To quantify extracellular matrix expansion with the cardiovascular magnetic resonance (CMR) T1 mapping technique and the derived extracellular volume fraction (ECV) in diabetic cardiomyopathy (DbCM) patients and to detect the relationship among ECV, duration of diabetes, and diastolic function.  Thirty-eight patients with diabetic cardiomyopathy  and thirty-two matched normal controls  were prospectively enrolled. All of them were scanned by T1 mapping to obtain the native and postcontrast T1 values of myocardium and blood, and ECV was calculated accordingly. All patients also underwent transthoracic echocardiographic tissue Doppler imaging to assess left-ventricular diastolic function. P < 0.001). The duration of diabetes was positively and strongly associated with ECV . There was also a significant difference in ECV (P ≤ 0.001) among four groups . ECV was negatively associated with LV E'/A' .  There was a significant difference in ECV between the two groups (DbCMs 30.4 ± 2.9% versus controls 27.1 ± 2.4%,  CMR T1 mapping can reflect myocardial extracellular matrix expansion in DbCM and can be a powerful technique for the early diagnosis of DbCM. Type 2 diabetes mellitus (T2DM), one of the most common chronic diseases globally, affects nearly four hundred million individuals . DiabetiThe minimal criteria for the diagnosis of DbCM include the presence of left-ventricular (LV) diastolic dysfunction but preserved systolic function, which makes early diagnosis of DbCM difficult. Diffuse expression, accumulation, and crosslinking of interstitial collagen can expand the extracellular space of the myocardium, which contributes to the development and progression of DbCM . PatholoNovel cardiac MR T1 mapping techniques make it feasible to measure myocardial extracellular matrix (ECM) expansion in vivo. Extracellular volume fraction (ECV), derived from native-T1 mapping and postcontrast T1 mapping after the administration of a bolus of gadolinium (Gd) contrast, can quantify myocardial ECM expansion. ECV quantification correlates well with histology  and is hThe specific purpose of the present study was to quantify ECM expansion with the cardiac MR T1 mapping technique and the derived ECV in DbCM, detect the relationship between ECV and the duration of diabetes, and evaluate the relationship between ECV and diastolic function.2 and other standard contraindications to cardiac MR. Forty consecutive participants were recruited for cardiac MR examination. Two participants were excluded because of the presence of high heart rate (>100 beats/min) during physical examination. Thirty-two normal controls were recruited from the community population during the same period.This study was approved by the Institutional Review Board (IRB) of our hospital, and all subjects gave informed consent. This study was conducted in our hospital between June 2015 and September 2016. The inclusion criteria for DbCM patients included (1) an initial diagnosis of T2DM according to the criteria of the World Health Organization ; (2) lefAll DbCM patients and normal controls underwent height, weight, and blood pressure examinations. Blood samples were collected at about 30 minutes before scanning. Those blood samples were immediately sent to the Department of Clinical Laboratory and Nuclear Medicine and immediately analyzed to obtain haematocrit (HCT), serum glucose, glycated hemoglobin (HbA1c), insulin, C-peptide, creatinine, cystatin C, triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL) and low-density lipoprotein cholesterol (LDL) levels, myocardium zymogram examination, and markers of myocardial damage.All patients underwent transthoracic echocardiography at rest using a commercially available ultrasound machine and transducer . According to the guidelines of the American Society of Echocardiography , tissue All DbCM patients and normal controls underwent cardiac MR examination on a 3T system . They were placed in a supine position using a 6-channel body matrix plus 2 rows of the spine array. Breath holding after expiration and electrocardiographic gating were used when necessary. LGE was performed about 15 min after bolus injection of 0.2 mmol/kg i.v. gadoteric acid meglumine bolus  with the Phase Sensitive Inversion Recovery sequence  to exclude local myocardial fibrosis.2, matrix 256 × 166, 6 mm thickness, TR/TE 301.7/1.09 ms, flip angle 35 degrees, 6/8 partial-Fourier k-space sampling, PAT factor 2). Spacing in between inversion experiments and image acquisition were both heartbeat-based (precontrast T1 recovery: a 5 (4) 2 sampling scheme, trigger delay 80 msec; postcontrast T1 recovery: a 4 (1) 2 (2) 2 sampling scheme, trigger delay 160 msec). Native T1 mapping was performed at basal, middle, and apical short axis of left-ventricular slices. Postcontrast T1 mapping was performed 20 min after bolus injection at the identical slice positions. T1 maps were generated online immediately after the scan. The motion correction (MoCo) technique was used.T1 mapping was performed using a modified Look-Locker Inversion Recovery (MOLLI) prototype sequence )   with a multimodality processing platform . The region of interest (ROI) was selected manually on the middle third of interventricular septum myocardium to avoid epicardial and endocardial partial-volume effects. The other ROI in the left-ventricular blood pool was located far away from both papillary muscles and myocardium to avoid partial-volume effects . The ECVt-tests were used to evaluate the differences between the DbCM group and the normal control group; the Mann–Whitney U test was performed when standard variance was heterogeneous. One-way ANOVA was performed to test the differences among the four groups, and the Bonferroni test was used as a post hoc test. The Kolmogorov-Smirnov test was used as a normality test. The relationships between bivariate were analyzed using Pearson's or Spearman's method. Statistical tests were two-tailed, and P < 0.05 was considered statistically significant. Statistical analysis was performed using commercially available software .Categorical variables were presented as percentages. Continuous variables were summarized as the mean and standard deviation (SD). Independent The results of anthropometry and biochemistry assessments are shown in P > 0.05).Thirty-eight patients  with DbCM and thirty-two normal controls  were studied. Fasting blood glucose and HbA1c were higher in patients with DbCM than in normal controls. DbCM was also associated with higher TG, HDL, aspartate aminotransferase (AST), ischemia modified albumin (IMA), and troponin levels. There were no significant differences between the two groups in age, gender, height, weight, and so on  and systolic function have been published in our previous paper . There wP = 0.950) and postcontrast T1 values . However, there was a significant difference in ECV between the two groups . Postcontrast T1 value did not correlate with the duration of diabetes in uni- and multivariable correlation analyses , all DbCM patients were divided into three groups . There was a significant difference in ECV .All patients with DbCM exhibited decreased echocardiographic TDI mitral annulus velocity E'/A' , and Pearson's correlation analysis showed that ECV was negatively associated with E'/A' ∗(1/(T1 myo post) − 1/(T1 myo native))/(1/(T1 blood post) − 1/(T1 blood native)). Combination of the differences of native T1 and post contrast T1 may lead to statistical difference in ECV. It demonstrated that ECV may be more sensitive than native and postcontrast T1 to indicate DM-related myocardial change. This might have significant clinical implications for diseases that are characterized by an alteration in ECV, such as DbCM. With increased sensitivity, the disease could potentially be detected earlier when only subtle differences in ECV may be present.Several studies have shown that DbCM is associated with increased collagen, especially type III collagen, in the myocardial interstitium of humans  and animInterestingly, we found that duration of diabetes, not hyperglycemia, HbA1c, troponin, or IMA, was an independent predictor of ECV and group with the longer duration of diabetes was associated with higher ECV value. Recent studies showed that hyperglycemia, even transient hyperglycemia (a few hours), can cause persistent (a few days) damage to cells by disrupting the signal feedback loop  and hypeOur results show that there is a significant relationship between impaired LV diastolic function and increased ECV in patients with DbCM, although the association between ECV and diastolic dysfunction has been reported in patients with heart failure with preserved ejection fraction  and in c2, and the patients in the study received different treatments. Finally, a myocardium zymogram examination was performed, markers of myocardial damage were assessed in only 84% of the patients and controls, and urine microalbumin was examined in only 74% of individuals.There are some limitations in this preliminary study. First, the overall number of subjects was limited; thus, the inhomogeneity of the patient group may have introduced bias. Second, we did not recruit patients with a GFR ≤30 mL/min/1.7 mWhen compared to normal control participants matched to age, BMI, and BSA, patients with DbCM exhibited elevated ECV detected using cardiovascular magnetic resonance T1 mapping technique. LV ECV correlates well with the duration of diabetes and LV impaired diastolic function. Cardiovascular magnetic resonance T1 mapping can reflect myocardial extracellular matrix expansion in patients with diabetic cardiomyopathy and may be a powerful technique for early diagnosis of diabetic cardiomyopathy.


Cardiac magnetic resonance (CMR) was used to investigate the extracellular compartment and myocardial fibrosis in patients with aortic stenosis, as well as their association with other measures of left ventricular decompensation and mortality.Progressive myocardial fibrosis drives the transition from hypertrophy to heart failure in aortic stenosis. Diffuse fibrosis is associated with extracellular volume expansion that is detectable by T1 mapping, whereas late gadolinium enhancement (LGE) detects replacement fibrosis.2) was used to define extracellular compartment expansion. Areas of replacement mid-wall LGE were also identified. All-cause mortality was determined during 2.9 ± 0.8 years of follow up.In a prospective observational cohort study, 203 subjects  underwent comprehensive phenotypic characterization with clinical imaging and biomarker evaluation. On CMR, we quantified the total extracellular volume of the myocardium indexed to body surface area (iECV). The iECV upper limit of normal from the control group . iECV was used together with LGE to categorize patients with normal myocardium , extracellular expansion , and replacement fibrosis . There was evidence of increasing hypertrophy, myocardial injury, diastolic dysfunction, and longitudinal systolic dysfunction consistent with progressive left ventricular decompensation  across these groups. Moreover, this categorization was of prognostic value with stepwise increases in unadjusted all-cause mortality .iECV demonstrated a good correlation with diffuse histological fibrosis on myocardial biopsies  and was increased in patients with aortic stenosis (23.6 ± 7.2 ml/mNCT01755936)CMR detects ventricular decompensation in aortic stenosis through the identification of myocardial extracellular expansion and replacement fibrosis. This holds major promise in tracking myocardial health in valve disease and for optimizing the timing of valve replacement. (The Role of Myocardial Fibrosis in Patients With Aortic Stenosis;   Calcific aortic stenosis is the most common valvular heart condition in the western world and a major public health burden Cardiac magnetic resonance imaging (CMR) provides the noninvasive gold standard method for measuring LV wall thickness, mass, volumes, and ejection fraction. Moreover, it is able to detect structural changes in the LV myocardium, including replacement fibrosis with the late gadolinium technique and expansion of the extracellular volume using T1 mapping We report the largest prospective study to evaluate systematically the usefulness of CMR in patients with aortic stenosis. In particular, we investigated its ability to detect expansion of extracellular volume (ECV) and replacement myocardial fibrosis, and how these are related to other markers of LV decompensation, functional capacity, and clinical outcomes.All stable patients with at least mild aortic stenosis (aortic jet velocity ≥2 m/s) who attended the Edinburgh Heart Centre between March 2012 and August 2014 were invited to participate in this prospective observational cohort study. The exclusion criteria were other forms of valvular heart disease (≥ moderate severity), significant co-morbidities with limited life expectancy, contraindications to gadolinium-enhanced CMR, and acquired or inherited nonischemic cardiomyopathies . In addition, we recruited healthy volunteers from the community with similar demographic characteristics in terms of age and sex, but no history or clinical features consistent with current cardiovascular disease. The study was conducted in accordance with the Declaration of Helsinki and approved by the local research committee. Written informed consent was obtained from all participants.All subjects underwent detailed clinical evaluation including history, physical examination, and electrocardiography. In addition, venous blood samples were obtained for evaluation of biochemistry and cardiac biomarkers of interest.Plasma cardiac troponin I (cTnI) concentrations were determined by the ARCHITECT STAT high-sensitivity cTnI assay  A 6-min walk test was performed in 156 (94%) patients as an objective measure of functional capacity in our predominantly older adult cohort, many of whom could not perform an exercise tolerance test. Explicit instructions were given to patients asking them to walk as far as possible for 6 min.Comprehensive transthoracic echocardiography was performed in all patients  by a dedicated research ultrasonographer (A.C.W.) and a cardiologist certified in echocardiography (C.W.L.C.). The severity of aortic stenosis and diastolic function were assessed according to American Society of Echocardiography (ASE) guidelines .CMR was performed using a 3-T scanner . Short-axis cine images were acquired and used to calculate ventricular volumes, mass, and function. Left ventricular hypertrophy (LVH) was defined as LV mass (indexed to body surface area using the Du Bois formula) >95th percentile using age- and sex-specific reference ranges Focal replacement fibrosis and ECV expansion were assessed in all patients using late gadolinium enhancement (LGE) and myocardial T1 mapping, respectively. LGE was performed 15 min after administration of 0.1 mmol/kg of gadobutrol . The presence of mid-wall myocardial fibrosis was determined qualitatively by 2 independent and experienced operators (M.R.D. and C.W.L.C.), and its distribution was recorded T1 mapping was performed using the Modified Look-Locker Inversion recovery We also investigated a novel marker, the indexed extracellular volume (iECV), which modifies the ECV fraction to act as a measure of the total volume of the extracellular compartment in the left ventricle. It was derived using the formula: ECV fraction × LV end-diastolic myocardial volume normalized to the body surface area.All patients who underwent surgical aortic valve replacement were approached regarding intraoperative myocardial biopsy at the time of surgery. Biopsies were obtained from the basal muscular septum 2 cm below the outflow tract using a Tru-Cut needle , and then were stained with picrosirius red and analyzed using an automated segmentation tool . Two bliWe examined the prognostic value of the different patterns of fibrosis on all-cause mortality as our primary outcome. Patients were followed between March 2012 and September 2015. All deaths were identified through the General Register of Scotland. We also assessed aortic stenosis–related mortality. This was established from the official death certificate and defined as any death in which aortic stenosis was listed as either the primary cause or a contributing factor to that death by the clinical care team.t test and the Mann-Whitney test where appropriate. We presented all categorical variables as percentages and used the chi-square test for comparison. The relationship between 2 continuous variables was assessed using either Pearson’s r or Spearman’s rho, as appropriate. Potential confounders were adjusted using multivariable linear regression analyses. Time-to-first event survival curves associated with the categories of LV decompensation were estimated using the Kaplan-Meier method and compared with the log-rank test. All statistical analyses were performed using SPSS version 20  and GraphPad Prism version 6.0 . A 2-sided p < 0.05 was considered statistically significant.We assessed the distribution of all continuous variables using the Shapiro-Wilk test and presented them as mean ± SD or median (interquartile range [IQR]). Comparisons were made using the 2-sample A total of 203 subjects were recruited: 166 patients with aortic stenosis  and 37 healthy volunteers. These 2 groups were well matched for age, sex, chronic renal impairment, and diabetes. Although a history of hypertension was more common in the aortic stenosis group, blood pressure was well-controlled and similar between the 2 groups at enrollment .Table 1B2 = 0.23) of the variance observed , it accounted for less than one-quarter  , with th2 vs. 16.1 ± 3.2 ml/m2; p < 0.0001)   . Moreove< 0.001) . Notably< 0.001)  and showWe explored iECV in greater detail, dividing our entire patient cohort into tertiles of iECV . Using t2 vs. 82 ± 16 g/m2, respectively; p < 0.001). LV mass index was independently associated with mid-wall myocardial fibrosis in those with hypertrophy  after adjusting for aortic stenosis severity, age, sex, and systolic blood pressure.Replacement mid-wall fibrosis, as assessed by LGE, was present in 44 (27%) patients with aortic stenosis but in none of the healthy volunteers. We examined the association between mid-wall myocardial fibrosis and the severity of aortic stenosis . Althoug2; IQR: 29.1 to 34.9 ml/m2 vs. 21.5 ml/m2; IQR: 20.6 to 22.4 ml/m2; p < 0.0001; ECV fraction: 29.1 ± 2.4% vs. 26.9 ± 2.1%; p < 0.001). The iECV was independently associated with mid-wall fibrosis after adjusting for age, sex, severity of aortic stenosis, and even LV mass . Similar associations were observed using the ECV fraction.It has been suggested that replacement fibrosis represents the irreversible final stage of diffuse interstitial fibrosis and extracellular expansion. Consistent with this hypothesis, patients with replacement mid-wall fibrosis had evidence of increased ECV on T1 mapping compared with patients without (iECV: 32.0 ml/m2) was used to define expansion of the extracellular myocardium. Values below this threshold defined normal myocardium. This categorization was then validated in the 11 patients who underwent myocardial biopsy, with the percentage fibrosis on histology increasing progressively across the 3 groups   .Figure 32). These patients had largely mild-to-moderate aortic stenosis, a mild hypertrophic response, minimal cardiac injury, and good LV performance (2), with values for aortic stenosis severity, LV mass, myocardial injury, diastolic function, and longitudinal systolic function that were intermediate between patients with normal myocardium and replacement fibrosis. Finally, 37 patients had evidence of replacement myocardial fibrosis on LGE. These patients were confirmed as having the most severe aortic stenosis, LVH, myocardial injury, and impairment in LV performance  , 71 patients had normal myocardium (iECV <22.5 ml/mformance  and 4. Tformance . Compare 0.0001) , whereas 0.0001) . These f 0.0001) .Figure 4Participants were followed up for an average of 2.9 ± 0.8 years during which a total of 14 patients with aortic stenosis died: 2 with normal myocardium, 4 with extracellular expansion and 8 with replacement fibrosis. Unadjusted all-cause mortality rates rose progressively across the groups  can provide an assessment of myocardial ECV expansion. Potentially, this can reflect increased myocardial fibrosis, myocardial infiltration, or expansion in the intravascular compartment Controversy remains as to the optimal T1 image analysis strategy iECV demonstrated good correlation with histological assessment of fibrosis burden. Moreover, there was a clear stepwise increase across tertiles of iECV in each of the different clinical and imaging measures of LV decompensation, as well as clinical outcomes, supporting iECV as a marker of decompensation. Finally, iECV provided the best discrimination among disease states, being the only T1 measure to differentiate among patients with mild, moderate, and severe aortic stenosis. In combination, iECV would therefore appear to provide the most useful marker of LV decompensation in aortic stenosis with advantages compared with both the ECV fraction and LV mass in isolation.How do extracellular expansion and diffuse fibrosis relate to the development of replacement fibrosis as detected using mid-wall LGE? In agreement with previous studies Using our CMR assessments, we categorized our patients into 3 stages of LV decompensation. We used iECV to differentiate patients with normal myocardium from those with extracellular expansion and then LGE to define replacement fibrosis . Across Our categorization holds promise as a means of monitoring the development of LV decompensation and helping to optimize the timing of aortic valve replacement. Currently, the development of symptoms guides the need for surgery. However, symptoms are frequently difficult to assess in older adult patients with multiple co-morbidities. Objective imaging assessments that monitor the changes in myocardial structure that are themselves responsible for progressive LV decompensation are therefore potentially attractive There were insufficient deaths to perform multivariate analysis. Studies with longer follow-up are required to confirm whether iECV is of independent prognostic value and to assess the contribution of the intravascular volume to T1 mapping values. Finally, although similar to previous studies PerspectivesCOMPETENCY IN MEDICAL KNOWLEDGE: Decompensation of the hypertrophic response in aortic stenosis is driven by progressive myocardial fibrosis and the associated expansion in the ECV. Changes in the LV myocardium can be tracked using CMR, which can be used to categorize patients into 3 groups: normal myocardium, extracellular expansion, and replacement fibrosis. There is evidence of increasing myocyte injury, left ventricular dysfunction, functional impairment, and all-cause mortality across these groups.TRANSLATIONAL OUTLOOK: This categorization holds promise in tracking the transition from hypertrophy to heart failure in aortic stenosis and in identifying the optimal timing of aortic valve replacement. Prospective randomized controlled studies are required to investigate this further.CMR can detect progressive fibrosis in aortic stenosis and can be used to categorize patients with normal myocardium, extracellular expansion, or replacement fibrosis. Across these groups, there was a stepwise increase in myocardial injury, fibrosis, LV dysfunction, and unadjusted mortality that was consistent with progressive ventricular decompensation. This categorization may be able to track the transition of hypertrophy to heart failure in patients with aortic stenosis.


Multivariate analysis showed that male sex, a history of smoking, high systolic blood pressure, high body mass index, high levels of fasting glucose and total cholesterol, low levels of albumin and hemoglobin, and a low estimated glomerular filtration rate were associated with abnormal echocardiographic findings. The rates of inappropriate left ventricular mass, systolic and diastolic dysfunction were higher in our patients with CKD and DM than in those without DM.Type 2 Diabetes mellitus (DM) is the leading cause of chronic kidney disease (CKD) worldwide, and is associated with an increased risk of left ventricular (LV) hypertrophy, LV systolic and diastolic dysfunctions. The aim of this study was to investigate abnormal echocardiographic findings in patients with CKD with and without DM, and identify the factors associated with these abnormalities. We enrolled 356 pre-dialysis patients with CKD (stages 3–5), including 208 with DM and 148 without DM. The structure and systolic and diastolic functions of the left ventricle were assessed using echocardiography, and the clinical and echocardiographic parameters were analyzed. The patients with DM had higher rates of observed/predicted left ventricular mass > 128% (69.5% vs. 56.7%,  Type 2 diabetes mellitus (DM) is the major cause of chronic kidney disease (CKD) worldwide, and in Taiwanese patients undergoing dialysis it accounts for around 45% of cases of end-stage renal disease. In addition, type 2 DM has been associated with an increased risk of heart failure (HF), morbidity and mortality , 2. HoweStructural and functional abnormalities of the heart have frequently been reported in patients with renal insufficiency due to pressure and volume overload , 4. In an = 208) and without (n = 148) DM are shown in Table The mean age of the 356 patients was 66.3 ± 12.2 years. Comparisons of the baseline characteristics between the patients with  and low estimated glomerular filtration rate (eGFR)  were significantly associated with observed/predicted LVM > 128% after adjusting for age, sex, a history of smoking, HTN, CAD, cerebrovascular disease, systolic and diastolic BP, BMI, albumin, fasting glucose, triglycerides, total cholesterol, hemoglobin, eGFR, calcium-phosphorous (CaXP) product, uric acid, proteinuria, and the use of medications including ACEIs, ARBs, β-blockers, calcium channel blockers and diuretics.The possible risk factors for an observed/predicted LVM > 128% in the patients with DM in multivariate stepwise analysis are shown in Table vs. never, unstandardized coefficient β, 16.009; 95% CI, 0.761 to 31.257; p = 0.040), BMI , albumin level  and eGFR   and a low albumin level  were significantly associated with mwFS < 14%.Multivariate stepwise analysis Table  also revversus female sex, unstandardized coefficient β, −1.493; 95% CI, 2.641 to −0.345; p = 0.011), albumin level , and level of total cholesterol  were significantly correlated with mwFS , high fasting glucose level  and low hemoglobin level  and E/Ea > 12 in the patients with DM , levels of albumin , fasting glucose , and hemoglobin , and the use of β-blockers  and diuretics   with regards the pathobiology of HF, in that they may impair both diastolic and systolic LV function directly through extracellular matrix protein cross-linkage and/or altered calcium handling . Further2.7, and hemodynamic load of a patient can be used to assess inappropriate LVM, and that the appropriateness of LVM can be estimated by the ratio of observed to predicted LVM  – 13.6g [2.7) + 0.64 × stroke work - 18.07 × sex  [All echocardiographic examinations were performed by two experienced cardiologists using a VIVID 7 system , with the patient lying quietly in the left decubitus position. The cardiologists were blinded to the patients’ clinical data. Two-dimensional and two-dimensionally guided M-mode images were recorded from standardized views. Echocardiographic parameters including LV end-diastolic volume, LVESV, LA diameter, LV internal diameter in diastole (LVIDd), LV posterior wall thickness in diastole (LVPWTd), interventricular septal wall thickness in diastole (IVSTd), E, Ea, and E/Ea ratio were recorded. LV systolic function was assessed according to LVEF and mwFS . The LVM – 13.6g . LVMI wa – 13.6g . Inapproale = 2) . Stroke ale = 2) , 15. Rawvs. never), and comorbidities were recorded from the patients’ medical records or interviews. BMI was calculated as the weight in kilograms divided by the height in meters squared. Blood and urine samples were obtained from the patients within 1 month of enrollment into the study. and the laboratory data were obtained from fasting blood samples using an autoanalyzer . Levels of serum creatinine were measured using the compensated Jaffé method  using a Roche/Integra 400 Analyzer  with a calibrator that could be traced in isotope-dilution mass spectrometry [Data including age, sex, smoking history . Data were expressed as percentages, means ± standard deviations, and medians (25th-75th percentile) for triglycerides. Between-group differences were assessed using the chi-square test for categorical variables and the independent


The Multi-Ethnic Study of Atherosclerosis (MESA) is the first large-scale multi-ethnic population study in the U.S. to use advanced cardiovascular magnetic resonance (CMR) imaging. MESA participants were free of cardiovascular disease at baseline between 2000 and 2002, and were followed up between 2009 and 2011 with repeated CMR examinations as part of MESA. CMR allows the clinician to visualize and accurately quantify volume and dimensions of all four cardiac chambers; measure systolic and diastolic ventricular function; assess myocardial fibrosis; assess vessel lumen size, vessel wall morphology, and vessel stiffness. CMR has a number of advantages over other imaging modalities such as echocardiography, computed tomography, and invasive angiography, and has been proposed as a diagnostic strategy for high-risk populations. MESA has been extensively evaluating CMR imaging biomarkers, as markers of subclinical disease, in the last 15 years for low-risk populations. On a more practical level, some of the imaging biomarkers developed and studied are translatable to at-risk populations. In this review, we discuss the progression of subclinical cardiovascular disease and the mechanisms responsible for the transition to symptomatic clinical outcomes based on our findings from MESA. The Multi-Ethnic Study of Atherosclerosis (MESA) is a prospective study sponsored by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health. The major objective of MESA was to evaluate the mechanisms that underlie the development and progression of subclinical cardiovascular disease (CVD) among asymptomatic individuals in the general population. MESA was primarily designed to study the progression of subclinical CVD and the mechanisms responsible for the transition to symptomatic clinical outcomes . In brieCMR is a noninvasive medical test that creates detailed pictures of the beating heart and vessels to look at their structure and function. In MESA, CMR was used to accurately quantify volume and dimensions of all four cardiac chambers, systolic and diastolic ventricular and atrial function, assess extent of replacement and interstitial fibrosis, and measure aortic structure and function, to evaluate patterns of cardiac structural remodeling and the prevalence of myocardial fibrosis across the life course, identify the myocardial mechanical consequences of remodeling, explore ventricular-arterial coupling and the role of arterial stiffness in CVD, and to study the prognostic importance of CMR biomarkers.In this review, we discuss the progression of subclinical CVD and the mechanisms responsible for the transition to symptomatic clinical outcomes based on our findings from MESA.The observed variations in the structure of the left ventricle might be attributable to differences in demographic variables , traditional risk factors , other medical conditions, socioeconomic status, and genetic influences in general populations. In MESA, LV wall thickness by CMR was associated with gender, race, body size, and LV function . ChineseThe average age of populations around the globe is increasing; as a result, an increasing number of older individuals become afflicted by CVD . While aAging prolongs exposure to CVD risk factors, therefore, understanding the influences of adverse LV remodeling by risk factors in the general population is important. In cross-sectional studies, CVD risk factors were associated with LV concentric remodeling , even though variants of LV remodeling patterns were observed with each CVD risk factor  , 6, 9–12Progressive LV remodeling may identify individuals at high risk for cardiac events in the general population. For example, in contrast to the natural history of concentric remodeling, the risk of incident CVD is greater for those individuals who develop concentric remodeling at a younger age Fig. . This paHeart failure (HF) is an important contributor to the burden and cost of national healthcare expenditures, and with the aging of worldwide populations, the estimated prevalence and cost of care for HF will increase markedly for all sex and racial/ethnic subgroups , 17. TheThe Framingham study has suggested that early identification of LV hypertrophy by electrocardiogram (ECG) or echocardiography may provide an opportunity to prevent the development of cardiac events, however, the MESA CMR study found that ECG had low sensitivity (10% to 26%) for detecting CMR-defined hypertrophy , and thaIn MESA, higher LV mass at baseline (≥95th percentile compared to the reference group of the <50% percentile) is strongly associated with incident HF with a hazard ratio of 8.6  Fig.  21]. Th. Th21]. Late gadolinium-enhancement imaging (LGE) can be used to detect replacement or focal myocardial fibrosis (scar) with a high degree of accuracy , 25. CMRFrom a community-based cohort in Iceland with a median age of 76 years, the prevalence of unrecognized myocardial infarction (MI) detected by CMR with LGE was 17% (157/936), and was associated with increased mortality similar to recognized MI, compared to individuals with no MI . In MESAFrom a clinical longitudinal study of patients with idiopathic, dilated cardiomyopathy (non-ischemic) receiving optimal medical therapy, LV systolic function decreased during a 24-month follow-up in patients with myocardial scar at baseline, while reverse remodeling was observed in patients without myocardial scar . MESA reAlthough LGE CMR allows for the assessment of replacement myocardial fibrosis, it is limited in the evaluation of diffuse interstitial fibrosis. T1 myocardial mapping—a fairly new technique that can be used to identify the exact T1 value of tissue—enables direct myocardial signal quantification, characterization of myocardial tissue composition and assessment of interstitial fibrosis, and correlates with interstitial fibrosis as assessed by means of invasive biopsy , 25.Our study, using contrast T1 found the following two main results: First, the age-related remodeling pattern of left ventricule—which is a progressive decline in LV volumes leading to concentric remodeling—is seen with progressive LV diffuse fibrosis. In other words, persions with either greater LV mass or without concentric remodeling are likely to have less interstitial fibrosis on average , 32. CarIn MESA, both replacement and interstitial fibrosis are important determinants of LV function, as shown in Fig. CMR tissue tagging provides precise quantification of incipient myocardial dysfunction through the assessment of myocardial strain and torsion, and has been used as the reference standard to validate two-dimensional speckle tracking echocardiography.In the MESA population, reduced regional peak systolic circumferential strain was associated with impaired regional myocardial perfusion in participants who did not have relevant coronary artery stenosis Fig.  38]. Th. Th38]. Finally, progression of symptomatic events from asymptomatic individuals is summarized in Fig. Clinically, LV noncompaction is a myocardial disorder characterized by excessive LV trabeculae. Although a high degree of noncompacted (trabeculated) myocardium in relationship to compact myocardium (trabeculated to compact myocardium [T/M] ratio > 2.3) has been associated with a diagnosis of LV noncompaction, MESA found that 43% of subjects without cardiac disease or hypertension had a T/M ratio > 2.3 in at least 1 myocardial segment . Using fCMR is the preferred method for evaluating right ventricular structure and function due to its crescent-shape in cross-sectional images. In MESA, older age was associated with lower RV (right ventricular) mass and higher RV ejection fraction; men had greater RV mass and larger RV volumes than women, but had lower RV ejection fraction; African-Americans had lower RV mass than whites, whereas Hispanics had higher RV mass . TrafficIn normal sinus rhythm, LA performance is characterized by a complex of three basic functions: reservoir function (collection of pulmonary venous flow during LV systole), conduit function (passage of blood to the LV during early diastole), and active booster pump function (augments LV filling during LV late diastole) , 55. HoiTissue-tracking on LA wall from cine CMR can provide an alternative and additional assessment of risk stratification or diastolic function beyond LA volume assessment. Data from a clinical study using this technique on 169 patients with a history of atrial fibrillation indicated that lower LA strain and strain rate during LV diastole (impaired LA reservoir function) is significantly associated with a prior history of stroke, and that the incremental value of LA strain for diagnosis of stroke is further increased by adding LA global strain to LA volume . SimilarOur study also reported the following: first, a presence of replacement scar on LV was associated with all three basic LA performance functions including an impaired reservoir function (lower maximum LA strain and strain rate), a conduit function (lower absolute strain rate), and a pump function (lower absolute strain rate), but was not significantly associated with total LAEF. Second, LV diffuse myocardial fibrosis assessed by contrast T1 was associated with an impaired reservoir function (lower LA strain) and a pump function (lower LA strain rate) but was not significantly associated with LA volumes . These fCMR has a distinct advantage over ultrasound in that three-dimensional visualization of the vessel wall and identification of components on the atherosclerotic plaque are possible. CMR has the unique ability to assess aortic geometry and function, representing vascular stiffness by vessel distensibility and pulse wave velocity with high reproducibility , 60.Of over 3500 MESA participants with a mean age of 61 years, ascending aorta diameter was increased with age; higher aortic stiffness as measured by aortic distensibility was associated with hypertension, larger left ventricle, and incident CVD events Fig.  60–63].–63.60–63In a longitudinal MESA study over 10 years of follow-up, aortic stiffness was associated with wall thickness of the aorta, which increases by 0.032 mm/year . Age, smAtherosclerotic coronary artery plaque rupture is a key event leading to acute coronary syndromes. Black-blood coronary arterial wall CMR provides a unique new method to nonivasively image and assess the morphological features of the coronary arteries Fig. . MESA haMESA also has used black-blood sequences to noninvasively characterize carotid-artery atheroma composition Fig. . Using tMESA is one of the first large-scale population studies to use advanced CMR imaging techniques among asymptomatic individuals, and to follow up with repeated CMR examinations as part of a large multi-ethnic population study. A dominant pattern of LV remodeling across the life course is concentric remodeling by progressively reduced LV volumes. Progressively increased LV concentric remodeling is associated with interstitial fibrosis and is a marker of CVD events. Abnormal remodeling with LV hypertrophy is associated with replacement fibrosis, and a high risk for developing HF. Replacement scar, however, in more than half of the participants with scar by CMR LGE is undetected by ECG or by clinical adjudication.Assessing LA and vascular geometry and function can be alternative tools to detect early stage subclinical disease. These CMR markers may significantly improve risk stratification in the general population. Finally, further advances in imaging are required to understand the role of risk factors and the progression of symptomatic disease pathways in the asymptomatic.


Risk stratification and early monitoring of anthracycline-induced cardiotoxicity is crucial. It has been shown that early histopathological changes occur well before myocardial functional abnormalities can be detected. Additionally a long period of latency with clinical recovery of systolic function before the development of overt heart failure has been described, further emphasizing the importance of early recognition of cardiac injury and defining routine follow-up.Long-term childhood cancer survivors were prospectively recruited after written informed consent. Study protocol was approved by the institutional review board. Subjects underwent a cardiovascular magnetic resonance (CMR) study on a 1.5 Tesla scanner  with routine cine acquisition in long and short axis planes, tissue characterization with native T1 mapping and late gadolinium enhancement (LGE), selected 2D phase contrast flow imaging and 3D whole heart anatomy. Ventricular volumes, mass, and ejection fraction (EF) were obtained via standard planimetry techniques using a semiautomated commercial software . Myocardial and left atrial (LA) strain parameters were derived from balanced SSFP cine images using dedicated software . LA reservoir, conduit and contractile functions were then quantified by both fractional volume changes and CMR feature tracking derived strain and strain rate. Transit times for pulse wave velocity (PWV) computations were determined using the foot-to-foot methodology.2, 83 months on average post-exposure. There was no significant difference between both groups in terms of volumetric analysis (table Twenty patients (mean age 18 ± 2 years) were enrolled. Twenty age-matched healthy controls (p = 0.109) were also recruited for comparison. Patients were studied after a mean anthracycline cumulative dose of 207 mg/mCMR can detect subtle myocardial and vascular abnormalities in young cancer survivors with normal EF exposed to anthracycline chemotherapy in the months following exposure. CMR may provide the short term markers of future cardiac morbidity necessary to design safer treatment regimens for younger cancer survivors.


Heart failure has a high prevalence in the general population. Morbidity and mortality of heart failure patients remain high, despite improvements in drug therapy, implantable cardioverter-defibrillators and cardiac resynchronisation therapy. New transcatheter implantable devices have been developed to improve the treatment of heart failure. There has been a rapid development of minimally invasive or transcatheter devices used in the treatment of heart failure associated with aortic and mitral valve disease and these devices are being incorporated into routine clinical practice at a fast rate. Several other new transcatheter structural heart interventions for chronic heart failure aimed at a variety of pathophysiologic approaches are currently being developed. In this review, we focus on devices used in the treatment of chronic heart failure by means of left ventricular remodelling, left atrial pressure reduction, tricuspid regurgitation reduction and neuromodulation. The clinical evaluations of these devices are early-stage evaluations of initial feasibility and safety studies and additional clinical evidence needs to be gathered in appropriately designed clinical trials. Heart failure (HF) is a major public health issue in both developed and developing countries . In the In an attempt to further improve the prognosis and quality of life of HF patients, several transcatheter implantable devices have emerged. In this review, we aim to describe a spectrum of recently introduced devices for the treatment of chronic HF by means of left ventricular (LV) remodelling, reduction of left atrial (LA) pressure, reduction of tricuspid regurgitation and neuromodulation. To provide an overview of these devices, this review focusses on describing these devices, their main procedural characteristics, patient eligibility, procedural results and clinical outcomes. Transcatheter devices for aortic valve implantation, mitral valve replacement/repair, paravalvular leak closure, percutaneously delivered biological therapies and interventions for acute HF fall beyond the scope of this review.Ischaemic heart disease is one of the main causes of HFrEF . Scar foIn classical surgical ventricular reconstruction procedures, the LV aneurysm is resected to reduce volume and obtain an elliptical shape. Results in multicentre registries for patients with ischaemic cardiomyopathy have been promising –11. HoweThe Revivent TC Ventricular Enhancement System  allows major LV reconstruction on a beating heart without cardiac incisions. The device is composed of titanium anchor pairs covered in polyester cloth Fig. b and conFirst, the scarred LV segments are exposed. A dedicated curved needle is inserted in the LV free wall to reach the septum and right ventricle where its tip can be ‘captured’ through a jugular venous access catheter. This creates a connection wire between the LV access site and the jugular access site. Over this wire, a fastening anchor is introduced through the catheter and subsequently retracted until it comes into contact with the right ventricular side of the intraventricular septum. Next, the catheter is removed and another fixing anchor is placed on the outer face of the ventricular wall via the site of needle insertion. Several anchors are implanted until optimal plication of the aneurysm is achieved Fig. c.Initial, published, data showed good durability and satisfactory results of the Revivent device in 11 patients . RecentlThe Parachute device  is comprised of a self-expanding frame, a polytetrafluoroethylene impermeable membrane and an atraumatic foot. The nitinol frame has a conical shape with 16 struts that ends in a 2 mm anchor to engage the myocardium for device stabilisation. The distal foot is radio-opaque and provides a contact point between the LV apex and the device in addition to facilitating visualisation for placement. The device is available in 4 sizes, all in two heights.Upon implantation, the left ventricle is accessed via the transfemoral approach using a conventional pig-tail wire. A stiff wire is then positioned for support and finally a pre-shaped catheter is placed near the LV apex. The device is advanced through the sheath until the foot is exposed and is advanced further until the foot contacts the apex. The device is deployed by pulling back on the guide catheter while the delivery catheter is held motionless, i. e. the device is ‘unsheathed’ by pulling back the outer sheath. The self-expansion is facilitated by inflating a low-pressure balloon until the anchors are fully expanded and in contact with the LV wall. Contrast angiography of the left ventricle is performed to confirm positioning before releasing the device.The first-in-human study (PARACHUTE IV: PercutAneous Ventricular RestorAtion in Chronic Heart FailUre due to Ischemic HearT DiseasE), demonstrated feasibility and safety of the device in 34 patients . ProceduThe main causes of tricuspid regurgitation (TR) are annular dilation and right ventricular enlargement, often secondary to left-sided heart disease . ModeratThe anatomy of the tricuspid valve apparatus is complex. The aim of minimally invasive approaches for the treatment of severe, symptomatic TR is placement of transcatheter valves, either in the position of the native tricuspid valve or in the caval veins. Here, we will discuss the devices for direct transcatheter tricuspid repair Tab. .Table 2TThe TriCinch System  is a percutaneous device designed for tricuspid valve remodelling. Transfemoral fixation of a stainless steel corkscrew into the anteroposterior tricuspid annulus is performed to assure stability. By pulling the system towards the inferior vena cava through a Dacron band the anchoring corkscrew remodels the annulus and tension is maintained by fixation of a self-expanding nitinol stent in the inferior vena cava Fig. . The steThe first-in-man case demonstrated the feasibility of the TriCinch device and showed a reduction in annular dimensions and TR severity . The TriThe Forma Repair System  is a transcatheter system designed to reduce TR by occupying the regurgitant orifice area with a foam-filled polymer balloon, providing a surface for native leaflet coaptation Fig. . In a fiThe Millipede IRIS  is an adjustable, semi-rigid, complete annuloplasty ring that has been used clinically in the mitral and tricuspid position. The implant consists of a frame, anchors and a cinching mechanism. With the eight points of the cinching mechanism surrounding the implant the diameter of the frame can be customised to achieve proper valve leaflet coaptation.Nine surgical patients have been treated with the IRIS ring, initially with a temporary placement series. A series of permanent implants reduced the valve diameter by up to 50% and the MR grade to zero in all but one patient. Recently, the data of the longest follow-up of approximately six months with echocardiography and computed tomography were presented . The datThe Cardioband  is the first transcatheter direct annuloplasty system designed for mitral and tricuspid repair. The Cardioband received its CE Mark for mitral valve repair in September 2015 . A modifThe MitraClip  is a single-size clip device  with grippers above the arms to capture the leaflets making an Alfieri-like repair of the mitral valve. Recently, it has been implanted via transjugular access in 3 patients with severe TR. Using edge-to-edge repair in between all three tricuspid commissures resulted in improvement in the TR and HF symptoms . FurtherThe Trialign Percutaneous Annuloplasty System  has been used successfully in the treatment of functional TR , 30. In Approximately half of the patients with HF suffer from HFpEF . HoweverPercutaneous perforation, balloon dilation and stent implantation of the interatrial septum are established techniques to create or enlarge atrial communication , 38. HowThe InterAtrial Shunt Device (IASD) system  consists of a nitinol device (outer diameter 19 mm) inserted percutaneously in the interatrial septum to produce a permanent 8 mm atrial septal communication Fig. . The desResults of a pilot study have been published , 41. TheThe V‑Wave shunt device  is a percutaneously implanted device that creates a unidirectional shunt from the left to the right atrium. It is a self-expanding nitinol structure encapsulated with expanded polytetrafluoroethylene. The exit funnel contains three glutaraldehyde-fixed, porcine pericardial leaflets that remain in the open position and are expected to close when RA pressure exceeds LA pressure by 1–2 mmHg, preventing reverse right-to-left shunting.A transseptal introducer sheath is advanced into the left atrium after puncturing the fossa ovalis. The device is attached with a three latches mechanism to a delivery cable, loaded into the catheter. After opening the left side in the left atrium, the system is pulled back into the interatrial septum, where the device is detached and released.Initial safety and beneficial outcomes were reported in a single-centre proof-of-principle cohort study of 10 HFrEF patients with successful implantation . At 1 moThe Atrial Flow Regulator  is a self-expandable double-disc wire mesh device constructed from 0.004–0.0075 inch nitinol braided into two flat discs connected by a waist of 1–2 mm and central fenestration. The device is available in 6, 8 and 10 mm fenestration diameters with a total device diameter of 18, 24 and 30 mm. The first-in-man procedure was presented in a patient with severe irreversible pulmonary arterial hypertension . BesidesIncreased sympathetic activation and reduced parasympathetic tone, as reflected by reduced carotid baroreceptor reflex sensitivity and/or decreased heart rate variability, are potentially important contributors to HF progression associated with poor outcome. Experimentally increasing the parasympathetic tone by vagal nerve stimulation to normalise the autonomic imbalance has recently emerged as a potential therapy for HF. Several devices for vagal nerve stimulation are being developed and studied in patients with HF Tab. .Table 4TThe CardioFit  is an implantable neurostimulator system that can deliver low current adjustable electrical pulses to stimulate the vagal nerve. Parameters can be remotely programmed using a wireless system. The stimulator senses the heart rate via an intracardiac electrode and delivers stimulation at a fixed delay from the R wave. Upon implantation, the intracardiac sensing electrode is positioned at the right ventricular apex using a subclavian puncture. A cuff electrode is implanted on the cervical vagus below the carotid artery bifurcation and a stimulation lead is tunnelled under the skin to join the sensing electrode and the stimulator. An open-label study with 32 HF patients showed that chronic vagal nerve stimulation may be safe and tolerable and may improve quality of life and LV function at 1 year . More reThe Rheos device  is a carotid baroreceptor reflex stimulator intended for the treatment of resistant hypertension and HF. The non-randomised feasibility DEBuT-HT (Device Based Therapy in Hypertension) trial showed a sustained reduction of blood pressure in 17 resistant hypertensive subjects and improved functional capacity . A sub-sThe Harmony Aortic Stimulation System  is a minimally invasive implantable neurostimulator system capable of delivering stimulation to the aortic wall. An increase in pressure suppresses the sympathetic tone of the heart and vasculature and increases the parasympathetic tone of the heart. Impulses from the Harmony system are sent to the brain through neural pathways and result in a reduced arterial stiffness and a reduced heart rate leading to a lowered myocardial oxygen consumption and LV afterload. The stimulation parameters can be remotely programmed using a dedicated wireless communication system. Currently, the ENDO-HF  feasibility Study, in which the St. Antonius Hospital will be participating, is recruiting to evaluate the safety and performance of the HASS device in the treatment of 20 HF subjects during a 5-year follow-up.Newer transcatheter structural heart interventions for chronic HF are often based on surgical techniques. Some of these surgical techniques have been abandoned due to a low procedural success rate or unpredictable results. For example, surgical LV remodelling, such as the Batista procedure, in patients with a dilated cardiomyopathy was inferred not a predictable reliable alternative to transplantation . ConsequSeveral new transcatheter structural heart interventions for chronic HF, aiming at a variety of pathophysiologic approaches, are currently being developed. Preliminary results associated with most of these new interventions are promising, with significant improvements in symptoms, functional status, quality of life and haemodynamic performance. However, the devices covered in this review are in relatively early stages of development and it is too early to compare devices within the same group based on clinical results. Data from most of these technologies are therefore restricted to first-in-man cases and observational studies, limited by experience and number of patients. We need larger randomised studies that can provide definite data on the efficacy of these devices.


ATnorm) and active tension at the resting sarcomere length . Myocardial contractility was inversely determined from personalized heart models by matching CMR-imaged LV dynamics. Compared with controls, patients with recent STEMI exhibited increased LV wall active tension when normalized by SBP. We observed a linear relationship between Treq 2 days post-MI and global longitudinal strain 6 months later . Treq may be associated with changes in LV function in the longer term in STEMI patients complicated by LV dysfunction. Further studies seem warranted.Biomechanical computational models have potential prognostic utility in patients after an acute ST-segment–elevation myocardial infarction (STEMI). In a proof-of-concept study, we defined two groups (1) an acute STEMI group  complicated by left ventricular (LV) systolic dysfunction; (2) an age- and sex- matched hyper-control group , no prior history of cardiovascular disease and normal systolic blood pressure (SBP < 130 mmHg). Cardiac MRI was performed in the patients (2 days & 6 months post-STEMI) and the volunteers, and biomechanical heart models were synthesized for each subject. The candidate parameters included normalized active tension ( Adverse left ventricular remodelling after acute MI portends an increased risk of heart failure5, based on the pathophysiology of impaired left ventricular systolic function7, infarct size8 and microvascular pathology10. Approximately one half of all patients who survive a STEMI have persistent, irreversible myocardial damage that is associated with a longer-term risk of heart failure10.Death rates after acute ST-segment–elevation myocardial infarction (STEMI) have fallen markedly in recent years1. On the other hand, LVEF reflects changes in left ventricular dimensions during the cardiac cycle, rather than contractility (pump function), and the majority of patients who die prematurely have a normal or mildly reduced LVEF11. Therefore, on an individual patient basis, risk prediction using LVEF remains somewhat limited. Advances in myocardial strain imaging hold promise12. Clinicians usually lack information on left ventricular biomechanics in their patients after an acute STEMI, but even if biomechanics were described, their clinical significance in this setting is unknown. Personalized computational heart modelling have emerging potential to quantitatively assess biomechanical parameters which directly reflect left ventricular pump function14.In clinical practice, therapeutic decisions are informed by an evidence base linked to surrogate biomarkers, notably left ventricular ejection fraction (LVEF)16, including post-MI18. Biomechanical models that are based on cardiac magnetic resonance (CMR) imaging, although complex and time-intensive, have potential to realise computational heart modelling for personalized risk prediction in the clinic13.Biomechanical heart models have advanced from idealized theoretical concepts to subject-specific models with multi-scale i.e. intra-cellular, whole cell, inter-cellular tissue, organ, and multi-physics e.g. electrophysiology, myocardial biomechanics, blood flow, coupling under physiological and pathological conditionsAT) in the left ventricular wall, defined as We designated candidate biomechanical parameters implicated in left ventricular pump function including in vivo were assessed using an immersed boundary-finite element (IB/FE) method incorporating data on myocardial function and infarct characteristics from the CMR scans obtained from patients with acute severe STEMI and healthy controls without any history of cardiovascular disease.There is a knowledge gap on the clinical significance of biomechanical parameters in patients following an acute STEMI. We aimed to investigate the discriminative value of candidate biomechanical indices estimated by computational heart modelling in patients with acute STEMI and healthy control subjects matched for age and sex. Left ventricular biomechanics The characteristics of the study participants, including their CMR findings, are described in Table in vivo CMR measurements. The relative difference of LV end-diastolic volume (LVEDV) in both the hyper-control group and the STEMI group were within in 2%. Systolic circumferential strain difference in the hyper-control group was slightly higher than the STEMI group, which was because the objective function in the hyper-control group incorporated left ventricular end-systolic volume (Eq. (Table ume (Eq. ). Figurep = 0.04), as shown in Fig. p = 0.08), as shown in Fig. p < 0.01). This difference may indicate that following an acute STEMI, higher active tension was necessary to maintain normal left ventricular pump function to compensate the loss of functional myocardium in MI region.The biomechanical parameters, myocardial active tension , as shown in Fig. p = 0.38), however, the result was not statistically significant.Table in vivo CMR data along with detailed models of active myocardial tension generation. For the first time, we have shown that, compared with the hyper-control group, patients with recent STEMI complicated by left ventricular systolic dysfunction, exhibited increased active tension generation. The biomechanical parameters, required contractility  compared to healthy subjects (5–10 mmHg)25  six months later. Details are provided in the supplement. In the healthy group, the relative mean bias was 0.4 ± 6.5% for intra-observer, and 0.3 ± 8.1% for inter-observer. Similar results were found in the MI group. The inter-correlation coefficient was > 0.93 for all analysis. This is consistent with findings from the study by Mangion et al.27, in which they demonstrated that cine-estimated circumferential strain using this b-spline deformable registration method has similar diagnostic performance as DENSE within healthy individuals, and more reproducible than feature tracking27. Similar as in other strain estimation techniques using MR imaging, the overall accuracy of our cine strain estimation approaches would be affected by imaging quality, out-of-plane motion, respiratory motion, etc.28.Regional circumferential strains from cine images were estimated using in-house developed b-spline deformable registration method31 to model in vivo ventricular function, but avoid to determining many different parameters at cellular level, which is nearly impossible from in vivo CMR imaging. To evaluate how sensitive the modelled left ventricular contractile function was to uncertainties in strain measurements, simulations were rerun by varying measured strains with 10% change (subtracting 0.015 in magnitude). We found that a 10% decrease in average systolic circumferential strain would result in 20% decrease in optimized 32, as reported by Sun et al.19. As discussed above, strain estimation from cine images has high reproducibility with nearly zero bias in intra-/inter observer variability in both the healthy and MI groups, and similar diagnostic performance as in DENSE27, and is well within the reported ranges from other studies35. Moreover, extreme-case’–‘hyper-control’ study, uncertainties in circumferential strain estimation using cine images will not affect our findings on 36.In systolic phase, only data Eqs  and 9 andata Eqs . Therefo36. Chabiniok et al.37 found that in a pig model of reperfused MI, the estimated contractility in the remote zones increased progressively up to one-month later. We found that left ventricular contractility directly reflected by et al.38 found that the maximum myocardial contractility was not reduced in cardiomyocytes obtained from failing hearts compared to non-failing control hearts, rather reduced beta-adrenoceptor sensitivity was the distinguishing functional problem associated with clinical heart failure and increasing with age. Houser and Margulies39 further confirmed that the basal contractility was well preserved under resting conditions in dysfunctional hearts, but the ability to increase contractility (contractility reserve) in response to inotropic stimuli was severely depressed. The enhanced overall left ventricular contractility in the STEMI patients compared to controls in our study may be explained by adaptive mechanisms40, such as sympatho-adrenal and neurohumoral mechanisms, in order to preserve left ventricular pump function and cardiac output. Taken together, our results may provide insights into left ventricular biomechanics that complement the Frank-Starling law of the heart7. On the other hand, myocardial contractile reserve is finite and left ventricular remodelling in the longer term may have maladaptive consequences7. A cardiomyocyte with a lower Our results on myocardial contractile function after acute MI are consistent with prior mathematical modelling of animal and human hearts, in which myocardial contractility was shown to paradoxically increase in diseased hearts, potentially reflecting a compensatory responseWe have shown that biomechanical parameters of left ventricular function may present new insights into the pathophysiology of acute MI over and above standard measures of left ventricular pump function Table . Our casThe t Figure .41, to clinical images42 and to different computational models22. Directly measuring in vivo, even in vitro. Moreover, in vitro measurements can differ significantly from in vivo assessments. For example, much higher Ca2+ sensitivity and isometric tension were reported in ‘intact’ myocytes than in ‘skinned’ myocytes43. Indirect validation can be achieved by comparing modelling results with other computational models. Table in vivo clinical data. Although there are variations among different studies, required contractility in the healthy group and the STEMI group in our study are within the values reported by other studies. The variations might be due to inter-individual variations, sample size, different mathematical descriptions, etc. Furthermore, we also observed that estimated myocardial contractility is higher in diseased heart compared to healthy subjects  because these parameters are the final output of myocardial contraction, not the determinants of the contraction. However, the proposed biomechanical parameters  the “extreme case” design, which helped reduce the number for identifying the difference, however, it was still not clear to which extent the proposed biomechanical parameters can have prognostic values; (2) future work shall include different patient types, i.e. STEMI patients with preserved left ventricular function with/without ‘no-reflow’, and shall evaluate how biomechanical factors vary according to age and sex, and how they evolve after acute MI; (3) we only estimated the overall In summary, we have simulated left ventricular dynamics using CMR imaging at end-diastole and end-systole for a group of patients with acute severe STEMI complicated by ‘no-reflow’ and an age-/sex-matched hyper-control group with normal blood pressure. Our results showed that the required contractility  or accept (Type 2 error) a true null hypothesis, we implemented an ‘extreme-case’ – ‘hyper-control’ design in a proof-of-concept study of the potential discriminative value of novel biomechanical parameters46.The UK Research Ethics Service (ethics committee references: 10/S0703/28 and 11/AL/0190) approved the study and all of the participants provided written informed consent. All methods, including MRIextreme case group) with acute severe left ventricular dysfunction from a population of patients (n = 324) with acute STEMI who had been enrolled into a single centre prospective CMR cohort study between July 14, 2011 and November 22, 2012. Patients with acute STEMI were eligible for enrolment in this study if they had an indication for emergency PCI due to a history of symptoms consistent with acute myocardial ischemia and with supporting changes on the electrocardiogram (i.e. ST-segment elevation or new left bundle-branch block). Exclusion criteria represented standard contra-indications to contrast CMR, including a pacemaker and estimated glomerular filtration rate <30 ml/min/1.73 m2.Patients were identified from the British Heart Foundation MR-MI study population . We identified six patients  and a normal CMR scan. Six healthy volunteers were selected as the hyper-control group with normal office blood pressure (<130/80 mmHg) at the time of the scan per ESC Guidelines for the management of arterial hypertension50. Subjects were invited to rest for ten or more minutes prior to the BP measurement. Two arm-cuff BP measurements were obtained in the sitting position at least 5 minutes apart. The standard size cuff was used and a larger or smaller bladder was used for large or thin arms, respectively. The cuff was placed at the level of the heart. We used auscultation of phase I and V (disappearance) Korotkoff sounds to identify systolic and diastolic BP, respectively.Blood pressure (BP) was measured according to standard guidelinesCMR was performed at 1.5 Tesla  in the six patients with acute STEMI 2 days after hospital admission and six months later. CMR was also performed in the healthy volunteers. Patients and healthy volunteers underwent the same imaging protocol except that healthy volunteers <45 years did not receive intravenous gadolinium contrast.3. Cine images were acquired in the three-chamber, horizontal long-axis, and vertical long-axis planes.The CMR protocol for imaging left ventricular structure and functional assessment involved steady-state free precession cine scans with a short-axis left ventricular stack from the base to the apex. The slice thickness was 7 mm with 3mm gap, typical cine imaging parameters were matrix = 180 × 256, flip angle = 80°, TR: 3.3 ms, TE: 1.2ms, bandwidth: 930 Hz/pixel. The voxel size was 1.32 × 1.32 × 7 mm3. Inversion times were individually adjusted to optimize nulling of apparently normal myocardium .In the STEMI group, late gadolinium enhancement (LGE) images covering the entire left ventricle were acquired 10–15 minutes after an intravenous injection of 0.15 mmol/kg of gadoterate meglumine  using segmented phase-sensitive inversion recovery (PSIR) turbo fast low-angle shot sequence. Typical LGE imaging parameters were matrix = 192 × 256, flip angle = 25°, TE = 3.36 ms, bandwidth = 130 Hz/pixel, echo spacing = 8.7 ms and trigger pulse = 2. The voxel size was 1.32 × 1.32 × 8 mmLeft ventricular outcomes were assessed at 6 months using the same CMR protocol. We assessed change in LVEF (%) at six months from baseline after the acute STEMI and global longitudiual systolic strain at six months. Diogenes feature-tracking software  was used to quantify systolic strain from long axis cine images  in related to end-diastole, then these three longitudinal systolic strains were averaged to derive global longitudinal strain (GLS).in vivo cine CMR images in early diastole when left ventricular pressure is lowest, as shown in Fig. 18.Left ventricular geometries were reconstructed from 51, which employs a finite element description of the myocardial mechanics that enables the use of realistic constitutive models. The formulation of the IB/FE approach and application in left ventricular dynamics can be found in refs21.Left ventricular dynamics at end-diastole and end-systole were solved using an in-house developed IB/FE methodu is the fluid velocity, I is the identity matrix, and W18,The total myocardial stress was defined asAssuming the fibre can only bear the loading when it is stretched, the terms involving f is the myofibre orientation at current configuration. The active stress 18. In brief, the contractile force T in Eq., the same approach as in our prior study24. To estimate 27, N is the total number of the segments from short-axis images, To personalize the left ventricular models, material parameters were determined by minimizing the difference between the simulated left ventricular dynamics and entclass1pt{minimaion (Eq. ), other 31. The passive response for myocardium remote from the infarct zone, i.e. remote zone myocardium, was determined using a similar approach as used in the healthy left ventricular models. In systole, the infarct zone was modelled as a purely passive material, and 19. Therefore, our estimates of left ventricular contractility may be more robust than the estimates of passive myocardial stiffness.In the MI models, we assumed that the passive response of the infarct zone was 50 times stiffer than hypo- or akinetic myocardium which did not exhibit late gadolinium enhancement , as previously described46, and because of the computational complexity of modelling left ventricular biomechanics, the sample size was necessarily limited in order to be computationally efficient. Based on the study from Wang et al.30, the mean difference in the average required myocardial contractility  and a p-value ≤ 0.05 was taken as statistically significant.Supplemental Material


The assessment of post-myocardial infarction (MI) left ventricular (LV) remodeling by cardiovascular magnetic resonance (CMR) currently uses criteria defined by echocardiography. Our aim was to provide CMR criteria for assessing LV remodeling following acute MI.Firstly, 40 reperfused ST-segment elevation myocardial infarction (STEMI) patients with paired acute (4 ± 2 days) and follow-up (5 ± 2 months) CMR scans were analyzed by 2 independent reviewers and the minimal detectable changes (MDCs) for percentage change in LV end-diastolic volume (%ΔLVEDV), LV end-systolic volume (%ΔLVESV), and LV ejection fraction (%ΔLVEF) between the acute and follow-up scans were determined. Secondly, in 146 reperfused STEMI patients, receiver operator characteristic curve analyses for predicting LVEF <50% at follow-up  were undertaken to obtain cut-off values for %ΔLVEDV and %ΔLVESV.The MDCs for %ΔLVEDV, %ΔLVESV, and %ΔLVEF were similar at 12%, 12%, 13%, respectively. The cut-off values for predicting LVEF < 50% at follow-up were 11% for %ΔLVEDV on receiver operating characteristic curve analysis (area under the curve (AUC) 0.75, 95% CI 0.6 to 0.83, sensitivity 72% specificity 70%), and 5% for %ΔLVESV . Using cut-off MDC values  of 12% for both %ΔLVEDV and %ΔLVESV, 4 main patterns of LV remodeling were identified in our cohort: reverse LV remodeling (LVEF predominantly improved); no LV remodeling (LVEF predominantly unchanged); adverse LV remodeling with compensation (LVEF predominantly improved); and adverse LV remodeling (LVEF unchanged or worsened).The MDCs for %ΔLVEDV and %ΔLVESV between the acute and follow-up CMR scans of 12% each may be used to define adverse or reverse LV remodeling post-STEMI. The MDC for %ΔLVEF of 13%, relative to baseline, provides the minimal effect size required for investigating treatments aimed at improving LVEF following acute STEMI.The online version of this article (doi:10.1186/s12968-017-0343-9) contains supplementary material, which is available to authorized users. Despite prompt reperfusion of acute ST-elevation myocardial infarction (STEMI) by primary percutaneous coronary intervention (PPCI), adverse left ventricular (LV) remodeling still occurs in a significant proportion of patients , and itsCardiovascular magnetic resonance (CMR) is considered the gold-standard imaging modality for quantifying myocardial infarct (MI) size , and meaTherefore, the first aim of this study was to perform intra-observer and inter-observer measurements of LV parameters in paired acute and follow-up CMR scans in reperfused STEMI patients, in order to determine the minimal detectable changes (MDCs) that could be used as cut-off values for defining post-STEMI remodeling. Secondly, we aimed to identify the cut-off values for clinically important %ΔLVEDV and %ΔLVESV to predict LVEF <50% at follow-up , as a suPatients included in this study have been reported previously in 4 separate studies –19 as suAnalysis was performed using CVI42 software . Forty STEMI patients reperfused by PPCI, with paired acute and follow-up scans from one of the cohorts reported recently –21 were Patient level data were obtained from our 2 previously reported cohorts , 19, andt test/Wilcoxon signed rank test or unpaired Student t test/Mann Whitney U test where appropriate. One-way analysis of variance was used to obtain the mean squared error for each LV parameter for inter and intra-observer measurements and their corresponding square root provided their standard error of the measurement (SEM). The 95% confidence interval (CI) for each SEM was calculated as previously described [P < 0.05 was considered statistically significant.Statistical analysis was performed using SPSS version 22 . Normality was assessed using Shapiro-Wilk Test. Continuous data was expressed as mean ± standard deviation (SD) or median (interquartile range) and categorical data was reported as frequencies and percentages. Groups were compared using paired Student The mean age of the 40 STEMI patients used for intra-observer and inter-observer measurements was 59 ± 13 years old and 35 (88%) were male. Details of the paired acute and follow-up CMR scans are shown in Table P values between 0.15 and 0.97).Table P = 0.17).The LVEDV and LVESV were significantly higher and the LVM and LVEF were significantly lower both on the acute and follow-up scans when the T&P were included as part of the LV volume as shown in Fig. Details on the intra-observer and inter-observer measurements for %ΔLVEDV, %ΔLVESV, %ΔLVM and %ΔLVEF, both for when T&P was included as part of either LV volume or LV mass, are provided in Table Irrespective of how the T&P were dealt with, the highest MDC95 was 11% for %ΔLVEDV and 10% for %ΔLVESV for intra-observer measurements. The corresponding values for inter-observer measurements were 12% for both %ΔLVEDV and %ΔLVESV. Further details for %ΔLVM and %ΔLVEF are provided in Table A total of 146 STEMI patients had matching acute (mean of 4 ± 2 days) and follow-up CMR scans (median of 4 4–5) months). 12/146 (8%) patients had their scans on a 3 T scanner and the rest were acquired on 1.5 T scanners. Table  months).P = 0.03 for ROC curves comparison  of 0.83 (95% CI 0.77 to 0.90), when compared to an AUC of 0.75 (95% CI 0.67 to 0.83) for %ΔLVESV, These cut-off values were lower than the MDC95 for inter-observer measurements. Therefore, using the cut-off values for MDC95 for inter-observer measurements (given that the scans from different studies were by different observers), an increase in LVEDV of 12% had a sensitivity of 73% and a specificity of 69% and an increase in LVESV of 12% had a sensitivity of 89% and a specificity of 62% to detect an LVEF of <50%.Figure Figure P = 0.002. Although those with larger MI size and MVO were more likely to have adverse LV remodeling (Group 4 - red box), there were also patients with small MI sizes and no MVO who went on to develop adverse LV remodeling  The MDC95 in %ΔLVEDV and %ΔLVESV of 12% was higher than the corresponding cut-off values for predicting LVEF < 50% at follow-up , providing cut-off values for assessing adverse and reverse LV remodeling following STEMI by CMR; (2) The MDC95 for %ΔLVM and %ΔLVEF from the acute to follow-up CMR scan were 12% and 13%, respectively, providing cut-off values for assessing changes in these LV parameters following STEMI by CMR; (3) By assessing the combined %ΔLVEDV and %ΔLVESV between the acute and follow-up CMR, we observed 4 different patterns of LV remodeling following STEMI.In this study, we measured both intra-observer and inter-observer variability, and as expected, the MDC95s for all these LV parameters were greater for inter-observer than intra-observer measurements. Our analyses on the whole cohort mainly focused on the inter-observer rather than the intra-observer measurements because different operators analyzed the scans from each study. We found that the inter-observer MDC95s for %ΔLVEDV and %ΔLVESV between the acute and the follow-up CMR were 12% each. Using these cut-off values for defining LV remodeling following STEMI, a combination of an increase in LVEDV (≥12%) and in LVESV (≥12%) could be used to identify adverse LV remodeling, whereas a decrease in LVESV (≥12%) with or without a decrease in LVEDV (≥12%) could be used to identify reverse LV remodeling. However, further studies are required to investigate the prognostic implications of these proposed cut-off values for defining adverse and reverse LV remodeling following STEMI.As expected, the cut-off value of 12% or more for %ΔLVEDV to define adverse LV remodeling obtained in our cohort is significantly lower than that defined by echocardiography (20% or more for %ΔLVEDV). This is due to the better spatial resolution of CMR and superior intra-observer and inter-observer variability . On the Currently there is no consensus on whether T&P should be included as part of the LV volume or as part of LV mass during LVEF and LVM assessment by CMR . We therIn the absence of clinical outcomes, LVEF <50% in patients with scars have previously been shown to be associated with poor clinical outcomes . Using tUsing the combination of %ΔLVEDV and %ΔLVESV from the acute to the follow-up CMR, we observed 4 different patterns of post-STEMI remodeling Figs.  and 6 Th2 increase in indexed LVEDV). Several studies have also shown that MVO was a strong predictor of adverse LV remodeling [Westman et al.  recentlymodeling . Using tmodeling , the devWe found the MDC95 in %ΔLVM between acute and follow-up scans to be ≥12%, suggesting that this would be the minimal change in LVM that is unlikely due to inter-observer measurement errors. However, the interpretation of changes in LVM following STEMI is complicated by the fact that on the acute scan, the presence of myocardial edema also contributes to the changes in LVM acutely and therefore we did not investigate %ΔLVM in post-STEMI LV remodeling. However, it would be interesting to determine the MDC95 for assessing %ΔLVM in patients with LV hypertrophy related to hypertension or aortic valve disease, in order to provide cut-off values which can be used in studies assessing the regression of LV hypertrophy.Finally, we found the MDC95 for % ΔLVEF to be ≥13% in STEMI patients when using CMR. This finding suggests that only a relative change in LVEF of 13% or more can be reliably detected by CMR as being beyond inter-observer measurement errors. This is equivalent to an absolute change of 6.5% in a patient with an acute LVEF of 50%. This needs to be taken into consideration when planning future studies designed to investigate new treatments for improving LVEF following STEMI.n = 10) providing the minimal detectable change in LVEF by echocardiography in patients undergoing chemotherapy (10 patients with echocardiography at 2 time-points) [Inter-observer and intra-observer measurements were performed in only 40 patients (80 scans) but this is significantly larger than the number of patients used in a previous study (-points) . We only-points)  There waThe MDCs for %ΔLVEDV and %ΔLVESV between the acute and follow-up CMR scans of 12% each may be used to help define adverse and reverse LV remodeling post-STEMI. Combining %ΔLVEDV and %ΔLVESV following STEMI may provide additional insights into the different pattern of LV remodeling, but their prognostic impact needs to be assessed in future studies. Finally, the MDC for %ΔLVEF of 13% relative to baseline provides the minimal effect size that needs to be taken into consideration when investigating treatments aimed at improving LVEF following acute STEMI.