Primary impairment of left ventricular function in Marfan syndrome

Backer, Julie De; Devos, Daniël; Segers, Patrick; Matthys, Dirk; François, Katrien; Gillebert, Thierry C.; Paepe, Anne M. De; Sutter, Johan De

doi:10.1016/j.ijcard.2005.10.010

Cited by 112 publications

(84 citation statements)

References 20 publications

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“…In view of our results obtained in mice, we aimed to provide longitudinal human data for which we analyzed echocardiographic studies at different time-points available from our MFS patient population. An initial detailed study of left ventricular function in this population indicated mild intrinsic LV systolic and diastolic dysfunction (20). Data obtained from the subsequent preliminary retrospective analysis demonstrate stable LV dimensions and no clinically significant decline of LV systolic or diastolic function ( Table 2).…”

Section: Clinical Studiesmentioning

confidence: 81%

“…In order to correlate evolutionary findings obtained in MFS mice to the human MFS-related CMP phenotype, we analyzed serial ultrasound images, collected during the past 6 ± 1.9 y (range 3.4-10.3 y), of 19 MFS patients, previously reported by our group (20). In this previous study, we evidenced mild systolic and diastolic LV dysfunction as a primary manifestation of MFS.…”

Section: Clinical Studiesmentioning

confidence: 96%

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Intrinsic cardiomyopathy in Marfan syndrome: results from in-vivo and ex-vivo studies of the Fbn1C1039G/+ model and longitudinal findings in humans

et al. 2015

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Background: Mild intrinsic cardiomyopathy in patients with Marfan syndrome (MFS) has consistently been evidenced by independent research groups. So far, little is known about the long-term evolution and pathophysiology of this finding. Methods: To gain more insights into the pathophysiology of MFS-related cardiomyopathy, we performed in-vivo and ex-vivo studies of 11 Fbn1 C1039G/+ mice and 9 wild-type (WT) littermates. Serial ultrasound findings obtained in mice were correlated to the human phenotype. We therefore reassessed left ventricular (LV) function parameters over a 6-y follow-up period in 19 previously reported MFS patients, in whom we documented mild LV dysfunction. results: Fbn1C1039G/+ mice demonstrated LV contractile dysfunction. Subsequent ex-vivo studies of the myocardium of adult mutant mice revealed upregulation of TGFβ-related pathways and consistent abnormalities of the microfibrillar network, implicating a role for microfibrils in the mechanical properties of the myocardium. Echocardiographic parameters did not indicate clinical significant deterioration of LV function during follow-up in our patient cohort. conclusion: In analogy with what is observed in the majority of MFS patients, the Fbn1 C1039G/+ mouse model demonstrates mild intrinsic LV dysfunction. Both extracellular matrix and molecular alterations are implicated in MFS-related cardiomyopathy. This model may now enable us to study therapeutic interventions on the myocardium in MFS. M arfan syndrome (MFS, GenBank accession nos. L13923)is an autosomal dominant inherited connective tissue disorder caused by mutations in the fibrillin-1 gene (FBN1) encoding the extracellular matrix protein fibrillin-1. The clinical diagnosis of MFS relies on the identification of characteristic clinical manifestations, mainly occurring in the cardiovascular, musculoskeletal, and ocular system, as summarized in the ''Revised Ghent Nosology'' , and may be supplemented by the identification of a causal FBN1 mutation (1).Cardiovascular involvement in MFS is characterized by progressive dilatation of the ascending aorta at the level of the sinuses of Valsalva, ensuing a risk for type A aortic dissection or -rupture and aortic valve regurgitation (2). Other established cardiovascular manifestations of MFS include mitral valve prolapse and pulmonary artery dilatation. More recently, several independent studies demonstrated the presence ofmostly subclinical-intrinsic cardiomyopathy (CMP) with both left and right ventricular (LV and RV) systolic and diastolic dysfunction in MFS patients (3,4). The current knowledge of MFS-related CMP is based on cross-sectional studies, but little is known about the long-term evolution and pathophysiology of this finding.To unravel the underlying pathophysiology of MFS-related CMP, the knowledge obtained from the study of other MFS manifestations may at least be partly translated to the cardiac phenotype. Upregulation of TGFβ signaling, with activation of the canonical (SMAD2/3) and noncanonical (predominantly ERK1/2) pathways, i...

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Section: Clinical Studiesmentioning

confidence: 81%

Section: Clinical Studiesmentioning

confidence: 96%

Intrinsic cardiomyopathy in Marfan syndrome: results from in-vivo and ex-vivo studies of the Fbn1C1039G/+ model and longitudinal findings in humans

et al. 2015

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“…For example, a retrospective study of 143 MFS patients identified that the long-term mortality rate associated with aortic repair was 20% and that congestive heart failure was almost as great a risk factor as rupture/dissection of a secondary aneurysm (19% vs. 23%, respectively) (31). Since first described in a 1985 report (9), cardiomyopathy in MFS has been evaluated in several clinical studies totaling over 800 patients and collectively suggesting an average disease prevalence of approximately 20% with cohort-specific ranges from 0% to 68% (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Different factors are likely to have contributed to this extreme variance; among others, they include the exclusion criteria used in the studies, the size and age of the cohorts examined, the medication status of individual patients, the parameters used to normalize cardiac measurements, and the accuracy and resolution across different imaging modalities.…”

Section: Discussionmentioning

confidence: 99%

“…While the prevailing view is that thoracic aortic aneurysm (TAA) and cardiac valve abnormalities overload the left ventricle (LV) by respectively stiffening the aortic wall and increasing valve regurgitation (6), several clinical studies of relatively small cohorts of MFS patients have reported LV pathology in the absence of severe valve regurgitation or aortic surgery, or that is out of proportion with aneurysm growth (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). These findings have been used to argue that mutations in fibrillin 1 may cause ventricular dysfunction by altering the structural properties of myocardial tissue and/ or the local bioavailability of TGF-β signals (6,18).…”

Section: Introductionmentioning

confidence: 99%

Abnormal muscle mechanosignaling triggers cardiomyopathy in mice with Marfan syndrome

Cook¹,

Carta²,

Bénard³

et al. 2014

J. Clin. Invest.

121

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Patients with Marfan syndrome (MFS), a multisystem disorder caused by mutations in the gene encoding the extracellular matrix (ECM) protein fibrillin 1, are unusually vulnerable to stress-induced cardiac dysfunction. The prevailing view is that MFS-associated cardiac dysfunction is the result of aortic and/or valvular disease. Here, we determined that dilated cardiomyopathy (DCM) in fibrillin 1-deficient mice is a primary manifestation resulting from ECM-induced abnormal mechanosignaling by cardiomyocytes. MFS mice displayed spontaneous emergence of an enlarged and dysfunctional heart, altered physical properties of myocardial tissue, and biochemical evidence of chronic mechanical stress, including increased angiotensin II type I receptor (AT1R) signaling and abated focal adhesion kinase (FAK) activity. Partial fibrillin 1 gene inactivation in cardiomyocytes was sufficient to precipitate DCM in otherwise phenotypically normal mice. Consistent with abnormal mechanosignaling, normal cardiac size and function were restored in MFS mice treated with an AT1R antagonist and in MFS mice lacking AT1R or β-arrestin 2, but not in MFS mice treated with an angiotensin-converting enzyme inhibitor or lacking angiotensinogen. Conversely, DCM associated with abnormal AT1R and FAK signaling was the sole abnormality in mice that were haploinsufficient for both fibrillin 1 and β1 integrin. Collectively, these findings implicate fibrillin 1 in the physiological adaptation of cardiac muscle to elevated workload.

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“…Accord-ingly, mild but significant impairment of LV systolic and diastolic function have been reported in adult patients. [57][58][59][60] Moreover, Das, et al reported that children and young adult MFS patients were predisposed to prolonged mitral deceleration times (DT) and mitral E/A ratios in echocardiography, suggesting impaired LV relaxation (diastolic dysfunction). 61) In other studies, some patients developed dilated cardiomyopathy (DCM)-like features that were not consistent with aortopathy and valvulopathy, 62,63) but these patients could receive heart transplantation under careful monitoring.…”

Section: Marfan Cardiomyopathymentioning

confidence: 99%

Pathophysiology and Management of Cardiovascular Manifestations in Marfan and Loeys–Dietz Syndromes

et al. 2016

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SummaryMarfan syndrome (MFS) is an autosomal dominant heritable disorder of connective tissue that affects the cardiovascular, skeletal, ocular, pulmonary, and nervous systems and is usually caused by mutations in the FBN1 gene, which encodes fibrillin-1. MFS is traditionally considered to result from the structural weakness of connective tissue. However, recent investigations on molecular mechanisms indicate that increased transforming growth factor-β (TGF-β) activity plays a crucial role in the pathogenesis of MFS and related disorders, such as Loeys-Dietz syndrome (LDS), which is caused by mutation in TGF-β signaling-related genes. In addition, recent studies show that angiotensin II type 1 receptor (AT1R) signaling enhances cardiovascular pathologies in MFS, and the angiotensin II receptor blocker losartan has the potential to inhibit aortic aneurysm formation. However, the relationship between TGF-β and AT1R signaling pathways remains poorly characterized. In this review, we discuss the recent studies on the molecular mechanisms underlying cardiovascular manifestations of MFS and LDS and the ensuing strategies for management. (Int Heart J 2016; 57: 271-277)

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Primary impairment of left ventricular function in Marfan syndrome

Cited by 112 publications

References 20 publications

Intrinsic cardiomyopathy in Marfan syndrome: results from in-vivo and ex-vivo studies of the Fbn1C1039G/+ model and longitudinal findings in humans

Intrinsic cardiomyopathy in Marfan syndrome: results from in-vivo and ex-vivo studies of the Fbn1C1039G/+ model and longitudinal findings in humans

Abnormal muscle mechanosignaling triggers cardiomyopathy in mice with Marfan syndrome

Pathophysiology and Management of Cardiovascular Manifestations in Marfan and Loeys–Dietz Syndromes

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