period was relatively small to observe overt cardiac dysfunction, but DXR-ICM is variable and some patients develop acute toxicity, while others may have no symptoms for 10 years . This poInvasive measurements over multiple time intervals suggested that impairment in systolic function precedes decreasing diastolic function following the administration of DXR. A progressive decline in elastic recoil of the LV wall during the systolic period may lead to a decrease in the IVPG following a deterioration in the suction force. The IVPG may be the key to promote the early detection of DXR-ICM from the novel perspective that the IVPG is not only an index of diastolic function but also a potential sensitive marker of contractility in subclinical cardiac toxicity.