Evaluate the ability of Internal Flow Fraction to diagnose left ventricular dyssynchrony using standard cine MRI.internally within the left ventricle (LV). This "internal flow" represents wasted energy due to the dyssynchronous motion of the LV walls. We developed a new method to quantify internal flow from cine cardiac MRI which may provide a better, more physiologic measure of dyssynchrony than existing methods.Better methods to quantify mechanical dyssynchrony in the heart may improve patient selection for cardiac resynchronization therapy. Dyssynchrony creates inefficient "sloshing" of blood volume LV internal flow will be significantly increased in patients with dyssynchronous heart failure compared to healthy, age and sex-matched volunteers.IF(t) = ∑|ΔV(t)regional| - |Δ∑V(t)regional|. This difference is zero if no internal flow has occurred. Internal Flow Fraction (IFF) was defined as the total internal flow as a percentage of stroke volume.Images were obtained with a 1.5 T Philips Intera scanner using a 5-element phased array cardiac coil. Short-axis steady-state free-precession (SSFP) cines were acquired over the length of the LV during breath-holds . Two and four-chamber long-axis cine images were also acquired. Ten patients with dyssynchronous heart failure  and 10 age and sex-matched healthy controls were imaged. The 3-dimensional LV volume was reconstructed and divided into 16 wedge-shaped volumes adjacent to the American Heart Association standardized myocardial segments Fig . InternaIFF was significantly increased in the patients . An IFF threshold of 4% discriminated between patients and controls with 90% sensitivity and 100% specificity Fig . There wLeft ventricular Internal Flow Fraction can be quantified from images acquired in a standard cine cardiac MRI exam. Internal flow during the isovolumic periods is a normal, physiologic component of left ventricular contraction and relaxation. A left ventricular Internal Flow Fraction of 4% discriminated patients with dyssynchronous heart failure from age and sex-matched healthy controls with 95% accuracy.


Myocardial dysfunction is a known risk factor for morbidity and mortality in hypoplastic left heart syndrome (HLHS). Variants in some transcription factor and contractility genes, which are known to cause cardiomyopathy, have previously been associated with impaired right ventricular function in some HLHS patients. The care of HLHS patients is resource demanding. Identifying genetic variants associated with myocardial dysfunction would be helpful in tailoring the follow-up and therapeutic strategies. We tested whether a commercial cardiomyopathy gene panel could serve as a diagnostic tool in a Finnish cohort of HLHS patients with impaired right ventricular function to identify potentially pathogenic variants associated with poor prognosis. None of the patients had pathogenic or likely pathogenic variants in the studied cardiomyopathy-associated genes. Thus, our approach of performing a cardiomyopathy gene panel to identify pathogenic variants as directly causal or as modifiers for worse outcomes in hypoplastic left heart syndrome is not useful in clinical practice at the moment. Congenital heart defects (CHD), structural defects of the heart and great vessels, are the most common congenital malformations affecting nearly 1% of the population . HypoplaNOTCH1 being the predominant monogenic cause . Written informed consent was obtained from the legal guardians of the participants and also directly from all participants aged over 6 years.From a national cohort of all 134 hypoplastic left heart syndrome patients born in Finland between 1/1998 and 9/2012, we identified 10 non-syndromic patients with impaired right ventricular function, but no clear anatomic problem explaining the impairment . The patin silico tools , amino acid conservation in species and existing public and private mutation databases.DNA was extracted from peripheral blood or saliva samples. DNA was analyzed by next-generation sequencing using a targeted commercial cardiomyopathy panel including 103 genes by Blueprint Genetics Ltd. , VACTERL association (genetic origin unknown), Rubinstein-Taybi (single gene variants in CBP and EP300), Adams-Oliver syndrome , and Beckwith-Wiedemann syndrome (single gene variants in CDKNIC)  .MYH6 variants were enriched in a large cohort of CHD individuals where most of the MYH6 variant carriers were left ventricular outflow tract obstruction patients  had MYH6 variants in contrast to 2.9% of controls ; ST: Full-time geneticist at BpG . The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The prolongation of repolarization time between the myocardial epicardium and endocardial cells is closely related to malignant ventricular arrhythmias. The purpose of our study was to compare repolarization markers, namely, T‐wave peak‐end interval (Tp‐e), QT, corrected QT (QTc), Tp‐e/QT, Tp‐e/corrected QT (QTc), and Heart Rate Variability (HRV) values in healthy men and women and to investigate their daily variations.A total of 74 male and 78 female participants, being a government employee, and having no health problems, were included in the two study groups . A 24‐hour, 12‐lead Holter monitoring was performed on the volunteers. Then, the Tp‐e interval and QT interval were measured on recordings. cTp‐e and QTc were calculated by the use of Bazzet's formula.pm; however, it was significantly lower in the female group as compared with the male group at 07.00 am and 01.00 pm. It was significantly higher in the female group at 01.00 am compared with the male group. There were statistically significant moderate negative correlations between Tp‐e intervals and a standard deviation of between two normal beats interval (SDNN) values at various hours of the same day.There was no statistically significant difference between the groups in the cTp‐e interval at 07.00 There were statistically significant differences in terms of Tp‐e and cTp‐e intervals at various hours of the same day in both groups. In addition, there were statistically significant moderate negative correlations between Tp‐e intervals and SDNN at various hours of the same day. Malign ventricular arrhythmia is observed mostly in individuals with heart disease, but it may also occur in individuals without underlying heart disease. Ventricular arrhythmias may occur more frequently at certain times. For example, it can follow an increasing trend from Saturday to Monday, while decreasing trend from Monday to Friday. Furthermore, Ventricular arrhythmias can occur at different times on the same day. It can become more frequent and decrease at certain times of the day. Men also have a higher incidence of SCD than women. Therefore, Tp‐e interval, cTp‐e interval, Tp‐e/ QT and Tp‐e/ QTc ratios, which are ventricular repolarization, and Heart Rate Variability Values may vary in healthy men and women at different times of the day. BMIBody Mass IndexBPBlood PressureCOPDChronic Obstructive Pulmonary DiseasecTp‐eCorrected T peak‐endCVECerebrovascular EventECGElectrocardiographyLDLLow‐Density LipoproteinLFAbsolute power of the low‐frequency band (0.04‐0.15 Hz)LF/HFRatio of LF‐to‐HF powerLVLeft ventriclepNN50Percentage of successive RR intervals that differ by more than 50 msQTcCorrected QTRMSSDRoot mean square of successive RR interval differencesSCDSudden Cardiac DeathSDANN IndexStandard deviation of the average NN intervals for each 5 min segment of a 24 h heart rate variability recordingSDNN IndexMean of the standard deviations of all the NN intervals for each 5 min segment of a 24 h heart rate variability recordingSDNNStandard Deviation of all NN intervalsTCTotal CholesterolTp‐eT peak‐endTSHThyroid Stimulating HormoneTTETransthoracic EchocardiographyVLFAbsolute power of the very‐low‐frequency band (0.0033‐0.04 Hz)1Cardiovascular system‐related deaths are still the most common cause of death in both men and women worldwide. However, there are major differences between men and women. For example, CVS events start in men at an earlier age, and their mortality and morbidity are higher than in women.Heart rate variability (HRV) is a unit of measurement of the effects of heart‐related functions on the heart of the vagal and sympathetic system. An imbalance or reduction in this unit of measure is closely related to cardiovascular mortality and morbidity.Many studies show that many mortality and morbid cardiovascular events occur more in the morning than at other times of the day.It is well known that the electrophysiology of men and women is very different. And it has been proven that women have longer rate‐corrected ventricular repolarization intervals and show a different repolarization pattern than men.The T wave typically shows the repolarization of myocardial M cells. The T wave is as a result of complex myocardial repolarization including the difference between right and left ventricular repolarization and the gradient between the left ventricular apex and the base.In general, simple manual methods of T‐wave measurements can be used for cardiovascular risk stratification both in patients with underlying structural heart disease and in the general healthy population.22.12 were excluded from the study. After the routine physical examination, routine blood tests and transthoracic echocardiograms (TTE) were performed. In routine blood tests, participants with anemia; poor thyroid, liver, or kidney function; antidepressant medication history, electrolyte disorder, white blood cell count >10,000/dl; patients diagnosed with cancer or receiving chemotherapy, patients with past cerebrovascular event, chronic obstructive pulmonary disease history, and those receiving bronchodilator treatment; patients who had coronary angiography and receiving any treatment, and patients with significant valvular heart disease, left ventricular hypertrophy, and systolic pulmonary arterial pressure >25 mm Hg in TTE were also excluded from the study. We did not find any statistically significant difference in terms of sociodemographic and basic clinical characteristics between the two groups  and 78 female participants with a mean age of 47.35 ± 10.84 years  were included in the study. Three consecutive blood pressure measurements were taken for both groups after a 5‐min rest, and the mean value of these readings was recorded. Participants with mean blood pressure higher than 149/90 mm Hg, a previous diagnosis of hypertension, and those on any antihypertensive medication were excluded from the study. Arterial blood pressures of the patients were recorded, and resting electrocardiograms (ECG) were acquired at 25 mm/sec speed and 10 mm/mV amplitude. The participants were then taken for routine physical examination during which those with smoking history, with findings that may impact the electrophysiology of the heart, and those with a body mass index (BMI) higher than 30 kg/m2.2am, 01.00 pm, 07.00 pm, and 01.00 am were measured manually with a 0.01 mm accuracy.The 12‐lead ECG recordings were obtained from 24‐hour Holter recordings. The ECG length was 10 seconds; therefore, depending on the heart rate, there were 4 to 6 beats per lead. ECGs were measured manually with the use of a magnifying glass  by two blinded cardiologists. The RR interval, QT interval, and T peak‐end interval of the ECG recordings obtained from 24‐hour Holter monitorization at 07.00 The RR interval was recorded as the time from the peak of an R wave to the peak point of the next R wave. This measurement was calculated at least in three leads and between at least three consecutive R waves. The QT interval was accepted as the point where the T wave returned to the isoelectric line from the onset of the QRS wave. This measurement was calculated at least in nine leads and three consecutive QRS waves in one lead. The data of ECG with papers at a speed of 25 mm/sec and amplitude of 10 mm/mV, measured in mm with the digital caliper, were calculated as millisecond multiplied by 40. The QTc was calculated using Bazett's formula.2–5 leads. The Tp‐e interval was calculated as a millisecond with the measured value in millimeter by multiplying 40. If the U wave was present, the T wave end was defined as the nadir between the T and U waves. The cTp‐e interval was calculated using Bazett's formula, and the arithmetic averages of measurements were used for analysis.Tp‐e interval was calculated by including the T wave from the peak to the baseline in the V2.3pm and removed at 02.00 pm the next day. A 24‐hour detailed evaluation was performed for assessing the 24‐hour rhythm Holter. During the evaluation, patients having the right or left bundle branch block, patients detected with more than 200/day atrial or ventricular extra‐systoles, those having irregular or persistent supraventricular or ventricular tachycardia, patients with ST‐T wave variations in ECG screening, and those with less than 22 hours of Holter recording were excluded from the study. ECG records including minimum and maximum heart rates of patients were acquired and calculations were made. In addition, ECG and SDNN values of the patients were recorded at 07.00 pm, 01.00 am, 07.00 am, and 01.00 pm, followed by appropriate calculations. And Heart Rate Variability values were recorded and compared for each group. SDNN , SDANN Index , SDNN Index , RMSSD , pNN50 , VLF (Absolute power of the very‐low‐frequency band [0.0033‐0.04 H]), LF (Absolute power of the low‐frequency band [0.04‐0.15 Hz]), and LF/HF (Ratio of LF‐to‐HF power) values were recorded and compared between two groups.A 12‐lead Holter  monitor was connected to the patients at 02.00 2.4P < .05 was considered to be statistically significant. Statistical analysis was performed using a commercially available statistical package SPSS version 20.0 (IBM Co.).Continuous variables were expressed as a mean ± standard deviation. Categorical variables were expressed as percentages. Student's t test and the Chi‐square test were used for the comparison of continuous and categorical variables, respectively. For repeated variables, one‐way analysis of variance (ANOVA) for repeated measures was used. Pearson's correlation coefficient was used to examine the correlation between the two variables. A 2.5All participants underwent two‐dimensional echocardiography examination. We obtained standard parasternal long‐axis, mid‐ventricular short‐axis, apical long‐axis, apical 2‐ and 4‐chamber images using the Philips HD11XE, 2012 Netherlands.2.6All procedures performed in studies involving human participants were in accordance with the ethical standards of the Turkey Research Committee and with the 1964 Helsinki declaration and its later comparable ethical standards. Written permission was obtained from the Hospital Management Committee. The informed patient consent was obtained from each subject.3P > .05).There was no statistically significant difference between the male and female groups in terms of sociodemographic and basal clinical findings Table , P > .05pm, and Tp‐e intervals at 01.00 am and 07.00 am. However, Tp‐e at maximum HR, cTp‐e at maximum HR, HR at 07.00 pm, 07.00 am, and 01.00 pm, cTp‐e intervals at 07.00 am and 01.00 pm, and Tp‐e interval at 01.00 pm were statistically significantly higher in males than females. In addition, the females had significantly higher cTp‐e and HR at 01.00 am when compared with that in the males , Tp‐e and cTp‐e intervals at 07.00 es Table .am values were significantly higher than in the female group. There were no differences between the two groups in terms of pNN50, VLF, LF/HF ratio, minimum Spectral Power, maximum QT and minimum QT interval, and SDNN values at 07.00 pm. In addition, in the male group, SDNN at 07.00 am, SDNN at 01.00 pm, and HF values were significantly lower than in the female group . In addition, there was no correlation at maximum HR between age and Tp‐e interval values in the male group . In the female group, there was a strong positive correlation at minimum HR between age and Tp‐e interval values (R = 0.81 and P < .01). In addition, there was no correlation at maximum HR between age and Tp‐e interval values in the female group  , which is the distance from the peak of the T wave to the isoelectric line. Significant prolongations in Tp‐e  interval was closely associated with increased cardiovascular deaths.Electrophysiological studies have shown that different repolarization patterns occur in men and women.Tp‐e interval, Tp‐e/QT, and Tp‐e/QTc are markers that indirectly show repolarization differences of the heart and, when increased, have been proven to be closely associated with malignant ventricular arrhythmias. These markers were found to be prolonged in many diseases in which malignant ventricular arrhythmia and sudden cardiac death rates were significantly increased, compared with the normal population and increased compared with the control group. Some of them are Brugada syndrome, coronary artery disease, heart failure5Variations in Tp‐e, cTp‐e interval, and Tp‐e/QT, Tp‐e/QTc, and cTp‐e/QTc ratios at different time intervals in a day have not been previously investigated in healthy individuals. In our study, we found that Tp‐e interval, cTp‐e interval, and Tp‐e/QT, Tp‐e/QTc, and cTp‐e/QTc ratios varied significantly throughout the day in both men and women. In addition, there were significant negative correlations between the Tp‐e interval and the SDNN values. These results will contribute to an understanding of the importance of pharmacochronotherapy.Authors declare no Conflict of Interest for this article.In our study, there are relatively few cases. A greater number of case studies will contribute to obtaining more accurate information. In addition, a comparison of healthy males and females with malignant ventricular arrhythmias and the occurrence of malignant ventricular arrhythmias will contribute to obtaining more healthy data.


BackgroundChronic secondary mitral regurgitation (SMR) is a common form of valvular heart disease. Its diagnosis through echocardiography is challenging and dependent on subjective interpretations. The subjective error to diagnose SMR can be reduced by developing accurate predictive quantitative parameters that support echocardiographic interpretations and clinical manifestations. The present study aims to develop a new diagnostic indicator for chronic SMR. The new indicator called MR product is the product of left atrial diameter (LAD) and left ventricular internal dimension at end-systole (LVIDs).Materials and MethodsAn analytical, case-control study was conducted from transthoracic echocardiography (TTE) reports of 720 patients performed according to the guidelines of the American Society of Echocardiography. The LAD and LVIDs were measured using the standard M Mode TTE. Out of the 720 patients who underwent TTE, 300 patients were diagnosed with chronic SMR by experienced clinicians. Only 115 of those 300 patients met the inclusion criteria for chronic SMR. Results2.The MR product was significantly associated with chronic SMR (rho = 0.83) and predicted it with an odds ratio of 1.014 (p < 0.001). The MR product was able to diagnose SMR with a sensitivity of 94.8% and a specificity of 92.2%, respectively, for a cut off value of 1,045 mmConclusionA new parameter called MR product (LAD multiplied with LVIDs) has very high sensitivity and specificity for SMR. Therefore, it can aid in establishing its diagnosis, along with other diagnostic modalities. The new parameter may also potentially increase the diagnostic accuracy of the disease. Mitral regurgitation (MR) is a common form of valvular heart disease present in approximately 10% of adults over 75 years of age . It is lSMR is almost always associated with heart failure (HF) and one in every five patients with HF develops SMR . About 2The diagnosis of SMR usually begins with the detection of a heart murmur on routine cardiac examination of a heart failure patient who is typically in Grade 2 or 3 of SMR. Over the years, Doppler flow echocardiography has emerged as the standard method to diagnose a suspected case of SMR . HoweverThe accurate interpretation of a Doppler study requires a sound clinical acumen because it is dependent upon the clinician’s subjective assessment. Moreover, interpersonal differences between the interpretations may give rise to false diagnoses . Hence, The subjective error in diagnosing certain heart pathologies can be reduced by developing accurate predictive quantitative parameters that support echocardiographic interpretations so that the final diagnosis is not solely based upon the clinician’s opinion. One such parameter developed in a study by Haq et al. was the ratio of a left atrial to a left ventricular diastolic diameter which supports the diagnosis of Grade 2 diastolic dysfunction . Thus, iThe present study is concerned with the development of a new diagnostic indicator for chronic SMR. The new indicator is the product of the left atrial diameter (LAD) and the left ventricular internal dimension at end-systole (LVIDs). For the sake of simplicity, the product will be referred to as the MR product in the study. Increased LAD in SMR is well-established -14, but The echocardiography machine measures both diameters of the MR product which minimizes the errors in subjective interpretation. The new indicator, when combined with other modalities, will help in establishing the diagnosis of this condition and may improve the diagnostic accuracy of chronic SMR. It will also help the clinicians to be more confident regarding their opinion on the echocardiography reports of such cases. Thus, the results of this study may add to the diagnostic arsenal for patients with SMR. The MR product can be measured by simple echocardiography (performed without contrast). If it is a valuable diagnostic indicator in our study, the MR product can be used as an initial diagnostic test for SMR, especially in those areas where contrast-based Doppler studies are not readily available.Study designAn analytical, case-control study was conducted from March 2017 to September 2018 at the Department of Cardiology of the Holy Family Hospital, Rawalpindi, Pakistan. This study was approved by the Institutional Review Board of Rawalpindi Medical University (IRB-2016-MC-0420).Echocardiography informationTransthoracic echocardiography (TTE) reports of 720 patients performed according to the guidelines of the American Society of Echocardiography were collected and documented . The LADSelection of casesThree hundred of 720 patients (41.67%) were diagnosed with chronic SMR by experienced clinicians based on the report of the TTE Doppler echocardiography. We excluded patients with any autoimmune condition, malignancy, structural mitral valve disease , mitral repair surgery or mitral valve implant, diastolic dysfunction of any grade, pericarditis, and sepsis from the study. Based on these criteria, 115 cases were then selected. Selection of controlsThe patients who underwent Doppler echocardiography but did not have chronic SMR constituted our control population. The same exclusion criteria were applied and 115 controls were then selected after careful age and gender-based matching with the cases. Statistical techniquesThe descriptive analysis of the study parameters was performed using the IBM Statistical Package for Social Sciences (SPSS), version 23.0 . Spearman’s correlation was used to observe the correlation between study variables. A Mann-Whitney U test was employed to assess significant differences in the study variables between cases and controls. A binary logistic regression was performed and the receiver operating characteristic (ROC) curve was constructed to evaluate the predictive power of the MR product for chronic SMR. A p-value of less than 0.05 was considered statistically significant.Population parameters and their correlation with heart dimensions, indicated by Spearman’s correlation coefficient, are provided in Table Table Table Table The receiver operating characteristic (ROC) curve characteristics of the three parameters  are provided in Table Despite the heavy clinical burden of chronic secondary mitral regurgitation, its diagnosis and management offer many challenges, and long-term outcomes of surgical procedures have not been well-established, even in developed countries . In deveThe MR product employs two heart dimensions, LAD and LVIDs. Many studies have correlated LAD with chronic SMR and a few studies have established left atrial enlargement as a contributing factor for SMR . WhetherWhen used alone as a diagnostic marker of SMR, the ROC curve of LAD shows sensitivity and specificity of 75.7% and 61.8%, respectively, at a cut off value of 43.5 mm, whereas the normal accepted left atrial diameter is 33.6 mm ± 4.1 . The rea2. This high predictive power is further validated by a binary logistic model which reports a predictive accuracy of 90.1% and Nagelkerke R2 of 0.84, meaning that our model, based on the MR product as a diagnostic indicator, is accurate in 90% of cases and explains 84% of the variability in the observations. The odds ratio of 1.014 was also highly significant (p < 0.001), indicating a strong relationship between the MR product and SMR. Thus, the statistics provide a strong logical basis for using the MR product as a diagnostic indicator of chronic SMR.The new parameter uses the product of these two dimensions and shows a marked increase in predictive accuracy and strength of correlation than either LAD or LVIDs alone. The rho value of 0.83 indicates a very high strength of correlation with chronic SMR. At the area under the curve (AOC) of 0.98, the optimal sensitivity and specificity are 92.2% and 94.8%, respectively, for a cut off value of 1,045 mmBased on these statistics, the MR product has the potential for many clinical applications in SMR. It may improve diagnostic accuracy when combined with other modalities, such as echocardiography and electrocardiography. It can be also be used for screening of suspected individuals before ordering a detailed contrast-based study, especially in areas where Doppler studies are expensive and not readily available. This application can increase the diagnostic rate and reduce health care burden by earlier diagnosis, timely interventions, and eventually, reduced mortality rates in such areas.The study has certain limitations. Firstly, the diagnostic accuracy of the MR product needs to be confirmed by large clinical trials involving many geographic areas and it should be correlated with different patient parameters. Secondly, although the MR product may increase the diagnostic accuracy, its routine clinical use will require the proof of improved diagnostic rate of SMR by multiple studies.Chronic secondary mitral regurgitation (SMR) is a relatively prevalent condition with numerous diagnostic challenges and a poor clinical outcome when left undiagnosed and untreated. A new parameter called the MR product (LAD multiplied with LVIDs) has a very high sensitivity and specificity of 92.2% and 94.8%, respectively, for this condition. It can aid in establishing the diagnosis of SMR, along with other modalities, and may potentially increase the diagnostic accuracy for the disease. The MR product can also be used as a screening test for SMR in areas where contrast-based studies are not accessible on a large scale, thus ensuring better medical care for patients in these areas.


The method has improved over the years in terms of MR acquisition, focus on relative artifact‐free myocardium regions, and T2* quantification. Several improvement factors involved include blood pool signal suppression, the reproducibility of T2* measurement as affected by scanner hardware, and acquisition software. Regarding the T2* quantification, improvement factors include the applied curve‐fitting method with or without truncation of the signals acquired at longer echo times and whether or not T2* measurement focuses on multiple segmental regions or the midventricular septum only. Although already widely applied in clinical practice, data processing still differs between centers, contributing to measurement outcome variations. State of the art T2* measurement involves pixelwise quantification providing better spatial iron loading information than region of interest‐based quantification. Improvements have been proposed, such as on MR acquisition for free‐breathing mapping, the generation of fast mapping, noise reduction, automatic myocardial contour delineation, and different T2* quantification methods. This review deals with the pro and cons of different methods used to quantify T2* and generate T2* maps. The purpose is to recommend a combination of MR acquisition and T2* mapping quantification techniques for reliable outcomes in measuring and follow‐up of myocardial iron overload. The clinical application of cardiac T2* mapping for iron overload's early detection, monitoring, and treatment is addressed. The prospects of T2* mapping combined with different MR acquisition methods, such as cardiac T1 mapping, are also described.Cardiac TLevel of Evidence: 4Technical Efficacy Stage: 5J. Magn. Reson. Imaging 2019. HEREDITARY HEMOCHROMATOSIS, sickle cell disease, and β‐thalassemia major are common blood diseases with a worldwide spread.2* MRI quantification. The relation between cardiac iron deposition and T2* value was verified by several postmortem studies.2* values were measured with confirmation of increased iron content by atomic emission spectroscopy and synchrotron x‐ray fluorescence microscopy.2* value detects iron overload status in blood disease patients. On its detection, T2* >20 msec reflects no cardiac iron overload; T2* between 10 and 20 msec reflects mild to moderate iron load; and T2* <10 msec reflects severe iron overload.2* methods have improved over the years, the pros and cons of the various methods have only been discussed briefly in clinical and technical‐scientific reports. Therefore, the roadmap for optimal application of T2* measurements in the detection and monitoring of myocardial iron deposition in blood diseases such as hemochromatosis and transfusion‐dependent anemia has not yet been laid out. This review discusses various aspects of T2* quantification proposed and in use to generate T2* maps. First, the technical aspects of T2* quantification are dealt with, including recently proposed methods for T2* mapping. Second, the position of T2* mapping in measuring iron overload in hemochromatosis and transfusion‐dependent anemia is discussed for several clinical applications, such as its early detection, heart function status, iron chelation monitoring, and its prospective combination with T1 mapping methods. The purpose is to recommend a combination of MR acquisition and T2* mapping quantification techniques for reliable outcomes in myocardial iron overload measurement and follow‐up.Cardiac magnetic resonance imaging (MRI) provides a noninvasive method to detect cardiac iron overload by myocardial T2* is measured using a bright‐blood2* value is derived by fitting signal intensities of left ventricular (LV) myocardium regions of interests (ROIs) at different echo times (TEs) to a monoexponential equationIn general, myocardial T2* the myocardium transverse relaxation time. For acquiring a representative signal intensity of a myocardium region, epicardial and endocardial contours are drawn on a short‐axis image and propagated to all TEs  sequences.2* values to determine iron status at 1.5T and 3.0T are tabulated in Table Analyzing the T2* assessment, a single breath‐hold technique with electrocardiogram‐gating is used to acquire multiple TE images by the MGE sequence.2* measurement has been an alternative, even though used sparingly up to now.In bright‐blood gradient echo for T2* measurements when compared with synthetic T2* values.2* values under 3 msec.The experiment showed that the influence of water and fat protons at the first out‐of‐phase and in‐phase TE points is minimized when the first TE was set near to 1 msec. This setting yields more accurate TWhen applying the bright‐blood MGE at 1.5T MRI, artifacts tend to appear at different TE images of the myocardium Fig. , which m2* measurement at a higher global T2* value  and become negligible in heavily iron‐loaded myocardium2* measurement method.2* measurement.Susceptibility artifact was reported to mainly influence myocardial TA single breath‐hold with electrocardiogram‐triggered MGE is commonly used to reduce the influence of motion artifact. However, in a case when the patient is unable to perform the breath‐hold, another method such as a free‐breathing method can be an alternative. An example is a single‐shot gradient‐echo echo‐planar‐imaging (GRE EPI) sequence combined with a nonrigid motion correction.In MRI, signal intensity alteration due to different proton precession resonance frequencies can induce a chemical shift phenomenon. This induction causes spatial misregistration artifact on image data along the frequency‐encoded direction.The effect of chemical shift artifact can be minimized by implementing fat‐suppression techniques such as spectral saturation or by setting a specific MR sequence setup such as frequency‐encoding direction, the field of view (FOV), and receiver bandwidth.The application of less than 180° radiofrequency pulse in gradient echo sequences influences the in‐phase and out‐of‐phase condition between water photon and fat signals over time. At 1.5T, the in‐phase precession signal of every ±4.4 msec between fat and water gives an additional signal contribution to the resultant image, while at its out‐of‐phase condition, the resultant image will receive the contribution of fat and water signal differences.Another method to generate a series of MGE images is known as the black‐blood sequence.2* measurement has been shown to improve image quality, the goodness of monoexponential curve fitting, and intraobserver and interobserver reproducibility compared with the use of bright‐blood MGE.2* values measured by the two with higher T2* reproducibility when using the black‐blood MGE sequence.2* measurement when available.Application of the black‐blood MGE sequence in T2* measurements in global myocardium.The entire midventricular septum is used to measure iron in LV myocardium,2* in the ROI of LV myocardium. The first method, known as ROI‐based, averages signal intensity in the ROI on each MGE image before fitting its value monoexponentially, while the other so‐called pixelwise method fits the signal intensity of each pixel in the ROI of MGE image series separately. Both methods were reported to perform similarly in measuring the T2* value of normal and moderate iron status on a synthetic T2* map.2* <10 msec the pixelwise method can identify more precisely the correct T2* value than the ROI‐based method.2* measurement by the pixelwise method has also been reported to be small compared with the ROI‐based method.In general, there are two ways to calculate T2* measurement by the pixelwise method can be achieved by evaluating the median of pixelwise T2* rather than its mean value yielding higher T2* measurement reproducibility.2* value distributions can lead to misleading iron deposition status, interfering with the early detection of iron loading in borderline T2* threshold situations, affecting the decision for appropriate chelation therapy.The pixelwise method has the benefit of detecting iron heterogeneity across myocardial regions both on a bright‐blood MGE sequence Fig. j and a b2* measurement.2* imaging protocol, ie, by using parallel imaging acceleration to identify any random error in the image while failing to identify any systematic bias due to the susceptibility of gradients.Noise bias reportedly reduces the accuracy and precision of the pixelwise method and is related to the number of MR receiver coil elements used.2* values  as a criterion to exclude data points at longer TEs. In this method, different R2 values of 0.990,12 or 2.5.2 method.Due to the presence of signal plateau or offset at longer TEs, different modifications of monoexponential fitting were introduced to acquired more reliable Tes Figs. , 6. A moes Figs. , furtheres Figs. c:(3)y=Kehod Fig. d. The me2* values are produced by the offset method by using the lower number of excitations.2* value by the offset with the decrease of "true" model T2*, while both SNR and R2 truncation methods were able to fit the model properly until lower T2*, confirming higher accuracy and precision of the truncation methods in measuring T2*.2* measurement by the offset method compared with other monoexponential fitting methods in the presence of artifacts of a real patient's data. However, to our knowledge, the two truncation methods were not compared in the presence of major susceptibility or motion artifacts. Moreover, different thresholds in excluding longer TE points by the two methods also need to be validated for more accurate and precise T2* measurement.A comparison between the offset method and the truncation method shows that lower TThe delineation technique to determine the myocardial region plays an essential role in detecting iron overload in the whole myocardial area while avoiding any adjacent regions, ie, blood pool, lung, or stomach. Manual delineation of myocardial borders necessarily produces variability between observers that decrease with higher cardiac imaging experience.2* that shows a moderate or severe cardiac iron overload condition at initial cardiac MR scanning.2* measurement is needed and followed by an appropriate iron chelation therapy to improve the survival rate of hemochromatosis and transfusion‐dependent anemia patients.2* screening for thalassemia major patients from 10 years old to as early as 5 years old. The reduction promotes early detection of iron loading in pediatric patients.2* scanning as additional decision information for iron chelation therapy regimens, showing that the information works to drastically reduce cardiac‐related death by 45% compared with patients lacking the information on iron content.Carpenter et al reported a worldwide survey of cardiac MR T2* <20 msec.The monitoring of changes in functional cardiac MR and echocardiography can detect the progression of heart function impairment due to iron loading. The normal range value of LV function in thalassemia major patients without myocardial iron overload has been documented2* value lower than 10 msec indicates a high‐risk development of heart failure.2* values are below 10 msec.2* measurement thus plays a vital role in updating the patient's iron status during the chelation therapy monitoring,In hemochromatosis and transfusion‐dependent anemia patients, the detection of the T2* mapping is able to differentiate patients with and without myocardial fibrosis in hypertrophic cardiomyopathy patients,2* mapping values under 20 msec are related to the presence of microvascular injury.Improvement of LV function such as ejection fraction can be obtained by iron‐chelation therapy, leading to prolonged survival age and reduction of death rate by cardiac failure. However, when the therapy fails to improve the LV function, or there is no access to regular therapy,1 value, compared with controls, is identified in transfusion‐dependent anemia patients having a T2* value under 20 msec.1 mapping value of 900 msec by using the modified Look–Locker inversion recovery sequence (MOLLI) at 1.5T MRI in thalassemia patients with cardiac iron overload,1 value was slightly lower compared with MOLLI.95 T1 measurement in the case of cardiac iron overload at 3T revealed a modest increase of T1 value compared with the value measured at 1.5T. However, the measured T1 value is still lower compared with the controls measured at that field strength.1 mapping in postmortem studies.1 mapping and ECV measurement can be used as complementary information of T2* mapping to identify LV impairment and iron status in cardiac iron overload patients.Lower T2* mapping in myocardial iron overload measurement. The application of a black‐blood gradient echo sequence to generate pixelwise T2* mapping is recommended to improve the contrast between myocardium and its surroundings and to remove any blood signals inducing susceptibility artifact. A standard deviation map can be used as additional information to detect the presence of artifacts in the T2* map. Image series should be acquired in eight TEs ranging from 1–18 msec at recommended 1.5T. In bright‐blood gradient echo sequence, some delay after the R‐wave at the end‐diastolic phase is suggested to avoid the heart motion artifact with advisedly increasing the number of excitations for patients having difficulties maintaining breath‐hold. Free‐breathing gradient‐echo using single‐shot GRE EPI with a respiratory motion correction can also be an alternative technique to produce higher quality of the T2* map when the reproducibility can be validated at different MR centers and scanners.In conclusion, we recommend several techniques to generate T2* map, the median assessment is proposed to quantify its pixelwise regional values. Automatic segmentation of LV myocardium can serve as an alternative method to gain higher reproducibility in myocardial region definition, and thus improves accurate iron overload detection. A modification of monoexponential fitting with truncating longer TE in the presence of signal plateau was shown to produce more reliable T2* measurement with the need for further validation of the methods in detecting true iron in the presence of unwanted artifact. Automatic truncation in SNR and R2 truncation methods potentially serves as an objective technique to exclude longer TE data in T2* map generation. The presence of iron overload is recommended to be confirmed by other techniques, such as T1 mapping and ECV quantification, for a better understanding of the progression of the disease.Due to its ability to suppress artifact, the use of a black‐blood sequence facilitates iron heterogeneity identification on different AHA segments for early detection of myocardial iron overload and chelation treatment monitoring. In order to identify iron heterogeneity on the T


Mitral valve prolapse (MVP) is a common valvular disease, which may remain a benign condition for a long period of time. However, some patients experience malignant ventricular arrhythmias and sudden cardiac death (SCD). It is still largely unknown how to risk-stratify these patients, and no specific recommendations have been proposed to help the clinical decision-making. We present the case of a young man whose first clinical presentation was an out-of-hospital cardiac arrest and was subsequently diagnosed with MVP. We highlighted the possible risk factors for SCD and the challenges in the clinical management of these patients. Mitral valve prolapse (MVP) is one of the most common valvular heart diseases, which may remain a benign condition for a long period of time, unless accompanied by severe mitral regurgitation (MR) which requires surgical treatment when patients develop symptoms or the left ventricle (LV) begins to dilate and dysfunction. However, some patients, usually young and without any significant comorbidities, experience malignant ventricular arrhythmias (VA) and sudden cardiac death (SCD), estimated in 0.2–0.4% per year, and up to 1.8% per year in the presence of a flail leaflet ,4,5, (v)We present the case of a young man whose first clinical presentation was an out-of-hospital cardiac arrest and was subsequently diagnosed with MVP, with the aim of highlighting the diagnostic tests performed to exclude other causes of SCD and to identify possible specific risk factors in MVP, and of creating further awareness of the challenges in the clinical management of these patients.A 44-year-old man was admitted to the hospital after an out-of-hospital cardiac arrest, with a successful resuscitation including nine shocks for ventricular tachycardia/ventricular fibrillation (VT/VF). Retrospectively, it was discovered that he had hypertension and hyperlipidemia and had been treated with an angiotensin-converting enzyme inhibitor and a statin. His family medical history included early coronary heart disease (father’s side) and SCD in his mother’s family, which was never further explored. Before the event, he had no specific cardiac complaints.2), and right ventricle systolic pressure within normal range.Upon arrival to the emergency room, he was hemodynamically unstable with a blood pressure of 80/50 mmHg, and on physical examination, a grade II/III systolic murmur was noted at the apex. The electrocardiogram (ECG) showed a junctional rhythm without signs of acute coronary syndrome, but the patient was brought immediately to the catheterization-laboratory, where no significant coronary artery disease was found, and a temporarily LV support device was positioned . The blood tests did not show any abnormalities except a peak troponin T of 1392 ng/L. After hemodynamic stabilization, the LV support device was removed, and at the fourth day of hospitalization he was weaned from ventilation support. The ECG then showed a sinus rhythm with T wave inversion on lead III and AVF ; at the 2) with no regional wall motion abnormalities, good systolic function (ejection fraction = 56%) and no presence of myocardial fibrosis; the presence of the bi-leaflet prolapse was confirmed with mild mitral annular disjunction (A contrast-enhanced cardiac magnetic resonance (CMR) imaging was performed on the eighth day of admission to exclude cardiomyopathy, and showed a dilated LV  was implanted, and the patient was discharged. Before discharge, genetic counseling was performed according to standard practice including whole exome sequencing. Firstly, 522 genes associated with cardiovascular development and disease were evaluated, with special attention to the genes know to be associated with mitral valve prolapse (Dachsous Cadherin-Related 1(DCHS1), Filamin A (FLNA), Phospholipase D1 (PLD1), and DAZ interacting protein 1(DZIP1) . FurtherDuring the out-patient clinical follow-up, two months after discharge, a Holter recording was performed and showed sinus rhythm with no complex arrhythmias and 1% PVCs. A few months later, the patient developed mild symptoms (reduced exercise capacity), and based on the presence of LV dilatation and significant MR, he was referred for mitral valve repair and concomitant tricuspid valve repair (based on a tricuspid annuls of 40 mm and tricuspid regurgitation grade 2+). In particular, mitral ring annuloplasty was performed (Edwards Physio-II ring 38) and two pairs of neochordae were placed on P2. Tricuspid valve ring annuloplasty was also performed (Edwards Physio Tricuspid ring 32). The surgical operation was successful with no residual mitral regurgitation, and an echocardiogram six months after the operation showed normalization of the LV dimension with good systolic function. The ECG abnormalities also disappeared with normalization of the negative T waves . The patIdentification of MVP patients at risk of malignant arrhythmias is still a major clinical challenge. Studies published so far on the topic have been performed retrospectively, and mainly include a selected population based on the outcome of SCD ,3,6; theIn the patient of the current case, extensive analysis has been performed to exclude all possible causes of SCD and identify the proposed risk factors for malignant VA in MVP; however, the patient presented few of the proposed risk factors that might have helped in refining his risk profile. At the first echocardiographic analysis, a clear Barlow’s-like valve with a bi-leaflet prolapse and a significant annular dilatation and valvular regurgitation was observed, but the mitral annulus disjunction was only mild (<5 mm). Mitral annulus disjunction has been proposed to be associated with VA, but particularly when ≥5 mm, and in patients without significant MR . Our patAdvanced imaging such as CMR, has been proposed to better characterize the myocardial substrate in these patients and particularly to identify the presence of late gadolinium enhancement (LGE) at the level of the papillary muscles or basal inferolateral LV wall, which have been associated with VA. In the study by Basso et al , 93% of Initial studies have tried to identify novel markers to refine risk stratification for VA in these patients. On top of the above-mentioned MV abnormalities, advanced echocardiographic measures such as global longitudinal strain (GLS), post-systolic index and mechanical dispersion were found to be associated with VA , and migIn our patient, a potential point of clinical attention was the family history of SCD which was not further investigated before the event. A screening including echocardiography and Holter could have been indicated at the time of death of his mother. Similarly, when the diagnosis of MVP is made in a patient, thorough family anamnesis for valvular heart disease and SCD should be performed  and a Holter recording may be considered even without symptoms. More importantly, family screening should be advised, as for our patient whose sister was also consequently diagnosed with MVP. A familial distribution of MVP has been largely documented especially in Barlow’s patients ,17 and fDue to a lack of evidence, current guidelines unfortunately cannot provide specific indications for the treatment of VA in these patients, but only management advice according to known risk factors for other cardiovascular disease. Medical therapy should be the same as for a non-MVP population, with a potential use of catheter-based ablation in the case of high burden and symptomatic arrhythmias . ICD impIn conclusion, the current case aims at creating further awareness on the comprehensive diagnostic analysis (including genetic testing) necessary when a patient presents with SCD and MVP as the only possible cause, and the challenges a cardiologist faces in the management and decision-making of these patients due to the lack of specific recommendations.


The development of cardiac resynchronization therapy (CRT) has been crucial in reducing morbidity and mortality in patients with advanced heart failure. However, a significant proportion of patients who receive CRT fail to derive significant clinical benefits from this therapy. Successful CRT depends on a multitude of factors, including appropriate patient selection, left ventricular lead positioning, and postimplant management. Newer device-based algorithms, multipoint ventricular pacing, and the development of leadless CRT devices constitute important facets of both the present and near-future evolution of this therapy. Thus, some segments of the left ventricle (LV), for instance, may contract in a dyssynchronous fashion when compared with other regions, with examples of such being the known delay in the depolarization and subsequent contraction of the LV free  wall seen in patients with left bundle branch block (LBBB). This phenomenon decreases the overall efficiency of global LV contraction.3 While precise cellular and biochemical mechanisms remain incompletely understood, CRT has been shown to reverse many of the changes that have been noted during periods of dyssynchrony as well as reduce the levels of both clinical and experimental HF biomarkers.3CRT aims to improve  the synchrony of the ventricular contraction, thereby improving pump efficiency. Over time, CRT aims to increase LV contractility, stroke volume, and ejection fraction and, in some cases, can induce mechanical reverse remodeling.8 However, about one-third of eligible patients do not receive the intended benefits of CRT.9 Therefore, active basic, translational, and clinical research is currently being undertaken in an effort to determine how appropriate patient selection, LV lead placement optimization, and postimplantation device programming and patient care can potentially maximize CRT benefits. Ultimately, restoring conduction to near-normal physiology is the primary aim and, in a select group of patients with suitable anatomy free of infra-Hisian disease, His-bundle pacing could also be applied to achieve this aim.11 This, however, is an interesting separate topic and will not be a part of the present review.Optimal CRT delivery has been demonstrated to reduce HF hospitalizations and patient mortality and improve patient quality of life.12. Historically, an array of endpoints were originally used to show CRT response including surrogate echocardiographic and physiological variables that include LV ejection fraction (LVEF), LV end-systolic volume (LVESV), LV end-diastolic diameter (LVEDD), and peak oxygen consumption (VO2)16; subsequently, from 2004 to 2005, larger clinical trials indicated benefits attributable to CRT in the reduction in mortality and/or HF-related hospitalizations . In all, the evidence gathered from these trials informed the current American College of Cardiology (ACC) clinical practice guidelines,17 as summarized in Table 2.CRT response is predicated on modifying the natural history of HF and may actually represent a spectrum of response levels from near-normalization of the LV contractile function, termed a “super-response,” to worsened survival and LV function post–CRT implant, termed a “negative response”Criteria for appropriate patient selection can be derived from the currently accumulated evidence. Overwhelmingly, certain electrocardiogram (ECG) criteria that indicate ventricular dyssynchrony and the clinical assessment of HF severity consistently show the best predictive ability for the prediction of response to CRT. These and other novel criteria for predicting CRT response continue to be studied and are summarized henceforth.18 showed that CRT in patients with a QRS duration of more than 150 ms was associated with a reduction in composite clinical endpoints such as death or hospitalization, while CRT in patients with a moderately prolonged QRS complex duration (120–149 ms) did not confer the same benefit. Similarly, in another meta-analysis, the presence of a LBBB pattern on surface ECG was the only strong predictor for a reduction in clinical endpoints as compared with the presence of non-LBBB conduction abnormalities.19 Therefore, while patients with moderately prolonged QRS or non-LBBB morphology may be considered for CRT, the strength of evidence suggesting a good response remains weaker17 and so other criteria should be used to predict CRT response.The QRS complex width and a morphology pattern suggestive of LBBB appear to be the most powerful predictors for CRT response. While trials have shown a benefit of CRT in patients with a QRS complex duration of greater than 120 ms to 150 ms, a meta-analysis by Sipahi et al.20 The presence of a bifascicular block was, however, not predictive of CRT benefit in the Multicenter Automatic Defibrillator Implantation with Cardiac Resynchronization Therapy (MADIT-CRT) trial.21 CRT is not indicated in patients with a QRS complex duration of less than 120 ms and may even cause harm in such scenarios.22It has been hypothesized that a sufficiently wide QRS complex would reflect a delay even in the left bundle in a patient with a right bundle branch block pattern, which would make CRT effective.23 In a recent retrospective analysis of 197 consecutive patients with a PRp of less than 200 ms prior to CRT implantation, PRp was independently associated with worsened outcomes of death or the need for advanced HF therapies.24 PRp was strongly associated with adverse outcomes, particularly in LBBB-morphology patients, and remained an independent predictor of adverse outcomes regardless of the QRS complex duration in patients with LBBB morphology.Other ECG markers, such as P–R-interval prolongation (PRp), have also been studied as potential indicators of CRT response.13 While subsequent trials showed a response to CRT in less-sick patient cohorts, such as NYHA functional classes I and II patients,8 the evidence remains strongest for patients with symptomatic HF (NYHA classes II–IV). There are, however, some specific patient scenarios in which earlier implementation of CRT may be considered. Needless to say, any evidence of an added benefit from CRT in patients with a clinical diagnosis of advanced HF has to start from the principle that optimal medical therapy has previously been adopted and maintained over time.Most of the evidence for the benefits of CRT comes from trials that enrolled New York Heart Association (NYHA) functional classes III and IV patients.20 CRT aims to rectify this issue by restoring intraventricular and interventricular synchrony.25 Thus, it was a natural side effect of this understanding to also evaluate the utility of CRT in patients with mechanical dyssynchrony in the absence of electrical dyssynchrony—in other words, in those with a normal QRS complex duration and/or morphology. Three large trials, however, did not show any benefit with the use of CRT in patients with mechanical dyssynchrony upon assessment with cardiac imaging.27 Furthermore, one of these trials actually showed a potential for harm with CRT use in patients with a QRS complex duration of less than 130 ms and echocardiographic evidence of mechanical dyssynchrony.22Hypothetically, the electrical dyssynchrony seen with the prolongation of QRS complex duration and morphology changes underpins mechanical dyssynchrony, leading to ineffective LV function.26 This trial aimed to assess 12 predefined echocardiographic parameters regarding their ability to predict clinical and echocardiographic responses to CRT. Accordingly, 498 patients in 53 clinical centers from around the world who were eligible to undergo CRT implantation according to published guidelines had preprocedure echocardiogram recordings taken to assess, in a blinded manner, conventional and tissue Doppler imaging–based parameters. Thereafter, patients were followed for six months to discern whether any improvement occurred in a clinical composite score as well as whether there was any reduction in their LVESV. Ultimately, the ability of these parameters to predict benefit with CRT remained modest at best, with significant interobserver variability noted in the analysis of dyssynchrony parameters despite specific training.The utility of imaging markers, such as echocardiographic parameters, to assess dyssynchrony was initially called into question after the publication of the Predictors of Response to CRT (PROSPECT) large international observational study.28 It also increased the predictive value of a statistical risk model already incorporating QRS duration and ischemic etiology to predict reverse remodeling. Similarly, Fournet et al. in their pilot study discussed the potential role of analyzing three-dimensional strain curves using automated quantification by way of computerized algorithms to predict CRT response.29 Tao et al. separately shared their observations upon using gated single-photon-emission computed tomography myocardial perfusion imaging to assess both scar burden and contractility pattern, with a U-shaped contractility pattern significantly associated with LVEF improvement versus a non-U-shaped contractility pattern.30 Similarly, cardiac magnetic resonance imaging has also been effective in assessing scar burden, which is associated with a reduced response to CRT, as well as global ventricular dyssynchrony pattern.31Following the PROSPECT trial, while interest in utilizing imaging-based parameters to assess dyssynchrony with the goal of predicting CRT response has waned somewhat, smaller studies continue to show some degree of utility of imaging parameters in predicting CRT response. A recent study by Wang et al. revealed that, in a cohort of 80 patients, LBBB contraction pattern identified via radial or longitudinal strain methods using speckle-tracking predicted reverse remodeling at six months.32 Though the analysis had evidence of publication bias, an imputation of missing data  still maintained the predictive association between contractile reserve and CRT response with an odds ratio of 2.42 . Furthermore, there is additional evidence from Vukajlovic et al. that DSE can also help identify potential individuals likely to experience near-normalization of LV function, i.e., “super-responders.”33 However, this enthusiasm is tempered by the unavailability of evidence of an improvement in hard outcomes  in borderline candidates who do not meet conventional CRT criteria as defined by established guidelines and therefore must be balanced with implantation and long-term risks of the deployment of resynchronization device therapy.Finally, of interest is the fact that dobutamine stress echocardiography (DSE) can be applied to assess myocardial functional reserve. Hence, its utility in appropriate patient selection for CRT has also been studied to some extent. In a meta-analysis of nine observational studies with a total of 767 patients, Kloosterman et al. concluded that contractile reserve assessment via DSE had a significant association with CRT response.34 In a MADIT-CRT trial substudy conducted among patients who were deemed to be super-responders (defined in the study as those in the top quartile for LVEF change), female sex was the second strongest independent predictor of super-response (odds ratio: 1.96).35 The other predictors in the order of strength of association were the presence of a LBBB pattern on surface ECG, no prior history of myocardial infarction, a QRS complex duration of 150 ms or more, a body mass index of less than 30 kg/m2, and a smaller baseline left atrial volume index.Among other patient-related characteristics, women have almost consistently shown a better response to CRT than men.36Similarly, in a meta-analysis by Yin et al. that analyzed 11 observational studies including 149,259 patients, women experienced lower all-cause mortality and better improvement in echocardiographic parameters than did men.An analysis of the role of CRT in patients with atrial fibrillation (AF) and for patients requiring antibradycardia pacing is presented separately at the end of this review.Finally, due to the abundance of risk factors and other predictors summarized above, risk scores have been created in an effort to better predict the individual patient’s clinical response to CRT. While evidence of their usefulness remains limited beyond that from the initial reporting centers, studies have continued to show some indication of their ability to predict CRT response.37 with the following items: LBBB (two points), age older than 70 years (one point), cardiomyopathy of nonischemic etiology (one point), an LVEDD of less than 40 mm/m2 (one point), and the presence of septal flash (two points). Their study reported a predictive accuracy of 0.75 (C-statistic) via a cohort of 45 patients demonstrating a greater-than-15% improvement in LVESV as assessed at six months post–CRT implant. A more recent follow-up study authored by the same group included 275 patients followed for two years and showed a predictive accuracy of 0.78 (C-statistic) for CRT response, which was defined as an improvement in LVESV and freedom from major cardiovascular events .38 This scoring system, however, has not yet been validated in other populations beyond the initial study sites and so its utility in clinical practice remains undefined.In 2014, Brunet-Bernard et al. reported the development of a seven-point scoring system called L2ANDS39 However, this can be particularly challenging in a right atrium that is either very small or enlarged with significant tricuspid regurgitation or in patients with a persistent left-sided vena cava. Particularly in these cases, preprocedure planning via imaging with computed tomography or magnetic resonance technology or intraprocedure planning using fluoroscopy may help to better define optimal positioning of the LV pacing lead.39 Guidelines for step-by-step procedures recommended for LV lead implantation are beyond the scope of this paper; however, it is important to note that rates of successful LV lead implantation in major previous CRT trials were around 90%,8 with challenging CS anatomy being the most common reason for implantation failure. Furthermore, LV lead dislodgement rates have been found to be around 6% in clinical trials,40 which again is the most important procedural complication. A wide variety of specialized tools have been developed to facilitate LV lead implantation, and it is important for the operator to be at least familiar with less frequently applied techniques and equipment like venoplasty or active fixation leads, as these can be useful in select cases such as venous occlusion or dissection. If all else fails, surgical LV lead implantation may be considered via thoracotomy, video-assisted thoracic surgery, or robotic approaches. These methods do have their limitations in achieving a suitable posterolateral lead position and in some cases have been reported to lead to higher LV lead failure rates.39Optimal LV lead placement is another factor that can significantly impact the amount of benefit derived from CRT. Coronary sinus (CS) anatomy can be highly variable, with procedural difficulty frequently encountered in cannulating the CS and in landing the lead in a stable position to promote appropriate capture of the LV. This usually is possible through cannulation of a highly variable posterolateral, lateral, or anterolateral branch of the CS between the middle cardiac vein and the anterior interventricular vein.Broadly, three methods have emerged for targeted LV lead placement to maximize CRT benefit: anatomic distance, electrical delay, and/or mechanical delay. Additionally, the use of multipoint pacing LV leads continues to promote an evolution in our understanding of optimal LV lead placement and pacing vectors.41 Furthermore, a MADIT-CRT trial substudy showed that apical positioning of the LV lead was less favorable,42 in part due to the nonphysiological activation sequence of the LV and also by further reducing the area of the ventricular myocardium activated via CRT. However, beyond these “rules,” larger studies have failed to show any significant differences in response between the anterior, posterior, and lateral lead positions,39 with a slight advantage reported when the LV pacing lead was positioned in a posterolateral or lateral CS tributary.Intuitively, maximizing the distance between the LV and the RV leads would potentially lead to the largest region of ventricular capture for the optimal delivery of CRT, an observation that also agrees with findings in previous clinical studies.43 A recent study, the ENHANCE CRT trial, failed to show the benefit of this approach to optimize CRT delivery in a small population of patients with non-LBBB QRS complex morphology.44A variety of algorithms have been developed to identify the site of the latest electrical activation using the timing of the local LV depolarization wave recorded during lead implantation. The difference between the start of the QRS complex as measured via surface ECG to the local electrogram  has been used in many of these algorithms to determine the optimal site for implantation of the LV lead. In general, the longer this delay period, which is indexed to the QRS width , then the better the responses to CRT are, according to smaller studies.45 This trial found higher rates of clinical response in the intervention group (83% versus 65%) and lower rates of combined clinical endpoints. Similarly, the Speckle Tracking–assisted Resynchronization Therapy for Electrode Region (STARTER) trial assessed the utility of echocardiography-guided lead placement and found better event-free survival (hazard ratio: 0.48) in the intervention group.46Imaging modalities can also be used to target the region of maximum mechanical delay and avoid regions with scar as part of an effort to maximize the response to CRT. In this regard, the randomized Targeted LV Lead Placement to Guide CRT (TARGET) trial assessed the utility of echocardiographic radial-strain imaging to target the site of latest mechanical activation with the avoidance of scar as compared with standard CRT placement.47 as well as three-dimensional echocardiography also continue to be investigated in this regard.48The role of magnetic resonance–based LV lead placement to avoid LV scar20 These factors subsequently led to the development of single-lead multipoint pacing (MMP) systems.A natural evaluation of the concept of dyssynchrony and resynchronization led to the hypothesis of using pacing from multiple sites as another alternative to better deliver CRT. Hence, multilead and/or multisite pacing strategies were evaluated and, although deemed safe in the short-term, have encountered clinically relevant problems in pragmatic terms, including a difficulty to consistently ensure multisite capture with the use of Y-adaptors and issues related to accelerated battery depletion.49 More recently, the ability to use simultaneous MPP cathodes has been studied and demonstrated favorable changes with respect to hemodynamic and echocardiographic parameters following CRT implantation.51 Multiple larger trials are currently ongoing to better evaluate the safety and efficacy of MPP systems to enhance CRT response in all-comers,52 CRT nonresponders,53 and patients with narrow QRS complexes.54Generally, MPP leads have been sought after for some time, as they allow for the involvement of multiple programmable vectors, thereby decreasing the chances of undesirable outcomes such as very elevated capture thresholds or phrenic nerve stimulation. This strategy has also been shown to be associated with a reduction in mortality in a large nationwide database.55 In routine clinical practice, target CRT percentages of greater than 95% are typically used.Postimplant device management remains critical and an optimal response to CRT depends on appropriate postprocedure programming and ongoing device optimization. A high percentage of biventricular pacing is essential for the delivery of optimal CRT: Hayes et al. reported that effective CRT present for more than 98.4% of the time is associated with better clinical outcomes.. The absence of these features may indicate a loss of LV capture, lead malfunction or dislodgement, fusion between paced and intrinsic complexes, or LV activation delay due to possible scar or anodal capture.20 The LV lead capture threshold test should be performed with the RV lead turned off and with real-time ECG data acquisition occurring whenever feasible  in order to better evaluate the occurrence of LV capture .A 12-lead ECG is often the most useful method to detect poor (or absent) LV capture due to lead failure or dislodgement or other issues related to programming . In general, optimal LV capture is determined by a dominant R-wave in lead V1 and a QS complex in leads I and aVL ; however, echocardiography-based methodologies have been the most widely studied in the literature thus far.25Several studies have evaluated the role of A–V and V–V interval optimization using ECG-based, echocardiography-based, or intracardiac electrogram (IEGM)–based methods in order to improve the clinical response to CRT. Iterative QRS complex–based methodologies aimed to improve the morphology of the paced QRS complexes based on optimizing AV delays and V–V intervals are commonly used 25 it is unclear whether these benefits translate into persistent clinical improvement by optimizing CRT delivery over time.These methods involve algorithms that aim to optimize LV diastolic filling by assessing mitral valve inflow velocity patterns, cardiac output (stroke volume) by assessing the aortic valve pulse wave Doppler velocity–time integral, or various M-mode or tissue Doppler-derived parameters, respectively. While smaller studies have shown their usefulness in improving acute hemodynamic measures with CRT,25 These algorithms include QuickOpt and SyncAV ; SmartDelay ; and Adaptive CRT . They have been evaluated to date in a few randomized trials58 and compared with empiric interval programming and echocardiography-based methods. While these trials have demonstrated safety when using these novel algorithms, benefits involving clinical endpoints as compared with empiric device settings or echocardiography-based approaches are yet to be displayed.Three IEGM-based algorithms are available today, with the common goal of correcting intrinsic electrical activation delays via the optimal setting of A–V and V–V intervals.59 The Adaptive CRT algorithm is a continuous ambulatory-based algorithm that aims to modify the CRT delivery mode and programmed intervals based on dynamic rhythm characteristics, such as heart rate, PR interval, and the development of AV block. Due to these observations, which may support the delivery of LV-only pacing in select patients, the larger AdaptResponse trial is currently ongoing and has the goal of testing the superiority of this algorithm to reduce deaths or HF decompensation as compared with conventional CRT delivery.60It must be mentioned, however, that the Adaptive CRT study, in a post-hoc analysis, did confirm improved clinical outcomes in patients receiving LV-only pacing  versus the echocardiography-optimized arm.20 CRT devices have the ability to trigger LV pacing in response to sensed events detected by RV leads, leading to fusion or pseudofusion complexes. These are thought to be less effective hemodynamically when compared with LV lead–initiated events. Interestingly, most CRT devices tend to overestimate the CRT percentage in this setting and do not indicate the percentage of “effective” biventricular-paced QRS complexes61; therefore, other ancillary methods such as ambulatory ECG recording  have been used to better estimate the actual CRT percentage. Here, a mention should be made about eCRTAF, which is a proprietary algorithm from Medtronic  that can distinguish effective biventricular-paced QRS complexes from fusion and pseudofusion complexes and adjusts the pacing rate to maximize effective CRT delivery62; at this time, further larger studies, however, are needed to evaluate its efficacy in improving HF outcomes related to effective CRT delivery.Suboptimal biventricular pacing percentages are often related to conducted atrial tachyarrhythmias (ATs), frequent ventricular ectopy, or inappropriately programmed AV delays.63 Treatment with β-blocker agents, dedicated antiarrhythmic therapy (often class III drugs), and invasive management in selected cases  may improve outcomes in these patients.64Premature atrial and ventricular beats also reduce the efficacy of CRT delivery. In a MADIT-CRT substudy, there was a threefold increase in the probability of low CRT pacing percentage in patients with 0.1% to 1.5% ectopic beats, which translated into an increased risk of death, HF hospitalization, and ventricular arrhythmias in patients as compared with in controls.65 At this time, there have been no trials objectively performed to test the efficacy of CRT in patients with AF; consequently, CRT use in this setting has only been given a class IIa status according to current practice guidelines.14 AF and other ATs pose a special challenge in CRT delivery due to the irregularity of the intrinsic rhythm, the loss of atrial contraction, and frequently noted rate control problems that limit effective biventricular triggered responses.65 Furthermore, new-onset AF is relatively common in CRT recipients, likely due to its association with advanced HF.68 The prognosis of AF in this setting remains uncertain; a MADIT-CRT substudy showed no difference in the clinical benefits obtained with CRT therapy in a cohort of patients with a history of intermittent AF/ATs versus controls.66 However, a post-hoc analysis of the Comparison of Medical Therapy, Pacing, and Defibrillation in HF (COMPANION) trial suggested that AF patients did not draw any greater benefit from CRT in comparison with controls.69The role of CRT in AF and other ATs remains incompletely studied to date.65 AV nodal ablation has been shown to be effective in restoring effective CRT delivery and thereby achieving favorable clinical endpoints.71 Questions still remain regarding the role of AV nodal ablation in patients with intermittent or paroxysmal AF/ATs as compared with adequate pharmacological therapy. AV nodal ablation has its own disadvantages, including permanent pacemaker dependency and associated risks if complications arise following generator and/or lead replacement.Practical recommendations for the management of such patients continue to emphasize the role of effective CRT delivery in these individuals. Guidelines and expert recommendations emphasize the role of antiarrhythmic drugs, such as amiodarone, in an effort to restore and maintain sinus rhythm, with escalation to AV nodal ablation warranted if adequate CRT pacing percentages are not achieved.72 The Biventricular Versus RV Pacing in HF Patients with AV Block (Block-HF) trial was designed to test the efficacy of CRT in patients with NYHA functional classes I through III HF with a LVEF of 50% of less who were predicted to require higher percentages of ventricular pacing.73 CRT was effective in reducing the combined endpoint of death, acute HF exacerbation, or increase in LVESV. Hence, preemptive CRT-based device therapy is considered reasonable in such patients .17Higher percentages of right ventricular (RV) pacing have been associated with electrical and mechanical dyssynchrony, especially in patients with depressed LV systolic function at baseline.After the development and subsequent approval of leadless RV pacing systems, interest has concomitantly increased regarding the development and application of a reliable leadless system capable of providing CRT.74 CRT delivery is often limited by anatomical challenges relating to the positioning of the LV pacing lead. In a transvenous CRT delivery system, this specifically includes obtaining access to the CS, whose anatomy may be highly variable across individual patients, including in some cases where the CS is atretic or does not include any tributaries deemed suitable for the implant of a pacing lead.75 Furthermore, higher LV pacing thresholds and phrenic nerve stimulation pose additional challenges for safe implantation of the LV lead.76 These have historically been dealt with by either surgically implanting epicardial leads or by placing endocardial LV leads, which both come with their own sets of unique risks and potential complications.20Beyond the limitations of conventional lead systems, including the established risks of lead fracture, thrombogenicity, and potential nidus for bacteremia and infection,77 This is a multicomponent system that consists of a conventional right-sided dual-chamber defibrillator that communicates with a phased-array ultrasound pulse generator implanted subcutaneously in the lateral thorax. This generator transmits ultrasound energy to a small  electrode implanted in the LV endocardium . The initial trial evaluating this system was stopped early due to a high incidence of cardiac tamponade, including one fatal event associated with the LV electrode delivery77; this led to modifications in the design of the delivery system with the delivery sheath now equipped with a balloon to ensure safe delivery of the LV endocardial electrode.In this regard, the only leadless LV-based pacing system to undergo clinical testing to date is the WiSE-CRT system .78 There were three periprocedural adverse events, including one case of ventricular fibrillation, one electrode embolization, and one vascular access–related event. There was also a 23% rate of device-related adverse events observed during the first month of follow-up. Of note, regarding the optimal anticoagulation strategy in patients who are not already candidates for systemic anticoagulation therapy due to other indications, a dual antiplatelet strategy was used in this study without any significant risk in the short follow-up period reported.Subsequent experience published in the Safety and Performance of Electrodes Implanted in the LV (SELECT-LV) study included a cohort of 35 patients and showed a 97.1% success rate of LV pacing system implantation as well as a 97% rate of successful biventricular capture at one month, with 88% of the patients demonstrating improvement in a clinical composite score at six months.CRT therapy has progressed significantly from its intuitive first concepts and applications to actually impacting in a very significant way the mortality, clinical care, and quality of life of patients with advanced HF. Currently, there remain several areas of active investigation aimed at reducing nonresponder to CRT rates and also expanding CRT’s indications to populations beyond those detailed in current practice guidelines. The impact of multipoint pacing, adaptive CRT programming optimization, and the development and use of wireless CRT systems also are areas of excitement and ongoing research, with eventual findings possibly further increasing the impact of electrical resynchronization on the care of these patients in the future.


Radiotherapy has been associated with late dose-dependent cardiovascular toxicity. In this cross-sectional pilot study, radiation dose distributions were correlated with areas of localized and diffuse myocardial fibrosis as measured by novel cardiac MRI (CMR) sequences including late gadolinium enhancement (LGE) and T1 mapping with the goal to identify early markers of myocardial damage.Twenty-eight patients with chest tumors including lung, breast, esophagus, and lymphoma underwent CMR per study protocol on average 46.4 months (range 1.7–344.5) after radiotherapy. Patients without pretreatment cardiac history were included if the volume of heart receiving 5 Gy or more was at least 10% (V5Gy ≥ 10%). The association of LGE with cardiac dosimetric factors, clinical factors , and T1 values was analyzed.p = 0.16 and 0.56, respectively). The average T1 value of the left ventricle myocardium was 1009 ms (range 933–1117). No significant correlation was seen for heart Dmax and Dmean and T1 values . In addition, no significant association between clinical factors and the development of LGE was identified.Cardiac maximum (Dmax) and mean dose (Dmean) equivalent to doses delivered in 2 Gy fractions (EQD2) were on average 50.9 Gy (range 6.2–108.0) and 8.2 Gy (range 1.0–35.7), respectively, compared to 60.8 Gy (40.8–108.0) and 6.8 Gy (1.8–21.8) among the 9 patients with LGE. Doses were not different between patients with and without LGE (No relation between cardiac doses, the presence of LGE or T1 values was observed. Further study is needed to determine the benefit of CMR for detecting radiotherapy-related myocardial fibrosis. Cardiac toxicity is a well-established complication of radiotherapy for mediastinal lymphomas , lung 22–4, esopIn spite of decades of research, fundamental questions about the etiology of radiation-induced heart disease (RIHD) remain . MultiplVarious imaging modalities have been used to evaluate RIHD including echocardiography, stress echocardiography, SPECT perfusion, cardiac computed tomography (cardiac CT), and cardiac magnetic resonance (CMR) imaging . While eLGE has become the radiologic non-invasive standard for determining both ischemic and non-ischemic focal fibrosis of the myocardiu –23. Its In the current study, a CMR protocol including late gadolinium enhancement (LGE) and T1 mapping was used to evaluate local and diffuse fibrotic changes within the myocardia of patients who had previously received thoracic radiotherapy. Our hypothesis was that high dose regions of radiotherapy correlate to areas of LGE and T1 mapping on CMR. The purpose of this cross-sectional study was to determine the usefulness of CMR in the early detection of myocardial RIHD, with the eventual goal to develop methods for early intervention in the disease process.Any patient who had previously undergone radiotherapy for tumors within the thorax including lung, breast, esophagus cancer, and lymphoma was eligible after informed consent for enrollment in a cross-sectional protocol approved by our institutional review board, as long as the volume of heart receiving 5 Gy or more was at least 10% (V5Gy ≥ 10%). Patients were excluded if they had documented previous cardiac disease history, either prior to or after radiotherapy. In addition to CMR, patients received comprehensive cardiac evaluation, including cardiopulmonary exercise testing, baseline transthoracic echocardiograms, and laboratory evaluation, with results published previously .CMR was performed on 28 patients using the same 1.5 Tesla MRI scanner  and imaging protocol for all patients. ECG-gated imaging was performed as follows: balanced steady-state free precession (bSSFP) short axis cine images were obtained  from above the mitral valve through the left ventricular (LV) apex. Two-, 3-, and 4-chamber cine views were also obtained. T1 maps were obtained in three locations covering the left ventricle  using a Modified Look-Locker Inversion recovery (MOLLI) pulse sequence prior to contrast administration. T2 mapping images were obtained at similar locations. Contrast was administered using 0.2 mmol/kg of IV Prohance . After a 2-min delay, long inversion time single-shot bSSFP inversion recovery images were obtained using a 550–600 ms inversion time. After 8–10 min, post-contrast images were obtained using an inversion time chosen to null normal myocardium. High-resolution gradient echo inversion recovery LGE images were obtained starting at 10 min post-contrast. These images were spatially matched to the cine images and covered the left ventricle. Post-contrast T1 mapping images were obtained at the end of the study. Post-processing was then performed using dedicated Precession imaging analysis software .The analysis of LGE images was performed using Precession software and MIM image registration software . Computed tomography (CT) radiation therapy planning scans and corresponding radiotherapy plans were imported from radiation treatment planning software  into MIM, in addition to the acquired CMR images. Cardiac structures including right and left ventricles, right and left atria, pericardium, and cardiac vasculature were contoured on CT by one radiation oncologist for consistency using a contouring atlas .Three-dimensional rigid registrations of the left ventricles were performed fusing CMR to the CT simulation scans in MIM. A combination of auto-matching the left ventricle followed by manual adjustments was done to finalize the registration. An example of the rigid registration process is shown in Fig. The location and volume of LGE was evaluated within the left ventricular myocardium and septum. LGE volumes were well demarcated and easily visualized due to their higher signal compared to surrounding normal myocardium. For this study, the volume of LGE was delineated and LGE volumes were calculated by one radiation oncologist in conjunction with board certified radiologists who were blinded to the radiotherapy dose distribution. T1 values were calculated using Precession software by determining average T1 values (relaxation time measured in ms) using the mid-ventricle short axis slice which showed larger ventricle thickness and had higher spatial reproducibility compared to the apex and base slices.All patients had T1 mapping and LGE sequences acquired. Dosimetric analysis was undertaken to explore if a dose response relationship existed between cardiac dose and both left ventricular T1 values and areas of LGE. Visualization of isodose distributions and areas of LGE were performed on the axial CT plane , with attention to heart dosimetric differences (discussed above) and clinical factors among patients both who did and did not experience LGE. We specifically considered differences in several oncology-relevant factors, including tumor site , body mass index, smoking status, hypertension diagnosis, and Adriamycin use. Finally, we used a two-sided t-test to consider the association between T1 mapping values and LGE. We also performed a linear regression using the ordinary least squares method to correlate Dmax and Dmean doses to T1 values. Microsoft Office Excel 2016  and Stata MP 15  were used for statistical analyses.The cohort included 28 patients of which the majority had lung and breast cancer (see Table The Dmax and Dmean EQD2 doses to the heart for the entire cohort were on average 50.9 Gy (range 6.2–108.0) and 8.2 Gy (range 1.0–35.7), respectively. As the T1 value analysis was focused on the left ventricle and septum, Dmax and Dmean EQD2 doses to the left ventricle were analyzed as well. These doses were on average 34.0 Gy (0.2–94.7) and 8.2 Gy (0.1–34.4), respectively. Further patient characteristics are presented in Table p = 0.33).Nine patients demonstrated areas of LGE, all within their left myocardium or septum. These 9 patients provided the data discussed below, with their treatment characteristics listed in Table p = 0.16 and 0.57, respectively) and EQD2 Dmax or Dmean of the left ventricle . Further dosimetric parameters including heart and left ventricle V5Gy/V30Gy/V40Gy/V50Gy, as well as D95 to the LGE volume, were also investigated. No significant difference was identified between patients with and without LGE . The cardiac EQD2 Dmax and Dmean in patients with LGE were on average 60.8 Gy (40.8–108.0) and 6.8 Gy (1.8–21.8), respectively. The EQD2 Dmax and Dmean to the left ventricle were on average 43.8 Gy (13.6–94.7) and 7.6 Gy (1.4–34.4), respectively. The 19 patients without LGE had cardiac EQD2 Dmax and Dmean on average of 46.1 Gy (6.2–82.6) and 8.8 Gy (1.0–35.7), respectively. Among these patients, the cardiac EQD2 Dmax and Dmean to the left ventricle were on average 29.4 Gy (0.2–74.7) and 8.4 Gy (0.1–30.0), respectively. Between individuals with and without LGE, no significant difference was seen in EQD2 Dmax or Dmean total heart doses . Patients who had evidence of LGE also had a trend towards higher T1 values  and 7.5 Gy (0.4–16.5), respectively, which were lower or similar compared to whole heart and left ventricle doses. D95 doses of the LGE volumes also clearly show that doses in these volumes were in general low. The location of the maximum heart dose was located outside the contoured LGE volume in all 9 patients. There was no geographic relationship between dose to coronary vessels and downstream myocardial areas of enhancement. There was no association between EQD2 Dmax and Dmean in the LGE area and the size of the LGE volume .All patients had diffuse T1 mapping performed. The average T1 value of the left myocardium and septum of patients on study was 1009 ms (range 933–1117). The association between T1 values and the heart and left ventricle EQD2 Dmax and Dmean values were analyzed. Linear correlations between heart Dmax and Dmean (in EQD2 Gy) and T1 mapping values (in ms) were also evaluated , 1.5 years = 1238 ms (p = 0.024)). Interestingly, the left lateral ventricle segment, which would have been outside of the traditional 3D conformal field and received only low dose, did not see differences between pre-treatment and post-treatment T1 values [The most comprehensive study on T1 mapping in the detection of RIHD is also by Takagi et al. as described above. Mean T1 values for CMR at baseline prior to radiotherapy were 1183 ms (+/− 46); however, values taken at the basal septum which received sizeable radiation doses were significantly elevated above baseline pretreatment values , but the significance of this absolute difference is unclear and likely subject to bias and confounders.The time to the development of cardiac fibrosis is not known, but it is assumed to develop within 6 months after radiotherapy and is not reversible once deposited. The median time from end of treatment to CMR acquisition in our sample was 24.6 months, similar to the studies by Huang et al. and Umezawa et al. who detected fibrosis at a median 37.2 months and 23.5 months following radiotherapy, respectively, which confirms this assumption. Patients demonstrating enhancement had a median interval between radiotherapy and CMR of 11.9 months compared to 31.4 months in patients without enhancement (There are several limitations to the current study. While RIHD can have many causes, CMR in this study primarily assessed myocardial damage and therefore cardiomyopathy. Due to the cross-sectional study design, no pre-radiotherapy CMRs were acquired and therefore areas of LGE on post-treatment CMRs may actually be related to “silent” undiagnosed cardiac events or may have been pre-existing. In addition, we cannot exclude that chemotherapy might have been related to LGE development. Although not demonstrated in the present study, with radiotherapy being a localized treatment a correlation between the location and volume of the LGE with the high dose distribution was anticipated whereas for systemic treatments more diffuse myocardial effects would be expected. While ideally investigating one primary tumor site only would have provided a more homogeneous patient cohort, dose standardization and investigation of a large spectrum of dose parameters in the present study are expected to account for interpatient differences in dose distribution and treatment techniques. Image fusion in this study was completed with rigid registrations; given the time interval between CT simulation and CMR, patient anatomy might have changed. To account for these anatomical changes, rigid registrations included rotations, translations and changes in magnitude aligned to the organ of interest, namely the left ventricle. The power of the current study is limited due to its small sample size. With the large variations in cardiac dose in our study, any clinically relevant relation between cardiac dose and myocardial fibrosis or LGE development should have been noticeable despite the limited sample size. In fact, patients with LGE in our study typically had lower maximum and mean doses compared to no-LGE patients. In addition, for all investigated dose levels, heart and left ventricle volumes were in general smaller for patients with LGE than without LGE development. Evaluation of LGE and T1 values on longitudinal studies are expected to further clarify the effect of radiotherapy on myocardial changes.In this pilot study, no relationship between cardiac radiation dose and localized fibrosis was seen using LGE on CMR. There was also no association between cardiac doses and T1 values as a measure of diffuse fibrosis. Further study, including volumetric CMR imaging and longitudinal assessment, is needed to determine the benefit of cardiac MRI in the detection of myocardial fibrosis following radiotherapy.