Continued high mortality in heart failure patients indicates the need for additional methods of risk stratification and phenotyping.We hypothesized that ventricular arrhythmias that do not meet test‐termination criteria (non‐terminating ventricular arrhythmias [NTVA]) during cardiopulmonary exercise testing (CPET) may help in phenotyping disease severity and prognosis in heart failure with reduced (HFrEF) and midrange (HFmrEF)/preserved (HFpEF) left ventricular ejection fraction (LVEF).About 319 patients with heart failure  underwent CPET. Tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PASP) were measured by echocardiography. B‐type natriuretic peptide (BNP) at rest and peak exercise was also determined. The patients were tracked for primary (cardiac death) and secondary composite outcomes .P < .05), TAPSE/PASP ratio (P < .001), peak oxygen consumption (P < .01), lower resting and peak BNP (P < .001), and the minute ventilation/carbon dioxide production slope (P < .001) compared to those with NTVA. Seventy‐one patients died during the tracking period, 54 for cardiac reasons. NTVA during CPET was a significant predictor of primary and secondary outcomes in the total heart failure cohort , as well as in subgroups categorized according to reduced and middle‐range/preserved LVEF (P < .001).Forty‐seven (15%) of the patients demonstrated NTVA during CPET, regardless of coronary artery disease prevalence. Patients without arrhythmias had a significantly higher LVEF (Exercise‐induced ventricular arrhythmias that do not reach test‐termination criteria are nonetheless indicative of an advanced disease severity phenotype and worse prognosis. They are common, increase in frequency according to disease severity and portends poor prognosis.Given the important clinical implications and current lack of firm evidence in the area, the purpose of the current investigation was to define the prognostic significance of NTVA during CPET in a HF cohort across left ventricular ejection fraction category.22.1From 1994 to 2015, 319 consecutive HF patients were referred for a clinically indicated hemodynamic and functional assessment at the Cardiomyopathy Program at the Cardiopulmonary Laboratory at San Paolo Hospital, University of Milano.Subjects underwent a 2D echocardiographic/Doppler evaluation and CPET. Inclusion criteria were (a) signs and symptoms of HF and (b) adequate echocardiographic windows. The diagnosis of HF was based on the recommended criteria of the European Society of Cardiology.2.2Subjects were followed for primary outcome (cardiac death) and secondary outcome of composite cardiac events , via hospital and outpatient medical chart review for up to maximum 193 months. Subjects were followed by the HF program providing a high likelihood that all events were captured. Cardiac death was considered to be death due to cardiac reasons, and hospitalization for cardiac reasons and admission to the heart failure unit.2.3A 2D and Doppler echocardiography was performed with a Hewlett‐Packard 77 020/A  and Philips IE33 devices (Andover) by two experienced cardiologists following current guidelines.2.4Blood for NT‐pro‐BNP analysis (20 mL) was taken at rest and at the peak effort, from intravenous cannula placed into the patient's brachial vein before the test. Samples were kept at −80°C and centrifuged on 4000 Hz. NT‐pro‐BNP was measured in all samples by immunoassay sandwich technique  with lower sensitivity limit of 5 pg/mL.2.52, STPD), and carbon dioxide output  were acquired breath‐by‐breath and printed using rolling averages every 10 seconds. Peak VO2 and peak respiratory exchange ratio (RER) were expressed as the highest 10‐second averaged sample obtained during the last 20 seconds of testing. VE and VCO2 values, acquired from the initiation of exercise to peak, were input into spreadsheet software  to calculate the VE/VCO2 slope via least squares linear regression . Exercise oscillatory ventilation during CPET was defined as previously described in detail.Symptom‐limited CPET was performed on a bicycle ergometer for all subjects, according to established guidelines.2.6t test was used to assess differences in key continuous variables between subjects who did and did not demonstrate NTVA during the test. The chi‐square test assessed differences in categorical data between these subgroups. Univariate and multivariate Cox regression analysis was used to assess the prognostic value of key CPET and Echo measures. For the multivariate regression, we used a forward conditional model with stepwise entry and removal criteria set at 0.05 and 0.10, respectively. Maximal iterations were set at 20. Kaplan‐Meier analysis was further used to assess the prognostic value of an exercise induced NTVA. The SPSS 22.0  statistical software package was used for all analyses. All tests with a P‐value <.05 were considered statistically significant.The results are expressed by classic descriptive parameters—mean and SD for parametric variables and median for variables that were not normally distributed. In order to apply parametric statistics, analysis of distribution was performed by the Kolmogorov‐Smirnov test, followed by power transformation of not normally distributed data. Categorical data are expressed as percentages. The unpaired 3Of 319 subjects with HF enrolled, mean age 63.0 ± 9.9 years, 78% were male. LVEF of studied population was 36.0 ± 11.1% and 62% of them had ischemic etiology of HF. Of 319 subjects, 198 (62.1%) were diagnosed with HFrEF; 80 (25.2%) with HFmrEF, and 41 (12.9%) with HFpEF. There were no major cardiac events, implantable cardioverter defibrillator activations or deaths during testing. Of 319 subjects with HF 47 (15%) demonstrated NTVA during CPET, whereas one patient with HFrEF (0.3%) demonstrated sustained VT that indicated test termination and died 42 days after; this subject was excluded from further analysis. 31/166 (18.7%) patients with HFrEF, 12/80 (15.0%) patients with HFmrEF and 4/41 (9.8%) patients with HFpEF demonstrated a NTVA during CPET.Clinical and echocardiographic data of patients with and without NTVA during CPET are shown in Table P > .05). There was no difference in beta blockers, statins, and angiotensin converting enzyme or angiotensin II receptor blocker usage in patients with and without NTVA, whereas patients with NTVA were more frequently prescribed a mineralocorticoid receptor blocker. Resting TAPSE was highly significantly lower and PASP higher in the subjects who exhibited NTVA (P < .001). Moreover, the TAPSE/PASP ratio, a measure of right ventricular‐pulmonary vasculature (RV‐PV) uncoupling,P < .001).Patients with NTVA had a lower LVEF, higher plasma NT‐pro‐BNP at rest and peak exercise, higher NYHA class and heart rate (HR) at rest, whereas 6MWT distance tended to be shorter but did not reach statistical significance. Age, body mass index and the distribution of males and females and the presence of CAD were similar between patients with and without NTVA, as well as HFrEF, HFmrEF, and HFpEF etiology  as well as a higher VE/VCO2 slope, and EOV prevalence.Subjects divided into groups according to presence or absence of the NTVA during CPET, showed a number of significant differences in CPET responses, as listed in Table P > .05). For echocardiographic study, interobserver variability, assessed in a sample size of 20% of total population, was 3.5% for M‐mode and 2D echocardiography, and 4.7% for Doppler variables.The trend of differences in crucial clinical, echocardiographic and CPET variables between patients with and without NTVA was held in subgroups of patients with HFrEF, HFmrEF, and HFpEF together, as shown in P < .001), whereas it did not predict noncardiac mortality (P = .36). In a multivariate model including NTVA appearance, peak VO2, the VE/VCO2 slope and EOV, only NTVA, EOV and the VE/VCO2 slope were retained in the regression, as shown in Table Seventy‐one patients died during the tracking period (25.8 ± 26.4 months), 17 for noncardiac, and 54 for cardiac reasons including the one subject who exhibited sustained VT during testing and was thus excluded from the analysis. There were 2 cardiac transplantations, 4 LVAD implantations, and 41 cardiac rehospitalizations during the tracking period. Data on cardiac events and noncardiac mortality in subgroups of patients with HFrEF, HFmrEF, and HFpEF during the follow‐up period are reported in Table P < .001) and secondary outcome  during the tracking period, as shown in Figure P < .001) and (b) 2005‐2015 .On Kaplan Meier analysis, NTVA significantly distinguished patients with and without the primary , and HFmrEF and HFpEF together , as shown in Figures Kaplan Meier analysis showed that NTVA appearance during CPET significantly distinguished patients with and without primary and secondary outcome during the tracking period in subgroups of patients with HFrEF (log‐rank Mantel‐Cox = 23.6, 30.3, 42 and the VE/VCO2 slope. NTVA during CPET was related to higher rest and peak plasma NT‐pro‐BNP levels, lower LVEF, and a more unfavorable response of a host of CPET variables, including peak HR and HRR‐1. In the subjects with NTVA during CPET, indirectly measured pulmonary systolic pressure was increased, right ventricular systolic function depressed and the TAPSE/PASP ratio, a measure of RV‐PV uncoupling, low. Additionally, NTVA appearance during CPET occurred in a similar rate in all phenotypes, that is, HFrEF, HFmrEF, and HFpEF holding comparable prognostic power.This is the first study addressing the potential for phenotyping HF severity and prediction of cardiovascular risk by looking at CPET variables in the presence of VA. The notable information is that the risk is remarkably increased even though subjects did not reach clinically recommended criteria to end the test. Subject with VA may exercise at maximum as suggested by RER at peak exercise. VA occurred in 15% of patients diagnosed with HF regardless of CAD prevalence, showing a strong predictive value for cardiac mortality and all‐cause mortality in combination with composite cardiac events, outperforming well‐established CPET parameters, such as peak VO4.1It is well established that the VA rate in HF patients is associated with electrical conduction heterogeneity secondary to myocardial scar, ischemia or QT dispersion due to certain drugs, myocardial late potentials or re‐entry phenomena, and sympathetic system activation.Actually, we do not have specific elements to dissect, which trigger mechanism may be predominant in our population. Nonetheless, no association was found between NTVA with older age, obesity, or increased CAD prevalence, suggesting that HF itself promotes some hemodynamic and metabolic derangements responsible for a lower oxygenation of myocardial cells. One explanation of this phenomenon may be the drop in cardiac output in association with the high catecholamine levels, followed by generalized vasodilation in exercising muscles, further affecting cardiac output.NTVA during CPET was associated with lower EF and RV to PC coupling, which is indicative for lower cardiac output during CPET. Accordingly, patients with NTVA demonstrated increased plasma BNP at rest and peak exercise which reflect higher myocardial stress and consequently lower contractility.A role would have been played by chronotropic incompetence,The fact that in patients with NTVA during CPET pulmonary vascular pressure was increased, systolic function of the right ventricle diminished, and the TAPSE/PASP ratio, a measure of RV‐PV uncoupling, decreased, may point toward a role of the right heart and pulmonary vasculature activity in generating arrhythmias.It was shown previously that patients prescribed with nitrates show VA less likely.Altogether, NTVA appearance during exercise in HF patients is apparently multifactorial, including lower oxygenation of the heart due to decreased cardiac output and usurped both the right and left ventricle, as well as endothelial dysfunction, metabolic derangements, autonomic dysregulation and therapeutic interventions.4.22, an elevated VE/VCO2 slope and EOV.Regardless of underlying mechanisms for VA appearance, an added novelty of the present study is the demonstrated prognostic significance of NTVA during CPET in HF patients. There is extensive literature demonstrating the prognostic value of abnormal responses during CPET in patients diagnosed with HF, such as low peak VOThe finding that NTVA appearance during CPET demonstrated strong predictive value for cardiac events in the subgroups of patients with HFrEF, HFmrEF and HFpEF has to be stressed taking into consideration the poor availability of prognostic criteria for HFmrEF.Finally, considering the link of NTVA and worse prognosis, their occurrence should be a flywheel for rephrasing therapeutic approach, pharmacological or invasive, in order to prevent unwanted outcome.Of note, in the present study, prognostic value of NTVA was not analyzed independently of EF and NT‐pro‐BNP, since the focus was to examine the overall power of CPET in HF risk stratification. Precise quantification of NTVA and determination of level of effort when NTVA appear may further improve prognostic power. Possible limitation of NTVA prognostic power may be presence of other conditions, such as respiratory diseases, sleep apnea, autonomic dysregulation, LV diastolic dysfunction or the use of different medications.In conclusion, exercise‐induced arrhythmias not reaching criteria for test termination seem nonetheless indicative of an advanced HF severity phenotype, and worse prognosis, independently of HF subtype. Marked abnormalities in CPET‐derived variables drive the outcome prediction. Among the many potential causes, our data suggest a role of unfavorable combination of RV‐PV uncoupling and autonomic dysregulation leading to reduced cardiac output during exercise.4.3In HF of any left ventricular ejection fraction, mortality remains high and multiparametric assessment of risk is of basic importance. The search for best phenotyping at different stages and with multiparametric approach is challenging and matter of intense investigation. Ventricular arrhythmias triggered by exercise testing not meeting test‐termination criteria appear an underestimated manifestation that increases in rate of presentation according to disease severity and portends an unfavorable prognosis in HF, regardless of left ventricular EF.The authors have no conflicts of interest to disclose.Table 1S Clinical and echocardiographic characteristics of study patients with and without NTVA during CPETClick here for additional data file.Table 2S Table 2A Clinical, echocardiographic and CPET characteristics of patients diagnosed with HFrEF, with and without NTVATable 2bS. Clinical, echocardiographic and CPET characteristics of patients diagnosed with HFmrEF and HFpEF, with and without NTVAClick here for additional data file.Table 3S Follow up of patients with HFrEF, HFmrEF and HFpEFClick here for additional data file.Table 4S Cox analysis for key CPET variables in the prediction of secondary outcomeClick here for additional data file.


Most importantly, T2-mapping was able to characterize IVD differences in individuals with different training histories (p < 0.005). Dixon displayed weak correlations with the Pfirrmann scale, but presented significantly higher water content in the IVDs of the long-distance runners (p < 0.005). (4) Conclusions: Findings suggested that T2-mapping best reflects IVD differences in asymptomatic individuals with distinct physical activity histories changes. Dixon characterized new aspects of IVD, probably associated with IVD hypertrophy. This complementary information may help us to better understand the biological function of the disc.(1) Background: Assessments of intervertebral disc (IVD) changes, and IVD tissue adaptations due to physical activity, for example, remains challenging. Newer magnetic resonance imaging techniques can quantify detailed features of the IVD, where T2-mapping and T2-weighted (T2w) and Dixon imaging are potential candidates. Yet, their relative utility has not been examined. The performances of these techniques were investigated to characterize IVD differences in asymptomatic individuals with distinct physical activity histories. (2) Methods: In total, 101 participants (54 women) aged 25–35 years with distinct physical activity histories but without histories of spinal disease were included. T11/12 to L5/S1 IVDs were examined with sagittal T2-mapping, T2w and Dixon imaging. (3) Results: T2-mapping differentiated Pfirrmann grade-1 from all other grades ( The intervertebral disc (IVD) consists of the outer annulus fibrosus and the gelatinous central nucleus pulposus . The higQualitative or categorical scales have been used to grade IVD degeneration . In addT2-mapping is commonly used in spine research for the characterization of degenerative disc changes. With T2-mapping, objective and quantitative measures of the disc are provided, reflecting both water content and the orientation of collagen fibers. Moreover, the group of Belavy has recently reported significant differences in IVD composition between groups with different training histories ,8,9 and Another quantitative MRI technique for the characterization of degenerative disc changes is T2-weighted (T2w) imaging ,12,13. SIn this study, we investigated the performances of the three different quantitative techniques, T2-mapping and T2w and Dixon imaging, to characterize IVD differences in asymptomatic individuals with distinct physical activity histories.This study was a secondary analysis of an existing dataset ,10 on thExclusion criteria included current spinal  pain, history of spinal surgery, history of traumatic injury to the spine, known scoliosis for which prior medical consultation had been sought, current or prior smoker, known claustrophobia and possible pregnancy.All subjects gave their informed consent for inclusion before they participated in the study. The study was conducted in accordance with the Declaration of Helsinki. The study was approved by the Deakin University Faculty of Health human ethics advisory group.Sagittal T2-mapping using spin-echo multi-echo sequences .Sagittal T2w imaging .Sagittal Dixon imaging . A Dixon technique with asymmetrical echoes (mDIXON) was utilized .Participants were instructed to perform no exercise on the day of their scan. To avoid the impact of normal diurnal variation on the spine , all teswww.random.org). A radiologist determined the Pfirrmann grade of each lumbar IVD using the T2w images. All Pfirrmann grades, except Pfirrmann grade 5 IVDs, were observed in the cohort. An off-line software was used to perform all quantitative MR measurements and a custom written ImageJ plugin was used to implement the IVD measurements after manual segmentation of the IVD using the native “polygon selections” tool in ImageJ.To ensure the blinding of the examiner in offline image measurements, each subject was assigned a random numeric code  were excluded. One hypoplastic L5/S1 IVD at a sacralized L5 vertebral level was included in analysis. The image number corresponding to each vertebral and IVD level was noted. IVDs were segmented in five subregions from the anterior to posterior aspect of the disc, as shown in Depending on the MRI technique, the following calculations were performed:T2-mapping: To reconstruct T2-maps, the T2-time in each pixel was calculated from the spin-echo multi-echo images using a linear fit to the natural logarithm of the image intensity in each of the eight MR echoes.T2w imaging: For normalization, the ratio of the average T2w signal intensity (T2w-SI) in the nucleus to the average T2w-SI in the anterior and posterior subregions (annulus) was calculated.Dixon imaging: An iterative algorithm with least-squares estimation was used to maximize the noise performance of the water signal .A detailed analysis of all MR images was then performed. In addition to the mean values of the whole IVD, values of the nucleus sub-region and values of the ratio of the nuclear subregion to anterior and to posterior subregions (ratio nucleus/annulus) were determined for all techniques using the central three sagittal slices to capture the central (most hydrated) region of the nucleus to be comparable to prior works ,12.Moreover, three-dimensional (3D) plots of the IVD were generated for all MRI techniques. To generate the plots, the pre-processed data for the T2-mapping, T2w imaging and Dixon imaging were interpolated across the width of the IVD in each subregion.t-tests. Sub-analysis was also performed to examine the covariation of the MRI techniques, and Pearson’s product moment correlation between each variable was calculated. Additionally, unpaired t-tests were used to examine the difference in variables obtained from each MRI technique on Pfirrmann grades 2, 3 and 4 IVDs compared to the Pfirrmann grade 1 IVDs.To examine the sensitivity of each MRI technique to differentiate between IVD characteristics in people with distinct training histories, IVD variables in each athletic group were compared to the sedentary referent group using unpaired An alpha level of 0.05 was considered statistically significant. The “R” statistical environment (version 2.10.1) was used for all analyses.As previously reported ,10, the In comparison with the sedentary group, higher water content by Dixon imaging of the IVD was detected in the long-distance runners, but not in groups with other training histories, as shown in r = 0.66, p < 0.001) regarding nucleus/annulus ratio. For Dixon imaging, the whole IVD and the nucleus correlated only weakly  with the T2-time and the T2w signal, as shown in There was a strong correlation between T2-mapping and T2w imaging regarding whole IVD and a moderate correlation  were used to characterize the IVDs in a young, asymptomatic, population with different training histories. Compared with T2w imaging, T2-mapping was the most sensitive technique to detect IVD changes. While there was a good correlation between the T2-mapping and the T2w imaging technique, only T2-mapping detected differences associated with physical activity history in cyclists, joggers and long-distance runners, compared to the sedentary referents. Additionally, only T2-mapping consistently distinguished between Pfirrmann grades 1 and 2.To our knowledge, this is the first work that evaluated the feasibility of the Dixon imaging technique to characterize IVD hydration. As shown in this study, long-distance runners presented significantly higher water content than the other groups. All groups displayed differences in the T2-value, but only in the long-distance runners did the IVD changes correspond to an increased water signal. The Dixon images did not display large differences in the water content between nucleus pulposus and annulus fibrosus. In fact, the images displayed only a slow variation across the IVD, contrary to the T2-maps and T2w images that display large drops at the outer edges of annulus fibrosus where the water is strongly bound to the extracellular matrix. This can be explained by Dixon imaging only detecting the water content without reflecting the structure of the IVD matrix as both T2 contrast techniques do. Moreover, Dixon imaging did not correlate with the Pfirrmann scoring system or with the other MRI techniques. Hence, the technique characterized aspects of the IVD structure which complemented the information obtained by the other techniques. Previous studies on the impact of physical activity and inactivity on the spine in an asymptomatic population report significant differences in IVD height relative to the vertebral bodies in long-distance runners ,10. The IVD images generated with T2-mapping display the water content of the IVD . The T2-In this study, the whole IVDs were delineated in addition to five sub-regions, the central nucleus and the anterior and posterior annulus. Current MRI technology cannot produce images that can precisely separate nucleus from annulus. Therefore, it is possible that nucleus tissue was incorporated in the anterior and posterior subregions, labelled as annulus tissue. Anatomical-based manual segmentation was impractical for a study of over 100 patients using three MRI techniques measuring six IVD levels (909 disks). Therefore, multiple sagittal slices were segmented in five subregions . Since tAmong the three quantitative techniques, T2-mapping best reflected changes in IVD degeneration, according to the Pfirrmann scoring system. Most importantly, T2-mapping characterized IVD differences in individuals with different training histories. The Dixon imaging technique identified significantly higher water content in the IVDs of long-distance runners compared to the other training groups, probably associated with IVD hypertrophy. Additionally, Dixon displayed a weak correlation with the Pfirrmann scale and the other MRI techniques. Hence, Dixon may present information on new aspects of the IVD, irrespective of matrix changes and add complementary information to the assessment and understanding of the biology of the IVD.


Atrial fibrillation (AF) is a frequent finding in HFpEF. However, its association with invasive haemodynamics, imaging parameters and outcome in HFpEF is not well established. Furthermore, the relevance of AF subtype with regard to outcome is unclear. This study sought to investigate the prognostic impact of paroxysmal and persistent AF in a well‐defined heart failure with preserved ejection fraction (HFpEF) population.Between 2010 and 2016, 254 HFpEF patients were prospectively enrolled. All patients underwent echocardiography as well as left and right heart catheterization. Patients without contraindications underwent CMR including T1 mapping. Follow‐up and outcome data were collected. Patients with significant coronary artery disease were excluded.P = .003), NYHA functional class (P = .040), left and right atrial size , cardiac output (P = .002) and COPD (P = .034). After a median follow‐up of 23 months (interquartile range 5‐48), 92 patients (36%) reached the primary end point defined as hospitalization for heart failure or cardiovascular death. By multivariate Cox regression analysis, only persistent AF (P = .005) and six‐minute walk distance (P = .011) were independently associated with the primary end point.A total of 153 patients (60%) suffered from AF, 119 (47%) had persistent and 34 (13%) had paroxysmal AF. By multiple logistic regression analysis, persistent AF was independently associated with NT‐proBNP (Sixty percent of our HFpEF patients suffered from AF. Persistent but not paroxysmal AF was strongly associated with event‐free survival and was independently related to NYHA functional class, serum NT‐proBNP, atrial size, cardiac ouput and presence of COPD. The same holds true for atrial fibrillation (AF), which may occur independently from heart failure, but is frequently linked to it.Increasing left ventricular stiffness is accompanied by LA remodelling, which corresponds to the development of LA fibrosis.The present study was designed to investigate the prevalence of paroxysmal and persistent AF in a well‐defined prospective HFpEF cohort and relate it with clinical, imaging and invasive haemodynamic parameters, and with event‐free survival.22.1This was a prospective observational study performed at the Medical University of Vienna. Between December 2011 and November 2016, consecutive patients with suspected HFpEF were invited to participate. The local Ethics Committee approved the study protocol (EK No. 796/2010). All participants gave written informed consent.2.2HFpEF was diagnosed according to the Guidelines of the European Society of CardiologyAtrial fibrillation lasting <7 days was defined as paroxysmal AF and AF ≥7 days as persistent AF. AF lasting longer than one year was defined as longstanding persistent AF.99mTc‐3,3‐diphosphono‐1,2‐propanodicarboxylic acid scintigraphy and, if necessary, endomyocardial biopsy.Reasons for exclusion were invasively confirmed significant coronary artery disease, moderate to severe and severe aortic and mitral valve heart disease irrespective of aetiology as evaluated by transthoracic echocardiography.2.3Patients were prospectively followed by ambulatory visits including electrocardiograms and telephone calls at 6‐month intervals. Additionally, electrocardiograms and/or Holter monitoring was performed in case of palpitations. The main outcome measure was a combined end point consisting of hospitalization for heart failure or death from cardiovascular causes. End points were ascertained by follow‐up visits and phone calls and adjudicated by our internal adjudication committee consisting of DB and JM, who were blinded to patient characteristics as well as imaging and haemodynamic data.2.42.4.12, regurgitant volume ≥60 mL/beat).All transthoracic echocardiography studies were performed by board‐certified physicians using scanners such as GE Vivid 7 and Vivid S70 . Left ventricular ejection fraction was assessed by biplane Simpson technique. Transmitral inflow was measured by pulsed wave Doppler, septal and lateral e' by pulsed wave tissue Doppler. Signs for severe mitral regurgitation were a vena contracta jet width ≥0.7 cm with a large central regurgitant jet (area >40% of left atrium) or a wall impinging jet of any size accompanied by corresponding quantitative measurements  on a 50 metre indoor track was used. For statistical analysis, the percentage of the predicted 6MWD ([6MWD/predicted 6MWD] ×100) was calculated.2.4.3For right heart catheterization, a 7F Swan‐Ganz catheter (Baxter) was inserted via a jugular or femoral access. Pressures were documented as a digitized mean over the whole respiratory cycle including at least eight consecutive heart cycles using CathCorLX (Siemens AG). In addition to mean pulmonary artery wedge pressure, the systolic, diastolic and mean pulmonary artery pressures were documented. Left ventricular end‐diastolic pressure was manually checked in each patient.Cardiac output was measured by thermodilution. Furthermore, the transpulmonary gradient was calculated by subtracting wedge pressure from mean pulmonary artery pressure. Diastolic pulmonary vascular pressure gradient was defined as the difference between diastolic pulmonary artery pressure and pulmonary artery wedge pressure during a pullback. Pulmonary vascular resistance was calculated by dividing transpulmonary gradient by cardiac output. Following right heart catheterization, coronary angiography was performed in the same procedure.2.4.42 were excluded. CMR was only performed when the heart rate was below 90/min. CMR examinations were performed according to standard protocolscardiac magnetic resonance imaging examinations were performed on a 1.5 Tesla scanner . Patients with an estimated glomerular filtration rate of <30 mL/min/1.73 mMOLLI‐extracellular volume (ECV) was calculated according to the following formulaT1 myo pre/T1 blood pre indicates myocardial/blood native T1 times, and T1 myo post/T1 blood post indicates T1 times of myocardium/blood 15 minutes after gadobutrol application.2.4.5P < .05. Continuous variables are expressed as mean ± standard deviation or as median and interquartile ranges. Categorical variables are presented as numbers and per cent. Continuous variables were compared using the Mann‐Whitney U test, for dichotomous variables the chi‐square test was applied. Parameters were divided into clinical, echocardiographic, CMR and invasive haemodynamic categories. To define factors associated with persistent AF, univariate logistic regression analysis was calculated for each parameter. Significant parameters then entered the multivariate analysis in the respective parameter category. Significance limit to enter this model was P < .05.IBM SPSS version 21 (SPSS Inc) was used for statistical analyses. For all tests, the significance level was set to To assess associations with event‐free survival, separate univariate Cox regression models were performed for all baseline parameters, followed by a multivariate Cox regression model for each parameter category with stepwise forward selection. The significance level for a predictor to enter the model was 0.05, and the limit to stay in the model was 0.1. In a final step, all parameters associated with outcome within the respective group were entered into an additional combined pooled multivariate model using forced entry. Kaplan‐Meier plots (log‐rank test) were applied to verify the time‐dependent discriminative power of paroxysmal and persistent AF on cardiovascular outcome.33.1Between December 2010 and November 2016, 296 HFpEF patients were screened for enrollment. After exclusion of 42 patients , 254 patients were prospectively enrolled. All patients with paroxysmal AF were in sinus rhythm at the time of CMR scan and invasive haemodynamic assessment. On the other hand, all patients with persistent AF were in AF at the time of CMR and invasive haemodynamic assessment.P = .040), presented with worse exercise capacity (P = .026), more frequent COPD (P = .006), worse functional status (P = .003) and higher levels of NT‐pro BNP and gamma‐glutamyl‐transferase . Regarding medical therapy, persistent AF patients were less often on 3‐hydroxy‐3‐methyl‐glutaryl‐coenzyme A reductase inhibitors (P = .023) and compared to patients with paroxysmal AF they were also less often on specific antiarrhythmic drugs (P < .001). Echocardiography as well as CMR revealed more pronounced LA, right atrial and right ventricular dilatation in persistent AF patients . Furthermore, by CMR these patients had worse right ventricular ejection fractions (P < .001) and higher levels of ECV (P = .007).Baseline characteristics are summarized in Table At study enrollment 153 (60%) patients presented with AF. A total of 119 patients (47%) had persistent AF. Of these, 116 (97%) had been diagnosed with AF at least one year prior to enrollment and thus were in longstanding persistent AF. A total of 34 patients (13%) had paroxysmal AF. During the course of the study, four patients developed a new onset of paroxysmal AF. None of these patients experienced a cardiovascular event. Eight patients developed new (direct) onset of persistent AF. Two of them patients experienced a cardiovascular event. However, no close temporal correlation of persistent AF onset and cardiovascular event was observed. In one case, the event of left sided heart failure was 24 months before persistent AF onset, in the other case it was vice versa. Only one conversion from paroxysmal to persistent AF was observed. This patient suffered an episode of left‐sided heart failure 14 months prior the conversion from paroxysmal to persistent AF. Thus, the cumulative incidence of AF over the whole study duration was 165 (65%) with 127 patients (50%) in persistent AF and 38 patients (15%) in paroxysmal AF. Only 16 patients of the AF cohort were on specific antiarrhythmic drugs, namely 13 on amiodarone, 1 on dronedarone and 1 on flecainide. One patient was switched from flecainide to amiodarone during the course of the study.3.2P = .034), New York Heart Association (NYHA) functional class (P = .040), serum NT‐proBNP (P = .003), LA (P = .022) and right atrial size (P < .001) and cardiac output by CMR (P = .002).The association of clinical, imaging and invasive haemodynamic parameters with persistent AF was tested by uni‐ and multivariate logistic regression analyses Table . By mult3.3After a median follow‐up of 23 months (interquartile range 5‐48), 92 patients (36%) reached the combined end point. In nine patients, cardiovascular death was the first event and 83 were hospitalized for acute heart failure.P < .001). This was not the case for patients with paroxysmal AF , 6MWD (P < .001) and reduced estimated glomerular filtration rate (P = .030) were significantly associated with outcome in the multivariate analysis. Among invasive haemodynamic parameters, only diastolic pulmonary arterial pressure (P = .001) and, among imaging variables, right ventricular size (P < .001) and function (P = .017) were independently related to event‐free survival.Table P = .005) and 6MWD (P = .011) remained independently associated with cardiovascular outcome.However, after pooled multivariate Cox regression analysis, only persistent AF (4In the present study, persistent AF was found in nearly 50% of patients. Persistent but not paroxysmal AF was independently associated with event‐free survival. Furthermore, persistent AF was closely related to important markers of disease severity such as NYHA functional class, serum NT‐proBNP, atrial dilatation, cardiac output and presence of COPD.Several prior studies have addressed the prognostic influence of AF on HFpEF.4.1We identified several parameters independently associated with persistent AF. By multivariate analysis, NYHA functional status, serum levels of NT‐proBNP, atrial dilatation, low cardiac output and COPD were associated with persistent AF Table . ImpaireCompared with published reference values,4.2Our data indicate a strong and independent association of persistent AF with cardiovascular outcome in HFpEF. Most studies that investigated AF and heart failure included both HFpEF and heart failure due to reduced ejection fraction populations and thus compared AF in HFpEF with AF in heart failure in reduced ejection fraction rather than with HFpEF in sinus rhythm.Our findings are in line with a previous large, population‐based study that showed AF to be associated with increased mortality after adjustment for age, sex, body size, kidney function, hypertension, COPD, angiotensin receptor‐, ß‐blocker and statin use.4.3This was a single‐centre study, thus a centre‐specific bias cannot be ruled out although single‐centre studies have several advantages such as homogenous patient selection, continuous workflow and constant follow‐up. As continuous electrocardiogram monitoring by implantable loop recorders was not provided, asymptomatic AF episodes may have been missed and real‐life burden of AF episodes might be higher. In incident AF, we observed a high rate of direct onset of persistent AF. This rate may be overestimated as persistent AF might be preceded by asymptomatic and not documented short episodes of paroxysmal AF. The fact that no differences with regard to baseline characteristics and outcome were observed between patients in SR and with paroxysmal AF may be due to the low rate of paroxysmal AF in the present study. Functional imaging parameters such as ejection fraction and cardiac output on CMR may be influenced by heart rate and irregular heart rhythm. However, baseline heart rate was 73/min in persistent AF patients and did not differ significantly from patients with paroxysmal AF or SR. The cross‐sectional observational study design limits conclusions about cause—effect relationships.5AF is a frequent finding in HFpEF and may affect more than 60% of patients in the course of their disease. In the present study, persistent AF was the predominant AF subtype. It was closely and independently related to event‐free survival and related to NYHA class, NT‐proBNP, atrial size, cardiac function and COPD. Up to now, no specific treatment has been approved for HFpEF patients.None.RS and JM were responsible for concept and drafting of the manuscript; FD, AAK, SA, CB, CZ‐T, MK, LF FXR, and DB performed data collection, interpretation and approved the final version.


Accurate assessment of left ventricular (LV) systolic function is important after coronary artery bypass grafting (CABG). LV ejection fraction (LVEF) is conventionally used to evaluate LV systolic function; deformation parameters can be used to detect subtle LV systolic dysfunction. It is unclear whether an incised pericardium without sutures during CABG could affect LV morphology and function. We investigated the effect of pericardial incision on LV morphology and systolic function during CABG.Intraoperative transesophageal echocardiography was performed in 27 patients during elective off-pump beating heart CABG 5 min before and after pericardial incision. LV longitudinal and mid-cavity transversal diameters, sphericity index, volumes, and LVEF were measured. LV global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain (GRS), and twist obtained by two-dimensional speckle tracking echocardiography were measured simultaneously.P < 0.001) immediately after pericardial incision. The GLS, GCS, and twist significantly decreased, while the GRS notably increased (P < 0.001). The LV volumes and LVEF remained unchanged.LV mid-cavity transversal diameter increased, while the LV sphericity index decreased (Pericardial incision immediately transformed LV morphology from an ellipsoid to sphere, with decreased longitudinal and circumferential strain and twist, and increased radial strain, while LVEF remained unchanged. This should be considered when evaluating LV systolic function in patients after CABG. As a coronary artery revascularization therapeutic strategy, coronary artery bypass grafting (CABG) can effectively improve the myocardial blood supply for complex coronary artery disease. Echocardiography is an optimal, noninvasive method for precisely evaluating left ventricular (LV) systolic function, which has an important role in estimating the therapeutic effect in patients after CABG.LV ejection fraction (LVEF) is conventionally used as a marker of LV systolic function. Deformation parameters obtained by two-dimensional speckle tracking echocardiography (2D STE) can sensitively detect subtle LV dysfunction at an early stage, LV global longitudinal strain (GLS), in particular, appears to be a more robust parameter and has incremental value in patients referred for cardiac surgery including CABG –6.The pericardium is often incised during CABG without sutures after the surgery, which may affect ventricular morphology and systolic function. Unsworth et al.  reportedwww.syntaxscore.com) [Patients who underwent elective off-pump beating heart CABG between January 2019 and June 2019 in our hospital were consecutive recruited for this study. Patients were excluded if they had a prior history of cardiac surgery, a combination of other cardiac surgery, pericardial disease, arrhythmia, or contraindication to TEE. All patients underwent coronary angiography before CABG and their results were assessed by experienced cardiologist. The SYNTAX score was calculated using the SYNTAX score algorithm (ore.com) . All proAfter induction of anesthesia, an intraoperative TEE examination was performed 5 min before and after pericardial incision during the surgery using the CX50 ultrasound system  equipped with an X7-2t transducer. The TEE probe was inserted into the patient’s esophagus to obtain mid-esophageal 4-chamber (ME 4C), 2-chamber (ME 2C), and long-axis (ME LAX) views, and into the patient’s stomach to obtain transgastric basal, mid-papillary, and apical short-axis views. The basal level was identified by the mitral valve, and the apical level was defined as proximal to the level with ventricular cavity obliteration at end-systole. All manipulations of image acquisition were performed according to the recommendations from the American Society of Echocardiography . StandarAll data were transferred to a workstation for further offline analysis using the Qlab software package . LV longitudinal and mid-cavity transversal diameters were measured at end-diastole in ME 4C view, and the LV sphericity index (LVSI) was defined as the ratio of the LV longitudinal to mid-cavity transversal diameter . The LV Deformation parameters, including LV GLS, global circumferential (GCS), and global radial strain (GRS), were measured using 2D STE. Endocardial contour was manually adjusted to optimize tracking when necessary, and patients with inadequate tracking, which was defined by the mismatch between the region of interest and the myocardium during dynamic loops, of more than two segments were excluded from the study. The degree of LV peak systolic apical and basal rotation was measured at the apical and basal levels, respectively. Twist was defined as the net difference between apical and basal rotation. The absolute change rates of LV GLS, GCS, GRS, twist, and LVSI were calculated as the percentage of the difference in these parameters before and after pericardial incision divided by that before pericardial incision. A significant reduction of GLS was defined as a decrease of GLS by > 15% immediately after pericardial incision .The RV basal, mid-cavity transversal, and longitudinal diameters were measured at end-diastole in ME 4C view, and the RV sphericity index was defined as the ratio of the RV longitudinal to mid-cavity transversal diameter . The RV Hemodynamic monitors were supplemented by radial arterial and central venous catheters. Hemodynamic parameters including systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MAP), central venous pressure (CVP), and heart rate (HR) were recorded simultaneously at the time of image acquisition.Intra- and inter-observer agreement for global strain and rotation were examined in 10 randomly selected patients. The same observer, who was blinded to the initial measurements, repeated the measurements to assess intra-observer agreement after more than 4 weeks had elapsed. And another independent observer repeated the measurements twice to assess inter-observer agreement.t-test. The Pearson coefficient was used for correlation analysis. The relationship between the change rate of GLS and continuous variables was analyzed using simple linear regression analysis. Intra-observer and inter-observer agreement analyses of global strain and rotation were assessed using Bland-Altman analysis in 10 randomly selected patients. A P-value < 0.05 was considered significant.Statistical analyses were performed using SPSS 25.0 . Normality plots with tests were performed using the Shapiro–Wilk test. Categorical data are presented as frequencies and percentages, normally distributed data as mean ± SD, and non-normally distributed data as median and interquartile range. Comparisons of continuous variables before and after pericardial incision were made using the paired Student t-test or Wilcoxon test, as appropriate. Comparisons of SYNTAX score between patients with and without reduction of GLS by > 15% were made using the independent Student n = 1) and transgastric short-axis views (n = 4). Finally, 27 patients  were enrolled in the analyses , while the LV sphericity index significantly decreased immediately after pericardial incision (P < 0.001), and the posterior and relative wall thicknesses increased , while the LV volumes and LVEF remained unchanged. Meanwhile, the reduction of LV twist was accompanied by decreased apical and basal rotation , and the change rate of GLS was significantly and inversely correlation with the SYNTAX score .In the 27 patients, there were 16 (9.9%) views were manually adjusted to optimize the tracking of LV myocardium. After pericardial incision, LV GLS and GCS decreased, and the GRS increased simultaneously (P < 0.001).Seventeen patients had a significant reduction of GLS by > 15% immediately after pericardial opening, and the SYNTAX score was lower in these patients than in the other 10 patients with nonsignificant variability of GLS , while the RV fractional area change remained unaltered, which indicated that the right ventricle became more round in shape (Table The RV mid-cavity transversal diameter significantly increased and the RV sphericity index decreased (pe Table .Table 4Results of the intra-observer and inter-observer agreement analyses of global strain and rotation are presented in Table In the present study, we found that the pericardial incision can immediately induce the obvious change of LV morphology and contractile pattern. LV morphology changed from an ellipsoid to a sphere, and the relative wall thickness increased immediately after pericardial incision. Additionally, LV deformation parameters markedly changed with a reduced LV global longitudinal and circumferential strain and twist, and an increased global radial strain; however, LV volumes and ejection fraction remained unchanged.The pericardium maintains the anatomic position of the heart and limits its displacement through ligaments; besides, the relatively inelastic parietal pericardium retracts when it is cut, indicating that it exerts pressure on the underlying myocardial chambers –14. TherTo date, the existing researches has mainly focused on the influences of pericardial incision on RV. However, only a few studies have researched the effect of the pericardium on LV morphology and systolic function. Tanaka et al.  reportedOur study revealed the change of LV morphology from an ellipsoid to sphere after pericardial incision in the patients with CABG, as well as the reduced LV global longitudinal and circumferential strain, reduced twist and increased global radial strain. In the normal heart, pericardial incision may lead to the change of LV preload, filling pressure, and blood pressure . HoweverThe LV myocardium is made up by the three-dimensional arrangement of the myocardial cells, which are supported loosely within a continuous matrix of fibrous tissue. Groups of myocytes are surrounded by condensations of the endomysial weave, thus forming the perimysium, which aggregates a meshwork of myocytes into the so-called myofibers , 23. ForDeformation parameters change in different directions during the progression of myocardial disease, however, its instantaneous change in this investigation could not be attributed to this. The paradoxical phenomenon in our study that decreased longitudinal and circumferential shortening with preserved ejection fraction is commonly seen in patients with hypertension –29. As tLeft ventricular ejection fraction is determined by both myocardial strain and wall thickness, which can increase with the increased strain and wall thickness, and even if the strain decreases, it could keep constant because of increased wall thickness –32. WallWe could not provide a definite mechanism for the change in contraction pattern in our study, we speculated that the variations in sheet dynamic and geometry caused by the changes in the arrangement of myocytes due to lack of pericardial constraints may play a potential role. Although we did not find significant correlation between wall thickness and ejection fraction, we found the decreased circumferential strain was corelated with the increased radial strain. Therefore, we speculated that the increased radial strain may offset the reduction in longitudinal and circumferential shortening and twisting, allowing for an unchanged ejection fraction.LV global longitudinal strain as a valuable parameter of LV systolic function has been used in clinical application with a better reproducibility, and it could be a predictor of prognosis and therapeutic effect in patients after CABG , 35, 36.Transesophageal 2D STE was used to evaluate LV systolic function during CABG in our study, which showed a high degree of intra-observer and inter-observer agreement. Intraoperative TEE is one of the cornerstones for evaluating immediate changes in myocardial function and helps provide critical information during cardiac surgery. Myocardial strain imaging derived from speckle tracking using TEE is a feasible, reproducible method for assessing LV deformation, which has good agreement with transthoracic strain imaging –40.In the present study, LV morphology and systolic function were investigated only immediately after pericardial incision, and a long-term follow-up was not performed to assess whether any aspect of recovery of contractile patterns would occur because we could not eliminate the interference of myocardial revascularization after CABG. However, the depressed RV systolic function after pericardial incision did not recover within 1 month after CABG in patients without interference of the right coronary artery,  suggestiThis study has several limitations. First, the correlation between the lower SYNTAX score and the reduction of GLS > 15% was analyzed based on the limited sample size in the present study. Therefore, a further study with adequate samples from multicenter should be designed to verify these findings. In addition, the invasive LV filling pressure and pulmonary capillary wedge pressure were unable to be obtained during the off-pump beating heart CABG, which may provide the pathophysiological basis for LV modification. However, we provided the LV diastolic indices by noninvasive echocardiography, such as mitral E, mitral A, E/A, septal e’, lateral e’ and average E/e’, and tricuspid regurgitation velocity, which can indirectly reflect the LV filling pressure. Furthermore, we measured the tricuspid regurgitation velocity using ME 4C, and its value may be influenced by the angle of ultrasound beams and may be different from that measured by TTE; however, the present study highlighted its change after pericardial incision and the difference may not influence the research objective. Moreover, it is also worth mentioning that we obtained the results of this work with the Qlab software, which was originally developed for transthoracic images. The absolute values of strain and rotation in the present study may not be identical to the values by transthoracic echocardiography. Currently, there are no recognized standards for the definition of a reduction in LV global systolic function using GLS. We referred to the standard on cancer therapy from the American Society of Echocardiography, which recommended that a reduction in GLS > 15% from baseline is very likely to be abnormal during chemotherapy. The results should be further analyzed using special standards in the future.Pericardial incision immediately transformed LV morphology from a prolate spheroid to a sphere during CABG, the LV contractile pattern changed with a decrease in longitudinal and circumferential shortening and twisting, and radial thickening increased despite an unchanged ejection fraction. The altered global longitudinal strain resulting from pericardial incision should be taken into account when evaluating LV systolic function in patients after CABG, especially in patients with a lower SYNTAX score.


To provide an overview of the potential iatrogenic causes of acute decompensated heart failure (AHF) and an evidence-based management strategy to address this.As the heart failure (HF) population continues to age and become burdened with greater comorbidities and polypharmacy, patients become more susceptible to the iatrogenic precipitants of HF. The following clinical scenarios are familiar to clinicians, but the sequelae to AHF are often unanticipated: HF medications withdrawn during an intercurrent illness and not restarted, cardiotoxic therapy prescribed for cancer without timely and regular monitoring of left ventricular function, excessive intravenous fluids administered for sepsis or postoperatively, a blood transfusion volume not adjusted for body weight, iatrogenic anaemia that goes unnoticed or an inappropriate type of pacemaker implanted in a patient with underlying left ventricular systolic dysfunction.Iatrogenic decompensated HF is a phenomenon that is infrequently documented in the literature but increasingly confronted by clinicians of all specialties. It is associated with a high mortality and morbidity rate. By having greater awareness of these triggers, iatrogenic AHF should be one that is prevented rather than managed when it occurs. One of the major challenges of managing acute decompensated heart failure (AHF) is identifying and addressing the precipitating factors, which are often multifactorial. The European Society of Cardiology (ESC) guidelines for heart failure (HF) emphasize on recognizing intrinsic cardiovascular triggers  and extrinsic insults such as infection and respiratory and renal dysfunction . HoweverIt is well-established that in patients with HF with reduced ejection fraction (HFrEF), renin-angiotensin-aldosterone system inhibitors (RAASi), e.g. ACE inhibitors (ACEi) and angiotensin-receptor blockers (ARBs), beta-blockers, mineralocorticoid-receptor antagonists (MRAs), the more recent combination sacubitril/valsartan, and sodium-glucose transport protein 2 inhibitors (regardless of diabetes status) markedly improve survival and reduce HF hospitalizations against placebo , 5. The RAASi is often misunderstood as a nephrotoxic drug. Introduction of the UK electronic acute kidney injury alert  system has exacerbated this anxiety, and a reflex cessation of RAASi amongst hospital and community practitioners occurs when a small serum urea or creatinine (sCr) rise is seen . RAASi iThe rationale follows for beta-blockers: the benefits are higher with increasing severity of HFrEF but with greatest risk when stopped. This is usually due to anxiety about its negative inotropic effects or in context of hypotension . Unless Even planned withdrawal of HF medications can lead to AHF in apparently asymptomatic chronic HF. In a prospective randomized trial of patients with stable dilated cardiomyopathy, MRA, beta-blockers and RAASi were sequentially weaned off. However, even with a controlled withdrawal of these medications, it resulted in a substantial fall in the left ventricular ejection fraction in 40% of patients, which was detected within 8 weeks . This em2 anthracycline, while surveillance should be more frequent in high-risk patients. After completion of treatment, follow-up scans should be arranged at 1 and 5 years, and sometimes continued longer depending on the patient’s initial risk stratification. If clinical HF develops during or following treatment, it should be treated according to current ESC guidelines for HF with the initiation of cardio-protective medications such as ACEi and beta-blockers, usually prescribed together. Interruption or continuation of cancer treatment will depend on the risks versus benefits, determined by factors such as the degree of left ventricular systolic dysfunction (LVSD), cancer prognosis and responsiveness to the cancer therapy [Direct myocardial toxicity and fluctuations in afterload and preload are common mechanisms behind drugs implicated in AHF. An established phenomenon is cancer therapy–related cardiac dysfunction, whereby left ventricular ejection fraction (LVEF) falls by > 10 to < 53%, manifesting acutely or delayed, even as long as 20 years after completion of therapy . Anthrac therapy , 22.An estimated 50% of HF patients aged ≥ 65 suffer from at least 5 comorbidities. This results in greater exposure to other drugs such as steroids for chronic obstructive pulmonary disease, non-steroidal anti-inflammatory drugs (NSAIDs) for osteoarthritis and pioglitazone for type 2 diabetes mellitus (T2DM) . These mAnother comorbidity that frequently coexists is atrial fibrillation. For rate control, non-dihydropyridine calcium channel blockers should be avoided in HFrEF due to their negative inotropic activity and association with AHF . For rhyFinally, AHF can occur postoperatively and one explanation may be the general anaesthesia. Inhalational agents, e.g. isoflurane and propofol, can lead to myocardial depression. Ketamine, a non-competitive NDMA glutamate receptor antagonist, exhibits both negative inotropy and sympathetic activation which may counteract the former. Nevertheless, in patients with significant baseline LV impairment, it can still decompensate HF .The first Surviving Sepsis Campaign initiative recommended rapid intravenous fluid administration of up to 30 ml/kg to restore BP from third-space fluid losses . HoweverYet, fluid management will only be as accurate as the clinical evaluation of fluid status which can be challenging and contradictory between clinicians. Jugular venous pressure can be subjective and chest radiographic signs of HF can be non-specific , 40. To There is growing evidence that the use of N-terminal pro-B-type natriuretic peptide (BNP) and ultrasonography can help in fluid assessment. With serial BNPs, a falling level correlates well with a trend towards euvolaemia . EchocarHeart Failure, CKD and hypertension may be associated risk factors with transfusion-related circulatory overload (TACO) which manifests as pulmonary oedema within 6 h of transfusion and is associated with raised BP, BNP and a high mortality . Small fSevere anaemia can also worsen LVOTO as described above, but it is better known for unmasking myocardial ischaemia and causing high-output heart failure . AnaemiaLess commonly, the low systemic vascular resistance from a systemic arterio-venous shunt can similarly activate the systematic neurohormonal system. The degree of CO augmentation depends on the shunt size and magnitude of flow. Nephrologists should be wary that dialysis patients are at further risk of HF due to the additive effects of co-existing anaemia . An arteA complication more familiar to cardiologists is pacing-induced cardiomyopathy defined by > 10% reduction in LVEF after pacemaker implantation (having excluded other causes). There are several mechanisms behind this . FirstlyIatrogenic decompensated HF is a phenomenon that is infrequently documented in the literature but increasingly confronted by clinicians of all specialties. It is associated with a high mortality and morbidity rate. As the HF population continues to age and become burdened with greater comorbidities and polypharmacy, patients become more susceptible to the iatrogenic precipitants of HF. Understandably, IAHF is sometimes unavoidable when concomitant renal dysfunction deteriorates, and the need to stop RAASi outweighs its benefit, or when an overarching concurrent illness develops, such as cancer which necessitates cardiotoxic chemotherapy. However, as long as clinicians are wary of the potential sequelae of AHF from these acts of commission or omission, we can anticipate and act promptly with timely monitoring of LV function and initiation of HF medications before AHF ensues. The already complex management of HF can be further complicated when a patient becomes acutely unwell with sepsis or significant anaemia. An effective yet simple approach would be regular clinical assessment integrated with the use of pulmonary ultrasound and biochemical markers such as BNP. Above all, by having greater awareness of these iatrogenic triggers, this phenomenon should be one that is prevented rather than managed when it occurs.


Chemotherapy-induced cardiotoxicity is a known condition, however, bortezomib and melphalan do not typically cause cardiotoxicity. With the rise in the use of newer chemotherapeutic agents, it is important to identify and understand the cardiac implications of chemotherapeutic agents. We present a case of a 70-year-old female with no known significant cardiac history presenting with partially reversible cardiomyopathy with initial presentation only being as sinus tachycardia. Multiple myeloma (MM) is a neoplastic proliferation of plasma cells . The useA 70-year-old female with a diagnosis stage II multiple myeloma (MM) by international staging system for multiple myeloma, high risk according to mSMART (Mayo stratification of myeloma and risk-adapted therapy) classification, on chemotherapy with lenalidomide, bortezomib, and dexamethasone presented to our office for a pre-stem cell transplant appointment. In addition to multiple myeloma, she had a past medical history of hyperlipidemia and anxiety. She denied cigarette or alcohol use. She did not have any known cardiovascular history. Family history was significant for myocardial infarction in a brother at the age of 35 and myocardial infarction in her mother at the age of 50. A routine echocardiogram obtained one month prior to stem cell transplant revealed a normal left ventricular ejection fraction of 62% with a resting tachycardia Video . Two monShe was admitted to the hospital for an autologous stem cell transplant. Her vitals were significant for a heart rate (HR) of 124 bpm, temperature (T) 37 C, respiratory rate (R) 16/min, and blood pressure (BP) 120/69 mmHg. Baseline electrocardiogram (EKG) at the time of admission showed sinus tachycardia with a heart rate of 113 bpm without any ST-T abnormalities  obtained at the time was elevated at 12,436 pg/ml. A chest X-ray showed pulmonary edema and small bilateral pleural effusions (Figure The patient was initiated on metoprolol tartrate 25 mg twice a day, ivabradine 5 mg twice a day, and losartan 25 mg daily to control tachycardia and medical management of systolic heart failure with reduced ejection fraction. IV furosemide was given for pulmonary congestion while hospitalized. She was discharged on metoprolol succinate 200 mg daily, ivabradine 5 mg twice a day, losartan 25 mg daily, and furosemide 20 mg daily.Two months later, during her follow-up visits, her heart rate remained between 70-80 bpm. A repeat echocardiogram performed four weeks later showed partial resolution of heart failure with a visually estimated ejection fraction of 45-50%.Heart failure in this patient is believed to be due to bortezomib and exacerbated by melphalan. Sinus tachycardia and heart failure were attributed to the use of these agents since she had no sinus tachycardia before starting chemotherapy. This case demonstrates the rare adverse effects of bortezomib and melphalan when used concurrently.Bortezomib is a dipeptidyl boronic acid and has a role in worsening ischemic heart disease , 15. It Melphalan cardiotoxicity presents more commonly as atrial fibrillation and supraventricular tachycardia , but venCardiomyopathy in our patient was likely a result of the concurrent use of bortezomib and melphalan. Improvement of ejection fraction within four weeks of completion of treatment and starting medical management of heart failure shows reversibility. Sinus tachycardia, with the commencement of bortezomib, has not been observed in prior studies. We believe that even subtle signs such as sinus tachycardia should be given importance for early identification of cardiotoxicity. Thus, we recommend close monitoring of cardiac parameters in patients treated with bortezomib and melphalan.


Background: Non-invasive determination of liver iron concentration (LIC) is a valuable tool that guides iron chelation therapy in transfusion-dependent patients. Multiple methods have been utilized to measure LIC by MRI. The purpose of this study was to compare free breathing R2* (1/T2*) to whole-liver Ferriscan R2 method for estimation of LIC in a pediatric and young adult population who predominantly have hemoglobinopathies. Methods: Clinical liver and cardiac MRI scans from April 2016 to May 2018 on a Phillips 1.5 T scanner were reviewed. Free breathing T2 and T2* weighted images were acquired on each patient. For T2, multi-slice spin echo sequences were obtained. For T2*, a single mid-liver slice fast gradient echo was performed starting at 0.6 ms with 1.2 ms increments with signal averaging. R2 measurements were performed by Ferriscan analysis. R2* measurements were performed by quantitative T2* map analysis. Results: 107 patients underwent liver scans with the following diagnoses: 76 sickle cell anemia, 20 Thalassemia, 9 malignancies and 2 Blackfan Diamond anemia. Mean age was 12.5 ± 4.5 years. Average scan time for R2 sequences was 10 min, while R2* sequence time was 20 s. R2* estimation of LIC correlated closely with R2 with a correlation coefficient of 0.94. Agreement was strongest for LIC < 15 mg Fe/g dry weight. Overall bias from Bland–Altman plot was 0.66 with a standard deviation of 2.8 and 95% limits of agreement −4.8 to 6.1. Conclusion: LIC estimation by R2* correlates well with R2-Ferriscan in the pediatric age group. Due to the very short scan time of R2*, it allows imaging without sedation or anesthesia. Cardiac involvement was uncommon in this cohort. Chronic iron overload affects predominantly the liver, pancreas and heart, leading to systemic complications, including liver fibrosis, diabetes and cardiomyopathy ,2. StudiMeasurement of cardiac and liver iron concentration (LIC) by MRI is accurate and reproducible, and has become the test of choice ,9. SeverIn many institutions, R2 Ferriscan has been the standard method to measure LIC. These two methods have been previously compared in children employing breath holding and multiple slice acquisition for T2* . In thisWe conducted a single institution retrospective observational study on liver iron MRIs from April 2016 to May 2018. The study was approved by the local ethics committee (IRB STU 032016-009 10 June 2016) for retrospective analysis of MRI and clinical data, with a waiver of individual patient consent. Clinically indicated liver iron MRI studies were performed on a 1.5 T scanner  using a 32-channel torso coil. Free breathing T2 and T2* weighted images were acquired on each patient. For T2, transverse images were obtained via a multi-slice spin echo sequence with repetition time (TR) of 1000 ms over five acquisitions with echo times of 6, 9, 12, 15 and 18 ms. To cover the whole liver, 11 slices were acquired with a flip angle of 90 degrees, slice thickness of 6 mm, and gap of 6 mm. A saline bag (1L) was positioned over the patient’s left side to correct for signal changes. For T2*, transverse images were acquired via a single mid-hepatic slice fast gradient echo sequence with TR 13–25 ms and 10 echo times starting at 0.6 ms with 1.2 ms increments with 8 signal averages. The slice thickness was 20 mm, flip angle 30 degrees and in-plane resolution 2 × 2 mm. For occasional patients with T2* decay from qualitative viewing of greater than 6 ms, a second sequence was acquired to allow greater sampling of the decay at low iron concentrations. This sequence has 10 echo times starting at 2.3 ms and increases in 2.3 ms increments. There are three signal averages, a slice thickness of 10 mm, in-plane resolution 2 × 2 mm and a flip angle of 30 degrees.Myocardial T2* imaging was performed per hospital protocol for cases with severe iron overload. Images were acquired using a single short axis diastolic mid-ventricular slice fast gradient echo sequence with eight echoes starting at 2.6 ms with 2.6 ms increment with electrocardiogram (ECG) gating and breath holding when possible, or otherwise signal averages. The slice thickness was 10 mm, repetition time 21 ms, flip angle 30 degrees and in-plane resolution 1.2 × 1.2 mm with a black blood preparation pre-pulse.T2 images were commercially analyzed off-site at Resonance Health using Ferriscan analysis with a turnaround time of 2–3 business days. Quantitative T2* maps were calculated offline. T2* gradient echo images were fitted to a mono-exponential decay curve for data validation and noise filtration using Osirix MD software . Subsequent quantitative analysis was performed using cmr42 software . Multiple regions of interest (ROI) were drawn on T2* maps on homogenous regions within the right lobe of the liver parenchyma avoiding major vessels and bile ducts. Mean T2* values were converted to R2* using the formula R2*[Hz] = 1000/T2*[ms]. Then, LIC (in mg/g dry weight) was calculated using the equation: [Fe]R2* = 0.0254 × R2* + 0.202 . CardiacMean ± standard deviation was used to describe continuous variables. Agreement between the two methods was evaluated by linear regression and Bland–Altman analysis using 95% confidence intervals . A scattOne hundred and seven patients were included in this study . Mean agr2 = 0.88 and a correlation coefficient of 0.94 . Mean LIC by R2 was 8.9 ± 8.1 mg Fe/g dry weight . LIC by R2* was plotted against LIC by R2 in a linear fit with a regression slope of 1.01 ± 0.03, a y intercept of −0.8 ± 0.4,  of 0.94 . Bland–A of 0.94 .Agreement between the two methods was strongest for LIC ≤ 15 mg Fe/g dry weight. More scatter was observed with increasing LIC, specifically LIC > 15 mg Fe/g dry weight. Using LIC ≥ 15 mg Fe/g dry weight as the cutoff for severe iron overload ,12, R2* Twelve (11%) patients with severe liver iron loading underwent cardiac iron imaging and quantification using T2*. Two of these patients had T2* < 10 ms, consistent with severe cardiac iron overload .This study is a real-world experience comparing LIC estimation by free breathing R2* with R2 Ferriscan method in 107 patients who predominantly have hemoglobinopathies on chronic transfusion therapy. It demonstrates excellent agreement of LIC R2* with LIC R2 Ferriscan at clinically relevant LIC levels with low classification error rates. This strong agreement between the two methods has been demonstrated in separate cohorts of thalassemia and sickle cell anemia patients ,19. T2* R2 relaxometry analysis by Ferriscan is an FDA approved technique. It has high sensitivity and specificity at clinically important LICs . R2 FerrSickle cell and thalassemia patients comprised the majority of our cohort. It has been shown that distribution of hepatic iron is similar in these two diseases and remains comparable with iron chelation . The incCardiac involvement in our cohort of children and young adults was uncommon. This is probably due to the large proportion of sickle cell patients and to the relative younger age of this cohort. Chronically transfused thalassemia patients develop myocardial iron deposition many years before sickle cell patients on chronic transfusions . Mid-venOne limitation of this study is that no liver biopsies were performed. Although liver biopsy has long been considered the gold standard for measurement of LICs, this concept has been challenged secondary to its high sampling variability . In addiLIC estimation by R2* correlates well with R2 Ferriscan in the pediatric age group. Some scatter is observed at higher iron levels but with a low R2* classification error rate. The free-breathing R2* method is highly advantageous in children due to the very short scan time, which allows imaging of most young patients without sedation or anesthesia. Cardiac involvement in our cohort of children and young adults was uncommon.


Post-infarction perforation of the ventricular septum is recognized as a major complication of post-myocardial infarction. However, post-infarction ventricle dissection is seldom reported, as the ventricular shunt often accompanying this condition is a significant cause of cardiogenic shock. We encountered a rare case of ventricular dissection unaccompanied by a shunt, which caused a state of shock.A 67-year-old man was diagnosed with acute myocardial infarction with a left ventricular oozing rupture. The occlusion of the left anterior descending artery was aspirated, followed by drainage of the pericardial bleeding and hemostasis of the left ventricle. After 15 h, he presented with sudden cardiogenic shock requiring extra-corporeal membrane oxygenation. The transesophageal echocardiogram showed a left ventricular septal aneurysm. Five days later, he underwent an operation, in which a ventricular septal wall dissection with a tear-forming large pseudoaneurysm was found. The tear was closed with a patch. He was weaned off extra-corporeal membrane oxygenation the next day. Αfter 4 months, he was discharged in a stable condition.Recognizing and identifying the cause of cardiogenic shock after myocardial infarction is crucial to provide the best treatment and surgical approach. Ventricular septal dissection should be considered, in addition to the usual complications, such as possible papillary muscle rupture, cardiac rupture, and perforation of the interventricular septum. Post-myocardial infarction ventricular rupture is a major serious complication following myocardial infarction. The rupture usually penetrates the interventricular septum, forming a shunt, which leads to heart failure. In rare cases, a shunt is created by peeling and perforation of the interventricular septum, termed ventricular dissection –4. Howev2) level was 98% with 8 L/min of oxygen therapy. His chest radiography findings showed remarkable cardiomegaly with pulmonary congestion. The 12-lead electrocardiogram findings demonstrated sinus rhythm with ST elevation and poor R progression in leads V1–4. Laboratory findings showed that the cardiac enzymes, creatine kinase and creatine kinase-MB, were elevated at 196 and 17 IU/L (peak level of creatine kinase-MB), respectively, and reached 2223 and 14 IU/L 3 days later. Troponin I level was remarkably elevated at 19.26 ng/mL on admission. A median sternotomy was performed, and he underwent drainage of the pericardial bleeding and hemostasis of the left ventricular oozing rupture without cardiopulmonary bypass. A tissue-sealing seat was applied to the left ventricle epicardium using human fibrinogen, thrombin, and aprotinin. During surgery, we performed a transesophageal echocardiogram (TEE), which revealed a small slit formation of the ventricular septum; however, it showed no shunt between the right and left ventricles. The patient was transferred to the intensive care unit in a stable condition. A transthoracic echocardiogram showed akinetic regions of the large anterior segment and apex of the left ventricle. Although the slitted interventricle septum was depicted with fluttering motions, no shunt was indicated  was inserted, and he was taken to the catheter room. His angiogram findings revealed left anterior descending coronary artery occlusion with a thrombus that was aspirated immediately. Echocardiography revealed a pericardial effusion suggestive of left ventricular rupture, and he was referred to our unit for surgery. The patient had been consulting a local physician for hypertension, diabetes mellitus, and hyperlipidemia. He had a 47-year history of daily smoking. His blood pressure was 143/92 mmHg, and the pulse rate was 86 beats/min. His blood oxygen saturation (SpOThere have been many reports regarding post-myocardial infarction complications, such as left ventricular rupture, ventricular septal perforation, and papillary muscle rupture . Some reTo date, there are few anatomical and clinical reports of septal dissection without shunting from the interventricular septum after myocardial infarction. Furthermore, it is extremely rare for a case of ventricular dissection without a shunt to be shocked and successfully repaired surgically. Although the method of surgical repair is simple, anatomical and hemodynamic changes in the remaining interventricular septal pseudo-lumen aneurysm and related complications remain unknown and require close follow-up examination.Additional file 1.Video S1. A transthoracic echocardiogram after first surgery showing akinetic regions of the large anterior segment of the left ventricle and a color Doppler image showing the slitted interventricle septum with fluttering motions and no shunt.Additional file 2.Video S2. Intraoperative transesophageal echocardiogram showing a left ventricular septal aneurysm causing acute heart failure.


Echocardiography (echo) is widely used for right ventricular (RV) assessment. Current techniques for RV evaluation require additional imaging and manual analysis; machine learning (ML) approaches have the potential to provide efficient, fully automated quantification of RV function.An automated ML model was developed to track the tricuspid annulus on echo using a convolutional neural network approach. The model was trained using 7791 image frames, and automated linear and circumferential indices quantifying annular displacement were generated. Automated indices were compared to an independent reference of cardiac magnetic resonance (CMR) defined RV dysfunction (RVEF < 50%).P < .001). Magnitude of ML annular displacement decreased stepwise in relation to population‐based tertiles of TAPSE, with similar results when ML analyses were localized to the septal or lateral annulus . Automated segmentation techniques provided good diagnostic performance (AUC 0.69–0.73) in relation to CMR reference and compared to conventional RV indices (TAPSE and S′) with high negative predictive value (NPV 84%–87% vs 83%–88%). Reproducibility was higher for ML algorithm as compared to manual segmentation with zero inter‐ and intra‐observer variability and ICC 1.0 .A total of 101 patients prospectively underwent echo and CMR: Fully automated annular tracking was uniformly successful; analyses entailed minimal processing time  and no user editing. Findings demonstrate all automated annular shortening indices to be lower among patients with CMR‐quantified RV dysfunction (all This study provides an initial validation of a deep learning system for RV assessment using automated tracking of the tricuspid annulus. Conventional neural networks–based segmentation techniques have been applied to echo, though with focus primarily on left ventricular chamber size and systolic function quantification.This study examined RV functional assessment using a novel ML‐derived fully automated approach for RV quantification on routine 2D echo. The primary study aim was to determine the feasibility and reproducibility of automated ML algorithm for cardiac magnetic resonance (CMR) quantified RV dysfunction among a prospectively enrolled cohort of patients undergoing echo and CMR.22.12, ferromagnetic implants) were excluded. In all patients, comprehensive demographic data were collected using standardized questionnaires, including cardiac risk factors and medications. This study was conducted with approval of the Weill Cornell Medical College Institutional Review Board, which was in compliance with the Declaration of Helsinki; written informed consent was obtained at time of enrollment.The study population comprised prospectively enrolled patients with known or suspected coronary artery disease (CAD) between September 2015 and December 2018 in a multimodality imaging protocol focused on cardiac chamber remodeling. Patients underwent echo and CMR within a narrow interval (99% the same day). Patients with contraindications to contrast‐enhanced CMR . Cardiac chamber volumes were assessed via cine‐CMR (steady‐state free precession), which included long‐axis2.2.2S′). Measurements were acquired in accordance with American Society of Echocardiography (ASE) guidelines; established cutoffs  were used to define RVDYS by each parameter.Transthoracic echoes were acquired using commercial equipment (Philips iE33). Echoes were interpreted by experienced investigators within a high‐volume laboratory for which expertise and reproducibility for quantitative RV indices have been previously reported.2.3Manual segmentation maps were created by annotating the free‐wall  and septal tricuspid annulus in each echo frame (n = 7791 frames) within the echo examinations (n = 101) with a small circular segmentation map of uniform size. Segmentation entailed labeling pixels in the magnitude images using 3DSlicer, an open‐source medical image postprocessing application.Images were resampled and (if necessary) zero‐padded to 256 × 256 pixels. Pixel intensity values were then rescaled to values between zero and one. Aggressive data augmentation was employed in the form of random zoom, rotation, crop (224 × 224), horizontal/vertical flip, and addition of Gaussian noise.2.4The automated segmentation model was based on neural network architecture described by Han, In this case, a different model instance was trained and tested for each of the six holdout subsets and test metrics were averaged per‐case for the entire dataset. As is typical of cross‐validation, no model instance was tested on data from which it was trained. Cross‐validation was chosen in place of splitting into solitary train, validation, and test subsets because it better demonstrates the true performance of a model under a size‐constrained dataset. To minimize the risk of overfitting, neural network architecture, hyperparameters, cross‐validation groupings, and training protocols were not modified in any way after the model was exposed to the cross‐validation dataset. Modification of these parameters could result in improved measures of accuracy but this could be at the expense of generalizability.The ML algorithm was initially trained and tested using sixfold cross‐validation. Cross‐validation is a procedure whereby data are randomly split into nonoverlapping subsets such that a model can be trained on all but one subset and tested on the remaining subset.x is the output logit vector at a given pixel, i the true class label, w the vector of class weights, and C the number of classes. Weighting was employed to combat class imbalance given that the vast majority of pixels in each image were nonannular. A class weight of 0.2 was empirically assigned to the nonannular class and 0.8 to the annular class. RMSProp was used to apply incremental parameter updates.A weighted softmax/cross‐entropy loss function was used for training as follows:The following automated and manual indices were derived using a segmentation map: (a) linear tricuspid annular displacement (LTAD), which corresponded to the maximum displacement between two positions of the tricuspid annulus, and (b) circumferential tricuspid annular displacement (CTAD), which represented the total bidirectional circumferential distance traversed by the annulus. LTAD and CTAD were calculated for both the lateral tricuspid annulus and the septal tricuspid annulus. All distances were calculated by considering the center of mass of all pixels containing an annular label as the position of the annulus. Annular motion was smoothed with a median filter.https://github.com/akbratt/RVTracker.The model was built in Python using the deep learning framework PyTorch. Training and testing were performed on a workstation with four CPU cores, 64 GB of system memory, and a graphics‐processing unit (GPU) with 11 GB of video memory (NVIDIA [Santa Clara] GTX 1080 Ti). Software code pertaining to both training and testing of the ML model can be found on line at:2.5The model was evaluated by comparing values of maximal displacement obtained from the automated segmentation compared to the manual segmentation. Measurements obtained from automated segmentation maps were compared to standard echo indices and RVEF on CMR, defined as the reference standard of RV functional assessment.2.6t test (expressed as mean ± SD) for continuous variables. Inter‐ and intra‐observer agreement between methods was assessed using the method of Bland and Altman,P < .05 was considered indicative of statistical significance.Comparisons between groups were made using Student's 33.1Tricuspid annular shortening indices for RV functional assessment via manual and automated ML segmentation were tested in 101 patients equating to 7791 frames, among whom nearly one third (31%) had RV dysfunction (RVEF < 50%) as defined by CMR reference standard. Table P < .001 for all) with similar decrements regardless of quantification in the septal versus lateral tricuspid annulus. These results paralleled conventional annular displacement indices as evidenced by similar impairments in TAPSE and RV S’ among those with RV dysfunction (P < .001 for both).Table 3.2r = .61–.82) with reasonable limit of agreement for both . Scatter plot and Bland–Altman analyses using ML‐derived annular tracking in relation to manual quantification are shown in Figure When comparing manual and automated quantification of annular segmentation, all displacement correlations were good . Figure S′ (0.78–0.80). Manual and ML‐derived RV annular shortening indices were tested with regard to diagnostic performance for RV dysfunction as defined by CMR. Applying ML‐derived annular cutoffs to maximize sensitivity (>80%), findings yielded comparable high negative predictive value (84%–87%) but lower positive predictive value (37%–40%) in relation to conventional RV indices, TAPSE and RV S′  with no user editing required. Taken together, findings of this study demonstrate fully automated tricuspid annular displacement derived from a novel deep learning model to perform similarly to manual echo indices for the detection of CMR‐evidenced RV dysfunction, providing proof of concept regarding the feasibility of automated ML for 2D echo assessment of the RV.Artificial intelligence, specifically ML, is currently being applied in medicine with the promise of providing physicians with a novel method of accurately and efficiently interpreting large amounts of quantitative information.More recently, ML‐based 3D echo algorithm to quantify RV volumes and RV ejection fraction was tested in a retrospective cohort.S′. Such bias could contribute to higher diagnostic performance of conventional versus automated measurements. In this context, it is also important to note that TAPSE itself is not without limitation, as suboptimal placement of the M‐mode cursor can result in angle‐dependent inaccuracy of RV function. Automated annular segmentation has the potential to overcome this limitation. These concepts need further testing within the framework of a larger population with wider range of RV function and further training, which itself has the potential to improve diagnostic performance. Future machine learning techniques could also include an ensemble of models evaluating several parameters  as opposed to a single measurement, which has the potential to further improve its diagnostic performance.Our findings should be noted in the context of the following limitations. The study population included 101 CAD patients from a single institution, and although automated measurements were reliable and comparable to manual measurements, they did not provide substantially higher diagnostic utility. It is important to note that while equivalent views for conventional and aML segmentation were utilized whenever available for measurement, it is possible that slight variations in transducer angulation and resultant views could have yielded differences in displacement values between conventional aML segmentation. It is also possible that visualization of cardiac structure and function itself could have led to reader bias when in assessing TAPSE and In conclusion, fully automated tricuspid annular displacement from a novel deep learning model performs well in relation to manual echo indices for the detection of CMR‐evidenced RV dysfunction. This study adds to the growing literature that ML‐based algorithms can improve image interpretation efficiency and reliability and is the first of its kind to systematically test and validate ML‐derived 2D RV indices. Further research is warranted to test diagnostic and prognostic utility of ML‐derived tricuspid annular displacement in large population‐based cohorts.None.


Coronary microvascular dysfunction (CMD) is present in various non-ischemic cardiomyopathies and in particular in those with left-ventricular hypertrophy. This study evaluated the diagnostic value of the novel cardiovascular magnetic resonance (CMR) parameter “myocardial transit-time” (MyoTT) in distinguishing cardiac amyloidosis from other hypertrophic cardiomyopathies.N = 20 patients with biopsy-proven cardiac amyloidosis (CA), N = 20 patients with known hypertrophic cardiomyopathy (HCM), and N = 20 control patients without relevant cardiac disease underwent dedicated CMR studies on a 1.5-T MR scanner. The CMR protocol comprised cine and late-gadolinium-enhancement (LGE) imaging as well as first-pass perfusion acquisitions at rest for MyoTT measurement. MyoTT was defined as the blood circulation time from the orifice of the coronary arteries to the pooling in the coronary sinus (CS) reflecting the transit-time of gadolinium in the myocardial microvasculature.p = 0.043) vs. 7.2 ± 2.6 s in controls (p < 0.001). Native T1 and extracellular volume (ECV) were significantly higher in CA compared to HCM and controls (p < 0.001). Both parameters were associated with a higher diagnostic accuracy in predicting the presence of CA compared to MyoTT: area under the curve (AUC) for native T1 = 0.93  = 0.83–1.00; p < 0.001) and AUC for ECV = 0.95 —compared to the AUC for MyoTT = 0.76 . In contrast, MyoTT performed better than all other CMR parameters in differentiating HCM from controls .MyoTT was significantly prolonged in patients with CA compared to both groups: 14.8 ± 4.1 s in CA vs. 12.2 ± 2.5 s in HCM (The relative severity of CMD (measured by MyoTT) in relationship to extracellular changes (measured by native T1 and/or ECV) is more pronounced in HCM compared to CA—in spite of a higher absolute MyoTT value in CA patients. Hence, MyoTT may improve our understanding of the interplay between extracellular/intracellular and intravasal changes that occur in the myocardium during the disease course of different cardiomyopathies. Systemic amyloidoses comprise a growing group of disorders caused by the extracellular deposition of misfolded proteins in various organs such as heart, liver, kidney, skin, eyes, lungs, and nervous system, thereby resulting in different clinical manifestations . CardiacCardiac amyloidosis (CA) is characterized by rapid progressive heart failure, arrhythmias, orthostatic dysregulation, and conduction abnormalities . Due to In contrast to CA, other forms of hypertrophic cardiomyopathy (HCM) are more frequent : In partCardiovascular magnetic resonance (CMR) plays an important role in the diagnosis and differentiation of both pathological entities (CA and HCM) that are characterized by hypertrophied ventricular walls. In case of CA, late gadolinium enhancement (LGE) imaging reveals a characteristic pattern of diffuse LGE starting from the subendocardial layer of the myocardium and eventually involving all myocardial layers and segments –22. In cIn a recent study, we introduced a novel CMR parameter called “myocardial transit-time” (MyoTT) allowing a non-invasive and very quick assessment of coronary microvascular dysfunction (CMD) . Based oN = 20 patients with biopsy-proven cardiac amyloidosis (including both AL and ATTR subtypes). The second study group (HCM group) comprised N = 20 patients with “conventional” HCM showing normal LV ejection fraction (LV-EF) ≥ 50%, LV wall thickness ≥ 15 mm , absence of LV outflow tract obstruction and of known CAD, or any other infiltrative cardiomyopathy. Patients with any history of relevant valvular disease (at least grade II in echocardiography and/or at least moderate in CMR), prosthetic valves, and congenital heart disease were excluded. In addition, a control group (N = 20) without any structural and functional cardiac abnormalities and a low pre-test probability of CAD was recruited. The local ethics committee approved the study protocol and written informed consent was obtained from every patient prior to the CMR study.All patients included in this prospective, single-center study who underwent a routine CMR examination for work-up of suspected non-ischemic cardiomyopathy. The first study group (CA group) comprised CMR imaging was performed on a 1.5-T system  during breath-hold and with ECG-triggering. The CMR protocol . Ventricular volumes and LV mass were determined by contouring short-axis cine images. For the assessment of MyoTT, the temporal difference between the arrivals of contrast agent in the aortic root and the coronary sinus was measured as described in more detail in a previous publication . LGE imap value ≤ 0.05 was considered statistically significant.Statistical analysis was performed with SPSS . Continuous variables are expressed as mean with ± standard deviation, whereas skewed variables as median ± interquartile range. Categorical variables are expressed as frequency with percentage. One-way ANOVA was used for comparison of normally distributed, homogenous data, and when the data failed the assumption on homogeneity of variances (Levene’s test), Welch–ANOVA was used instead. Kruskal–Wallis test was used for comparison of non-normally distributed variables. The Chi-square test with Bonferroni correction was used to compare non-continuous variables. For the assessment of the relationship between different CMR parameters, Spearman correlation was performed. Receiver-operating characteristic curves (ROC) were analyzed to assess the specificity and sensitivity of different CMR measurements to identify patients with CA within the whole cohort as well as to differentiate HCM patients from controls. A p < 0.001) as expected due to the higher prevalence of CA in elderly patients. There were no significant differences regarding major cardiovascular disease risk factors that could theoretically influence the extent of coronary microvascular dysfunction (CMD) in our patients.The study population characteristics are summarized in Table p = 0.002). No LGE was present in the control group (p < 0.001).All anatomic, functional, and structural CMR findings are listed in Table p = 0.043) vs. 7.2 ± 2.6 s in controls (p < 0.001), as illustrated in Fig. p < 0.001). In addition, LV-GLS was also significantly impaired in CA compared to HCM as well as controls , LV-GLS , and global ECV  (Table p < 0.001). In contrast, MyoTT showed a higher diagnostic yield than all the other CMR parameters  regarding the differentiation of patients with “conventional” HCM from healthy controls with an AUC of 0.93 (p = 0.003)  in distinguishing HCM from controls  are expected to precede potential intravascular changes, resulting in CMD . In addiIn contrast to CA, the histological characteristics of “conventional” HCM comprise myocyte hypertrophy and disarray as well as diffuse interstitial and perivascular fibrosis . CoronarAs shown in our previous study  and confIt should be emphasized that a direct comparison regarding the diagnostic yield of MyoTT vs. routine CMR work-up (comprising cine- and LGE-imaging) for CA and/or HCM was not performed. Since the diagnostic value of the aforementioned routine CMR sequences in the assessment of unclear LV hypertrophy is already high, it is fair to assume that the addition of MyoTT will add only little to overall diagnostic certainty.CA comprises different subtypes dependent on the precursor protein. For the purpose of this hypothesis-generating pilot study, no distinction was made between the different types of CA (AL and ATTR), because the underlying mechanism of cardiac involvement seems to be similar . In addiMyoTT provides additive information to the data that can be obtained from parametric mapping and strain measurement. The relative severity of CMD (measured by MyoTT) in relationship to extracellular changes (measured by ECV) is more pronounced in HCM compared to CA—in spite of a higher absolute MyoTT value in CA patients. Hence, MyoTT may improve our understanding of the interplay between extracellular/intracellular and intravasal changes that occur in the myocardium during the disease course of different cardiomyopathies.