Kan N. Hor

Comparison of magnetic resonance feature tracking for strain calculation with harmonic phase imaging analysis.

OBJECTIVES To compare a steady-state free precession cine sequence-based technique (feature tracking [FT]) to tagged harmonic phase (HARP) analysis for peak average circumferential myocardial strain (epsilon(cc)) analysis in a large and heterogeneous population of boys with Duchenne muscular dystrophy (DMD). BACKGROUND Current epsilon(cc) assessment techniques require cardiac magnetic resonance-tagged imaging sequences, and their analysis is complex. The FT method can readily be performed on standard cine (steady-state free precession) sequences. METHODS We compared mid-left ventricular whole-slice epsilon(cc) by the 2 techniques in 191 DMD patients grouped according to age and severity of cardiac dysfunction: group B: DMD patients 10 years and younger with normal ejection fraction (EF); group C: DMD patients older than 10 years with normal EF; group D: DMD patients older than 10 years with reduced EF but negative myocardial delayed enhancement (MDE); group E: DMD patients older than 10 years with reduced EF and positive MDE; and group A: 42 control subjects. Retrospective, offline analysis was performed on matched tagged and steady-state free precession slices. RESULTS For the entire study population (N = 233), mean FT epsilon(cc) values (-13.3 +/- 3.8%) were highly correlated with HARP epsilon(cc) values (-13.6 +/- 3.4%), with a Pearson correlation coefficient of 0.899. The mean epsilon(cc) of DMD patients determined by HARP (-12.52 +/- 2.69%) and FT (-12.16 +/- 3.12%) was not significantly different (p = NS). Similarly, the mean epsilon(cc) of the control subjects by determined HARP (-18.85 +/- 1.86) and FT (-18.81 +/- 1.83) was not significantly different (p = NS). Excellent correlation between the 2 methods was found among subgroups A through E, except there was no significant difference in strain between groups B and C with FT analysis. CONCLUSIONS FT-based assessment of epsilon(cc) correlates highly with epsilon(cc) derived from tagged images in a large DMD patient population with a wide range of cardiac dysfunction and can be performed without additional imaging.

Circumferential strain analysis identifies strata of cardiomyopathy in Duchenne muscular dystrophy: a cardiac magnetic resonance tagging study.

OBJECTIVES This study sought to evaluate the natural history of occult cardiac dysfunction in Duchenne muscular dystrophy (DMD). BACKGROUND Duchenne muscular dystrophy is characterized by progressive cardiac dysfunction and myocardial fibrosis late in the disease process. We hypothesized that left ventricular myocardial peak circumferential strain (epsilon(cc)) would decrease in DMD before global systolic functional abnormalities regardless of age or ventricular ejection fraction (EF). METHODS We evaluated cardiac magnetic resonance image (MRI) data from 70 DMD patients and 16 aged-matched control subjects. Standard imaging data included steady-state free precession short-axis cine stack images, cine myocardial tagged images, and myocardial delayed enhancement (MDE) (an indicator of myocardial fibrosis) sequences. Analysis was performed with QMASS (Medis Medical Imaging Systems, Leiden, the Netherlands) and HARP (Diagnosoft, Palo Alto, California) software. The DMD patient data were subdivided by age (<10 or >10 years), EF (>55% or <55%), and the presence or absence of MDE. RESULTS The DMD patients with normal EF had reduced epsilon(cc) at an early age (<10 years) compared with control subjects (p < 0.01). The DMD patients age >10 years with normal EF had further decline in epsilon(cc) compared with younger DMD patients (p < 0.01). There was further decline in epsilon(cc) with age in patients with reduced EF (p < 0.01) without MDE. The oldest patients, with both reduced EF and positive MDE, exhibited the lowest epsilon(cc). None of the patients had ventricular hypertrophy. CONCLUSIONS Myocardial strain abnormalities are prevalent in young DMD patients despite normal EF, and these strain values continue to decline with advancing age. Strain analysis in combination with standard MRI and MDE imaging provides a means to stratify DMD cardiomyopathy.

Magnetic Resonance Derived Myocardial Strain Assessment Using Feature Tracking

Purpose: An accurate and practical method to measure parameters like strain in myocardial tissue is of great clinical value, since it has been shown, that strain is a more sensitive and earlier marker for contractile dysfunction than the frequently used parameter EF. Current technologies for CMR are time consuming and difficult to implement in clinical practice. Feature tracking is a technology that can lead to more automization and robustness of quantitative analysis of medical images with less time consumption than comparable methods. Methods: An automatic or manual input in a single phase serves as an initialization from which the system starts to track the displacement of individual patterns representing anatomical structures over time. The specialty of this method is that the images do not need to be manipulated in any way beforehand like e.g. tagging of CMR images. Results: The method is very well suited for tracking muscular tissue and with this allowing quantitative elaboration of myocardium and also blood flow. Conclusions: This new method offers a robust and time saving procedure to quantify myocardial tissue and blood with displacement, velocity and deformation parameters on regular sequences of CMR imaging. It therefore can be implemented in clinical practice.

Eplerenone for early cardiomyopathy in Duchenne muscular dystrophy: a randomised, double-blind, placebo-controlled trial

BACKGROUND Cardiomyopathy is a leading cause of death in patients with Duchenne muscular dystrophy and myocardial damage precedes decline in left ventricular systolic function. We tested the efficacy of eplerenone on top of background therapy in patients with Duchenne muscular dystrophy with early myocardial disease. METHODS In this randomised, double-blind, placebo-controlled trial, boys from three centres in the USA aged 7 years or older with Duchenne muscular dystrophy, myocardial damage by late gadolinium enhancement cardiac MRI and preserved ejection fraction received either eplerenone 25 mg or placebo orally, every other day for the first month and once daily thereafter, in addition to background clinician-directed therapy with either angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Computer-generated randomisation was done centrally using block sizes of four and six, and only the study statistician and the investigational pharmacy had the preset randomisation assignments. The primary outcome was change in left ventricular circumferential strain (Ecc) at 12 months, a measure of contractile dysfunction. Safety was established through serial serum potassium levels and measurement of cystatin C, a non-creatinine measure of kidney function. This trial is registered with ClinicalTrials.gov, number NCT01521546. FINDINGS Between Jan 26, 2012, and July 3, 2013, 188 boys were screened and 42 were enrolled. 20 were randomly assigned to receive eplerenone and 22 to receive placebo, of whom 20 in the eplerenone group and 20 in the placebo group completed baseline, 6-month, and 12-month visits. After 12 months, decline in left ventricular circumferential strain was less in those who received eplerenone than in those who received placebo (median ΔEcc 1·0 [IQR 0·3-2·2] vs 2·2 [1·3-3·1]; p=0·020). Cystatin C concentrations remained normal in both groups, and all non-haemolysed blood samples showed normal potassium concentrations. One 23-year-old patient in the placebo group died of fat embolism, and another patient in the placebo group withdrew from the trial to address long-standing digestive issues. All other adverse events were mild: short-lived headaches coincident with seasonal allergies occurred in one patient given eplerenone, flushing occurred in one patient given placebo, and anxiety occurred in another patient given placebo. INTERPRETATION In boys with Duchenne muscular dystrophy and preserved ejection fraction, addition of eplerenone to background ACEI or ARB therapy attenuates the progressive decline in left ventricular systolic function. Early use of available drugs warrants consideration in this population at high risk of cardiac death, but further studies are needed to determine the effect of combination cardioprotective therapy on event-free survival in Duchenne muscular dystrophy. FUNDING BallouSkies, Parent Project for Muscular Dystrophy, US National Center for Advancing Translational Sciences, and US National Institutes of Health.

Myocardial strain measurement with feature-tracking cardiovascular magnetic resonance: normal values.

AIMS Myocardial deformation is a key to clinical decision-making. Feature-tracking cardiovascular magnetic resonance (FT-CMR) provides quantification of motion and strain using standard steady-state in free-precession (SSFP) imaging, which is part of a routine CMR left ventricular (LV) study protocol. An accepted definition of a normal range is essential if this technique is to enter the clinical arena. METHODS AND RESULTS One hundred healthy individuals, with 10 men and women in each of 5 age deciles from 20 to 70 years, without a history of cardiovascular disease, diabetes, renal impairment, or family history of cardiovascular disease, and with a normal stress echocardiogram, underwent FT-CMR assessment of LV myocardial strain and strain rate using SSFP cines.Peak systolic longitudinal strain (Ell) was -21.3 ± 4.8%, peak systolic circumferential strain (Ecc) was -26.1 ± 3.8%, and peak systolic radial strain (Err) was 39.8 ± 8.3%. On Bland-Altman analyses, peak systolic Ecc had the best inter-observer agreement (bias 0.63 ± 1.29% and 95% CI -1.90 to 3.16) and peak systolic Err the least inter-observer agreement (bias 0.13 ± 6.41 and 95% CI -12.44 to 12.71). There was an increase in the magnitude of peak systolic Ecc with advancing age, which was greatest in subjects over the age of 50 years (R(2) = 0.11, P = 0.003). There were significant gender differences (P < 0.001) in peak systolic Ell, with a greater magnitude of deformation in females (-22.7%) than in males (-19.3%). CONCLUSION Normal values for myocardial strain measurements using FT-CMR are provided. All circumferential and longitudinal based variables had excellent intra- and inter-observer variability.

Occult Cardiotoxicity in Childhood Cancer Survivors Exposed to Anthracycline Therapy

Background—More than 50% of >270 000 childhood cancer survivors in the United States have been treated with anthracyclines and are therefore at risk of developing cardiotoxicity. Cardiac magnetic resonance (CMR) has demonstrated utility to detect diffuse interstitial fibrosis and changes in regional myocardial function. We hypothesized that CMR would identify occult cardiotoxicity characterized by structural and functional myocardial abnormalities in a cohort of asymptomatic pediatric cancer survivors with normal global systolic function. Methods and Results—Forty-six long-term childhood cancer survivors with a cumulative anthracycline dose ≥200 mg/m2 and normal systolic function were studied 2.5 to 26.9 years after anthracycline exposure. Subjects underwent transthoracic echocardiography, CMR with routine cine acquisition, tissue characterization, and left ventricular strain analysis using a modified 16-segment model. Extracellular volume was measured in 27 subjects, all of whom were late gadolinium enhancement negative. End-systolic fiber stress was elevated in 45 of 46 subjects. Low average circumferential strain magnitude (&egr;cc) −14.9±1.4; P<0.001, longitudinal strain magnitude (&egr;ll) −13.5±1.9; P<0.001, and regional peak circumferential strain were seen in multiple myocardial segments, despite normal global systolic function by transthoracic echocardiography and CMR. The mean T1 values of the myocardium were significantly lower than that of control subjects at 20 minutes (458±69 versus 487±44 milliseconds; P=0.01). Higher mean extracellular volume was observed in female subjects (0.34 versus 0.22; P=0.01). Conclusions—Asymptomatic postchemotherapy pediatric patients have abnormal myocardial characteristics and strain parameters by CMR despite normal global cardiac function by standard transthoracic echocardiography and CMR measures.

Myocardial Fibrosis Burden Predicts Left Ventricular Ejection Fraction and Is Associated With Age and Steroid Treatment Duration in Duchenne Muscular Dystrophy

Background Patients with Duchenne muscular dystrophy exhibit progressive cardiac and skeletal muscle dysfunction. Based on prior data, cardiac dysfunction in Duchenne muscular dystrophy patients may be influenced by myocardial fibrosis and steroid therapy. We examined the longitudinal relationship of myocardial fibrosis and ventricular dysfunction using cardiac magnetic resonance in a large Duchenne muscular dystrophy cohort. Methods and Results We reviewed 465 serial cardiac magnetic resonance studies (98 Duchenne muscular dystrophy patients with ≥4 cardiac magnetic resonance studies) for left ventricular ejection fraction (LVEF) and presence of late gadolinium enhancement (LGE), a marker for myocardial fibrosis. LVEF was modeled by examining LGE status, myocardial fibrosis burden (as assessed by the number of LGE‐positive left ventricular segments), patient age, and steroid treatment duration. An age‐only model demonstrated that LVEF declined 0.58±0.10% per year. In patients with both LGE‐negative and LGE‐positive studies (n=51), LVEF did not decline significantly over time if LGE was absent but declined 2.2±0.31% per year when LGE was present. Univariate modeling showed significant associations between LVEF and steroid treatment duration, presence of LGE, and number of LGE‐positive left ventricular segments; multivariate modeling showed that LVEF declined by 0.93±0.09% for each LGE‐positive left ventricular segment, whereas age and steroid treatment duration were not significant. The number of LGE‐positive left ventricular segments increased with age, and longer steroid treatment duration was associated with lower age‐related increases. Conclusion Progressive myocardial fibrosis, as detected by LGE, was strongly correlated with the LVEF decline in Duchenne muscular dystrophy patients. Longer steroid treatment duration was associated with a lower age‐related increase in myocardial fibrosis burden.

Prevalence and distribution of late gadolinium enhancement in a large population of patients with Duchenne muscular dystrophy: effect of age and left ventricular systolic function

BackgroundDuchenne muscular dystrophy (DMD), an X-linked disorder affects approximately 1 in 5000 males, is universally associated with heart disease. We previously identified myocardial disease by late gadolinium enhancement (LGE) in DMD subjects at various stages of disease, but the true prevalence is unclear. Cardiovascular magnetic resonance (CMR) is well established for both assessment of ventricular function and myocardial fibrosis by LGE. We sought to establish i) prevalence and distribution of LGE in a large DMD population and ii) relationship among LGE, age, LVEF by CMR and current living status.MethodsCurrent living status, demographic and CMR data including ventricular volumes, LVEF and LGE from 314 DMD patients undergoing evaluation at a single large tertiary referral center were analyzed.Results113 of 314 (36%) of DMD subjects showed LGE positivity with prevalence increasing from 17% of patients <10 years to 34% of those aged 10–15 years and 59% of those >15 years-old. Patients with LVEF ≥55% were LGE positive in 30% of cases; this increased to 84% for LVEF <55%. LGE was more prevalent in the free wall (531/1243, 42.7%) vs. septal segments (30/565, 5.3%). Patients with septal involvement were significantly older and had lower LVEF than those with isolated free wall LGE. Ten percent (11/113) patients who had LGE died 10.8 months after CMR. Only one patient from the LGE negative group died. Patients who died had higher heart rate, larger left ventricular volume and mass, greater number of positive LGE segment and increase incident of septal LGE compared to those who remained alive.ConclusionIn DMD patients, LGE occurs early, is progressive and increases with both age and decreasing LVEF. Segmentally, the incidence of the number of positive LGE segments increase with age and lower LVEF. Older patients and those who died during the study period had more septal LGE involvement. The current studies suggest that the time course and distribution of LGE-positivity may be an important clinical biomarker to aid in the management of DMD-associated cardiac disease.

Detection of progressive cardiac dysfunction by serial evaluation of circumferential strain in patients with Duchenne muscular dystrophy.

The present study evaluated progressive cardiac dysfunction using serial circumferential strain (epsilon(cc)) measurements in patients with Duchenne muscular dystrophy (DMD). DMD is characterized by progressive cardiac dysfunction and myocardial fibrosis late in the disease process. We hypothesized that serial epsilon(cc) changes could be detected in individual patients with DMD during a time when the left ventricular ejection fraction (EF) changes are insignificant. Cardiac magnetic resonance imaging data from patients with DMD were evaluated. The left ventricular EF was calculated from steady-state free precession cine images and the composite epsilon(cc) measurement from tagged cine images. The serial epsilon(cc) and EF values for each patient were analyzed using the Wilcoxon sign rank test. Data from 51 patients with DMD (2 studies per patient, mean age at the initial study 11.8 +/- 3.5 years, range 7.4 to 25.4) were analyzed, with a mean interval between cardiac magnetic resonance studies of 15.6 +/- 6.0 months (range 6.2 to 28.1). In the interval between studies, the epsilon(cc) had decreased in all patients with DMD. The average decrease was 1.8 +/- 1.3 (p <0.001). However, the EF had decreased in 33 of the 51 patients and had increased in 18 of the 51 patients. On average, the EF decreased by 2.9 +/- 8.57% (p = NS). In conclusion, in patients with DMD, epsilon(cc) abnormalities indicate progression within a relatively short period when the EF changes were not significant. Serial epsilon(cc) measurements might provide reliable monitoring of the progression of DMD-associated cardiac dysfunction before overt heart failure develops, because it is more sensitive than the EF.

Effects of steroids and angiotensin converting enzyme inhibition on circumferential strain in boys with duchenne muscular dystrophy: a cross-sectional and longitudinal study utilizing cardiac magnetic resonance imaging

BackgroundSteroid use has prolonged ambulation in Duchenne muscular dystrophy (DMD) and combined with advances in respiratory care overall management has improved such that cardiac manifestations have become the major cause of death. Unfortunately, there is no consensus for DMD-associated cardiac disease management. Our purpose was to assess effects of steroid use alone or in combination with angiotensin converting enzyme inhibitors (ACEI) or angiotension receptor blocker (ARB) on cardiovascular magnetic resonance (CMR) derived circumferential strain (εcc).MethodsWe used CMR to assess effects of corticosteroids alone (Group A) or in combination with ACEI or ARB (Group B) on heart rate (HR), left ventricular ejection fraction (LVEF), mass (LVM), end diastolic volume (LVEDV) and circumferential strain (εcc) in a cohort of 171 DMD patients >5 years of age. Treatment decisions were made independently by physicians at both our institution and referral centers and not based on CMR results.ResultsPatients in Group A (114 studies) were younger than those in Group B (92 studies)(10 ± 2.4 vs. 12.4 ± 3.2 years, p < 0.0001), but HR, LVEF, LVEDV and LVM were not different. Although εcc magnitude was lower in Group B than Group A (-13.8 ± 1.9 vs. -12.8 ± 2.0, p = 0.0004), age correction using covariance analysis eliminated this effect. In a subset of patients who underwent serial CMR exams with an inter-study time of ~15 months, εcc worsened regardless of treatment group.ConclusionsThese results support the need for prospective clinical trials to identify more effective treatment regimens for DMD associated cardiac disease.