P = 0.002) when compared to 6-month measurements and was correlated with an ischemia risk area  and infarct size . Following ischemia median citrulline/arginine index decreased when compared with 6-month result (P = 0.002), while citrulline/ornithine and arginine/ADMA ratios maintained unchanged indicating a shift of arginine metabolism from nitric oxide synthase (NOS) towards arginase. The 6-month arginine concentration reached the area under the ROC curve of 0.67  for prediction of death, myocardial infarction or heart failure hospitalization and its value of < 29 µM was associated with lower event free survival (P = 0.02). In STEMI patients, during ischemia conversion of elevated plasma arginine was shifted from NOS towards arginase. Decreased 6-month arginine concentrations were associated with worse long-term outcomes.The arginine metabolism as a target for cardioprotection in patients with ST-segment elevation myocardial infarction (STEMI) remains insufficiently understood. Arginine, ornithine, citrulline, asymmetric dimethylarginine (ADMA) and proline plasma levels were measured using liquid chromatography and tandem mass spectrometry in 70 consecutive STEMI patients upon admission and at 6-month follow-up and were compared with left ventricular function, volumes, and infarct characteristics determined by cardiac magnetic resonance imaging, and with 5-year clinical outcomes. Baseline median concentration of arginine was higher by 49% ( Competing of both enzymes for the same L-arginine may lead to diminished production of an unstable molecule of NO which undergoes non-enzymatic oxidation to nitrite and finally to stable nitrate. In stable conditions endothelial NOS produces majority of NO, however changes in NO and L-citrulline levels may also reflect activation of inducible NOS especially in response to hypoxia or cardiac injury and non-enzymatic NO formation5. It has been demonstrated that NO synthesis is not exclusively attributed to the vascular endothelium but also red blood cells express a functional endothelial NOS and constitutively produce NO7 and contribute to the regulation of systemic blood pressure and nitrite homeostasis8. Apart from NOS and arginase, arginine is a substrate for arginine decarboxylase that synthesize L-agmatine linked directly to polyamine metabolism or for arginine:glycine amidinotransferase producing ornithine, guanidinoacetate and L-homoarginine9. In turn, asymmetric dimethylarginine (ADMA) is derived from the methylation of arginine residues of various proteins and acts as an endogenous NOS inhibitor.Arginine is both a substrate for arginase and the sole source for nitric oxide (NO) synthesis by three main isoforms of NO synthases (NOS)10. Kloner et al. showed that structural changes in coronary microcirculation were preceded by and limited to the areas of irreversible cardiomyocyte injury11, and were substrate for intramyocardial hemorrhage12. The endothelial damage is associated with impaired endothelial-dependent vasodilatation and diminished NO bioavailability13. In cultured endothelial cells, exposure to hypoxia leads to an increased intracellular concentration of L-arginine released from cellular storages or protein proteolysis14 whereas impaired uptake of L-arginine is a consequence of plasma membrane depolarization15. Although intra- and extracellular arginine concentration was elevated during I/R, it was inaccessible for NO production due to endothelial damage.There is evidence that endothelial damage following ischemia/reperfusion (I/R) injury is a component of no-reflow phenomenon and favors infarct area expansion18. Moreover, patients who presented symptoms of cardiogenic shock following MI had plasma levels of arginine that were twice as low, along with a 42% lower GABR when compared with stable CAD patients19. Recent studies on red blood cells provide evidence that their endothelial NOS activity is compromised in patients with coronary artery disease7 while elevated arginine I activity in patients with type 2 diabetes is associated with induction of endothelial dysfunction20.Diminished arginine bioavailability and its dysfunctional metabolism have been shown to be associated with increased cardiovascular risk. Reduced global arginine bioavailability ratio (GABR), but not arginine concentration, was associated with both higher prevalence of coronary artery disease (CAD) and an increased incidence of long-term cardiovascular events21. Simultaneous assessment using two ratios of citrulline/ornithine and citrulline/arginine provided indirect insight pertaining to the balancing activity of NOS and arginase. In turn, an arginine/ADMA ratio provided information about arginine availability for NO production dependent on NOS inhibitor22 and was identified as a marker of heart failure23, hypertension24, atherosclerosis25 and of major cardiovascular events26. In contrast, a nitrate anion as a dietary element that can be reduced via nitrite into NO does not reflect NO availability27. Lauer et al.28 have shown that plasma nitrite, but not nitrate correlated with NO production from endothelial NOS in humans. Additionally, in patients with increased cardiovascular risk, there is a decreased availability of tetrahydrobiopterin which results in an endothelial NOS-dependent formation of superoxide instead of NO and promotes the oxidation of NO to nitrate29.In animal model of myocardial infarction (MI) a systemic inhibition of arginase was associated with an increase of plasma citrulline, citrulline/arginine ratio and citrulline/ornithine ratio and a decrease of plasma ornithineTo date an unclear role of arginine metabolism in acute MI precluded the development of effective arginine-based cardioprotective therapies. We hypothesize that in patients with ST-segment elevation myocardial infarction (STEMI) elevated plasma arginine together with its metabolites released following ischemia from damaged cardiac myocytes may reflect myocardial and microvascular injury, a shifted metabolic balance between NOS and arginase and potentially might be useful in prediction of clinical outcomes.Seventy consecutive STEMI patients who underwent primary percutaneous coronary intervention (PCI) were enrolled. They qualified for inclusion if presented with chest pain duration at rest no longer than 12 h with concomitant ST-segment elevation > 1 mm in 2 or more limb leads or > 2 mm in 2 precordial leads, or if revealed a new left bundle branch block. Criteria for exclusion included lack of informed consent, the presence of cardiogenic shock or pulmonary edema, history of MI or PCI at the same location or coronary artery bypass surgery, history of cancer, venous thromboembolism, renal or liver failure, and contraindications of cardiac magnetic resonance (CMR) imaging.The demographic characteristics, anthropometric parameters, cardiovascular risk factors, history of cardiovascular diseases and comorbidities were collected for all patients. Upon admission, hemoglobin, hematocrit, red and white blood cell count, platelet count, lipid profile, glucose, creatinine, high sensitivity C-reactive protein and fibrinogen were determined using standard laboratory techniques. Serum activity of creatine kinase , isoenzyme MB of creatine kinase  as well as concentration of cardiac high sensitivity troponin T (ng/ml) were measured upon admission and then subsequently at 8, 16, 24 and 48 h. Diagnosis of diabetes mellitus was derived from patient history. A new diabetes mellitus diagnosis was given based upon hyperglycemic presentation at intake or after a glucose tolerance test. Chronic kidney disease was diagnosed when creatinine clearance using the Cockcroft-Gault formula was calculated to be lower than 60 ml/min.The study was approved by the Ethics Committee of Jagiellonian University and all methods were performed in accordance with the relevant guidelines and regulations. All study participants provided written informed consent prior to their inclusion to the study procedures.x) were measured in duplicates using ultra-performance liquid chromatography—tandem mass spectrometer (UPLC-MS/MS) with Waters ACQUITY UPLC  coupled to a Waters TQD mass spectrometer (electrospray ionization mode ESI-tandem quadrupole).Blood samples were drawn into citrate tubes upon admission in acute phase of MI before PCI and again, 6 months later. Before 6-month follow-up visit all patients were on low-nitrate/nitrite diet for three days. The samples were centrifuged at 2,500 g at 18 °C to 22 °C for 20 min and processed immediately or stored in aliquots at − 80 °C until analysis. Plasma proteins for amino acid analysis were precipitated with 80% methanol before measurements were recorded. Plasma concentrations of arginine, ornithine, citrulline, proline, ADMA and nitrite/nitrate (NOx measurement procedure was performed in two ways30. For nitrites the procedure included direct derivatization to azo compound—4-((4-((2-aminoethyl)amino)naphthalen-1-yl)diazenyl)benzenesulfonamide, which was later quantified using the developed UPLC-MS/MS procedure. The procedure for nitrates included two stages of enzymatic reduction to nitrites and subsequent derivatization to azo compound and quantification as above described. Procedures in plasma samples were performed in parallel, and the final content of nitrates was calculated based upon the difference between values obtained from both procedures since the second procedure simultaneously quantifying nitrites and nitrates within the sample. Chromatographic separations were carried out using Acquity UPLC BEH C18 column, 2.1 × 100 mm, and 1.7 µm particle size equipped with Acquity UPLC BEH C18 VanGuard pre-column. The column was maintained at 40 °C and eluted under the following conditions: linear gradient elution from 100 to 20% of eluent A over a 4 min timeframe, followed by isocratic elution from 20% of eluent A over 2 min, and linear gradient elution from 20 to 100% of eluent A over 1 min at a flow rate of 0.3 mL/min ; eluent B: acetonitrile/formic acid . 10 μL of each sample was injected in triplicate.NOChromatographic separations of amino acids were carried out with the Acquity UPLC BEH Amide column, 2.1 × 100 mm, and the 1.7 µm particle size equipped with VanGuard Acquity UPLC BEH Amide pre-column. The column was maintained at 40 °C and eluted under linear gradient elution from 20 to 35% of eluent A over 4 min followed by linear gradient elution from 35 to 40% of eluent A over 6 min, with a flow rate of 0.3 mL/min. ; eluent B: acetonitrile/formic acid ).G, NG-dimethylarginine, L-citrulline, L-ornithine, L-proline, 4-((4-((2-aminoethyl)amino)naphthalen-1-yl)diazenyl)benzenesulfonamide, and chloramphenicol in concentration 10 μg/mL at flow 20 μL/min and mixture of eluent A and B 1:1 (v/v) at flow 0.28 mL/min.Waters’ TQD mass spectrometer parameters were optimized for quantitative analysis using the solutions of L-arginine, N32.Coronary angiograms were acquired with Axiom Artis dFC  and were analyzed offline using two contralateral projections for each artery before and after angioplasty. All coronary segments were evaluated for the presence of visible thrombus in the epicardial artery, distal embolization during and after primary PCI as well as degree of stenosis based on visual inspection. Epicardial segments with coronary lesions with at least 50% narrowing were considered significant. Epicardial blood flow in the infarct-related artery (IRA) was evaluated using the TIMI scale33. Briefly, using ECG gating technique, left ventricular (LV) function was assessed with cine imaging in a spoiled gradient echo sequence. Following cine sequences, imaging of myocardial edema reflecting area at risk (AAR) of ischemia was performed using the breathhold, T2-weighted sequence. Then, the late-enhancement imaging was performed 10 to 20 min after contrast injection of 0.1 mmol/kg of gadobutrolum  with a gradient echo readout. The entire left ventricle was covered by contiguous, short-axis oriented 8-mm slices in all CMR techniques.CMR imaging was performed using a 1.5-T scanner  at baseline, between the 2nd and the 4th day following primary PCI, and then again, at 6 months, as previously described34 was used for blinded analysis of all images. The borders of endocardium and epicardium were delineated on images with the largest and smallest LV volumes in order to determine end-diastolic and end-systolic LV volumes, respectively. Based on LV volumes measurements, LV ejection fraction and myocardial volumes were calculated. The myocardial edema, infarct size (IS), and microvascular obstruction (MVO) were delineated on T2-weigted as well as late gadolinium-enhanced images, respectively. The area of delineation multiplied by the thickness of the slice and by the myocardial tissue density (1.05 g/ml) served as formula to calculate the mass of AAR, IS and MVO. The AAR was expressed as the ratio of LV mass. The hyper-enhanced area of the infarct was expressed using a ratio of myocardial edema or LV mass, while MVO was expressed using a ratio of the infarct area.An in-house-developed, vendor-independent, cardiac-dedicated software Death, recurrent MI confirmed by enzyme release, stroke, or hospitalization due to heart failure (HF) decompensation were collected within 5-year follow-up at the outpatient clinic. Data was supplemented by an in-person or telephone interview with the patient or in the case of death, data was obtained through an immediate relative. Ischemic symptoms were assessed according to the Canadian Cardiovascular Society (CCS) scale. The HF hospitalization was defined as an episode of cardiac decompensation, including pulmonary edema or worsening of dyspnea up to at least class III-IV according to the New York Heart Association (NYHA) classification requiring hospital admission.To demonstrate a 10% relative decrease of arginine concentration during 6-month follow-up with a 90% power and a standard deviation of 20% using a P value of 0.05, 67 patients were required in the whole group.33. Categorical variables are shown as numbers (percentages) and compared by Fisher’s exact test. Continuous variables are shown as median (interquartile range). Continuous variables with normal distribution were compared by Student t test whereas non-normally distributed with the Mann–Whitney U test. Between two time-points normally distributed variables were compared with t test for paired samples or in case of non-normal distribution with the Wilcoxon signed-rank. The correlation of two normally distributed variables was calculated with the Pearson test whereas for non-normal distributed data Spearman rank correlation coefficient was performed. Receiver operating characteristic (ROC) curves and the Youden index were used to determine the optimal cut-off value of arginine or NOx and their sensitivity and specificity in prediction of death, recurrent MI or HF requiring hospitalization. A log-rank test was computed to evaluate differences in survival free of death, recurrent MI or HF requiring hospitalization between patients with estimated cut-off values of arginine or NOx concentration. Finally, all independent variables with the potential for confounding both the outcome and exposure were included in the Cox proportional hazard regression to find predictors of long-term death, recurrent MI or HF requiring hospitalization. A two-tailed P value of less than 0.05 was statistically significant.Statistical analyses were performed with SPSS Statistics software  as previouslyBaseline clinical and laboratory characteristics are reported in Table P = 0.005) and LV mass decreased (P = 0.011).The median time interval between STEMI and first CMR was 3 2–4) days and between the first and second CMR was 6 (5.5–6.5) months. There were no significant differences in LV end-diastolic or end-systolic volumes and LV ejection fraction between baseline and follow-up (Table –4 days aP < 0.001). The MVO was detected in 54 of 70 patients, and among these subjects, median MVO extent was 8% of IS , ADMA by 42% (P = 0.032) and NOx by 28% (P < 0.001) when compared to 6-month follow-up results. However, there were no significant differences between baseline and follow-up concentrations of ornithine, citrulline and proline  when compared with 6-month results . An association was found between collateral blood flow to the IRA classified by Rentrop scale versus arginine  and NOx   and ADMA  were higher but NOx  was lower in patients with MVO when compared to subjects without MVO   . There were no correlations between the storage time versus concentrations of arginine metabolites  and NOx . There were no differences in concentrations of baseline arginine  between patients with or without composite endpoint. In turn, the follow-up arginine concentration reached the area under the ROC curve of 0.67  for prediction of death, recurrent MI or HF hospitalization with sensitivity of 66% and specificity of 65%. Its cut-off value of < 29 µM was associated with lower event free survival (P = 0.02) (Fig. The median time elapsed since baseline blood sampling to UPLC-MS/MS measurements was similar in patients with versus without composite endpoint including death, recurrent MI or HF hospitalization (84 [79–88] versus 84 [80–87] months respectively, The present study provides new findings. First, it enables indirect insight into the balance of arginine metabolites in patients with acute MI. Second, the association of arginine metabolites to myocardial I/R injury can strengthen prognostics to improve clinical outcomes.We have found that plasma levels of ADMA and arginine are elevated following an ischemic phase of MI. Moreover, a higher arginine concentration has been noticed in patients with better developed collateral blood flow to the infarct territory, suggesting their wash out from necrotic myocardium through efficient collaterals. Simultaneously, in acute phase of MI the citrulline/arginine ratio was significantly decreased when compared with stable follow-up phase whereas ratios of citrulline/ornithine and arginine/ADMA maintained unchanged at both time points indirectly indicating that following ischemia conversion of elevated plasma arginine concentration is shifted from NOS towards arginase, despite the lack of enhanced suppressive potential of ADMA for NOS. In turn, the constant balance between metabolites of urea cycle suggested that its enzymes had the same effectiveness in both ischemic phase of MI and in stable chronic conditions, nevertheless it should be remembered that the amount of substrate for arginase was higher in acute condition.35. Based on the results of animal studies, it is commonly accepted that in cardiac tissue induction of expression and activation of arginase I is an early response to hypoxic stress36. At the same time, metabolic activity of NOS competing for the same substrate arginine is reduced or even blocked, because NO formation from arginine requires oxygen37. McQuillan et al. proved that during hypoxia expression of constitutive NOS was reduced by 40–60% in the endothelial cells for at least 48 h38. The question whether this metabolic shift from NOS towards arginase is beneficial for the survival of ischemic tissues remains a matter of debate. One hypothesis maintains that under the condition of inactive NOS, the reduction of arginine pool by activated arginase may protect cells36. The observed shift during acute phase of MI was accompanied by unchanged suppressive potential of ADMA. ADMA however, was identified in several studies as a prognostic marker for cardiovascular risk39 including MI patients40.Arginine metabolism in patients with myocardial I/R is insufficiently understood. Most human studies of arginine metabolism examine various pathologies based on indirect methods assessing the concentration of substrates and products involved in arginine-related pathways41 while ischemic preconditioning attenuated both of them via endothelial NOS activation42. Recently Fernández-Jiménez et al.43 have shown temporal dynamics and extent of edema, IS, MVO and intramyocardial hemorrhage during myocardial I/R. Edema formation had a bimodal temporal distribution and was ameliorated only with cardioprotective interventions. In turn, the area of intramyocardial hemorrhage and MVO varied according to the time of ischemia, CMR timing and cardioprotective strategy. In this context, beyond infarct size reduction also the attenuation of coronary microvascular injury seems to be of particular importance46. On the other hand, our results indicate that under stable conditions higher proline levels were associated with larger LV volumes and mass. Moreover, the lower the ratio of citrulline/ornithine suggesting metabolic shift from NOS towards arginase, the larger LV volumes and mass. Experimental studies revealed that activation of arginase-dependent polyamine metabolism associated with proline synthesis has a pro-hypertrophic significance47.In this study we have shown for the first time that in patients with acute MI, plasma concentration of arginine and its metabolites ornithine, citrulline and ADMA when measured upon admission, were associated with the severity of all morphological features of I/R injury of the left ventricle including AAR, IS and the presence of MVO. Experimental studies indicate that a non-selective NOS inhibitor L-NAME administered 10 min before reperfusion did not reduce no-reflow phenomenon and infarct sizex in stable chronic phase, but not in acute phase of MI, was correlated with plasma concentration of arginine, citrulline and ornithine. Undoubtedly, in acute phase of MI, activation of inducible NOS and the fact that patients were non-fasting could affect NOx plasma level. The concentrations of ADMA and L-arginine as measured by HPLC both in MI patients as well as in healthy volunteers were comparable with our results49 but NOx levels in healthy volunteers determined with a Griess method were higher than ours48. Keeping in mind all the limitations associated with non-fasting measurements of plasma NOx level during acute phase of MI, in this study the new ratios of NOx/arginine and NOx/ADMA were analyzed. These indices were inversely correlated with both morphological features of I/R injury including territory of ischemia, myocardial necrosis and area of damaged microvasculature as well as with LV end-systolic and end-diastolic volumes. Nevertheless, our preliminary data regarding ratios of NOx/arginine and NOx/ADMA need to be interpreted with caution, require further validation and their biological relevance remains unknown, the more that NOx cannot be used as a marker of NO production27.We found also that the total amount of NO21. Also, local intracoronary arginase inhibitor infusion started 5 min before reperfusion in a pig model of MI reduced IS by 50%50. In turn, an intravenous co-administration of L-arginine and tetrahydrobiopterin 5 min before reperfusion reduced IS and this effect was mediated by NOS-dependent pathways resulting in diminished superoxide generation51. Although, several specific inhibitors of arginase are available, their systemic mechanism of action is a major limitation of such therapy in humans1. Our findings also suggest that in the acute phase of MI, when arginine plasma concentration is high, its supplementation may not bring expected benefit. In contrast, in stable conditions following MI, higher arginine concentrations were associated with better long-term outcomes. Thus, arginine supplementation at that moment might be beneficial. However, available data from VINTAGE MI clinical trial has demonstrated increased mortality associated with arginine supplementation after MI52.Can interventions interfering arginine metabolism reduce I/R injury and/or improve MI outcomes? Theoretically, therapies that lead to NO increase may potentially show benefit in cardiovascular disorders, as its decreased concentration plays a key role in multiple dysfunctions. The shifted balance of arginine metabolites from arginase towards NOS found in our study indicates that treatment with arginase inhibitors administered in acute phase of MI may be effective. Jung et al. demonstrated that systemic arginase inhibition reduced IS in rats by 50% in a mechanism dependent on NOS activity and NO bioavailabilityx associated with diet. However, before follow-up blood sampling dietary intake was controlled for nitrate/nitrite. Nevertheless, both acute and chronic measurements of NOx could be confounded by liver metabolism, formation by gastric bacteria, nitrate renal clearance, or contamination27. Fourth, as the red blood cells are involved in metabolism of arginine and were not examined in this study, the analysis of blood plasma represents only a part of the L-arginine-NO metabolism in the whole blood7. Another limitation of this study is lack of age matched control group, however all patients were examined twice in acute and chronic phase. Finally, the study population is homogenous in terms of race and ethnicity, thus the data may not be reflective of other more heterogeneous populations.Our study has several limitations. First, the analyzed group is relatively small, however sample size was appropriately calculated whereas arginine metabolites and myocardial injury were meticulously measured using the recommended methods. Second, arginine metabolites were not measured in acute phase following reperfusion. Third, non-fasting blood samples in acute phase of MI have been taken, therefore we cannot exclude alternative sources of NOIn conclusion, our findings provide arguments that during acute ischemia in patients with STEMI, conversion of elevated plasma arginine concentration released from damaged cardiac myocytes is shifted from NOS towards arginase, despite the lack of enhanced suppressive potential of asymmetric dimethylarginine for NOS. Measured upon admission, arginine metabolites reflected myocardial and microvascular I/R injury. Simultaneously, decreased arginine concentrations during stable chronic phase were associated with worse long-term clinical outcomes. These findings of potentially clinical relevance may be useful in the development of cardioprotective therapy based on the arginine metabolism in STEMI patients.Supplementary information.


Restrictive cardiomyopathy (CM) usually develops and progresses slowly, over a course of years. The rapid development of idiopathic restrictive CM immediately following a liver transplant is unusual. We describe the case of a patient who developed idiopathic restrictive CM fairly rapidly following a liver transplant. It progressed within a few months to the point where the patient required scheduled paracenteses and dialysis. The morphological definition of restrictive CM consists of bi-atrial dilation with non-dilated and non-hypertrophic ventricles. A cardiac biopsy may be needed when the underlying cause is not evident. When a cardiac biopsy is not able to identify a specific cause, then the word "idiopathic" is used to describe the CM. Most restrictive cardiomyopathies (RCMs) are due to the infiltration of abnormal substances between myocytes, storage of abnormal metabolic products within myocytes, or fibrotic injury . RCM usuA 62-year-old male with a known history of cirrhosis secondary to alcohol use and untreated hepatitis C was scheduled for orthotropic liver transplant (OLT). As a part of pre-operative optimization, he was found to have severe aortic stenosis and underwent trans-catheter aortic valve replacement followed by an uneventful liver transplant. Routine subsequent immunosuppression included tacrolimus and mycophenolate.A few months later, the patient started having exertional dyspnea with ascites and lower extremity edema. NT-proBNP  was mildly elevated at 400 pg/mL . Echocardiogram showed bi-atrial dilation, with non-dilated, non-hypertrophied ventricles and worsening bi-ventricular systolic function with elevated right atrial and pulmonary artery pressures, consistent with an RCM  showed elevated right- and left-sided pressures with moderate pulmonary hypertension (PH). A careful review did not reveal any history of pericarditis. New-onset ascites was considered to be cardiac in etiology as liver function tests, abdominal ultrasound, and liver biopsy all demonstrated normal allograft function. Left ventricular function showed improvement with medication optimization, but the PH and right ventricular function continued to worsen, resulting in diuretic refractory ascites that mandated multiple sequential paracenteses. Renal function also declined, necessitating hemodialysis for fluid removal. An outpatient RHC with constriction/restriction study was non-diagnostic. An endomyocardial biopsy was performed, which did not reveal an infiltrative disease and demonstrated patchy endocardial and interstitial fibrosis with compensatory myofibril hypertrophy without myofiber disarray, hence favoring the diagnosis of 'idiopathic restrictive cardiomyopathy'. Cardiac MRI was deferred due to renal insufficiency, whereas nuclear imaging such as cardiac single-photon emission computed tomography could not be performed due to a lack of institutional availability.Most RCMs are due to the infiltration of abnormal substances between myocytes, storage of abnormal metabolic products within myocytes, or fibrotic injury. In idiopathic RCM, however, no definitive cause can be elucidated on cardiac biopsy . RCM usuDifferential diagnosis of RCM due to myocardial causes are divided into non-infiltrative pattern, which includes familial CM, hypertrophic CM, scleroderma, pseudoxanthoma elasticum, diabetic CM, and idiopathic CM. The infiltrative pattern of RCM includes amyloidosis, sarcoidosis, Gaucher’s disease, Hurler’s disease, and fatty infiltration. Storage diseases such as hemochromatosis, Fabry’s disease, and glycogen storage diseases also are myocardial causes of RCM. Endomyocardial etiologies include hyper-eosinophilic syndrome, carcinoid heart, metastatic cancer, radiation, and drugs  -7.The morphological definition of idiopathic RCM is based on echocardiographic features demonstrating non-dilated, non-hypertrophied ventricles, with marked bi-atrial enlargement in the absence of ischemic, valvular, hypertensive, congenital, inflammatory, or infiltrative heart diseases. Elevated RA pressures and PH are usually present . In idioThis is a rare case of idiopathic RCM occurring less than one year after a liver transplant that was rapidly progressive, with the development of refractory ascites and renal failure necessitating dialysis. A similar phenomenon has not been described in the past. Though the underlying mechanism is not known, a relationship with OLT is suspected.We conclude that idiopathic RCM can rarely develop following a liver transplant and can progress rapidly over the course of months, leading to refractory heart failure symptoms and end-organ damage. This should be considered as a differential diagnosis in patients who develop worsening ascites and edema with normally functioning liver allograft. Cardiac biopsy is usually non-diagnostic and reveals focal interstitial fibrosis with mild myocyte hypertrophy without specific evidence of any infiltrative disease. Transthoracic echocardiographic findings of bi-atrial dilation with non-dilated and non-hypertrophied ventricles usually suggest the diagnosis of idiopathic RCM in these cases.


The increase in the sympathetic activity is induced by a number of mechanisms, including chemoreflex stimulation by hypoxia and hypercapnia, baroreflex, endothelial dysfunction, and venous return and cardiac output alterations.4The abnormal pattern of breathing during sleeP , associated with repeated awakenings, results in hemodynamic, autonomic, inflammatory, and metabolic effects that may contribute to the pathogenesis of several cardiovascular diseases: systemic arterial hypertension, coronary disease, cardiac arrhythmias , heart failure, left ventricular (LV) hypertrophy, cerebrovascular accident, and pulmonary hypertension.5OSA should be suspected whenever a patient presents with excessive daytime drowsiness, snoring and asphyxiation during sleeP , particularly in the presence of risk factors such as obesity, male gender and older age. However, OSA is not a clinical diagnosis and objective tests should be performed for the diagnosis.6 show the correlation between the risk of OSA and echocardiographic parameters related to LV diastolic dysfunction. A total of 354 individuals included in the study answered the Berlin Questionnaire (BQ), a tool used to estimate the risk of OSA, with 63% of them being classified as having a high risk for this disorder.In this issue of the Brazilian Archives of Cardiology, Leite et al.7Most sleeP disorder researchers do not recommend the routine use of assessment tools such as questionnaires or algorithms to select patients at higher risk for OSA, as these tools have not shown to be superior to the clinical history and physical examination in the clinical assessment of these patients.7 These tools are considered to be of low diagnostic accuracy. Regarding the QB, used in the aforementioned study in this issue,6 the literature discloses a large number of false negative results, thus limiting its usefulness as a tool for OSA diagnosis. A review of 19 studies that analyzed the performance of the BQ compared to polysomnography data showed an overall sensitivity of 0.76 (95% CI: 0.72 to 0.80), whereas the overall specificity was 0.45 (95% CI: 0.34 to 0.56). This result discloses a very high number of false negative results , with compromised diagnostic accuracy.The American Academy of SleeP Medicine clinical guideline published in 2017 strongly recommends that questionnaires and clinical prediction algorithms should not be used to diagnose OSA in the absence of polysomnography.Therefore, this is a limitation of the study under analysis, since we do not study a population of OSA patients, but individuals at high risk of OSA, using a diagnostic tool considered to be of low diagnostic accuracy.7It is understood that, in an environment without sleeP disorder specialists, the assessment tools, such as questionnaires and clinical prediction algorithms, may be useful because they promote the uniformity of sleeP assessment, and, when necessary, expand their use counting on other health team professionals to apply them. However, one should bear in mind that the application of these tests does not replace a good clinical evaluation, with anamnesis and physical examination, much less the polysomnography, which remains the gold standard for the diagnosis of OSA.6 aimed to evaluate the behavior of echocardiographic parameters in OSA. Restrictions are made to the characterization of the studied population (patients at risk of OSA according to the BQ), but the results obtained were consistent with the literature findings. Increased left atrial volume and the behavior of mitral flow indices characterize LV diastolic dysfunction.6The study by Leite et al.8 who analyzed 55 patients diagnosed with OSA through polysomnography. Left atrial volume and left atrial deformation parameters were assessed through speckle-tracking echocardiography (strain and strain rate). Exercise capacity was also assessed through exercise testing. It was concluded that LV diastolic dysfunction is more prevalent in patients with severe OSA and is associated with reduced exercise performance. Left atrial remodeling contributed to exercise capacity prediction in this subgrouP of patients.8Left atrial enlargement in OSA was characterized in a recent study by Cetin et al.,9 concluded that this syndrome leads to left atrial dilation, and LV hypertrophy, dilation, increased mass and systolic function reduction.9 The treatment of OSA may be beneficial in preserving LV structure and function.9A meta-analysis of 17 studies on LV remodeling and dysfunction in OSA,10 demonstrates that the moderate and severe forms of OSA are associated with increased atrial volumes, altered LV diastolic function and then LV systolic function. The assessment of right ventricular ejection fraction may also be compromised, being better evaluated by three-dimensional echocardiography. Moreover, the contribution of two-dimensional speckle-tracking echocardiography has been very effective, differentiating between active and passive wall movements. Abnormal strain values, a subclinical marker of myocardial dysfunction, can be detected even in patients with normal ejection fraction and volumes. LV longitudinal strain is more affected by the presence of OSA.10An interesting review carried out in Romania by Sascau et al.,6 highlights the contribution of echocardiography in OSA evaluation, a frequent disorder with different facets of pathophysiological interaction with cardiovascular diseases. The technological development of echocardiography, particularly with three-dimensional and speckle tracking techniques, shows a continuing contribution to the study of OSA.In conclusion, the work by Leite et al.


A leadless pacemaker is a new concept in which a miniaturized pacing device is self-contained within the heart. Recently published data show that leadless pacemakers are associated with a decreased risk of major complications when compared with transvenous cardiac pacemakers. This seems to be of particular importance in children and young adults in whom various complications may occur during their lifetime.Herein, we report the successful implantation of Micra™ Transcatheter Pacing System in two children: 12-year-old boy and 13-year-old girl, along with a long-term follow-up. The children had indications for pacemaker implantation, however, with an expected low percentage of pacing due to paroxysmal nature of the third-degree atrioventricular block. The implantation procedures were performed in general anaesthesia. There were no complications. During the 2-year follow-up, there were no adverse events and the electrical parameters of the device remained stable. Pacing percentage was below 0.1%.Transvenous cardiac pacemakers improve quality of life and reduce mortality but may be associated with various short- and long-term complications, mainly related to the presence of transvenous leads and the pulse generator. Compared with adult patients, the implantation of conventional pacemakers in children is still a challenge, not only because of their smaller size but also due to continuing growth, as well as a higher rate of lead and device-related complications. We demonstrate that the implantation of leadless pacemakers in children is feasible and could be worth considering in certain clinical scenarios, especially when ventricular pacing is required rarely. A leadless pacemaker is a new miniaturized pacing device which allows to eliminate potential complications associated with the presence of transvenous leads and the pulse generator.Our case series shows that the implantation of leadless pacemakers in children is feasible and could be the worth considering solution when ventricular pacing is required rarely. During the 3-year follow-up, there were no adverse events and the electrical parameters of the leadless pacemaker in our paediatric patients remained stable.Transvenous cardiac pacemakers not only significantly improve quality of life but also reduce mortality. Unfortunately, despite the substantial progress achieved throughout decades in the pacing technology, conventional cardiac pacemakers are still associated with various short- and long-term complications mainly related to transvenous leads.,,A leadless pacemaker is a new concept in which a miniaturized pacing device is self-contained within the heart. This technology allows to eliminate potential complications associated with the presence of transvenous leads and the pulse generator. The safety and clinical performance of transcatheter leadless pacemakers have previously been assessed in clinical trials.A 12-year-old boy who underwent surgical repair of congenital heart defect  at the age of 3 months was urgently transferred from a regional hospital to our centre due to highly symptomatic third-degree atrioventricular (AV) block. The patient was brought by ambulance after three episodes of syncope with seizures lasting for 2 min followed by spontaneous recovery of consciousness. Both the neurological examination and computed tomography of the head revealed no abnormalities. Due to the recurrence of complete AV block with significant bradycardia and hypotension, temporary transvenous cardiac pacing was initiated in the referring hospital.3/µL, red blood cells of 5.85 × 106/µL, haemoglobin—8.2 mmol/L, creatinine—55 µmol/L, potassium—4.70 mmol/L, and C-reactive protein—2.71 mg/L.On admission, the patient was drowsy, but conscious, without any neurological deficits, with a heart rate of 85/min (temporary pacing in the VVI mode) and blood pressure of 115/42 mmHg. The physical examination revealed no other abnormalities except for a median sternotomy scar. The body weight and height of the boy were 45 kg and 140 cm, respectively. A 12-lead electrocardiogram (ECG) showed VVI pacing, however, when the pacing was temporarily turned off there was a sinus rhythm 60–70/min with 1:1 AV conduction. The transthoracic echocardiography showed normal chamber dimensions, good systolic function of both ventricles (left ventricular ejection fraction of 78%), mild tricuspid regurgitation, and no residual shunting through interatrial and interventricular septum. Laboratory results were within normal ranges: white blood cells of 8.9 × 10During the follow-up since 2003, asymptomatic episodes of both first- and second-degree paroxysmal AV block (2:1) have already been observed, however, parents repeatedly refused pacemaker implantation and the boy was treated with metaproterenol with a good dromotropic effect remaining asymptomatic over the years . Regardless of the past, the child now had strong and unquestioned indications for pacemaker implantation, however, with an expected low percentage of right ventricular (RV) pacing due to previously asymptomatic follow-up and paroxysmal nature of the AV block. Both, parents and the boy repeatedly expressed their psychological resistance to a traditional device. They were afraid of the cosmetic effect of the implant, various restrictions related to traditional pacemaker and long-term device-related complications. Having considered the overall clinical situation and having thoroughly discussed the issue with the parents, who continuously showed considerable reluctance to conventional pacemaker implantation, the consulting electrophysiologist decided to implant a single chamber leadless pacemaker Micra™. A written informed consent was obtained from parents prior to the procedure.Figure 1). Appropriate and stable device fixation was achieved after the first deployment and was assessed by the following: fluoroscopic visualization, pull and hold test, tactile feel, and appropriate electrical measurements. Having confirmed proper device implantation, the tether was cut, the delivery system was removed and the insertion site was closed with a haemostatic suture. Total fluoroscopy and procedure duration was 3 min 7 s and 55 min, whereas the fluoroscopy dose and dose area product were 64 mGy and 378.6 µGym2, respectively. There were no peri- or post-procedural complications. The location of the device is shown in Figure 1.The implantation procedure was performed in general anaesthesia on February 2016. A dedicated Transfemoral Delivery Catheter was used to advance the device into the right ventricle through the 23-Fr Micra Introducer placed in the right femoral vein. We performed a predilatation with 8-Fr, 12-Fr, and 18-Fr sheaths, receptively, followed by a proper 23-Fr introducer sheath insertion. At the time of 8-Fr femoral sheath use, we also performed angiography of femoral vein. Micra™ was attached to the middle part of the intraventricular septum with two out of four self-expanding nitinol tines . The boy was discharged home on the 14th day post-implantation with 65% of intrinsic AV conduction and Micra™ programmed to VVI 40/min. Since then, the child has been carefully observed in the cardiology outpatient clinic. During the 32-month follow-up, there were no adverse events or recurrences of either pre- or syncope with the proper device function and significant reduction of RV pacing to less than 0.1%. The electrical parameters of the device have been presented in A 13-year-old girl with permanent first-degree AV block diagnosed at the age of 10 during routine pre-participation screening for sport activity was admitted to the same department 2 months later. The reason for admission was an episode of asymptomatic paroxysmal third-degree AV block with a 6-s pause registered in one of ambulatory ECG Holter recordings performed routinely in the last 3 years.3/µL, red blood cells—4.8 × 106/µL, potassium—4.7 mmol/L, and C-reactive protein—2.3 mg/L. Having excluded secondary causes of conduction abnormalities, the initial decision was made to perform conventional cardiac pacemaker implantation. However, parents refused the implantation of a traditional pacemaker. They would accept only the leadless device for their child. Of note, neither cardiology guidelines nor any expert consensus have been published with regard to leadless pacemakers. Thus, any decision on implantation of Micra has to be based only on previous papers reporting feasibility and safety of the method.,The development of the girl was normal without any episodes of presyncope or syncope in the past. The physical examination revealed no abnormalities except for a silent systolic murmur heard at the Erb’s point. The body weight and height of the girl were 60 kg and 156 cm, respectively. The 12-lead ECG demonstrated no other abnormalities except for the first-degree AV block . Transthoracic echocardiography revealed no structural heart disease, the left ventricular ejection fraction was 66%. The girl showed good exercise tolerance, with a normal blood pressure response, appropriate chronotropic reaction and first-degree AV block throughout the exercise test. Laboratory blood results were within normal ranges: white blood cells of 9.3 × 10Figure 3). Secure fixation to the myocardium was confirmed by intraprocedural measurements, fluoroscopic visualization, and the pull and hold test which showed that two nitinol tines were engaged . From the initial venous puncture to the closure of the insertion site, the procedure lasted 29 min. Total fluoroscopy duration was 2 min 5 s, while the fluoroscopy dose was 35 mGy (dose area product: 305.2 µGym2). After the procedure, the device was re-evaluated and programmed to VVI with the lower rate 45/min. No peri- or post-procedural complications were observed. Seven days after the procedure, the child was discharged from the hospital and has been followed up in the cardiology outpatient clinic since then. During the 37-month follow-up, there were no adverse events and the electrical parameters of the device remained stable . Right ventricular pacing percentage was below 0.1%. Estimated maximum and minimum longevity of the battery at the end of 37 months of follow-up were above 7 and 7 years, respectively.The implantation was performed in general anaesthesia on April 2016 using the same technique as described previously. Micra™ was attached to the inferior part of the intraventricular septum . Such an approach could be sufficient for a safe back-up VVI pacing over the next 30 years. The constantly evolving technology may possibly allow for increasingly safe and straightforward removal of such devices in the future or perhaps even percutaneous re-charging.We have demonstrated that the implantation of Micra™ TPS in children is possible and worth considering in certain clinical scenarios when ventricular pacing is required very rarely. However, further studies are needed to definitely assess feasibility and safety of leadless pacing technology in children in long-term observation.Ewa Jędrzejczyk-Patej is a cardiologist. She has graduated from the Medical University of Silesia in Katowice. She is working at the Department of Cardiology, Congenital Heart Diseases and Electrotherapy, Silesian Center for Heart Diseases in Zabrze since 2008. Her specialty is clinical electrophysiology. She is a Professional member of European Society of Cardiology and EHRA and member of Polish Cardiac Society and Polish Heart Rhythm Section.European Heart Journal - Case Reports online.Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Consent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patients in line with COPE guidance.Conflict of interest: A.W.—consultant fees from Biotronik and Medtronic. E.J.-P., M.M., R.L., O.K.—consultant fees from Biotronik, Medtronic, Abbott and Boston Scientific. All other authors have declared no conflict of interest.ytaa064_Supplementary_Slide-SetClick here for additional data file.


Idiopathic inflammatory myopathy (IIM) manifest as systematic muscle involvement. Multiparametric cardiovascular magnetic resonance (CMR) could be a useful technique to detect systemic involvement and disease progression in IIM patients. This study aimed to describe the tissue characteristics and dynamic changes in myocardial and skeletal muscles after treatment in IIM patients.Forty-four consecutively recruited IIM patients  underwent 3 T CMR at first diagnosis, and 28 patients underwent follow-up scan after receiving standard treatment for more than 1 year. Thirty age- and sex-matched healthy subjects served as controls. The CMR protocol included: cines, T2-weighted (T2w), late gadolinium enhancement (LGE), T1 and T2 mapping, and extracellular volume (ECV) evaluated for the myocardium, and T1 and T2 mapping and ECV evaluated for skeletal muscles. Correlations between laboratory biomarkers and myocardial and skeletal tissue characteristics were analyzed. Comparisons between baseline and follow-up scans were performed using paired t-tests.At baseline, IIM patients showed significantly decreased hematocrit, higher left ventricular (LV) mass index, right ventricular (RV) volume index, myocardial and skeletal native T1, T2 mapping, and ECV than healthy controls. Significant correlations were found among myocardial native T1, T2 mapping, and ECV values and N-terminal pro b-type natriuretic peptide (NT-proBNP) levels, and significant correlations between skeletal T2 mapping and inflammatory biomarkers in IIM patients.During the follow-up, 28 patients underwent repeated CMR scan . Significant relief from clinical symptoms and decreased inflammatory biomarkers levels were observed. Significant reduction in myocardial native T1, T2, ECV, and skeletal native T1, T2, and ECV were observed during the follow-up assessment.Both myocardial and skeletal muscles in newly diagnosed IIM patients show distinct characteristics on multiparametric CMR. In addition, significant changes were observed in patients showing clinical remission after effective treatment, which suggests that quantitative T1, T2, and ECV techniques may have potential clinical value in IIM patients. Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of autoimmune myositis affecting skeletal muscles and multiple internal organs . The typIn the present study, we hypothesized that multiparametric CMR would help identify myocardial and skeletal involvement in patients with IIM and facilitate further dynamic monitoring of the effect of therapy during the clinical convalescence period of the disease.2; and (6) patients with incomplete or poor-quality images. For all patients with IIM, baseline image acquisition was performed before the administration of regular treatment. Thirty age- and sex-matched healthy controls without any known cardiac disease or hypertension, diabetes mellitus, cerebrovascular disease, nervous system disease, or pulmonary or renal diseases were included. The first CMR scan was performed within 1 week of the IIM diagnosis and the follow-up CMR scans were performed among patients who received at least 1 year of regular treatment.This was a prospective observational cohort study involving 44 patients with newly diagnosed IIM who were consecutively enrolled from January 2017 to April 2018. The diagnosis of IIM was made according to the criteria of the European Neuromuscular Centre (ENMC) International Workshop (2004) . All patAll participants underwent the same CMR protocol and provided written informed consent. The study complied with the Declaration of Helsinki and ethical approval was obtained from the local institutional ethics committee at West China Hospital (2016355).2; matrix size, 162 × 192; average temporal resolution, 35–45 ms; and slice thickness, 8 mm with no gap. Cardiac T2-weighted (T2w) images were acquired with the short TI inversion recovery (STIR) sequence on three short-axis views  and the 4-chamber long-axis view. The typical scan parameters were as follows: TR = 2 RR intervals during breath-hold; TE, 67 ms; flip angle, 180°; FOV, 280 × 340 mm2; matrix size, 166 × 256; and slice thickness, 10 mm. Phase-sensitive inversion recovery (PSIR) sequence with a segmented FLASH readout scheme was performed 10–15 min after gadolinium  injection with 0.15 mmol/kg per bolus on consecutive short-axis views from the basal to apical level of LV and 2-, 3-, and 4-chamber long-axis views to obtain the LGE images. The typical scan parameters were as follows: TR, 700 ms; TE, 2.0 ms; delay time after the inversion pulse, 300–380 ms; flip angle, 20°; FOV, 260 × 340 mm2; matrix size, 116 × 192; and slice thickness, 8 mm. T1 mapping images were acquired on three short-axis and 4-chamber views, as in the previous sequence, by using the Modified Look-Locker Inversion-recovery (MOLLI) sequence with a 5b(3b)3b (b stands for heartbeat) scheme and a 4b(1b)3b(1b)2b scheme before and 10–15 min after the gadolinium injection. The typical scan parameters were as follows: TR, 300 ms; TE, 1.2 ms; flip angle, 35°; FOV, 270 × 320 mm2; matrix size, 144 × 256; and slice thickness, 8 mm. T2 mapping images were acquired by T2-prepared single-shot bSSFP technique before administration of gadolinium on the short- and long-axis views identical to those associated with T1 mapping images. The typical scan parameters were as follows: TR, 240 ms; TE, 1.0 ms; flip angle, 12°; FOV, 320 × 340 mm2; matrix, 114 × 176; slice thickness, 8 mm; and T2 preparation pulse with 0, 30, 55 ms spin echo times.All participants underwent CMR examinations on a 3 T scanner  using an eight-channel phased-array body coil. All the images were acquired by breath-holding and ECG gating. A balanced steady-state free precession (bSSFP) sequence was used for cine images with continuous sampling from the basal to the apical levels on short-axis views and 2-, 3-, 4-chamber long-axis views. The typical scan parameters were as follows: repetition time (TR), 34 ms; echo time (TE), 1.3 ms; flip angle, 50°; field of view (FOV), 280 × 340 mmBiventricular volumes, ejection fraction, and LV mass were analyzed using a commercially dedicated post-processing software  according to the standardized protocol of Society of Cardiovascular Magnetic Resonance (SCMR) post-processing guideline . Biventrmyo) to the signal of the adjacent skeletal muscles (SIsk) on the same slice.The T2w signal intensity (SI) ratio was calculated as the ratio of the signal of the LV myocardium on mid-ventricular short-axis (SImuscle post - 1/T1muscle pre) / (1/T1blood post - 1/T1blood pre). Hematocrit was obtained on the same day as the CMR examination in normal controls and within 3-days of CMR in patients. Care was taken to exclude image artifacts on myocardiaum and skeletal muscles. The illustrative images of bSSFP cine, native T1 mapping, T2 mapping, and ECV on short-axis views of a healthy subjects and one IIM patient at baseline (visit 1) and CMR follow-up (visit 2) are shown in Fig. Native T1, T2 relaxation times, and ECV of both the myocardium and skeletal muscles were measured on the same mid-ventricular short-axis slice by using Medis Suite 2.1 (Medis). The myocardial region of interest (ROI) was manually delineated on the end-diastolic phase with the endo- and epicardial contours to avoid endocardial trabeculations, blood pool, and epicardial fat. The selection of ROI on T1 and T2 mapping images of the adjacent skeletal muscles included five groups  with carefully avoidance of adipose tissue. The analyses of tissue characteristics of skeletal muscles were performed by calculating the average values for the five groups. The native T1 and T2 relaxation times of both myocardium and skeletal muscles were generated from motion-corrected images by fitting an exponential decay curve of each pixel in ROIs. For both myocardial and skeletal muscles, the T1 relaxation time before and after contrast injection was used to calculate ECV according to the following formula: (1-hematocrit) (1/T1The presence of LGE was judged by two independent experienced CMR observers blinded to patient information. The extent of LGE was measured with the threshold defined as 3 standard derivations (SDs) above the signal of the remote normal myocardial region .Clinical presentation and symptoms including symmetric proximal muscle weakness, rash, myalgia, and dysphagia, and laboratory biomarkers including hematocrit (Hct), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), creatine kinase (CK), creatine kinase-myocardial band (CKMB), cardiac troponins T (cTnT), and NT-proBNP were evaluated both at the time of the first diagnosis and at the follow-up within 3 days of the CMR examination in IIM patients.After the diagnosis of IIM, corticosteroids were chosen as the first-line medications in all patients, and immunosuppressive therapies including cyclophosphamide, methotrexate, and/or mycophenolate mofetil were personalized based on the patient’s disease severity and immune response. High-dose prednisone was initially administrated with gradually tapered doses until the lowest dose which could keep the patient in sustained remission .The follow-up data were last updated in Jun 2019 by collecting information by outpatient follow-up and telephone contact. Clinical remission of IIM was defined as (1) the improvement of muscle strength to normal level, accompanied by being able to move with resisting force; (2) remission of dermatitis, including the extinction of heliotrope, periorbital oedema, Gottron’s papules/sign, V-sign, shawl sign, and holster sign ; and (3)p < 0.05 was considered statistically significant. Statistical analyses were performed using MedCalc .The normality of variables was tested using the Kolmogorov-Smirnov method. Continuous variables were expressed as mean ± SD or median (interquartile range) values. Categorical variables were expressed as percentages. Parameters between IIM patients and healthy controls were compared with independent-sample T, Mann-Whitney or chi-square tests as appropriate. The differences between baseline and follow-up parameters in the subgroup of IIM patients with follow-up CMR scans were assessed by paired t-test or Mann-Whitney U test. Logarithmic transformation was performed on biomarker parameters for normal distribution. Correlations between CMR parameters and biomarkers were evaluated using Pearson’s correlation (r). Reproducibility of tissue mapping parameters was evaluated in 20 randomly selected IIM patients. The intra- and inter-observer variability was assessed by Bland-Altman analysis (bias and 95% limit of agreement), coefficients of variation (CoVs), and intra-class correlation coefficients (ICCs). Two-tailed p < 0.001) and T2  relaxation times, and higher ECV  than normal controls. Eleven patients (25%) were LGE-positive with an average extent of 12.0% ± 3.1% by the threshold of 3SD. For the evaluation of skeletal tissue characteristics, IIM patients showed significantly longer native T1  and T2  relaxation times, and higher ECV  at baseline compared to normal controls.We enrolled 46 IIM patients, among which two patients (4.3%) were excluded due to poor image quality. The study cohort consisted of 44 newly diagnosed IIM patients, and the demographic, clinical, and CMR parameters of IIM patients and healthy controls are summarized in Table p < 0.001), T2 , and ECV  values showed moderate positive correlation with the log NT-proBNP. Among the multiparametric tissue characteristics of skeletal muscles, we found that skeletal T2 relaxation times showed significant positive correlation with the log ESR , log CK-MB , and log cTnT  levels, while skeletal native T1 and ECV did not show significant correlations with the levels of laboratory biomarkers. The results are presented in Fig.The increased myocardial native T1, T2, and ECV values were significantly correlated with a larger LV volume index, higher LV mass index, and lower LV ejection fraction (EF) Table p = 0.036), while no significant correlation was found among T1 or ECV values on myocardium with those on skeletal muscles. The scatterplots are presented in Fig. In the study, we also found that elevation of myocardial T2 value was significantly correlated with the skeletal T2 value , had a treatment time of less than 1 year (n = 6), or were reluctant to undergo a second CMR for personal reasons were excluded from the subgroup analysis. All 28 patients reached clinical remission during the CMR follow-up, with no patients demonstrating proximal muscle weakness or skin rash. Patients also showed significantly decreased CRP, CK, CK-MB, TnT and NT-proBNP levels and increased Hct during follow-up in comparision with those at baseline. While a significant decrease in LV mass index was observed , no significant changes were observed in the biventricular volume index or ejection function. Seven LGE-positive patients at baseline were still LGE-positive at CMR follow-up with a trend of a reduced extent of LGE with no statistically significant difference . Patients showed significantly decreased myocardial T1 mapping , T2 mapping , and ECV  during the follow-up CMR. However, the myocardial native T1 and T2 values were still significantly higher than those for normal controls. The comparison between baseline and follow-up CMR of the subgroup IIM patients is summarized in Table During the follow-up, 28 IIM patients were arranged to consecutively undergo repeated scans with a median CMR interval of 14.5 mo (interquartile: 13.2–15.5 mo). Those who have not been treated regularly (p < 0.001), T2 relaxation time  time, and ECV , with the native T1, T2 and ECV values of skeletal muscles still significantly higher than those of normal controls. The results are summarized in Table In the assessment of skeletal tissue characteristics, patients showed significantly decreased skeletal native T1 relaxation time  multiparametric CMR could detect both myocardial and skeletal involvement in newly diagnosed IIM patients in comparision with normal controls. (2) In newly diagnosed IIM patients, the myocardial T1, T2, and ECV were correlated with LV volume, function, and the log NT-proBNP level, while skeletal T2 was significantly correlated with biomarkers reflecting disease activity. (3) The follow-up CMR showed significantly decreased myocardial T1, T2, and ECV, as well as skeletal T1, T2, and ECV, which may indicate that the involvement of myocardium and skeletal muscles was reversible. This is the first study to show the potential role of multiparametric CMR in non-invasively monitoring the treatment effect on both cardiac and skeletal systems of IIM patients.It is not uncommon for the myocardium to be affected in systemic inflammatory diseases. In this context, the clinical value of CMR parametric mapping techniques in quantifying myocardial tissue alterations has been gaining recognition in many diseases . Ntusi equantitative mapping parameters can be used as potential imaging markers for detecting subclinical cardiac involvement in newly diagnosed IIM patients. The significant correlation between myocardial ECV and serum CRP level, as well as the significant correlation between myocardial and skeletal T2 values, may indicate that the degree of myocardial inflammation is positively correlated with the systematic inflammation level. In addition, for the assessment of skeletal tissue characteristics, elevated skeletal T2 relaxation time was shown to be correlated with biomarkers such as the ESR, CK, CK-MB, and cTnT levels. Our findings suggested that the skeletal inflammation reflected by CMR multiparametric mapping techniques is related to the disease activity.CMR mapping technologies have shown good reproducibility and sensitivity in dynamic monitoring for different diseases. Hinojar et al. found that lupus myocarditis patients had elevated myocardial native T1 and T2 relaxation times and showed a significant decrease after intensive therapy, which suggests an attenuation of myocardial inflammation . Bohnen In the present study, we found that newly diagnosed IIM patients had significantly elevated T1, T2, and ECV values on both myocardium and skeletal muscles, which are consistent with the findings of previous studies , 12. In Although the cellular and molecular pathophysiology underlying the myocardial involvement in IIM patients is not clear, the increased T2 relaxation time at baseline suggested that myocardial inflammation might be a major pathophysiological change in IIM patients . ConsistWe found that IIM patients had elevated T1 values at both newly diagnosed and clinical remission stages in comparison with normal controls. While a previous study found that native T1 shows high diagnostic accuracy in discriminating the acute and convalescent stages of myocarditis , the incOne previous study had demonstrated that in cases with coexisting inflammation and diffuse fibrosis, the ECV would reflect the sum of both pathologies . ECV hasIn contrast to the findings for quantitative T1, T2, and ECV techniques, the T2W images showed limited ability to distinguish IIM patients from normal controls. This lack of sensitivity may be explained by the concurrent abnormality on skeletal muscles . The T2 In the current study, IIM patients with positive LGE at baseline still showed LGE during follow-up, without a significant decrease in the LGE extent. This may be explained by the fact that LGE reflects irreversible myocardial injury . PreviouIn the current study, we found that elevated myocardial native T1, T2, and ECV significantly correlated with LV systolic dysfunction and enlargement, while the myocardial T2 value also correlated with RV dysfunction. These results suggest that myocardial inflammation and the possible presence of myocardial fibrosis in IIM patients can adversely impact cardiac function and structure.This study had several limitations. First, this is a single-center study with a relatively small number of patients. Further studies with larger sample sizes and external validation are needed. Second, not all IIM patients enrolled at baseline underwent follow-up CMR scans. Although this could potentially lead to study bias, we focused on the subsequent observation CMR scans to analyze the dynamic changes in both myocardial and skeletal tissue characterizations. Third, the imaging data for the myocardium were not supported by biopsy findings. Future studies on the prognostic value of multiparametric CMR in IIM patients are required to validate these findings.The study demonstrates that multiparametric CMR could allow early detection of myocardial and skeletal muscles involvement in IIM patients, and help monitor dynamic changes after effective treatment.


Atrial fibrillation (AF) is the most common arrhythmia observed in HCM, developing in approximately 20% of all cases, with an annual incidence of 1–3% per year. The risk of AF developing is 4–6 fold greater in HCM than in the general population. Its' development is associated with an increased risk of systemic thromoboembolism, heart failure and death. Myocardial fibrosis is an important risk factor for the development of atrial fibrillation as demonstrated in post mortem studies. Cardiovascular magnetic resonance (CMR) is the gold standard imaging tool to visualise replacement myocardial fibrosis in vivo. The presence of fibrosis has been shown to be an important predictor of cardiovascular morbidity and mortality in both ischaemic and dilated cardiomyopathies, and more recently an important predictor of arrhythmia as detected by Holter monitoring in HCM.We hypothesised that the presence of myocardial fibrosis is an independent predictor of atrial fibrillation in patients with HCM in a prospective cohort of patients.Between 2001 and 2005, 126 patients with an established diagnosis of HCM were scanned with gadolinium late enhancement. Clinical data, cardiac events, and investigations were collected prospectively to identify outcomes. Relevant data including severity of mitral regurgitation, left atrial indexed volumes, and ejection fraction were noted. The median duration of follow up was 1076 days. CMR volumes, mass, and ejection fraction were analysed using customised software . Myocardial fibrosis was assessed using standard late enhancement techniques with gadolinium-DTPA contrast agent apex using customised software . Myocardial epicardial and endocardial contours were delineated. Regions of normal and abnormal myocardium were identified and the total amount of fibrosis was quantified on a per segment basis using the full width half maximum technique. The total amount of fibrosis was expressed as a percentage per segment, as a total in grams, and as a percentage of the total left ventricular mass. A Cox proportional hazard model was applied to correlate the incidence of atrial fibrillation with the presence of myocardial fibrosis.Of 126 patients studied, 87 (69%) had detectable myocardial fibrosis. In those with myocardial fibrosis the incidence of atrial fibrillation over the follow up period was 21% vs 5% for those without (p = 0.033). The presence of myocardial fibrosis was associated with an 8 fold increased risk of the development of atrial fibrillation . Mutivariate analysis demonstrated that fibrosis remained an independent predictor of AF regardless of mitral regurgitant severity, ejection fraction, and LA indexed volumes.The presence of LV myocardial fibrosis in HCM is an independent predictor of the development of atrial fibrillation over a median of approximately three years. This may have important implications for risk stratification, decision to anticoagulate, and maintenance of sinus rhythm in this population. A potential mechanism may relate to associated diastolic dysfunction resulting in changes to atrial architecture. It is also possible that LV changes reflect increased atrial fibrosis as part of the disease spectrum but that is more difficult to detect with present techniques.


Targeted hypothermia, as used after cardiac arrest, increases electrical and mechanical systolic duration. Differences in duration of electrical and mechanical systole are correlated to ventricular arrhythmias. The electromechanical window (EMW) becomes negative when the electrical systole outlasts the mechanical systole. Prolonged electrical systole corresponds to prolonged QT interval, and is associated with increased dispersion of repolarization and mechanical dispersion. These three factors predispose for arrhythmias. The electromechanical relations during targeted hypothermia are unknown.We wanted to explore the electromechanical relations during hypothermia at 33 °C. We hypothesized that targeted hypothermia would increase electrical and mechanical systolic duration without more profound EMW negativity, nor an increase in dispersion of repolarization and mechanical dispersion.n = 14), we registered electrocardiogram (ECG) and echocardiographic recordings during 38 °C and 33 °C, at spontaneous and atrial paced heart rate 100 beats/min. EMW was calculated by subtracting electrical systole; QT interval, from the corresponding mechanical systole; QRS onset to aortic valve closure. Dispersion of repolarization was measured as time from peak to end of the ECG T wave. Mechanical dispersion was calculated by strain echocardiography as standard deviation of time to peak strain.In a porcine model (p < 0.001) and heart rate 100 beats/min (p = 0.005). Mechanical systolic duration was prolonged and outlasted electrical systole independently of heart rate (p < 0.001). EMW changed from negative to positive value . The positivity was even more pronounced at heart rate 100 beats/min . Dispersion of repolarization decreased (p = 0.027 and p = 0.003), while mechanical dispersion did not differ (p = 0.078 and p = 0.297).Electrical systole increased during hypothermia at spontaneous heart rate (Targeted hypothermia increased electrical and mechanical systolic duration, the electromechanical window became positive, dispersion of repolarization was slightly reduced and mechanical dispersion was unchanged. These alterations may have clinical importance. Further clinical studies are required to clarify whether corresponding electromechanical alterations are accommodating in humans. Targeted hypothermia 32–36 °C) is recommended in comatose cardiac arrest survivors to improve outcome . However–36 °C isHowever, there has not been observed increased incidence of adverse ventricular arrhythmic events during treatment with targeted hypothermia in cardiac arrest survivors –13. EMW,The experiment was performed in an open chest porcine model. Data for the present study were collected from experiment series published in two previous articles , 14. TheThe study was approved by Nationals Animal Research Authority of Norway  and carried out in accordance to the European Convention for the protection of vertebrate animals used for experimental and other scientific purposes, the European Union Directive 2010/63/EU .n = 14, Norwegian land race swine, mean weight 52 ± 4.3 kg) were fasting overnight aside from free water access. They were pre-medicated by an intramuscular injection with ketamine (20 mg/kg), azaperone (3 mg/kg) and atropine (20 µg/kg). Anaesthesia was induced with intravenous pentobarbital (3 mg/kg) and morphine (2 mg/kg), and maintained with morphine infusion (1–2 mg/kg/h) and isoflurane inhalation (1–1.5%). Neuromuscular blocking agents were not used. Level of anaesthesia was monitored by continually haemodynamic measurements and observation of clinical signs. When the protocol was finished, the animals were euthanatized by bolus infusion of 80 mmol potassium chloride and 1000 mg pentobarbital. The animals were mechanically ventilated via a tracheostomy tube by a fraction of air/oxygen (FiO2 0.4), with tidal volumes of 10–15 ml/kg and surgically prepared with sternotomy as previously reported [The animals  and 33 °C. 33 °C was chosen representing median temperature recommended from cardiac resuscitation guidelines at that time, with a targeted temperature of 32–34 °C . MeasureThe ECG lead II was used for electrical measurements. The electrical systole , was measured from onset of QRS to end of T wave (Te) in ECG. The QT interval was heart rate corrected according to the Bazett’s formula (QTc) . Te was PW) and from AVO to AVC. The interval from onset of QRS to the registered AVC represented the duration of the mechanical systole (QAVC). EMW was calculated by subtracting the electrical systole from the duration of the mechanical systole in the same heartbeat, QAVC-QT interval  and isovolumic relaxation time (IVRT) were measured in long axis view from mitral valve closing (MVC) to aortic valve opening (AVO) and aortic valve closing (AVC) to mitral valve opening (MVO), respectively. Ejection time was measured as the duration of the pulsed wave Doppler signal in left ventricular outflow tract , and ejection fraction was calculated by the modified Simpson biplane method. Systolic velocity was recorded from mitral ring tissue Doppler velocity images in apical 4-chamber views. Cardiac output was measured by pulmonary artery catheter thermodilution and stroke volume was calculated. Peak systolic left ventricular pressure was recorded by the micro-manometer catheter placed in the left ventricle.Longitudinal strain was obtained by speckle tracking echocardiography from the basal and mid segments in three apical left ventricular projections . The endocardial border was traced manually, and region of interest was adjusted to fit the myocardial thickness. Segments that failed to track were manually adjusted, and if subsequent failing the segments were excluded. The echocardiographic probe was directly placed on the heart with a subsequent loss of the apical segments, whereof peak strain was derived from 12 segments. Time to peak strain in each segment was defined as the time from Q onset on ECG to peak longitudinal strain in three cycles and averaged. Mechanical dispersion was defined as the standard deviation of time to peak negative strain  in the 1Doppler registered QT and QAVC were re-measured by the same observer to assess intraobserver repeatability. A second observer measured the same variables in seven random selected animals to assess interobserver reproducibility.t-test. P-value, p < 0.05 was considered statistically significant. Intra- and interobserver variations were analysed by using intraclass correlation coefficient concerning single measures [Statistical analyses were performed in SPSSv.25 software . Parametric data are presented as mean ± standard deviation. Data from normothermia and hypothermia at spontaneous and heart rate 100 bpm were compared by Student’s measures .All recordings were of good quality. Three animals had a spontaneous heart rate above 100 bpm at 38 °C, and were not paced during normothermia. One animal did not receive pacing due to malfunction of the pacemaker electrode.During hypothermia mean arterial pressure and left ventricular pressure were reduced at both spontaneous rhythm and heart rate 100 bpm . The mechanical systolic duration outlasted the electrical systole, and EMW changed from − 20 ± 19 to 27 ± 34 ms (p = 0.001)   Fig. . Dispersed Table . There wed Table .Table 4SIntraobserver correlation coefficient for QT and QAVC were 0.99  0.98–1.0) and 0.99 (95% CI 0.99–1.0). Interobserver correlation coefficient for the same parameters were 0.99 (95% CI 0.98–1.0) and 0.99 (95% CI 0.77–1.0).In this experimental study, targeted hypothermia increased both electrical and mechanical systolic duration. Indeed, the mechanical systole outlasted the electrical systole independently of heart rate and therefore the EMW became positive. Dispersion of repolarization was slightly reduced, and mechanical dispersion was unchanged, at both spontaneous and at heart rate 100 bpm.Cardiac arrhythmic diseases are primarily perceived as electrical disorders. Prolonged QT interval with EMW negativity is an independent pro-arrhythmic predictor. This arrhythmogenicity may be a consequence not only of electrical alterations, but likely also of mechanical influences. In one study increased EMW negativity for any QTc in long QT syndrome was found, indicating an electrical-independent mechanical influence . In our In our in vivo model, baseline EMW was slightly negative at both heart rates. The normal value for EMW in land race pigs during normothermia is unknown, but an open chest model can lead to a prolonged QT interval which may contribute to EMW negativity . In an eTpTe is a marker for dispersion of repolarization with a strong association to arrhythmic risk. Whether the ECG measured dispersion represents transmural repolarization, global or both is still not clarified , 27. In The prolongation and slowing of systolic contraction during targeted hypothermia at 33 °C is previously described . HoweverOverall, we found no increase in mechanical dispersion but slightly prolonged ventricular depolarization, prolonged QT interval with reduced dispersion of repolarization and increased ventricular contraction duration. The registered increase in contraction duration may be explained by a synchronous contraction prolongation since there was no increase in dispersion of repolarization. However, it is still somewhat unclear how electrical and mechanical activities are coupled. The absence of mechanical dispersion does not necessarily indicate a synchronous pattern. Mechanical dispersion is measured as SD of time to peak systolic strain. Contraction end is not taken into account, which may be displaced. Hypothermia induced electrical delay with increased action potentials or affected electrical conduction in the myocardium, might have an additional coexisting influence on the systolic contraction pattern. Based on our experiments it is difficult to draw any conclusion regarding either mechanism.The beneficial and harmful effects of targeted hypothermia and the optimal temperature are not completely clarified. After cardiac arrest it might be difficult to distinguish whether myocardial dysfunction, arrhythmias or other adverse events are due to myocardial injury or to hypothermia itself. This may contribute to a possible restrain regarding clinical implementation , 37. OurThree-lead ECG were connected to the echocardiographic scanner. TpTe interval measurements from the bipolar limb lead II have limitations as discussed above. ECG TpTe interval from bipolar limb leads is thought to represent global dispersion, including apicobasal and interventricular dispersion of repolarization. Transmural dispersion of repolarization is most represented in precordial leads and is suggested to be the preferred leads when estimating arrhythmic risk . Our stuThe open chest model may have altered the preload and afterload conditions . HoweverTargeted hypothermia increased the duration of both the electrical and mechanical systole. The prolonged duration of the mechanical systole was relatively greater and outlasted the electrical systole at hypothermia. This led to a positive EMW. Hypothermia slightly reduced dispersion of repolarization, while mechanical dispersion remained unchanged. Further clinical studies are required to elucidate whether these electromechanical relations during hypothermia are presented in humans.