Background: Pulmonary arterial hypertension (PAH) is a progressive proliferative vasculopathy associated with mechanical and electrical changes, culminating in increased vascular resistance, right ventricular (RV) failure, and death. With a main focus on invasive tools, there has been an underutilization of echocardiography, electrocardiography, and biomarkers to non-invasively assess the changes in myocardial and pulmonary vascular structure and function during the course of PAH.Methods: A SU5416-hypoxia rat model was used for inducing PAH. Biventricular functions were measured using transthoracic two-dimensional (2D) echocardiography/Doppler (echo/Doppler) at disease onset (0 week), during progression (3 weeks), and establishment (5 weeks). Similarly, electrocardiography was performed at 0, 3, and 5 weeks. Invasive hemodynamic measurements and markers of cardiac injury in plasma were assessed at 0, 3, and 5 weeks.Results: Increased RV systolic pressure (RVSP) and rate of isovolumic pressure rise and decline were observed at 0, 3, and 5 weeks in PAH animals. EKG showed a steady increase in QT-interval with progression of PAH, whereas P-wave height and RS width were increased only during the initial stages of PAH progression. Echocardiographic markers of PAH progression and severity were also identified. Three echocardiographic patterns were observed: a steady pattern (0–5 weeks) in which echo parameter changed progressively with severity [inferior vena cava (IVC) expiratory diameter and pulmonary artery acceleration time (PAAT)], an early pattern (0–3 weeks) where there is an early change in parameters , and a late pattern (3–5 weeks) in which there is only a late rise at advanced stages of PAH (LV diastolic eccentricity index). RVSP correlated with PAAT, PAAT/PA ejection times, IVC diameters, RV-FAC, tricuspid systolic excursion, LV systolic eccentricity and output, and transmitral flow. Plasma myosin light chain (Myl-3) and cardiac troponin I (cTnI) increased progressively across the three time points. Cardiac troponin T (cTnT) and fatty acid-binding protein-3 (FABP-3) were significantly elevated only at the 5-week time point.Conclusion: Distinct electrocardiographic and echocardiographic patterns along with plasma biomarkers were identified as useful non-invasive tools for monitoring PAH progression. Pulmonary arterial hypertension (PAH) is a progressive proliferative vasculopathy affecting small pulmonary arterioles culminating in increased vascular resistance and right ventricular afterload . AccordiFailure of the RV to adapt to increased afterload is the principal cause of death in patients with pulmonary hypertension (PH) , 4. FactDespite the prognostic significance of the RV status in PH, gaps still remain in the assessment of RV function and structure both during the course of the disease and during treatment . This stTo address these gaps, we sought to perform a comprehensive analysis to assess electrical, biochemical, and mechanical changes that occur in the heart and in the pulmonary circulation during the progression of PAH in a SU5416-hypoxia rat model. Our objective is to identify sensitive indices that can be obtained and monitored non-invasively in the early diagnosis of PAH and during the course of PAH.2) for 3 weeks (SuHyx rats). They were then returned to normoxia  for two additional weeks. For invasive measurements, separate sets of animals were used for the control, 3- and 5-week time points groups. For echocardiographic measurements, the same animals were used for the control (0 week), 3- and 5-week measurements. The number of animals used in each measurement is indicated in the figure legends. Experiments in each group were carried out independently for a minimum of two times.All animal experiments were performed under the University of Alabama Institutional Animal Care and Use Committee approval and in accordance with the National Institutes of Health Guide for the care and use of laboratory animals. This manuscript adheres to the ARRIVE guidelines. PAH was induced in rats using an established model . Brieflymaximum) and subsequent fall during diastole (dP/dTminimum) were measured. Systemic blood pressure was also monitored using the same catheter inserted in the carotid artery. In animals where echocardiography was carried out, invasive measurements were performed at the end of the 5-week protocol before the animals (n = 10) were euthanized. Separate sets of animals were used for invasive measurements of naïve (n = 17) and 3-week exposed animals (n = 11).Hemodynamic measurements were performed in rats under 2% isoflurane anesthesia using a 1.4 F high-fidelity Millar catheter as described by us before . Using aAnimals were euthanatized, and the left lung was inflation fixed with low-melting agarose and immersed in a solution of 10% formalin in ethanol for up to 48 h. The tissues were then processed for paraffin embedding. Five-micrometer-thick sections were cut on positively charged slides, and deparaffinization and antigen retrieval was performed. Sections were then blocked in 5% normal goat serum and incubated overnight with anti-von Willebrand factor (vWF) antibody (Dako cat# A0082) and anti-alpha smooth muscle actin (α-SMA) (Abcam cat# 18147). After washing with TBST , fluorescence tagged secondary antibodies, anti-rabbit Alexa fluor 488 (vWF), and anti-mouse Alexa fluor 594 (α-SMA) were applied, and sections were incubated for 1 h. Sections were then washed, rinsed with PBS, and mounted with VECTASHIELD containing DAPI (Vector laboratories). Images were captured at ×20 using the BZ-X800 Keyence microscope.Levels of cardiac and skeletal muscle markers of injury were measured in the plasma of rats from 0-, 3-, and 5-week time points using the meso scale discovery  muscle injury panel 1 kit. A multiplex assay to quantitate plasma levels of cTnI (cardiac troponin I), cTnT (cardiac troponin T), FABP3 (fatty acid-binding protein 3), Myl3 (myosin light chain 3), and sTnI  were carried out using standards and as per protocol of the manufacturer.Transthoracic echocardiography and electrocardiography were performed in anesthetized animals (2% isoflurane) as described by us before . EchocarE) and atrial (A) wave peak velocities, isovolumic relaxation time (IVRT), E-wave deceleration time, and isovolumic contraction time, with the ratio of E to A calculated across both the mitral and tricuspid valves. A tricuspid regurgitant jet was sought to estimate the RVSP when discernable (E′), late atrial (A′), systolic (S′) annular velocities, and (E) to (E′) ratios were calculated. Myocardial performance index (MPI) for both ventricles was calculated from the spectral Doppler tracing of transmitral and transtricuspid flows as described  directly in derivation DII. To determine the intervals RR, PR, QT, corrected QT (QTc), and QRS complex, a period of 10 s was analyzed in the ECG tracing of each animal. The QT interval was measured starting from the onset of the QRS complex until the end of the T wave, which is the return of the T wave to the baseline. QTc was obtained using Bazett's formula (QTc = QT/HRR) . Parametpost-hoc pairwise t-tests were conducted using Tukey's method for correcting for multiple comparisons. To assess the relationship between invasively measured RVSP and echocardiographic parameters, control and study animals were pooled, and Pearson correlations were calculated. Fisher's z transformation was used to calculate 95% confidence intervals. Due to the large number of tested parameters, a Bonferroni correction was applied to adjust for multiple comparisons.Values were expressed as mean ±SEM. Statistical analyses were performed using Prism software. Repeated measures one-way ANOVA was used to test for differences in each parameter at 0, 3, and 5 weeks. For statistically significant parameters, maximum was substantially elevated in the PAH animals at 3 and 5 weeks when compared with the controls . Representative tracing at all three time points shows changes with progression of PAH . A signiTo validate PAH pathology, the lung sections were stained for vWF and α-SMA to highlight changes in the intima and media of the arteries, respectively, during disease progression. As expected, the lung histology showed increased muscularization of the arteries with time demonstrating the progressive nature of the disease in this model . MarkersIn addition to the invasive RVSP, we also measured non-invasive surrogates of PH using echo Doppler across three time points. PAAT and PAAT/PAET were reduced with disease progression . A non-sRV fractional area of change (RV-FAC) and ejection fraction (EF) reflect global RV systolic function. Tricuspid annular plane systolic excursion (TAPSE) and tricuspid valve systolic wave (TV-Sa) can serve as surrogates of the systolic function of the RV. Although, variable, RV systolic function was significantly reduced with progression of PAH. RV-FAC was significantly reduced at 3 weeks and continued to decline over 5 weeks . Both EFIncreased RV pressure overload results in RV hypertrophy. The RV free wall thickness (RV-FWT), an indicator of RV hypertrophy, was significantly increased at 3 weeks. Furthermore, modest non-significant FWT changes occurred at 3- to 5-week time point . An incrThe hepatic venous (HV) flows and IVC diameter indicate the flow upstream from the PA and can be altered in PAH. The IVC diameters progressively increased from 0 to 5 weeks . An incrThe progressive increase in RV afterload can compromise LV function, structure, and filling. The inter-ventricular septum was flattened with a leftward shift . The LV Pooled analyses of the study and control animals revealed significant correlation between invasively measured RVSP and each of the following parameters: pulmonary artery acceleration time (PAAT), PAAT/PAET (pulmonary artery ejection time), IVC diameter, RV-FAC, TAPSE, LV-EIs, LV-CO, LV-SV, and trans-mitral E/A .Using serial measurements, we identified distinct patterns of EKG, and biochemical and echocardiographic parameters that together can potentially be used to detect PAH early, monitor PAH progression, and assess RV dysfunction and its response to treatment. Knowledge of these patterns addresses the current gap in practice that focuses primarily on PAP reduction rather than on holistically reversing myocardial and vascular remodeling . EchocarPAH is characterized by a decrease in pulmonary vascular compliance and an increase in PVR causing initial adaptive compensation followed by a maladaptive decompensatory phase of the RV failure . The patWith progressive increase in mPAP, less time is spent during ejection, and a faster rise in peak systolic pressure occurs due to a rapid closure of the pulmonary valve, causing reduction in PAAT and PAAT/PAET ratio . The redmax increased significantly during the early phase of PAH development and consistent with other reports  signifies an important compensatory mechanism by which the RV reduces its wall stress induced by the increase in pressure overload. Here we used the RV-FWT as a surrogate of RV hypertrophy rather than measuring the RV mass, given the limitations of measuring the RV mass by M-mode echocardiography . These f reports , 27. How failure . In adva failure .Increased PA pressures can alter hepatic venous (HV) flows and IVC diameter leading to a reduction in the forward flow from the HV to the RV. An increase in IVC diameter reflects an increase in back pressure from the right atrium as a result of increase in RV afterload and can serve as a prognostic indicator of PH . HepaticWe analyzed the correlation between the echocardiographic markers of progression of PAH and RVSP in order to assess their association with the severity of PAH. Markers associated with severity of PAH may be used for prognostication, whereas those associated with progression of PAH may be sought for monitoring of the disease progression and response to therapy. The correlation of TAPSE with RVSP confirms its prognostic significance and is consistent with previous reports. However, its failure to reduce beyond 3 weeks of PAH progression can be explained by the RV assuming a more spherical configuration during advanced stages of PAH and that TAPSE, being representative of the longitudinal motion of the RV and only of the free wall of the TV annulus, may be less contributing to RV ejection at this advanced stage of PAH. We are aware of the limitations of M-mode echocardiography in measuring RVEF compared with 3D echocardiography, which we did not possess at the time of the study. Similarly, RV-FAC, while being a prognostic marker of PAH, may not be an ideal marker of progression since it lacks representation of the RV outflow tract and may not represent the intrinsic contractility of the RV. Overall, echocardiography is a valuable tool in monitoring the severity and progression of PAH and may be helpful in its early diagnosis.In the model, serial changes in the LV with progressive PAH were also characterized. The rise in LVSP pattern is consistent with previous reports . FlattenIn our EKG studies, progressive prolongation in QT-interval reflects an abnormality in ventricular depolarization or repolarization, which may predispose to ventricular arrhythmias reportedly common in PH . ProlongMakers of cardiac injury are frequently used in stratification of disease. Our findings of increased levels of cTnT and FABP3 only during the late stages of PAH suggests their potential use as markers of disease severity. It is therefore not surprising that both of these markers were shown to correlate with major adverse events and were also predictors of mortality , 41. On In summary, recognizing biochemical, electrocardiographic, and echocardiographic patterns of PAH progression and severity may help in the monitoring and prognostication of RV function in PAH. Despite limitations, echocardiography is invaluable not only in diagnosing PAH but also in follow-up. There is a need for a “collective” assessment of the entire cardiovascular system in PAH. More studies are needed to mechanistically correlate electrical, vascular, and mechanical remodeling to non-invasive echo- and electrocardiographic findings.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The animal study was reviewed and approved by Institutional Animal Care and Use Committee (IACUC), University of Alabama at Birmingham, Birmingham, Alabama, USA.AZ and AA helped conceive the idea, design the study, analyze the data, and write the manuscript. IZ, MH, and NM helped acquire and analyze the data and review and write the manuscript. JM-J and TH helped analyze the data and review and write the manuscript. CM and MF helped with the statistical analysis of the data and reviewed and edited the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Dear Editor, about a proposal for heterotopic heart transplantation (HHT). It has called our attention that the authors are recommending to suture the pulmonary artery (PA) to the right atrium (RA), closing the donor inferior vena cava, as originally reported by Barnard and Losman in their initial clinical experience, in 1974, with HHT as assistance to left ventricular failure. Those authors predicted in their paper, published in 1975, that “This technique can be used as permanent assistance in patients with extensive irreversible damage of the left ventricular muscle. On the other hand, it can be used as a temporary device to assist the left ventricle in patients whose lives are threatened by a reversible condition, for example, cardiogenic shock after myocardial infarction.”. However, this technique has the disadvantage of not supporting the right ventricle (RV) circulation when the recipient’s heart fibrillates or the recipient RV function deteriorates, being not applicable to biventricular dysfunction.We read with interest the article published by Gaiotto et al. is a mixing of two techniques applied in 1974, and it is not new, being previously employed and published by the Yacoub team, associated with myocardial revascularization.Barnard and Losman also wrote about assisting the RV by anastomosing the stump of the donor superior vena cava (SVC) to the recipient SVC in an end-to-lateral anastomosis, making the anastomosis of the PA donor to the PA recipient, creating a parallel heart circulation. .This method demonstrated shortcomings, so after two cases, Novitzky, Cooper, and Barnard adopted the biventricular support HHT technique completing systemic venous return connection by the side-to-side donor and recipient RA anastomosis, and the donor PA was connected to the recipient PA by the interposition of a Dacron conduit,7.To prevent the potential complications of a PA prosthetic conduit  and to avoid the heavy adhesions involving the recipient PA, in 1993, Da Silva et al. performed and published a new technique that allowed the connection of the donor PA to the recipient right PA without a conduit interposition and direct end-to-end SVC anastomosis. Endomyocardial biopsy is in this way facilitated because the SVC anastomosis easily leads the bioptome forceps to the transplanted RV. In two subsequent patients, the HHT was indicated as assistance to biventricular function recovery after congenital heart disease repair. After six and a half years of her heart transplant, the third patient is alive and in good clinical condition. The fourth patient had explantation of the donor’s heart 11 months after HHT, with full recovery of his native heart function, growing in excellent clinical condition four and half years after his last surgical procedure. Therefore, the current proposalis not new in this aspect either.After that initial patient, we applied the same technique in three other situations. The long-term survival was 25 years in the first patient and seven and a half years in the second case; in both, the HHT indication was elevated pulmonary vascular resistance (PVR) in a set of cardiomyopathy has used the combination of the two initial HHT approaches described by Barnard, then keeping the SVC’s partial blood flow directed to the RA. This donor PA to recipient RA anastomosis prevents its use in patients with biventricular failure,4. Therefore, Copeland et al. and Gaiotto et al. are suppressing the benefit of donor RV support in future recipient’s arrhythmic events or progressive right ventricular dysfunction, reducing the likelihood of long-term survival with HHT, which in many reports has been demonstrated to be possible-12.Copeland. The impaired ventricular contractility against a normal systemic pressure generated by the donor LV causes a low blood flow velocity inside the enlarged recipient LV with a predisposition to thrombogenesis. Clot formation will not be modified by a right-side anastomosis modification, except as we did, by excluding conduit graft interposition, directly anastomosing the donor PA to the recipient right PA.The clot formation mentioned by authors in HHT usually occurs in the recipient left ventricle (LV). Our HHT approach has demonstrated excellent clinical outcomes and allowed biventricular function recovery.The potential benefit of HHT functioning as a temporary ventricular assist device (or VAD) was predicted by Drs. Barnard and Losman in 1975 and demonstrated in one of our patients and by other authorPreviously described HHT techniques do not preclude the idea of subsequently rotating the recipient heart to a central position. However, it will be extremely rare to confront a situation where the transplanted patient has a clinical indication to remove his native heart in clinical practice. The PVR needs to decrease enough to allow orthotopic heart transplant while the donated heart is still free of allograft coronary artery disease, justifying keeping the previously transplanted heart instead of replacing it with a new donor heart in orthotopic position. The argument that an RV connected to the RA will be adequate in such a situation is most unlikely since the RV managing SVC blood flow against a low RA pressure will be unprepared even to face normal PVR and can complicate the postoperative period.Therefore, we conclude with a word of caution against this proposed technique.The history of HHT has demonstrated valuable and safer ways to apply it and demands at least to be precisely alluded in modern era.


In the management of atrial fibrillation in patients with heart failure, rate control is recommended, whereas the implication of rhythm control remains controversial. We experienced a 65-year-old man who had compensated heart failure due to hypertensive heart disease and atrial fibrillation with well-controlled heart rate (<100 bpm). At three months following the catheter ablation procedure, the left ventricular ejection fraction improved from 40% up to 65%. The implication of rhythm control using catheter ablation in improving cardiac reverse remodeling should be validated in large-scale clinical studies. There is a considerable association between atrial fibrillation and heart failure. The presence of one increases the likelihood of another . Atrial Atrial fibrillation facilitates the progression of heart failure . The incThe first-line therapy for those with heart failure and atrial fibrillation is a rate control using beta-blocker in combination with other medications if necessary . The rhyA 65-year-old man with a history of two times of hospitalizations due to worsening heart failure and long-standing untreated hypertension admitted to our institute for further treatment. At his first decompensated heart failure, bisoprolol and amiodarone were initiated for his systolic heart failure (45% of left ventricular ejection fraction) and sustained ventricular tachycardia. Following the discharge, persistent atrial fibrillation developed. At his second decompensated heart failure, the etiology was diagnosed as hypertensive heart disease according to the findings of endomyocardial biopsy with no myocardial fibrosis and heterogeneous myocardium and 25% of left ventricular ejection fraction as well as no significant coronary artery stenosis demonstrated by coronary angiography. His heart rate was controlled below 100 bpm during the observational period. His heart failure was relatively compensated with New York Heart Association functional class II using 100 mg of amiodarone, 5 mg of enalapril, 5.0 mg of bisoprolol, 25 mg of spironolactone, 60 mg of azosemide, and 20 mg of furosemide which was added at the second decompensated heart failure re-admission thoroughly. 2.5 mg of warfarin also administrated. Body height was 166 cm and body weight was 65 kg (body mass index 23.7). Blood pressure was 100/74 mmHg and pulse rate was 86 bpm (irregular). An institutional review board approved the method  and an informed consent was obtained from the patient. 2, plasma B-type natriuretic peptide was 72 pg/mL, and hemoglobin A1c was 6.7%. Chest X-ray showed 46% of cardiothoracic ratio without obvious pulmonary congestion . Left atrial voltage mapping using a multipolar catheter  showed healthy electrical voltage except for in the antrum of left inferior pulmonary vein and left atrial septum A. First,Following the index discharge, anti-heart failure agents remained unchanged. The post-procedural course was uneventful without any adverse events including the recurrence of atrial fibrillation. The patient was evaluated for AF recurrence by a clinical interview, electrocardiogram, and portable electrocardiograph  every month. New York Heart Association functional class was I with 21 pg/mL of plasma B-type natriuretic peptide at three-month follow-up. Transthoracic echocardiography showed 41 mm of left atrial diameter and 53 mm of left ventricular end-diastolic diameter B. Of notHeart failure increases both preload and afterload of the left atrium and progresses its’ remodeling, causing the development of atrial fibrillation . The exiThe first-line to manage atrial fibrillation in patients with heart failure is rate control . If hemoThe Atrial Fibrillation and Congestive Heart Failure (AF-CHF) trial was the first randomized trial that compared the prognostic implication of rhythm control with drug therapy versus rate control (with beta-blockers) in patients with atrial fibrillation and systolic heart failure . The rhyRecently, the Cather Ablation for Atrial Fibrillation with Heart Failure (CASTLE-AF) trial demonstrated the superiority of catheter ablation over the conventional medical therapy for rate or rhythm control in improving all-cause mortality and worsening heart failure in selected patients with atrial fibrillation and systolic heart failure . Given aOur patient experienced a drastic improvement in left ventricular ejection fraction (approximately 25% increase). Given that guideline-directed medical therapy could not prevent his repeated heart failure recurrences, a dominant cause of his cardiac reverse remodeling would be AF ablation. Such an extreme cardiac reverse remodeling would improve patients’ quality of life and exercise capacity as well as preventing recurrent heart failure. His left ventricular end-diastolic diameter slightly enlarged after AF ablation, probably because of the prolonged diastolic duration by decreased heart rate with converted sinus rhythm. Several small studies also found an approximately 10% increase in left ventricular ejection fraction . The detFurther analyses are required for optimal patient selection . ShorterIn conclusion, a rhythm control of atrial fibrillation using catheter ablation would achieve drastic cardiac reverse remodeling in carefully selected patients with systolic heart failure.


Despite wide utilization, the accuracy of echocardiography to estimate PA pressures has been debated. We aimed to evaluate echocardiographic accuracy to estimate right heart catheterization (RHC) based PA pressures in a large, dual-centre hemodynamic database. Consecutive PH referrals that underwent comprehensive echocardiography within 3 h of clinically indicated right heart catheterization were enrolled. Subjects with absent or severe, free-flowing tricuspid regurgitation (TR) were excluded. Accuracy was defined as mean bias between echocardiographic and invasive measurements on Bland–Altman analysis for the cohort and estimate difference within ± 10 mmHg of invasive measurements for individual diagnosis. In 419 subjects, echocardiographic PA systolic and mean pressures demonstrated minimal bias with invasive measurements (+ 2.4 and + 1.9 mmHg respectively) but displayed wide limits of agreement (− 20 to + 25 and − 14 to + 18 mmHg respectively) and frequently misclassified subjects. Recommendation-based right atrial pressure (RAP) demonstrated poor precision and was falsely elevated in 32% of individual cases. Applying a fixed, median RAP to echocardiographic estimates resulted in relatively lower bias between modalities when assessing PA systolic  and PA mean pressures . Echocardiography accurately represents invasive PA pressures for population studies but may be misleading for individual diagnosis owing to modest precision and frequent misclassification. Recommendation-based estimates of RAPThe online version contains supplementary material available at 10.1007/s10554-021-02315-y. Accurate hemodynamic evaluation of pulmonary hypertension (PH) is essential for early disease identification, selection for potential therapy and during follow-up. Although PH diagnosis is established using right heart catheterization (RHC), transthoracic echocardiography is recommended for screening patients  and routmean) and systolic pressures (PAPsystolic) employing Bland–Altman analysis, suggesting appropriate utility in population studies  for analysis. Clinical characteristics, invasive and echocardiographic data are provided in Table 0% patienmax demonstrated strong association with invasive PAPmean  and a cut-off of 2.8 m/sec demonstrated good ability to identify PH, defined as invasive PAPmean ≥ 25 mmHg . Sensitivity analysis for different echocardiographic cut-offs to is presented in Table max demonstrated 89% sensitivity and 62% specificity to identify PH, with a 38% false positive rate. Forty-five patients (15%) with a TRVmax > 2.8 m/sec demonstrated normal PA pressures on RHC. At 3.4 m/sec, TRVmax demonstrated 94% specificity and 62% sensitivity, and false positive rate fell to 5.9%. Even when balanced sensitivity and specificity was identified at a 3.0 m/sec cut-off , a 20% false positive rate was observed. Supplementary sensitivity analysis was also performed considering PAPmean ≥ 20 mmHg which revealed similar results (Online Appendix Table 1). On Bland–Altman analysis, echocardiographic TR gradient demonstrated a mean bias of + 2.5 mmHg with invasive RV-RA gradient (95% limits of agreement + 23 to − 18 mmHg).TRVmean estimated as per ASE/EACVI recommendations [mean > 7 mmHg . However, Sensitivity analysis demonstrated a modest 68% specificity and 69% PPV  for the 3, 8 and 15 mmHg IVC-estimated subgroups were 5 (3–7 mmHg), 8 (5–10 mmHg) and 13 (8–16 mmHg) (p < 0.001 for comparison between groups). A total of 122 patients displayed an IVC-estimated RAPmean of 15 mmHg. In this subgroup, 15 (12%) demonstrated an invasive RAPmean < 5 mmHg, and 45 (37%), an RAPmean ≤ 10 mmHg. On Bland–Altman analysis, minimal bias but poor precision was observed between modalities .RAPndations  demonstrPV Table . Furthersystolic as per the ASE/EACVI approach demonstrated strong association with invasive PAPsystolic   was incorporated instead of IVC-based estimates [systolic remained strong   Fig. a. Bias astimates , associamean incorporating recommendation-based RAP estimates [mean   and showcased comparable limits of agreement (− 16 to + 19 mmHg)  Fig. a. Bias amean were falsely elevated in more than 1 in 3 subjects and incorporation of these estimates to calculate PAPsystolic and PAPmean resulted in relatively higher mean bias with RHC than when the median estimate was considered for all subjects.In the large, dual-centre KARUM hemodynamic database, echocardiographic PA pressures were reasonably accurate, demonstrating strong association and minimal bias with corresponding pressures obtained by RHC. However, wide limits of agreement in addition to frequent misclassification suggests modest precision and precludes wider echocardiographic utilization to quantify PH severity in individual cases. An important observation was that recommended echocardiographic estimates of RAPmax has been routinely utilized to grade PH probability [systolic estimates. Certain international recommendations hence encourage the use of absolute velocities instead [systolic [. The reliability of this method to represent invasive RAPmean has been debated [mean in our study, accuracy of recommended cut-offs to represent invasive pressures was poor and may explain the frequent misrepresentation of pulmonary systolic pressures. When a fixed median RAP of 7 mmHg was considered in the population, association was still strong and bias between echocardiographic and invasive PAPsystolic and PAPmean readings was actually lower in our study, suggesting that these recommended estimates may offer no additional advantage to PA pressure assessment [mean is frequently inaccurate even during rest, and results in frequent overestimation of invasive pressures. Objective assessment of the IVC demonstrates inherent technical limitations related to excessive translation during rapid inspiration [mean, but these findings require further validation in larger cohorts.Interest in the utility of echocardiography to estimate PA pressures emerged with early studies suggesting a significant correlation between TR-derived estimates and invasive pulmonary pressures –15. Sincbability  and to dbability , 4. A nubability  and sevebability . Both th instead . Our datsystolic . The rel debated –24, with debated , 21, 24.sessment . A recenpiration  and has piration  and patipiration  and 3D vpiration  may provOur study also corroborates earlier findings that suggest modest echocardiographic precision to reflect invasive PA pressures when individual cases are concerned , 9, 30, The use of fluid-filled catheters instead of high-fidelity manometer-tipped catheters for pressure measurement might introduce additional error and may be considered a limitation in this study. Additionally, we did not adopt a core lab approach to evaluation of echocardiographic images in this study and inter-operator and inter-evaluator variability may be considered a limitation. However, a standard international acquisition and analysis protocol was followed by two experienced echocardiographers with over 15 years’ experience. Finally, we did not employ agitated saline to boost weak TR signals in this study, but chose instead to exclude unanalyzable signal registrations from the analysis. Fewer cases may have been excluded with contrast use and this may be considered a limitation.mean frequently overestimate corresponding invasive measurements and do not necessarily contribute to greater accuracy of pulmonary artery (PA) pressure estimates.Echocardiography accurately represents invasive PA pressures and is, hence, appropriate for population studies. However, modest precision and frequent misclassification preclude its utility for evaluation of PH severity in individual cases. Recommendation-based estimates of RAPSupplementary file1 (DOC 34 kb)Below is the link to the electronic supplementary material.


Type‐2‐phosphatidylinositol‐5‐phosphate‐4‐kinase‐gamma (Pip4k2c) is a known mTORC1 regulator. It is shown that Pip4k2c is significantly downregulated in the hearts of CH and HF patients as compared to non‐injured hearts. The role of Pip4k2c in the heart during development and disease is unknown. It is shown that deleting Pip4k2c does not affect normal embryonic cardiac development; however, three weeks after TAC, adult Pip4k2c−/− mice has higher rates of CH, CF, and sudden death than wild‐type mice. In a gain‐of‐function study using a TAC mouse model, Pip4k2c is transiently upregulated using a modified mRNA (modRNA) gene delivery platform, which significantly improve heart function, reverse CH and CF, and lead to increased survival. Mechanistically, it is shown that Pip4k2c inhibits TGFβ1 via its N‐terminal motif, Pip5k1α, phospho‐AKT 1/2/3, and phospho‐Smad3. In sum, loss‐and‐gain‐of‐function studies in a TAC mouse model are used to identify Pip4k2c as a potential therapeutic target for CF, CH, and HF, for which modRNA is a highly translatable gene therapy approach.Heart failure (HF) remains a major cause of morbidity and mortality worldwide. One of the risk factors for HF is cardiac hypertrophy (CH), which is frequently accompanied by cardiac fibrosis (CF). CH and CF are controlled by master regulators mTORC1 and TGF‐ β1 pathways, respectively.Heart failure remains a major cause of morbidity and mortality worldwide. One of the risk factors for HF is cardiac hypertrophy (CH), which is frequently accompanied by cardiac fibrosis (CF). Here, gain‐ and loss‐of‐function studies are used to identify the therapeutic role of Pip4k2c in preventing CH and CF via inhibition of mTOR and TGF More common causes of CF, which is a key risk factor for arrhythmia and sudden death, are hypertension, valve issues, and congenital heart disease. Unraveling the mechanistic molecular pathways that underlie pathological stress and HF may lead to the development of new therapeutic options for CH and CF in HF.HF is a major worldwide health problem and a huge socioeconomic burden.1 Pathα, PI5P4Kβ, and PI5P4Kγ – that play important roles in development, homeostasis, and disease. Pip4k2c is expressed primarily in the kidney, brain, heart, and testes. To date, Pip4k2c has been studied for its regulatory roles in insulin resistance, via catalytic‐independent suppression of PIP5k synthesis, and immune response, via mTORC1‐signaling inhibition in the kidney, testes, muscle, or brain. The N‐terminal motif of Pip4k2c was found to be crucial to mTOR inhibition. Research produced during the last decade has clarified that mTORC1 signaling is important to promoting CH in response to chronic pressure overload. Moreover, TGFβ1 engenders CF via the downstream mediator Smad3, which activates the extracellular matrix (ECM)‐related genes. What remains unclear, however, is 1) the role of pip4k2c in the heart during development and disease, 2) whether or not Pip4k2c affects TGFβ1 signaling in cardiovascular pathophysiology, and 3) the nature of the interplay between Pip4k2c and mTORC1 in the context of cardiac disease. Here, we use gain‐ and loss‐of‐function studies to explore the role of Pip4k2c in preventing cardiac hypertrophy and fibrosis in the failing heart.Pip4k2c is a Type 2 phosphatidylinositol‐5‐phosphate 4‐kinase (PI5P4K) that converts phosphatidylinositol‐5‐phosphate to Phosphatidylinositol 4,5‐bisphosphate in mammals. The mammalian gene PI5P4K encodes three enzymes – PI5P4K disease.12 Pip22.1 we hypothesized that human PIP4K2C levels would be higher in heart tissue taken from the left ventricular myocardium of a Non‐Failing (NF) heart than in samples taken from patients with CF or HF. To test our hypothesis and to investigate the role of PIP4K2C in heart diseases, we analyzed PIP4K2C mRNA or protein levels in the left ventricle (LV) of hearts taken from patients with CH, HF, or NF  mouse model (pressure overload). TAC was performed, and cardiac tissue was collected 4, 7, and 21 days later Figure . We obse2.2−/− (KO‐Pip4k2c) mice. During mouse heart development, we saw no significant change in mouse viability, growth, weight, heart weight, heart weight to body weight ratio (HW/BW), or CM number in E18 KO‐Pip4k2c mice versus littermate control mice (WT) . In order to analyze the effect of Pip4k2c on cardiac function, CH, and CF, we used a TAC mouse model in 8‐ to 12‐week‐old KO‐Pip4k2c or WT mice and compared them to sham‐operated KO‐Pip4k2c or WT mice 21 days after the procedures  modRNA and R26mTmG mice to evaluate modRNA biodistribution in the mouse heart following TAC  and found that modRNA‐delivered Cre led to more than 40% LV transfection in a TAC model . We also showed, in vivo using western blot analysis ) protein, which is a known mTORC1 pathway marker. 21 days after TAC, phosphorylated p70s6k was significantly higher in KO‐Pip4k2c mice than WT and sham‐operated WT or KO‐Pip4k2c mice 35 to 7 Figure . This tr7 Figure ,f and no7 Figure ,h 14 and7 Figure –k. Using7 Figure ,m. Final7 Figure . These d2.5Figure β1 pathway, and because our loss‐ and gain‐of‐function studies  and CF (via TGFβ1 in cardiac fibroblasts), both of which can lead to HF. Using a TAC mouse model, we demonstrated that Pip4k2c modRNA could therapeutically attenuate detrimental effects and promote better cardiac function and survival  daily to further study the TGFC Figure . We showC Figure ,f and noC Figure ,h 21 dayC Figure ,j accompC Figure ,l in KO‐l Figure .2.6 We then used the TAC mouse model to compare Pip4k2c and mutant Pip4k2c modRNA ; such phosphorylation is crucial for TGFβ1 expression and pro‐fibrotic activity. We therefore wanted to evaluate if phospho‐AKT and phospho‐smad3 (208) play a role in inhibiting Pip4k2c on TGFβ1 in the heart. To accomplish this, we collected KO‐Pip4k2c cardiac fibroblasts 6 or 24 hours post transfection with Luc or Pip4k2c modRNA, isolated and sorted the fibroblasts, and then evaluated them using western blot. Our data show significantly elevated Pip4k2c that leads to remarkably reduced Pip5k1α, phospho‐AKT 1/2/3, and phospho‐Smad3 (208) after transfection with Pip4k2c modRNA as compared to control. These findings indicate that Pip4k2c negatively regulates TGFβ1 via its N‐terminal motif (VMLLPDD); reduces Pip5k1α, phospho‐AKT 1/2/3, and phospho‐Smad3 6 in cardiac fibroblasts; and thereby lowers their proliferation and fibrotic activity  was replaced with the mutant motif EIFLPNN. This mutation was previously shown to abolish Pip4k2c's ability to inhibit the mTOR pathway.16 We A Figure –f or CH A Figure , in compy Figure .β1 pathway in cardiac fibroblasts post TAC, thereby reducing CH and CF, resulting in better cardiac function and survival following TAC injury .Overall, our data demonstrate that Pip4k2c modRNA inhibits the mTORC1 pathway in CMs and the TGF3β1 in cardiac fibroblasts by suppressing Pip5k1α, phospho‐AKT 1/2/3, and phospho‐Smad3; prevents CH (of CM) and CF (in cardiac fibroblasts); and improves TAC injury outcomes  recruitment. In the canonical TGFβ1 signaling pathways, Smads 2 and 3 are activated via ALK5 while Smads 1 and 5 are activated via Smads 1 and 5. The two Smads pairs create a complex that binds to Smad 4, which leads the complex into the nucleus to promote expression of the TGFβ1, extracellular matrix, matrix metalloproteases, and myofibroblast‐related genes. Several strategies to inhibit TGFβ1 signaling have been tested, with limited success. Therefore, identifying new targets that can control TGFβ1 signaling may have important therapeutic potential in heart disease. It is not clear if PIP4k2a and PIP4k2b suppress mTORC1 or TGFβ1 in the mouse TAC model. The fact that it can simultaneously suppress two fundamental pathways, mTORC1 in CM and TGFβ1 in cardiac fibroblasts, posits PIP4k2c as a key target for regulating CH and CF in HF patients. As the TGFβ1 and, in some cases, mTORC1 pathways are crucial to other fibrotic diseases, such as pulmonary fibrosis and chronic renal fibrosis, it will be vital to evaluate the effect of PIP4k2c in these settings. Further, we show that immune cell composition in KO‐Pip4k2c mice is similar to that in WT mice 21 days post TAC . Together with our Pip4k2c modRNA data, this strongly suggests that Pip4k2c impacts cardiac cells directly and not via suppressing the immune system.PIP4Ks  play important roles in insulin production16 and Figures , 4, 5, 6β1, respectively, and have been widely used in the clinic, it would be intriguing to determine whether or not they can be replaced with Pip4k2c modRNA. The longer pharmacokinetics of Pip4k2c modRNA allow it to be administered in a single dose, without known toxicity, and its activity localizes only in the target tissue , whereas small‐molecule drugs need daily administration, have some toxicity , and are active in all tissues and organs within a treated individual.Our current project also shows that the small‐molecule drugs rapamycin and SB4311542 partially overcome Pip4k2c loss in the heart following TAC injury , a naked modRNA translates 20 times higher than capsulated modRNA using commercially available nanoparticles. Furthermore, in moderna and AstraZeneca Phase 2a human clinical trials in Finland (AZD8601), patients with ischemic heart disease receive VEGFA modRNA delivered naked in citrate‐sucrose buffer. The mechanism of action that allows naked modRNA to enter the cell, as both modRNA and the cell membrane are negatively charged, is not yet clear. Additionally, modRNA was recently shown to be a safe, effective Spike protein gene delivery system for vaccination against SARS‐CoV‐2 to prevent COVID‐19 in humans. Both companies  producing these vaccines chose to capsulate Spike modRNA in nanoparticles to insure consistent delivery. While capsulated modRNA can lead to lower translation, it also protects against RNase cleavage in the blood. In our published cardiac studies and our current work, we use a dissecting microscope to perform intramyocardial injections, allowing us to avoid injecting the naked modRNA into blood vessels, which can lead to it's cleavage.Our study transfected modRNA in vitro using RNAiMAX, while in vivo we used naked modRNA transfected with sucrose‐citrate buffer. In vitro, naked modRNA transfection was not successful, as the modRNA floated over the cells (data not shown). In vivo, as we have shown previously,24 nak IGF1, mutant hFSTL1, aYAP, AC, or Pkm2) in I/R or MI models in order to promote cardiovascular effects, induce epicardial fat, or support CM proliferation. Here, in a TAC model, we show that modRNA has high biodistribution, as over 40% of the LV is transfected , and that Pip4k2c modRNA pharmacokinetics show expression for more than 10 days . Indeed, a single dose of Pip4k2c modRNA engenders cardioprotection and reduces CH and CF in a TAC mouse model, with translational capacity. It is not yet clear if a single dose is sufficient for long‐lasting effects in mice or larger animals. As intramyocardially injected Pip4k2c modRNA upregulates Pip4k2c protein for 10–12 days , we should seek new, minimally invasive routes to deliver modRNA into the injured heart.Overall, modRNA is a transient, safe, controlled, dose‐dependent gene delivery method that has thus far been used to upregulate a gene of interest Wtsi). For long‐term survival, 8‐ to 10‐week‐old C57BL/6J or Pip4k2c−/− mice were treated without or with Luc or Pip4k2c modRNAs (n = 10) post TAC and allowed to recover for the specified time in the animal facility. Deaths were monitored and documented. Tissues were harvested from C57BL/6J or Pip4k2c−/− mice on E18 for analysis. Mouse husbandry was carried out according to the protocol approved by the IACUC. Oligonucleotide sequences for genotyping the above mouse lines: Pip4k2c ‐F‐ CACACCTCCCCCTGAACCTGAAAC, Pip4k2c ‐R‐ AGCCGCTGGGGCCAGATGAT.All animal procedures were performed under protocols approved by the Icahn School of Medicine at Mount Sinai Institutional Animal Care and Use Committee (IACUC). Male and female C57BL/6J or CFW mice were used. Different modRNAs (100 µg per heart) were injected directly into the myocardium during open chest surgery. 3 to 10 animals were used for each experiment. The Pip4k2c were obtained from: 1) Afro‐American, Male, 47 years old, died on 5/22/2000; 2) Caucasian, Female, 51 years old, died on 7/13/1995; 3) Caucasian, Male, 68 years old, died on 9/4/2000; 4) Afro‐American, Male, 37 years old, died on 11/27/2005; 5) Caucasian, Female, 58 years old, died on 7/30/2006. Samples of HF hearts were obtained from patients with either ischemic heart disease: 1) Caucasian, Female, 66 years old, died on 10/11/2000; 2) Caucasian, Male, 69 years old, died on 4/1/1993; 3) Caucasian, Male, 52 years old, died on 12/29/1993; 4) Afro‐American, Female, 62 years old, died on 10/12/2001; or dilated cardiomyopathy: 5) Caucasian, Male, 53 years old, died on 9/23/1997.Human heart tissue specimens were obtained from the National Disease Research Interchange through the Human Tissues and Organs for Research Resource program. HF heart samples were obtained from patients with end‐stage heart failure undergoing heart transplantation. Normal or CH heart samples were procured from donors who died in accidents and who had either CH or hearts unsuitable for transplantation for non‐cardiac reasons . Normal and CH conditions were defined by cardiac pathology. The control samples were obtained from donors with uninjured normal hearts: 1) Caucasian, Male, 54 years old, died on 4/19/1994; 2) Caucasian, Male, 58 years old, died on 9/24/2000; 3) Caucasian, Female, 68 years old, died on 9/1/1993; 4) Caucasian, Male, 53 years old, died on 9/24/1997; 5) Hispanic, Female, 39 years old, died on 11/26/1998. Samples of CH hearts, defined by cardiac pathology using known criteria,59 wer−3m, TriLink Biotechnologies); guanosine triphosphate ; adenosine triphosphate ; cytidine triphosphate ; and N1‐Methylpseudouridine‐5'‐Triphosphate  as described previously in the recent protocol paper. The mRNA was purified using the Megaclear kit (Life Technology) and treated with antarctic phosphatase (New England Biolabs), followed by re‐purification using the Megaclear kit. The mRNA was quantitated by Nanodrop (Thermo Scientific), precipitated with ethanol and ammonium acetate, and resuspended in 10 × 10−3m TrisHCl, 1 × 10−3m EDTA.ModRNAs were transcribed in vitro from plasmid templates (see Table S1 (Supporting Information) for a complete list of open reading frame sequences used to make the modRNA for this study) using a customized ribonucleotide blend of anti‐reverse cap analog; 3 ´‐O‐Me‐m7G (5')ppp(5')G (6 × 10 using sucrose citrate buffer containing 20 µL of sucrose in nuclease‐free water (0.3 g mL−1), with 20 µL of citrate  mixed with 20 µL of different modRNA concentrations in saline, to a total volume of 60 µL. The transfection mixture was directly injected  into the myocardium. For in vitro transfection, RNAiMAX transfection reagent was used (Life Technologies) according to the manufacturer's instructions.In vivo modRNA transfection was performed as described in the recent method paper,24 usiFor additional methods please see the Supporting Information.The authors declare no conflict of interest.Supporting InformationClick here for additional data file.


As sign of impaired diastolic function, TAU, a preload-independent measure of isovolumic relaxation  and end-diastolic pressure  raised after valve implantation. Contrarily, a smaller ratio of end-systolic to arterial elastance  indicates an improvement of global cardiovascular energy efficiency (1.40 vs. 0.97 p = 0.036). Arterial elastance had a strong correlation with the number of conducted rapid ventricular pacings . Invasive left ventricular pressure volume loop analysis revealed impaired systolic and diastolic function in the early phase after TAVI with self-expandable valve for the treatment of severe aortic stenosis. Contrarily, we found indications for early improvement of global cardiovascular energy efficiency.Replacement of a stenotic aortic valve reduces immediately the ventricular to aortic gradient and is expected to improve diastolic and systolic left ventricular function over the long term. However, the hemodynamic changes immediately after valve implantation are so far poorly understood. Within this pilot study, we performed an invasive pressure volume loop analysis to describe the early hemodynamic changes after transcatheter aortic valve implantation (TAVI) with self-expandable prostheses. Invasive left ventricular pressure volume loop analysis was performed in 8 patients with aortic stenosis (mean 81.3 years) prior and immediately after transfemoral TAVI with a self-expandable valve system . Parameters for global hemodynamics, afterload, contractility and the interaction of the cardiovascular system were analyzed. Left ventricular ejection fraction, (53.9% vs. 44.8%,  L,. L14],.p < 0.05 for all analyses, which were always 2-tailed and performed with SPSS, version 25 .Continuous variables are shown as mean ± standard deviation and categorical data are shown as number + percentage. Hemodynamic parameters were taken as means for every patient  and analyzed by paired two-sided Wilcoxon–Mann–Whitney-Test for continuous variables. Subgroups  were analyzed separately and differences in hemodynamic changes assessed by Wilcoxon–Mann–Whitney-Test. Non-parametric Kendall’s Tau was calculated to measure the correlation of the amount of administered contrast medium with parameters for global hemodynamics and myocardial contractility. The a priori level of statistical significance was set at n = 3 women, 37.5%) with a median STS score of 2.1%  was implanted and a mean of one RVP per procedure either for pre-dilatation or prosthesis post-dilatation was performed  and CI , on the other hand SW  and LVEF  decreased post prosthesis implantation  and EES  both decreased significantly compared to baseline (Table p = 0.018) and dP/dtmin  increased and reflect a state of impaired diastolic function early after prosthesis implantation. Moreover, LVEDP (13.1 vs. 16.4 mmHg p = 0.015) as well as ESV  raised after valve implantation.Marker for myocardial contractility, such as PRSW . We found a strong correlation of the absolute change in arterial elastance  with the number of conducted rapid ventricular pacings . The postprocedural course and the short-term outcome of the cohort is displayed in Table Arterial elastance, a measure for arterial load, remained stable after prosthesis implantation . A correlation analysis ruled out relevant associations between administered contrast medium and parameters for global hemodynamics and myocardial contractility Table .Table 8CThe study cohort was inhomogeneous concerning relevant comorbidities known to impact hemodynamics during TAVI, such as reduced systolic left ventricular function, prevalence of severe mitral insufficiency and atrial fibrillation. Cardiac index as well as preload recruitable stroke work declined significantly in patients with LVEF < 40% compared to patients with preserved LVEF Table . FurtherValve replacement in patients with severe stenosis is expected to reduce immediately the ventricular to aortic gradient in patients with preserved ejection fraction.Beneficial long-term effects of TAVI are driven by positive remodelling of the LV, morphologically mainly due to reduction in LV wall thickness . HoweverImmediately after TAVI we observed reduced LVEF, assessed invasively by PV Loop conductance catheter. Nevertheless, over the long-term TAVI is known to improve LVEF in patients with preserved as well as with reduced LVEF. The follow-up of the randomized controlled Partner A trial comparing TAVI with surgical aortic valve replacement in patients with severe aortic stenosis (PARTNER A) demonstrated, that ejection fraction improves after TAVI with most improvement occurring within the first 30 days after the procedure and independently of preoperative LVEF . Markus Immediately after TAVI, we found markers for myocardial contractility to be reduced. Preload recruitable stroke work and end-systolic elastance declined significantly compared to baseline. Both are a valid marker for myocardial contractility. Moreover, preload recruitable stroke work is considered to be insensitive to preload and afterload , 20. CabP/dtmin increased in our cohort compared to baseline. Consequently, end-diastolic pressure as well as end-systolic volume was raised after valve implantation. This finding is surprising, as over the long-term diastolic function is expected to recover and, therefore, EDP to decline. The fundament for these favorable hemodynamic changes are a larger valve orifice and remodeling of the LV after TAVI ; RT, total mean vascular resistance; ts and td, systolic and diastolic period; tau, diastolic pressure decay time constant . Our analysis is consistent with the report of Freeman et al., who described the enhancement of arterial elastance during rapid ventricular pacing in an experimental dog model. Appropriate interpretation of the dynamics of arterial elastance during TAVI might help to improve periprocedural fluid and hemodynamic support management. Further studies are warranted to explain the intraprocedural changes in arterial elastance and possible implications for clinical care.Moreover, we found a strong correlation of the absolute change in arterial elastance with the number of conducted rapid ventricular pacings. Arterial elastance incorporates vascular load including peripheral resistance, vascular compliance and impedance as well as systolic and diastolic time intervals . It is eThe interaction between left ventricle and arterial system can be expressed comprehensively by the ratio of arterial to end-systolic elastance, named ventricular-arterial coupling. It is recognized as an important determinant of global cardiovascular performance , 39. If The early phase post TAVI is often the most critical part of a TAVI procedure, sometimes requiring aggressive and prompt hemodynamic management. Our findings may give a small insight of the underlying pathophysiolocigal mechanism causing these phenomena. Our data suggest a reduction of myocardial contractility and diastolic function early after valve implantation. Especially, patients with impaired systolic or diastolic ventricular function are endangered in this part of the procedure. Our results underline the importance of a few key requirements for a successful TAVI procedure, such as avoiding unnecessary RVP, optimization of body fluid balance to reduce ventricular filling pressures and decisive vasopressor and inotropic support if needed. Besides that, PV loop analysis may help to detect and evaluate the hemodynamic relevance of a paravalvular leakage post TAVI, a condition known to be associated with worse long-term outcomes. However, larger studies with detailed hemodynamic measurements and follow-up are needed to understand the long-term effects these early hemodynamic changes may imply.Our study has important limitations. This is a single-center study and we analyzed the data of a small and heterogeneous patient cohort, because recruitment of a larger patient sample is mainly limited by the complexity of this analysis method. Baselines left ventricular geometries were not homogeneous and due to the small cohort, a subgroup analysis to determine the impact of left ventricular geometry on hemodyanamics during TAVI was not feasible. We only performed PV loop measurements in TAVI with one self-expandable valve system, and our findings have no validity for TAVI procedures with other valve employment systems or self-expandable valves of other manufactures. Due to the small number of enrolled patients and investigators, who performed the measurements, relevant bias, such as selection bias, measurement bias, observer bias an ascertainment bias may influence our results significantly. We present observations and no statistical certainties. Therefore, a general extrapolation of our results is not valid.Invasive left ventricular pressure volume loop analysis revealed impaired systolic and diastolic function in the early phase after TAVI with self-expandable valves for the treatment of severe aortic stenosis. Left ventricular ejection fraction was impaired and end-diastolic pressure and end-systolic volume increased after valve implantation compared to baseline. Contrarily, a smaller ratio of arterial to end-systolic elastance, known as ventricular-arterial coupling, suggests an early improvement of global cardiovascular energy efficiency.


Pearson’s correlation coefficient analysis was used to compare two processes of T1 analysis. The results show a global native T1 mean value of 1124.9 ± 55.2 ms , that of women being statistically higher than men . There were no specific tendencies for T1 times in different ventricular slices. We found a strong correlation  with T1 times derived from parametric maps (1136.4 ± 60.2 ms). Native T1 reference values for a Canon 3T scanner were provided, and they are on par with those already reported from other vendors for a similar sequence. We also found a correlation between native T1 and gender, with higher values for women.This study aimed at establishing native T1 reference values for a Canon Vantage Galan 3T system and comparing them with previously published values from different vendors. A total of 20 healthy volunteers  underwent left ventricular T1 mapping at 3T MR. A MOLLI 5(3)3 sequence was used, acquiring three short-axis slices. Native T1 values are shown as means (±standard deviation) and Student’s independent samples  Cardiac magnetic resonance (CMR) is considered the gold standard for ventricular volume and function determination, but the advantages of the technique span from anatomic to tissue characterization, perfusion and viability ,2. ThereAs a state-of-the-art method, CMR is continuously evolving, and its tissue quantification techniques, such as T1 mapping, are among those most unanimously lately adopted by the scientific community . This teT1 mapping contributes to the non-invasive characterization of the myocardial health state, which is helpful to identify abnormalities in the context of both acute and chronic events, such as edema and fibrosis, as well as detection of fat, iron and amyloid accumulation ,6,15. TyThe aim of this research was to determine the native T1 values for a population of healthy individuals with our 3T MR scanner, comparing them with the published values of different vendors, more widely reported so far.The research was performed at Hospital da Luz Aveiro , using a 3T clinical MR scanner . Healthy volunteers were screened from local publishing. After signing the internal consent form, approved by the institution’s ethics committee, non-contrast cardiac MR was performed between July 2019 and September 2021 (the prolonged recruitment was impacted by the COVID-19 pandemic). The confidentiality and anonymity of all volunteers was guaranteed, and any abnormal findings on the images, cardiac or extra cardiac, were conveyed to the participants.diabetes mellitus and family history of premature cardiovascular disease, that is ≤55 years for men and ≤65 years for women).CMR was performed on 22 volunteers without main cardiovascular disease risk factors  and 40-channel posterior (spine coil) coils. All participants were scanned using the same CMR protocol, as shown in The parametric T1 map’s quality can be affected by many artifacts, such as motion (respiratory and cardiac), miss-triggering and magnetic susceptibility . In acco42) software, client version 5.12.4, Canada, and they were analyzed in two ways:The images’ post processing was performed using Circle Cardiovascular Imaging , according to the exponential curve of the respective type of T1 mapping sequence  7,18,1919,20.42− derived), allowing further qualitative assessment but also containing pixel-wise information of the T1 values  and were compared using Student´s independent samples t-test. Categorical variables were expressed as a percentage. Pearson’s correlation coefficient analysis was used to compare native T1 values estimated from exponential and map analysis. Univariate predictors of native myocardial T1 times were assessed with a multiple linear regression model that included age, gender and left ventricular ejection fraction. A two-sided n = 11). Demographic and CMR gender characteristics are compared in A total of 22 volunteers completed the study protocol, although after image analysis, two volunteers were excluded, one due to a mild pericardial effusion and the other due to severely impaired T1 mapping evaluation due to artifacts. Thus, our study population consisted of 20 volunteers, with a mean age of 33.9 ± 11.1 years, and 55% of participants were women , with lesser myocardial mass . For the remaining features there were no gender differences on the overall population. Global myocardial T2 in relation to striated muscle was 1.2 ± 0.3 ms, translating to the absence of myocardial edema.Women had smaller ventricles on systole , with no specific tendencies on the different ventricular slices. T1 times derived from map analysis (1136.4 ± 60.2 ms) showed good correlation with the those from exponential analysis ), with similar gender differences observed . This difference was in agreement with the results found by both Roy et al. [2 vs. 64 ± 9 g/m2, respectively) and Dong et al. [2 vs. 50 ± 10 g/m2, respectively). Reference ranges for cardiac structure and function using CMR were published by Petersen et al. [2 for women and 35–70 g/m2 for men were reported as normal, and our results were in agreement with this reference.As reported in previous publications, different T1 mapping sequences and field strengths are associated with some variation in normal values . There ay et al.  3(3)5 sequence ; A totalThe characteristics of the T1 mapping sequence such as TE, TR and FA were reported as capable of modifying T1 values . PopescuThe correlation between native T1 values and gender has been widely studied, and it is known that, usually, native T1 values are higher in women than men . The resFor this study three slices were acquired at the base, midventricular level and apex of the left ventricle to evaluate possible variations of T1 values according to slice location ,32. Reit42 software). This is extremely important from a clinical perspective, because native T1 values are normally complemented by the acquisition of late post-contrast ones to compute extracellular volume (ECV) fraction [The results from this study show good correlation between the T1 values derived from the exponential analysis and the map analysis . Intra- or inter-reader reproducibility was not performed. Although that type of analysis could have strengthen the results, the native T1 values reported here only constitute general indication, as we recommend that the normal ranges are performed in every institution and scanner. Therefore, we used the analysis of the clinical reader in our institution. In future work it will be important to report values from different groups with cardiac disease from the vendor.This study provides first reference values of native T1 for healthy individuals for MOLLI at a Canon Vantage Galan 3T, demonstrating that these results were on par with others previously published from different vendors. Nevertheless, native T1 values are influenced by several factors, and definition of local normal range values is encouraged, preferably with robust-sized samples. These values demonstrated gender dependency, with higher values for women, and it is necessary to take this into account in interpretation and clinical decision. Future standardization of T1 mapping protocols is warranted, as it could reduce some of the variability of values between scanners or even between vendors. Professional societies should work in collaboration with all the vendors to try further regulate those protocols.


The assessment of right ventricular (RV) function in patients undergoing elective cardiac surgery is paramount for providing optimal perioperative care. The role of regional RV function assessment employing sophisticated state-of-the-art cardiac imaging modalities has not been investigated in this cohort. Hence, this study investigated the association of 3D echocardiography-based regional RV volumetry with short-term outcomes.In a retrospective single-center study, patients undergoing elective cardiac surgery were included if they underwent 3D transesophageal echocardiography prior to thoracotomy. A dedicated software quantified regional RV volumes of the inflow tract, apical body and RV outflow tract employing meshes derived from 3D speckle-tracking. Echocardiographic, clinical and laboratory data were entered into univariable and multivariable logistic regression analyses to determine association with the endpoint .p = 0.01) and relative stroke volume (rel. SV) were significantly lower in patients who reached the endpoint , while the rel. SV of the apex was higher . Global left and right ventricular function including RVEF and left ventricular global longitudinal strain did not differ. In univariable logistic regression, tricuspid regurgitation grade ≥ 2 , inflow RVEF , inflow rel. SV , apex rel. SV  and apex to inflow rel. SV ratio  were significantly associated with the endpoint. In a multivariable model, only the presence of tricuspid regurgitation  and apex to inflow rel. SV ratio  were independently associated with the endpoint.Out of 357 included patients, 25 (7%) reached the endpoint. Inflow RV ejection fraction (RVEF, 32 ± 8% vs. 37 ± 11%, Regional RV function is associated with short-term outcomes in patients undergoing elective cardiac surgery and might be helpful for optimizing risk stratification. Perioperative right ventricular (RV) dysfunction dramatically limits patient outcomes following cardiac surgery , 2. WhilEthical approval for retrospective patient inclusion was granted by the Ethics Committee of the Medical School at the University of Tuebingen  and the study was conducted in accordance with the Declaration of Helsinki. Patients were screened for inclusion to this single-center cohort study if they underwent one of the following elective cardiac surgery procedures between November 2013 and October 2018: on-pump coronary artery bypass grafting, off-pump coronary artery bypass grafting (OPCAB), left-sided valve surgery, thoracic aortic surgery or left ventricular assist device (LVAD) implantation. Surgeries were categorized as “mixed” if one of the major procedures (except LVAD implantation) was combined with other procedures, or a combination of two or more major procedures (except LVAD implantation) was performed. Of the screened patients, only those with standardized intraoperative 3D transesophageal echocardiograms available in the institutional database were included in the study. Patients were excluded if they were underage (<18 years) at the time of surgery, needed extracorporeal circulatory support preoperatively or electronic patient records were incomplete for clinical data analysis.The institutional regimen for standardized anesthesia during cardiac surgery and intraoperative echocardiography was described previously , 15. BriThe institutional standard for intraoperative TEE requires recordings after the establishment of hemodynamic stability following anesthesia induction but prior to thoracotomy. TEE was performed by specially trained cardiac anesthesiologists using commercially available 3D-compatible probes . Representative 3D loops of the fully projected right and left ventricles at a frame rate above 20 fps were acquired.All functional parameters were derived offline from the intraoperatively acquired 3D TEE studies using commercially available 3D-STE software packages. Left ventricular volumes, ejection fraction (LVEF) and global longitudinal strain (LV-GLS) were calculated using 4D LV-ANALYSIS software . If 3D LV datasets of sufficient quality were not available, left ventricular volumes, LVEF and LV-GLS were derived from two-dimensional recordings using appropriate speckle-tracking software. RV volumes, RVEF, fractional area change (FAC) and tricuspid annular plane systolic excursion (TAPSE) were calculated with the widely used 4D RV-Function software . Image acquisition and measurements were carried out in accordance with guideline recommendations –18.After exporting the endocardial RV mesh files derived from 3D-STE (UCD file format), offline regional volumetry was performed using custom-made post-processing software as previously reported . The sof“inflow”—comprising mainly the anatomic region of the tricuspid annulus leaflets, also referred to as the “inlet.”“apex”—comprising the apical trabecular region.“RVOT”—comprising the right ventricular outflow tract, also referred to as the “outlet.”RVEF , end-diastolic volume , end-diastolic volume index , stroke volume  and the relative stroke volume  individually for each region.Virtual cutting surfaces derived from an annular set of mesh points around the border of two regions served as the borders to divide the RV into the three regions. A set of two neighboring mesh points and the common center point each formed a triangle, all of which formed the cutting surface. The cutting points were manually defined and evaluated on a set of exemplary meshes, and the same set of cutting points was applied to all meshes analyzed for the study . RegionaEpidemiologic, laboratory, clinical and outcome data were extracted from electronic patient records. The following baseline parameters were recorded: age, body mass index, body surface, estimated glomerular filtration rate (eGFR), hematocrit, lactate, the presence of chronic lung disease (defined as long-term use of bronchodilators or steroids for lung disease), the presence of pulmonary hypertension (defined as systolic pulmonary artery pressure > 30 mmHg assessed by Doppler echocardiography), the presence of tricuspid regurgitation (defined as grade 2 or 3 measured by color Doppler echocardiographic jet size and RA dimensions), the presence of diabetes (defined as insulin-dependent), the New York Heart Association (NYHA) functional class and the European System for Cardiac Operative Risk Evaluation II (EuroSCORE II). For short-term outcome analysis, the combined endpoint reflecting short-term outcome was defined as a composite of in-hospital mortality and/or the need for extracorporeal life support  within the postoperative hospital period.t-tests, while non-normally distributed samples were compared using Mann–Whitney U tests. Proportions were compared using chi-square tests. Binomial logistic regression was used to examine risk factors that could influence the endpoint, which are depicted with odds ratios (ORs) and their 95% confidence intervals (CIs). Variables that were significantly associated with the endpoint in univariable logistic regression were considered for inclusion in multivariable analysis. Multivariable logistic regression was performed with a forward stepwise conditional selection method  with respect to collinearity and the number of events per variable , MedCalc  and SPSS  were used for statistical calculations and data presentation.Normally distributed continuous variables are presented as the mean ± standard deviation, and non-normally distributed continuous variables are presented as the median (interquartile range). Categorial variables are displayed as absolute numbers and percentages. Normally distributed samples were compared with unpaired Student's variable . The omnn = 357 patients could be included. Baseline clinical data are displayed in 2) and predominantly male (73%). Chronic lung disease, pulmonary hypertension, tricuspid regurgitation or diabetes were only present in a small number of patients . Mixed procedures were most common  or resection of an intramural hematoma (n = 1) by performing supracoronary ascending aortic replacement (n = 8), hybrid frozen elephant trunk procedures (n = 4), aortic root and ascending aorta replacement (n = 4) or resection of ascending aorta intramural hematoma (n = 1). Overall, baseline lactate levels, hematocrit, and eGFR were within the normal ranges.Out of 3,561 patients in the institutional database screened for inclusion, r = 0.50, 95% CI 0.42–0.58, p < 0.001). Global and regional RVEF decreased with increased systolic pulmonary artery pressures  reached the endpoint. Nineteen patients died during the primary hospital stay (5%), and 11 of those required postoperative ECLS (3%). Six patients required postoperative ECLS but were successfully discharged (2%). The endpoint incidence was 6% (3/51) among on-pump coronary artery bypass grafting patients, 7% (5/69) among OPCAB patients, 8% (8/96) among left-sided valve surgery patients, 6% (1/17) among thoracic aortic surgery patients, 4% (1/25) among LVAD patients and 7% (7/99) among mixed procedure patients. In univariable logistic regression of the investigated clinical and conventional echocardiographic parameters, only tricuspid regurgitation grade ≥ 2 was significantly associated with the endpoint . The odds ratio of a binary variable defines the relative risk change of reaching the endpoint in case the variable is present: e.g., 375% increased risk of patients with tricuspid regurgitation grade ≥ 2 to reach the endpoint compared with patients with tricuspid regurgitation grade 0 or 1. The surgical categories were not significantly associated with the endpoint in univariable logistic regression (p = 0.01), rel. SV of the inflow , rel. SV of the apex  and apex to inflow rel. SV ratio  showed a significant association with short-term outcome (p < 0.01) and apex to inflow rel. SV ratio  remained independently associated with the endpoint. In this model, apex to inflow rel. SV ratio carried incremental value and added significantly to the model fit . Reproducibility was better for global RVEF analysis than for regional RVEF analysis. While intraobserver and interobserver variability was fairly low for inflow and apex RVEF measurements, RVOT RVEF showed the poorest comparability, with wide 95% limits of agreement (−10 to 21) and an ICC of 0.840 (95% CI: 0.524–0.937). Interobserver variability of apex to inflow rel. SV ratio was moderate .In a mixed cohort of elective cardiac surgery patients, most baseline clinical and intraoperative echocardiographic parameters showed no significant association with short-term outcome, including sophisticated measures such as 3D-derived RVEF and LV-GLS. Strikingly, an established score for perioperative risk assessment (EuroSCORE II) did not correlate with adverse outcomes in these patients. Using a simple approach to quantify regional systolic function in three anatomically different regions of the RV, a novel parameter incorporating the relative contributions of the apex and the inflow tract to volume ejection (apex to inflow rel. SV ratio) was significantly and independently associated with the combined endpoint of in-hospital death and life-threatening hemodynamic failure requiring ECLS. Only the presence of significant tricuspid regurgitation (grade ≥ 2) showed similar associations in logistic regression. Furthermore, the novel technique for regional RV analysis is feasible and reproducible, with higher observer variabilities in the RVOT region, potentially because of its complex anatomy and relatively small volume. Reproducibility was further warranted by an identical definition of the segmental borders in all meshes, avoiding errors due to manual border determination. Overall, parameters of cardiac function acquired intraoperatively using novel 3D techniques were lower than conventional reference ranges, a phenomenon that has been discussed previously .McConnell-esque contraction pattern, indicating subclinical RV dysfunction.Assessment of systolic RV function by intraoperative TEE is crucial. The induction of general anesthesia and positive pressure ventilation have distinct effects on RV function , and theThe prediction of postoperative outcomes following cardiac surgery is important but challenging. If the onset or progression of cardiovascular disease indicates surgery, interdisciplinary teams involving cardiac surgeons, cardiologists and anesthesiologists need to decide for or against the procedure based on the individual benefit-risk assessment. Currently, a wide variety of clinical features are available, but their interpretation and integration are complex. Established current risk scores, such as the EuroSCORE II or the Society of Thoracic Surgeons Risk Score, have been shown to predict unfavorable postoperative outcomes but do not incorporate a direct measure of RV systolic function , 29. TheNaturally, there are some limitations to the interpretation of the results and their generalizability. The investigated patients were retrospectively included, resulting in a strictly observational study design. As not all patients underwent intraoperative 3D echocardiography, a potential inclusion bias needs to be considered during interpretation of the results. Furthermore, incidence of the endpoint is low resulting in a limited number of events. Prospective randomized trials are necessary to fully characterize the association between the reported parameters and patient outcomes following cardiac surgery. Baseline cardiac function was not characterized by other techniques, such as invasive hemodynamics, awake transthoracic echocardiography or cardiac magnetic resonance imaging. Hence, a comparison of the novel measures with reference methods cannot be provided. Awake pulmonary artery pressures and the underlying cause of present pulmonary hypertension might be associated with the outcome but were not systematically available in this cohort. The severity of tricuspid regurgitation was a variable of interest in regression analysis but the reproducibility of the assessment of tricuspid regurgitation was not investigated systematically in this cohort. Since only the association of clinical and echocardiographic parameters with short-term outcome was studied, the report does not allow for conclusions regarding long-term prognosis.Regional right ventricular systolic function assessed by intraoperative three-dimensional transesophageal speckle-tracking echocardiography is feasible. The apex to inflow relative stroke volume ratio is associated with increased in-hospital mortality and life-threatening postoperative hemodynamic failure. These findings might be useful to improve perioperative risk estimation in patients with baseline RV dysfunction in which conventional echocardiographic parameters are within normal range.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethics Committee of the Medical School at the University of Tuebingen, Gartenstraße 47 72074 Tuebingen, Germany. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.MK and HM contributed to conception and design of the study. MK, M-MD, and TH performed data acquisition. MK and HM performed the statistical analysis. MK, AK, CS, PR, and HM performed data interpretation. MK wrote the first draft of the manuscript. AK, CS, and PR critically revised the manuscript. HM contributed substantially to the final revision of the manuscript. All authors read and approved the submitted version.This work was supported by Deutsche Forschungsgemeinschaft (DFG) (Grant DFG-INST 2388/71–1 FUGG) and funded by departmental funds.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Mean LV ejection fraction (EF) was 61% in athletes, below normal in 7 (18%) athletes vs. EF 29% in DCM, below normal in 46 (96%) patients (p < 0.0001). Mean RV-EF was 54% in athletes vs. 60% in HCM, 46% in ARVC, and 41% in DCM (p < 0.0001). Mean interventricular myocardial thickness was 10 mm in athletes vs. 12 mm in HCM (p = 0.0005), 9 mm in ARVC, and 9 mm in DCM. LGE was present in 1 (5%) athlete, 8 (57%) HCM, 10 (56%) ARVC, and 21 (44%) DCM patients (p < 0.0001). Healthy athletes’ hearts are characterized by both hypertrophy and dilation, low EF of both ventricles at rest, and increased interventricular septal thickness with a low prevalence of LGE. Differentiation of athlete’s heart from other non-ischemic cardiomyopathies in MRI can be challenging due to a significant overlap of characteristics also seen in HCM, ARVC, and DCM.To provide clinically relevant criteria for differentiation between the athlete’s heart and similar appearing hypertrophic (HCM), dilated (DCM), and arrhythmogenic right-ventricular cardiomyopathy (ARVC) in MRI. 40 top-level athletes were prospectively examined with cardiac MR (CMR) in two university centres and compared to retrospectively recruited patients diagnosed with HCM (n = 14), ARVC (n = 18), and DCM (n = 48). Analysed MR imaging parameters in the whole study cohort included morphology, functional parameters and late gadolinium enhancement (LGE). Mean left-ventricular enddiastolic volume index (LVEDVI) was high in athletes (105 ml/mThe online version contains supplementary material available at 10.1007/s10554-021-02280-6. Highly trained athletes show morphological and functional changes of the cardiovascular system as a response to intensive exercise. The associated process of cardiac remodelling leads to the so called “athlete’s heart” and is considered a physiologic adaptation to repetitively increased volume load and blood pressure –3. HowevThe aim of this multicentre study was to provide clinically relevant criteria to help differentiate between the athlete’s heart and cardiomyopathies.We included 40 German Caucasian top-level athletes participating in top national and international competitions, mainly endurance athletes, who were prospectively examined for this multicentre trial. In 19 athletes CMR was performed at the University Hospital Tübingen (Tübingen Germany), and in 21 CMR was performed at the University Hospital of the Technical University Munich .The study protocol was designed according to ethical standards in Sport and Exercise Science Research.Patients who underwent a CMR between 2008 and 2019 and were diagnosed with HCM (n = 14), ARVC (n = 18) or DCM (n = 48) were included retrospectively. Diagnosis of DCM was proven by endomyocardial biopsy in all patients, the diagnosis of ARVC in nine patients respectively. Endomyocardial biopsies (EMB) and histopathologic workup was performed as previously described .HCM patients were clinically diagnosed with HCM in the Sports Medicine Clinic in Tübingen. Patients with additional alternative cardiac diagnosis in CMR or EMB were excluded.The study protocol was approved by the Institutional Review Board (IRB) of the University of Tübingen .CMR was performed using a 1.5-T system . Sequences were ECG-triggered and performed in breath hold technique using a body array coil as previously described , 12.Myocardial function was assessed with cine steady state free precession (SSFP) loops that were acquired in four chamber view (4CV), two chamber view (2CV) in both ventricles, three chamber view (3CV), and a stack of short axis (SA) slices covering both ventricles from base to apex.Late Gadolinium Enhancement (LGE) imaging was performed with 2D inversion recovery gradient echo sequences acquired in 4CV, 2CV and a stack of SA views 10 min after intravenous administration of contrast agent Gadobutrol  at a dosage of 0.15 mmol/kg body weight. To suppress signal from healthy myocardium, an inversion time localizer was used, to determine the optimal inversion time (TI scout). The inversion time was adjusted individually to 260–340 ms, to minimize signal from normal myocardium.Analysis of CMR images was performed by two readers in consensus at an offline workstation using cmr42 .End-diastolic LV myocardial thickness was measured using a mid-ventricular short-axis slice at the interventricular septum (IVS) and infero-lateral wall (ILW). LV end-diastolic diameter (LVEDD), RV end-diastolic diameter (RVEDD), and RV myocardial thickness were measured at the inferior wall in the same image. Left and right atrial sizes were quantified using planimetry in 4CV as previously described .For functional analysis of left and right ventricle, endocardial (both ventricles) and epicardial (only LV) contours were semi-automatically drawn and carefully adjusted manually: Left and right ventricular end-diastolic volume , end-systolic volume , stroke volume , ejection fraction , and myocardial mass (LVMM). Left ventricular global function index (LVGFI) in % was calculated according to the equation introduced by Mewton et al., and myocardial density is defined as 1.05 g/ml :\documenLV-remodelling index was calculated as the ratio between indexed LV myocardial mass and indexed LV end-diastolic volume .Body surface normalization was applied to determine index values and calculated on the basis of height and weight by using the Mosteller method. Assessed morphological and functional parameters were compared to normal reference values as published by Kawel-Boehm et al. and Hergan et al. , 17.LGE imaging was evaluated visually according to the recommendations of the Society for Cardiovascular Magnetic Resonance task force . Image cStatistical analysis was performed using JMP  and SPSS 22.0 . Continuous variables are expressed as mean value ± standard deviation (SD). Range is given in square brackets. Normal distribution of functional parameters was assessed visually in curves using Saphiro–Wilk test . Two-sid2. Most athletes (82%) had normal LVEF (61% ± 5). LVSVI was within reference range in all subjects (63 ± 9 ml/m2). LVEDVI and RVEDVI were elevated in 58% and 50% of athletes . RVEF was reduced in 40% of athletes (54 ± 5 ml). The majority of athletes (68%) showed increased RVEDD (49 ± 8 mm). Indexed LV myocardial mass was elevated in 40% of athletes (84 ± 22 g/m2). Interventricular myocardial thickness was elevated beyond normal range in one athlete (10 ± 2 mm) and inferolateral wall thickness was elevated in 2 athletes (8 ± 2 mm). Cine-sequences demonstrated no kinetic disorders. Septal linear mid-myocardial LGE was present in one athlete. A representative example of an athlete’s heart is demonstrated in Fig. Athlete’s characteristics are summarized in Tables al LVEF 6% ± 5. LV2, p = 0.47) but thickness of the interventricular septum was significantly higher in HCM patients compared to athletes . LVMMI was similar . RVEF was reduced in 72% of ARVC patients and significantly lower than in athletes . RVEDVI was elevated beyond reference range in 33%, but lower in ARVC patients than in athletes . LVEDV/RVEDV ratio was very similar to athletes (0.89 ± 0.22 vs. 0.89 ± 0.08). Kinetic disorders, especially hypokinesia, were common in ARVC patients affecting both the right and the left ventricle . The majority of ARVC patients (56%) showed LGE, mostly involving the right ventricle  and significantly lower than in athletes , LVSVI was reduced in 39%  and 96% increased LVESVI (96 ± 40 ml/m2), both significantly higher compared to athletes . LVEDD was elevated in 79% and significantly larger than in athletes . RVEDVI was normal in most DCM patients (90 ± 25 ml/m2), but RVEF was reduced in 75% (41 ± 14%). The ratio of LVEDV/RVEDV was significantly higher compared to athletes . LVGFI and LV-remodelling index were both lowest among all groups and significantly different from athletes . 75% showed kinetic disorders of the left ventricle and some patients (6%) also dyskinesia of the right ventricle. LGE was present in almost half of patients and predominantly subepicardial in a linear or patchy pattern  were almost all (96%) characterized by reduced LVEF (29 ± 13%). 71% showed increased LVEDVI  linked with significantly increased LVEDD above average.2  or > 100 ml/m2  in CMR are major ARVC task force criteria when combined with wall motion abnormalities [Enlargement of the right ventricle was common in ARVC patients. RVEDVI > 110 ml/mmalities . HoweverIn contrast LVGFI and LV-remodelling index were not helpful to differentiate athlete’s hearts from HCM or ARVC. LVGFI had previously failed in differentiation of cardiac function in different groups of chronic coronary syndrome with and without myocardial infarction but seems to be most sensitive to detect DCM in our study . The incBalanced enlargement of the left and right ventricle, which can be observed in most athletes, had already been described previously as a physiologic adaptation attributed to symmetric volume load in endurance sports , 25. EjeA significantly reduced LV and RV function were observed both in ARVC and DCM. Reduction of RVEF below 45 or 40% is an alternative ARVC task force criterion to RV dilatation in CMR when combined with wall motion abnormalities . As expeCine sequences in CMR allow sensitive detection and precise localization of kinetic disorders. Wall motion abnormalities, mainly hypokinesia and akinesia, were common in all cardiomyopathies, but not present in any of the athletes.An increase in LV myocardial mass was observed in athletes, HCM, and DCM patients.Athletes show LV hypertrophy as a physiologic response to training . HCM patLGE is a valuable but non-specific imaging technique for identification of myocardial damage  which waThe detection of LGE in cardiomyopathies is known to be associated with increased risk for sudden cardiac death . TherefoOur study has several limitations. Only Caucasian national top-level athletes were examined. Whereas athletes were investigated prospectively, cardiomyopathy patients were retrospectively enrolled. There is a significant difference in age between athletes and cardiomyopathy patients, with most patients being older than athletes. We addressed this issue in applying age-adjusted reference values for comparison between groups. Furthermore, this study investigates only one time point in athletes and dynamic changes could not be included as parameters for differentiation. Clinically, in indistinct cases repetition of a scan after a period of time may provide further information. Whereas cardiomyopathies show deterioration without treatment, detraining effects can be a characteristic feature in athletes . In addiHealthy highly-trained athlete hearts are characterized by: (1) a balanced hypertrophy and dilation, and (2) low EF of both ventricles, (3) (slightly) increased interventricular septal thickness, and (4) increased LV-remodelling index. Differentiation of athlete’s heart from other cardiomyopathies can be challenging due to significant overlap in features of HCM, ARVC, and DCM.However, both absences of kinetic disorders or LGE as well as normal indexed SV are representative for athlete hearts.Supplementary file1 (PPTX 442 kb)Figure 5 : Visualization of myocardial damage in endomyocardial biopsies by Masson Trichrome staining. (A) Arrhythmogenic right ventricular cardiomyopathy, × 100, (B) Dilated cardiomyopathy (DCM), × 200.Below is the link to the electronic supplementary material.