Sex differences exist in both the prevalence and survival of patients with idiopathic pulmonary arterial hypertension (IPAH). Men are less frequently affected by the condition but have worse outcome as compared to females. We sought to characterise the sex related differences in right ventricular remodelling in age matched male and female patients with IPAH using cardiac magnetic resonance imaging (MRI).A case controlled pair-matched study was conducted with patients matched by age and sex. Steady state free precession (SSFP) MRI of the heart was performed at 1.5T. Cardiac volume, function and mass measurements were corrected for age, sex and BSA according to reference data.40 age and sex matched patients with IPAH were identified. The mean age was 57 (SD 17) in both male and female cohorts. Men had proportionally lower right ventricular (RV) ejection fraction, RV stroke volume and LV stroke volume than females, p=0.028, p=0.007 and p=0.013, respectively. However, there was no significant difference in RV mass or haemodynamic indices of mPAP and PVR between males and females.Male patients with IPAH have proportionally worse RV function despite similar afterload. We hypothesise that adaptive remodelling of the RV in response to increased afterload in IPAH is more effective in females. Sex differences exist in both the prevalence and survival of patients with idiopathic pulmonary arterial hypertension (IPAH) , 2. The Cardiac magnetic resonance imaging (MRI) is considered the gold standard method of assessing biventricular mass, volume and function , allowinIn this work we sought to characterise the sex related differences in right ventricular mass and ejection fraction corrected for age, sex and BSA with MRI in treatment naïve age matched male and female patients with IPAH.Consecutive patients with IPAH who underwent MRI and right heart catheterisation (RHC) within a 48-hour period between May 2009 to April 2013 were identified from a database of a large volume, nationally designated PH referral centre . PatientMRI was performed on a GE HDx  whole body scanner at 1.5T using an 8 channel cardiac coil. Using a cardiac-gated, multi-slice, balanced SSFP sequence  short axis cine images were acquired. A stack of images in the short axis plane with slice thickness of 8 mm (2mm inter-slice gap) or 10mm (0mm inter-slice gap) were acquired fully covering both ventricles from base to apex. End-systole was defined as the smallest chamber area on each slice and end-diastole was defined as the first cine phase of the R-wave triggered acquisition.3) then provide an estimate of RV mass. Ventricular mass index was defined as RV mass divided by LV mass, expressed as a ratio.Image analysis was performed prospectively on a GE Advantage Workstation 4.1 and the observer was blinded to the patient clinical information. RV and LV endocardial and epicardial surfaces were traced manually using the stack of short axis cine images, to obtain RV end-diastolic (RVEDV) and end-systolic (RVESV), and LV end-diastolic (LVEDV) and end-systolic volumes (LVESV). From end-diastolic volume and end-systolic volumes, RV and LV ejection fraction (RVEF and LVEF) and RV and LV stroke volume (RVSV and LVSV) were calculated. Cardiac volumes, but not RVEF and LVEF, were indexed for BSA. To calculate right ventricular mass the inter-ventricular septum was considered as part of the LV. RV myocardial volume was calculated by multiplying the area of the RV wall by the slice thickness on each short axis slice using Simpson’s method . TrabecuRHC was performed with a 7.5 Fr balloon-tipped thermodilution catheter . RHC was typically performed via the internal jugular vein using a Swan-Ganz catheter. IPAH was defined at RHC by a mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg at rest and with a pulmonary capillary wedge pressure (PCWP) of ≤15 mmHg. Cardiac output (CO) was measured by thermodilution. Pulmonary vascular resistance (PVR) was determined as follows: PVR = (mPAP—PCWP)/CO.Cardiac MRI volumetric measurements indexed for BSA were corrected for age and sex and presented as percentage (%) predicted, using methods as described previously . To estaThe interval from diagnostic evaluation until all-cause mortality or census was considered as the follow-up period. The prognostic significance of sex was assessed using uni-variate Cox proportional hazards regression analysis and Kaplan-Meier analysis was also performed to determine the prognostic significance of sex. Statistical analysis was performed using SPSS 19  and for presentation of the data GraphPad Prism 5.05  software was used. A p-value < 0.05 was considered statistically significant.40 female and 40 male patients were identified from a cohort of 134 patients with IPAH. The mean age was 57 (SD 17) in males and 57 (SD 16) in the female patient cohorts. et al, men had proportionally lower corrected values of right ventricular (RV) ejection fraction and stroke volume, p = 0.028 and p = 0.007 respectively when compared to females, see et al [Corrected for reference data, Maceira ee et al , RV ejecThere is a large systematic bias between Maceria et al and Kawut et al RV mass data, 34g +/- 9g higher by Maceria data. Estimated RV mass in our population for age, gender and BSA (Maceria) and height and weight (Kawut) correlate well (r = 0.917 p<0.0001). Only moderate agreement was identified at intraclass correlation coefficient analysis, 0.740 (CI 0.596 to 0.833). Estimated RV end diastolic volume for age, sex and BSA by Maceria and Kawut data show a strong correlation , and good agreement, intraclass correlation coefficient 0.981 (0.971 to 0.988). Estimated RV end-diastolic volume measured by Maceria et al data was 15ml +/- 9ml higher than by Kawut data. Right ventricular measurements had a good inter-observer reproducibility, with the intraclass correlation coefficient measuring 0.900–0.967. At Cox proportional hazards regression analysis male patients had significantly worse outcome than females Hazard Ratio 2.30 , in addition males have higher mortality at Kaplan Meier analysis, p = 0.033, see This study has shown that male treatment-naïve patients with IPAH have proportionally worse RV ejection fraction than females, despite having similar haemodynamic indices. This is the first study to compare cardiac MR indices in male and female patients with IPAH with correction of ventricular measurements for age, sex and BSA. We have shown that RV mass corrected for all three demographics tended to be lower in males, though was not significantly different between men and women. We postulate that the RV in men with IPAH does not adapt to elevated afterload as efficiently, and this may in part explain the worse outcome of male patients suffering from this condition.In our study, uncorrected RV mass and end-diastolic volumes tended to be higher in male patient’s as is the trend in normal populations and as has been shown by Jacobs at al . HoweverGardener et al studied the sex differences in left venticular (LV) myocardial remodelling using an animal model . In thisIt has been postulated that the sex differences may be the results of the protective effect of oestrogen. Animal studies in female and male mice have demonstrated acute vasodilator effects of oestrogen in vascular rings from both sexes and oestrogen level variations have been observed with menstruation, with less vasodilation found prior to ovulation at lower oestrogen levels . In the Previous studies have suggested that female sex is associated with a lower prevalence and a better outcome of adult patients with heart failure , 23. A pThis is a single centre study. Failure to identify a significant difference in corrected RV mass between male and female patients could be due to type II error and should be validated at other centres. Relatively small numbers of patients in the less than 50 versus older than 50 female subgroups limits is a further potential source of type II error. Differences in the approach to segmentation of the ventricles between this study and others and whether trabeculations are included in right ventricular mass measurements and excluded from ventricular volume measurements is a potential source of error both for calculation of right ventricular mass and volume. Maceria et al, used a 3D segmentation approach as opposed to the manual multislice approach that we have used. Kawut et al’s method of cardiac segmentation was similar to ours, however the major difference is that Kawut et al included trabeculations in the blood pool whereas in this study and that of Maceria et al, RV trabeculations were considered to be part of the RV mass and therefore excluded from volume measurements.There is a large difference in estimated RV mass in this study cohort when using regression equations derived from the two normal populations ; the likely explanation is the inclusion of trabeculae in mass measurements by Maceria et al. Trabeculations make up a large proportion of the RV muscle mass and as such this difference is expected. The difference in RV end-diastolic is more surprising, Kawut et al find a smaller RV end-diastolic volume compared to Maceria et al, 15ml lower on average. Trabeculations were included in the RV volume measurements by Kawut et al, which would be expected to lead to a higher RV volume rather than lower. One explanation is that the 3D segmentation and tricuspid valve tracking method by Maceria et al may resulted in inclusion of a greater blood volume towards the base of the right ventricle. The second explanation is the relative small size of the study populations, limiting the applicability for use in other populations. However despite these observed differences in the scale of the variables, the trends with age and sex are similar between the two cohorts.This study indicates that there are sex differences in RV remodelling in patients with PAH. Despite males and females having a similar severity of disease, RV function was not preserved as effectively in response to elevated afterload.


Subclinical left (LV) and right ventricular (RV) dysfunction has been demonstrated in type 2 diabetes mellitus and evidence indicates impaired LV diastolic function in type 1 diabetes mellitus (T1DM) as well. The aim of our study was to evaluate the role of tissue Doppler imaging (TDI) in assessment of global LV and RV function in T1DM patients.A detailed two-dimensional, pulsed wave Doppler and pulsed wave TDI analysis was performed in 53 normotensive middle-aged T1DM patients and compared to healthy controls.p < 0.001; E’lat 12.29 ± 2.58 cm/s vs.15.30 ± 2.95 cm/s, p < 0,001; E’t 13.56 ± 2.91 cm/s vs. 15.60 ± 2.99 cm/s, p = 0.001). Mean ratios E/E’sept, E/E’lat and E/E’t were significantly higher in diabetics with cutoff value of 7.4 for E/E’sept and 3.4 for E/E’t, differentiating diabetics with LV and RV diastolic impairement from matched healthy controls . Myocardial acceleration during isovolumetric contraction (IVA) measured at the septal mitral (LV IVA) and lateral tricuspid annulus (RV IVA) was the only parameter indicating reduced contractility of both ventricles in diabetics compared to controls . LV IVA had better diagnostic accuracy than RV IVA to predict early contractile impairement in T1DM patients .In T1DM patients TDI analysis revealed reduced mean mitral septal and lateral E’ velocities as well as reduced mean tricuspid E˙t velocity compared to healthy controls (E’sept 8.89 ± 1.89 cm/s vs. 11.50 ± 2.41 cm/s, TDI is essential to detect subclinical diastolic deterioration of both ventricles in T1DM patients. TDI-derived IVA might be useful to assess early systolic alterations of both ventricles in T1DM patients. Patients with diabetes mellitus (DM) have high incidence of heart failure , 2. DM pMost echocardiographic studies have been performed in populations with type 2 diabetes mellitus (T2DM), while in type 1 DM (T1DM) patients the developement of left ventricular (LV) and right ventricular (RV) dysfunction has been much less studied –6. RecenThe objective of the present study was to evaluate the potential role of TDI in detection of subclinical global LV and RV dysfunction in normotensive T1DM patients without other comorbidities.This was a cross-sectional study, conducted in the Functional Diagnostic Unit of the Department of Cardiology and Angiology at University Medical Centre Maribor, Slovenia. The study was approved by the National Medical Ethics Committee of the Republic of Slovenia . Written informed consent was obtained from all the participants. The study protocol conformed to the ethical guidelines of the Declaration of Helsinki.We enrolled 53 normotensive patients with T1DM known for more than 5 years . Patients were asymptomatic at enrollement and in the past; they had no history of heart failure or coronary artery disease. They were all in sinus rhythm.The control group consisted of 48 healthy volunteers with mean age of 42.7 ± 6.1 years (56.3 % men and 43.7 % women). All patients and healthy subjects were recruited on the outpatient basis.Before enrollment all medical records of included diabetic patients and controls were verified and clinical history obtained. Smoking was documented in all participants. Detailed clinical examination was performed in all subjects, including measurements of blood pressure twice in supine position, body height and weight to calculate body mass index (BMI). Electrocardiogram (ECG) was recorded in supine position.Exclusion criteria were age above 53 and below 33 years, arterial hypertension, duration of T1DM less than 5 years, ischaemic heart disease , overt left ventricular systolic dysfunction-left ventricular ejection fraction (LVEF) < 50 %, bundle branch block, more than mild valvular regurgitations and valvular stenosis of any degree, cardiomyopathies , congenital heart diseases, arrhythmias, chronic pulmonary disease, pulmonary hypertension, untreated thyroid disease, systemic connective tissue diseases, pregnancy, extreme obesity (BMI above 35), advanced diabetic nephropathy (glomerular filtration rate below 60 ml/min), low quality echocardiographic image. The same exclusion criteria were used for both groups.Before echocardiographic examination blood samples were drawn in patients with T1DM to measure serum creatinine, lipid profile and glycosylated hemoglobin (HbA1c). In addition, all results of HbA1c measurements in the last 5 years were collected – HbA1c measurements were performed in the diabetes outpatient clinic of our institution at regular 6-month follow-up.Serum creatinine was measured by IDMS-traceable enzymatic assay  .The lipid profile consisted of serum triglycerides, total serum cholesterol, LDL and HDL cholesterol. Triglycerides were measured the by the enzymatic method  and total serum cholesterol by the cholesterol esterase enzymatic assay ; high density lipoproteins (HDL) and low density lipoproteins (LDL) were measured by the homogenous direct method  .HbA1c was measured by the ion-exchange high performance liquid chromatography  .The degree of albuminuria was assessed in the second morning urine sample by the nephelometric method  and expressed as urine albumin-to-creatinine ratio . Albuminuria was defined as UACR ≥ 30 mg albumin/g creatinine .All echocardiographic examinations were performed by a single experienced echocardiographer on the same ultrasound machine  at the same institution. A detailed two-dimensional (2D), pulsed wave Doppler (PWD) and pulsed wave TDI (pwTDI) analysis of the LV and RV were performed. Color Doppler recordings were obtained to exclude valvular dysfunction. All measurements were performed on the basis of the American Society of Echocardiography and European Association of Cardiovascular Imaging recommendations –16.The maximal end-systolic volume of the left atrium (LA) was measured by the 2D biplane area-length formula and indexed to body surface area (BSA). Right atrial (RA) area was measured in four-chamber view and indexed to BSA. Modified biplane Simpson’s method was used to determine LVEF.Mitral and tricuspid inflow velocities were evaluated by PWD from the apical four-chamber view and the following parameters were measured: peak early mitral inflow velocity (E), peak late mitral inflow velocity (A), E/A ratio, deceleration time of the E velocity (DT). From the tricuspid inflow pattern we measured peak early (Et) and late (At) diastolic velocity, Et/At ratio and deceleration time (DT-t).2) was calculated for both ventricles (LV IVA and RV IVA) as the ratio of IVV devided by the acceleration time (AT), which was defined as the time spent from baseline to the peak velocity of isovolumetric contraction.PwTDI recordings were acquired from the apical four-chamber view and were used to measure peak myocardial systolic an diastolic velocities at the septal  and lateral corner  of the mitral annulus and peak myocardial systolic and diastolic velocities at the lateral tricuspid annulus . PwTDI-derived peak myocardial velocity during isovolumetric contraction (IVV) (cm/s) was measured at the septal mitral (LV IVV) and lateral tricuspid annulus (RV IVV). Myocardial acceleration during isovolumetric contraction (IVA)  was assessed by pwTDI and calculated as the sum of the isovolumetric contraction time and isovolumetric relaxation time divided by ventricular ejection time.All Doppler parameters except IVV and AT were recorded at a sweep speed of 75 mm/s at end expiration, while IVV and AT were recorded at a speed of 150 mm/s. The average value of three consecutive cardiac cycles was considered in statistical analysis. Settings were adjusted for a frame rate of above 150 Hz.P < 0.05 was considered statistically significant. Also, we performed receiver operating characteristic (ROC) curve analysis of LV IVA, LVEF, RV IVA, E/E’sept, E/E’t, LA volume index and RA area index to select optimal cutoff values based on equally balanced sensitivity and specificity to detect early LV and RV impairement in diabetic patients.SPSS Statistics 22.0  was used for statistical analysis. The Shapiro–Wilks test was used to confirm normal distribution of data for all variables. Categorical variables were presented as percentages and compared with two-tailed Fisher’s exact test. Normally distributed continuous variables were presented as mean ± standard deviation and compared with unpaired Student’s t-test. The correlations between continuous variables were assessed with the Pearson’s correlation coefficient (r). To assess intraobserver variability a TDI dataset of 16 randomly selected participants was analyzed for LV IVV, LV IVA, RV IVV and RV IVA by the same observer on two different days. For interobserver variability assessment a second observer blinded to the clinical information and to the results of the first observer analyzed the same TDI recordings. Variability was calculated in two ways: a) as the mean percent error, derived as the difference between two measurements, divided by the mean value of these two measurements and b) by intraclass correlation coefficients (ICC) for absolute agreement.Ninety-seven T1DM patients treated at our diabetes outpatient clinic met inclusion criteria and were invited to participate in the study. Thirty-four patients refused to join the study and ten patients were later excluded because of poor echocardiographic image quality or valvular abnormalities. Finally, fifty-three T1DM patients were enrolled to the study.Demographic and clinical data are presented in Table Laboratory data are presented in Table Standard echocardiographic measurements, PWD and TDI-derived data are summarised in Table Regarding LV echocardiographic measurements, in T1DM patients we observed significantly increased interventricular septal (IVS) and LV posterior wall (LVPW) thickness, but equal values of end diastolic LV dimension (LVIDd) and LVEF in comparison to healthy controls Table .Regarding right ventricular dimensions  and TAPSE we did not observe any significant difference in T1DM patients compared to healthy controls , significantly lower ratios E’/A’sept and E’/A’lat, significantly increased ratios E/E’sept, E/E’lat, significantly decreased S’sept, while the difference in S’lat was nonsignificant between T1DM patients and controls. LV IVA was significantly reduced in T1DM group compared to controls, while there was no significant difference in LV IVV between the groups Table .E’t was significantly decreased in T1DM patients while S’t was similar between the groups. The ratio E/E’t was significantly increased and E’/A’t was significantly decreased in diabetics in comparison to controls. RV IVV and RV IVA were both significantly reduced in diabetics compared to controls Table .We did not observe any significant difference in LV MPI and RV MPI between the groups Table .2 were characteristic for diabetics with 69.2 % sensitivity and 63.0 % specificity (p < 0.001). LVEF was not useful to predict early LV contractile impairement in diabetics . RV IVA below 295 cm/s2 was characteristic to detect early RV systolic dysfunction in diabetics , but sensitivity and specificity were very low .ROC curves of systolic parameters  are presented in Fig. p < 0.001 and AUC of RA area index 0.833, 95 % CI 0.744–0.923, p < 0.001) to detect diabetics with early LV and RV diastolic impairement compared to healthy controls with the cutoff value of 26.0 ml/m2 for LA volume index  and 7.2 cm2/m2 for RA area index . Diagnostic accuracy of E/E’sept and E/E’t was also high . Values above 7.4 for E/E’sept  and 3.4 for E/E’t  were characteristic for diabetic patients.ROC curves of diastolic parameters  are presented in Fig. r = −0.38, p = 0.008) and S’lat . RV IVA correlated with BMI (r = 0.307), but the correlation met only borderline statistical significance (p = 0.045). No relationship was found between LV IVA and the following parameters: age, DM duration, BMI, E’sept, E’lat, E/E’sept, S’sept, S’t, E’t and E/E’t. Similarly, no correlation was found between RV IVA and age, DM duration, S’t, E’t, E/E’t, S’lat, S’sept, E/E’sept and E/E’lat. Furthermore, no correlations were confirmed between LV IVA/RV IVA and parameters of long-term glycemic control (HbA1c at enrollment and average HbA1c in the last 5 years). We found no correlation between LV IVA/RV IVA and other laboratory parameters  , 7.22 % (95 % CI 5.46–9.22), 6.6 % (95 % CI 4.72–8.66) and 8.31 % (95 % CI 6.76–9.96), respectively. Interobserver variabilities for the corresponding measurements were 5.12 % (95 % CI 4.01–6.12), 11.54 (95 % CI 10.17–12.92), 5.05 % (95 % CI 4.11–5.96) and 9.70 % (95 % CI 8.49–10.82). ICC for intraobserver variability of LV IVV, LV IVA, RV IVV, RV IVA was 0.953 (95 % CI 0.871–0.983), 0.976 (95 % CI 0.933–0.992), 0.953 (95 % CI 0.872–0.983) and 0.958 (95 % CI 0.886–0.985), respectively. ICC for interobserver variabilty of the corresponding measurements was 0.987 (95 % CI 0.962–0.995), 0.946 (95 % CI 0.854–0.981), 0.986 (95 % CI 0.961–0.995) and 0.952 (95 % CI 0.868–0.983).Our TDI results suggest that in T1DM patients diastolic function of both ventricles is impaired in comparison to matched healthy individuals and that there is a possible systolic impairement of both ventricles in T1DM patients as assessed by IVA.Most of our mean PWD and TDI findings were in normal range for both groups according to current guidelines. However, small but statistically significant differences were detected in diabetics compared to healthy controls. E’sept, E’lat and E’t were decreased and E/E’sept, E/E’lat, E/E’t were all increased in diabetic group compared to controls, indicating worse diastolic function of both ventricles in this relatively young T1DM population. Mean LA volume index and mean RA area were in both groups still in normal range, but they were significantly higher in diabetics, suggesting long-term increase of LV and RV filling pressures in T1DM patients compared to healthy controls.Recently, in a large observational echocardiographic study including 1091 T1DM patients  a high degree (30.8 %) of LV diastolic dysfunction has been documented among diabetics, which is more than expected in age-matched nondiabetic population ; similarSince first published data on RV diastolic dysfunction in diabetic patients in 2004 , only feLimited data exist on potential LV systolic dysfunction in T1DM patients. Most studies could not demonstrate LV contractile dysfunction by conventional echocardiography nor even by TDI , 10, 20.Data on RV systolic function in T1DM are sparse. First research on RV contractile function in diabetics was published by Kosmala et al. in 2004 – they found no differences in color TDI-derived longitudinal shortening velocities of basal and mid segments of the RV free wall in a non-uniform diabetic group (including both T1DM and T2DM patients) compared to healthy controls . SimilarA recent myocardial deformation study based on 2D speckle tracking echocardiography gave evidence of reduced global longitudinal strain of both ventricles in T1DM patients, while LV global radial strain and LV twist were not affected significantly . This waOur TDI findings give additional evidence of impaired longitudinal contractility of the LV revealing significantly reduced S’sept and nonsignificantly reduced S’lat in diabetics. On the other hand we could not demonstrate reduced RV longitudinal shortening neither by TAPSE nor by S’t, which was consistent with previous reports . This miAn important finding of our study is the potential of TDI-derived IVA to assess global systolic function of both ventricles in T1DM patients. In our study, IVA has proven to be the only useful TDI-derived parameter to evaluate potential early systolic impairement of both ventricles in T1DM patients, though sensitivity and specificity of RV IVA were low. At present we are not aware of any other study using this relatively novel TDI-derived parameter in T1DM population. A similar ability of IVA to detect LV systolic dysfunction was presented in a study including T2DM patients, whereas RV contractile dysfunction could not be confirmed by IVA in this study . IVA wasIVA is supposed to be a robust index of global contractility like dP/dt, as both indices reflect the change of contractile force during isovolumetric contraction . IVA hasOur data show that in diabetics a moderate, but statistically significant positive correlation exists between LV IVA and S’lat - another parameter of LV contractility. Furthermore, LV IVA showed a moderate, but significant negative correlation with E/E’lat. This suggests that subclinical LV systolic and diastolic alterations might develop concurrently in T1DM patients, which has not been observed till now. However, we did not confirm these correlations for the RV.Considering ethical issues we did not perform coronary angiography to exclude coronary artery disease in our patients. However, based on detailed medical history all symptomatic patients with history of exertional angina or prior myocardial infarction were excluded from the study. Furthermore, we carefully excluded all patients with ischemic changes in the resting ECG, echocardiographic LV wall motion abnormalities and LVEF below 50 %. We believe that this limitation did not influence our results.Baseline characteristics were not completely balanced, as diabetic patients had slightly elevated blood pressure compared to controls, but the difference was not statistically significant. As 24-h ambulatory blood pressure was not measured before enrollment, we cannot exclude potential masked hypertension in our patients. However, blood pressure was regularly checked in diabetic patients at our diabetes outpatient clinic and detailed medical hystory of home blood pressure measurements was taken in all participants before enrollment.All echocardiographic measurements were performed by a single experienced echocardiographer who was not blinded to the diabetic status of participants. However, intraobserver and interobserver variabilities of IVV and IVA measurements were very good, suggesting adequate reproducibility of our results.As exclusion criteria were very restrictive the number of diabetic patients was limited.PwTDI is a sensitive echocardiographic technique to detect subclinical LV and RV diastolic dysfunction in T1DM patients. Reduced IVA might be an early indicator of subclinical contractile (systolic) dysfunction of both ventricles in T1DM patients, though its diagnostic value is hampered by low sensitivity and specificity. Further research is warranted to compare the predictive value of pwTDI-derived LV IVA/RV IVA with 2D and 3D tissue deformation imaging to evaluate potential subclinical LV and RV contractile impairement in this subset of patients.https://figshare.com/articles/T1DM_echo_database_xlsx/3120979).The dataset supporting the conclusions of this article is available in the »Figshare« repository (doi:10.6084/m9.figshare.3120979;


Giant cell myocarditis is a rare and often fatal disease. The most obvious presentation often described in the literature is one of rapid hemodynamic deterioration due to cardiogenic shock necessitating urgent consideration of mechanical circulatory support and heart transplantation. We present the case of a 60-year-old man whose initial presentation was consistent with myopericarditis but who went on to develop a rapid decline in left ventricular systolic function without overt hemodynamic compromise or dramatic symptomatology. Giant cell myocarditis was confirmed via endomyocardial biopsy. Combined immunosuppression with corticosteroids and calcineurin inhibitor resulted in resolution of symptoms and sustained recovery of left ventricular function one year later. Our case highlights that giant cell myocarditis does not always present with cardiogenic shock and should be considered in the evaluation of new onset cardiomyopathy of uncertain etiology as a timely diagnosis has distinct clinical implications on management and prognosis. Giant cell myocarditis (GCM) is a rare and often fatal disease with the most obvious presentation being a rapid hemodynamic deterioration with declining left ventricular (LV) systolic function and cardiogenic shock . We repohttp://dx.doi.org/10.1155/2015/173826). This was followed by a contrast-enhanced cardiac magnetic resonance (CMR) imaging that showed normal left ventricular (LV) systolic function with an ejection fraction (EF) of 55% and multiple patchy areas of transmural and midwall late gadolinium enhancement (LGE) in a noncoronary distribution . Emergent cardiac catheterization revealed angiographically normal coronary arteries. On hospital day one, a transthoracic echocardiogram (TTE) was notable for normal left ventricular function, chamber size, and wall thickness  of 110 bpm. The jugular venous pressure was 7 cm HOver the next two days, serial TTEs showed a rapid decline in LV systolic function from 45% to 25%, increased wall thickness suggestive of myocardial edema, and spontaneous echo contrast in the left ventricle consistent with stasis of blood flow , Movie 2Given the rapid and dramatic decline in LV systolic function, an endomyocardial biopsy was performed. Microscopic analysis revealed widespread necrosis and an inflammatory infiltrate comprising neutrophils, eosinophils, and multinucleated giant cells consistent with the pathological diagnosis of giant cell myocarditis (GCM) . ImmunosTwo weeks following hospital discharge, the patient was free of heart failure (HF) symptoms. TTE showed improved contractility with an EF of 45%. Repeat CMR 6 weeks later demonstrated residual patchy areas of midwall late gadolinium enhancement but the overall extent of enhancement was significantly reduced. CMR-measured EF had normalized to 55% with resolution of all wall motion abnormalities and no evidence of diastolic dysfunction . The patIdiopathic GCM is a rare and often fatal disease . InitialA rapid hemodynamic deterioration with declining LV systolic function and cardiogenic shock is the most obvious presentation of GCM requiring urgent consideration of inotropes, mechanical circulatory support, and transplant, in addition to immunotherapy –7. The cP < .001) [A strong index of suspicion for GCM is required in the appropriate clinical context with less fulminant presentations, since the diagnosis has distinct implications for treatment and prognosis . As show < .001) , 4, 9. CGCM does not always present with rapid hemodynamic deterioration and cardiogenic shock but can also be diagnosed in patients with initially normal left ventricular function and among those with nonfulminant acute HF of uncertain etiology. Establishing the diagnosis of GCM is critical for the management and prognosis of the disease as combination immunosuppression versus corticosteroids alone significantly improves transplant-free survival –4, 9. CuMovie 1: Transthoracic echocardiogram (TTE) in the apical four chamber view from hospital day 1 shows normal ventricular function, normal ventricular size, and normal ventricular wall thickness.Movie 2: Repeat transthoracic echocardiogram (TTE) in the apical four chamber view from hospital day 7 shows a dramatic decline in left ventricular systolic function with a severely depressed EF 25%, thickened ventricular walls consistent with edema, and dilation and hypokinesis of the right ventricle. Spontaneous echocontrast or "smoke" can be seen in the left ventricle due to low flow and stasis.


Introduction: Congestive heart failure (CHF) is a common disease and its prevalence is increasing in industrialized countries. NT-proBNP measurement is an established diagnostic test for diagnosis of CHF in patients who present to emergency room with acute dyspnea. The primary object of this study was to determine the relationship between levels of brain natriuretic peptide precursor and severity of lung function impairment in patients with chronic CHF.Methods: This cross-sectional and analytical study that performed in Tuberculosis and Lung Disease Research Center of Tabriz University of Medical Sciences on 95 patients with chronic heart failure, and relation between NT-proBNP levels and pulmonary function parameters were examined.Results: Sixty-four patients were male and 31 were female. The average age of male and females was 62.90 ± 11.54 and 61.61 ± 11.98 years, respectively. A significant inverse linear correlation was found between NT-proBNP and FEV1 , FVC , TLC , maximal midexpiratory flow (MMEF)  and left ventricular ejection fraction (LVEF) . A significant positive linear correlation was found between NT-proBNP and FEV1/FVC , RV/TLC  and 5 Hz Raw .Conclusion: This study showed that, both restrictive and obstructive ventilator impairments can occur in chronic CHF and as NT-proBNP increases appropriate to hemodynamic deterioration, pulmonary dysfunction increases. Heart failure (HF) is a clinical syndrome which occurs due to hereditary or acquired abnormality of structure or function of the heart. The prevalence of HF increases with age and affects 6%-10% of people older than 65 years.Any changes in the structure or function of the LV (left ventricle), would predispose the patient to HF. According to the pathophysiology, patients are mainly divided into two groups; systolic and diastolic heart failure.1In industrial societies, coronary artery disease (CAD) is known as the major cause of HF both in men and women (60%-70% of cases). In 75% of the patients suffering from CAD, hypertension is an added risk for development of HF.1Routine preclinical tests for hospitalized patient with HF include routine laboratory tests, electrocardiography, chest radiography (CXR), two-dimensional Doppler echocardiography and biomarkers. These biomarkers are BNP and its precursor which are released from the dysfunctional heart.BNP is a peptide hormone that is released from the cardiac ventricles as a result of myocyte stretch. This hormone is an inactive pro-hormones that would be broken into two hormones; Active BNP and inactive NT-proBNP.3The pro-hormone is released due to the hemodynamic stress such as ventricular dilatation, ventricular hypertrophy and increased ventricular wall tension. Systemic effects of BNP include vasodilatation, increased urine output with high sodium level, inhibition of the nervous system and the rennin-angiotensin-aldosterone system.2Prognostic significance of BNP and NT-pro BNP has been widely studied in patients with heart failure, and the levels of pro-hormones are associated with hemodynamic status in patients with HF and are strong predictor of morbidity and mortality.7 There are several mechanisms such as interstitial edema and airway mucosal vasodilatation, and also vagotonia which result in decreased airway cross-section and airway hyper-responsiveness in CHF.9 Inhaled glucocorticoids can reduce the airway obstruction, so the inflammatory mediators such as arachidonic acid metabolites, platelet-activating factor, TNF, IL1 and IL6 may play a role in bronchial hyper-responsiveness. Glucocorticoids act in several ways such as inhibition of histamine and IgE dependent LTC4 release and reduction of vascular permeability and mucus secretion.9 Increased vagal efferent activity resulting from activation of sensory-neural terminals in the lower airways following edema and hyperemia may lead to bronchospasm. The improvement of forced expiratory volume in one second (FEV1), maximal midexpiratory flow (MMEF) and maximum voluntary ventilation (MVV) following the inhalation of ipratropium bromide confirms the involvement of vagal mechanisms in bronchial obstruction in the patients with CHF. Possible involvement of angiotensin converting enzyme inhibitors in bronchial hyper-responsiveness in patients under treatment for CHF has been studied.10Restrictive pattern, characterized by decreased vital capacity (VC) and total lung capacity (TLC) and impaired gas exchange have been recognized in the patients with CHF. On the other hands, small airway obstruction and the airway hyper-responsiveness are reported in patients with CHF.Since the respiratory dysfunction is definitely observed in patients with heart failure and NT-proBNP level is associated with the severity of cardiac dysfunction, the association between NT-proBNP and lung function is the subject of this study.The aim of this study is to evaluate the relationship between the NT-proBNP levels and the severity of lung function impairment in the patients with chronic CHF.In a cross-sectional analytic study conducted at the Tuberculosis and Lung Disease Research Center at Tabriz University of Medical Sciences. The relationship between the NT-proBNP levels and the severity of lung function impairment studied in patients with CHF.Patients with a diagnosis of chronic systolic HF were enrolled in this study. After a thorough physical examination, CXR and echocardiography were performed. All patients with known lung diseases, respiratory infections and who have a history of smoking were excluded from study.The included patients were referred to the pulmonary function laboratory and the lung function tests such as spirometry, body plethysmography and impulse oscillometry (IOS) were performed. Then two ml of venous blood sample were taken from the patients and the plasma level of NT-pro BNP was measured by electrochemiluminesence.The studied variables were age, sex, severity of congestive heart failure, EF, plasma levels of NT-pro BNP, FEV1, forced vital capacity (FVC), FEV1/FVC, TLC, residual volume (RV), RV/TLC, intrathoracic gas volume (ITGV), ITGV/TLC, airway resistance at 5 and 20 Hz  and MMEF rate.2 test were used and then P<0.05 considered significant.Estimated sample size with α= 0.05 and power= 0.80 and by using power and sample size calculation software version 2.1.3 was 87 patients and we enrolled 95 cases. We used simple random sampling method. Statistical analysis performed by SPSS version 6. For quantitative data analysis, analysis of variance (ANOVA) test and for qualitative data analysis, χA total of 95 patients;  with CHF were enrolled. The average age of males and females was 62.90 ± 11.54 and 61.61 ± 11.98 years, respectively.The main cause of heart failure was CAD in 69 cases (72.6%), and other causes were hypertension 14 (14.7%) cases, cardiomyopathy 6 (6.3%) cases, valvular diseases 4 (4.2%) cases and myocarditis 2 (2.1%) cases.The average LVEF in males and females was 30.26 ± 9.25 and 29.35 ± 7.22%, respectively.The average NT-proBNP in males and females was 1358.40 ± 2649.03 and 465.06 ± 624.42, respectively (P=0.013).There was an significant inverse linear correlation between NT-proBNP and FEV1 , FVC , TLC , MMEF  and LVEF .On the other hand, there was a significant linear correlation between NT-proBNP and FEV1/FVC , RV/TLC  and 5 Hz Raw .There was not any significant linear correlation between NT-proBNP and RV , ITGV , ITGV/TLC  and Raw 20 Htz . Relation between NT-proBNP and FVC and RV/TLC are illustrated in 13CHF is a common disease that its prevalence is increasing in industrial countries.7Pulmonary manifestations of heart failure are very well known. In the previous studies, restrictive and obstructive ventilatory impairments and airway hyper reactivity have been shown.9 Moreover, stimulation of sensory-neural endings in lower airways by edema and hyperemia-induced efferent vagal activity may play a role in bronchoconstriction.10In spite of numerous studies, the main mechanism of lung dysfunctions is unknown, but various mechanisms, including; interstitial edema, airways mucosal edema, and vasodilation of bronchiolar vessels have been proposed. These changes lead to a reduction in the cross section of airways and vagotonia.23 This marker is a cardiac neurohormone that is released by ventricles in response to overload and increase in volume of ventricles.17Measurement of NT-proBNP is a simple, noninvasive and available tool to put the possibility of heart failure and can assist to diagnose HF from other causes of acute dyspnea in patients presenting to the emergency room.24 They found that the levels of NT-proBNP and BNP in patients with pulmonary diseases are significantly related to the levels of VO2 max and FEV1.24There are some studies performed on the serum level of NT-proBNP in pulmonary diseases. For example, a study was carried out by Maeder et al.25 measured the level of NT-proBNP in patients with Chronic Obstructive Pulmonary Disease. The NT-proBNP levels were increased and associated with mortality of these patients.Lee et al.26 carried out a study in Detroit (USA) to examine the level of NT-proBNP in critically ill patients. There was a meaningful association between the level of NT-proBNP and respiratory failure among patients.26Wange et al.7 These findings suggest that pulmonary dysfunction is related to the severity of heart failure.In our study, the level of NT-proBNP was measured in patients with heart failure. There was a significant inverse linear relationship between serum levels of NT-proBNP and left ventricular ejection fraction (P>0.001 and r=-0.461). This is in agreement with findings of previous studies which showed inverse relationship between serum levels of NT-proBNP severity of left ventricular dysfunction. On the other hand there was a direct significant linear relationship between left ventricular ejection fraction (LVEF) and FEV1, FVC and MMEF. We also found a significant inverse linear relationship between EF and Raw 5 Hz. These findings are consistent with the results of previous research which showed obstructive and restrictive ventilatory impairments in patients with heart failure.24 There was no significant association was found between NT-proBNP and Raw 20 Hz in our study.We showed a significant inverse linear relationship between NT-proBNP levels and FVC, FEV1, TLC and MMEF. Also, there was a significant linear relationship between NT-proBNP levels and FEV1/FVC, RV/TLC, and Raw 5 Hz. Maeder et al, reported similar association between the serum NT-proBNP and FEV1.3, it can be concluded that with an increase in the severity of hemodynamic disturbance, lung volume decreases as a result of congestion. On the other hand, reduction in MMEF and increase in RV/TLC associated with NT-proBNP level elevation, are in favor of obstructive ventilator impairment in these patients.The above results suggest that with an increase in NT-proBNP level, pulmonary volume decreases significantly. Since the level of the aforementioned neurohormone is directly influenced by cardiac outputThe main innovation of this study is direct measurement of airway resistance by IOS which showed that small airway resistance increases with intensification of hemodynamic disturbance reflected by elevated NT-proBNP level. This increase in airway resistance explains the decrease in MMEF and the increase in RV/TLC.The main mechanism of obstructive changes in lung function in CHF has not been clarified, but some mechanisms including; airway mucosal edema, stimulation of nerve endings, vagotonia, or activation of inflammatory processes has been suggested. However, considering the evident relationship between pulmonary dysfunction and hemodynamic changes, it is likely that other mechanisms involved in pulmonary dysfunction may contribute to the development of hyperemia and congestion.We thank Tabriz Danesh Pathobiology Laboratory directorship for their kindly contribution in measurement of NT-proBNP on our samples. We also acknowledge Mrs.Mozhgan Khosravi for her contribution in this study by performing pulmonary function tests at Shahid Madani pulmonary function laboratory.The research purposes were explained to the patients and informed written consent was obtained. The patients were assured about their personal information secrecy. According to the research design of study, no costs were paid by the patients for performed tests.Authors declare no conflict of interests in this study.


Dilated cardiomyopathy (DCM) is a heart muscle disease that is endemic in Africa. Over the past 50 years, South African investigators have made significant contributions to scientific elucidation of the condition. The objective of this review was to summarise their research on the subject of DCM.We searched PubMed for articles originating from South Africa and focusing on DCM or the related condition, peripartum cardiomyopathy (PCM). Reference lists and prominent South African researchers on DCM were also consulted. The prevalence of DCM is comparable in magnitude to that of other endemic heart conditions such as hypertension and rheumatic heart disease, although by comparison, DCM may cause disproportionate morbidity from heart failure. In the African context, malnutrition, excessive alcohol intake, prior myocarditis and genetic make-up have been proposed as aetiologies, and some or all of these factors may play an interrelated role in individual disease expression. The pathogenesis of DCM is partially due to the mechanical effects of fibrosis, and the immune response to myocardial damage likely affects disease progression. Small trials of pentoxifylline plus conventional therapy have demonstrated a trend towards reduced mortality from heart failure.Despite half a century of noteworthy research, the pathogenic mechanisms of DCM are still incompletely understood. South Africans have, however, played and should continue to play a critical role in advancing research on DCM. As in industrialised countries, heart failure is an important cause of morbidity and mortality in developing countries. In the latter settings, however, heart failure arises primarily from non-ischaemic causes, such as hypertension, rheumatic heart disease and cardiomyopathy.The primary aim of this article is to summarise the contributions of South African research in the field of DCM. We include research dealing with peripartum cardiomyopathy (PCM), because PCM is regarded by some authorities to be a variant of idiopathic DCM, although others consider it to be a separate entity.cardiomyopathy, dilated cardiomyopathy, and congestive cardiomyopathy, with and without the modifiers Africa and South Africa. Reference lists from relevant articles were reviewed. We also consulted several of the original South African investigators of DCM and PCM. Only studies published in English and with a first or last author based in South Africa have been included.We searched PubMed using the terms The earliest reports of DCM in South Africa were small clinical or pathological case series, mostly of black patients in the Johannesburg area. In 1951, Gillanders reported 30 cases of unexplained congestive heart failure among urban black patients presenting to the Chris Hani-Baragwanath Hospital,13By contrast, PCM had been described in other parts of the world decades before it was reported in Africa.13Complicating early research and discussions about DCM were conflicting systems of nomenclature and classification. South African physicians had a unique role in both the origin of these systems and the evolution of a more standardised terminology. In a 1968 review of the literature from South Africa, Böhm found 27 different terms for what he called ‘South African endomyocardiopathy’. The variety of terms proposed – some even by the same authors in different publications – reflected a lack of knowledge about its aetiology and relation to other causes of heart failure.6The specific term ‘cardiomyopathy’ came into favour over several years, between the time of Brigden (1957) and the International Symposium on Cardiomyopathies,16 which was held in 1971 in Tiervlei, South Africa.18The true burden of DCM and PCM in Africa is unknown. In contrast to more industrialised regions, there have been no population-based studies to assess its true prevalence on this continent.Unfortunately, only one study from South Africa has estimated the frequency of PCM specifically. Based on 97 patients seen over four years, its incidence was proposed to be one in 1 000 deliveries.Therefore the frequency of diagnosis of DCM, especially at hospital admission for heart failure, is relatively high, while the rate of death from DCM, especially compared with other cardiovascular diseases, e.g. hypertensive or rheumatic heart disease, is still relatively low. These data imply that compared to other conditions, DCM carries a disproportionate share of the morbidity from heart disease.Perhaps the most perplexing aspect of DCM is its aetiology. Much has been written on this subject over the past 50 years, yet its precise cause is still unknown. Currently, it is held that DCM represents a ‘final common expression’ of a wide variety of insults, rather than the effects of one causative agent.Nutritional deficiency was the first causative agent proposed for DCM, and most of the early studies focused on the relationship between diet and heart failure. Gillanders’ original work, titled ‘Nutritional heart disease’, postulated a connection between an urban ‘Bantu’ diet deficient in certain vitamins and protein, and the development of heart failure.30It must also be noted that beriberi heart disease, which is due to thiamine deficiency, was distinguished early on from ‘idiopathic’ DCM. In the latter, red blood cell thiamine concentrations were shown to be normal, in contrast with those in beriberi.346 deficiency in many patients with DCM, although beriberi heart disease as a specific entity was relatively rare.38Excessive alcohol intake has been identified in many populations at risk for DCM, but in contrast to nutritional hypotheses, alcohol is still widely accepted as a common cause of DCM.In the 1980s, it was hypothesised that DCM might be a sequela of prior myocarditis, and two studies by Rose and colleagues sought to define the relationship between myocarditis and DCM.In the last two decades, one of South Africa’s major contributions to the field of DCM has been in elucidating its genetic basis. Initially, reports were on familial cases, but later more extensive studies were undertaken. Brink and colleagues were the first in South Africa to describe a case of familial DCM with prominent ventricular arrhythmias.44More recently, mutation screening of 57 patients demonstrated that actin mutations do not play a major role in dilated cardiomyopathy.51Regarding the aetiology of PCM, Seftel and Susser’s original article outlined two early hypotheses, one related to environmental factors and the other to physiological stresses in susceptible patients.52Important contributions dealing with the pathogenesis of DCM and PCM have also come from South Africa. During the 1960s and 1970s, research focused primarily on the biochemical and metabolic effects of DCM on the myocardium and its mechanical and structural characteristics. Since the 1990s, however, investigators have written mostly on the relationship between myocardial damage and immunity.Brink and colleagues quantified myocardial blood flow and metabolismOther investigators found that hypokinesis was universal in DCM, but in contrast to ischaemic heart disease, ‘asynergy’, i.e. non-coordinated myocardial contraction, was variable.58Immune response to myocardial damage most likely plays a significant role in the progression of DCM, and a variety of inflammatory molecules appear to be involved. One study found that HLA-DR1 and HLA-DRw10 were more common in patients with DCM, suggesting a genetically determined immune response contributes to the pathogenesis of this disease.61A similar inflammatory response was found in PCM, except that Fas/Apo-1 was also elevated;67In spite of its unknown aetiology, DCM has been reported to have distinctive clinical features that contrast with other forms of heart disease. Gillanders noted congestive heart failure with an extreme degree of oedema.69In early paediatric reports, DCM was also shown to have similar clinical and pathological characteristics as in adults.71Lowenthal39DCM in Africa was found to carry a lower incidence of associated anaemia and renal failure versus western heart-failure cohorts, most likely due to differences in the prevalence of ischaemic heart disease and treatments that affected renal function.75While South African researchers have written extensively on conventional treatments for DCM and associated heart failure, they have also contributed to the development – and in many cases success – of alternative therapies as well. Diuretics79Cardiac transplantation is a standard therapeutic option for advanced heart failure and was pioneered in South Africa.33Perhaps the most unique contribution of South African investigators in the treatment of DCM was the investigation of pentoxifylline for heart failure. This drug suppresses the immune response to DCM, particularly TNF-α67In general, treatment of PCM has been dealt with similarly to DCM. However the prognosis of PCM is better than DCM, which originally led Seftel to advocate for more aggressive treatment, aiming for full recovery. The variety of drugs available was more limited at the time, so his recommendations focused on optimisation of nutrition, limitation of breastfeeding, and avoidance of future pregnancy.83Although DCM and PCM are important causes of heart failure in resource-poor settings, much has been accomplished in elucidating the nature of these diseases since they were first described in Africa. The work of South African physicians and scientists in assessing the prevalence, causes, clinical features and treatment of cardiomyopathy is a biomedical success story and should be an inspiration for future research.This review has shown, however, that work on cardiomyopathy is far from complete. The contributions of genetics and immunology to DCM and PCM are far from clear. Basic research on cardiomyopathy needs to continue, ideally with more international financial support and collaboration. Treatments for cardiomyopathy-associated heart failure are far from optimal, and more rigorous clinical trials will be required to advance the newest therapies.On a population level, the social determinants of cardiomyopathy are not well understood, and neither is its true epidemiology. Population-based studies and detailed international registries will provide better information on the global burden of disease, and they will facilitate the development of an appropriate multi-national research agenda, as well as the implementation of public health measures to modify environmental risk factors where possible.


Myocarditis has been reported in up to 20% of sudden cardiac death in young adults and is a frequent precursor of dilated cardiomyopathy. Unfortunately, the diagnostic tools for detection of myocarditis are still imperfect: Sensitivity of endomyocardial biopsy (EMB) is reduced largely due to the inherent sampling error. Cardiac magnetic resonance (CMR) offers the advantage of analysing the whole myocardium, but contrast-enhanced as well as T2-weighted CMR exhibit inadequate sensitivity, especially during early stages of inflammation.Our hypothesis was that quantitative T2 relaxation mapping increases diagnostic sensitivity in CMR-based diagnosis of myocarditis.We carried out a prospective observational study in patients with probable acute myocarditis characterized by clinical presentation, new global or regional wall abnormalities or arrhythmias or hsTNT-elevation. Of the 55 patients screened, two patients did not undergo CMR  and 16 patients refused EMB. The remaining 37 patients underwent EMB and CMR examination  within 36h. Histological evaluation was performed by two independent pathologists  and by molecular analysis for viral replication/genome. CMR data were analysed blinded with respect to ventricular volumes and ejection fraction as well as T2, LGE and Strain Encoded (SENC)-Imaging. A GRASE sequence  was used for localized T2 mapping. Age-matched volunteers (37) served as controls for ROC curve analysis in terms of quantitative T2-mapping. Results were compared by two-sided t-Test; p<0.05 was considered significant.In the 37 patients with "probable myocarditis" undergoing EMB+CMR, 26 patients were identified as "biopsy-proven myocarditis" (70%). To apply quantitative analysis strategies we determined the mean physiological T2 relaxation in healthy, age matched controls and performed ROC-curve analysis compared to patients with biopsy-proven myocarditis. We determined that a threshold of 3% myocardium with absolute T2 times above 80ms detected patients with "biopsy-proven myocarditis" with a sensitivity 0,93 and a specificity of 0,96. Larger areas of myocardium with pathological T2 times correlated significantly with reduced LV-function (*p<0.05). Applying this technique to patients with "probable myocarditis", a diagnosis of myocarditis was made in 34 (92%) of the patients. Among all patients, 60% were characterized as myocarditis on the basis of LGE and only 9% on the basis of T2 Imaging alone. There was no significant correlation of local myocardial systolic strain with elevated T2 values.Conventional CMR and EMB are of additive diagnostic value in patients with possible myocarditis. However, T2 mapping facilitates generation of objective, quantitative criteria for the diagnosis of myocarditis and enhances the sensitivity in CMR-based diagnosis.None.


This prospective study aimed to assess whether use of the subxiphoid acoustic window in transthoracic echocardiography (TTE) can be an accurate alternative in the absence of an apical view to assess hemodynamic parameters.This prospective study took place in a teaching hospital medical ICU. Over a 4-month period, TTE was performed in patients admitted for more than 24 hours. Two operators rated the quality of parasternal, apical, and subxiphoid acoustic windows as Excellent, Good, Acceptable, Poor, or No image. In the subpopulation presenting adequate (rated as acceptable or higher) apical and subxiphoid views, we compared the left ventricular ejection fraction (LVEF), the ratio between right and left ventricular end-diastolic areas (RVEDA/LVEDA), the ratio between early and late mitral inflow on pulsed Doppler (E/A ratio), the aortic velocity time integral (Ao VTI), and the ratio between early mitral inflow and displacement of the mitral annulus on tissue Doppler imaging (E/Ea ratio).n = 65), LVEF, E/A, and RVEDA/LVEDA were comparable on both views, and were strongly correlated (r > 0.80) with acceptable biases and precision. However, the Ao VTI and the E/Ea ratio were lower on the subxiphoid view than on the apical view .An adequate apical view was obtained in 80%, and an adequate subxiphoid view was obtained in 63% of the 107 patients included. Only 5% of patients presented an adequate subxiphoid view without an adequate apical view. In the subpopulation of patients with adequate apical and subxiphoid windows (An adequate TTE subxiphoid window was obtained in fewer than two thirds of ICU patients. In addition to the classic indication for the subxiphoid window to study the vena cava and pericardium, this view can be used to study right and left ventricular morphology and function, but does not provide accurate hemodynamic Doppler information. ICU echocardiographers should therefore record both apical and subxiphoid views to assess comprehensively the cardiac function and hemodynamic status. Transthoracic echocardiography (TTE) has become the leading noninvasive examination to assess the hemodynamic status of patients hospitalized in intensive care units (ICUs) -3. It alTo complete the examination in this setting, the echocardiographer may perform transesophageal echocardiography. However, transesophageal echocardiography is more invasive and can be difficult to perform, especially in nonintubated ICU patients. In this setting, use of the transthoracic subxiphoid view can be an attractive alternative to transesophageal echocardiography for less-experienced operators who may be reluctant to perform an invasive examination. The subcostal view is classically used to study respiratory variations of the inferior vena cava and the presence of pericardial effusion. This view can provide additional hemodynamic parameters, such as LVEF, mitral or aortic flows, and RV/LV areas. Although the subxiphoid view does not provide the same alignment as the apical view, it is not known to what degree this different alignment affects the results of the hemodynamic examination.To address this issue, we tried to determine the accuracy of the subxiphoid window to record various echocardiographic parameters usually recorded on the apical view for hemodynamic assessment.In accordance with French legislation, the local institutional review board  approved the study protocol, and all patients or their relatives gave their informed consent. This single-center prospective study was performed in an eight-bed teaching hospital medical ICU . Over a 4-month period, all patients admitted to the ICU were included in the study, except when one of the two experienced echocardiographers (JM and AS) was absent and except for patients admitted to the unit for less than 24 hours. Patient characteristics were recorded.Transthoracic echocardiography was performed during the first 2 days after admission in all patients by one of the two operators (JM or AS) by using a Vivid i  equipped with a 3-MHz probe. Parasternal (long and short axis), apical four-chamber, and subxiphoid four-chamber views were obtained successively in 2D mode, and a cine-loop was stored for offline analysis. In the apical and subxiphoid windows, pulsed Doppler mitral inflow was recorded with the sample cursor placed at the mitral valve tips; early diastolic velocity (Ea) was determined from Doppler tissue imaging with the sample cursor placed in the lateral mitral annulus, and aortic blood flow was measured with the sample volume placed at the aortic annulus. The size of the sample volume was not modified between apical and subxiphoid views.The two operators then blindly reviewed the quality of the 2D images recorded with these windows offline on a computer , according to the following scoring system: Excellent ; Good ; Acceptable ; Poor ; and No image . An adequate acoustic window was defined by an acceptable, good, or excellent score. Each physician separately scored the video recording of the three windows  and compared their results. When both scores were identical, the final score was accepted. When the two scores were different, the physicians jointly visualized the video, discussed their points of view, and reached a consensus to establish a final score.In the subpopulation of patients with adequate apical and subxiphoid windows , LVEF (according to the Monoplane Simpson method) and RVEDA/LVEDA ratio were measured on both the apical and subxiphoid 2D cine-loops. The mitral peak E velocity (E), peak A velocity (A), E/A ratio, Ao VTI, and E/Ea ratio were measured on Doppler images in the apical and subxiphoid windows. All data were the average of three end-expiratory measurements (excluding outliers). In the presence of an outlier, an additional assessment was recorded. In the subxiphoid window, LVEF and RVEDA/LVEDA were recorded on a longitudinal four-chamber view visualizing both right and left ventricles in their largest dimensions. On a modified four-chamber view, the operator tried to obtain the best alignment between flow and the Doppler axis by obtaining the highest maximum Doppler velocity to record mitral and aortic flows on the subxiphoid view.t test, and proportions were compared with a χ2 test.All variables are expressed as mean ± 1 SD or proportions. The normal distribution was tested with a Kolmogorov-Smirnov test. Quantitative variables were compared by using a Student n = 65). The bias and limit of agreement (LOA) around the bias were given by the Bland-Altman representation. However, no consensus has been reached concerning the acceptable LOA to confirm validation of the subcostal view. To define an acceptable LOA, Cecconi et al. [Pearson correlation coefficient and Bland-Altman analysis were used to assess the adequacy of the various parameters obtained in the subxiphoid and apical windows. This analysis was performed in the subpopulation of patients in whom apical and subxiphoid windows were scored as excellent, good, or acceptable  in both the apical and subxiphoid windows. All intraobserver variabilities were <5%, and interobserver variabilities were <9%.Statistical analysis was performed by using MedCalc version 12.0.4.0 . The limit of significance was set at ≤ 0.05.Patient characteristics are presented in Table P = 0.9 with or without mechanical ventilation, respectively), the mode of ventilation , the level of PEEP , or a history of COPD .The mean number of adequate acoustic windows per patient was 2.2 ± 0.9. An adequate parasternal view was obtained in 69% of patients; an adequate apical view was obtained in 86% of patients; and an adequate subxiphoid view was obtained in 66% of patients. The proportion of adequate views was significantly higher for the apical window than for the subxiphoid window for the overall population and the subpopulation of mechanically ventilated patients and was close to significant in COPD patients (Table P = 0.001). When considered separately, each parameter was recorded significantly more frequently on the apical view than on the subxiphoid view  was obtained on the apical view than on the subxiphoid view . The various parameters obtained on each of these two views were compared in this group of 65 patients .a priori defined criteria.A strong correlation was observed between apical and subxiphoid values for all parameters Figure . The BlaSemiquantitative evaluation of the diagnostic accuracy of the subxiphoid view was determined for the three parameters selected  by identifying several previously published criteria obtained on the apical view Figure .In this study, the apical view was the view most frequently obtained (86%), and only a small proportion (5%) of patients did not have an adequate apical view, but had an adequate subxiphoid view. These results emphasize the good feasibility of the apical view in TTE, even in ventilated or COPD patients. This study also shows that the subxiphoid view is a reliable view to study the right- and left-ventricular morphology and function on two-dimensional echocardiography, but not in Doppler mode. The subxiphoid view should be used to explore only the vena cava, pericardium, and the morphology of the left or right ventricles.The useful window most frequently obtained in our population was the apical window (86%), followed by the parasternal window (66%), and finally the subxiphoid window (49%), as already reported -13. OnlyThe proportion of mechanically ventilated patients in our population was 45%, which is lower than the proportion usually reported in ICU . HoweverThe subxiphoid view is an essential element of echocardiography in an ICU, particularly to analyze the inferior vena cava  and pericardium . According to our results, only parameters recorded in two-dimensional mode (LVEF and RVEDA/LVEDA) can be recorded on the subxiphoid window without any bias. The bias of E/A was almost nil, but this ratio alone does not constitute a reliable parameter to analyze LV filling pressure in this setting of critically ill patients . The faiFigure The discrepancy between apical and subxiphoid values for E, A, E/Ea, and Ao VTI can be explained by the angle between the Doppler axis and blood flow or myocardial movement in the various acoustic windows. With the Doppler mode, red blood cell velocity  depends on the cosine of the angle between the axis of the Doppler beam and blood flow : the smaller the angle, the higher the velocity . On the An adequate apical view could not be obtained in the present study in fewer than 15% of cases, whereas use of the subxiphoid view was incomplete, as Doppler analysis appears to be unreliable. Therefore, in the unusual situation of absence of an apical window, the use of another monitoring device should be considered .This study presents several limitations. The lower velocities obtained on the subxiphoid view are due to the poor alignment between the Doppler axis and blood flow. Some echocardiography devices apply a correction of this angle by aligning the Doppler beam with blood flow, but this angle correction was not tested in this study. However, accurate determination of the appropriate angle correction for velocity is difficult, essentially because this angle can be measured only in a two-dimensional plane, which therefore disregards the angle in the third dimension of the heart. Moreover, angle correction would not be sufficient to correct the velocity of Ea, as the observed decrease is not exclusively due to poor alignment, but also because this view measures a different relaxation property of the myocardium: radial instead of longitudinal. Not all hemodynamic parameters were evaluated by TTE in this study. Right ventricular function was not extensively analyzed, apart from RVEDA/LVEDA (an important parameter of biventricular interaction). However, the misalignment observed in Doppler mode would also be expected to affect measurement of the tricuspid proto-systolic S-wave velocity on tissue Doppler, tricuspid annular plane systolic excursion in M mode (TAPSE), or pulmonary artery pressure. We also did not study the variation of aortic blood flow during passive leg raising or mechanical ventilation to predict fluid responsiveness, as this would have required a strictly selected population . AlthougEchocardiography comprises a combination of various acoustic windows. The subxiphoid view is already established as an essential part of echocardiography in the ICU to explore the inferior vena cava and pericardium. The results of this study also emphasize that the subxiphoid view cannot replace the apical view to perform complete hemodynamic assessment. In the absence of an apical view, the subxiphoid view can provide only partial information based on analysis of two-dimensional images. To obtain a complete hemodynamic examination, echocardiographers should therefore record both apical and subxiphoid views or use another monitoring device, such as transesophageal echocardiography.• The apical view appears to be more accurate and more feasible than the subxiphoid window, even in mechanically ventilated or COPD patients.• The E/Ea ratio and Ao VTI appear to be significantly underestimated on the subxiphoid view and therefore should not be recorded.• In addition to its ability to explore the vena cava and pericardium, the subxiphoid view can provide information based on morphologic analysis of the ventricles in two-dimensional mode.Ao VTI: velocity time integral of aortic blood flow; BMI: body mass index; CE: coefficient of error; COPD: chronic obstructive pulmonary disease; CV: coefficient of variation; E/A: ratio between early and late mitral inflow on pulsed Doppler; E/Ea: ratio between early mitral inflow and displacement of the mitral annulus on tissue Doppler imaging; HR: heart rate; ICU: intensive care unit; LOA: limit of agreement; LVEDA: left ventricular end-diastolic area; LVEF: left ventricular ejection fraction; MAP: mean arterial pressure; PEEP: positive end-expiratory pressure; PSV: pressure support ventilation; RVEDA: right ventricular end-diastolic area; SAPS2: simplified acute physiologic score 2; TTE: transthoracic echocardiography; VC: volume controlled.The authors declare that they have no competing interests.JM and AS contributed to the acquisition and analysis of data and drafting the manuscriptJM and MS contributed to the conception and design of the study. CT, ZM, GC, and MS were involved in interpretation of data, critically revising the manuscript, and giving final approval. All authors read and approved the final manuscript.


Early stage chronic kidney disease (CKD) is an under recognised, highly prevalent cardiovascular (CV) risk factor. Despite a clustering of conventional atherosclerotic risk factors, there is a disproportionate rate of sudden cardiac death, heart failure and stroke rather than myocardial infarction. It is hypothesised that non-atherosclerotic processes, including left ventricular (LV) hypertrophy and fibrosis account for most of the excess CV risk.In total, 30 patients (mean age 57 +/- 8 years) with CKD stage 2-4 (mean GFR 58 ± 22 ml/min/1.73 m2) with no history of cardiovascular disease (mean BP 129 mmHg ± 13/70 mmHg ± 11) or diabetes were compared with age and gender matched controls. All subjects underwent cardiac MRI (1.5T Siemens Avanto) for assessment of LV volumes, myocardial deformation (SPAMM tagging) and aortic distensibility. Late gadolinium enhancement (LE) and T1-mapping using a modified look-locker inversion recovery sequence (MOLLI) before and 15 minutes post gadolinium (0.1 mmol/Kg) for myocardial extracellular volume (ECV) were performed. Global ECV was the average measure from basal and mid short axis slices excluding LGE indicative of infarcted myocardium.Global ECV was increased in CKD  with associated reductions in long axis systolic deformation , early relaxation  and MAPSE . Aortic distensibility was reduced in CKD (Table Diffuse LV fibrosis is increased in early CKD with associated reductions in aortic distensibility and abnormal regional systolic and diastolic function. An increase in ECV detected by T1 mapping might be a key intermediate phenotype and follow-up studies are required to determine if it is predictive of impaired LV systolic function, heart failure events and mortality in CKD.Nil.


Intravitreal injections (IVI) have become a part of daily practice for a growing number of procedures. We evaluated the retinal function by recording intraoperative photopic electroretinograms (ERGs) before an injection (T1), just after the injection (T2), and after the aspiration of the anterior chamber fluid (T3) of 19 eyes of 19 patients  who received an IVI of an anti-vascular endothelial growth factor. The mean amplitudes of the b-wave, photopic negative responses (PhNR), and oscillatory potentials (OPs) 1 and 2 at T2 were significantly smaller than that at T1, but no significant difference was observed between T3 and T1. The mean implicit times of the a-wave and OP1, 2, and 3 at T2 and the a-wave and the OP2 at T3 were significantly longer than that at T1. The mean intraocular pressure (IOP) at T2 (49.32 mm Hg) was significantly higher and the IOP at T3 (8.74 mm Hg) was significantly lower than that at T1 (21.05 mm Hg). The retinal function was reduced and the IOP elevated just after the IVI. The response of each ERG component was different suggesting a different sensitivity of each type of retinal neuron to IVI. An intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents has become a common procedure for several types of retinal diseases, e.g., exudative age-related macular degeneration (AMD), macular edema associated with retinal vein occlusion (RVO), diabetic retinopathy, and other retinal diseases associated with vascular abnormalities1234567910The adverse effects of intravitreal injections include endophthalmitis, cataract progression, vitreous hemorrhage, and retinal tears1212141517Miyake and colleagues1920Thus, the purpose of this study was to determine whether the retinal function is altered during and after an intravitreal injection of anti-VEGF drugs. In addition, the effect of the intravitreal injection on the IOP was determined. To accomplish this, we recorded photopic ERGs and measured the IOPs before and just after the intravitreal injection. In addition, ERGs were recorded after the IOP was lowered by anterior chamber (AC) paracentesis2223The participants were scheduled to undergo an intravitreal injection of an anti-VEGF antibody for different reasons at the Teikyo University Hospital in Tokyo, Japan in 2015. All of the patients gave an informed consent for the operation with intraoperative ERG recordings and IOP measurements. Patients with severe high myopia  and/or glaucoma were excluded to minimize the effect of more vulnerable retinas.We studied 11 eyes of 11 men and 8 eyes of 8 women. The average age of the patients was 70.6 ± 13.7 years (±SD) with a range from 35 to 87 years. The vitreoretinal pathologies were; 8 with exudative AMD, 3 with macular edema due to branch RVO, 2 with central RVO, and 7 with diabetic macular edema (DME). The number of previous IVI received by the patients varied from 0 to 16 with a mean of 3.7 ± 1.0, mean ± SD). Eight eyes received ranibizumab and 11 eyes received aflibercept.This study was conducted according to the guidelines of the Declaration of Helsinki, and all of the procedures were approved by the Ethics Committee of the Teikyo University School of Medicine. An informed consent was obtained from all subjects.The procedures were performed in accordance with the approved guidelines. All of the intravitreal injections were performed under topical anesthesia by 4% lidocaine. Patients were prepped and draped in the usual sterile fashion, and after sterilization of the ocular surface with povidone iodine, either ranibizumab (0.5 mg/0.05 ml) or aflibercept (2.0 mg/0.05 ml) was injected into the vitreous cavity through the pars plana using a 30-gauge needle. After the injection, a paracentesis was performed to normalize the IOP. The room temperature was set at 25.0 degree centigrade throughout the operation.et al. . ERGs were recorded before the injection (T1), just after the injection (T2), and after the aspiration of the anterior chamber fluid (T3). The IOP was recorded just before each ERG recording with the Tono-pen AVIA .Intraoperative ERGs (iERGs) were recorded using a contact lens with a built-in light-emitting diode  according to the method reported by Miyake 2. The luminance of the constant background was 25.1 cd/m2.A contact lens with a built-in light-emitting diode  was sterilized and used as both the stimulus source and the recording electrode for the photopic iERGs. The reference electrode was a silver plate placed on the forehead and the ground electrode was attached to one ear lobe. The photopic ERGs were elicited by 2-Hz rectangular stimuli of 3-ms duration and a luminance of 1000 cd/mThe iERGs were amplified, A/D converted, and averaged with a bioamplifier . Twenty responses were averaged at a sampling rate of 10 kHz. The responses were filtered with a hardwired band pass filter between 2 Hz to 1 kHz to record the a- and b -waves and between 100 Hz to 500 Hz to record the oscillatory potentials (OPs). The analysis time was 300 ms. All ERG recordings were performed after 5 minutes of light-adaptation to the room light.The amplitudes and implicit times of the a- and b-waves, photopic negative responses (PhNRs) following the b-wave, and OPs were analyzed. Briefly, the implicit times of the a-, and b-waves, the PhNR, and the OPs were measured from stimulus onset to the peak of each wave . The ampTo examine the reproducibility of the ERG recordings, two recordings were recorded and evaluated. The intraclass correlation coefficients  was used to test for the significance of the procedural effects, and the null hypothesis was that there were no effects of the procedures. Post hoc tests were performed at the three time points. Paired The procedures used conformed to the tenets of the Declaration of Helsinki. The study was a observational case series with approval of the Ethics Committee of the Teikyo University School of Medicine (Study ID Number: 10-033-2) and informed consent was obtained from all participants to participate in research.The intraobserver reproducibility of the ERG measurements was excellent. The ICC Representative ERGs are shown in (P < 0.001 for both amplitude and implicit time). Scheffe’s F tests showed that the amplitude was significantly different between T1 and T2 (P = 0.004) and T2 and T3 (P = 0.024), and the implicit time was significantly different between T1 and T2 (P = 0.003).Two-way ANOVA showed that the ERG parameters were not consistent at the three time points P < 0.006, P > 0.006, P < 0.006, P > 0.006, The mean amplitude of the b-wave at T2 was significantly smaller than that at T1 . The IOP recovered to 8.74 ± 6.81 mmHg at T3, which was significantly lower than that at T1 and T2  at T1 and T2, i.e., T2 minus T1, of each component and the differences of the IOPs at T1 and T2, i.e., T2 minus T1 (ΔIOP), were not significant , for each component, and the differences in the IOPs at T1 and T2, i.e., T2 minus T1 (ΔIOP) were not significant  did not significantly increase the ERG amplitude but decreased the implicit time. The explanation may be that the T3 measurement values were between the T1 and T2 values, i.e., a partial return to normal. The partial recovery resulted in T3 values that were not different statistically from either of the other two measures.Thus, the changes in the iERGs are likely related to the IOP increase, but other confounding factors might also be involved, e.g., temperature changes in the vitreous cavity, the effects of the contents of the injected drugs, and condition of the optic nerve. In terms of the intravitreal temperature, a slightly decrease in the temperature probably occurred after the injection. However, measurements of the intraocular temperature with an intravitreal probe would be invasive and was not done. Because the amount of the anti-VEGF agent injected was relative small compared to the volume of the vitreous cavity, the change in the intraocular temperature was small, and its influence on the ERG responses was most likely limited.in situ keratomileusis26272829303132Several investigators have reported that the IOP can increase to 40 to 100 mmHg during different types of eye surgery, e.g., vitrectomy, scleral indentation, phacoemulsification, femtosecond laser-assisted cataract surgery, and laser et al.2) under dark-adapted conditions in feline eyes. They reported that the choroidal PO2 and b-wave amplitudes were decreased with increases in the IOP. Tazawa et al.et al.The depression of the retinal function in conjunction with the IOP elevation was most likely due to an impairment of ocular circulation. Yancey et al.Animal experiments4142et al. reported that prior intravitreal anti-VEGF injections may be a risk factor for cataract surgery-related intraoperative complications and endophthalmitisAlthough these changes may be transient and generally do not cause severe and permanent adverse changes, we should remember that the number of intravitreal injections is rapidly increasing, and it may be performed repeatedly on the same eye. Intravitreal injection-associated visual depression has been reported45Interestingly, the changes were different for the different components of the iERGs. The differences in the degree of alterations of each ERG component suggests different sensitivities of each type of retinal neuron. Some ERG components may respond differently depending on the disease process. For example, the OPs are attenuated in the early stage of diabetic retinopathy495253The changes in the ERGs and IOPs were not significantly correlated although there was a tendency that the higher IOP elevations were associated with a greater decrease in some of the components when the T1 and T2 times were compared. These findings should be interpreted cautiously because IOPs over 55 mmHg and under 5 mmHg could not be measured. In addition, the ERG recordings and IOP measurements were not made simultaneously. Therefore, the IOP might be changed during the ERG recordings. The lack of the significant correlation between the ERG and IOP may be attributed to these factors.et al.Interestingly, the implicit time of the OP2 was more prolonged with a decrease in the IOP from T1 to T3. In addition, there was a similar tendency for the a-waves, the PhNRs, the OP1s, and the OP3s. These findings contradict the observations by Niyadurupola Our study has several limitations. One is that the retinal pathology of the patients was different. A second limitation is that the tolerance of the retinal function in specific retinal disease against the IOP changes is not well understood. A larger number of patients would enable subgroup analysis with each vitreoretinal disease and then ERG changes during intravitreal injections for specific vitreoretinal diseases can be determined. In addition, the IOP values had a limited range. Taking these limitations into consideration, we still believe that the current data are clinically important.In conclusion, the results show that the retinal function is reduced and the IOP is elevated just after the intravitreal injection of anti-VEGF drugs. The response of each ERG component to the injections varied suggesting different sensitivities of each type of retinal neuron to the rise in the IOP.How to cite this article: Yagura, K. et al. Electroretinographic evaluations of retinal function before, just after, and after intravitreal injections. Sci. Rep.6, 31104; doi: 10.1038/srep31104 (2016).


T2 mapping has been shown to detect myocardial oedema as assessed by histology in animals, and is a promising sequence to detect the area at risk in STEMI. The specific cut off value to identify abnormal myocardium in STEMI has not been identified nor have the effects of infarct characteristics on T2 valves. The extra cellular volume fraction (ECV) has been validated against histology in humans. The aims of this study were to identify a cut-off T2 for prediction of myocardial oedema following acute reperfused myocardial infarction and determine if infarct characteristics affect T2 values. In addition, this study aims to determine if T2 values are associated with the ECV following STEMI.50 consecutive patients presenting with STEMI to the Bristol Heart Institute Primary PCI service were approached for inclusion in the study. Patients had a CMR scan day 2 following STEMI. T2 values were assessed by T2 mapping. The myocardium was divided according to the AHA segments. Regional wall motion, LGE transmurality, presence of persistent microvascular obstruction (PMVO) and T2 values were assessed per segment. Segments were deemed affected if they did not have normal wall motion. In addition, a further 30 patients had a CMR day 2 following STEMI. Pre-contrast T1, T2 valves were assessed. Post contrast T1 was measured at 25 minutes following contrast administration. ECV was calculated as: Myocardial ECV = (1−hematocrit) × (ΔR1myocardium/Δ R1blood), where R1=1/T1. All patients gave written informed consent. The study was approved by the local ethics committee.2=617, p< 0.001). There was a significant association between T2 values and ECV measured at 25 minutes following contrast administration , with a sensitivity of 0.79 and a 1-specificity of 0.33 Figure . T2 valu1)Figure .Figure 1The optimal cut off value to determine affected myocardium following acute myocardial infarction is 55ms. However, this must be taken in context with the knowledge that infarct characteristics can affect T2 values. There is a significant association between both native T1 and T2 values with a significant association between T2 values and ECV.This study was funded by the National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol.