Yaxin Lu

Perturbations of mechanotransduction and aneurysm formation in heritable aortopathies

Thoracic aortic aneurysm and dissection in young and middle aged patients is increasingly recognised as due to genetic aortopathy. Mutations in multiple genes affecting proteins in the extracellular matrix, microfibrillar structure, the endothelium and cell signalling pathways have been associated with thoracic aortic disease. The TGFß signalling pathway appears to play a key role in mediating abnormal aortic growth and aneurysm formation. A challenge remains in understanding how the many different gene mutations can result in deranged TGFß signalling. This review examines the functional relationships between key structural and signalling proteins, with reference to the need for maintenance of homeostasis in mechanotransduction within the aortic wall. A mechanism, through which perturbations in mechanotransduction, arising from different gene mutations, results in altered TGFß signalling is described.

Angiotensin-converting enzyme gene DD genotype is associated with increased systolic blood pressure in an Australian Rural Type 2 Diabetic Cohort

Angiotensin-converting enzyme gene DD genotype is associated with increased systolic blood pressure in an Australian Rural Type 2 Diabetic Cohort

Ventricular‐Vascular Coupling in Marfan and Non‐Marfan Aortopathies

Background Marfan syndrome (MFS) and familial non–syndromal thoracic aortic aneurysm and dissection (ns‐TAAD) are genetic aortopathies causing aortic dilatation with increased aortic stiffness. Left ventricular (LV) contractility and ventricular‐vascular coupling index (VVI) were compared between MFS and ns‐TAAD and determinants of VVI were investigated. Methods and Results Patients with MFS (M 57, F 47) and ns‐TAAD (M 72, F 39) were studied by echocardiography and compared with controls (M 77, F 71). Aortic geometry, hemodynamics, LV work, LV contractility (end‐systolic elastance [Ees]), and VVI were documented. Aortic sinuses were equally dilated in MFS (19.7±2.4) and ns‐TAAD (19.8±1.8) compared to controls (16.2±1.4 mm·m−2, P<0.001). Aortic stiffness index was increased in MFS (9.7±5.1) and ns‐TAAD (10.8±4.7) versus controls (5.4±2.0, P<0.01); LV stroke work was unchanged in MFS (436±74) compared to controls (435±60) but increased in ns‐TAAD (492±109 mJ·m−2 P<0.01). The LV Ees was reduced in MFS (1.32±0.19) compared to controls (1.65±0.29 mm Hg·mL−1, P<0.01) but increased in ns‐TAAD (1.83±0.30, P<0.01) and VVI was abnormal in MFS (0.71±0.11) compared to controls (0.62±0.07, P<0.01) and ns‐TAAD (0.62±0.09). Treatment with β‐blockers was associated with partial normalization of VVI in MFS. A VVI ≥0.8 was associated with increased risk of death and heart failure in MFS. Conclusions Left ventricular contractility and ventricular‐vascular coupling are abnormal in MFS but preserved in ns‐TAAD, and are independent of aortic stiffness, consistent with intrinsic impairment of myocardial contractility in MFS.

Methodological Comparisons of Heart Rate Variability Analysis in Patients With Type 2 Diabetes and Angiotensin Converting Enzyme Polymorphism

Angiotensin converting enzyme (ACE) polymorphism has been shown to be important in hypertension progression and also in diabetes complications, especially associated with heart disease. Heart rate variability (HRV) is an established measure for classification of autonomic function regulating heart rate, based on the interbeat interval time series derived from a raw ECG recording. Results of this paper show that the length (number of interbeat intervals) and preprocessing of the tachogram affect the HRV analysis outcome. The comparison was based on tachogram lengths of 250, 300, 350, and 400 RR-intervals and five preprocessing approaches. An automated adaptive preprocessing method for the heart rate biosignal and tachogram length of 400 interbeat intervals provided the best classification. HRV results differed for the Type 2 Diabetes Mellitus (T2DM) group between the I/I genotype and the I/D and D/D genotypes, whereas for controls there was no significant difference in HRV between genotypes. Selecting an appropriate length of recording and automated preprocessing has confirmed that there is an effect of ACE polymorphism including the I/I genotype and that I/I should not be combined with I/D genotype in determining the extent of autonomic modulation of the heart rate.

Molecular mechanisms of inherited thoracic aortic disease – from gene variant to surgical aneurysm

Aortic dissection is a catastrophic event that has a high mortality rate. Thoracic aortic aneurysms are the clinically silent precursor that confers an increased risk of acute aortic dissection. There are several gene mutations that have been identified in key structural and regulatory proteins within the aortic wall that predispose to thoracic aneurysm formation. The most common and well characterised of these is the FBN1 gene mutation that is known to cause Marfan syndrome. Others less well-known mutations include TGF-β1 and TGF-β2 receptor mutations that cause Loeys–Dietz syndrome, Col3A1 mutations causing Ehlers–Danlos Type 4 syndrome and Smad3 and-4, ACTA2 and MYHII mutations that cause familial thoracic aortic aneurysm and dissection. Despite the variation in the proteins affected by these genetic mutations, there is a unifying pathological end point of medial degeneration within the wall of the aorta characterised by vascular smooth muscle cell loss, fragmentation and loss of elastic fibers, and accumulation of proteoglycans and glycosaminoglycans within vascular smooth muscle cell-depleted areas of the aortic media. Our understanding of these mutations and their post-translational effects has led to a greater understanding of the pathophysiology that underlies thoracic aortic aneurysm formation. Despite this, there are still many unanswered questions regarding the molecular mechanisms. Further elucidation of the signalling pathways will help us identify targets that may be suitable modifiers to enhance treatment of this often fatal condition.