Radiomics and artificial intelligence have the potential to become a valuable tool in clinical applications. Frequently, radiomic analyses through machine learning methods present issues caused by high dimensionality and multicollinearity, and redundant radiomic features are usually removed based on correlation analysis. We assessed the effect of preprocessing—in terms of voxel size resampling, discretization, and filtering—on correlation-based dimensionality reduction in radiomic features from cardiac T1 and T2 maps of patients with hypertrophic cardiomyopathy. For different combinations of preprocessing parameters, we performed a dimensionality reduction of radiomic features based on either Pearson’s or Spearman’s correlation coefficient, followed by the computation of the stability index. With varying resampling voxel size and discretization bin width, for both T1 and T2 maps, Pearson’s and Spearman’s dimensionality reduction produced a slightly different percentage of remaining radiomic features, with a relatively high stability index. For different filters, the remaining features’ stability was instead relatively low. Overall, the percentage of eliminated radiomic features through correlation-based dimensionality reduction was more dependent on resampling voxel size and discretization bin width for textural features than for shape or first-order features. Notably, correlation-based dimensionality reduction was less sensitive to preprocessing when considering radiomic features from T2 compared with T1 maps. Radiomics is a novel tool allowing the extraction of many quantitative morphological, histogram-based, and textural characteristics  from digital medical images . The undFor these reasons, redundant radiomic features are usually removed based on the results of a correlation analysis. This step is critical because the right choice of which features should be eliminated could either improve the performance and explainability of the AI model or affect its performance by removing interesting correlations between features and the study objective . In the Image resampling and discretization, as well as filtering, are some steps of the radiomic workflow that may be performed as preprocessing before radiomic features extraction from the acquired image data ,34. In pCardiac magnetic resonance (CMR) has a crucial role in diagnosis, risk stratification, and treatment planning in hypertrophic cardiomiopathy (HCM) , a genetIn recent years, in addition to the traditional CMR sequences, T1 and T2 mapping sequences have been developed, allowing a more quantitative evaluation of myocardial changes, signally fibrosis (T1 maps), and edema (T1 and T2 maps). T1 and T2 mapping have shown to feature a possible important diagnostic and prognostic role in HCM patients . A complete MRI scan with both T1 and T2 mapping sequences was executed for these patients. The HCM diagnoses were made following the most recent recommendations of the European Society of Cardiology. They were based on the detection of the left ventricular wall thickness ≥15 mm in one or more myocardial segments, which was not due mainly to loading conditions . Table 1A 1.5 T MRI scanning system  with 45 mT/m gradients strength and a 12-channel phased array coil was used for all cardiac MRI examinations.Cine scans were obtained using a TrueFISP sequence  in the 2- and 4-chamber view planes (3 slices each), as well as in the short-axis view (8–14 slices comprising the entire left ventricle).The short-axis view was used to obtain both T1 and T2 maps . A modified look-locker inversion recovery (MOLLI) pulse sequence with a 3-3-5 acquisition method was employed to perform T1 mapping . The folA cardiac MRI specialist with 15 years of expertise manually segmented the whole myocardium of each subject using 3D Slicer software (version 4.11.2) ,53. In oIn this study, we independently applied three preprocessing steps on T1 and T2 maps: (1) voxel size resampling, (2) discretization, and (3) filtering.Given that T1 and T2 mapping only enabled the acquisition of a single slice, we performed voxel size resampling by 2D interpolation using the B-spline interpolation algorithm . CalculThe Image Biomarker Standardisation Initiative (IBSI) has suggested carrying out image discretization with fixed bin width when dealing with quantitative data, such as T1 and T2 maps . In thisDifferent filters were applied to T1 and T2 maps, including the gradient magnitude of the map , the square of the map values , the square root of the absolute map value , and 2D wavelets (Daubechies 3). The last one yielded four filtered maps obtained through different combinations of 2D wavelets , where L/H refers to the combination of low-/high filters applied in the horizontal and vertical direction. Specifically, filtering was carried out at fixed isotropic in-plane resampling voxel size of 2.1 mm and at fixed discretization bin width of 6 ms and 0.56 ms for T1 and T2 maps, respectively. These bin width values ensured a median (across subjects) number of quantization levels between 30 and 130 ,58,59.All preprocessing steps and subsequent radiomic features estimations were carried out by using the open-source PyRadiomics library  , and 73 second-order features  from gray-level co-occurrence matrix , gray-level run length matrix , gray-level size zone matrix , gray-level dependence matrix  with absolute value above a predefined threshold were counted and represented in a correlation heatmap. In particular, according to previous studies, we considered cut-off thresholds of 0.8 and 0.9 for the |PCC|  mm, the corresponding numbers of significant |PCC| values greater than 0.8 were  and  for fixed discretization bin width values of 3.60 ms and 3.95 ms, respectively , both the PCC- and SCC-based correlation analysis showed different numbers of pair-wise significant correlation coefficients with absolute value greater than or equal to the defined threshold value. For instance, when considering the discretization bin width values of  ms, the number of significant correlations with |PCC| values greater than 0.8 were  and  for fixed resampling voxel sizes of 1.8 mm and 1.9 mm, respectively  and B , our results suggest a greater influence on correlation-based dimensionality reduction in resampling voxel size than discretization bin width . In factDigital image filters can be applied before radiomic features extraction to detect and emphasize tissue characteristics different from those usually obtained from original images. In this regard, the IBSI has proposed a new reference manual to define and standardize the implementation of image filters in radiomics software . Given tA remarkable difference between T1 and T2 maps in sensitivity of collinearity analysis and dimensionality reduction to preprocessing was found. Performing the correlation-based dimensionality reduction on radiomic features from T2 maps was characterized by lower sensitivity to voxel size resampling and discretization than radiomic features from T1 maps. Regardless of whether PCC or SCC is used, the percentage of T2-derived features eliminated by the dimensionality reduction procedure is less than the percentage of removed T1-derived radiomic features. In addition, the remaining subsets of T2-derived features showed greater stability than the corresponding subsets of T1-derived features. These results, along with the previous findings by Marfisi et al. , also suWe acknowledge the following issues as potential study limitations. First, we focused only on T1 and T2 maps, albeit they are particularly suitable for radiomic analysis, given their quantitative nature. Additional studies will be necessary to investigate the effect of preprocessing on correlation-based dimensionality reduction in radiomic features for classical cine, LGE, and STIR sequences. In HCM patients, T1 maps are usually obtained before and after contrast administration to calculate extracellular volume, a surrogate marker of interstitial remodeling and interstitial fibrosis ,48,72. HSecond, even though we only looked at single-slice T1 and T2 mapping acquisitions, myocardial alterations in HCM patients may also affect visibly non-hypertrophied cardiac parts. Consequently, a whole-heart coverage might offer a more thorough assessment of disease load and improve the diagnostic effectiveness of cardiac MRI. However, evaluating a single ROI on the mid-cavity short-axis map for a global/diffuse illness is considered sufficient . Our tecThird, we included only twenty-six patients with HCM, representing a homogeneous group with the same pathology. Nonetheless, the findings of this technical investigation may be helpful and prodromic for future clinical studies, which should enroll a larger number of participants and include control subjects to specifically assess the clinical potential of radiomic analysis of T1 and T2 maps in HCM patients. This could lead to a better understanding of the role of CMR in differentiating HCM from hypertensive heart disease and other cardiomyopathies and in discriminating different genotypes of HCM, as well as in assessing arrhythmic risk in these patients ,47,48.Finally, our results depend on the cut-off thresholds defined for PCC and SCC. We decided to use the most chosen thresholds from previous studies that have performed correlation-based dimensionality reduction in a machine learning workflow  to understand this procedure’s sensitivity to preprocessing in a real scenario. Studying the changes in dimensionality reduction as the cut-off threshold changes was beyond the scope of this work.In this HCM study, using radiomic features extracted from T1 and T2 maps, we observed a moderate sensitivity of collinearity analysis and correlation-based dimensionality reduction to some conventional image preprocessing procedures. While, as a whole, this effect is relatively moderate for voxel size resampling and discretization, it is remarkable when considering filtering. Moreover, correlation-based dimensionality reduction is less sensitive to preprocessing when considering radiomic features from T2 compared with T1 maps. Our findings further confirm the effect of preprocessing in radiomic analyses, with the consequent need of considering it toward a standardization of methods and when comparing data/results from different clinical studies.


Subsequently, CRT reduced it approximately back to baseline values . The study showed the feasibility of using miniaturized sensors for continuous monitoring of the abnormal systolic motion of the LV in LBBB and how such sensors can be used to assess response to pacing in real time to guide CRT implantation.An abnormal systolic motion is frequently observed in patients with left bundle branch block (LBBB), and it has been proposed as a predictor of response to cardiac resynchronization therapy (CRT). Our goal was to investigate if this motion can be monitored with miniaturized sensors feasible for clinical use to identify response to CRT in real time. Motion sensors were attached to the septum and the left ventricular (LV) lateral wall of eighteen anesthetized dogs. Recordings were performed during baseline, after induction of LBBB, and during biventricular pacing. The abnormal contraction pattern in LBBB was quantified by the septal flash index (SFI) equal to the early systolic shortening of the LV septal-to-lateral wall diameter divided by the maximum shortening achieved during ejection. In baseline, with normal electrical activation, there was limited early-systolic shortening and SFI was low (9 ± 8%). After induction of LBBB, this shortening and the SFI significantly increased (88 ± 34%,  Left bundle branch block (LBBB) causes asynchronous electrical activation of the ventricular myocardium, resulting in discoordinated contraction and inefficient pump function . CardiacHowever, there is yet no consensus on which hemodynamic parameter should be used to evaluate acute response , althougA commonly observed feature of LBBB is an abnormal early systolic left-right motion of the septum referred to as septal beaking or septal flash (SF) . SF occuTM which consists on an accelerometer embedded in the atrial lead. The sensor then measures mechanical vibrations to optimize the CRT timings  tracking sensors. EM sensors are commonly used in humans for tracking catheter positions in the body , and the timings . Thus, E timings . The stun = 4) and a prospective study where EM tracking sensors were implanted (n = 22). Thus, a total of 26 mongrel canines  of average weight 32 kg (±3 kg SD) were used in acute experiments for validation of the measurement of motion during pre-ejection period with sonomicrometry and EM tracking sensors. The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board (or Ethics Committee) of The Norwegian Food Safety Authority . The animals were supplied by the Center for Comparative Medicine . The animals were ventilated, anesthetized by propofol/opioids and surgically prepared as previously described  to assess regional electrical activation times of the LV.An epicardial pacemaker lead was attached to the right atrium, allowing measurements at a fixed heart rate. RV and LV pacing leads were placed to facilitate CRT by biventricular pacing. The endocardial RV lead was placed on the septum in the RV apex, while three epicardial pacing leads were placed on the LV free wall: in a lateral position, in an apical position and close to the base on the anterior wall. The reason for placing three LV leads was to allow biventricular pacing from different LV locations to vary the degree of improvement. One EM tracking sensor  was inserted into the septum near the septal sonomicrometric crystal. Additionally, another pair of sonomicrometric and EM tracking sensors where sutured to the LV lateral wall. This allowed measurements of the diameter between the septum and the LV free wall with both sensors . A Mid-REDV, was obtained from the beats with the highest common EDV values from baseline, LBBB and CRT recordings. SWEDV was then used as an index of global cardiac performance. All pressures, sonomicrometry, and EM tracking data were recorded simultaneously; EM data at 250 S/s and the other data at 200 S/s.Data were obtained at a fixed heart rate by atrial pacing (AP) at 120 beats per minute in all settings to avoid alterations in hemodynamic response parameters from differences in heart rate alone. After baseline recordings, LBBB was induced by radio-frequency ablation , with confirmation of successful induction by QRS widening, limb lead R wave notching and LV contraction patterns. When applying CRT, different pacing locations were tested. As CRT decreases both end-systolic and end-diastolic volumes, effectively reducing preload , it may We used the Python programming language  for allThe SF index (SFI) which was used to examine if CRT was able to correct the dyssynchrony, was calculated as the early systolic shortening of the LV septal-to-lateral wall diameter divided by the maximum shortening achieved after the early systolic motion during the cycle . This diTo check the accuracy of the EM tracking sensors and study its ability to measure the SFI, we compared the diameter trace and the derived SFI with the ones obtained with sonomicrometry.t-test on those with normal distribution and Wilcoxon signed-ranks test for the rest. Statistical significance was determined as p < 0.05. All values represent the mean of five consecutive heart cycles except data collected during transient caval constriction where only one beat was used. Values are reported as mean ± SD. No outliers have been excluded from the statistical tests.All statistical analyses were computed with SPSS software . No statistical power calculation was conducted prior to the study as it was intended as a proof of concept. The sample size in this study is therefore relatively low and the statistical tests must therefore be considered with caution. Normality of distributions was determined using Shapiro-Wilks test. To test for significant effects of the interventions we used two-tailed Student’s paired sample EDV. Only 12 of these experiments had EM tracking sensors connected.A total of 26 experiments were conducted. Out of all of them, a total of 8 were excluded due to failure to induce LBBB or due to equipment malfunction. The protocol of each experiment varied slightly, so that only 14 out of the remaining 18 experiments included caval occlusions that allowed for preload adjustment of volumetric measurements, i.e. SWEDV).Hemodynamic values from baseline, LBBB, and the three CRT positions of all 18 experiments are shown in p = 0.096 vs. lateral position) which was reflected also by a trend of lowest SFI value at this position . The SFI measured by the EM sensors showed qualitatively a similar pattern as measured using sonomicrometry and furthermore, reflected the corresponding changes in cardiac function by SWEDV . Those sensors had a sampling rate of 40 S/s, which did not allow an accurate tracking of the rapid motions during septal pre-ejection deformation. Data from those experiments could therefore not be used for the study, and the EM tracking system was changed to the one described in The proposed SF index in this study, is able to act as an indicator for acute changes in LV function during CRT. This index could become a simple and reproducible tool for clinicians to assess baseline contraction characteristics and acute effects from CRT. The change in SFI could furthermore inform clinician about optimization strategies when testing capture and response to pacing. By measuring the reduction of SFI in real time, a clinician can determine whether the therapy is having the desired effect. If there is no reduction, or if it is a minor one, other pacing settings or lead positions should be tested. Ultimately, the baseline SFI characteristic or the SFI response to pacing could provide necessary information for the operator to avoid implantations associated with poor clinical outcomes . If the Nowadays, SF can be reliably assessed by echocardiography, which is a non-invasive and harmless alternative. However, it seems less practical for use during CRT implantation as it requires extra personnel, time to obtain images and time for post-processing the images to quantify the desired indices as well as extra space in the operating-room for the ultrasound equipment. Another limitation when measuring SF by echocardiography, is the inter- and intra-observer variability. By using standardized mechanical devices, such as EM tracking sensors, this variability could be largely omitted. Hence, an automated sensor system for real-time analysis of the SF pattern seems a more attractive alternative which may become an important tool during CRT implantation.The present study used data from long interventions performed on heavily instrumented animals under anesthesia, hence heart function was depressed also at baseline. Furthermore, sonometric crystals were used to calculate LV volume. These crystals were not placed on the endocardium but somewhere in the wall and hence the LV cavity volume calculations were exaggerated as it included some myocardial mass and as a result the derived ejection fraction values were underestimated. We were not able to obtain statistically significant different responses from different pacing sites in our animal model. Hence, we were only able to evaluate correct capture and response to CRT, while the method’s ability to guide optimal lead placement needs to be further investigated. As previously discussed, the EM sensors used in this study presented some limitations and did not always reflect accurately the heart wall motion. Hence, different sensors should be tested in future studies to find more suitable ones for this purpose.This study showed first that measurements of the septal flash index in the LV septal-to-lateral wall diameter can be used to evaluate the acute improvements in LV function by CRT, and secondly that electromagnetic tracking sensors can be used for measuring this index. Such technology could thus have a role for assessing acute response to CRT and guide implantation.


Over the past few decades, a drastic increase in the prevalence of heart failure (HF) has been observed worldwide, and is now often referred to as the “Heart failure pandemic”. Despite recent advances in the diagnosis and treatment of HF, its prognosis remains poor. In particular, cardiomyopathy exhibits the highest percentage of etiologies of advanced HF requiring cardiac transplantation. In this Special Issue, many researchers provided their latest findings regarding the diagnosis, risk stratification and treatment of HF and cardiomyopathies, which all may potentially lead to future personalized disease approaches.Secondary cardiomyopathy is still a major challenge in terms of its diagnosis and treatment. Amyloid cardiomyopathy used to be considered to be a relatively rare disease, but now, is increasingly being recognized as a cause of left ventricular (LV) hypertrophy. Notably, transthyretin amyloid cardiomyopathy (ATTR-CM) comprises a not negligible proportion of HF in the elderly and presents as rapidly progressive HF, leading to a poor prognosis. Recently, novel drugs for ATTR-CM have emerged and can be prescribed to patients in clinical practice; hence, a timely diagnosis is crucial. Nakano et al. demonstrated the correlation of the extent of TTR deposition with LV diastolic dysfunction as a marker of reactive oxygen species . This paArrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare condition of cardiomyopathy arising from a genetic disorder. The diagnosis of ARVC is sometimes challenging and difficult to differentiate from dilated cardiomyopathy. Magnetic resonance imaging (MRI) is a tool to help with the diagnosis of cardiomyopathies including ARVC. Manole et al. summarized the problem and limitations of the currently available criteria for ARVC and the additive value of cardiac MRI for a better diagnosis and risk stratification .Over the last two decades, the progress in regard to pharmacological and nonpharmacological therapies has caused the dramatic improvement in survival and cardiovascular outcomes for HF with a reduced ejection fraction (HFrEF). Particularly, guideline-directed medical therapy (GDMT) is a cornerstone of HFrEF treatment. On the other hand, the insufficient use and titration of GDMT has been indicated in clinical practice. Among GDMTs, β-blocker therapy is one of the most potent drugs used to improve the symptoms and clinical outcomes for HFrEF. The mechanisms mediating its beneficial effects include, but are not limited to, the amelioration of sympathetic nerve overactivation, an anti-ischemic effect, an anti-arrhythmic effect, promoted reverse remodeling and the prevention of sudden cardiac death. Since the mortality benefit caused by β-blocker therapy was shown to be correlated with the reduction in heart rate, it can be determined that heart rate is an important hallmark of β-blockers’ effect. In this context, questions have been raised. Do we need a maximum dose of β-blockers for all patients? If this is the case, what should we do if the heart rate goes too low? These questions converge into the next question: what is the optimal heart rate? However, the target heart rate (THR) we should aim for has not been thoroughly investigated. In order to answer this question, Yumita et al. focused on the overlap between E and A waves in mitral inflow and they hypothesized that a heart rate which yields no E-A overlap might be hemodynamically ideal and could be a reasonable target . This THAs a nonpharmacological therapy, cardiac resynchronization therapy (CRT) is a therapeutic strategy efficacious against advanced HFrEF with dyssynchronous LV motion. There has been a long debate on its indication and responder prediction. The personalized CRT setting after implantation has also been under debate, but there has been no consensus. Leitz et al. demonstrated the extended findings of their prospective observational study, where they followed their study patients for as long as approximately 10 years . In thisWithin human bodies, there are trillions of bacterial organisms belonging to >2000 species, the vast majority being in the gut. There is increasing evidence that the nature of the microbiome plays an important role in human health and disease. On the other hand, accumulating evidence suggests that the interaction between multiple organs plays a crucial role in the pathology of various diseases, including HF. In this context, the interaction between heart and gut, or the “gut-heart axis”, has emerged as a novel concept to provide new insights into the intricate mechanisms of HF. Since gut microbiota is highly variable from person to person, the microbiome approach to HF or cardiomyopathy potentially offers a new possibility for personalized medicine. Short-chain fatty acids (SCFAs) are gut microbiota-derived substances which might mediate the microbiota-driven pathology, leading to various organ dysfunctions. Yukino-Iwashita et al. summarized the current knowledge and perspectives on the possible role of SCFAs in the pathology of HF . SCFAs aAs a Guest Editor, I would like to thank all authors and reviewers for their contribution to this Special Issue and for the quality of submitted papers. I hope the presented novel findings will facilitate further developments and the refinement of personalized medicine in this area.


Ice hockey is a high-intensity dynamic sport for which competitive athletes train for longer than 20 hours each week for several years. The cumulative time of myocardial exposure to hemodynamic stress affects cardiac remodeling. However, the intracardiac pressure distribution of the elite ice hockey athletes' heart during adaptation to long-term training remains to be explored. This study aimed to compare the diastolic intraventricular pressure difference (IVPD) of the left ventricle (LV) between healthy volunteers and ice hockey athletes with different training times.Fifty-three female ice hockey athletes  and 24 healthy controls were included. The diastolic IVPD of the LV during diastole was measured by vector flow mapping. The peak amplitude of the IVPD during isovolumic relaxation (P0), diastolic rapid filling (P1), and atrial systole (P4); the difference in the peak amplitude between adjacent phases ; the time interval between the peak amplitude of adjacent phases ; and the maximum decrease rate in diastolic IVPD were calculated. Differences between groups, as well as correlations between hemodynamic parameters and training time, were analyzed.p < 0.001 for all). An increased P1P4 was significantly associated with an increased training year .Structural parameters of the LV were significantly higher in elite athletes than in casual players and controls. No significant difference in the peak amplitude of the IVPD during the diastolic phase was found among the three groups. The analysis of covariance with heart rate as a covariate showed that P1P4 in the elite athlete and casual player groups was significantly longer than that in the healthy control group (The diastolic cardiac hemodynamics of the LV in elite female ice hockey athletes could be characterized by a prolonged diastolic IVPD, and P1P4 prolonged with an increase in the training years, reflecting a time–domain adaptation in diastolic hemodynamics after long-term training. Long-term intense exercise induces adaptive changes in cardiac structure and function, which enable the heart to meet hemodynamic demands during exertion . The intDetailed study of diastolic hemodynamic adaptation to training load could provide new insights into the cardiac diastolic remodeling . A previThe myocardial adaptation to exercise is expected to result from the exercise intensity and the amount of time during which hemodynamic stress acts on the cardiovascular system . With reResearchers have postulated that repeated insults to the ventricle following prolonged and intensive endurance exercise (probably >20 h/week for >20 years) may lead to irreversible ventricular remodeling . TransthRelative pressure imaging enables the non-invasive quantification of the IVPD using vector flow mapping (VFM) and visualization of the regional pressure distribution . VFM meaThis study was performed in accordance with the Helsinki Declaration, and was approved by the Ethics Committee of The Institute of Sports Medicine of the General Administration of Sport of China (2021-15). All of the participants provided written informed consent. The participants also volunteered to participate in a cardiac function assessment study from April 2021 to January 2022 during the period of medical supervision and physical examination. All of the examinations were performed during the in-competition phase and 24 h following the last athletic training. Detailed medical history and training regimens were obtained along with routine physical examinations. The basic information of the participants, such as the age, training years, athlete's technical hierarchy, WTT in the last 6 months, height, weight, body surface area, heart rate, systolic blood pressure, and diastolic blood pressure, was collected.The inclusion criteria were as follows: (1) women aged 18–30 years; (2) athletes who played ice hockey and healthy controls without regular exercise habits; (3) no specific medical history or chronic illness; and (4) normal cardiac structure and sinus rhythm. The exclusion criteria were as follows: (1) poor echocardiographic image quality, and (2) abnormal segmental ventricular wall movement. Seventy-seven women (53 athletes and 24 non-athletes) were included in the study.We referred to the ice hockey athlete's technical hierarchy standards promoted by the Competitive Sports Department of the General Administration of Sport of China . The tecUsing the approach recommended by the American Society of Echocardiography , a standinterventricular septal thickness + LV posterior wall thickness)/LV end-diastolic dimension. The LV mass (g) was calculated as: 0.8 × 10.4 × [3 – LVend−diastolicdimension3] + 0.6. The LV mass, LV end-diastolic volume, and LV end-systolic volume, as well as cardiac output were indexed to body surface area.Echocardiographic measurements included the interventricular septal thickness, LV end-diastolic dimension, LV posterior wall thickness, LV end-systolic dimension, LV end-diastolic volume, LV end-systolic volume, peak early diastolic transmitral flow velocity (E peak), peak late diastolic transmitral flow velocity (A peak), ratio of early to late atrial mitral Doppler peak flow velocity (E/A), and cardiac output. The relative wall thickness was calculated as follows:  were extracted referring to the frame numbers of P0, P1, and P4. Differences in the peak IVPD between P0 and P1 (DiffP01), and between P1 and P4 (DiffP14) were calculated. The time intervals between P0 and P1 (P0P1), and between P1 and P4 (P1P4), were calculated by examining the frame differences between the peak IVPD of P0 and P1, and between the peak IVPD of P1 and P4, divided by the frame frequency. The peak rate of pressure decline was calculated through the steepest downward (negative) slope of the time–IVPD curve, reflecting the maximal decay in chamber pressure as the LV relaxed. All of the parameters were averaged over three consecutive cardiac cycles. The offline analyses of the IVPD parameters were processed with Matlab .p value of < 0.05. All calculations were performed using IBM SPSS 20 .All continuous variables were tested for normality using the Shapiro-Wilk test. If the data did not conform to a normal distribution, the transformation process was performed. Variables with a normal distribution are expressed as the mean ± standard deviation. Non-parametric variables are presented as the median [25th to 75th percentile]. Differences in continuous parameters were compared using one-way analysis of variance or the non-parametric Kruskal–Wallis test, as applicable, while the Bonferroni test was used to adjust the α level for pairwise comparisons. To control for the effect of heart rate on hemodynamic parameters, an analysis of covariance among groups of hemodynamic parameters (P0P1 and P1P4) was performed with heart rate as a covariate. Correlation analyses were used to analyze the relationships between the hemodynamic parameters and training time, basic physiological information, and echocardiography data. A multiple linear regression analyses for P1P4 and training time, physiological parameters, LV structural, and functional parameters, which was significantly correlated, was also conducted. Statistical significance was set at a p < 0.001), a longer training years  and a longer WTT  than causal players (p = 0.005), weight , and body surface area  in the elite athlete group were significantly higher than in the healthy control group  in the elite athlete group was significantly higher than in the casual player and healthy control groups , LV end-systolic dimension  in the elite athlete group were significantly higher than in the casual player and healthy control groups  in the elite athlete group was significantly higher than in the casual player and healthy control groups  in the elite athlete group was significantly higher than in the casual player group , but the significant difference in P0P1 between the elite athlete group and the healthy control group disappeared.There was no significant difference in the peak IVPD or IVPG in each diastolic phase among the groups –F. P0P1 The WTT was significantly positively correlated with height, weight, body surface area, technical hierarchy, training year, interventricular septal thickness, LV end-diastolic/systolic dimension, LV mass index, sample line from LV apex to base, LV end-diastolic/systolic volume index, E/A, P0P1, and P1P4 . Additiop < 0.001) and E/A (p < 0.001), as well as a decrease in heart rate (p < 0.001), systolic blood pressure (p = 0.007) and relative wall thickness (p = 0.009). The R2 value was 0.713 after model adjustment .P1P4 was statistically significant after the covariance analysis, and thus the correlation and multiple linear regression analyses were conducted. P1P4 was significantly positively correlated with weight, technical hierarchy, training year, WTT, LV end-diastolic/systolic dimension, LV end-diastolic/systolic volume index, E/A, and P0P1 . P1P4 waThe parameters of cardiac structure in elite athletes demonstrated significantly higher values than in casual players and healthy controls, which supported our hypothesis that female ice hockey athletes show cardiac structural remodeling. The peak amplitudes of the IVPD and IVPG in three diastolic phases were similar among groups, and thus these results did not confirm the hypothesis that female ice hockey athletes with different training year/WTT show differences in the cardiac diastolic IVPD of the LV. The main findings of the present study were that female elite ice hockey athletes (with more than 10 training years and WTT of longer than 20 h) had longer P1P4 than casual players (with fewer than 10 training years and WTT of shorter than 20 h) and healthy controls. An increase in P1P4 was correlated with an increase in the training year, which supported the hypothesis of correlations between hemodynamic parameters and training time.The peak amplitudes of the IVPD and IVPG in three diastolic phases were not significantly different among the three groups –F. A preIn this study, the P0P1 and P1P4 in the elite athlete were significantly longer than in the healthy control groups , K. LowePavlik et al.  concludeThe correlation analysis showed that P1P4 was significantly positively correlated with technical hierarchy, training year and WTT. The multiple linear regression analysis showed that an increase in P1P4 was related to an increase in training year. The hypothesis that the training time would be significantly correlated with the hemodynamics of the LV was verified. Beaudry speculated that the cumulative years of exercise exposure would influence the extent of cardiac remodeling . CompareThe cardiac structural parameters of the LV in elite athletes showed significantly higher than those in casual players and healthy controls . These fThe LV mass index in elite athletes was significantly higher than in casual players and healthy controls . This obThis study has three main limitations. First, it is worth noting that the sampling line from LV apex to base was determined during the isovolumic diastolic phase (P0), and the pressure distribution of the sample line during other diastolic phases was automatically tracked with a fixed length of the sample line. However, the variation in the apex to base length may differed among the three groups. Therefore, the relative pressure distribution from the LV apex to the mitral valve with variations in the length of the sample line in LV diastole needs to be further explored. Second, as the adaptations in the athlete's heart mainly occur during exertion, future studies should focus on the IVPD during exertion in elite athletes. Third, sex differences exist in cardiac structural remodeling and function in athletes, but this study only focused on female ice hockey players. Therefore, further studies on the cardiac hemodynamic characteristics of male athletes should be considered, and correlations between hemodynamic parameters and maximal oxygen uptake, training intensity, and performance should be further examined to explore the hemodynamic mechanisms of cardiac adaptation to the training load.The hearts of elite female ice hockey athletes show typical dilated remodeling. The diastolic cardiac hemodynamics of the LV in female elite ice hockey athletes could be characterized by the longer duration of the diastolic IVPD. Moreover, P1P4 prolonged with training year, reflecting a time–domain adaptation in cardiac diastolic hemodynamics in elite athletes. The results of this study provide an effective basis for understanding the hemodynamic mechanism of cardiac adaptation to long-term training and provide a reliable reference for the scientific training of female ice hockey athletes.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 the Institute of Sports Medicine of the General Administration of Sport of China. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.PY and JZ  contributed to the conception and design of the study. JX and YB contributed to the acquisition of data. PY, HY, and RZ contributed to the analysis and interpretation of data. PY drafting the article and revising it critically for important intellectual content. BH final approval of the version to be submitted. All authors contributed to the article and approved the submitted version.


Despite advances in diagnosing and treating chronic heart failure (HF), the underlying mechanisms in different HF phenotypes remain unclear. Mitochondrial energy metabolism is crucial in HF etiology. Our study aimed to explore the value of metabolic-associated biomarker peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) in identifying different HF phenotypes.N = 46), heart failure with reduced ejection fraction , heart failure with mildly reduced ejection fraction , and heart failure with preserved ejection fraction  groups. Each participant’s baseline data were recorded, blood samples were taken, and echocardiography was conducted. The level of PGC1α expression was determined using an enzyme-linked immunosorbent assay (ELISA) kit. The receiver operative characteristics (ROC) curve was further established in the four groups to assess the diagnostic value for overall HF and each HF phenotype with the calculation of the area under the curve (AUC) and 95% confidence interval (CI).A total of 172 participants were enrolled in the Affiliated Hospital of Xuzhou Medical University and were subsequently divided into four groups based on the European Society of Cardiology HF management guideline: the non-HF control  compared to non-HF participants (233.3 ± 32.69 nmol/L). Considering different HF phenotypes, PGC1α expression was considerably higher in the HFmrEF group (401.6 ± 45.1 nmol/L)than in the other two phenotypes .Furthermore, the AUCs of PGC1α in overall HF and each HF phenotype were all over 0.8, showing the ideal diagnostic value. Additionally, we provided the cut-off criteria for clinical use, which needs further validation. There was no significant correlation between PGC1α and N-terminal (NT)-prohormone B-type natriuretic peptide (BNP)/blood glucose, suggesting that PGC1α might exert a unique function in HF yet in a different pattern.We discovered that PGC1α could be used as a potential biomarker for differentiating HF patients from those without HF and for distinguishing HFmrEF from HFrEF and HFpEF. As one of the most stumbling blocks in the cardiovascular field, chronic heart failure (HF) remains a clinical and public health problem with high morbidity and mortality . In receThe current guidelines propose that HF diagnostic process should be constructed based on these aspects: left ventricular ejection fraction (LVEF) as determined by echocardiography, blood N-terminal pro-B-type natriuretic peptide (NT-proBNP) or BNP level, and clinical signs or symptoms of the patients. HF phenotypes can be divided into three main categories: heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), and heart failure with mildly reduced ejection fraction (HFmrEF) . HoweverMetabolism is crucial in the pathophysiology of cardiovascular diseases, particularly HF . The eneAdenosine 5′-monophosphate-activated protein kinase (AMPK)/Sirtuin 1 (Sirt1)/peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) is a critical pathway in cardiac metabolism. Li et al.  have fouThe clinical study was constructed according to the Declaration of Helsinki, and the study protocol was approved by the Ethics Committee of the Affiliated Hospital of Xuzhou Medical University .A total of 172 participants were recruited for the study from May 2021 to December 2021 and divided into four groups  based on the inclusion and exclusion criteria  displayeWe recorded the participants’ demographic data  and drug use , measured several items , collected data on cardiovascular disease events , assessed cardiac function using echocardiography and NYHA classification, and performed blood biochemistry tests.Transthoracic echocardiography was performed on all participants using a commercial echocardiographic device . Measurements of left ventricular diastolic function were performed according to the guidelines. Trans-mitral early (E) and mitral annular early (e′) diastolic velocity indices were obtained, and E/e′ ratio was calculated to reflect diastolic function.Whole blood samples were collected, and routine laboratory tests  were performed in the clinical lab of the Affiliated Hospital of Xuzhou Medical University according to the manufacturer’s instruction. A dedicated kit-based NT-proBNP assay  was used to measure plasma NT-proBNP levels.PGC1α expression was quantified using an enzyme-linked immunosorbent assay (ELISA) kit . In brief, we added serum, standards, and HRP-labeled detection antibodies to pre-coated PGC1α antibody-coated micropores. For color rendering, 3,3′,5,5′-tetramethylbenzidine (TMB) was used after incubation and thorough washing. TMB is converted to blue by peroxidase and to yellow by acid finally. A positive correlation was observed between color depth and PGC1α in the samples. We measured the absorbance [optic density (OD) value] at 450 nm with a microplate reader and finally calculated the sample concentration.To evaluate the diagnostic value of PGC1α in identifying HF and each HF phenotype, the Receiver operative characteristics (ROC) curve was established using “pROC” R package (R version 3.6.3). To assess the sensitivity and specificity of the ROC curve, the area under curve (AUC) and 95% confidence interval (CI) were calculated via the “ggplot2” R package.post-hoc test. Data with a normal distribution were represented by mean ± standard deviation (SD), whereas median [interquartile range (IQR)] was used to represent data of a non-normal distribution. The χ2 test was used to compare categorical variables that were presented as numbers and percentages. P < 0.05 was considered statistically significant.Data were analyzed using SPSS software Version 20.0 ; GraphPad Prism Version 8.3.0 . Regarding continuous variables, initial analyses of the normality were conducted using the Kolmogorov-Smirnov (KS) test in conjunction with Q-Q plots . DiffereFurthermore, we assessed all participants by echocardiography. We mainly focused on LVEF and E/e′ ratio to assess cardiac systolic and diastolic functions. The results showed that LVEF (mean ± SD) in the non-HF, HFrEF, HFmrEF, and HFpEF groups were 62.13 ± 4.064, 33.33 ± 4.979, 43.73 ± 2.208, and 58.24 ± 5.057, respectively, which was consistent with the guidelines. Also, the E/e′ ratio for the four groups was 11.43 ± 5.084, 20.84 ± 12.92, 16.25 ± 5.437, and 19.6 ± 8.486, respectively, indicating that the diastolic cardiac function was impaired in HF.N = 46 for the non-HF group, N = 54 for the HFrEF group, N = 22 for the HFmrEF group, and N = 50 for the HFpEF group). There was no difference in terms of gender or height. Intriguingly, several items showed significant differences among the four groups. HF patients had a higher coronary heart disease rate and used more angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) and diuretic drugs. Regarding blood biochemistry tests, HF patients had lower hemoglobin, higher creatinine, and higher C-reactive protein levels, indicating that HF patients are prone to inflammation when compared with non-HF controls.As shown in The ROC curve analysis showed that the AUC of PGC1α for the diagnosis of HF compared to non-HF was 0.843 (CI: 0.785–0.900), and the cut-off criterium was 293.918 nmol/L, suggesting that 293.918 could be used as the criterion for distinguishing HF from non-HF. Additionally, the AUC for diagnosing HFrEF, HFmrEF, and HFpEF compared to non-HF was 0.804, 1.000, and 0.815, respectively. The above-mentioned results revealed the ideal diagnostic value in identifying HF and its phenotypes from non-HF controls . FurtherCompared to the most widely accepted categories of HF (HFrEF and HFpEF), HFmrEF represents a borderline group that has received little attention, lacking effective diagnostic methods and treatment . HoweverPGC1α has been initially identified as a cofactor for nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARγ) in adipocytes, which is required for the adaptive thermogenic response to a lower temperature . It reguIn our study, we revealed that PGC1α had the highest expression level in the HFmrEF group, which could be considered the transitory stage from HFpEF to HFrEF. PGC1α participates in mitochondrial biosynthesis ; hence, The value of PGC1α in diagnosing HF and identifying HF phenotypes is important, as shown on the ROC curve. The AUCs of the four groups were all greater than 0.8. Furthermore, AUC and Youden index were equal to 1in HFmrEF, showing the highest sensitivity and specificity in diagnosing HFmrEF. Meanwhile, we established a detailed threshold of PGC1α in diagnosing different HF phenotypes, which could be helpful for clinical practice. Additionally, we conducted the correlation analysis using Pearson test to investigate the relationship between PGC1α and blood glucose/NT-proBNP in HFmrEF patients. The results showed that there was no statistically significant correlation between PGC1α and blood glucose/NT-proBNP in HFmrEF group . TherefoThe newest AHA/ACC/HFSA Guideline for the Management of Heart Failure  publisheWe discovered that PGC1α expression was significantly upregulated in HF patients compared with non-HF participants. Besides, HFmrEF patients had a higher PGC1α expression level than HFrEF and HFpEF patients, which could be employed as a potential biomarker for differentiating HF patients from those without HF, as well as for distinguishing HFmrEF from HFrEF and HFpEF.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The study protocol was approved by the Ethics Committee of the Affiliated Hospital of Xuzhou Medical University  . The patients/participants provided their written informed consent to participate in this study.SZ and YH contributed to hypothesis development and manuscript preparation. SZ and YZ contributed to the study design, drafted and revised the manuscript. SZ was responsible for collecting clinical samples. YM and ZL undertook data analyses. All authors contributed to the article and approved the submitted version.


Case Presentation. This case report describes left ventricular thrombus progression/recurrence in a patient anticoagulated with Apixaban undergoing implantable cardioverter defibrillator to cardiac resynchronisation therapy with defibrillator upgrade procedure. He was thereafter changed to warfarin. Contrast echocardiogram at 6 months follow-up did not identify the previously demonstrated mural thrombus.  Anticoagulation with warfarin remains the mainstay treatment for left ventricular thrombi. Although successful thrombus resolution has been reported with direct oral anticoagulants' (DOACs') recurrence/progression while resuming Apixaban therapy is yet to be reported.  Prospective randomised control trials should be conducted in patients with left ventricular thrombus to compare anticoagulants, assess the efficacy and safety of DOACs, and evaluate uninterrupted DOAC versus transient withdrawal for cardiac device procedures. Left ventricular thrombus (LVT) complicates between 2.5 and 15% acute myocardial infarctions (MIs) .Anticoagulation with warfarin or low-molecular weight heparin (LMWH) remains the mainstay of treatment whilst successful thrombus resolution is reported with direct oral anticoagulants (DOACs) , 5. RecuA 75 year-old gentleman was admitted for elective upgrade of his ICD to a CRT-D. He had a background of ischaemic cardiomyopathy, severe left ventricular systolic dysfunction (LVSD), ICD implant (2017), chronic obstructive pulmonary disease, hypothyroidism, glaucoma, and gout.In 2017, he presented to the cardiology service with unexplained shortness of breath. Echocardiogram showed severe LVSD (LVEF < 30%) with extensive regional wall motion abnormalities (RWMAs) and akinesia of the apex. ECG showed sinus rhythm with narrow-complex QRS. His angiogram revealed significant coronary artery disease involving proximal chronic subtotal occlusion of the left anterior descending artery and focal tight stenosis of the midright coronary artery.Cardiac magnetic resonance (CMR) demonstrated marked ischemic cardiomyopathy, severe LV dilation  and LVSD (EF 24%), transmural MI of midanteroseptum and true apex, partial MI of apical, inferior, anterior walls, and midinferoseptal and apical septal walls. The multidisciplinary team meeting (MDT) decided that surgical and percutaneous revascularisation were unsuitable. A small apical laminar thrombus was noted , whereupRepeat echocardiogram in 2019 showed unchanged severe LVSD; the previous apical laminar thrombus noted on CMR that was not identified on the echocardiogram. Given the akinetic apex, severe LVSD, and high risk for development of further intraventricular thrombus, Apixaban was continued.During review in November 2019, it was noted that his narrow-complex tachycardia had changed to right bundle branch block with QRS duration of >150 ms. He met the criteria for upgrade to a CRT-D and was admitted for device upgrade. Post procedure ECHO demonstrated a mural thrombus at the left ventricular apex (1.8 × 1.1 cm) Figures . The patAnticoagulation with DOACs is increasingly utilised as off-label alternatives to warfarin in managing patients with LVT, with several case reports and observational studies demonstrating successful resolution on follow-up imaging .In a retrospective observational study involving echocardiographic surveillance of 108 patients receiving long-term anticoagulation after diagnosis of LVT , completIn a further study where 35 of 52 patients (67%) treated with DOAC for LVT proceeded to imaging follow-up, 83% had complete resolution of LVT with mean duration to complete resolution being 264 days [A systematic review of thirty articles involving patients diagnosed with LVT and treated with DOACs found that thrombus resolution rates were 81%, 100%, and 88.9% for rivaroxaban, apixaban and dabigatran, respectively, with a median time to resolution of 40, 36, and 24 days, respectively [Little is published on formation of new LVT whilst taking DOAC therapy, with one article describing this at the time of our report. Degheim et al. described a patient who developed LVT whilst on rivaroxaban for atrial fibrillation with subsequent subacute parietal lobe infarction .CMR is superior to ECHO (with or without contrast) at detecting LVT . It is pIt raises the prospect that whether transiently withholding Apixaban for 48 hours prior to device upgrade may be a factor in formation or extension into the mural LV thrombus subsequently identified, given our patient's significantly impaired LV and akinetic apex.Predisposition to significant thrombophilia appears unlikely in our patient by observations of no personal or family history of clinical thromboembolism and background coagulation profiles (×3) within normal limits.Our observations raise the question as to whether patients diagnosed with LVT having underlying severe LVSD, significant RWMAs, or akinetic/aneurysmal apex should continue anticoagulation rather than withholding it prior to device upgrade procedures. In the event uninterrupted anticoagulation emerges as beneficial in LVT, it also remains to be determined as to what form this should take.The BRUCE CONTROL 2 study  found noThe importance of the minimising risk of LVT formation is evidenced from patients with LVT having significantly increased risk of major adverse cardiovascular events (MACEs) and death, as highlighted in a present report from a single-centre French study examining 159 patients with LVT for effects of anticoagulation therapy on patient outcomes . They reWith median follow-up of 632 days, 35.4% of patients with total LVT regression and 40.0% of patients with persistent LVT experienced MACE. Compared with other patients, those with LVT regression had lower risk of mortality, while anticoagulation therapy for more than 3 months and LVEF ≥35% were independently associated with lower rates of MACE.At a median follow-up with ECHO of approximately 1 year, 76% of thrombi had regression from baseline. Independent predictors of complete resolution were nonischemic cardiomyopathy and smaller thrombus size at baseline.While patients with LVT are at increased risk of adverse outcomes, there is also a lower mortality risk in patients showing LVT regression.Nonpharmacologic mechanisms have also been suggested to aid the formation or progression of left ventricular thrombi in patient with aneurysmal apex. Fakhry and Siddique  suggesteIn conclusion, prospective randomised control trials should be conducted in patients with LV thrombus to compare anticoagulants, assess the efficacy and safety of DOACs, and evaluate uninterrupted DOAC versus transient withdrawal for cardiac device procedures. This data may yield factors that enable individualised anticoagulation regime's periprocedure in LV thrombus.In this case report, the authors highlight to be mindful that LVT may propagate/recur in patients on DOAC therapy and transient withholding of DOAC therapy for cardiac device procedures may increase possible risk.


The treatment of moderate functionalmitral regurgitation (FMR) during coronary artery bypass grafting (CABG) is still debated. Our primary end point was to assess the improvement of “mitral valve reserve” (MVR) after CABG alone as a clinical demonstration of left ventricular (LV) recovery.Between June 2019 and June 2021, we prospectively enrolled 104 consecutive patients undergoing CABG with moderate FMR. Inclusion criteria were inferior-posterior-lateral wall hypokinesia and revascularization of the circumflex or right coronary artery. MVR was calculated as the ratio between anterior and posterior leaflets’ straight length. All patients were followed for 1 year. The improvement of MVR has been considered as a reduction of the ratio between anterior and posterior leaflets straight length.Compared to baseline, mean MVR was significantly reduced both at 6  and 12 months follow-up . Left ventricular (LV) reverse remodeling, meant as improvement of LV ejection fraction and reduction of LV end-systolic volume index and mitral anulus diameter were evaluated at 6 months and 1 year. Mitral regurgitation grade were also significantly reduced at 6 months (p < .001).The benefits of myocardial revascularization in term of improvement of mitral regurgitation’s degree can be explained by the changes of MVR. The patients with FMR, who could have more advantages from CABG alone, should be the ones who have LVESVi just moderately increased. Functional mitral regurgitation (IMR) is a clinical condition secondary to left ventricular pathological remodeling, occurring in about 50% of patients with chronic coronary artery disease, being of moderate degree in almost 10% of cases .In normal valves, mitral valve coaptation line is asymmetric, with a clear anterior dominance . In chroAlthough in the last 10 years moderate FMR was considered a clear indication for surgery in patients undergoing CABG, the most recent evidences questioned the utility to treat the mitral valve in case of less than severe insufficiency. Accordingly, current guidelines equalized the qualitative and semi-quantitative echocardiographic parameters for the estimation of severity grade, supporting mitral valve surgery only in case of severe insufficiency , 7. On tIn this study, we sought to investigate changes in mitral valve reserve in patients with moderate FMR undergoing isolated CABG.Between June 2019 and June 2021, data from all patients undergoing isolated CABG were prospectively enrolled in an institutional database.All patients underwent preoperative transthoracic echocardiography. Intraoperative transesophageal echocardiography was always performed to confirm the absence of a mitral-valve structural abnormality. Mitral valve anterior and posterior leaflets’ straight length, the coaptation depth (CD) and the septo-lateral anulus diameter (distance from anterior to posterior anulus) were measured from the apical four chamber view. Mitral valve reserve was calculated as the ratio between the anterior and posterior leaflets’ straight length  Fig. 1)1). The eFor the specific aim of this study, the selection criteria were moderate functional mitral regurgitation, hypokinesia of the left ventricular inferior-posterior-lateral region and the ability to revascularize of one or more branches of circumflex and/or right coronary arteries. Mitral valve surgery was not performed, according to current guidelines , 7.Patients with akinesia, reduced thickness, aneurysm, scar and absence of myocardial vitality at myocardial stress test of the of left ventricular inferior-posterior-lateral wall or severe ischemic mitral regurgitation were excluded.patients’ characteristics and type of interventions performed.The degree of mitral valve regurgitation was defined according to vena contracta width. The mechanism of mitral regurgitation was an asymmetric tethering of the posterior leaflets in all patients. A single imaging specialist evaluated all echocardiograms blinded to Among 531 patients included, 104 fulfilled the inclusion criteria and were part of the present analysis.All patients were prospectively followed for 2 year. Mitral valve function and left ventricular remodeling were assessed at baseline, at 6 and 12 months postoperatively.The primary endpoint was the improvement of mitral valve reserve, defined as the reduction of the ratio between the anterior and posterior leaflet length . The secContinuous variables are expressed as means and standard deviation, whereas categorical variables are reported as counts and percentages. Change over time of mitral valve reserve, leaflet lengths, annular septo-lateral diameter, LVESVi, LVEF and degree of MR were assessed with repeated measure ANOVA and Friedman’s two was analysis of variance by ranks.Data were analyzed with SPSS 24 . Statistical significance was set at a p-value < 0.05.± 0,91. Mean follow-up was 19,64 ± 8,5 months .Patients’ preoperative characteristics are summarized in Table All patients were successfully discharged from hospital. During follow-up, four patients died for non-cardiac-related cause. Accordingly, follow-up was 96.1% and 48% complete respectively at 1 years and 2 years.When mitral valve was considered, posterior leaflet length significantly change overtime, whereas no significant changed in anterior leaftlet was observed Table . ConversThe rank-based assessment of mitral regurgitation’s degree at 6 months over showed a significant reduction compared to baseline : particularly, at 6 months the mitral insufficiency was mild or no in the 70% of patients. At 1 year all followed patients had mild or no mitral valve regurgitation as well as at 2 years. At the admission, 23% of patients were in NYHA > 3. At 1 and 2 years all followed patients were in NYHA 1.Left ventricular reverse remodeling was evident at follow-up with a borderline reduction of LVESVi . . In the moderate MR group, all followed patients have mild mitral regurgitation at 12 months.Afterwards, patients were divided in two groups, based on the baseline mitral regurgitation’s degree (Group 1: mild MR vs. Group 2: moderate MR). The baseline characteristics of two groups are summarized in the Table In the current study from a highly selected cohort of patients with moderate FMR, undergoing target vessel revascularization without concomitant valve repair, we observed an improvement of mitral valve reserve, reduction of valve insufficiency and improved LV performance at short-term follow-up.Occurrence of ischemic mitral regurgitation depends on an imbalance between increased tethering forces and reduced closing forces, the latter including reduction in left ventricular (LV) contractility and altered systolic annular contraction.  The postModerate FMR is common in patients needing myocardial revascularization, ranging from 10 to 50% . In the Although a general agreement exists about the need to treat severe mitral valve insufficiency, the functional etiology of this peculiar entity, that is left ventricular dysfunction, may suggest to focus the surgical attention more on the recovery of myocardial perfusion and vitality rather than only restricting the annulus of a mitral valve with almost anatomical intact leaflets. Indeed, in the normal mitral valve, the leaflet’s contribution to the coaptation is asymmetric for the dominance of the anterior one as pointed out by Gogoladze G. et al. . FMR is The reduction of “mitral valve reserve” observed in the present study supports the knowledge that functional insufficiency is primarily a ventricular disease, rather than a leaflet disease. It could be speculated that the significant reduction of the ratio between the anterior and posterior leaflet straight lengths might be explained by the anterior relocation of the coaptation line as a consequence of the recovery of left ventricular inferior-posterior-lateral contractility leading to the improvement of the posterior leaflet motion.Although the study might be underpowered because of the small size of the sample, target myocardial revascularization allows achieving a positive reverse left ventricular remodeling, with reduced LVESVi and annular diameters, as well as an increase in LVEF, provided the evidence of underlying vital myocardium.The observed reduction of mitral regurgitation grade, which has been already described after CABG –21, may In our experience, we did not observe any worsening of mitral regurgitation during follow-up so that as the insufficiency was mild in the 70% of patients at 6 months. All followed patients had mild or no mitral regurgitation at 12 months and 2 years.Comparing our results to similar surgical series, we observed a greater reduction of mitral regurgitation degree than in other studies. Indeed, Smith P.K and colleagues found that the 69% of patients had no or mild mitral valve regurgitation at 12 months in the group of CAGB alone as compared with 89% of patients in the group of CABG plus mitral valve repair. –24.It may be speculated that the more evident reduction of mitral regurgitation grade might depend on the lower left ventricular volumes at baseline recorded in our study rather than the result of the published trials. –17Reserve LV remodeling is well known to have been associated with an improved outcome, although, a recent randomized trial showed that there is no significant difference between patients undergoing CABG alone and combined treatment .Moreover, the data published in the literature show that the recurrence of moderate or severe mitral valve regurgitation after CABG with mitral valve repair is roughly 30% at 2 year.Currently, scientific evidence suggest that the addition of mitral valve repair in patients undergoing CABG with moderate FMR had no incremental effect on reverse LV remodeling and survival. The small sample size is the main limitation of our study, which might underpower our results. Accordingly, we tried to overcome such limitation with strict inclusion and exclusion criteria, in order to limit as much as possible the interferences of unaddressed confounders. On the other hand, the single center design guarantees uniformity of surgical technique, data collection and analysis.Our results show an improvement of the MVR that explain the significant reduction of the degree of mitral valve regurgitation.In our experience, the patients with moderate FMR, who benefit more from isolated CABG, are those with only moderate increased LVESVi.Further studies, specifically designed to address the pathophysiological changes of left ventricular remodeling also in terms of mitral valve reserve, are needed to identify an optimal LVESVi cut-off for treatment decisions in moderate ischemic mitral regurgitation.


A) receptor blockade on the course of volume-overload heart failure in rats with angiotensin II-dependent hypertension.Evaluation of the effect of endothelin type A . Animals first underwent ACF creation and 2 weeks later the treatment with atrasentan or trandolapril, alone or combined, was applied; the follow-up period was 20 weeks.Ren-2 renin transgenic rats (TGR) were used as a model of hypertension. Heart failure was induced by creating an aorto-caval fistula (ACF). Selective ETA receptor blockade improved the final survival rate to 52% . The effects of the three treatment regimens on the survival rate did not significantly differ. All three treatment regimens suppressed the development of cardiac hypertrophy and lung congestion, decreased left ventricle (LV) end-diastolic volume and LV end-diastolic pressure, and improved LV systolic contractility in ACF TGR as compared with their untreated counterparts.Eighteen days after creating ACF, untreated TGR began to die, and none was alive by day 79. Both atrasentan and trandolapril treatment improved the survival rate, ultimately to 56%  and 69% , respectively. Combined ACEi and ETA receptor antagonist delays the onset of decompensation of volume-overload heart failure and improves the survival rate in hypertensive TGR with ACF-induced heart failure. However, the addition of ETA receptor blockade did not enhance the beneficial effects beyond those obtained with standard treatment with ACEi alone.The treatment with ET Over the past 40 years, substantial progress has been made in the treatment of acute coronary syndromes. However, many surviving patients still develop substantial myocardial damage eventually leading to heart failure . Heart fA) receptors induces vasoconstriction; activation of endothelin type B receptors leads to vasodilatation and natriuresis. Inappropriate activation of ETA receptors is thought important in the pathophysiology of cardiovascular and renal diseases [It has long been proposed that persistent inappropriate activation of various neurohormonal systems underlies the progression of heart failure . Mordiseases –25. The diseases ,27, and diseases ,24,25.et al.[A blockade improved the survival rate, an analogy to the improvement obtained with angiotensin-converting enzyme (ACE) inhibition which resulted in the introduction of angiotensin-converting enzyme inhibitor (ACEi) as a gold standard therapy of heart failure [A antagonist (darusentan) were disappointing: early fluid retention actually leading to worsening of heart failure was a common finding [A receptor blockade on the natural course of heart failure have not yet been evaluated [A receptor antagonist, atrasentan [Therefore, the upregulated endothelin system might be an important target for therapeutic intervention in heart failure ,24,25. Iet al. reported failure . However failure ,22,30–32 finding –35. In t finding  endothel finding . Evidentvaluated –25. The rasentan , enablesrasentan –41.A receptor antagonist, we evaluated the effects of chronic atrasentan treatment on morbidity and mortality in ACF TGR.The rat model of volume overload induced by the creation of the aorto-caval fistula (ACF) reasonably well mimics human heart failure ,15,42–47To explore in more detail a possible role of interaction of the RAAS and endothelin system and sympathetic nervous system (SNS) ,54–56 inn values were used  to enable a valid comparison of the long-term survival rate. Such required n values were established using the statistical power analysis method developed by Cohen [The studies were performed in accordance with guidelines and practices established by the Animal Care and Use Committee of the Institute for Clinical and Experimental Medicine, Prague, which accord with the European Convention on Animal Protection and Guidelines on Research Animal Use and approved by the Ministry of Health of the Czech Republic (project decision 26306/2020-4/OVZ). Heterozygous TGR were generated by breeding male homozygous TGR with female homozygous Hannover Sprague-Dawley (HanSD) rats. Male TGR and HanSD rats, at the initial age of 9 weeks, derived from several litters, were randomly assigned to experimental groups to make sure that the animals from a single litter did not prevail in any group. To obtain reliable data regarding the effects of two treatment regimens on the survival rate, high initial by Cohen .Rats were anesthetized  and heart failure was induced by volume overload caused by ACF created using needle technique as employed and validated by many investigators, including our own group –47,58,59A receptor blockade was achieved with atrasentan . The dose of atrasentan was adjusted weekly to actual water intake; such dosage was previously found to effectively block ETA receptors [Trandolapril , was used to inhibit ACE because in our previous studies and here in preliminary experiments we demonstrated that at this dose the ACEi, trandolapril, provided maximal blockade of the RAAS and was well tolerated both by rats with ACF-induced heart failure and by sham-operated animals ,47,59. Eeceptors ,40.The whole experimental design of the study, with a presentation of the detailed time sequence of experimental maneuvers and different treatment regimes, is given in Fig. Animals underwent either sham-operation or ACF creation and were left without treatment for 2 weeks. At this time point (day 0) they were assigned to the following experimental groups:n = 12).Group 1: Sham-operated HanSD rats + placebo .Group 2: Sham-operated TGR + placebo .Group 3: ACF TGR + placebo (i.e. untreated ACF TGR) .Group 4: ACF TGR + ETn = 32).Group 5: ACF TGR + ACEi .Group 6: ACF TGR + ACEi + ETet al.[The follow-up period was 20 weeks. At the end of the experiment (on day +140), the survived rats were anesthetized and echocardiography was performed. Subsequently, LV functions were invasively assessed by employing pressure–volume analysis by techniques and protocols developed and validated for mice and rats by Pacher et al.. This meet al.,47,61,62et al.. Before et al.,47,61,62n = 11 each) were investigated:Animals underwent either sham-operation or ACF creation and were left without treatment for 2 weeks and then were killed by decapitation. Whole kidney ANG II, angiotensin 1–7 (ANG 1–7) and norepinephrine levels, and ET-1 concentrations in the kidney cortex, kidney papilla, and lung tissue were measured, as described in our previous studies ,51,63,64Group 1: Sham-operated HanSD rats.Group 2: Sham-operated TGR.Group 3: ACF TGR.Animals were prepared as described in series 1 and 2, and at week 0 the pharmacological treatment was applied for a period of 2 weeks. On day +14, the measurements were performed in the following groups:n = 7).Group 1: Sham-operated HanSD rats + placebo (n = 7).Group 2: Sham-operated TGR + placebo .Group 3: ACF TGR + placebo  (A receptor antagonist (n = 9).Group 4: ACF TGR + ETn = 9).Group 5: ACF TGR + ACEi (A receptor antagonist (n = 9).Group 6: ACF TGR + ACEi + ETt test, Wilcoxon's signed-rank test for unpaired data, or one-way analysis of variance when appropriate. The values are expressed as the means ± standard error of the mean and n represents the number of animals. A P value less than 0.05 was considered statistically significant.Statistical analysis of the data was performed using Graph-Pad Prism software . Comparison of survival curves was performed by log-rank (Mantel-Cox) test followed by Gehan-Breslow-Wilcoxon test. Statistical comparison of other results was made by Student's A receptor antagonist and ACEi, applied alone, improved survival: the final rate was 56%  and 69% , respectively. With the combined treatment the final survival rate was 52% . The three variants of treatment did not significantly differ in their effectiveness.All sham-operated HanSD rats and TGR survived until the end of the study, and for clarity of presentation they are omitted from Fig. A receptor blockade was the most effective. Remarkably, in ACF TGR receiving the combined treatment albuminuria was even 22-fold lower than in sham-operated HanSD rats .At the start of the treatment (2 weeks after sham-operation or creation of ACF), the sham-operated TGR showed about 35-fold higher albuminuria than observed in sham-operated HanSD rats  hypertrophy Table . In addiTwo weeks after the creation of ACF or sham-operation tissue concentrations of ANG II, ANG 1–7, norepinephrine, and ET-1 were as shown in Fig. Sham-operated TGR displayed whole cardiac and LV hypertrophy as compared with sham-operated HanSD rats Table . In TGR A receptor antagonist alone or ACEi alone reduced both the LV and RV diameters but did not change the LV wall thickness and systolic function of the LV in ACF TGR. Notably, combined treatment with ACEi and ETA receptor antagonists did not modify the LV and RV diameters but further decreased the LV anterior and posterior wall thickness and LV relative wall thickness and, unexpectedly, decreased RV ejection fraction.Evaluation of cardiac structure and function by echocardiography showed that sham-operated TGR displayed higher LV anterior and posterior wall thickness and the LV relative wall thickness as compared with sham-operated HanSD rats Table , showingmax max max and ESPVR. ETA receptor blockade, applied alone or with ACEi, increased PRSW . On the other hand, the extent of lung congestion was lower than observed in untreated ACF TGR  indicates that even though early activation of the vasoconstrictor/sodium retaining axis of the RAAS may be beneficial, its long-term pleiotropic actions are detrimental and contribute to the progression of heart failure.We found that both ETA receptor antagonist [Since both treatment regimens substantially delayed the heart failure-related morbidity and mortality in ACF TGR, we hypothesized that combined treatment with trandolapril and atrasentan should provide additive protective actions. However, this hypothesis has not been corroborated: the results of the combined therapy did not significantly differ from those of either single treatment. Therefore, one should consider individual aspects of heart failure-related morbidity as related to interaction at various levels of the RAAS and endothelin systems ,66. ANG tagonist . EvidentA system in chronic kidney disease, heart failure, and similar disorders. If so, understanding the underlying mechanism(s) is important.Notably, the combined treatment exhibited more pronounced effect on albuminuria and was more effective in reducing bilateral cardiac hypertrophy and lung congestion. Since albuminuria and cardiac hypertrophy are independent risk factors for cardiovascular morbidity and mortality  ,64,71–73To address this issue, we examined the effects of the three treatments  on cardiac function after 2-weeks’ treatment, at a time when untreated animals were showing high mortality. Untreated ACF TGR not only exhibited bilateral cardiac hypertrophy and prominent eccentric chamber remodeling but also an impairment of load-sensitive systolic and diastolic function and load-independent contractile function of the LV, which confirmed the view that the ACF-induced model of heart failure well represents heart failure with reduced ejection fraction elicited by chronic volume-overload insult ,49,74.We hypothesized that the beneficial effects of the treatment regimens on long-term survival were preferentially mediated by cardiac mechanisms, in agreement with the recent evidence that 15 weeks’ ACEi treatment significantly improved LV ejection fraction in ACF TGR . Here weOverall, each of the treatment regimens applied within the long-term protocol (20 weeks) improved cardiac morphology, systolic and diastolic function of the LV and reduced lung congestion. Most probably, the beneficial effects on the survival rate observed with atresan or trandolapril, alone or combined, are mostly mediated by cardiac mechanisms. This notion is further supported by the effectiveness of 2-weeks’ treatment on cardiac morphology and function. At the onset of heart failure decompensation (when untreated rats were beginning to die) all treatment regimens substantially attenuated bilateral cardiac hypertrophy and lung congestion, reduced LVEDP, LVEDV, LV wall stress, and improved LV systolic contractility.What was the degree of activation of the intrarenal neurohormonal systems in the earliest phase of ACF-induced heart failure? Two weeks after ACF creation, just before the treatment was initiated, ACF TGR did not display any significant increase in kidney ANG II levels. This suggests no substantial activation of the intrarenal vasoconstrictor/sodium retaining axis of the RAAS. In contrast, elevated kidney ANG 1–7 and increased ANG 1–7/ANG II ratio indicates activation of the intrarenal vasodilator/natriuretic axis of the RAAS. There was no increase in kidney norepinephrine concentration, that is, an absence of substantial activation of the intrarenal SNS. In addition, ACF TGR did not show increased concentrations of ET-1 in the renal cortex, papilla, and lung tissue, which suggests no substantial activation of the tissue endothelin system. Evidently, in the very early phase of volume-overload heart failure, ACF TGR did not show intrarenal activation of the vasoconstrictor/sodium retaining axis of the RAAS, SNS, or endothelin system. However, there was a marked activation of the intrarenal vasodilator/natriuretic axis of the RAAS.The evidence that kidney activity of RAAS, SNS, and endothelin system is not increased in ACF TGR seems incompatible with the neurohormonal theory of the pathophysiology of heart failure, which proposes that in heart failure the activity of the RAAS and SNS is increased and compensates for the initial insult, even though in the long run such hyperactivity is known to be deleterious and critically contributes to the progression of heart failure –19,54–56One limitation of the current study is the application of the ACF TGR model. On the other hand, its major advantage is that the rats are highly hypertensive and display marked systemic and intrarenal activation of the RAAS ,51, thusIt is also admitted that all our series which evaluated cardiac functions were performed in long-term anesthetized and surgically stressed animals, which must have caused the increased activity of neurohormonal systems, particularly of the RAAS and SNS. Possibly, the resultant changes in neurohumoral and volume status could alter cardiac function to some extent, both in healthy animals and in those with ACF-induced heart failure. However, we demonstrated previously, in the initial comprehensive reference study and in our previous studies ,47,61,62A receptor blockade delays the onset of heart failure decompensation and improves the survival in ACF TGR. Second, the beneficial effects of each of the treatment regimens on long-term survival are most probably mediated by partial recovery of cardiac function, specifically by attenuation of bilateral cardiac hypertrophy, of lung congestion, by reducing LVEDP, LVEDV, LV wall stress, and also by improving LV systolic contractility. Third, the addition of ETA receptor blockade did not increase the protection against heart failure-related mortality in ACF TGR beyond the improvement obtained with the treatment with ACEi alone.In conclusion, our results showed that, first, even in the absence of pronounced activation of the tissue endothelin system in the early phase of volume-overload heart failure, ETOn the whole, our results suggest that targeting the endothelin system should again be considered for the treatment of heart failure, at least of its volume-overload variant, and in individuals with background hypertension and enhanced RAAS activity.Previous presentations: none.The current study was supported by the project National Institute for Research of Metabolic and Cardiovascular Diseases  – funded by the European Union – Next Generation EU.The current study was also supported by the Ministry of Health of the Czech Republic grant number 20-02-00052 awarded to H.M. and P.K. was supported by the Grant Agency of Charles University, grant number 68121.There are no conflicts of interest.


Dobutamine stress echocardiography is an alternative method to exercise stress echocardiography for the evaluation of ischemia. Recently, the novel speckle tracking imaging derived parameter, myocardial work index, was suggested for the evaluation of cardiac performance and was evaluated during exercise stress echocardiography. In this study, we analyzed the effect of dobutamine on myocardial work index variables during normal dobutamine stress echocardiography. Echocardiography examinations of patients with normal dobutamine stress echocardiography were collected and underwent off-line speckle tracking imaging analysis. Myocardial work index parameters were calculated at each dose of dobutamine and compared. 286 patients underwent dobutamine stress echocardiography during the study period. 102 patients were excluded due to pre-existed coronary artery disease or ischemia at dobutamine stress echocardiography. 65 patients were excluded due to suboptimal image quality unsuitable for speckle tracking imaging analysis. The remaining 119 patients with normal results were included. The global work index decreased from 2393.3 to 1864.7 mmHg%, p < 0.0004. Global constructive work decreased from 2681.7 to 2152.6 mmHg%, p = 0.001. Global wasted work increased from 78.8 to 128.3 mmHg%, p < 0.003. Global work efficacy decreased from 96.1 to 91.9%, p < 0.00001. Global strain increased from—19.6 to − 23.7%, p < 0.00001. Dobutamine stress echocardiography results in a decrease of all specific myocardial work index parameters even in normal subjects. Only global myocardial strain improved. Visual assessment of contractility is based on the evaluation of wall thickening that’s subjective and often completely depends on the experience of the interpreting physician. Recently, few studies evaluated cardiac mechanics during dobutamine stress echocardiography4 using speckle tracking imaging. The applicability of speckle tracking imaging in dobutamine stress echocardiography is limited by high heart rates. Recently a new speckle tracking imaging parameter, the myocardial work index was introduced5. To better understand the physiology of dobutamine stress echocardiography, we applied speckle tracking imaging, in particular a myocardial work index, in patients with normal dobutamine stress echocardiography.Dobutamine stress echocardiography (DSE) allows dynamic evaluation of cardiac function during pharmacological stimulation of heart rate, cardiac output, and myocardial oxygen demand. Diagnosis of ischemia is done by visual comparison of left ventricular contraction during dobutamine infusion. In contrast, to exercise stress echocardiography, dobutamine stress echocardiography isn’t expected to provide physiological information. Diagnostic accuracy of dobutamine stress echocardiography is determined by sensitivity for detection of coronary artery disease 61–96%, and specificity 70–100%6. The myocardial work index variables included: Global work index (GWI), Global constructive work (GCW), Global wasted work (GWW), and Global work efficacy (GWE) and were calculated according to the recent recommendations7.Digital files of the patients that undergo dobutamine stress echocardiography examination were examined. All echocardiography exams were performed using Vivid E95,  with a standard transducer of 1.7–4 Hz. Frame rate during dobutamine stress echocardiography examinations was in a range of 50–70 fps. Studies with normal results were selected. The clinical characteristics of these patients were obtained from the hospital files. Offline echocardiography analysis included a revision of conventional echocardiography and calculation of myocardial work index variables at baseline and each dose of dobutamine infusion. Speckle tracking imaging analysis was done according to the original recommendations from apical 3-chamber, 4-chamber, and 2-chamber views8, particularly if the heart rate was not increased as expected. ECG and blood pressure measurements were registered every 3 min. The target heart rate was determined as 85% of maximal predicted heart rate, 85% × (220 − age).All the patients underwent a standard protocol of dobutamine stress echocardiography with the incremental rise of dobutamine doses every 3 min, from 10 up to 40 mcg/kg/min. Atropine was delivered at the 20 or 30 mg/kg/min dose of dobutamine as recommendedStatistical methods. Continuous data were expressed as means ± standard deviations. The normal distribution for all differences was tested using the Kolmogorov–Smirnov test. A two-tailed, dependent T-test was used. Categorical data were expressed in numbers and percentages. Univariate analysis was performed using Chi-Square/Fisher’s exact test (where appropriate) or to identify significant variables (p < 0.05).The study was approved by the Ethics (Helsinki) Committee at Shamir (Assaf Harofeh) Medical Center for the conduct of clinical Studies (No.: 0034-19-ASF). All methods were carried out following relevant guidelines and regulations..Informed consent was not required as data collection was retrospective, anonymous, and speckle tracking imaging analysis didn’t influence clinical diagnosis. The Ethics (Helsinki) Committee at Shamir (Assaf Harofeh) Medical Center for the conduct of clinical Studies has approved the nonrequirement of informed consentDuring 01.2019–06.2019, dobutamine stress echocardiography examinations were performed in 286 patients. 102 patients were excluded due to a prior history of coronary artery disease or inducible ischemia at dobutamine stress echocardiography. 65 patients were excluded due to reduced echocardiography image quality, which wasn’t sufficient for adequate speckle tracking. The remaining 119 patients with normal dobutamine stress echocardiography were included in the current study. The mean age was 66, there were 38 males (32%). The main indications for the study were chest pain (53%) and shortness of breath (47%), while the most of patients had risk factors for coronary artery disease (Table The mean ejection fraction (EF) was 59.8%. 53 patients, 45%, received atropine at dobutamine dose 20 or 30 mcg/kg/min, mean atropine dose was 0.7 ± 0.3 mg. All the patients reached target heart rate: 13—at dobutamine doses of 40 mcg/kg/min, 79 at 30 mcg/kg/min, 27 patients reached target heart rate at dobutamine dose 20 mcg/kg/min. Peak heart rate was 89 ± 4% of maximal predicted heart rate. Myocardial work index parameters during each stage of dobutamine stress echocardiography and hemodynamic parameters are represented  decreased from 2393.3 ± 503.4 to 1864.7 ± 424.4 mmHg%, p < 0.0004. Global constructive work (GCW) decreased from 2681.7 ± 549.6 to 2152.6 ± 521.7 mmHg%, p = 0.001. Global wasted work (GWW) increased from 78.8 ± 56.5 to 128.3 ± 45.2 mmHg%, p < 0.003. Global work efficacy (GWE) decreased from 96.1 ± 3.1 to 91.9 ± 4.5%, p < 0.00001. Changes in the strain pressure loops during dobutamine stress echocardiography show  according to the current guidelines8. Oxygen consumption during dobutamine stress echocardiography is not known, but extrapolating the data from exercise echocardiography and for safety considerations, the target heart rate is empirically set as 85% of maximal predicted heart rate8.Calculation of target heart rate during exercise stress test based on the real data about oxygen consumption response to exercise, that is linear. A stage of the plateau is reached at near maximal exercise when a heart rate is of about 220 − age, that is the maximal predicted heart rateOur results indicate that the dobutamine stress test can overload the heart and age-related heart rate may not be the optimal criterion for interrupting the dobutamine infusion that probably, can be terminated earlier. There is a question if the sensitivity of such a study will not be impaired and further evaluation is needed.Only normal examinations were recruited into the study, therefore the researchers were not blinded to the results.In our study we compared our data of dobutamine stress echocardiography with the literature data regarding exercise stress echocardiography that was done on other patients’ populations.Although all our patients achieved a target heart rate, we can’t exclude the possibility of false-negative results.As we found in our study, during normal dobutamine stress echocardiography, although global myocardial strain increases, all the specific parameters of myocardial work index deteriorate. We can suppose, that the calculated target heart rate may not be the optimal parameter to define termination of dobutamine infusion. Myocardial work index and global strain can be used too. Further investigations of myocardial work index variables in patients with ischemia are needed.