Undisturbed bioelectricity is a prerequisite for normal organ function. This is especially true for organs with high electrical activity such as the heart and the nervous system. Under clinical conditions, however, this can hardly be determined in patients with disturbed organ function and is therefore largely ignored. Here, based on clinical data, we will discuss whether the direct application of an external electric current  together with an electrical field to hearts with impaired pump function can explain the functional improvement of the hearts by edema reduction triggered by electro-osmosis. A recently reported longitudinal study identified an increased left ventricular ejection fraction with a reduction in end-systolic and end-diastolic left ventricular size along with an increase in 6-min walk, NYHA functional class, and quality of life.3 This short report proposes a mechanism of action for the early recovery of cardiac function that has been observed in the initial experience of microcurrent application.There is a rapid functional improvement that can be demonstrated after only a few hours of microcurrent application . If the 4–6 Physical forces govern fluid filtration to a certain degree. Myocardial edema, the excess accumulation of fluid in the myocardial interstitium, develops when there is an imbalance between filtration from the coronary microvasculature, removal of interstitial fluid through lymphatic vessels, and epicardial transudation.8 Under pathophysiological conditions, large quantities of proteins accumulate in the interstitial space, producing an osmotic/oncotic sucking force that drives fluid flow into the tissue and prevents fluid absorption back into the circulation. This chain of events creates the essential conditions for the formation of edema.9Although it receives little attention because of the lack of direct therapeutic interventional options and because its exact effect on the impairment of cardiac function is unknown, myocardial edema plays an essential role in the physiology of cardiac function and the pathology of heart failure.10–14 Myocardial edema impairs myocyte contractility and is responsible for systolic and diastolic dysfunction.15–17 Experimental data suggest that when myocardial fluid content is increased by only a few percent, cardiac output can easily be compromised by >15%.19 Recently, a murine model of increased coronary sinus pressure inducing myocardial edema demonstrated significant cardiac contractile dysfunction within 24 h and the subsequent development of epicardial inflammation and fibrosis in the left ventricle.20 Postmortem data of patients who died from cardiovascular diseases show a 30% increase in heart weight for men and a 22% increase for women, largely because of myocardial edema.22Alteration of capillary permeability by inflammation (capillary leakage), loss of charge of the highly negatively charged glycocalyx, the inability of lymphatic system to drain the increased fluid, or a combination of these factors leads to the formation of myocardial edema.23–26 Moreover, beyond acute inflammatory cardiomyopathies associated with severe myocardial edema, a number of other cardiac conditions predispose to interstitial edema in the myocardium. After myocardial infarction, myocardial edema remains detectable for as long as 6 months.27 Untreated acute myocardial edema is at least partially responsible for early death after myocardial infarction.29 Consequently, cardiac contractile (systolic) dysfunction is probably an important factor contributing to the insufficient cardiac lymphatic drainage observed after myocardial infarction.30 Myocardial edema has been detected among patients with arrhythmias who require support with defibrillators.31 Patients with diabetes are more likely to experience long-lasting myocardial edema after infarction than are patients without diabetes.32 Pulmonary hypertension has been associated with myocardial edema in patients with impaired left ventricular function.33 Across the spectrum of heart failure, patients with dilated cardiomyopathy and reduced ejection fraction (HFrEF), mid-range ejection fraction (HFmEF), as well as patients with preserved ejection fraction (HFpEF), can exhibit substantial degrees of interstitial edema in the heart.34–37Patients have been known to experience massive myocardial edema during acute myocarditis, requiring immediate intervention with mechanical assist pumps.38 For adequate drainage of the interstitium and transport of lymph, the lymphatic vessels require normal pumping function of the heart within certain limits. Thus, impaired cardiac function contributes to impaired lymphatic flow and leads to myocardial edema39Furthermore, because of capillary leakage and overstrained lymphatic drainage, any type of myocardial or systemic inflammation, including SIRS and sepsis, can probably also be associated with various degrees of myocardial edema.41 In addition, there is evidence indicating that the excitation-contraction uncoupling induced by myocardial edema causes contractile dysfunction.42 Experimental removal of edema leads to an immediate improvement in the contractility of the heart.30The fatal feature of myocardial edema formation is that it not only impedes the pumping function of the heart in a purely mechanical manner but also exerts a proinflammatory effect, induces fibrosis, stimulates exuberant collagen synthesis in the interstitium by upregulating transforming growth factor-beta and the pro-collagen type I and type III, resulting in increased collagen deposition.43Thus, a therapeutic strategy is needed to allow patients to escape the vicious circle of edema, inflammation, and fibrosis associated with the frequently observed decline in cardiac function. This strategy should improve lymphatic flow independent of capillary permeability  and pressure conditions (hydrostatic and colloid osmotic) in the capillaries and the interstitium.45Electrorheology, electrokinetics, and, in particular, electrophoresis and electro-osmosis describe the transport mechanisms of fluids or charged particles, mechanisms that are induced by the application of an electrical field or a direct current, in which an electrical field is inherent. Electrophoresis is well known in medicine as a method of inducing the migration of charged colloidal particles or molecules suspended in a solution by means of an electrical field, with the intention of separating and analyzing them in turn. In addition, within a living organism electrophoresis plays a relevant role in the distribution of molecules.47 Electro-osmotic flow may occur through small-channel structures such as gap junctions, capillaries, cells, and cell membranes across a heterogenous group of tissues. In particular, electro-osmotic flow can be found in areas of high electrical activity.48–50 In addition to the flow generated by pulsatile or osmotic and hydrostatic pressure differences, electrokinetic flow is a relevant transport mechanism in even the smallest lymphatic and blood vessels.51 Thus, edema formation can be interpreted in part as a disturbed electrical environment generating a potential gradient in the myocardium. This environment includes the negatively charged intraluminal layer  of the fluid exchange vessels; this layer controls the permeability of the capillary wall and, in turn, the fluid balance and pressure conditions in the interstitium.52Although electro-osmosis is well known in biophysics and biology, it is hardly known in medicine. It describes the phenomenon of the movement of a liquid through a capillary vessel bearing a surface charge caused by an electrical field parallel to the surfaces of the vessel.50An externally applied weak electric current together with an electrical field can interrupt the vicious circle of edema formation and impaired cardiac performance. It normalizes the electrical environment with the consequence of increasing lymphatic flow by supporting the electrokinetically induced transport of electro-osmosis and electrophoresis and may also influence the charge of the glycocalyx.EO of the electro-osmotic flow in response to an electrical field can be described by the Helmholtz–Smoluchowski relation:The velocity V0 the dielectric constant of vacuum, ζ is the zeta-potential of the relevant particles in the fluid, V is the strength of the external applied electrical field, and η is the viscosity of the fluid (blood and lymphatic fluid). More details about this process have been previously published.53where ɛ is the permittivity of the medium (blood and lymphatic fluid), ɛFrom this mathematical description, one can roughly estimate the strength of the electrical field that must be applied to achieve a certain velocity of lymphatic drainage. It must be recognized that the applied electrical field is inhomogeneous and cannot always be perfectly aligned in parallel with the vessels. Interestingly, the direct proportionality between flow velocity and external electrical field allows the determination of flow velocity by field strength within certain limits .25Future translational work using cardiac magnetic resonance imaging to quantitate the degree of myocardial edema will determine if there is a correlation between the cardiac improvement achieved and the degree of resolution of myocardial edema induced by the application of a microcurrent. These studies could have important implications in acute cardiomyopathy syndromes, where the ability to reduce interstitial edema in the myocardium may promote cardiac recovery and prevent patients from progressive heart failure into cardiogenic shock.Today's heart failure therapy with pulsatile devices does not allow to clearly predict whether a patient will profit from the implantation of such a device. Information on existing edema might be used to stratify patients before implantation of a microcurrent device. Patients without myocardial edema will most likely not show a rapid increase in cardiac function immediately after the implantation; they must wait for the anti-inflammatory effect of long-term application of microcurrent on myocardial function.Without prejudging clinical confirmation, one could hypothesize that the spectrum of patients with heart failure who benefit from the application of microcurrent directly to the heart may be largely independent of the cause of the disease, depending only on the extent of myocardial edema.In conclusion, the early improvement in cardiac function after the application of a microcurrent directly to and around the heart could implicate favorable changes in myocardial edema, which heretofore has not been a clinical target in human heart failure.


Observational evidence suggests that physical activity (PA) is inversely and sedentarism positively related with cardiovascular disease risk. We performed a two-sample Mendelian randomization (MR) analysis to examine whether genetically predicted PA and sedentary behavior are related to coronary artery disease, myocardial infarction, and ischemic stroke.n = 17), accelerometer based PA (n = 7) and accelerometer fraction of accelerations > 425 milli-gravities (n = 7) as well as sedentary behavior (n = 6) in the UK Biobank as instrumental variables in a two sample MR approach to assess whether these exposures are related to coronary artery disease and myocardial infarction in the CARDIoGRAMplusC4D genome-wide association study (GWAS) or ischemic stroke in the MEGASTROKE GWAS. The study population included 42,096 cases of coronary artery disease , 27,509 cases of myocardial infarction , and 34,217 cases of ischemic stroke . We found no associations between genetically predicted self-reported moderate to vigorous PA, accelerometer-based PA or accelerometer fraction of accelerations > 425 milli-gravities as well as sedentary behavior with coronary artery disease, myocardial infarction, and ischemic stroke.We used single nucleotide polymorphisms (SNPs) associated with self-reported moderate to vigorous PA (These results do not support a causal relationship between PA and sedentary behavior with risk of coronary artery disease, myocardial infarction, and ischemic stroke. Hence, previous observational studies may have been biased.The online version contains supplementary material available at 10.1007/s00392-021-01846-7. Cardiovascular disease, including coronary artery disease and myocardial infarction are the main causes of morbidity and mortality worldwide –3. To reHowever, the causal relationship between PA and cardiovascular disease risk is not clear. One drawback of the current state of knowledge is that the majority of previous studies used questionnaires to assess PA . The useWe tried to disentangle the role of PA and cardiovascular disease risk using a two-sample Mendelian randomization (MR). MR is a form of causal inference employing instrumental variable analysis which utilizes genetic variants (SNPs) as instruments. This method has also been referred to as nature’s randomized controlled trial, since the genetic variants are allocated randomly at conception , 20. ThiWe used a five step approach for this two-sample MR analysis. We first identified genetic variants which are associated with MVPA, accelerometer assessed PA, accelerometer assessed fraction accelerations > 425 milli-gravities as well as sedentary behavior in the UK Biobank to be used as exposures. Second, the outcome variables for this two-sample MR were identified from genome-wide association studies (GWAS) for coronary artery disease, myocardial infarction, and ischemic stroke. Third, the SNP-exposure and SNP-outcome datasets were harmonized. Fourth, we performed the two-sample MR analyses. The last step included sensitivity analyses to ensure that the assumptions for MR analyses are met.Data for the genetic associations with self-reported and accelerometer-based PA to be used as exposures were obtained from two published GWAS conducted in the UK Biobank , 23. TheKlimentidis et al.  identifiP < 5 × 10–8) in the GWAS by Klimentidis et al. [r2 threshold = 0.001 and window size = 10 mB) [P < 5 × 10–8 [We initially selected 19 SNPs associated with self-reported MVPA at a genome-wide significance level    , myocardWritten informed consent was obtained from UK Biobank study participants and ethics approval of the UK Biobank was given by the North West Multicentre Research Ethics Committee, the National Information Governance Board for Health & Social Care and the Community Health Index Advisory Group. Both GWAS studies , 23 wereFor the studies participating in the coronary artery disease , myocardThe SNPs used as instrumental variables for MVPA, accelerometer-assessed PA and fraction accelerations > 425 milli-gravities explained 0.15%, 0.24%, and 0.23% of the variance, respectively. A total of 0.22% of the variance in sedentary behavior was explained by the SNPs identified by Doherty et al. .2) of acceleration in a mean 5-s window [A multiplicative random effects inverse-variance weighted (IWV) estimate was used as the principal outcome for this two-sample MR , 32. IVWs window . For dics window . Analyses window , Mendelis window . Reportis window .First, we examined the instrumental variable assumptions: i.e. the strength of the genetic instruments (IV1), IVs are not associated with confounders (IV2), and there is no residual IV-outcome association given exposure and confounders (IV3) . Additior2 > 0.8) in PhenoScanner [P < 5 × 10–8) with confounders or cardiovascular outcomes. Previous research has identified spiroergometric markers  [IV1 was assessed by calculating the F statistic for each instrumental variable . IV2 wasoScanner , GWAS caoScanner  and GWASoScanner  to identapacity) , anthropapacity)  and educapacity)  as potenapacity)  to assesapacity) , 48. IV3The two-sample MR assumptions were evaluated by performing additional sensitivity analyses. The weighted median MR method is robust to potential unbalanced horizontal pleiotropy. Horizontal pleiotropy violates the exclusion restriction assumption, because in this case the instrumental variables are associated with other traits (i.e. intermediates) which influence the outcome . To detehttps://klimentidis.lab.arizona.edu/content/data (access date: 2020/01/27) and summary data for the GWAS by Doherty et al. [https://doi.org/10.5287/bodleian:yJp6zZmdj (access date: 2020/03/22). The GWAS for coronary artery disease and myocardial infarction [http://www.cardiogramplusc4d.org/data-downloads/). The GWAS for ischemic stroke [https://www.megastroke.org/download.html).Summary statistics for the physical activity GWAS by Klimentidis et al.  are avaiy et al.  are avaic stroke  can alsoP > 0.730), myocardial infarction , and ischemic stroke  , myocardial infarction , and ischemic stroke   were sufficient as evidenced by the high F-statistics with values of 29.9 or higher. Hence, IV1 was not violated since weak instrument bias was not present  and sedentary behavior  with coronary artery disease. Additionally, significant heterogeneity was found for the relationship between sedentary behavior with myocardial infarction . The results between MVPA and ischemic stroke were also influenced by heterogeneity .A modified Q-statistic was used to identify heterogeneity across individual SNPs (suppl. Table 7). Heterogeneity was identified for the association of fraction accelerations > 425 milli-gravities (Cochran’s P = 0.008) as well as myocardial infarction . To address potential balanced horizontal pleiotropy, weighted median estimates are reported. These results were similar to the IVW estimates. MR-Presso and MR-Egger methodologies were used to assess potential pleiotropy of the genetic instruments. These results did not differ from the observed effects for MVPA, accelerometer-assessed PA, and fraction accelerations > 425 milli-gravities on coronary artery disease, myocardial infarction and ischemic stroke in the primary analyses Tables , 4 and 5The current two-sample MR study used GWAS data on self-reported PA from 377,234 individuals, data from 91,084 UK Biobank participants with accelerometer-assessed PA as well as 91,105 subjects with information on sedentary behavior. Further, GWAS data from 42,096 coronary artery disease cases, 27,509 myocardial infarction cases and 40,585 ischemic stroke cases were employed. We found little evidence for an association between PA and sedentary behavior with risk of these cardiovascular outcomes. Although we used the largest currently available GWAS for PA, sedentary behavior, coronary artery disease, myocardial infarction and ischemic stroke, our results are in disagreement with the current scientific concensus with regards to the benefits of regular PA [In line with our findings, Doherty et al. recently performed a one-sample MR analysis to assess potential relations between device measured PA and sedentary behavior with coronary artery disease, stroke, heart failure, blood pressure, hypertension and anthropometric traits (BMI and body fat %) . No assoA possible explanation for our results is the relation between PA and cardiorespiratory fitness (CRF). We have previously shown that leisure time PA and sports are both positively related to CRF and inversely associated with cardiovascular mortality, whereas occupational PA is neither related to CRF nor to cardiovascular mortality . There iOur analysis has several notable strengths. The two-sample MR analysis enabled us to combine the largest GWAS on coronary artery disease, myocardial infarction and stroke to date with the largest GWAS on self-reported and device measured PA as well as sedentary behavior to increase the precision of genetically estimated PA, to reduce the potential for weak instrument bias, and to increase statistical power. Objectively measured PA is less prone to recall and response bias than self-reported PA .2 are very small and may be considered a limitation.Our study also had certain limitations. A two-sample MR analysis only provides unbiased risk estimates if the risk factor and outcome sample are derived from the same underlying population. The discovery GWAS of PA and sedentary behavior was based on data from UK Biobank participants of European descent aged 40–70 years . The undCardiovascular disease is the number one cause for morbidity and mortality worldwide –3. PA isSupplementary file1 (DOCX 565 kb)Below is the link to the electronic supplementary material.


Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe life-threatening manifestation of SARS-CoV-2 infection. Acute cardiac dysfunction and resultant cardiogenic shock are common in children with MIS-C. While most children recover rapidly from acute illness, the long-term impact on the myocardium and cardiac function is unknown.In this prospective study, cardiac MRI (CMR) was performed on patients <21 years of age with a history of MIS-C, 6–9 months following hospitalization. Per institutional protocol, patients with any history of LVEF<50%, persistent cardiorespiratory symptoms, or ECG abnormalities underwent clinical CMR. Research CMRs were offered to all others >10 years old. Native T1 and T2 mapping values were compared with 20 children with normal CMR examinations.We performed CMRs on 13 subjects at a median age of 13.6 years (interquartile range [IQR] 11.9–16.0) and a median time from hospitalization of 8.2 months (IQR 6.8–9.6). Twelve subjects displayed normal ventricular function with a median left ventricle ejection fraction (LVEF) of 57.2% (IQR 56.1–58.4) and median right ventricular (RV) EF of 53.1% (IQR 52.0–55.7). One subject had low normal EF (52%). There was normal T2 and native T1 as compared to normal controls. There was qualitatively no evidence of edema by T2 weighted imaging. One subject had late gadolinium enhancement (LGE) at the inferior insertion point and mid-ventricular inferolateral region, with normal EF, no evidence of edema or perfusion defects, and normal T1 and T2 times. When stratifying by a history of abnormal LVEF (LVEF <55%) on echocardiography, there was no difference in or parametric mapping values, though LVEF and LVEDV approached significance .Although many children with MIS-C present acutely with cardiac dysfunction, myocardial recovery is overall excellent with minimal to no evidence of residual cardiac dysfunction or myocardial involvement. LVEF by CMR at 6–9 months among children with history of echocardiographic LV dysfunction is slightly lower, though does not meet statistical significance and is still within normal range. The long-term functional implications of this finding and the cardiac implications of MIS-C more broadly are unclear and warrant further study. While children were relatively spared from severe acute disease secondary to the initial strains of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, some developed a severe hyperinflammatory process associated with SARS-CoV2–2 infection, termed multisystem inflammatory syndrome in children (MIS-C).–4 This sWhile mid-term clinical and echocardiographic reports to date have been encouraging, echocardiography cannot characterize the myocardium for the presence of fibrosis or edema that may be associated with long-term cardiac dysfunction or poor outcomes. Considering the similar degrees of systemic inflammation and myocardial disease noted in other viral-induced myocarditis during initial hospitalization, evaluating for the presence of significant long-term myocardial involvement is necessary. , 6 DespiCardiac magnetic resonance imaging (CMR) is the gold standard non-invasive tool for tissue characterization, and is now mainstay for diagnosing the presence of edema and fibrosis in the diagnosis of viral induced myocarditis., 8 More To date, CMR publications in children recovering from MIS-C are predominantly within the initial 3 months following hospitalization, and larger studies on mid-term outcomes have not incorporated quantitative markers of fibrosis or edema. –22 We peThis study was approved by the Institutional Review Board at Columbia University Irving Medical Center. Children and adolescents <21 years of age with a history of hospitalization for MIS-C and no known prior cardiac disease were recruited for participation in this study. All children with suspected MIS-C are evaluated by the Columbia University Interdisciplinary MIS-C Team and offered longitudinal follow-up by the Columbia University Interdisciplinary MIS-C Follow-up Program. Diagnosis and management of MIS-C at our institution follows our institutional protocol and has been previously described. All suspBy institutional protocol, all children with history of ventricular dysfunction (LVEF <50%), residual cardiac symptoms, including chest pain, palpitations, or exercise intolerance, persistently elevated inflammatory markers, or ECG changes/persistent dysrhythmia were referred for CMR 6–9 months following hospitalization for MIS-C. Families of all other children 10 years of older in the Interdisciplinary MIS-C Follow-up Clinic were approached for research CMR. This age cutoff was chosen to maximize the likelihood of a successful completion of the CMR exam without the need for sedation. Informed consent and assent were obtained for all subjects.All CMR studies were performed on a 1.5T GE Explorer CMR scanner . The CMR protocol included conventional balanced steady state free procession (bSSFP) cine imaging in long and short axis planes using end-expiratory breath holding or apnea based on anesthesia requirement. Cine imaging slice thickness was modified to obtain 10–12 images per short axis stack. Pre-contrast T2 mapping was performed in basal, mid, and apical short axis slices using a breath-held or apnea motion corrected turbo spin echo sequence with a T2 preparatory pulse and bSSFP readout with the following typical parameters: echo times: 11 ms, 41 ms, 71 ms, 100 ms; slice thickness, 8mm; bandwidth 780Hz/pixel; pixel size, 2.2 × 2.2 mm; FOV (mm) 350; phase FOV (%), 70%; temporal resolution, 127 ms; phase resolution, 160 × 160; acceleration factor of 2. and T2-weighted turbo spin echo (TSE) in basal, mid, and apical short axis slices was acquired. Native T1 mapping was obtained using electrocardiogram triggered modified Look-Locker inversion recovery (MOLLI) sequences in basal, mid, and apical short axis slices during diastole using a 5(3)3 sequence. Typical sequence parameters were: slice thickness, 8mm; flip angle, 35°; echo time, 1.6 ms, repetition time, 3.8ms, bandwidth 1250Hz/pixel; pixel size, 2.2 × 2.2 mm; FOV (mm) 350; phase FOV (%), 70%; temporal resolution, 261 ms; phase resolution, 160 × 160; acceleration factor of 2. First pass perfusion imaging was performed immediately following the administration of 0.2mmol/kg of Gadobutrol. Phase sensitive inversion recovery imaging was performed in long and short axis planes to assess for late gadolinium enhancement (LGE). All static sequences except for first pass perfusion, were performed using breath holding or apnea (based on anesthesia needs) at end-diastole.Image post-processing was performed using Circle CVI42 . Left and right ventricular  end-diastole and end-systole endocardial and epicardial borders were traced to determine end-diastolic and end-systolic volumes  were calculated by the equation ((EDV-ESV)/EDV)*100 and reported as percentages. Indexed EDV, ESV, and masses were calculated by dividing by body surface area (BSA). Volume and LV mass Z-scores were generated using published data. Z-scores between 2.0 and 3.5 were considered mildly enlarged, between 3.5 and 5.0 were considered moderately enlarged, and >5.0 were considered severely enlarged.T2 and T1 mapping were analyzed in the respective CVI42 modules. Endocardial and epicardial borders were traced with 10% offset to ensure that only myocardium was included in tracings . T2 and T2 TSE, first pass perfusion, and inversion recovery imaging were reviewed to determine the presence of edema, perfusion defects, and LGE, respectively. All imaging analyses were performed by a single pediatric cardiologist with extensive training and experience in pediatric CMR (MPD).Controls for native T1 and T2 mapping were retrospectively identified by review of the CMR database for patients with structurally normal hearts undergoing CMR to evaluate coronary anatomy with normal coronary origins, ECG abnormalities, or isolated PVCs/PACs to rule out arrhythmogenic RV dysplasia with normal biventricular size and systolic function and no evidence of LGE. CMR imaging performed solely to assess normal scanner T2 and native T1 times per Society of Cardiovascular Magnetic Resonance (SCMR) recommendation with qualitatively normal biventricular size and function were also included as controls.Descriptive statistics were presented as frequency counts and percentages for categorical variables and mean ± standard deviation (SD) or median  for continuous variables, as appropriate. Based on the distribution of the data, Student’s t-test or Wilcoxon rank sum was used to compare T1 and T2 values between subjects and controls. Spearman rho or Pearson correlation coefficient was used to assess associations between T1, T2, and LVEF as compared to lowest LVEF by echocardiography during hospitalization. The two-sided statistical significance level was set at 0.05. All data analyses were performed using STATA 14.1 .In total, 54 patients were admitted to Morgan Stanley Children’s Hospital with MIS-C between April 2020 and February 2021 and were eligible for inclusion. Thirty-two were followed for at least six months. Eight of these had cardiac dysfunction during initial hospitalization and, therefore, met clinical criteria for CMR. Of these, seven underwent CMR at our institution. Of these seven, one family declined to participate in this research. Two additional patients, hospitalized at an affiliated institution, were referred to our center for CMR. Of the eight children 10 years or older with normal cardiac function on admission followed for more than six months at our clinic, five agreed to participate .In total, 13 subjects were included in this analysis  and underwent CMR. Two subjects (15%) required anesthesia with endotracheal intubation for CMR. Of the subjects who underwent CMR, 9 (69%) were male. The median age at hospitalization was 13.1 years (IQR 11.3–15.0), with a median length of hospital stay of 5 days (IQR 4–6). Nine (69%) subjects required ICU admission. Five (41 %) subjects required inotropic support and 5 (41 %) required respiratory support, including intubation in one subject. All subjects received IVIG, aspirin, and pulse steroids during the acute presentation with a steroid taper following discharge. LV dysfunction and coronary artery dilation or prominence was present in the majority . Two subjects had residual ventricular dysfunction on discharge echocardiogram, which resolved by 3 months following discharge. Demographics and hospitalization data are described in CMRs were performed at a median of 8.2 months (IQR 6.8–9.6) months post hospital discharge and at a median age of 15.3 years . Twelve subjects (93%) had follow-up echocardiograms around the time of CMR at a median of 6.4 (IQR 5.9–7.4) months following hospitalization. By echocardiography, eleven subjects had normal biventricular function, and one subject had mildly diminished biventricular function. All subjects were asymptomatic and had normal ventricular size with no evidence of significant mitral or tricuspid regurgitation.On CMR, subjects had largely normal LV and RV ejection fraction (LVEF 57.2% (IQR 56.1–58.4); RVEF 53.1% (IQR 52.0–55.7)). Subjects overall had normal biventricular size and LV mass based on indexed ventricular size and mass and Z-score . One subThere was no evidence of edema based on T2 TSE imaging and no perfusion defects noted on first pass perfusion. One subject—different from the aforementioned—had LGE at the inferior insertion point and mid-ventricular inferolateral region, with normal ventricular function, no evidence of edema or perfusion defects, and normal T1 and T2 times. This subject had a prior history of moderate LV dysfunction by echocardiography, with an LVEF of 44%. Characteristics of the two subjects with diminished function and LGE are presented in Table 3T2 and native T1 times are presented in When stratifying subjects by ventricular function during initial admission, LVEF and LVEDV medians on CMR were marginally lower but not statistically different among those with and without a history of ventricular dysfunction . There was no difference in indexed ventricular volumes, RVEF, or T1 and T2 mapping values . SubjectThe emergence of SARS-CoV-2 has resulted in significant morbidity and mortality across the globe. We are only just starting to ascertain the long-term impact that this new virus will have on human health. Acute cardiac dysfunction is a prominent and critical manifestation for children who develop MIS-C following infection with SARS-CoV-2. Whether acute cardiac dysfunction during MIS-C ultimately results in permanent cardiac dysfunction or persistent inflammation as seen in other viral induced myocarditis syndromes remains undefined. Determining the presence of cardiac inflammation and myocardial damage has significant implications towards counseling, as the presence of residual inflammation may necessitate restrictions from sports participation until such inflammation has resolved.Improving our understanding of the potential lifelong impact that MIS-C will have on children’s cardiac health is therefore essential to our ability to guide families and determine treatment plans.We report on the mid-term CMR findings in children 6–9 months following hospitalization for MIS-C. Subjects overall have normal ventricular size and systolic function, with LV dysfunction present in only one subject. There is no evidence of edema and parametric mapping values were normal as compared to controls. LGE was present in only one subject with no evidence of perfusion defects and overall normal T1 times in this subject. Importantly, we show near-complete recovery in ejection fraction among subjects with a history of ventricular dysfunction.Our group previously reported on six-month echocardiographic findings in this population and demonstrated excellent recovery in almost all patients. While ecEarly CMR data among patients hospitalized with MIS-C has previously been reported, with variable degrees of edema and LGE, as well as diminished LV strain in those with LV dysfunction., 20, 22 Webster et al. previously reported on early term outcomes among children with a history of symptomatic COVID 1–3 months following presentation, including 6 subjects with MIS-C. They demBeyond presenting prospective data further from hospitalization, our study is novel in that we incorporated the use of a parametric mapping for myocardial tissue characterization in a cohort exclusively comprised of a MIS-C population. Parametric mapping is quickly becoming a standard of care method in the evaluation of myocardial edema and diffuse fibrosis in patients, and has recently been incorporated as part of revised Lake Louise criteria in the evaluation of myocarditis. Webster a priori decision to only obtain clinical CMR to patients who had evidence of cardiac dysfunction during initial presentation and few subjects willing to consent to a research CMR with contrast administration. Therefore, we may have been underpowered to detect differences in functional and myocardial tissue characterization parameters. Furthermore, younger subjects were excluded from research CMR; as a result, we may not be able to extrapolate our findings to those hospitalized at a younger age. That said, our sample is biased to those with initial cardiac dysfunction, and therefore would be biased to those most at risk. Finally, control data were available for native T1 and T2 values as part of recommendations by SCMR to obtain local references;(There are several limitations to this study. Our sample size is limited, due to an ferences; as contrferences;Our study demonstrates overall excellent midterm cardiac outcomes among this cohort of children with MIS-C. Recovery of ventricular function was nearly universal with minimal evidence of residual myocardial disease in our cohort. Long-term, larger-scale studies are needed to ensure complete recovery in those with residual disease and to identify if any children remain at risk for long-term myocardial disease and dysfunction after MIS-C.


Moreover, native T1 times and GLS were significantly lower in Lyso-Gb3 positive FD patients (p < 0.005 and p = 0.03). GLS, native T1 times showed significant moderate correlations to LysoGb3 (p = 0.002 and p < 0.001). Furthermore, GLS and native T1 times reduce when LysoGb3 was elevated and increasingly with presence of left ventricular hypertrophy (LVH) or late gadolinium enhancement (LGE). Conclusions: Native T1 times and strain values differ significantly between FD patients and control subjects and showed promising correlations to the FD specific biomarker LysoGb3. We therefore conclude that strain abnormalities occur early beside native T1 reductions in cardiac FD involvement. Large scale trials are needed to verify our findings.Purpose: Detection of cardiac involvement in Fabry disease (FD) is of high importance for treatment management. Native T1 mapping especially showed great potential for detection of early cardiac manifestations. Echocardiographic studies showed strain abnormalities in FD patients, but data on MRI feature tracking strain analysis (FT-SA) is limited. Therefore, the aim of our study was to evaluate the potential of FT-SA compared to native T1 and the FD specific biomarker Globotriaosylsphingosine (LysoGb3). Methods: 28 consecutive FD patients ) and 28 control subjects  underwent cardiac MRI at 1.5 Tesla. Global native T1 times and left ventricular FT-SA were evaluated. Results were correlated to serum Lyso-Gb3-levels. Results: Native T1 times, global longitudinal (GLS) and global radial strain (GRS) were significantly reduced in FD patients ( Fabry disease (FD) is an X-linked disorder of lysosomal metabolism. It is characterized by accumulation of glycosphingolipids (more precisely globotriaosylceramide) in many organs  due to a deficiency of the enzyme alpha-galactosidase . ClassicDue to the storage of glycosphingolipids in cardiomyocytes, left ventricular hypertrophy (LVH) is induced, moreover, valves and vascular endothelium are also affected . Later oCardiac magnetic resonance imaging (CMRI) is well established to verify cardiac involvement. Midmyocardial inferolateral late gadolinium enhancement (LGE) without endocardial affection is a characteristic hallmark beside unspecific cardiac findings such as reduced left ventricular (LV) function and LVH . In geneNative cardiac T1 mapping may solve the diagnostic dilemma. Low native T1 values are postulated to indicate accumulation of glycosphingolipids in FD and can be demonstrated in up to 59% of LVH-negative FD patients .Moreover, different studies showed significant reductions of native T1 times in patients with FD ,13,14 coFT-SA allows quantification of myocardial deformation on the basis of standardized acquired cine images without the need for additional dedicated sequences. Post myocardial infarction and in hypertrophic cardiomyopathy prediction of adverse clinical outcomes can be shown via FT-SA ,21. TherStudy population: 28 consecutive and genetically confirmed enzyme replacement therapy naive FD patients  and 28 control subjects  were enrolled in this prospective cohort study from January 2014 to June 2020. 2, incompatible implants , gadolinium intolerance, claustrophobia, or patient inability.FD diagnosis was based on a molecular genetic analysis demonstrating a heterozygous or homozygous mutation in the α-GAL-A-gene . All FD CMR technique: Standardized imaging was performed at a 1.5 Tesla MRI system  using a six-element phased array cardiac coil. The CMRI protocol contained thoracic survey images, CINE sequences, steady-state-free precession sequences (SSFP) aligned to short-axis, 2-, 3- and 4-chamber view , T2-wighted imaging (“black-blood” T2 turbo spin echo), LGE imaging (T1 gradient echo with inversion recovery) and native T1-mapping. Gadoteridol  was injected at a dose of 0.15 mmol/kg. LGE imaging was performed 12 min after contrast media injection. SSFP and CINE images were obtained during breath hold. The LV volume  was calculated from short-axis CINE images. Measurements were performed on end-diastolic images and end-systolic images. Endocardial contours of the LV were obtained by manual tracing with exclusion of papillary muscles and trabeculae from the cavity. Ventricular volumes were estimated using the Simpson rule. T1 mapping images were acquired at basal, mid-ventricular, and apical short-axis section by using a modified Look-Locker inversion-recovery (MOLLI “3-3-5”) sequence—11 images were acquired during 17 heartbeats, and after in-line motion, correction maps were generated . ImagingCMR analysis: Postprocessing was performed by using the cardiovascular imaging version 42 (cvi42) software including feature and tissue tracking . LV strain was quantified on contiguous SA CINE images  and log-axis CINE images aligned to 2-, 3- and 4-CV using the feature and tissue tracking software tool. Global longitudinal (GLS), radial (GRS) and circumferential (GCS) strains were analyzed for the left ventricle and were defined as the peak value of each strain. GLS analysis was performed via 4-CH CINE imaging and GRS or GCS was based on SA CINE imaging at midventricular level.Septal native T1 times were measured in region of interest (ROI) at basal short-axis section to guarantee proper T1 measurements caused by greater septal myocardial diameters compared to midventricular and apical sections. To avoid measuring of partial volume-averaging artefacts and registration errors with gradual T1 changes at myocardial borders, the ROI were drawn carefully, and software assisted by predefining an epicardial and endocardial offset of 10 percent. All measurements were performed by two experienced radiologists with 10 and 25 years of experience in cardiovascular imaging. LGE assessment was performed blinded to native T1 maps and CINE images. All T1 maps and LGE images were of diagnostic quality and could sufficient be evaluated. Intraobserver and interobserver variability were analyzed for septal native T1 mapping and feature tracking strain analysis including GLS, GRS and GCS. Initially, the first investigator (10 years of experience in cardiovascular imaging) performed septal native T1 measurements and feature tracking strain analysis blinded to patient demographics. To assess intraobserver variability, measurements were repeated after a period of 14 days. Moreover, a second experienced investigator (25 years of experience in cardiovascular imaging), who was also blinded to patient demographics, performed septal native T1 measurements and feature tracking strain analysis to determine interobserver variabilities.Laboratory assessment: Lyso-globotriaosylceramide (LysoGb3) was measured in serum at the (blinded for review). LysoGb3 values > 1.0 ng/mL were interpreted as elevated.t-test was used, and if the data were not distributed normally, the Mann–Whitney test (non-parametric) was used. Strengths of correlations were tested using the Spearman correlation coefficient. The correlation coefficient r was interpreted according to Hinkle et al. [Statistical analysis was performed using PRISM statistical software version 9 . Patient characteristics were described by mean ± SD. All data were tested for normal distribution using the Shapiro–Wilk test. In cases of normal distribution, Student’s e et al.  where r p = 0.025 and p = 0.026), whereas end systolic volume (ESV) differed not significantly. Intra- and interobserver variability were excellent for LVEF and for all measured cardiac volumes  in FD patients and control subjects (r between 0.9488 and 0.9823).LVH, defined as a septal myocardial diameter equally or greater than 13 mm in diastole, was present in six FD patients (21.4%) and in none of the control subjects. Septal diameter and myocardial mass did not differ significantly between FD patients and control subjects. The mean septal myocardial diameter was 9.8 mm ± 3.6 SD for FD patients and 8.4 m ± 1.6 SD for control subjects and the mean LV myocardial mass was 123.1 g ± 55.5 SD for FD patients and 103.6 g ± 30.0 SD for control subjects. p = 0.0064) compared to the control subjects, who had a mean native septal T1 time of 951.0 ms ± 47.3 SD . LGE at the inferolateral wall was present in seven of the FD patients (25%) and in none of the control subjects.The mean septal native T1 time for the FD patients was 921.1 ms ± 49.4 SD  and was statistically significant lower (p = 0.1218), FD patients had significant GLS and GRS reductions compared to the control subjects: GLS −18.0% ± 3.3 versus −20.5% ± 1.7 SD (p = 0.0009), GRS 33.6% ± 8.7 versus 41.4% ± 11.0 SD (p = 0.0184). Intra- and interobserver variability were excellent for septal native T1 time in FD patients  and for control subjects , for GLS  and , GRS  and , GCS  and .With exception of GCS  and a significant negative moderate correlation for septal native T1 times and LysoGb3 . All correlations are presented in Correlation of septal native T1 times, strain values and LysoGb3: The mean LysoGb3 level of the FD patients was 17.8 ng/mL ± 38.1 SD . Septal native T1 time and GLS revealed the best correlations to LysoGb3 with a significant moderate positive correlation for GLS and LysoGb3 . Cardiac function, cardiac morphology and strain values for LysoGb3 positive and negative FD patients are presented in p = 0.0053). Apart from the correlation of septal native T1 times to GLS all other correlations of septal native T1 times, strain values  were increased in LysoGb3 positive patients compared to all FD patients. Correlations are presented in p = 0.0069) and a significant moderate correlation for GCS and LysoGb3 .LysoGb3 positive and LysoGb3 negative FD patients: LGE was only present in LysoGb3 positive FD patients. Cardiac function, septal diameter and myocardial mass differed not significantly between LysoGb3 positive and LysoGb3 negative FD patients, whereas septal native T1 times and GLS were significantly reduced in LysoGb3 positive FD compared to LysoGb3 negative patients , septal diameter and myocardial mass differed not significantly. Moreover, septal native T1 times and GLS showed moderate correlations to LysoGb3 (FD specific biomarker);Compared to LysoGb3 negative FD patients, LysoGb3 positive FD patients had significantly reduced septal T1 times. Furthermore, correlations of strain values with LysoGb3 and septal native T1 times increased in LysoGb3 positive FD patients.Finally, subgroup analysis between 1. LysoGb3 negative FD patients, 2. LysoGb3 positive FD patients without LVH or LGE and 3. LysoGb3 positive FD patients with either LVH or LGE showed a steady decrease of septal native T1 time and GLS accompanied by a steady increase of LysoGb3. Hence, GLS initially reduces with storage (low native T1 times and elevated LysoGb3 level) and later with increasing LysoGb3 level and hypertrophy or scar (LGE).The main findings of our study are:Consistent with the results of previously published studies ,13,14, tThe main limitation of our study is the small number of patients. Otherwise, it is a prospective cohort analysis in a rare disease with untreated patients, and the results of the FD subgroup analysis revealed significant differences regarding native T1 times and FT-SA values. Our results may therefore serve as a starting point for further investigations assessing biomarkers, native T1 times and strain values in the course of FD.The steady GLS and native T1 decrease from LysoGb3 negative FD patients over LysoGb3 positive FD patients to LysoGb3 positive FD patients with presence of LVH or LGE and the promising correlations of strain values, native T1 times and LysoGb3 suggests that wall motion abnormalities occur early in cardiac FD involvement. We therefore suggest a diagnostic cardiac MRI algorithm in FD containing FT-SA beside native T1 measurements and LysoGb3 analysis to enable best possible early cardiac disease manifestation detection with the goal to avoid unfavorable disease progression due to early initiation of ERT. 1. LysoGb3 elevation and native T1 or FT-SA decrease—cardiac FD manifestation seems to be likely, 2. LysoGb3 elevation with both, native T1 and FT-SA decrease—cardiac FD manifestation seems likely, 3. LysoGb3 elevation with normal native T1 and FT-SA values—cardiac FD manifestation remains unclear and close controls should be performed.


The prevalence of both organic valvular heart disease (VHD) and cardiac arrhythmias is high in the general population, and their coexistence is common. Both VHD and arrhythmias in the elderly lead to an elevated risk of hospitalization and use of health services. However, the relationships of the two conditions is not fully understood and our understanding of their coexistence in terms of contemporary management and prognosis is still limited. VHD-induced left ventricular dysfunction/hypertrophy and left atrial dilation lead to both atrial and ventricular arrhythmias. On the other hand, arrhythmias can be considered as an independent condition resulting from a coexisting ischemic or non-ischemic substrate or idiopathic ectopy. Both atrial and ventricular VHD-induced arrhythmias may contribute to clinical worsening and be a turning point in the natural history of VHD. Symptoms developed in patients with VHD are not specific and may be attributable to hemodynamical consequences of valve disease but also to other cardiac conditions including arrhythmias which are notably prevalent in this population. The issue how to distinguish symptoms related to VHD from those related to atrial fibrillation (AF) during decision making process remains challenging. Moreover, AF is a traditional limit of echocardiography and an important source of errors in assessment of the severity of VHD. Despite recent progress in understanding the pathophysiology and prognosis of postoperative AF, many questions remain regarding its prevention and management. Furthermore, life-threatening ventricular arrhythmias can predispose patients with VHD to sudden cardiac death. Evidence for a putative link between arrhythmias and outcome in VHD is growing but available data on targeted therapies for VHD-related arrhythmias, including monitoring and catheter ablation, is scarce. Despite growing evidences, more research focused on the prognosis and optimal management of VHD-related arrhythmias is still required. We aimed to review the current evidence and identify gaps in knowledge about the prevalence, prognostic considerations, and treatment of atrial and ventricular arrhythmias in common subtypes of organic VHD. Valvular heart diseases (VHD) are frequent in the population, with estimated prevalence of 2.5% increasing with age in relation with predominance of degenerative causes in the elderly , 2. AtriCurrent guidelines reflect the underestimated relation between arrhythmias and VHD. Both atrial and VAs are poorly represented in AHA/ACC and ESC/EACTS guidelines on the managements of VHD , 12. TheNot only is management uncertain but mechanistic data on arrhythmia genesis in VHD remain rare. VA conceptualized as resulting from myocardial hypertrophy/fibrosis, has recently been attributed to the valve disease itself in the “arrhythmic MVP” , 15. EnlTherefore, it is crucial to review the available evidence to clarify management and plan appropriate trials for each type of VHD by identifying gaps in knowledge about prevalence, prognostic considerations and therapeutic options for atrial and VAs in VHD. We organized this review into chapters corresponding to the most common of VHD. Each chapter is further divided into sections addressing atrial and VAs. Separate sections successively describe the prognostic impact and current medical and interventional therapies of VHD-associated arrhythmias and highlight relevant questions for daily clinical practice. Conduction disturbances are beyond the scope of this review.The prevalence of AF in MR varies in the literature from 16 to 50%, depending on the method of detection, the definition of arrhythmia, and the populations studied  17, 18), 1817, 1via LA volume and pressure overload, progressive atrial fibrosis, and dilation, resulting in electroanatomical remodeling  regardless of symptomatic and rhythmic status when performed in a Heart Valve Center and a durable repair is likely  at the time of VHD surgery is growing but limited , 68. ResThere is an increasing emphasis on CA to prevent AF occurrence after mitral surgery. New-onset AF identified in 19-23% of patients 10 years after surgical correction of MR independently predicts subsequent stroke, heart failure and morbidity , 71. CA Valvular AF is intended to imply rheumatic VHD with mitral stenosis (MS) or mechanical heart valves, and is considered contraindicating non-vitamin K oral anticoagulants (NOACs)  13). In. In13). Bridging of oral anticoagulation therapy (OAC), when interruption is needed, is recommended in patients with mechanical prosthetic heart valve, AF with a CHA2DS2-VASc score ≥ 3 for women or 2 for men, acute thrombotic event within the previous 4 weeks and high acute thromboembolic risk .VKA therapy with target international normalized ratio (INR) 2.5 is recommended for the first 3 months after bioprosthetic mitral-valve replacement (MVR), regardless of the heart rhythm status, but after that period NOACs appear equivalent (2020 ACC/AHA) or should be considered over VKA (2021 ESC/EACTS) to prevent embolisms due to secondary AF , 12, 76.MVP prevalence in the general population is estimated between 1.7 and 2.4% . The yeaThere is currently a renewed interest in the study of this association of MVP with life-threatening VAs and this has led to the development of new concepts. Clinical presentation of “arrhythmic MVP” is often for palpitations and rarely syncope , but in Most cases of severe organic MR are treated by surgery. Correction of the flail leaflet MR has been suggested to be associated with a lower risk of SCD , 80, butIf mild to moderate MR is associated with PVCs or non-sustained VT, therapies that prevent SCD and provide symptomatic benefits should be considered. A history of palpitations or syncope or the detection of the phenotype associated with “arrhythmic MVP”   should pThere are no specific data on beta-blockers efficacy for prevention of SCD in the setting of organic MR or MVP, but they are widely used as a first-line medical therapy for suppressing frequent symptomatic or complex PVCs and VTs. Other anti-arrhythmic agents may also be effective in the management of VHD-associated VA but must be used cautiously, given their potential to cause adverse events. Class I C sodium channel blockers should be avoided in cases of VHD with prior myocardial infarction (MI) or hemodynamically significant VHD .In cases of non-responsiveness or a contraindication to antiarrhythmic agents, CA of symptomatic VAs originating from the papillary muscle in the presence of mild-to-moderate MVP has been reported to be effective –91. CathMitral stenosis is characterized by obstruction of left ventricular inflow, with a chronic increase in LA pressure, resulting in progressive LA enlargement . The preThe risk of the combined endpoint of stroke, systemic embolism, and all-cause mortality, is 4.2-fold higher in AF patients with MS as compared to patients with AF but without VHD , 12. In In patients with severe MS and recent onset AF, the 2021 ESC/EACTS guidelines recommend cardioversion soon after PMC . The useMS-associated AF is considered “valvular AF.” Accordingly, patients with moderate to severe MS and AF should be kept on VKA treatment, and NOACs are not recommended in this setting though recent data highlighted their potential efficacy , 12. VKAAS induces hemodynamic LV afterload increase, resulting in LV hypertrophy, chronically increased LV filling pressure, and LA enlargement, leading to increased AF risk . AF is, 2 incur the highest risk of death while those in SR with LAV ≤ 50 ml/m2 have the lowest mortality rate. Interestingly, patients with AF and LAV ≤ 50 ml/m2 show the same prognosis as those in SR with LAVI > 50 ml/m2—thus forming an intermediate-risk group , as compared to patients without documented AF (8-25%). Furthermore, preoperative AF has been identified as an independent predictor of perioperative and 5-year mortality in severe AS with low ejection fraction ( ≤ 35%) undergoing surgical AVR  or a class IIa recommendation (2021 ESC/EACTS) , 12. In Myocardial hypertrophy and fibrosis due to increased LV systolic afterload constitute a structural substrate for VAs . FrequenVAs in AS are clinically considered to be a marker of impaired ventricular function and a harbinger of syncope and SCD . In non-Mild-to moderate AS patients manifesting palpitations or syncope evocative of arrythmia should undergo a diagnostic work-up that includes heart-rhythm monitoring and treadmill test , 92, 112Specific data on medical and ICD therapy of VA in patients with AS is lacking. Beta-blockers for primary prevention of SCD have not been specifically evaluated in AS , but canAfter AVR, electrophysiology studies for VT demonstrated that most cases were consistent with macro-reentrant mechanism in relation to LV periaortic low-voltage area  measurement is recommended , 12. In In symptomatic patients with severe VHD in AF, it is extremely difficult for the clinician to distinguish symptoms related to VHD from those related to AF. This difficult issue has not been studied in the literature and is not discussed in current guidelines , 12. In In clinical practice, AF complicates the evaluation of all VHD and makes their quantification more difficult because most of the criteria used routinely are impacted by the arrhythmia. However, despite the widespread association between AF and VHD, there is no specific data in the literature on this subject. Therefore, the severity thresholds of VHD are not different for patients evaluated in AF , 130. HoAF is a common perioperative complication of cardiac valvular surgery . After eTarget INR for mechanical protheses in patients with AF are 0.5 higher than in patients in SR and varies between 3.0 and 4.0 depending on the type of protheses , 12. GivSeminal data suggest that arrhythmias are frequent in patients with VHD and may yield higher risk of cardiovascular complications and excess mortality. However, data are few and retrospective, implying that incidence, prevalence and outcome/management implications of clinical and subclinical arrhythmias remain undefined. Therefore, guidelines regarding detection and management of arrythmias in the context of VHD remain vague and limited. Hence, structured investigations are warranted to clarify pathophysiology, epidemiology, prognosis and treatment of VHD-associated arrhythmias.Holter monitoring is not systematically recommended and diagnosis of arrythmias in VHD still remains at individual cardiologist discretion. Little is known about prevalence and patterns of arrhythmias, particularly transient or subclinical, in specific subtypes of VHD. Thus, yield and indications of cardiac monitoring, using 12-lead Holter monitoring and more recent diagnostic tools such as sensitive loop recorders, should be determined prospectively in various VHD. Establishing burden, type, sites of origin and severity of atrial and ventricular arrhythmias using these methods and exploiting large registries is a starting point for further appropriate prospective research that warrants careful planning.Second, severity and prognostic implications of arrhythmias in patients with VHD will require large registries providing sufficient power to define clinical determinants and outcome implications accounting for well-defined covariates. The role of advanced electrophysiologic testing including programmed ventricular stimulation needs to be determined for complex clinical cases such as malignant MVP. Defining pathophysiology will require advanced imaging techniques, including cardiac MRI for the detection of ventricular fibrosis, hypertrophy and ischemic scars. Emphasis should be placed on quantifying the identified abnormalities such as fibrosis and to establish data-driven thresholds of severity for arrhythmogenic substrates. Similarly, identifying substrate for atrial arrhythmias will require imaging techniques aimed at overcoming uncertainties linked to wide variations of atrial alterations.Pilot data suggest that targeted therapies for VHD-related arrhythmia may be effective, clinical trials will be required to define indications and optimal timing of electrophysiologic interventions in specific VHDs. While beneficial effect of surgical ablation of AF during mitral valve surgery has been demonstrated, more research is needed to define optimal lesion sets for improved outcome and to analyze comparative efficacy and timing of percutaneous AF ablation. Approaches to arrhythmias in each specific VHD type and stage (mild to severe), regarding timing and type of interventions will require well designed clinical trials.While the risk of life-threatening VAs appears attenuated after valve surgery, the benefits and indications for ICD remains poorly defined. PVC ablation is more often performed recently, but it is unclear whether it is effective in improving quality of life or survival itself. Thresholds of PVC burden, type and severity for ablation therapy need to be defined as a preamble to clinical trials of this therapy.Therefore, while data on arrhythmias in VHD may raise alarms, their paucity yields poorly understood clinical implications and underpin the present call for new research that may ultimately improve outcomes of the large segment of the population affected by VHD.Valvular heart disease is often associated with arrhythmia, which predisposes patients to a higher risk of cardiovascular complications and excess mortality. Both atrial and ventricular arrhythmias may contribute to clinical worsening and be a turning point in the natural history of VHD. Symptoms developed in patients with VHD are not specific and may be also attributable to other cardiac conditions including arrhythmias. Atrial fibrillation, the most common atrial arrhythmia, is an important source of errors in echocardiographic evaluation of VHD. Evidences on prognostic impact and treatment of VHD-associated arrhythmias based mostly on retrospective studies are growing but the guidelines regarding detection and management of arrythmias in the context of VHD remain limited. Postoperative AF complicating valvular interventions is frequent and many questions remain regarding its prevention and optimal management. Despite the known evidences, and undeniable recent progress in understanding of underlying mechanisms, the association of VHD with arrhythmias still remains underestimated and structured research on its pathophysiological genesis, diagnosis, prognostic impact and optimal management are warranted.MK: conception and design of the research, analysis and interpretation of the data, and drafting of the manuscript. CC: critical revision of the manuscript for important intellectual content. YB: acquisition of data, analysis, and interpretation of the data. PL: critical revision of the manuscript. ME-S: critical revision of the manuscript for important intellectual content. CT: conception and design of the research, analysis and interpretation of the data, statistical analysis, critical revision of the manuscript for important intellectual content, and supervision. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Two variables in the EUROMACS score  were not predictive of RVF in our cohort. Overall, the EUROMACS score had poor external discrimination in our cohort with area under the curve of 58% (95% CI 52–66%). Further work is necessary to enhance our ability to predict RVF after LVAD implantation.The EUROMACS Right-Sided Heart Failure Risk Score was developed to predict right ventricular failure (RVF) after left ventricular assist device (LVAD) placement. The predictive ability of the EUROMACS score has not been tested in other cohorts. We performed a single center analysis of a continuous-flow (CF) LVAD cohort (n = 254) where we calculated EUROMACS risk scores and assessed for right ventricular heart failure after LVAD implantation. Thirty-nine percent of patients (100/254) had post-operative RVF, of which 9% (23/254) required prolonged inotropic support and 5% (12/254) required RVAD placement. For patients who developed RVF after LVAD implantation, there was a 45% increase in the hazards of death on LVAD support (HR 1.45, 95% CI 0.98–2.2,  A number of definitions of early right ventricular failure after LVAD exist. All include unplanned right ventricular assist device (RVAD) placement after LVAD implantation, however definitions vary by length and use of pulmonary vasodilators or intravenous inotropes5. Several prediction tools have been developed to try to capture risk of post-operative RV failure with pre-operative variables, however the performance of these models has been variable to poor on external validation6. One of the more recently published risk models was developed from the EUROMACS database7. This analysis included 2,988 patients implanted with LVADs in Europe in which 433 patients (21.7%) developed right ventricular failure. After performing logistic regression, a combination of five variables were found to be highly predictive of right sided heart failure. These variables include right atrial/pulmonary capillary wedge pressure > 0.54, hemoglobin < 10 g/dL, use of multiple intravenous inotropes prior to LVAD implantation, INTERMACS Class 1–3, and severe right ventricular dysfunction on echocardiography. The C-Statistic for this risk score was 0.7, which was higher than other risk scores that have been published. The performance of this score has been less than the development cohort in several small to intermediate sized external validation datasets (n = 93–194)10. The purpose of this study was to assess the performance of the EUROMACs score in a large, external continuous flow LVAD dataset and assess for other univariate predictors of RV failure.Right ventricular (RV) failure remains common after left ventricular assist device placement (LVAD) even in contemporary continuous flow eraThe institutional review board of the University of Minnesota Medical Center approved this study. The requirement of informed consent for the study is waived by the institutional review board of the University of Minnesota. All methods were carried out in accordance with relevant guidelines and regulations. At the time of this analysis, the larger continuous-flow LVAD cohort consisted of 451 patients implanted between 2007 and 2017. Of these, 254 patients met the following inclusion criteria 1) first time, continuous-flow LVAD implantation 2) complete pre-operative variables to complete EUORMACS score calculation, and 3) complete post-operative data to determine date of inotrope wean, pulmonary vasodilator wean and RVAD use.The following demographic and clinical covariate data are available in the University of Minnesota LVAD database, which is updated through data extraction and manual chart review: age, gender, body mass index (BMI), serum creatinine, albumin, Interagency Registry for Mechanical Circulatory Support (INTERMACS) profile, pre-operative hemodynamics, bridge to transplant status, cardiomyopathy type, presence of diabetes, and NT pro b-type natriuretic peptide (NT-proBNP). Vital status was obtained from chart review. The date of the last clinic visit was recorded for patients who were still alive at the end of follow up. For cardiac transplantation, the date of cardiac transplant was obtained from the electronic medical record and confirmed with an operative report.The primary predictor for this analysis was follow up EUROMACS RV score, which was calculated by totaling points for the following pre-LVAD clinical variables. RA/PCWP > 0.54: 2 points, hemoglobin ≤ 10 g/dL:1 point, multiple inotropes: 2.5 points, INTERMACS 1–3: 2 points, and severe RV dysfunction: 2 points. The primary outcome was early severe post-operative right ventricular failure defined as need for short/long-term mechanical right-sided circulatory support within 30 days of LVAD implantation, continuous inotropic support greater than or equal to 14 days, or need for pulmonary vasodilators for greater than 48 h.p value of < 0.05 was considered statistically significant. Baseline characteristics between cohort subjects who developed early RVF and those who did not develop early RVF were compared with normally distributed continuous variables were compared with t-tests and Wilcoxon rank sum tests for non-normally distributed continuous variables. Categorical variables were compared with Pearson chi-squared tests or Fishers exact test, where appropriate. In order to determine the relationship between baseline co-variates and follow up pulmonary capillary wedge pressure, multivariable linear regression analyses were performed.All statistical analyses were performed using STATA 16 . A In order to assess EUROMACS model discrimination, a receiver operator curve was generated with EUROMACS score as the predictor and post LVAD RVF as the outcome. This was repeated using the RVF definition of RVAD or prolonged inotropes use only. The EUROMACS score was also assessed as a predictor of RVF using logistic regression. In order to determine the relationship between other pre-operative variables and RVF, logistic regression was performed. The relationship between RVF  and subsequent LVAD mortality was assessed with cox regression.The mean age of the cohort was 59 years of age. Eighty two percent were male, 80% were Caucasian, and 51% were designated as bridge to transplantation. The majority of patients (52%) were INTERMACS profile 2–3. A total of 100 patients (39%) were diagnosed with early right ventricular failure and 154 patients (61%) did not have post-operative right heart failure. There were no significant differences in age, sex, race, baseline atrial fibrillation, cardiomyopathy type, diabetes, chronic obstructive pulmonary disease, LVAD surgical strategy, INTERMACS profile, pulmonary artery systolic pressure or cardiac index between both groups (Table p = 0.066). Use of RVAD after LVAD surgery was the primary driver of increased mortality  of patients who were defined as having post-operative RVF. Early right-sided heart failure was associated with increased mortality . The EUROMACS score had an area under the curve of 59%, (95% CI 52–66%)  met this definition due to prolonged pulmonary vasodilator use, while the EUROMACs data only had 1% of patients with prolonged pulmonary vasodilator use. RV failure defined by prolonged vasodilator use was not associated with increased mortality in our cohort, which questions the clinical significance of this part of the RV failure definition. The use of pulmonary vasodilators and time course of weaning these medications appears to be different between the University of Minnesota and EUROMACS derivation cohorts, which reflects significant variability in practice. When restricting the RVF definition to inotropes ≥ 14 days and/or need for RVAD, the performance of the EUROMACS score improved. Another difference between the cohorts was the lower numbers of destination therapy CF-LVAD implantations in the EUROMACs cohort (14% vs. 49%). The larger number of patients with comorbid conditions in the University of Minnesota dataset may have explained some of the lower performance observed in the model, as these populations have real differences.14. Other studies have shown that certain echocardiographic features of RV dysfunction such as TAPSE and semi-quantitative RV function are predictive of RV failure after LVAD16. In our cohort, none of the previously mentioned hemodynamic variables were predictive of RV failure. Similar to previous analyses, higher creatinine, lower albumin, and higher total bilirubin were all associated with increased risk of RV failure after LVAD. Pre-operative ventilator support, multiple inotropes, extra corporal membrane oxygenation, and non-elective IABP were also associated with higher risk of RVF in this cohort. All of the associated variables are direct or indirect markers of patient acuity, and may suggest longer standing heart failure is a risk factor for post-operative RV failure.There have been several previous studies designed to predict those patients at high likelihood of developing RV failure following LVAD implantation. Many of these include hemodynamic variables such as right atrial pressure, pulmonary artery pulsatility index, and right atrial pressure: pulmonary capillary wedge pressure ratio17. For example, the widely used INTERMACS criteria for RV failure does not include pulmonary vasodilators as definition for RVF. With regard to the hemodynamic variables, these can change dramatically over a 24 h period as patient are managed with diuretics, inotropes and temporary support. Lastly, insults that occur to the RV in the operating room, such as RV ischemia from hypotension, prolonged cardiopulmonary bypass time, surgical positioning of the inflow cannula, fluid resuscitation and blood transfusions are not predictable ahead of time18. These intraoperative conditions can “unmask” underlying RV failure that might not have been predicted with traditional risk scores using clinical, hemodynamic, and echocardiographic data.There are many reasons why published risk scores may perform poorly in validation cohorts. First, RV failure after LVAD does not have a universal definitionThis study has several limitations. First, this was a single-center observational analysis. Second, our sample size is smaller than the EUROMACs cohort, which could limit the power of our study to determine variables that are associated with severe RV failure.The EUROMACS Right-Sided Heart Failure Risk Score had poor external discrimination on external validation. In the present cohort, variables associated with long-standing heart failure  were more predictive of right ventricular heart failure. As RV failure post LVAD is a complex syndrome influenced by pre-operative, intra-operative, and post-operative factors, it remains difficult to predict. Further work will be required to enhance our understanding of the post-LVAD right ventricular failure syndrome.


Left ventricular (LV) restoring forces are primed by ventricular deformation during systole and contribute to cardiac relaxation and early diastolic suction. Systolic–diastolic coupling, the relationship between systolic contraction and diastolic recoil, is a novel marker of restoring forces, but the effect of left atrial pressure (LAP) is unknown. We tested preliminary methods of systolic–diastolic coupling comparing mitral annular velocities versus excursion distances and hypothesized a recoil/contraction distance ratio would remain unaffected across varying LAP, providing a surrogate for quantifying LV restoring forces.n = 61, age 52 ± 5 years) underwent manipulation of LAP with lower body negative pressure (LBNP) and rapid normal saline (NS) infusion. Pulmonary capillary wedge pressure  and tissue Doppler imaging of the mitral annulus were measured. Two models of systolic–diastolic coupling––early diastolic excursion (EDexc)/systolic contraction (Sexc) distances and e’/systolic (s’) velocities were compared. Velocity (e’/s’) coupling ratios varied significantly  in relationship with PCWP (5–20 mmHg). Excursion (EDexc/Sexc) coupling ratio did not vary in relationship with PCWP .Healthy subjects ( Systolic–diastolic coupling using mitral annular distance ratios to standardize early diastolic recoil to systolic contraction was not significantly impacted by LAP, in contrast to coupling ratios using velocities. The pressure invariance of annular distance coupling ratios suggests this metric quantifies the efficiency of LV restoring forces by isolating systolic contributions to early diastolic restoring forces independent from changes in LAP. Left ventricular restoring forces are primed by ventricular deformation during systole and contribute to cardiac relaxation and early diastolic suction. Systolic–diastolic coupling, the relationship between systolic contraction and diastolic recoil, is a novel and load independent marker of restoring forces. The pressure invariance of the systolic–diastolic distance coupling ratios suggests this metric quantifies the efficiency of LV restoring forces by isolating systolic contributions to early diastolic restoring forces independent from changes in LAP. Early diastolic excursion (EDexc) measures the distance the mitral annulus recoils during early diastole. The combination of EDexc and late diastolic excursion, driven by the atrial contraction, would return the annulus to its presystolic position  relaxation are important criteria for diagnosing diastolic dysfunction. The most common clinical metric to characterize cardiac relaxation is e’, the early diastolic tissue Doppler velocity. e’ quantifies the velocity of early diastolic re‐lengthening, which is a complex and multifactorial process influenced by active relaxation mediated by sarco/endoplasmic reticulum CaAs a marker of diastolic function, the hemodynamic influences of preload on systolic–diastolic coupling are important and unknown. In animal models, elastic recoil from restoring forces is responsible for generating diastolic suction and pressure decay within the ventricle even when the mitral valve is experimentally closed during diastole, blocking the LA pressure gradient , untreated hypo‐ or hyperthyroidism, obstructive sleep apnea, chronic obstructive pulmonary disease, tobacco use during past 10 years, coronary artery disease, or structural heart disease. Subjects were sedentary and reported completing less than 90 min of exercise per week. All subjects were screened for abnormal systolic function and inducible cardiac ischemia with an exercise stress echocardiogram. Study procedures were approved by the institutional review boards of the University of Texas Southwestern Medical Center and Texas Health Presbyterian Hospital Dallas, and all subject signed informed consent. The study protocols conformed to the principles outlined in the Declaration of Helsinki.This study was an analysis of the baseline echocardiographic and hemodynamic data from a previously reported prospective study  chamber and performed in two conditions, LBNP −15 mm Hg and LBNP −30 mm Hg. Subjects were given a 20‐min break and a light lunch after cardiac unloading. Baseline measurements were repeated, and cardiac loading was accomplished by rapid infusion (~200 ml/min) of warm isotonic normal saline (NS) and performed in two conditions, 15 ml/kg (NS +15) and 30 ml/kg (NS +30). Hemodynamic measurements and an echocardiogram were performed 5 min after the initiation of each level of LBNP and immediately after each dose of saline infusion.2.3Echocardiograms were performed using an iE33  at baseline and during each unloading and loading condition in the left lateral decubitus position. Mitral annular velocities were acquired using Tissue Doppler imaging and pulsed wave Doppler with a 5‐mm sample volume at tracking rate of 100 cm/s on the septal and lateral mitral annulus. Mitral inflow was acquired using pulsed wave Doppler with a 2‐mm sample volume at the mitral leaflet tips. Cardiac volumes were measured using 4‐beat 3D acquisition and were analyzed offline using QLab 9.0 (Philips). Doppler and 2D measures were analyzed offline using Xcelera (Philips).exc) and early diastolic signal to measure early diastolic excursion (EDexc). Care was taken to avoid the isovolumetric contraction and isovolumetric relaxation signal. Every systolic measurement was paired with an early diastolic measurement to prevent comparing different heart beats. Measures with a fused e’ and a’ signal were excluded. Lateral and septal signals were evaluated individually and averaged together resulting in a “mean” signal. Forty randomly chosen signals were repeated blinded to initial results by multiple readers  for intra‐ and inter‐observer variability.Doppler velocities were measured in triplicate as the peak velocities of the entire systolic signal and early diastolic signal, taking care to avoid over or under gaining. Velocity time integrals were measured in triplicate by tracing the systolic signal to measure systolic excursion (S2.4K*distance) governs the compressibility of a spring, and the force needed to compress a spring scales linearly with distance of compression . Tissue Doppler imaging (TDI) was chosen to define LV longitudinal motion for several reasons. First, TDI permitted simultaneous measurement of the peak velocities and excursion distances of the mitral annulus for comparison  and one repeated factor (condition) with a compound symmetry model was used. A p < 0.05 was considered statistically significant.Statistical analysis was performed using SAS V9.4, and figures were made using GraphPad Prism 8.2.0 and SPSS Statistics 20. Continuous variables were represented as mean ± standard deviation. To assess the influence of PCWP on Doppler measures of cardiac motion, random regression coefficients models were used to assess changes in hemodynamic and cardiac parameters across all six loading conditions separately. The covariance between the intercept and slope for each model were tested and if this covariance was not significant, the results are presented for the model with the covariance set to 0. To test goodness of fit, mean 3Baseline characteristics of the population are represented in Table 3.1p < 0.001 across conditions). There was an increase in systolic blood pressure  and a decrease in diastolic blood pressure . Heart rate increased both with loading and unloading (p < 0.001 across conditions). Cardiac output increased from LBNP to NS infusion .Comprehensive hemodynamic alterations with loading and unloading are shown in Table 3.2p < 0.001, mean r2 = 0.57). There was no significant effect of changes in PCWP on systolic velocities . e’ increased by 51.3% from LBNP −30 mm Hg to NS +30 ml/kg/min. s’ decreased by 4.5% from LBNP −30 mm Hg to NS +30 ml/kg/min. Both systolic and early diastolic excursion distances were significantly changed as PCWP was altered . Sexc increased by 45.6% from LBNP −30 mm Hg to NS +30 ml/kg/min. EDexc increased by 40.7% from LBNP −30 mm Hg to NS +30 ml/kg/min , and the results were unchanged when adjusted for gender . The EDexc/Sexc ratio decreased by 4.1% from LBNP −30 mm Hg to NS +30 ml/kg/min . The mean e’/s’ ratio increased 53.8% from LBNP −30 mm Hg to NS +30 ml/kg/min. This relative change of the annular velocity ratio was significantly different compared to the annular excursion ratio as a function of loading condition (interaction < 0.001).Excursion ratios are shown in Table 3.4exc/Sexc measurements, only 10 (1.4%) could not be performed due to fusion of e’ and a’ or image quality. Mean coefficient of variation for each intra‐subject excursion ratio at baseline was 6.0% for septal annulus and 5.3% for lateral annulus. Typical error for between blinded interpreters was 3.5% for Sexc, 5.1% for EDexc, and 5.1% for EDexc/Sexc ratio. Intra‐observer typical error was 4.4% for EDexc/Sexc ratio.Of 732 septal and lateral ED4The key finding of this study is that systolic–diastolic coupling using mitral annular distance ratios to standardize early diastolic recoil to systolic contraction was not significantly impacted by changes in LAP, in contrast to coupling ratios using annular velocities. The pressure invariance of annular distance coupling ratios suggests this metric estimates the efficiency of LV restoring forces by linking systolic contributions to early diastolic restoring forces independent from changes in LAP. By normalizing the LV early diastolic recoil excursion to the systolic excursion, we were able to further characterize this novel measure of diastolic function.exc/Sexc ratio measures efficiency of diastolic excursion as a function of restoring forces. This data supports our previous study which found that the EDexc/Sexc ratio declined with age and was further decreased in patients with HFpEF  and standing . The EDexc/Sexc ratio was superior for discriminating HFpEF from healthy age‐matched controls to E/e’ or e’. Diastolic function changes with healthy aging, particularly sedentary aging, and can confound the echocardiographic assessment of diastolic dysfunction  this relationship appears to isolate left ventricular restoring forces independent from LA pressure. This novel metric may be useful in identifying subclinical diastolic dysfunction.Early diastolic re‐lengthening is significantly influenced by prior systolic excursion. A ratio of these measures, the EDNone declared.Conception and Design of Work: James P. MacNamara, Katrin A. Dias, Christopher M. Hearon, Linda S. Hynan, Benjamin D. Levine, and Satyam Sarma. Acquisition and Analysis: James P. MacNamara, V.K., E.H., I.C., L.H, Benjamin D. Levine, and Satyam Sarma. Drafting and Revising Intellectual Content: James P. MacNamara, V.K., Katrin A. Dias, Christopher M. Hearon, E.H., I.C., Linda S. Hynan, Benjamin D. Levine, and Satyam Sarma. All authors approved the final version of the manuscript, agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved, and all persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.


Exercise intolerance in systemic sclerosis (SSc) is typically attributed to cardiopulmonary limitations. However, problems with skeletal muscle oxygen extraction have not been fully investigated. This study used cardiovascular magnetic resonance (CMR)-augmented cardiopulmonary exercise testing (CMR-CPET) to simultaneously measure oxygen consumption and cardiac output. This allowed calculation of arteriovenous oxygen content gradient, a recognized marker of oxygen extraction. We performed CMR-CPET in 4 groups: systemic sclerosis (SSc); systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH); non-connective tissue disease pulmonary hypertension (NC-PAH); and healthy controls.We performed CMR-CPET in 60 subjects (15 in each group) using a supine ergometer following a ramped exercise protocol until exhaustion. Values for oxygen consumption, cardiac output and oxygen content gradient, as well as ventricular volumes, were obtained at rest and peak-exercise for all subjects. In addition, T1 and T2 maps were acquired at rest, and the most recent clinical measures  were collected.All patient groups had reduced peak oxygen consumption compared to healthy controls (p < 0.022). The SSc and SSc-PAH groups had reduced peak oxygen content gradient compared to healthy controls (p < 0.03). Conversely, the SSc-PAH and NC-PH patients had reduced peak cardiac output compared to healthy controls and SSc patients (p < 0.006). Higher hemoglobin was associated with higher peak oxygen content gradient (p = 0.025) and higher myocardial T1 was associated with lower peak stroke volume (p = 0.011).Reduced peak oxygen consumption in SSc patients is predominantly driven by reduced oxygen content gradient and in SSc-PAH patients this was amplified by reduced peak cardiac output.Trial registration The study is registered with ClinicalTrials.gov Protocol Registration and Results System .The online version contains supplementary material available at 10.1186/s12968-021-00817-1. Exercise intolerance is common in systemic sclerosis (SSc), due to lung disease, myocardial involvement, pulmonary artery hypertension (PAH) or anemia. A relatively underinvestigated cause of reduced exercise capacity in these patients is skeletal muscle dysfunction. It has been shown that SSc patients have skeletal muscle inflammation, fibrosis and vasculopathy , all of 2) is directly measured. We have recently developed a novel technique that combines exercise cardiovascular magnetic resonance (CMR) with conventional CPET  are shown in Table p = 0.042) and (2) the measured diffuse lung capacity (DLCO) as a percentage of the predicted value was significantly lower in the SSc-PAH group compared to the other 2 patient groups (p < 0.001). There were no other significant differences in clinical characteristics (including predicted forced expiratory volume in one second (FEV1), predicted forced vital capacity (FVC), and Hb). Medications for all patients are shown in Additional file The main findings were that 1) 6MWT was significantly shorter in the SSc-PAH group compared to NC-PAH group ( 6MWT wasp ≤ 0.023). In SSc patients this was associated with higher stroke volume index (p = 0.017) compared to healthy controls whilst in NC-PAH patients, higher HR was observed compared to healthy controls (p = 0.005). There were no group differences in biventricular function.Resting CMR metrics for each of the groups are shown in Table p < 0.006). Myocardial T1 was higher in all patient groups compared to healthy controls (p < 0.006) and was higher in SSc-PAH compared to NC-PAH patients (p = 0.042).Myocardial T2 was higher in the SSc and SSc-PAH groups compared to both controls and NC-PAH patients (2 (Table 2 was significantly lower in the SSc patients (p < 0.001) and NC-PAH patients (p = 0.049) compared to healthy controls.There were no group differences in resting iVO2 Table  but restAll subjects successfully completed the exercise protocol and no subjects required medical intervention. The peak-exercise RER ≥ 1.0 in 59/60 patients, with 1 SSc-PAH patient, who exercised to exhaustion, achieving an RER of 0.97. Comparisons of exercise duration and peak workload are shown in Table p < 0.003 for peak workload, p < 0.006 for exercise duration). Peak workload was also lower in NC-PAH patients compared to controls (p < 0.002).The SSc-PAH group had the lowest peak workload and shortest exercise duration  as seen in Fig. CMR-CPET metrics at peak exercise are shown in Table 2 . This was associated with lower peak cardiac index compared to both healthy controls and SSc patients (p ≤ 0.004) and lower ∆avO2 than healthy controls (p = 0.003)—Fig. p = 0.015)—Fig. p = 0.042)—Fig. The SSc-PAH group had the lowest peak iVO p = 0.00—Fig. p = p = 0.00—Fig. p =2 and ∆avO2 (p = 0.03) compared to healthy controls. However, they did have significantly higher peak iVO2 than SSc-PAH patients (p = 0.01). SSc patients failed to augment stroke inde during exercise —Fig. p = 0.034) and RVEF —Fig. The NC-PAH group was characterized by significantly lower peak cardiac index compared to both healthy controls and SSc patients . There was no correlation between 6MWT and peak RVEF, LVEF, stroke index or HR.Peak iVOp = 0.015; peak LVEF rho = 0.31, p = 0.040). In addition, there was a significant correlation (adjusted for diagnosis) between peak ∆avO2 and Hb .There was no correlation between predicted FVC and FEV1 and any peak-exercise metrics. There was a correlation (adjusted for diagnosis) between DLCO and peak RVEF and LVEF  and HR . There were no other significant associations.There were no significant associations between CMR-CPET and myocardial T2 after adjusting for diagnosis. Myocardial T1 correlated (adjusted for diagnosis) with peak stroke volume index  SSc and SSc-PAH had reduced peak ∆avO2 compared to healthy controls and NC-PAH patients (2) SSc-PAH and NC-PAH patients had reduced peak cardiac index compared to healthy controls and SSc patients, (4) Higher hemoglobin was associated with higher peak ∆avO2 independent of disease type and (5) Higher myocardial T1 was associated with lower peak SV.It is well recognized that systemic sclerosis causes reduced exercise capacity , which i2, associated with lower peak ∆avO2 in both groups. It is well recognized that ∆avO2 is a marker of skeletal muscle oxygen extraction, and our data suggest that reduced oxygen extraction is a ubiquitous problem in SSc. The ability of skeletal muscle to extract oxygen is vital for normal aerobic respiration and thus cellular function. From our data, we propose the following in SSc patients during exercise—(1) reduced muscle oxygen extraction, (2) reduced aerobic respiration and ATP production, (3) reduced skeletal muscle sarcomeric contraction and (4) resultant exercise intolerance. This chain of events has previously been suggested for left-sided heart failure [2 in these patients is probably generalized skeletal muscle dysfunction/sarcopenia. Sarcopenia is common in SSc [2 delivery, intramuscular shunting and mitochondrial dysfunction [The defining exercise feature of SSc and SSc-PAH patients was reduced peak VO failure  and pedi failure  and we bn in SSc , and disexercise— reduced n in SSc , muscle n in SSc . These ffunction . In this2. There were no group differences in hemoglobin and, therefore, this finding cannot explain the group differences in oxygen extraction but may contribute to within-group variance. Several animal studies have shown that low hemoglobin causes reduced oxygen extraction through impaired oxygen delivery. There is also some evidence that anemia lowers muscle oxidative capacity [Interestingly, we found a strong relationship between hemoglobin and peak ∆avOcapacity  and thiscapacity . Anemia capacity . On the capacity –28, whic2, patients with SSc-PAH also had lower peak cardiac index. This ‘dual pathology’ probably explains why SSc-PAH patients had the lowest peak VO2 and a lower 6MWT than NC-PAH patients. Reduced peak cardiac index was also seen in NC-PAH patients, and in both groups this was largely due to an inability to augment stroke index during exercise. Interestingly, SSc patients also failed to augment stroke index, but higher resting stroke index resulted in normal peak values. Higher baseline stroke index in SSc patients may simply be a response to a systemic inflammatory disease, but this requires more investigation. The failure to augment stroke index can be explained by poor RV contractile reserve and this is reflected by lower peak RVEF in both PAH groups. Reduced contractile reserve is well recognized in PAH [In addition to reduced peak ∆avOd in PAH , 30 due d in PAH  and incrd in PAH . In addi2 in SSc is lung disease, which is why we excluded patients with radiological evidence of extensive parenchymal lung disease. We did not find any association between lung function metrics and peak ∆avO2, implying that reduced pulmonary O2 uptake was not the cause of lower ∆avO2. However, there was an association between predicted DLCO and peak biventricular EF, but the direction of causation is unclear, and the exact cause is to be determined.Another possible cause of reduced ∆avO2 and cardiac index and subsequent calculation of ∆avO2. We used PC-CMR to measure aortic flow as this provides accurate quantification of cardiac output even in the presence of left-sided valvar regurgitation and shunts. This contrasts with measurement of cardiac output from ventricular volumetric data. Aortic flow can also be estimated using Doppler echocardiography, but this method is often unreliable [2 provides new insights into the role of skeletal muscle in reduced exercise capacity. Due to the comprehensive evaluation that CMR-CPET provides, we believe that this technique may have a future role in clinical diagnosis, risk stratification and follow-up, as well as providing end points for clinical trials.In this study, we used CMR-augmented CPET to investigate exercise dysfunction. The benefit of this relatively novel technology is that it allows simultaneous quantification of peak iVOreliable  and diff2 obtained during CMR-CPET and conventional CPET [2 and HR during supine exercise are lower than for upright exercise, RER > 1 was achieved in most subjects. Therefore, we believe that CMR-CPET metrics measured during supine exercise remain good markers of exercise capacity.The main limitation of this study is that achieving true peak-exercise using a supine exercise protocol is challenging. Our form of supine exercise is not directly comparable with conventional CPET, and this should be considered when interpreting the results. Nevertheless, we have previously demonstrated good correlation between peak iVOAnother limitation was the long time interval between clinical measures  and CMR-CPET. This may affect the robustness of correlations between these markers and future, larger studies should endeavor to assess clinical characteristics at the same time as CMR-CPET.Finally, skeletal muscle biopsy could have answered some of our questions regarding the cause of reduced oxygen extraction (fibrosis/inflammation/capillary rarefaction). However, this is highly invasive and would have been difficult to perform. Thus, future studies could evaluate skeletal muscle mass, perfusion, T2 and extracellular volume as a non-invasive alternative.2. In SSc patients, this appears related to reduced peak ∆avO2; in SSc-PAH patients, it is related to both reduced peak cardiac index and ∆avO2. This suggests that tissue oxygen extraction is an important determinant of exercise intolerance in SSc and could be used as a biomarker of disease and response to therapy.Patients with SSc and SSc-PAH have reduced peak iVOAdditional file 1. Table S1. Subject characteristics.