Orthotopic Heart Transplantation in Patients With Marfan Syndrome

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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“…More severe presentations of ventricular dysfunction requiring cardiac transplantation are rare, but have also been reported (29).…”

Section: Discussionmentioning

confidence: 99%

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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“…The largest group of patients (10 patients) with MFS and severe heart failure who underwent heart transplantation was reported by Knosalla et al (7); type-A aortic dissection was present in three patients and ascending aortic aneurysm was present in seven patients. They noted that transplantation in patients with MFS results in good long-term survival, similar to that of patients without MFS (7).…”

Section: F I G U R E 3 Ch E S T X-r a Y S H O Wi N G A N I N C R E mentioning

confidence: 99%

Dilated Cardiomyopathy in a Patient with Marfan Syndrome Accompanied by Chronic Type A Aortic Dissection and Right Atrial Thrombus

Kahveci¹,

Erkol

Yılmaz

2010

Intern. Med.

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Marfan's syndrome (MFS) is an autosomal dominant disorder of connective tissue involving musculoskeletal, cardiovascular and ocular systems. Aortic disease is the leading cause of mortality in MFS. Among all, dilated cardiomyopathy in the absence of severe valvular dysfunction is a very rare cardiovascular feature of MFS. We report a case of biventricular heart failure in a patient with MFS, complicated by chronic type A aortic dissection and right atrial thrombus. This report clearly highlights the importance of close cardiovascular follow-up in patients with MFS.

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“…1,2 Moreover, as reported on Marfan syndrome patients presenting with aortic aneurysm or dissection, encouraging results for both survival and freedom from aortic re-operation after heart transplant have been achieved. 3 In severely cardiac-decompensated patients, a successful approach of paracorporeal LVAD support combined with resection of symptomatic Type B dissection, as well as implantable LVAD placement facilitated by endovascular abdominal AA repair, has been described. 4,5 A particular clinical problem is the combination of a symptomatic aneurysm of the thoracic aorta and endstage heart failure in patients contraindicated to HTx due to fixed secondary pulmonary hypertension.…”

Section: Discussionmentioning

confidence: 99%

Single-stage Extensive Chronic Type A Dissecting Aortic Aneurysm Repair and Continuous-flow Ventricular Assist Device Implantation

Netuka

Malý

Szárszoi

et al. 2009

The Journal of Heart and Lung Transplantation

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Orthotopic Heart Transplantation in Patients With Marfan Syndrome

Cited by 57 publications

References 22 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

Dilated Cardiomyopathy in a Patient with Marfan Syndrome Accompanied by Chronic Type A Aortic Dissection and Right Atrial Thrombus

Single-stage Extensive Chronic Type A Dissecting Aortic Aneurysm Repair and Continuous-flow Ventricular Assist Device Implantation

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