Abnormal myocardial perfusion–fibrosis pattern in sickle cell disease assessed by cardiac magnetic resonance imaging

Bratis, Konstantinos; Kattamis, Antonis; Athanasiou, Konstantinos; Hautemann, David; Wijk, Kees van; Reiber, Hans J; Mavrogeni, Sophie

doi:10.1016/j.ijcard.2013.01.055

Cited by 14 publications

(10 citation statements)

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“…It has been recently reported that some degree of focal LV fibrosis measured using late gadolinium enhancement can be seen in young adults with SCA by CMR (42,48), and LV fibrosis was also reported in autopsies of young adults with SCA who died suddenly (77). Moreover, recent reports suggest dysregulated profibrotic pathways are up-regulated in SCA in general, as polymorphisms in TGF-β signaling pathway genes have been found in this patient population (78).…”

Section: Berk-ss Mice Develop Corrected Qt Prolongation and Widening supporting

confidence: 53%

“…Right heart catheterization studies have been largely restricted to patients with echocardiographically estimated elevation of PAP or those with clinical signs of PH (45,46). Few studies have been performed with cardiac MRI (CMR) (42,47,48), although this noninvasive imaging modality does offer unique advantages. Therefore, the bulk of the cardiac data reported in SCA is based on cross-sectional cardiac imaging using echocardiography.…”

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confidence: 99%

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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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Section: Berk-ss Mice Develop Corrected Qt Prolongation and Widening supporting

confidence: 53%

mentioning

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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“…CMR studies have been inconsistent in detecting the extent of fibrosis in SCD, and microscopic fibrosis, in particular, has not yet been well studied. Most studies have shown small degrees of LV focal fibrosis(31,43–45). Fibrosis was described in autopsy studies in SCD without atherosclerosis(40–42,46).…”

Section: Discussionmentioning

confidence: 99%

Cardiomyopathy With Restrictive Physiology in Sickle Cell Disease

Niss¹,

Quinn²,

Lane³

et al. 2016

JACC: Cardiovascular Imaging

115

137

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Objective To identify a unifying cardiac pathophysiology that explains the cardiac pathology in SCD. Background Cardiopulmonary complications, the leading cause of adult mortality in sickle cell disease (SCD), are associated with heart chamber dilation, diastolic dysfunction, elevated tricuspid regurgitant jet velocity (TRV) and pulmonary hypertension (PH). However, no unifying cardiac pathophysiology has been identified to explain these findings. Methods In a two-part study, we first examined SCD patients who underwent screening echocardiography during steady state at our institution. We then conducted a meta-analysis of cardiac studies in SCD. Results In the 134 SCD patients studied (median age 11 years), a significant enlargement of the left atrial volume was present (z-score 3.1, P=0.002), shortening fraction (SF) was normal (37.6 ± 4.7%), and lateral and septal ratios of mitral velocity to early diastolic velocity of the mitral annulus (E/e′) were severely abnormal in 8% and 14% of patients, respectively, indicating impaired diastolic function. Both TRV and lateral E/e′ correlated with enlarged left atrial volume in SCD (P=0.003 and P=0.006, respectively). Meta-analysis of 68 studies confirmed significant left atrial diameter enlargement in SCD patients compared to controls, evidence of diastolic dysfunction and enlarged left ventricular end-diastolic dimension with normal SF. The majority of patients with catheter-confirmed PH had mild pulmonary venous hypertension consistent with restrictive cardiac physiology. Conclusions Patients with SCD have a unique cardiomyopathy with restrictive physiology that is superimposed on hyperdynamic physiology, and is characterized by diastolic dysfunction, left atrial dilation and normal systolic function. This results in mild, secondary, pulmonary venous hypertension and elevated TRV. Sudden death is common in other forms of restrictive cardiomyopathy. Our finding of this unique restrictive cardiomyopathy may explain the increased mortality and sudden death seen in patients with SCD with mildly elevated TRV.

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“…Myocyte damage resulting in gross myocardial fibrosis/scarring can be detected by the CMR‐based late gadolinium enhancement (LGE) technique. The presence of gross myocardial fibrosis determined by LGE was reported in up to 25% of SCA patients . Autopsy studies have also shown varying degrees of fibrosis in the absence of atherosclerosis in specimens from individuals with SCA .…”

Section: Left Ventricular Diastolic Dysfunctionmentioning

confidence: 99%

“…LGE was reported in up to 25% of SCA patients. 5,68,85,86 Autopsy studies have also shown varying degrees of fibrosis in the absence of atherosclerosis in specimens from individuals with SCA. 5,87,88 One study found no association between myocardial fibrosis assessed by…”

Section: Technique the Presence Of Gross Myocardial Fibrosis Determimentioning

confidence: 99%

A reappraisal of the mechanisms underlying the cardiac complications of sickle cell anemia

Rai

Niss

2017

Pediatric Blood & Cancer

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Anemia, hemolysis-driven vasculopathy, and intrinsic myocardial injury have been proposed as predisposing factors to cardiac disease in sickle cell anemia (SCA). The individual impact of these mechanisms on the cardiac features of SCA and the way they influence complications such as sudden death and dysrhythmias have been unclear. Recent findings of an acquired restrictive SCA-related cardiomyopathy, driven by myocardial fibrosis, may explain some of these cardiac features. Given the complexity of cardiac pathology in SCA, using additional parameters to tricuspid regurgitant jet velocity (left atrial volume, diastolic parameters, NT-proBNP) may improve the accuracy of noninvasive screening for cardiopulmonary complications in SCA.

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Abnormal myocardial perfusion–fibrosis pattern in sickle cell disease assessed by cardiac magnetic resonance imaging

Cited by 14 publications

References 5 publications

Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology

Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology

Cardiomyopathy With Restrictive Physiology in Sickle Cell Disease

A reappraisal of the mechanisms underlying the cardiac complications of sickle cell anemia

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