ORIGINAL ARTICLE Cardiomyopathy in patients with Marfan syndrome and marfanoid habitus Ekaterina Luneva MD, PhD1, Eduard Malev MD, PhD1,2, Alexandra Korshunova MD1,2, Svetlana Reeva MD PhD1,2, Eugeniy Timofeev MD PhD1,2 and Eduard Zemtsovsky Prof MD PhD1,2 Lunev E, Malev E, Korshunova A, et al. Cardiomyopathy in patients with worsening was detected in MS group comparing to control group. In marfanoid Marfan syndrome and marfanoid habitus. Curr Res Cardiol 2017;4(1): 9-13. habitus subjects, we found significant decrease of the circumferential strain in the interventricular septum and inferior wall. transforming growth factor-β1 OBJECTIVES: The term “Marfan cardiomyopathy” is used to indicate and -β2 serum levels were elevated in patients with Marfan syndrome. changes in left ventricular function in the absence of significant valvular Elevation of transforming growth factor-β1 was statistically nonsignificant pathology in Marfan syndrome. It is still unknown if there are any changes in unlike to transforming growth factor-β2 in the marfanoid habitus group. cardiac function in patients with similar connective tissue abnormality such Negative correlations between the serum level of transforming growth as marfanoid habitus. factor-β2 and systolic radial strain in the marfanoid habitus group also have been found. METHODS: In the study were included 98 persons - 8 patients with Marfan syndrome, 24 with marfanoid habitus and 66 healthy subjects. CONCLUSION: Worsening of regional myocardial deformation may be Echocardiography was performed to all patients. Speckle tracking the first sign of deterioration of the left ventricular systolic function and the echocardiography was used to assess the left ventricular deformation indices. existence of primary cardiomyopathy in asymptomatic marfanoid habitus Concentrations of transforming growth factor-β1 and -β2 in serum were patients, which could affect their long-term prognosis and may be caused by determined by enzyme-linked immunosorbent assay. increased transforming growth factor-β signaling. RESULTS: Systolic left ventricular function was significantly lower in the Key Words: Marfan syndrome; Marfanoid habitus; Cardiomyopathy; Left Marfan syndrome group; as well global longitudinal left ventricular strain ventricular systolic function; Myocardial deformation; Transforming growth factor-β is one of the most common heritable disorder of connective tissue. Marfanoid features are present in several heritable disorders of connective MS In the range of MS complications are aortic aneurism, mitral tissue, mimicking some of the changes of Marfan syndrome but not valve prolapses and myocardial dysfunction (1). MS manifestations caused accompanied by luxation of lens, and aneurysm of aorta. Incomplete forms by mutations of fibrillin-1, a structural component of extracellular matrix, of the marfanoid habitus are commonplace and likely to be benign; however, and also violation of the regulation of transforming growth factor-β. A their presence should trigger an assessment for another feature of heritable number of studies (2,3) showed that excessive activation of TGF-β signaling disorders of connective tissue (6). pathway is the main reason of the impairment of LV function and aorta In this paper, we evaluated the morphological and functional characteristics pathology in MS. Deterioration of systolic and diastolic function and of the LV in patients with MS and marfanoid habitus. enlargement of LV dimensions was found in patients with MS regardless the absence of hemodynamic overload due to mitral or aortic regurgitation MATERIALS AND METHODS in presence of mitral valve prolapse or aortic dilatation. The term “Marfan In the study were included 98 persons, 8 of them were patients with MS, 24 cardiomyopathy” is used to indicate changes in left ventricular function in patients with marfanoid habitus and 66 healthy subjects. the absence of significant valvular pathology in MS (4,5). In spite the fact that cardiomyopathy in MS is well studied it is still unknown if there are changes Patients with MS were under regular follow-up at Almazov Federal Centre. in the cardiac function in patients with similar connective tissue abnormality The diagnosis of MS was made applying Ghent criteria (7). Mutations of such as marfanoid habitus. marfanoid habitus includes arachnodactyly, long fibrillin-1 didn’t screen for this study. Patients did not have significant (more hands and feet, increased skin stretch, joint hypermobility and changes in than mild) mitral or aortic regurgitation. Subjects with marfanoid habitus the physiology of the pectus (Table 1). were screened out of patients with non-confirmed MS and have no signs of aortic aneurism and lens subluxation. Table 1 represents marfanoid habitus criteria according to Grahame R, et al. (6). Control group consisted of TABLE 1 healthy students of Pediatric Medical University. Marfanoid habitus criteria Echocardiography was performed in all patients by an experienced Measurable skeletal signs Other features of the marfanoid habitus echocardiographer using a Vivid 7 ultrasound system (GE Healthcare), · Arm span to height ratio > 1.03 · Scoliosis of > 5 degrees equipped with a harmonic 3.5 Hz phased-array transducer and included · Pectus deformities (excavatum or · Hand length to height ratio > 11% assessment of heart chambers dimensions, and systolic function of LV carinatum) measured by Simpson biplane rule. Standard 2-dimensional transthoracic · Foot length to height ratio > 15% · Jaw deformities with overcrowding of teeth echocardiographic recordings were used to assess left ventricular as LV end- · Upper body segment to lower diastolic diameter, to assess right ventricle as right ventricle end-diastolic · High-arched palate body segment ratio < 0.89 diameter, for left atria we used left artia diameter according to current · Long feet (often with hammer toes) that guideline (8). Additionally, we used speckle tracking echocardiography flatten and pronate on weight-bearing to assess the left ventricular deformation indices (strain and strain rate) 1Department of connective tissue disorders, Almazov North-West Federal Medical Research Centre, Saint-Petersburg, Russia; 2Department of propaedeutics of internal diseases, State Pediatric Medical University, Saint-Petersburg, Russia Correspondence: Dr. Ekaterina Luneva, MD, PhD, Almazov North-West Federal Medical Research Centre, 2 Akkuratova str., Saint-Petersburg, 197341, Russia, Telephone +7-8127023749; Fax: +7-8127023744, E-mail [email protected] Received: December 29, 2016, Accepted: March 17, 2017, Published: March 20, 2017 This open-access article is distributed under the terms of the Creative Commons Attribution Non-Commercial License (CC BY-NC) (http:// creativecommons.org/licenses/by-nc/4.0/), which permits reuse, distribution and reproduction of the article, provided that the original work is properly cited and the reuse is restricted to noncommercial purposes. For commercial reuse, contact [email protected] Curr Res Cardiol Vol 4 No 1 Spring 2017 9 Luneva et al (9). The longitudinal strain is obtained from apical 4-, 3- and 2-chamber (1-2) 1.0 Pneumothorax, images. Radial and circumferential strains were obtained from LV short- 0(0%) 1 (4%) 0 (0%) (1-3) 1.0 n (%) axis images at the level of the mitral valve, papillary muscles and apex. (2-3) 0.27 Image analysis was performed offline on an EchoPAC’08 workstation (1-2) 1.0 (GE Healthcare). The LV was divided into 18 segments. Strain rate was Dural ectasia, n 0 (0%) 0 (0%) 0 (0%) (1-3) 1.0 determined as the maximal negative value during the ejection phase. (%) Peak systolic strain was defined as the magnitude of strain at the aortic (2-3) 1.0 valve closure. The peak longitudinal early diastolic filling strain rate was (1-2) 1.0 Protrusio acetabuli, 0 (0%) 0 (0%) 0 (0%) (1-3) 1.0 also measured. n (%) (2-3) 1.0 We assess biologically active transforming growth factor-β1 and -β2 protein concentrations from EDTA blood samples using standard procedures by Reduced US/LS (1-2) 0.15 AND increased (1-3) 0.15 enzyme-linked immunosorbent assays using the Human Platinum ELISA arm/height AND no 2 (25%) 0 (0%) 0 (0%) test system (Bender MedSysteMarfan syndrome Diagnostics GmbH, Vienna, severe scoliosis, (2-3) 1.0 Austria). The inter-assay and intra-assay variations were 8% and 6%, n (%)* respectively. The sensitivity was 5 pg/ml. Scoliosis or (1-2) 0.54 STATISTICAL ANALYSIS thoracolumbar 7 (88%) 23 (96%) 20 (30%) (1-3) 0.0016 kyphosis, n (%) (2-3) <0.00001 All data are presented as mean ± standard deviation. The significance of (1-2) 1,0 differences between quantitative traits was determined using Student’s t-test, Reduced elbow 1(13%) 0 (0%) 0 (0%) (1-3) 1,0 between small samples and qualitative characteristics determined using the extension, n (%) non-parametric methods: Fisher’s exact test or chi-square test (p<0.05). The (2-3) 1.0 relationship between pairs of continuous variables was expressed by the (1-2) 0.15 Facial features 6 (75%) 1 (4%) 0 (0%) (1-3) 0.0018 Pearson correlation. Effect sizes for deformation indices were measured (3/5)**, n (%) by Cohen’s d using means and standard deviations. Statistical significance (2-3) 1.0 was set at p<0.05. All statistical analyses were performed using Statistica 10 (1-2) 1.0 software (StatSoft, Inc.). Skin striae, n (%) 0 (0%) 1 (4%) 0 (0%) (1-3) 1.0 (2-3) 1.0 (1-2) 0.69 TABLE 2 Myopia > 3 4 (50%) 10 (42%) 8 (12%) (1-3) 0.066 Characteristics of patients included in the study diopters, n (%) (2-3) 0.011 Marfan Marfanoid