Themed imaging-endpoint guidance on trial design to support drug-discovery or change in clinical practice (part II), will be presented in a follow-up paper in due course. As CMR continues to undergo rapid development, regular updates of the present recommendations are foreseen.Cardiovascular disease remains a leading cause of morbidity and mortality globally. Changing natural history of the disease due to improved care of acute conditions and ageing population necessitates new strategies to tackle conditions which have more chronic and indolent course. These include an increased deployment of safe screening methods, life-long surveillance, and monitoring of both disease activity and tailored-treatment, by way of increasingly personalized medical care. Cardiovascular magnetic resonance (CMR) is a non-invasive, ionising radiation-free method, which can support a significant number of clinically relevant measurements and offers new opportunities to advance the state of art of diagnosis, prognosis and treatment. The objective of the SCMR Clinical Trial Taskforce was to summarizes the evidence to emphasize where currently CMR-guided clinical care can indeed translate into meaningful use and efficient deployment of resources results in meaningful and efficient use. The objective of the present initiative was to provide an appraisal of evidence on The online version of this article (10.1186/s12968-018-0484-5) contains supplementary material, which is available to authorized users. RationaleImaging measures as biomarkers and surrogate endpoints – review of the definitions and guiding principlesExecutive Statements of the SCMR CT Committee Writing Groupi.Global volumes, mass, thickness and functionii.Regional wall motion, deformation and dyssynchronyiii.Diastolic functionQuantification of ventricular volumes and massi.LGE ii.T2 imaging Tissue characterisation - visualisationi.T1 mappingii.T2 mappingiii.T2* mappingQuantitative tissue characterization Myocardial perfusion imagingVascular endpointsanalytical validation, including the accuracy and precision, and qualification of parameters in disease context (part I). The manuscript structure, preparation and evidence appraisal procedures were based on a prior agreement within the SCMR CT Writing Group (WG) , as well as general guidance of the SCMR on Expert Consensus publications. This included the assignment of themed subsection to a minimum of 2 and a maximum of 5 authors with background of contribution to the field, which are included in the authors’ list (Table Cardiovascular disease (CVD) remains the greatest cause of morbidity and mortality globally. The changing natural history of CVD due to improved care of acute conditions and ageing population necessitates new strategies to tackle conditions with a more chronic and indolent course. These include an increased deployment of safe screening methods, life-long surveillance, and monitoring of both disease activity and tailored-treatment, by way of increasingly personalised medical care. Cardiovascular magnetic resonance (CMR), is a non-invasive, radiation-free method, which can support a significant number of clinically relevant measurements, offers many new opportunities to advance the state of art of diagnosis, prognosis and treatment of patients with CVD. Several key CMR measurements are highly accurate and reproducible, providing gold-standard measures in cardiovascular imaging. Published agreements on standardized acquisition and post-processing ensure robustness and transferability for widespread use , 2. WithAnalytical validation involves assessment of assays or techniques supporting the acquisition of measurements, as well as establishing the range of conditions, under which the measurement will give reproducible and accurate data. Important performance metrics include precision, accuracy, lab-to-lab reproducibility, limits of detection and signal-to-noise, as well as determination of the reference values. Qualification refers to summation of the available evidence about the biomarker-disease-relationship, including its relevance, diagnostic and prognostic value. Also, causal relationships to disease pathogenesis are considered, including the effects of therapeutic intervention on the imaging marker and to the clinical endpoints of interest. (4)Utilization is a contextual analysis of the above evidence with regards to the definition of the context for the biomarker’ proposed clinical use. In addition, factors such as prevalence, heterogeneity, morbidity and mortality of the disease, as well as the risks and benefits of an intervention are considered.A biomarker is a characteristic that can be objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological response to a therapeutic intervention . They caCMR uniquely provides quantitative information on cardiac function  and myocardial tissue characteristics that are diagnostic of acute and chronic disease. CMR involves contrast- and non-contrast media imaging techniques. CMR does not involve ionising radiation and can be safely repeated.The ability of CMR to assess left ventricular (LV) and right ventricular (RV) volumes and function accurately and precisely has been demonstrated in excellent validation studies with a large body of evidence on inter-study reproducibility. Standardised approach to quantification is available. There are extensive sets of normal values for gradient echo (GRE) sequences, whereas smaller sets support the modern acquisition techniques ). Thus, the appropriate reference ranges need to be selected for the technique used. The accuracy and reproducibility of novel post-processing algorithms based on signal intensity thresholding remains unknown. CMR is rightly regarded as the reference standard for the assessment of left and right ventricular volumes and left ventricular mass. CMR should be considered as the first line technique in clinical trials requiring one of these parameters for in- or exclusion or as an endpoint. The evidence for the use of quantification of cardiac function and volumes is favourable.CMR tagging techniques have been well validated. Other CMR based strain imaging techniques have been either directly compared with tagging or indirectly against a technique originally compared to tagging. Accuracy, precision and normal values are still to be further improved especially for radial strain and strain velocities. While normal values are available they show considerable regional variation as well as variation between different studies. There is very limited data on inter-study reproducibility. CMR-based strain-imaging techniques seem similarly suited as echocardiographic techniques for assessing longitudinal motion and strain. The evidence for the use of CMR-based strain imaging techniques is promising.CMR has been reasonably well validated versus pressure volume (PV) loops and echocardiography for diastolic filling, atrial volumes and function and transmitral and pulmonary venous flow. More work is required to fully establish its role based on classic LV inflow (filling) parameters (e.g. E/e’). Although CMR may have advantages over other techniques by direct assessment of myocardial tissue, more evidence to support the use of CMR-based assessment of diastolic function is needed.Late gadolinium enhancement (LGE) has been extensively validated as a marker of irreversible damage post myocardial infarction in animals as well as versus biopsies and in explanted hearts, demonstrating excellent accuracy and precision superior to alternative techniques. There are strong data on inter-study reproducibility. LGE is a strong parameter to predict outcome and has been shown to be superior to volumes and function. CMR based LGE should be used as the first line technique in clinical trials requiring the assessment of regional scar or fibrosis for inclusion or exclusion or as an endpoint. CMR should also be employed for optimal risk-classification of trial subjects with ischemic or non-ischemic cardiomyopathies. The evidence for the use of LGE imaging for visual detection of regional myocardial fibrosis and quantification of ischaemic scar is favourable. The quantification of non-ischaemic scar remains promising.T2-weighted imaging (T2W) has been well validated in animals, phantoms and humans and demonstrates an excellent ability to visualize areas of significantly increased tissue water or myocardial haemorrhage. There are scarce data on inter-study reproducibility in acute myocardial infarction. There is a small number of outcome studies in area at risk (AAR), including an application in a clinical trial. There is lack of reproducibility data and outcome studies for T2W-oedema imaging (or Lake-Louise criteria) in inflammatory cardiac conditions. Due to the availability of many different sequences no generally accepted standard has been defined. For clinical trials, it is important to use a validated and standardized approach amongst different centres and vendors and use normal values and effect sizes specifically for these sequences. Timing of imaging after an acute event must be highly standardized. Contrast-enhanced cine bSSFP imaging is emerging as possible time-efficient option for imaging the AAR. The evidence for the use of T2W imaging of AAR is promising.Myocardial T1-mapping has been well validated in phantoms, animal models, and human biopsies and explanted hearts. In model diseases, the various acquisition techniques demonstrate the ability to relate to diffuse fibrosis, increased extracellular space and oedema, in a quantifiable fashion. T1-mapping indices have been shown to be strong predictors of outcome in non-ischaemic dilated cardiomyopathies, superior to volumes, function and LGE. Due to the availability of many different sequences, no generally accepted standard has been defined. To employ T1 mapping in clinical trials, the use of validated (well understood sequence) and standardized approach amongst different centres and vendors is mandatory, due to the different normal values and effect sizes between various sequences. CMR T1-mapping may be considered as a standard for adequate risk-assessment of patients with non-ischemic dilated cardiomyopathy in clinical trials. The evidence for the use of T1 mapping is promising.Myocardial T2-mapping has been well-validated in phantoms, animal models, and human biopsies. The various techniques demonstrate an excellent ability to relate to myocardial water content/oedema, in a quantifiable fashion. Due to the availability of many different sequences no generally accepted standard has been defined. Similar to T1 mapping above, the use a validated and standardized approaches amongst different centres and vendors is mandatory for the use in clinical trials, due to the different normal values and effect sizes specifically for these sequences. The timing of imaging after an acute event must be highly standardized. The evidence for the use of T2 mapping is promising.Myocardial T2* mapping measurements in thalassemia have been excellently validated and standardized for 1.5 T and provide superior outcome data if used for therapy guidance. As such T2* can be regarded as the clinical reference standard in thalassemia. T2* measurements during or shortly after an acute coronary or vascular event provides important prognostic information in terms of short-term LV remodelling. The evidence for the use of T2* mapping is favourable.CMR perfusion imaging has been well-validated against animal models, alternative techniques as well as related to outcomes. In various meta-analyses, CMR perfusion imaging has been confirmed as the most accurate technique for non-invasive assessment of myocardial ischemia. However, due to the availability of many different sequences and post-processing parameters, no generally accepted standard for (semi-) quantification has been defined. While there is good correlation of quantification techniques with microspheres and positron emission tomography (PET), normal values are variable and show high inter-study variability. Perfusion imaging should be considered as a first line technique for assessing the presence, extent and localization of inducible ischemia, its use for full quantification requires locally validated and standardized sequences with specific normal values. Trials assessing reduction in ischaemic burden following intervention are currently lacking. The evidence for the use of myocardial perfusion imaging for visual detection of ischaemia is favourable. Quantitative perfusion imaging is increasingly becoming available. At this stage the various approaches require more validation, especially as large outcome studies have been performed with visual analysis.Vascular imaging provides robust quantifiable data on vessel diameters, vessel wall thickness and vessel distensibility. Vascular stiffness measurements aside, there are limited data on truth validation or interstudy reproducibility for some vascular areas. Limited data supports CMR being non-inferior to computed tomography (CT) for aortic visualization and dimensions. Large databases of normal data are available. CMR vascular imaging is well suited to assess vascular anatomy and function. Aortic and carotid vessel wall imaging, are robust markers of atherosclerotic burden in these vessels and can be used in clinical trials. Coronary vessel wall imaging and tissue characterization is a promising research tool but require further advances in the robustness and simplicity of the methods.Quantification of cardiac volumes at end-diastole and end-systole, LV mass and global systolic function represent the measurements of cardiac imaging, which are fundamental to decision making in clinical cardiology. These are obtained using standard cine images by CMR and can be processed by virtually every available post-processing software. Cine imaging also supports assessment of regional wall motion abnormalities, either visually or by strain quantification (presently limited to research).Cine imaging (bSSFP sequences)Acquisition defined in SCMR Standardized Protocols :○ complete LV and RV coverage using short axis (SAX) stack of slices○ long axis LV views.Older approaches of cine imaging based on fast gradient recalled echo (GRE) sequences: compared to bSSFP sequences, GRE sequences lead to larger LV mass and smaller LV volumes.Standardised approach defined in SCMR Standardized Post-processing recommendations ○ LV mass measurement: inclusion of papillary muscles into LV cavity reduces accuracy compared to autopsy, but results in higher precision ;○ LV dimensions and wall thickness: most reproducible in 3-chamber view ;○ An early study showed higher reproducibility of RV volumes; measured in a transverse (TRA) stack , a later○ TRA stack does not support reproducible RV mass measurements , 7. No d○ The accuracy and reproducibility of novel post-processing algorithms based on signal intensity thresholding is unknownLV mass: excellent validation against gold-standard in animals and excised human hearts after transplantation ) ○ transthoracic 2- and 3D echocardiography , 13○ cardiac CT A body of evidence supports superior precision of CMR-derived measurements compared to:Benchmarking datasets available Normal values available have been derived for various field strengths, imaging sequences, post-processing approaches, age-, sex- and ethnicity groups .Diagnostic interpretation and clinical decision making underlying practice guidelines is based on evidence derived with echocardiography. The cut-off values (most notably for LV ejection fraction) have been adopted by other imaging modalities, including CMR. The original evidence base by transthoracic echocardiography has been revalidated and expanded upon by CMR  –20. ReceMyocardial strain imaging enables time-resolved quantification of myocardial contraction and relaxation, which is less influenced by the ventricular pressure/volume loading conditions. Characterisation of these events in various conditions, with aim to better understanding of tissue architecture and the underlying efficiency of deformation, remains an active research domain. Once a complex and often time-consuming acquisition and post-processing, strain imaging with CMR is now made possible using standard cine imaging. Owing to the issues with the reproducibility and an overall lack of incremental diagnostic and prognostic data, the value of strain imaging in clinical use remains investigational.○ Cine imaging (feature tracking)○ Tagging  , harmoni○ Displacement ENcoding with Stimulated Echoes (DENSE) ○ Strain encoding imaging (SENC) ○ Visual segmental analysis ○ Regional wall motion score○ Deformation/strain analysis ○ Dyssynchrony Results may be presented either segmental (provided for 17 segments as per AHA/ACC) or global  values.Validation in phantoms and animals○ Tagging is referred to as the reference standard for strain imaging  28, 29], 2928, 2○ DENSE ○ DENSE can provide greater reliability and resolution of segmental analysis ○ Feature tracking Comparative studies to tagging:○ Strain by DENSE, tagging, feature tracking ○ Dyssynchrony by feature tracking Comparative studies to echocardiography:Wall motion based on visual assessment of each segment, observer dependent on training and experience  .○ Considerable inter-vendor variability of outputs , 40Feature-tracking reproducibility remains problematic, especially for radial strain , 39.○ CiBenchmarking datasets available .Normal values available for global strain components Determination of reversibility of parameters/signatures with treatmentUtility in guiding treatment through clinical trials.Assessment of diastolic relaxation is an indirect approach to myocardial tissue characterisation and can be done by CMR by employing analogous approaches to those used in echocardiography. Increased myocardial stiffness commonly coincides with the states of increased LV wall thickness, either due to global pathological myocardial processes, such as accumulation of myocardial fibrosis or amyloid, or due to regional myocardial injury, such as ischaemic scar. Because CMR provides means of direct tissue characterisation, by LGE and T1 mapping, assessment of diastolic function by CMR is not commonly used.Time resolved curve of left ventricular diastolic filling from cine SAX stack , 49. As 2- and 4-chamber cine views for measurement of left atrial (LA) volume○ Through-plane flow measurement across mitral valve, pulmonary venous inflow (velocity encoding 130 cm/sec)○ Basal SAX slice measurement of mitral flow and annulus velocities (velocity encoding < 30 cm/sec)Phase-contrast gradient echo sequence acquisitions:Tagging Transmitral E and A wavesPulmonary venous inflow S, D and A wavesMitral annulus velocity e’LA sizePeak early diastolic strain rate (PEDSR)Against PV loops Comparative studies with echo –54Normal values available for early diastolic velocitiesStandardisation of acquisition and post-processing approachesDevelopment of robust normal values for vendor-specific acquisition/post-processingEstablishment of characteristic disease-specific or pathophysiology specific signatures of diastolic abnormalities (diagnostic and prognostic relevance)Determination of reversibility of parameters/signatures with treatmentUtility in guiding treatment through clinical trials.LGE is a myocardial tissue characterization technique, which demonstrates regional myocardial tissue differences based on differential uptake/washout of gadolinium-based contrast agent (GBCA). LGE is optimally suited to visualize myocardial infarction and scar, as well as areas of regional scar/fibrosis in non-ischaemic cardiomyopathies, such as in hypertrophic and dilated cardiomyopathy, sarcoidosis or myocarditis. In acute myocardial infarction or myocarditis, LGE co-localises with areas of cell-necrosis or oedema. Conversely, LGE can also reveal unenhanced areas in the core of the contrast-enhanced regions, representing either microvascular obstruction (MVO) (a no-(re)flow phenomenon) or intramyocardial haemorrhage (IMH).Inversion recovery (IR) prepared T1 weighted gradient echo sequences with either individually adapted prepulse delay  and/or inline Phase-Sensitive Inversion-Recovery (PSIR)-based reconstruction algorithm [Acquired as in full LV coverage in short axis and long axis views during mid-diastole~ 10 min delay time from administration of GBCA [○ shortening of T1 - > increased signal intensity in areas of intense GBCA accumulation compared to areas with quick wash-out, such as normal myocardium;○ differential distribution between myocardial regions with intact myocardial cells (membranes) and expanded extracellular space due to necrosis, fibrosis or scar;○ in amyloidosis, there is commonly poor contrast difference between the blood and myocardium due to expansion of the extracellular volume throughout the myocardium, resulting in lower gradient in GBCA concentration between these two tissues, save for the bright endocardial border;GBCAs lead to:Evidence of LGE is a marker of expanded extracellular space, most commonly seen due to necrotic myocardium or scar tissue○ first pass perfusion imaging,○ early IR-TFE imaging ○ LGE (app. 10–20 min)○ native T1○ Contrast-enhanced cine-bSSFP○ First pass and early hypoenhancement less strongly related to remodelling and clinical outcomes than LGEMethods to assess microvascular obstruction (MVO) (and IMH) include –57:○ firAlternative ways to IMH imaging by T2* (see section Mapping) .Visual assessment reporting on the presence, type (ischemic/non-ischemic), location, and transmurality ○ Manual approach ○ full width half maximum (FHWM)○ The “n”-SD approach : 2SD (for nonischaemic scar)/5SD of the noise (for infarction) above the signal intensity of normal myocardium [○ LGE extent is reported as % of LV massQuantitative assessment (i.e. LGE extent) can be based on several approaches:MVO can be measured manually or by SD-thresholds. The strong contrast between scar and MVO results in a highly reproducible delineation .○ In acute myocardial infarction, LGE overestimates infarct size (see T2 imaging section) reviewed in .○ CMR favourably compares to alternative techniques  due to its higher sensitivity and spatial resolution to resolve infarct transmurality  , explanted hearts) , localization , transmurality .Excellent diagnostic tool for the determination of chronic myocardial infarction and regional fibrosis in cardiomyopathies.Stronger predictor of outcome than LVejection fraction (EF) and LV volumes in chronic stable disease Stronger predictor of outcome than LV-EF and LV volumes in acute myocardial infarctionStronger predictor of malignant ventricular arrhythmia, sudden death and lower likelihood of improvement with medical therapy in various patient groups with cardiomyopathyLGE transmurality able to inform on reversibility of underlying regional wall motion abnormalityMVO and IMH - predictors of poor outcome, but uncertainty whether these are independent  of infarStandardization of acquisition methods and nulling approaches to achieve similar relative signal-to-noise ratios of fibrotic tissue versus normal myocardium .Improved definition of transmurality and segmental allocation for visual interpretation○ To determine the cut-off value, the method with the best prognostic/ diagnostic value.○ The different data acquisition techniques and post-processing algorithms may require different post-processing approaches.Standardization of quantification methods for LGE. Studies used the FWHM and the SD-based methods, however, this remains suboptimally standardized in terms ofMyocardial tissue characterization using electrocardiogram (ECG)-triggered T2 weighted (T2W) sequences is used to demonstrate the regional differences in myocardial water content. T2W imaging is optimally suited to visualize regional oedema, such as in acute myocardial infarction, supporting assessment of area at risk (AAR)/myocardial salvage index (MSI). It was also applied in myocarditis imaging, as a part of Lake-Louise Criteria (LLC). Owing to lengthy and artefact-prone acquisitions, T2W imaging is less fit for use in everyday clinical practice, and increasingly replaced by the modern quantifiable acquisition alternatives, T1 and T2-mapping.Several sequences/approaches are available for T2W cardiac imaging :○ T2W black-blood turbo spin echo (T2W-TSE)○ T2W short tau inversion recovery (STIR),○ T2-prepared SSFP○ Emerging new approach for AAR using contrast-enhanced SSFP (based on T2 and T1 contrast) for AAR assessment based on the acquisition of the cine LV stack ○ long acquisition time over 2 heart beats result in long breath-holds and artefacts due to cardiorespiratory motion;○ variations in phase array coil sensitivity○ high signal from slow moving blood (e.g. at the subendocardium and in the ventricular apex)○ low contrast-noise ratio in differentiating oedematous vs. normal tissueTechnical limitations of T2W CMR pulse sequences are susceptible to various influences causing some limitations as endpoints and in clinical practice: from percent AAR (by T2W imaging) , 65.○ MSI is calculated by dividing the salvage area by the AAR.○ Post processing is subjective ○ Optimal imaging time for AAR assessment is ideally 4–7 days after acute MI .T2W imaging of AAR/myocardial salvage  :○ Visual relaxation times reflect tissue hydration.○ Alterations in T2 signal enable visualisation of regional myocardial oedema as area of hyperintense signalPhantom and Tissue studies○ The ischemic AAR consists of oedema and is typically greater than infarct size - > T2W imaging represents a non-invasive approach to AAR estimation.○ T2W imaging enables retrospective determination of the ischaemic area-at-risk○ Comparison of contrast-enhanced bSSFP with myocardial perfusion SPECTAnimal models○ Dynamic changes of AAR after acute myocardial infarction , 67, 68○ Comparison of T2W AAR by CMR with myocardial perfusion SPECT○ Comparison of contrast enhanced bSSFP with myocardial perfusion SPECT ○ LLC vs. EMB-criteria for myocarditis  revealed that manual contouring provided the lowest inter, intraobserver, and interstudy variability for both infarct size and oedema quantification .The FWHM method for infarct size quantification and the Otsu method for myocardial oedema quantification are acceptable alternatives .No data available for contrast-enhanced bSSFPNo data available for oedema ratio in myocarditisNormal reference = absence of hyperintense signal In myocarditis: semiquantitative ‘oedema ratio’ of < 1.9  ○ Detection of myocardial damage in patients with acute coronary syndrome (ACS) ○ Determination of salvaged myocardium in STEMI patients, prediction of higher revascularisation rate and adverse prognosis The utility of T2W-imaging in excluding ACS in the emergency room has become less prominent since the advent of high-sensitivity troponin assays.T1 mapping is a quantitative tissue characterization technique, which allows quantifying the rate of longitudinal relaxation of myocardial tissue (and blood). The resulting measurements come as an absolute number , which is sequence-specific, requiring standardization of acquisition and calibration of values in health and disease.Acquisition in mid-diastole Magnetisation preparation by inversion (180°) or saturation (90°) prepulses○ resulting in differences in T1 accuracy .Several imaging schemes with differences in number of images, pauses for magnetization recovery (which can be defined as either beats or seconds), flip angles, use of adiabatic prepulses, acceleration techniques Native (without GBCA) and post-contrast T1 mapping Single (midventricular) short axis slice  or three short axis slices  ○ for myocardial T1 with most sequences not relevant within physiological heart rates < 80 bpm;○ less important for post-contrast images, more relevant for long T1 values such as native blood, or in very severe myocardial disease , as more time needed for full relaxation;○ every other beat acquisition  may be used in tachycardiaHeart-rate dependency:Extracellular volume fraction (ECV) calculation based on pre- and postcontrast T1 mapping acquisitions and blood values which requires standardization and heart rate correction for each component Sequences allowing acquisition of a series of images (using increasing time delays) during the evolution of the longitudinal relaxation:○ magnitude image detection: SMAG(t) = abs(A – B exp.(−t/T1*)○ phase sensitive inversion recovery (PSIR) detection : SPSIR(t) = A – B exp.(−t/T1*).Pixel-wise image reconstruction and exponential curve-fitting of signal intensity values (3-parameter fitting model):T1 value equates with the time at 63% recovery of longitudinal magnetisationPost-processing affected by the regional variation due to variable sensitivity of phase array coils and artefacts in the lateral wall  more precise compared to SAX ROI, segmental values difficult to normalise)▪ septal ROI  or SAX R▪ excluding areas of LGE▪ conservatively within the myocardium ○ diffuse  myocardial involvement:▪ Segmental ROI placement :▪ Significant regional differences in T1 values - > difficulty in normalising segmental T1 values▪ No significant differences between septal values for basal and midventricular slice, however considerable overestimation in apical slice ○ regional myocardial T1 values:Myocardial ROI placement:Blood ROI placed in the centre of the blood pool using same acquisition as above, avoiding papillary musclesPost-contrast T1 blood: less in-flow effect compared to native T1○ direct measurements: native T1, post-contrast T1▪ lambda (partition coefficient of contrast agent distribution between blood and myocardium) = (R1myocardiumnative-R1myocardiumpost-contrast)/ (R1bloodnative- R1bloodpost-contrast), where R1 = 1/T1▪ ECV is partition coefficient lambda, which relates to the extracellular space only, by accounting for intracellular space of blood by haematocrit (requires contemporaneous blood sampling): =(1-Ht)x lambda• derived from a relationship between haematocrit and longitudinal relaxation rate of blood (R2 = 0.51)• derived for selected sequences and a single vendor only , 81▪ synthetic ECV calculation○ calculated indices based on pre- and post-contrast T1 mapping acquisitions:T1 indices ○ Correlations vary between reports○ Differences in staining techniques, inclusion/exclusion of areas of LGE○ Differences in sequence parameters, type/dose/timing of GBCA, different sequences used in pre/postcontrast acquisitions, post-processing (ROI placement)Histological correlation with collagen volume fraction  myocardial T1 values indicate the presence of diseased myocardium and relate to worse outcome:Sequence and vendor specific standardization of acquisition, normal values and calibration of values in health and diseaseOutcome dataData on guiding management○ unclear whether identical sequences or different schemes for pre/post-contrast acquisitions amount to a justifiable counterpart of pre/post-contrast acquisition, but rather a mix of poorly related diagnostic tests.Pre- and post-contrast T1 mapping acquisitionsT2 mapping is a quantitative tissue characterization method mainly reflecting the water content of the myocardium. It is based on a series of images with different time delays acquired during the diastolic standstill to map the T2 magnetization decay. Increasing evidence base for T2 mapping supports its utility in detection of myocardial inflammation and oedema, in myocarditis and in assessment of acute myocardial infarction (AMI). Myocardial T2 values were shown to decrease with anti-inflammatory treatment.Sequences acquiring separate images during the evolution of the transverse relaxation in diastolic standstill○ T2-prepared bSSFP sequence○ T2-hybrid gradient echo and spin echo (GraSE) sequenceT2 prepared spin echo sequences with several different schemes with differences in number of image acquisitions, flip angles, accelerating techniques, single-shot vs. multiechoNative acquisition (no contrast agent)Single (midventricular) short axis slice  or three short axis slices  No regional variation due to variable sensitivity of phase array coilPixel-wise image reconstruction and exponential curve fittingT2 value equates with the time at 63% decay of transverse magnetisation, direct myocardial measurement○ Myocardial septal ROI or SAX ROI ○ Segmental ROI placement ROI placement:No significant difference in segmental values for basal and midventricular slice, overestimation in apical slice Phantom sequence characterisation (T2 accuracy and precision)Histological validation ○ AMI reperfused and non-reperfusedin animal modelsModel diseases: AMI, myocarditis, transplant rejectionValidation of water component difficult in animals and biopsiesHas been shown to be superior to T2W imaging and Lake-Louise Criteria for the diagnosis of acute myocarditis  ○ a single midventricular SAX slice - > septal T2*measurement○ 3 short axis slices - > global T2* measurementAs per SCMR protocols:Each sequence yields sequence specific “absolute” T2* values (in ms)Each sequence requires standardisation  prior to clinical useOnly 1.5 T and 3 T datasets are validated for measurement of cardiac iron content , 86;As per SCMR standardised image interpretation and post-processing T2* values = the time delay taken for decay of the myocardial signal by 63%○ Myocardial septal ROI in midventricular slice encompassing both epicardial and endocardial borders, to prevent the epicardium-endocardium heterogeneity of iron deposition ○ Segmental ROI placement ○ Complete SAX coverage in basal, midventricular and apical slice generates a global T2* value, however, this is less frequently used.ROI placement:Significant differences in segmental values reported. Regional variation most likely due to variable sensitivity of phase array coils to different regions.○ Ex vivo histological validation - > good correlation of T2* measurements versus chemically assayed iron○ Biopsy not useful as reference standard○ Therapy guidance by T2* imaging is superior to other tests – as such T2* in thalassemia can be regarded as the clinical reference standardValidation against myocardial and liver iron content :Iron loading:○ A myocardial region of interest with a T2* < 20 ms is taken to represent haemorrhage○ T2* (< 20 ms) is highly discriminative of haemorrhagic transformation within the infarct zone vs. infarct zone without haemorrhage or the remote zoneIMH - intramyocardial hemorrhageT2* useful in detecting relevant cardiac iron overload involvement in thalassemia major – > at T2* < 20 msec○ negative cardiac remodelling ) and diastolic dysfunction  and○ response to iron-depletion treatment  is used to demonstrate regional reduction in myocardial perfusion to assess the presence of hemodynamically significant coronary artery stenosis. Myocardial stress perfusion CMR imaging is a routinely used diagnostic test in patients presenting with symptoms and signs of stable angina. It is also used in patients with medium-to-high pretest likelihood of significant (flow-limiting) coronary artery disease (CAD), patients with known coronary artery stenosis to assess significance of specific lesion(s) and patients with previous revascularization or myocardial infarction. Myocardial stress perfusion CMR imaging can also demonstrate the presence of microvascular disease e.g. in patients with angina and normal coronary arteries. In this case, the imaging abnormality during stress testing is typically hypoperfusion of the sub-endocardium with a circumferential distribution. Myocardial stress perfusion CMR imaging may be useful to demonstrate potential CAD aetiology in patients with HF with or without reduced LV ejection fraction. Quantitative perfusion imaging is increasingly becoming available.○ Dynamic acquisition during the passage of the contrast agent bolus (dose 0.05–0.1 mmol/kg body weight) through the left ventricular cavity and the myocardium;○ First pass acquisition during pharmacological stress;○ Repeat pass acquisition at rest ○ 3 short axis slices  every heart beat for a minimum of 40–50 heart beats→ a minimum of 40–50 dynamic measurements);○ 3D whole heart acquisition methods available, currently no demonstrated diagnostic advantage over 2D 3-SAX slice acquisition ;Acquisition as per SCMR Standardized Protocols ○ Dynamic○ spoiled fast gradient echo (GrE);○ bSSFP pulse sequences;▪ echo planar imaging (GrE-EPI);▪ spatial undersampling (e.g. sensitivity encoding (SENSE)▪ generalized autocalibrating partially parallel acquisitions (GRAPPA),▪ spatio-temporal undersampling ;○ typically combined with acceleration techniques:○ differing in the acquired spatial (3x3x8 mm to 1.3 × 1.3x8mm) resolution.Sequences: various sequences available based on saturation prepulse for preparation of magnetization and acquisition of data with either:Diagnostically relevant is the stress acquisition.○ discern possible artefacts○ to support calculation of parameters based on the change of stress and rest perfusion .The rest acquisition is used to:Pharmacological stress is the standard approach ; exercise stress has shown feasibility in research settings.○ Visual interpretation is the standard clinical approach:▪ not present at rest,▪ outside the enhanced myocardium on LGE images.○ Hypoperfusion is defined as segmentally reduced contrast agent uptake at peak stress persisting for 5 consecutive heart beats○ several diagnostic standards of test positivity proposed demonstrating a reduced increase of flow or reduced peak flow in areas subtended by vessels with significant coronary stenosis (see below)as per SCMR Standardized Postprocessing ○ Visual ○ stress and rest acquisition to calculate perfusion reserve or perfusion reserve indices; peak perfusion can be determined from stress images only○ dual bolus, dual contrast sequences or other algorithms to correct for the non-linearity of signal intensity and contrast agent at higher doses○ correction for baseline signal differences○ efficient motion correction○ a myocardial perfusion reserve index (MPRI) can be calculated from various parameters, usually using the relative upslope between rest and stress (corrected for changes of upslope of the contrast bolus in the left ventricle)○ full quantification can be achieved with various mathematical algorithms .The benefits of quantitative and semi-quantitative over qualitative interpretation remain at present investigational. Quantitative and semi-quantitative evaluation require:○ Flow in phantoms and microspheres in animals;○ Comparative effectiveness diagnostic studies and meta-analyses studies of CMR to PET, SPECT, invasive coronary angiography and invasive flow measurements  (negative test)▪ ≥ 3/16 segments defined as prognostically relevant (warrants attempt to revascularize on prognostic grounds (positive test)○ ESC guidelines on stable CAD (16 segment ACC/AHA segmentation) :▪ ≤2/16 ▪ ≤ 3/32 segments indicate a good prognosis with OMT▪ ≥4/32 segments defined as prognostically relevant ○ Subsegmentation into 32 segments :▪ Either transmural hypoperfusion defect or perfusion defect affecting 2 slices or > 60% in basal and midventricular slice, > 90% in apical slice.○ MR-INFORM: prognostically relevant ischaemia :▪ EitherVisual assessment: several diagnostic standards on the interpretation of the presence/severity/prognostic relevance of myocardial hypoperfusion based on number of affected segments:(Semi-) quantitative assessment of MBF, MPR or MPRI: experimental data available for different field strengthsData from prospective observational studies using stress myocardial perfusion CMR have shown significant predictive association for the presence/severity of myocardial ischemia with outcome Standardization of post processing methods (semi quantitative and quantitative) to allow definition of normal values, effect sizes and improvement of reproducibility. Different post processing methods may apply for different data acquisition techniques.Improvement of spatial resolution / coverage based on faster acquisition techniques (e.g. compressed sensing)Quantitative perfusion imaging is increasingly becoming available. At this stage the various approaches require more validation, especially as large outcome studies have been performed with visual analysis.CMR allows a comprehensive assessment structure and function of the great vessels by anatomical assessment of vessels dimensions and cross-sectional areas, functional assessment of the vessel wall  pulse wave velocity (PWV)). Tissue characterisation by T1-, T2- and proton density-weighted imaging and, more recently, by T2 mapping allows characterization of tissue composition.○ cardiac triggered-contrast enhanced CMR angiography○ free-breathing 3D balanced acquisition.Anatomy and dimensions:Wall thickness and wall volume by black blood CMRDistensibility and strain: balanced (cine) image acquisitions orthogonal to the vessel of interest;○ ‘through plane’ flow acquisitions in ascending or descending aorta and an anatomical image of thoracic aorta.○ ‘inplane’ velocity acquisition of thoracic aortic candy-canePWV: measurement of pulse wave travel time/path between ascending and descending aorta○ T2 weighted sequences○ T1 inversion recovery GRE sequences Wall tissue characterisation by:Acquisition as per SCMR standardised protocolsInner-vessel diameters, cross-sectional areas○ Foot-to-foot○ Upslope measurementsPWV: travelled path divided by time delay.○ Visual assessment○ Contrast-to-noise (CNR) measurementsTissue characterisationComparative studies for aortic PWV and distensibility with alternative techniques, including invasive and tonometric PWV measurements   or exercise-induced blood flow in peripheral artery disease , 98Not applicable.Additional file 1:Table 3i.1: Validation ex-vivo CMR cine imaging for ventricular volumes, mass and function. Table 3i.2: Reproducibility of the measurement of LV and RV in healthy volunteers. Tables 3i.3: Normal values. Table 3i.4: Outcomes studies against clinical endpoints for LV (Table A) and RV (Table B) function, mass or volumes. Table 3ii.1: Validation studies and comparative studies of strain imaging. Table 3ii.2. Reproducibility values reported for main strain measurements. Table 3ii.3: Normal values reported by different studies for main strain measurements. Table 3ii.4: Outcome studies for RWMA and strain parameters. (DOCX 101 kb)Ventricular volumes and function. Additional file 2:Table 3b-i.1: Validation studies with LGE. Table 3b-i.2: Reproducibility of measurements for LGE. Table 3b-i.3: Comparative studies with other imaging techniques in ischaemic heart disease. Table 3b-i.4: Outcome studies with LGE. (DOCX 79 kb)Late gadolinium enhancement. Additional file 3:Table 3c-i.1: Overview of the T1 mapping indices. Table 3c-i.2: Histological correlations with T1 mapping indices in various cardiac conditions. Table 3c-i.3: Intra, interobserver and interstudy variability reported for various sequences and field strengths. Table 3c-i.4: Overview of studies reporting normative ranges for T1 mapping indices. Table 3c-i.5: Proof of concept studies using T1 mapping in health and disease. Table 3c-i.6: Outcome studies for all-cause mortality (A) and composite cardiac/heart failure (B) endpoints. (DOCX 113 kb)T1 mapping tables. Additional file 4:Table 3b-ii.1: Validation studies with T2 weighted imaging (T2W). Table 3b-ii.2: Correlations with other relevant parameters for T2W-AAR. Table 3b-ii.3: Proof of concept studies using T2W imaging in health and disease. Table 3b-ii.4: Outcome studies for all-cause mortality or major adverse cardiac events (MACE). (DOCX 53 kb)T2 weighted imaging. Additional file 5:Table 3c-ii.1: Correlation of T2 mapping indices with histological substrates. Table 3c-ii.2: Correlation of T2 mapping indices with other imaging biomarkers. Table 3c-ii.3: Reproducibility for native T2 using various sequences and field strengths. Studies included if reported interstudy reproducibility. Table 3c-ii.4: Normal values for native T2 reported for different sequences and magnetic fields. Studies included if n>50 subjects. Table 3c-ii.5: Proof of concept studies with T2 indices differentiating between health and disease. Studies included if n>25 per patients’ group (unless the only study published). (DOCX 46 kb)T2 mapping Tables. Additional file 6:Table 3c-iii.1: Correlation of T2* mapping indices with histological substrates. Table 3c-iii.2: Correlation of myocardial native T2* mapping with other imaging biomarkers. Table 3c-iii.3: Intra, interobserver and interstudy variability reported for native T2* using various sequences and field strengths. Studies reported if included interstudy reproducibility. Table 3c-iii.4: Normal values for myocardial and liver native T2* reported for different sequences and magnetic fields. Table 3c-iii.5: Proof of concept studies with T2* indices differentiating between health and disease. Table 3c-iii.6: Outcome studies and treatment comparisons’ studies using T2* indices. (DOCX 66 kb)T2* mapping tables. Additional file 7:Table 3d.1: Studies comparing CMR perfusion against microspheres and alternative diagnostic approaches. Table 3d.2: Interstudy reproducibility and normal values of myocardial perfusion reserve (index). Table 3d.3: Prospective outcome studies using stress CMR. (DOCX 107 kb)Myocardial perfusion imaging with CMR. Additional file 8:Table 3e.1: Comparative  studies for CMR vascular endpoints with alternative techniques. Table 3e.2: Reproducibility of vascular endpoints. Table 3: Normal values for aortic dimensions (Table A), PWV and aortic distensibility (Table B) with CMR according to age and sex. Table 4: Outcome studies with PWV with CMR confirming the predictive associations. (DOCX 49 kb)Vascular CMR measurements.


BPD). Systemic hypertension, arterial thickness and stiffness, and increased systemic afterload may all contribute to BPD pathophysiology by altering left ventricular (LV) function and increasing pulmonary venous congestion by lowering end‐diastolic compliance. This case series studied the usefulness of angiotensin‐converting enzyme (ACE) inhibition by measuring clinical and echocardiographic improvements in six consecutive infants with “severe” BPD unresponsive to conventional therapy. The range of gestation and birthweight were 23–29 weeks and 505–814 g, respectively. All required mechanical ventilation (including high‐frequency oscillation) and all but one were administered postnatal corticosteroids. Other treatments including sildenafil and diuretics made no clinical improvements. Captopril was started for systemic hypertension after cardiac and vascular ultrasounds which were repeated 5 weeks later. A significant reduction in oxygen  and ventilator requirements, and improved cardiovascular parameters were noted. This included a trend toward reduction in aorta intima media thickness  and an increased pulsatile diameter ). Improvements were observed for both systolic  and diastolic  function which was accompanied by increased pulmonary vein flow. Right ventricular output increased accompanied by a significant lowering of pulmonary vascular resistance. These findings suggest that improving respiratory and cardiac indices  warrants further exploration of ACE inhibition in BPD infants unresponsive to conventional therapy.Premature infants have a high incidence of bronchopulmonary dysplasia ( Bronchopulmonary dysplasia (BPD) is the most common and the most important respiratory consequence of preterm birth with incidence of approximately 60% in infants’ ≤25 weeks gestational age (GA) Chow . In infasystemic (left sided) pathology were limited to the management of systemic hypertension. The incidence of systemic hypertension has been variously reported between 7 and 43% and was associated with longer duration of hospital stay, home oxygen, and a higher mortality   reduction  are physiologically very suited to the proposed BPD pathophysiology. We evaluated a series of consecutive infants with severe BPD unresponsive to standard therapy and systemic hypertension, using focused functional ECHO. The objective was to generate hypothesis regarding the use of ACE inhibitors that would need to be tested in appropriately designed randomized controlled trials.EchoPAC™ . Standard ECHO indices were measured as described in detail previously . The study conformed to the standards set by the latest version of Declaration of Helsinki, except for registration in a database. Standard practice in our Unit is to start captopril in consultation with renal and cardiac physicians after informed discussion with the parents when systolic BP is consistently above 99th centile for PMA  to between 50 and 95th centile for PMA at repeat assessment.Table Table systemic arterial measures (afterload reduction) using ACE inhibitors was associated with significant improvement in cardiac function and clinical features (respiratory support). Assessment of LV function  and the systemic vasculature may be warranted in infants with severe BPD with persistent radiological features of pulmonary edema despite diuretic therapy or where pulmonary edema worsens and respiratory support requirements increase, in response to the management of PH with pulmonary vasodilators. Such physiology‐driven approach toward therapy should be explored in infants with severe BPD and hypertension, especially in those unresponsive to standard therapy.The study of arterial biomechanics and left heart function in infants with BPD is relatively recent compared to well‐studied monitoring and management of PH  have been implicated as possible mechanisms of systemic hypertension in this cohort  were found to be significantly thicker in BPD cases  and vasodilatation/antiproliferation  of the vascular wall. Figure β‐blockers, diuretics, and ACE inhibitors. While all drug classes were equally effective in reducing BP, only the ACE inhibitors improved endothelial function and endothelium‐dependent vasodilation  caused regression of the media to lumen ratio in rats  effects of ACE inhibition.Given the angiogenic function of angiotensin‐II, ACE seems to play a role in vascular remodeling, pulmonary hypertension, and in the pathologic mechanism of neonatal lung diseases  may improve outcomes of infants with severe BPD, unresponsive to standard therapy with diuretics and pulmonary vasodilators  are not routinely assessed using bedside ECHO. Assessments made much later in gestation (as in our cohort) probably mean prolonged duration of respiratory support and greater morbidity, longer duration of hospital stay and dedication of precious healthcare resources. As a future research direction for physiology‐driven care of this critically sick population, we propose that infants with severe BPD be assessed at close to 36 weeks corrected GA . Routine assessments of left heart function  and systemic arteries in addition to conventional right‐sided assessments will give greater insight into physiology‐driven care.None of the authors has any conflicts of interests.


T1 mapping sequences such as MOLLI, ShMOLLI and SASHA make use of different technical approaches, bearing strengths and weaknesses. It is well known that obtained T1 relaxation times differ between the sequence techniques as well as between different hardware. Yet, T1 quantification is a promising tool for myocardial tissue characterization, disregarding the absence of established reference values. The purpose of this study was to evaluate the feasibility of native and post-contrast T1 mapping methods as well as ECV maps and its diagnostic benefits in a clinical environment when scanning patients with various cardiac diseases at 3 T.Native and post-contrast T1 mapping data acquired on a 3 T full-body scanner using the three pulse sequences 5(3)3 MOLLI, ShMOLLI and SASHA in 19 patients with clinical indication for contrast enhanced MRI were compared. We analyzed global and segmental T1 relaxation times as well as respective extracellular volumes and compared the emerged differences between the used pulse sequences.T1 times acquired with MOLLI and ShMOLLI exhibited systematic T1 deviation compared to SASHA. Myocardial MOLLI T1 times were 19% lower and ShMOLLI T1 times 25% lower compared to SASHA. Native blood T1 times from MOLLI were 13% lower than SASHA, while post-contrast MOLLI T1-times were only 5% lower. ECV values exhibited comparably biased estimation with MOLLI and ShMOLLI compared to SASHA in good agreement with results reported in literature. Pathology-suspect segments were clearly differentiated from remote myocardium with all three sequences.Myocardial T1 mapping yields systematically biased pre- and post-contrast T1 times depending on the applied pulse sequence. Additionally calculating ECV attenuates this bias, making MOLLI, ShMOLLI and SASHA better comparable. Therefore, myocardial T1 mapping is a powerful clinical tool for classification of soft tissue abnormalities in spite of the absence of established reference values. Quantification of myocardial longitudinal relaxation T1) times is a promising method in cardiovascular magnetic resonance, bearing the ability to characterize myocardial tissue and to identify abnormalities in the context of both acute and chronic events  times is. EvaluatTo date, a variety of T1 mapping sequences is available which use different technical approaches for determination of T1 relaxation times. The most commonly known sequences are the modified look-locker inversion-recovery protocols (MOLLI)  and shor. Teixeira et al. provided native T1 mapping data at 3 T for MOLLI, ShMOLLI and SASHA, demonstrating poor correlation between cardiovascular risk factors and the measured T1 times [So far, few studies directly compared in vivo data of different T1 mapping methods at a field strength of 3 T. Reference T1 times and ECV in healthy volunteers with MOLLI and SASHA were just recently published by Weingärtner et al. . TeixeirT1 times .The purpose of this study was to evaluate the feasibility and robustness of native and post-contrast T1 mapping methods as well as ECV maps and its diagnostic benefits in a clinical environment when scanning patients with various cardiac diseases at 3 T.n = 13; LVH-negative, n = 13; fibrosis, n = 4; reduced EF, n = 6; confirmed cardiac involvement, n = 8), acute myocardial infarction , cardiac amyloidosis (n = 1), Friedreich’s ataxia (n = 1), history of cardiac liposarcoma (n = 1), and myocarditis (n = 1). Blood samples were drawn routinely prior to examination to exclude patients with contraindications for MRI and to assess hematocrit for calculation of ECVs. The study was approved by the local IRB and conforms to the ethical guidelines of the 1975 Declaration of Helsinki. Written informed consent was obtained from all study participants prior to inclusion.19 patients with clinical indication for contrast enhanced cardiac MRI were examined. In all patients additional native and post-contrast T1 mapping was performed with the three established mapping methods MOLLI, ShMOLLI and SASHA. The study population was comprised of the following cardiac diseases: Anderson-Fabry disease  and 1.8 × 1.8 mm2 (ShMOLLI); slice thickness, 8 mm; 75% phase resolution, 7/8ths partial Fourier, and GRAPPA rate 2; flip angle MOLLI/ShMOLLI, 35°; flip angle SASHA, 70°; bandwidth, 1085 Hz/pixel. The following sampling schemes were used: native MOLLI: 5(3)3; post contrast MOLLI: 4(1)3(1)2; native ShMOLLI: 5(1)1(1)1; post contrast ShMOLLI: 5(1)1(1)1; native SASHA: 5(3)3; post contrast SASHA: 4(1)3(1)2. Inline motion correction (MOCO) was applied in each sequence.All CMR examinations were performed on a clinical 3 T whole body MRI Scanner . Myocardial T1 mapping was performed before and in consecutive order 15–20 min after bolus injection of 0.2 mmol/kg gadobenate dimeglumine  or gadoterate meglumine  using the prototype sequences MOLLI, ShMOLLI and SASHA provided by Siemens Healthcare. Each sequence was performed in end-expiration breath holds with the following parameters: TE, 1.04–1.12 ms; echo spacing, 2.6–2.9 ms; acquisition matrix, 256 × 144  and 192 × 144 (ShMOLLI); field-of-view, 270 × 360 mmPixelwise T1 maps were generated online by Siemens Healthcare directly at the scanner. Further segmentation of the T1 maps was done with cvi42® : Endo- and epicardial contours were drawn manually with conservative approach. A further automatic erosion of 15% was applied to avoid accidental inclusion of blood pool or extracardial tissue. The mid-ventricular slice of each patient was segmented into 6 standard segments, which were compared between the different methods. ECV maps were calculated from T1 maps and lab drawn hematocrit values. Segments affected by artifacts were excluded from further analysis. The obtained MRI data was analyzed by allocated radiologists during daily routine. Pathologic segments were identified by consideration of LGE and clinical findings. Segments with inconspicuous LGE and no further pathological alterations were referred to as remote segments.p values p <  0.05 were considered statistically significant (*).If not stated otherwise, variables are depicted as mean ± standard deviation (SD). Comparison of techniques was statistically analyzed by a paired non-parametric Wilcoxon test. Statistical analysis of pathologic and remote segments was performed by an unpaired non-parametric Mann-Whitney-U test. Only two-sided tests were used and 19 patients with cardiac diseases underwent pre- and post-contrast T1 mapping with the three mapping sequences MOLLI, ShMOLLI and SASHA. Pathologic lesions were identified by consideration of T1 relaxation times and LGE and data of the three pulse sequences was compared  are slightly shorter compared to previously published data , 19–21. T1 mapping subsequent to contrast bolus injection provides post-contrast T1 times and thereby gives further information for tissue characterization. Recently, Weingärtner et al. published reference values for pre- and post-contrast T1 times using the mapping sequences MOLLI and SASHA . Post-co. In line with this, our data demonstrates that T1 deviation of the blood pool was 2.5 fold higher under native conditions (long T1) compared to post-contrast conditions  and pathologic myocardium was determined by consideration of LGE, however, LGE-free segments cannot necessarily be considered as healthy myocardium as shown before , 23. FurCMR-protocols were modified during the time of data acquisition, which is why T1 mapping was performed either with gadobenate dimeglumine (Multihance) or gadoterate meglumine (Dotarem). To overcome these inconsistencies, we did not compare absolute T1 times, but calculated the ratios between MOLLI/ShMOLLI and SASHA. These limitations may be also considered as a strength since robustness and error proneness of T1 mapping sequences were evaluated. Furthermore, T1 mapping was performed after a single bolus contrast-agent application with MOLLI, ShMOLLI and SASHA in consecutive order, which in turn may lead to higher post-contrast T1 times and lower ECV with SASHA.It is important to single out, that the focus of this study was not to establish reference values for T1 times at 3 T or to proof the deviance of T1 relaxation times between remote and pathologic myocardium. The aim was rather to analyze differences of the three T1 mapping sequences amongst each other before and after contrast bolus administration, the obtained ECV maps and moreover the robustness during clinical routine.T1 mapping at 3 T is a feasible and robust method for characterization of myocardial tissue during clinical routine. Systematic deviation of T1 relaxation times from MOLLI, ShMOLLI compared to SASHA occurred in clinical routine. Post-contrast mapping allows the generation of ECV maps, which are similarly biased by deviation of T1 estimation. Combined analysis of ECV and native T1 times might enhance the diagnosis of myocardial pathologies. SASHA may provide the most accurate absolute T1 times, but reference values are needed for each mapping technique in order to bring T1 mapping into routine clinical CMR imaging.


Dilative cardiomyopathy is an uncommon cardiac complication of electric shock.We report a case of a 12-year-old German boy with a high voltage injury who developed a four-chamber dilative cardiomyopathy, which was diagnosed on the 13th week postburn. One year after the accident, echocardiography showed a normal function of his heart with 64% ejection fraction and normal cavities’ dimensions.Despite the fact that dilative cardiomyopathy is not very common in electrical injuries but can be fatal, a prolonged echocardiography follow-up for patients with electrical injury could be recommended. Until now this case is the first child with severe burns after electrocution, who developed a reversible dilative cardiomyopathy. Electrical burns typically comprise only a small percentage (approximately 3–4%) of total admissions to burn care units , 2. HoweThe most common cause of death continues to be cardiac arrest after acute arrhythmias at the scene of the incident secondary to either asystolia or ventricular fibrillation . ElectriDilative cardiomyopathy (DCM) is an uncommon cardiac complication of an electric shock. Only three cases of DCM caused by electrical injury have been reported in the international literature.We report a case of a young boy with a high voltage injury who developed a reversible four-chamber DCM.A 12-year-old German boy suffered from an accidental electrocution with 15,000 volts as he was playing in a railroad car. The boy was intubated at the site of the accident and immediately admitted to our burn care unit with deep partial-thickness and full-thickness burns. He sustained a 70% total body surface area (TBSA) burn of the face, neck, spine, thorax, abdomen, both arms, and both legs Fig. . A sourcHe was resuscitated according to the Parkland formula. In the first 24 hours, only Ringer lactate solutions and no colloids were used. He was started on a high-calorie diet . Cardiac monitoring was done for 24 hours and no cardiac dysrhythmias were observed.Within the first 3 weeks seven operations were performed including dermabrasion, application of Suprathel® , tangential excision and split-thickness skin graft, epifascial excision, application of Integra™ , and autologous keratinocyte transplantation.The duration of the mechanical ventilation reached 85 days.In the course of the stationary treatment (135 days) he developed acute renal failure treated with veno-venous hemofiltration for 7 days and acute liver failure treated conservatively.The boy developed persisting hypotension, edema, and ascites after the 10th week postburn. The hypotension required dobutamine therapy. A chest X-ray showed an increase of the cardiothoracic ratio from 0.50 (at the time of admission) to 0.63  Fig. . In ordeThe most common possible causes of DCM  were tested and excluded.Inotropic therapy was initially required. It began with digitalis and then an application with phosphodiesterase inhibitor (milrinone) followed. A diuretic therapy with torasemide was also applied. Then, heart failure therapy followed with angiotensin-converting enzyme (ACE) inhibitor , beta blocker, diuretics, and digoxin.At the point of hospital discharge there was an increase of EF (22%) as well as an increase of the contractility of his heart. The LV end diastolic diameter (LVEDD) reached 58 mm.One year after the accident, echocardiography showed a normal function of his heart with 64% EF and normal cavities’ dimensions (LVEDD 51 mm). No mitral and tricuspid insufficiency was present.To the best of our knowledge, there are only three cases of DCM caused by electrical injury reported in the international literature. In these cases the victims were all adults aged 24–57 years without predisposing conditions. Two suffered from a high-voltage electrical injury . One patient died on the third day postburn and an autopsy showed that the cause of death was severe heart failure by acute four-chamber dilated cardiomyopathy. The other two patients died within 18 months after the incident.The pathophysiological mechanism of DCM secondary to electric shock is not clear. Myocardial dysfunction may be a complication of thermal/electrical injury . This caUntil now the above-mentioned case is the first child with severe burns after electrocution , who developed a reversible DCM. Despite the fact that DCM is not very common in electrical injuries but can be fatal, a prolonged echocardiography follow-up for patients with electrical injury could be recommended.


The most commonly used parameter of cardiac function in the chronic kidney disease (CKD) patient is ejection fraction (EF), using transthoracic echocardiography (TTE). EF is a highly load-dependent measurement, which varies considerably in CKD patients undergoing haemodialysis. The aim of this pilot study was to evaluate a novel measure of myocardial function, left ventricular twist, which is defined as the ‘wringing action of the heart’, using speckletracking echocardiography in CKD patients before and after haemodialysis.Twenty-six patients were recruited from the Chris Hani Baragwanath Hospital haemodialysis unit. TTE was performed according to a detailed standardised protocol before and after a single haemodialysis session. Echocardiography was also performed on 26 age- and gendermatched healthy subjects.The mean age of the control versus CKD group was 44 ± 11.4 and 43.4 ± 12.2 years, respectively; 46% were male. Apical rotation was diminished in CKD patients compared to controls  despite no difference in EF . There were no differences in the components of twist: apical rotation, basal rotation and net twist before and after dialysis, despite an increase in EF  following dialysis.Unlike EF, the components of twist are relatively independent of changes in haemodynamic load seen during dialysis. The decrease in apical rotation may represent an early marker of cardiac pathology in the late-stage CKD patient. Cardiovascular pathology accounts for half of the deaths in chronic kidney disease (CKD) patients.7Cardio-renal specialists have explored other measures to evaluate cardiac function in CKD, using myocardial deformation or strain, which more accurately describes ventricular movement during systolic and diastolic function. It consists of longitudinal, radial and circumferential strain, and ventricular twist.9STE is an echocardiographic modality based on the accurate tracking of groups of pixels called ‘speckles’ throughout the cardiac cycle.12Left ventricular (LV) twist is described as a ‘wringing’ action of the heart. It represents a clockwise rotation of the base and a counter-clockwise rotation of the apex during systole.The aim of this pilot study was to examine LV twist in African patients with stage 5 CKD before and after a single haemodialysis session.This prospective, longitudinal, single-centre study was conducted at the Chris Hani Baragwanath Hospital Renal Unit in Johannesburg, South Africa. Volunteers were screened from November 2010 until February 2011. Inclusion criteria were: ages between 20 and 65 years and documented CKD on intermittent haemodialysis three times weekly. Exclusion criteria were: pre-existing cardiac disease, known coronary artery disease, valvular heart disease, arrhythmias, and poor echocardiography windows that precluded speckle tracking.Of the 71 patients receiving intermittent haemodialysis in this unit, 26 meeting the entry criteria were recruited among volunteers  conformed to the 1975 Declaration of Helsinki.Patients with CKD with end-stage kidney failure (ESKF) were on three-times-a-week intermittent haemodialysis (HD). Haemodialysis was performed for an average of four hours with mean ultrafiltration volume of 2.2 ± 0.9 litres, using bicarbonate dialysate. Fresenius FX dialysers were used, with most patients dialysed on the FX 80 dialysers, although the range of dialysers used were FX 60, FX 80 and FX 100, according to the patient’s weight.The recombinant erythropoietin, epoetin-beta, was used to maintain haemoglobin levels at a target of 11 to 12 g/dl, in keeping with KDIGO guidelines at the time. An average of 12 000 units was given subcutaneously per patient per week. Eighty-eight per cent of patients receiving haemodialysis were on an ACE inhibitor or angiotensin receptor blocker, with the most frequently used agents being perindopril and telmisartan.All 52 participants underwent complete transthoracic echocardiographic evaluation. CKD patients were evaluated before and within an hour of a single haemodialysis session. According to a standardised protocol used by our institution,Chamber size measurements and function were performed according to the American Society of Echocardiography (ASE) chamber quantification guidelines of 2006.28Left ventricular end-diastolic volume (LVEDV) was taken as representative markers of preload. Pulse pressure over stroke volume (PP/SV) was used as a surrogate of arterial stiffness,Speckle-tracking basal images were obtained in the parasternal short axis at the level of the mitral valve, showing the tips of leaflets with the most circular image possible. Apical images were acquired by moving the transducer one or two spaces caudally, using a method described by van Dalen.33Images were acquired at a frame rate of 50–80 frames/s during sinus rhythm with less than 10% variability in heart rate for optimal speckle tracking.Peak apical rotation was measured during the ejection systolic phase. Basal rotation was measured at a time isochronous to peak apical systolic rotation, in keeping with a standard protocol used by our institution, which has previously been published.Measurements were independently made by two cardiologists trained in STE. The combined mean inter-observer variability for measurements of apical, basal and net twist of renal patients pre-dialysis was 3.67% (range 2–37%) and post-dialysis 3.7% (range 2.5–31%). The mean intra-observer variability pre-dialysis was 2.76% (range 2–10%) and post-dialysis 3.72% (range 2.5–26%).Data were analysed using the Statistica version 11  program. Results are expressed as means with standard deviations or medians for non-normal distribution or frequencies, and percentages for categorical variables. To assess differences between the control groups versus pre-dialysis patients, and control versus post-dialysis patients, the Mann–Whitney test for non-normally distributed variables was used. Pre-dialysis and post-dialysis comparisons were performed with the Wilcoxon matched paired test. Significance was assumed at two-sided values of p < 0.05. Fisher’s exact test was used to compare categorical data. The Schapiro–Wilk test was used to assess normality. Univariate linear regression analysis was used to identify independent factors associated with twist pre-dialysis and post-dialysis, and change in twist.Clinical characteristics of control participants and CKD patients are summarised in On echocardiography, patients on haemodialysis had significantly higher pre-dialysis LV diastolic volumes, LV end-systolic volumes, LV end-systolic diameter (LVESD) and stroke volume compared to the controls, whereas there was no difference in EF and PP/SV . In addiDuring dialysis, CKD patients were ultra-filtrated a mean of 2.2 ± 0.9 litres, with a mean change in weight of 2.2 ± 1.0 kg. As a result, there was a significant difference in pre- and post-dialysis weights . No statThere was a significant decrease in LVEDV, LVESV, E/E′ and LA volume index (LAVI) after dialysis whereas a significant increment in EF was noted compared to pre-dialysis values . HoweverAt baseline, there was no difference in net speckle-tracking twist and basal rotation between controls compared to CKD patients prior to their dialysis session. However, there was a significant decrease in apical rotation between the control and pre-dialysis group . There was no statistically significant difference when comparing net twist, basal rotation or apical rotation in CKD patients before and after dialysis .In the univariate linear regression analysis of twist, the presence of hypertension, diabetes, the use of ACE inhibitor or angiotensin receptor blocker (ARB), and change in weight before and after dialysis were compared against the difference in apical, basal and net twist before and after dialysis. These variables showed a trend towards statistical significance with an independent association between hypertension and the difference in apical twist , and in the use of an ACE inhibitor or ARB versus net twist . A significant association was demonstrated between the differences in systolic and diastolic blood pressure versus basal twist post-dialysis , and the difference in diastolic blood pressure and apical twist post-dialysis (p = 0.04).The major findings of this study are (1) apical rotation appears to be reduced in patients on chronic haemodialysis with net twist remaining unchanged; and (2) LV twist is less susceptible to haemodynamic fluctuations associated with dialysis than EF.The use of EF as a measure of systolic function in CKD is suboptimal because of the variable load changes and the effects of uraemic metabolites during dialysis. According to the ‘Starling effect’, LV function is determined by load, with increasing preload resulting in improved LV function, and vice versa. Similarly, systolic function is inversely related to afterload. However, it is not only load changes that play a role in systolic function in CKD patients on dialysis. An additional possibility is that the removal of negatively inotropic uraemic toxins during haemodialysis improves cardiac function.7In this study, CKD patients had similar EF to the control participants at baseline, which is not surprising since systolic dysfunction is seen in only 15% of CKD patients.7Considering these changes, one might suppose that if apical, basal and net twist were subject to load changes, any or all of these parameters would decrease with reduced preload. These measures of rotation did not change with dialysis. This lack of significant change after dialysis implies that the components of myocardial rotation: apical rotation, basal rotation and net LV twist are relatively load independent, but whether they are also relatively immune to the acute metabolic changes of uraemia requires further study.The key to understanding LV twist and its contribution to cardiac systolic function is in understanding the arrangement of myocardial fibres in a ‘left-handed’ helix sub-endocardially with clockwise rotation, and a ‘right-handed’ helix sub-epicardially with counter-clockwise rotation . In norm22This compensatory increase in twist present in the CKD patient was documented in a study by Panoulas et al.The limitations of this study are that it was a pilot study using a single vendor . The small sample size was due to the size of the haemodialysis patient population at our institution. This did not allow adequate numbers to perform multiple linear regression analysis. The homogenous nature of our study population may not translate to other patient cohorts. It would be useful in larger studies to determine how twist is affected in CKD patients with and without hypertension. Multicentre studies with longitudinal follow up may confirm the findings of this study.LV twist and its derived rotational parameters did not change significantly post-dialysis compared to pre-dialysis. This may suggest that these parameters are less affected by varying loading conditions post-dialysis. The decrease in apical rotation observed in late-stage CKD patients compared to controls may represent an early marker of loss of rotational compensation, which preserves EF in the CKD patient


Hematopoietic stem-cell transplantation (HSCT) is a complex procedure that has been increasingly successful in treating malignant and nonmalignant conditions. Despite its effectiveness, it can be associated with potentially life-threatening adverse effects. New onset heart failure, ischemic disease, and arrhythmias are among the most notable cardiovascular complications post-HSCT. As a result, appropriate cardiac risk stratification prior to transplant could result in decreased morbidity and mortality by identifying patients with a higher probability of tolerating possible toxicities associated with HSCT. In this review, we aim to discuss the utility of cardiac screening using novel modalities of imaging technology in the pre-HSCT phase. The most notable complications related to high-dose chemotherapy or irradiation in the conditioning phase are cardiovascular in nature . These aCardiac complications associated with HSCT can manifest even years after transplantation ,9. HSCT Malignancies and CVD share similar risk factors . As a reIn this review, we aim to discuss the utility of cardiac screening using novel modalities of imaging technology in the pre-HSCT phase.While early life-threatening cardiac complications such as large pericardial effusion, cardiac tamponade, acute heart failure, and life threatening arrythmias following HSCT are rare ,18,19, tCurrently, the most widely used cardiac screening modality prior to HSCT is 2-dimensional echocardiography (2D echo) . This caCurrently, a reduction in LVEF is considered a marker of cardiotoxicity related to the chemotherapy phase of HSCT . HoweverSpeckle tracking echocardiography (STE) is a widely used technique to assess regional myocardial dysfunction. STE is a type of strain imaging used to describe local shortening, thickening, and lengthening of the myocardium . Simply One of the most well studied strain modalities is global longitudinal strain (GLS). GLS represents shortening or lengthening of the myocardium from base to apex. A normal mean value of GLS among studies and different vendors varied between −16.7% to −23.6% ,29. A faAdditionally, a multicenter study compared GLS and LVEF as biomarkers in predicting future cardiac dysfunction in patients receiving doxorubicin chemotherapy. Impairment in GLS at three months follow-up was a predictor of the development of cardiotoxicity at six months. Conversely, LVEF did not predict cardiotoxicity . In a seTo further illustrate the advantages of GLS, changes in LV function using STE in children who underwent HSCT in the setting of acute leukemia was assessed. Compared to controls, post-HSCT patients had similar LVEF using conventional echocardiography. However, STE parameters including GLS were significantly decreased in post-HSCT patients compared to controls. The authors of the study concluded that STE is a useful tool in detecting early myocardial dysfunction and may be considered as a routine imaging modality in this patient population . Despite its overwhelming advantages, STE is not without important limitations. The most important limitation is inter-vendor variability . DiffereCMR is the gold standard imaging modality for detecting ventricular volumes and function . CMR proGadolinium (Gd)-containing contrast media is used in CMR to differentiate diseased vs. healthy myocardium. Both normal and diseased myocardium take up Gd. However, the rate of Gd washout is slower in the presence of underlying heart disease. For example, cellular lysis and edema occurring post myocardial infarction result in increased extracellular space and delayed washout of Gd. While LGE was originally developed to detect scared myocardium, it has also been found useful in diagnosing cardiomyopathies based on differences in LGE patterns. The role of CMR/LGE in HSCT patients receiving cardiotoxic agents such as anthracyclines is not well described in the literature. In one study, 22 patients with baseline normal cardiac function were investigated using CMR to measure LGE before, at three days, and at 28 days after treatment with anthracyclines. An increase in LGE >5 on day three was a significant predictor of decreased LVEF at 28 days of follow up . In anotThoracic aortic stiffness occurs as a consequence of aging and is considered a marker for increased overall mortality and adverse cardiovascular outcomes in the general population . Using CCMR myocardial T1 mapping is another powerful diagnostic parameter that detects subtle changes in extracellular matrix. Numerous studies emphasized the importance of focusing on changes that occur in the interstitium, including fibrosis, rather than purely on the structure and function of myocyte . These cCMR is a sensitive imaging modality that allows detection of subclinical cardiovascular disease not detected by standard echocardiography. However, larger patient cohorts and longer follow-up periods are needed to evaluate CMR as a predictor of adverse cardiovascular outcomes in patients receiving cardiotoxic agents as part of HSCT. Additionally, its high cost and low availability at most centers preclude its use for serial monitoring of cardiotoxicity in patients with HSCT. The evolution of 3D cardiac ultrasound dates to 1974 . The 3D As mentioned previously, measurement of LVEF using 2D echo is limited by lack of accuracy due to ventricular foreshortening and the use of mathematical models with geometrical assumptions to calculate volumes. Several studies have suggested that when compared to 2D echo, 3D echo allows for reduced analysis time, lower interobserver variability, and higher reproducibility ,52.Given the risk for cardiotoxicity with chemotherapy and the need for serial imaging, it is crucial to have reproducible and consistent results when images are acquired/analyzed by different observers. In a recent study, different echocardiographic techniques were compared for serial evaluation of LVEF in patients undergoing treatment with cardiotoxic agents. At one year of follow-up, 3D echo showed significantly lower temporal variability and desirable longitudinal reproducibility when compared with all other techniques . Despite its several advantages, the role of 3D echo in HSCT patients is yet to be described in the literature.Stress echocardiography involves the administration of stressors, most commonly exercise, dobutamine, and dipyrimadole, to assess the ionotropic response of the myocardium. In the cancer population, routine echocardiography is normally performed as an initial test for the assessment of CAD to depict cardiac function and rule out other diseases that may be causing the patients symptoms. However, with routine echocardiogram, regional wall motion abnormalities caused by CAD are only observed in patients with critical ischemia or prior infarction. Therefore, in patients with stable angina, stress echocardiography is acceptable, especially in those whom exercise is not feasible and those who have undergone treatment with agents associated with ischemia including 5-fluorouracil, capecitabine, bevacizumab, sorafenib, and sunitinib. Stress echocardiography has better sensitivity and specificity compared to exercise stress electrocardiography and is of great value in those patients whose stress electrocardiogram is inconclusive. Additionally, the prognostic value of revascularization therapy with interventional angiography is increased with stress echocardiogram . CoronarCardiac SPECT is a noninvasive nuclear imaging modality whereby radioactive tracer, typically technetium or thallium, is intravenously injected at rest or under some form of stress (pharmacologic or exercise). The tracer is taken up by the myocardium in quantities proportional to perfusion. Therefore, in areas where perfusion is decreased  there is a decrease in radioactive uptake. This technique is often used to evaluate for CAD, wall motion abnormalities, myocardial infarction, heart failure, and for therapy guidance . It can CCT is a noninvasive approach with high sensitivity for detecting CAD and a high negative predictive value for excluding the presence of CAD. CCT enables the acquisition of thin slices (0.25 to 0.5 mm) of the heart and coronary arteries in diastole when coronary motion is minimized. Images are acquired using a multidetector  CT scanner, which is more than 64 slices for coronary evaluation. Noncontrast coronary CT can also be used to quantify the coronary artery calcium score (CCS), which is a marker of atherosclerosis that is proportional to the extent of the disease. The latter has the advantage of lower radiation and lack of iodinated contrast administration but cannot visualize coronary luminal stenoses. CCT angiography (CCTA) can reliably identify more than 90% of the coronary arterial segments and in appropriately selected scenarios, can also visualize myocardial scarring based on delayed contrast enhancement and measured ejection fraction, if so desired . p < 0.001) [The scanner software quantifies the amount of calcium, typically using the Agatston scoring system . The cur< 0.001) . This stHSCT is often preceded by chemotherapy with or without radiation. Mediastinal radiotherapy and anthracycline-containing chemotherapy are major risk factors for the future development of CVD. Two studies to date have examined the relationship between CCS and CAD in asymptomatic patients with Hodgkin Lymphoma (HL) who had survived 15 or more years following treatment with radiation therapy with or without anthracycline-containing chemotherapy ,68. In tCCTA is mainly used for the evaluation of cardiac anatomy, suspected CAD, and for follow up after percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) . As mentThe use of CCTA in HSCT patients has not been well studied. However, in the study of HSCT patients mentioned above that examined CCS with concomitant CCTA, CAD was detected in 4/15 (26.6%) patients that would be considered low risk by conventional FRS classification. There was one patient in this study with a FRS <1% who had a CCS of zero in which nonobstructive plaques were identified on CCTA. This suggests that CCS with CCTA is an acceptable and sensitive screening method amongst asymptomatic low FRS SCT candidates. As mentioned previously, HSCT is often preceded by chemotherapy with or without radiation therapy, which are independent risk factors for cardiovascular disease. One study examined CCS with CCTA in nine patients with HL . Eight oThere are currently no guidelines for comprehensive cardiovascular screening protocols for patients undergoing HSCT. Screening these patients is important because they are at increased risk for developing cardiovascular complications peri-HSCT, possibly leading to increased mortality at a relatively young age. The current method used to screen patients for cardiotoxicity related to chemotherapy is through LVEF assessment by 2D echo; and further testing by stress testing with or without coronary angiography by cardiac catheterization, as warranted. However, cardiac catheterization is somewhat invasive with some associated risks. Emerging technologies such as STE and CMR can potentially detect cardiac dysfunction earlier than conventional LVEF measurements. Furthermore, a noninvasive screening tool, such as CCS with or without CCTA could potentially help to identify HSCT patients at risk for CAD. Future studies are needed that examine major adverse cardiovascular events such as increased mortality that correlate with newer myocardial imaging modalities such as STE and CMR. Similarly, more large-scale prospective studies are needed to determine the prognostic yield of CCS with or without CCTA for CAD assessment prior to HSCT, and confirm their value as screening tests in this population.