Myocardial ischemia is a pathophysiological state characterized by inadequate perfusion of the myocardium, resulting in an imbalance between myocardial oxygen demand and supply. It is most commonly caused by coronary artery disease, in which atherosclerotic plaques lead to luminal narrowing and reduced blood flow to the heart. Myocardial ischemia can manifest as angina pectoris or silent myocardial ischemia and can progress to myocardial infarction or heart failure if left untreated. Diagnosis of myocardial ischemia typically involves a combination of clinical evaluation, electrocardiography and imaging studies. Electrocardiographic parameters, as assessed by 24 h Holter ECG monitoring, can predict the occurrence of major adverse cardiovascular events in patients with myocardial ischemia, independent of other risk factors. The T-waves in patients with myocardial ischemia have prognostic value for predicting major adverse cardiovascular events, and their electrophysiological heterogeneity can be visualized using various techniques. Combining the electrocardiographic findings with the assessment of myocardial substrate may offer a better picture of the factors that can contribute to cardiovascular death. Myocardial ischemia is a pathological condition described by a reduction in blood flow and oxygen supply to the myocardium, resulting in cellular damage and dysfunction ,2. MyocaMI is a prevalent condition that affects millions of people worldwide, responsible for 16% of all deaths globally ,4. The rThus, we proposed conducting a review of various publications that describe the observed T-wave patterns captured during 24 h Holter ECG monitoring in patients with myocardial ischemia and the risk of developing a major adverse cardiovascular event (MACE), as well as what future perspectives are.We conducted a thorough search on PubMed and Google Scholar for articles published between 1993 and August 2022 and created a database by using specific keywords: “myocardial ischemia”, “Holter ECG”, “T-wave”, “repolarization”, “T-wave alternans”, “T-wave patterns”, “myocardial infarction”, “acute coronary syndrome”, “major adverse cardiovascular events”, “stroke”, “cardiac magnetic resonance imaging”, “electroanatomic mapping”, “artificial intelligence” and all combinations of them. The findings comprised 257 papers, including various types of research, such as original papers, reports, prospective studies, systematic reviews, retrospective studies, meta-analyses and case reports, which examined T-wave patterns and their relevance to risk stratification in myocardial infarction. We conducted a comprehensive analysis of relevant articles to obtain data and present a detailed overview of the various aspects of the T-wave aspects observed on 24 h Holter ECG monitoring in patients with myocardial infarction who had been followed-up for several years. In our study, we employed exclusion criteria to ensure the integrity of our analysis. Specifically, we omitted papers that lacked patient follow-up, were incomplete or inconclusive, or were pilot studies. Additionally, we excluded reviews that substantially overlapped with our existing findings.MI is a clinical condition that results from a prolonged blockage of blood supply to the heart, causing necrosis of the myocardium ,2,3,4. AIn cardiovascular research, MACE are commonly used as an endpoint, which consists of both mortality and morbidity among patients who have suffered a myocardial infarction ,19. MACEThe T-wave is an important aspect of the ECG that represents ventricular repolarization, with a standard orientation pattern characterized by inversion in lead aVR and upward deflection in other leads ,43,44. TCardiac electrical alternans is characterized by alternating changes in the ECG waveform morphology every second cardiac cycle and is typically represented by T-wave alternans (TWA). TWA has been linked to increased susceptibility to SCD in a variety of cardiac pathologies and is considered a valuable risk marker for stratifying the risk of malignant arrhythmia and SCD in patients with structural heart disease ,50. Its Several studies showed different results for the prediction of MACE in TWA-positive patients ,66,67.De Ferrari et al. conducted a meta-analysis in which they incorporated a sample size of nearly 1500 patients and demonstrated that individuals with anomalous TWA exhibit a risk that is three times greater in comparison to those with regular TWA. However, the authors focused on patients with chronic heart failure .The etiology of an acute myocardial pathology is an important aspect because it can influence the results of the TWA recording. The extend of TWA may vary as a result of myocardial disfunction following an acute myocardial infarction ,66,68. AAnother important aspect is the time when the TWA is measured since the acute event, especially in patients with MI. Garcia conducted TWA testing on patients who had experienced an acute MI at least 14 days prior. The results showed that 17% of the tests were positive, 75% were negative and 9% were indeterminate. The study also calculated the sensitivity and negative predictive value of the TWA test for predicting arrhythmic events. Furthermore, when assessing various parameters such as baroreflex sensitivity, TWA and heart rate turbulence within the 2–4 week acute phase following MI, no singular parameter was found to effectively predict outcomes. However, during the non-acute phase (10–14 weeks) after MI, the combination of abnormal TWA and LVEF below 50% yielded the most accurate diagnostic results . A diffeNishibe et al. proposed in their study one potentially valuable metric for assessing alternans, known as Alternans Ratio. The study demonstrated that a set of alternans indices was established for every heartbeat, which comprised the orthogonal waveform distance between the target beat and the neighboring two beats. In the presence of alternans, the first index was found to be greater than the second index .Therefore, TWA meets the fundamental criteria for serving as a therapeutic marker, particularly in individuals diagnosed with myocardial infarction, being the causal pathway of arrhythmogenesis . HistoriAlthough the existence of macroscopic TWA has been documented, it was regarded as an uncommon discovery, consistently linked to an unfavorable prognosis, until microscopic TWA was initially reported in the 1980s .Microvolt T-wave alternans (MTWA) is a phenomenon characterized by fluctuations in the form and magnitude of the T-wave, resulting in an oscillatory pattern, and has been shown to be useful in predicting malignant ventricular arrhythmias and SCD in various cardiac disorders ,76,77,78MTWA reflects beat-to-beat variation in the spatial and temporal repolarization heterogeneity, caused by cellular repolarization alternans, and may provide a substrate for reentry ,80,81. TThe identification of microvolt T-wave alternans (MTWA) can be accomplished through two methodologies: the spectral approach and the modified moving average (MMA) method applied in the time domain ,72. BothIn the domain of clinical research for the assessment of Holter ECG MTWA, the preeminent method employed is the non-spectral approach referred to as MMA ,73,83. TMTWA has a high negative predictive value of 98%, but a low positive predictive value of 8–10% in low-risk populations. Studies have shown that the absence of notable MTWA in individuals with myocardial infarction significantly reduces the likelihood of SCD. However, the low positive predictive value of MTWA has led to an interest in exploring a composite of noninvasive parameters, primarily autonomic indices such as heart rate turbulence ,92,93. CThe use of 24 h ambulatory ECG monitoring to evaluate TWA has shown potential in predicting cardiac mortality ,94,95,96Given that certain patients, including those receiving medications such as beta-blockers and digoxin, and those with physical constraints, are not suitable candidates for spectral MTWA testing, the majority of studies have concentrated on employing the MMA technique . The preMaeda et al. found that in patients with myocardial infarction, a positive MTWA was a significant covariate for the incidence of life-threatening ventricular arrhythmias during a mean follow-up of 6 years . FurtherSelvaraj et al. observed that while a positive MTWA test indicated a higher risk of cardiac death and life-threatening arrhythmia in both ischemic and nonischemic cardiomyopathy, in the context of patients with myocardial infarction, the incidence of sudden cardiac death was significant, yet no association was found between SCD and MTWA ,107,108.The Eplerone Post-Acute Myocardial Infarction Hear Failure Efficacy and Survival Study (EPHESUS) showed that the amplitude of MTWA was observed to be greater in patients who suffered from sudden cardiac death compared to survivors or those without sudden cardiac death, irrespective of the lead used for measurement. According to research, Holter ECG-based MTWA measured by MMA is a strong predictor of SCD in high-risk post-MI patients with left ventricular dysfunction. The maximum MTWA was higher in patients who suffered sudden cardiac death, but there was no significant difference between survivors and non-SCD patients. The study also noted that the highest levels of MTWA were typically found in the early afternoon, which deviates from the usual circadian pattern of SCD that peaks in the early morning hours. However, this timing aligns with the increased risk of SCD in heart failure patients . SulimovThe initial trial that utilized MTWA as a tool to direct prophylactic ICD placement is the Alternans Before Cardioverter Defibrillator (ABCD) study. Over a median follow-up period of 1.9 years, a primary endpoint of either appropriate ICD discharge or SCD at one year was met by 7.5% of the patients ,113. In Assessment of myocardial substrate pertains to the evaluation of the underlying structural and functional abnormalities of the heart, which can precipitate arrhythmias and sudden cardiac death. This includes conditions such as ischemic heart disease, cardiomyopathy, heart failure, and valvular heart disease ,117. DiaThe combination of TWA and assessment of myocardial substrate has been demonstrated to improve the risk stratification for arrhythmic events and sudden cardiac death compared to using either parameter alone ,121. ForIn a study of patients with ischemic cardiomyopathy and abnormal electrograms on electroanatomic mapping, both TWA and left ventricular EF were found to be independent predictors of MACE. Patients with both TWA and EF ≤ 30% had the highest risk of MACE, followed by those with TWA or EF ≤ 30% alone . AdditioSeveral studies have explored the predictive value of both MTWA and myocardial scars for MACE. For instance, a 2017 study in the Journal of the American Heart Association investigated the prognostic value of TWA and late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (MRI) for predicting MACE in patients with nonischemic cardiomyopathy ,134,135.Similarly, a 2016 study in the Journal of the American College of Cardiology assessed the prognostic value of T-wave inversion (TWI) and LGE on cardiac MRI for predicting MACE in patients with hypertrophic cardiomyopathy (HCM). The study found that the presence of both TWI and LGE was associated with a higher risk of MACE compared to either TWI or LGE alone  .Several studies have investigated the prognostic value of combining T-wave aspects and myocardial scars for predicting MACE in different patient populations ,138,139.In addition, in patients with ischemic heart disease, T-wave patterns on the ECG and findings on CMR have been found to correlate with MACE. TWA has also been identified as a predictor of future MACE in patients with ischemic heart disease .While these findings suggest that combining T-wave patterns and myocardial scars on cardiac MRI may provide valuable information for risk stratification in certain patient populations, more research is needed to validate these findings and determine their clinical relevance ,144.TWA has been associated with myocardial ischemia and infarction. In a study involving patients with chronic stable angina, TWA was found to be a predictor of myocardial ischemia on CMR and was also linked to a higher risk of major cardiac events during follow-up .In addition to T-wave patterns, other ECG parameters such as QRS duration and QT interval have also been found to correlate with CMR findings in ischemic heart disease. For example, prolonged QRS duration has been associated with a higher incidence of myocardial fibrosis on CMR, as well as an increased risk of MACE . SimilarTaken together, these findings underscore the value of integrating ECG parameters with CMR imaging to stratify the risk of patients with ischemic heart disease ,145,146.Electroanatomic mapping (EAM) is a non-invasive imaging technique that generates a 3D map of the heart’s electrical activity and is widely utilized in the management of arrhythmias. Although limited research has been conducted on the association between T-wave patterns and EAM findings in predicting MACE, some studies have provided insights into this relationship. For instance, in patients with ventricular tachycardia and structural heart disease, the presence of TWA on the surface ECG was linked to an elevated probability of identifying critical isthmus sites on EAM, defined as the location of the slow conduction that sustained the VT. Furthermore, patients with TWA were found to have a higher risk of recurrent VT during follow-up . SimilarA study conducted on patients with nonischemic cardiomyopathy revealed that the presence of TWA on the ECG was linked with abnormal local activation time (LAT) on EAM in the right ventricular outflow tract. This abnormal LAT was characterized as a delay in the timing of the electrical signal relative to neighboring sites, indicating slow conduction or conduction block. Patients with TWA and abnormal LAT had a higher probability of developing sustained ventricular arrhythmias . These sAccording to several studies, TWA on the Holter ECG/24 h monitoring is associated with abnormal electrograms on EAM in the region of the infarcted myocardium in patients with ischemic cardiomyopathy or heart disease. Abnormal electrograms are defined as low-amplitude, high-frequency signals indicative of scar tissue or conduction block, or as fragmented electrograms with complex waveforms suggesting conduction abnormalities . DelayedThere is a scarcity of research that directly compares the predictive value of T-wave features with residual ischemia detected through perfusion imaging in forecasting MACE. In one study that evaluated patients with stable coronary artery disease, TWA was identified as an independent predictor of cardiac events, including MACE, over a follow-up period of 2.2 years. The inclusion of TWA in clinical and myocardial perfusion imaging variables enhanced the prediction of MACE, but the study did not explore the role of residual ischemia on perfusion imaging specifically . In contSeveral studies have investigated the prognostic value of T-wave aspects in conjunction with coronary angiography for the prediction of MACE. In a study by Ghanbari et al., 603 patients with stable coronary artery disease who underwent coronary angiography were monitored for a median of 2.6 years. TWA was measured using a modified moving average method during exercise treadmill testing, while the severity of coronary artery disease was assessed via angiography. The results showed that TWA was a significant independent predictor of MACE, although the addition of angiographic variables did not significantly improve risk prediction beyond TWA alone .In a study by Haigney et al. (2004), 219 patients with stable coronary artery disease who underwent coronary angiography were followed for a mean of 16 months. T-wave amplitude and TWA were measured during exercise treadmill testing, while the extent and severity of coronary artery stenosis were assessed using the Gensini score. The study found that T-wave amplitude and TWA were significant predictors of cardiac events, independent of the Gensini score and other clinical variables. However, the contribution of residual ischemia on angiography to risk prediction was not specifically examined .The studies conducted by Schuster et al., Verrier et al. and Maytin et al. investigated the predictive value of T-wave aspects, particularly TWA, in patients with stable angina or coronary artery disease ,155. In The studies conducted by Schuster et al., Verrier et al. and Maytin et al. investigated the predictive value of T-wave aspects, particularly TWA, in patients with stable angina or coronary artery disease ,155. In A study by Baman et al. followed 1149 patients with acute coronary syndrome who underwent coronary angiography for a mean of 3.8 years. TWA was measured using the spectral method during exercise treadmill testing, while coronary angiography was utilized to determine the presence and severity of coronary artery disease. During the follow-up period, there were 311 MACE events, including cardiac death, nonfatal myocardial infarction, and revascularization. TWA was found to be a significant predictor of MACE, even after adjusting for angiographic and clinical variables .In summary, these studies indicate that T-wave parameters, particularly TWA, may be valuable in predicting MACE in patients with stable or unstable coronary artery disease, regardless of coronary angiography results. Nevertheless, further research is required to establish the optimal application of T-wave parameters in clinical decision-making and risk stratification ,154,155.The SYNTAX score is a tool utilized to evaluate the complexity of coronary artery disease, based on the severity, location, and number of stenoses present in the coronary arteries. It is frequently employed to inform decision-making for coronary revascularization procedures, such as percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). While the SYNTAX score has demonstrated predictive value for adverse cardiovascular events, it is not typically used in conjunction with T-wave patterns as a predictor .Nevertheless, there is some research suggesting that T-wave patterns may be helpful in predicting outcomes following revascularization procedures. For instance, one study found that T-wave alternans was linked to worse outcomes following PCI in patients with stable angina. Another study found that the presence of abnormal T-wave morphology was associated with higher rates of major adverse cardiac events after CABG .Although the SYNTAX score has demonstrated some predictive value for adverse cardiovascular events, there is limited research on combining T-wave patterns and the SYNTAX score to predict outcomes. Further studies are necessary to determine the potential utility of combining these factors in predicting major adverse cardiovascular events ,157.The presence of inhomogeneous repolarization has been linked to an elevated likelihood of ventricular arrhythmias. T-wave morphologies have been extensively researched over the past few decades in association with this phenomenon . MultiplRecent research has investigated the application of advanced techniques, such as wavelet transform and principal component analysis, for analyzing T-wave morphology in order to enhance the accuracy of predicting MACE. These techniques enable more precise measurements of various T-wave attributes, including amplitude, duration, and shape, and can detect subtle changes in these features to improve the accuracy of MACE prediction ,179.T-wave discordance refers to the incongruity between the T-wave direction and the QRS complex direction observed on an ECG or Holter ECG/24 h monitoring. Such disparity is indicative of ventricular repolarization heterogeneity and is linked to an increased risk of ventricular arrhythmias and sudden cardiac death. Some studies have demonstrated that T-wave discordance can also forecast MACE in individuals with acute coronary syndrome ,181.Furthermore, machine learning algorithms have been developed to evaluate T-wave patterns and predict MACE. These algorithms utilize vast datasets to recognize patterns and correlations that may be overlooked by conventional statistical methods. Several studies have reported that machine learning algorithms can effectively predict MACE in patients with heart failure and other cardiovascular diseases based on T-wave characteristics ,183.In patients with myocardial disfunction following a myocardial infarction, the overall cosine of the angle formed between the wavefront of depolarization and repolarization is represented by the term Total Cosine R-to-T (TCRT), yielded an independent predictive value for MACE . In an iHowever, there is a greater abundance of information available in the literature about the T-wave aspects in patients with chronic heart failure that showed a correlation with MACE and that needed to be studied in patients with an acute myocardial infarction ,176,177 Nearing et al. analyzed the TWH within a time frame of 30 to 45 min prior to the initiation of ventricular tachycardia, as an alternative phrasing. The researchers reached a conclusion that crescendos exist in the level of electrical instability that may serve as early indicators of the onset of non-sustained ventricular tachycardia. They observed that in 91% of patients, the elevated levels of T-wave heterogeneity persisted prior to the initiation of non-sustained ventricular tachycardia, thereby indicating that alterations in T-wave heterogeneity may potentially serve as premonitory signs of heightened cardiac electrical instability. It is noteworthy, however, that the authors have not published any specific investigations focusing on patients with myocardial infarction ,166,167.Kumar et al. focused on isolated minor T-wave irregularities, represented by flat or minimally inverted T-waves, measuring less than 1 mm amplitude. The study conducted a 15-year follow-up of the patients, revealing that a positive finding for minor T-wave abnormalities was linked to a significantly elevated risk of primary arrhythmic death, but no significant association was found between such findings and the incidence of nonfatal myocardial infarction . AccordiThe T-wave morphology restitution (TMR) method analyzes the T-wave morphology in association with the heart rate. The quantification of TMR involved the use of time-warping metrics to measure the extent of morphological variation in the T-wave for each RR increment. The results indicated a statistically significant increase in TMR values among SCD victims in comparison to other patients. Therefore, a correlation between T-wave morphology and other aspects, such as heart rate, could better quantify the risk of SCD . HoweverT-wave loop morphology represents repolarization abnormalities and is strongly correlated with subsequent onset of myocardial infarction . MoreoveIn Rahola’s investigation, which involved a mean follow-up duration of 8.6 years, a proportion of 3.9% of the patients suffered sudden cardiac death (SCD) or received resuscitation following a sudden cardiac arrest. The measure of TMD evinced a robust correlation with the risk of SCD and was significantly elevated in patients with a history of SCD relative to their living counterparts. However, TMD did not demonstrate statistically significant differences between those who experienced non-SCD or non-cardiac death and the living population. As such, the temporal fluctuations in electrocardiographic spatial heterogeneity of repolarization, as gauged by TMD, can independently prognosticate the long-term risk of SCD in individuals diagnosed with myocardial infarction .The conventional definition of TWI involves the presence of a negative T-wave that exceeds or equals 1 mm in depth in at least two adjacent leads while omitting leads aVR, III and V1 from the evaluation . TWI is Krittayaphong’s research identified TWI in 20% of the study population, with 4.4% of patients experiencing MACE. However, the study found no significant interplay between the presence of TWI, whether in conjunction with ST-segment depression or as an independent feature, and the likelihood of MACE .Although T-wave inversion predicted SCD or malignant ventricular arrhythmias, an important observed issue was the inversion of the T-wave in the anterolateral leads, which may be linked to arrhythmogenic cardiomyopathy. Therefore, extended studies that exclude this pathology and include only patients with myocardial infarction are needed .Research indicates that abnormal T-wave patterns can indicate underlying cardiac pathology and increase the risk of cardiovascular mortality. Specifically, T-wave inversion in leads V1-V3 has been identified as a predictor of sudden cardiac death in individuals with hypertrophic cardiomyopathy, whereas T-wave inversion in the inferior leads has been linked to an elevated risk of cardiovascular events in patients experiencing acute coronary syndrome ,185.As we mentioned, the combination of T-wave patterns and myocardial substrate assessment has been suggested to improve risk stratification for cardiovascular events and sudden cardiac death compared to either parameter alone. For instance, a 2016 study in the Journal of the American College of Cardiology demonstrated that T-wave inversion in leads V1-V3 and late gadolinium enhancement on cardiac magnetic resonance imaging were a superior predictor of adverse cardiovascular events than each parameter alone in patients with hypertrophic cardiomyopathy . AdditioIn patients with ischemic heart disease, the presence of T-wave inversion on the ECG or Holter ECG/24 h monitoring and the findings on cardiac magnetic resonance imaging (CMR) have been demonstrated to correlate with MACE. Studies have shown that T-wave inversion in leads V1 to V3 on the ECG is associated with the presence of myocardial scarring on CMR in patients with previous MI and is a predictor of future MACE . FurtherHence, in Pirkola’s study, T-wave area dispersion (TWAD), T-wave morphology dispersion (TMD) and temporal complexity of repolarization (TCRT) showed a substantial correlation with cardiac mortality, with these parameters being more strongly linked with non-sudden cardiac deaths than with SCD. The parameters related to T-wave morphology, which represent the heterogeneity of repolarization, enhance the predictive capacity of the clinical risk model for myocardial infarction in the present treatment era .Artificial intelligence (AI) is a computer-based technology that simulates human intelligence and performs tasks that typically require human cognition, such as visual perception, speech recognition, and decision-making. In the field of cardiovascular disease, AI has shown promise in enabling more accurate and efficient diagnosis and treatment. AI has been applied to various aspects of cardiovascular disease, including risk prediction, image analysis and drug discovery ,194,195.While there is limited research specifically on the combination of T-wave aspects and AI for predicting MACE, these studies suggest that machine learning and AI may have potential for predicting cardiovascular events in patients with known or suspected cardiovascular disease ,195. A dThe prognostic value of T-wave morphology assessed by 24 h Holter ECG monitoring is paramount in identifying patients at risk for MACE. As such, preemptive therapeutic interventions may be warranted for those displaying aberrant T-wave patterns . The depPatients with LVEF less than 35% are at an increased risk of ventricular arrhythmias, which may require ICD placement. The decision to implant an ICD is based on multiple factors, such as LVEF, history of ventricular arrhythmia, underlying structural heart disease, and certain genetic conditions, to assess the patient’s risk of sudden cardiac death. Several studies have attempted to identify predictors of ventricular arrhythmias in these patients, including T-wave alternans, QT dispersion and heart rate variability ,201,202.Although T-wave patterns alone are not sufficient to warrant ICD implantation, the analysis of T-wave morphology can assist in the decision-making process for ICD implantation in specific clinical scenarios. The current clinical guidelines recommend ICD implantation for primary prevention in patients with reduced EF due to prior MI, nonischemic dilated cardiomyopathy, or genetic or acquired arrhythmogenic disorders associated with an increased risk of sudden cardiac death ,200,201.The decision to implant an ICD typically involves multiple factors, such as clinical history, physical examination, imaging studies, electrophysiological testing and risk stratification tools. T-wave patterns and other electrocardiographic findings may be utilized as adjunctive tools to refine risk stratification in certain clinical situations, but they are not considered the sole criterion for ICD implantation ,204,205.It is crucial to acknowledge that the decision to implant an ICD is complex and should be tailored to each patient based on their individual clinical characteristics and risk factors. Therefore, patients with suspected or established cardiac disease should undergo a comprehensive evaluation by a qualified cardiologist to determine the most appropriate management plan ,204,205.The current study results propose that T-wave morphology may be effectively employed to discern a subgroup of patients who are unlikely to derive significant therapeutic benefit from ICD therapy, although further confirmatory investigations are required before endorsing modifications to existing treatment guidelines . DespiteThe repolarization heterogeneity, observed through the different aspects of the T-wave patterns measured on Holter ECG monitoring, is a potent predictor of unfavorable outcomes and significant adverse cardiovascular events in patients with myocardial infarction. Nevertheless, several T-wave aspects showed a correlation with MACE in various cardiovascular pathologies and need to be studied also in patients with myocardial infarction. Because in myocardial infarction the electrical instability can interfere with the results, future studies should focus on the T-wave analysis by finesse methods, which remove most of the artifacts and electrical instability and create a universal analysis algorithm. Not least, AI is a promising tool for research, offering improved accuracy and efficiency in data analysis, identifying complex patterns and supporting informed decision-making processes.


Cardiac growth and remodeling (G&R) patterns change ventricular size, shape, and function both globally and locally. Biomechanical, neurohormonal, and genetic stimuli drive these patterns through changes in myocyte dimension and fibrosis. We propose a novel microstructure-motivated model that predicts organ-scale G&R in the heart based on the homogenized constrained mixture theory. Previous models, based on the kinematic growth theory, reproduced consequences of G&R in bulk myocardial tissue by prescribing the direction and extent of growth but neglected underlying cellular mechanisms. In our model, the direction and extent of G&R emerge naturally from intra- and extracellular turnover processes in myocardial tissue constituents and their preferred homeostatic stretch state. We additionally propose a method to obtain a mechanobiologically equilibrated reference configuration. We test our model on an idealized 3D left ventricular geometry and demonstrate that our model aims to maintain tensional homeostasis in hypertension conditions. In a stability map, we identify regions of stable and unstable G&R from an identical parameter set with varying systolic pressures and growth factors. Furthermore, we show the extent of G&R reversal after returning the systolic pressure to baseline following stage 1 and 2 hypertension. A realistic model of organ-scale cardiac G&R has the potential to identify patients at risk of heart failure, enable personalized cardiac therapies, and facilitate the optimal design of medical devices.The online version contains supplementary material available at 10.1007/s10237-023-01747-w. Cardiac growth and remodeling (G&R) occur in various situations throughout a human’s life. Developmental growth occurs between birth and adulthood and ensures the adaption of the cardiac function to the changing needs. Changing needs also occur in adulthood, for example, due to pregnancy or exercise resulting in physiological growth of the myocardium. Disease-induced stimuli, however, often result in pathologic, maladaptive G&R that develop toward heart failure. Common diseases stimulating pathologic G&R are myocardial infarction, aortic stenosis, hypertension, or valvular regurgitation  and the ratio of LV wall thickness to the diastolic diameter, denoted as relative wall thickness. With these two measures, cardiac G&R can be classified into two distinct patterns:concentric hypertrophy. This pattern is typically observed in patients with increased resistance to ejection, e. g., aortic stenosis or hypertension. On the cellular level, contractile-protein units (sarcomeres) in cardiomyocytes are added in parallel so that the length to width ratio of individual cardiomyocytes decreases  does not store elastic energy and therefore does not directly create stresses.We assume that the primarily structurally relevant constituents of the myocardium are collagen fibers  remodeling. Still missing is the modeling of the volume change due to mass increase or decrease, that is, growth.There are different approaches that describe the volume change due to mass growth. An often chosen approach is to define an additional inelastic deformation Braeu et al.  proposedWe are following this approach and modify the penalty type strain energy term u et al. , who thep and the surrounding tissue, result in an in vivo reference configuration that is not stress-free. Since we model the tissue as a constrained mixture, each constituent can have its own (incompatible) stress-free configuration. Note that it is necessary that the in vivo configuration is not stress-free such that all constituents can be in their homeostatic state for a given left ventricular pressure p.The geometry for a G&R simulation is usually a configuration obtained from magnetic resonance imaging (MRI) through segmentation. External loads present during imaging, e. g., from the blood pressure In our examples, we assume that the imaged configuration represents a healthy state before some physiological event occurs that stimulates G&R. The configuration must therefore be in mechanobiological equilibrium, which requires mechanical equilibrium and additionally that all constituents are in their preferred homeostatic mechanical state 14) usingCompute the remodeling deformation gradient of each constituent using Eq. .Compute the elastic part of the deformation of each constituent by Eq. .Compute the stress response of the mixture with Eqs. –9) and  and 9) aThe nonlinear equilibrium Eq. 14) are ii in Eq. ). We verFigure The parameters used for the simulation can be found in Table In the following, we analyze the prestress algorithm presented in Sect. We investigate 3 different prestress convergence thresholds Figure After 136 timesteps, the maximum nodal displacement falls below the first threshold of If we choose the threshold The lowest investigated threshold Figure In the following, we analyze the prestretch of elastin. We analyze the case with The largest principal stretch occurs at the basal plane at the endocardium, with a principal stretch of around 1.5. A slightly lower principal stretch occurs in the apical region. Generally, the principal stretches are larger at the endocardium and smaller at the epicardium. At the endocardium, elastin is under expansion in the plane of cardiomyocytes and collagen fibers, and under compression perpendicular to the plane (to bear the load of the blood pressure). On the epicardium, elastin is under expansion perpendicular to the fiber plane, where the springs of the pericardial boundary condition pull on the contracted ventricle see Fig. .In the following, we examine mechanobiological stability of the model of cardiac G&R described in Sect. To this end, we performed a series of G&R simulations all starting from a prestressed configuration at mechanobiologically stable if the systems returns to a (new) mechanobiological equilibrium . If the deviation from homeostasis increases for all constituents, we classify the simulation as mechanobiologically unstable:A simulation is Figure We have shown the influence of the systolic pressure and the growth constant on mechanobiological stability. In the supplementary materials, we show that the stiffness of the spring boundary conditions also influences mechanobiological stability. These results show that the higher the spring stiffness, the smaller is the deviation of the fiber Cauchy stress from homeostasis. The stiffer boundary conditions can bear more of the load. As a consequence, the results of G&R are less pronounced . The mechanobiological stability region is larger if the spring stiffness is higher.In Fig. Figure The sudden increase in left ventricular systolic blood pressure results in an elastic elongation of the fibers and therefore in increased stress. In case of stage 1 hypertension, the cardiomyocyte fiber stress increases from the homeostatic value of The elastic deformation due to stage 2 hypertension results in a sudden increase in the Cauchy stress of cardiomyocytes to In the following section, we study to what extent G&R can be reversed when the pressure returns to its baseline value. Physiologically, this corresponds to an intervention that treats hypertension by lowering blood pressure, e g., through ACE inhibitors.In this section, we focus on the intervals with pressures restored to baseline values in Fig. As shown in Sect. In this work, we developed a computational model of organ-scale cardiac G&R that is based on mechanobiological principles and motivated by myocardial microstructure. We modeled G&R as a consequence of continuous deposition and degradation of sarcomeres and collagen using the homogenized constrained mixture theory and applied it on an idealized 3D left ventricular geometry. We then analyzed mechanobiological stability of our G&R model depending on key mechanobiological parameters and external loading. Additionally, we demonstrated that our model captures the partial reversal of G&R if systolic pressure is returned to its baseline value.To start our simulations from a state that is in mechanical and homeostatic equilibrium, we introduced a prestressing algorithm which puts the myocardium in a mechanobiologically equilibrated state for a given ventricular pressure. We demonstrated that our prestressing algorithm yields a physiologically meaningful distribution of elastin prestretch.We assumed in this exploratory study that on the macroscopic scale, the preferred mechanical environment of the constituents is defined by mechanical stress. We critically note, however, that the question which quantity is the target of homeostasis remains unclear and part of ongoing research  need an increased theoretical understanding of soft tissue G&R Humphrey .Currently, we assumed that only the myocardial tissue itself adapts to changed loads. We assumed that the behavior of the pericardial boundary condition, the cut-off of the atria and the hemodynamic loads do not change over time. However, the pericardium is known to enlarge in size and shape during cardiac dilatation Below is the link to the electronic supplementary material.


Clinical characteristics and echocardiographic parameters were recorded. Cardiac uptake was quantified by standardized uptake values  and left ventricular metabolism volume. The relationship between 68Ga-FAPI-04 uptake with clinical and echocardiography parameters was investigated.Twenty-nine consecutive patients with symptomatic non-ischemic cardiomyopathies who underwent 68Ga-FAPI-04 uptake was observed in different subtypes of non-ischemic cardiomyopathies. Twenty-two (75.9%) patients showed elevated 68Ga-FAPI-04 uptake in the left ventricle, and 10 (34.5%) patients also showed slightly diffuse elevated uptake in the right ventricle. Cardiac uptake values were significantly correlated with enlarged ventricular volume evaluated by echocardiography.Heterogeneous FAPI PET/CT presents a potential value for in vivo visualization and quantification of fibroblast activation on the molecular level. Further study is warranted for investigating the theranostic and prognostic value of elevated FAP signal. Non-ischemic cardiomyopathy (NICM) is an essential risk factor for developing heart failure and sudden cardiac death. NICMs include a variety of myocardial disorders and could be classified according to morphofunctional phenotype, organ involvement, genetic inheritance pattern, etiological annotation, and functional status into different subtypes . Activat68Gallium-labeled fibroblast activation protein inhibitor presented great potential in specific detection and characterization of cardiac fibroblasts activation [68Gallium-labeled FAPI PET ligand was demonstrated in patients with acute myocardial infarction [A recently developed PET tracer tivation . A pilotfarction . In vivofarction . NowadayIn this prospective pilot study, we aimed to perform a pilot visualization study to investigate in vivo myocardial fibroblast activation in different subtypes of NICMs. It would allow us to provide a preliminary mapping of multiple NICMs and investigate whether myocardial FAPI activity is an independent biomarker of myocardial dysfunction or myocardial remodeling, irrespective of the types of cardiomyopathy. We hope our findings can inspire potential readers and researchers to perform further studies on the mechanisms of these diseases and the identification of new therapeutic agents.This study was approved by the Institutional Ethics Committee of Peking Union Medical College Hospital (ZS1810), and all subjects provided written informed consent. Twenty-nine consecutive patients with distinct subtypes of NICMs were recruited. The diagnosis of NICMS was made by cardiology department based on the contemporary definitions and classification of cardiomyopathies . Besides68Ga-FAPI-04 PET/CT scans  60 min after intravenous injection of 157.3 ± 25.2 MBq of the tracer. One bed position was acquired , and the heart was set at the center of the view. Visual analysis was evaluated, and increased cardiac 68Ga-FAPI-04 activity than blood pool (descending thoracic aorta) was considered as elevated tracer uptake. Quantification analysis of myocardial 68Ga-FAPI-04 uptake was performed using PMOD package 4.1. The standardized uptake value (SUV) of the myocardium was measured by drawing the contour of the whole left ventricle and right ventricle on PET images. Maximal SUV (SUVmax) and mean SUV (SUVmean) were recorded. SUVR is defined as the SUVmean of the myocardial VOI divided by the SUVmean of the blood pool of descending thoracic aorta VOI (1 cm3). The left ventricular metabolism volume (LVMV) was automatically calculated as the sum of all voxels with SUV > 50% of the SUVmax. In those patients absenting visible uptake (cardiac activity lower than descending thoracic aorta blood pool), SUV was recorded by drawing a 1-cm circle at the middle of the left ventricle wall.All patients underwent 68Ga-FAPI-04 PET/CT parameters with echocardiography parameters. A P value < 0.05 was considered statistically significant.Pearson’s correlation analysis was conducted to demonstrate the relationship of n = 10), inflammatory cardiomyopathies (IC) with connective tissue disorders (n = 10), hypertrophic cardiomyopathy (HCM) (n = 3), left ventricular noncompaction (LVNC) (n = 3), restrictive cardiomyopathy (RCM) (n = 1), hyperthyroidism-induced cardiomyopathy (HTC) (n = 1) and immune checkpoint inhibitor-related myocarditis (ICIM) (n = 1). Baseline clinical characteristics and echocardiographic parameters are presented in Table Twenty-nine consecutive patients  with different subtypes of NICMs were included. Among these 29 patients, the diagnosis included dilated cardiomyopathy (DCM)  patients showed slightly diffuse activity in the right ventricle, including 1 RCM patient, 2 DCM patients, 3 HCM patients and 4 IC patients. The myocardial uptake in 68Ga-FAPI-04-avid patients (n = 22) was SUVmax = 4.16 ± 2.75, SUVmean = 2.09 ± 1.31, SUVR = 1.92 ± 1.18, along with the diverse radioactive volume of LVMV = 196.13 ± 64.93, respectively. Since patient numbers were not sufficient to compare tracer uptake among different subtypes of NICMs, we demonstrated the data in a pooled fashion , and LVMV was significantly correlated with LVESD .Twenty-two (75.9%) patients showed heterogeneous elevated them, 10 4.5% patiMolecular characterization of the extracellular matrix (ECM) in NICM may help identify therapeutic pathways to attenuate cardiomyocyte dysfunction and enhance myocardial regeneration. Fibroblast activation protein is one of the matricellular ECM proteins, which is involved in fibroblast activation and myofibroblast generation underlying myocyte injury. Cardiac fibroblasts activation and expansion significantly contribute to the pathogenesis of multiple cardiac diseases . Pioneer68Ga-FAPI-04 PET targeting FAP in different subtypes of NICM patients. We found that most enrolled patients presented elevated myocardial uptake with heterogeneous patterns and FAPI signal density is associated with cardiac contractility. In our previous cohort conducting 68Ga-FAPI-04 PET in patients with noncardiovascular indications, we did not observe elevated cardiac FAPI signal [In this study, we observed in vivo molecular imaging of In this preliminary study, we found heterogeneous diffused elevated FAPI signals within the left ventricular wall in different subtypes of NICM patients, and a distinct FAPI uptake value was observed within the same category of disease. We thought various disease pathogeny might be an explanation. For instance, for the enrolled inflammatory cardiomyopathies patients, the underlying diseases include inflammatory myopathy, vasculitis, systemic sclerosis, and systemic lupus erythematosus. Although inflammatory cardiomyopathies are associated with inflammatory cell infiltration into the myocardium, the underlying mechanism of the autoimmune response might be different . FAPI siAll in all, NICMs are essential and heterogeneous groups of diseases. Conventional imaging features for defined describing disease entities of cardiomyopathies may be limited with low sensitivity. FAPI PET imaging might provide essential information regarding the derivation and function of cardiac tissue or disease severity, potentially implicating a preferable strategy for visualizing cardiac diseases. The prognostic value of cardiac FAPI PET imaging in multiple NICMs post-systemic or targeted therapy also needs to be investigated. Although our study has some limitations, including a relatively small sample size and lack of a control group, we believe it provides important preliminary data on the potential use of the FAPI signal as a noninvasive biomarker for NICMs and warrants further investigation in larger and more diverse patient populations. Another limitation is that the fibro-activation signal in cardiac disease is transient, disease-dependent, and cannot be accurately associated with disease staging. The limitations of FAPI imaging underscore the need for a more comprehensive and nuanced approach to evaluating cardiac disease, which takes into account the dynamic changes in macrophage and fibroblast activity over time.68Ga-FAPI-04 cardiac PET, myocardial fibroblast activation density showed a significant correlation with ventricular function and remodeling. Thereby, this novel diagnostic strategy might be expected to further clinical validation and translation.To summarize, in this preliminary study, FAPI PET presented promising sensitivity in the detection of different subtypes of NICM diseases. As quantified by


Lung hyperinflation and systemic inflammation are currently believed to be the most important causes of right heart alterations in chronic obstructive pulmonary disease (COPD) patients. A multicentre observational study was performed to assess the morphological and functional parameters of right ventricle (RV) in COPD subjects, as well as to evaluate the potential prognostic impact on the development of major cardiovascular adverse events (MACEs).For this retrospective study, from 1 January 2010 to 31 December 2021, we enrolled COPD patients on the basis of their airflow limitation. In particular, we selected subjects spanning across GOLD 1 and 2 functional stages. Clinical, laboratory and functional parameters were collected at baseline. Echocardiography was routinely performed in all COPD patients. RV dysfunction was defined on the basis of tricuspid annular plane systolic excursion (TAPSE) values. MACE occurrence  was evaluated during a median follow‐up of 55 (36–72) months.p < .0001). The multivariate analysis model confirmed the association between RV dysfunction and MACE. Indeed, a 1‐mm increase in TAPSE value and the intake of long‐acting β2‐receptor agonists (LABA)/long‐acting muscarinic antagonist (LAMA) inhaled therapy were protective factors for the onset of MACE, while the presence of diabetes mellitus and high values of both uric acid (UA) and systolic pulmonary arterial pressure (S‐PAP) enhanced the risk of MACE in study participants.Among the 749 enrolled patients, 408 subjects had a TAPSE value ≥20 mm, while the remaining 341 had a TAPSE value <20 mm. In patients with TAPSE ≥20 mm the observed MACEs were 1.9 events/100 patient‐year, while in the group with a worse right heart function there were 4.2 events/100 patient‐year (The results of this study showed that in patients with mild COPD there is an association between right heart dysfunction and the risk of MACE during follow‐up. PH is often induced by COPD, idiopathic pulmonary fibrosis or chronic pulmonary thromboembolism. Among the different mechanisms underpinning an increase in pulmonary vascular resistance (PVR), the most studied is alveolar hypoxia. In this regard, pulmonary vasoconstriction is the result of either acute hypoxia or vascular structural remodelling due to hypoxaemia.Severity of pulmonary hypertension and development of cor pulmonale are two of the main factors involved in the mortality of patients with COPD. It has been observed that in these patients the onset of chronic cor pulmonale reduces survival up to 30%The main purpose of our present study was to assess the morphological and functional parameters of the right ventricle (RV) in COPD patients at early disease stages , as well as to evaluate the potential prognostic impact on the development of major cardiovascular adverse events (MACEs) during follow‐up.22.1In the present retrospective study, subjects of Caucasian ethnicity with COPD (GOLD stages 1 and 2) were recruited from 1 January 2010 to 31 December 2021 at the Clinic Units of Geriatrics and Respiratory Diseases of ‘Magna Graecia’ University Hospital of Catanzaro, Italy, and at the First Internal Medicine Unit of Sapienza University of Rome, Italy. A careful medical history was collected in all subjects by evaluating comorbidities, cardiovascular risk factors and drug therapy. A complete cardiovascular physical examination was carried out, and both body weight and body mass index (BMI) were also measured. Blood samples were collected for the determination of several laboratory parameters (see next paragraph). Spirometry and cardiac ultrasonography were also carried out. In particular, in our clinical practice echocardiography is routinely performed in all COPD patients referring to the above centres, with the aim of assessing the eventual impact of this respiratory disease on cardiac function.2) were excluded from the study. In addition, other exclusion criteria were the presence of inflammatory bowel disease or systemic autoimmune disorders . Reporting of the study conforms to broad EQUATOR guidelines.We selected study participants under bronchodilator treatment, according to their stratification across GOLD 1 and 2 functional stages. Patients included within GOLD stages 3 and 4 were not considered in this investigation, because our aim was to detect early COPD subjects with RV dysfunction before the occurrence of a severe worsening of their airflow limitation. Individuals with active cancer, heart failure with reduced or mid‐range ejection fraction (left ventricular ejection fraction <50%), advanced liver cirrhosis (Child‐Pugh C) and renal insufficiency . Blood levels of total cholesterol, low‐density lipoprotein (LDL) cholesterol, high‐density lipoprotein (HDL) cholesterol and triglycerides were analysed by enzymatic methods . Creatinine levels were measured using the Jaffe method. The estimation of glomerular filtration rate (eGFR) was based on the new CKD‐EPI (Chronic Kidney Disease Epidemiology Collaboration) equation.2.32. Left atrial diameter (LAD) was assessed using M‐mode or two‐dimensional echocardiography. Right ventricular systolic parameters were also measured, by estimating the systolic pulmonary arterial pressure (S‐PAP).Standard left ventricular ultrasonography in both M‐mode (motion mode) and B‐mode  was performed in all patients, according to the recommendations of the American Society of Echocardiography (ASE).2.4MACE and total mortality were identified as study endpoints. MACE included non‐fatal ischemic stroke, non‐fatal myocardial infarction (MI), coronary revascularization  and cardiovascular death. The diagnosis of myocardial infarction was made according to the universal definition proposed by the Joint ESC/ACCF/AHA/WHF.2.5t‐test was performed for unpaired data for continuous variables, Wilcoxon's test for unpaired data for non‐continuous variables and χ2 tests for categorical variables. The overall population was divided into two groups based on the TAPSE value (20 mm) as the main parameter of right ventricular function. The accuracy of the TAPSE parameter as a predictor of the onset of MACE, both as a continuous and categorical variable, was evaluated by processing a receiver operating characteristic (ROC) curve. The area under the curve (AUC) described how measure the value of TAPSE was associated with the onset of events. The incidence of events was calculated as the number of events per 100 patient‐year. Since the follow‐up was not uniform for all patients, the onset of MACE was not assessed at the same time, but a regression analysis based on the Cox proportional model was used, correcting the analysis for possible covariates associated with the finding of MACE. In particular, a univariate Cox regression model was performed on the incidence of MACE; subsequently, the variables that significantly correlated with the appearance of MACE were included in a multivariate Cox regression model to calculate the hazard ratio (HR) for the independent predictors associated with the incidence of MACE. The differences were considered statistically significant for p value <.05. All analyses were performed using the SPSS 26.0 statistical program for Windows .Data were expressed as mean ± standard deviation (SD) for normally distributed data, as median and interquartile range (IQR) for data not normally distributed, and as number and percentage for categorical variables. Student's 3Overall, 1121 COPD patients (GOLD stages 1 and 2) were screened. Among these, 749 subjects met the inclusion criteria, whereas 372 were excluded because of several reasons , and inhalation therapy with either long‐acting muscarinic antagonist (LAMA)  or long‐acting β2‐receptor agonists (LABA)/LAMA associations . On the other hand, they did not differ with regard to the assumption of monotherapy with LABA (p = .054).Table Table p = .340).During a median follow‐up of 55 (36–72) months, a total of 77 exacerbations (2.13 events/100 patient‐year) were observed, including 38 in the group of patients with TAPSE ≥20 mm (1.88 events/100 patient‐year) and 39 in the group of patients with TAPSE <20 mm (2.45 events/100 patient‐year) (p < .0001); non‐fatal coronary events were 20 (52.6%) in the first group (0.99 events/100 patient‐year) and 40 (60.6%) in the second group (2.51 events/100 patient‐year) (p = .0006), while non‐fatal cerebrovascular events were 16 (42.1%) (0.79 events/100 patient‐year) in the first group and 21 (31.8%) (1.31 events/100 patient‐year) in the second group (p = .154) . Cardiovascular deaths were 2 (16.7%) (0.09 events/100 patient‐year) in the first group and 5 (29.4%) (0.31 events/100 patient‐year) in the second one (p = .166) . Of these, 60 (57.7%) were non‐fatal coronary events (1.66 events/100 patient‐year), and 37 (35.6%) were non‐fatal cerebrovascular events (1.02 events/100 patient‐year) , compared with TAPSE as a dichotomous value   and as a dichotomous variable above and below the median (B). Figure ) Figure . Figure From the results of Cox linear regression analysis of the incidence of MACE, a statistically significant association was found with 1 mm increase in TAPSE value, 5 mmHg increase in S‐PAP and 1 mg/dl increase in UA values, presence of obesity, diabetes mellitus and exacerbations, intake of statins and dual inhalation therapy with LABA/LAMA Table . The var4The results of this study, conducted on a large population of patients with COPD (GOLD stages 1 and 2) and several cardiovascular risk factors, showed that there is an association between a good function of the right heart and a lower incidence of the main cardiovascular adverse events during follow‐up. In fact, in the entire population of COPD patients, it emerged that a higher TAPSE value, and therefore a better right heart function, was associated with a lower onset of MACE. In particular, a 1 mm increase in the TAPSE value is associated with a 33% reduction in the risk of developing a MACE. The analysis of the processed ROC curve and the measurement of the relative AUC have also demonstrated the accuracy of TAPSE as a predictor of MACE onset. The latter, on the other hand, is not significantly affected by the functional parameters of the left heart. Rather than FAC, RV strain or other RV function parameters, we chose TAPSE because it is easily detectable and reproducible in real‐life routinary echocardiographic evaluation of COPD patients with eventual cardiovascular comorbidities. Therefore, these results can be possibly explained by considering that several risk factors for COPD and MACE are similar. In this regard, it is noteworthy that smoking, diabetes and other metabolic dysfunctions such as hypercholesterolemia are frequently associated with both COPD and MACE, rather than RV function.Another data that emerged from our study concerns the intake of inhalation therapy with LABA/LAMA, which reduces the risk of developing MACE by 19%, so that patients under dual inhaled therapy have a better prognosis than patients treated with single inhaled therapy. This result is quite interesting. Indeed, it is likely that more symptomatic COPD patients often complain of decreased RV function. On the other hand, by significantly decreasing lung hyperinflation, LABA/LAMA dual bronchodilation probably provides relevant benefits also with regard to cardiac outcomes. Independent predictors of MACE onset were found to be the presence of cardio‐metabolic risk factors, such as diabetes mellitus and an increased UA value, as well as the presence of higher S‐PAP values. In particular, our present results strongly suggest that TAPSE and S‐PAP are potentially crucial for prediction of MACE onset. In our opinion, this association represents the major strength of this study.The presence of diabetes increased by more than double the risk of MACE in COPD patients. Emerging data also show that diabetes mellitus is associated with right heart dysfunction; the results of a previous study conducted by our group have indeed shown that in patients with newly diagnosed and never treated hypertension, subjected to an oral glucose load curve and with glycaemic values at one hour ≥155 mg/dl, with intolerance to carbon hydrates or diabetics, worse right heart function parameters were found , as well as higher values of S‐PAP and PVR.Furthermore, we herein demonstrate the influence of another parameter, namely UA, on the prognosis of our population with COPD; in fact, it was observed that in these patients a 1 mg/dl‐increase of UA resulted in a 12.5% increased risk of developing MACE. The role of UA in subjects with COPD in the initial phase of the disease was also analysed in a previous study carried out by our group, which documented that UA is an independent predictor of the onset of renal dysfunction as well as of the rapid decline in renal function in these patients; the 1 mg/dl increase in serum UA values increased the risk of the incidence of chronic kidney disease by 14.8%.In light of these results, it should be essential to implement and optimize a combined therapeutic strategy aimed to improve both cardiac and respiratory function, as well as to evaluate coexisting risk factors, in order to reduce comorbidity and mortality in COPD patients, thus improving the overall prognosis.All authors contributed to design and carry out the study protocol as well as to write the text.This research received no specific grant from any funding agency in the public, commercial or not‐for‐profit sectors.The authors declare that there is no conflict of interest.


However, electrical and mechanical function are often studied separately—despite growing proof of a complex electro-mechanical interaction in cardiac physiology and pathology. Therefore, we developed an isolated mouse heart perfusion system that allows simultaneous recording of electrical and mechanical function.The Langendorff-perfused Isolated mouse hearts were mounted on a Langendorff setup and electrical function was assessed via a pseudo-ECG and an octapolar catheter inserted in the right atrium and ventricle. Mechanical function was simultaneously assessed via a balloon inserted into the left ventricle coupled with pressure determination. Hearts were then submitted to an ischemia-reperfusion protocol.At baseline, heart rate, PR and QT intervals, intra-atrial and intra-ventricular conduction times, as well as ventricular effective refractory period, could be measured as parameters of cardiac electrical function. Left ventricular developed pressure (DP), left ventricular work (DP-heart rate product) and maximal velocities of contraction and relaxation were used to assess cardiac mechanical function. Cardiac arrhythmias were observed with episodes of bigeminy during which DP was significantly increased compared to that of sinus rhythm episodes. In addition, the extrasystole-triggered contraction was only 50% of that of sinus rhythm, recapitulating the “pulse deficit” phenomenon observed in bigeminy patients. After ischemia, the mechanical function significantly decreased and slowly recovered during reperfusion while most of the electrical parameters remained unchanged. Finally, the same electro-mechanical interaction during episodes of bigeminy at baseline was observed during reperfusion.Our modified Langendorff setup allows simultaneous recording of electrical and mechanical function on a beat-to-beat scale and can be used to study electro-mechanical interaction in isolated mouse hearts. With thIsolated mouse heart models have been widely used to test the effect of gene mutations on cardiac physiology due to the fast and easy manipulation of the mouse genome. However, in most of the isolated mouse heart models used to investigate IR described in scientific literature, contractile and electrical cardiac function are studied separately. Yet, there is a complex relationship between electrical and mechanical function in cardiac physiology. Electrical excitation triggers the contractile activity of the heart (through excitation-contraction coupling), but mechanical activity can also affect the electrical activity  –12. IndeTherefore, we developed an isolated mouse heart perfusion system to simultaneously assess cardiac electrical and mechanical function. We showed that our model can recapitulate pathophysiological electro-mechanical interactions, and we tested this approach in a specific example of a global ischemia-reperfusion protocol. We finally suggest that this approach might be useful to better understand the complex mutual influence between electrical and mechanical cardiac function.2.Equipment and reagents used in this study are listed in 3.3.1.All performed experiments were in accordance with EU legislation (directive 2010/63/EU) and the Swiss animal welfare law and have been approved by the Swiss animal welfare authorities .−/−) and transgenic K18-hACE2 mice were purchased from the Jackson laboratory and cross bred to obtain K18-hACE2-Ldlr-/-mice. Eight-week-old female and male animals were housed in groups at 22°C with a 12 h day/night cycle, food/water supply ad libitum and 12 weeks of Western-type diet (WD) to induce a cardiovascular disease phenotype. One week before the end of the WD feeding period, mice were also treated with 50 µg CpG oligodeoxynucleotides + 100 µg Polyinosinic:polycytidylic acid [Poly(I:C)] antigens every second day and three times in total to induce an inflammatory setting. The animals were euthanized three days after the last injection. These mice represent the control group of larger set of animals investigated during a Covid-19 research project, which will be published separately. However, to establish and validate the method of simultaneous mechanical and electrical function determination in Langendorff-perfused mouse hearts, as well as to allow proper understanding and replication of our experimental set up, we aimed to generate a separate paper to concentrate on technical aspects of the experimental system.Low-density lipoprotein receptor knock-out mice  perfusion, followed by 25’ normothermic, global ischemia, and 60’ aerobic reperfusion .3.3.1.P wave and QRS complex of the extracardiac electrocardiogram. Representative traces are shown in Mice were administered 100 µg/g bodyweight ketamine  and 8 µg/g bodyweight xylazine  by intraperitoneal injection. The pedal pain withdrawal reflex was used to ensure sufficient depth of anesthesia. Mice were brought into a supine position and the thoracic cavity was accessed via midline skin incision and bilateral thoracotomy. The heart was then carefully explanted and transferred to a petri dish containing 50 ml ice-cold 0.9% NaCl and 0.5 ml of heparin . While fully submerged in the solution, the aorta was cannulated with a blunt 22 G needle using a stereomicroscope . The cannulated heart was then quickly connected to the perfusion system. The 1.1 F intracardiac octapolar catheter was gently inserted into the right atrium through a small incision and was then advanced to the right ventricle with an angle following the axis of the heart. Then, two silver wires were put in place at the root of the aorta and base of the heart. Proper positioning of the electrodes was visualized by an overlay of the intracardiac electrocardiogram signals with the 3.3.2.2PO4 1.2, CaCl2 1.5, MgSO4 1.2, (D+) Glucose 11.1, NaHCO3 25, Pyruvate 2) using the non-recirculating Langendorff circuit at a constant pressure of 60 mmHg. The system was then switched to the recirculating Langendorff circuit for all aerobic periods and perfused with the same modified Krebs-Henseleit buffer supplemented with 1.2 mM palmitate and 3% albumin at a constant pressure of 60 mmHg. To make this buffer the palmitate was initially dissolved in 40% ethanol containing 0.5–0.6 g Na2CO3 per g of palmitate. After evaporating the ethanol by boiling the mixture, it was quickly added to a 3% albumin Krebs-Henseleit solution to bind the palmitate to the albumin with continuous stirring. This solution was then filtered with a sterile filter system. During ischemia, hearts were immersed in a warm (37°C) ischemic bath with energy-substrate-free modified Krebs-Henseleit buffer   was used to monitor and record temperature, electrical signals, left ventricular pressure, and flow data throughout the perfusion protocol. Two-minute time windows were then analyzed after 20 min of baseline and 10, 20, 30, 40, and 60 min of reperfusion using LabChart Pro v8  as shown in 3.3.3.Left ventricular systolic pressure (LVSP) as well as left ventricular diastolic pressure (LVDP) were measured  to measure heart rate, PR and QT intervals. Intra-cardiac EP signals and intra-atrial and intra-ventricular conduction times were determined using the 1.1 F octapolar intracardiac catheter as shown in the representative traces in 3.4.P < 0.05 was considered statistically significant and tests used in each experiment are specified in the figure legends.Statistical analyses were performed using Prism 9.5.1 (GraphPad Software). Data are expressed as mean ± the standard error of the mean (SEM) unless stated otherwise [4.4.1.ex-vivo perfused mouse hearts. From the octapolar catheter inserted in the right atrium and ventricle  and ventricle (channels 1–3). Finally, the ventricular effective refractory period (VERP) can be measured by pacing the ventricles with a S1–S2 stimulation protocol   . At basefemales) . On averart rate . As expe4.2.ex-vivo perfused hearts to see how the mechanical function reacts to a change in the electrical activity.The advantage of simultaneous assessment of electrical and mechanical function is that it allows a better understanding of the electro-mechanical interaction, i.e., how electrical activity impacts on contraction, and vice versa. We, therefore, looked at spontaneous arrhythmia occurrence in The combined use of the intracardiac octapolar catheter with the ECG allowed us to better define arrhythmia, such as extrasystole, and whether the ectopic signal originates from the atria  or the ventricles  . At base−1), and a significant decrease in LV work  and dP/dt min   . InteresmHG.s−1) .4.3.ex-vivo Langendorff perfused hearts can be combined with any experimental conditions. Here we decided to perform global ischemia for 25 min followed by 1 h of reperfusion. After ischemia, the mechanical function dropped drastically with a significant decrease in DP , LV work , dP/dt max  and dP/dt min  at 10 min reperfusion  and decreases in LV work  and dP/dt min   . In addimHg.s−1) . TherefomHg.s−1) .These results suggest that the electro-mechanical interaction is preserved after global ischemia-reperfusion and that the decrease in mechanical function  after is5.ex-vivo perfused mouse hearts. We also demonstrate that this approach can be combined with varied experimental conditions such as global ischemia-reperfusion. In addition, although this Langendorff setup was designed for mouse hearts, this should be readily transposable to larger mammal hearts such as rabbits with some adjustments for size.This manuscript presents an approach to simultaneously assess electrical and mechanical function in 5.1.ex-vivo perfused hearts are investigated separately  can affect the mechanical function. Inversely, one can see how changes in the mechanical function  can influence electrical properties.Here we investigated the effect of brief episodes of bigeminy on the cardiac mechanical function. Comparison between episodes of bigeminy and episodes of sinus rhythm within the same hearts showed a significant improvement in DP and maximal velocity of contraction and relaxation in the subsequent beats following the extrasystole . In cont5.3.ex-vivo Langendorff-perfused hearts. Here we showed an example of global ischemia-reperfusion with continuous monitoring of both electrical and mechanical function. Interestingly, except for the increased VERP, global ischemia-reperfusion did not affect electrical parameters, even at an early stage of reperfusion (10 min) (2+ overload due to increased Na+/H+ exchange and subsequent reverse mode of the Na+/Ca2+ exchanger (2+ responsiveness where Ca2+ dynamics (Ca2+ transient generation) is normal, but the contractile response is reduced  . Diastol(10 min) , 40. On (10 min) . This de(10 min) . It is m(10 min) –44. Uponxchanger , 45, 46, reduced , 47, 48.Interestingly, during reperfusion, we still observed the same contractile response during bigeminy as what was previously seen at baseline. Indeed, the extrasystole-triggered contractions were only 50% as strong as in sinus rhythm, while the subsequent contraction had an increased DP and maximal velocity of contraction and relaxation . Therefo6.Our approach was designed for heart perfusion with the Langendorff method, a technique for which the perfusion is forced into the coronaries. Hence, the left ventricle is not exposed to blood/perfusate-induced mechanical strains. Therefore, it will be interesting to try adapting our approach to a perfusion system of working hearts to recreate a more physiological electro-mechanical interaction.7.Our study presents an approach for simultaneously assessing electrical and mechanical function in Langendorff-perfused mouse hearts on a beat-to-beat scale. We show that this approach can be combined with any experimental conditions in Langendorff-perfused heart with an example of global ischemia-reperfusion. With this approach, we hope to better understand the complex mutual influence of cardiac electrical and mechanical function under physiological and pathophysiological conditions.


The right ventricle (RV) plays a central  role in the maintenance of effective cardiac pump function. Despite overwhelming evidence that perioperative RV dysfunction (RVD) and failure (RVF) are associated with poor clinical outcomes, there are very few published recommendations or guidelines for comprehensive, evidence-based RV assessment on the risk of developing either during the perioperative period.To address this gap, the Perioperative Quality Initiative-IX (POQI-IX) investigators group, comprised of clinical experts in anesthesiology, cardiovascular surgery, internal medicine, critical care medicine, and advanced practice nursing, has developed a consensus statement based on current literature, published society recommendations, and the clinical expertise of the group. Herein, the group provides recommendations and evidence-based tools related to perioperative RV assessment, functional screening, staging, and the clinical implications of each. These assessment tools are based on comprehensive patient evaluation consisting of physical examination, biomarker data, imaging, and hemodynamic assessment.This review presents a comprehensive tool for assessing perioperative RV function. We hope that this simple, intuitive tool can be applied to all phases of perioperative care and thereby improve patient outcomes. Right ventricular (RV) function is integral to cardiac pump function through providing preload to the left ventricle and systemic circulation and maintaining interventricular interdependence  that combines patient and surgical risk factors before surgery. The following is an account of how PIRRAT can be used in different clinical circumstances and settings. As a novel clinical tool however, PIRRAT would benefit from further testing and validation against usual standard practices in a broad sample of practice settings including inpatient, outpatient, multi-specialty, and single-specialty centers. The screening tool should be subjected to sensitivity and specificity analysis, and practicality, feasibility, and cost-effectiveness in a real clinical setting should be evaluated to ensure the tool’s suitability for use in healthcare practice. As an initial step toward developing a much-needed clinical screening tool, the POQI-IX group devised an instrument that we believe can accurately measure the clinical construct it is intended to assess based on a review of the literature and multidisciplinary expertise.PIRRAT aims to provide an initial framework for research to validate its accuracy for identifying at-risk patients. We propose that PIRRAT be used to preoperatively screen all patients with no known advanced cardiac disease using available clinical information. In patients with elevated PIRRAT scores, additional testing such as BNP and/or TTE and optimization of RV function is recommended prior to proceeding to surgery. As a disclaimer, patients with a known history of comorbidities associated with elevated risk to RVD , pulmonary hypertension, congestive heart failure, and severe cardiac valvulopathies) should undergo comprehensive perioperative cardiac testing appropriate for the disease process and planned surgical procedure.The PIRRAT scoring tool is divided into three categories: medical risk factors, surgical or procedural risk factors, and functional status Table . In addiSurgical or procedural approaches that increase intrabdominal and thoracic pressure, increase the risk of hypercarbia and hypoxemia, or last longer than 3 h have the potential to cause right heart strain and RVD  and no surgical risk factor. With a functional status of 2, this patient’s total score is 4 + 0 = 4 × 2 = 8. With a PIRRAT score of 8, no additional assessment is warranted.A 58-year-old long-time smoker with chronic obstructive pulmonary disease who presents to the operating room for a laparoscopic hysterectomy in the Trendelenburg position has two patient risk factors (smoking and chronic lung disease) and two surgical risk factors (pneumoperitoneum and Trendelenburg position). With a functional status of 4, this patient’s total score is 2 + 2 = 4 × 4 = 16. With a PIRRAT score of 16, a BNP measurement is warranted. If the institution does not provide BNP measurements, this patient should have a TTE or TEE assessment of the right ventricular function before surgery.A 76-year-old obese smoker with OSA with wheezing on expiration is scheduled for laparoscopic cholecystectomy and has four patient risk factors  and two surgical risk factors (pneumoperitoneum and Trendelenburg position). With a functional status of 4, this patient’s total score is 4 + 2 = 6 × 4 = 24. With a PIRRAT score > 20, a BNP measurement and a TTE or TEE assessment of the right ventricular function are warranted. If the RV function is reduced, consider referral to a specialist for hemodynamic assessment.In addition to the example provided in the Table The PIRRAT scoring system described above can be used preoperatively to identify patients who have or are at risk of developing RVD and to guide further preoperative testing. Once a patient has been assigned to one of the 3 PIRRAT scoring categories Table  and the “Low risk” for RVD describes a patient who is not experiencing any signs or symptoms of RVD but is at risk for developing RVD during the perioperative period. Patients like this may appear well with a normal physical examination and laboratory values. However, they may have a history of chronic lung disease, high body mass index, or venous thromboembolic disease predisposing them to perioperative RVD. They may be scheduled for a high-risk procedure  that can lead to increased pulmonary vascular resistance and RVD. For the comprehensive list of risk factors, please refer to Table “At risk” for RVD describes a patient who has no clinical evidence of RVD but has two or more predisposing risk factors  describes a patient with signs and symptoms of heart failure and systemic hypotension. These patients may present with jugular venous distension, hepatomegaly and ascites, lower extremity edema, and reduced urine output. RVF is associated with impaired kidney function ; elevated lactate, BNP, and liver enzymes; and decreased synthetic function  and/or low albumin). Patients with RVF have low CO and low mixed venous oxygen saturation.“RV shock” describes a patient with RVF who is resistant to pharmacological intervention and requires mechanical circulatory support. Patients in RV shock may have altered mental status with cold, clammy, or even mottled and dusky extremities. BNP is elevated, and cardiac imaging and advanced hemodynamic assessment reveal a profoundly underperforming RV.Established modalities for assessing RV function, for which normal values have been defined, are essential for reliable of diagnosis and monitoring of perioperative RVD. Understanding the roles, strengths, and limitations of each modality will enable more accurate assessment for clinical management. Each modality, including biomarkers, imaging, and hemodynamic assessment, may have multiple types of measurements that can be performed. Given a choice, the preferred measurement should always be the most consistent measurement available for each stage of care. Since the most accurate measurement is not always feasible, this group will also recommend the most commonly used measurement or an alternative that should be available in most institutions.A thorough history and physical examination should always be the initial step in clinical diagnosis and care delivery. Jugular venous distension (JVD) and peripheral edema are non-sensitive and non-specific signs of RVD and should be used cautiously when diagnosing and treating perioperative RVD  measurement is a well-validated biomarker of LV failure, and it is a useful prognostic and risk stratification marker for RVD in patients with pulmonary hypertension. There is a paucity of data supporting its use specifically in RVD screening, but there is reasonable data supporting BNP as a screening tool for perioperative assessment of early or not previously known at-risk cardiac disease at large (Casserly and Klinger Cardiac magnetic resonance (CMR) is considered the gold standard imaging tool for assessing RV function against which other modalities should be compared  is the most consistent imaging measurement of systolic RV function, with the strongest prognostic value regardless of modality . FAC is a global assessment that incorporates radial and longitudinal components of RV contraction. It outperforms unidirectional measures of RV function and correlates more closely with CMR when compared to peak RV systolic myocardial velocity (S’) and tricuspid annular planar systolic excursion (TAPSE). TAPSE and S’ are reasonable alternatives as they are easy to perform and can identify patients with abnormal RVD within limitations  provides a range of essential hemodynamic measures including RA or central venous pressure (CVP), pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP) as a surrogate for left ventricular end-diastolic pressure, RV cardiac output (CO), and mixed venous oxygen saturation. In the setting of established RVD going for an at-risk surgery, we recommend using a PAC for measuring CVP, PAP, PCWP, and CO. This is concordant with recommendations of major societies ?” Echocardiographically, early signs of RVF include progressive RV dilation and interatrial leftward septal bulging. In addition, continuous monitoring and assessment of right heart waveform morphology are emerging as a potentially useful way to predict RVD. Moreover, continuous monitoring and assessment of right heart waveform morphology is emerging as a potentially useful way to predict RVD. For example, right atrial A wave equal to or greater than V wave indicates RVD, while A wave less than V wave and a pronounced Y-descent indicates RVF. Continuous right ventricular pressure waveform monitoring using an Oximetry Swan Ganz Paceport catheter  is another emerging technique to detect early signs of deteriorating RV function  and outline how this may synthesize patient and surgical risk factors to guide preoperative workup before surgery. We have also drafted an RV function staging system to aid perioperative risk stratification, resource allocation, and when to escalate care. In creating these tools, we hope to provide a simple yet comprehensive system that may permit busy clinicians to organize their approach to the assessment and management of right heart dysfunction in the perioperative setting. Before adoption, both tools will need validation. We hope that these tools eventually lead to improved clinical care delivery and patient outcomes.


The present study aims to assess and describe the intracardiac blood flow dynamic in patients with mitral regurgitation (MR), repaired mitral valves (MV) and mitral valve prostheses using vector flow mapping (VFM).Patients with different MV pathologies and MV disease treatments were analysed. All patients underwent 2D transthoracic echocardiography, and images for flow visualization were acquired in VFM mode in an apical three-chamber view and four-chamber view. Vectors and vortices were qualitatively analyzed.thirty-two (32) patients underwent 2D transthoracic echocardiography (TTE) with VFM analysis. We evaluated intracardiac flow dynamics in 3 healthy subjects, 10 patients with MR , 4 patients who underwent MV repair, 5 who underwent MV replacement , 2 surgically implanted transcatheter heart valve (THV), 2 transcatheter edge-to-edge MV repair with MitraClip (TEER), 3 transcatheter MV replacement (TMVR) and 3 transapical off-pump MV repair with NeoChord implantation. Blood flow patterns are significantly altered in patients with MV disease and MV repair compared to control patients. MV repair is superior to replacement in restoring more physiologicalpatterns, while TMVR reproducesan intraventricular flowcloser to normal than surgical MVR and TEER.Intracardiac flow patterns can be clearly defined using VFM. Restoration of a physiological blood flow pattern inside the LV directly depends on the procedure used to address MV disease. The study of intracardiac flow patterns has been initially performed using cardiac magnetic resonance –4. More The present article aims to systematically describe the intracardiac blood flow patterns of the entire spectrum of MV regurgitation disease and the possible alternative techniques to address it.Between June 1st, 2021 and January 31st, 2022, healthy subjects, patients with functional and degenerative MV disease and patients who underwent MV treatments at our Centre, either surgical or transcatheter, were included in the study. The reason for MV surgical or transcatheter MV treatment was isolated MR, either degenerative or functional. All patients who underwent MVRe or MVR presented with degenerative disease, while patients undergoing transcatheter procedures presented variably with degenerative or functional disease. No other procedures were performed. Patients with inadequate acoustic window and/or atrial fibrillation at the time of image acquisition were excluded from the study. All patients signed a dedicated informed consent before being included in the present study that was approved by the local Ethical Committee. At 1 month after surgery all patients underwent dedicated 2D transthoracic echocardiography. None of the patients had TTE both before and after surgery. Intracardiac flow images were recorded using a 5-MHz matrix array single crystal technology ultrasound transducer . Images for flow visualisation were acquired in VFM mode in an apical three-chamber view and four-chamber view. All images were acquired in three consecutive cardiac cycles with a target frame rate set inthe range of 20–25 frames/s. The color Nyquist limit was set sufficiently high to mitigate aliasing phenomena, and automatic self-aliasing was used as well. The Doppler signal provided the axial component of the blood velocity, while the time-varying position of the boundaries  was obtained from 2D STE. The offline analysis was computed with dedicated software . The cardiac cycles were determined according to the valve openings and closings with the synchronous ECG: T wave defined the end of the contraction, while the R peak of the QRS complex set the end of the diastolic phase. The LV endocardial border was traced in the first frame image, and the software automatically tracked the endocardial border throughout the cardiac cycle. After determining the ROI, qualitative images (velocity vectors and streamlines) were displayed in 2D for each frame of the cine loop image.Energy loss expresses the amount of energy dissipated as heat in the LV by viscous friction in turbulent blood during the process of relaxation (diastole) and contraction (systole). Since turbulent flow results in an irreversible loss of the total fluid energy, the higher the EL, the greater the LV inefficiency. After tracing the ROI of the LV cavity, a sample line was placed at the level of the mitral annulus  and in the LV outflow tract to acquire the time-flow curves of the diastolic and systolic period, respectively. Therefore, EL is quantified as the sum of the square of the difference between adjacent velocity vectors:Thirty-two (32) patients were evaluated. We included 3 healthy individuals to describe the normal intracardiac flow patterns. Ten (10) patients presented severe mitral regurgitation (MR) , 4 patients underwent MVRe , 5 patients had a surgical mitral prosthesis , 2 patients had a Sapien 3 transcatheter heart valve  surgically implanted through the left atrium with anterior mitral leaflet resection, 2 patients underwent transcatheter edge-to-edge mitral valve repair (TEER) with a MitraClip , 3 patients had a transcatheter mitral valve replacement (TMVR) with a Tendyne prosthesis  and 3 patients underwent transapical off-pump mitral valve repair with NeoChord implantation .Out of the 5 patients with DMR 2 had an extensive posterior multi-scallop disease (Barlow-type), while the other 3 presented with fibroelastic deficiency and less extensive leaflet involvement . Patients with FMR had underlying ischemic cardiomyopathy in 2 cases while primitive dilative cardiomyopathy in 3 cases.All mechanical valves were bileaflet Regent prostheses , while all implanted biological valves were Mosaic porcine prostheses . All patients had their subvalvular apparatus preserved, and in case of mechanical replacement, the prosthesis had an antianatomical orientation.In all cases of MVRe, a semi-rigid Simulus annuloplasty ring was used .Both patients who underwent TEER primarily presented with ischemic cardiomyopathy and showeda residual mild-to-moderate MR after the procedure. TMVR with low-profile Tendyne prosthesis was performed in patients with FMR due to dilative or ischemic cardiomyopathy. All patients treated with Sapien 3 prosthesis presented severe mitral annular calcification (MAC) and underwent concomitant anterior mitral leaflet resection (AML) to prevent the occurrence of potential left ventricular outflow tract (LVOT) obstruction.The three patients who underwent Neochord procedure presented degenerative MR involving the posterior mitral leaflet (PML) with preserved LV function. One of them previously underwent mitral valve repair receiving isolated annular ring implantation.Complete transthoracic echocardiography data and procedural details of the patients which were selcted as images and video examples for each condition are reported in In the healthy controls , blood eIn patients with DMR ,the diasAfter MVRe, the intracavitary blood flow pattern is mostly restored . WhetherAfter MVR with bioprostehsis , we can After TEER , during The three patients who underwent TMVR presented a nearly normal flow pattern . During In the two subjects who underwent surgical implantation of a Sapien 3 THV , there wAfter Neochord Procedure , we obseGraphical representation of our findings is also shown in More images and videos depicting the intracavitary vortices and the enery loss loops are available as There is increasing interest in studying intracardiac blood flow patterns to clarify the physiopathological mechanisms at the base of different cardiac conditions, and various imaging techniques have been developed over the last few years , 14. ApaThis is the first comprehensive description of LV flow patterns in MV disease using VFM. The main findings of our descriptive analysis are that intracardiac blood flow patterns are restored after MVRe independently from the repair technique, MVR  is affected by the persistence of altered blood flows, TEER completely alters LV vortices and TMVR with Tendyne valve has a similar effect to MVRe on flow patterns restoration .Our findings in healthy subjects are largely comparable to those reported in the literature. The physiological flow pattern was also confirmed in our healthy subjects. However, we did not observe prolonged persistence of vortices during early systole as elsewhere described , 23. ThiThe conservation of the kinetic energy is enabled by the presence of vortices, particularly the anterior clockwise vortex, which appears beneath the AML. The formation of this vortex is guaranteed by the higher length of the AML comparedto the PML and the apical direction of the flow through the MV, as previously described by Pedrizzetti et al. .MVRe preserves this difference in length since surgeons usually try to maintain the physiological 2/3:1/3 ratio between AML and PML surface mostly reducing the PML height to prevent an anteriorly displaced coaptation line that would increase the risk of AML systolic anterior motion. Our observations were consistent with these findings since in all patients who underwent MVRe we could appreciate the formation of a large anterior vortex that pushed the blood flow towards the posterior LV wall helping the flow entering the LVOT. In our experience, similarly to what was reported by other groups , the typAlso, our observations confirm that MVR does not restore physiological flow patterns , 9. OtheFinally, TEER completely disrupts the LV physiological vortices creating turbulent flow during diastole and systole. There are no reports about intracardiac patterns after TEER, and ours are the first descriptive findings. We hypothesize that this flow disarray is due to the combination of two elements. First, the creation of a double orifice valve with the major axis oriented at 90° with respect to the LV major axis as it is observed for mechanical valves in antianatomic orientation; second, the presence of a rigid element (the clip) attached to the leaflets that prevents the normal swirling of the blood flow around the tips of the leaflets. This finding should be carefully evaluated since TEER is frequently indicated in patients with reduced LV function, who might be the ones that might benefit the most from the restoration of normal LV flow patterns reducing LV workload and enhancing LV function recovery.Three subjects of the study population presented HFrEF, one of them underwent TEER, another received a surgical bioprosthesis, and the third one had TMVR. In all cases, LV impairment was due to global hypokinesia with no regional wall motion abnormalities and with PML tethering. HFrEF was associated with altered intracardiac flow patterns  in the pThe main limitation of the present research is the small, heterogeneous sample size. However, this is a pivotal study analyzing all currently available MV treatments. It couldopen up the field of VFM analysis of MV surgery to define the optimal strategy to address MV disease.Moreover, VFM evaluation is based on echocardiography which is operator dependent. All studies and post-processing analyses were performed by the same operator. More reproducible imaging techniques exist, such as cardiac MR, butthey are more expensive, present several limitationsand are less tolerated by the patient.Finally, this is a 2D-TTE study. As demonstrated by the wide flow disruption after TEER in all 3 dimensions of the space, it is plausible that some of the vortices might have been missed because out of the imaging plane. 3D-TTEmight overcome this problem and shed new light on intracardiac flow mapping.In conclusion, our findings confirm that intracardiac flow patterns are altered in patients with mitral disease and that MVRe is superior to MVR in restoring normal patterns. Based on our observations, TMVR might represent a better strategy than TEER to optimize LV function in the mid and long-term, thanks to its nearly normal flow patterns. Finally, better angulation of prosthetic valves and anatomical orientation can lead to more physiological intracardiac flow dynamics.Our findings, even if qualitative and limited to a small study population, suggest that the treatment used to correct MR have an impact on postoperative intracardiac flow patterns. In the surgical community is a shared knowledge that MVRe is preferable over MVR because of better long-term outcomes. Similarly, TEER is associated with improved survival and symptoms only in selected patients. We believe that further studies of postprocedural intracardiac flow patterns can explain these differences supporting one therapy over another because more efficient in preserving or restoring physiological flow patterns.