Endocarditis parietalis fibroplastica Löfflein (EPF) is a rare form of primary restrictive cardiomyopathy with poor prognosis. It is generally caused by hypereosinophilic syndrome with eosinophilic penetration of the heart. This leads to congestive heart failure in three different stages. As a frequent manifestation of neoplastic diseases, cardiac involvement means poor prognosis.The present report deals with a case of EPF caused by non-specified T-cell lymphoma (T-NOS). Besides an elevated Troponin-T enzyme, the electrocardiogram and the transthoracic echocardiography did not show any characteristic results. Due to risk/benefit assessment and low thrombocyte amounts, endomyocardial biopsy and catheterization were discarded. Using cardiovascular magnetic resonance (CMR) with steady-state free precession sequences, T2-mappping, strain analysis and late gadolinium enhancement, we were able to clearly highlight cardiac involvement at different stages. These findings characterized T-NOS as a palliative situation.Multiparametric CMR can not only identify EPF but also characterize the patchy disease state. This provides an individual prognosis assessment. Aside from prognosis estimation, it can also be used for therapy monitoring. HES syndrome can be idiopathic or correlated to clonal interleukin 5 (IL-5) over-production of T-helper cells. Once the heart is affected, the disease passes three steps: 1. Acute necrosis followed by 2. thrombosis and 3. end stage of fibrosis [Endocarditis parietalis fibroplastica (Loeffler’s disease) (EPF) is a disease with poor prognosis, first described by Loeffler in 1936. A diagnosis requires blood eosinophilia and affection of the endocardium as key steps . In morefibrosis . The undA 38-year-old man with a medical history of non-specified T-cell lymphoma (T-NOS) including immunosuppressive therapy regimes and a stem cell transplantation came to the emergency unit of the university hospital in Duesseldorf because of his uncontrolled nose bleeding Table . Next todoubled arrows), LV and RV walls were thickened and displayed subendocardial susceptibility artefacts (arrow). Despite normal LV-EF, myocardial feature tracking analysis  revealed impaired systolic endocardial and epicardial global longitudinal strain (GLS) compared to literature standards  [-1 vs. 1.7 s-1 for endocardial diastolic SRe; 1.0 s-1 vs. 1.5 s-1 for epicardial diastolic SRe)  images revealed normal left and right ventricular function (LV ejection fraction (EF) 61%, RV-EF 61%). As can be seen in Fig. Re) Fig. .Fig. 1Farrows). This phenomenon was aggravated during regadenoson induced hyperaemia, that showed highly impaired perfusion in endocardial layers, indicating altered coronary microcirculation .To analyse myocardial tissue texture, a parametric CMR was conducted to separate oedema or acute necrosis to other tissue texture components with T2 mapping . As showTaking the localisation of fibrosis, the T2 map and the perfusion abnormalities into account, the hypotheses of vascular coronary disease or myocarditis were discarded since there was neither an endocardial lesion corresponding to a coronary territory nor an epicardial lesion. Additional details of the patient’s history revealed a hypereosinophilia  for more than 6 months. On the basis of the CMR findings and the patient’s history of T-NOS with hypereosinophilia, he was diagnosed to have Endocarditis parietalis fibroplastica Löfflein (EPF). Interestingly, the multiparametric CMR workup revealed different stages of myocardial involvement: reduced GLS, diffuse LGE, perfusion defect and slightly lower T2-time displayed fibrosis and reduced coronary flow of the endocardium already under resting conditions. The epicardium, however, was characterized by abnormal GLS with abnormal diastolic function, lack of LGE, preserved perfusion, but elevated T2 times suggesting an inflammatory stadium. A high-dose corticoid drug (Dexamethasone 40 mg) was added to the existing everolimus-therapy and the patient was transferred to the department of haematology for further diagnostics. His bone marrow showed elevated numbers of eosinophilia up to 10% during completion of diagnostic steps.Cardiac involvement at different stages of EPF as shown by multiparametric CMR characterized T-NOS as a palliative situation, as recent therapeutic regimes such as immunosuppressive drugs and stem cell transplantation did not lead to a lasting remission.Since multiparametric CMR workup could not only identify EPF but also characterize the patchy disease state  and stratify the patient’s individual prognosis, invasive coronary angiography and endomyocardial biopsy were not conducted.The present case of EPF illustrates that multiparametric CMR can not only identify EPF, but also characterize EPF according to the disease state. CMR is a highly efficient tool for the process of diagnosis if invasive procedures are discarded due to risk/benefit assessment. In this particular case, myocarditis and coronary artery disease could be excluded without EMB or angiography due to multiparametric CMR. In addition, CMR detected advanced endocardial fibrosis with wall thickening as morphological hallmarks of the disease, while those features would have technically impeded adequate EMB.


Although altered cardiac substrate selection has been proposed to be the cause for many cardiac diseases and has been suggested to be a target to improve cardiac function, the effect of modulating substrate availability on global LV function in the normal heart has not been investigated. Our aim was to use CMR to investigate global cardiac function and strain before and after modulation of substrate availability2), underwent CMR imaging (1.5T) before and 4 hours after substrate manipulation. All measurements were performed after an overnight fast. Circulating free fatty acid (FFA) levels were elevated with a triglyceride infusion  co-administered with unfractionated heparin (0.4 U/kg per min). Reduction of circulating free fatty acids, and increased myocardial glucose uptake, was promoted with a single dose of nicotinic acid (Niaspam 400 mg). Analysis was undertaken in cvi42® with 1) tissue tracking to derive global LV measures of systolic radial and circumferential strain (%), diastolic radial strain rate (%/s), and 2) left ventricular ejection fraction .Six subjects  with no cardiac risk factors . Intralipid infusion resulted in elevation of; circulating FFA , B-hydroxybutyrate levels , systolic blood pressure , and a fall in glucose levels . In every subject, this was associated with an increase in LVEF, , and improved systolic peak global radial  and circumferential  strain. In contrast, nicotinic acid caused a fall in; circulating FFA  with no change in B-hydroxybutyrate , glucose  or SBP . In almost every subject, this was associate with decreased LVEF , and impairment of both systolic peak global radial  and circumferential strain . Diastolic strain rate also worsened with nicotinic acid ., LV function in the normal heart is affected substantially by altering substrate availability. Whilst elevating FFA acutely results in increased LVEF and improved systolic strain, in the same hearts, lowering FFA and potentially increasing glucose uptake with nicotinic acid results in reduced LVEF and impaired systolic and diastolic strain. This suggest that even in the normal heart cardiac altering substrate selection can substantially affect LV function.In the fasting state


The search for effective methods of myocardial cytoprotection against ischemia is the most significant issue in modern cardiology and cardiac surgery. Glucocorticoids are deemed very strong modulators of inflammatory response and thus can potentially protect heart muscle from postreperfusion injury and myocardial ischemia during cardiac surgery. Ultrastructural examination of the left ventricle heart samples revealed that the intravenous application of dexamethasone and hydrocortisone proved to exert cytoprotective effect on cardiomyocytes during experimentally induced acute ischemia in rats. The search for effective methods of myocardial cytoprotection against acute and chronic ischemia is the most desirable and relevant issue in modern cardiology and especially cardiac surgery. The protection of myocardial muscle from ischemia-induced left ventricular dysfunction during coronary artery bypass grafting, valve surgery, or heart transplantation is an essential matter for further success of the cardiac procedure. With age, this protection is reduced by altered mitochondrial metabolism. The defective mitochondria persist in the aged heart, leading to enhanced oxidant production and oxidative injury and the activation of oxidant signaling for cell death .α). The aforementioned cytokines enhance production of adhesion molecules  and their presentation on the surface of endothelial cells. The adhesion molecules allow lymphocytes to adhere to the vessel wall and then migrate from the blood into the vascular wall. Within the vessel wall lymphocytes become disintegrated, which strengthens permeability of the vasculature and causes vascular leakage. Concomitantly activated complement enhances this pathological process. All these factors and processes trigger the multiorgan damage, including lungs, liver, brain, and kidneys [The extracorporeal circulation  and surgical trauma (chest cutting) together with vigorous release of bacterial lipopolysaccharide (LPS) during cardiac surgery are very strong activators of immunological and inflammatory response  , 3. The  kidneys , 5. This kidneys . The stuThe study was approved by a local Ethics Committee for Animal Experiments. The study was performed on 30 Wistar male (15) and female (15) rats of body weight of 250–280 g, treated in compliance with the Guide for Care and Use of Laboratory Animals of the National Institutes of Health . The rats were divided into four groups: Group I: rats with induced acute myocardial ischemia; Group II: rats which were administered hydrocortisone hemisuccinate  15 min before the acute myocardial ischemia was induced; Group III: rats which were administered dexamethasone  1.0 h before acute ischemia; Group IV: the control group, not submitted to acute myocardial ischemia.3 were embedded in Epon 812 resin and ultrathin sections were stained with uranyl acetate and lead citrate and examined under a Tesla BS500 electron microscope .The acute myocardial ischemia was induced in following procedure. All the studied animals were anesthetized with thiopental in a dose of 30 mg/kg, intubated, and connected to a mechanical respirator . The heart action was monitored by ECG Aspekt 700  to the moment heart arrest. The chest was cut open in the midline. Acute myocardial ischemia was induced by disconnecting the respirator and compressing the tracheal tube, which was shortly followed by heart arrest. Samples from the left ventricle were taken for electron microscopy after 15 min of heart arrest. The tissue was fixed overnight at 4°C in 2.0% glutaraldehyde and postfixed in 2.0% buffered osmium tetraoxide. After dehydration in acetone series cubic samples 0.25 mmTo determine and compare changes in size of the mitochondria, the EM images were analyzed with Photoshop CS3, using area analysis function. For area measurement, the mitochondria were circled by the lasso tool and then the areas of the circles were calculated and converted to their actual values using the scale bar.The vast pathological changes in the ultrastructure of cardiomyocytes were observed in group I. The previously well-marked areas of euchromatin and heterochromatin within the structure of cellular nuclei became diffused. The following changes were also found during the electron microscope evaluation: clearly visible enlargement of the area of heterochromatin in the periphery of nuclei, atrophy and shortening of mitochondrial crests, mitochondrial inclusions, and disruption of mitochondrial structure. Beyond that the enlargement of Golgi cisterns and endoplasmatic reticulum, distortion, and further disintegration of myofilament structure were observed . The cytHowever, the glycogen granules were not visualized within the cytoplasm of cardiomyocytes.In the groups II and III the main changes were associated with sarcolemma and mitochondria. Myelin-like structures and some vacuoles in cytoplasm, giant mitochondria formation, and enlargement of intercellular space in intercalated disk were observed.The morphological abnormalities found in the myocardial ultrastructure in the groups II and III, that is, aggregation and further fusion of mitochondria, were mostly reversible and not so conspicuous as compared with the group I Figures  and 3. TIn summary of the obtained results, we must point out that the devastating pathological changes in myocardial structure, especially in mitochondria, vacuolization of cytoplasm, enlargement of cell-organelle lumen , enlargement of intercellular spaces within intercalated discs, and lack of glycogen granules in cytoplasm were found in rats submitted to the acute myocardial ischemia.Morphometric analysis revealed reduction in mitochondria size in group I whereas in groups II and III their enlargement when compared to the control group IV . The decThe observed abnormalities in the ultrastructure of cardiomyocytes are the consequence of acute myocardial ischemia and further the enhanced anaerobic metabolism within the myocardial cells followed by significant increase in lactic acid level and intracellular acidity. During acute myocardial ischemia, the functionally impaired mitochondria do not produce sufficient quantity of ATP. The ATP deficiency disturbs osmotic balance through blocking sodium-potassium ion pump , 7. All β-blockers.The majority of ultrastructural changes in rats from the group I were irreversible and brought to the total destruction of myocardial cells. The cytoprotective effect of hydrocortisone and dexamethasone administered in rats from the group II and III was validated. The steroids proved to stabilize cytoplasmatic membranes and intracellular structures thus preventing formation of destructive necrotic foci in myocardial ultrastructure. Most of the pathological changes found in the myocardial ultrastructure of these two groups (group II and III) were reversible. Glucocorticoids have been well-known and generally used group of medicaments in acute and chronic inflammation-related diseases for many years. They are also supposed to be effective in treatment of postcardiac surgery SIRS . In thisThe results of the study demonstrated potential cytoprotective effect of steroid administration at the respectably high dosage and regardless of the timing of the dose before experimentally induced acute myocardial ischemia .We need to emphasize that glucocorticoids can exert both positive and negative effects on the heart. Glucocorticoid administration improves contractile performance of the heart and inhibits cardiomyocyte apoptosis triggered by ischemia, cytokines, and cardiotoxic drugs. Conversely, elevated levels of glucocorticoids have also been linked to a variety of negative cardiac outcomes, for example, reduced heart rate in healthy human and induction of cardiac hypertrophy .Some authors suggest sex differences associated with presence of testosterone and estrogen influence calcium levels in heart muscle cells . We did


It is unclear whether obesity and type 2 diabetes (T2D), either alone or in combination, induce left ventricular hypertrophy (LVH) independent of hypertension. In the current study, we provide clarity on this issue by rigorously analysing patient left ventricular (LV) structure via clinical indices and via LV geometric patterns (more commonly used in research settings). Importantly, our sample consisted of hypertensive patients that are routinely screened for LVH via echocardiography and normotensive patients that would normally be deemed low risk with no further action required.This cross sectional study comprised a total of 353 Caucasian patients, grouped based on diagnosis of obesity, T2D and hypertension, with normotensive obese patients further separated based on metabolic health. Basic metabolic parameters were collected and LV structure and function were assessed via transthoracic echocardiography. Multivariable logistic and linear regression analyses were used to identify predictors of LVH and diastolic dysfunction.Metabolically healthy normotensive obese patients exhibited relatively low risk of LVH. However, normotensive metabolically non-healthy obese, T2D and obese/T2D patients all presented with reduced normal LV geometry that coincided with increased LV concentric remodelling. Furthermore, normotensive patients presenting with both obesity and T2D had a higher incidence of concentric hypertrophy and grade 3 diastolic dysfunction than normotensive patients with either condition alone, indicating an additive effect of obesity and T2D. Alarmingly these alterations were at a comparable prevalence to that observed in hypertensive patients. Interestingly, assessment of LVPWd, a traditional index of LVH, underestimated the presence of LV concentric remodelling. The implications for which were demonstrated by concentric remodelling and concentric hypertrophy strongly associating with grade 1 and 3 diastolic dysfunction respectively, independent of sex, age and BMI. Finally, pulse pressure was identified as a strong predictor of LV remodelling within normotensive patients.These findings show that metabolically non-healthy obese, T2D and obese/T2D patients can develop LVH independent of hypertension. Furthermore, that LVPWd may underestimate LV remodelling in these patient groups and that pulse pressure can be used as convenient predictor of hypertrophy status.The online version of this article (doi:10.1186/s12933-017-0504-z) contains supplementary material, which is available to authorized users. Obesity and T2D are well-accepted risk factors for the development of left ventricular hypertrophy (LVH) , 2. HoweLVH is traditionally characterised by increased thickness of the LV posterior wall diameter (LVPWd) and/or increased LV mass . There aMajor limitations of past studies are that obesity and T2D have often been considered one disease state, and the individual contributions of these diseases to LVH in the absence of hypertension have remained obscured. Furthermore, in studies that have appropriately distinguished obesity , 5 and TThe current study aimed to determine whether patients presenting with obesity and type 2 diabetes, either alone or in combination, exhibit LVH in the absence of hypertension. Both traditional indices of LVH and LV geometric patterns were used to identify LVH. Furthermore, we sought to determine whether LV geometry predicted the presence of diastolic dysfunction and whether routine metabolic parameters can be used to predict LVH in these patients.This cross sectional study comprised a total of 353 Caucasian patients, from the University Hospital Geelong and the Geelong Endocrinology and Diabetes Centre. The study was conducted in accordance with National Health and Medical Research Council (NHMRC) guidelines and was approved by the Human Research Ethics Committee (HREC) via the Barwon Health Research and Integrity Unit, in accordance to guidelines outlined in section 5 of the National Statement on Ethical Conduct in Human Research.Based on the diagnosis of obesity, T2D and hypertension, patients were designated into one of the following groups; normotensive obese (N.Obese) n = 58, normotensive T2D (N.T2D) n = 41, normotensive obese/T2D (N.Obese/T2D) n = 42, hypertensive obese (H.Obese) n = 71, hypertensive T2D (H.T2D) n = 74 and hypertensive obese/T2D (H.Obese/T2D) n = 67. For the diagnosis of obesity, T2D and hypertension, basic clinical and metabolic data were collected for each participant consisting of age, sex, height, weight, blood pressure, HbA1c %, fasting glucose, LDL-C, HLD-C, cholesterol and triglyceride levels , any history of anti-hyperglycaemic or anti-hypertensive medication, and any history of cardiovascular and/or systemic disease.2. Patients with a history of anti-hyperglycaemic medication were permitted within the obese group, due to the increasingly common use of biguanides in pre-diabetic/obese patients. T2D was characterised as having three or more elevated fasting glucose levels within a 12-month period, of ≥7 mmol/l, with or without a history of anti-hyperglycaemic medication. Hypertension was characterised as having both elevated diastolic and systolic blood pressure of ≥140/90 mmHg, with or without a history of anti-hypertensive medication. Those patients with controlled hypertension  were excluded from the study. Additional exclusion criteria for patients of all groups included history of cardiac disease or systemic disease, age <18 years, or the collection of accompanying clinical and metabolic medical records within a time period >6 months before or after TTE procedure. For a more detailed description of the study design see Additional file Obesity was characterised as a BMI ≥30 kg/mIntelli sense HEM-907 or HBF-1300 and cuff bladder at least 80% of the patient’s arm circumference. In the incidence of an elevated BP reading (≥140/90 mmHg), the measurement was repeated up to three times. With the lowest BP measurement recorded. Pulse pressure mmHg was calculated by subtracting diastolic BP from systolic BP (systolic BP mmHg–diastolic BP mmHg).Blood pressure (BP) was recorded as per the American Heart Association guidelines, with the use of OMRON To separate normotensive obese patients based on metabolic health. We adhered to Karelis criteria. With metabolically healthy patients determined as; fasting glucose ≤5.5 mmol/l, HDL-C ≥1.4 mmol/l, LDL-C ≤2.6 mmol/l, cholesterol ≤5.5 mmol/l and triglycerides ≤1.8 mmol/l. Patients were categorised as being metabolically unhealthy if they exhibited >1 more parameter outside these normal ranges.Sonographers were qualified with a Diploma of Medial Ultrasonography or equivalent. Both the sonographers that performed the echocardiography and cardiologists that analysed the results were blinded to the study groups, due to the retrospective nature of the study. All echocardiograms were performed using the Phillips Ie33 with a S5-1 transducer. A combination of two dimensional, M-mode, pulsed wave and continuous wave Doppler and tissue Doppler were used. Left ventricular diameter and wall thicknesses were measured in the parasternal long axis view using two-dimensional or M-mode measurements . Of note, while M-mode was used to measure the LV wall thickness whenever possible, in cases where the M-mode was not able to be properly aligned  two dimensional echocardiography was used. Mitral inflow velocities  and deceleration times (DT) were measured using pulsed wave Doppler in the apical 4 chamber view. Echocardiographic data was analysed using proprietary software.Diastolic dysfunction (DD) was characterised according to the American Society of Echocardiography (ASE) guidelines . Patient3 − (LVEDd)3]) + 0.6). LV mass was then indexed to body surface area  and to height (g/m2.7). RWT was calculated using the formula, RWT = ((IVSd + LVPWd)/LVEDd) and via ((2·LVPWd)/LVEDd). LV geometry was characterised using the following criteria; Normal LV geometry, RWT ≤ 42, LVMI (g/m2.7) ≤51; eccentric hypertrophy (EH), RWT ≤ 42, LVMI (g/m2.7) >51; concentric remodelling (CR), RWT > 42, LVMI (g/m2.7) ≤51 and concentric hypertrophy (CH), RWT > 42, LVMI (g/m2.7) >51.LV mass was estimated according to ASE guidelines , in whicContinuous variables were represented as means  ±1 standard deviation (SD), unless otherwise stated. Means of continuous variables were analyzed via ANOVA assessed with Bonferroni, and associations were determined by performing linear regression analysis, assessed with Pearson’s correlation coefficient. Categorical variables were expressed as percentages or prevalence and analyzed via Chi square tests, using fisher’s exact test. To determine independent predictors of categorical variables, multivariable logistic regression analysis was performed with variables adjusted for as detailed. Of note, aortic stenosis was not adjusted for as the presence of aortic stenosis (characterised by an ascending aorta of <3.7 cm) did not associate with diastolic dysfunction or LV geometric patterns in the normotensive patients. p < 0.05 was considered significant. All statistical analysis were performed using SPSS version 23.Basic clinical data are presented in Table The presence of LVH was determined by assessing the clinical hypertrophy indices LVPWd and LV mass, which were derived from M-Mode measurements Table . Additio2 = 0.35, p < 0.001), LV mass , LV mass/BSA (g/m2) , LV mass/height (g/m2.7)  and RWT  in both normotensive and hypertensive subjects. BMI independently correlated with LVPWd , LV mass  and LV mass/height . The same was true for hypertensive patients with the addition of a correlation between BMI and LV mass/BSA  and in H.Obese/T2D patients vs all other groups , LV mass remained increased between only H.Obese vs H.Obese/T2D  was increased in H.Obese vs N.Obese , N.Obese/T2D vs N.Obese  and between H.Obese/T2D vs both H.Obese and H.T2D   was increased between N.Obese vs H.Obese , N.Obese/T2D vs H.Obese/T2D  and in both H.Obese and H.T2D groups vs H.Obese/T2D . When indexed to BSA  3.487, p = 0.038) and grade 3 DD  when including sex and BMI as covariates. With the addition of age as a covariate, the association with grade 1 DD remained , and was lost with grade 3 DD . CH proved to be a stronger predictor of grade 3 DD  with the inclusion of sex and BMI as covariates. This association was only slightly attenuated with the addition of age as a covariate . Supporting these findings, RWT and LV mass/height were identified as predictors of grade 3 DD  when including sex and BMI as covariates. With the addition of age as covariate, the association between LV mass/height with grade 3 DD was lost  and was moderately attenuated in relation to RWT . Specifically, pulse pressure ≥54 mmHg and fasting glucose ≥7.7 mmol/l were associated with a RWT > 42, a value characteristic of concentric remodelling and also concentric hypertrophy when accompanied by an increase in LV mass. When accounting for sex, age and BMI, the correlations between pulse pressure , fasting glucose  and RWT were slightly strengthened. This suggests that these parameters can be used to predict risk in normotensive obese and/or T2D patients, independent of age and BMI. The same associations were not detected in hypertensive obese and/or T2D patients  Significant alterations in LV remodelling indicative of LVH were detected in normotensive metabolically non-healthy obese, T2D and obese/T2D patients. (2) Assessment of LVPWd via recommended ASE guidelines underestimated the presence of LV remodelling. (3) Concentric remodelling was a predictor of grade 1 DD and concentric hypertrophy and RWT predictors of grade 3 DD, independent of sex, age and BMI. (4) Normotensive patients with an increased risk of a RWT > 42 with those exhibiting pulse pressure ≥54 mmHg.2), does not promote the development of concentric remodelling, but rather it is the metabolic health status of the patient with a BMI ≥ 30 (kg/m2) that has the greatest influence on increases in RWT. Supporting this claim, our study showed that BMI had no association with RWT or diagnosis of concentric remodelling. Therefore, these results suggest additional risk assessment should be performed in normotensive obese patients with more than one of the following metabolic parameters; fasting glucose >5.5 mmol/l, HDL-C <1.4 mmol/l, LDL-C >2.6 mmol/l, cholesterol >5.5 mmol/l and triglycerides >1.8 mmol.Considering obese patients first, metabolically healthy N.Obese patients exhibited a relatively low prevalence of LV remodelling, with >80% of these patients exhibiting normal LV geometry. It was only in those N.Obese patients characterised with “poor” metabolic health that significant alterations in LV geometry were detected. This was particularly true for concentric remodelling (47%), which was 9.4 times higher than that in metabolically healthy N.Obese patients and 1.6 times higher than that in H.Obese patients. This suggests that obesity per se, as defined by a BMI ≥ 30 (kg/mH.Obese patients on the other hand exhibited not only concentric remodelling (28%) but also concentric hypertrophy (25%), at a prevalence 4.8 and 2 times higher than that in metabolically healthy and non-healthy N.Obese patients respectively. This is consistent with previous studies in which autopsy results identified hypertensive obese patients to exhibit both concentric remodelling and concentric hypertrophy and for normotensive obese patients to present with mainly concentric remodelling . N.T2D pTo our knowledge, this is the first study reporting that the use of unadjusted LVPWd vs RWT underestimated the presence of LV remodelling in obese and T2D patients. This had particular relevance in normotensive patients, with 45% of those characterised with concentric remodelling exhibiting LVPWd within the ranges of normal ASE guidelines. This result was unchanged regardless of how RWT was derived. However, consideration of septal wall thickening was preferred due to the presence of asymmetric LV remodelling in some patients, with IVSd showing similar patterns of enlargement as LVPWd within our groups . This suggests that reliance on unadjusted LVPWd in normotensive obese and T2D patients underestimates not only LV remodelling, but also associated cardiovascular risk. While previous studies have identified associations between LV geometry with adverse cardiac function and cardiovascular risk –24, thes2) and percentage of T2D subjects (3.97%) compared to current study.While subject numbers in the present study were low, the identification that pulse pressure and fasting glucose to be associated with RWT may assist health practitioners in narrowing down the otherwise large patient pool of at risk individuals to which this study relates, with pulse pressure ≥54 mmHg and fasting glucose ≥7.7 mmol predictors of RWT > 42. RWT was chosen as an independent variable to detect risk of LVH due to concentric remodelling and concentric hypertrophy being the predominant LV geometric patterns detected for which both have the common requirement for increased RWT. In addition, RWT provided a more sensitive measure to detected LV remodelling in our patients and increases in RWT have previously been associated with adverse cardiovascular events , 25, 26.Fasting glucose, has been associated with indices of LVH in the past . FurtherThere are some limitations that need to be considered when interpreting the findings from this study. In regards to diastolic function, the reader is reminded that these measurements were obtained from an assessment at one time point and that diastolic function may vary between examinations. Furthermore, the size of the research groups were limited, more hypertensive vs normotensive patients were included in the study and analysis was restricted to patients of one ethnic group. The strengths of the study included providing clearly separated normotensive and hypertensive obese, T2D and obese/T2D patients. Allowing us to tease out the influences of these conditions individually and in combination. Furthermore, despite the restricted patient numbers in the study we ensured that our dataset exhibited the normal associations between age with diastolic decline and LV structure, adding confidence that the findings from this study are relevant to the wider population. In addition, we have focused our analysis on echocardiography techniques and clinical measurements that are already routinely measured in day to day practice, increasing the application potential of the study.In summary, the data from this current study suggest that in the absence of hypertension, metabolically non-healthy obese, T2D and obese/T2D patients are at risk of LVH and LV remodelling and that this risk is increased when accompanied by increased pulse pressure or fasting glucose. The identification of LVPWd vs RWT to underestimate LV remodelling in normotensive obese and/or T2D patients suggests that the use of RWT may provide a more sensitive measure in future studies and in risk assessment in these patient groups.


Left ventricular (LV) thickening can be due to hypertrophy  or remodelling (concentric or asymmetric). Pathological thickening may be caused by pressure overload, volume overload, infiltrative disorders, hypertrophic cardiomyopathy, athlete’s heart or neoplastic infiltration. Magnetic resonance imaging (MRI) plays an important role in the comprehensive evaluation of LV thickening, including: establishing diagnosis, determining LV geometry, establishing aetiology, quantification, identifying prognostic factors, serial follow-up and treatment response. In this article, we review the aetiologies and pathophysiology of LV thickening, and demonstrate the comprehensive role of MRI in the evaluation of LV thickening.MRI plays an important role in the evaluation of LV thickening.• LV thickening can be due to either hypertrophy or remodelling.• Pathological thickening can be due to pressure/volume overload or infiltrative disorders.• The online version of this article (doi:10.1007/s13244-017-0549-2) contains supplementary material, which is available to authorized users. Left ventricular (LV) thickening is a commonly encountered finding in several imaging modalities. LV thickening can be either due to hypertrophy or remodelling. Pathological LV thickening may be caused by pressure/volume overload, infiltrative disorders, hypertrophic cardiomyopathy, athlete’s heart or neoplastic infiltration Table  1]. LV . LV 1]. Regardless of the aetiology, LV thickening is an adverse prognostic determinant and requires treatment . LV thicSeveral imaging modalities are available and utilized in the evaluation of LV thickening, including echocardiography, computed tomography (CT) and MRI, each with their own advantages and disadvantages.Echocardiography is the most commonly used imaging modality in the evaluation of LV thickening. LV thickness and mass is reliably measured using the M-mode . SystoliCT is also occasionally used to evaluate LV thickening, particularly in patients with contraindications for MRI. CT can outperform conventional echocardiography in diagnosing and quantifying the amount of LVH . HoweverMRI is the most valuable imaging modality in the evaluation of LV thickening and enables comprehensive evaluation of LV thickening, including establishing diagnosis of LV thickening, determining LV geometry, establishing aetiology, quantification, identifying prognostic factors, serial follow-up and assessment of treatment response. In certain instances, particularly with suboptimal echocardiography, MRI is used in establishing the diagnosis of LV thickening. MRI can exquisitely demonstrate the specific LV geometric pattern, which has therapeutic and prognostic implications (see below). The tissue characterization capabilities of MRI help in establishing a specific aetiology of LV thickening, which is essential for determining the appropriate treatment strategy. MRI is considered the gold standard in quantification of LV mass as well as volumes and function due to its high accuracy and reproducibility . This maLV wall-thickness (LVWT) measured in an end-diastolic cine image is the most commonly used measurement. Normal LV myocardial thickness is < 11 mm. Myocardial thickening is considered mild if it measures 11–13 mm, moderate if it measures 14–15 mm and severe if it measures > 15 mm. LV mass (LVM) is quantified from end-diastolic phase images of short axis cine SSFP stack by drawing endocardial and epicardial contours. Using the modified Simpson’s rule, the myocardial volume is obtained and multiplying this by myocardial density (1.05 g/ml) gives the myocardial mass. An absolute mass > 184 g in males and 144 g in females, BMI-indexed mass > 91 g/m2 in males and > 77 g/m2 in females and height-indexed mass of > 83 g/m in males and > 69 g/m in females is considered LV thickening . No. No55]. Myocardial oxalosis is characterized by the deposition of oxalic acid crystals in the heart due to its higher production. Clinical presentation includes LVH, heart block and conduction abnormalities. On MRI, there is concentric left and right ventricular thickening. Diastolic dysfunction may be seen. Friedreich ataxia is characterized by mitochondrial ion accumulation, with cardiomyopathy seen in 63%. On MRI, concentric or asymmetric LVH is seen, without evidence of LVOT obstruction. Diastolic dysfunction and fibrosis may be seen [Mucopolysaccharidoses can present with variable MRI appearance depending on the phenotype, including asymmetrical septal thickening, mitral and or aortic valve stenosis/insufficiency with normal EF [obesity, LVH with high LVM, LVEDV and RWM is seen, with preserved EF [DM Type II, correlating with BMI and HbA1c [ be seen . Mucopolormal EF . In obeserved EF  which cond HbA1c .Hypertrophic cardiomyopathy (HCM) is characterized by myocardial hypertrophy without an underlying cause such as HT or AS. It is caused by sarcomeric gene mutations and has variable phenotypic expression. It has a prevalence of 0.2%, and LVH is seen in 60% of these patients . The mosAthlete’s heart is a physiological hypertrophy seen as an adaptive response to the altered loading conditions of prolonged and intensive training. This has been reported in an estimated 2% of athletes . At a ceMRI shows hypertrophy, which may be concentric, eccentric or mixed concentric-eccentric Fig. . DistingDiffuse LV thickening may also be seen due to diffuse or multifocal neoplastic infiltration. This includes neoplasms such as metastases, lymphoma, leukemia or sarcoma. B cell lymphoma is the most common type of lymphoma to produce diffuse myocardial infiltration . AlthougOccasionally, pseudohypertrophy may be seen due to partial averaging of normal structures. This may be seen due to a prominent moderator band, which may give a false impression of septal hypertrophy Movies  and 2.MRI plays an important role in the comprehensive evaluation of patients with LV thickening. The unique tissue characterization capabilities of MRI enable establishing the aetiology of LV thickening, which is important for selecting the appropriate treatment. The high accuracy and reproducibility of MRI measured indices such as mass, volumes and function make it the ideal modality for serial follow-up in clinical scenarios and trials to evaluate treatment response. In addition, MRI also provides prognostic information.Movie 1Short axis cine SSFP sequence shows a focal area of thickening in the mid-portion of the ventricular septum. (AVI 147172 kb)Movie 23-chamber cine SSFP sequence in the same patient shows that the abovementioned finding is indeed pseudohypertrophy due to a prominent moderator band. (AVI 147172 kb)Below is the link to the electronic supplementary material.


Patients with heart transplant are susceptible to developing chronic allograft vasculopathy (CAV) which increases in frequency over time. Traditional methods for diagnosing CAV rely on invasive catheter based angiography and intravascular ultrasound (IVUS). Stress perfusion cardiac MRI (CMR) is frequently used to noninvasively diagnose ischemic heart disease and has also been used to assess CAV in heart transplant patients. The purpose of this study was to evaluate semiquantitative measures of ischemia using noninvasive stress perfusion CMR in the detection of CAV using invasive coronary angiography and IVUS as the standard reference.A cohort of 43 chronic heart transplant patients was studied using both stress CMR and coronary angiography. Stress CMR was performed in the standard manner using an IV injection of regadenoson and 0.2 mM/kg of a gadolinium based contrast agent. Based on the coronary angiogram, the patients were divided into groups of no disease (group 1), mild chronic allograft vasculopathy (CAV) (group 2), and moderate to severe CAV (group 3), based on the International Heart Lung Transplantation (IHLT) guidelines for diagnosis of CAV. The time between the angiogram and perfusion results varies from less than 6 months to just over 2 years, with an average of about 1 year between studies. The rest and stress perfusion images were analyzed by segment based on the AHA 16 segment model of the heart using dedicated myocardial perfusion software . The upslope was measured for each segment on both stress and rest images and then an average upslope value was calculated for each patient. The myocardial perfusion reserve was calculated by dividing the upslope values of rest and stress images. The semiquantitative results of the perfusion studies, both stress perfusion upslope values and myocardial perfusion reserve, were then correlated to the angiogram results.Group 1 consisted of 19 patients, group 2 had 19 patients, and group 3 had 5 patients. The calculated upslopes for each group were as follows: 3.28, 3.03, and 2.30, for groups 1, 2, and 3, respectively. There was a statistical difference between group 1 and 3 (p = 0.035), and no statistical difference between groups 1 and 2 (p = 0.234), and groups 2 and 3 (p = 0.054). For myocardial perfusion reserve, the calculated ratios were 4.71, 3.66, and 2.36 for groups 1, 2, and 3, respectively. The difference between groups 1 and 3 was significant (p = 0.033), while the differences between groups 1 and 2 (p = 0.176), and groups 2 and 3 (p = 0.073) were not.Semiquantitative parameters of upslope and myocardial perfusion reserve as measured from stress perfusion CMR can detect moderate to severe CAV in heart transplant patients. Stress perfusion CMR is a promising noninvasive tool for detecting CAV potentially obviating the need for regular invasive coronary angiography.


In this retrospective analysis we investigated the predictive performance of orthostatic hypotension (OH) and ambulatory blood pressure monitoring (ABP) to predict autonomic dysfunction.Statistical associations among the candidate variables were investigated and comparisons of predictive performances were performed using Receiver Operating Characteristics (ROC) curves.r = 0.12, p = 0.237) with autonomic reflex screen, but postprandial hypotension  and heart rate variability  demonstrated significant correlations. Postprandial hypotension was associated with a five-fold  increased risk and heart rate variability with a four-fold  increased risk for autonomic dysfunction. Per ROC curves, heart rate variability  and postprandial hypotension  were among the best predictors of autonomic dysfunction in routine clinical practice.Ninety-four patients were included for analysis. No significant correlations could be demonstrated between OH and components of ABP , nor between OH and autonomic reflex screen. Reversal of circadian pattern did not demonstrate significant correlation (Postprandial hypotension and heart rate variability on ambulatory blood pressure monitoring are among the best predictors of autonomic dysfunction in routine clinical practice. Orthostatic hypotension (OH) is present in a heterogeneous group of disease states. Although not synonymous with autonomic dysfunction, OH is often suggested as a marker of autonomic dysfunction . PatientN = 1680) [Database of a previously published study of patients who underwent ABP were reviewed  = 1680) . To inve80 . To i = 1680) . Postprahttps://www.aan.com/Guidelines/home/GetGuidelineContent/39.Autonomic function was evaluated using the autonomic reflex screen consisting of an array of tests that noninvasively evaluate the sudomotor, cardiovagal and adrenergic limbs of the autonomic nervous system . The autp-value. P value <0.05 was considered statistically significant. Continuous variables were compared with a two-sample t-test or Wilcoxon rank sum test and dichotomous variables with chi-squared test or Fisher’s exact test. Potential, clinically meaningful determinants of autonomic dysfunction were investigated in a univariate screening procedure using Pearson correlation of coefficients (r) test. The nonparametric Spearman rho coefficient of correlation was used to assess correlations between variables without normal distribution. Significant determinants identified from this analysis were studied in a multiple regression model. Area Under the Curve (AUC) of the Receiver-Operating Characteristic (ROC) curves was used to compare the predictive performance of OH, reversal of circadian pattern, postprandial hypotension and heart rate variability to detect autonomic dysfunction. All analyses were conducted using SPSS version 20, Chicago Ill., USA. The study conception, design, execution, data collection, analysis, and manuscript preparation were performed in its entirety and independently by the investigators. All authors had independent access to data and analysis. Institutional Review Board’s requirement of approval was waived for this previously published dataset.All results are presented as mean ± standard deviation (or standard error of mean) with OH was present per office blood pressure measurements in 77.6% of the patients. Lightheadedness or dizziness was the presenting symptoms in 36.4% of the patients. The characteristics of the patients are shown in Table r = 0.04, p = 0.687), postprandial hypotension  could not be demonstrated. Neither were any significant correlations between the deltaOH and reversal of circadian pattern , postprandial hypotension  or heart rate variability .The contributions of the individual components of ABP are shown in Table p = 0.217) or CASS score , nor between deltaOH and autonomic reflex screen  or CASS score .Autonomic reflex screen, according to the CASS score, was positive in 80.8% (76/94) of the patients. The mean CASS score was 1.9 ± 0.2, median 2.0 . No significant correlation could be demonstrated between OH and autonomic reflex screen  or to individual components of autonomic reflex screen . Postprandial hypotension demonstrated significant correlation with CASS score  and autonomic reflex screen . Heart rate variability also showed significant correlations with CASS score  and autonomic reflex screen . The relationship of the sum of the number of abnormal components of ABP  and CASS score and autonomic reflex screen were also examined. Significant correlation was noted between ABPTotal and CASS score  and autonomic reflex screen . In unadjusted model, reversal of circadian pattern did not significantly increase the risk for autonomic dysfunction . In contrast, postprandial hypotension was associated with a five-fold  increased risk for and heart rate variability with a four-fold  increased risk for autonomic dysfunction. In the adjusted model that included conditions usually associated with autonomic dysfunction , OH and components of ABP, postprandial hypotension was associated with a four-fold . Further analysis revealed that in comparison to patients without postprandial hypotension, patients with postprandial hypotension had significantly higher CASS scores  but no significant differences in individual components of the autonomic reflex screen test: sudomotor, postprandial hypotension (p = 0.795), cardiovagal (p = 0.298) and adrenergic (0.852).Examination of the components of ABP showed that reversal of circadian pattern did not demonstrate significant correlation with autonomic reflex screen (N = 73), reversal of circadian pattern did not demonstrate significant correlation with autonomic reflex screen  or to individual components of autonomic reflex screen . Heart rate variability did not demonstrate significant correlation with autonomic reflex screen  or to individual components of autonomic reflex screen . Postprandial hypotension did not demonstrate significant correlation with individual components of autonomic reflex screen . Similar to results in the full cohort above, postprandial hypotension and ABPTotal demonstrated significant correlation with autonomic reflex screen  and CASS score . We also analyzed the patients with diabetes (N = 9). No significant correlations could be demonstrated between ABP (or components) and autonomic reflex screen  or with CASS score.In the subgroup analysis of patients without cancer  were utilized, postprandial hypotension and heart rate variability independently demonstrated comparable predictive power. In the subset of patients with neurological disorders (N = 14) comparison of AUCs were as follows: OH- 0.500 , deltaOH- 0.885 , ABPTotal- 0.385 , reversal of circadian pattern- 0.500 , postprandial hypotension- 0.462  and heart rate variability- 0.500 , respectively. In the subset of patients with non-neurological disorders (N = 80), ABPTotal , postprandial hypotension  and heart rate variability  demonstrated best predictive performances followed by reversal of circadian pattern , OH  and deltaOH , respectively. In the subset that included neurological or diabetes patients (N = 21), AUCs of the variables were as follows: OH- 0.500 , deltaOH- 0.833 , ABPTotal- 0.333 , reversal of circadian pattern- 0.452 , postprandial hypotension- 0.452  and heart rate variability- 0.429 , respectively.Comparison of AUCs of OH, deltaOH, ABPOH is a common clinical finding, occurring in 5% in patients <50 years of age to 30% in those >70 years of age . OH is a2 and in 100% of Parkinson’s disease patients [The major findings of the study were that two of the ABP components, i.e., heart rate variability and postprandial hypotension were major predictors of and were associated with a four- and five-fold increased risk for autonomic dysfunction, respectively. Interestingly, heart rate variability was the least common among ABP findings, present in only 60% of the patients. Heart rate variability has been well documented in diabetes, hypertension, chronic kidney disease and conditions associated with autonomic dysfunction including in paraplegics –17. Postpatients . Perhapspatients . Postprapatients  perhaps An important finding was the lack of correlation of reversal of circadian pattern with autonomic dysfunction, considering that reversal of circadian pattern and autonomic dysfunction are primary hallmarks of many diseases with abnormal neurohormonal regulation , 23 and We could not demonstrate significant correlation of OH or deltaOH with ABP or autonomic dysfunction. Others have reported that approximately 83% of patients with OH showed at least one generalized autonomic failure of sympathetic adrenergic and parasympathetic cardiovagal functions . This diBedside observations in clinical medicine trigger investigations to uncover etiology of the patients’ signs and symptoms and can lead to further clinical and basic science research to understand their mechanisms. However, associations are not causative and findings in a particular illness often cannot be extrapolated to a different disease state. Such is the case for orthostatic hypotension that is often used synonymously to denote autonomic dysfunction and to infer the presence of reversal of circadian pattern. In this study the majority of the diagnosis of OH was established in the primary care settings and there was no correlation of orthostatic hypotension with ambulatory blood pressure monitoring and with autonomic dysfunction. It was not the reversal of circadian pattern, but the often overlooked postprandial hypotension and heart rate variability that were strong predictors of autonomic dysfunction.2 Another issue concerns the accuracy of heart rate variability derived from photoplethysmographic versus electrocardiographic signals. Although comprehensive investigations of all heart rate variability indices in large populations have yet to be performed, recent report suggests sufficient accuracy between them [A limitation of this study was the underrepresentation of hypertension patients who underwent autonomic reflex screen testing and the severity of OH. A simple explanation is that neurologically asymptomatic, hypertension patients are not usually referred for autonomic reflex screen testing. However, we have previously reported that in age-matched hypertension patients reversal of circadian pattern, postprandial hypotension and heart rate variability were present in 15, 2 and 1%, respectively compared to 80, 80 and 75% respectively in patients with OH.een them . The anaWe have demonstrated that postprandial hypotension and heart rate variability on ambulatory blood pressure monitoring are strong predictors of autonomic dysfunction in routine clinical practice. Further studies are warranted.


Renalase decreases circulating catecholamines concentration and is important in maintaining primary cellular metabolism. Renalase acts through the plasma membrane calcium ATPase 4b in the heart, which affects pressure overload but not exercise induced heart hypertrophy. The aim of this study was to test the association between a functional polymorphism Glu37Asp (rs2296545) of the renalase gene and left ventricular hypertrophy in a large cohort of patients with aortic stenosis. The study group consisted of 657 patients with aortic stenosis referred for aortic valve replacement. Preoperative echocardiographic assessment was performed to obtain cardiac phenotypes. Generalized-linear models were implemented to analyze data using crude or full model adjusted for selected clinical factors. In females, the Asp37 variant of the Glu37Asp polymorphism was associated with higher left ventricular mass (p = 0.0021 and p = 0.055 crude and full model respectively), intraventricular septal thickness (p = 0.0003 and p = 0.0143) and posterior wall thickness (p = 0.0005 and p = 0.0219) all indexed to body surface area, as well as relative wall thickness (p = 0.001 and p = 0.0097). No significant associations were found among the male patients. In conclusion, we have found the association of the renalase Glu37Asp polymorphism with left ventricle hypertrophy in large group of females with aortic stenosis. The Glu37Asp polymorphism causes not only amino-acid substitution in FAD binding domain but may also change binding affinity of the hypoxia- and hypertrophy-related transcription factors and influence renalase gene expression. Our data suggest that renalase might play a role in hypertrophic response to pressure overload, but the exact mechanism requires further investigation. Left ventricular hypertrophy (LVH) which develops in patients with aortic stenosis (AS) is associated with increased mortality and morbidity before and after aortic valve replacement. The hypertrophic response to pressure overload from AS is heterogeneous and may depend on many factors including gender and genetic predisposition. The famThe study group consisted of 657 patients (387 men and 270 women) referred to the Department of Acquired Cardiac Defects at the Institute of Cardiology in Warsaw for surgical intervention due to severe AS over the years 1995 to 2006. Patients with coexisting mitral and/or tricuspid valve disease or moderate/severe aortic regurgitation were excluded from the study. This study was approved by the Human Ethics Committees of the Medical University of Warsaw  and the Institute of Cardiology  and conformed to the ethical guidelines of the 1975 Declaration of Helsinki. Written informed consent was obtained from all study participants. All patients with a history of angina or aged >50 years underwent coronary arteriography. Significant coronary artery disease was defined as a reduction of at least 70% in the diameter of a major coronary artery or a 50% reduction in the left main coronary artery diameter.3—LVEDD3] - 13.6 where LVEDD is the left ventricular end-diastolic diameter, IVST is the intraventricular septal thickness in diastole, and PWT is the posterior wall thickness in diastole. The body surface area (BSA) was calculated using the modified DuBois formula: BSA = (height (m)0.73 × body weight (kg)0.4 × 71.84)/10,000. The relative wall thickness (RWT) was calculated as RWT = PWT/ (0.5) LVEDD. The left ventricular geometry was classified as proposed by Duncan et al.[Echocardiographic examination and calculations were done as previously described. Brieflyan et al.: a) conc™ 7 Real-Time PCR System was used to perform genotyping of rs2296545 polymorphism using the 5’ nuclease allelic discrimination assay according to the manufacturer's protocol . The assay number C__15753060_10 was designed on forward strand, therefore reference allele C corresponded to G in renalase’s mRNA and finally Glutamic Acid (Glu) at amino acid residue 37 of the protein (since RNLS gene is located on reverse strand), consequently reference allele G corresponded to C in the mRNA sequence and Aspartic Acid (Asp) in the protein. Ten percent of randomly selected samples were done in duplicates.DNA was isolated from frozen peripheral blood samples with QiaAmp DNA Mini Kit (Qiagen). The ViiAhttp://www.nature.com/ng/journal/v47/n12/extref/ng.3432-S5.txt [We used a Supplementary Data Set 1. SNPs tested for imbalance in DNA accessibility, which can be retrieved from 2-S5.txt . Additiohttp://genome.ufl.edu/mapper/).For the computational identification of transcription factor which binding sites are affected by rs2296545 a MAPPER2, 21 the The Statistical analysis was performed as previously described. The echThe study group was described previously. The demGenotyping was successful for 99.38% of the samples. Concordance rate between replicates was as high as 100%. The genotypes distribution was consistent with Hardy-Weinberg equilibrium (p = 0.99).The analysis  of all oThe gender-specific analyses showed a significant association of the Asp37 variant of rs2296545  with hig2.7 (p = 0.0005) in the crude model and suggestive association in full model  in the additive genetic model. Furthermore the Asp37 variant in the same genetic model was strongly associated  with higher thickness of the cardiac walls regardless of indexation method and the associations remained significant after adjustment for clinical factors in the full model. The association of the Asp37 variant with higher RWT was better described by dominant genetic model .The subsequent detailed analysis of the echocardiographic parameters in females  revealedNo significant associations were found among the male patients except borderline association of the Asp37 variant with high IVST (p = 0.0499) .In females, rs2296545 x CAD interaction included in crude and full models was not significant for any of the echocardiographic parameters.To test for homogeneity of the effect of rs2296545 on LVM/BSA and RWT across clinically relevant subgroups, we divided the cohort into two groups. The first group consisted of patients without significant coronary artery disease or hypertension, with EF > = 50% and transaortic maximum velocity > = 4.0 (symptomatic severe high-gradient AS) which accounted for 40% of patients (n = 243). The remaining patients formed the second group (n = 362) which included the other subgroups: symptomatic severe high-gradient AS with at least one of the following characteristic: reduced EF, hypertension, significant coronary artery disease (n = 244); symptomatic severe low-flow/low-gradient AS with reduced EF (n = 25); symptomatic severe low-gradient AS with normal EF or paradoxical low-flow severe AS (n = 24). Belonging to the first (1) or the second (0) group was used as an interaction term with rs2296545. In females, the tested interaction was not significant for LVM/BSA  in the additive genetic model as well as for RWT  in the dominant genetic model. The above interactions were not significant in males as well. These results allowed us to conclude that the effect of rs2296545 on LVM/BSA or RWT is not different in the two groups.C allele on the reference DNA strand, which corresponds to Asp at amino acid residue 37, increased the predicted DNA binding affinity of the following transcription factors: ATF, CBF2, CREB, GATA-1, Nkx5-1, PEBP, TGA1, TREB-1, but decreased binding probability for CACCC-binding factor, COUP-TF2, GCN4, HNF-4, Nrf-2.In the present study of 657 patients with severe AS, we found an association of Asp37 variant at amino acid residue 37 of renalase protein with left ventricular hypertrophy in female subjects in an additive genetic model. In another study reported by Farzaneh-Far et al, Asp37 variant was associated with higher cardiac mass in recessive genetic model in patients with stable coronary disease. HoweverIn women Asp37 variant was strongly associated with thickness of the posterior wall and interventricular septum as well as LVM, regardless of indexation method. Women heterozygous or homozygous for Asp37 had also higher RWT. In males, only a weak association of IVST with renalase Asp37 variant was observed. In previous studies we also reported sex-related differences in the association between common genetic polymorphism of the chymase CMA1 gene and ACE There are significant sex differences in the response to pressure overload. Females develop more concentric hypertrophy with greater RWT, IVST/BSA, PWT/BSA and a better systolic function and higher transvalvular gradients than males as we previously described using a large number of patients with AS. ObservaHypertrophic response to pressure overload initially comprises an increase in cardiomyocyte size and amount of contractile proteins without cellular proliferation. Hypertrophy later becomes maladaptive with an increased formation of fibrotic tissue, resulting in dilatation and impaired function of the left ventricle, 30. DifRenalase circulates in peripheral blood and is strongly expressed in the heart and kidney. There are no data on sex-related differences in these organs and circulating levels of renalase. Until now, renalase was considered a kidney-derived enzyme degrading catecholamines. In experimental models lower expression of the renalase gene was associated with higher blood pressure and administration of recombinant protein had a hypotensive effect in Dahl salt-sensitive rats. NephrecCatecholamines promote hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts and they can arrive to the heart from the periphery or can be synthesized locally. Both loIn our study Glu37Asp polymorphism was strongly associated with the thickness of the left ventricle walls but not with its internal dimension. Therefore adrenergic stimulation of cardiomyocytes seems more important for this pattern of LVH than catecholamine-related activation of cardiac fibroblasts, resulting not only in fibrosis but also in collagen degradation in mice[Recent findings question the role of renalase as a catecholamine degrading enzyme. Studies by Moran et al suggest that the metabolic function of renalase is to oxidize isomeric NAD(P)H molecules 2- and 6-dihydroNAD (which are potent inhibitors of primary metabolism dehydrogenases) to β-NAD(P)+ and thereby eliminating potential injury to intracellular respiratory activity, 38.Among the three dehydrogenases tested, both 2- and 6-dihydroNAD had high affinity for lactate dehydrogenase (LDH) but no significant affinity for lipoamide dehydrogenase. 6-dihydroNAD had exceedingly high affinity for malate dehydrogenase (MDH) but 2-dihydroNAD had only a modest inhibitory effect for this enzyme. MDH is The plasma membrane calcium/calmodulin dependent ATPase (PMCA4b)is an extracellular receptor of renalase. The action mediated through this receptor promotes cell survival and defense against cisplatin toxicity through phosphorylation of p38 (MAPK) in human kidney embryonic cell line (HK-2). This was established using PMCA4b-targeting siRNAs and Caloxin1b, a peptide inhibitor of PMCA4b. PMCA4b Interestingly, PMCA4b is involved in the regulation of catecholamine secretion by the rat adrenal medulla cells and is iIt was initially suggested that a conserved amino acid change at residue 37 (glutamic to aspartic acid) is located within the flavin-adenine dinucleotide-binding domain and Asp37 variant is associated with a 24-fold decrease in affinity for NADH, a 2.3-fold reduction in maximal renalase enzymatic activity and a lower catecholamine degradation rate. RecentlApproximately 15% of human codons are dual-use codons (“duons”) that simultaneously specify both amino acids and transcription factor recognition sites. Single-In analysis of over 114 cell and tissue types and states sampled from 166 individuals, rs2296545 did not directly influence the chromatin architecture of individual regulatory regions in an allele-specific fashion, but onlThere are some limitations in our study which should be taken into consideration. First, we did not investigate the functional consequences of the polymorphism in individual patients at the left ventricular tissue level, such as RNA and protein concentration. Functional studies using animal models of pressure overload hypertrophy are required to elucidate the molecular mechanism through which rs2296545 affects the RNLS promoter activity in cardiac cells subjected to pressure overload, cardiac catecholamine concentration, cardiac primary metabolism, and finally cardiac hypertrophy in gender-related manner. Second, the present study consisted solely of Caucasians and the results may not apply to other populations. Third, the AS patient population is heterogeneous but the In conclusion, we have found the association of the renalase Glu37Asp polymorphism with left ventricle hypertrophy in large group of females with AS. Our data suggest that renalase plays a role in the hypertrophic response to pressure overload, however, the exact mechanism requires further investigation.S1 Table(PDF)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.


Congenital heart disease (CHD) is the most common category of birth defect, affecting 1% of the population and requiring cardiovascular surgery in the first months of life in many patients. Due to advances in congenital cardiovascular surgery and patient management, most children with CHD now survive into adulthood. However, residual and postoperative defects are common resulting in abnormal hemodynamics, which may interact further with scar formation related to surgical procedures. Cardiovascular magnetic resonance (CMR) has become an important diagnostic imaging modality in the long-term management of CHD patients. It is the gold standard technique to assess ventricular volumes and systolic function. Besides this, advanced CMR techniques allow the acquisition of more detailed information about myocardial architecture, ventricular mechanics, and fibrosis. The left ventricle (LV) and right ventricle have unique myocardial architecture that underpins their mechanics; however, this becomes disorganized under conditions of volume and pressure overload. CMR diffusion tensor imaging is able to interrogate non-invasively the principal alignments of microstructures in the left ventricular wall. Myocardial tissue tagging (displacement encoding using stimulated echoes) and feature tracking are CMR techniques that can be used to examine the deformation and strain of the myocardium in CHD, whereas 3D feature tracking can assess the twisting motion of the LV chamber. Late gadolinium enhancement imaging and more recently T1 mapping can help in detecting fibrotic myocardial changes and evolve our understanding of the pathophysiology of CHD patients. This review not only gives an overview about available or emerging CMR techniques for assessing myocardial mechanics and fibrosis but it also describes their clinical value and how they can be used to detect abnormalities in myocardial architecture and mechanics in CHD patients. The normal myo-architecture of the heart differs between the LV and the right ventricle (RV). The LV has a thicker compact layer with its myocytes arrayed in varying orientations through its depth, while the more apical parts of the human RV are predominantly trabeculated, with only a thin outermost compact layer.The LV subepicardial layer contains fibers orientated in a left-handed helical arrangement, which is largely responsible for torsion of the apex relative to the base. The mid-wall layer contains circumferential fibers that generate radial contraction. The subendocardial layer has right-handed helical as well as longitudinal fibers that function in conjunction with the helical subepicardial layer and papillary muscles to generate longitudinal strain , 2. The It may also be the case that diastolic relaxation of the laminar structures facilitates perfusion, in diastole, of blood through microvessels passing between the sheetlets; however, the papillary muscles and the trabeculars that are particularly prevalent in the RV lack laminar microstructures . Their lIn conditions with pressure or volume overloading, changes in LV myo-architecture have been reported. An increase in the amount of longitudinal fibers was found in the subendocardial layer, and a decreased number of circumferential fibers in the mid-layer were found. Furthermore, a change in orientation of the subendocardial fibers was noted , 14.The myo-architecture of a normal RV wall is not considered to contain a middle layer of circumferential fibers apart from the right ventricular outflow tract (RVOT) . HoweverHistological studies have demonstrated disorganization in the RV myocardial architecture in patients with ToF. They have been found to have a more substantial proportion of circumferential fibers in the hypertrophied sub-pulmonary infundibulum . A key dvia the interventricular septum. Likewise, the RV subepicardial fibers are shared with the LV subepicardial layer  sequence is used in conjunction with echo planer imaging, a hybrid single-shot spin echo and gradient echo sequence. This sequence works over two cardiac cycles and assumes that myocardial tissue returns to the same position, at both diffusion encoding times at end systole. Parallel imaging is applied to reduce the length of single-shot imaging in each cardiac cycle. Each 2D slice can be acquired in breath-holds of 18 heart beats duration. Typically eight breath-hold acquisitions are performed per 2D slice and the data averaged to improve signal-to-noise ratio (SNR)  . Complexio (SNR) , and it Cardiac DTI has been applied in some studies to interrogate myocardial fiber orientation in certain disease processes; however, to date, very little has been trialed with respect to CHD. Investigators have studied hypertrophic cardiomyopathy and have identified abnormal orientation of myocardial fibers in diastole that remains in a relatively systolic conformation . This waCardiovascular magnetic resonance (CMR) has the capability of providing important data on global and regional ventricular function. It is the gold standard in the estimation of ventricular volumes and ejection fraction using a disk-area summation method and in comparison to other modalities as it does not rely on assuming ventricular geometry , 28. ForWhile acquiring SSFP images in breath-hold, misregistration artifact may arise. This is due the natural variability in the size and depth of breath a patient may take that can cause small changes in the location of the heart each time between acquisitions. Secondly, there are the physiological effects of respiration  that may affect reproducibility. Four-dimensional, multiphase, steady-state imaging with contrast enhancement is a respiratory gated technique that may overcome breath-holding problems that was developed by Han and colleagues in 2014 to study pediatric patients with complex CHD. The results of this small study showed good correlation of cardiac volumes with conventional 2D cines .Markers of intrinsic myocardial contractility are investigated with the aim of identifying early myocardial abnormalities that are subclinical and precede ventricular systolic dysfunction. Myocardial strain is a measure of how much myocardial tissue gets larger and thickens (positive strain) or how much it gets smaller or thins (negative strain) in relation to its state in end diastole. It occurs in three different planes in accordance with the orientation of myofibers in the LV subepicardial , middle , and subendocardial  layers as described above. Several CMR methods have been developed to interrogate myocardial strain in these planes. Myocardial tagging has been long established as a gold standard technique . In thisDisplacement encoding using stimulated echoes is a newer MRI technique that was developed after myocardial tagging. It has a relatively high spatial resolution that can be used to quantify the displacement and strain of the myocardium on a pixel by pixel basis. With this technique, displacement information is directly encoded in to the phase of the sequence for each voxel 2D or 3D image, and a displacement map can be produced. This is used to calculate strains in longitudinal, circumferential, and radial directions in tissue.The original DENSE sequence produced a displacement-encoded image at a single-time point in the cardiac cycle. Subsequently, cineDENSE incorporated highly efficient data acquisition to produce images throughout the cardiac cycle , 35, whiFeature tracking-CMR is a technique that is comparable to speckle tracking in echocardiography. Although it is not a direct measure of “true” strain in the myocardium, it is an estimate of endocardial contractility and relaxation properties. The postprocessing technique identifies patterns of features or irregularities in a small window and searches for the same pattern of features in the following images. The measured displacements between the two patterns enable a feature-tracked strain-related index (FTSI) to be calculated. The tissue represented by each voxel in the cine images has their FTSI measured in the longitudinal, radial, and circumferential directions .Longitudinal and circumferential FTSI are derived by tracking tissue components along the length of the myocardium in the long axis. Radial FTSI is estimated from tracking tissue components in the perpendicular direction to the myocardium in the short axis. In a normal heart, there is predominantly a positive radial strain that thickens the LV wall and negative longitudinal and circumferential strains that reduce LV cavity size in systole. Tissue components of interest are preferably selected along the endocardial border rather than the epicardial border as the reduction of the endocardial surface is a better representation of the efficiency of the LV cavity emptying its stroke volume .Rapid acquisition of images is performed using a bSSFP sequence. Current bSSFP images are good at distinguishing blood pool from myocardium with a spatial resolution of 1–2 mm (in-plane). However, with CMR, it is difficult to distinguish features within the compact myocardium due to its homogeneity and large size voxels. Therefore, instead of tracking features within the myocardium, FT-CMR utilizes the endocardial border features that become easily distinguishable by CMR. One limitation of CMR is its limited spatial resolution through-plane (6–10 mm), which means that FT-CMR is unable to track features that move out of plane in subsequent frames in the through-plane direction .3D-FT-CMR is an area of growing interest where all three strain parameters can be measured from a single-3D acquisition. An assumption of shear motion between the layers  may be made. The shear motion between the circumferential–longitudinal layers in particular is responsible for LV torsional motion. 3D-FT-CMR is again limited by lower through-plane spatial resolution, and therefore it is not ideal in measuring longitudinal strain in the short-axis LV stacks; however, it has shown comparable results for radial and circumferential strains. 3D-FT-CMR involves longer acquisitions and so a navigator is required for avoiding respiratory motion artifact.Several studies have compared FT-CMR with myocardial tagging techniques and have demonstrated good agreement in circumferential strain measurements recorded between both techniques in healthy subjects, aortic stenosis, and non-ischemic cardiomyopathy –41. FT-CToF commonly have RV dysfunction that can progress through their adult life and several mechanisms for this have been described (please see above). RV dysfunction is in keeping with impaired myocardial strain and intraventricular RV dyssynchrony and interventricular dyssynchrony. Several studies have used FT-CMR to examine strain and its prognostic significance.Patients with It has been reported ToF patients who experience adverse outcomes (death or sustained ventricular tachycardia), all have globally lower RV FTSI indices compared to patients with no adverse outcome. Impaired longitudinal “strain” of both ventricles was strongly associated with adverse clinical outcomes . Orwat eFeature tracking-CMR has been used to investigate RV function following different types of RVOT obstruction (RVOTO) repair. The current move in surgical approach to relieve RV infundibular obstruction is to do perform minimum resection and preserve the pulmonary valve in order to prevent pulmonary valve incompetence . The effthe great arteries (TGA), Tutarel et al. also found that circumferential FTSI correlated moderately with RV (systemic) ejection fraction and that there was a negative correlation with QRS duration; weak correlations between FTSI and LVEF were found  or indexed RVESV between 80 and 90 ml (and 82 ml/m2 from our center) are when pulmonary valve replacement for pulmonary regurgitation should be considered for asymptomatic patients  in patients with repaired ToF . The INDCardiovascular magnetic resonance ventricular function parameters are a useful risk stratification tool for patients with Eisenmenger’s syndrome. A study by Jensen et al. found that CMR derived RVEF less than 40% and LVEF less than 50% was associated with increased risk of death in Eisenmenger’s patients with post-tricuspid shunts .Myocardial fibrosis may be a final common pathophysiological pathway that links a wide spectrum of congenital heart conditions. There is great importance in detecting its various forms and understanding its prognostic significance for a more targeted treatment approach. Broadly, there are two forms of fibrotic processes that can occur: replacement fibrosis and interstitial fibrosis.Replacement fibrosis is irreversible and occurs following an insult to myocytes, commonly ischemia. This focal type of fibrosis can be detected usually by LGE imaging, assuming there is a neighboring normal myocardium.Interstitial fibrosis is secondary to increased collagen deposition within the extracellular matrix (ECM) as a response to abnormal loading conditions on the myocardium such as typically occurs in CHD patients. It can be detected with T1 mapping and extracellular (ECV) measurements and remains undetected by LGE imaging because it is more diffuse and widespread throughout the myocardium preventing identification by comparison to neighboring “normal” myocardium.Technical developments in LGE imaging, T1 mapping, and ECV measurements have enabled the non-invasive quantification of myocardial fibrosis that was previously only possible on a biopsy or during postmortem. A recent study has demonstrated that the incremental value of detecting focal fibrosis using LGE alongside conventional parameter (LVEF), in predicting 5-year mortality in patients with aortic stenosis . FurtherDiffuse myocardial fibrosis or interstitial disease is increasingly of interest. Its presence leads to abnormal T1 (pre- and postcontrast agent) and abnormal ECV measurements, which is speculated to predate cardiac dysfunction. Previous studies of cardiomyopathy have demonstrated correlation between increased ECV with diastolic dysfunction  and reduThe differences between normal and abnormal myocardial tissue may be subtle on CMR; however, differences between these tissues are emphasized after the administration of intravenous gadolinium-based contrast agent (GBCA). Gadolinium, in its chelated form, is rendered non-toxic, and its distribution is confined to the extracellular compartment due to its large molecular weight. The proportion of extracellular space in a healthy myocardium is ~15% and increases in with heart disease due to increased collagen deposition and fibrosis. This results in an increased volume of distribution of gadolinium that further is compounded in conditions where the myocardial function is depressed; slowing down the gadolinium washout kinetics. Gadolinium has paramagnetic properties that allow it to interact with spins promoting more rapid exchange of energy thus T1 is shorter and results in a high signal (bright).In practice, 0.5 μg to 0.1 μg/kg bolus GBCA is injected, and after 10–30 min, images are acquired. An inversion recovery fast gradient echo sequence is used in breath-hold. LGE imaging is performed using a non-selective 180° inversion preparation pulse. Following the inversion pulse, the longitudinal magnetization returns to its original value exponentially with a time constant T1. Due to the difference in GBCA concentrations between normal and abnormal myocardium, there is a difference in T1 values and hence different magnetization recovery curves. The inversion time (Ti) of normal myocardium is the time after the inversion pulse when the magnetization of normal myocardium is passing through 0 (the null point). At this Ti, normal myocardium is black in the resulting images. This Ti varies with GBCA dose, time after administration, and with patient-specific factors such as kidney function and disease state. In order to maximize the contrast between abnormal and normal myocardium, normal myocardium should be nulled. The Ti can be determined empirically or by performing a breath-hold Ti scout acquisition (using a Look–Locker sequence). This is either calculated manually or by performing a Ti scout (Look–Locker sequence). The Ti scout sequence acquires images at multiple time points following a single-inversion recovery pulse. Each image is therefore effectively acquired with a different Ti, and visual inspection allows the Ti to null the signal from normal myocardium to be determined. The optimal Ti needs to be increased as the study proceeds as the GBCA washes out of the myocardium. The inversion pulse and data acquisition are repeated on every second R–R interval to allow full T1 relaxation between pulses, which improves the SNR and makes the sequence less sensitive to variability in the R–R interval. In cases of tachycardia, images can be acquired on every third R–R interval at the expense of increasing the imaging time. With conventional LGE imaging, incorrect setting of the Ti adversely affects the contrast between normal and abnormal myocardium.Common challenges in patients with CHD are difficulties of ECG gating due to arrhythmia, wide and abnormally shaped QRS complexes, breath-holding difficulties as well as metallic artifacts from sternal wires and transcatheter devices. LGE false positive scans occur more commonly when imaging the thin-walled RV due to partial volume effects. Partial volume effects are seen when one pixel contains both normal tissue and abnormal myocardium . Partial volume effects can be reduced by acquiring images with higher spatial resolution and in a shorter acquisition window (to reduce motion blurring) but both of these will increase breath-hold duration. Acquiring images in systole  can be beneficial. In patients who have intracardiac shunts, the washout kinetics of gadolinium are different and hard to predict as GBCA clearance can be rapid .To reduce false positive diagnosis of LGE phase swapping, cross cutting and comparing the LGE images with cine images are helpful. Imaging the RV for small areas of fibrosis requires meticulous choices in Ti.While conventional LGE images are magnitude reconstructions that take no account of the polarity of the magnetization following the inversion pulse, phase sensitive inversion recovery (PSIR) LGE image reconstructions take into account both the magnitude and the polarity. With this type of reconstruction, the sequence is more tolerant to incorrect setting of the Ti to null normal myocardium, and the contrast between normal and abnormal myocardium is maintained over a range of values . While tIn cases where patients may find breath-holding difficult, motion corrected, free breathing, PSIR LGE imaging helps . In thisFor 3D coverage of the heart with high spatial resolution, respiratory-gated free breathing acquisitions can be performed. These navigated sequences may enable the assessment of thin walled structures such as atria and RV free wall although acquisition durations are long  and unpredictable .repaired ToF encounter problems in adulthood relating to RV dysfunction, pulmonary regurgitation, and clinical arrhythmia and are at greater risk of SCD. Detection of myocardial scarring has contributed to the understanding of RV dysfunction late after repair. We systematically investigated LGE and clinical status in a cohort of adult ToF patients and found focal areas of fibrosis not only at the ventriculotomy, VSD repair, and apical vent sites but also in remote locations in the LV and RV wall and trabeculations  with a hazard ration of 4.95  see Fig and 4. Tarterial switch operation for TGA, a population at risk for coronary stenosis, occlusions, and late death. Despite the reported prevalence of 3–7% for coronary problems, LGE was only found in 1.8% of 220 patients. Approximately 20% of patients had (mostly mild) LV dysfunction post-arterial switch surgery , of which 70% was found in the RV myocardium but LV LGE was also found. No correlation with ventricular size and function, exercise capacity, or survival was found. Fast gadolinium washout kinetics was also found  iron and (complex chelated ionic) gadolinium shorten T1. With T1 mapping, an estimate is calculated from a series of different T1-weighted images during the magnetization recovery process and is written as a “T1 map” where the T1 value of each pixel is encoded in to the intensity of the T1-map pixels. This involves a series of assumptions about alignment of the pixels in all images of the supporting series  , 87.Following a 180° inversion pulse, single-shot images are acquired in typically diastole, typically over three to five heart beats at different inversion recovery times (Ti). After a recovery period to allow for complete T1 recovery another, inversion pulse is applied followed by a similar series of images but slightly different Ti values thereby sampling more points along the T1 recovery curve. Images are then organized in order of increasing Ti . When thAn “shMOLLI” is a shorter sequence that involves image acquisition during fewer heart beats thereby shortening breath-hold time . An examFollowing an initial acquisition of an image taken with the magnetization vector being in the equilibrium state, a saturation recovery pulse is used multiple times instead of an inversion pulse. At varies times from the application of the saturation pulse (Ts), images are acquired. The signal intensity of the pixels is fitted as a function of the Ts values acquired to calculate the pixel-wise T1 map. The SASHA technique is more accurate at estimating T1 whereas MOLLI and shMOLLI may underestimate T1 with various reasons for their bias; however, SASHA is less precise mainly because it uses of a saturation pulse compared to an inversion pulse leading to reduced “contrast-to-noise” in the fitting process and therefore more random noise in the T1 maps. An advantage is that it is less susceptible to changes in R–R intervals and therefore may perform better in arrhythmias. Some debate continues over the optimum T1-mapping approach for maximum sensitivity to disease , while also having minimal scatter (imprecision) for technical factors: these aspects are to a large extent contradictory in the physics requiring further development for early detection of diffuse fibrosis as no adequate solution seems evident.There are two main techniques involving T1 mapping: native T1 is a non-contrast technique that detects pathological changes in the myocardium that occur associated with a relative increase in the concentration of water (edema) or increased interstitial space caused by protein deposition (from increased collagen causing fibrosis) or other proteins such as amyloid. The increase in native T1 is not specific to diffuse fibrosis because it occurs also (and somewhat more strongly) in other disease processes such as myocarditis and infarction. The advantage is that it can be used in patients with severe renal failure as it does not involve contrast agent. Crucially, it avoids contrast agent in CHD patients who are likely to require multiple follow-up scans from a young age .This requires the application of extracellular GBCA. The volume of the myocardium that is not taken up by cardiomyocytes is the extracellular compartment, which contains the ECM. ECV is not identical to the ECM, which cannot be measured. However, ECV is a surrogate marker that is to some unclear extent sensitive to an abnormal amount of ECM.ECV is derived by measuring the change in tissue T1-relaxation rate (R1 = 1/T1) and comparing this to the change in blood T1-relaxation rate pre- and postcontrast application, built on several assumptions, also requiring knowledge of the hematocrit . The morIn the absence of edema, the pathological expansion of the ECM is primarily due to the increased proportion of myocardial collagen within the matrix. This fibrotic process leads to mechanical, electrical, and vasomotor dysfunction. Investigators have reported the interstitial disease association with SCD , 85, 93.Clinical studies reported to date mostly include the systemic LV. The RV is much thinner. For the RV myocardium, unless it is systemic or for some other reason abnormally thickened or immobile, the T1-mapping methods face major technical limitations affecting reliability, such as adjoining fat and blood signals next to the thin trabeculated highly mobile RV wall. Suppression of these corrupting signals is usually associated with some additional unreliability or loss of myocardial data, further complicated by the proximity of sternal wires, and new MRI methods are needed to make RV T1 or ECV clinically reliable . The difThe presence of interstitial fibrosis has been shown to be of prognostic significance in the general adult cardiology population. In the CHD population, we can speculate that non-invasive detection of interstitial fibrosis may offer better tracking of RV disease than currently utilized volumes and ejection fraction. However, even in those patients with CHD and relatively thicker RV such as systemic RV after atrial redirection surgery, HLHS, ToF, and CHD patients with pulmonary hypertension but extrapolation of current techniques for the LV cannot be assumed.The only prospective study of T1 mapping and outcomes in tetralogy of Fallot relates to LV ECV in the study by Broberg and colleagues. Approximately 25% of subjects with rToF had elevated LV ECV compared to the control group, of which subjects with LV ECV >30% had significant clinical events  during their follow-up . More paIn a different study, 11 patients with a systemic RV had higher ECV, which correlated with elevated end-diastolic volumes and impaired ejection fraction . A furthSeveral studies have investigated biventricular diffuse fibrosis in ToF subjects using T1 mapping and ECV. However, these were cross-sectional studies with limitations in their methodology, namely, using postcontrast T1 times only due to unavailable hematocrit values   and limiNative T1 times and ECV in LV myocardium were measured in 31 rToF patients and compared to controls. Prolonged cardiopulmonary bypass and aortic cross-clamp time during their previous surgery, biventricular enlargement, and reduced exercise tolerance correlated with higher native T1 times and ECV in the LV .From the interrogation of the intricate myocardial architecture and its properties, to assessment of regional and global myocardial function, cardiac MRI has proven invaluable in providing data that have several important clinical implications for CHD patients.The functional assessment of the RV is very important for CHD patients as it is the chamber that is most often affected, yet it is also the chamber that is most challenging to image due to its thin, highly mobile wall, and more complex geometry. The RV wall location may change between cardiac cycles due to inter-cycle variations in returning venous flow. Imaging of the RV can be further complicated by the proximity of postsurgical sternal wires. These factors make RV imaging an extreme technical challenge for the reliability of conventional cardiac MRI. On the other hand, as the RV is adjacent to the anterior surface coil in cardiac MRI, it can be imaged with high SNR.A technique that shows potential in the study of the RV is black-blood LGE imaging. LGE imaging with the addition of PSIR is excellent in differentiating myocardial scar from normal myocardium; however, the contrast between subendocardial scar and blood pool on the white-blood images may be reduced and therefore scar may be difficult to identify. Furthermore, differentiation of fibrosis from fat and metallic artifact can be difficult. Black-blood LGE images using an inversion recovery T2 weighted SSFP have been proposed as one possible solution to this . RecentlQuantification of diffuse fibrosis with T1 mapping until now has largely been for research interest rather than clinical application. Its clinical value in CHD patients still requires clarification. Technical challenges that lie ahead include the difficulty of mapping the relatively thin-structured RV walls. Furthermore, the potential role for T1 mapping and ECV to help identify and target treatment for “reversible” interstitial disease remains unclear. A study investigated diffuse fibrosis post-aortic valve replacement for aortic stenosis with T1 mapping and found that diffuse fibrosis persistent at 6 months following aortic valve replacements despite normalization of LV-loading conditions and regression of LVH , suggestCardiac DTI may have potential future use in identifying intrinsic differences in myo-architecture that predates fibrosis associated with remodeling. With further development, cDTI may provide non-invasive means of identifying areas of myocardial disarray as potential substrates  for arrhythmia propagation, which can help guide electrophysiological therapeutic intervention. Further development, however, is required to improve the spatial resolution of cDTI including to enable it to differentiate myocardial fiber orientation in the relatively thinned walled RV , and therefore its use today is limited to that of a research tool.SB-N and SG were responsible for the conception and design of the work. SB-N and IV substantially contributed to CMR and CHD content. MG substantially contributed toward CHD content. PG and JK substantially contributed to MRI physics content. PK substantially contributed to the myocardial mechanics and myocardial architecture section. SB-N and SG contributed to the first draft and revisions. All authors contributed to revising the work critically for important intellectual content prior to final approval. The final approval of the manuscript was done by SB-N.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.