Abstract
Background Left atrial enlargement is a mortality and heart failure risk factor in primary mitral regurgitation (MR) patients. Pig models of MR have shown differential expression of genes linked to the renin-angiotensin system. Therefore, the aim of this study was to investigate the key genes of the renin-angiotensin that are expressed differentially in the left atrial myocardium in MR patients. Methods Quantitative RT-PCR was used to compare gene expression in the renin-angiotensin system in the left atrium in MR patients, aortic valve disease patients, and normal subjects. Results Plasma angiotensin II concentrations did not significantly differ between MR patients and aortic valve disease patients (P = 0.582). Compared to normal controls, however, MR patients had significantly downregulated expressions of angiotensin-converting enzyme, angiotensin I converting enzyme 2, type 1 angiotensin II receptor, glutamyl aminopeptidase, angiotensinogen, cathepsin A (CTSA), thimet oligopeptidase 1, neurolysin, alanyl aminopeptidase, cathepsin G, leucyl/cystinyl aminopeptidase (LNPEP), neprilysin, and carboxypeptidase A3 in the left atrium. The MR patients also had significantly upregulated expressions of MAS1 oncogene (MAS1) and mineralocorticoid receptor compared to normal controls. Additionally, in comparison with aortic valve disease patients, MR patients had significantly downregulated CTSA and LNPEP expression and significantly upregulated MAS1 expression in the left atrium. Conclusions Expressions of genes in the renin-angiotensin system, especially CTSA, LNPEP, and MAS1, in the left atrium in MR patients significantly differed from expressions of these genes in aortic valve disease patients and normal controls. Notably, differences in expression were independent of circulating angiotensin II levels. The results of this study provide a rationale for pharmacological therapies or posttranslational regulation therapies targeting genes expressed differentially in the renin-angiotensin system to remedy structural remodeling associated with atrial enlargement and heart failure progression in patients with MR.
Highlights
Mitral regurgitation (MR) is the second most prevalent valvular heart disease after aortic valve stenosis [1] and a major cause of heart failure (HF)
Since the left atrium is smaller in aortic valve disease patients compared to mitral regurgitation (MR) patients, the left atrial myocardium specimens from severe aortic valve disease patients with HF were used as a separate cohort for gene analyses
Left atrial size was significantly larger in the MR patients with HF compared to the aortic valve disease patients with HF (P = 0 019)
Summary
Mitral regurgitation (MR) is the second most prevalent valvular heart disease after aortic valve stenosis [1] and a major cause of heart failure (HF). The aim of this study was to determine what key genes of the renin-angiotensin system are expressed differentially in the left atrium in severe MR patients with HF compared to normal controls. This study revealed that several key element genes of the renin-angiotensin system were differentially expressed in the left atrium in MR patients in comparison with aortic valve disease patients and normal controls. Expressions of genes in the renin-angiotensin system, especially CTSA, LNPEP, and MAS1, in the left atrium in MR patients significantly differed from expressions of these genes in aortic valve disease patients and normal controls.
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