The PI (%) was assessed at baseline and PEEP 5, 10, and 15 cmH2O. Echocardiographic and hemodynamic parameters were recorded. Results. In total, 144 patients were screened from February 2018 to March 2019 and 29 were enrolled. Central venous pressure significantly increased for each PEEP increment. Stroke volumes were significantly lower after PEEP incrementation, with 52 mL (50–55) at PEEP 0 cmH2O and 30 mL (25–45) at PEEP 15 cmH2O, (p < 0.0001). The PI significantly increased with PEEP incrementation, from 9% (5–15) at PEEP 0 cmH2O to 15% (5–22) at PEEP 5 cmH2O, 34% (23–44) at PEEP 10 cmH2O, and 45% (25–49) at PEEP 15 cmH2O (p < 0.001). Conclusion. In the present study, PI appears to be a dynamic marker of the interaction between mechanical ventilation and right heart pressure after cardiac surgery. The PI could be a useful noninvasive tool to monitor venous congestion associated with mechanical ventilation.We aimed to assess variations in the portal vein pulsatility index (PI) during mechanical ventilation following cardiac surgery. Method. After ethical approval, we conducted a prospective monocentric study at Amiens University Hospital. Patients under mechanical ventilation following cardiac surgery were enrolled. Doppler evaluation of the portal vein (PV) was performed by transthoracic echography. The maximum velocity (VMAX) and minimum velocity (VMIN) of the PV were measured in pulsed Doppler mode. The PI was calculated using the following formula (VMAX − VMIN)/(VMax). A positive end-expiratory pressure (PEEP) incremental trial was performed from 0 to 15 cmH The early detection of venous congestion is strongly recommended during critical-care management to prevent higher mortality and adverse outcomes as well as reduce the length of hospital stay associated with fluid overload ,2,3.Central venous pressure (CVP) is the standard measure of venous hypertension but it is an invasive measurement and there is no agreement on the critical value that should be considered in clinical practice . HoweverThe portal vein (PV) pulsatility index (PI) has been developed and described as a noninvasive alternative to measuring CVP to monitor venous congestion . The PI There are currently no data on variations in the PI during mechanical ventilation. Clinical data confirmed that mechanical ventilation is a risk factor for AKI in a recent meta-analysis . As highWe aimed to assess how an incremental PEEP could influence PI supposing a backward transmission of PEEP in the venous system. We assume that a high PEEP leads to an increase in the pulsatility index. The higher the PEEP the higher the PI.The study protocol was approved by the local independent ethics committee  on 24 March 2016. The present report was drafted in accordance with the STROBE statement for cohort studies /maximum diastolic velocity (cm/s). In normal subjects, the S wave is wider than the D wave, with an S/D ratio > 1. To assess the S/D ratio, we performed a hepatic-vein Doppler. The S wave is a result of ventricular systolic flow and shows a negative systolic wave. The D wave is a result of passive filling of right ventricle. Right ventricular dysfunction was defined as an alteration of systolic function parameters with one of the following: S wave < 10 cm/sec, TAPSE < 16 mm cm, FeVD < 45%, RV fractional area change <35%, or presence of right ventricular dilatation [Several other echocardiographic and hemodynamic parameters were recorded. Stroke volume (SV) was measured by TTE , which was performed by a single experienced physician. The left ventricular ejection fraction (LVEF), end-systolic volume (ESV), and end-diastolic volume (EDV) were measured using Simpson’s biplane method with a four-chamber view. The diameter of the left ventricular outflow tract (LVOT) was measured in a long-axis parasternal view upon patient inclusion. The aortic surface area  was calculated as π × LVOT2/4. The aortic velocity-time integral (VTIAo) was measured by pulsed Doppler and a five-chamber apical view. SV (mL) was calculated as VTIAo × Sao and CO . Data were acquired and off-line images were reviewed by the operator blind to the PV measurements.−1 ideal body weight [2O by increments of 5 cmH2O. Echocardiography, PV flow (mL min−1), portal sectional area (m2), PI (%), and hepatic venous blood velocity were assessed at baseline and at PEEP 5, 10, and 15. Baseline and post-PEEP increment data were collected, along with the following experimental data: systolic arterial pressure, diastolic arterial pressure and mean arterial pressure, and heart rate. We also collected the following demographic data for all patients: weight (kg), height (m), and body mass index (BMI), expressed as the ratio of the weight to height2 (kg m−2).Operative and post-operative interventions were standardized for all patients . Sedatioy weight . Ventilap < 0.05.Data are expressed as means ± standard deviations (SDs), medians (interquartile ranges), or numbers (percentages), as appropriate. Variables were compared using Wilcoxon–Mann–Whitney, chi-2, or Wilcoxon rank sum tests, as appropriate. Correlations between SV, PI, and portal blood flow were assessed using the non-parametric Spearman correlation test. A receiver operating curve was generated to assess the predictive value of the portal flow and the PI to decrease SV following PEEP incrementation. All statistical analyses were performed using IBM SPSS software . The threshold for statistical significance was set to Demographic Data .−2. At inclusion, no patients showed acute circulatory failure or criteria of acute respiratory syndrome. Baseline data are presented in In total, 144 patients were screened from February 2018 to March 2019 and 29 were included, as presented in the flow chart . OverallHemodynamics and Echocardiographic Changes after PEEP Incrementation .2O and 30 mL (25–45) at PEEP 15 cmH2O, (p < 0.0001). In addition, the cardiac index decreased from 2.2 L·min−1 (2.07–2.42) to 1.2 L·min−1 from PEEP 0 to PEEP 15 (p < 0.0001).Systolic, diastolic, and mean arterial pressure were significantly lower after PEEP incrementation. SVs were also significantly lower after PEEP incrementation, with 52 mL (50–55) at PEEP 0 cmH2O and significantly increased for each PEEP increment, with CVPs at PEEP 5, 10, and 15 cmH2O of 7 (5–10), 11 (8–13), and 12 (9–15) cmH2O, respectively, p < 0.001. The S/D ratio decreased, from an S/D ratio of 2.0 (1.30–2.99) at PEEP 0 cmH2O to 1.08 (0.92–1.34) at PEEP 15 cmH2O (p < 0.0001). We observed a nonsignificant decrease in the right ventricular systolic parameters with the TAPSE and S wave.At baseline, the CVP was 6 (4–10) cmHPortal Hemodynamic Changes after PEEP Incrementation .2O to 15% (5–22) at PEEP 5 cmH2O, 34% (23–44) at PEEP 10 cmH2O, and 45% (25–49) at PEEP 15 cmH2O (p < 0.001).PI significantly increased with PEEP incrementation, from 9% (5–15) at PEEP 0 cmHRelationship between Portal Flow Pulsatility Fraction (PI) and Variations in Stroke Volume (SV) .p = 0.084). There was no correlation between the SV and mean arterial pressure, regardless of the PEEP level.SV was negatively correlated with the PI . The pressure variations in the right atrium during the cardiac cycle were transmitted through the noncompliant venous system and then the PI increased. We observed a decrease in cardiac output (associated with the increase in PEEP), which does not explicate the increase in PI .A previous study performed a single assessment of the PI during an ICU stay and concluded that a single measurement could predict adverse outcomes . We perfRight-side pressure and CVP have been shown to be associated with AKI and worse outcomes in the ICU . In the Our study had several limitations. We did not assess AKI. Thus, we could not show a relationship between PI and AKI, but several publications have reported an association between AKI and PI through venous congestion ,13. PatiPI appears to be a dynamic marker of the interaction between mechanical ventilation and right heart pressure after cardiac surgery. Future studies are needed to clarify the benefit of routine monitoring of the PI during mechanical ventilation to prevent organ failure.


Obstructive sleep apnoea (OSA) increases left ventricular transmural pressure more than central sleep apnoea (CSA) owing to negative intrathoracic pressure swings. We tested the hypothesis that the severity of OSA, and not CSA, is therefore associated with spheric cardiac remodelling after acute myocardial infarction.This sub-analysis of a prospective observational study included 24 patients with acute myocardial infarction who underwent primary percutaneous coronary intervention. Spheric remodelling, calculated according to the sphericity index, was assessed by cardiac magnetic resonance imaging at baseline and 12 weeks after acute myocardial infarction. OSA and CSA [apnoea-hypopnoea index (AHI) ≥ 5/hour] were diagnosed by polysomnography.p = 0.002). In contrast to CSA, the severity of OSA was associated with an increase in systolic sphericity index after accounting for TIMI-flow before percutaneous coronary intervention, infarct size, pain-to-balloon-time and systolic blood pressure .Within 12 weeks after acute myocardial infarction, patients with OSA exhibited a significant increase in systolic sphericity index compared to patients without sleep-disordered breathing (no SDB) and patients with CSA  contains supplementary material, which is available to authorized users. Over recent decades, patient survival after ST-elevation myocardial infarction (STEMI) has improved tremendously due to innovative therapeutic advances in the treatment and management of this condition . HoweverMost cardiac aneurysms after STEMI affect the anterior wall of the left ventricle and are a strong predictor for heart failure and surval after myocardial infarction . InfarctSleep-disordered breathing (SDB) manifests in two distinct types, obstructive and central sleep apnoea  . The hal2 below the apnoea threshold and leads to intermittent hypoxaemia without inspiratory efforts and negative intrathoracic pressure. Therefore, in contrast to OSA, CSA may result in a smaller effect on afterload .Reduction in wall thickness was similar between groups in end-systole  compared to the analysis with obstructive apneas and hypopneas. This finding may underline, that in particular obstructive apnoeas and to a lower extend hypopnoeas may contribute to the intrathoracic negative pressure changes and might affect cardiac remodeling.In addition, arousals from sleep may contribute to increased afterload and thus spheric cardiac remodeling. The association between the frequency of arousals may differ between obstructive and central respiratory events, because arousals occur in OSA to terminate apnoeas and activate pharyngeal muscles in order to re-open the occluded upper airways, while in CSA the association between arousals and respiratory events is modest . In the Activation of the sympathetic nervous system seems to be lower in CSA patients with congestive heart failure compared to those with OSA . SeveralThus, the increased left ventricular transmural pressure  in OSA patients, but not in CSA patients, may promote spheric cardiac remodelling and thinning of the left ventricular wall in the region of the myocardial infarction. Accordingly, in the present analysis, sphericity index is correlated with the quantity of obstructive apnoeas and hypopnoeas, but not central apnoeas and hypopnoeas. These results are robust, even after accounting for potentially confounding clinical factors such as age, sex and BMI.The prevalence of sleep apnoea after myocardial infarction is high (approximately 54%) . Within The results from this sub-analysis must be interpreted in the light of several limitations. The sample size is relatively small, since only patients with infarcted left anterior descending artery were included. Furthermore, cardiac aneurysm is a rare event. However, the selected sample is appropriate considering that sphericity index was first evaluated in patients with anterior wall myocardial infarction. A direct causal relationship cannot be inferred due to the observational nature of the study design. Neither intrathoracic pressures nor oesophageal pressures were recorded to quantify the postulated negative intrathorathic pressure swings during obstructive apneas . Larger,In contrast to CSA and no SDB, OSA is associated with spheric cardiac remodelling within the first 12 weeks after acute myocardial infarction. Data suggest that OSA-related negative intrathoracic pressure swings may contribute to spheric cardiac remodelling after acute myocardial infarction. Findings add an argument that differentiation of OSA and CSA is needed in patients with acute myocardial infarction.Supplementary file 1 (DOCX 122 kb)Below is the link to the electronic supplementary material.


Patients who have unexplained giant T-wave inversions but do not meet criteria for hypertrophic cardiomyopathy (HCM) (left ventricular (LV) wall thickness < 1.5 cm) demonstrate LV apical morphological features that differ from healthy subjects. Currently, it remains unknown how the abnormal LV apical morphology in this patient population changes over time. The purpose of this study was to investigate LV morphological and functional changes in these patients using a mid-term cardiovascular magnetic resonance (CMR) exam.Seventy-one patients with unexplained giant T-wave inversion who did not fulfill HCM criteria were studied. The mean interval time of the follow-up CMR was 24.4 ± 8.3 months. The LV wall thickness was measured in each LV segment according to the American Heart Association 17-segmented model. The apical angle (ApA) was also measured. A receiver operating curve (ROC) was used to identify the predictive values of the CMR variables.p < 0.001). There was a significant difference between the two groups in the change of ApA  over time. The combination of mean apical wall thickness and ApA proved to be the best predictor for fulfilling criteria for apical HCM with a threshold value of 8.1 mm and 90° .Of 71 patients, 16 (22.5%) progressed to typical apical HCM, while 55 (77.5%) did not progress to HCM criteria. The mean apical wall thickness was significantly different between the two groups at both baseline and follow-up, with the apical HCM group having greater wall thickness at both time points (all CMR metrics identify predictors for progression to HCM in patients with unexplained giant T-wave inversion.The online version contains supplementary material available at 10.1186/s12968-020-00700-5. Apical hypertrophic cardiomyopathy (HCM), a variant of HCM , 2, is cAs of now, the diagnostic criteria of HCM is defined by LV wall thickness ≥ 15 mm (≥ 13 mm with HCM family history). This diagnostic criteria for HCM was published by American Heart Association (AHA)/American College of Cardiology Foundation (ACCF) in 2011  and subsConsecutive subjects with unexplained ECG giant T-wave inversion from January 2006 to December 2017 were retrospectively identified. Patients who met all of the following inclusion criteria were enrolled in this study: (1) standard 12-lead ECG with deep T-wave inversion, most prominent in the anterolateral leads (V3–V5 leads) with the negative T wave voltage ≥ 5 mm, (2) Non-obstructive coronary artery disease (< 50% narrowing of a coronary artery secondary to plaque) on coronary computed tomography or invasive coronary angiography, (3) end-diastolic apical wall thickness < 15 mm (< 13 mm if family history of HCM), and (4) at least two CMR examinations were performed, and the minimum interval between two CMR examinations was at least 6 months. Subjects were routinely excluded if they had one of the followings conditions: (1) non-sinus rhythm, (2) T-wave inversion in ≤ 2 contiguous leads, concomitant bundle branch block or QRS > 80 ms or QTC > 440 ms, (3) hypertension (systolic blood pressure ≥ 140 mmHg and/or diastolic pressure ≥ 90 mmHg on two or more consecutive visits without anti-hypertensive medications), (4) severe valvular lesions, pericardial disease, cardiac tumor, immunological or metabolic disease involving heart, (5) history of cardiac surgery. The study protocol was approved by the institutional review board of our hospital and written informed consent was waived. The study was conducted in accordance with the Declaration of Helsinki.2, matrix of 134 × 256, time to repetition/time to echo of RR interval/3.38 ms; FA 35◦, slice thickness of 6 mm) was used for the late gadolinium enhancement(LGE) imaging, which was acquired approximately 10–15 min after a 0.2 mmol/kg intravenous dose of gadolium  during breath hold in a series of short-axis planes and four- and two-chamber long-axis planes [CMR exams were performed on three different CMR scanners: a 1.5 T scanner . A three-lead vector cardiogram was used for ECG gating. A complete short-axis stack, 4-chamber and 2-chamber balanced steady state free precession cine images of the LV were acquired using retrospective ECG-gating. Sequence parameters included: slice thickness: 6–8 mm, slice gap 30–50% wall thickness; matrix: (156–256) × (192–256); flip angle: 80°; parallel acquisition technique factor: 2; and bandwidth: 930 Hz/PX. A phase-sensitive inversion-recovery gradient-echo pulse sequence with coil intensity correction . LV wall thickness was manually measured in all 16 segments at the end-diastolic phase. The true apex was excluded (17th segment). These segmental LV wall thickness measurements were performed as detailed in our previous publication  was used to identify the predictive values of the CMR variables. Univariable Cox regression models were used to estimate the unadjusted hazard prediction of apical HCM. Hazard ratios were generated and expressed together with their 95% confidence intervals (CIs). All data were analyzed using SPSS . Intraclass correlation coefficients and Bland–Altman plots were used to assess intra- and interobserver variability by using SPSS and GraphPad , respectively [p< 0.05 were regarded as statistically significant.Continuous variables with normal distribution were expressed as mean ± standard deviation. Category variables were presented as numbers (proportion) and differences between groups and were analyzed by Fisher’s exact test or chi-square test. The Student paired ectively . A two-tThree hundred and six patients fulfilled the initial study inclusion criteria of which 212 were excluded due to absence of a follow-up CMR examination. Another 21 patients were excluded for hypertension (n = 12), acute myocardial infarction (n = 4), chronic myocardial infarction (n = 2), valvular disease (n = 2) and amyloidosis (n = 1). The remaining 71 patients (61 (85.9%) males; 49.4 ± 12.9 years) were enrolled  and more ECG abnormalities  in group 1 (both  p < 0.001). Of the 16 patients in group 1, three patients were diagnosed as apical HCM and 7 were diagnosed as suspicious for apical HCM on echocardiography. However, there was only one group 2 subject diagnosed as suspicious for apical HCM. There were no differences in other baseline characters between two groups. The detailed baseline clinical characteristics of the patients were listed in Table The cohort was divided into two groups based on the absolute apical wall thickness as well as increased percentage of apical wall thickness at follow-up CMR. Group 1: typical apical HCM, n = 16 22.5%) met criteria for apical HCM at follow-up  at follow-up. LVEDVI, LVESVI and LV CI were all decreased . At follow-up, the ApA was decreased 1.8º (p = 0.002) when compared with baseline . There was no significant difference in other parameters including LA dimension, LVEDVI and LV CI . The detailed global morphological and functional measures changes were presented in Table When further comparison between the two subgroups was performed, there was no significant difference in all global morphological and functional measures on CMR at baseline Table . The ApAp < 0.001). Further subgroup analysis demonstrated that there were no significant differences in LV wall thickness at basal and middle parts at baseline or at follow-up . However, the mean apical wall thickness was significantly different between the two groups at both baseline and at follow-up, with Group 1 have greater wall thickness at both time points , and the changes in apical wall thickness was the most significant.We studiedchanges of LV wall thickness in the basal (segment 1–6), middle (segment 7–12) and apical (segment 13–16) segments based on the AHA 17-segment model. Compared with the baseline exam, the basal, mid, and apical LV wall thickness were all increased by a mean of 0.3 mm, 0.2 mm and 0.8 mm, respectively  in mean apical thickness at baseline, 0.80  in maximum apical segmental thickness, and 0.77  in ApA, respectively. Further analysis indicated that the cutoff thickness of 7.6 mm  yielded a sensitivity of 100% and a specificity of 69%; the cutoff thickness of 9.5 mm  yielded a sensitivity of 81% and specificity of 64%; and a cutoff of 75° of ApA yielded a sensitivity of 63% and specificity of 93% for prediction of development to fulfill criteria for apical HCM  of the ROC were 0.87  and unexplained giant T-wave inversion on ECG. To the best of our knowledge, this is the first study to follow-up the abnormal CMR morphological features of these patients. Our results demonstrated several important findings. First, during a mean 2 year follow-up, over one-fifth of these patients progress to fulfill criteria for apical HCM. This finding provides convincing CMR-based evidence that this patient group could be considered to have an early or pre-apical HCM phenotype . Second,As of now, there have been no studies of the segmental LV thickness of normal, healthy subjectsand only a few studies on the overall LV mass in normal subjects –21. A loTraditionally, apical HCM was diagnosed in patents with an apical wall thickness ≥ 15 mm (or ≥ 13 with family history of HCM) at end-diastole based on the guidelines recommended by AHA/ACCF, or ESC. Until nIt has been reported that even early, mild apical hypertrophy  without the classic spade configuration presents with giant negative T waves on ECG , 22. FroOur study has several limitations. First, genetic testing was not routinely obtained, but does not affect our primary conclusion. However, HCM-related gene variants and their clinical outcome have been shown to be inconsistent due to heterogeneity of both genotype and phenotype , 24, 25.Morphological and functional changes occur in patients who did not meet apical HCM criteria but have baseline abnormal LV apical morphology and unexplained giant T-wave inversions on ECG. More than one-fifth of these patients progress to typical apical HCM on CMR and another half will have a significant (> 15%) increase of LV apical wall thickness. The combination of mean apical wall thickness and ApA is the best predictor for development of apical HCM with a threshold value of 90° and 8.1 mm yielding a sensitivity of 93.8% and a specificity of 85.5%. Further prospective studies and longer follow-up are needed to further validate our results.Additional file 1. morphological characteristics of normals on CMR. As shown in this figure, considerable variation in LV wall thickness was observed with progressive thinning from the base to apex. (A–C) Location of basal and middle LV slices for measurement. Apical segments were measured on two- and four-chamber views (D and E). Three measurements were taken at the thickest region of each segment (C and D), and then the average was collected. Two 1-cm-long lines were drawn out from the apex vertex to bilateral endocardium, and the angle formed was apA (E).


Creatine is a key player in heart contraction and energy metabolism. Creatine supplementation  increases creatine content even in the normal heart, and it is generally safe. In heart failure, creatine and phosphocreatine decrease because of decreased expression of the creatine transporter, and because phosphocreatine degrades to prevent adenosine triphosphate (ATP) exhaustion. This causes decreased contractility reserve of the myocardium and correlates with left ventricular ejection fraction, and it is a predictor of mortality. Thus, there is a strong rationale to supplement with creatine the failing heart. Pending additional trials, creatine supplementation in heart failure may be useful given data showing its effectiveness (1) against specific parameters of heart failure, and (2) against the decrease in muscle strength and endurance of heart failure patients. In heart ischemia, the majority of trials used phosphocreatine, whose mechanism of action is mostly unrelated to changes in the ergogenic creatine-phosphocreatine system. Nevertheless, preliminary data with creatine supplementation are encouraging, and warrant additional studies. Prevention of cardiac toxicity of the chemotherapy compounds anthracyclines is a novel field where creatine supplementation may also be useful. Creatine effectiveness in this case may be because anthracyclines reduce expression of the creatine transporter, and because of the pleiotropic antioxidant properties of creatine. Moreover, creatine may also reduce concomitant muscle damage by anthracyclines.  Creatine plays a key role in cellular energy metabolism. The creatine kinase enzyme reversibly phosphorylates it to phosphocreatine. Then, when phosphocreatine is reverted to creatine, its phosphate bond breaks, and such a break provides enough energy to allow phosphorylating a molecule of adenosine diphosphate (ADP) to adenosine triphosphate (ATP). Thus, phosphocreatine acts as an energy reserve to synthesize ATP rapidly, with no need for oxygen. The reaction is the following one:This reaction plays a crucial role in heart contraction . Its rol(1) Transfer of ATP from its production site (mitochondria) to its place of exploitation . This function is often called “the ATP shuttle”. To carry out this transport (“shuttle”) of ATP energy, creatine first receives the phosphate from ATP near the mitochondria, becoming phosphocreatine. It then diffuses through its concentration gradient to the periphery of the cell. Near cytoplasmic ATPase, it donates its phosphate to ADP, effectively forming ATP far away from the mitochondria and delivering it precisely where and when it is required. In doing so, it reverts to creatine and diffuses back, again along its concentration gradient, to the mitochondrion to start the cycle again. The reason why the cell needs this complex mechanism to transport energy between mitochondria and cytoplasmic ATPase is that ATP is a very large molecule, therefore its diffusion through the organelle-filled cytoplasm is slow and cumbersome. By contrast, phosphocreatine is a much smaller molecule, thus it diffuses more quickly through the cytoplasm.(2) Restoration by phosphocreatine of ATP concentration in conditions of increased energy demand and in diseases involving a reduced supply of blood or oxygen. In the first scenario, the consumption of ATP is excessive compared to the ability of the cell to synthesize it. For instance, a muscle exposed to a particularly intense effort quickly uses more ATP than it can produce, thus exhausting its reserve. In the second scenario, an organ cannot produce enough ATP because of a blood deficiency (ischemia) or an oxygen deficiency (anoxia). For example, in case of a myocardial infarction, phosphocreatine intervenes by transferring its phosphoric group to ADP, to provide ATP at a time when the heart cannot synthesize it due to ischemia.Among all the biochemical reactions that our cells use to synthesize ATP, the one that starts from the creatine/phosphocreatine system is the quickest in buffering ATP levels at times of increased energy expenditure . This exCreatine is normally degraded to creatinine , leadingIn the body as a whole, creatine is synthesized in the kidney and in the liver . SpecifiAbout half of the creatine that the organism needs is normally ingested and taken up from dietary sources . CreatinMoreover, exogenous supplementation of creatine permits administering high amounts of this compound, and increasing its content above normal levels ,21,22. TThe metabolism and functions of creatine in the heart is similar to that in the muscle and in other tissues. Restoration of normal creatine content when it is lower than normal due to lifestyle  or to dIncrease in energy availability (obtained by increasing phosphocreatine concentration in the tissue) in cases where the balance between energy availability and requirement is limited by decreased energy production (as is the case in hypoxia or ischemia), or by increased demand .Specific mechanisms of the benefit provided by creatine supplementation include:Finally, we should note that creatine by itself does not enter cells, instead it needs a specific transporter to cross plasma membranes . The samBefore discussing the effects of creatine supplementation in normal subjects, we shall mention some effects of creatine supplementation in in vitro normal heart preparations.In heart strips prepared from frog ventricles, the force of contraction was increased when the preparation was perfused with a rather high concentration of creatine (9.2 mM) . In an iThe normal heart has a high creatine content in comparison to other organs, as all excitable tissues have. For example, Horn et al.  reportedA different approach to experimentally increasing creatine in the normal heart involved genetically modified rodents where the creatine transporter was overexpressed, thus increasing intracellular creatine. The research group that first used this approach to increase myocardial creatine reported that increasing creatine transporter expression did cause increased intracellular creatine up to four times its basal value. However, they unexpectedly found that such increase in creatine content in normal hearts was attended by left ventricular hypertrophy and heart failure ,41. ThosThe above data suggest that increase in creatine content of normal hearts is possible upon creatine supplementation. As reported above, in vitro data suggest improvement in cardiac function by creatine supplementation even in normal cardiac preparations. Such improvement has not been reported in vivo in healthy subjects, however the above reviewed in vitro data suggest that creatine supplementation might possibly be useful to healthy subjects as well. Moreover, in vivo data suggest that creatine supplementation is safe in normal subjects. In fact, although animal data suggest that harmful effects on cardiac performance may unexpectedly accompany a very large creatine increase, this risk seems not to exist at all when creatine increases only by about 60% of its baseline level . Therefop = 0.048). By contrast, systolic and diastolic blood pressure, interval of the QT segment of the electrocardiogram (both raw and corrected using the Bazett’s formula) did not differ between groups. Although the mechanism of the different heart rate is unclear, it is certainly not a harmful effect, given that the typical resting heart rate for adults is between 50 and 90 beats per minute [Some confirmation of the cardiac safety of creatine supplementation in normal subjects comes from an interesting paper that studied the cardiac effects of creatine supplementation in bodybuilders . Those ar minute . AlthougHeart failure, heart ischemia and anthracycline cardiotoxicity are the disease conditions of the heart where creatine supplementation has been proposed and investigated . IndividThe European Society of Cardiology  defines This section will report numerous data across a long period showing that creatine, phosphocreatine, or both decrease in heart failure.In preclinical research, Feinstein  demonstrAs said, the decrease in creatine content of the failing heart is thought to be due to the down regulation of the creatine transporter that was demonstrated in the failing hearts of both rodents and humans ,50. HoweSummarizing these preclinical studies, they suggest that in the failing heart the content of creatine decreases because of (1) a decrease in its uptake due to down-regulation of the creatine transporter and (2) a consumption of phosphocreatine, which is used to prevent or delay exhaustion of ATP.Moving to studies in humans affected by heart failure, Nascimben et al.  found thIndeed, decreasing heart creatine per se has harmful effects on contractility. Saks et al.  showed iField  proposedThe above data show that (1) decreased creatine content of failing hearts and (2) its correlation with decreased contractility strength are both robust findings, and provide a rationale to investigate the effects of creatine supplementation in heart failure patients.Creatine supplementation of the failing heart aims to normalize the decreased creatine content that, as reported above, is known to occur in this condition. The effects of creatine supplementation in heart failure have been investigated in a few trials, either preclinical or clinical.At the preclinical level, Faller et al.  used, wiAt the clinical level, Fumagalli et al.  investigMoreover, some studies showed that in heart failure patients creatine supplementation is able to improve muscle performance, leading to a global functional improvement. Gordon et al.  found inIschemia is probably the condition where creatine supplementation has the strongest rationale, given its energy-boosting properties. At times of ischemia all organs, including the heart, decrease or lose their ability to synthesize ATP because of the decreased supply of nutrients such as glucose and oxygen. In the case of the heart, ischemia leads to life-threatening conditions like angina pectoris and myocardial infarction. There is a strong rationale for increasing the intracellular level of creatine, phosphocreatine or both in conditions of ischemia, because as already said (see above) phosphocreatine acts as an extra energy source, effectively synthesizing ATP even in the absence of oxygen and glucose , thus imTen Hove et al.  found thIn a preclinical study, Webster et al.  found thNo trial has investigated the effects of creatine supplementation in human patients with myocardial infarction. Accordingly, a 2011 Cochrane meta-analysis  reached While creatine has not been studied in human myocardial infarction (see above), numerous investigations have studied the effects of phosphocreatine. These effects have been reviewed elsewhere ,67 and iAnthracyclines are antitumor agents used in many types of cancers, including breast cancer and hematological malignancies . The twoProduction by anthracyclines of ROS leads to mitochondrial damage, and is a prominent mechanism of the antitumor activity of anthracyclines. It occurs because of reduction in the anthracycline molecule by cellular oxido-reductases . In the presence of molecular oxygen, the molecule resulting from this reduction spontaneously auto-oxidizes to generate again the parent anthracycline and a superoxide anion, starting a self-perpetuating loop ,83. MoreAlthough anthracyclines have widespread toxic effects, cardiac adverse effects are especially important for their high frequency of occurrence and their ability to limit the clinical use of these compounds. They range from mild cases showing only elevation of markers of cardiac damage with no or few symptoms to life-threatening heart failure . Some caSeveral preclinical studies link anthracyclines toxicity with the creatine metabolism.Darrabie et al.  found thAlthough the above studies provide a specific framework for cardiac protection by creatine, we should not forget that besides its ergogenic effects, creatine is also an antioxidant , thus it2O2) as well as by doxorubicin treatment caused a decrease in the force of contraction. However, they did not find any protection by increasing creatine content through the over-expression of the creatine transporter, nor by addition of creatine to the heart perfusion medium.Very importantly, Gupta et al.  found thSeveral papers investigated in animal models the effects of creatine supplementation on cardiac anthracycline toxicity.The first one  investigLater, Santacruz et al.  demonstrOf particular interest are two papers that demonstrate creatine efficacy in countering the toxic effects of anthracyclines on the skeletal muscle. In in vitro isolated muscles , doxorubThus, preclinical papers investigating the effects of creatine supplementation on cardiac or muscular toxicity by anthracyclines reported improvement, both on cardiac toxicity and on the associated muscle damage. We should emphasize that all of them administered creatine before, not after, the challenge with anthracyclines.Researchers investigated phosphocreatine, too, in anthracycline toxicity.In in vivo rodents, adriamycin  decreased the expression of a micro-RNA (miRNA 378/378*) and of the calcium-binding protein calumenin, and both these effects were reversed by phosphocreatine . AnotherAs for clinical research on human patients, Parve et al.  reportedThus, treatment with phosphocreatine showed some encouraging preliminary data that may warrant further research. However, we repeat that, as discussed above, it is doubtful that phosphocreatine enters cells, thus its mechanisms of action are probably unrelated to changes in the creatine-phosphocreatine complex (see above).The above data allow some conclusions to be drawn. Since such conclusions descend strictly from all the above-discussed data, individual references will not be quoted again in the ensuing paragraphs. Instead, the reader who looks for more details and references is referred to the preceding sections of this paper.In vitro studies suggest some improvement by creatine supplementation in the function even of the healthy heart; however, such improvements could not be confirmed in in vivo studies of healthy subjects.Creatine supplementation in the healthy heart is safe. Some harmful effects that were reported in preclinical experiments on transgenic animals were consequent to very high increases in creatine content, so high that they are not possible with creatine supplementation alone. In fact, in vivo creatine supplementation increases cardiomyocyte content by about 11–28%, and no adverse events were observed when creatine increase was limited to 60% of its basal value. Furthermore, extensive use of creatine in human placebo-controlled trials have concluded that creatine supplementation is safe even at high doses and for extended time, with the possible exception of subjects affected by kidney damage.In heart failure creatine, phosphocreatine or both decrease in both animal and human studies. The mechanisms for this decrease are both a decrease in the creatine transporter that decreases uptake, and a consumption of phosphocreatine that attempts to prevent or delay exhaustion of ATP.The decrease in phosphocreatine in heart failure is highly clinically relevant, because it causes a decreased contractility reserve of the myocardium and correlates with left ventricular ejection fraction. Phosphocreatine decrease is so clinically relevant that in individual patients it is a predictor of mortality.Thus, the above data provide a strong rationale to supplement with creatine the failing heart, in an attempt to reverse the above-described harmful effects.So far, studies of creatine supplementation in heart failure demonstrated encouraging results, which warrant further investigations. Especially, it would be useful to understand in which patients  creatine supplementation is useful. Such a study would require dosing cardiac creatine in vivo using, for example, magnetic resonance spectroscopy, but it would be very valuable and useful. Despite the described paucity of current evidence, and pending additional trials, creatine supplementation in heart failure may nevertheless be useful, at least in selected patients, given (1) the additional evidence showing that in heart failure patients creatine improves muscle strength and endurance, and (2) the evidence that demonstrates that such creatine supplementation is feasible and safe. Pending additional trials, at least heart failure patients in whom weakness and fatigue are prominent symptoms, and in whom kidney function is normal, should trial creatine supplementation.There is a strong rationale to use creatine supplementation in heart ischemia; however, the majority of the studies so far have used phosphocreatine, not creatine, supplementation. Although the two molecules are obviously strictly related to each other, there is currently no clear evidence that phosphocreatine can enter cells as creatine does. For this reason, its mechanism of action is mostly unrelated to changes in the ergogenic creatine-phosphocreatine system.Antagonism of cardiac toxicity of the anti-tumor compounds belonging to the anthracycline family is a novel, clinically relevant field where creatine supplementation may be useful. Several studies suggest that anthracyclines damage the creatine-phosphocreatine system by reducing the expression of the creatine transporter and by impairing the activity of creatine kinase. Moreover, anthracycline cardiac toxicity is largely due to generation of reacting oxygen and nitrogen species, therefore creatine may counter it because of its anti-oxidant properties, too.Studies on genetically modified rodents over-expressing the creatine transporter gave conflicting results in the prevention of anthracycline toxicity. However, supplementation with creatine before anthracycline administration has proved very effective in preventing cardiac toxicity in preclinical studies, both in vitro and in vivo. Furthermore, supplementation with creatine before anthracycline challenge fully prevents the damage by these compounds on skeletal muscle, both in vitro and in vivo. Thus, we should definitely carry out clinical studies to investigate whether or not administration of creatine before a planned anthracycline treatment is able to prevent or decrease the cardiac toxicity that currently limits in a significant way the use of these important chemotherapy agents. In designing such studies, we should bear in mind that creatine may be superior to other antioxidants in clinical contexts because of its additional effects improving muscle anthracycline toxicity. Phosphocreatine should also be further investigated; however, its mechanism of action is probably unrelated to the ergogenic creatine-phosphocreatine system.From the scientific point of view, the value of a literature review consists of delivering a comprehensive view of a clinical issue, in such a way as to put individual papers in a global perspective that may suggest translational opportunities. The above-reported review on creatine supplementation in the heart makes it possible to formulate the following suggestions for clinical translation. Again, the reader should refer to the above paragraphs for details and quotes. Please note that, as already stated, we discuss only supplementation with creatine monohydrate, not with other forms of creatine.In healthy hearts, there is currently no demonstration that creatine supplementation may improve cardiac function. However, creatine supplementation is safe, with the possible exception of subjects with renal failure (elevated plasma creatinine), thus fear of adverse events should not prevent willing subjects from trialing creatine supplementation.Creatine supplementation should be trialed in heart failure patients, especially when weakness and fatigue are prominent symptoms.Further research should correlate, in individual patients, creatine and phosphocreatine content of the myocardium with the clinical benefits obtained from supplementation.In heart failure, there is a decrease in the creatine content of the myocytes, and such a decrease is highly relevant from the clinical point of view. Moreover, creatine supplementation improves muscle function in these patients. Thus:Further research should be carried out on the effects of creatine supplementation in heart ischemia.Mitigation of anthracyclines toxicity is an unmet clinical need. Thus, treatment of oncological patients with anthracyclines might even now be preceded by an adequate period of creatine supplementation, possibly together with vitamins C and E, to prevent chemotherapy toxicity both to the heart and to the muscle. Moreover, research should be carried out in ample clinical cohorts to definitively determine the usefulness of this supplementation in anthracyclines chemotherapy.


Quantitative Doppler echocardiography is the gold standard method for assessing the degree of aortic stenosis (AS), which is classified as mild, moderate or severe. This technique was validated in the latter part of the 20th century against the gold standard of that time, cardiac catheterisation derived valve area using the Gorlin hydraulic principle.concordant whereas in the latter they are discordant.Assessing AS is straight forward when all parameters indicate the same severity of stenosis—for example, if the AV Vmax, mean gradient and EOA all indicate mild AS—but becomes more challenging when the parameters do not all indicate the same severity—for example, the AV Vmax and mean gradient indicate moderate AS, yet the EOA suggests severe AS. In the former example, the parameters are et al analysed 3483 echocardiograms to assess the frequency of these inconsistencies and they found that almost a third of patients with severe AS based on EOA (<1.0 cm2) had a mean gradient in the moderate AS category .2 correlated to a mean gradient of 21 mm Hg and an AV Vmax of 3.3 m/s. Conversely, a mean gradient of 40 mm Hg corresponded to an EOA of 0.75 cm2 (not 1.0 cm2) and an AV Vmax of 4.0 m/s corresponded to an EOA of 0.82 cm2. Thus, in their cohort, severe AS was diagnosed in 69% of patients based on EOA but only 45% by AV Vmax and just 40% by mean gradient. They also noted that left ventricular (LV) stroke volume was significantly lower in the patients with discordant parameters.Over a decade ago, Minners A <1.0 cm had a meet al,2. These observations gave rise to the recognition of the paradoxical scenario in which LV EF is normal (>50%) though transvalvular flow is low—low-flow low-gradient severe AS with normal EF. Assessing flow using the transvalvular flow rate (in which stroke volume is indexed to LV ejection time rather than body surface area) has seen a renewed interestThis followed on from a paper published the previous year by Hachicha et al in 2019 shone the spotlight on moderate AS when they found that 1-year and 5-year outcomes were similar in moderate and severe patients with AS.A retrospective Australian study from Strange Open Heart, Pio and colleagues have now examined how frequently discordant Doppler data are found in moderate patients with AS.2, which they used as the marker of moderate AS. This revealed 790 patients (mean age 71 years) and the authors found that nearly one in five patients  had discordant Doppler parameters—that is, a valve area of 1.0–1.5 cm2 but a mean gradient <20 mm Hg. Over a median follow-up period of 4.9 years, the discordant AS cohort were less likely to undergo aortic valve replacement (26.7% vs 44.1%) and had higher mortality (60% vs 43%) compared with patients with concordant moderate AS parameters . On multivariable Cox regression analysis, moderate AS with LV EF <50% was an independent predictor of mortality, irrespective of concordant or discordant AS parameters.In this issue of 2) was more common in the discordant group, this was only present in 26% cases (vs 1.5% in the concordant group), meaning that roughly three-quarters of the discordant cohort had a normal SVi. Data on transvalvular flow rate are not presented.Demographic  and echocardiographic factors that were independently associated with discordant AS were age, coronary heart disease, LV EF and SVi. Interestingly, although a low flow status  diameter, which is used to derive an LVOT area for the continuity equation and it is known that transthoracic echocardiography (TTE) frequently under-estimates this area compared with cross-sectional imaging modalities. Importantly, the way in which the LVOT diameter should be measured changed during the lengthy period of this study. Previously, it was recommended to measure the LVOT diameter approximately 0.5–1.0 cm below the valve leaflets in the parasternal long axis view. However, as it became apparent that this frequently under-estimated the true LVOT area, practice was changed and now measurement is recommended at the hinge points (base) of the leaflets. Thus, many of the echocardiograms included in this study all patients with aortic stenosis (time pressures frequently prevent this).Second, when assessing AS, multiple insonation windows should be used to obtain the maximum transvalvular velocity. This frequently necessitates the suprasternal and right parasternal windows—and sometimes even the right supraclavicular fossa or subcostal views—but none of these were apparently used in the current study . It also appears that the PEDOF probe was not used in these studies either, which can also increase the peak velocities recorded. These alternate windows and probe techniques are not only applicable to patients with suspected severe AS—as the image in Third, it is not clear how patients in atrial fibrillation were assessed. Atrial fibrillation was prevalent in these patients  and practice can vary from taking an average of 3 beats to an average of 5 beats to using a peak pulsed wave Doppler and a peak continuous wave Doppler tracing. Variation in practice for AF patients between the two centres (in different continents over a length period of time) is likely and may account for some of these differences.However, in many respects, these findings also should not come as a significant surprise. Prior studies have highlighted the shortcomings of our current severity grading system. Considerable research into the factors associated with discrepant AS parameters has made the assessment of AS severity increasingly challenging and has led to a renaissance of interest in parameters such as the transvalvular flow rate (FR). In a post-hoc analysis of the Simvastatin and Ezetimibe in Aortic Stenosis trial, where patients with mild-moderate patients with AS were enrolled, discordant AS was observed in 28% of the population and almost 60% of these patients had low transvalvular FR.The prognostic data are of great interest; we note that discordant moderate AS per se did not affect survival but did so in association with low LV EF. Although a much-maligned parameter in recent years, these data underscore the oft-seen prognostic power of reduced LV EF. Furthermore, SVi was not associated with mortality—in the aforementioned study transvalvular flow rate, but not SVi, predicted mortality in moderate patients with AS.4In summary, these data highlight that discrepancies between Doppler indices of stenosis severity are not restricted to patients with severe AS (as judged by EOA), but lesser degrees of stenosis severity also. Care should be taken to ensure high-quality studies are performed and to eliminate errors in measurements before diagnosing discordant AS. Low transvalvular flow rate and LV systolic dysfunction are markers of poor outcome.


Cardiovascular magnetic resonance permits assessment of irreversible myocardial fibrosis and contractile function in patients with previous myocardial infarction. We aimed to assess the prognostic value of myocardial fibrotic tissue with preserved/restored contractile activity.In 730 consecutive myocardial infarction patients (64 ± 11 years), we quantified left ventricular (LV) end-diastolic (EDV) and end-systolic (ESV) volumes, ejection fraction (EF), regional wall motion (WM) , and WM score index (WMSI), and measured the transmural (1–50 and 51–100) and global extent of the infarct scar by late gadolinium enhancement (LGE). Contractile fibrotic (CT-F) segments were identified as those showing WM-1 and WM-2 with LGE ≤ or ≥ 50%.During follow-up , cardiac events (cardiac death or appropriate implantable defibrillator shocks) occurred in 123 patients (17%). At univariate analysis, age, LVEDV, LVESV, LVEF, WMSI, extent of LGE, segments with transmural extent > 50%, and CT-F segments were associated with cardiac events. At multivariate analysis, age > 65 years, LVEF < 30%, WMSI > 1.7, and dilated LVEDV independently predicted cardiac events, while CT-F tissue was the only independent predictor of better outcome. After adjustment for LVEF < 30% and LVEDV dilatation, the presence of CT-F tissue was associated with good prognosis.In addition to CMR imaging parameters associated with adverse outcome , the presence of fibrotic myocardium showing contractile activity in patients with previous myocardial infarction yields a beneficial effect on patient survival.The online version contains supplementary material available at 10.1186/s12968-021-00818-0. Left ventricular (LV) dysfunction is a common finding after myocardial infarction (MI) that is associated with high morbidity and mortality in patients with heart failure , 2. It iContractile function is synonymous with myocardial viability, although several definitions exist based on the markers used by different cardiac imaging techniques: wall thickness (echocardiography and cine cardiovascular magnetic resonance [CMR]), myocardial contractile reserve (dobutamine stress echocardiography/CMR), myocyte cellular integrity (single-photon emission computed tomography (SPECT)), myocardial metabolism (positron emission tomography (PET)), and myocardial scar/fibrosis (late gadolinium enhancement [LGE]) –9. It isTherefore, although the clinical and prognostic impact of the different markers of myocardial viability have been extensively investigated, it is still unknown whether partially scarred segments showing contractile activity yield a prognostic value. The aim of this observational, multicenter study was to analyze the prognostic value of partially scarred myocardial segments yielding contractile activity and the potential additive impact in respect to the other predictors of adverse outcome in patients with previous MI.We studied 862 consecutive patients with clinical evidence of a prior MI (> 90 days) and a clinical indication for CMR, i.e., quantification of LV function and volumes and identification of LV thrombi, extent of scar tissue, and myocardial viability. Previous MI was documented by clinical record, Q-waves at electrocardiography (ECG), and angiographic evidence of coronary artery stenosis . All patients were in stable clinical condition at enrollment. Patients were excluded if they had: (1) unstable angina or recent evidence of myocardial ischemia (absence of elevated troponin) ; (2) prosthetic annuloplasty and/or prosthetic heart valve ; (3) hypertrophic cardiomyopathy ; (4) history of malignancy and/or prior chemotherapy treatment ; (5) low-quality (non-diagnostic images) or incomplete CMR scan . We also excluded patients with contraindications for CMR, irregular heart rhythm, and New York Heart Association class IV because of the difficulty of performing a diagnostic CMR scan. Eventually, 730 patients (85%) were included in the final stage of the study. Patients were studied either as outpatients (n = 160) or during hospitalization (n = 570). Clinical variables were collected before the CMR scan.Institutional internal review boards of the involved hospitals approved our observational and retrospective study; the investigation complies with the principles outlined in the Declaration of Helsinki. All patients gave informed consent before being enrolled.CMR was performed using a 1.5 T whole-body CMR scanner .According to the protocols recommended by the Society for Cardiovascular Magnetic Resonance, a breath-hold  balanced steady-state free-precession ECG triggered sequence was used to evaluate global LV function. LGE images were obtained 10–20 min after a bolus injection of gadolinium-based contrast medium  using fast gradient-echocardiography inversion recovery sequences. Inversion time was individually adapted to null the signal of remote myocardium . Cine and LGE images were acquired in at least one set of matched views including a contiguous LV short-axis and one vertical and one horizontal long-axis view.All CMR data were analyzed off-line using commercial software . CMR studies were centrally analyzed in a core-lab with consensus among 3 experienced observers (> 5 years’ experience) who were blinded to the clinical results and follow-up data.Endocardial and epicardial LV contours were drawn on short-axis cine images at end-diastole and end-systole. Papillary muscle and trabeculations were considered part of the cavity. From these contours, LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), LV ejection fraction (LVEF), and LV mass were calculated. Volumetric measures were normalized to body surface area . A 17-seThe total extent of myocardial LGE was determined semi-automatically, using a cut-off of 5 standard deviations (SD) above the average of remote myocardium. If needed, contours were manually corrected , 13. TheFollow-up was performed using a questionnaire administered to the physician during periodic ambulatory workup at our institutions  or by telephone call . This questionnaire was administered every year. Cardiac events (CEs) were defined as cardiac death and appropriate implantable cardioverter-defibrillator (ICD) shock. Appropriate ICD shock was considered equivalent to cardiac death. The cause of death was documented from medical records or death certificates. The definition of cardiac death required the documentation of life-threatening arrhythmia or cardiac arrest, or death attributable to heart failure or MI in the absence of any other precipitating factor. In the case of out-of-hospital death not followed by an autopsy, a sudden, unexpected death was considered cardiac death. ICD shocks were appropriate if triggered by malignant arrhythmia . A complete interrogation of the ICD was performed by the referring physician in order to confirm the appropriateness of the shock .Post-CMR coronary revascularization  also was recorded. Coronary artery disease events included MI and post-CMR coronary revascularization.P < 0.05; all statistical tests were two-sided. Continuous variables were expressed as mean ± SD or median  as appropriate; categorical variables were expressed as number and percentage. The comparison between continuous variables in patients with and without CEs was performed by Student’s independent samples t-test (Gaussian variables) or Wilcoxon test (skewed variables). The comparison between categorical variables was performed either by the chi-squared test or by the Fisher’s exact test if an expected cell count was < 5. The correlation between continuous variables was quantified by Pearson’s correlation coefficient.Data analyses were performed using SPSS . Statistical significance was considered The inter- and intraobserver analysis of CT-F segments was performed by calculating the intraclass correlation coefficient (ICC).LVEDV and LVEF were dichotomized according to validated cut-offs. In post-hoc analysis, median value was used to discriminate large extent/involvement of WMSI (> 1.7), LGE extent (> 13%), and number of segments with LGE > 50% (≥ 3 segments).P < 0.05) were included as potential predictors. Given that LVEDV and LVEF were strongly interrelated (r = −0.70), two multivariate models including either LVEF (model 1) or LVEDV (model 2) were computed separately; conversely, both WMSI and LGE were included in the same multivariate model as there was no substantial collinearity (tolerance > 0.6) that might have affected estimation.Univariate Cox regression analysis was used to determine which variables were associated with CEs. In multivariate stepwise analysis using the forward selection technique based on the Wald statistic, all significant continuous or dichotomous variables at univariate analysis  instead of presence of CT-F to parallel the prognostic meaning of the other variables included in the risk score calculation.The Kaplan–Meier survival function was used to represent the free-event survival in the population.P = 0.002), more likely to use diuretic and aldosterone receptor antagonist therapies (P < 0.001), and more likely to have > 1 MI (P = 0.005) (Table P < 0.001). The amount of scarring was greater in the CE group (P = 0.003), and these patients had significantly more LGE segments, in particular, segments with LGE > 50% (P = 0.002).The median interval between MI and CMR was 7.5 months (IQR 3–80). Patients with CEs were older .During follow-up, a new coronary event was observed in 212 (29%) of 730 patients. Of these, 62/197 coronary events (31%) were in patients with absence of CT-F and 150/533 (28%) in patients with presence of CT-F (P = 0.02). There was strong intraobserver consistency  and interobserver consistency .A total of 1429 of 12,410 segments (11%) were defined as CT-F. Of these segments, most were WM-1 and LGE < 50%  or WM-2 and LGE < 50% , 500 (35%) were WM-2 and LGE > 50%, and 385 (27%) were WM-1 and LGE > 50%. None of the segments in the last group had a transmural LGE extension of > 75%. On the contrary, WM-3 and -4 were associated with LGE < 50% in 1896 segments  and with LGE > 50% in 578 segments . The group without CEs had a higher number of CT-F segments at follow-up than the CE group , 123 patients (17%) had CEs (68 cardiac-related deaths and 55 appropriate ICD shocks).At univariate analysis, age, LV volumes, LVEF, WMSI, extent of LGE, segments with transmural extent > 50%, and CT-F segments—both when considered as a continuous variable Table  or as diP < 0.001) compared to segments with transmural extent > 50% (chi-square 7.7). Also, at multivariate analysis, selected identical parameters—both when considered as continuous (Table CT-F segments (chi-square 28.1) had an incremental predictive value (us Table  variableP < 0.001) than those without .On survival analysis Fig. A, patienPatients with the presence of CT-F myocardium had a higher cumulative survival at 2, 5, and 7 years than those without Table .Table 4S2 [Fig. The estimated Kaplan–Meier survival curves in high-risk patients , and one point to the absence of CT-F. Subjects were then divided into four groups based on the values of their individual risk score, which allowed the identification of subsets of patients at no risk , low risk , moderate risk  and high risk   or increased LVEDV, it has a positive prognostic value. The strength of this study is that we used comprehensive CMR to assess both WM and myocardial fibrosis, reflecting two faces of the same medal, i.e., myocardial viability. WM, as a viability marker, is used by echocardiography and CMR both at rest and after functional or pharmacological stress tests, whereas fibrosis, reflecting the amount of irreversibly damaged myocardium, is typically shown by LGE CMR , 16. To Indeed, using this CMR definition of myocardial viability, Pegg et al. showed that the amount of viable and normal tissue (≥ 10 segments) was predictive of functional improvement after revascularization .More recently, Kwon et al. used this parameter to define jeopardized myocardial segments, concluding that these segments were predictive of mortality when revascularization was not performed . In contPrediction of functional recovery in the presence or absence of necrosis was not the goal of this study. In fact, the true novelty of our study was the assessment of the prognostic role of the combined presence of fibrosis and contractility in the same segment.This is important because segments with non-transmural extent of fibrosis, according to the CMR criteria, are not a homogenous group since functional recovery occurs in a portion of them. Indeed, in the study of Pegg et al., about 63% of segments with < 50% transmural extent of necrosis had recovered function .In regard to the results of our study, the presence of contractility in the partially scarred segments highlights the importance of segmental function in the prognostic stratification of patients with previous MI. This result confirms previous findings showing the independent prognostic role of WMSI in the prediction of CEs in patients with previous MI , 21–24.In our study, the weight of segmental function/fibrosis was confirmed when CT-F tissue was included in the risk score together with age and other stronger prognostic CMR data, such as severe LV dysfunction and dilated LV.The improvement of LV regional systolic function is a complex and dynamic phenomenon observed not only after coronary revascularization but also due to many medications –29. LosaA major limitation of our study is that we do not have data about WM and LGE during the acute phase of MI, and thus we did not assess the possible contractile recovery of the partially fibrotic segments. However, based on previous studies, we supposed that CT-F tissue had a transient and reversible dysfunction due to necrosis and a successive improvement in WM due to acute or chronic revascularization and/or pharmacological data , 25–29.Neither the number of CT-F segments per patient nor the different CT-F patterns per each patient were assessed in terms of prognostic weight. Further studies are needed to show the potential prognostic impact of both the number of CT-F segments and the different CT-F patterns.We did not measure systolic wall thickening. However, we used wall motion analysis, which is a well-defined and accepted semiquantitative method to assess regional systolic function in daily clinical practice, with the aim to assess the prognostic impact of variables used in this context. Also, we did not use a T1 mapping sequence because several examinations were dated and, thus, this sequence was not available. Further, this was a multicenter study using CMR units from different vendors, which would make comparison of T1 mapping data difficult. Moreover, we used semiquantitative methods to assess both WM and transmural extent of LGE. However, one of the objects of this study was to assess the current impact of CMR in daily clinical practice, where LGE technique and WM analysis are largely applied in the context of diagnostic and therapeutic decision-making; in opposition, T1 mapping and quantitative methods of LGE extent and contractility are actually outside the clinical scenario.In patients with previous MI, cardiac death is the result of multifactorial elements including clinical, bio-humoral, electrocardiographic, and several imaging variables. In the context of imaging parameters, in addition to adverse prognostic factors , the presence of fibrotic segments having contractile activity had an independent protective effect on survival of patients with previous MI. Larger studies are needed to allow generation of a multiparametric score for risk stratification of these patients.Additional file 1: Table S1. Stepwise analyses, including the C-statistics at each step. Table S2. Hazard ratios of continuous variables for cardiac events (cardiac death and appropriate ICD shocks) within 5 years of follow-up at multivariate analysis in patients with previous MI. Table S3. Hazard ratios of dichotomic variables for cardiac events (cardiac death and appropriate ICD shocks) within 5 years of follow-up at multivariate analysis in patients with previous MI. Table S4. Risk score data distribution (range: 0–6) by 4 steps to risk score category with adequate sample size.


Ventricular septal defect (VSD) is the most common congenital heart disease. In patients with large VSD, left side chambers are subjected to volume overload with subsequent chambers dilatation and eccentric left ventricular hypertrophy. Percutaneous closure of VSD has been shown to be an effective method with equal safety and efficacy when compared to surgery. The effect of VSD closure on LV remodeling has been mainly assessed in patients treated with surgery and to date published data remain scarce. Therefore, we aim to evaluate the effect of percutaneous VSD closure on different LV parameters.2 vs. 42.9 mm/m2, p = 0.03), LVESD/BSA ], indexed LV volumes  and indexed LV mass . There was a significant reduction in LVEDD Z-score (p = 0.01) and LVESD Z-score (p = 0.04). There was no significant change in LV EF.Seventeen patients (median age 6 years (IQR 4.75–8 years), 70.6% females) who underwent percutaneous VSD closure were enrolled in the study. Sixteen patients (94%) had perimembranous VSD, and one patient had muscular VSD. The procedure was successful in all patients with no major complications. Nit Occlud® Lê coil device was implanted in 16 patients (94%), and one patient received Amplatzer PDA duct occlude device. At 6-months follow-up, there was a significant reduction in indexed LV dimensions [LVEDD/BSA (median 46.5 mm/mPercutaneous VSD closure is associated with improvement of various LV parameters with consequential favorable LV remodeling and function. Ventricular septal defect (VSD) is the most common form of congenital heart diseases, being responsible for 20% of the various congenital heart diseases with an overall incidence rate of 3–3.5 per 1000 live birth . Any clinical evidence of extra cardiac lesions detected during examination was recorded. A 12-lead electrocardiogram was performed before and immediately after the procedure and at 1- and 6-months post-VSD closure to detect any rhythm or conduction abnormalities.A detailed and informed written consent was obtained from all the eligible patients or parents. The study was approved by the institutional review board and local ethical Committee.Patients underwent transthoracic echocardiography using IE33 Phillips echocardiography machine equipped with a phased array transducer of suitable frequency. The echocardiography study was done before and immediately after the procedure and repeated at 1- and 6-months post-VSD closure. LV internal dimensions, septal and posterior wall thickness were measured at end-diastole and end-systole from cross-sectional guided M-mode echocardiograms. Measurements were done at the level of tips of mitral leaflets in parasternal long axis view and were averaged over 3 cardiac cycles. End-diastole was defined as the frame at which the mitral valve closes and end systole as the frame preceding mitral valve opening .Pre-procedure echocardiography focused on full assessment of the VSD  and assessment of various LV parameters  using Biplane method). LV dimensions and volumes were indexed to the body surface area. Aneurysmal tissue was considered complete if it forms a complete circle around the defect; otherwise, it was considered incomplete. The left ventricular end-diastolic dimension Z-score (LVEDD-Z) and left ventricular end-systolic dimension Z-score (LVESD-Z) were calculated as the number of standard deviations from the mean value of the normal population relative to the BSA .Doppler echocardiography was done to determine pressure gradients across VSD, pulmonary flow: systemic flow ratio (Qp:Qs), presence of aortic regurgitation and estimated pulmonary artery systolic pressure from tricuspid regurgitation velocity if detected by color flow mapping before VSD closure.Post-percutaneous closure of the VSD, an echocardiography was done immediately to detect any complications related to the procedure and assess the result of procedure , encroachment and relation of the device to the surrounding structures, residual shunt across the device, Qp:Qs in the presence of residual shunt and presence of aortic regurgitation).During the period of follow-up, an echocardiography was done at 1- and 6-months post-procedure to record changes in indexed LV parameters and detect the fate of any residual shunt present post-procedure.Percutaneous closure of VSD was performed under general anesthesia in all patients. All procedures were guided by trans-thoracic echocardiography or trans-esophageal echocardiography and fluoroscopy. All patients received intravenous heparin (100 units/kg) and antibiotics before the procedure. Right and left heart catheterization was preformed through percutaneous transfemoral route.Assessment of the defect was performed in multiple views. The angiographic view that best profiled the defect was used as a reference for closure. In most cases, modified left anterior oblique 60° cranial 20° and left anterior oblique 45° cranial 45° were used. Measurements of the defect size from left and right ventricular sides and its distance from the aortic and tricuspid valve were confirmed using angiography and echocardiography. Device selection was done based on operator preference on case-by-case bases. Patients were prescribed antiplatelet therapy in the form of oral aspirin 5 mg/kg/day for 6 months.Procedural success was defined by device implantation in the appropriate position with no need for surgery due to significant residual shunt and/or valve regurgitation .A residual shunt was diagnosed if the color-Doppler flow mapping showed a left to right shunt across the interventricular septum. It was classified as follows: trivial (< 1 mm color jet width), small (1–2 mm color jet width), moderate (> 2–4 mm color jet width) and large (> 4 mm color jet width) .p < 0.05 was considered statistically significant.Statistical analysis was carried out using SPSS 20. Numerical data were presented as number and percentages, while categorical data were presented as median and interquartile range (IQR). Comparison between pre-closure and post-closure data was done using Wilcoxon Signed-Rank test. A probability value of This study included 17 patients who underwent percutaneous closure of VSD from June 2015 to February 2017 and completed follow-up period. The demographic characteristics of the patients are shown in Table VSDs and baseline echocardiographic characteristics are demonstrated in Tables Nit Occlud® Lê VSD coil device  was implanted in 16 patients (94%), and the other patient received Amplatzer PDA duct occluder device. All devices were implanted successfully in the defect. Post-device implantation, 2 patients (12%) developed bradyarrhythmia; one patient suffered from transient 2:1 heart block which resolved after 3 days with steroid therapy and the other developed asymptomatic sinus bradycardia which resolved spontaneously. None of the patients developed tachyarrhythmia during or after procedure.Immediately post-procedure, residual shunt was detected in 11 patients (64.7%); 7 patients (63.6%) had mild, 3 patients (27.3%) had moderate, and 1 patient (9.1%) had large residual shunts. At 6-month follow-up, 4 patients (23.5%) had mild residual shunts. Significant valvular affection was present in 3 patients (17.6%) post-procedure; one patient developed mild aortic regurgitation, and 2 patients had mild tricuspid regurgitation.Changes in echocardiographic LV parameters, LVEDD and LVESD Z-scores at 6-month follow-up are represented in Table Our study demonstrated that percutaneous closure of VSD is associated with favorable LV remodeling demonstrated by significant reduction in indexed LV dimensions, volumes and mass. There was also significant reduction in LVEDD Z-score and LVESD Z-score.VSD is one of the most common forms of congenital heart disease which may occur isolated or in combination with other congenital defects. Isolated large VSD, if left untreated, may be associated with unfavorable outcome due to chronic LV volume overload .Due to pressure difference between systemic and pulmonary circulation, VSD is associated with left to right shunting of blood; this will lead to increased pulmonary blood flow and subsequently pulmonary venous return to the left sided heart chambers. This continued volume overload will eventually cause left side chambers dilatation and eccentric LV hypertrophy due to increased wall stress , 11.The amount of left to right shunt associated with VSD is determined mainly by the defect size and the gradient between systemic and pulmonary circulation. In large VSD, the key determinant of left to right shunt amount is the relation between pulmonary and systemic vascular bed resistance; a relation that is variable and dependent on age. Due to the high pulmonary vascular resistance in neonatal period, the amount of shunt will be minimal in babies. With lung expansion and exposure of alveoli to oxygen, a potent pulmonary vasodilator, there will be fall in pulmonary vascular resistance and increase in left to right shunt and pulmonary blood flow , 12.The chronic volume overload associated with VSD leads to structural changes at the myocyte level. The reversibility of such changes depends mainly on the duration and amount of volume overload. Thus, the age of VSD closure plays a pivotal role in the restoration of normal LV parameters post-volume overload removal .Timely corrected VSD closure is associated with reduction in LV dimensions, volumes and masses; however, the time course of reduction in such parameters is not uniform with slower pace of LV mass regression compared to other parameters . Such deFor several decades, surgical closure was the treatment of choice for VSD with favorable effect on LV parameters. Pacileo et al.  demonstrp < 0.02). This discrepancy in results may be related to the age of VSD correction, as delayed correction may be associated with irreversible changes at the myocyte level causing myocardial dysfunction [There is a controversy in the data determining the effect of VSD surgical closure on LV EF. Cordell et al.  showed tfunction , 6.Due to abnormal loading conditions seen in patients with VSD in the form of increased LV preload due to left to right shunt and afterload reduction due ejection of blood into low resistance pulmonary circulation, any underlying myocardial dysfunction may be obscured . Such abAlso, the surgical technique used and permanent damaging effect of intra-operative myocardial ischemia during intra-cardiac manipulation may have a deleterious effect on EF, a disadvantage that is not encountered by percutaneous closure as demonstrated by our study that showed no significant change in LV EF at follow-up .p < 0.001) after percutaneous VSD closure and above all, there was no significant difference in LVEDD Z-score reduction between surgical and percutaneous VSD closure (p = 0.319). Also, Haddad et al. [Measurement of different cardiac structures by echocardiography plays a pivotal role in medical decision making in children with structural cardiac disease. Since body growth is a continuous process in this phase of life, normalization of echocardiographic dimensions to body size is a vital step for accurate analysis of these measurements . For thie p = 0.3. Also, HThe presence of significant residual shunt post-percutaneous VSD closure may be associated with unfavorable LV remodeling due to incomplete correction of volume overload status. The rate of residual shunt in our study is similar to what reported by the European VSD registry , but higFirst, the duration of follow-up was short and a longer period of follow-up is needed to confirm the regression of various LV parameters, maintenance of normal systolic function and absence of device related complications on the long term. Second, the number of procedures was low, and this was related to the fact that surgical closure is still the method of choice for VSD closure especially for symptomatic patients and thus, a larger number of patients are needed to confirm the findings of our study. Third, only one type of VSD occlude device was used in almost all patients and thus, the results of our study especially procedural success and complications rate cannot be generalized to other devices.Percutaneous VSD closure is associated with favorable LV remodeling as demonstrated by improvement of indexed LV volumes, dimensions and mass and preservation of normal LV systolic function. The results of our study need to be validated in larger study population.


Alterations in cardiac contraction impact electrophysiological parameters through mechanoelectric feedback. This has been shown to promote arrhythmias in experimental studies, but its effect in the The purpose of this study was to quantify the impact of regional myocardial deformation provoked by a sudden increase in ventricular loading (aortic occlusion) on human cardiac electrophysiology.In 10 patients undergoing open heart cardiac surgery, left ventricular (LV) afterload was modified by transient aortic occlusion. Simultaneous assessment of whole-heart electrophysiology and LV deformation was performed using an epicardial sock (240 electrodes) and speckle-tracking transesophageal echocardiography. Parameters were matched to 6 American Heart Association LV model segments. The association between changes in regional myocardial segment length and activation-recovery interval  was studied using mixed-effect models.P = .01) and shortened ARI (P = .02), but changes were heterogeneous between cardiac segments. Increased regional longitudinal shortening was associated with ARI shortening  and increased local ARI dispersion . At the whole organ level, increased mechanical dispersion translated into increased dispersion of repolarization .Increased ventricular loading reduced longitudinal shortening (Mechanoelectric feedback can establish a potentially proarrhythmic substrate in the human heart and should be considered to advance our understanding and prevention of cardiac arrhythmias.  Mechanoelectric feedback (MEF) is an established mechanism whereby myocardial deformation causes changes in cardiac electrophysiological parameters.in vivo human heart. This was achieved through a unique experimental model that enabled simultaneous quantification of electrophysiology  and cardiac mechanics (through speckle-tracking echocardiography) during manipulation of ventricular loading using the established method of transient aortic occlusion in patients undergoing open heart surgery  and was conducted in accordance with the Declaration of Helsinki. All patients gave written informed consent. Cardiac mapping and transesophageal echocardiography (TEE) were simultaneously performed in 10 patients  undergoing cardiac surgery incorporating cardiopulmonary bypass .,,Activation time (AT) and repolarization time (RT) were estimated from the unipolar electrograms using validated methods, and activation-recovery interval (ARI), an established measure of action potential duration (APD), was calculated as ARI = RT – AT .18,19 SiTEE segments were analyzed using commercial software integrating speckle tracking . Image segmentation was performed semiautomatically by an expert cardiologist blinded to electrophysiological results, according to international consensus.Continuous variables are presented as median (interquartile range). The Wilcoxon sign-rank test was used to test paired comparisons (before vs during occlusion). Changes due to aortic occlusion were measured in terms of differences between parameters registered during and before occlusion. Correlation was assessed using the Spearman correlation coefficient. Mixed-effect regression models were used to study the association between electrophysiological changes and deformation parameters at the regional level. These models use data structured in a hierarchical way efficiently while reducing problems related to pseudo-replication. Electromechanical interactions across cardiac segments within the same subject were modeled as fixed effects, whereas interpatient variability was considered a random effect.In 2 patients, ectopic beats were induced during the first aortic clamp but not during the second one. Increased ventricular loading increased LV cavity size and altered myocardial contractility and ventricular repolarization. An example from a representative patient is shown in P = .004), global longitudinal (P = .01) and circumferential shortening (P = .004), and transverse thickening (P = .014). These changes indicate a worsening of myocardial function with increased ventricular loading compared to baseline conditions. ARI values changed by up to 15 ms during increased loading, with median ARI across the entire LV decreasing from 255 (228–268) ms before clamp to 252 (227–263) ms during clamp (P = .02).Transient aortic occlusion induced significant changes in parameters describing global contractility and electrophysiology . These iP = .04). This indicates regional ARI reduction in segments with increased longitudinal shortening and regional ARI increase in segments with reduced longitudinal shortening (P = .01). This indicates that spatial heterogeneity of ARI increased in segments with greater longitudinal shortening  ms, some cardiac sites showed substantial reductions in ARI, with maximal ARI decreases of 15 (13–20) ms. At the same time, 18.3% of all cardiac segments showed an increase in ARI. Similarly, although longitudinal segment shortening was decreased during occlusion in most segments, 36.7% of all segments showed an increase in longitudinal segment shortening. At the regional level, changes in longitudinal segment shortening significantly correlated to regional ARI and ARI dispersion . Mixed-effect models identified a significant positive association between changes in ARI and changes in longitudinal strain  and regional ARI dispersion (P = .024)  were associated with regional ARI ( = .024) . No sign = .024) .P = .01) (P = .14).At the patient level, changes in global dispersion of ARI  strongly correlated to mechanical dispersion  . This inSensitivity analysis conducted using peak strain values showed similar results . RegionaP = .01_, respectively. Median value of ARI shortening for late-activated LV sites was numerically greater than for early-activated sites (4.2 [2.5–6.04] ms vs 3.3 [2.7–4.3] ms), but the difference was not statistically significant (P = .19).Experimental models in animals have shown that the normal inverse relationship between AT and RT is modulated by alterations in ventricular loading.This study provides quantitative and simultaneous assessment of the effect of myocardial deformation on ventricular electrophysiology during a sudden change in ventricular loading. The transient aortic occlusion utilized in this model to alter ventricular loading significantly modified contractility  and electrophysiology. The main findings of the study are that (1) global changes in ventricular loading produce regional changes in mechanical function and electrophysiology, which were inhomogeneous; (2) changes in regional longitudinal shortening were directly related to changes of both regional repolarization and regional repolarization dispersion; and (3) global mechanical dispersion, a measurement of desynchrony in contraction, increased global dispersion of repolarization. These results are consistent with the hypothesis that increase in ventricular loading produces inhomogeneous changes in both mechanical function and electrophysiology between different regions as well locally within regions through the intermediary of MEF. This is especially important in the presence of underlying heart disease, such as ischemic heart disease and cardiomyopathy, which are characteristically associated with the development of scar and fibrosis, both of which are patchy and promote contraction inhomogeneity. These results have important implications in the understanding of fundamental mechanisms underlying potentially life-threating ventricular arrhythmias in the human heart because they implicate impaired myocardial contraction and desynchrony in the modulation of regional and global spatial dispersion of repolarization, which are well-established proarrhythmic factors.11The analysis of regional mechanoelectric interactions shows that changes in the mechanical properties of a given cardiac segment not only directly impact on the electrophysiology of the same segment  but alsoA previous study using a similar model of increased afterload in patients found a reduction in APD that correlated with peak systolic pressure.Changes in the mechanical environment of the myocardial cell influence APD by MEF pathways involving stretch-activated channels, calcium cycling, and chemical signaling.in silico has identified a range of cellular mechanisms and electrophysiological responses to specific alterations in ventricular loading, extrapolation to the in vivo human heart is challenging in view of the 3-dimensional complexity of the stress/strain relationships during the cardiac cycle and species differences in cardiomyocyte electrophysiology and species-dependent mechanisms underlying arrhythmias.,2+ for troponin C.,,,2+ release that is not reflected in global Ca2+ but confined to localized regions such as the narrow dyadic space between ryanodine receptors and the L-type Ca2+ channels.,Although experimental work on cells, tissues, and Stretch-activated ventricular arrhythmias are a well-recognized phenomenon in clinical practice, including ventricular fibrillation triggered by commotio cordis. Recently, the role of stretch-activated premature ventricular contractions has become recognized as a mechanism of triggering ventricular fibrillation in mitral valve prolapse.Mechanisms of arrhythmogenesis in the infarct border zone operate on a number of levels, including activation of stretch-activated channels that change APD, slow conduction velocity, and increased dispersion of repolarization on the physiological level, to changes in expression of mechanically modulated ion channels and alterations in connexin phosphorylation at the molecular level through to structural remodeling of tissue architecture, composition, and innervation.Mechanical deformation parameters are also becoming recognized predictors of arrhythmic events in structural heart disease.The number of patients included in the study was limited by the inherent difficulty of conducting experimental studies, including electrophysiological and speckle-tracking recordings in the cardiac operating suite. However, the statistical methods utilized make efficient use of the data and detected significant associations. Coregistration of regional strain and electrophysiological data was performed using anatomic landmarks and labels on the heart sock, but remaining imprecision may have affected the results, possibly reducing the significance of some associations. Measurement of electrophysiological and strain parameters may be challenging in some cases. However, to ensure accuracy and robustness, analyses were performed independently utilizing validated software, automatic exclusion of outliers was performed using predetermined criteria, and sensitivity analysis was conducted to check for consistency. We cannot exclude the possibility that placement of the sock around the heart may influence the electrophysiology. However, the sock fits gently around the heart, and if any mechanically induced repolarization changes were induced by its placement, we would expect them to be trivial.in vivo human experimental model of acutely increased ventricular loading by combining multisite electrophysiological mapping with simultaneous transesophageal ultrasound and an established aortic cross-clamping protocol in patients undergoing cardiac surgery. The results show that global ventricular loading conditions induce regional differences in myocardial shortening. These changes in myocardial shortening are associated with changes in electrophysiology, most probably by MEF whereby increased mechanical dispersion results in greater dispersion of repolarization. This suggests that MEF can contribute to the establishment of proarrhythmic substrates in patients and may provide a mechanistic explanation for the association between myocardial strain parameters and sudden cardiac death reported in clinical studies.This study developed a unique