Article

Biventricular Performance in Patients with Marfan Syndrome without Significant Valvular Disease: Comparison to Normal Subjects and Longitudinal Follow-Up

Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
Journal of the American Society of Echocardiography: official publication of the American Society of Echocardiography (Impact Factor: 4.06). 12/2011; 24(12):1392-1399.e1. DOI: 10.1016/j.echo.2011.09.004
Source: PubMed

ABSTRACT

The presence and progressive nature of primary myocardial involvement in Marfan syndrome are debated. The aim of this study was to evaluate the clinical relevance of left ventricular (LV) and right ventricular (RV) strain in adult patients with Marfan syndrome without significant valvular disease.
Adult patients with Marfan syndrome (n = 50; mean age, 35.2 ± 12.9 years) were followed prospectively. Echocardiography was performed annually and consisted of comprehensive assessment of ventricular and valvular function. Using speckle-tracking imaging, the baseline strain values of the Marfan population were calculated and compared with the values of normal controls. The follow-up evaluations were used to assess changes in ventricular strain. The association between the incidence of adverse events (heart failure, [supra]ventricular arrhythmias, and proximal aorta surgery) and baseline strain values was investigated.
Compared with controls, patients with Marfan syndrome had significantly lower peak longitudinal LV strain (-18.9 ± 2.3% vs -20.1 ± 1.9%, P < .01) and RV strain (±26.9 ± 5.2% vs ±29.3 ± 4.25%, P < .01). The absolute changes in LV longitudinal, radial, and circumferential strain and RV longitudinal strain during a median 4 years of follow-up were 0.1 ± 2.8%, 1.12 ± 7.6%, 0.3 ± 3.7%, and 0.9 ± 5.5%, respectively, which was not statistically significant. Cox regression demonstrated that reduced LV or RV strain was not associated with adverse outcome (supraventricular arrhythmias, n = 3; proximal aorta surgery, n = 4).
This study suggests that patients with Marfan syndrome show lower ventricular strain and strain rate values compared with healthy controls. However, no relevant changes in LV and RV function occurred during midterm follow-up in patients with Marfan syndrome without valvular disease at baseline. Although ventricular strain and strain rate were mildly reduced in patients with Marfan syndrome, this did not affect outcomes negatively in the present study.

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    • "Progressive dilatation of the aorta is the main cardiovascular irregularity of MFS individuals, and acute aortic dissection originating from dilation of the ascending aorta is the leading cause of premature death in untreated MFS individuals [2]. Other manifestations, including spontaneous pneumothorax, apical blebs, striae atrophicae, and lumbosacral dural ectasia, can also be observed in MFS patients [3,4]. "
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    ABSTRACT: Transforming growth factor beta receptor II (TGFBR2) gene mutations are associated with Marfan syndrome; however, the relationship between the mutations and clinical phenotypes are not clear. Genomic DNA from peripheral blood leukocytes of a Chinese proband with Marfan syndrome, five of the proband's relatives, and 100 unrelated Chinese control subjects were isolated and screened for fibrillin-1 (FBN1) and TGFBR2 gene mutations by direct sequencing, and a genotype-phenotype study was performed following a review of the literature on TGFBR2 mutations in the search area. Also, the structure of TGFBR2 protein before and after gene mutation was analyzed. The results identified a novel missense TGFBR2 mutation p.V453E (c.1358T>A) in the proband and two relatives that was located in the F-helix in the kinase domain of TGFBR2. No such genetic change was observed in the unrelated controls. No FBN1 mutation was detected in any of the subjects. Genotype-phenotype analyses indicated that F-helix mutations are related to type 2 Marfan syndrome and Loeys-Dietz syndrome, and these mutations can lead to severe cardiovascular (93.8%) and skeletal (81.3%) lesions and minor ocular lesions (25%). Losartan treatment can slow-down the progression of aortic lesions. The findings extend the mutation spectrum of Marfan syndrome, and that mutations at the F-helix in the kinase domain of TGFBR2 may be associated with the development of severe cardiovascular and skeletal lesions and minor ocular lesions. These findings have implications for genetic testing, diagnosis, and treatment in individuals with transforming growth factor beta (TGF-β) signaling-related disorders.
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    ABSTRACT: The classical Marfan syndrome results from a heterozygous mutation in the fibrillin-1-gene on chromosome 15, that encodes the structure of fibrillin and the elastic fibers. As MFS has a "variable expression", not everyone has the same symptoms to the same degree and the clinical picture varies from patient to patients During their life about 90% of the patients develop a cardiovascular involvement which determines the survival. Beside the aortic aneurysm the mitral valve prolaps with consecutive mitral regurgitation represents the most frequent cardiovascular symptom. In children frequently a tricuspid prolaps is seen. Independent of valvular pathologies a most often subclinical cardiomyopathy with impaired biventricular impairement can develop. In addition, the diagnosis and treatment of malignant arrhythmias becomes increasingly relevant, as they are probably responsible for sudden cardiac death. Sleep apnea, either obstructive or central, is commonly observed and might have adverse effects on aortic dilatation. Most important is the formation of an aortic aneurysm with aortic rupture and dissection. The speed of progression cannot be predicted precisely. Due to progressive aortic dilatation an aortic regurgitation can develop. Betablockers are established as standard medical prophylaxis. Newer treatment includes angiotensin receptor 1 antagonists, angiotensin converting enzyme inhibitors and sometimes calcium channel blockers. A preventive aortic replacement of dilated parts of the aorta should be performed depending on the degree of aortic dilatation, considering the age and height of the patient, rapidity of progression of the dilatation and family history for dissection.
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    ABSTRACT: Valvular disease is common in patients with Marfan syndrome and can lead to cardiomyopathy. However, some patients develop cardiomyopathy in the absence of hemodynamically significant valve dysfunction, suggesting alternative mechanisms of disease progression. Disruption of LDL receptor-related protein-1 (Lrp1) in smooth muscle cells has been shown to cause vascular pathologies similar to Marfan syndrome, with activation of smooth muscle cells, vascular dysfunction and aortic aneurysms. This study used echocardiography and blood pressure monitoring in mouse models to determine whether inactivation of Lrp1 in vascular smooth muscle leads to cardiomyopathy, and if so, whether the mechanism is a consequence of valvular disease. Hemodynamic changes during treatment with captopril were also assessed. Dilation of aortic roots was observed in young Lrp1-knockout mice and progressed as they aged, whereas no significant aortic dilation was detected in wild type littermates. Diastolic blood pressure was lower and pulse pressure higher in Lrp1-knockout mice, which was normalized by treatment with captopril. Aortic dilation was followed by development of aortic insufficiency and subsequent dilated cardiomyopathy due to valvular disease. Thus, smooth muscle cell Lrp1 deficiency results in aortic dilation and insufficiency that causes secondary cardiomyopathy that can be improved by captopril. These findings provide novel insights into mechanisms of cardiomyopathy associated with vascular activation and offer a new model of valvular cardiomyopathy.
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