We demonstrated that rats with LV failure induced by extensive LV myocardial infarction also develop RV failure, leading to symptomatic biventricular HF, despite only mildly increased RV afterload. The contractility of RV cardiomyocytes was significantly increased, which could be related to increased amplitude of Ca2+ transient, preserved SERCA2a activity and reduced Ca2+ efflux via NCX1 and PMCA. Our study indicates that RV failure associated with post-MI LV failure in a rat model cannot be explained by a decline in cardiomyocyte function. This indicates that other factors may play a role here, pointing to the need for further research to better understand the biology of RV failure in order to ultimately develop therapies targeting the RV.Right ventricular dysfunction (RVD) can follow primary pulmonary diseases, but the most common cause of its development is left-sided heart failure (HF). RVD is associated with HF progression, increased risk of death and hospitalisation. The mechanism of right ventricle (RV) remodelling leading to RVD due to left-sided HF is not fully elucidated. Rats underwent LAD ligation to induce extensive left ventricle (LV) myocardial infarction (MI) and subsequent left-sided HF. Sham-operated animals served as controls. After 8 weeks of follow-up, the animals underwent LV and RV catheterisation, and systolic function and intracellular Ca Right ventricular dysfunction (RVD) manifests as decreased contractility, diastolic dysfunction and right ventricular (RV) dilatation. RVD can follow primary pulmonary diseases, such as pulmonary arterial hypertension, right coronary artery infarction or genetically determined RV cardiomyopathies, such as arrhythmogenic RV dysplasia. However, the most common cause (65–80%) of RVD development is left heart disease, leading to left-sided heart failure (HF) ,2. In patients with HF, the prevalence of RVD is estimated to range from 36 to 75%, depending on the criterion adopted to qualify the right ventricle as dysfunctional  < 45%, Tricuspid Annular Plane Systolic Excursion (TAPSE) < 15 mmHg or systolic dysfunction visualised by speckle-tracking echocardiography) ,9. RV fuThe mechanism of RV remodelling and development of RVD in left-sided HF is not fully elucidated. One possible mechanism that may induce RV dysfunction is an increase in RV afterload due to passive ‘backward’ transmission of pressure from LV. In both subtypes of left-sided HF, with reduced and preserved LV ejection fraction , there is an increase in left ventricular end-diastolic pressure (LVEDP). In HFrEF, impaired systolic function leads to a decrease in EF and an increase in LV late diastolic volume (LVEDV). In turn, in HFpEF, passive LV wall stiffness increases due to impaired active and passive relaxation and increased fibrosis. In both cases, LV filling is impaired and LV filling pressure increases. This may lead to a sequential increase in the left atrial (LA) pressure and an increase in pulmonary venous pressure, leading to pulmonary congestion (isolated post-capillary pulmonary hypertension (PH)). Persistent post-capillary PH may result in pulmonary arteriole remodelling, including medial hypertrophy, intimal and adventitial fibrosis and small-vessel luminal occlusion and increase in pulmonary vascular resistance (PVR) (pre-capillary PH) ,14. In c2+ signalling. Chronic neurohormonal activation in HF is now recognised as one of the most important mechanisms underlying the progression of heart failure [Another mechanism that may be responsible for RV remodelling and the development of RVD in left-sided HF is systemic neurohumoral activation. Activation of the sympathetic nervous system (SNS) and renin-angiotensin-aldosterone system (RAAS) in the short term induces a number of changes in the heart muscle, kidneys and vasculature to maintain cardiovascular homeostasis. However, with chronic activation, they exert deleterious effects, leading to fluid retention, increased myocardial preload and afterload, cardiomyocyte loss, hypertrophy, fibrosis, extracellular matrix degradation, dilatation of heart chambers and impaired intracellular Ca failure .2+ concentration. The functional remodelling of LV cardiomyocytes during the development of LV failure has been studied in detail in animal models and in humans, with indications that significant changes in intracellular Ca2+ signalling develop over time and are ultimately responsible for the decline in cardiomyocyte contractile function. It has been shown that with the development of HF, there is a decrease in Ca2+ transport to the sarcoplasmic reticulum (SR) by the SR Ca2+-ATPase (SERCA2a), an increase in Ca2+ efflux by the Na2+/Ca2+ exchanger (NCX1) and dysfunction of the SR Ca2+ channels (ryanodine receptors-RyRs), leading to diastolic Ca2+ leak from the SR [2+ content is reduced, contraction and relaxation kinetics are slowed and, ultimately, the amplitude of cardiomyocyte shortening is reduced. Furthermore, due to impaired Ca2+ signalling, the arrhythmic risk strongly increased [2+ signalling has not been studied in RV exposed to the failure of LV.An important determinant of both LV and RV function is cardiomyocyte contractility, which is closely dependent on changes in intracellular Cam the SR ,21,22. Ancreased . Contrar2+ signalling and function of the main Ca2+ transporters. We related the results to those obtained similarly in the LV.Therefore, the aim of our study was to characterise RV performance in rats with LV failure following induction of LV myocardial infarction. We investigated RV function at the organ level by recording pressure-volume loops and at the cellular level. In isolated RV cardiomyocytes, we examined contractile performance, intracellular CaMale Wistar rats at 13 weeks of age (310–380 g) were used in the study in compliance with local and institutional regulations. The study conforms to the Guide for the Care and Use of Laboratory Animals, US National Institutes of Health  and was approved by the local Ethics Committee .Rats were subjected to induction of the LV myocardial infarction (MI) (HF group) or sham operation (Sh group). After 8 weeks of follow-up, the animals underwent echocardiographic imaging to evaluate the size of MI. Only rats with large MI (≥40% of the LV) were enrolled in the HF group in this study. Subsequently rats underwent LV and RV and catheterization. Ketamine HCl/xylazine overdose was given to euthanize the animals and hearts were excised for LV and RV cardiomyocyte isolation.The animals were anaesthetized by intraperitoneal administration of a mixture of ketamine (100 mg/kg body weight) and xylazine (5 mg/kg body weight). Subsequently, the chest was opened and a 6-0 suture was put around the proximal left anterior descending artery. It was tightened in the MI group, but in the Sh group it was removed. Subsequently, the chest was closed and the pneumothorax was evacuated. Approximately 1 h after the surgery a single dose of an antibiotic narcotic analgesic agent was given intraperitoneally. The procedure was described previously in detail .Echocardiography was performed using MyLab25  with 13 MHz linear array transducer. Under light anaesthesia  LV end-diastolic and end-systolic dimensions were determined from the short-axis view at the midpapillary level and long-axis view. Regional LV wall motion abnormalities were quantitated as described previously. Contractility of 12 wall segments visualized in the midpapillary short-axis view and 11 segments visualized in the long-axis view were graded as 1  or 0  and the total wall motion score index (WMI) was calculated. The normal hearts have WMI = 23. Our previous results revealed that WMI closely correlated with infarct size and that WMI = 15 corresponded to infarct size ~40% .Rats were put on a heating pad, anaesthetized with ketamine and xylazine, intubated and put on an animal ventilator. The upper abdominal cavity was opened and through the cutting of the diaphragm, the heart was exposed. The left and subsequently right ventricular apex was punctured with a 25 G needle and a microtip P–V catheter  was inserted into the LV and RV. Its position was established based on pressure and volume signals. After stabilization for 5 min, the signals were continuously recorded at a sampling rate of 1000/s using an ARIA P–V conductance system (Millar Instruments) coupled to a PowerLab/4SP A/D converter  and a personal computer. To characterize cardiac function, first the inferior vena cava was compressed for 10 s and then released to achieve reduction and augmentation of venous return and cardiac preload, respectively. Heart rate, maximal systolic pressure (ESP), end-diastolic pressure (EDP), maximal slope of systolic pressure increment (+dP/dt max) and maximal slope of diastolic pressure decrement (−dP/dt max), ejection fraction (EF), end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), and cardiac output (CO) were computed using a cardiac P–V analysis program  for both ventricles. Indexes of contractility and stiffness (slope of end-systolic and end-diastolic P–V relations (ESPVR and EDPVR)) were also calculated using PVAN3.2.2+ free Tyrode’s solution containing 100 mmol/l EGTA. The initial washout period was followed by 20 min of perfusion with Ca2+ free Tyrode’s solution containing 20 mg collagenase B (Roche) and 3 mg protease (Sigma) per 30 mL. Thereafter, the right and left ventricles were separated, placed in the glass dishes and mechanically disrupted. The cell suspension was filtered and allowed to sediment. The supernatant was discarded and cells were washed twice with Tyrode’s solution. The Ca2+ concentration was increased gradually to 1.8 mmol/L.The heart was rapidly excised and perfused for 10 min with nominally Ca2+. The difference between the systolic and diastolic Indo-1 fluorescence (excited at 365 and measured as ratio of fluorescence at 405 and 495 nm) was used as a measure of the amplitude of Ca2+ transients . The rate of Ca2+ transport by sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a), Na+/Ca2+ exchanger (NCX1) and plasma membrane Ca2+-ATPase (PMCA) was estimated from the rate constants  of the single exponential curves fitted to electrically and caffeine-evoked Ca2+ transient decay [2+ transient decay for SERCA2a and NCX1 were calculated according to formulas: rSERCA = r1−r2 and rNCX = r2−r3, respectively, while r3 was taken as the measure of the rate of Ca2+ transport by PMCA (r3 = rPMCA). rSERCA, rNCX and rPMCA describe the average velocity of Ca2+ transport. SR Ca2+ content was estimated from the amplitude of caffeine-evoked Ca2+ transients in myocytes superfused with Na+-, Ca2+-free (0Na0Ca) solution. ISO2 Multitask-Patch-Clamp Software (University of Dresden) was used to fit mono-exponential curves to decaying part of Ca2+ transients and calculate r1, r2 and r3 rate constants.The myocytes were incubated for 20 min with 10 μM Indo-1 and perfused at 37 °C with a Tyrode solution containing 1.8 mmol/L Cant decay .. The raMyocyte contractions were recorded by a video-edge detection system including a fast digital dimensioning video camera  enabling acquisition of the cell length changes in real time. Myocyte contractions were elicited by electrical pacing at 1 Hz. Cell shortening was taken as a measure of myocyte contractile performance. The amplitude and time course of the signal were analysed by the IonWizard software (IonOptix). Contraction amplitude was expressed as the difference between systolic and diastolic cell length and normalized as a percentage of the resting cell length. The contraction time (time to peak) was calculated as the time from the initiation of contraction to the maximal cell shortening. The time required for re-lengthening cell to 90% of the resting cell length was taken as the relaxation time. The maximal rate of contraction and relaxation was evaluated to describe the kinetics of contraction and relaxation process.p < 0.05.Normal data distribution was verified by the Shapiro–Wilk test. For normally distributed data, two-way ANOVA followed by the Student–Newman–Keuls as post hoc test. In case of a lack of normality, the Kruskal–Wallis test and Dunn’s post hoc test were used for all pairwise comparisons. Differences between the 2 groups were detected using the Mann–Whitney Rank Sum test or t-student test, depending on the normality of data distribution (Sigma Plot v.11.0). Differences were considered significant at a level of An average MI size was 42.5% in the HF group . PressurSince arterial elastance (Ea), a marker of arterial component of LV afterload, was increased and contractility was impaired, a very sensitive index of LV ventricular–arterial coupling (Ea/ESPVR) was increased by more than five-fold, indicating severe uncoupling C. MarkedRV systolic function was also reduced, which was evidenced by impaired RV EF A, +dP/dt2+ transient was slightly increased compared to that in cardiomyocytes from sham-operated animals   in post-MI animals compared to sham-operated ones  B,C. The ted ones E. SERCA2ted ones F, while g hearts D, which 2+ release from the SR (Representative recordings of cell shortening in cardiomyocytes isolated from Sh and MI rats are presented in m the SR C.2+ transient amplitude in these cardiomyocytes (p = 0.276).In contrast, in RV cardiomyocytes isolated from rats after induction of LV infarction, we found both an enhancement of the amplitude of myocyte shortening and an increase in kinetics of the contraction–relaxation cycle. The amplitude of the myocyte shortening was increased by approximately 25%, which corresponds well with the increase in Camyocytes B. In addmyocytes D. Howevemyocytes C. Howeve2+ retention, resulting from reduced Ca2+ efflux through sarcolemmal Ca2+ transporters, NCX1 and PMCA. This suggests that RV failure in the rat model of post-MI LV failure can neither by explained by extensive pulmonary hypertension and the resulting increase in RV afterload nor by RV cardiomyocyte dysfunction.Here, we show that rats with LV failure induced by a large LV myocardial infarction develop also RV failure, resulting in symptomatic biventricular HF, despite only mildly increased RV afterload. Furthermore, to our best knowledge, we are the first to show that contractility of RV cardiomyocytes is increased in this model due to preserved SERCA2a function and intracellular CaHere, we show that 8 weeks after induction of MI, rats develop typical systolic LV failure with markedly reduced contractility, LV dilation, elevated LVEDP, ventricular–arterial uncoupling due to markedly reduced LV contractility/mildly increased arterial elastance  and pulmonary congestion. It is accompanied by RV failure, as evidenced by reduced RV contractility, RV dilation and ventricular–arterial uncoupling due to both increased Ea (caused by increased PVR) and reduced contractility; however, the increase in RV Ea was quite mild (approx. 30%) as compared to that in the models of monocrotaline-induced pulmonary hypertension and pulmonary artery banding, where three–five-fold increases were found ,27. ModeIn LV cardiomyocytes, the amplitude of myocyte shortening was preserved. However, the duration of the systolic–diastolic cycle was prolonged. In our previous papers, we obtained similar results in cardiomyocytes after induction of a large MI of LV ,28. Main2+ content in the SR. In spite of that, the amplitude of the Ca2+ transient was increased, which indicated enhanced fractional release. It suggests a higher sensitivity of RyRs to Ca2+ ions, which is strictly dependent on their phosphorylation and oxidation level [2+ release comes at the expense of diastolic Ca2+ leak from the SR, which acutely leads to a decrease in the SR Ca2+ content and, consequently, to a decrease in cardiomyocyte contractility and haemodynamic decompensation and increases the propensity to arrhythmias. In our model, at this stage of HF development, the Ca2+ transient amplitude is still amplified. This maintains the contractility of the LV cardiomyocytes and prevents complete LV decompensation.Moreover, in LV cardiomyocytes, we observed the well-known major signs of cellular remodelling of failing heart ,22. SERCon level . However2+ content showed an increasing trend, which corresponded to increased Ca2+ transient amplitude and suggested normal RyRs function without increased diastolic Ca2+ leak from the SR. The main change observed at the level of Ca2+ signalling in RV cardiomyocytes was a marked decrease in sarcolemmal Ca2+ efflux by NCX and PMCA. This interesting compensatory mechanism leads to intracellular Ca2+ retention, which exposes the SERCA2a to higher Ca2+ concentrations and sustains its function and ultimately translates into higher amplitude of Ca2+ transient. Further, the amplitude of myocyte shortening was significantly increased and the duration of contraction and relaxation was not prolonged due to the preserved function of SERCA2a and the increased maximum rate of the contraction and relaxation. These results suggest that in this model, the RV is at a different stage of cellular remodelling than the LV.In contrast, in cardiomyocytes isolated from the RV, despite its marked haemodynamic dysfunction, no such changes were apparent. SERCA2a function was preserved. The SR Ca2+ transient amplitude due to a decrease in NCX1 function. Furthermore, we showed that the decrease in NCX1 transport activity in LV cardiomyocytes is associated with calcineurin activation and is abolished by its blockade by cyclosporine [Interestingly, in our previous study, also in the LV cardiomyocytes at an early stage of remodelling (3 days after MI induction), we showed an increase in Caosporine . In addiosporine  showed tosporine . Thus, iosporine  and lead2+ signalling by miRNAs [Another mechanism responsible for the decrease in NCX1 activity in RV myocytes may be the regulation of the expression of proteins involved in intracellular Cay miRNAs . Van Rooy miRNAs  showed ty miRNAs  showed t2 partial pressure also occurs in the RV in monocrotaline-induced pulmonary hypertension [However, despite enhanced RV cardiomyocyte contractility, RV dysfunction is present. We can only speculate that there is a reduction in the number of cardiomyocytes in the RV by their gradual loss (vs. sudden loss in the LV) through apoptosis and/or necrosis, followed by replacement with fibrous tissue. Perhaps this is due to inadequate oxygen supply, resulting from pulmonary congestion and impaired gas exchange. In our previous work, we showed that a decrease in the Ortension . RV aftertension . Hence, Another factor responsible for the development of RV dysfunction despite the enhanced contractility of its individual cardiomyocytes may be impaired synchronisation of myocyte contraction due to disturbances in propagation of the depolarization wave. Impaired electrical impulse conduction may occur due to decreased expression and localisation of intercellular gap-junction channels or enhanced myocardial fibrosis. Increased connective tissue deposition between cardiomyocytes separates them, impeding the formation of connexons and complicating the conduction pathway, which prolongs the depolarisation time of the ventricle and reduces synchronization of contractile activity of individual cardiomyocytes . Moreove2+ signalling increasing cardiomyocyte contractility are transient. In the LV cardiomyocytes, the increase in Ca2+ transient amplitude due to the decline in NCX1 function was short lived and disappeared over time after MI induction and was replaced by a progressive decline in SERCA2a activity [Based on observations of the LV undergoing remodelling after extensive MI, ultimately leading to the development of HF, changes in intracellular Caactivity . If an aOur study indicates that RV failure associated with post-MI left-sided HF in a rat model cannot be explained by abnormalities in cardiomyocytes. Furthermore, a compensatory increase in cardiomyocyte contractility cannot prevent the development of HF. This points to the need for further research to better understand the biology of RV failure, with the consequent development of therapies for this disease.


Sacubitril/valsartan, the first angiotensin receptor neprilysin inhibitor approved by the Food and Drug Administration for marketing, has been shown to reduce the risk of cardiovascular death or heart failure hospitalization and improve symptoms in patients with chronic heart failure with a reduced ejection fraction. However, some researchers have also found that sacubitril/valsartan has an antiarrhythmic effect. The mechanism by which sacubitril/valsartan reduces the mortality associated with malignant ventricular arrhythmias is not precise. Many studies have concluded that ventricular arrhythmia is associated with a reduction in myocardial fibrosis. This article reviews the current understanding of the effects of sacubitril/valsartan on the reduction of ventricular arrhythmia and explains its possible mechanisms. The results of this study suggest that sacubitril/valsartan reduces the occurrence of appropriate implantable cardioverter-defibrillator shocks. Meanwhile, sacubitril/valsartan may reduce the occurrence of ventricular arrhythmias by affecting 3 pathways of B-type natriuretic peptide, Angiotensin II, and Bradykinin. The conclusion of this study is that sacubitril/valsartan reduces the number of implantable cardioverter-defibrillator shocks and ventricular arrhythmias in heart failure with reduced ejection fraction patients. Research into the use of sacubitril/valsartan for treating heart failure has made substantial progress, including positive results from many large-scale clinical trials, such as the PARADIGM-HF trial ,3 and the PARAMOUNT trial . However, with the widespread use of sacubitril/valsartan, some researchers have found that sacubitril/valsartan reduced the incidence of ventricular arrhythmia in patients. This leads to the question of whether sacubitril/valsartan has the value of clinical application as an antiarrhythmic drug. This review supplements the previous review and aims to evaluate the potential antiarrhythmic uses of sacubitril/valsartan and elucidate their possible mechanisms.In recent years, angiotensin receptor neprilysin inhibitor (ARNI) has gradually replaced angiotensin-converting enzyme inhibitors (ACEI) to become the cornerstone of treatment for heart failure and a reduced ejection fraction since ARNI was better at reducing the risk of cardiac death. Sacubitril/valsartan, the first ARNI approved by the Food and Drug Administration, is mainly composed of sacubitril and valsartan in the form of a sodium salt complex in a 1:1 ratio. Desai et al think the reduction in both sudden cardiac deaths and deaths from worsening heart failure was probably due to the modification of the substrate for fatal ventricular arrhythmias such as myocardial fibrosis, ventricular hypertrophy, and progressive ventricular remodeling. However, no clinical trials have been conducted to verify these hypotheses. Until 2018, prospective research found that the application of sacubitril/valsartan decreased ventricular arrhythmias and appropriate implantable cardioverter-defibrillator (ICD) shocks in HFrEF patients under home monitoring compared with angiotensin inhibition. Subsequently, some scholars proposed the hypothesis of sacubitril/valsartan as an antiarrhythmic drug and believed that applying sacubitril/valsartan in combination with other drugs to treat heart failure would narrow the additional survival benefit provided by an ICD. Researchers believe that the need for cardiac implantable devices  in patients with HFrEF could be reduced significantly by treatment with sacubitril/valsartan. Dominguez et al think that the improvement in left ventricular reverse remodeling and ejection fraction after the use of sacubitril/valsartan decreased the need for ICD implantation. However, other researchers believe that clinical decision making cannot merely be based on echocardiographic results. The evaluation of a patient’s risk of arrhythmia should be the first choice.Sacubitril/valsartan is mainly used in patients with chronic heart failure with a reduced ejection fraction (HFrEF). Therefore, current research on the antiarrhythmic effect of sacubitril/valsartan has focused on this patient population. In 2014, the PARADIGM-HF trial concluded that sacubitril/valsartan was superior to enalapril in reducing the risks of death and hospitalization for heart failure, but the specific mechanism was not fully elucidated at that time. Compared with enalapril therapy, sacubitril/valsartan therapy led to improved left ventricular ejection fraction (LVEF), reduced ventricular arrhythmia inducibility, and upregulated the expression of K + channel proteins.P < .001]).,12–14 Similarly, a 6-minute walk test and echocardiographic evaluation of patients who underwent both ICD implantation and sacubitril/valsartan showed that even in ICD patients with a higher risk of arrhythmia, clinical, and functional improvements were significantly improved.Regarding whether the initiation of sacubitril/valsartan is associated with fewer ICD interventions, we selected 4 studies for data analysis , and the results are presented in a forest plot Fig. . As can  report 6 cases of arrhythmic storm shortly after the initiation of sacubitril/valsartan, but the outcome is not enough to infer a cause-and-effect relationship between taking sacubitril/valsartan and arrhythmia due to the small sample size. Soon after, other researchers also reported cases of ventricular arrhythmia during the application of sacubitril/valsartan. Similarly, in 2019, a retrospective study found that sacubitril/valsartan did not reduce the risk of ventricular arrhythmias in chronic HFrEF over 1 year of follow-up. Somberg and Molnar believed that the patients included in the experiment of Vicent et al were very sick patients, all of whom were more likely to develop arrhythmia, the arrhythmia storm after drug initiation, and could have been a coincidence. Additionally, a study by Gatti et al showed that sudden cardiac death occurred early after sacubitril/valsartan administration. While Vincent et al believe that the antiarrhythmic effect of sacubitril/valsartan is unquestionable, an initial proarrhythmic effect in a subgroup of patients could still occur. At the same time, more patients who develop ventricular arrhythmia after sacubitril/valsartan administration have been reported. Discontinuing sacubitril/valsartan and switching to essential and conventional medications may better control ventricular arrhythmia in some patients.On the contrary, Vicent et al In addition, de Carlos et al showed that sacubitril/valsartan reduced the incidence of sudden cardiac death caused by ventricular tachycardia. The mechanisms underlying this effect include recovery of contractile function, reduced fibrosis, reduced wall stress, and reconstruction of ion channels.Prospective research evaluated chronic heart failure patients with LVEF ≤ 40% by comparing electrocardiographic parameters and the mechanical dispersion index before and after sacubitril/valsartan therapy. In conclusion, sacubitril/valsartan therapy has a reductive effect on the QTc interval, QRS duration, and mechanical dispersion index. Patients who received a higher initial dose of sacubitril/valsartan tended to have a better recovery of left ventricular function. In patients whose left ventricular function has recovered, a gradual decrease in the dose of sacubitril/valsartan is associated with deterioration of restored cardiac function. The results of the PARADIGM-HF trial showed that LVEF was an effective predictor of prognosis in patients with heart failure, and that the use of sacubitril/valsartan significantly reduced cardiovascular mortality and the number of hospitalizations due to heart failure. Sudden cardiac death in patients with heart failure is primarily associated with the occurrence of ventricular arrhythmia. Although the current research results show that sacubitril/valsartan can reduce the occurrence of ventricular arrhythmia, more evidence is needed to support the clinical use of sacubitril/valsartan as an antiarrhythmic drug.Sacubitril/valsartan improves LVEF and significantly reduces emergency treatment rate in patients with HFrEF.Studies were identified by searching electronic databases (Emabase and PubMed) from their inception to January 20, 2022. Our search query in Pubmed is ) AND ((“heart ventricles”[MeSH Terms] OR ventricular[Text Word]))) AND  OR  OR Arrythmia[Text Word]) OR )). No language restriction was applied. The reference lists of identified articles were also reviewed to identify additional citations.Studies with the following characteristics were considered eligible: included patients are taking sacubitril/valsartan; using implantable cardioverter-defibrillator (ICD) to monitor the incidence of arrhythmias and ICD shocks in patients taking sacubitril/valsartan; and the number of ICD shocks before and after taking sacubitril/valsartan was compared. Case reports, case series, conference presentations, reviews, and expert opinions were excluded from our analysis.Two investigators (Z.W. and M.Z.) independently screened all titles, abstracts and manually searched the full text of all relevant studies that met the inclusion criteria. Included articles were independently reviewed by each investigator, and disagreements were resolved by discussion. A total of 90 studies were identified using specified search criteria. After a detailed evaluation of these studies, 4 relevant studies that met our predefined eligibility criteria were included Fig. .2 was used to test for heterogeneity between studies and I2 ≤ 25% was assumed to indicate homogeneity. Results that met these criteria were then included in the fixed-effects model.Data were analyzed using RevMan 5.4 software. I,12–14 Similarly, the conclusion of the PARADIGM-HF trial showed that sacubitril/valsartan reduces the patient’s risk of death. However, the mechanism underlying the reduction of ventricular arrhythmia has not been fully elucidated. A study investigating the effect of sacubitril/valsartan on the occurrence of ventricular arrhythmia in a rat model of myocardial infarction heart failure found that the recovery of myocardial fibrosis may explain the reduced ventricular arrhythmia inducibility, which may partly explain the mechanisms of decreased sudden cardiac death in the PARADIGM-HF trial. Another study showed that ARNI ameliorates postinfarction ventricular arrhythmias in rats with ischemic cardiomyopathy through sympathetic nerve remodeling and structural remodeling. In a study on rabbits, sacubitril/valsartan reduced fibrosis and the expression of phosphorylated calcium/calmodulin-dependent protein kinase II protein. Related to this is that some fibrosis formations are Ca2+-dependent. Previous studies have shown that sacubitril/valsartan reduces ventricular arrhythmias by changing the ion concentration and ion channels. Here, we describe the mechanism by which sacubitril/valsartan reduces arrhythmia by reducing myocardial fibrosis.The effect of sacubitril/valsartan in reducing ventricular arrhythmia involves neprilysin and renin-angiotensin-aldosterone system (RAAS) inhibition. Both involve many pathways. Therefore, the exact mechanism of the effect of sacubitril/valsartan in reducing ventricular arrhythmia is very complicated. Previous research has shown that the initiation of sacubitril/valsartan administration could reduce ventricular arrhythmia. Many of these mechanisms are associated with the structural and molecular changes in cardiomyocytes, including myocardial fibrosis is one of them. Various studies have shown that fibrosis plays an essential role in cardiac arrhythmias.,34 Furthermore, improving myocardial fibrosis with sacubitril/valsartan may reduce the occurrence of ventricular arrhythmias. On the other hand, after entering the human body, sacubitril/valsartan is decomposed into sacubitril and valsartan, which are further metabolized into LBQ657 to play a role in inhibition of neprilysin. However, >50 putative peptide substrates of neprilysin have been proposed until 2016. Many of these proteins have unclear functions. The substrates of cardiorenal neprilysin include natriuretic peptides, angiotensin, endothelin, adrenomedullin, and bradykinin. Sacubitril/valsartan works by inhibiting the function of neprilysin by reducing the degradation of these substances. Moreover, valsartan inhibits angiotensin type 1 (AT1) receptor. In general, sacubitril and valsartan synergistically inhibit myocardial fibrosis and ventricular arrhythmia via different mechanisms.On the one hand, ventricular arrhythmia can be induced by impulse initiation and impulse propagation abnormalities, including many mechanisms.,39 Therefore, the mechanism by which sacubitril/valsartan reduces ventricular arrhythmia is described in 3 sections.Accordingly, the majority of studies on the mechanism of ventricular arrhythmia reduction while taking sacubitril/valsartan are based on the changes in the bioactive peptides mentioned above. Among these 5 substrates, endothelin and adrenomedullin increase ventricular arrhythmia. BNP is released mainly by ventricular myocytes in precursor hormone form, which is then cleaved into 2 parts: BNP and N-terminal pro-BNP. The main effects of BNP are diuresis and natriuretic and vasodilator effects.Three main natriuretic peptides are produced by the human body: atrial natriuretic peptide, B-type natriuretic peptide (BNP), and C-type natriuretic peptide. Atrial natriuretic peptide and C-type natriuretic peptide have a short half-life, and BNP plays a significant role in regulating cardiovascular physiology.,43 Some studies have shown that a decrease in myocardial fibrosis and electrophysiological remodeling reduces the occurrence of ventricular arrhythmia.,45 At the same time, injection of exogenous BNP also showed that recombinant human BNP improved cardiac function, increased ejection fraction, dilated vessels, and had antifibrotic effects. In addition, a meta-analysis defining the predictors of sudden cardiac death and ventricular arrhythmia in patients with ICD found that high baseline BNP or N-terminal pro-BNP levels were independently associated with the occurrence of ventricular tachyarrhythmia.BNP is a well-recognized predictor of sudden cardiac death in heart failure patients with impaired LVEF or heart failure with ischemic disease because it is directly related to the progressive deterioration of heart failure. Current research suggests that the antifibrotic effect of BNP is related to guanylate cyclase. After binding to the corresponding receptors, BNP catalyzes the conversion of guanosine triphosphate to guanosine cyclophosphate by activating guanylate cyclase. After guanylate cyclase activation, cyclic guanosine monophosphate is produced in large quantities. Protein kinase G (PKG) is activated to act on the effector protein phospholamban and protein kinase C, increasing sarcoplasmic reticulum calcium uptake through phospholamban phosphorylation, and has a synergistic effect with valsartan in inhibiting protein kinase C channels, which ultimately leads to the reduction of cardiac fibrosis. However, its specific mechanism of action in the nucleus remains unclear.,49–52Gene deletion experiments in mice have indicated that BNP preventing cardiac fibrosis. After entering the human body, valsartan inhibits the actions of angiotensin II (Ang II) by antagonizing the AT1 receptor, thus reducing blood pressure, reversing cardiac remodeling, and playing a therapeutic role in heart failure. The aforementioned studies have shown that RAAS activation promotes ventricular fibrosis. These findings suggest a direct interaction between the RAAS and cardiac fibroblasts. Myocardial fibrosis can be prevented by inhibiting RAAS.Long-term myocardial fibrosis and cardiac remodeling can increase the occurrence of malignant arrhythmias. Metalloproteinase I is a critical enzyme that degrades the fibrous collagen in the interstitium of the heart. Its inhibition leads to the excessive accumulation of collagen, which in turn leads to myocardial fibrosis. Similarly, in cultured adult cardiac fibroblasts, Ang II and aldosterone have been shown to stimulate collagen synthesis and Ang II inhibits the activity of metalloproteinase I.A previous study found that Ang II could stimulate collagen synthesis and inhibit matrix metalloproteinase I activity, thus leading to excessive collagen accumulation and causing structural changes in myopathy. Ang II-induced AT1 receptor activation stimulates a variety of intracellular signaling pathways through G proteins, including phospholipase C, phospholipase D, phospholipase A2, Ca2 + channels, adenylate cyclase (AC), and mitogen-activated protein kinase.AT1 receptor binding of Ang II also activates tyrosine kinase phosphorylation and phospholipase C, leading to the activation of downstream signals, such as mitogen-activated protein kinase, ultimately leading to other cellular effects of gene transcription changes. Ang II activation of the AT1 receptor leads to the opening of Ca2 + channels and extracellular Ca2 + into cells.,59 More importantly, the combination of sacubitril and valsartan synergistically prevented myocardial cell death, showing that valsartan enhanced the effect of sacubitril.After Ang II acts on cardiomyocytes, the AT1 receptor in the cardiomyocytes is activated, and then the signal is transmitted to phospholipase C through the G protein. Phospholipase C transfers 4,5-bisphosphate phosphatidylinositol, which is hydrolyzed into inositol triphosphate and diacylglycerol. Then, diacylglycerol activates protein kinase C, which acts on the nucleus to produce biological effects. Simultaneously, inositol triphosphate acts on the nuclear inositol triphosphate receptor, causing the intracellular Ca2 + concentration to increase. Intracellular Ca2 + and calmodulin combine to form the calcium/calmodulin-dependent protein kinase II. Then, calcium/calmodulin-dependent protein kinase II acts on the effector protein to produce biological effects. Bradykinin is a substrate of both angiotensin-converting enzymes and neprilysin. Studies have suggested that neprilysin seems to be more critical than the angiotensin-converting enzyme in removing bradykinin from cardiac fibroblasts and cardiomyocytes. There is some evidence that bradykinin may play a role in the therapeutic benefits of sacubitril/valsartan therapy and angioedema associated with this therapy. Furthermore, studies have shown that bradykinin promotes vasodilation, prevents ischemia and fibrosis, and highlights its cardioprotective effects. These effects may be related to the reduction in ventricular arrhythmia.,64 Bradykinin is a nonapeptide produced by the cleavage of high-molecular-weight kininogen after factor XII (FXII) and prekallikrein (PK) in plasma are activated to form FXIIa and PKa. After bradykinin is produced, it acts mainly on 2 receptor subtypes, B1 and B2. The B1 receptor mainly mediates the pain-causing effect of kinin, while the B2 receptor mainly mediates vasodilation. Current research suggests that bradykinin acts through G-protein-coupled receptors. Bradykinin binds to the B2 receptor to stimulate the release of nitric oxide, prostaglandin I2, and endothelium-dependent hyperpolarizing factor, resulting in a strong vasodilation effect. Although bradykinin’s vasodilatory effect benefits the heart, its accumulation also leads to angioedema. Because neprilysin inhibition involves variable peptides and many pathways, the precise mechanisms of the ventricular arrhythmia reduction effects of neprilysin inhibition are complex and poorly defined. Further research is required to elucidate this mechanism.Neprilysin degrades several peptides, including bradykinin.In general, sacubitril and valsartan may reduce the occurrence of myocardial fibrosis and ventricular arrhythmia through the BNP, angiotensin II, and bradykinin pathways. Among them, the result of acting on the BNP and angiotensin II pathways is fibrosis reduction, and the result of acting on the bradykinin pathway is vasodilation. Subsequently, vasodilation can eventually lead to a reduction in cardiac afterload and the occurrence of ventricular arrhythmias Fig. .Although the positive effects of sacubitril/valsartan in patients with heart failure have been widely confirmed, there are still some problems with its clinical application. Ferre-Valverdu et al studied 322 patients with HFrEF treated with sacubitril/valsartan. The results showed that 12.4% of the patients could not tolerate sacubitril/valsartan owing to the development of symptomatic hypotension, renal dysfunction, gastrointestinal symptoms, and hyperkalemia. Symptomatic hypotension is the main obstacle to achieving the necessary clinical experimental dose, followed by deterioration of renal function, hyperkalemia, and gastrointestinal symptoms. Hypotension that limits the use of heart failure drugs is a common problem in the elderly, and hypotension in the elderly is associated with worse outcomes in heart failure.In the PARADIGM-HF trial, the incidence of hypotension in the sacubitril/valsartan group was 14%, which was significantly higher than that in the enalapril group. think that because Asian people often have a lower body mass index, lower blood pressure, and are more intolerant to the clinical dose of ACEIs/ARBs, this population may not be able to tolerate the dose of sacubitril/valsartan used in clinical trials. At present, the recommended dose given by European research results may not be suitable for Asian populations. A large-scale research is needed to determine the correct dosage of sacubitril/valsartan for Asian populations.Hsu et alPatients with heart failure in the PARADIGM-HF trial were previously treated with ACEI or ARB, but the trial did not address the possibility of safe initiation of sacubitril/valsartan therapy in HFrEF patients who were not sensitive to RAAS inhibition.,22 reported that 6 patients with heart failure developed ventricular arrhythmia after sacubitril/valsartan treatment, which disappeared after drug withdrawal. Similarly, a study by Gatti et al showed that sudden cardiac death occurred early after sacubitril/valsartan administration. These reports raise the question of whether sacubitril/valsartan has an arrhythmogenic effect. However, the patients included in the above studies were relatively ill, and many had ischemic heart disease. One previous study has suggested that changes in myocardial perfusion conditions caused by ischemia may also lead to arrhythmias. Therefore, more clinical studies are needed to confirm the validity of this finding.Although sacubitril/valsartan can reduce ventricular arrhythmia, Vicent et al,75Long-term use of sacubitril/valsartan inhibits neprilysin, which plays an essential role in degrading the β-amyloid protein. Therefore, sacubitril/valsartan could result in amyloid deposition in the brain, raising concerns about whether the drug will increase the risk of Alzheimer disease. Clinical studies are underway to assess whether the drug affects cognitive function, and the results are expected to be published soon.Current research is limited to treating ventricular arrhythmias in patients with HFrEF, and the use of sacubitril/valsartan in patients with heart failure with preserved ejection fraction is still at the research stage. Therefore, the scope of the antiarrhythmic application of sacubitril/valsartan is currently limited, and more clinical trial results are needed to determine whether sacubitril/valsartan can be used to treat ventricular arrhythmia.The clinical use of sacubitril/valsartan has dramatically improved the prognosis of patients with HFrEF and reduced the incidence of sudden death in patients with heart failure. Reduction in myocardial fibrosis may be one of the reasons for the reduction in ventricular arrhythmia. Furthermore, the reduction of ventricular arrhythmia caused by sacubitril/valsartan may be vital in reducing the rate of sudden death in patients with heart failure. Collectively, sacubitril/valsartan reduced the occurrence of ventricular arrhythmia in multiple ways. However, further studies are needed to elucidate the complex mechanisms by which sacubitril/valsartan changes the electrophysiology of the heart. At the same time, the potential proarrhythmic effects of sacubitril/valsartan reported in some studies need to be confirmed in more studies.Z.W. conceived, wrote, and revised the manuscript. M.Z., Q.Z., L.G., X.W., and Z.W. participated in the discussion and provided suggestions. M.G. provided financial support for writing the manuscript and the proposed amendments. Z.Z. provided guidance for writing the manuscript. All authors have read and approved the final manuscript.


A 37-year-old woman with atypical chest pain was referred to Emergency Department for clinical evaluation. Vital signs at admission were stable, and the physical exam was normal.Panel A). Transthoracic echocardiography showed hypokinesis of the mid-anterior septum, anterior, and inferior walls with preserved ejection fraction (Panel B). Relevant laboratory tests included elevated high sensitivity troponin-I of 3176 ng/L  and B-type natriuretic peptide of 276 pg/mL .ECG showed only biphasic T wave in V3 (Panel C).The patient was diagnosed with non-ST segment elevation myocardial infarction and addressed to invasive coronary angiography, with the evidence of non-obstructive coronary artery disease. Left ventriculography identified hypokinesia of mid-left ventricular segments and hyperkinesia of apical and basal segments (Panel D). At tissue characterization, while traditional T2-weighted (Panels E and F) and late gadolinium enhancement (Panel G) imaging did not show abnormalities, mapping sequences detected a marked increase of native T1 , T2 , and extracellular volume (ECV)  values at all mid-ventricular segments, particularly at anterior, septal, and inferior walls. All these findings were related to the presence of oedema, then supporting the diagnosis of mid-ventricular Takotsubo cardiomyopathy (TC).Cardiac magnetic resonance (CMR) confirmed hypokinesia of all mid-ventricular segments and preserved contraction of apical and basal segments (The apical ballooning pattern in TC is seen in the majority of patients. A very small group of TC presents with atypical features such as mid-ventricular patterns. In this case, CMR was crucial to identify not only peculiar wall motion abnormalities but also to detect, thanks to mapping sequences, the underlying tissue damage, thus leading to the correct diagnosis.


Patients with Q-STE ≥ 2 leads  displayed lower MACE-free survival, more depressed LVEF, and larger IS at 6-month CMR . Residual ST-segment elevation after STEMI represents a universally available tool that predicts worse long-term clinical and CMR-derived structural outcomes.Residual ST-segment elevation after ST-segment elevation myocardial infarction (STEMI) has traditionally been considered a predictor of left ventricular (LV) dysfunction and ventricular aneurism. However, the implications in terms of long-term prognosis and cardiac magnetic resonance (CMR)-derived structural consequences are unclear. A total of 488 reperfused STEMI patients were prospectively included. The number of Q wave leads with residual ST-segment elevation > 1 mm (Q-STE) at pre-discharge ECG was assessed. LV ejection fraction  and infarct size  were quantified in 319 patients at 6-month CMR. Major adverse cardiac events (MACE) were defined as all-cause death and/or re-admission for acute heart failure (HF), whichever occurred first. During a mean follow-up of 6.1 years, 92 MACE (18.9%), 39 deaths and 53 HF were recorded. After adjustment for baseline characteristics, Q-STE (per lead with > 1 mm) was independently associated with a higher risk of long-term MACE (HR 1.24 [1.07–1.44] per lead,  Systematic echocardiography performed before discharge should be recommended given the valuable prognostic information yielded by left ventricular (LV) ejection fraction (LVEF)6.Despite the spectacular improvement in prognosis of patients with ST-segment elevation myocardial infarction (STEMI) during recent decades8. Residual ST-segment elevation after STEMI has conventionally been interpreted as predicting LV dysfunction and aneurysm10. More recently it has also been associated with more severe structural consequences in cardiac magnetic resonance (CMR) performed soon after STEMI12. Presence of Q waves on the presenting ECG or its development after STEMI have also been associated with worse clinical outcomes15 and more adverse early CMR-derived structural parameters17.Electrocardiogram (ECG) is the paradigmatic non-invasive, inexpensive and universally available tool for risk stratification after STEMI. ST-segment resolution is a well-established predictor of coronary reperfusion and prognosisHowever, the contribution of pre-discharge ECG to predict long-term adverse events and the structural consequences in CMR performed late after STEMI is unclear. The aim of this study was to evaluate the relationship of combined Q wave and residual ST-segment elevation (Q-STE) with long-term cardiovascular events and CMR-derived LVEF and infarct size (IS).3 and scheduled to undergo CMR 6 months after infarction. Out of 488 prospectively recruited patients, 6-month CMR was performed in 319. The exclusion criteria were death (n = 9) or severe clinical instability (n = 7) before 6-month CMR. Unavailable or incomplete CMR studies (n = 49) or any contraindications to CMR (n = 17) were also criteria for exclusion. Other reasons for non-performance of 6-month CMR were medical decision (n = 58) or patient rejection (n = 29). The final study group therefore comprised 488 patients for evaluating the relationship between residual ST-segment elevation and long-term cardiovascular events, and 319 to evaluate the association of residual ST-segment elevation with LVEF and IS at 6-month CMR. The patient flowchart can be consulted in Supplementary Fig. From 2012 to 2017, discharged STEMI patients treated with percutaneous coronary intervention were referred to a specific STEMI outpatient clinic, managed following current recommendations19. The study protocol conforms to the principles of the Declaration of Helsinki and was approved by the local Human Research Ethics Committee. Patient informed consent was obtained.This study is part of an ongoing STEMI registry of which several analyses have been previously reportedPatient characteristics including Killip class at admission, peak creatine kinase MB mass, Thrombolysis in Myocardial Infarction (TIMI) flow grade in the culprit artery (before and after reperfusion) and the Global Registry of Acute Coronary Events (GRACE) and TIMI scores were recorded.Standard 12-lead electrocardiogram (ECG) was recorded in all patients at admission, at 90 min, 6, 24, 48, and 96 h after primary percutaneous coronary intervention (pPCI), and at pre-discharge. We used a standard calibration of the ECG (10 mm/mV amplification and paper speed of 25 mm/s). ECG data was retrospectively evaluated by an independent observer blinded to clinical and angiographic data.12. Maximum and minimum sum of ST-segment elevation (sum-STE) before and after pPCI and at any time were quantified in mm and calculated in V1 to V6, I and aVL leads for anterior infarction and II, III, aVF, V5 and V6 for non-anterior infarction. ST-segment resolution (STR) was defined as the percentage reduction in the sum-STE from baseline (ECG on admission) to 90 min after pPCI. Finally, the number of leads with Q wave and residual STE > 1 mm (Q-STE) at pre-discharge ECG were registered.ST-segment elevation (STE) was measured manually in every lead 20 ms after the J-point, in accordance with previous studies11. (2) In the hierarchical multivariable model, Q-STE emerged as the ECG index most potently associated with the pre-defined clinical and CMR-derived endpoints.In the present study, we focused our analyses on the impact of residual ST-segment elevation (as derived from the number of leads with Q-STE at pre-discharge ECG). The rationale underpinning this assessment was as follows: (1) Residual ST-segment elevation in Q wave leads has been previously used and validated by our group as a marker of short-term prognostic and structural outcomes after STEMI11.Q-STE ≥ 2 leads was used for dichotomic analyses. This approach uses the best Youden index-derived cut-off point applied to the receiver operating characteristic analysis of Q-STE to predict clinical and structural endpoints. This same definition has been previously used by our group to predict the short-term consequences of STEMIAll patients were studied with pre-discharge (5 ± 2 days post-STEMI) echocardiography, carried out by local cardiologists who quantified parameters and prospectively included the data in the database. LVEF (%), LV end-diastolic volume (mL) and LV end-systolic volume (mL) were assessed using the biplane method of disks (modified Simpson’s rule). Tricuspid annular plane systolic excursion (mm), as a proxy of right ventricle function, was measured in the apical 4-chamber view by means of M-mode. A wave velocity (m/s), E wave velocity (m/s), and left atrium diameter (mm) were also recorded.Six-month CMR (197 [181–232] days) was performed in a subgroup of 319 patients, following the exclusion criteria depicted in Supplementary Fig. 18. Images were acquired by phased-array body surface coil during breath-holds and were ECG triggered. Studies were interpreted by local cardiologists specialized in CMR imaging with > 15 years of experience.Patients were examined with a 1.5 T system  according to a previously described standard protocolCine images were acquired in two-, three-, and four-chamber views, and in short-axis views using a steady-state free precession sequence .LV end-diastolic volume index , end-systolic volume index  and LVEF (%) were quantified by manual planimetry of endocardial and epicardial borders in short-axis view cine images.Late gadolinium enhancement imaging was performed 10 min after administering gadolinium-based contrast in the same locations as in the cine images using a segmented inversion recovery steady-state free precession sequence . Inversion time was adjusted to nullify normal myocardium. IS was measured by manual planimetry and defined as percentage of LV mass showing late gadolinium enhancement.20. Clinical cardiologists prospectively adjudicated events by periodic electronic regional health system registry review.The primary endpoint of the study was MACE (major adverse cardiovascular events), defined as all-cause mortality or re-admission for acute heart failure, whichever occurred first. Current criteria for acute heart failure were used21.We measured two adverse structural endpoints at 6-month CMR: LVEF < 40% was used to define patients with reduced LV systolic function at chronic phase, while IS > 30% of LV mass was used to select patients with large myocardial infarction. The deleterious prognostic effects of these indexes and the respective cut-off points applied have already been validated by our study group in the same patient seriesThe one-sample Kolmogorov–Smirnov test was used to test normal data distribution. For continuous parametric variables, data are expressed as mean ± standard deviation and analysed by Student’s t test. Continuous non-parametric variables are shown as median plus interquartile range and compared with Mann–Whitney U test. Qualitative variables are presented as percentages and compared by chi-square test or Fisher’s exact test.Univariate analyses were performed to identify baseline, echocardiographic and ECG variables associated with clinical (MACE) and structural (LVEF < 40% and IS > 30% at 6-month CMR) endpoints.p value < 0.1 in univariate analysis were included as cofactors in multivariate analysis. Hierarchical models were used to avoid overfitting of variables. Model 1 included only baseline characteristics. In Model 2, variables of Model 1 plus echocardiographic indices were used. In Model 3 , variables of Model 2 plus ECG indices were tested.The association of baseline, echocardiographic and ECG variables before discharge with time to first MACE was assessed by means of multivariable Cox proportional hazard regression models. Results are presented as hazard ratio (HR) and 95% confidence interval (CI). Variables with A multivariate binary logistic regression model using the same methodology was performed to assess the association of variables with 6-month CMR structural (LVEF < 40% and IS > 30% at 6-month CMR) endpoints.p < 0.05.The SPSS statistical package version 20.0  and STATA version 9.0  were used for statistical analysis. Statistical significance was set at The study protocol was approved by the Drug Research Ethics Committee of the Hospital Clínico Universitario of Valencia. Patient informed consent was obtained.We included 488 patients in our registry. Baseline characteristics are displayed in Table Pre-discharge echocardiographic and ECG variables are shown in Table p = 0.004). Hypertension, previous CAD, GRACE, and echocardiographic LVEF were also independently associated with MACE  cases of MACE . In hierarchical multivariable analysis, the number of leads with Q-STE > 1 mm at pre-discharge ECG was the most potent ECG predictor of MACE  experienced MACE during follow-up, compared to 47 out of 316 (14.9%) patients with Q-STE in 0–1 leads. The adjusted survival curves are displayed in Fig. p = 0.04) and large (> 30% of LV mass) IS  at 6-month CMR (Supplementary Tables p < 0.001) and large IS  at 6-month CMR.In hierarchical multivariable analysis, the number of leads with Q-STE > 1 mm at pre-discharge ECG was the most potent ECG predictor of reduced (< 40%) LVEF and large (> 30% of LV mass) IS. After adjustment for baseline and ECG characteristics, the number of leads with Q-STE was independently and positively associated with risk of reduced (< 40%) LVEF  and more extensive IS (24.9 ± 11.6% vs. 14.4 ± 11.4%) at 6-month CMR .Among patients with Q-STE ≥ 2 leads, 22.7% (n = 27) displayed LVEF < 40% and 33.9% (n = 41) had IS > 30% of LV mass at 6-month CMR, compared to 9.1% (n = 18) and 9.1% (n = 18) in patients with Q-STE in 0–1 leads, respectively  is non-negligible in recent registries3, which highlights a need for early risk stratification of STEMI patients. Several combined risk scores such as the GRACE and TIMI scores have been developed for this purpose3. Age is a relevant predictor of prognosis since older patients are more likely to experience all-cause death or other adverse outcomes. Nonetheless, validation of easy-to-obtain and broadly available indexes for accurate prediction of long-term clinical and structural outcomes after reperfused STEMI is still of utmost importance.Current management strategies in STEMI, including widespread primary percutaneous coronary intervention and optimized medical treatment, have delivered remarkable improvements in patient prognosis22.LVEF by echocardiography is the cornerstone of non-invasive imaging risk stratification after STEMI, and lower pre-discharge values have been associated with an increased long-term risk of death and re-admission for heart failure24, permitting highly accurate and reproducible quantification of systolic function and IS in this setting. In recent years, we and other authors have demonstrated the solid prognostic value of CMR-derived LVEF and IS26. Unfortunately, restrictions deriving from availability, costs and need for expertise limit the generalized use of CMR.CMR has become the most reliable and reproducible method for a comprehensive evaluation of the structural consequences of STEMIElectrocardiography represents a non-invasive, lower cost, and universally attainable test that is sequentially performed in every STEMI patient. In the present study, we evaluated the long-term prognostic value of residual ST-segment elevation (as derived from the number of leads with Q-STE at pre-discharge) beyond traditional baseline and echocardiographic risk stratification. Additionally, we tested the value of this index to predict CMR-derived LVEF and IS in chronic phase after STEMI.7. Lower percentage post-reperfusion ST resolution29 and higher residual ST-segment elevation, either sum30 or residual single-lead ST-deviation29, have been associated with worse short-term clinical outcomes after reperfused STEMI31. Also, Q waves (either on the presenting ECG or developing after STEMI) have also been associated with worse clinical outcomes15 and more adverse early CMR-derived structural parameters17.ST-segment resolution has been widely used as a proxy for successful coronary reperfusionOur findings show that assessment of the number of Q wave leads with residual ST-segment elevation > 1 mm (Q-STE) at pre-discharge ECG permits immediate, robust long-term risk prediction above and beyond routine clinical and echocardiographic stratification. After adjustment, the extent of Q-STE (per number of leads) at pre-discharge appeared as an independent predictor of MACE over a 6.1-year mean follow-up. Moreover, Q-STE outperformed the rest of the collected ECG indexes for this purpose and the cut-off point proposed (Q-STE ≥ 2 leads) identified patients at high risk of MACE in a long-term perspective.35. Absence of ST-segment resolution has been associated with lower pre-discharge echocardiography-derived LVEF9. We and others have previously shown that residual ST-segment elevation associates with larger IS, more microvascular obstruction, less myocardial salvage, lower LVEF, and larger indexed LV volumes in CMR performed soon (1 week) after STEMI12 as well as more extensive IS by single-photon emission computed tomography31. However, the value of residual ST-segment elevation at pre-discharge ECG to predict CMR-derived LVEF and IS in chronic phase was unknown.The deleterious effects of depressed LVEF and large IS are largely acknowledged, and as derived from CMR in chronic phase after STEMI, these indexes represent the cornerstone for evaluating the overall structural cardiac consequences of myocardial infarctionOur study is the first to explore in STEMI patients the association of pre-discharge ECG indexes with the long-term (6-month) CMR-derived structural consequences. Extent of Q-STE (per number of leads) was independently associated with reduced (< 40%) LVEF and large (> 30% of LV mass) IS, and the presence of Q-STE in ≥ 2 leads at pre-discharge ECG permitted good discrimination of patients at highest risk of severe structural deterioration at follow-up CMR.As a primary limitation, referral bias cannot be excluded due to the observational nature of our study and the retrospective revision of several variables. Second, this is a single-centre study and patients referred for 6-month CMR may not be entirely representative of the whole STEMI population. Prospectively designed studies could overcome these limitations. Third, several biochemical and cardiac imaging parameters that could have shown additional prognostic value were not collected. Last, changes in treatment could have influenced clinical and/or structural outcomes, requiring an in-depth analysis of the effect of therapies that is beyond the scope of the present study.Analysis of the number of Q wave leads with residual ST-segment elevation at pre-discharge ECG represents an easy-to-obtain and universally obtainable parameter which contributes rapid, valuable data on the risk of MACE, depressed LVEF and large IS at long-term follow-up. This justifies further exploration of the clinical implications of these findings, to guide more intensive follow-up, selective use of other non-invasive tests and improved therapeutic strategies.Supplementary Information.


Right heart failure (RHF) can occur as the result of an acute or chronic disease process and is a challenging clinical condition for surgeons and interventionalists to treat. RHF occurs in approximately 0.1% of patients after cardiac surgery, in 2–3% of patients following heart transplantation, and in up to 42% of patients after LVAD implantation. Regardless of the cause, RHF portends high morbidity and mortality and is associated with longer hospital stays and higher healthcare costs. The mainstays of traditional therapy for severe RHF have included pharmacological support, such as inotropes and vasopressors, and surgical right ventricular (RV) assist devices. However, in recent years catheter-based mechanical circulatory support (MCS) strategies have offered novel solutions for addressing RHF without the morbidity of open surgery. This manuscript will review the pathophysiology of RHF, including the molecular underpinnings, gross structural mechanisms, and hemodynamic consequences. The evolution of techniques for supporting the right ventricle will be explored, with a focus on various institutional experiences with percutaneous ventricular assist devices. Right heart failure (RHF) is characterized by systemic congestion as a result of reduced right ventricular (RV) forward flow. RHF is a challenging clinical condition that can occur as the end result of chronic disease, including decompensated biventricular heart failure due to cardiomyopathy or left-sided ischemic and valvular diseases, cor pulmonale, and pulmonary hypertension (pHTN). Acute processes such as myocardial infarction, postcardiotomy cardiogenic shock, massive pulmonary embolism, heart transplantation, and left ventricular assist device (LVAD) implantation can also lead to acute RHF –4. CliniStandard therapy for severe RHF consists of pharmacological support to improve myocardial contractility, including inotropes and vasopressors, as well as volume unloading and the application of pulmonary vasodilators  . If maxiThis manuscript will review the pathophysiology of RHF and the evolution of mechanical circulatory devices for supporting the RV. The current literature will be surveyed, with a specific emphasis on various institutional experiences with percutaneous RVADs.The RV has long been regarded as the “forgotten” cardiac chamber, as historically the emphasis in both cardiology and cardiac surgery has been placed on the LV and its ejection fraction. Consequently, RHF has historically been a poorly understood pathology, relegated to an afterthought despite substantial advances in the understanding and management of left heart failure. Owing to the complex nature of RHF, the International Right Heart Foundation was convened with the mandate of devising a common language to describe right RHF. The group defined RHF as “a clinical syndrome due to an alteration of structure and/or function of the right heart circulatory system that leads to suboptimal delivery of blood flow (high or low) to the pulmonary circulation and/or elevated venous pressures—at rest or with exercise” . This brTo understand the pathophysiology of RHF, it is necessary to begin with a brief overview of some of the molecular mechanisms that may contribute to remodeling of the RV. Macro- and micro-vascular ischemia have both been implicated in the evolution of RV failure. Under physiologic conditions, the RV is perfused during both systole and diastole by the right coronary artery (RCA). In conditions of increased RV afterload there is systolic flow impediment and the myocardium of the RV only receives blood flow during diastole, making adequate perfusion dependent on lower heart rates and longer filling times. Increases in the RV end-diastolic pressure (RVEDP) and RV hypertrophy decrease coronary perfusion pressure and limit flow to the RV myocardium , 25. ThiThe physical properties of the RV also play an important role in the pathophysiology of RHF. Triangular in shape and crescent on cross-section, the RV has a lower ejection fraction compared to the LV, with a normal range of 40–45%. To generate the same stroke volume and cardiac output, the RV maintains a higher end-diastolic volume . The traThere are four primary mechanisms which underlie the development of acute RHF: contractile failure secondary to myocardial ischemia or inflammation caused by myocarditis, volume overload as a result of right-sided valvular insufficiency, volume overload caused by increased venous return or displacement of the interventricular septum toward the LV after placement of a LVAD, and pressure overload resulting from decompensated left-sided heart failure, worsening pHTN, or acute pulmonary embolism  5, 31)., 31.5, 32 in the absence of elevated left atrial or pulmonary capillary wedge pressure (>18 mmHg), cardiac tamponade, ventricular arrhythmias, or pneumothorax , the RAP-to-pulmonary artery wedge pressure (RAP/PAWP) ratio, RV stroke work index, the pulmonary artery pulsatility index (PAPi), and tricuspid annular plane systolic excursion (TAPSE) , 38. WhiGiven that patients who receive LVADs and develop acute RHF have poor outcomes, there has been significant interest in developing clinical models to better predict which patients are at the highest risk , 43–47. Despite advances in the perioperative management of patients undergoing heart transplantation, acute RHF accounts for a significant number of early complications and early deaths . MultiplIn cases where acute RHF results from a mechanical insult in the perioperative setting, such as graft occlusion following CABG, compression of the PA, or stricture at the PA anastomosis , surgical or procedural interventions to address the underlying cause may be sufficient to improve the function of the failing ventricle. Pharmacotherapy for acute RHF focuses on managing volume and preload, improving myocardial contractility, and reducing RV afterload . Volume Most MCS options for supporting the right heart include cannulation of the RA and the PA to deliver flow into and out of a continuous flow pump, respectively. The pressure gradient between the RA pressure (preload) and the PA pressure (afterload) is referred to as the pressure head and varies throughout the cardiac cycle. In patients with severe RHF resulting from acute ischemia or impaired cardiac contractility, the pressure head is often small and for fixed rotations per minute, device flow will be high. Conversely, for patients with RHF caused by severe pHTN, the pressure head may be large, and for the same rotations per minute setting, device flow will be low .There are several relatively new minimally invasive RVAD strategies that enable intervention on the failing RV without the morbidity of open surgery for device removal. Temporary RVAD configurations include venoarterial extracorporeal membrane oxygenation (VA-ECMO), surgically implanted grafts combined with a centrifugal-flow pump, and percutaneous RVADs (pRVAD), including the Impella RP  and the ProtekDuo  cannula. There are currently no U.S. Food and Drug Administration (FDA)-approved long-term implantable devices designed to support the RV. Most reports of long-term RV support have been limited to off-label applications of devices designed and approved for the treatment of advanced LV failure, such as the HeartWare Ventricular Assist Device  and the Heartmate 3  –60. OtheTemporary RVAD configurations can be categorized according to their mechanism of action as either direct or indirect RV bypass systems . The ImpIt should be noted that it is difficult to generalize about the utility of pRVADs in the management of patients with acute RHF owing to the variations in the definition of RHF from study to study. Similarly, institutions may also have different thresholds for initiating MCS in acute RHF. The majority of studies have been retrospective in nature, are limited to single-center experiences, and include small numbers of patients. This prohibits any definitive conclusions from being drawn about the indications for pRVAD use and the potential benefits this device may confer.VA-ECMO is a well-established and effective MCS option for acute RVF, as it can be placed rapidly and peripherally using either a cutdown technique or percutaneous insertion. ECMO provides indirect support to the RV by reducing preload, reducing RV wall tension, and delivering oxygenated blood to the coronary circulation while supporting the systemic circulation and end-organ function , 65. TheThe Impella RP is an intracorporeal axial-flow pRVAD that uses a 22 Fr microaxial continuous-flow pump mounted on an 11 Fr catheter that diverts blood from the RA into the PA. The device is introduced most commonly via a 23 Fr venous peel-away sheath at the right femoral vein over a 0.025 wire under fluoroscopic guidance and sits across the tricuspid valve and RV, with the pump inflow positioned in the inferior vena cava and the pump outflow situated in the PA. The Impella RP can deliver up to 4 L/min of flow and the intended use of the device is 14 days. Unfortunately groin cannulation is easily dislocated, limiting patient mobilization. After removal, the venous access site is closed with manual compression and a purse-string or deep mattress suture. Importantly, the Impella RP cannot be used to oxygenate blood; in the setting of RHF with concomitant hypoxemic or hypercarbic respiratory failure, alternative support strategies should be considered. The Impella RP has been used successfully for RHF in the setting of cardiac surgery and after LVAD placement. The prospective RECOVER RIGHT study investigated the safety and efficacy of the Impella RP in patients with medically refractory RVF  , 18.Following FDA approval of the Impella RP for the treatment of RHF, Continuous Access Protocol (CA) and Post-Approval Study (PAS) assessments were undertaken to monitor the post-market experience and demonstrate the outcome trends of pooled data of all Impella RP clinical studies in patients presenting with acute RHF . This 20Surgically implanted temporary RVADs require sternotomy, followed by anastomosis of grafts to the RA and PA. The grafts are subsequently tunneled obliquely through the chest wall and intercostal spaces, enabling chest closure and ambulation. This strategy employs a continuous centrifugal-flow pump within a circuit that is capable of incorporating an oxygenator, which is referred to as an oxy-RVAD , 69. A vThe ProtekDuo is a dual-lumen cannula percutaneously inserted in the right internal jugular vein that, when connected to a pump, functions as a pRVAD . One lumSeveral case reports and case series have described the use of the ProtekDuo for acute RHF in the setting of LVAD implantation, cardiogenic shock resulting from decompensated severe pHTN, and cardiogenic shock secondary to massive pulmonary embolism –74 Tabl. SchmackIn 2020, Kremer et al. described a series of 10 patients in which the ProtekDuo was used for temporary RV support after acute myocardial infarction and reported a 30-day survival rate of 60% . OliveroA case series by Badu et al. reviewed 40 patients who received RVAD support with the ProtekDuo and compared outcomes among three subgroups based on the indications for RV MCS  . In all,Salna and colleagues from Columbia University retrospectively reviewed their experience with the ProtekDuo in 27 patients who developed severe acute RHF following LVAD implantation . ImplantThe ProtekDuo has also been used in the setting of primary graft dysfunction (PGD) after heart transplant when the PGD was attributed to isolated RV failure. Carrozzini described the application of the ProtekDuo in 3 such cases . All patCoromilas and colleagues compared patients who received pRVAD (19 patients) with those who received sRVAD (21 patients) after implantation of durable LVAD . pRVADs While experience with ProtekDuo cannula continues to grow, it is worth noting that this approach is relatively costly. Our group has moved to an alternative strategy that involves two access sites. We use a long 25 Fr venous cannula from the femoral vein for pump inflow and place a 19 Fr to 23 Fr cannula from the right internal jugular vein into the PA for return. This represents a slight modification from our most common cannulation strategy for venovenous ECMO (VV-ECMO), which uses right femoral vein and right internal jugular vein cannulation. We are comfortable adopting this approach because of our growing experience ambulating patients on VV-ECMO with a long venous cannula in place. Consequently, we do not view a long venous cannula as a contraindication to patient ambulation and participation in physical therapy.Acute RHF remains a major cause of global morbidity and mortality, irrespective of the injurious mechanism. Multiple studies have demonstrated poorer clinical outcomes in patients with RHF in the setting of left-sided heart failure, acute myocardial infarction, pHTN, and following major cardiac surgery. Historically, algorithms for the management of RHF focused on medical therapies to reverse the underlying cause, maintain adequate preload, reduce RV afterload, and enhance RV contractility. The development of MCS strategies to support the failing RV has been critically important to these sick patients, and in many instances life-saving. More recently, pRVAD allow patients to recover from RHF in the ICU setting without the necessity of returning to the operating room for additional procedures once RV function has improved. Even in their nascent use, these minimally invasive strategies have equivalent or better outcomes compared to sRVAD. Surgeons and interventionalists will continue to innovate and improve the quality and safety of devices used to support the failing RV, providing patients the best opportunity for survival.LJ: literature review and writing—original draft, review, and editing. DS: conceptualization and writing—review and editing. Both authors contributed to the article and approved the submitted version.


We aimed to determine sex- and sport-specific normative values of LV dimensions in elite white adult athletes.There is debate about the magnitude of geometrical remodeling [https://sites.google.com/lapolart.es/athlete-lv/welcome?authuser=0) to provide clinicians with sports- and Mitchell’s category-specific Z-scores for different LV dimensions.This was a single-center, retrospective study of Spanish elite athletes. Athletes were grouped by sport and its relative dynamic/static component (Mitchell’s classification). LV dimensions were measured with two-dimensional-guided M-mode echocardiography imaging to compute normative values. We also developed an online and app-based calculator . The majority (85.4%) showed normal cardiac geometry, particularly women (90.9%). Eccentric hypertrophy was relatively prevalent (13.4%), and concentric remodeling or hypertrophy was a rare finding . The proportion of normal cardiac geometry and eccentric hypertrophy decreased and increased, respectively, with the dynamic (in both sexes) or static component  of the sport irrespective of the other (static or dynamic) component. The 95th percentile values of LV dimensions did not exceed the following limits in any of the Mitchell categories: septal wall thickness, 12 mm  and 10 mm ; LV posterior wall, 11 mm and 10 mm; and LV end-diastolic diameter, 64 mm and 57 mm.i.e., those exceeding the 95th percentile for their sex and sport).The majority of elite athletes had normal LV geometry, and although some presented with LV eccentric hypertrophy, concentric remodeling or hypertrophy was very uncommon. The present study provides sport-specific normative values that can serve to identify those athletes for whom a detailed examination might be recommendable (The online version contains supplementary material available at 10.1186/s40798-022-00510-2. The present study, which includes data from 3282 elite white athletes  of 46 different sports, suggests that the great majority (85.4%) of these athletes have normal LV geometry.Although some present with LV eccentric hypertrophy (13.4%), cardiac remodeling and concentric hypertrophy seem very uncommon .Sport-specific normative values of LV dimensions in elite white adult athletes are presented along with an online and app-based calculator, which can serve to easily identify those athletes for whom a detailed examination might be recommendable.Participation in competition sports can induce cardiac tissue adaptations collectively known as “athlete’s heart.” Geometrical remodeling can affect the four cardiac chambers, with specific adaptations at the left ventricle (LV) level usually manifesting as increases in cavity size or wall thickness  of varyii.e., ‘LV hypertrophy’) is commonly found in healthy athletes. Yet, according to a recent review from the American Society of Echocardiography (ASE), LV wall thickness rarely exceeds 13 mm or 11 mm in male and female athletes, respectively ) componentIA, low static (< 20% of maximum voluntary contraction [MVC] and low dynamic (< 40% of maximum oxygen uptake  × LVEDD3; and LV mass (g) = 0.8 × {1.04 [(LVEDD + SWT + LVPW)3 − LVEDD3]} + 0.6, where LVEDD, SWT and LVPW are measured in cm; and LVEF (%) = [(LVEDV – LVESV)/LVEDV] × 100.Septal wall thickness (SWT), LV posterior wall thickness (LVPW), LVEDD, and LV end-systolic diameter (LVESD)  were measured in the parasternal long-axis view, directly from the screen using the scale of the device itself, with the 2D-guided M-mode approach in real time and also guided by the ECG signal in bipolar lead CM5. All the echocardiographic measures corresponding to diastole and systole were obtained coinciding with the start of the QRS complex and with the maximal posterior displacement of the interventricular septum, respectively. Special care was taken when measuring SWT and LVPW to avoid including as part of the wall the different trabeculae both from the LV  and right ventricle ), because inclusion of these structures could erroneously reflect LV hypertrophy. All LV measures were obtained using the mean of three  cardiac cycles. We used the following equations to measure LV end-systolic volume (LVSV), LV end-diastolic volume (LVEDV), LV mass and LV ejection fraction (LVEF), respectively: LVESV (mL) = [7.0/(2.4 + LVESD)] × LVESDE and A wave velocities (both in cm/s).Diastolic function was assessed by measuring the transmitral flow rate  and determining 2 Normal geometry, RWT ≤ 0.42 cm and LV mass/BSA  ≤116  or ≤ 96 g/m2Concentric remodeling, RWT > 0.42 cm and LV mass/BSA ≤ 116 (or 96) g/m2Concentric hypertrophy, RWT > 0.42 cm and LV mass/BSA > 116 (or 96) g/m2Eccentric hypertrophy, RWT ≤ 0.42 cm and LV mass/BSA > 116 (or 96) g/mRelative wall thickness (RWT) was calculated with the formula RWT = (SWT + LVPW)/(LVEDD), which allowed grouping the athletes into four categories :Normal g2, calculated as 0.007184 × height (cm)0.725 × weight (kg)0.425 [LV dimensions were expressed relative to BSA (in mkg)0.425 ). We alskg)0.425 .2max using a breath-by-breath metabolic cart , as detailed elsewhere [In addition, all participants underwent a cardiopulmonary exercise test until volitional exhaustion to determine VOlsewhere , 16. DepWe developed a web application using Google Sheets as a database, Javascript for statistical calculations, and HTML 5 for presentation. The data of the athletes that are entered into the application user interface are statistically evaluated against (but not stored in) our reference database.2 test (or Fisher’s exact test if > 20% of the cells in the cross-table had an expected frequency < 5) was used to compare the proportion of the four types of cardiac geometry between the two sexes and also attending to the dynamic/static component of each sport. Unpaired Student’s t test and one-way analysis of variance (ANOVA) were used for comparisons of LV dimensions for sex and sport category, respectively, with the Bonferroni test used post hoc for pairwise comparisons when a significant group  effect was found. Effect size was determined with partial eta squared  and Cohen’s d (for comparisons of the different LV dimensions) and was considered small (η2p ≥ 0.01 or d ≥ 0.2), medium (η2p ≥ 0.06 or d ≥ 0.5) or large (η2p ≥ 0.14 or d ≥ 0.8) [2max and the different LV dimensions. Finally, for the cardiac dimension variables shown in the App online calculator, we reported Z-scores , where Z = (x – μ)/SD. Statistical analyses were performed with Statistical Package for Social Sciences (SPSS) .Data are shown as mean (standard deviation (SD)), and the 95th percentile (P95) is also shown for each variable, as a measure of the upper limit of normality. The χd ≥ 0.8) . We alsoi.e., within the national team and participating in international events) for 1 to 22 years. The proportion of those with ≤ 1-year experience at such high competition level was essentially minor for all sport categories, especially in male athletes   and 1.68 ± 0.16 m2 (1.18–2.36). Except for male athletes participating in sports with a low (or moderate) dynamic component, the proportion of participants aged > 35 years was low   showed normal cardiac geometry  component. The proportion of normal cardiac geometry and eccentric hypertrophy also showed a significant decrease and increase, respectively, with the static component of the sport in male  allows the determination of sport- and Mitchell-category-specific Z-scores for LV geometry, SWT, LVPW, LV mass/BSA, RWT, and LVEDD and the corresponding percentile value for each of the LV measures in a given healthy adult athlete.The online and app-based calculator  and female  athletes had SWT values > 13 mm and > 11 mm, respectively, with SWT values between 12 and 13 mm found in 1.3% (n = 26) of male athletes. No male or female athlete had LVPW values > 13 mm or > 11 mm, respectively, with seven male athletes (0.3%) presenting values between 12 and 13 mm. Five hundred and fifty-nine (27%) and 280 female (23%) athletes had LVEDD values > 58 mm and > 52 mm, respectively, and 89 male (4%) and 62 (6%) female athletes had LVEDD values > 63 mm and > 56 mm, respectively. Four male athletes with LVEDD values > 63 mm had an abnormally low LVEF   are within the established limits for the general population; however, some LV dimensions are above these limits in a non-negligible proportion of athletes.The present study describes the LV dimensions in a large cohort of white elite athletes—to our knowledge, the largest one assessed to date—and determines how sex and sport type (with the corresponding changes in static and dynamic component) are associated with different LV characteristics. Our main finding is that most LV measures in elite white athletes  had normal LV geometry. Yet, in line with previous research , eccentr. , in whic.  found a l. study ), or in Female athletes had a lower LV mass than males, as well as a greater prevalence of normal LV geometry. These findings point to a sex-specific pattern of exercise-induced cardiac remodeling among elite athletes, which is consistent with the previous studies showing that female athletes seemed to have a different pattern of remodeling than their male counterparts, including higher BSA-indexed dimensions , lower values of LV wall thickness and LV mass, and a higher prevalence of normal LV geometry , 20. On i.e., increased LV mass mostly due to an increased LVEDV in the former, or to an increased SWT and LVPW in the latter) [Regarding the type of sport, the highest actual and BSA-indexed values of LV thickness (SWT or LVPW) and mass were found for sports with a greater dynamic (‘endurance’) component. Although the trend was less marked than for the dynamic component, the aforementioned variables (at least when BSA-corrected) also increased with the static (‘resistance’) component of the sport in male athletes. Importantly, these findings are overall at odds with the Morganroth hypothesis of a dichotomous LV remodeling pattern in endurance and resistance athletes ( latter) , 22. In  latter) . Indeed, latter) , 19, 24.. [i.e., 14% had a LVEDD > 60 mm). The differences between their study and ours might be attributable to the lower proportion of female athletes in the former .There is common agreement that regular endurance training results in cardiac chamber enlargement; however, studies in endurance athletes show that LV dimensions are usually within normal ranges , 25, 26..  found ove.g., IIA), particularly in female athletes. The use of the classic Mitchell’s classification for sports categorization might also be viewed as a potential limitation. In this regard, we believe there is no unanimity as to the best means of categorizing the different sports based on hemodynamic and overall physiological loads, especially at the highest competition level, which was the case of our cohort. More recent alternatives to the Mitchell’s classification are available, notably those recently proposed by the 2020 European Society of Cardiology guidelines on sports cardiology and exercise in patients with cardiovascular disease [e.g., in soccer, midfielders or wingbacks are exposed to much higher dynamic loads and exercise intensities than goalkeepers despite both enrolled in the same sport) but also within the same athlete over his/her career . To further complicate the issue, all athletes spend much more time in training than in competition, and thus numerous different modes of exercise skills, modalities and intensities are likely to be involved to a lesser or a higher degree in weekly workouts irrespective of the essential nature of the main competition event in question. On the other hand, although the use of the 2D-guided M-mode approach used here to measure LV mass might not be the best option for assessing patients, here, we assessed healthy athletes and the M-method also has advantages  [e.g., to predict cardiovascular outcomes from LV mass measures [Some limitations of the present study should be acknowledged, such as the uneven representation of athletes in the different sports categories, with some underrepresented ( disease . In this2D-mode) , and in measures ).2max), and the practical applicability of the normative values computed here, which can be easily used by clinicians to identify ‘at risk’ athletes  with the help of the online/mobile app we provide. The provision of cutoff values for LV dimensions according to sport practiced and sex should allow differentiation between normal  and pathological cardiac remodeling in athletes, which could be useful in pre-participation screening and annual follow-ups.Strengths of our study include the large number of elite athletes of both sexes participating in a wide variety of sports .Most athletes (~ 85%) had normal LV geometry, with approximately one of eight athletes presenting with eccentric hypertrophy and only a minority showing concentric remodeling or hypertrophy (less than 1% for both conditions in either sex). The sex- and sport-specific normative values for LV dimensions provided here can serve to identify those athletes in which a detailed examination might be recommendable  measures attending to the dynamic component of the sport in male athletes.Additional file 3: Cardiac geometry and left ventricular (LV) measures attending to the dynamic component of the sport in female athletes.Additional file 4: Cardiac geometry and left ventricular (LV) measures attending to the static component of the sport in male athletes.Additional file 5: Cardiac geometry and left ventricular (LV) measures attending to the static component of the sport in female athletes.Additional file 6: Pearson’s correlations between maximum oxygen uptake and left ventricular (LV) measures by sex .