MRI T2 mapping has been proven to be sensitive to the level of blood oxygenation. We hypothesized that impaired exercise capacity in chronic heart failure is associated with a greater difference between right (RV) to left ventricular (LV) blood pool T2 relaxation times due to a higher level of peripheral blood desaturation, compared to patients with preserved exercise capacity and to healthy controls.Patients with chronic heart failure (n = 70) who had undergone both cardiac MRI (CMR) and a 6-min walk test (6MWT) were retrospectively identified. Propensity score matched healthy individuals (n = 35) served as control group. CMR analyses included cine acquisitions and T2 mapping to obtain blood pool T2 relaxation times of the RV and LV. Following common practice, age- and gender-adjusted nominal distances and respective percentiles were calculated for the 6MWT. The relationship between the RV/LV T2 blood pool ratio and the results from 6MWT were evaluated by Spearman’s correlation coefficients and regression analyses. Inter-group differences were assessed by independent t-tests and univariate analysis of variance.The RV/LV T2 ratio moderately correlated with the percentiles of nominal distances in the 6MWT (r = 0.66) while ejection fraction, end-diastolic and end-systolic volumes showed no correlation . In addition, there were significant differences in the RV/LV T2 ratio between patients with and without significant post-exercise dyspnea (p = 0.001). Regression analyses showed that RV/LV T2 ratio was an independent predictor of the distance walked and the presence of post-exercise dyspnea (p < 0.001).The proposed RV/LV T2 ratio, obtained by two simple measurements on a routinely acquired four-chamber T2 map, was superior to established parameters of cardiac function to predict exercise capacity and the presence of post-exercise dyspnea in patients with chronic heart failure.The online version contains supplementary material available at 10.1186/s12968-023-00943-y. Heart failure (HF) is estimated to affect approximately 26 million people worldwide with prevalence steadily increasing due to an aging society –3. DespiOne of those, the 6-min walking test (6MWT), a simple walking exercise, was first proposed in 1985 and since has been rigorously validated in clinical and scientific contexts . The 6MWCardiac MRI (CMR) has a class I recommendation for the characterization of myocardial tissue and ventricular function according to the joint recommendations by the Society for Cardiovascular Magnetic Resonance (SCMR) and the European Association for Cardiovascular Imaging (EACVI) as well as the guidelines by the European Society of Cardiology (ESC) , 13.In addition, the current clinical recommendations by the SCMR state that parametric mapping provides incremental value in the workup of patients with heart failure . SpecifiBased on this mechanism, we hypothesized that impaired exercise capacity in HF is associated with a greater difference between right (RV) to left ventricular (LV) blood pool T2 relaxation times due to a higher level of peripheral blood desaturation, compared to patients with preserved exercise capacity and to healthy controls (HC). Thus, the aim of this study was to correlate the RV/LV T2 ratio with functional exercise capacity in patients with chronic HF who had previously undergone both CMR and 6MWT.The local ethics committee approved the protocol of this retrospective study with a waiver for informed consent [reference number 837.196.13 (8881-F)].A total of 271 patients who underwent CMR in 2021 were screened for the following inclusion criteria: (1) presence of chronic HF according to current guidelines ; (2) com. within the European CMR registry [Image quality assessment was performed by 2 independent observers (T.E. and M.C.H.) with 13 and 5 years of experience in the field, respectively. A third observer  mediated disagreement. The quality assessment was conducted based on the protocol validated by Klinke et alregistry . Image sAdditionally, 35 propensity score matched HC, who had previously participated in a prospective study to establish institutional CMR reference values, were included in this study. Propensity score matching was performed based on factors that are known to influence 6MWT including age, sex, weight, and height.Demographic parameters, results from the 6MWT, objective lung function analysis results, and HF symptoms as rated on the New York Heart Association (NYHA) scale were derived from the electronic patient records.All subjects underwent CMR  at 3 Tesla (T). Short- and long-axis views of standard balanced steady-state free precession cine acquisitions, T1 and T2 maps in short-axis views and four-chamber views were included among other routine sequences in a comprehensive clinical protocol. For T2 mapping, a commercially available sequence with 3 preparation pulses (0/30/55 ms) and a 3-heartbeat recovery period was used. All maps were acquired in the diastolic phase. Additional pulse sequence parameters can be found in Table End-diastolic (EDV) and end-systolic (ESV) volumes, ejection fraction (EF), and cardiac output index (CI) were calculated for both ventricles by semi-automatically drawn endocardial contours on the short-axis stack, using all three long-axis views as references. Subsequently, all volumes were indexed to body surface area (BSA).2 were placed in artefact free areas of the RV and LV blood pool, and the mean relaxation times were recorded  with a minimum size of 1.5 cmMidventricular short-axis slices of native and post-contrast maps were semi-automatically segmented with a 25% endo- and epicardial offset margin. Together with haematocrit values, these were then used to calculate extracellular volume fraction (ECV). Quantitative assessment of late gadolinium enhancement (LGE) was performed using the semi-automated 5-standard deviation (SD) method on basal, midventricular and apical short-axis slices on phase-sensitive inversion recovery (PSIR) sequences acquired 10 min after administration of 0.2 mmol/kg gadoteric acid, as recommended by the SCMR . Using tsys), heart rate (HR) and peripheral capillary oxygen saturation (SpO2) were measured. Patients were then instructed to walk as fast as possible on a marked course without changes of direction for six minutes. Changes in speed and breaks were allowed. After six minutes, the distance reached was recorded and post-exercise parameters were measured . In addition, the patient was asked to subjectively rate the level of dyspnoea on a modified Borg scale from 0 to 10. Patients with a subjective rating of 4 (“somewhat severe”) or higher were considered as having significant post-exercise dyspnoea in further analysis. As common practice, age and gender adjusted nominal distances and respective percentiles were calculated using the established formula by Troosters et al. [A trained nurse performed the 6MWT according to international guidelines , 22. Pris et al. .Statistical analysis was performed using SPSS version 23 . All data were tested for normal distribution using the Kolmogorov–Smirnov test and were subsequently either reported as mean ± standard deviation or median with an interquartile range. Categorical data were reported as absolute frequencies and proportions.https://www.psychologie.hhu.de/arbeitsgruppen/allgemeine-psychologie-und-arbeitspsychologie/gpower [Comparisons between groups and sub-groups were evaluated using independent t-tests or univariate analysis of variance (ANOVA), where appropriate. Correlations between distances and the RV/LV T2 ratio were assessed using Spearman's correlation coefficient. Univariate and multivariate linear regressions with block enter method and respective hazard-ratios were used to investigate predictors of the distance walked in the 6MWT. For multivariate regression analysis, variance inflation factors were calculated to test for multicollinearity. Factors of 5 or lower were considered acceptable. In addition, a binary logistic regression analysis was used to determine predictors for post exercise dyspnoea. In this retrospective study, statistical power for both the comparisons between cohorts and sub-cohorts as well as the regression models was assessed using a dedicated freeware tool . A p-vaFor reproducibility analysis, intra- and inter-reader agreement were assessed by intraclass correlation coefficients. In addition, agreement between different methods of ROI placement was evaluated by Bland–Altman analysis and coefficient of variance determination.2, p = 0.01).The mean age in the patient cohort was 60 ± 15 years with 18 (26%) women while in HC the mean age was 55 ± 11 years with 14 (40%) women. Electronic patient records revealed that 39 (56%) of patients had never smoked, 17 (24%) were past-smokers and 14 (20%) were actively smoking. Despite matching efforts, the HF group had significantly higher body mass index (BMI) . Together with the mediation observer, a consensus was reached resulting in the following distribution of reasons for exclusion: Failure to adhere to in-house guidelines or incomplete LV-coverage , shortened study protocol without T2 mapping , wrap around artifacts , respiratory/cardiac ghosting , image blurring/mis-triggering  metallic artifacts , shimming artifacts/signal loss .Biventricular functional CMR analysis showed significant differences between HF patients and HC for all parameters except for CI  and RVEDVi . Additionally, the patient population was stratified by aetiology of HF as well as the categories of HF with reduced ejection fraction (HFrEF), HF with mildly reduced ejection fraction (HFmrEF) and HF with preserved ejection fraction (HFpEF). This information, along further baseline characteristics, can be found in Table sys, HR or SpO2 between patients with and without relevant post-exercise dyspnoea. However, patients with dyspnoea reached significantly lower distances  patients rated their post-exercise dyspnoea as 4 (“somewhat severe”) or higher on the modified Borg dyspnoea scale. There were no significant differences in baseline and post-exercise RR2 = 0.89, mean difference 0.0008 ± 0.040, limits of agreement − 0.077, 0.077). High rates of intrarater (ICC ≥ 0.93) as well as interrater reproducibility (ICC ≥ 0.96) were found for both methods. In addition, strong intraclass correlations were observed for measurements derived from basal, midventricular and apical short axis slices and four-chamber view long axis slices .There was excellent agreement between the RV/LV T2 ratio derived from the circular ROIs compared to planar ROIs encompassing the entire ventricular cavity  between the RV/LV T2 ratio and the percentile of the adjusted nominal distances  and HC  as well as NYHA I versus other classes (p ≤ 0.012). There were no significant differences amongst patients with HFrEF (0.50 ± 0.11), HFmrEF (0.50 ± 0.10) and HFpEF (0.54 ± 0.14). Detailed results from the post-hoc subgroup analyses between types of HF and HC can be found in Additional file Linear regression analyses showed that the RV/LV T2 ratio was the strongest tested predictor for the distance reached in the 6MWT among sex, age, NYHA class and CI Fig. . SubsequThis study investigated the relationship between RV-to-LV blood pool T2 relaxation times and exercise capacity in HF patients. The two main findings of this study can be summarized as follows: First, the RV/LV T2 ratio showed a moderate correlation with the distance patients with HF reached in the 6MWT. Second, age, sex and the RV/LV T2 ratio independently predicted the distance walked while the RV/LV T2 ratio was the only predictor of post-exercise dyspnoea.HF is a major global health problem with increasing relevance in aging populations. All major cardiovascular societies have published HF guidelines with consistent recommendations for the diagnosis, treatment and risk stratification. In these, CMR has a central role for the analysis of ventricular function and especially for tissue characterization , 25.However, routine CMR only evaluates cardiac function at rest in a supine position, in which most patients with heart failure in NYHA stage lower than 3 are asymptomatic. This could also explain why, in agreement with previous literature, no significant correlations between the 6MWT and parameters of LV function at rest were found , 26, 27.This diagnostic discrepancy between rest cardiac volumetry and symptom burden is especially relevant in patients whose day-to-day activity level approaches the maximal exercise capacity and in patients with preserved ejection fraction (HFpEF). In such patients, additional exercise test imaging has been shown to substantially improve the detection of HF –30, and Oxygen take-up in the lungs and delivery to the tissues rely on haemoglobin. The relationship between oxygen and haemoglobin is commonly described through the oxygen dissociation curve. In brief, physiological compensation mechanisms either increase oxygen affinity to improve oxygen uptake (left shift) or decrease it to facilitate delivery to target tissues (right shift) , 36. It In HF patients, upregulation of the exchange surface (i.e. increased perfusion of the capillary beds) is limited and the oxygen dissociation curve therefore has to shift to the right. Hence, it can be hypothesized that blood oxygenation levels at the end of the systemic circulation (i.e. in the RV) are lower due to increased oxygen delivery at the target tissues.T2 mapping usually plays an important role for non-invasive tissue characterization . In hearWhile T2-based non-invasive methods for direct quantification of blood oxygenation levels exist, they mostly require scanner-specific calibration, time-consuming examination protocols, or extensive post-processing , 39–42. Despite not allowing direct quantification, the mean RV/LV T2 ratio was significantly different between HF patients exhibiting relevant post-exercise dyspnoea, none-to-insignificant dyspnoea and HC. Thus, additional physiological information, which could not be extracted from established parameters such as biventricular function or myocardial tissue characterization, was derived from a routine resting-state CMR. Furthermore, the RV/LV T2 ratio showed a stronger correlation to reduced exercise capabilities of patients with heart failure than the relative myocardial scar burden while biventricular volumetric parameters showed no significant association with exercise capacities at all.As this is study had a cross-sectional design, causal relationship between the RV/LV T2 ratio and reduced exercise capacity will have to be determined in further studies. Similarly, prognostic implications of the reported data will have to be subject to further studies, despite the fact that the 6MWT is already an established independent predictor for prognosis. In a clinical setting, this could then lead to the RV/LV T2 ratio potentially being used to identify patients needing a closer follow-up and be evaluated as an easy-to-use tool to monitor therapeutic success.Another interesting approach would be to apply the proposed method to exercise CMR in order to compare rest and exercise RV/LV T2 ratios, potentially making exercise reserve quantifiable by CMR.This is a single centre retrospective study performed with a single type of commercially available T2 mapping sequence. Despite this approach not needing a specifically tailored pulse sequence, results have to be validated at different field strengths and using different sequences. To facilitate this, a RV/LV ratio was chosen rather than RV T2 blood pool relaxation times alone. In previous work, the ratio approach has demonstrated convincing agreement at field strengths of 1.5 and 3 T . In addiWhile this study demonstrated that the RV/LV T2 ratio is an independent predictor of exercise capacity in patients with HF, further studies will have to evaluate whether it is also an independent predictor of prognosis in these patients. Similarly, it is important to recognize pulmonary function as an additional factor on exercise function. In this retrospective study design, patients with known pulmonary disease as the leading cause of symptoms were therefore excluded. Nevertheless, in the small subset of patients with objective lung function data, it was shown that reduced pulmonary function is a significant predictor for less distance walked in the 6MWT. Unfortunately, the subgroup was too small for multivariate regression analysis and therefore, future prospective validation efforts will have to evaluate the interrelationship between the RV/LV T2 ratio and pulmonary function.Furthermore, this study included patients with HF due to all aetiologies and also investigated patients with HFrEF, HFmrEF as well as HFpEF, resulting in a heterogeneous cohort of patients. Because of the size of the HFmrEF subgroup (n = 8) and due to the fact that it only included males, results of the post-hoc analysis have to be interpreted cautiously as they might not be representative for this cohort. Further studies will have to investigate whether results are applicable for sub-cohorts (i.e. HFpEF only). Finally, multiple equations for the calculation of age-, height-, weight-, and gender-adjusted nominal distances from 6MWT have been proposed and validated. The most commonly-used equations are by Troosters et al.  and EnriThe proposed RV/LV T2 ratio is a simple tool using routinely acquired data in the diagnostic work-up of HF patients. It independently predicts exercise capabilities and moderately correlates with the 6MWT. Further studies are needed to investigate its relationship to prognosis and its potential to aid in selecting patients who need a closer follow-up.Additional file 1: Table S1. Comparison of CMR parameters between patient groups. Table S2. Results from post-hoc tests between types of HF and HC. Table S3. Multivariate regression analyses for distance walked in 6MWT. Table S4. Univariate regression analyses for distance walked in 6MWT.


Epidemiological data from the Indian subcontinent on the burden of Heart failure (HF) is scarce. Mineralocorticoid receptor antagonists (MRAs) are usually used in the management of HF and hypertension. A consortium of experts reviewed and opined on the pathophysiological role of aldosterone in HF and its cascading effects on the heart in terms of cardiac fibrosis, cardiac hypertrophy, and remodeling, increased propensity to cause arrhythmias in addition to its effect on sodium and water retention. This expert opinion document highlights the various mechanisms of action of MRAs. It provides clinical experience and practice-based expert opinion on the use of spironolactone and eplerenone in patients with HF. The role of MRAs in diabetic patients with HF has also been profiled. Heart failure (HF) is affecting 26 million people worldwide and it is responsible for 1.8 million hospitalizations annually in India. The high prevalence of HF in India is proportionate to the increased presence of risk factors such as coronary artery disease, diabetes, hypertension, and chronic kidney disease on one side and diseases like rheumatic heart disease on the other side making HF “a dual burden” [Epidemiological data from the Indian subcontinent on the burden of HF is scarce. Still, the estimate of HF incidence in India is around 1.3 to 23 million [The chief pathogenic feature of HF is the inability of the heart to pump blood commensurate with the body’s requirement and need, secondary to either a structural or functional abnormality. Neurohormonal activation is an important compensatory mechanism that aids in the maintenance of mean arterial pressure in HF. When the mean arterial pressure falls, the renin-angiotensin-aldosterone system is activated, resulting in the conversion of angiotensinogen to angiotensin I and then to angiotensin II by the angiotensin-converting enzyme (ACE) released from the lungs. Angiotensin II directly increases vasoconstriction and stimulates the release of aldosterone, which causes water and sodium retention. This leads to further deterioration in the condition of the patient, who presents with congestion and dyspnea .Mineralocorticoid receptor antagonists (MRAs) are a unique class of drugs that oppose/block the action of aldosterone and its harmful effects on the renal and extra renal system. They are usually used in the management of HF and hypertension. However, remained underutilized in clinical settings . The objMineralocorticoid receptor in heart failureAldosterone is a mineralocorticoid hormone produced majorly by the adrenal cortex in response to angiotensin II release, hyperkalemia, and corticotropin . AldosteIn addition to the epithelial effects, aldosterone has multiple negative non-epithelial effects on cardiomyocytes, endothelial cells, vascular smooth muscle cells (VSMCs), mesangial cells, and podocytes leading to induction of inflammation, stiffening of blood vessels, collagen formation, myocardial necrosis and stimulation of fibrosis ,7.Aldosterone plays an important role in heart failure pathogenesis. An elevated level of aldosterone tends to promote myocardial hypertrophy and remodeling, induction of fibrosis and apoptosis, contribute to endothelial dysfunction, and reduce myocardial perfusion, which results in increased incidence of cardiovascular events ,7.Aldosterone and its effects on sodium and fluid retention result in an undesired impact on fluid balance in patients with congestive HF, causing hypervolemia and promoting congestion. Furthermore, conditions like hypertension, atrial fibrillation, myocardial infarction, and diastolic HF increase the cardiac expression of MR. Therefore, increased MR activation levels could be observed even with normal levels of aldosterone and glucocorticoids .MRA-mechanism of actionMRAs directly bind to and block MR, inhibiting aldosterone or 11-deoxycorticosterone from activating it, which reduces the degree of inflammation and remodeling in the heart. MRAs are classified as specific or non-specific based on their chemical class. Non-specific MRAs include spironolactone and specific MRAs include eplerenone . MRAs arEffect of spironolactone and eplerenone on myocardial fibrosis and cardiac extracellular matrix turnover in heart failureA sub-analysis of the randomized aldactone evaluation study (RALES) trial assessed the interactions between serum markers of cardiac fibrosis and the effect of spironolactone on outcomes in heart failure with reduced ejection fraction (HFrEF) and New York Heart Association (NYHA) Class III-IV . In thisThe EPHESUS trial sub-analysis evaluated the effect of eplerenone in HFrEF patients post-acute myocardial infarction (AMI) with left ventricular systolic dysfunction (LVSD) by assessing the biomarkers of cardiac extracellular matrix turnover (PINP and PIIINP). The study demonstrated a significant reduction in PINP and PIIINP after treatment with eplerenone at six and nine months . InsightEffect of MRA on neurohormonal markers in heart failureIn RALES neuro-hormonal sub-group analysis a total of 107 patients with NYHA class III-IV (with a mean ejection fraction of 25%) were randomized to treatment with either spironolactone (25mg) or placebo. In the spironolactone-treated patients, the brain natriuretic peptide (BNP) plasma concentrations were reduced by 23% compared to the placebo (P<0.05) at six months. This reduction in natriuretic peptides is attributed to changes in left ventricular diastolic filling pressure and/or compliance .In the TOPCAT  Bio-repository study (n=247 HFpEF patients), a significant reduction in the BNP levels from the baseline was observed in the spironolactone-treated group (122 ng/L to 102 ng/L) as compared to the placebo-treated group (118 ng/L to 137 ng/L); P=0.003. Moreover, a significant reduction in NT-proBNP in the spironolactone group (from 626 ng/L to 579 ng/L) compared to placebo (from 614 ng/L to 707 ng/L), P=0.044. Stating that the treatment with spironolactone in HFpEF patients has the potential effect of reducing cardiac and renal biomarkers after 12 months .MRA in HFrEFThe RALES study demonstrated that the HFrEF patients (left ventricular ejection fraction (LVEF) 35%) on 25 mg spironolactone once daily had a 30% reduction in the risk of death from all causes, a 32% reduction in the risk of death from cardiovascular causes, 35% lower frequency of hospitalization for worsening HF, and a 30% reduction in the risk of hospitalizations from cardiac causes compared to placebo (P<0.001) .The real-world study OPTIMIZE-HF evaluated spironolactone in elderly patients HFrEF and demonstrated that spironolactone use reduced all-cause mortality by 8% (P=0.13) and HF readmissions by 13% (P=0.04) compared to patients without spironolactone. In older patients with HFrEF, spironolactone was more effective regardless of the renal eligibility criteria used .The EMPHASIS-HF trial (n=2737) evaluated the effect of eplerenone (25 to 50 mg) in patients with NYHA class II and EF ≤35%. The patients treated with eplerenone reported a 27% lower risk of hospitalization due to HF and a 23% lower risk of hospitalization for any cause compared to placebo (P<0.001) . The EPHThe summary of treatment benefits of MRA compared to other HF drugs in the treatment of patients with symptomatic HF (stage C) and HFrEF is given in Table The overview of guideline recommendations on MRA for patients with HFrEF is given in Table MRA in heart failure with mildly reduced ejection fraction (HFmrEF)Enzan et al. studied the prognostic impact of spironolactone treatment on mortality and HF rehospitalization in patients with heart failure with mildly reduced ejection fraction (HFmrEF) in the Japanese Cardiac Registry of HF in Cardiology (JCARE‐CARD) database. At a mean follow-up of 2.2 years, a lower incidence rate of a composite of all-cause death or HF rehospitalization was observed in patients on spironolactone compared to patients without spironolactone (P=0.004) .The TOPCAT sub-group analysis evaluated the relationship between LVEF and the efficacy of spironolactone. The incidence of cardiovascular death was highest in the patients with ejection fraction <50%. Ejection fraction had an impact on the effect of spironolactone on the primary outcome of HF hospitalization/CV death and patients at the lower end of the spectrum of LVEF had significantly greater benefits than the patients on the upper spectrum .An expert consensus document endorsed by ESC recommended that spironolactone may be considered for ambulatory patients (who have no contraindications to the use of spironolactone) with symptomatic HFmrEF to reduce the risk of CV death and HF hospitalization .MRA in heart failure with preserved ejection fraction (HFpEF)The HF with preserved ejection fraction (HFpEF) refers to the clinical syndrome of heart failure associated with normal or near-normal systolic function. The incidence of HFpEF increases with age and it mostly affects women. HFpEF showed similar morbidity and mortality as those of heart failure with systolic dysfunction .The TOPCAT trial on HFpEF patients reported that 18.6% of patients on spironolactone experienced the primary outcome  as compared to 20.4% of patients on placebo (P= 0.14). An increase in the levels of serum creatinine and a doubling of the rate of hyperkalemia was observed in 18.7% of spironolactone-treated patients as compared to 9.1% of patients treated with placebo .MRA initiation in heart failure patientsThe efficacy and safety of spironolactone and eplerenone in mortality and hospitalizations are well established from pivotal clinical trials such as RALES, EMPHASIS, and EPHESUS ,18,19. HEarly evidence indicating the impact of timing of initiation of MRA comes from a study by Rossi et al., which evaluated the association between timing of MRA initiation  and mortality in patients with HF discharged alive after a first episode of decompensated HF (n=689). A total of 7.1% of patients in the early treatment group, as compared to 13.4% in the late treatment group died after hospitalization at the end of 1-year post-discharge . A delay of only one month in administering an MRA implies approximately doubling mortality risk after one year .A posthoc analysis of the EMPHASIS HF trial by Girerd et al. evaluated the timing of initiation of eplerenone in patients with a CV Hospitalization within the past six months. Eplerenone was initiated post-CV hospitalization at a median of 42 days. The event rates were lower in the 42+ days group. A total of 23.6% in the 42+ days met the primary outcome  and 28.6% in the 42 days group. The study provides strong evidence of the safety of early initiation of eplerenone after a cardiovascular hospitalization (CVH) .MRAs in acute decompensated heart failureThere is scant data regarding the association between MRA use and outcomes of all-cause mortality and hospital readmission in acute decompensated heart failure (ADHF). This association was evaluated in the Kyoto Congestive Heart Failure (KCHF) registry from Japan . In thisMRAs and new-onset atrial fibrillationA meta-analysis and systematic review has shown that MRAs are potential atrial fibrillation (AF) preventive therapy. In MRA-treated patients, a significant overall reduction in AF occurrence was observed as compared to control groups ). The greatest benefit was observed regarding the prevention of recurrent AF episodes ). MRAs appear to be effective in AF prevention, especially recurrent AF episodes [MRAs in worsening renal failure (WRF), hyperkalemiaAldosterone receptor antagonism influences serum K+ levels by impairing aldosterone-mediated effects on K+ homeostasis in the principal cells of the kidney. Antagonism of the aldosterone receptor, therefore, decreases luminal K+ excretion, thereby increasing the possibility of clinically significant hyperkalemia; when severe, hyperkalemia may precipitate cardiomyocyte membrane potential destabilization and unstable ventricular arrhythmias .Although no death attributable to hyperkalemia was reported in the RALES, EPHESUS, or EMPHASIS-HF studies, the subsequent pharmacovigilance studies published after the RALES study found an increase in the reporting of hyperkalemia in CHF patients treated with spironolactone .The EMPHASIS-HF study reported an increased incidence of hyperkalemia among patients receiving eplerenone. A serum potassium level above 5.5 mmol/L was reported in 11.8% of the eplerenone group and 7.2% in the placebo group (P<0.001). Moreover, a serum potassium level above 6.0 mmol/L was reported in 2.5% in the eplerenone group and 1.9% in the placebo group (P=0.29). Although 8% of HF patients on eplerenone develop hyperkalemia, only 1% withdrew due to an adverse event .The association with hyperkalemia and worsening renal function (WRF) with eplerenone was assessed in a post hoc analysis of the EMPHASIS- HF study. In this post hoc analysis, all 2737 patients with HFrEF were included. The addition of eplerenone was associated with an increased incidence of WRF and hyperkalemia. Although eplerenone induced a significant rise in K+ levels (P<0.004), the rise was modest . These aThe management of hyperkalemia and hypokalemia and spironolactone and eplerenone dose adjustment proposal is given in Table Expert opinion recommendationsA panel of expert cardiologists from India convened to develop this expert opinion document to guide physicians on the optimal use of MRAs in HF patients. Clinical practice-based recommendations are provided in Table The reason for the underutilization of MRA is multifactorial. The chief limiting factor in the mind of the treating doctor is the fear of hyperkalemia associated with using MRA in HF patients. Secondly, an apprehension that the patient might not comply with serum K+ monitoring. In a multispecialty setup, the prescription of MRA is often considered far down in the algorithm of HF management and is missed out in the discharge medications.This expert group opines that there is an urgent need to highlight the pathophysiological role and mechanism of action of MRAs as well as to educate physicians involved in HF management about the need and benefit of safe use of MRAs in HF.


No patient in this cohort experienced TSP-related complications. Conclusion: Our study describes a fluoroscopy-free or low-dose fluoroscopy approach for TSP in ACHD patients undergoing catheter ablation of left-sided tachyarrhythmias who had been previously treated surgically or interventionally due to congenital heart defects. By superimposing 3D electroanatomic mapping with cardiac CT anatomy, this protocol proved to be highly effective, feasible and safe.Aims: The widespread use of three-dimensional (3D) mapping systems and echocardiography in the field of cardiac electrophysiology has made it possible to perform transseptal punctures (TSP) with low or no fluoroscopy. However, such attempts in adults with congenital heart disease (ACHD) who have previously undergone surgical or interventional treatment are limited. Therefore, we sought to explore the feasibility and safety of an approach to perform zero- or low-fluoroscopy TSP in ACHD patients undergoing left atrial cardiac ablation procedures. Methods and results: This study included 45 ACHD patients who underwent TSP for ablation of left-sided tachycardias (left atrium or pulmonary venous atrium). Computed tomography (CT) of the heart was performed in all patients prior to ablation. 3D mapping of the right-sided heart chambers before TSP was used to superimpose the registered anatomy, which was subsequently used for the mapping-guided TSP technique. TSP was performed with zero-fluoroscopy in 27 patients, and the remaining 18 patients had a mean fluoroscopy exposure of 315.88 ± 598.43 μGy.m The introduction of three-dimensional 3D) electroanatomic mapping (EAM) systems and the use of intracardiac echocardiography have made it possible to perform a transseptal puncture (TSP) for cardiac ablation of left-sided arrhythmias with very low or no fluoroscopy ,2. DespiD electroForty-five ACHD patients after surgical correction or interventional repair, who were scheduled to undergo arrhythmia ablation in the left or pulmonary venous atrium at the University Heart Center Zurich, were included in this study. Prior to ablation, CT scanning of the heart was performed in all patients. Arrhythmias included left-sided atrial tachycardias and atrial flutters, atrioventricular (AV) reentry tachycardias due to accessory pathways, and atrial fibrillation. Patients with preexisting interatrial connections, such as persistent patent foramen ovale (PFO) or baffle leak, were excluded. Patients with cardiac implantable electronic devices (CIEDs) were also excluded. Upon giving consent, patients were informed of the benefits, risks and alternative approaches. The duration of the procedure was documented on a step-by-step basis, from the initial venous access to the final removal of all sheaths. During the procedure, TSP was performed, employing a “non-radiation where possible, low radiation where necessary” approach. The use of fluoroscopy was at the discretion of the operator to ensure maximum patient safety. The feasibility and safety of TSP, including intra- and periprocedural complications, were assessed.The procedure was generally performed under conscious sedation. General anesthesia was used in patients undergoing atrial fibrillation ablation. Ultrasound-guided femoral venous or arterial access was performed in all patients. CARTO 3D EAM system  TSP was performed in combination with the Agilis long sheath with a dilator , the BRK™ transseptal needle , and the SafeSept guidewire . In the presence of a postsurgical prosthetic septum, such as a Fontan conduit or fabric septal patch/occluder, an NRG transseptal needle  was used to facilitate TSP.Prior to the procedure, the CARTO system and the TSP system were set up for mutual communication to enable 3D visualization. RF pins, stackable 2 mm pin jumpers, and quadrupole catheters were attached to the CARTO pin block, as shown in the schematic in During the procedure, right-sided intracardiac mapping was performed with a 20-polar Pentaray mapping catheter . A decapolar catheter  was introduced into the CS position. The position of the His bundle as an anatomical reference was also labeled at multiple points by the mapping catheter. Special consideration was given to mapping the interatrial septal portion of the heart for TSP.The 3D mapped right-sided cardiac anatomy was registered and superimposed with the CT scan reconstructed 3D anatomy in the CARTO system, which permitted real-time visualization of the TSP needle tip and guiding wire within this comprehensive 3D model. This visualization was automatically updated to alter 3D map projections on the CARTO system. Amid this maneuver, the aortic root, the pulmonary veins, and the interatrial septum were used as landmarks, which were repeatedly visualized with a slight clockwise or counterclockwise rotation of the CT scan-merged 3D images. Prior to performing TSP, the TSP location was annotated on the mapping system with the ablation catheter to avoid adjacent tissue injury. Puncture with the TSP needle into the left/pulmonary venous atrium and the following advancement of the guiding wire into the left/right superior pulmonary vein was visualized by the preset 3D mapping system, shown in This study complied with the Declaration of Helsinki and was approved by the local Ethics Committee . All patients gave informed written consent for the procedure and the use of clinical data for scientific study.p-value < 0.05 was considered significant. All analysis was performed using SAS Statistical software .Baseline characteristics are reported as means ± standard deviations (SD), and categorical characteristics as counts and percentages. Parameters associated with TSP are reported as numbers and percentages. For the likelihood ratio test, the Chi-Square test was used and a ® Savage® filamentous knitted polyester fabric, Bard Peripheral Vascular Inc., Tempe, AZ, USA)) patches and occluders , Amplatzer ) (76%) or pericardial patches (24%), as a partial or full substrate of the septum, were present in all patients due to a surgically corrected/palliated condition or an interventional repair a mean (± SD) of 25 ± 16 years before  included atrial septal defect (ASD), atrioventricular septal defect (AVSD), dextro-transposition of great arteries (d-TGA), congenitally corrected transposition of great arteries (ccTGA) with tricuspid atresia (TA), and double inlet left ventricle (DILV) with TA. Fabric , Dacron  fabric septa in both groups (35% vs. 24%). The fabric septa included ASD/AVSD septal occluders, extracardiac Fontan conduits and baffles after the Mustard operation. TSP was performed in a total of 11 (24%) pericardial/atrial septa in patients with surgically repaired ASD/AVSD and Senning operation (13% vs. 11%). Furthermore, the TSP parameters were analyzed by the congenital conditions of the patient, among which there were 36 (80%) cases of AVSD/ASD (49% vs. 31%), 1 (2%) case of TA (2% vs. 0%), and 8 (18%) cases of TGA (9% vs. 9%) A,B.2. Multivariate analysis showed that the application of fluoroscopy was not associated with the clinical characteristics of the patients as well as the status of ACHD and the IAS substrates (p > 0.05).In the 18 patients who underwent TSP with fluoroscopy, the mean fluoroscopy time for TSP was 1.9 ± 5.4 min and the dose area product was 315.88 ± 598.43 μGy.mbstrates . Despitebstrates C. MoreovThis study demonstrates that a 3D mapping-guided TSP approach is feasible and safe in ACHD patients after surgical or interventional treatment with no or low-dose fluoroscopy. This can be performed by real-time visualization of the TSP needle and guidewire within the 3D electroanatomic map, superimposed with a pre-procedurally acquired cardiac CT anatomy. The target location for a successful TSP can be defined after taking into account all adjacent anatomical structures to reduce possible complications.A transseptal puncture is usually performed under the guidance of conventional fluoroscopy or TEE. Previous studies have combined CT-scan reconstructed cardiac anatomy with fluoroscopic acquisition with Carto Univu, which allows for the overlay of catheter-acquired cardiac maps into fluoroscopy, which can then be used as a reference for cardiac anatomy during atrial fibrillation ablation . Given tBased on the real-time visualization of the tip of the catheter in the target cardiac chamber, an accurate 3D reconstruction of the anatomy derived from a CT scan or cardiac magnetic resonance imaging (CartoMerge) can be superimposed, with the 3D mapping anatomy, and used during the procedure. Thus, 3D EAM systems have not only greatly improved the efficacy and success of cardiac mapping and catheter ablation, but have also been further applied to the field of cardiac pacing and other cardiac interventions such as endomyocardial biopsy (EMB) ,12,13. AIt is important to note that a large percentage of ACHD patients have abnormal interatrial septa with altered tissue substrate due to surgical or interventional repair or as a result of hemodynamic and structural changes associated with the underlying congenital condition ,17,18,19In our present approach, the 3D map of the right-sided heart was superimposed with a CT 3D reconstruction of the cardiac anatomy integrated into the CARTO system. This allowed visualization of the important anatomical landmarks, such as the aortic root and the relationship between the posterior atrial wall and the atrial septum, which are difficult to see in real-time from multiple projections under conventional fluoroscopy and TEE. With the present CARTO-guided TSP approach, we are able to accurately determine the optimal position of the TSP and its relationship to the adjacent structures. By linking the CARTO system to the TSP set, the TSP needle and guidewire could be visualized within the cardiac anatomical structures in real-time. Due to the overall diversity and complexity of the congenital conditions of the patients, it was not possible to completely avoid fluoroscopy, although the lack of or low exposure to fluoroscopy makes this approach attractive. The passage of the atrial septum was difficult to achieve in some cases, either due to tissue changes with increased resistance after surgical or interventional repair of the septum, or due to anatomical conditions after the atrial switch or Fontan operations. Moreover, in some cases, it was impossible to smoothly advance the guidewire into LA/SVA or the target PVs. In these cases, by confirming the coaxiality of the puncture system or excluding the guidewire advancing to the pericardial cavity, using fluoroscopy or even a small amount of contrast injection was adopted. Therefore, the operator applied fluoroscopy in some cases in order not to compromise patient safety. Our present analysis of the cohort did not reveal any association between fluoroscopy application and patients’ clinical risk factors such as age, BMI, comorbidities, etc., as well as ACHD status, which includes years of surgical or interventional treatment, IAS substrates, and altered cardiac structures. Detailed correlation analysis requires further prospective studies with large samples.In our study, reliable real-time tracking of the TSP needle position and guidewire movement in a 3D mapping system could be achieved during catheter ablations in ACHD patients. In this regard, it may be hypothesized that a 3D-guided fluoroscopy-free TSP approach may be feasible in patients with normal cardiac anatomy whose fossa ovalis can be clearly mapped and is therefore suitable as a target for TSP. Moreover, in patients with severe heart rotation and malformation due to systemic disease, such as chronic obstructive pulmonary disease, diaphragmatic elevation or sternal deviation, for whom TSP may be complicated even with the guidance of fluoroscopy and/or TEE, our TSP protocol might possibly be of help.This is a single-center study with a relatively small sample size. The included patients with ACHD had different congenital diseases and surgical histories, so the TSP technique and anatomy could not be standardized, making it impossible to draw a uniform atlas related to cardiac anatomy.In conclusion, in ACHD patients with surgically or interventionally altered interatrial septum, 3D EAM combined with 3D reconstructed anatomy from cardiac CT scans can safely guide TSP. This 3D EAM-guided TSP procedure may be performed with zero or very low fluoroscopy exposure.


To date, little is known about the contribution of different PA types to adherence to the PA guidelines. This study aims to identify which (combination of) PA types  are the main contributors to adherence to the Dutch PA guidelines and whether this varies across population groups.Data of the Dutch Health Survey/Lifestyle monitor 2019 was used including 7616 respondents of 18 years and older. PA was assessed using the Short Questionnaire to Assess Health-enhancing physical activity (SQUASH). Prevalence rates of adherence to the PA guidelines were examined and the impact of excluding a particular PA type on these rates was assessed. Univariate and multiple logistic regression analyses were used to examine associations between demographic characteristics and adherence to the PA guidelines.Prevalence rates decreased the most when either sports (12 percent points) or walking (17 percent points) or cycling (11 percent points) during leisure time was excluded in the total population and almost all population groups. Nevertheless, unadjusted- and adjusted odds ratios revealed that the importance of these PA types for adherence to the PA guidelines differed between population groups. For example, when all PA types were included, women had lower odds  to adhere to the PA guidelines compared to men. When excluding sports, the odds increased towards 1.02 (0.92-1.12). This means that for men sports is a more important contributor to adherence to the PA guidelines than for women.Sports, walking- and cycling during leisure time contributed the most to adherence to the PA guidelines. Nevertheless, differences in the contribution of PA types between population groups exist. PA policies should target different population groups by stimulating the PA types that are main contributors for adherence to the PA guidelines, but also look for the barriers to participate in PA types that have a smaller contribution to adherence to the PA guidelines.This research was funded by the Ministry of Health, Welfare and Sports of the Netherlands.


The identification of patients with mitral valve prolapse (MVP) presenting high arrhythmic risk remains challenging. Cardiovascular Magnetic Resonance (CMR) feature tracking (FT) may improve risk stratification. We analyzed the role of CMR-FT parameters in relation to the incidence of complex ventricular arrhythmias (cVA) in patients with MVP and mitral annular disjunction (MAD).42 patients with MVP and MAD who underwent 1.5 T CMR were classified as MAD-cVA  in case of cVA diagnosed on a 24-h Holter monitoring and as MAD-noVA in the absence of cVA . MAD length, late gadolinium enhancement (LGE), basal segments myocardial extracellular volume (ECV) and CMR-FT were assessed.LGE was more frequent in the MAD-cVA group in comparison with the MAD-noVA group  while no difference was observed in terms of basal ECV. Global longitudinal strain (GLS) was reduced in MAD-cVA compared to MAD-noVA  as well as global circumferential strain (GCS) at the mid-ventricular level . Univariate analysis identified as predictors of the incidence of cVA: GCS, circumferential strain (CS) in the basal and mid infero-lateral wall, GLS, regional longitudinal strain (LS) in the basal and mid-ventricular inferolateral wall. Reduced GLS  and regional LS in the basal inferolateral wall [OR: 1.62 ] remained independent prognostic factors in multivariate analysis.In patients with MVP and MAD, CMR-FT parameters are correlated with the incidence of cVA and may be of interest in arrhythmic risk stratification.The online version contains supplementary material available at 10.1186/s12968-023-00944-x. Mitral valve prolapse (MVP) is the most frequent cause of primary mitral regurgitation (MR) in Western countries with an estimated prevalence of 2%. Despite its overall good prognosis –3 since CMR feature tracking (CMR-FT) is emerging as a potential tool for early detection of subtle morphologic and functional alterations in various cardiac conditions since it is able to identify LV deformation abnormalities even in the presence of normal parameters of systolic function. Subtle myocardial deformation changes have been associated with tissue changes in MVP patients detected by native T1 . To dateAll consecutive patients with a bileaflet MVP and MAD referred to CMR between January 2016 and July 2021 in the setting of risk assessment were retrospectively included in the present study. Inclusion criteria were age > 18 years old and the presence of isolated bileaflet MVP. MVP was defined as a systolic excursion of the mitral leaflets > 2 mm behind the mitral annular plane in the long axis view, i.e. a displacement of > 2 mm into the left atrium (LA). MAD was defined as an anatomic variant of the posterior mitral annulus resulting in an abnormal separation (≥ 2.0 mm) between the left atrial wall/mitral valve junction and LV inferolateral wall on the cine 3-chamber end-systolic image, as previously reported in literature –9  with a 32-channel phased-array surface receiver coil. Cine images were acquired using a breath-hold steady-state free precession (SSFP) sequence in long-axis  and short-axis orientations .Ten minutes after the administration of a 0.2 mmol/kg intravenous bolus of Gadobutrol  at a flow rate of 4 mL/s followed by saline flush/ LGE images were acquired using a 2D breath-hold phase-sensitive segmented inversion-recovery gradient echo pulse sequence in the same orientations as cine images. The following parameters were used: FOV: 380 to 420 mm; TR/TE: 4.6/1.3 ms; α: 20°; matrix: 256 × 192; slice thickness: 8 mm; no interslice gap. Inversion time was individually optimized to null normal myocardium .For pre-contrast T1 mapping, we used the ECG-triggered modified Look-Locker inversion recovery (MOLLI) sequence (using the scheme 3 (3)3(3)5) on a single short-axis basal LV slice. Post-contrast T1-mapping was acquired following LGE imaging (20 min after Gadobutrol bolus injection) using a MOLLI sequence (4(1)3(1)2 scheme). The basal slice was defined as the slice position of the most basal cine SSFP slice, where a complete ring of myocardium was visible throughout diastole and systole.MR severity was assessed by phase contrast flow images. MR volume was calculated according to the standard indirect method, by subtracting the forward aortic flow volume from the total LV stroke volume (LV stroke volume − forward aortic flow). The MR regurgitant fraction was quantified using the following equation: (regurgitant volume × 100)/(LV stroke volume). According to the literature MR was graded as mild if MR regurgitant fraction was < 20%, moderate if 20–39% and severe if > 40% .All CMR examinations were analyzed blinded to clinical characteristics and outcome using the Syngo.via software  to calculate LV volumes, LV mass and LVEF by delineating endocardial and epicardial borders in the stack of short-axis cine images. MAD was assessed on a 3-chamber view in systole and defined as any detachment of the MV leaflet junction from the top of the basal LV inferolateral wall to the left atrial wall , 9.The presence of myocardial LGE was defined as hyperintense myocardium with a signal intensity > 5 SDs above the mean signal intensity of normal myocardium. The extent of LGE was semi-quantitatively reported according to the American Heart Association 17 segments model .Pre- and post-contrast T1 mapping images were obtained in the basal slice and first visually reviewed to assess quality. Myocardial T1 relaxation times and ECV were then measured in every myocardial segment according to AHA classification and divided in anterior, anteroseptal, inferoseptal, inferior, inferolateral and anterolateral wall as previously reported in literature .CMR-FT analysis was performed using commercially available software . Long-axis SSFP cine images  were used to derive global longitudinal strain (GLS). Segments with poor tracking were excluded from further analysis and if more than two segments demonstrated poor tracking, the view was excluded from further analysis. GLS values were obtained by averaging the segmental strain values . Global circumferential strain (GCS) was evaluated considering the basal slice, mid-ventricular slice, at the level of papillary muscle, and apical slice. Regional longitudinal strain (LS) and regional circumferential strain (CS) were also assessed. To assess regional LS strain values for the six basal, six mid, and six apical segments of the LV were analyzed separately as antero-lateral, infero-lateral, inferior, infero-septal and antero-septal wall at basal, mid-ventricular, and apical level and successively averaged to obtain regional LS longitudinal strain values . Regional CS was assessed considering strain values for the six basal, six mid and 4 apical segments of the LV. All segments were analyzed separately as antero-lateral, infero-lateral, inferior, infero-septal and antero-septal wall at basal, mid-ventricular, and apical level and successively averaged to obtain regional CS strain values  . The repAll patients underwent 24-h Holter monitoring within 6 months from CMR. Isolated ventricular premature beats (PVC), couplets, bigeminal PVC and non-sustained ventricular tachycardia (NSVT) or sustained ventricular tachycardia (SVT) were reported. Patients were divided into 2 groups according to the results of the Holter monitoring: the MAD-cVA group in case of cVA occurrence and the MAD-noVA group in the absence of cVA. Complex ventricular arrhythmias (cVA) were defined according to the classification proposed by Essayagh et all. As the following: mild with PVCs above the median (> 5%) and/or with documented ventricular tachycardia (VT) runs no faster than 120 beats/min (34); moderate with VT runs of 120 to 179 beats/min; and as severe with VT > 180 beats/min and/or proven history of VT/ventricular fibrillation (VF)/aborted sudden cardiac death (SCD), indicating a need for an implantable cardioverter-defibrillator (ICD) . The MADhttp://www.R-project.org).Normality of continuous variables was investigated with the Shapiro-Wilks test. Continuous variables are expressed as mean ± SD in case of a normal distribution or as median [interquartile range] in case of a non-normal distribution. Comparison of continuous variables between two groups were performed using the independent-sample Student’s t test in case of normal distribution or the Mann–Whitney test in case of non-normal distribution. One-way analysis of variance (ANOVA) was used to determine statistically significant differences in the presence of three or more independent groups normally distributed. The association between any categorical variable and outcome was analyzed using Fisher’s exact test. Correlation analysis was performed using Spearman’s correlation test. A whole series of univariate binary logistic models was used to estimate the potential relation between cVA (dependent variable) and every independent variable. A multivariate analysis was performed to estimate the potential relation between cVA (dependent variable) and a set of independent variables. We performed a univariate analysis considering all variables possibly correlated with higher incidence of arrhythmias . Multivariable analysis was performed in a stepwise fashion based on p model. In the iterative process of variable selection, covariates were removed from the model if they are non-significant and not a confounder. Significance was evaluated at the 0.1 alpha level. A Hosmer–Lemeshow goodness of fit (GOF) test was made in order to validate the multivariate model. Reproducibility analyses for the measurement of myocardial pre-contrast T1, ECV and strain parameters (GLS and GCS) were performed using Pearson’s correlation and Bland–Altman statistics. All reported p-values were obtained by the two-sided exact method at the 5% significance level. Data analysis was performed as of August 2021 by using the software package R  in the MAD-cVA group and 19 patients (45%) in the MAD-noVA group.2 vs 61.2 ± 17.3 ml/m2, p = 0.003). No statistically significant differences in terms of LV end-diastolic volume index were found between MAD-noVA and MAD-cVA . No difference in terms of LVEF were found between patients in MAD-cVA and MAD-noVA (p = 0.833). MR severity grade was graded as mild in 7 patients (16%), moderate in 25 (60%) and severe in 10 (24%). MAD length was not different between MAD-noVA and MAD-cVA patients .Mean age was 48.1 ± 15.4 years and similar across MVP patients vs control group (p = 0.198); 50% of the population were females. LV end-diastolic volume index was higher in patients with MVP compared with controls . Baseline clinical and CMR characteristics of the overall study population are presented in Table No segments with poor tracking were present. No significant differences were found between patients with MVP and control group in terms of GLS . Similarly, GCS was not different between patients with MVP and control group at the basal , mid-ventricular  and apical levels . On the contrary, GLS was significantly reduced in MAD-cVA patients in comparison with MAD-noVA patients  as well as GCS at the mid-ventricular level . No difference was found in terms of GCS at the basal and apical levels  , except for the regional LS of the basal inferior wall . Regional LS and CS measures are presented in Table Baseline clinical and CMR characteristics and strain parameters of MAD-noVA and MAD-cVA are reported in Table The proportion of patients with LGE was higher in the MAD-cVA group in comparison with the MAD-noVA group . The LGE extension was of 3 [2–4] in the group with cVA vs 0 [0–1] in the group without cVA (p = 0.001). LGE was most frequently detected in the basal to mid-ventricular inferior and inferolateral walls  as opposed to the anterior and anterolateral walls  and the anteroseptal and inferoseptal walls .Patients with MVP had higher mean pre-contrast T1 relaxation times compared with controls  and higher ECV values . Patients with cVA had higher pre contrast T1 relaxation times of the inferior basal wall  and inferolateral basal wall levels  when compared to noVA patients, while no difference was found in terms of ECV values . Native T1 and ECV values are presented in Table Seven patients presented with polymorphic arrhythmias, all of them in the MAD-cVA group. Five patients with polymorphic arrhythmias presented > 5%.Univariate logistic regression analysis identified the following covariates as unadjusted predictors of the incidence of cVA: presence of LGE (OR: 9.52 [2.28–39.7] p = 0.002), the number of segments with LGE , GLS , regional CS in the basal infero-lateral wall  regional CS in the infero-lateral mid ventricular wall , regional LS in the basal and mid-ventricular infero-lateral wall , pre contrast T1 relaxation times and ECV in the basal inferolateral wall . MAD length and mitral regurgitant fraction were not predictors of cVA.We performed a multivariate analysis including all the possible parameters that may be connected to cVA such as the degree of MR, the presence and extent of LGE, the presence of interstitial fibrosis evaluated in native T1 mapping end ECV and myocardial deformation parameters. In our cohort, the presence of LGE [OR: 8.5 ], GLS [OR:1.56 ] and the regional LS in the basal infero-lateral wall [OR: 1.62 ] were independent prognostic factors in multivariate analysis. The ROC curve analysis showed an area under the curve of 0.92 (IC95%: 0.824–1) and the Hosmer and Lemeshow GOF test confirmed the validity of the model. Logistic univariate and multivariate analyses are presented in Table the presence and extent of macroscopic fibrosis detected by LGE was associated with a higher incidence of cVA;patients with cVA had a higher degree of ventricular remodeling highlighted by higher values of native T1 relaxation times and ECV;cVA was associated with alterations in deformation parameters evaluated by CMR-FT.The main findings of the present study are:Although a benign condition in the vast majority of cases, MVP has been linked to cVA and SCD in a subgroup of patients, justifying efforts to identify risk factors of ventricular arrhythmia , 6. AmonKitkungvan et al. demonstrated that the prevalence of LV LGE in MVP patients is higher compared to non-MVP patients, suggesting that MVP fibrosis has a unique pathophysiology beyond volume overload . MoreoveThe concept of MAD was first introduced by Bharati et al. in 1981 , and sinOur results are in line with these findings as 78% of patients with known cVA or aborted SCD had macroscopic fibrosis detected in LGE sequences, while only 42% of patients in the no-cVA group were LGE positive, further supporting the importance of fibrosis in the stratification of the arrhythmic risk.In addition to focal fibrosis, interstitial fibrosis assessed by T1 mapping may contribute to arrhythmogenesis in patients with MVP Bui et al. suggested that patients with MVP may present with higher levels of interstitial fibrosis as evaluated with native T1 mapping . The autThis aspect has also recently been validated in a series  that higIn our population, MVP and MAD also correlates with the presence of diffuse interstitial fibrosis with higher values of native T1 relaxation times and ECV compared to controls. However, the difference between mean ECV values in MAD-cVA and MAD-noVA was not statistically significant, even though mean ECV values showed a higher trend in MAD-cVA compared to MAD-noVA. On the contrary, higher values of native T1 relaxation times in the inferior and infero-lateral wall were detected in MAD-cVA.Strain deformation parameters are known to be superior in the evaluation of EF in predicting LV dysfunction and major adverse cardiac events in different cardiac conditions .Using 2D speckle tracking echocardiography (STE), Huttin et al. showed an abnormal strain pattern in MVP patients compared with controls, with pathological pre-systolic shortening and systolic, late systolic and post-systolic strain . MoreoveHowever, echocardiography is limited in the presence of inadequate acoustic windows. On the other hand, CMR-FT is obtained by post-processing conventional cine sequences which are characterized by a high natural contrast difference between the myocardium and the blood cavity. This novel technique which allows quantitative analysis of myocardial deformation, is based on optical flow methods .CMR-FT is not necessarily comparable to speckle tracking echocardiography. In particular, because cine SSFP images show relatively homogeneous gray levels, CMR FT does not seem to be able to distinguish intramyocardial features as STE does. Indeed, CMR FT involves the detection of anatomical characteristics located along the myocardial boundaries within the image. It then proceeds to pinpoint regions of interest in proximity to these features and subsequently tracks them throughout the cardiac cycle by comparing corresponding regions in successive images . FurtherFuthermore, we evaluated regional LS and CS at basal, mid-ventricular and apical level, demonstrating that regional changes in CMR-FT parameters in the inferior and inferolateral wall are also associated with cVA.primum movens of macroscopic fibrosis that can be later detected in LGE sequences. However, the clinical role and the potential therapeutic target of interstitial fibrosis in patients with MVP still need further investigation in larger longitudinal studies.Taken together, the alterations in deformation, myocardial parameters and T1 mapping highlight the presence of ventricular remodeling that goes beyond the mere evidence of macroscopic fibrosis detected by LGE . It can Finally, the logistic univariate regression analysis suggests an important role for myocardial composition and deformation in the genesis of complex arrhythmias, since we found as stronger predictor of cVA the presence of macroscopic fibrosis detected in LGE as well as higher value of GLS and regional LS in the basal inferior wall. On the contrary, MAD length and MR severity failed to predict the incidence of cVA in our population in both univariate and multivariate analysis. Surely, these interesting results are limited by the number of patients and a more extensive analysis in a larger population on the role of MAD in arrhythmogenesis of patients with MVP is needed.This study presents several limitations. Firstly, it is an observational study on a relatively limited number of patients. Moreover, we studied a highly selected population of patients with concomitant MVP and MAD that underwent ECG Holter monitoring. As a consequence, a selection bias may be present, and the multivariate analysis can be affected by model overfitting. Larger, prospective studies are required to confirm our data. However, although the combination between MVP and MAD is relatively rare in the general population, it appears particularly relevant from a clinical point of view, as it identifies a subgroup of patients at higher risk of arrhythmic events . In addiSecondly, we derived information from ventricular arrhythmias on standard 3-lead Holter; consequently, information about the location of PVC is unavailable. Moreover, given the limited number of patients, no specific conclusion can be derived on the polymorphic or monomorphic nature of PVCs and their association with CMR-FT parameters and outcome. Finally, although high resolution bright blood LGE CMR were used and all images were interpreted by expert operators, routine evaluation of the presence of fibrosis in the papillary muscles area could be challenging and was not part of our analysis.In patients with bileaflet MVP and MAD, CMR identifies markers of fibrosis and subtle modification of myocardial deformation indexes which are associated with complex ventricular arrhythmias. LGE, T1 mapping and CMR-FT may represent potential tools to help the prognostic stratification of MVP patients at risk of SCD.Additional file 1: Figure S1. steady-state-free precessioncine image of a 3-chamber view, the presence on MADin highlighted with a red arrow. MAD: mitral-annular disjunction. Figure S2. Considering the literature CMR evaluation in patients with suspicion of arrhythmic MVP includes the detection of MAD and curling in cine images, the presence of macroscopic fibrosis in LGE and the quantification of mitral regurgitation in 2D-phase contrast sequences of 4D flow, if available. The presence of interstitial fibrosisas well as the role of myocardial deformation by CMR feature tracking as possible marker of risk stratification are currently being evaluated.


Seven decades have lapsed since the first description of primary aldosteronism (PA) by Jerome W. Conn . DespiteParasiliti-Caprino et al., the accuracy of simple and adjusted aldosterone indices for assessing selectivity and lateralization of adrenal vein sampling (AVS) is evaluated. AVS is regarded as the gold standard test for PA subtyping . However, with no standardized cut-off levels, this limits the applicability of AVS when cortisol is being utilized , 6. The Ozeki et al. present a new chemiluminescent enzyme immunoassay (CLEIA) based on a two- step sandwich method to measure 24-hour urine aldosterone excretion. The accuracy of aldosterone measurement in urine samples using various methods have also been examined previously. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was noted to have the highest accuracy  sodium chloride cotransporter (NCC) in PA subtyping. In view of the invasive nature and technical difficulties of AVS, identifying a non-invasive alternative is crucial. The authors show that NCC can be potentially used to distinguish between different subtypes of PA as the expression of phosphorylated form of NCC (pNCC) in uEVs are different in various subtypes and genotypes. Previous studies have explored the use of uEVs as a biomarker in lupus nephritis and diabetic nephropathy where the presence of uEVs provide insights into the pathophysiology and aid the diagnosis and management , 14. TheNguyen et al. recruited 300 patients with a recent stroke and reported the prevalence of PA amongst those with hypertension, resistant hypertension and hypertension with atrial fibrillation (AF) as 4%, 11% and 30% respectively. Previous studies have shown that patients with PA are at increased risk of stroke and AF  systolic function, using speckle-tracking echocardiography to assess LV global longitudinal strain (GLS). While previous studies have shown that patients with PA have impaired LV systolic function  in patients with newly diagnosed PA. In this study carotid intima-media thickness (cIMT) is significantly associated with left ventricular hypertrophy (LVH) whilst brachial-ankle pulse wave velocity (baPWV) is significantly associated with LVCG. While the study has some limitations, such as its retrospective and single-center design, its findings are consistent with previous research. Wang et al. . Given the high prevalence of hypertension, PA, and OSA, understanding their potential association and clinical implications is important. The authors critically analyzed the existing literature and identified several limitations in the currently available studies, which include heterogeneity in the study designs and populations, lack of uniform criteria for diagnosis and treatment of PA and OSA, and potential confounding factors such as obesity and diabetes. Although other studies have also suggested a potential link between PA and OSA  harbour known somatic mutations, which are associated with membrane depolarisation and increased aldosterone production. However, mechanisms driving cell proliferation of these adenomas remained unknown. In conclusion, this Research Topic provides a timely overview of the latest advances in the diagnosis and treatment of PA and its associated sequelae. The articles included in this Research Topic provide valuable insights into the expanding pathophysiology of PA and the need for ongoing research to fill up the gap of this important disease entity.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.


Likewise, the regional parameters of myocardial deformation were reduced in patients with culprit LCx lesions compared to those with non-culprit LCx lesions and in patients with culprit RCA legions compared to those with non-culprit RCA lesions . In the multivariate analysis, the △ regional PSS ) and the △ regional SR ) for LAD territories predicted the presence of LAD lesions. Similarly, in a multivariable analysis, the △ regional PSS and the △SR predicted LCx culprit lesions and RCA culprit lesions . In an ROC analysis, the PSS and SR had higher accuracies compared to the regional WMSI in predicting culprit lesions. A △ regional SR of −0.24 for the LAD territories was 88% sensitive and 76% specific , a △ regional PSS of −1.20 was 78% sensitive and 71% specific  and a △ WMSI of −0.35 was 67% sensitive and 68% specific  in predicting LAD culprit lesions. Similarly, the △ SR for LCx and RCA territories had higher accuracies in predicting LCx and RCA culprit lesions. Conclusions. The myocardial deformation parameters, particularly the change in regional strain rate, are the most powerful predictors of culprit lesions. These findings strengthen the role of myocardial deformation in increasing the accuracy of DSE analyses in patients with prior cardiac events and revascularization.Background and Aims. Dobutamine stress echocardiography (DSE) is a well-established non-invasive investigation for the detection of ischemic myocardial dysfunction. The aim of this study was to evaluate the accuracy of myocardial deformation parameters measured by speckle tracking echocardiography (STE) in predicting culprit coronary artery lesions in patients with prior revascularization and acute coronary syndrome (ACS). Methods. We prospectively studied 33 patients with ischemic heart disease, a history of at least one episode of ACS and prior revascularization. All patients underwent a complete stress Doppler echocardiographic examination, including the myocardial deformation parameters of peak systolic strain (PSS), peak systolic strain rate (SR) and wall motion score index (WMSI). The regional PSS and SR were analyzed for different culprit lesions. Results. The mean age of patients was 59 ± 11 years and 72.7% were males. At peak dobutamine stress, the change in regional PSS and SR in territories supplied by the LAD showed smaller increases compared to those in patients without culprit LAD lesions ( Globally, in 2017, ischemic heart diseases (IHD) affected 126.5 million people worldwide, an increase of 74.9% compared to 1990 , includiVisual assessment of segmental wall motion in the form of wall thickening and inward endocardial movement remains the primary method of analysis of stress echocardiograms ,18. HoweThe aim of this study was to compare the accuracy of two-dimensional wall motion assessments of ischemia in patients with chronic stable angina during conventional dobutamine stress echocardiography, with myocardial deformation parameters measured by speckle tracking echocardiography (STE), in predicting the culprit coronary artery lesions in patients with prior revascularization and ACS.Thirty-three patients were recruited in this study who presented to the International Cardiac Center hospital (ICC) in Alexandria, Egypt, between September 2021 and October 2022 because of symptoms suggestive of ischemia . All patients had a previous history of at least one episode of acute coronary syndrome, percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery.All patients underwent DSE to assess the presence and/or extent of ischemia to justify a referral for a coronary angiogram. Written consent was obtained from each patient and a full medical history was taken by a cardiology specialist, with details about coronary artery disease risk factors including hypertension, diabetes mellitus, dyslipidemia, smoking history, obesity and family history of CAD.Echocardiographic examination: An intravenous line was established in all patients and ECG lead II was connected. A baseline echocardiogram using an Affinity 30 echocardiograph  was performed on all patients with visually assessed wall motion abnormalities, applying the conventional segmental scoring system: (1) normal or hyperkinetic, (2) hypokinetic (reduced thickening or motion), (3) akinetic (absent or negligible thickening) and (4) dyskinetic (systolic thinning or stretching or aneurysm). The left ventricular ejection fraction (EF) was estimated using the modified Simpson method or conventional M-mode measurements. The presence of mitral regurgitation (if any) was noted, and the severity was assessed according to published guidelines . DobutamAfter the test, an offline analysis of myocardial deformation parameters including peak systolic strain (PSS) and peak systolic strain rate (SR) was made using speckle tracking echocardiography (STE) technology software . Resting and peak stress images and measurements were compared. Speckle tracking images were obtained with patients in the left lateral decubitus position from apical 4-, 3- and 2-chamber views at rest and at peak stress. Two-dimensional greyscale images were obtained at a frame rate of 70–80 Hz during three cardiac cycles and were then digitally stored for offline analysis. An offline analysis of the STE cine loops was performed using commercially available software . After manually outlining the clear myocardial border at the end systole, the ROI (the region of interest), generated automatically by the software, was manually adjusted and the peak systolic strain (PSS) and the peak systolic strain rate (SR) at basal, middle and apical levels were all determined ,24.Coronary angiogram: DSE examination was performed prior to coronary angiography and possible revascularization was performed based on the results. All patients underwent a coronary angiogram using the Judkins procedure and an onsite Toshiba or Philips lab using the conventional protocol.Inclusion criteria: Patients who presented with new onset of dyspnea, chest pains or both and were free of symptoms after their last coronary episode with a history of at least one episode of ACS and patients with reduced resting EF by conventional echocardiography or available data of a recent coronary.Exclusion criteria: Patients with a permanent pacemaker (PPM), an intra cardiac defibrillator (ICD) or cardiac resynchronization therapy devices (CRT) and patients with left ventricular (LV) thrombus or more than mild valve regurgitation. Additionally, we excluded patients with overt signs of heart failure, patients with a high NT-pro BNP and patients with other causes of dyspnea such as chest infections or anemia.This study conformed with the Helsinki convention guidelines, the protocol was approved by the local Ethics Committee  and all patients gave informed consent to participate in the study.t test and discrete data were compared with a Chi-square test. Variables were compared between any two groups using an unpaired Student’s t test or a Fisher’s exact probability test. The degrees of association between clinical and biochemical scales were determined using Pearson’s correlation coefficient in the case of continuous variables, a Chi-square test for categorical variables and point biserial correlation for categorical and continuous variables.Statistical analyses were performed using SPSS Software Package version 26.0 . Values are expressed as means ± standard deviation (SD) for continuous variables and frequencies (percentage) for categorical variables. Continuous data were compared with a two-tailed Student’s p value of <0.05 (two-tailed).Predictors of the culprit lesions were identified using a univariate analysis and multivariate logistic regression. The method and the number of predictors in the model, the anticipated effect size and the desired statistical power level were calculated. As a result of the small sample size, to have a desired statistical power level of about 0.8, we calculated the a priori sample size for multiple regression. Receiver operational characteristic (ROC) analyses were performed, and the best cut-off value, sensitivity and specificity were determined. A significant difference was defined as a Of the 33 studied patients with a mean age of 59 ± 11 years, 72.7% were males. A total of 17 (51.5%) had diabetes, 16 (48.5%) had dyslipidemia, 18 (54%) had hypertension, 42.4% smoked and 7 (21.2%) were obese. Eighteen patients had a previous PCI (54.5%) and nine patients had a previous CABG (27.3%). Out of 33 patients, 18 patients (54.5%) presented with typical chest pain, 9 (27.2%) patients presented with breathlessness and 6 patients (18.2%) had mixed symptoms .Significant luminal stenosis was found in 16 patients with left anterior descending (LAD) artery lesions, in 25 patients with left circumflex (LCx) artery lesions and in 25 patients with right coronary artery (RCA) lesions, while sub occlusion was found in 17 patients with LAD lesions, 8 patients with LCx artery lesions and 8 patients with RCA lesions .p > 0.05 for all; At rest, the mean LV EF was 36.2 ± 8.9%, the global wall motion score index was 2.07 ± 0.5 and the parameters of global myocardial deformation (PSS and SR) were 10.4 ± 2.6 and −0.55 ± 0.2, respectively, without significant difference in sub-regions supplied by different arteries (p < 0.0) but to a lesser extent compared to patients without culprit LAD (LVEF (8.0 ± 4.3 (21.0%) vs. 3.2 ± 3.5 (10.6%); p = 0.005), PSS (−2.9 ± 0.9 (25.4%) vs. −0.9 ± 1.1 (9.9%); p < 0.01), SR (−0.29 ± 1.1 (48.3%) vs. −0.17 ± 0.2 (34.1%); p = 0.02)). Similarly, the longitudinal PSS and SR in the territories supplied by LAD showed a lower increase in patients with culprit LAD lesions compared to those without culprit LAD lesions . The other territories supplied by RCA and LCx did not show any difference between the two respective groups. WMSI divided by territories did not show any significant difference  vs. −1.81 ± 0.9 (17.3%)), while the delta SR was −0.23 ± 0.6 (41.8%). Likewise, the delta global WMSI was 0.22 ± 0.2 (10.6%), with a similar extent in territories supplied by LAD and LCx (0.27 ± 0.23 (12.0%) vs. 0.20 ± 0.4 (11.8%)) but significantly less (0.11 ± 0.3 (4.84%)) in the territories supplied by RCA . In the fference . Likewisp = 0.001), △ global SR , △ global PSS  and △ global WMSI  in patients with significant LAD lesions, while △ SR in territories supplied by the LAD had a higher correlation . Similarly, a significant correlation was found between △ LVEF , △ global SR , △ global PSS  and △ global WMSI  in patients with significant LCx lesions. Additionally, the △ SR in territories supplied by the LCx had moderate correlation with significant LAD lesions . Likewise, there was a modest correlation between the global systolic function parameters and RCA significant lesions  and △ regional SR of the same LAD segments (p = 0.001) predicted culprit LAD lesions. △ regional PSS and △ regional SR also were the univariate predictors of RCA and LCx culprit arteries , but the regional WMSI significantly predicted the culprit lesion in LCx disease.In the univariate analysis, △ regional PSS of segments supplied by the LAD (p = 0.02)) and △ regional SR ) for territories supplied by the LAD predicted LAD lesions. Similarly, in the multivariable analysis, △ regional PSS and △ SR were also predictors of LCx culprit lesions and RCA culprit lesions , a △ PSS of −1.20 for LAD territories was 78% sensitive and 71% specific  and a △ WMSI of −0.35 for LAD territories was 67% sensitive and 68% specific  in predicting LAD culprit lesions  in patients with prior ACS and revascularization, the myocardial deformation parameters are more accurate than the conventional wall motion score index in detecting the coronary lesions responsible for recent admission/symptom development; (2) the myocardial longitudinal SR was consistently more accurate than the myocardial PSS in predicting the culprit lesions; (3) the myocardial SR accuracy in predicting the culprit lesions was higher in the territories subtended by the LAD and LCx arteries compared to those subtended by the right coronary arteries.Data interpretation: Although the wall motion score index is currently used as the conventional echocardiographic parameter for diagnosing ischemic dysfunction  and for The WMSI reflects the extent of inward displacement of different myocardial segments around the LV cavity, which is of course also contributed to by segmental systolic thickening. Such a function is controlled mainly by the circumferential myocardial muscle fibers of the ventricle. On the other hand, the longitudinal deformation function is mainly contributed to by shortening and lengthening of the subendocardial myocardial fibers, which are the most sensitive layer to ischemia. Such anatomical differences explain the different accuracies between the two methods we compared. Finally, even comparing the two longitudinal myocardial deformation parameters showed the superior accuracy of the strain rate in predicting culprit lesions over and above that of the myocardial strain. This finding is compatible with what we previously documented as a result of successful coronary angioplasty, despite using a different modality ,37. ThusClinical implications: In patients with complex coronary artery disease and prior cardiac events, myocardial deformation in the form of the SR is the most accurate marker of ischemia and the strongest predictor of coronary culprit lesions that need revascularization. Although our findings are not exactly in line with the current guidelines, they could be seen as eye opener for the additional application of stress echocardiography in symptomatic patients irrespective of the acuity of their condition or the occurrence of prior events, particularly for those with no additional significant valve diseases.Study Limitations: Our study has limitations. We could not perform power calculations because of the lack of previous publications for similar groups of patients. This limitation resulted in underpowering the study. This is shown clearly when dividing the patients into subgroups. We would have liked to study patients with prior myocardial infarctions and compare them with those with unstable angina, but the small numbers limited the relevance of this objective. Additionally, we would have liked to compare myocardial deformation parameters with other echo modalities in the same group of patients, including tissue Doppler velocities, but the need for a fast acquisition time prohibited achieving this desire.Myocardial deformation in the form of the SR is a powerful predictor of culprit coronary artery lesions in symptomatic patients with prior coronary artery interventions. These findings add to the valuable application of myocardial strain rate measurements as part of stress echocardiography, irrespective of patient presentation.


Aims: The differentiation of left ventricular (LV) hypertrophic phenotypes is challenging in patients with normal ejection fraction (EF). The myocardial contraction fraction (MCF) is a simple dimensionless index useful for specifically identifying cardiac amyloidosis (CA) and hypertrophic cardiomyopathy (HCM) when calculated by cardiac magnetic resonance. The purpose of this study was to evaluate the value of MCF measured by three-dimensional automated, machine-learning-based LV chamber metrics (dynamic heart model [DHM]) for the discrimination of different forms of hypertrophic phenotypes. Methods and Results: We analyzed the DHM LV metrics of patients with CA (n = 10), hypertrophic cardiomyopathy , isolated hypertension , and 54 healthy controls. MCF was calculated by dividing LV stroke volume by LV myocardial volume. Compared with controls , mean values for MCF were significantly reduced in HCM—48.55% (43.46–54.86% p < 0.001)—and CA—40.92% (36.68–46.84% p < 0.002)—but not in IH—59.35% (53.22–64.93% p < 0.7). MCF showed a weak correlation with EF in the overall cohort (R2 = 0.136) and the four study subgroups . ROC analyses showed that MCF could differentiate between healthy adults and HCM  and between healthy adults and CA . The best cut-off values were 55.3% and 52.8%. Conclusions: The easily derived quantification of MCF by DHM can refine our echocardiographic discrimination capacity in patients with hypertrophic phenotype and normal EF. It should be added to the diagnostic workup of these patients. When conventional endocardial measurements of ejection fraction (EF) are used to assess left ventricular (LV) function, the increases in wall thickness or decreases in diameters might mask the existence of a significant impairment in systolic performance ,2. ExperOne of the most intriguing parameters in this context is the ratio of stroke volume to myocardial volume, which determines the myocardial contraction fraction (MCF). It is a measure of how much the myocardium contracts during systole (as measured by stroke volume [SV]) in comparison to its ability to contract  ,8.There is ample evidence that the MCF can discriminate between pathological and normal hypertrophy ,9,10 andYet, many of these issues are now solved by automated three-dimensional echocardiography (3DE) . RecentlTo address this, we describe the measure of MCF by DHM and compare it in normal subjects in patients with isolated hypertension, CA, and HCM.2, BMI < 18.5 kg/m2, respectively).The study population comprised patients aged ≥18 who underwent standard transthoracic Doppler echocardiography for any indication from 14 September 2020 to 9 November 2021 at Modena University Hospital’s echocardiography laboratory. Criteria for enrollment included age ≥18 years, complete resting 2D and 3D echocardiographic assessment, and EF ≥ 50%. We excluded patients with unsatisfactory images—the margins were not seen well and thus deemed untraceable, patients on dialysis or end-stage liver failure, since large fluid shifts in these patients may cause significant extemporaneous differences in LA and LV measurements, patients with moderate or severe valvular heart disease, pregnant women and those who are in the six months following childbirth, and patients with morbid obesity or leanness  heaAge, sex, height, weight, body surface area (BSA), cardiac rhythm, clinical indications, and history of cardiovascular diseases were recorded at the time of the echocardiography. The study protocol followed the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the local ethic committee .A complete 2D and 3D transthoracic echocardiographic examination was performed, according to current guidelines ,24, usinUsing the automated DHM program, which automatically detects LV endo- and epicardial borders at the end-diastole, 3D-LV mass was analyzed, enabling direct LV mass thickness. Although it is possible to correct the LV and LA endocardial–epicardial borders at the end-diastole and and-systole, manual border adjustments were performed when deemed indicated by the operator. We considered the following DHM measures: LV end-diastolic volume indexed to BSA (EDVi), LV end-systolic volume indexed to BSA (ESVi), EF, SV, LA maximum volume indexed to BSA (LAVi max), LA minimum volume indexed to BSA (LAVi min), LA ejection fraction (LAEF), automatically calculated as LA maximum volume-LA minimum volume/LA maximum volume), LV mass, LV mass indexed to BSA, LV mass: LV end-diastolic volume ratio (LVM/LVEDV). We considered the MCF as an additional measure of the LV function as LV stroke volume/LV myocardial volume × 100. The myocardial volume was assessed by directly measuring the LV mass between the epicardium and endocardium by DHM and calculated by dividing the LV mass by 1.05 . When correctly performed, the calculation of LV myocardial volume is the same whether performed during systole or diastole because myocardial tissue, being not compressible, does not change during contraction . All 3D 2 < 1.0; good: 0.6 < R2 < 0.8; moderate: 0.4 < R2 < 0.6; or poor: R2 < 0.4. The discriminatory performance of the MCF for each study subgroup was explored using receiver-operating characteristic (ROC) curves and the area under the curve (AUC) analysis; the Youden index was used to determine the best cut-off values. A p-value < 0.05 was considered to be statistically significant in all the analyses. Analyses were performed using SPSS® version 26 .Data are shown as counts and percentages or median and interquartile range (IQR). Categorical variables were compared with the Chi-square test (or Fisher’s exact test if appropriate). For continuous variables, a comparison was made with the Mann–Whitney U test. Linear regression analysis was used to compare MCF and LVEF. The quality standards for correlations were defined as: very good: 0.8 < Rp < 0.001), they were more frequently female  and less frequently had a history of coronary artery disease . A detailed description of the patient’s demographic and clinical characteristics according to their baseline MCF value is shown in The original dataset consisted of 1349 consecutive patients. Among them, we identified 54 healthy adults, 87 patients affected by isolated hypertension, 36 by HCM, and 10 by CA. Median age was 49 (37–69) years, 61 (52–75) years, 63 (56–69) years, and 81 (79–82) years, respectively. Females accounted for 51.9% of healthy adults, 55.2% of isolated hypertension, 32.4% of HCM, and 10% of CA. Of note, 10.8% of HCM patients and 50% of CA patients had a history of atrial fibrillation. Most healthy adults (90.7%) and isolated hypertension (87.4%) showed an MCF ≥ 50%, while this finding was observed only in 41.7% of HCM patients and 10% of CA patients. Patients with MCF ≥ 50% were younger as compared with patients with MCF < 50% (57 (46–70) vs. 72 (59–81) years, 2; p = 0.469 and 28.6 (23.0–35.8) vs. 32.0 (24.6–38.7) mL/m2; p = 0.154, respectively). On the other hand, patients with MCF ≥ 50% showed a significantly lower LAVi max (34.4 (28.4–42.7) vs. 54.0 (41.3–65.3) mL/m2; p < 0.001) and LAVi min (12.7 (9.4–17.1) vs. 30.3 (17.7–40.2) mL/m2; p < 0.001) and a higher LAEF (62.0% (56.0–68.0) vs. 45% (29.0–59.0); p < 0.001). The median MCF in the overall cohort was 57.34 (50.1–64.9). Healthy adults showed higher MCF values than HCM (p < 0.001) and CA patients (p = 0.002), while they did not differ as compared with isolated hypertension (p = 0.756) (Echocardiographic parameters are shown in = 0.756) .2 = 0.136) and the four study subgroups as well . ROC analyses showed that MCF had a high capability to differentiate between healthy adults and HCM patients  and between healthy adults and CA patients , but not between healthy adults and isolated hypertension . The best cut-off values were 55.37, 52.86, and 62.24, respectively  typically falls into the normal or near-normal range even though myocardial shortening and systolic function are significantly hampered . As a reOur study was retrospective in design, and the sub-analysis of the patients with HCM and CA was restricted to a small group. However, all our groups were strictly defined, and the number of patients included is similar compared with other studies investigating LV hypertrophy differential diagnosis.The healthy sedentary subjects and those involved in competitive sports were not differentiated. Indeed, the MCF is increased in subjects with physiologic hypertrophy, reflecting a relatively greater increase in SV than myocardial volume .We do not account for LV global longitudinal strain because it was not feasible in a non-negligible percentage of the sample analyzed. However, conceptually, the MCF is comparable to myocardial strain because it is a generalized measure of myocardial shortening . Yet, thA more appropriately powered study examining associations would allow for a more granular disease-specific sub-analysis highlighting eventual variations of the MCF concerning HCM phenotypes, different stages of CA, and hypertensive heart disease. This issue may contribute to future studies on disease stages and risk stratification. Indeed, the probability of MCF becoming abnormal gradually increases across the spectrum of CA deposition .The MCF by DHM was not performed on top of conventional 2DE evaluation for comparative analysis ,35,36,37We were unable to gather more detailed information on the history and severity of hypertension since this was a retrospective analysis of a group that had transthoracic echocardiography.Finally, although easy to calculate, MCF by DHM is still a derived parameter. Therefore, postprocessing algorithms should hopefully be developed quickly to estimate MCF within an even shorter time delay regarding transferability to the clinical practice.The present data suggested that the quantification of the MCF by DHM can refine our echocardiographic discrimination capacity in patients with hypertrophic phenotype and normal EF. The following steps will require assessing its utility in other groups and different clinical scenarios for more general application in clinical practice.