Marfan syndrome (MFS) is a disease in which connective tissue becomes weak secondary to fibrillin-1 mutations, resulting in aortic dilatation, aneurysm formation, aortic dissection, aortic regurgitation and mitral valve prolapse (MVP; see Table 1). Epidemiology MFS is an autosomal dominant condition: 75 % of all patients inherit the condition from one affected parent and 25 % are affected as the result of a new mutation. The population incidence is 2-3 per 10,000. 1 The autosomal dominant inheritance of this disorder was described in 1934, 2 and has been ascribed to abnormalities in fibrillin-1 protein (discovered in 1990), 3 which is encoded by the FBN1 gene (reported in 1991). 4 The most common causes of death in MFS are cardiovascular, especially aortic dissection and rupture. According to a Taiwanese study, aortic dissection is the most serious complication, occurring in 9.7 % of individuals with MFS (nearly 61 % of these patients are male) and carrying an average mortality of approximately 10.6 %. 5 Cardiovascular Manifestations In MFS, the main cardiovascular manifestations are aortic dilatation and MVP. Tricuspid regurgitation (TR), pulmonary artery (PA) dilatation, ventricular arrhythmia and dilated cardiomyopathy also occur. Pro-transforming growth factor-beta (TGF-beta) binds to the latent TGF-beta binding protein-1 (LTBP-1) and forms the latency-associated peptide (LAP), followed by a complex termed the large latent TGF-beta complex (LLC). This is secreted and sequestered in the extracellular matrix (ECM). FBN1 is a matrix glycoprotein and the major constituent of ECM microfibrils comprising elastic fibres. In MFS, the ECM is not normal and when the ECM is damaged due to the force of the blood flow ejected from the heart, the mesenchymal cells promote active TGF-beta to restore the ECM. This results in excessive TGF-beta signalling, causing ECM degradation, apoptosis and an inflammatory state, leading to aneurysm formation or dissection (see Figure 1). 6,7 At present, more than 3,000 FBN1 mutations have been discovered. Almost all of them develop similar manifestations such as heart, eye and skeletal problems, and are related to excessive TGF-beta signalling via integrin, which provides a common mechanism by promoting latent TGF-beta and expressing TGF-beta. 6 Endothelial cells, smooth muscle cells and fibroblasts sense and respond to blood flow and blood pressure. Increasing or decreasing blood pressure increases or decreases wall stress. Cells sense and regulate the ECM through integrins and cytoskeletal components. Sensing high versus low stress causes different cell signalling. Misperception of high stress as low stress can cause maladaptive remodelling by activating the pathways observed in thoracic aortic aneurysms and aortic dissections (TAAD). 8 The Aorta In MFS, aortic dilatation and aneurysm formation are caused by cystic medial necrosis, in which the medial layer of the aorta demonstrates fewer cells and a lacunar appearance. Most aortic dilatation starts in the sinuses of Valsalva. A reduce...
We describe a mutation in LMOD1, which predisposes individuals to thoracic aortic aneurysms and dissections in a large multi-generation British family. Exome variant profiles for the proband and two distantly related affected relatives were generated and a rare protein-altering, heterozygous variant was identified, present in all the exome-sequenced affected individuals. The allele c.1784T>C, p.(V595A) in LMOD1 is located in a known actin-binding WH2 domain and is carried by all living affected individuals in the family. LMOD1 was further assessed in a consecutive series of 98 UK TAAD patients and one further mutation was found, yielding an incidence of ∼2% in our study group. Assessment of LMOD1 in international TAAD cohorts discovered nine other missense variants of which three were classed as likely pathogenic.Validation of LMOD1 was undertaken using a zebrafish animal model. Knock-down of both lmod1a and lmod1b paralogs using morpholino oligonucleotides showed a reproducible abnormal phenotype involving the aortic arches under off-target controls. Injection of the human LMOD1 c.1784T>C, p.(V595A) mutation demonstrated a likely dominant negative effect and illustrated a loss of function cause.Mutations found in the WH2 actin-binding domain of LMOD1 may delay actin polymerization and therefore compromise actin length, dynamics and interaction with myosin in the smooth muscle contraction pathway.
Introduction: It is reported that aortic valve reconstruction (AVrC) by using autologous pericardium is useful in patients with various aortic valve diseases. This method may be more effective in preserving the natural motion of the aortic valve annulus. Significant dynamic changes in the aortic annulus have previously been reported in animal models and clinical studies. The purpose of this study is to analize the cyclic changes of the aortic annulus using speckle-tracking trans-esophageal echocardiography in patients who underwent AVrC surgery. Methods: The subjects were 35 patients underwent AVrC surgery for aortic regurgitation or aortic stenosis and 40 controls. Cyclic aortic annulus diameter of the maximum and minimum diameters were determined from a speckle-tracking displacement curve (figure). These data was used to calculate the absolute change in the diameter of the aortic annulus, which was defined as the difference in diameters throughout the cardiac cycle. Results: There was significant difference between maximum and minimum aortic annulus diameter in AVrC group (18.7±3.0 mm vs 16.1±2.9 mm, p<0.0001). There was significant difference in the maximum and minimum aortic annulus diameter in control group (22.9±2.7 mm vs 20.0±2.9 mm, p<0.0001). AVrC group had significant cyclic change of aortic annulus as same as control group (AVrC group : 2.6±1.0 mm vs control group : 2.9±0.7 mm, p= NS). Conclusions: Our study suggests that dynamic changes of the aortic annulus occur in the cardiac cycle and can be measured using speckle-tracking trans-esophageal echocardiography. AVrC may preserve the coordination of the left ventricle, aortic annulus, sinus of Valsalva and aorta compared with conventional aortic valve replacement.
Introduction: Takotsubo cardiomyopathy (TTC) is characterized by a transient systolic dysfunction of the left ventricle. A few case was reported about left ventricular apical hypertrophy (APH) during recovery from TTC. The purpose of this study was to investigate the incidence of transient APH and the differences in clinical characteristics in TTC patients. Methods: Forty seven TTC patients were enrolled in this study. Patients were divided into two groups as N-APH group which did not show APH like findings in the process of wall motion recovery and T-APH group which showed transient APH findings. Cardiac complications were defined as cardiac death, pump failure, sustained ventricular tachycardia or ventricular fibrillation and advanced atrioventricular block. Results: Twelve of 47 (25.5%) TTC patients demonstrate typical APH findings during recovery from wall motion abnormality. Finally, this APH findings disappeared and left ventricular morphology recovered to normal structure. There is no significant difference between two groups in clinical characteristics (table). Incidence of cardiac complication showed significantly lower in T-APH group than that in N-APH group (P< 0.005). Conclusions: Transient left ventricular APH were observed in 25.5% in TCC patient by serial echocardiographic observation. Incidence of cardiac complications in T-APH group is significantly lower than that in N-APH group. Detection of T-APH is useful as a prognostic indicator in patients with TTC.
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