Background: Cardiovascular disease is the commonest cause of death in hemodialysis (HD) patients but accurate risk prediction is lacking. The spatial QRS – T angle is a promising electrophysiological marker for sudden cardiac death risk stratification. The aim of this study was to assess the prognostic value of spatial QRS-T angle derived from standard 12 lead electrocardiograms (ECG) and its association with echocardiographic parameters in HD patients.Methods: This prospective study of 178 prevalent HD patients  collected ECG and echocardiographic data on an annual basis. Baseline echocardiograms at study entry were used for cross-sectional comparisons with ECGs. Study endpoints were all-cause mortality, cardiovascular mortality, and major adverse cardiac events (MACE). The QRS – T angle was calculated from standard 10-s ECG as the total cosine R to T (TCRT) using singular value decomposition and expressed in degrees. TCRT above 100° was defined as abnormal.Results: During a follow-up period of 36 ± 19 months, 74 patients died, including 17 cardiac deaths, and 54 suffered from MACE. In multivariate Cox regression analysis, QRS-T angle by TCRT at baseline was associated with increased cardiovascular mortality both as a continuous value and dichotomized below or above 100°  and with MACE dichotomized at 100° . In multivariate regression analysis including baseline parameters, echocardiographic global longitudinal strain (GLS) was significantly correlated with TCRT .Conclusion: TCRT correlates with GLS and is independently associated with cardiac deaths and MACE in HD patients. Cardiovascular mortality and morbidity is elevated in End Stage Renal Disease (ESRD) . Renal rA recent study identified spatial QRS-T angle, an established marker of repolarization heterogeneity in cardiac patients  and in tAmongst the existing methods of calculating the spatial QRS-T angle,  the TotaRepolarization heterogeneity has been recently associated with structural and functional cardiac abnormalities including global longitudinal strain (GLS) derived from speckle tracking echocardiography in the general population . GLS is The purpose of this study was to confirm the predictive value of TCRT calculated from standard 10-s resting ECGs and to examine the association between TCRT and various echocardiographic parameters, including GLS, in HD patients.Digital ECG recordings collected as part of a recently published prospective study in prevalent hemodialysis patients  that evaDemographic data were extracted from medical records. Coronary artery disease (CAD) was defined as previous history of myocardial infarction and/or angina.The study endpoints were all-cause mortality, cardiovascular mortality defined as death due to myocardial infarction, heart failure, arrhythmia or sudden cardiac death, and a composite endpoint of major cardiac events (MACE). MACE included acute coronary syndrome, coronary revascularization, hospitalization due to heart failure or arrhythmia, and sudden cardiac death. Sudden cardiac death was defined as sudden and unexpected death occurring within an hour of the onset of symptoms, or presumably due to a cardiac arrhythmia occurring in previously asymptomatic patients found dead within 24 h of last clinical contact . Follow ∗ [1.04  3 – LV internal diameter 3) + 0.6 g]. LV mass was indexed to height 2.7 (LVMI/HT 2.7). PWV was measured with the Vicorder TM device  using a neck and femoral cuff that were inflated to 65 mm Hg and the obtained oscillometric signal was used to calculate the pulse time delay between the two sites and consequently the aortic PWV. The mean result of two consecutive measurements was used for the analysis.Transthoracic two-dimensional echocardiographic imaging and PWV measurements and 12-lead ECGs were obtained on single visits during a mid-week non-dialysis day. The detailed protocol of echocardiographic and PWV measurement has been described elsewhere . In brie3√RR. Software conversion routines were programmed allowing the signal to be exported from the XML Schiller format to a format suitable for further computer processing with a custom developed software. The calculation of TCRT has been previously described in detail (All 12-lead ECGs were recorded at a sampling rate of 500 Hz in a recumbent position and with standard lead placement (Phillips Pagewriter TC 20 electrocardiograph). Automated measurements by Phillips measurement algorithm of heart rate and ECG intervals for QRS and QT were used in the analysis. QTc was calculated using the Fridericia’s formula: QTcF = QT/n detail . In brien detail  and convn detail . AnalysiT-test and Mann–Whitney U test were used for comparisons of parametric and non-parametric data as appropriate. The chi-squared test was used for categorical values where appropriate. Pearson’s correlation coefficient was used to measure the relationship between the variables and TCRT. Variables found to be significantly associated were entered into linear regression analysis to determine independent relationship with TCRT. Univariate Cox Regression analysis was used to calculate the effect of variables upon the time to outcome. TCRT and all other statistically significant variables in the univariate analysis, apart from those which correlated with TCRT in linear regression analysis, were included in multivariate Cox regression analysis to determine associations between the endpoints and variables. In the Cox regression analysis, TCRT was entered as a continuous value as well as also dichotomized at 100° based on previously published cut–off values for risk stratification for sudden cardiac death in the general population  between baseline TRCT and first available follow up TRCT was calculated as ΔTCRT = TCRT (follow up)-TCRT (baseline). Paired sample ° showed significant differences in sex, ethnicity, diastolic BP, biplane left ventricular Ejection Fraction, GLS and LVMIht2.7 (p = 0.036) consistent with previous physiologic observations , LVMIht2.7 , systolic BP  and diastolic BP . On multivariate linear regression analysis including LVMIht2.7, systolic BP, diastolic BP and GLS, only GLS remained significantly correlated with TCRT in the model explaining 19% of the variance . The relationship between GLS and TCRT is shown in On univariate analysis TCRT correlated with GLS , 54 MACE and 32 subjects received a kidney transplant. TCRT values according to outcomes are presented in On univariate Cox regression analysis, the factors associated with increased all-cause mortality were: age, history of CAD, QRS duration, QTc duration, End Diastolic Volume, BNP, Systolic Blood Pressure and PWV. TCRT was found not to have a statistically significant association with all-cause mortality. On multivariate analysis, only age and PWV maintained an association with all-cause mortality. Results of univariate and multivariate Cox regression analysis for all-cause mortality are presented in °, GLS, Troponin I and history of CAD. Patients with TCRT greater than 100° had higher cardiovascular mortality . There was no significant increase in TCRT at follow up in the group with baseline TCRT > 100°  as opposed to the group with baseline TCRT < 100° . Longitudinal changes of TCRT according to baseline values dichotomized at 100° are presented in There were 98 analyzable follow up ECGs. Median time interval from baseline to follow up ECG was 13 (IQR 7) months. There were 31 MACE events, 9 cardiovascular deaths and 40 all-cause deaths in this patient sub-group. From the 31 MACE events, 20 MACE events occurred after the follow up ECG. TCRT increased from baseline to follow up  as an expression of the QRS – T angle. In a recent comparative study between different methods of calculation of the QRS-T angle in cardiac patients and healthy individuals, TCRT was found to be more reliable for risk prediction in cardiac patients compared to other methods for QRS –T angle calculation . It has During follow up, TCRT increased in those patients with baseline values below 100°. Large studies in the general population have reported that abnormal increases  or rapidIn contrast to the two previous studies in HD patients  we did nTwo previous studies have explored the association between echocardiographic abnormalities and QRS-T angle in dialysis patients. In the study by The potential impact of repolarization heterogeneity on cardiac function is also supported by the observation that changes in repolarization heterogeneity measured by 5 ECG parameters including QRS-T angle typically preceded echocardiographic abnormalities in a recently published large general population study .The potential relative contribution of repolarization heterogeneity on cardiac function and its relationship with underlying myocardial fibrosis cannot be established from our observational study. Future research to elucidate the link between repolarization heterogeneity and mechanical dysfunction may have important implications in understanding the pathophysiology of uremic cardiomyopathy and in optimizing risk assessment in HD patients. The QRS-T angle assessed by TCRT and GLS, although interrelated, carry prognostic information that is independent of each other and which should be assessed in combination in risk assessment models.The limitations of this study including the relatively small sized population and recruitment selection bias leading to lower mortality have previously been described ,b. Due tIn conclusion, our study has demonstrated that QRS-T angle calculated by TCRT, an electrocardiographic marker of repolarization heterogeneity that can be derived from standard 10 s ECGs, carries independent prognostic significance for cardiac mortality risk in our HD cohort and it is correlated with GLS. Further prospective studies with longitudinal cardiovascular monitoring including a combination of electrophysiologic and cardiac structural and functional assessment from patients with earlier stages of chronic kidney disease are required to characterize the determinants of the progression of uremic cardiomyopathy and identify potential opportunities for interventions. In light of the consistently strong risk prediction signal of the QRS-T angle in the renal population we suggest that standardization of the assessment of QRS-T angle is important to enable identification of cut-off points indicating high risk to be used in routine clinical practice.SS and DG collected, analyzed, and interpreted the data, drafted the article, and contributed to statistical expertise. KH processed ECG signal and drafted the article. MM conceived and designed the study, processed the ECG signal, interpreted the data, and critically revised the article. PK conceived and designed the study, interpreted the data, and critically revised the article. DP conceived and designed the work, analyzed and interpreted the data, contributed to statistical expertise, and critically revised the article.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.


This study sought to investigate whether left ventricular (LV) fibrosis quantified by T1 mapping can be used as a biomarker to predict outcome in patients with atrial fibrillation (AF) and heart failure (HF). 108 patients with AF and HF were included in this study. They underwent cardiac magnetic resonance, including T1 mapping sequence to assess LV fibrosis between May 2014 to May 2016. Patients received catheter ablation for AF and pharmacological treatment for HF. The primary endpoint was a composite adverse outcome of cardiac death, subsequent HF or stroke, subsequent HF was the secondary endpoint. During follow up , 1 cardiac death, 12 strokes, and 42 HF episodes occurred. LV extracellular volume fraction (ECV) was predictive of composite adverse outcome and subsequent HF . In multivariable analysis, LV ECV was an independent predictor of composite adverse outcome (hazard ratio (HR): 1.258, 95% confidence interval (CI): 1.140–1.388, p < 0.001) and subsequent HF . LV fibrosis measured by T1 mapping indices significantly predicts composite adverse outcomes and subsequent HF in patients with AF and HF. When present in combination, the prognosis appears to be worse4. However, the predictors of adverse outcome in this cohort remain unclear. In patients with AF, left ventricular (LV) fibrosis has been demonstrated by histopathology and noninvasive imaging6. Similarly, in patients with HF, LV fibrosis plays an essential pathophysiological role9. Although its clinical significance in HF and AF is not fully understood, LV fibrosis represents a potential link between AF and HF10. Assessing the degree of LV fibrosis may provide information for predicting outcomes in patients with coexisting AF and HF.Atrial fibrillation (AF) and heart failure (HF) are increasingly prevalent and frequently coexist11. Recent innovations in CMR permit quantitative measurements of both replacement fibrosis and interstitial fibrosis using T1 mapping techniques regardless of its distribution13. The detection and quantification of LV fibrosis with T1 mapping have been validated against collagen content in subjects with a variety of cardiomyopathies15. T1 mapping method including two important indices: 1) native T1 reflects myocardial abnormality involving the myocyte and interstitium; 2) after use of gadolinium-based contrast agents, extracellular volume fraction (ECV) measures the extent of the extracellular space, reflecting myocyte loss and interstitial disease16. Suksaranjit et al. showed the prognostic impact of LV replacement fibrosis assessed by LGE in patients with AF17. However, the clinical value of T1 mapping for identification of LV fibrosis in patients with coexisting AF and HF is still unclear.Ventricular myocardial fibrosis includes replacement fibrosis and interstitial fibrosis. Using late gadolinium enhancement (LGE) sequence, cardiovascular magnetic resonance (CMR) provides excellent visualization of replacement fibrosis. Interstitial fibrosis is difficult to distinguish by LGE because it is extensively distributed, the myocardial signal intensity may be nearly isointense which is hard to differentiate from normal tissuesWe hypothesized that quantification of LV fibrosis with T1 mapping would predict adverse outcome in patients with AF and HF. The purpose of our study was to assess LV fibrosis by determining the ranges of T1 mapping indices in patients with AF and HF, and investigate whether T1 mapping could be used as a quantitative imaging biomarker to predict the adverse outcome.18. We excluded patients with valvular heart disease, acute myocardial infarction, myocarditis, evidence of infiltrative cardiomyopathy, and severe impairment of renal function (glomerular filtration rate <30 ml/min/1.73 m2). Finally, 108 patients with AF and HF who underwent CMR with T1 mapping in our hospital prior to AF catheter ablation were included in this study. All underwent catheter ablation for AF and adjustment of pharmacological treatment for HF prior to discharge. Thorough clinical data were obtained by reviewing medical records, physical examination, and routine lab tests. Follow up was performed by telephone interview of the patients, their general practitioner/cardiologist and/or family members. The primary study endpoint was the composite of cardiac death, stroke, and HF readmission. The second study endpoint was HF readmission. In addition, recurrence of AF after ablation (defined as any AF episode >30 seconds identified by12-lead ECG or on repeat Holter monitoring after 3 months of blank period) were recorded. Complete follow-up was obtained for all patients. The T1 mapping indices of 49 gender and age-matched healthy volunteers scanned at our site with the same MR system were included as the reference standard. The investigation conformed with the principles outlined in the Declaration of Helsinki. The study was approved by the Beijing Anzhen Hospital ethical committee, and written informed consent was obtained from all patients.We performed a prospective observational study of patients with coexisting AF and HF who admitted to our hospital for AF catheter ablation between May 2014 to May 2016. All patients had ECG documented AF, they were symptomatic, and refractory to at least one antiarrhythmic drug. Presence and severity of HF were ascertained according to 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic HF, and classified as HF with preserved ejection fraction , HF with mid-range EF , and HF with reduced EF All CMR exams were performed using a 3T MR system  with a 32-channel cardiac coil. Steady-state free-precession cine images were obtained during repeated breath-holding in two long-axis views (two chambers and four chambers) and in a stack of short-axis views covering the LV for quantification of cardiac chamber volumes and function. In the case of AF episodes during the exam, the acquisition was performed with a 2-dimensional (2D) real-time true fast imaging sequence with steady precession during a single breath-hold. Late gadolinium enhancement (LGE) imaging was performed in the same planes as cine imaging using a phase-sensitive inversion-recovery sequence approximately 10 minutes after administration of 0.1 mmol/kg gadopentetate dimeglumine.19. Imaging parameters were TR = 2.6–2.7 ms, TE = 1.0–1.1 ms, FA = 35°, FOV = 270 × 360 mm2, matrix 256 for heart rate <90 bpm, 192 for heart rate ≥90 bpm, BW = 1045–1028 Hz/px, GRAPPA acceleration factor 2, minimum TI = 120 ms. Quality control was performed during scanning by reviewing the “goodness of fit” map and source images to allow an immediate repetition of suboptimal measurements to minimize the respiratory motion and off-resonance effects. A blood sample was taken just before the CMR exam to measure haematocrit for the ECV calculation.T1 mapping was obtained using a modified look-locker inversion recovery sequence (MOLLI). Data were acquired in basal, mid-ventricular, and apical short-axis planes before and 15 min after contrast administration. T1 mapping images were acquired in the systolic phase (trigger delay = 0 ms) with a heart-rate-dependent pulse sequence sampling scheme as previously described in order to eliminate the impact of the irregular and usually rapid ventricular rate of AF (the number of inversions (n) was determined by referencing the highest heart rate before the actual scan, 5(n)3 and 4(n)3(n)2 for precontrast and postcontrast T1 mapping, respectively)All CMR images were analysed by a radiologist who was blinded to clinical and study participant information. Both the LV systolic and diastolic function were assessed. Global LV functional indices were analysed using dedicated software . The following indices were measured: LV EF, LV end-diastolic volume (EDV), LV end-systolic volume (ESV), LV stroke volume (SV) and LV mass. Except for LV EF, all parameters were adjusted by body surface area (BSA).s), peak systolic circumferential strain rate (SRs), and peak diastolic circumferential strain rate (SRe) data directly from cine mid-ventricular short-axis view images, as previously described20. Left atrium (LA) volume was measured at end-systole using the biplane area-length method. LA volume and SRe were used as LV diastolic functional indices.2D cardiac performance analysis software  was used to obtain LV peak systolic circumferential strain  for offline analysis. LV replacement fibrosis was identified qualitatively by LGE within the myocardium; it was considered present only if confirmed on both short-axis and matching long-axis myocardial locations. Then the quantitative measurement of LV fibrosis was performed with native T1 and ECV. The LV myocardium was delineated by manually contouring the endocardial and epicardial borders of precontrast and postcontrast T1 maps. According to the AHA 16-segment model, segments with artefact were excluded from the LV myocardium delineation. The overall LV myocardial native T1 time was the mean of myocardial T1 times of the basal, mid-ventricular and apical levels on precontrast T1 maps. The overall LV ECV was calculated from precontrast and postcontrast T1 mapping images that were calibrated by blood haematocrit22. The procedural endpoint was pulmonary vein isolation and block of all ablated lines which was achieved in all the cases. The vascular access-site hematoma was observed in 2 cases, which were resolved conservatively.All antiarrhythmic drugs were stopped before catheter ablation. After transseptal puncture under sedation, a bolus of intravenous heparin (100 U/kg) was administered. During the procedure, an activated clotting time of >300 s was maintained. A 3.5 mm open-irrigation ablation catheter  was advanced into the left atrium for mapping and ablation with a 3D electroanatomical mapping system . For patients with PAF, pulmonary vein electrical isolation was achieved by continuous circumferential pulmonary vein ablation. For persistent AF patients, we also use a fixed strategy called “2C3L” including PV isolation and linear ablation across mitral annulus, LA roof and tricuspid isthmus23, and comparison of survival rate was performed using a log-rank test. The reference value was derived from 49 healthy volunteers  who were scanned in our site using the same MR scanner, LV native T1 average = 1251 ms ± 36; LV ECV average = 25.7% ± 2.4. The interobserver agreement was assessed using the intraclass correlation coefficient. A p-value of <0.05 was considered significant, and all reported p values are 2-tailed. The sample size was calculated on the basis of a proposed difference of 3.0% in absolute ECV values between patients with and without composite adverse outcomes, a standard deviation of 2.5% for ECV measurements. To identify this difference with a power of 80% , 9 patients in each group (with vs. without events) were needed.The analysis was conducted using SPSS software . Normality of data was assessed with Kolmogorov-Smirnov tests. All data are expressed as the means ± standard deviation (SD) unless otherwise indicated. Comparisons between different HF groups were made using 1-way analysis of variance or Kruskal Wallis test for continuous variables and chi-square test for categorical variables, as appropriate. Univariate Cox proportional hazards model was used to test the association between baseline covariates and primary endpoint, between baseline covariates and secondary endpoint respectively. Multivariable analysis was performed with a selection of variables with p < 0.1 to enter the model. Event-free survival was determined according to the Kaplan-Meier method using the median ECV valueThe baseline general demographic data and imaging characteristics of patients are presented in Table average = 1305 ms ± 46; LV ECV average = 29.8% ± 3.8) had a greater LV mean native T1 time and ECV than patients with paroxysmal AF . When patients were compared according to the HF types, patients with HFrEF  had more severe LV fibrosis than patients with HFmrEF  and patients with HFpEF .In the 108 patients, 42 segments in 8 pre-contrast T1 maps and 59 segments in 11 post-contrast T1 maps were excluded due to the presence of artefacts . LV mean native T1 time and ECV of all patients are presented in Table High levels of inter-observer agreement were achieved for pre-contrast T1 (intraclass correlation coefficient (ICC), 0.958; 95% confidence interval (CI): 0.939, 0.971), post-contrast T1 .55 adverse outcomes were observed in 51 patients including 1 cardiac death, 12 strokes , and 42 subsequent episodes of acute decompensated HF over a median follow up period of 23 months (Q1–Q3: 11 to 28 months). This included 23 events (17 HF readmission and 6 stroke) in 22 patients with paroxysmal AF, 32 events  in 29 patients with persistent AF; 19 events (11 HF readmission and 8 stroke) in 18 patients with HFpEF, 20 events  in 19 patients with HFmrEF, and 16 events  in 14 patients with HFrEF.e) function, and greater LV native T1 time and ECV. In addition, LV native T1 time and ECV were significantly greater in patients with HF readmission compared to those without HF readmission , respectively. The LV native T1 time and ECV of 12 patients with subsequent stroke were 1299 ms ± 51, 29.6% ± 4.0 respectively.The clinical and imaging characteristic of patients with and without composite endpoint events are presented in Table e, LV EF, and LV ECV showed significant predictive associations with composite adverse outcome (p < 0.05). AF patterns, CHA2DS2-VaSc score, LGE were less strongly associated with composite adverse outcome . In multivariate analyses, only LV ECV was independently associated with composite adverse outcome and HF readmission respectively  may have a more obvious adverse impact on cardiac function. The prognostic impact of LV fibrosis, which is considered a common pathophysiologic process shared by AF and HF, has been suggested by prior studies, focusing on the patient with either AF or HF. In a larger study, Neilan et al. showed that LV replacement fibrosis detected by LGE is a frequent finding in AF predicting mortality24. Ling et al. demonstrated that LV diffuse fibrosis assessed by T1 mapping is associated with systolic dysfunction in patients with AF6. LV fibrosis assessed by LGE or T1 mapping indices also predicts recurrent AF after ablation26. LV LGE was detected in 39 patients (36%) in our study. Different from previous studies, LV LGE wasn’t associated with the composite adverse outcome in multivariate analysis. The potential explanation is the relatively small extent of LGE in our patients weakened its effect in predicting adverse outcomes, and some small extent subendocardial LGE may be missed by conventional LGE sequence27. LV fibrosis quantified by T1 mapping indices is associated with adverse outcomes across the spectrum of aetiologies and stages of HF28. However, to the best of our knowledge, this is the first report on the association between adverse outcome and T1 mapping indices in patients with coexisting AF and HF, demonstrating the clinical relevance of LV fibrosis in this population. In patients with coexisting AF and HF, our results demonstrate that LV fibrosis measured by T1 mapping indices  is strongly associated with adverse outcomes and can be used as an independent predictor.AF and HF frequently coexist and together adversely affect patient prognosis, yet evidence-based evaluation of this patient group is lacking30. However, identification and analysis of atrial fibrosis remain challenging at most of the centers with current technique and available software. In fact, atrial and ventricular fibrosis may develop and progress simultaneously and to a similar extent under many situations, given the difficulty in the quantitative assessment of atrial fibrosis, whether we could use ventricular fibrosis as a surrogate of atrial fibrosis warrants further study in AF patients. Comparing to general AF population, our results showed that LV ECV was associated with recurrence of AF in patients with AF and HF. Indeed, patients with AF and HF can benefit from catheter ablation which leads to lower rates of death and HF readmission32. It is worth noting that the association between severity of LV fibrosis and recurrence of AF in this population. Whether there are differences in the incidence and impact of AF recurrence on AF patients with and without HF remain unclear and need further investigation.In patients with AF, atrial fibrosis identified by LGE was independently associated with recurrent arrhythmia after catheter ablation and increased risk of stroke from a series of CAMERA-MRI trials29. Suksaranjit et al. reported a negative association between male gender  and adverse outcome26. The association of female gender and adverse outcomes in patients with AF and HF need to be verified by further studies.In the present study, the multivariable model showed that female gender was associated with composite adverse outcome and subsequent HF in patients with AF and HF. Interpretation is limited because only 19% of patients in our study population was female. However, in prior studies that demonstrated an association between severe LA fibrosis and increased major adverse cardiovascular and cerebrovascular events in AF patients, female patients were more prevalent in the advanced LA fibrosis group than the mild LA fibrosis group (51.7% vs. 35.6%)33. Real-time cine sequence results in a slight overestimation of the ESV and subsequent underestimation of EF; however, differences in the values were in the reasonable range34. Fourth, we used a 16-segment model for fibrosis assessment. The 17th segment was too thin to accurately assess due to the limited spatial resolution.Our study has several limitations. First, we did not exclude patients with common concomitant diseases (such as diabetes mellitus and hypertension), all these comorbidities to a certain degree contribute to the development of LV fibrosis, but this study was not specifically powered to evaluate the aetiology of LV fibrosis. Second, we included patients who underwent catheter ablation for AF, adjustment of pharmacological treatment for HF were at the discretion of the treating physician. There was potential for selection bias which may have influenced clinical outcome. Third, some patients experienced AF episodes during the CMR exam, real-time cine sequence and motion-corrected LGE sequence were usedIn summary, LV fibrosis quantified by T1 mapping indices could potentially predict composite adverse outcome and subsequent HF in patients with coexisting AF and HF. The predictive associations support the independent clinical relevance of LV fibrosis in patients with coexisting AF and HF. Our findings identify the value of noninvasive quantitative assessment of LV fibrosis for risk stratification of patients with coexisting AF and HF.Supplementary Tables


Rheumatic heart disease (RHD), a sequela of pharyngeal and skin infection with group A β–haemolytic Streptococcus, affects approximately 33 million persons globally, with low– and middleincome countries (LMICs) disproportionately more affected.4Complications secondary to RHD cause disability–adjusted life–years (DALYs) of 142.6 per 100 000 individuals globally, translating to 0.43% of total global DALYs.5Multiple cardiovascular imaging modalities are important for the assessment of CVD and many are entrenched into the modern practice of cardiovascular medicine . CardiovCMR creates images from atomic nuclei with uneven spin using radiofrequency pulses in the presence of a powerful magnetic field. Hydrogen, which is abundant in fat and water, is the most commonly used atom for MR imaging; and tissue contrast in CMR is accounted for by three important parameters: T1 and T2 relaxation and proton density. CMR is safe, especially when compared with X–ray–based techniques. The main MR contrast agent, gadolinium, has been shown to be safe in millions of patients who have received it over decades, and nephrogenic systemic sclerosis has not been reported with the newer macrocyclic gadolinium–based agents, which are preferentially used in patients with renal dysfunction due to the high risk posed by iodinated contrast agents.7Characterisation of myocardial tissue is a unique feature of CMR, traditionally achieved through late gadolinium enhancement (LGE) imaging, and based on the relative difference in volume of distribution of intravenously administered gadolinium [and subsequent alteration of longitudinal relaxation (T1) times] between normal and abnormal myocardium.10Echocardiographic studies of RHD are established in clinical practice and are indispensable for the comprehensive assessment of valve lesions secondary to RHD, through confirmation of aetiology of the valvular lesion and exclusion of non–rheumatic causes of valve lesions. M–mode and two–dimensional crosssectional echocardiography are important for the assessment of chamber size and function, diastolic dysfunction, valve morphology and function, and both atrial and myocardial remodelling. Colour–flow Doppler evaluates flow across valves and can assess the haemodynamic effects of both stenotic and regurgitant lesions.Furthermore, serial echocardiography is important for monitoring of disease progress as well as efficacy of surgical repair or replacement. The use of strain imaging and threedimensional echocardiography is important for risk stratification and in planning and predicting surgical outcomes.12CMR has been demonstrated to be capable of performing many of the applications described above.16Edwards and colleagues reported on a CMR cross–sectional study of 35 patients (mean age 60 years) with asymptomatic moderate and severe primary degenerative mitral regurgitation but impaired VO2 max and found dilated left ventricular (LV) volumes, preserved LV systolic function, evidence of impaired longitudinal and circumferential strain, LGE in 30% of subjects, and evidence of diffuse myocardial fibrosis from elevated ECV.In this issue of the journal (page 150), Meel and colleagues report, similarly, on a study of 22 patients with chronic rheumatic mitral regurgitation and 14 age– and gender–matched controls characterised by echocardiography, LGE–CMR  and serum biomarkers of collagen turnover.RHD is characterised by chronic inflammation which, in many other inflammatory cardiac conditions, 19In the future, CMR may play an increasingly important and complementary role to echocardiography in the evaluation and management of patients with RHD. An advantage of CMR over echocardiography in RHD is the ability to provide accurate and reproducible information on tissue characteristics, including myocardial fibrosis and oedema, without dependence on the presence of adequate acoustic windows and operator experience.5


Although the mechanism of the occurrence and development of heart failure has been continuously explored in the past ten years, the mortality and readmission rate of heart failure is still very high. Modern studies have shown that gut microbiota is associated with a variety of cardiovascular diseases, among which the study of gut microbiota and heart failure attracts particular attention. Therefore, understanding the role of gut microbiota in the occurrence and development of heart failure will help us further understand the pathogenesis of heart failure and provide new ideas for its treatment. This paper introduced intestinal flora and its metabolites, summarized the changes of intestinal flora in patients with heart failure, clarified that intestinal barrier damage and bacterial translocation induced inflammation and immune response aggravated heart failure, and altered intestinal microflora affected various metabolic pathways including trimethylamine/TMAO, SCFA, and Bile acid pathway leads to heart failure. At the same time, regulating intestinal microflora through diet, probiotics, antibiotics, fecal transplantation and microbial enzyme inhibitors has grown up to be a potential treatment for many metabolic disorders. Heart failure is a severe and terminal stage of many cardiovascular diseases and is an important part of the global prevention and treatment of chronic cardiovascular diseases. Epidemiological data show that the prevalence of heart failure in adults is 1% to 2% and increases to more than 10% of people over the age of 70 . CurrentBacteroides, Firmicutes, Actinobacteria,Proteobacteria and Verrucomicrobia. Among them, Firmicutes and Bacteroides are dominant, accounting for more than 90% of the total intestinal microflora, and the remaining bacteria are less than 1% of the total gut microbiota [Intestinal micro-ecosystem is composed of gastrointestinal tract lumen, epithelial cell secretion, gut microbiota and substances entering the intestinal tract. Gut microbiota is the most important active ingredient in intestinal microecosystem . The humcrobiota , 11. Owicrobiota , 13. Flocrobiota .At present, gut microbiota interacts with the host through metabolism-independent pathways, such as lipopolysaccharide (LPS) and peptidoglycan, which are bacterial cell wall products, and metabolite-driven pathways, such as short-chain fatty acid (SCFA), trimethylamine (TMA)/trimethylamine N-oxide (TMAO) and bile acid (BA) . IntestiCampylobacter, Shigella, Salmonella, Yersinia enterocolitica and Candida species [Coriobacteriaceae, Erysipelotrichaceae and Ruminococcaceae at the family level and a significant decrease in Blautia, Collinsella, unclassifified (uncl.) Erysipelotrichaceae and uncl. Ruminococcaceae at the genus level [Eubacterium rectale and Dorea longicatena [Exogenous factors such as diet, exposure to bacterial infections or taking drugs can reduce the diversity of intestinal flora; endogenous factors such as acute humoral imbalance, chronic intestinal congestion or ischemia-hypoxia, acid-base imbalance, weakened gastrointestinal motility, and nutritional deficiency can potentially change intestinal flora . With th species . Accordius level . A 16SrDgicatena . In addigicatena . Butyratgicatena . Cui et gicatena . In concα (TNF-α), interleukin (IL)-1 and IL-6 [Recently, more and more studies have confirmed that the intestinal tract plays an important role in the pathogenesis of heart failure, which is often referred to as the “gut hypothesis of heart failure”. The gut hypothesis implies that decreased cardiac output and redistribution of systemic circulation can lead to a decrease in intestinal perfusion and mucosal ischemia, which creates hypoxia and a hypercapnia status . Subsequand IL-6 . Howeverand IL-6 . Additioand IL-6 , 41, and4+ helper T cells, which is critical to the body to resist bacterial and fungal infections. Th17 cells play a role in the development of autoimmune diseases by secreting inflammatory factors such as IL-17, IL-22, IL-21 and recruiting neutrophils. Studies have demonstrated that sectional filamentous bacteria can promote the differentiation of Th17 cells in mice. The mechanism may be that sectional filamentous bacteria can induce the expression of serum amyloid A after colonisation into host epithelial cells, which can stimulate the secretion of IL-6 and IL-23 by dendritic cells in the lamina propria of the intestine, thereby promoting the differentiation of Th17 cells [B cells to generate anti-myocardial antibodies [Bacteroides fragilis can induce CD4+ T cells to transform into Foxp3+ Treg cells, and Foxp3+ Treg cells can secrete anti-inflammatory factor IL-10 to regulate intestinal mucosal immune tolerance [4+ T cell proliferation, inhibit intestinal inflammation, and secrete inflammatory inhibitors TGF-β and IL-10, which mediate intestinal mucosal immune stability [Recent studies have shown that the immune activation mechanism marked by elevated inflammatory cytokines plays a vital role in the development of chronic heart failure. The interaction between gut microbiota and mucosal immunity is related to the occurrence of heart failure. Th17 cells are a subtype of CD17 cells . Clinicatibodies . Necessatibodies , 45. Theolerance . Treg cetability . In additability . TherefoCompared with patients with no heart failure, TMAO levels were higher in patients with chronic heart failure and associated with NYHA (New York Heart Association) grades, ischaemic aetiology and adverse outcomes . A meta-β-myosin heavy chain [We have mentioned that TMAO levels are raised in chronic heart failure patients, but the mechanism of their increase is multifactorial. Changes in the composition of intestinal bacteria have turned out to be the principal drivers of TMAO levels . Of courvy chain . In addivy chain , and alsvy chain . TMAO cavy chain . These rvy chain . In micevy chain . Savi anvy chain  observedvy chain . Therefovy chain . TherefoSCFA signal via G-protein-coupled-receptors(GPCRS) such as GPR41, GPR43, and GPR109A and are essential regulators of gut homeostasis and epithelial barrier maintenance , 65. AccBAs are currently recognized as signalling molecules, and emerging evidence suggests that BAs affect cardiovascular function. The understanding of bile acid physiology was greatly expanded by the discovery of bile acid-responsive receptors, such as the farnesoid X receptor (known as FXR) and G-protein coupled bile acid receptor 1 . According to a cross-sectional study, an increased ratio of secondary to primary BAs in serum was found in patients with chronic heart failure, and this ratio was revealed to be associated with reduced overall survival in univariate analysis . HoweverNumerous physiological processes in the body are accomplished through two-way interaction between the intestine and the liver. Through the portal vein system, intestinal flora transports various metabolic or immune substances, bacterial components or products to the liver , and theIntestinal flora is closely related to the kidney. It was found that there were significant differences in the types and quantity of intestinal flora between patients with end-stage renal disease and healthy people . In patiTypically, the intestinal flora is in balance and protects the cardiovascular system through metabolites. For example, enterolactone is produced primarily by intestinal digestion of fibre-rich foods.A study shows that a high serum enterolactone level is associated with reduced cardiovascular diseases mortality . ProtocaAt present, the improvement or reversal of intestinal microflora has become a hot spot for heart failure, which contains the dietary intervention, prebiotic and probiotic therapy, faecal microbiota transplantation, antibiotic intervention, TMA-lyase inhibitors and so on.Diversity of gut microbiota was substantially correlated dietary habits, which confirmed the effect of long-term dietary patterns on gut microbiota. Studies have shown that adjusting diet for five days (short-term) can change the number and species of gut microbiota and produce corresponding changes to be adapted to dietary changes . DietaryLactobacillus rhamnosus GR-1) could significantly improve left ventricular hypertrophy and ejection fraction in rats with acute myocardial infarction after six weeks of coronary artery occlusion [Saccharomyces boulardii can improve left atrial diameter and left ventricular ejection fraction in patients with chronic heart failure [Lactobacillus Plantarum 299V can reduce infarct size and improve left ventricular function in rats [Probiotics mainly include bifidobacteria, yeasts, lactic acid bacteria, and so on. They can inhibit inflammation, protect and repair intestinal mucosal barrier, and improve intestinal function. A study in rats showed that probiotics  to inhibit the key enzyme CutC/D in the synthesis of TMA, thereby reducing the risk of cardiovascular disease by reducing the plasma TMAO level in mice . AnotherIn conclusion, there are increasing shreds of evidence that gut microbiota disorders, intestinal barrier dysfunction and metabolites of gut microbiota are associated with heart failure. Intestinal barrier dysfunction and changes in the gut microbiota of composition may lead to abnormal production and absorption of gut microbiota metabolites in patients with heart failure. This imbalance can be expected to result in other complications such as heart dysfunction, inflammation, and so on. The composition of intestinal microflora in patients with heart failure is different from that in a healthy state. Reduction of SCFA-producing bacteria in patients with heart failure may be a noteworthy feature of patients with heart failure. In addition, the microbial potential for TMAO and LPS production increased significantly. More research has focused on the mechanism of microbial metabolites, and there is a need for clinical application of various therapeutic interventions. However, few studies have investigated in depth a direct role of the gut microbiota in heart failure and associated complications at the mechanistic and causal levels.Therefore, we need to further understand the role of gut microbiota in heart failure to better foster the development of diagnosis and treatment of heart failure.


Accessory mitral valve tissue rarely causes left ventricular outflow tract obstruction in adults. It is often associated with other cardiac and vascular congenital malformations. Here, we report the rarest presentation of accessory mitral valve tissue (AMVT) causing left ventricular outflow tract obstruction.A 22-year-old female patient presented with a history of shortness of breath and chest pain for more than 5 years. A diagnosis of AMVT with parachute mitral valve, ventricular septal defect (VSD), bicuspid aortic valve, unruptured aneurysm of aortic sinus, and left ventricular outflow tract obstruction was made. Successful closure of VSD with mitral valve replacement, excision of AMVT, and repair of the aortic sinus were performed. The post-operative course was uneventful, and an echocardiogram showed complete resection of the accessory mitral valve, no residual shunt and no left ventricular outflow gradient. Additionally, the peak gradient of rapid filling phase and atrial systolic phase across the prosthetic mitral valve were 16 mmHg and 4 mmHg, respectively. The peak velocity across left ventricular outflow tract was 1.4 m/s.Accessory mitral valve tissue is associated with other cardiac abnormalities and is usually diagnosed in the first or second decade of life. It is responsible for left ventricular outflow tract obstruction. The obstruction can occur in the early period of life due to continued deposition of fibrous tissues within left ventricular outflow tract. Accessory mitral valve tissue should be considered a rare but important cause of left ventricular outflow tract obstruction. Accessory mitral valve tissue is a rare congenital anomaly of endocardial cushion development. It rarely causes left ventricular outflow tract obstruction in adults and is often associated with other cardiac and vascular congenital malformations.Accessory mitral valve tissue has been described as parachute-like, sail-shaped, sac-like, leaflet-like, or as a sheet.Accessory mitral valve tissue (AMVT) is a rare congenital anomaly that develops because of an incomplete separation of the mitral valve from the endocardial cushion tissue.9 cells/L , elevated C-reactive protein levels 25.36 mg/L  and NT-proBNP 628 ng/L . Chest radiography showed a cardiothoracic ratio of 60%, pulmonary congestion, bilateral pleural thickening and scoliosis.A 22-year-old female patient was referred to the Department of Cardiology with exertional shortness of breath and a history of congenital heart disease with mitral stenosis (MS), VSD and pulmonary hypertension as an outpatient. Five days previously, her condition had deteriorated rapidly, the patient became progressively dyspnoeic and developed orthopnoea, and she was unable to perform daily activities due to severe shortness of breath associated with exertional atypical chest pain. An electrocardiogram showed an ectopic rhythm (78 b.p.m./m), rapid atrial arrhythmias, and a left QRS axis. Upon physical examination, her blood pressure was found to be normal (100/60 mmHg) and the cardiac auscultation showed a 3/6 systolic murmur along the left sternal border. On auscultation of the chest, there were normal vesicular breath sounds. Scoliosis was observed in chest findings. There were no peripheral oedema and jugular venous distention. Blood and biochemical laboratory tests revealed leucocytosis, white blood cell count 10.18 × 10Figure 1). Therefore, we diagnosed it as AMVT. The peak blood flow velocity across LVOT had accelerated to 5.0 m/s . The MV had a parachute-like appearance. There were two normally positioned papillary muscles in the left ventricle, but they did not have chordae tendineae inserted into it. The chordae tendineae were located in the left ventricular wall between the two papillary muscles  that revealed an abnormal membranous structure (1.3 cm × 1.2 cm) attached to the ventricular side of anterior mitral valve (MV) leaflet, with a subaortic chordal attachment. The abnormal tissue was similar to a MV leaflet. The parasternal short-axis view showed the relationship between the normal MV and the accessory valve  that confirmed the TTE findings, showing a fixed, membrane-like structure arising from the anterior mitral leaflet causing the LVOT obstruction Video S4.Figure 3). Histological examination showed valvular tissue associated with mucous degeneration and inflammatory cell infiltration.After a comprehensive clinical evaluation, elective surgical treatment was performed because of the presence of VSD, severity of the MV stenosis and LVOT obstruction. The BAV was functioning normally and was not replaced. The operative findings correlated with the imaging diagnosis. During the operation, excision of the AMV and MV replacement were performed. In addition, the peri-membranous VSD and aneurysm of the aortic sinus were repaired. Grossly, the membranous structure specimens confirmed that it was AMVT (A post-operative echocardiography showed complete resection of AMV, no residual shunt, no left ventricular outflow gradient or mitral regurgitation. The mosaic flow signals in the left ventricular outflow were diminished using colour Doppler, and the peak blood flow velocity decreased to 1.4 m/s. The peak pressure of rapid filling phase and atrial systolic phase across the prosthetic MV were 16 mmHg and 4 mmHg, respectively. The post-operative course was uneventful, and the patient was most recently reviewed 1 week, 1 month, 3 months after the surgical procedure by ultrasound, electrocardiogram, and chest radiography. The function of BAV was evaluated by ultrasound regularly. In the most recent follow-up, the patient’s shortness of breath disappeared, with no further episodes of chest pain.In this study, we report an extremely rare case of AMVT causing LVOT obstruction associated with PMV, VSD, BAV, and an unruptured aneurysm of the aortic sinus. This combination of symptoms has not been previously reported in literature.et al.Accessory mitral valve tissue is a rare congenital anomaly of endocardial cushion development and is commonly associated with other congenital cardiac anomalies. Accessory mitral valve tissue arises from the anterior mitral leaflet and causes LVOT obstruction. Transthoracic echocardiography and TOE are considered the primary imaging modalities for AMVT diagnosis and patient follow-up.et al.Accessory mitral valve tissue is associated with other cardiac abnormalities. Manganaro The obstruction can occur in the early period of life due to continued deposition of fibrous tissues within LVOT. Accessory mitral valve tissue is usually diagnosed in the first or second decade of life, and the main symptoms are exercise intolerance with dyspnoea, chest pain, and syncope.Accessory mitral valve tissue rarely causes LVOT obstruction in adults. It is often associated with other cardiac and vascular congenital malformations. It should be considered a rare but important cause of LVOT obstruction.Supplementary Video 1Click here for additional data file.Supplementary Video 2Click here for additional data file.Supplementary Video 3Click here for additional data file.Supplementary Video 4Click here for additional data file.Supplementary Video 5Click here for additional data file.Supplementary Video 6Click here for additional data file.Supplementary Video 7Click here for additional data file.


Breath-hold (BH) requirement remains the limiting factor on the spatio-temporal resolution and coverage of the cine balanced steady-state free precession (bSSFP) cardiovascular magnetic resonance (CMR) imaging. In this prospective two-center clinical trial, we validated the performance of a respiratory triggered (RT) bSSFP cine sequence for evaluation of biventricular function.n = 39) and Institute B (n = 21) referred for a clinically indicated CMR study. We implemented a RT sequence with a respiratory synchronized drive to steady state (SS) of bSSFP signal, before the commencement of image data acquisition with prospective cardiac arrhythmia rejection and retrospectively cardiac gated reconstruction in real-time. Left (LV) and right (RV) ventricular function and LV mass were evaluated by using RT-bSSFP and conventional BH-bSSFP sequences with one cardiac cycle for SS preparation keeping all the imaging parameters identical. The performance of the sequences was evaluated by using quantitative and semi-quantitative metrics.Our study included 23 asymptomatic healthy subjects and 60 consecutive patients from Institute A .Cine RT-bSSFP is an alternative for evaluating global biventricular function with contrast and spatio-temporal resolutions that are similar to those attained by using the BH-bSSFP sequence, albeit with a modest time penalty and a small reduction in image quality. In secontrast . In ordecontrast , high flcontrast , and unicontrast  and articontrast , 15. In Approaches to combat artifacts introduced by respiratory motion in cine CMR imaging fall in three broad categories: (1) rapid imaging with data undersampling –18; (2) We have previously demonstrated respiratory synchronized bSSFP cine acquisitions using both respiratory bellows and diaphragmatic RF navigator, in a healthy cohort study . These i1, 950 ms; T2, 50 ms. The steady state magnetization (MSS) was defined as magnetization where the rate of change of magnetization was close to zero (< 0.5%).Numerical simulations were performed in MATLAB , to determine the minimum number of RF excitations required for myocardial tissue to reach SS in a bSSFP sequence starting with an α/2 preparation pulse, followed after a time period of TR/2 by successively alternating ±α excitation pulses every TR. Temporal evolution of myocardial magnetization from the unperturbed state to SS with uninterrupted RF excitations, characteristic of the bSSFP sequence, was numerically simulated with the following parameters: magnetic field strength, 1.5 T ± 3 ppm; TR/TE/flip angle, 3 ms/1.5 ms/65°; TSS. The subsequent arrival of the first cardiac R-top (at time point after the trigger > τ) was used as a cardiac synchronization point to accept data acquisition of the segment of phase-encoding steps in k-space in a multi-phase manner during that cardiac cycle. Upon arrival of the subsequent R-top, RF excitations were terminated, and the commercially available real-time arrhythmia rejection algorithm either accepted or rejected the data. In the case of rejection, the same phase-encoding segment was re-acquired. This process was repeated until the entire k-space was acquired, after which the retrospective cardiac gating reconstruction algorithm performed the required nonlinear stretching of variable R-R intervals to reconstruct cine images.A commercially available BH cine bSSFP sequence with retrospective cardiac gating and prospective arrhythmia rejection was modified to implement a free-breathing RT sequence on clinical scanner . A schematic showing the building blocks of this technique, described previously , is showThe prospective clinical validation studies were performed at Institute A and Institute B in patients referred for a clinical CMR for various indications. Institute A implemented the RT sequence and Institute B, located 2000 km away from Institute A, used this investigational sequence without supervision from Institute A. Institute A recruited 23 asymptomatic subjects (10 men). The mean age of these healthy subjects was 44 years . At Institute A, 39 consecutive patients (21 men) were enrolled in the study. The mean age of these patients was 50 years . At Institute B, 21 consecutive patients (12 men) were enrolled in the study. The mean age of these patients was 47 years . All patients underwent biventricular function evaluation as a part of routine clinical protocol to evaluate the following conditions: left and right ventricular  cardiomyopathies (31), myocardial viability (12), valvular function (9), pericarditis (7), and congenital heart disease (1). This study was approved by the Institutional Ethics Committee of Catholic Health Initiative’s Institute for Research and Innovation under evolution MRI techniques protocol and complied with the Health Insurance Portability and Accountability Act of 1996. All subjects gave written informed consent before being enrolled in the study. All healthy subject and patient imaging was performed at 1.5 T CMR scanner  with a 5-element or 32-element phased-array surface coil for signal reception and vector-cardiographic (VCG) gating, with respiratory bellows placed at mediastinum. Authors employed by the CMR scanner manufacturer were not part of the clinical patient data acquisition and image quality assessment.In all 83 study participants, scout images of the thoracic cavity were obtained along the three orthogonal planes by using a non-VCG-gated bSSFP technique. With these single-phase scout scans, a series of VCG-gated cine images were acquired during suspended respiration (BH technique) in the following order: a two-chamber view, a four-chamber view, and a series of 12 to 14 contiguous short-axis slices covering the entire LV from the apex to the base . Identical imaging parameters and short-axis slice prescription were used with the RT acquisition. Patients were completely blinded to the imaging sequences and were not given any special instructions for breathing during RT technique.3; SENSitivity Encoding (SENSE) acceleration factor = 1.3–1.9; temporal resolution = 40-50 ms. In the case of BH, each cine slice was acquired during suspended respiration . In the case of RT, a user controllable parameter, minimum time (τ) to drive SSFP signal to MSS, was kept fixed at the default value of 450 ms for all the subjects. For the purpose of evaluating the impact of signal evolution during approach to SS on image quality, additional single-shot cardiac-triggered cine bSSFP .SS. The signal intensity of ROIs was normalized to the minimum SI across the cardiac cycle. To construct a histogram, normalized signal intensity values were plotted against the PCC spent at that normalized intensity level. Cumulative density function of normalized signal intensity of myocardial ROI over the cardiac cycle was computed for all healthy subjects. The ratio of the normalized signal intensity values at 95 and 5% of cumulative density function was computed as a metric to characterize the extent of signal intensity variation during the cardiac cycle. A normalized signal intensity of 1.25, which corresponded to MSS based on the simulations, was used to compute the PCC spent in SS. The blood-myocardial contrast (BMC) was normalized to myocardial signal intensity. Box plots were used to evaluate the signal intenisty variation (SIV), the PCC spent in SS by the liver and myocardium, and BMC; in these plots, non-overlapping notches indicate that the medians of the two groups differed at the 5% significance level. In addition, paired two-sided Student’s t-statistics for SIV, PCC, and BMC were used to compare among cardiac triggered, BH, and RT sequences.For 23 healthy subjects, regions of interest (ROI) were drawn in the liver, myocardium, and blood pool at mid-ventricular level and were propagated across all cardiac phases in all cine bSSFP sequences. A histogram-based analysis was used to define two quantitative metrics designed to capture the extent of signal intensity (SI) variation across the cardiac cycle, as well as the percent duration of the cardiac cycle (PCC) during which tissue magnetization was close to the theoretically predicted Mt-statistics were used to compare each of these parameters computed using the BH sequence with those computed using the RT sequence in 60 patients. Inter-observer variability for each of these parameters was assessed using Bland-Altman analysis in both BH and RT acquisitions in 60 patients.Two independent CMR readers, each with at least a decade of experience in clinical CMR, independently drew the ventricular contours necessary to compute LV and RV volumetric indices  and LV mass. Descriptive statistics of each of these parameters for 60 patients using BH and RT are reported as mean ± standard deviation in absolute values and percentages. Bland-Altman analysis  and pairFor 60 patients, an independent expert with 12 years of experience in CMR who was blinded to the study design reviewed the stack of short-axis images. The image quality between the two techniques was compared by using the clinical scores, which were based on three parameters: BMC, endocardial-edge definition, and motion artifact. Each parameter was graded on a scale from 1 (non-diagnostic) to 5 (excellent) on review of all the images in the short-axis stack. In cases where all but one or two of the slices were of high quality, the clinical score was lowered for the entire stack. Details of the scoring criteria are provided in Table SS after the first few RF excitations, and as many as 140 continuous RF excitations (with a flip angle of 65o at a repetition time of 3 ms) were required to reach myocardial MSS. After the rate of change of myocardial magnetization fell below 0.5%, the magnetization corresponded to 125% of the MSS predicted by the analytical expression for the steady state signal   for both the BH and RT techniques because of through-plane motion of the myocardium  Fig. . In cont01) Fig. . Similar01) Fig. . The difium Fig. .Fig. 4Exp < 0.001). In two cases, RT scan time was three times longer than that of the BH sequence because of specific breathing patterns. Table The RT sequence ran successfully in all 60 patients. The mean heart rate was 74 bpm range 43–116), and the mean respiratory rate was 18 bpm range 12–20). Total image acquisition time for RT was significantly longer than that for conventional BH (7.9 ± 3.4 min vs. 5.1 ± 2.6 min) . Figure The combined clinical score was excellent 87%) to good (13%) for BH and excellent (38%) to good (45%) to moderate (17%) for RT Fig.  H. In 17% to goodThe results from the two-center clinical study show that RT-bSSFP yielded diagnostic image quality cine images in all 60 patients encompassing a wide range of heart rates (43–116 bpm), respiratory rates (12–20 bpm), and ventricular indices  with spatial, temporal, and contrast resolutions that were comparable to BH-bSSFP. To the best of our knowledge, this is the first study that has performed clinical validation of the free breathing cine bSSFP imaging in a large cohort of adult patients. The bias and limits of agreement between RT and BH sequences for LV and RV volumetric indices and LV mass were comparable to inter-observer variability in both RT and BH sequences. An interesting observation was that while the LV volumes were slightly overestimated (mean bias of  2–3 mL) with BH sequence compared to RT sequence, RV volumes were slightly underestimated (mean bias of 2–3 mL). Although such small differences in ventricular volumes may not be clinically significant, it may be worth investigating if the intra-thoracic pressure differences between respiratory suspended state and free breathing could be a contributing factor.ss prior to cardiac gated data acquisition. Metrics to quantify the temporal stability of the signal demonstrated that the RT sequence attained SS in synchrony with the physiologic cycle that is comparable to BH bSSFP. Importantly, the proposed acquisition technique and image quality evaluation metric have the potential to be used more broadly in other clinical applications. Also, it is worth noting that RT-bSSFP cine sequence is inherently compatible with prospective arrhythmia rejection and retrospective cardiac gating that are typically used with BH techniques, allowing the acquisition of a complete cardiac cycle. Furthermore, the cardiorespiratory synchronization approach can be seamlessly combined with other techniques such as non-cartesian sampling, sparse sampling, and self-navigation.There are several key findings from the study that are worth noting. Firstly, conventional respiratory triggering methods for circumventing the breath-holding in bSSFP imaging that do not account for signal intensity modulation during the approach to SS can introduce significant artifacts as demonstrated in this study. Interestingly, even in BH bSSFP acquisitions, through-plane motion of the base toward the apex of the ventricle during systole introduces quantifiable temporal signal heterogeneity in the myocardium. Compared to other previously published respiratory triggered bSSFP cine CMR implementations , 23, RT Secondly, bSSFP cine acquisition is feasible with both respiratory triggering using bellows and respiratory triggering with slice tracking using diaphragmatic RF navigators . One advThirdly, respiratory triggered cine bSSFP sequences have several strengths. In contrast to continuous multi-NSA sequences which are often used to obtain cine bSSFP images in sedated patients or those with compromised respiratory function , the RF Another advantage of the RT bSSFP cine sequence is that it would reduce the potential for errors in estimation of ventricular chamber volumes due to inconsistent breath-holds. Although CMR is considered the gold standard for the estimation of ventricular chamber volumes, inconsistencies in the level of the diaphragm across breath-holds for each slice can result in under and/or over sampling of the myocardium in the direction of the ventricular long axis. This too may lead to variability in calculated volumes and EF, especially sampling-dependent inclusion or exclusion of the basal slice in end-systole . This prAlthough we made no attempt to include only patients with compromised respiratory function, our clinical results suggest that the reduction in image quality of RT bSSFP was only small compared to the image quality attainable with the BH bSSFP technique. Notably, in our previous study, the image quality obtained with the RT-SSFP technique was better than that obtained with the multiple signal averaging that is routinely used in sedated pediatric patients . In thisSS). This is because the RT sequence, in its current implementation, acquires data for a single cardiac cycle after each respiratory trigger. Often, the expiratory phase of the respiratory cycle is longer than one cardiac cycle and may permit data acquisition for several cardiac cycles, which would reduce the acquisition time of the RT sequence. Although this was not considered in this study, data acquisition over consecutive cardiac cycles during expiration with prospective constraint for rejecting the data are an important area of future investigation [The current implementation of RT-SSFP cine sequence has two key limitations. First, image quality of RT-bSSFP, while good, was inferior to that of the BH-bSSFP sequence. In 10/60 subjects, RT-SSFP image quality scores were moderate (still diagnostic) and we speculate that this reduction in image quality may be partly because of inconsistent respiratory patterns, such as when a patient starts inspiration before data acquisition from the expiratory trigger has completed, or respiratory drift over the course of an examination. The extent of the image quality degradation is dependent on the location of the acquisition segment with respect to center of the k-space. The image quality of the RT sequence could be improved by imposing an additional prospective constraint for rejecting data that were acquired during such respiratory inconsistencies at the cost of increasing scan time. A second limitation of the RT-bSSFP sequence is that it takes on an average 55% more time than the conventional cine BH-bSSFP sequence. For a cardiac cine bSSFP technique that requires n shots for a complete data acquisition, the RT-bSSFP sequence takes the time required for n respiratory cycles, whereas the BH-bSSFP sequence takes the time required for n + 1 heartbeats (1 extra beat to drive to Mtigation  as respiIn conclusion, we have shown that the RT sequence is a robust, free-breathing alternative to BH-bSSFP for evaluating ventricular function in patients with impaired breath-holding capacity and/or arrhythmia. The RT sequence yields cine images with contrast and spatio-temporal resolutions that are identical to those attained by using the BH sequence, albeit with a modest time penalty and a small reduction in image quality. We believe that the elimination of the BH constraint on a cine bSSFP sequence has the potential to improve the evaluation of ventricular function in subjects with compromised respiratory capacity with small reduction in image quality. Moreover, this would allow one to acquire high temporal resolution cine images necessary for the assessment of transient phenomena, such as isovolumic relaxation time, as well as the ability to acquire multi-phase, high-resolution anatomic images, such as coronary MR angiography.


It has been reported that harmonics of radial pulse is related to coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM). It is still unclear whether or not the first harmonics of the radial pulse spectrum is an early independent predictor of silent coronary artery disease (SCAD) and adverse cardiac events (ACE). C1) of the radial pulse increases ACE.  To measure the risk of SCAD in patients with T2DM and also to survey whether or not an increment of the first harmonic . By comparing the data of patients with C1 smaller than the first quartile and the patients with C1 greater than the third quartile, the hazard ratios were listed as follows: ACE , heart failure , myocardial infarction , left ventricular dysfunction , and new symptoms and signs for coronary artery disease . As C1 increased, the risk for composite ACE (P < 0.001 for trend) and for coronary disease (P < 0.001 for trend) also increased. The hazard ratio and trend for cardiovascular-cause mortality were not significant.  Out of 1968 asymptomatic individuals with T2DM, ACE was detected in 239 (12%) of them during the follow-up period. The logrank test demonstrated that the cumulative incidence of ACE in patients with C1 of the radial pulse wave is correlated with cardiovascular events. Survival analysis showed that C1 value is an independent predictor of ACE and SCAD in asymptomatic patients with T2DM. Thus, screening for the first harmonic of the radial pulse may improve the risk stratification of cardiac events and SCAD in asymptomatic patients although they had no history of coronary artery disease or angina-related symptom. This study showed that  Coronary artery disease (CAD) is one of the leading causes of death and contributes to the adverse cardiovascular events. Compared with nondiabetics, patients with type 2 diabetes mellitus (T2DM) have 2- to 4-fold increase risk of CAD  and are Several studies made an effort on the identification of those diabetic patients with SCAD , using cThe emerging technical method to screen SCAD is using the harmonic index in arterial pulse spectrum analysis. In the 1970s, medical researchers introduced harmonic analysis to convert pressure pulses and flow pulses into numerical Fourier series . HarmoniP < 0.05) [In addition, the important relationship between the first harmonic of the radial pulse wave and cardiac risk has been studied recently. Wang et al. demonstrated that the first harmonics of the radial pulse increased with age . The cro < 0.05) . Since tThe present population included 1158 men and 810 women who had a record of T2DM and have already entered a diabetes management program in the Division of Endocrinology & Metabolism of Zhongxiao Branch of Taipei City Hospital. In order to investigate the asymptomatic patients, the key exclusion criteria were listed as follows: (1) angina pectoris or angina equivalent symptoms; (2) any stress test or coronary angiography before the enrollment; (3) shortness of breath either at rest or on exertion; (4) history of myocardial infarction, heart failure, or coronary revascularization; (5) electrocardiographic evidence of Q-wave abnormality, ischemic ST-segment, and T-wave abnormality; (6) clinically significant valvular heart disease or cardiomyopathy. Subjects were also excluded if the radial pulse wave measurement could not be carried out due to the severer diseases or acute symptoms such as end-stage renal disease or liver disease. A total of 1968 patients have been enrolled in the study between January 2017 and May 2018 in Taiwan. After the assessment of the first harmonic amplitude of the radial pulse wave at baseline, patients were followed for a mean of 14.7 ± 3.5 months. The study was approved by the Institutional Review Board of Taipei City Hospital (IRB number: ISRCTN14306167). Then, both oral and written information about the study will be given to the enrolled patients. All participants signed for their consent.The medical history and physical examination report were retrieved to determine the patient demographic data, the status of T2DM, and other clinical variables. Readings of radial pulse and harmonic analysis were taken in 1968 participants at baseline with a longest follow-up period that lasted for 16 months after the radial pulse measurement. Myocardial infarction, heart failure, and cardiovascular death were also documented.C1 is defined by the following equation:A0 is the mean value of pulse wave, and A1 is the 1st amplitude coefficient of Fourier series of the radial pulse wave. The mean value of C1 calculated from all pulses was used as a representative harmonic amplitude value within one measurement. After the assessment of radial pulse spectrum, the blood pressure and heart rate were assessed by an automatic blood pressure monitor  according to the instruction manual. The assessment was performed by a well-trained operator, without the doctors and nurse presented, to avoid the white coat effect.The baseline of the first harmonics of the radial pulse was carried out at the beginning of the study. Each subject was required to lie down in a supine position and rest for 5 minutes before the measurement. The pulse pressure was then obtained on the left-hand radial artery with a pulse wave analyzer TD01C . TD01C has been proved its intrinsic reliability using an artificial pulse generator . The intThe patients entering the diabetes management program will visit the research hospital every 4–6 months to conduct the clinical evaluation of cardiac risk, based on the risk factor assessment or cardiovascular events. The study used the risk factor evaluation to select the patients who need a further cardiac stress test such as SPECT myocardial perfusion image, or stress electrocardiogram (ECG), mostly following the guidelines , 25. TheThe primary study outcome was a composite of myocardial infarction, heart failure, or cardiovascular mortality. The secondary outcome was a composite of left ventricular dysfunction (LVEF ≤ 50%), and the new occurrence of symptoms and signs of coronary artery disease, which was defined by the related symptoms and signs of CAD diagnosed by the cardiology physicians.Enzyme rise: an increased value for cardiac troponin, exceeding the value of the 99th percentile of a reference control group, reflecting myocardial cell death.Abnormal electrocardiography: myocardial ischemia (ST-T segment changes) or evidence of loss of electrically functioning cardiac tissue (Q waves)The angina-related symptoms.Myocardial infarction was diagnosed by a cardiologist physician following the consensus guideline for Joint European Society of Cardiology/American College of Cardiology Committee  and the Heart failure was diagnosed by a cardiologist physician, including identification of a structural and functional abnormality, following the New York Heart Association (NYHA) Functional Classification and the guideline of American College of Cardiology , 34.The signs of coronary artery disease included the newly diagnosed single coronary stenosis (>70%), multicoronary stenoses (>50% stenosis for at least two major coronary vessels), and more than mild myocardial ischemia using semiquantitative 20-segment analysis of myocardial perfusion single-photon emission computed tomography . Each of these outcomes was also analyzed separately. Source data were derived from the database of the diabetes management program in Zhongxiao Branch of Taipei City Hospital and were verified by independent monitors.C1 levels , in which Cox proportional hazards model were adopted to compare hazard ratios of clinical events among quartile groups with reference to the first quartile (C1 < 0.89). The unadjusted hazard ratio and 95% confidence intervals of all outcomes in each quartile were recorded. Tests for linear trend across quartiles were examined using Cox regression analysis. Linear trend tests were assessed both before and after adjusting for age, sex, smoking, systolic pressure, diastolic blood pressure, dyslipidemia, and Hba1c. The curves of Kaplan–Meier for primary and secondary composite endpoints are plotted in C1. In order to determine if C1 has a significant effect on the risk of adverse heart events and loss of cardiac function, the logrank test was performed. Matlab version 9.2  was used to conduct all statistical analyses.The study was designed to follow the patients for 16 months. All the subjects were categorized by four quartiles of C1 and risk of ACE. The cumulative incidence of primary composite endpoint increased from 7.5% to 10.4% to 14% to 16.7% according to four quartiles of C1 levels. This relationship extended into the heart function loss and CAD. The cumulative incidence of secondary composite endpoint increased from 10.8% to 16.5% to 16.3% to 24.1% according to the same four quartiles of C1 levels.The baseline clinical characteristics of 1968 asymptomatic patients with T2DM were shown in C1 < 0.89), the hazard ratio of primary composite endpoint for each quartile was 1.39  for C1 of 0.89 to 0.96, 1.90  for C1 of 0.96 to 1.07, and 2.29  for C1 > 1.07. The linear trends were significant for major adverse cardiac events before and after controlling for age, sex, smoking, systolic pressure, diastolic blood pressure, dyslipidemia, and Hba1c (P < 0.001).The listed incidence and the hazard ratios are written in C1 < 0.89), the hazard ratio of secondary composite endpoint for each quartile were 1.56  for C1 of 0.89 to 0.96, 1.53  for C1 of 0.96 to 1.07, and 2.04  for C1 > 1.07. The linear trends were significant for the symptoms and signs of CAD before and after controlling for age, sex, smoking, systolic pressure, diastolic blood pressure, dyslipidemia, and Hba1c (P < 0.001).Similar findings were also found in the hazard ratio of the secondary composite endpoint for each quartile: Compared with the first quartile  is performed. The ambulatory ECG has been demonstrated useful in predicting CAD and future cardiovascular event in asymptomatic diabetic patients . HoweverRecently, the cross-sectional study screened the performance of ABI, microalbuminuria, and harmonics of the radial pulse to stratify the risk of SCAD and severe silent myocardial ischemia in patients with T2DM and had at least one traditional risk factor. The harmonics of the radial pulse , ABI , and microalbuminuria  showed different abilities to identify the patients at high risk of CAD . CombiniThis study, using noninvasive radial pulse waveform and harmonic analysis, further surveyed the predictive values of the first harmonic index for the heart disease, from the symptoms and signs of CAD and the left ventricular dysfunction to the ACE  in a prospective cohort study. The report demonstrated that the first harmonic of radial pulse is an independent risk factor for the symptoms and signs of CAD, the ventricular dysfunction, myocardial infarction, and heart failure. The possible mechanism could be deduced from the resonance effect of the whole arterial system, which was proposed and validated by Wang et al. . The furThe amplitude and phase of harmonic phases can be affected by arterial stiffness and the loading condition in the phantom study of the arterial system –60. ConsC1 had a larger risk of left ventricular dysfunction, myocardial infarction, and heart failure , if only warm water was consumed before the first measurement [C1 as a cardiac risk marker only depends on about 500 events within 16 months of follow-up. More clinical studies are needed to confirm the independence of C1 as a risk marker in a more general population. We have applied an extended study for 3 years of follow-up to investigate further the relationships among harmonics, traditional risk factors, and adverse cardiac events.This study has some limitations. First, the radial pulse measurements were performed at baseline when enrolled patients visited the study area for the first time. Therefore, it is necessary to determine the reliabilities of the TD01C measuring instrument for research purposes. In the previous clinical study for intraobserver reliability, the population mean and standard error of the difference of  ± 0.006 . In the  ± 0.008 . This shsurement . For eacsurement . This inC1, is associated with cardiovascular events. The risk of primary and secondary composite endpoint was all increased with increasing quartile of graded C1 levels. The results of the survival analysis demonstrated that the C1 value is an independent predictor of ACE in asymptomatic patients with T2DM. Hence, periodic screening for radial pulse spectrum may improve the identification of type 2 diabetic patients at high risk of SCAD and confronting ACE in the future, who may need a further investigation or preventive treatment to reduce the cardiac risk.This study showed that the first harmonics amplitude of the radial pulse,


We developed a fully automated method for estimating MEE based on a single 11C-acetate PET scan without ECG-gating.Myocardial external efficiency (MEE) is defined as the ratio of kinetic energy associated with cardiac work [forward cardiac output (FCO)*mean systemic pressure] and the chemical energy from oxygen consumed  in all subjects. The correlation between MEEPET-CMR and MEEPET was high  without significant bias. MEEPET was 23.6 ± 4.2% for controls and was lowered in AVS  and in MVR . MEEPET was strongly associated with both NYHA class (P < 0.001) and the magnitude of valvular dysfunction .Ten healthy controls, 34 patients with aortic valve stenosis (AVS), and 20 patients with mitral valve regurgitation (MVR) were recruited in a dual-center study. MVO11C-acetate PET yields accurate and automated MEE results on different scanners. MEE might provide an unbiased measurement of the phenotypic response to valvular disease.A single The online version of this article (10.1007/s12350-018-1338-0) contains supplementary material, which is available to authorized users. A common feature in most cardiomyopathies is a reduction in myocardial external efficiency (MEE)82), respectively. However, the requirement for dual-sided catheterization has ruled out this method in a clinical setting. Accurate non-invasive alternatives are available,15O-labeled PET tracers or, more commonly, 11C-acetate washout10–2, combined with cardiac magnetic resonance imaging (CMR) or echocardiography to assess Cardiac Output (CO) and LV mass (LVM).The gold standard for measuring MEE makes use of pressure-volume loops and the Fick-principle to estimate cardiac work and myocardial oxygen consumption  and mitral valve regurgitation (MVR) are compared with those of healthy controls.Since MEE integrates measurements of LV mass, function, and oxidative metabolism, a near-simultaneous acquisition of all measurements is preferred. This could be accomplished using hybrid PET/CMR or ECG-gated PET,2 and/or transaortic maximal velocity of 3.0–5.0 m s−1 based on echocardiography. The second group consisted of 20 patients  with significant mitral regurgitation (regurgitant fraction > 30% on echocardiography) and with no or mild symptoms of heart failure . The final group consisted of 10 healthy controls  with no signs or history of cardiac disease. AVS patients and controls were scanned at the Aarhus University Hospital, Aarhus, Denmark whilst MVR patients were scanned at the Uppsala University Hospital, Uppsala, Sweden. The study was approved by the respective local ethical committees and all subjects gave written informed consent prior to inclusion in this study.This study consists of a retrospective analysis of three groups of subjects undergoing efficiency measures in research studies from two different research sites. The first group consisted of 34 patients  with AVS and varying degrees of heart failure . All patients had sinus rhythm, no signs of myocardial ischemia and aortic valve area ≤ 1.2 cm11C-acetate synthesis was done according to Pike11C-acetate PET scan on a Siemens Biograph TruePoint TrueV 64 PET/CT scanner. Following a scout CT scan, a low-dose CT scan  was performed. After this, a 27-minute list mode emission scan was performed, starting simultaneously with automated injection of 407 ± 30 MBq 11C-acetate as a 5–10 mL bolus (1 mL·s−1) in a peripheral vein, followed by a 35-mL saline flush (2.0 mL·s−1). List mode emission data were rebinned into a dynamic series consisting of 29 time frames using all data. Dynamic images were reconstructed using the TrueX algorithm, applying all appropriate corrections as supplied by the vendor.MVR patients were scanned on a GE discovery ST with an acquisition protocol identical to that of AVS patients and controls. Data were reconstructed using the 3D IR algorithm with all appropriate corrections as supplied by the vendor.−1 gradient system, using similar imaging protocols. Details on exact settings can be found in the supplemental files.AVS patients and controls were scanned on an Ingenia 1.5 T whole body scanner  as described inMyocardial external efficiency (MEE) was calculated using the methods as described in−1); MVO2 is the myocardial oxygen consumption (mL·g−1·min−1); LVM is the mass of the left ventricle , and 1.33 · 10−4 and 20 are the conversion factors from 1 mmHg mL to J and from 1 mL of O2 to J, respectively. The numerator, output energy (Eout) is similar to cardiac work, expressed in Joules, and represents the area enclosed within a pressure-volume loop. The denominator represents input energy (Ein), the total energy consumed by the LV.In which EW is the effective external work performed by the heart (J); TE is the total energy use (J); MAP is the mean arterial pressure (mmHg); FCO is the forward cardiac output  or 11C-acetate PET data (FSVPET and LVMPET). Supplemental Figure 1 summarizes the steps required for calculation of MEE, which are outlined below. An example of a dynamic time-series and all relevant intermediate steps of the analysis for each of the patient categories is shown in Supplemental Figures 2, 3, and 4.HR and MAP were measured 1 minute before and 1 and 5 minutes after injection and averaged for calculation of MEE. MVOhttps://aquantsoft.com/go/aquantresearch). Arterial (CA(t)) and right-ventricular (CRV(t)) blood concentrations were obtained automatically using cluster analysis.CP(t)) by applying the average plasma metabolite correction as presented by Sun et al.CP(t) was used for calculation of washout rate k2 using a standard single compartment modelPET scans were analyzed using aQuantCPET(t) represents the myocardial time-activity curve, and CP(t), CA(t), and CRV(t) are the aforementioned blood time-activity curves. VA represents arterial blood volume fraction (dimensionless), K1 the uptake rate of 11C-acetate in tissue (mL·g−1·min−1), k2 the washout rate of 11C-acetate (in min−1), VRV is the right-ventricular spillover fraction (dimensionless).In which A, from which radial profiles are generated every 10°. Then, for each profile, the first and last point above 2/3rd of the maximum of each profile were considered to represent the endo- and epicardial borders. This process was repeated for each profile and each short-axis slice until the entire LV was segmented.Parametric images were generated using basis function methodsCPET(t) in Eq.  in Eq. , yieldin2 were used for both MEEPET-CMR and MEEPET.Identical values of MVOCMR) was calculated from phase contrast velocity measurement in the LV outflow tract. Flow analysis was performed using the freely available software Segment (version 1.9 R3746).CMR was calculated from phase contrast velocity measurement in the ascending aorta and flow analyses were performed on a ViewForum workstation . FSVCMR was multiplied with HR during PET to obtain FCOFor AVS patients and controls, CMR-based forward stroke volume (FSVPET) was calculated using indicator-dilution techniques using the methods described in PET-CMR and FSVPET as presented in that study. In brief, the peak of the first-pass of the 11C-acetate bolus through the arterial blood, obtained for calculation of MVO2 as described above, was isolated automatically from CA(t). Using this peak, forward cardiac output was estimated usingFSV based on PET (FSVPET is forward cardiac output (mL·min−1); I is the injected dose of 11C-acetate (Bq) and ∫CA(t) is the area under the curve of the isolated peak (Bq·mL−1·min).In which FCOCMR was derived by manually tracing the endo- and epicardium in end-diastole on short-axis cine images tracing using the software Segment v1.9 R2854PET was defined using the volume of interest of the LV used to obtain CPET(t). For both LVMPET-CMR and LVMPET, a density of myocardial tissue of 1.05 g cm3 was assumed.LVMt tests were used to evaluate systematic differences. Repeatability coefficient (RPC) was defined as 2 times the standard deviation of the difference. Differences between patient groups were assessed using One-way ANOVA followed by student’s t tests. The independent capacity of MEEPET and MEEPET-CMR for prediction of NYHA class was assessed by ordinal logistic fitting.Data are presented as mean ± SD. Correlation and agreement were assessed using linear regression and Bland Altman plots. Paired Data of one AVS patient showed significant motion during PET, and this patient was excluded from further analysis.PET for all three groups. Compared to controls, systolic blood pressure was significantly higher for AVS (P = 0.015) but not for MVR (P = 0.09). Neither MAP (P = 0.55 and 0.30) nor FCI (P = 0.27 and 0.17) were significantly different from controls, resulting in similar values for EW (P = 0.47 and 0.56 for AVS and MVR). MVO2 in patients did not differ from that of controls (P=0.26 and 0.92 for AVS and MVR) but LVM was larger (P = 0.003 and < 0.001), resulting in a significantly increased TE (P = 0.003 and 0.019).Table r = 0.83 and r = 0.94, respectively, Figure r = 0.89, and 0.97, respectively, Figure P = 0.445) or TE . Finally, correlation of MEEPET and MEEPET-CMR was high .Correlation between PET and CMR was good for both FCO and LVM  and significantly lower for controls . Finally, MEEPET was significantly different as compared to MEEPET-CMR for controls  and MVR  but not for AVS . Residual analysis identified the difference in FCO as the main source of difference in MEE in all groups .EWPET was significantly lower for both AVS (P < 0.001) and MVR (P = 0.006) as compared to controls  but not MVR (P = 0.49). Mean aortic gradient in AVS was correlated to MEEPET-CMR  and to MEEPET . In addition, regurgitant fraction was correlated to both MEEPET  and to MEEPET-CMR . Finally, MEEPET was strongly associated with NYHA class (ANOVA P < 0.001) and significantly separated most groups . Using Ordinal Logistic fitting only MEEPET was independently associated with NYHA class , compared to MEEPET-CMR .When comparing patient groups, MEEs Figure , whilst  P = 0.00 as compas Figure , while t11C-acetate PET/CT scan without the use of ECG-gating. This method eliminates the need for separate measurements of cardiac output and LV mass, reducing protocol duration, cost and analysis time. MEE is a sensitive marker of cardiac performance and has been used as surrogate end-point in several interventional studies,This study presents a fully automated method of calculating myocardial external efficiency (MEE) solely from a dynamic PET, the difference in FCO points to a significant change in LV loading conditions between the CMR and PET scans. This is encouraging in terms of using MEE from PET alone as an end-point in multicenter trials, but including other scanner models requires further validation against CMR to establish correction factors.Both FCO and LVM have been validated vs CMR beforePET-CMR and MEEPET were high and not significantly different .PET-CMR as compared to MEEPET, as can also be appreciated in Figure PET-CMR as marker for efficiency. However, Figure PET, suggesting that the (non-significantly) increased test-retest variability for MEEPET is largely off-set by an increased effect size. The exact benefit of using either MEEPET and MEEPET-CMR must be studied in larger clinical studies. Finally, the use of a combined PET-echocardiography protocol was not recommended from a reproducibility point of view.22In a test-retest study, we show that repeatability of MEEPET was significantly correlated to the echocardiographically derived mean pressure gradient of the aortic valve in AVS patients  and to the regurgitant fraction obtained from CMR in MVR patients . In addition, MEE corresponded to the subjective level of disease burden defined by the NYHA class. This indicates that MEE reflects the phenotypic response to the causative disease process in valvular disease. To what extent MEE can be used to define the optimal time point for valvuloplasty requires larger outcome studies, for which the current study suggests that a PET-alone approach might perform better than serial multimodality imaging.MEE calculated with both approaches resulted in control values ranging from 17 to 30%, which is in line with previously published invasive measurements.global LV efficiency and reflects both the metabolic and mechanical state of the heart. The result of this study suggests that global LV efficiency is a sensitive marker of generic cardiac performance. If, on the other hand, regurgitation or elevated LV pressures are taken into account, MEE represents the energetic cost of displacing blood in any direction which can be considered the efficiency of the cardiomyocytes, reflecting the metabolic state of the heart specifically i.e., the metabolic efficiency. Noteworthy, global LV and metabolic efficiency deviate only in the case of valvular dysfunction. When pressure gradients are essential, echocardiography can be performed during a PET examination,Care has to be taken when comparing different values for MEE in literature. In some studies, pressure gradient over the aortic valve is used in Eq.  replaci represenThis study has several limitations that need to be acknowledged. The PET acquisition protocols were aligned between both participating sites, but since differences between PET scanners were observed widespread implementation of this all-in-one approach in multicenter studies requires further validation. CMR equipment and protocols differed between sites, which is likely to induce bias.Secondly, this study mainly included subjects with valvular abnormalities which typically show discrepancies in pressure-volume loops. The assumption that EW, formally defined as the area encompassed in a patient’s pressure-volume loop, can be approximated by the product of MAP and SV is often incorrect in these patients.11C-acetate PET/CT scan, without the need for additional imaging modalities. Because of the more generic, highly automated, and less logistically demanding approach, this novel technique might widen the applicability of MEE to more patient groups.To conclude, myocardial efficiency can be measured accurately using a single 11C-acetate scan. Using a single scan protocol instead of a combined PET-CMR protocol leads to lower potential errors due to differences in loading conditions. When applying this method to a cohort of controls and patients with valvular diseases, MEE based on PET-only correlated more closely to the underlying disease state and to NYHA class.The work presented in this study enables a simplified, faster, and more automated assessment of myocardial external efficiency using a single Supplementary material 1 (DOCX 2271 kb)Below is the link to the electronic supplementary material.