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| Project Details |
| Funding Scheme : | General Research Fund | ||||||||||||||||||||
| Project Number : | 785611 | ||||||||||||||||||||
| Project Title(English) : | Mechanism and Reversibility of Myocardial Fibrosis in Patients with Diabetic Cardiomyopathy: Role of Aliskiren. | ||||||||||||||||||||
| Project Title(Chinese) : | 關於糖尿病性心肌病心臟纖維化的機制和轉歸: Aliskiren 的作用 | ||||||||||||||||||||
| Principal Investigator(English) : | Prof Yiu, Kai Hang | ||||||||||||||||||||
| Principal Investigator(Chinese) : | |||||||||||||||||||||
| Department : | Department of Medicine | ||||||||||||||||||||
| Institution : | The University of Hong Kong | ||||||||||||||||||||
| E-mail Address : | khkyiu@hku.hk | ||||||||||||||||||||
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| Co - Investigator(s) : |
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| Panel : | Biology & Medicine | ||||||||||||||||||||
| Subject Area : | Medicine, Dentistry & Health | ||||||||||||||||||||
| Exercise Year : | 2011 / 12 | ||||||||||||||||||||
| Fund Approved : | 950,000 | ||||||||||||||||||||
| Project Status : | Completed | ||||||||||||||||||||
| Completion Date : | 30-6-2015 | ||||||||||||||||||||
| Project Objectives : |
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| Abstract as per original application (English/Chinese): |
糖尿病正逐漸成為嚴重危害人們健康的殺手，即使在沒有冠心病的情況下，糖尿病也可造成心肌纖維化和心功能異常而形成糖尿病性心肌病。重要的是糖尿病性心肌病引起的心功能異常是預測糖尿病人死亡的獨立危險因素。然而到目前為止,心肌纖維化程度和心功能異常的關係還懸而未決。 雖然機理不明，但人體腎素-血管緊張素系統(RAS)在形成糖尿病性心肌病中起關鍵作用，而且腎素-血管緊張素系統和其他心血管疾病如高血壓的心肌纖維化形成有關。因此，腎素-血管緊張素系統的主要活性物質血管緊張素ǁ成為預防和治療糖尿病性心肌病的標靶。目前保護糖尿病心臟的藥物治療包括血管緊張素轉換酶抑制劑(ACEIs)和血管緊張素受體拮抗劑(ARB)，兩者分別在不同層面阻斷腎素-血管緊張素的活性。 然而血管緊張素轉換酶抑制劑和血管緊張素受體拮抗劑又會代償性增加腎素的分泌。目前，有研究表明腎素抑制劑-Aliskiren在糖尿病人中具有保護腎功能和改善血管的作用。這項研究的目的是觀察Aliskiren能否增效ACEIs/ARB的作用來預防和轉歸糖尿病心臟纖維化。 |
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| Realisation of objectives: | Regarding the 1st and 2nd objectives, we have evaluated the degree of myocardial fibrosis and cardiac dysfunction in relation with renin angiotensin system and extracellular matrix (ECM) regulation.A total of 264 subjects with T2DM, as defined by World Health Organization criteria, were recruited from Queen Mary Hospital, Hong Kong. Patients were excluded if they had a known history of cardiovascular disease including coronary artery disease, myocardial infarction, stroke or peripheral vascular disease, underlying malignancy, pregnancy, or if they refused to participate (n=78). Exercise echocardiography was performed in the remaining 186 patients. A total of 50 patients had regional wall motion abnormality during stress testing, suggestive of significant ischemic heart disease and 13 patients had suboptimal stress images for analysis. The population with suitable exercise echocardiography images for analysis was thus 123 (62 female, 60.8±8.8 years). The results demonstrated that in patients with T2DM, TIMP-1, an ECM regulator, is independently associated with myocardial diastolic dysfunction both at rest and during stress. This finding suggests that increased ECM turnover affects the myocardial response during stress and cardiac performance. Whether TIMP-1 contributes to adverse cardiovascular events nonetheless requires future prospective studies. Measures that could reduce TIMP-1 level may thus improve myocardial function. The finding has been presented in the European Society of Cardiology 2015 annual scientific meeting and the full manuscript has been submitted for international peer review. For the 3rd objective, we have successfully carried out a double-blind randomized trial, comparing aliskiren with placebo, in patients with T2DM. In total, 37 patients received aliskiren and 37 patients received placebo. Patients were follow up after 1 year of randomization and none had developed adverse events, including hyperkalaemia and renal dysfunction. The baseline echocardiography parameters were compared with the follow-up parameters. In particular, both diastolic function, systolic function and myocardial fibrosis evaluated by calibrated integrated backscatter was analyzed. The results demonstrated that the use of aliskiren, but not placebo, resulted in improved in myocardial function evaluated by strain analysis. The final results has been presented in the RGC abstract presentation, 2016 and full manuscript is in preparation. | ||||||||||||||||||||
| Summary of objectives addressed: |
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| Research Outcome | |||||||||||||||||||||
| Major findings and research outcome: | Regarding objective 1 and 2, we have evaluated 123 patients (62 female, 60.8±8.8 years) with T2DM and no evidence of underlying coronary artery disease. All patients underwent resting and exercise echocardiography. Plasma TIMP-1 level was positively associated with left ventricular systolic and diastolic function both at rest and during stress. The procollagen propeptides and RAS activity showed no association with either echocardiography parameter. For objective 3, we have successfully carried a double-blind randomized trial, comparing aliskiren with placebo, in patients with T2DM. In total, 37 patients received aliskiren and 37 patients received placebo. Patients were follow up after 1 year of randomization and none had developed adverse events, including hyperkalaemia and renal dysfunction. The baseline echocardiography parameters were compared with the follow-up parameters. The results demonstrated that the use of aliskiren, but not placebo, resulted in improved in myocardial function evaluated by strain analysis. | ||||||||||||||||||||
| Potential for further development of the research and the proposed course of action: |
Based on the results, we have demonstrated that TIMP-1 correlates closely with myocardial dysfunction in patients with T2DM. Further, aliskiren, a direct renin inhibitor, improves myocardial function in these patients. A larger randomized study should be done to evaluate the prognostic role of alikiren in patients with T2DM. | ||||||||||||||||||||
| Layman's Summary of Completion Report: | Patients with T2DM suffers from myocardial dysfunction before they develop cardiovascular adverse events. It was demonstrated that, TIMP-1, an extracellular matrix regulator correlates closely with myocardial dysfunction in these patients (Objective 1 and 2). Importantly, the use of aliskiren, a direct renin inhibitor, may improve myocardial function in patients with T2DM. None of the patients who received aliskiren developed significant side effects. Future studies thus should be done to evaluate the prognostic value of aliskiren in these patients. | ||||||||||||||||||||
| Research Output | |||||||||||||||||||||
| Peer-reviewed journal publication(s) arising directly from this research project : (* denotes the corresponding author) |
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| Recognized international conference(s) in which paper(s) related to this research project was/were delivered : |
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| Other impact (e.g. award of patents or prizes, collaboration with other research institutions, technology transfer, etc.): |
nil | ||||||||||||||||||||
| SCREEN ID: SCRRM00542 |