To evaluate the utility of oxygen challenge and report on temporal changes in blood oxygenation level‐dependent (BOLD) contrast in normal liver, hepatocellular carcinoma (HCC) and background fibrosis.t‐tests were performed to determine if the mean pre‐ and post‐O2 differences were statistically significant.Eleven volunteers  and 10 patients  with hepatocellular carcinoma on a background of diffuse liver disease were recruited. Imaging was performed on a 3T system using a multiphase, multiecho, fast gradient echo sequence. Oxygen was administered via a Hudson mask after 2 minutes of free‐breathing. Paired n = 8) the change in T2* following O2 administration was elevated  and the difference was significant (P = 0.004). The magnitude of the BOLD response in patients with HCC (n = 10) was larger, however the response was more variable , and the difference was borderline significant (P = 0.046). The BOLD response in the volunteer cohort was not significant .In patients with liver fibrosis (This work demonstrates that the BOLD response following oxygen challenge within cirrhotic liver is consistent with a breakdown in vascular autoregulatory mechanisms. Similarly, the elevated BOLD response within HCC is consistent with the abnormal capillary vasculature within tumors and the arterialization of the blood supply. Our results suggest that oxygen challenge may prove a viable BOLD contrast mechanism in the liver. J. Magn. Reson. Imaging 2016;44:739–744. Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer‐related death worldwide.2 and 5% CO2)Several studies have investigated the utility of blood oxygenation level‐dependent (BOLD) contrast changes in measuring oxygen perturbation within tumors. In 1997 Griffiths et al demonstrated that hyperoxic and hypercapnic gas mixtures can change the deoxyhemoglobin fraction of blood and act as a viable endogenous contrast mechanism in a variety of tumor etiologies.R2* (r = –0.773) and area of liver activation (r = –0.691) were inversely correlated with quantitative histopathological assessment of the percentage liver fibrosis (P < 0.001). This result warrants further investigation into BOLD contrast as a marker of hepatic fibrosis.HCC is often present on a background of diffuse liver disease; however, only one study to date has explicitly investigated BOLD response as a function of liver fibrosis. Jin et al used steady‐state and dynamic carbogen challenges with different diethylnitrosamine‐induced liver fibrosis stages to depict hemodynamic alterations during disease progression in a rat model.T2* in healthy volunteers and compares this to patients with HCC and background diffuse liver disease.The purpose of this study was to investigate the utility of oxygen challenge at inducing a BOLD response in the liver. This study reports the observed temporal changes in n = 7) or using imaging criteria (n = 3). The underlying etiologies were established following multidisciplinary review of biopsy, blood, and imaging data. All participants fasted for a minimum of 8 hours prior to the examination and had not undergone any tumor treatment.This prospective single‐center study was conducted following local Research Ethics committee approval. All participants gave informed written consent. Eleven healthy volunteers  with no history of hepatobiliary or cardiovascular disease and 10 patients  with a recent diagnosis of HCC were recruited. Four patients were diagnosed with HCC after biopsy and the remaining six were diagnosed using imaging following the EASL criteria (European Association for Study of Liver).All the examinations were performed on a 3T whole‐body magnetic resonance imaging (MRI) system . Participants were imaged feet first, supine, using an 8‐channel cardiac receive coil. A multiecho fast gradient echo sequence was prescribed in a sagittal plane centered on the tumor. The sequence acquired five slices each with 10 separate echoes, with the following parameters: echo times (TEs) = 2.3/6.9/11.5–43.7 msec; repetition time (TR) = 46 msec; flip angle = 15°; matrix size = 192 × 96; ASSET factor = 2; field of view (FOV) = 35 cm; slice thickness = 8 mm. The BOLD sequence was modified to enable multiecho, multiphase operation with respiratory triggering using abdominal bellows. Each slice was acquired in 2.3 seconds. The BOLD protocol consisted of a 10‐minute free‐breathing respiratory‐triggered acquisition. Medical‐grade oxygen  was administered via a Hudson mask at 10 L/min after 2 minutes of free‐breathing room air  to compute voxel‐wise www.itk.org).To account for residual differences in diaphragm position in the respiratory‐triggered acquisition, an affine transform was applied to register each temporal phase. A rectangular mask was used so that the rigid registration algorithm was optimal over the area of interest. The image registration was performed by developing bespoke software in C++ that utilized the Insight Toolkit (Regions of interest (ROIs) were defined on the spatially registered maps using in‐house software developed in MatLab. ROIs were defined to encompass background liver while excluding major blood vessels and to delineate the hepatocellular carcinoma. ROIs were defined by a radiologist (D.J.B.) with 4 years experience after comparing comatched contrast enhanced images. The radiologist also recorded the maximum diameter of each tumor.T2* pre‐O2 was computed by averaging the temporal phases prior to O2 administration. Similarly, the mean T2* post‐O2 was computed by averaging the temporal phases during O2 breathing, acquired after a 3‐minute delay to allow the BOLD effect to equilibrate. Normality assumptions were formally assessed using a Shapiro–Wilk's test. Paired t‐tests were subsequently performed to establish whether the differences between pre‐ and post‐O2T2* values were significant. Student's t‐tests were also used to compare native (pre‐O2) T2* in tumors against diffuse liver disease and healthy liver. P < 0.05 was defined as statistically significant. The statistical analysis was performed using the R programming language .Mean n = 4), alcohol‐related cirrhosis (n = 1), cirrhosis following alpha‐1 antitrypsin deficiency (n = 1), hepatitis B (n = 1), and hepatitis C (n = 1); one patient developed a spontaneous HCC and in one patient the etiology is unknown. The mean of the maximum tumor diameters was 4.4 cm (range 1.8–7.5 cm).Etiologies for the patient cohort included nonalcoholic steatohepatitis  was consistently elevated 0.88 ± 0.582 msec, range (0.03–1.69 msec), and the difference in T2* following O2 was statistically significant (P = 0.004). The response in tumor tissue (n = 10) was larger but also more variable 1.07 ± 1.458 msec (range –0.93–3.26 msec); the difference was borderline statistically significant (P = 0.046). The change in T2* was also positive following O2 administration in healthy volunteers ; however, the change was not significant (P = 0.121).The change in T2* of tumor pre‐O2 (23.7 ± 7.52 msec) was elevated with respect to the patients' background liver (15.2 ± 5.84 msec), P = 0.01, and with respect to the volunteer liver (17.1 ± 3.71 msec), P = 0.025  have been found in healthy liver in response to carbogen breathing,Physiological response to carbogen differs from response to 100% oxygen, as COT2* response seen in diseased liver tissue. This is consistent with a breakdown in autoregulatory function, and is similar to the reduced hemodynamic response to carbogen challenge observed by Jin et al in their rat model of fibrosis.With the evolution of hepatic fibrosis, progressive disruption of normal liver architecture is seen, which gives rise to regional and global changes in perfusion.T2* or change in T2* (ΔT2*) in response to a hyperoxic stimulus has been proposed as an intrinsic marker of tumor oxygenation,T2* is proportional to the concentration of deoxyhemoglobin, which in turn relates to arterial blood pO2. In this study we observed a larger but more variable response to oxygen challenge in HCC, which may be expected given variations in oxygenation and perfusion, even within the same tumor type. The initial pathogenesis of HCC involves an increased arterial supply; however, in late‐stage HCC the arterial blood supply may decrease.Measuring native T2* (pre‐O2) was elevated with respect to both the patients' background liver and with respect to the volunteer liver. This supports observations that elevated baseline T2* can discriminate between highly vascularized and avascular tumor types.We also observed that native tumor T2* within HCC. In some cases, proximity of the tumor to the lung could cause dephasing in the acquired images near the air–tissue boundary, the very effect we were trying to measure. In this study two of the HCC patients had tumors juxtapositional to lung. In this study we chose to include these cases to evaluate the mean effect of HCC in patients, given our sample size constraints.There were pragmatic issues noted when measuring Liver biopsy is the reference standard for diagnosis and staging chronic liver disease, but it is an invasive procedure with potential complications, and reproducibility is poor due to the heterogeneity of fibrosis, small sample size, and inter‐ and intraobserver variability in histologic assessment.T2* measurements, rather than simply measuring relative changes in T2*‐weighted signal intensity, which can be sensitive to blood flow via signal intensity enhancement from unsaturated spins flowing into the imaging plane. We also demonstrated that measuring hepatic T2* is feasible at 3T using a respiratory‐triggered, free‐breathing protocol, which enables dynamic measurements over time. Measuring the BOLD effect at 3T should be more sensitive than 1.5T to small perturbations in oxygenation, given the greater change in T2* for a proportional change in the deoxyhemoglobin fraction.BOLD, however, has the advantage that it is noninvasive and is based on an endogenous contrast mechanism. Breathing oxygen was well tolerated by all subjects. In this study we performed quantitative T2* maps pre‐O2; this would allow quantification of contrast repeatability and normal physiological variation. Future studies should also consider applying novel approaches that utilize the BOLD phenomena to assess vasomotor response.Limitations of this study include sample size constraints. Greater significance could have been achieved with a larger cohort; nevertheless, this exploratory study demonstrates the feasibility of oxygen challenge for evaluating healthy and diseased liver tissue and HCC. Lack of an age match control group may lead to some bias in the results, as volunteers were systematically younger than the patient cohort. Future studies should consider acquiring more baseline T2* observed within diffuse liver disease in response to hyperoxia is consistent with a breakdown in vascular autoregulatory mechanisms and an increased arterial fraction of flow. Similarly, the elevated BOLD response within HCC is consistent with the abnormal arterialized vasculature in tumors. Further studies are needed to evaluate the benefit of measuring BOLD response in HCC, particularly with respect to its potential role as a biomarker of outcome and treatment response.In conclusion, the BOLD response to oxygen challenge is a promising method for noninvasive diagnosis and staging of chronic liver disease. The increase in


Heart failure (HF) is a significant source of morbidity and mortality among African Americans. Ambient air pollution, including from traffic, is associated with HF, but the mechanisms remain unknown. The objectives of this study were to estimate the cross-sectional associations between residential distance to major roadways with markers of cardiac structure: left ventricular (LV) mass index, LV end-diastolic diameter, LV end-systolic diameter, and LV hypertrophy among African Americans.We studied baseline participants of the Jackson Heart Study (recruited 2000–2004), a prospective cohort of cardiovascular disease (CVD) among African Americans living in Jackson, Mississippi, USA. All cardiac measures were assessed from echocardiograms. We assessed the associations between residential distance to roads and cardiac structure indicators using multivariable linear regression or multivariable logistic regression, adjusting for potential confounders.Among 4826 participants, residential distance to road was <150 m for 103 participants, 150–299 m for 158, 300–999 for 1156, and ≥1000 m for 3409. Those who lived <150 m from a major road had mean 1.2 mm  greater LV diameter at end-systole compared to those who lived ≥1000 m. We did not observe statistically significant associations between distance to roads and LV mass index, LV end-diastolic diameter, or LV hypertrophy. Results did not materially change after additional adjustment for hypertension and diabetes or exclusion of those with CVD at baseline; results strengthened when modeling distance to A1 roads (such as interstate highways) as the exposure of interest.We found that residential distance to roads may be associated with LV end-systolic diameter, a marker of systolic dysfunction, in this cohort of African Americans, suggesting a potential mechanism by which exposure to traffic pollution increases the risk of HF.The online version of this article (doi:10.1186/s12940-017-0226-4) contains supplementary material, which is available to authorized users. Althougsed risk , 5 and msed risk .2.5 [2 greater LVMI compared to those who resided >150 m from a major roadway [2 or PM10 with LVMI [Air pollution from traffic is a major contributor to ambient air pollution and to cardiovascular morbidity and mortality in urban areas . Residen2.5 . A study roadway . Howeverith LVMI .African Americans are at an increased risk of HF incidence and mortality compared to white Americans , 20–22. Between 2000 and 2004, JHS recruited a total of 5301 non-institutionalized African American men and women aged 21 years and older, residing in the tri-county Jackson, Mississippi, USA Metropolitan Statistical Area (MSA), as previously described , 25. TheWe calculated residential distance to the nearest major roadway as a marker of long-term exposure to traffic-related pollution for each participant. We used ArcGIS  to geocode participants’ addresses and calculate the straight-line distance from each residence to the nearest major roadway, defined as roads with U.S. Census Feature Class Code A1 (primary highway with limited access—only accessible via ramps) or A2 (primary road without limited access), as previously described –29. Topo2.7 to account for body size [2.7, a threshold previously validated in the Jackson subcohort of the Atherosclerosis Risk in the Communities (ARIC) study [In this study, we considered the following indicators of cardiac structure as outcomes: left ventricular mass index (LVMI), LV hypertrophy, LV end-diastolic diameter, and LV end-systolic diameter. LVMI is a continuous measure of cardiac remodeling, LV hypertrophy is a cutpoint at which LVMI is pathologic, LV end-diastolic and end-systolic diameter are indicators of systolic function. These indicators are all commonly measured during electrocardiograms and are used as preclinical markers of heart disease. Long-term exposure to traffic pollution, over years, may lead to noticeable changes in these indicators. During the baseline clinic visit, JHS participants underwent prioritized 30-min two-dimensional and M-mode echocardiography with parasternal, apical, and subcostal windows . Echocarody size –35. LV hAt baseline, participants were given an in-person interview, detailing demographics, health history, lifestyle factors, and healthcare access. Shortly thereafter, participants were given a clinical exam. Details of the baseline interview and exam are described elsewhere . During www.census.gov): percent of adults >25 years with less than high school education, percent of males who were unemployed, percent of households with income below the poverty line, percent of households receiving public assistance, percent of households with children headed by a woman, and median household income, as described in Dubowitz et al [We examined the variables described below as potential covariates. Age and sex were based on self-report. Body mass index (BMI) was calculated from measured weight (kilograms) divided by measured height (meters) squared. Education was categorized as the highest level of education completed. Type of medical insurance was categorized as none, private only, public only, and both public and private. Occupation was categorized based on Sims et al  and the tz et al . NSES watz et al . Smokingtz et al , 41. Partz et al , 43. Partz et al . MedicatOur analytic sample excluded participants who were missing all LV measurements from echocardiograms, as well as those with aortic or mitral stenosis or regurgitation, as these conditions may affect LV measurements . We inclWe examined residential distance to A1 or A2 roads in categories of <150 m, 150–299 m, 300–999 m, and ≥1000 m and as a continuous variable with natural log transformation. We chose cutpoints of 150 m and 300 m because ultrafine particulate matter concentration from highway traffic pollution has been shown to decrease by 50% at 150 m from roads and fade into background levels after 300 m . We alsoWe examined the associations between residential distance to A1 or A2 roads and continuous indicators of cardiac structure  using multivariable linear regression adjusting for confounders. We examined the associations between residential distance to A1 or A2 roads and LV hypertrophy using multivariable logistic regression adjusting for confounders. We conducted a test for trend for categorical distance to roads.a priori to adjust all models for potential confounding by age, sex, and BMI. We determined additional covariates by conducting bivariate analyses  between the potential covariates and categories of residential proximity to A1 or A2 roads  and indicators of cardiac structure. We adjusted models for those covariates that were associated with residential proximity to A1 or A2 roads and cardiac structure at a p-value of 0.05 and were not collinear with other covariates (variance inflation factor <10). In the case of collinearity, we included the variable with the least missing data. We adjusted models incrementally, first for anthropomentric and health factors , then we added socioeconomic factors  for the fully adjusted models. Although associated with exposure at the p = 0.05 level, we did not adjust for household income status due to a great number of participants (n = 462) with missing values. Post-hoc analyses showed additional adjustment for household income did not substantially change estimates of association. Comorbid conditions, such as hypertension and diabetes, may be confounders or mediators in the relationship between residential distance to major roadway and heart failure. We calculated models with and without additional adjustment for diabetes and hypertension. We additionally considered the possibility that diabetes and hypertension may interact with residential distance to roads to influence cardiac structure; we tested interaction terms for diabetes and hypertension in fully adjusted models.We decided n = 254) participants were missing all LV measurements from echocardiograms, we compared descriptive characteristics of those who were and were not missing these data. Second, we redefined the exposure  as residential distance to A1 (primary highway with limited access) roads as A1 roads are typically busier and have more heavy-duty diesel traffic compared to A2 roads. We classified residential distance to A1 roads as <150 m, 150–299 m, 300–999 m, and ≥1000 m, as well as log-transformed distance as a continuous variable, similar to primary analyses, adjusting for the same covariates as in primary analyses. Third, we considered alternate classifications of residential distance to A1 or A2 roads, including cutpoints of 100 m, 200 m, and 400 m, modeling distance to roads as an un-transformed continuous variable, modeling the inverse of distance to roads, and truncating distance to roads at 400 m, as distances beyond 400 m are unlikely to be affected by traffic-related air pollution. Fourth, we excluded participants with CVD at baseline, defined as a history of myocardial infarction (based on self-report or electrocardiogram), carotid angioplasty (self-report), or stroke . Fifth, we limited our analyses to those participants who resided in urban areas, defined by the 2010 US Census Urban and Rural Classification (www.census.gov). Sixth, we restricted our analyses to those living within 5000 m of roads. All analyses were conducted using SAS version 9.4; results were considered statistically significant at a two-sided p-value of <0.05. We also plotted natural splines with 3° of freedom for the associations between log-transformed distance to A1 or A2 roads and LV end-systolic diameter, LV end-diastolic diameter, and LVMI, adjusting for covariates in the final regression model using R version 3.3.1 .We conducted additional sensitivity analyses. First, since many ; there were no statistically significant differences in LV end-diastolic diameter, or LV end-systolic diameter by residential distance to A1 or A2 roads.The Jackson Heart Study recruited a total of 5301 participants at baseline. We excluded 254 (5%) participants who were missing all LV echocardiographic measurements, 211 (4%) participants whose baseline addresses could not be geocoded, 5 (0.09%) participants with severe aortic stenosis, 5 participants with severe aortic regurgitation, and 4 (0.08%) participants who were missing information on residential distance to A1 and A2 roads, making our final sample size 4826 participants. The distribution of residential distance to A1 and A2 roads is shown in Fig. 2.7 greater LVMI , a nearly two-fold greater odds of LV hypertrophy , and a 1.1 mm larger LV end-systolic diameter  (results not shown). However, the associations between residential distance to roads and LVMI and LV hypertrophy were attenuated and no longer statistically significant after adjustment for covariates. After adjustment for anthropometric and health covariates, point estimates of association did not substantially change with additional adjustment for socioeconomic covariates. In the fully adjusted model, those who lived <150 m from A1 or A2 roads had a statistically significant 1.2 mm  greater LV end-systolic diameter, compared to those ≥1000 m . We observed statistically significant p values for interaction for the associations between distance to A1 or A2 roads and diabetes for LVMI  and LV hypertrophy  and between distance to A1 or A2 roads and hypertension for LVMI . Interaction terms were negative, indicating that those with diabetes and living further from roads have smaller LVMI and lower odds of LV hypertrophy, and those who live further from roads and have hypertension have smaller LVMI.In unadjusted models, we observed the following associations: those who lived <150 m from A1 or A2 roads had 2.5 g/mIn sensitivity analysis, those missing all LV measurements were more likely to have lower education levels (27.1% vs. 19.7% had less than high school education), lower income (21.4% vs. 15.2% were low-income), and more likely to be current smokers (19.1% vs. 12.8%) compared to those not missing all LV measurements. We did not observe any other differences in descriptive characteristics between these two groups.In our sensitivity analyses using residential distance to A1 roads, we observed associations with LV end-diastolic diameter and LV end-systolic diameter. Those living <150 m from A1 roads had a 1.7 mm  larger LV end-diastolic diameter, and 2.0 mm  larger LV end-systolic diameter, compared to those who lived ≥1000 m from A1 roads (Table n = 58) had 0.9 mm  larger LV end-systolic diameter and those who lived 100–199 m from A1 or A2 roads (n = 84) had 1.4 mm  larger LV end-systolic diameter; this association was only statistically significant among those who lived 100-199 m from A1 or A2 roads. Those who lived <100 m from A1 roads (n = 14) had 1.5 mm  larger LV end-systolic diameter and those who lived 100–199 m from A1 roads (n = 37) had 1.9 mm (95% CI 0.4–3.5) larger LV end-systolic diameter; this association was only statistically significant among those who lived 100–199 m from A1 roads  larger LV end-systolic diameter, compared to those residing ≥1000 m from A1 or A2 roads , we did not observe any associations between residential distance to A1 or A2 roads and indicators of cardiac structure (results not shown). When limiting analyses to those who resided within 5000 m of A1 or A2 roads (n = 4578), results were similar to those in the main analysis. Those residing <150 m from A1 or A2 roads had a 1.1 mm  larger LV end-systolic diameter (p = 0.02) compared to those residing ≥1000 m from A1 or A2 roads (results not shown).When limiting analyses to those who resided in urban areas  in order for one’s cardiac structure to be adversely affected by traffic pollution. Likewise, we did not observe associations between continuous measures of distance to road and cardiac structure. Since many individuals lived far from roads, it is possible any associations were diluted when examining distance as a continuous variable.2.5 has been shown to be associated with increases in LV diastolic and systolic diameters in mice [2.5 in mice [Our results show that residential proximity to A1 or A2 roads is associated with LV end-systolic diameter and proximity to A1 roads is associated with LV end-diastolic and end-systolic diameter. When analyzing residential distance to A1 roads as the exposure of interest, associations with LVMI, LV end-diastolic, and LV end-systolic diameter were of a greater magnitude compared to analyzing residential distance to A1 and A2 roads. It is likely that A1 roads are more frequently traveled and have a higher concentration of light and heavy duty compared to A2 roads. The strengthening of our results when examining distance to A1 roads supports our conclusions of an association between distance to major roads and cardiac remodeling. We are unaware of any other epidemiologic studies that examined the association between residential proximity to roads and LV end-diastolic or end-systolic diameter in humans. However, long-term exposure to PM in mice . In addi in mice , 47. Pro in mice , 13–15.  in mice .In our study, we did not observe an association between residential proximity to A1 or A2 roads and LVMI, as Van Hee et al. did in the MESA study . Howevern = 103) resided within 150 m of A1 or A2 roads. This may have substantially reduced our power to observe associations between residential distance to A1 and A2 roads and indicators of cardiac structure. Additionally, it is possible that those living closest to roads share risk factors other than those we adjusted for, leading to residual confounding [This study has several limitations. First, we observed that those missing echocardiographic data have poorer socioeconomic indicators and are more likely to be current smokers. There is potential bias in that those who were not missing data may be in better cardiovascular health. Second,, few people (founding . SpecifiAmong African Americans residing in the Jackson, Mississippi metropolitan area, participants residing <150 m from A1 or A2 roads had a 1.2 mm larger LV end-systolic diameter compared to those residing ≥1000 m. This result indicates that living closer to major roadways may be associated with systolic dysfunction and cardiac remodeling in a high-risk, understudied African American population.


Background: It is not clear whether the latest activation sites in the left ventricle (LV) are matched with infracted regions in patients with ischemic cardiomyopathy (ICM). We aimed to investigate whether the latest activation sites in the LV are in agreement with the region of akinesia in patients with ICM.Methods: Data were analyzed in 106 patients  with ICM (ejection fraction ≤ 35%) who were refractory to pharmacological therapy and were referred to the echocardiography department for an evaluation of the feasibility of cardiac resynchronization therapy. Wall motion abnormalities, time to peak systolic myocardial velocity (Ts) of 6 basal and 6 mid-portion segments of the LV, and 4 frequently used dyssynchrony indices were measured using 2-dimensional echocardiography and tissue Doppler imaging (TDI). To evaluate the influence of the electrocardiographic pattern, we categorized the patients into 2 groups: patients with QRS ≤ 120 ms and those with QRS >120 ms.Results: A total of 1 272 segments were studied. The latest activation sites (with longest Ts) were most frequently located in the mid-anterior  and basal-anterior segments , while the most common sites of akinesia were the mid-anteroseptal  and mid-septal  segments. Generally, no significant concordance was found between the latest activated segments and akinesia either in all the patients or in the QRS groups. Detailed analysis within the segments indicated a good agreement between akinesia and delayed activation in the basal-lateral segment solely in the patients with QRS duration ≤ 120 ms .Conclusion: The akinetic segment on 2-dimensional echocardiogram was not matched with the latest activation sites in the LV determined by TDI in patients with ICM.  Segmental akinesia is a sensitive indicator of transmural infarction,   18  and wall motion evaluation is regularly conducted via conventional echocardiography prior to CRT in patients with heart failure. Thus, in the current study, we sought to investigate whether there is any concordance between akinetic LV segment/s and latest activated site/s in patients with advanced heart failure secondary to ischemia.Cardiac resynchronization therapy (CRT) is a rapidly evolving and promising treatment option in drug-refractory heart failure patients with a depressed LV systolic function.5   19  All the patients underwent complete resting transthoracic echocardiography and TDI for the evaluation of regional wall motion and the extent of LV dyssynchrony as well as determination of the site of the latest mechanical activation. From January 2006 to December 2009, a retrospective review was conducted of the data on 106 patients with advanced heart failure secondary to ischemia who were referred to one of the echocardiography clinics in Tehran Heart Center, Tehran, Iran, for echocardiographic evaluation. All the patients had severe heart failure  and left ventricular ejection fraction (LVEF) ≤ 35%, which was refractory to optimized drug therapy. Patients with a history of recent (< 3 mon) unstable angina or myocardial infarction, valvular heart disease, or previous pacemaker implantation were excluded from the study. Ischemia was diagnosed as the cause of heart failure if the patients had a history of myocardial infarction or revascularization or angiographic evidence of stenosis > 75% of the left main or the proximal left anterior descending artery, or stenosis > 75% of 2 or more epicardial vessels.21 and tricuspid regurgitation was graded 1 as mild, 2 as moderate, and 3 as severe.   22 A combination of transthoracic 2-dimensional echocardiography, M-mode, pulsed, and continuous-wave Doppler with color-flow imaging was performed using a commercially available ultrasonographic system . All the following parameters were measured according to the guidelines of the American Society of Echocardiography   23 The opening and closing times of the aortic and pulmonic valves were also measured using the systolic blood flow by pulsed Doppler, with the sample volume placed at the level of the aortic and pulmonic annulus. Aortic pre-ejection time was measured from the beginning of the QRS complex to the beginning of the aortic flow velocity curve recorded by pulsed-wave Doppler in the apical view. Likewise, pulmonary pre-ejection time was measured from the beginning of the QRS complex to the beginning of the pulmonary flow velocity curve recorded in the left parasternal short-axis view. The difference between the 2 values determined interventricular mechanical delay (IVMD). A cut-off value = 40 ms was considered for interventricular dyssynchrony.24, 252D echocardiography is a safe and simple noninvasive technique to quantify LV regional wall motion. For a semiquantitative analysis of regional wall motion, a 12-segment model was employed that included the septal, anteroseptal, anterior, lateral, inferior, and posterior segments at the basal and mid-levels of the LV, respectively. All these segments were ranked based on the degree of both wall thickening and endocardial motion abnormalities as follows: normal , hypokinetic , akinetic , and aneurismal .   26  With adjustments of the filter frequency, gain settings, pulse repetition frequency, and color saturation, at least 3 consecutive beats were stored and the images were digitally stored for off-line analysis. Twelve segments , similar to those evaluated by 2-dimensional echocardiography, were analyzed. The timing of the systolic events was evaluated by measuring the time to peak systolic myocardial velocity (Ts) in each LV segment utilizing the onset of the QRS complex as the reference point : Differences between the longest and shortest Ts in 12 LV segments (105 ms).   27 Basal segments delay (Ts-bas-delay): Differences between the longest and shortest Ts in 6 LV basal segments (78 ms).   27 All segments standard deviation : SD of Ts of all the 12 LV segments (34.4 ms).Basal segments standard deviation (Ts-bas-SD): SD of Ts of 6 LV basal segments (34.5 ms).   27 Systolic synchronicity was assessed via TDI using the apical views  of the LV as previously described.ce point . The lat   26 According to our previous study, inter- and intraobserver variability for time to peak systolic velocity was 13 ± 11% and 18 ± 20% at our institution, respectively.The data are presented as means ± SDs for the numerical variables. The categorical variables are expressed in terms of absolute frequencies and percentages. The agreement between the regions with longest Ts and the presence of akinesia was computed using the phi (Φ) coefficient in various LV segments. To investigate the effect of the QRS duration on the concordance between the akinetic LV segment/s and the latest activated site/s, we performed additional analysis comparing the patients with QRS duration ≤ 120 ms and QRS duration > 120 ms. Probability values ≤ 0.05 were considered statistically significant. For the statistical analyses, the statistical software SPSS, version 13.0, for Windows  was used. The patients’ demographic data, clinical characteristics, pharmacological medication, and detailed conventional echocardiographic findings are summarized in Wall motion evaluation was technically feasible in 1 263 segments, from which 875 (69.3%) segments scored as normal or hypokinetic, 369 (29.2%) as akinetic, and 19 (1.5%) as aneurismal. The frequencies for the latest activated and akinetic sites within the different LV segments are depicted in The results of the present study demonstrated that the latest LV activation segments were most frequently the mid and basal anterior segments, while the akinetic sites were predominantly located in the mid-septal and mid-anteroseptal segments. Overall, the akinetic segments were not matched with the most delayed activation regions.12, 13 Based on our results, there was no concordance between the akinetic segments and the regions with latest mechanical activation. Thus, these akinetic areas may not appear to be ideal site/s for pacing. In this regard, Arzola-Castaner et al.   28  also reported no significant impact on the CRT outcome following lead positioned in proximity to akinetic segments. It should be noted that akinetic segments cannot be regarded exactly as infracted regions. Akinesia is a sensitive, but not specific, indicator of transmural infarction. While 100% of the pathologically transmural infracted segments are akinetic or dyskinetic, 8% of the akinetic or dyskinetic regions are histologically normal and 29% are subendocardially infracted zones.   18  Therefore, it is not correct to generalize our result to the infracted segments. Future studies using contrast-enhanced magnetic resonance imaging or myocardial contrast echocardiography16, 29 would help investigators to better evaluate the extent of transmural scar, myocardial viability, and association between mechanical activation timing and infracted segments. Previous studies have reported a favorable response following lead positioning in the most delayed LV activated site/s.30, 31 may explain a possible mismatch between the akinetic segments and the latest activated sites in patients with heart failure. Currently, there are several noninvasive imaging techniques such as 3-dimensional noncontact LV endocardial mapping and circumferential and longitudinal strain imaging which could help investigators to have better estimation on LV dyssynchrony patterns in the presence of akinesia by providing the exact characterization of the LV activation sequence.31, 32 The variable forms of LV activation and the heterogeneous pattern of systolic asynchrony in patients with severe heart failure, particularly in those with ischemic cardiomyopathy,Given the significant relationship between the QRS duration and regional Ts, we re-analyzed the data according to the QRS groups. The basal-lateral segments in the patients with a narrow QRS duration constituted the only site in which akinesia and latest activation showed a good agreement. Future studies applying more precise methods are needed to explain or even confirm the finding. 18, 33 because of its low ability to discriminate between the infracted and adjacent zones via an evaluation of wall motion abnormalities. Therefore, it is likely that the determined akinetic areas are not exclusively confined to the infracted zones. Furthermore, lack of any data on CRT long-term results hindered us from further analysis on association between the sites of lead placement and the CRT outcome. In addition, limitations of TDI such as measuring only the vector of motion that is parallel to the direction of the ultrasound beam and measuring absolute tissue velocity which makes it unable to discriminate passive motion (related tethering) from active motion (fiber shortening or lengthening) may affect the results.This study suffers from some limitations. 2D echocardiography appears to tend to overestimate the extent of dyssynergic areasThe akinetic segments on 2D echocardiogram were not matched with the area of maximal delay to peak velocity on TDI in our patients with the ischemic type of heart failure. Further studies are needed to elucidate the association between LV infracted regions and the latest activated sites in patients with the ischemic type of cardiomyopathy.


Cardiovascular magnetic resonance (CMR)-derived extracellular volume (ECV) and tissue tracking strain analyses are proposed as non-invasive methods for quantifying myocardial fibrosis and deformation. This study sought (1) to histologically validate myocardial ECV against the collagen volume fraction (CVF) measured from tissue samples of patients undergoing heart transplantation and (2) to detect the correlations between myocardial systolic strain and the myocardial ECV and histological CVF in patients undergoing heart transplantation.A total of 12 dilated cardiomyopathy (DCM) and 10 ischaemic cardiomyopathy (ICM) patients underwent T1 mapping with the Modified Look Locker Inversion recovery (MOLLI) sequence, T2 mapping and ECV. Myocardial systolic strain, including left ventricular global longitudinal (GLS), circumferential (GCS) and radial strain (GRS), were quantified using CMR cine images with tissue tracking analysis software. Tissue samples were collected from each of 16 segments of the explanted hearts and were stained with picrosirius red for histological CVF quantification.r = 0.904 and r = 0.901, respectively, p <  0.001). In the linear mixed-effects regression analysis, ECV correlated well with the histological CVF in the DCM and ICM patients on a per-segment basis . In the multivariate linear regression analysis, histological CVF was the strongest independent determinant of ECV in the patients awaiting heart transplantation . However, the T2 time, GLS, GCS and GRS showed no significant associations with ECV and CVF in the patients awaiting heart transplantation.A strong relationship was observed between the global myocardial ECV and histological CVF in the DCM and ICM patients based on a per-patient analysis (ECV derived from CMR correlated well with histological CVF, indicating its potential as a non-invasive tool for the quantification of myocardial fibrosis. Additionally, impaired myocardial systolic strains were not associated with the ECV and CVF in the patients awaiting heart transplantation. Myocardial fibrosis is a common feature and the pathological basis of a variety of heart diseases, regardless of aetiology –4. MyocaCardiovascular magnetic resonance (CMR) imaging is a reliable non-invasive imaging modality that is widely used to evaluate cardiac morphology, function and tissue characterisation. CMR with late gadolinium enhancement (LGE) is a well-established modality for detecting regional myocardial fibrosis associated with adverse cardiovascular outcomes –10. HoweAdditionally, myocardial deformation analysis can supply useful information for the evaluation of myocardial function, which is very important in the management of patients with heart failure –24. CMR Therefore, the purposes of this study were to examine the relationship between CMR-derived ECV and histological CVF measured from explanted hearts and to explore the role of T2 mapping in the histological validation of ECV. Additionally, we aimed to determine whether the alterations of myocardial systolic strain are associated with ECV and histological myocardial fibrosis in patients undergoing heart transplantation.2, an allergy to the contrast materials, and contraindications to CMR, including severe claustrophobia and device implantation. This study was approved by the Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology. Written informed consent was obtained from all the participants.Between June 2016 and July 2017, 40 consecutive patients with dilated cardiomyopathy (DCM) or ischaemic cardiomyopathy (ICM) on the heart transplant waiting list were referred for CMR. Of the 40 patients, 5 patients with DCM were prohibited from CMR due to a pacemaker; 5 DCM and 4 ICM patients were unable to complete CMR because of difficulties with breath-holding; and 2 DCM and 2 ICM patients lacked CMR images because they underwent CMR examinations in other hospitals. Thus, a total of 12 DCM and 10 ICM patients undergoing electrocardiogram, echocardiography, invasive coronary angiography, CMR and heart transplantation were included in the present study. The DCM diagnosis was based on (1) the presence of left ventricular (LV) dilatation with an increased LV end-diastolic volume index (EDVI) by CMR; (2) systolic dysfunction with a reduced LV ejection fraction (LVEF) < 35% and symptomatic heart failure with a New York Heart Association (NYHA) functional class III or greater; and (3) the absence of coronary artery disease by coronary angiography or subendocardial LGE indicating previous myocardial infarction , 28. For2, matrix of 186× 256 pixels and flip angle of 80°. T1 mapping was performed on three standard LV short-axis slices  before and 15 min after the administration of a bolus of gadopentetate dimeglumine contrast agent  using a modified Look Locker inversion recovery (MOLLI) sequence with a 5(3)3 sampling scheme. The following typical MOLLI sequence parameters were used: TR/TE of 3.8/1.1 ms, slice thickness of 8 mm, FOV of 360 × 270 mm2, matrix of 144 × 256 pixels, voxel size of 1.3 × 1.3 × 8.0 mm3, flip angle of 35° and scan time of 11 heartbeats. T2 mapping was acquired in basal, mid and apical ventricular short-axis slices  before the contrast agent injection using a T2-prepared single-shot bSSFP sequence. The parameters were as follows: TR/TE of 3.8/1.3 ms, slice thickness of 8 mm, FOV of 360 × 270 mm2, matrix of 144 × 256 pixels and flip angle of 70°. A motion-correction algorithm was applied to correct the breathing and cardiac motion artefacts. LGE imaging of whole left ventricular short-axis slices and two-, three-, and four-chamber long-axis slices was performed 10 min after the intravenous injection of gadopentetate dimeglumine using a phase sensitive inversion recovery (PSIR) sequence. The LGE image parameters were as follows: TR/TE of 12.4/1.2 ms, slice thickness of 8 mm, FOV of 360 × 270 mm2, matrix of 256 × 192 pixels and flip angle of 40°.All the subjects underwent standard CMR examinations with a 1.5T scanner . The cine images included the acquisition of three long-axis slices  and a stack of short-axis slices covering the entire LV using a balanced steady state free precession (bSSFP) sequence. The cine image parameters were as follows: repetition time (TR)/echo time (TE) of 2.9/1.2 ms, slice thickness of 6 mm, field-of-view (FOV) of 360 × 270 mmCMR images were analysed on a dedicated workstation using commercial software . Cardiac volumetric and functional parameters were quantified based on manual delineation of the endocardial and epicardial borders using a stack of continuous short-axis slice cine images (after excluding papillary muscles from the myocardium). All the parameters were indexed to the body surface area (BSA). The left ventricular EDVI, end-systolic volume index (ESVI), EF, stroke volume index (SVI), cardiac index and myocardial mass index were obtained automatically.The haematocrit was obtained through a blood sample analysis on the day of the CMR scanning. The ECV maps were automatically calculated from pre- and post-contrast T1 times and haematocrit using a prototype inline processing function from Siemens. The myocardial T1, T2 times and ECV measurements were determined by drawing a region-of-interest (ROI) in each segment of each subject on a dedicated workstation with a ROI measuring tool , according to the 16-segment model from the American Heart Association (AHA) . ROIs foThe LGE was quantified using a threshold of 4 standard deviations (SD) above the mean signal intensity of the remote normal myocardium within the same slice . The LGE42, Circle, Calgary, Canada). Myocardial systolic strain analysis was quantified through manual delineation of the LV endocardial and epicardial borders in a stack of short-axis and three long-axis slice cine images with the initial contour place at end-diastole, as previously described [Myocardial deformation analysis was performed using dedicated tissue tracking software , SAS® version 9.3  and GraphPad Prism 5.0 .Normality was detected using the Kolmogorov-Smirnov test. Continuous variables are presented as the mean ± SD, and categorical variables as percentages or frequencies. Comparisons between multiple groups were analysed using one-way ANOVA or the Kruskal-Wallis test, with the Bonferroni correction as the post hoc test, as appropriate. Categorical variables were analysed using the Chi-square test or the Fisher exact test. Correlation between ECV and CVF was assessed using Pearson’s or Spearman’s correlation coefficients, as appropriate. A linear mixed-effects regression analysis was used to assess the relationship between ECV and CVF for per-segment analyses. Univariate and multivariate linear regression analyses, with a stepwise algorithm, were performed to detect the determinants of ECV and CVF in the patients awaiting heart transplantation. Intra- and inter-observer variability of native T1 times, ECV and myocardial strain were assessed using an intra-class correlation coefficient (ICC) with 95% confidence intervals (CI). For all the tests, a two-sided p = 0.475). There were no significant differences in sex , height, weight, body mass index (BMI), BSA and haematocrit. Heart rate was significant higher in the DCM patients than that in the healthy controls. The DCM and ICM patients showed a mean symptom duration of 6.5 and 2.2 years, respectively. The mean time between heart transplantation and CMR was 15 days (range: 0–32 days) and 27 days (range: 1–114 days) in patients with DCM and ICM, respectively.The baseline characteristics of the study population are listed in Table p <  0.05 for all). No significant differences in the LVSVI and cardiac index were observed between the three groups. Myocardial systolic strain analysis demonstrated that the LV GLS, GCS and GRS were lower in the DCM and ICM patients compared with those in the controls . Myocardial LGE was present in all the DCM and ICM patients. The mean native T1 time, T2 time and ECV were significantly higher in the DCM and ICM patients than those in the controls .Table p <  0.001 for all). The ECV of all the segments from the ICM patients was significantly greater than that in the segments without LGE (p <  0.05).In the whole myocardium analysis, 11 of 192 (5.7%) myocardial segments in the DCM patients and 12 of 160 (7.5%) myocardial segments in the ICM patients were excluded due to artefacts identified by image quality assessment. In total, 64 segments with LGE and 117 segments without LGE from the DCM patients and 68 segments with LGE and 80 segments without LGE from the ICM patients were included in the analyses Table . The mear = 0.904, p <  0.001 and r = 0.901, p <  0.001, respectively; Fig. r = 0.750, p <  0.001 and r = 0.806, p <  0.001, respectively; Fig. r = 0.525, p <  0.001 and r = 0.650, p <  0.001, respectively; Fig. β = 0.838, p <  0.001 and β = 0.915, p <  0.001, respectively).The mean histological CVF was 14.3 ± 4.6% (range: 9.7–23.8%) and 17.0 ± 5.5% (range: 9.6–26.2%) in the DCM and ICM patients, respectively. Figure β = 0.250, p = 0.007 and standardised β = 0.860, p <  0.001, respectively). In addition, the univariate regression analysis showed that histological CVF was correlated with the NT-proBNP, time between CMR and transplantation, native T1 time and ECV in the patients awaiting heart transplantation. The multivariate regression analysis demonstrated that the ECV was the independent determinant of the histological CVF . However, no significant associations between ECV and histological CVF with left ventricular GLS, GCS, GRS and T2 mapping were observed in the patients awaiting heart transplantation .Table The intra-observer and inter-observer variability were analysed for the 15 healthy subjects. The ICCs and 95% CIs for intra-observer and inter-observer agreement were 0.974  and 0.967  for the ECV measurements and 0.942  and 0.922  for the native T1 times measurements, respectively. The ICCs and 95% CIs for intra-observer and inter-observer agreement were 0.882  and 0.894  for GLS, 0.964  and 0.911  for GCS, and 0.942  and 0.921  for GRS, respectively.The results of this study demonstrated that (1) myocardial ECV calculated by CMR T1 mapping correlated well with the degree of myocardial fibrosis measured in whole-heart histological samples from the patients undergoing heart transplantation; (2) T2 mapping was increased in the patients awaiting heart transplantation but was not related to myocardial ECV and histological CVF after adjusting for potential confounding factors in the multivariate regression analysis; and (3) in this cohort of patients, the LV GLS, GCS and GRS were decreased, and impaired myocardial systolic strain was not associated with CMR-derived ECV and histological myocardial fibrosis.CMR T1 mapping is increasingly being recommended as a non-invasive diagnostic tool for myocardial tissue characterisation. Previous studies have validated the use of CMR T1 times and myocardial ECV against biopsy samples in patients with severe aortic stenosis or regurgitation, DCM, hypertrophic cardiomyopathy and ICM –16, 34. Additionally, previous studies by Miller et al. and Iles et al. have validated CMR T1 mapping against histological samples from patients using 6 and 11 explanted hearts, respectively , 34. HowSimilar to CMR T1 mapping, T2 mapping techniques can also be used to assess myocardial tissue properties. It has been suggested that CMR T2 mapping can be used to detect myocardial oedema in acute myocardial infarction, myocarditis or cardiac allograft rejection –38. In tRecently, an advanced CMR tissue tracking technique was proposed as a non-invasive and accurate modality for myocardial deformation analysis using cine images. Myocardial systolic strains can be used to characterise early myocardial dysfunction in clinical practice . In the Our study evaluated the correlation between ECV and histological CVF using whole-heart tissue samples from 22 patients awaiting heart transplantation. Although the number of patients was limited, the sample sizes were relatively large, given that we used whole-heart tissue samples. Furthermore, we aim to collect more whole-heart tissue samples from patients awaiting heart transplantation at our institution for further study. The time delay between CMR and heart transplantation was a major factor affecting the results. However, the mean time between transplantation and CMR was less than one month in our study, which would not allow for a significant change in the myocardial collagen content . AdditioOur results show that CMR-derived ECV correlates well with the histological CVF, indicating its potential use as a novel non-invasive imaging technique for quantifying myocardial fibrosis and for guiding clinical interventions and monitoring clinical therapy. Decreased LV myocardial systolic strain was not related to histological myocardial fibrosis or ECV in the present study.


Even in absence of obstructive coronary artery disease women with angina pectoris have a poor prognosis possibly due to coronary microvascular disease. Coronary microvascular disease can be assessed by transthoracic Doppler echocardiography measuring coronary flow velocity reserve (CFVR) and by positron emission tomography measuring myocardial blood flow reserve (MBFR). Diffuse myocardial fibrosis can be assessed by cardiovascular magnetic resonance (CMR) T1 mapping. We hypothesized that coronary microvascular disease is associated with diffuse myocardial fibrosis.Women with angina, a clinically indicated coronary angiogram with <50 % stenosis and no diabetes were included. CFVR was measured using dipyridamole (0.84 mg/kg) and MBFR using adenosine (0.84 mg/kg). Focal fibrosis was assessed by 1.5 T CMR late gadolinium enhancement (0.1 mmol/kg) and diffuse myocardial fibrosis by T1 mapping using a modified Look-Locker pulse sequence measuring T1 and extracellular volume fraction (ECV).R2 = 0.02; p = 0.27 and R2 = 0.004; p = 0.61, respectively). There were also no correlations between MBFR and ECV or native T1 . CFVR and MBFR were correlated to hypertension and heart rate.CFVR and CMR were performed in 64 women, mean (SD) age 62.5 (8.3) years. MBFR was performed in a subgroup of 54 (84 %) of these women. Mean native T1 was 1023 (86) and ECV (%) was 33.7 (3.5); none had focal fibrosis. Median (IQR) CFVR was 2.3 , 23 (36 %) had CFVR < 2 indicating coronary microvascular disease, and median MBFR was 2.7  and 19 (35 %) had a MBFR value below 2.5. No significant correlations were found between CFVR and ECV or native T1 (In women with angina and no obstructive coronary artery disease we found no association between measures of coronary microvascular disease and myocardial fibrosis, suggesting that myocardial ischemia induced by coronary microvascular disease does not elicit myocardial fibrosis in this population. The examined parameters seem to provide independent information about myocardial and coronary disease. More than half of women with angina-like chest pain referred for clinical coronary angiography (CAG) have no obstructive coronary artery disease (CAD) . While pMyocardial tissue consists of myocytes, blood vessels and nerves distributed in the extracellular volume (ECV). Cardiovascular magnetic resonance (CMR) is a well-validated method to assess expansion of the myocardial ECV, e.g. as seen with fibrosis –21. FibrThe iPOWER study (ImProve diagnOsis and treatment of Women with angina pEctoris and micRovessel disease) aims to investigate diagnostic techniques and prognosis of CMD in women with angina-like chest pain and no obstructive CAD . To dateWomen with angina-like chest pain, no significant obstructive CAD assessed by diagnostic invasive CAG with <50 % stenosis of epicardial vessels, and with a successful TTDE CFVR examination were randomly selected for the iPOWER CMR and PET sub-studies . SelectiPrior to the TTDE, PET and CMR, participants were instructed to be abstinent for 24 h from caffeine or food containing significant amount of methylexanthine  which was confirmed by the study. Medication containing dipyridamole was paused for 48 h, long-lasting nitroglycerines, beta-blockers, ACE-inhibitors, angiotensin-II-antagonist, calcium antagonist, and diuretics for 24 h and short-lasting nitroglycerines 1 h before the examination. This was done in order to avoid an effect on the pharmacological induced hyperemia. Different vasodilators can be used to induce hyperemia, but adenosine and dipyridamole are regarded as equal to achieve peak coronary vasodilation , 29 and At baseline a TTDE of the LAD during rest and high-dose dipyridamole stress (0.84 mg/kg) was performed over 6 min to obtain coronary flow velocities (CFV). The examination was performed using GE Healthcare Vivid E9 cardiovascular ultrasound system  with a 2.7 - 8 MHz transducer (GE Vivid 6S probe). All examinations were performed by the same 3 experienced echocardiographers in the same settings. CFV was measured by pulsed-wave Doppler as a diastolic laminar flow towards the transducer. Blood pressure and heart rate were measured every 3 min during the examination and after the examination intravenous theophylline (maximum dose 220 mg) was administered to relieve potential side effects of dipyridamole. Diastolic peak flow velocities were analyzed at rest and at peak hyperemia and CFVR was calculated as the ratio between the two /PET 128-slice scanner  . ParticiMBF quantification was performed using syngo MBF software . MBFR was defined as MBF during maximal hyperaemia divided by MBF at rest. MBFR according to the coronary arteries  was analyzed according to the AHA 17 segment model . IndepenCMR was performed on a Magnetom Avanto 1.5 Tesla scanner . Prior to the scan hematocrit was measured for ECV calculation. A 32 channel chest coil combined with back surface coils was used. Initially scout images were obtained followed by a short-axis cine covering the heart using retrospective ECG gated steady-state free precession (SSFP) cine sequences; field of view 300x300 mm, matrix 192x192, slice thickness 8 mm with 25 number of phases. T1 mapping was performed using the modified look-locker inversion recovery technique (MOLLI) . Before LGE images were acquired as breath-hold ECG gated, inversion recovery fast gradient-echo images after the T1 post-contrast session. Initially an inversion time (TI) scout was performed to find the best inversion time to null the myocardium. Images were acquired to cover the whole length of the left ventricle; slice thickness 8 mm, TE 3.38 ms; TR 848.00 ms; flip angle 25°; field of view 340x340, matrix 192x192, GRAPPA acceleration factor 2.CMR analysis was performed using commercial available software CVI42 version 5.1.1  blinded to results of the TTDE and PET examination. All CMR analyses were performed by the same reader, trained by an expert CMR physician. The reader and expert performed double readings until the reader could reproduce the expert satisfactory. The coefficients of variation between the reader and an expert CMR physician were 6.0 %  for LVEF, 2.5 %  for native T1 and 4.4 %  for postcontrast T1 times. Furthermore intra-observer variability was 5.9 %  for LVEF, 1.7 %  for native T1 and 6.3  for postcontrast T1. Another group performed repeated MOLLI T1 mapping in 15 healthy volunteers. Mean difference (SD) for repeated examinations were 14.4 ms (34.7) for native T1 and 4.5 ms (15.4) for post-contrast T1. Both intra- and interobserver agreement (native T1) were high, mean difference (SD) 2.6 ms (6.7) and 1.1 ms (8.9), respectively .”Left ventricle mass and volumes were assessed by manually tracing the epi- and endocardial borders of the short-axis cine images and stroke volume and left ventricular ejection fraction calculated (LVEF) . Left veT1 times images were analyzed to construct a T1 map. Endo- and epicardial borders were drawn on all images divided on 3 slices pre- and post-contrast. The recovery curve was generated and dicom maps created by the software. For the T1 map analysis the CVI42 generated maps were used. Contours of the endo- and epicardial borders were drawn on the 3 slices using a 20 % endo- and epicardial offset and 6 segments per slice. For ECV analysis a region of interest was drawn in the blood pool avoiding the papillary muscles and the anterior and inferior insertion of the right ventricle was marked as reference points.ECV was calculated by the equation :\documen1/T1Fig. Fig. 3AnaT1 values (native and post-contrast) and ECV was given globally, for each slice  and according to the coronary arteries  segments calculated according to the AHA 17-segment model (true apex not imaged) . If a sedif with the mean value and expressed as a percentage. The 95 % CI for the estimated coefficient of variation was calculated according to the equation: (SDdif ± t · SE(SDdif)/mean) · 100 %.Continuous variables with a Gaussian distribution are expressed as mean ± standard deviation (SD). Median, interquartile range (IQR) is used for variables with a non-Gaussian distribution. Count in % is used for categorical variables. Distribution was assessed visually. The coefficient of variation between CMR readers was calculated by dividing SDDifference in T1 variables  according to slice  and artery territory  was tested by one-way ANOVA.Correlations were assessed by Pearson’s correlation coefficient. Logarithm transformed values was used in case of non-Gaussian distribution of one variable. In case both variables were skewed Spearman correlation coefficient was used.Participants were stratified according to tertiles of native T1 and ECV and into three groups using pre-defined CMD defining cut-off points for CFVR and MBFR to test for differences between groups. Trend-tests by logistic or linear regression analysis were used to evaluate the distribution of variables. Dependent variables with skewed distribution were transformed with the natural logarithm.To explore predictors of native T1, ECV, CFVR and MBFR multivariable linear regression analyses were performed. All potential explanatory variables with an a priori defined hypothesis were tested in a prioritized order as determinants. Outcome variables with a non-Gaussian distribution were logarithmically transformed using the natural logarithm.p-value below 0.05 was considered statistically significant.Statistical analysis was performed using SAS Enterprise Guide 7.1, windowed for SAS version 9.4 . A two-sided From the iPOWER population with a successful CFVR measurement 79 participants were recruited for the CMR study. Two participants could not complete the CMR scan due to claustrophobia and 13 were scanned with different software, making ECV calculation impossible and comparisons unreliable. Thus 64 had a complete CMR for T1 mapping. Mean age (SD) was 62.5 (8.3) years, 70.3 % had stable angina pectoris as indication for the clinical CAG and 45.3 % had non-obstructive atherosclerosis. The duration of angina varied; 38 % had had their angina symptoms under a year and 34 % for more than 3 years. The overall burden of cardiovascular risk factors was relatively high (Table Of the 64 participants included and in examined in the iPOWER CMR sub-study 54 (84 %) also had a PET scan performed measuring MBFR. Mean age was 62 (7.5) years and prevalence of cardiovascular risk factors was similar to the total study population Table . Median p < 0.001). When stratifying participants in tertiles according to native T1 and ECV no variables were associated with both CMR derived measures of fibrosis: low ECV was associated with more atherosclerosis on the CAG and low native T1 was associated with more hypertension. Native T1 increased with higher resting heart rate  ms, post-contrast T1 463  ms and Ep = 0.01, R2 = 0.132). When stratifying participants according to CMD defining cut-off points for CFVR and MBFR, impaired CFVR was associated with smoking and both CFVR and MBFR were associated with presence of hypertension and a higher resting heart rate  and 23 (36 %) had CFVR below the cut-off of 2. Median MBFR was 2.7  and 19 (35 %) had a MBFR value below 2.5. The two measures of CMD were only weakly correlated . Similarly, we did not find a correlation between MBFR and ECV or native T1  .No significant correlation was found between CFVR and ECV or native T1, In this study no patient with angina had focal fibrosis and we found no association between the degree of CMD assessed by TTDE and PET and the presence of diffuse myocardial fibrosis measured by CMR, indicating that myocardial ischemia in this population does not elicit myocardial fibrosis. This is a new finding, since no study to date has examined the presence of diffuse myocardial fibrosis in women with angina pectoris and no obstructive CAD.Arnold et al. investigated 50 patients with diabetes without CAD and 19 matched controls with T1 mapping . There wThe cut-off used to define CMD is currently unclear and should be seen as a continuum , but mosThis study used multiple imaging modalities to examine the association between CMD and presence of diffuse myocardial fibrosis. The participants were consecutively included and examined systematically and all had a clinical invasive CAG ruling out obstructive CAD. The use of Doppler echocardiography measuring CFVR is a difficult method that requires training and in un-experienced hands this would be a limitation. We assessed repeatability of TTDE CFVR in our group and found an intra class correlation coefficient of 0.97  and coefficient of variation (CI) of 7 % , 10 for In women with angina pectoris and no obstructive CAD we found no association between CMD defined by impaired CFVR or MBFR and diffuse or focal myocardial fibrosis measured by CMR derived T1 or ECV. This indicates that these methods and measurements may provide independent information about different aspects of myocardial and coronary disease in this population.That diffuse myocardial fibrosis is not a consequence of CMD in women with angina and no obstructive CAD adds knowledge to the field regarding mechanisms causing angina in these subjects. Such women represent a large patient group in increased risk of cardiovascular events for whom there is currently no effective treatment. Future prospective large-scale studies are required to define the mechanisms causing the diverse symptoms in this population.


Little is known about the clinical value of late gadolinium enhancement (LGE), in children affected by dilated cardiomyopathy (DCM).U test .We retrospectively evaluated 15 patients  with diagnosis of DCM who underwent cardiac magnetic resonance since 2014. All scans were performed with a 1.5 T system . Study protocol included cine steady-state free precession sequences, followed by administration of 0.2 mmol/kg of gadolinium-based contrast agent. Inversion recovery Turbo Flash sequences, in the same position of cine images, were acquired 10–15 min after the injection of contrast agent, in order to assess the presence of LGE. The latter was considered positive with a signal intensity >6 SD from normal myocardial tissue. Indexed end-diastolic volume (EDVi) and end-systolic volume (ESVi), and left ventricle (LV) ejection fraction (EF) were calculated by using dedicated software on off-line workstation. Global longitudinal strain and diastolic function were evaluated by echocardiography. Clinical follow-up, including death, transplant, and listing for heart transplant [major adverse cardiac events (MACE)], were evaluated. Patients were divided into two different subgroups: negative (Group A) and positive (Group B) for presence of LGE. Statistical analysis was performed by using Mann–Whitney E/e′ ratio = 10 ± 3, MACE = 1. Group B: EDVi = 130 ± 60 ml, ESVi = 89 ± 43 ml, LV EF = 31 ± 6%, global longitudinal strain = −13 ± 4%, E/e′ ratio = 9 ± 3, MACE = 3. There was no statistically significant difference between the two groups, in terms of EDVi (p: 0.2), ESVi (p: 0.2), and E/e′ ratio (0.9), whereas a significant difference of LV EF, presence of significative mitral regurgitation, and global longitudinal strain were observed .Seven patients (47%) showed LGE. A global diffuse subendocardial pattern was evident in all patients presenting LGE . The following main LV indexes were observed in the two subgroups. Group A: EDVi = 96 ± 33 ml, ESVi = 56 ± 29 ml, LV EF = 45 ± 10%, global longitudinal strain = −16 ± 5%, In our population of children with DCM, LGE shows a global diffuse subendocardial pattern. Presence of LGE seems to play a role in these patients determining a worst global systolic function. Dilated cardiomyopathy (DCM) is defined as a ventricular dilatation associated with systolic dysfunction not secondary to other cardiac abnormalities such as coronary artery disease, valvular, or congenital heart disease. Incidence of DCM in children is extremely rare   has gained a crucial role in adults with DCM, since CMR provides reliable information about cardiac function and muscle tissue characterization . In factIn adult patients, various studies demonstrated not only a diagnostic but also a prognostic role of LGE especially in non-ischemic disease , 8–11.Cardiac magnetic resonance assessment of myocardial fibrosis has been reported to be useful in patients with congenital heart disease –15 and cHence, our aim was to investigate the potential role of CMR and LGE in children affected by DCM.We retrospectively evaluated all patients affected by DCM who underwent cardiac MRI, between December 2014 and March 2016, at our institution.Z score >2 and LV EF <50%.Diagnosis of DCM was based on echocardiographic findings with LV end-diastolic dimension Patients younger than 8 years old underwent cardiac mitral regurgitation (MR) under general anesthesia.This study was carried out in accordance with the recommendations of the “Ethical Committee of the Ospedale Pediatrico Bambino Gesù” with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki.2, or frequent ventricular arrhythmias, were excluded from the study.Cardiac magnetic resonance was performed with 1.5 T magnet . Enrolled patients met the eligibility requirements, according to the guidelines of the American College of Radiology of 2013 . Patient2, slice thickness 6–8 mm, acquisition matrix 256 × 173, voxel size 1.5 mm × 1.5 mm × 7 mm, echo/repetition time (TE/TR) 1.1/40 ms, readout bandwidth 930 Hz/pixel, and flip angle 69°), followed by a “stack” of contiguous SSFP cine images, with the same technical parameters, acquired along cardiac short axis, to cover the whole ventricle—from base to apex.Our protocol included cine steady-state free precession (SSFP) sequences acquired on the long-axis cardiac planes: four chambers, two chambers, and three chambers  250–425 ms], were acquired along the same planes of the cine SSFP images, in order to evaluate the presence of LGE.After 10–15 min of intravenous administration of contrast agent , at 0.2 mmol/kg, T1-weighted inversion recovery sequences , but the small sample size did not allow any survival analysis.This study demonstrates that in children affected by DCM, despite comparable LV volumes, the presence of diffuse subendocardial LGE is associated with a decreased LV global systolic function and worst global longitudinal strain. Interestingly, a global diffuse subendocardial pattern, involving majority of LV segments, papillary muscles, and trabeculae, was evident in all patients presenting LGE.A typical pediatric cardiomyopathy, quite similar to our finding, had been already described in autopsy since the 1950s, and it was called primary endocardial fibroelastosis (EFE) . Such enOur findings seem to confirm this report and corroborate the hypothesis that in the presence of EFE the ventricular mechanic is compromised, leading to impaired contraction and expansibility of the cardiac cavity.Moreover, development of this peculiar LGE pattern does not seem to be related to disease duration, since age of the two subgroups is not significantly different.Our study also shows that significant MR is more frequent in patients with significant LGE. This finding should not be linked to a functional mechanism, since ventricular dilation is comparable in the two subgroups. Therefore, the increasing leakage seems to be related to a fibrotic involvement of the valve and subvalvar apparatus. This is in keeping with the original description of primary EFE where papillary muscles involvement and valve leaflets thickening were described. Our data hence confirm that the presence of global diffuse EFE in the setting of children affected by DCM identifies a subgroup of patients with a worse disease clinical expression.The etiology of EFE is still debated in literature. Some articles attribute the development of this condition to an increased response of fetal myocardium in case of viral illnesses including mumps, during pregnancy . The othE/e′ ratio. EFE is commonly believed to be a cause of diastolic dysfunction , and it shows a characteristic global diffuse subendocardial pattern. Despite comparable LV volumes, the presence of fibrosis seems to play a key role in these patients, determining a worst clinical expression of disease. If LGE is present, patients have a significant lower global systolic function and more frequently show a significant MR. More data confirming these findings on a larger population and investigating the prognostic role of LGE in this setting are needed.The authors declare that this study was performed in accordance with the research ethical guidelines. The study was conducted in retrospective analysis.GM, PC, and AS wrote the manuscript. DM, CN, and TS collected data and analyzed the images. GR, MC, and BL analyzed data and were involved in manuscript editing.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.


The diagnostic performance of cardiac magnetic resonance (CMR) imaging in suspected myocarditis is still limited. Recently, CMR T1 and T2 mapping has been suggested to yield excellent diagnostic accuracies in patients with suspected myocarditis as compared to healthy controls. However, the true diagnostic performance of CMR mapping when compared to endomyocardial biopsy (EMB) and the impact of CMR field strength in patients with a variety of pathologies is still unknown and was therefore assessed in this study.Within the final analyses, 129 consecutive patients with suspected acute or chronic myocarditis were included. Patients had to fulfill indications for CMR imaging according to the JACC White consensus paper.All patients underwent biventricular EMB, cardiac catheterization for exclusion of coronary artery disease, and CMR on a 1.5  and 3.0  Tesla tomography.The CMR protocol included standard Lake-Louise (LL) parameters as well as native and post contrast T1 and T2 mapping. Relative Enhancement was assessed with a T1 weighted TSE sequence, edema ratio with a T2 weighted STIR sequence. T1 Mapping was measured with a MOLLI-Sequence pre and post contast  and T2 Mapping with a Multi Echo Spin Echo sequence on the 1.5T scanner and a T2 prepared SSFP sequence on the 3T scanner. Patients were divided into 2 groups according to duration of symptoms: patients with acute symptoms (≤14 days) and those with chronic symptoms (>14 days).The diagnostic performance of LL criteria, native T1 and extracellular volume fraction (ECV) as well as T2 mapping is summarized in the table. On 1.5 Tesla, in patients with acute symptoms, native T1 yielded best diagnostic performance (81%) followed by ECV (75%) and T2 (72%). In chronic patients, T2 was the only technique achieving an acceptable accuracy (72%). Accuracies of imaging techniques on 3.0 Tesla CMR were slightly lower as compared to 1.5 Tesla. However, T2 mapping on 3.0 Tesla appeared to be unsatisfactory for the diagnosis of myocarditis.In patients with acute symptoms and suspected myocarditis, mapping techniques provides a useful tool for the confirming or rejecting the diagnosis of myocarditis and are superior to LL criteria. In contrast, only T2 mapping results in an acceptable diagnostic accuracy in patients with chronic symptoms. The impact of field strength on diagnostic accuracies requires further exploration.


Abnormal myocardial morphology of the left ventricle (LV) may be relevant in patients with LV pressure overload for developing heart failure despite having preserved ejection fraction. We aimed to detect subclinical myocardial tissue changes in patients with aortic stenosis (AS) and hypertensive heart disease (HYP) by quantitative cardiovascular magnetic resonance.1-maps (modified Look-Locker inversion recovery) and T2-maps (3 steady-state free-precession images with different preparation times) were obtained in a basal, mid-ventricular and apical short-axis slice. T1-maps were repeated after Gadobutrol i.v. T1- and T2-relaxation times and the partition coefficient were determined for every segment. Focal fibrosis was assessed with late enhancement images (LGE).Forty-eight patients with pressure overload  and 60 healthy controls were enrolled. T2- and T1-relaxation times as well as the partition coefficient for each segment. Figure 1-values were reduced at the base  indicating fibrosis, in the septum even without the presence of LGE. Apical segments differed from controls by reduced T2- and native T1-values and partition coefficient, indicating abnormal regional tissue composition. With increasing AS severity, the number of segments with abnormal tissue composition increased. In HYP, post-contrast T1-values were abnormal in the basal septum indicating fibrosis, even without the presence of LGE. Partition coefficient and T2-relaxation times were reduced in the apex compared to controls.Figure Severe AS, but also moderate AS and - to less extent - HYP exhibit abnormal regional tissue composition. Multiparametric segmental mapping has potential to detect organ damage at an early stage.


Evaluation of myocardial fibrosis has been identified as an important part of studying remodeling processes and arrhythmogenesis. While focal fibrosis associated with tissue necrosis is more likely found in those with prior cardiovascular disease (CVD), whether diffuse fibrosis (associated with cellular apoptosis and other pro-fibrotic processes) is also increased is unknown. We used contrast-enhanced CMR to evaluate the association between CVD in MESA over 10-years with myocardial fibrosis measured at year-10.The MESA study enrolled 6814 participants free of cardiovascular disease at baseline (2000-2002). We included MESA participants who underwent contrast-enhanced CMR at the MESA follow-up exam at year-10 (N = 1840). Coronary heart disease (CHD) was defined as myocardial infarction, resuscitated cardiac arrest, definite angina, or probable angina (if followed by revascularization) that occurred between the baseline and 10-year follow-up exams. We also defined a composite CVD endpoint which included CHD, congestive heart failure, atrial fibrillation, stroke and transient ischemic attack. Using CMR, we characterized left ventricular (LV) myocardial fibrosis with - late-gadolinium enhancement for focal fibrosis (10-12 short-axis and 2 long-axis slices covering the entire LV) and MOLLI T1 mapping for diffuse interstitial fibrosis (1 mid-ventricular short-axis slice). Logistic regression models were used to assess the relationship between the clinical events and the presence/absence of scar by LGE and T1 mapping indices  after adjustment for demographics - Model 1: age, gender and race; and traditional cardiovascular risk factors - Model 2: Model 1 + blood pressures, hypertension/lipid medication use, diabetes, HDL and total cholesterol, body mass index, smoking status, glomerular filtration rate (post-contrast T1 only). Models with T1 indices were also adjusted for myocardial scar.Participants were 68 ± 9 years, 52% male, 45% Caucasian, 9% Chinese, 25% African-American, 21% Hispanic, 55% had hypertension, and 16% diabetes. 146 of 1840 (7.9%) participants were observed to have myocardial scar by LGE. The mean values of T1 indices were - precontrast T1: 977 ± 45 ms; post-contrast T1 at 12': 456 ± 40 ms; post-contrast T1 at 25': 519 ± 41 ms; ECV: 27.1 ± 3.2%. In logistic regression analysis, the presence of LGE scar was strongly associated with prior events (see Table Prior CVD events were associated with a greater likelihood of focal LV myocardial fibrosis and a greater amount of diffuse LV interstitial fibrosis in a free-living multi-ethnic population.


Short 11-heart beat (11 HB) MOLLI have been proposed as a non-invasive method for the assessment of overall and diffuse fibrosis, but histological correlation has only been modest. We investigated an 11 HB MOLLI protocol with incremental acquisition of basal and mid-level images as a means for obtaining a global value of extracellular volume fraction (ECV). We validated this against intraoperative myocardial biopsies in patients with aortic stenosis.Ten patients  with aortic stenosis (AS) scheduled for surgical valve replacement (3 with coronary artery disease) underwent CMR at 1.5T  with native 5(3)3 and post-gadolinium 4(1)3(1)2 T1 maps (Siemens prototype WIP 448B). Gadolinium 0.1 mmol/kg was administered, and post-gadolinium T1 maps were taken 15 later. The hematocrit was measured in an approved biochemistry laboratory on the same day. The MOLLI sequence was acquired twice at a single basal short-axis left-ventricular level, and twice at a single mid-ventricular level. Regions of interest were drawn in the septum at both levels to acquire T1 values. ECV calculation utilized an increasing number of maps as shown in table 1, using ECV=(1-hematocrit)* [(1/T1myocardium post contrast-1/T1 myocardium native)]/[(1/T1 blood post contrast-1/T1 blood native)]."Trucut" biopsy taken intraoperatively from the apical anterior/ lateral wall through the epicardium to allow histological characterization of the full myocardial wall.A CMR imaging model including incrementally more acquisitions was applied as shown in Figure The following aspects of the methods are proposed as novel steps:The myocardial biopsies were fixed in warm buffered formalin. Analysis of formalin-fixed paraffin-embedded, transmural myocardial biopsies of the left ventricle was performed on hematoxylin/eosin and Picrosirius Red-stained 3-micron-thick sections by a blinded experienced cardiac pathologist. Images were analysed using a purpose-built software to determine the extent of overall and reactive interstitial fibrosis.2 = 0.36; Figure 2 = 0.76 when the average of a single basal and single mid-level image was used for ECV  and importantly R2 = 0.83 when acquisition was repeated at both basal and mid-levels .When only one mid-level MOLLI was taken correlation with histology was modest (RWe have confirmed that ECV can provide accurate correlation with histological overall fibrosis. This work has demonstrated that the accuracy increases when MOLLI sequences are acquired at both basal and mid-ventricular levels, and further improves if repeated at each level. We conclude that an average T1 over 2 basal and 2 mid-ventricular level acquisitions improves correlation with histology in aortic stenosis patients when using 11 HB MOLLI.


Native T1-mapping provides quantitative myocardial tissue characterization for cardiovascular diseases (CVD), without the need for gadolinium. However, its translation into clinical practice is hindered by differences between techniques and the lack of established reference values. We provide typical myocardial T1-ranges for 18 commonly encountered CVDs using a single T1-mapping technique – Shortened Look-Locker Inversion Recovery (ShMOLLI), also used in the large UK Biobank and Hypertrophic Cardiomyopathy Registry study.We analyzed 1291 subjects who underwent CMR  between 2009 and 2016, who had a single CVD diagnosis, with mid-ventricular T1-map assessment. A region of interest (ROI) was placed on native T1-maps in the “most-affected myocardium”, characterized by the presence of late gadolinium enhancement (LGE), or regional wall motion abnormalities (RWMA) on cines. Another ROI was placed in the “reference myocardium” as far as possible from LGE/RWMA, and in the septum if no focal abnormality was present. To further define normality, we included native T1 of healthy subjects from an existing dataset after sub-endocardial pixel-erosions.p < 0.001). In the affected myocardium, cardiac amyloidosis (1119 ± 61 ms) had the highest native T1 compared to normal and all other CVDs, while iron-overload (795 ± 58 ms) and Anderson-Fabry disease (863 ± 23 ms) had the lowest native reference T1 . Future studies designed to detect the large T1 differences between affected and reference myocardium are estimated to require small sample-sizes (n < 50). However, studies designed to detect the small T1 differences between reference myocardium in CVDs and healthy controls can require several thousand of subjects.Native T1 of patients with normal CMR (938 ± 21 ms) was similar compared to healthy subjects (941 ± 23 ms). Across all patient groups , focally affected myocardium had significantly different T1 value compared to reference myocardium  contains supplementary material, which is available to authorized users. Cardiovascular magnetic resonance (CMR) offers a range of methods for non-invasive myocardial tissue characterization in cardiovascular diseases –4. Late Native T1-mapping is a quantitative and GBCA-free myocardial tissue characterization method that can detect changes in a variety of cardiac conditions, sometimes beyond what LGE imaging can reveal , 17. T1 n < 100), typically highly pre-selected patient cohorts, often without accounting for regional variations in myocardial pathology [Currently, the application of T1-mapping for the clinical diagnosis of cardiovascular diseases is hindered by a lack of standardization for the methods used and the different reference T1 values. A wide range of different T1-mapping techniques, each with different normal T1 ranges, are being used to study relatively small  technique has been validated in single- and multi-center clinical studies for a variety of cardiovascular diseases , 30–41. n = 53) who had a history of cardiovascular risk factors (e.g. diabetes mellitus or smoking) and/or abnormal ECG, but had no clear-cut features of cardiovascular disease on CMR -weighted images, as previously published [To study myocardial T1 values of cardiovascular diseases, we screened CMR scans undertaken for relevant scans, clinical and research, performed between June 2009 and June 2016 in our tertiary-referral CMR unit, the Oxford Centre for Clinical Magnetic Resonance Research (OCMR), Oxford, United Kingdom. We included the scans of patients diagnosed with a single cardiovascular disease and patients with normal CMR , as determined by at least one clinical consultant cardiologist CMR expert. We excluded scans without T1-maps, in patients under 18 years old, repeated in the same patient and in patients diagnosed with more than one cardiovascular disease (e.g. hypertrophic cardiomyopathy and coronary artery disease). We also excluded patients (ublished . Followin = 1221), clinical and re-analysis of our prior research scans for patients with pheochromocytoma [n = 70, no cardiovascular history and normal ECG, Additional file In total, 1291 CMR scans were included in final analysis and all scans had a mid-ventricular short-axis T1-map, defined by the clear presence of LV papillary muscles and located approximately half-way between the mitral valve annulus and the LV apex on long-axis cines . The stumocytoma , Takotsumocytoma , and acumocytoma ), and clThis study was approved by the relevant local ethics authorities. All study subjects gave written informed consent.All CMR scans were performed at 1.5 T  using established techniques as previously described . These iSeparate data files containing all T1-maps were created and anonymized before analysis by an observer blinded to clinical information. To assess the impact of focal pathology on native T1 changes, regions of interest (ROIs) were manually placed on mid-ventricular T1-maps in areas corresponding to focal enhancement on LGE images. In diseases without focal LGE, ROIs were placed as follows. For Takotsubo cardiomyopathy, ROIs were placed in areas on T1-map corresponding to the maximal regional wall motion abnormality (RWMA) , defined = 1.0221*T1(WIP561) - 32.795, established with material previously described [All T1 values presented in this study apply to the contemporary WIP448C, 780B and 1048. A significant proportion of T1 values in this study (42% or 541/1273 of the subjects) was measured using the original ShMOLLI WIP561 , 19. Theescribed . Overallescribed , 19. Fort-test and unpaired samples were assessed by the unpaired 2-tailed Student t-test. Comparisons between ≥3 separate data groups were performed using analysis of variance (ANOVA) with Bonferroni post-hoc correction. The associations between native T1 values, clinical demographics and LV function were analyzed using multi-variable analysis with stepwise selection method for significant associations (p < 0.05). All data were analyzed on per-subject basis using MedCalc 12.7.8 . In all cases, p < 0.05 denotes statistical significance.All data are parametric, as determined by the Kolmogorov-Smirnov test, and were expressed as mean ± SD. Paired samples were assessed by paired Student 442-corrected; normal ShMOLLI T1 = 941 ± 23 ms) [Calculations of sample sizes and effect sizes (Cohen’s d) were performed for two comparisons, using methods as previously described –49: (1) ± 23 ms) .In brief, the sample size required for native T1 values to show a significant change with power of 80% and α error of 0.05 was calculated using the following formula , 49:P is the study power, and f is the value of the factor for different values of α and P, with σ as the inter-study standard deviation and δ as the difference to be detected [Where n is the sample size needed, α is the significance level, detected . The effdetected .Subject characteristics are summarized in Table p < 0.05); patients with obesity had higher body mass index; patients with dilated cardiomyopathy, cardiac amyloidosis and chronic coronary artery disease had significantly lower LV ejection fraction ; patients with hypertrophic cardiomyopathy and cardiac amyloidosis had significantly higher maximal LV wall thickness , while patients with dilated cardiomyopathy had a significantly lower minimum LV wall thickness .Compared to patients with normal CMR, patients with acute myocarditis were statistically younger  myocardium compared to ATTR amyloidosis , similar to previously published values [p < 0.01). In diseases with generally low T1 values, reference myocardium in patients with cardiac iron-overload  and Anderson-Fabry disease  had significantly lower native T1 compared to patients with normal CMR and the reference myocardium in all other cardiovascular diseases . Further, reference myocardium in patients with cardiac iron-overload had lower native T1 compared to Anderson-Fabry disease (p < 0.01). The above findings support that these diseases are likely global in nature, with myocardial abnormalities beyond LGE detection. In all other cardiovascular diseases, the reference myocardial T1 was comparable with patients with normal CMR and each other (p > 0.07 by ANOVA with Bonferroni post-hoc method).All cardiovascular diseases demonstrated focal enhancement on LGE imaging, except for Takotsubo cardiomyopathy and iron overload, where no LGE was detected, and regional wall motion abnormality (RWMA) was used to define abnormality. In all diseases with focal LGE, enhanced myocardium had significantly higher native T1 values compared to the unenhanced reference myocardium within the same disease type, all paired d values  With resAll data were normally distributed, as determined using the Kolmogorow-Smirnoff test , and were presented accordingly in Table The minimum estimated sample sizes for studies using ShMOLLI native T1-mapping with the typical power calculation assumptions are presented in Table This is the first large-scale study with over 1200 subjects to address the need for published normative ranges for myocardial native T1 in a wide variety of cardiac conditions, with a single T1-mapping technique at the most common for clinical CMR 1.5 T field strength.As study controls, we measured the mean native T1 using mid-ventricular septal ROI in patients with normal CMR Additional file 2:Table S2. Clinical indications in patients with normal CMR included in the study, with no history of cardiovascular diseases and had normal ECG. (DOCX 13 kb)