Assessment of Diffuse Myocardial Fibrosis in Rats Using Small-Animal Look-Locker Inversion Recovery T1 Mapping

Messroghli, Daniel; Nordmeyer, Sarah; Dietrich, Thore; Dirsch, Olaf; Kaschina, Elena; Savvatis, Kostas; h-Icí, Darach O; Klein, Christoph; Berger, Felix; Küehne, Titus

doi:10.1161/circimaging.111.966796

Cited by 106 publications

(74 citation statements)

References 22 publications

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“…All images were acquired in the short-axis plane at end diastole. Diffuse fibrosis was quantified in terms of T1-dependent ECV of the myocardium (85).…”

Section: Methodsmentioning

confidence: 99%

Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology

Bakeer

James

Roy

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cardiopulmonary complications are the leading cause of mortality in sickle cell anemia (SCA). Elevated tricuspid regurgitant jet velocity, pulmonary hypertension, diastolic, and autonomic dysfunction have all been described, but a unifying pathophysiology and mechanism explaining the poor prognosis and propensity to sudden death has been elusive. Herein, SCA mice underwent a longitudinal comprehensive cardiac analysis, combining state-of-the-art cardiac imaging with electrocardiography, histopathology, and molecular analysis to determine the basis of cardiac dysfunction. We show that in SCA mice, anemia-induced hyperdynamic physiology was gradually superimposed with restrictive physiology, characterized by progressive left atrial enlargement and diastolic dysfunction with preserved systolic function. This phenomenon was absent in WT mice with experimentally induced chronic anemia of similar degree and duration. Restrictive physiology was associated with microscopic cardiomyocyte loss and secondary fibrosis detectable as increased extracellular volume by cardiac-MRI. Ultrastructural mitochondrial changes were consistent with severe chronic hypoxia/ischemia and sarcomere diastolic-length was shortened. Transcriptome analysis revealed up-regulation of genes involving angiogenesis, extracellular-matrix, circadian-rhythm, oxidative stress, and hypoxia, whereas ion-channel transport and cardiac conduction were down-regulated. Indeed, progressive corrected QT prolongation, arrhythmias, and ischemic changes were noted in SCA mice before sudden death. Sudden cardiac death is common in humans with restrictive cardiomyopathies and long QT syndromes. Our findings may thus provide a unifying cardiac pathophysiology that explains the reported cardiac abnormalities and sudden death seen in humans with SCA.sickle cell anemia | cardiomyopathy | restrictive physiology | arrhythmias | sudden death S ickle cell anemia (SCA) results from a point mutation in the β-globin gene and affects millions world-wide. It is characterized by production of the mutant hemoglobin S (HbS), which polymerizes upon deoxygenation and distorts the shape of RBCs, increasing their propensity to hemolysis and microvascular occlusion. Recurrent cycles of HbS polymerization result in a host of acute and chronic complications, including vaso-occlusive pain crisis, chronic hemolytic anemia, and organ damage. SCA-associated mortality rates have improved because of early diagnosis with universal newborn screening, immunization, and penicillin prophylaxis, which has changed the natural history of SCA (1, 2) and the impact of SCA on organ pathologies is now becoming evident.Despite improved early survival, nearly one-third of young adults with SCA die suddenly (3-9). The sickle myocardium has been presumed to be relatively resistant to the effects of sickling (10), and studies/autopsies show little evidence of atherosclerosis or coronary disease (11)(12)(13)(14). Mildly increased systolic pulmonary arterial pressure (PAP) estimated by tricuspid regurgitant jet vel...

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“…All images were acquired in the short-axis plane at end diastole. Diffuse fibrosis was quantified in terms of T1-dependent ECV of the myocardium (85).…”

Section: Methodsmentioning

confidence: 99%

Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology

Bakeer

James

Roy

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Systematic in vivo histological validation of these techniques in humans is lacking. [24][25][26] The aims of the current study were to first provide comprehensive, whole-heart, histological validation of the DynEq-CMR technique for measurement of myocardial ECV. This, at the same time, allowed assessment of the validity of isolated-T 1 technique.…”

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confidence: 99%

Comprehensive Validation of Cardiovascular Magnetic Resonance Techniques for the Assessment of Myocardial Extracellular Volume

Miller

Naish

Bishop

et al. 2013

Circ: Cardiovascular Imaging

356

261

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Background-Extracellular matrix expansion is a key element of ventricular remodeling and a potential therapeutic target. Cardiovascular magnetic resonance (CMR) T 1 -mapping techniques are increasingly used to evaluate myocardial extracellular volume (ECV); however, the most widely applied methods are without histological validation. Our aim was to perform comprehensive validation of (1) dynamic-equilibrium CMR (DynEq-CMR), where ECV is quantified using hematocrit-adjusted myocardial and blood T 1 values measured before and after gadolinium bolus; and (2) isolated measurement of myocardial T 1 , used as an ECV surrogate. Methods and Results-Whole-heart histological validation was performed using 96 tissue samples, analyzed for picrosirius red collagen volume fraction, obtained from each of 16 segments of the explanted hearts of 6 patients undergoing heart transplantation who had prospectively undergone CMR before transplantation (median interval between CMR and transplantation, 29 days). DynEq-CMR-derived ECV was calculated from T 1 measurements made using a modified Look-Locker inversion recovery sequence before and 10 and 15 minutes post contrast. In addition, ECV was measured 2 to 20 minutes post contrast in 30 healthy volunteers. There was a strong linear relationship between DynEq-CMR-derived ECV and histological collagen volume fraction (P<0.001; within-subject: r=0.745; P<0.001; r 2 =0.555 and betweensubject: r=0.945; P<0.01; r 2 =0.893; for ECV calculated using 15-minute postcontrast T 1 ). Correlation was maintained throughout the entire heart. Isolated postcontrast T 1 measurement showed significant within-subject correlation with histological collagen volume fraction (r=−0.741; P<0.001; r 2 =0.550 for 15-minute postcontrast T 1 ), but between-subject correlations were not significant. DynEq-CMR-derived ECV varied significantly according to contrast dose, myocardial region, and sex. Conclusions-DynEq-CMR-derived

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“…Thus, T1 mapping should detect not only the patchy fibrosis detectable by LGE but also more diffuse fibrosis, a concept that has been confirmed in animal and human studies. 10,11 Therefore, one construct is that although LGE is a useful tool to assess for macroscopic myocardial scar/fibrosis, T1 mapping may be helpful in identifying diffuse or microscopic scar/fibrosis.…”

Section: Mri Methods For Detecting Fibrosismentioning

confidence: 99%

Myocardial Fibrosis in Asymptomatic Degenerative Mitral Regurgitation

Uretsky

Gillam

2014

Circ: Cardiovascular Imaging

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Assessment of Diffuse Myocardial Fibrosis in Rats Using Small-Animal Look-Locker Inversion Recovery T1 Mapping

Cited by 106 publications

References 22 publications

Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology

Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology

Comprehensive Validation of Cardiovascular Magnetic Resonance Techniques for the Assessment of Myocardial Extracellular Volume

Myocardial Fibrosis in Asymptomatic Degenerative Mitral Regurgitation

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