The aim of the study was to assess a relationship between the occurrence of rheumatoid arthritis (RA) and its selected clinical parameters, and left ventricular myocardial strain.Fifty-six subjects were qualified for the study: 30 RA patients and 26 subjects without rheumatoid diseases. The study design included taking medical history, assessment of the disease activity using selected scales of activity, collecting samples of venous blood to assess selected laboratory parameters and the assessment of cardiac magnetic resonance (CMR). Using the feature tracking method, the following parameters of the left ventricular myocardial strain were assessed: longitudinal strain (LS), radial strain (RS) and circumferential strain (CS).Regarding global values, peak LS and peak CS were statistically significantly lower in RA patients than in the control group. In the whole study group, the factors independently related to low global LS peaks were as follows: occurrence of RA, occurrence of arterial hypertension, increased activity of antibodies against cyclic citrullinated peptide and increased concentration of neutrophil gelatinase-associated lipocalin. The occurrence of RA, occurrence of diabetes, tobacco smoking, higher activity of antibodies against cyclic citrullinated peptide and current use of methotrexate are the risk factors for low peak of global CS. The current use of steroids constitutes a protecting factor against low global CS peaks.In subjects with no clinically manifested cardiac damage, RA is associated with a deteriorated left ventricular systolic function assessed by left ventricular myocardial strain measured by CMR feature tracking. Left ventricular systolic dysfunction assessed by myocardium strain on MRI is observed in rheumatoid arthritis.Left ventricular systolic dysfunction in rheumatoid arthritis manifests both general and regional strains.Rheumatoid arthritis is an independent risk factor for reduced peak global longitudinal and circumferential strain.Rheumatoid arthritis (RA) belongs to the most frequently diagnosed rheumatic diseases. Its prevalence in the population reaches 0.5% . As showThe basic function of the heart is its systolic function. A standard method of assessing the systolic function of the heart is, regarding its global function—quantitative assessment of the left ventricular systolic fraction, and regarding its regional function—qualitative, visual assessment of contractility of particular myocardial segments. Over the last few years, considering limitations of standard methods to assess left ventricular systolic function, a more precise method of assessment has been proposed, namely quantitative analysis of left ventricular myocardial strain , 10. IniSo far, literature has reported the assessment of left ventricular (LV) systolic function disorders with the use of left ventricular myocardial strain in certain diseases of interest for rheumatology, i.e. Duchenne muscular dystrophy, amyloidosis or systemic sclerosis –16. AccoThe aim of the study was to assess a relationship between the occurrence of rheumatoid arthritis and its selected clinical parameters, and left ventricular myocardial strain assessed with the use of cardiac magnetic resonance feature tracking.2, were enrolled in the study. Then, subjects with no rheumatoid diseases, having similar anthropometric features and similar characteristics regarding risk factors for cardiovascular diseases were added to the analysed group. Twenty-six subjects added in this way  aged 49.42 ± 7.16, with BMI of 25.51 ± 3.01 kg/m2, formed a control group. General characteristics of the study groups are presented in Table In total, 56 subjects were qualified for this prospective study. During the first stage, consecutive patients with a diagnosis of rheumatoid arthritis (RA) hospitalised at the department of internal diseases of a single site were enrolled in the study group. While qualifying RA patients, subjects with clinically manifested heart damage (reduced ejection fraction in routine echocardiography) were excluded. At this stage of the study, 30 RA patients  aged 49.93 ± 13.68, with a mean body mass index (BMI) of 25.41 ± 4.09 kg/mThe project received the approval of the local ethics committee. The studies were performed in accordance with the principles of Good Clinical Practise. The study participants give their written, informed consent to take part in the research project. The study design included taking medical history, assessment of the disease activity using selected scales of activity, collecting samples of venous blood to assess selected laboratory parameters and the assessment of cardiac magnetic resonance (CMR).Based on the medical history taken, data on the principal disease and comorbidities were obtained, and risk factors for cardiovascular system diseases were determined. The assessment of disease activity was based on the scales: DAS28 index and VAS cumulative assessment of the health state by patient and physician.Using the collected samples of venous blood, selected laboratory parameters characterising the course of rheumatoid arthritis were determined: concentration of C-reactive protein (CRP), activity of rheumatoid factor (RF), concentration of neutrophil gelatinase-associated lipocalin (NGAL) and activity of antibodies against cyclic citrullinated peptide (anti-CCP); also, seropositivity was assessed. The determinations were based on tests used in the department of laboratory diagnostics providing services for the department of internal diseases, where the study subjects were hospitalised. The department of diagnostic imaging is certified as part of the Randox International Quality Assessment Scheme (RIQAS).2; matrix, 256 × 154; slice thickness, 10 mm with a 2-mm gap; mean temporal resolution of 30 ms with 30 phases per cardiac cycle. CINE sequences were typically registered in the long axing in 2-chamber, 3-chamber and 4-chamber views and in the short axis of the left ventricle. Medis Suite MR software was used to assess post-processing CMR images .Cardiac magnetic resonance was performed with the use of a single 1.5-T device Magnetom Aera —according to the same protocol in all subjects. The image acquisition was gated by ECG, and it was performed during the patient's breath-hold. For the purposes of the present study, CINE-balanced SSFP (steady-state free precession sequence) sequences were analysed. The following sequence technical parameters were used: repetition time/echo time (ms), 45.60/1.19; flip angle, 70°; field of view, 350 mmIn the first stage of the CMR image analysis, using the QMass application , cardiac chamber size and functional parameters of the left ventricle were assessed.In the 3-chamber view along the long axis, the size of the left atrium (LA) and size of aortic root (Ao) were assessed. LA and Ao measurements were performed manually, as shown in Fig. The 2-chamber view, 4-chamber view in the long axis and the LV view in the short axis were used for volumetric assessment of the left ventricular function. End-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV) and ejection fraction (EF) were calculated. The left ventricular functional parameters were indexed to body surface area (BSA). In addition, left ventricular mass (LVM) and left ventricular mass index (LVMI) were assessed. Left ventricular volumetry analysis was performed semi-automatically with the ventricular analysis wizard.In a subsequent stage of the CMR image analysis, left ventricular myocardial strain was assessed with the use of the QStrain RE application . The short-axis and long-axis images were imported to the application. Then, end-systolic and end-diastolic images were selected, and epicardial and endocardial contours were manually drawn. Using the feature tracking method, the application automatically assessed the parameters of the left ventricular myocardial strain: longitudinal strain (LS), radial strain (RS) and circumferential strain (CS). Peak strain values were assessed for each of 16 AHA segments of the left ventricle: 6 basal segments, 6 mid-cavity segments and 4 apical segments . In the All CMR examinations were assessed by the same radiologist with over 5 years of experience in assessing this type of examination (about 150 examinations per year), certified by the Polish Medical Imaging Society in the field of imaging diagnostics of the heart and vessels.t-test. For variables showing distribution other than normal, nonparametric Mann–Whitney U test was used for independent quantitative variables. Results for qualitative variables were presented as percentage sizes/values. Chi-square test was used in the further analysis for independent qualitative variables. To assess a relationship between the study parameters, a stepwise backward multivariable regression analysis was performed. The parameters of the model obtained in the regression analysis were estimated using the least squares method. Values at p < 0.05 were considered statistically significant.Statistical analyses were performed with the use of “Dell Statistica 13″ statistical package . Quantitative variables are presented as arithmetic means ± standard deviations. The distribution of variables was verified by the Shapiro–Wilk test. In the case of independent quantitative variables with normal distribution, further statistical analysis was based on the one-tailed parametric The study groups did not differ in the basic anthropometric parameters or in coexistence of the study risk factors for cardiovascular diseases. As mentioned above, basic clinical features of the study groups are presented in Table The study group of RA patients was characterised by a mean time of principal disease of 8.35 ± 6.56 years, mean activity of rheumatoid factor of 163.83 ± 329.98 IU/mL, and seropositivity observed in 63.3% of the study patients. A vast majority of the study RA patients were treated with methotrexate (73.3%) and steroids (66.7%) during the study. At the same time, 40% patients also received other drugs modifying the course of the disease, especially leflunomide (23.3%). Selected clinical parameters assessed in the study group of patients with rheumatoid arthritis are presented in Table A comparative analysis did not show statistically significant differences between the RA patients and the control group in the basic parameters of CINE-balanced SSFP cardiac magnetic resonance. The study subjects with RA subjects from the control group did not differ either in the left ventricular dimensions, left ventricular mass, or volumetric parameters of the left ventricular systole. Basic parameters of CINE-balanced SSFP cardiac magnetic resonance imaging in the study groups are presented in Table The comparative analysis revealed, however, a presence of statistically significant differences in the left ventricular myocardial strain parameters assessed by cardiac magnetic resonance feature tracking between the RA patients and the control group. Regarding global values, peak GLS and peak GCS were statistically significantly lower in RA patients than in the control group patients. A complete analysis of particular LV layer showed that for the apical layer, peak LS and peak CS were significantly lower in RA patients versus patients from the control group. For the mid-cavity layer, there was a statistically significant difference regarding LS, whose peak was significantly lower in the RA group as compared with control. And for the basal layer, no statistically significance differences in myocardial strain were revealed. Parameters of left ventricular myocardial strain assessed by cardiac magnetic resonance feature tracking in the study groups of patients are presented in Fig. The analysis of particular 16 segments of the left ventricle showed numerous statistically significant differences between the groups regarding myocardial strain. Peak of longitudinal strain in RA patients compared to patients from the control group was statistically significantly lower in segments 2, 5, 6, 9, 11, 13, 14 and 16. A significantly lower peak of circumferential strain in RA patients compared to patients from the control group was observed for segments 2, 5, 9, 11, 14, 15 and 16. And the peak of radial strain in RA patients in comparison with patients from the control group was significantly lower in segments 5 and 11. Complete results of the analysis of left ventricular strain assessed by CMR feature tracking in the study groups are presented in Table With the use of stepwise backward multivariable regression analysis, a relationship between anthropometric, clinical and laboratory parameters, RA occurrence and coexistence of selected risk factors for cardiovascular diseases versus global longitudinal strain, global radial strain and global circumferential strain were assessed. The following statistically significant models of regression are achieved:On the basis of the obtained models, it was documented that in the study group of patients, the factors independently related to low GLS peaks were as follows: occurrence of RA, occurrence of arterial hypertension, increased activity of antibodies against cyclic citrullinated peptide and increased concentration of neutrophil gelatinase-associated lipocalin Table A. In theOn the basis of the presented results, it may be concluded that in subjects with no clinically manifested cardiac damage, rheumatoid arthritis is associated with a deteriorated left ventricular systolic function assessed by left ventricular myocardial strain measured by cardiac magnetic resonance feature tracking. Although a comparative analysis showed no statistically significant differences regarding basic parameters of CINE-balanced SSFP cardiac magnetic resonance imaging, in this aspect of left ventricular ejection fraction between RA group and control, there were numerous statistical differences regarding parameters of left ventricular myocardial strain assessed by cardiac magnetic resonance feature tracking between the groups of patients. The observed statistically significantly lower-peak strain values in the RA group vs control are interpreted as worse myocardium contractility in this group of patients. It was also documented that deteriorated left ventricular systolic function in RA patients refers to both global and regional strain parameters. Lower global contractility in RA patients is related to longitudinal and circumferential shortening. It has been shown that peak GLS and peak GCS were statistically significantly lower in RA patients than in the control group patients. On the other hand, lower regional contractility in RA patients affects a number of specific segments, especially associated with the interventricular septum and left ventricular lateral wall. It has been documented that in RA patients versus patients in the control group, peak of longitudinal strain was statistically significantly lower in segments 2, 5, 6, 9, 11, 13, 14 and 16; peak of circumferential strain was statistically significantly lower in segments 2, 5, 9, 11, 14, 15 and 16; and peak of radial strain was statistically significantly lower in segments 5 and 11. All the above-mentioned myocardial segments, except for segments 13  and 15 , are located within the interventricular septum and left ventricular lateral wall. Moreover, it has been demonstrated that the occurrence of rheumatoid arthritis in the study group is a risk factor for deteriorated left ventricular systolic function, independent of other variables, presenting as lower-peak global longitudinal strain and peak global circumferential strain. The stepwise backward multivariable regression analysis showed that rheumatoid arthritis was statistically significantly correlated with GLS and GCS values, independently of other anthropometric, clinical and laboratory variables considered in the achieved models.A relationship between rheumatoid arthritis and left ventricular systolic function assessed by strain in cardiac magnetic resonance has been discussed in the current literature only regarding a few studies. In the studies of above-quoted Ntusi et al., a case-to-case comparison of 39 RA patients with 39 patients from the control group showed that peak systolic circumferential strain and peak diastolic circumferential strain rate were diminished in RA patients, and the left ventricular ejection fraction did not differentiate the study groups . In the Results of the analysed studies are basically consistent with the cited data from studies of other research teams. It must be stated, however, that the majority of the above-mentioned studies, as well as our study, demonstrated deterioration in the left ventricular systolic function in subjects with RA assessed by strain, with no such deterioration using classic assessment by left ventricular ejection fraction. This proves that left ventricular myocardial strain may be “added value" to the ejection fraction , which provides higher sensitivity for lesion detection, especially in asymptomatic patients. It must also be emphasised that only in studies by Lehmonen et al. , as wellIn the studies conducted so far, left ventricular myocardial strain in subjects with rheumatoid arthritis was much more frequently analysed by echocardiography. Over the last few years, such studies have been published by, for example, Naseem et al., Baktir et al. and Fine et al., indicating a deterioration of thus-assessed left ventricular systolic function in subjects with RA versus healthy subjects –25. The The achieved results also make it possible to attempt the determination of the usefulness of selected clinical and laboratory parameters characterising the severity and course of RA for the purposes of risk prediction with regard to reduced left ventricular systolic function assessed by CMR strain in the study group of patients. The regression analysis showed that for the analysed clinical and laboratory variables characterising the severity and course of RA, lower-peak GLS was associated with higher activity of antibodies against cyclic citrullinated peptide and higher concentration of neutrophil gelatinase-associated lipocalin, while lower-peak GCS was associated with higher activity of antibodies against cyclic citrullinated peptide. The achieved results may indicate higher anti-CCP activity as the most useful laboratory predictor of deteriorated left ventricular systolic function in the study group of patients.Studies on the relationship between NGAL level and changes in the heart morphology and function assessed by cardiac magnetic resonance have not been published, so far. A demonstration in our study relationship, independent of other variables, between a higher NGAL level and lower-peak GLS, may be considered a novel aspect of the conducted studies. A relationship between the anti-CCP activity and changes in the cardiac magnetic resonance was shown by studies conducted by Giles et al. The study revealed that higher anti-CCP was correlated with lower left ventricular mass, lower end-diastolic volume and lower left ventricular ejection fraction; at the same time, no relationship was revealed between anti-CCP and left ventricular ejection fraction . HoweverThe present study has some limitations. First of all, the lack of CMR sequences to assess the morphology of the left ventricular myocardium  must be mentioned. One of the basic limitations of this study is also a small number of the study subjects. One may also discuss the purposefulness of excluding patients with clinically manifested heart damage and at the same time including patients with certain risk factors for the cardiovascular system, i.e. diabetes, arterial hypertension or smoking cigarettes. Another limitation is a subjective selection of laboratory parameters characterising the severity and course of RA, and of disease activity scales. An important shortcoming is also disregarding the parameters of strain assess by a different technique, e.g. echocardiography.In subjects with no clinically manifested cardiac damage, rheumatoid arthritis is associated with a deteriorated left ventricular systolic function assessed by left ventricular myocardial strain measured by cardiac magnetic resonance feature tracking.Deteriorated left ventricular systolic function in RA patients refers to both global and regional strain parameters. Lower global contractility in RA patients refers to longitudinal and circumferential shortening. Lower regional contractility refers to specific segments, especially associated with the interventricular septum and left ventricular lateral wall.The occurrence of rheumatoid arthritis is, aside to the occurrence of arterial hypertension, to increase the activity of antibodies against cyclic citrullinated peptide and higher concentration of neutrophil gelatinase-associated lipocalin and independent risk factor for reduced peak global longitudinal strain.The occurrence of rheumatoid arthritis is, similarly to the occurrence of diabetes, tobacco smoking, higher activity of antibodies against cyclic citrullinated peptide and current use of methotrexate, and independent risk factor for reduced peak global circumferential strain. And the current use of steroids in the therapy constitutes an independent protecting factor against reduced peak global circumferential strain.


The acquired von Willebrand syndrome (AvWS), which predisposes to bleeding events, is often related to valvular heart diseases. We investigated possible implications of AvWS and factor VIII levels in patients with moderate to severe mitral regurgitation (MR) undergoing transcatheter mitral valve repair (TMVR).123 patients with moderate to severe MR were prospectively enrolled. Complete measurements of von Willebrand Factor activity (vWFAct), von Willebrand Factor antigen (vWFAg), and factor VIII expression before and 4 weeks after TMVR were available in 85 patients. At baseline, seven patients had a history of gastrointestinal bleeding, two patients suffered bleeding events during their hospital stay, and one patient had a bleeding 4 weeks after TMVR. Even though vWFAct, vWFAct/vWFAg ratio and vWFAg values did not change after TMVR, we observed a significantly lower vWFAct/vWFAg ratio in patients with primary MR as compared to patients with secondary MR both at baseline (p = 0.022) and 4 weeks following the TMVR procedure (p = 0.003). Additionally, patients with a mean mitral valve gradient ≥4 mmHg after TMVR had significantly lower vWFAct/vWFAg ratios as compared to patients with a mean mitral valve gradient <4 mmHg (p = 0.001).MR of primary etiology was associated with lower vWFAct/vWFAg ratio, hinting toward HMWM loss due to shear stress caused by eccentric regurgitation jets. In addition, morphological changes leading to postprocedural transmitral gradients ≥4 mmHg were related to lower vWFAct/vWFAg ratio 4 weeks after the procedure. Alterations of the vWFAct/vWFAg ratio in turn did not translate into a greater risk for bleeding events. We therefore investigated AvWS and factor VIII in a large cohort of patients with moderate to severe mitral regurgitation undergoing a transcatheter mitral valve repair.22.1From August 2017 to May 2020 123 patients with symptomatic moderate to severe or severe mitral valve regurgitation were prospectively enrolled in our investigator initiated single‐center RETORT‐MR trial . All patients gave informed consent before enrollment and the RETORT‐MR trial was approved by the local ethics committee. No external funding was obtained to support the study. Comprehensive measurements of von Willebrand Factor activity (vWFAct), von Willebrand antigen (vWFAg), vWFAct/vWFAg ratio and factor VIII before and 4 weeks after the percutaneous mitral valve repair were available in 85 patients.Clinical data were collected from all participants and serial blood and urine sampling was performed. In addition, transthoracic (TTE) and transesophageal (TOE) echocardiography was conducted. Special attention was paid to history of bleeding events and antiplatelet or anticoagulant medication. EuroScore II and logEuroScore were calculated to assess operative risk.After discussion of every case in the interdisciplinary heart team 83 of the included patients underwent transcatheter mitral valve repair using the MitraClip NT, NTR, or XTR system, Abbott Vascular  and two patients received PASCAL devices, Edwards Lifesciences .2.2Technical aspects of the MitraClipAll patients were under general anesthesia during the procedure and both fluoroscopic and transesophageal echocardiographic guidance were used for percutaneous mitral valve repair. During the procedures, one to three MitraClips and one or two PASCAL devices were implanted in order to achieve a significant reduction of mitral regurgitation. Heparin was administered for periprocedural anticoagulation. After percutaneous mitral valve repair patients received dual antiplatelet therapy consisting of aspirin and clopidogrel for 4 weeks, followed by aspirin administration for 6 months. In case patients had already been treated with oral anticoagulants, aspirin or clopidogrel was added for 1 month.2.3Von Willebrand Factor activity, von Willebrand Factor antigen and factor VIII were measured at baseline and after 4 weeks and results at both points of time were available in 85 patients. Von Willebrand Factor activity was analyzed using the INNOVANCE® VWF Ac system provided by SIEMENS , and von Willebrand Factor antigen was measured by immunoturbidimetry using the measuring devices of Siemens Healthcare Diagnostics or SYSMEX (SYSMEX CORPORATION). The results of factor VIII were gained by in‐vitro diagnostics of coagulation factor VIII deficient plasma by SIEMENS .2.4Clinical assessment including bleeding history, standardized echocardiographic parameters and serial blood and urine sampling was performed 24 hours before and 4 weeks after percutaneous mitral valve repair. In addition, six‐minute walk tests and the EQ‐5D‐5L questionnaire were performed to investigate patients' physical and mental status.Two‐dimensional transthoracic echocardiography was conducted using the iE‐33 ultrasound system with a S5‐1 transducer  or the EPIQ CVx ultrasound system with a X5‐1 transducer . The quantification of mitral regurgitation was in accordance with the Endovascular Valve Edge‐to‐Edge Repair Study (EVEREST) criteria.2.5p‐value of <0.05 was considered statistically significant.Statistical analysis was performed with SPSS Version 25 . Data are presented as absolute and relative frequencies or as means ± standard deviations. Differences between continuous variables in paired data were tested with a paired t‐test, continuous variables in unpaired data were compared with an unpaired t‐test. Analysis of variance was used to compare continuous variables between more than two independent groups. For evaluating differences in unpaired data adjusted for covariates, analysis of covariance was performed. A 3Baseline characteristics of the study population are depicted in Table The frequency of gastrointestinal bleeding at baseline was 8.2% (n = 7). Two in‐hospital bleedings Table . It is nAfter adjustment for age and sex the results of vWFAct/vWFAg remained stable concerning MR etiology  and MV gradient ≥4 mmHg .By stratifying the cohort into low and high post mitral valve gradients (≥4 mmHg versus <4 mmHg), no significant results were found between the groups at baseline and 4 weeks follow‐up Table . FurtherTable Further no significant differences in the absolute values of vWFAct/vWFAg, vWFAg, vWFAct and Factor VIII were observed Table .Residual mitral regurgitation after TMVR did not significantly influence vWFAct, vWFAg, vWFAct/vWFAg ratio and factor VIII levels Table . The val4To the best of our knowledge, we investigated vWFAct, vWFAg, vWFAct/vWFAg ratio and factor VIII in the largest cohort of patients treated with transcatheter mitral valve repair so far. We were able to reveal significant differences in the values of vWFAct/vWFAg ratio at baseline and 4 weeks follow‐up in respect of MR etiologies and mean mitral valve gradients after percutaneous mitral valve repair.4.1In our study primary MR was associated with a significantly decreased vWFAct/vWFAg ratio compared to secondary MR indicating a HMWM loss. As stated by Chen et al. it is important to take the jet morphology into consideration.vWF levels are influenced by different hemodynamic conditions. As characterized by Heyde syndrome AvWS, valvular heart disease and bleeding tendency result in an increased clearance of vWF due to shear stress leading to a proteolysis of HMWM vWF during the passage of the abnormal heart valve.Interestingly, our distinctly larger RETORT‐MR trial could not confirm these results. Besides the considerably different sample sizes, which could have biased the results preferentially in smaller trials, the main reason for this finding could be the time when vWFAct and vWFAg were measured: Gragnano et al. analyzed vWFAct and vWFAg levels already 24 hours after percutaneous mitral valve repair,In patients with severe aortic valve stenosis undergoing transcatheter aortic valve replacement (TAVR) an acute recovery of HMWM‐vWF levels was observed within a few minutes after successful TAVR.4.2In terms of mitral valve stenosis only little data exist with regard to the AvWS. In a small study of Yetkin et al, higher plasma levels of vWF were found in patients with mitral stenosis (n = 21) compared to a control group.In our study patients with a mean mitral valve gradient ≥4 mmHg after percutaneous mitral valve repair had significantly lower vWFAct/vWFAg ratios compared to patients with a mean mitral valve gradient <4 mmHg. Both the MitraClip and the PASCAL device represent foreign material with possible effects on hemostasis. Furthermore, the geometry of the mitral valve is changed by percutaneous mitral valve repair, which may cause abnormal transvalvular flow patterns, resulting in regional hemodynamic shear stress.Facing the MV cut‐off gradients derived from our study, it is noteworthy, that Neuss et al. found a negative effect on the overall clinical outcome in their study, when the mean postprocedural mitral valve gradient exceeded 4.4 mmHg.Besides hemodynamic conditions it has also been shown by several studies that vWF levels are affected by age. In centenarians vWF values were significantly elevated.4.3Some limitations of the present study warrant consideration: Our trial was performed at an experienced academic institution, which means that our results might not completely be transferable to less trained centers. Finally, due to the limited number of bleeding events in our study, we were not able to estimate the effect of percutaneous mitral valve repair on an overall bleeding diathesis. We demonstrated significant differences in the values of vWFAct/Ag ratio in respect of degenerative and functional MR as well of elevated postprocedural gradients. In order to investigate the underlying pathophysiological mechanisms like shear stress further experimental studies would be needed.5In this largest investigation of AvWS in patients with mitral regurgitation so far, performing TMVR did not alter vWF levels or vWF activity 4 weeks after the procedure. MR of primary etiology was associated with lower vWFAct/vWFAg ratio, hinting toward HMWM loss due to shear stress caused by eccentric regurgitation jets. In addition, postprocedural transmitral gradient ≥4 mmHg was related to lower vWFAct/vWFAg ratio 4 weeks after the procedure. Bleeding events in the short‐term after TMVR were rare despite high perioperative risk, confirming the superior safety profile of percutaneous mitral valve repair.The authors declare no potential conflict of interest.AppendixS1: Supporting informationClick here for additional data file.


Cardiovascular disease is second only to cancer recurrence as a determinant of lifespan in cancer survivors, and cancer therapy-related cardiac dysfunction is a clinically important risk factor. We aim to investigate the use of cardiac magnetic resonance imaging (MRI) to evaluate early tissue changes and perform functional assessment of chemo- and radiation-induced cardiotoxicity and to identify MRI prognostic indicators of cardiotoxicity in breast cancer patients.A 3-min cardiac imaging protocol will be added to the breast MRI examination to diagnose cardiotoxicity in breast cancer patients. Standardized MRI-based evaluation of breast cancer and the left ventricular myocardium will be performed at baseline and at 3, 6, and 12 months and 2 years or more after cancer treatment. We will analyze both ventricular volume and ejection fraction (EF), strain of left ventricle (LV), native T1, extracellular volume fraction (ECV), and T2 values acquired in the mid LV.The primary result of this study will be the comparison of the prognostic value of MRI parameters  for cardiotoxicity. The endpoint is defined as the occurrence of a major adverse cardiac event (MACE). The secondary outcome will be an assessment of the temporal relationships between contractile dysfunction and microstructural injury over 4 years using MRI. This study will assess the usefulness of quantitative MRI to diagnose cardiotoxicity and will clarify the temporal relationships between contractile dysfunction and microstructural injury of the LV myocardium using MRI during breast cancer treatment.NCT03301389) on October 4, 2017.The protocol was registered at clinicaltrials.gov (Clinical trial no.  The side effects of cancer therapy have recently attracted significant attention . EarlierCancer therapy-related cardiac dysfunction (CTRCD) is the second leading cause of death in cancer survivors after cancer-related mortality , 5, 6. ICurrent guidelines consider left ventricular ejection fraction (LVEF) assessment using echocardiography as the standard diagnostic technique for detecting chemotherapy-induced cardiotoxicity , 8. HoweThe increasingly used T1 mapping sequences improved the usefulness of cardiac MRI, which enables tissue characterization through quantitative analysis of phenomena such as myocardial edema, inflammation, and fibrosis, thus playing an important role in the diagnosis of early and late cardiotoxicity in cancer patients , 11. HowThe objective of our proposed study is to investigate the use of cardiac MRI to evaluate early tissue changes and perform functional assessment in chemo- and radiation-induced cardiotoxicity and to identify cardiotoxicity prognostic factors in patients with breast cancer.Cardiac Magnetic Resonance for Early Detection of Cardiotoxicity in Breast Cancer (CareBest) study hypothesizes that the evaluation of early tissue changes and functional assessment using cardiac MRI would be useful in the early detection and risk stratification of chemotherapy- and radiation therapy-induced cardiotoxicity in patients with breast cancer.The In the early phase of exposure to an anthracycline agent, tissue injury and concurrent elevation of native T1 and extracellular volume fraction (ECV) values were noted in the preclinical study, without significant left ventricular (LV) reduction. Therefore, T1 mapping MRI allows for earlier detection of chemotherapy-induced cardiotoxicity . T1 mappMany studies suggest that CTRCD is not a functional but a structural disorder. The relationship between contractile dysfunction and microstructural injury, such as myocyte damage, fibrosis, and inflammation, remains poorly understood . It was CareBest is a single-center, large-scale prospective study. To achieve the goal of the study, cardiac MRI protocols for cardiotoxicity diagnosis will be applied to breast cancer patients who have received or are planning to receive chemotherapy. A 3-min cardiac imaging protocol was added to the breast MRI scanning protocol as a screening tool. The protocol includes T1 and T2 mapping and cine imaging of the LV myocardium. MRI is performed at 3 months, 6 months, and 2 years after treatment. Treatment protocols and MRI timing are shown in Fig. The primary objective of this study is to investigate and compare the prognostic value of cardiac MRI parameters , LV systolic function, and global longitudinal strain of LV) for cardiotoxicity. The endpoint is MACEs.The secondary objectives are to determine the temporal relationships between contractile dysfunction and microstructural injury over a four-year period using cardiac MRI across all patients and by subgroup analysis according to treatment  and to compare the diagnostic accuracy of MRI, echocardiography or multigated acquisition (MUGA) by subgroup analysis.This prospective study will enroll over 2000 participants referred for breast cancer evaluation using MRI in a single center. All enrolled patients will undergo standardized breast MRI including a cardiac imaging protocol at the time points specified above and blood analysis to assess hematocrit (Hct) levels immediately before each MRI examination.Patients ≥18 years of age are considered eligible if, following the initial oncology consultation, breast cancer is diagnosed and related therapeutic plans are formulated. All subjects will agree to participate by giving both verbal and written informed consent. This prospective study was approved by the institutional review board of Yonsei University College of Medicine.Exclusion criteria include prior mammoplasty, history of other cancers, confirmed benign breast disease, poor image quality due to uncontrolled breast holding, arrhythmia, or patients with contraindications to MRI  < 30).A standardized breast and cardiac MR examination will be performed with 3 T MR scanners with an 8-channel breast coil . Because breast MRI is performed with the patient in a prone position, peripheral pulse gating will be applied for cardiac imaging.The cardiac protocol includes pre- and postcontrast T1 mapping, T2 mapping, and cine imaging of both ventricular myocardia. Motion-corrected native T1 and postcontrast T1 and T2 mapping images will be acquired at the end of diastole in the short axis orientation of mid LV using a FIESTA-based 3(3)5 MOLLI sequence. Post-contrast T1 images will be acquired 15 min after the bolus injection of the contrast agent .The imaging parameters for the 2D FIESTA cardiac cine MRI will be set as follows: flip angle = 45°, repetition time (TR) = 3.0 ms, echo time (TE) = 1.1 ms, field of view (FOV) = 390 × 390 mm, matrix = 160 × 192, measured pixel size = 2.4 × 2.0 mm, slice thickness = 8 mm (2 mm gap between adjacent slices), number of slices = 9, temporal resolution = 60 ms, and ASSET factor = 2.The specific scan parameters for T1 mapping will be set as follows: flip angle = 35°, TR = 2.8 ms, TE = 0.9 ms, FOV = 300 × 300 mm, matrix = 160 × 128, delay time (TD) = 220 ms, measured pixel size = 1.9 × 2.3 mm, slice thickness = 8 mm, and acquisition window = 361 ms.The specific scan parameters for FSE-based black blood T2 mapping will be set as follows: TR = 1 RR; total echo train length (ETL) = 16; FOV = 300 × 300 mm; matrix = 160 × 128; measured pixel size = 1.9 × 2.3 mm; slice thickness = 8 mm; 4 echoes with effect TEs = 11.3, 33.9, 56.5, and 79.1 ms; acquisition window = 91 ms; and ASSET factor = 2.Sequential short axis cine imaging will be performed including the entire ventricular myocardium in addition to standard long-axis views using the 2D FIESTA sequence. The specific scan parameters will be set as follows: flip angle = 45°, TR = 3.0 ms, TE = 1.1 ms, FOV = 390 × 390 mm, matrix = 160 × 192, measured pixel size = 2.4 × 2.0 mm, slice thickness = 8 mm (2 mm gap between adjacent slices), number of slices = 9, temporal resolution = 60 ms, and ASSET factor = 2.The sequences for breast MR examination include a three-plane localizing sequence, axial T2-weighted fast-spin- echo and T2-stimulated inversion recovery (STIR) sequence, and diffusion-weighted imaging before contrast administration. 3D dynamic postcontrast-enhanced (DCE) images and a T1-weighted 3D delayed postcontrast sequence will be acquired in the sagittal plane after contrast injection.Native T1 and T2 images will be acquired between T2-STIR and diffusion images, while postcontrast T1 images will be acquired after delayed postcontrast images. Cine images will be acquired before dynamic images. Precontrast T1 and T2 mapping images will be acquired before DWI imaging, and postcontrast T1 mapping imaging will be performed after dynamic contrast imaging. The hematocrit (Hct) levels of the patients will be acquired on the day of cardiac MRI.42 image analysis software . Short-axis cine images will be analyzed using semi-automated contouring of the endocardial and epicardial borders of both ventricles at end-diastole and end-systole to calculate both ventricular function , end-systolic volume , cardiac output, stroke volume, RVEF, and LVEF).All MR images will be analyzed using cviOne native T1, one postcontrast T1, and one T2 mapping image acquired on the mid LV will be transferred to the software. A region of interest (ROI) will be freely drawn on the septum. Images with severe artifacts will be coded and removed from the analysis.Mean segmental native T1, T2, and postcontrast T1 values are calculated for each patient. ECV values are calculated using the mean values of native and postcontrast T1 and hematocrit, as previously established .Feature tracking analysis will also be performed using cvi42 software. The long axis and short-axis cine images will be loaded onto the software. Endocardial and epicardial borders of the LV in both the long- and short-axis views were semi-automatically delineated in the end-diastolic phase. The feature software automatically measured the global longitudinal strain in the two-dimensional (2D) longitudinal directions. Analysis of interobserver agreement in regard to MRI measurements will be performed.2 with cyclophosphamide (600 mg/m2) IV every 3 weeks for a total of 4 cycles (cumulative dose of doxorubicin: 240 mg/m2)AC regimen: doxorubicin 60 mg/m2 IV once a week for 12 weeks, or docetaxel 75 mg/m2 IV every 3 weeks, for a total of 4 cycles)AC followed by taxane: 4 cycles of AC followed by taxane (paclitaxel 80 mg/m2) with methotrexate (60 mg/m2) and fluorouracil (600 mg/m2) at days 1 and 8 every 4 weeks, for a total of 6 cyclesCMF regimen: cyclophosphamide  followed by 6 mg/kg IV (maintenance dose) every 3 weeks for a total of 18 cycles or trastuzumab 600 mg SC every 3 weeks for a total of 18 cycles for HER2-positive breast cancer: Trastuzumab will be given after the completion of the doxorubicin regimen regardless of the taxane regimen.The primary outcome is MACEs defined as CV death, hospitalization due to heart failure, and/or heart transplantation. The secondary outcome is left ventricular dysfunction, defined as a decrease in the LVEF of > 10 percentage points to a value < 53% . The folThere is no generally accepted approach to estimate the sample size for studies of risk prediction models . We willn = 15). All patients will undergo planned cardiac imaging with a cardiac coil in a supine position, without contrast agent. A native T1 cardiac image in a short axis plane will be acquired. After cardiac imaging, the planned breast+cardiac imaging protocol will be performed in a prone position with contrast agent.We will perform a preliminary study to evaluate the feasibility of cardiac imaging during breast MRI in control subjects .Categorical baseline characteristics will be expressed as numbers and percentages, and continuous variables will be expressed as the means and standard deviations. To evaluate the prognostic value of T1 mapping parameters for cardiotoxicity, Cox proportional hazard regression or other transformations will be used after checking the proportional hazard assumption. To determine and compare the prognostic value of native T1 and ECV and that of LVEF or global longitudinal strain of LV, time-dependent ROC curves, Harrell’s C statistic and bootstrapping with 1000 repetitions will be used. A linear mixed model will be used to evaluate the temporal relationship between LVEF, native T1, ECV, and T2 values. The diagnostic accuracies of MRI, MUGA, and echocardiography for cardiotoxicity will be evaluated by ROC curves, and the significance of the differences among the related areas under the curves (AUC) will be evaluated using Delong’s method . P-valueclinicaltrials.gov . A data and safety monitoring board was constituted to ensure the safe continuation of the study.The study protocol was approved by the regional institutional review board in October 2016 (IRB No. 4–2016-0730), and the protocol is registered at This prospective study will be the largest study investigating serial MRI-based evaluation of CTRCD. We will investigate the effects of chemotherapy, radiation therapy, and other therapies on myocardial function and structure, thus providing additional evidence on whether cardiac MRI is the optimal screening tool for the diagnosis of chemo or radiation therapy-induced cardiotoxicity, given its advantages in terms of quantitative assessment.Recently, significant attention has been focused on the field of cardio-oncology. Many influential clinical guidelines for cardiovascular toxicity have been developed , 16–19. Cardiac MRI is the gold standard for the evaluation of ventricular volumes and function, with greater intra- and inter-observer reproducibility than other methods, and quantitative cardiac MRI may play an important role in the cardiac evaluation and risk stratifications of cancer patients , 21. Rec2.Breast cancer therapy involves many adjuvant therapies in addition to surgery, most of which cause heart-related problems. Anthracycline, used as a primary chemotherapy agent in breast cancer, is a well-known cardiotoxic agent , 28, witOther conventional chemotherapy agents used in breast cancer treatment, including cyclophosphamide and taxanes, also induce myocardial dysfunction . The recRadiation therapy, another major treatment for breast cancer, induces myocardial fibrosis, microcirculatory injury, and myocardial infarction. High-dose radiation exposure is used on the thorax in the adjuvant setting after breast surgery .Therefore, cardiac evaluation during breast cancer treatment is clinically very important. This study is based on the observation that it is very efficient to perform an additional myocardium examination during the routine surveillance of breast cancer. Indeed, the separate assessment of cardiac function using echocardiography or MUGA on a regular basis during surveillance of breast cancer treatment is somewhat cumbersome. Moreover, serial MUGA evaluations may cause significant radiation exposure. For these reasons, we set up a short-term imaging protocol for the evaluation of myocardial tissue and myocardial dysfunction, and we tested the feasibility of cardiac imaging using a breast coil in the preliminary study.The limitation of this study is that it is a single-center prospective registry study. Although blood biomarkers such as NT proBNP or troponins have been demonstrated to be good early markers of cardiotoxicity, they are not included in the study protocol.In conclusion, the simultaneous evaluation of breast cancer and cardiac function during treatment can potentially be very effective in terms of cost and time. Moreover, it may help the early detection of cardiotoxicity during cancer therapy, while quantitative imaging methods may provide additional value for the surveillance of patients at risk of CTRCD.


To compare automated and manual magnetic resonance imaging protocols for estimating liver iron concentrations at 1.5 T.Magnetic resonance imaging examination of the liver was performed in 53 patients with clinically suspected hepatic iron overload and in 21 control subjects. Liver iron concentrations were then estimated by two examiners who were blinded to the groups. The examiners employed automated T2* and T1 mapping, as well as manual T2* and signal-intensity-ratio method. We analyzed accuracy by using ROC curves. Interobserver and intraobserver agreement were analyzed by calculating two-way intraclass correlation coefficients.p < 0.05). Correlations involving T1 mapping, although still significant, were lower.The area under the ROC curve (to discriminate between patients and controls) was 0.912 for automated T2* mapping, 0.934 for the signal-intensity-ratio method, 0.908 for manual T2*, and 0.80 for T1 mapping, the last method differing significantly from the other three. The level of interobserver and intraobserver agreement was good (intraclass correlation coefficient, 0.938-0.998; At 1.5 T, T2* mapping is a rapid tool that shows promise for the diagnosis of liver iron overload, whereas T1 mapping shows less accuracy. The performance of T1 mapping is poorer than is that of T2* methods. However, because liver biopsy is an invasive method, magnetic resonance imaging (MRI) is chosen as the method for LIC measurement with ever-increasing frequency-9. MRI emerged as the dominant modality for LIC measurement because of its sensitivity, reproducibility, availability, and ability to evaluate multiple organs of the body during a single imaging session,5,7,10. MRI quantifies iron indirectly by detecting the paramagnetic effects of iron stores in the forms of ferritin and hemosiderin, interacting with nearby hydrogen nuclei. A number of empirical MRI methods for the determination of tissue iron overload have been proposed. This has been traditionally done using manual methods, which are well-established and are validated and calibrated against the gold standard of liver biopsy, but are more user dependent and take more time to perform. More recently though, automatic methods have been proposed, with the advantage of speed and ease of use. The aim of this study was to compare automated and manual MRI protocols for estimating LIC at 1.5 T.Biochemical analysis of a liver biopsy is the gold standard for the measurement of LICThis was a prospective single-center study of patients who were referred to our department for liver MRI because of suspected hepatic iron overload. We included patients with an elevated serum ferritin level  or elevated transferrin saturation . Thus, 60 eligible patients were identified. Subjects with the following conditions were excluded from the study: claustrophobia (n = 2); inability to consent (n = 1); and liver nodules detected on MRI (n = 4). Therefore, the final study group comprised 53 patients. We also evaluated 21 healthy controls, selected by convenience, with no history of liver or metabolic disease. All examinations were performed between October 2014 and August 2017. Age, gender, and body mass index were recorded for patients and controls. The study was approved by the local research ethics committee, and all participants gave written informed consent.syngo MR B17. For the signal-intensity-ratio method proposed by the University of Rennes (URennes), we acquired five axial gradient-echo (GRE) sequences of the liver with a repetition time (TR) of 120 ms. A typical T1-weighted sequence-with an in-phase echo time (TE) of 4 ms and a flip angle of 90°-was followed by four sequences with a standard flip angle of 20° and progressively increasing T2-weighting-in-phase TE increasing from 4 to 21 ms,6,11,12. For the manual T2* protocol, a multi-echo GRE (mGRE) sequence was used in order to acquire 12 images with increasing TE , a TR of 200 ms, a flip angle of 20°, a field of view of 400 × 400 mm2, a matrix of 96-128 × 64-96, and a slice thickness of 10 mm.Unenhanced images were acquired in a 1.5 T scanner , with a body coil and dedicated software, version . Acquisition of mGRE sequences with radiofrequency spoiling was used in order to create the T2* map-16. The T1 map was acquired by using a modified look-locker inversion recovery (MOLLI) sequence with the 5(3)3 protocol,17,18.Automated T2* and T1 maps were generated by in-line processing prototype software, the same used in the All Iron Detected Multicenter StudyData were analyzed by two radiologists , both of whom were blinded to the clinical status of the subjects, and the level of interobserver agreement was assessed. One of the radiologists also repeated all measurements, in order to allow intraobserver agreement to be assessed.; and the manual T2* (relaxometry) method proposed by Hankins et al.. Both have been validated and calibrated against the gold standard of liver biopsy and show that MRI enables good quantification of LIC-12,19-25. The two automatic methods evaluated were the ultrafast scanning T2* and T1 mapping techniques-18, which were proposed more recentlyFour methods for estimating LIC values were evaluated in this study. The two manual methods were well-established at the time of the study design: the URennes  method proposed by Gandon et al.. That algorithm uses the liver-to-muscle signal intensity ratios in five axial GRE sequences of the liver. For every sequence, we measured liver signal intensity (SI) in three operator-defined regions of interest (ROIs) of 1-3 cm2 in the right lobe of the liver, avoiding large vessels, biliary tracts, parenchymatous lesions, and artifacts. Muscle SI was measured in two ROIs in the right and left paraspinal muscles. The ROIs were propagated to all five images. Values were entered manually on a website developed by the authors, which provides LIC values in µmol Fe/g.For quantification of the URennes values, we used the algorithm developed by Gandon et al.SI = KeT2*/TE−, with truncation of the decay curve to achieve the best results, in accordance with previous recommendations. The TEs were manually excluded from the fit in images with high iron-mediated signal loss.We drew freehand ROIs directly on the scanner console over source images in a homogeneous area of the right hepatic lobe, at the level of the origin of the main portal vein, avoiding blood vessels and visible bile ducts. The SI was obtained and transferred manually to the software on another computer. The mean SI in each slice with varying TEs was used in order to fit the T2* curve by using the formula .The T2* values were transformed into their reciprocal R2* . The LIC values (in mg Fe/g) were estimated from R2* values using the linear regression model described by Hankins et al.-16. The LIC values (in mg Fe/g) were estimated by using the linear regression model described by Hankins et al..Automated T2* maps were calculated using in-line processing prototype software and were based on the original mGRE images of the liver. The T2* values (in ms) were obtained by drawing an ROI directly onto the map generated2 . We placed four ROIs in the right lobe and two in the left lobe, avoiding artifacts, major vascular structures, and lesions. The prototype software generated a native image with multiple echoes, as well as final T1 maps that had already been processed automatically,17,18. In our calculations, we used the arithmetic mean of those ROIs. The T1 values were transformed into their reciprocal R1 values (R1[Hz] = 1000/T1[ms]), which increase during iron overload. It was not possible to estimate LIC values based on R1, because there is as yet no conversion formula for those two measures.The T1 map was measured in six circular ROIs larger than 1 cmFor the calculation of descriptive statistics, numerical variables were submitted to the Shapiro-Wilk test of normality. Those variables are presented as mean ± standard deviation (SD) when normally distributed and as median (interquartile range) when not. Categorical variables are presented as frequencies and percentages. We compared patients and control subjects using the t-test for normally distributed variables or the Mann-Whitney-Wilcoxon test for those not so distributed. Categorical values were compared by the chi-square test., and the Student’s t-test for independent samples  was used for the analysis of differences between means. Statistical analyses were performed with R software, version 3.3.2 . Values of p < 0.05 were considered statistically significant.Measures obtained with the URennes, manual T2*, automated T2* mapping, and T1 mapping protocols were compared by constructing receiver operating characteristic (ROC) curves, and the performance of the protocols was assessed by calculating the area under the curve (AUC) and the corresponding 95% confidence interval (95% CI). Correlations between measures were quantified by calculating Spearman’s correlation coefficient. The intraclass correlation coefficient (ICC) was calculated in order to determine the level of interobserver and intraobserver agreementp < 0.001). Among the patients, the mean serum ferritin was 974 µg/L in the males and 1542 µg/L in the females.In this study, we assessed LICs in 74 individuals (53 patients and 21 controls). The subject characteristics are summarized in p < 0.05), despite the fact that the ICC for agreement between the two raters was above 0.9 for all of the protocols ; manual T2* (p = 0.038); and T2* mapping (p = 0.031). The URennes, manual T2*, and T2* mapping protocols had similar power to detect patients with elevated ferritin or transferrin saturation and clinically suspected hepatic iron overload .To study the relationships among measures obtained by the URennes, T2* mapping, manual T2*, and T1 mapping protocols, we calculated the correlation coefficients. The results are shown in In this study, we applied different methods of LIC estimation using 1.5 T MRI in a group of 53 patients and 21 controls and compared the results between manual and automatic methods. The main advantages of the mapping techniques are speed and ease of use. That was confirmed in our study, in which the time required for image acquisition/processing was found to be significantly shorter for the T2* mapping and T1 mapping protocols than for the URennes and manual T2* protocols.. The authors of that study showed that the URennes method employed in the present study tends to overestimate LIC values and is susceptible to potentially serious errors if coils other than an antenna coil are employed. They recommended migrating to the Digital Imaging and Communication in Medicine MRQuantIF software that uses the Alústiza algorithm by default, which controls the acquisition parameters. Because that software would require the re-acquisition of imaging data using a different protocol, the remainder of the discussion will focus primarily on the manual T2*, T2* mapping, and T1 mapping protocols.Shortly after the conclusion of the data collection for this study in 2017, the URennes published a study proposing a new method that employs a proton density technique, involving the use of magnitude images, and has produced quite promising resultsIn the present study, the level of interobserver agreement was good, the ICC being above 0.9 for all four protocols. The level of intraobserver agreement was also good, although the t-test showed a significant difference between measures obtained with the T1 mapping protocol. That is likely related to the higher dispersion of R1 values estimated using this method., which is reflected in an increased T1 value. However, the presence of excess iron competes with this effect, reducing T1 (and conversely increasing R1). The most widely used T1 mapping sequence is based on the MOLLI technique. Described originally by Messroghli et al., it consists of a single-shot true fast imaging with steady-state precession sequence with acquisitions over different inversion time readouts, allowing for magnetization recovery of a few seconds after three to five readouts. The advantages of this sequence are its acquisition in only one relatively short breath-hold, the higher spatial resolution (1.6 × 2.3 × 8 mm), and the increased dynamic signal. T1 maps are generated automatically after MOLLI image acquisition, without the need for further post-processing, which accelerates image analysis. Similarly, in-line application of motion correction provides more accurate pixel-wise maps, avoiding artifacts due to respiratory motion. Torlasco et al. demonstrated that T1 mapping correlates better with cardiac and hepatic iron levels than does T2* mapping. Despite those advantages, we found that T1 mapping showed the lowest ICC, the weakest correlation with the other methods, and the lowest AUC for differentiating patients from controls. Therefore, although we found a significant correlation with the R1 and LIC values estimated by the other methods, there is no clear evidence that T1 mapping could consistently estimate LIC values through the use of the protocol applied in this study. Nevertheless, there are many T1 sequences other than MOLLI that could be used-including shortened MOLLI, saturation recovery single-shot acquisition, saturation-pulse prepared heart-rate-independent inversion-recovery, and inversion time scout-each with different reference values. Further studies are needed in order to examine the relationship between R1 values and LIC.Native T1 mapping detects elevated levels of extracellular water, thus identifying fibrosis. For T2* calculations, depending on the MRI scanner gradient system, liver T2* can measure LICs only up to 40 mg/g. That’s because GRE sequences are inaccurate at higher iron overload levels,10,22,25, given that the mGRE techniques employed are intrinsically limited when detecting rapidly decaying MRI signals. Nevertheless, higher LIC values can be measured with this method, because conventional mGRE techniques only start to become degraded during the measurement of signals with T2* times ≤ 1 ms, corresponding to LIC values above approximately 25 mg Fe/g liver (dry weight) at 1.5 T,25. In contrast, d’Assignies et al., in a study comparing and validating the signal-intensity-ratio method and the R2* method with liver biopsy at 3.0 T, demonstrated that the biopsy-determined LIC correlates better with that determined by the R2* method than with that determined by the signal-intensity-ratio method when the degree of iron overload is slight to moderate (< 130 µmol/g). However, in patients with a high biopsy-determined LIC (≥ 130 µmol/g), the signal-intensity-ratio method correlates better.There were strong correlations among the URennes, manual T2*, and T2* mapping protocols regarding LIC estimation, and all correlations with the URennes protocol were significant, although the correlations among LIC measures were weaker when the LIC was above 15 mg Fe/g. This corroborates current knowledge that there is saturation at 1.5 T with very high iron overload, consequently, the method cannot quantify LIC values greater than 375 µmol/kg (20.9 mg/kg) and hence does not capture the entire relevant range of valuesThe strongest correlation between methods was observed for that between the automated T2* mapping and manual T2* protocols. We find that interesting, because those two methods use the same image source for calculations, as well as because the time required for image acquisition and processing is approximately ten times shorter for the automated T2* mapping protocol than for the manual T2* protocol. for the manual T2* analysis. Those authors compared R2* values to the biopsy-determined LIC, using three different MRI methods, demonstrating that the estimations obtained with the shortest first TE correlated most strongly with the directly measured values,10. Those values are easily calculated with a Microsoft® Excel spreadsheet, on which myocardial and hepatic iron concentrations can be estimated by inputting the mean SI values for each TE.In the present study, we chose to use the conversion proposed by Hankins et al. and can accurately identify high concentrations of iron. In the present study, we found that T2* mapping produced results similar to those of manual T2*, with low levels intraobserver and interobserver variability.Parametric maps require specific sequences and software capable of performing the curve fits and generating maps without the need for manual user input. Unfortunately, there is great heterogeneity among the sequences and software implemented by different MRI equipment manufacturers, resulting in variation among estimated LIC measures. This is a major limiting factor for the use of this method in clinical practice. Nevertheless, studies have shown that T2* mapping can detect liver hemosiderosisOur study has some limitations. We employed only one 1.5 T MRI scanner, and it was therefore not possible to compare reproducibility between or among different devices. In addition, we included a limited number of subjects, especially in the control group. We also had no measure of serum ferritin in the control subjects and therefore cannot exclude the possibility of iron deposition, which can be seen in asymptomatic patients, in that group.Our findings indicate that T2* mapping of the liver is a promising new tool for the rapid diagnosis of hepatic iron overload, and that T1 mapping is less accurate for that purpose. Further studies are needed in order to improve understanding the value of T1 mapping in clinical practice and to propose changes to overcome intrinsic limitations of the manual T2* protocol in LIC estimation. There are various robust T2* methods that could be routinely used for estimating LIC.


Obesity represents one of the most challenging public health problems of our century. It accounts for approximately 5% of deaths worldwide, mostly owing to cardiovascular disease and its associated complications. Cardiovascular noninvasive imaging may provide early accurate information about hypertrophy and ischemia/fibrosis in obese subjects. Echocardiography and nuclear cardiology have serious limitations in obese subjects owing to poor acoustic window and attenuation artifacts, respectively. Coronary computed tomography angiography can provide information about obstructive coronary disease; however, the use of radiation is a serious disadvantage. Finally, cardiac magnetic resonance (CMR) holds the promise of an “all in one” examination by combining evaluation of function, wall motion/thickness, stress rest/perfusion, replacement and diffuse fibrosis without radiation. Future studies are required to document the cost/benefit ratio of the CMR in the evaluation of cardiovascular risk in overweight/obese children and adolescents. Obesity represents one of the most challenging public health problems of our century owing to both its epidemic proportions worldwide and the associated significant morbidity and mortality. Obesity accounts for approximately 5% of deaths worldwide, mainly due to cardiovascular disease (CVD) and its associated complications ,2,3. TheObesity in childhood and adolescence has also reached epidemic proportions worldwide. According to the World Health Organization (WHO), 41 million children under the age of 5 years and more than 340 million children and adolescents aged 5–19 years are overweight or obese ,3. OverwObesity promotes the development of CVD due to the increased prevalence of atherosclerosis. It has been documented that atherosclerotic vascular lesions have a more rapid evolution in obese patients compared with patients with normal body mass index (BMI); therefore, obesity represents an independent risk factor of coronary artery disease (CAD) ,14. FurtIn addition to the above, obesity increases both the aldosterone concentrations and the mineralocorticoid receptor expression, which promote interstitial cardiac fibrosis with concurrent platelet aggregation and endothelial dysfunction, finally leading to heart failure ,18. LastThe most typical cardiac change in obese children is the increase in myocardial mass, known as hypertrophy . AccordiIn a study of obese children, 42% of those with normal blood pressure had concentric remodeling and 23% concentric hypertrophy. However, hypertensive, obese children had a two-fold higher incidence of concentric hypertrophy compared to normotensive controls, which is not associated with fractional shortening .Various echocardiographic studies show increase , decreasThe noninvasive cardiac imaging modalities used for CVD assessment in obesity are detailed below.TTE represents the cornerstone of cardiac imaging. It is a widely available, inexpensive, bedside, radiation-free modality with great experience among cardiologists. However, it is limited by the operator and acoustic window dependency . In almoIt is difficult to evaluate the role of obesity in diastolic function because most of the obese patients are hypertensive, and 30% of them are diabetics. However, it is already known that there is a significant correlation between BMI and left atrial pressure, expressed by the E/Em ratio . FurtherIt is important to underline the significance of the left atrium in obesity. Left atrium enlargement usually coexists with LV hypertrophy, and BMI correlates with both left atrial dimensions and progressive dilation during the follow-up, independently of blood pressure . As a reFinally, epicardial fat is present between the epicardial and the parietal pericardium, mostly in obese subjects with increased cardiometabolic risk . SeveralTTE, including the new echocardiographic techniques, can identify early subclinical LV-RV changes related to obesity, but in many cases, the presence of epicardial fat leads to poor acoustic window ,48. Howe2A receptor agonist, has been proposed as the ideal representative of pharmacologic stress. It is a coronary vasodilator agent of immediate and short activities that can be administered as a fixed-dose bolus without modification according to body weight. It is safe for all patient groups and has great efficacy regardless of BMI [In nuclear cardiology, if exercise is used as a stress factor, the poor exercise capability of obese subjects may lead to underestimation of stress ischemia. To avoid the limitations of the exercise test, pharmacologic stress factors have been used. In this context, regadenoson, a selective adenosine As of BMI .Another important issue in nuclear cardiology is the soft tissue attenuation of radioactive tracers leading to artifacts and poor signal-to-noise ratios in single-photon emission computed tomography (SPECT) imaging . TherefoObesity can also alter the I-123 metaiodobenzylguanidine indices of cardiac sympathetic innervation in patients with heart failure, supporting a role of obesity in impairing sympathetic innervations . It is eCCTA can provide an accurate, reproducible and noninvasive evaluation of the atherosclerotic, coronary arteries plaques. New imaging algorithms using reduced radiation dose improve the diagnostic capability in heavily calcified arteries of patients with severe obesity or irregular cardiac rhythm. Furthermore, computed tomography myocardial perfusion imaging can quantify myocardial ischemia with simultaneous CCTA acquisition using a low amount of contrast agent and radiation . In seveThe great advantage of CMR is that it can provide direct information about the status of all cardiac tissues noninvasively and without radiation . The basCMR is the gold standard for quantification of visceral and epicardial fat, which can negatively affect cardiac function . FurtherCMR has also been used to evaluate changes in cardiac remodeling, which begins as early as the age of eight years. Obese patients with concentric hypertrophy and impaired strain are at higher risk demanding more intense evaluation . FurtherObesity is a significant risk factor for increased morbidity and mortality owing to cardiovascular disease. Cardiovascular noninvasive imaging can provide early accurate information about hypertrophy and ischemia/fibrosis in obese subjects. Echocardiography and nuclear cardiology have serious limitations in patients with obesity owing to poor acoustic window and attenuation artifacts, respectively. CCTA can provide information about obstructive coronary disease; however, the use of radiation is a serious disadvantage. Finally, CMR holds the promise of an “all in one” examination by combining evaluation of function, wall motion/thickness, stress rest/perfusion, replacement and diffuse fibrosis without radiation. Multicenter studies are required to assess the cost/benefit ratio of the routine use of CMR in the early CVD assessment in subjects with obesity.


Left ventricular dysfunction is quite common in septic shock. Speckle-tracking echocardiography (STE) is a novel, highly sensitive method for assessing left ventricular function, capable of detecting subclinical myocardial dysfunction, which is not identified with conventional echocardiography. We sought to evaluate subclinical left ventricular systolic function in patients with septic shock using speckle-tracking echocardiography.  From May 2017 to December 2018, patients aged ≥18 years admitted to the intensive care unit with the diagnosis of sepsis and septic shock based on the sepsis-3 definition were included. Patients with other causes of cardiac dysfunction were excluded. Transthoracic echocardiography was performed for all the patients within 24 hours of diagnosis. Left ventricular systolic function was assessed using conventional echocardiography and speckle-tracking echocardiography. n = 90) (study group) and 37 matched patients with sepsis but no septic shock (control group) were included. Left ventricular ejection fraction (LVEF) by conventional echocardiography showed no significant difference between two groups . The global longitudinal strain (GLS) by STE was significantly reduced in patients with septic shock compared with that in the control . Based on the cutoff value of GLS ≥ −15% for the definition of subclinical left ventricular systolic dysfunction, this dysfunction was detected in 50 patients with septic shock (55.6%) and in 6 patients in the control group (16.2%) (p < 0.05).  Patients with septic shock ( Speckle-tracking echocardiography can detect early subclinical left ventricular systolic dysfunction via the left ventricular global longitudinal strain compared with conventional echocardiographic parameters in patients with septic shock. Sepsis and septic shock are the main reasons for hospitalization and also the leading causes of death and disability in America and are associated with nearly US$17 billion in healthcare costs each year , 3. ThisSepsis-induced myocardial dysfunction may include left ventricular systolic dysfunction, left ventricular diastolic dysfunction, and right ventricular dysfunction, alone or in combination.Two-dimensional echocardiography is a noninvasive, low-cost imaging technique that allows both qualitative and quantitative evaluations of cardiac function in septic patients . HoweverSpeckle-tracking echocardiography (STE) is a new imaging technique that can overcome some of these limitations , 8. It mThe purpose of this study is to assess left ventricular systolic function using speckle-tracking echocardiography in patients with septic shock. We hypothesize that speckle-tracking echocardiography is a sensitive tool in the early identification of left ventricular systolic dysfunction, which is not diagnosed by conventional echocardiography in septic shock patients.We performed a cross-sectional study in a twenty-five-bed intensive care unit of 108 Military Central Hospital from May 2017 to December 2018. The research protocol was approved by the institutional review board of 108 Military Central Hospital, Vietnam. Written informed consent was obtained from all participating patients or their legal representatives.All patients aged 18 years or older admitted for sepsis and septic shock based on the sepsis-3 definition  that devExclusion criteria included a documented ischemic heart disease at any point in the medical history, the presence of heart failure, moderate to severe valvular disease, valvular prosthesis, postthoracic operation, cardiac arrhythmia, postcardiopulmonary resuscitation status, poor echocardiographic image quality, and patients or their relatives who declined participation.Baseline clinical variables within the first 24 hours after admission were collected from medical records including age, sex, comorbidities, hemodynamic parameters, vasopressor or inotropic dose, sequential organ failure assessment (SOFA) score , and acuSepsis and septic shock were defined according to the sepsis-3 definition . Sepsis Transthoracic echocardiography was performed for all the patients within 24 hours after the onset of septic shock or sepsis on the first day of ICU stay.Echocardiographic exams were performed using Vivid S5  equipped with a 1.5–4 MHz phased array probe. All studies were performed by cardiologists with advanced training in echocardiography. All images and measurements were collected from standard views and digitally stored for offline analysis. Conventional echocardiographic measurements were obtained according to the guideline by the American Society of Echocardiography . The folCardiac output is calculated using velocity-time integration derived from pulse-wave Doppler echocardiography at the left ventricular outflow tract.The LV global longitudinal strain (GLS) was calculated in the longitudinal three-chamber, two-chamber, and four-chamber views by 2D-speckle-tracking echocardiography with high-quality ECG gated images. The frame rate was set at between 50 and 90 frames/s, and a minimum of three cardiac cycles were obtained for each loop. The images were analyzed using software with the EchoPAC workstation . The left ventricular endocardial border was manually traced in the end systole. Subsequently, software generates a speckle-tracking region-of-interest (ROI) to include the entire myocardium between the endocardium and the epicardium. The left ventricular was divided into 18 myocardial segments. Longitudinal strains for each segment were recorded and presented as a bull's eye. The strain values for all the segments are recorded and averaged to obtain the global longitudinal strain. GLS is presented as a percent change (%). Negative values of GLS indicate myocardial contraction. The predefined cutoff for subclinical left ventricular systolic dysfunction in patients with septic shock was defined by a GLS ≥ −15% (less negative than −15%) according to the previous studies –16.t-test or Mann–Whitney test. Categorical data were analyzed using the chi-squared test or a Fisher exact test. p value <0.05 was considered significant in two-tailed statistical tests.Statistical analysis was performed using SPSS version 20.0 software . The descriptive data were presented as mean value ± SD for continuous variables and as frequency (%) for categorical variables. Continuous variables were compared based on the Student's Between May 2017 and December 2018, 174 consecutive adult patients were diagnosed with septic shock and sepsis, admitted to the ICU. Seven patients were excluded because of moderate to severe valvular disease, 2 because of prior cardiac surgery, 1 because of infective endocarditis, 6 because of ischemic heart disease, 2 because of postcardiopulmonary resuscitation status, 4 because of death before having echocardiography, and 25 because of insufficient image quality for STE analysis. The remaining 127 patients were eligible for assessment. All the patients were divided into two groups, including 90 patients with septic shock and 37 patients with sepsis as a control group. Details of the excluded patients are presented in The baseline clinical characteristics of the analyzed patients are shown in p < 0.001).The mean age was 68.8 ± 15.1 years and 64.1 ± 19.8 years in septic shock patients and control. There were no significant differences in age, sex, underlying diseases, or site of infection between the two groups. SOFA score and APACHE II score were significantly higher in patients with septic shock than the control (p < 0.001). In-hospital mortality rates in septic shock patients (43.3%) were significantly higher than those in the control (10.8%).The proportion of patients with continuous renal replacement therapy and mechanical ventilation was significantly higher in the septic shock group compared with the control group (p < 0.001) and a higher heart rate  compared with the control group. There were no significant differences in central venous pressure and cardiac output between the two groups.The septic shock group had a lower mean arterial pressure , in apical 4-chamber view (−14.5 ± 3.3 vs. −17.0 ± 2.7), in apical 2-chamber view (−14.3 ± 3.9 vs. − 16.9 ± 2.8), and in global longitudinal strain (−14.6 ± 3.3 vs. −17.1 ± 3.3), p < 0.001 (p < 0.001).Septic shock patients showed significantly less negative values of longitudinal strain in apical 3-chamber view . Our results are similar to the previous studies in which authors compared GLS by speckle-tracking echocardiography with LVEF measurement. Dalla et al. reported that septic shock patients have a lower GLS compared to patients with trauma and controls, despite no significant differences in LVEF [In the present study, we confirm the value of speckle-tracking echocardiography in evaluating left ventricular systolic dysfunction in septic shock. Our study demonstrated that the global longitudinal strain from STE was able to detect early impaired cardiac function, compared with LV ejection fraction from conventional echocardiography in septic shock. The septic shock group had a higher degree of myocardial dysfunction measured by left ventricular global longitudinal strain (GLS). Meanwhile, LVEF had no significant difference between the two groups of patients  is a well-known index of LV systolic function and is sensitive to subendocardial fiber impairment . So, it Global longitudinal strain can be measured by multiple methods, including speckle-tracking echocardiography (STE), tissue Doppler imaging (TDI), and cardiovascular magnetic resonance (CMR) . Specklep < 0.05). Several studies have shown similar results with an impaired left ventricular systolic function in 30 to 60% of patients with septic shock [Many previous studies have suggested that LV longitudinal systolic dysfunction should be defined when GLS ≥ −15% –16. Withic shock , 25.α and IL-1β, and mitochondrial dysfunction [This study revealed that although the LVEF was preserved, the GLS decreased in patients with septic shock. Thus, STE can detect impaired LV systolic function in early septic shock that may be missed by conventional echocardiography. The mechanisms underlying changes in the longitudinal strain with septic shock are not fully understood. Some hypotheses such as microvascular vasoconstriction in the subendocardial muscle layer  and altefunction . Severalfunction –31. Howefunction . Severalfunction , 19.β-blockers [The early identification of sepsis-induced myocardial dysfunction might play an important role in the management of patients with septic shock by using blockers , 33.This study had some limitations. Firstly, this was a single-center study with small sample size. Secondly, we did not evaluate the longitudinal strain during recovery from septic shock to determine whether longitudinal strain values are regressive baseline values. Thirdly, speckle-tracking echocardiography is a novel technique requiring adequate endocardial border identification, which may be challenging because of fluid resuscitation and mechanical ventilation. Fourthly, tachycardia is a common sign of sepsis and septic shock. However, a high heart rate may be a factor affecting global longitudinal strain measured by STE in sepsis and septic shock. Finally, our data were not compared to other modalities of quantifying ventricular function, such as cardiovascular magnetic resonance imaging.In summary, speckle-tracking echocardiography can detect early subclinical left ventricular systolic dysfunction via the left ventricular global longitudinal strain, compared with conventional echocardiographic parameters in patients with septic shock. Speckle-tracking echocardiography may be a useful tool for early detection of septic cardiomyopathy.


Cardiac arterial spin labeling (ASL) MRI might become an important technique for quantitative mapping of myocardial blood flow in humans. A previously proposed gradient echo ASL technique has provided high spatial resolution but without external validation against microspheres technique.in vivo myocardial perfusion measurements and coronary flow reserve by gradient echo arterial spin labeling (ASL) MRI in rats anesthetized with isoflurane against fluorescent microspheres technique as standard of reference.The purpose of this study was to validate 2. Heart rate, breath rate, temperature, blood oxygen saturation and arterial blood pressure were recorded. In 7 rats, myocardial perfusion was assessed on a Bruker Biospec 4.7 T horizontal MRI system using an ECG- and respiration-gated IR gradient-echo technique  at rest and during adenosine infusion (140 μg/kg/min). In the 14 other animals, under the same physiologic conditions, a mixture containing 200,000 fluorescent microspheres  was injected into the left ventricle at rest in 7 animals and during adenosine infusion in 7 other animals. The animals were killed by instantaneaous injection of pentobarbital. Hearts were harvested and samples were processed for fluorescence spectroscopy. A two-tailed unpaired Student's t-test was used to compare groups, All values are given as mean ± SD.Male Wistar rats  were anesthetized with 2.1% isoflurane added to 1 l/min of pure OThere was no statistical difference between myocardial perfusion at rest assessed with ASL (6.5 ± 1.4 ml/g/min; Figure Non-invasive gradient echo ASL MRI provides accurate and reliable myocardial perfusion maps and assessment of coronary flow reserve with high spatial resolution. This study has provided validation of gradient echo ASL against an external gold standard technique.


In this prospective cohort study of HIV patients with exercise limitation, we use cardiopulmonary exercise testing (CPET) coupled with exercise cardiovascular magnetic resonance (CMR) to elucidate etiologies of dyspnea.Human Immunodeficiency Virus 2) peak was reduced at 23.2 ± 6.9 ml/kg/min with 20 patients  achieving a respiratory exchange ratio > 1. The ventilatory efficiency (VE)/VCO2 slope was elevated at 36 ± 7.92, while ventilatory reserve ) was within normal limits. The mean absolute right ventricular (RV) and left ventricular (LV) contractile reserves were preserved at 9.0% ± 11.2 and 9.4% ± 9.4, respectively. The average resting and post-exercise mean average pulmonary artery velocities were 12.2 ± 3.9 cm/s and 18.9 ± 8.3 respectively, which suggested lack of exercise induced pulmonary artery hypertension (PAH). LV but not RV delayed enhancement were identified in five patients. Correlation analysis found no relationship between peak VO2 measures of contractile RV or LV reserve, but LV and RV stroke volume correlated with PET CO2 .Thirty-four HIV patients on antiretroviral therapy with dyspnea and exercise limitation  underwent comprehensive evaluation with combined rest and maximal exercise treadmill CMR and CPET. The overall mean oxygen consumption (VOWell treated patients with HIV appear to have conserved RV and LV function, contractile reserve and no evidence of exercise induced PAH. However, we found evidence of impaired ventilation suggesting a non-cardiopulmonary etiology for dyspnea. Unexplained dyspnea in patients with human immunodeficiency virus (HIV) can be multifactorial and may portend a poor prognosis especially with diagnoses such as HIV pulmonary arterial (PA) hypertension (PAH) –3. IndeeA total of 34 patients were enrolled out of 53 eligible patients with HIV that were referred for functional assessment between May 2017 and January 2019 ; acute coronary syndrome, transient ischemic attack, stroke or critical limb ischemia during the last 6 months or coronary/peripheral revascularization within the last 3 months; concurrent potentially life threatening arrhythmia or symptomatic arrhythmia; documented left ventricular (LV) ejection fraction (LVEF) < 45%; evidence of pulmonary infection in the past 4 weeks; Evidence of another etiology of individual’s dyspnea such as reactive airway disease, heart failure, intrinsic lung disease, and decompensated cirrhosis; chronic kidney disease with estimated glomerular filtration rate (eGFR) of < 40 ml/min/1.73 m> 1.0. A 10-s averaged sampling interval was used to measure baseline and peak exercise PetCO2, ventilatory efficiency (VE/VCO2), ventilatory threshold (VT), and oxygen consumption (VO2) values. VT was determined by the v-slope method [2 (ml/kg/min) was defined as the maximum oxygen uptake during the last 60 s leading up to exercise termination. Heart rate and blood pressure were monitored continuously throughout the post-exercise scan. Arteriovenous oxygen (A-VO2) difference was calculated as previously described [Subjects were scheduled for combined CPET and exercise CMR  using a 32-channel phased array coil and a standard clinical protocol for structural, functional, and phase-contrast breath-hold imaging at rest was followed according to published international guidelines . A real-The assessment of RV and LV fibrosis were obtained using late gadolinium enhancement (LGE) imaging 10 min after administration of multihance gadolinium agent (0.15 mmol/kg). Short axis images were acquired using a single shot breath hold phase contrast inversion recovery technique of the entire myocardium. Images were assessed using a semi-quantitive method with HeartIT (Precession) imaging software. This method uses the American Heart Association 17 segment model where six segments for both basal and mid portions, four segments for apical and one segment for apex are scored. Each segment can yield a minimum of 0 for normal myocardium, 1 for 0–25%, 2 for 25–50%, 3 for 50–75% and a maximum of 4 for transmural 75–100% LGE/scar. The sum of the score was used to derive estimated percentage of myocardium with late gadolinium enhancement.P values of < 0.05 were considered significant. Bland altman analysis was done in 10 subjects for right and left ventricle ejection fraction to assess for observer variability.Statistical analysis was performed using SAS . Categorical data were expressed as percentage while continuous variables were reported as mean ± SD along with 95% CI. Two-sided dependent group t-test (α = 0.05) was used to compare the differences between pre and post exercise CMR and CPET observations. To summarize the relationship between ΔCMR parameters and ΔCPET parameters univariate analysis was performed using simple linear regression. Predictors of RVand LV reserve were assessed using stepwise multiple linear regression. 2. The mean duration of HIV exposure was 23.9 years. Table 1) was 2.9 ± 8.6 L and a mean % predicted FEV1 of 91.9 ± 18.4 and mean % FEV1/ forced vital capacity (FVC) was 92.1 ± 12.0. Maximal voluntary ventilation (MVV), a surrogate for maximal ventilatory capacity, was calculated as FEV1 × 40 to measure ventilatory reserve. For the present cohort, the mean MVV was 116 and the mean VE (Max) 67.5 ± 29.2. The ventilatory reserve (VE:MVV) is a measurement of the intrinsic pulmonary limitations to exercise [2 was decreased at 23.2 ± 6.9 ml/kg/min and mean VE/VCO2 slope was increased at 35.8 ± 7.9 and overall with 20 patients  achieving a RER > 1 indicating a maximal exercise effort.Figure To assess contractile reserve, LVEF and RV ejection fraction (RVEF) and stroke volumes were quantified at rest and stress. Basal ventricular function ejection fraction for RV and LV were within normal limits Fig. , Table 42, VE/VCO2, PetCO2 relative to the change in RVEF, stroke volume and PA velocities  and quadricep  strength. Participants were graded on a scale of 0–5. Scores were averaged over 3 trials. We did not find significant evidence of muscle weakness in hand and quadriceps testing as all patients scored greater than 4 with testing.The presence of scar/fibrosis portends a poor prognosis in many cardiomyopathies. To assess for scar/fibrosis, we performed LGE imaging using single shot breath hold inversion recovery sequences in addition to stress imaging protocols. The presence of RV enhancement was not identified; however enhancement was seen in the LV in five (15%) of 34 patients with average scar burden of 5.6%. Predominant location of scar was found in the mid myocardium or junctional RV insertion site. Subendocardial or transmural scar indicative of prior infarct was not observed.For consistency, CMR images were read by two experienced cardiologists for RV and LV volumetric analysis as well as average velocities. We used random effects model to evaluate inter-rater reliability . Our resIn the present study, we sought to evaluate causes of dyspnea in a cohort of well treated HIV patients with exercise limitation and no overt signs of PAH using a comprehensive combined CPET/CMR platform that would allow unprecedented ability to simultaneously assess for multiple central and peripheral etiologies of dyspnea . Overt e2 peak and VCO2) in this HIV patient population with mild subjective dyspnea. This is well described and has been noted by us and others [2 capacity, we systemically interrogated for cardiac causes of dyspnea. We considered exercise-induced increase in pulmonary vascular resistance, given that this may present with dyspnea and considered an early marker for resting PAH [We initially identified substantially impaired maximal exercise capacity  and elevated peak VE/VCO2 (mean 35.8). The mean PetCO2 at VT was also reduced at 27 mmHg. Lewis et al., demonstrated in patients with heart failure with reduced ejection fraction, VE/VCO2 slope is negatively correlated to RVEF and significantly associated with pulmonary vascular resistance during exercise, without relationship to LVEF or systemic resistance [2 slope and resting RVEF or with RV contractile reserve. This may have been related to the fact that our patient population did not have evidence of resting or provoked abnormalities in contractile function. However, the variability of LV and RV stroke volume were directly related to changes in PetCO2  and left ventricular ejection fraction (LVEF) contractile reserve.Additional file 2: Figure S2 Bland Altman analysis of rest and stress average pulmonary artery velocity as assessed using real time velocity encoding sequence.Additional file 3 Table S1 Pearson Correlation Coefficients