In the current study, we found that LV diastolic dysfunction and hypertrophy were more prominent in patients with T2DM than in age-matched healthy controls, as previously reported [5
]. Furthermore, we identified the independent factors associated with LV diastolic dysfunction and hypertrophy. Gender, age, hypertension and VAT were all independently associated with diastolic dysfunction, and the waist/hip and VAT/SAT ratios were independently associated with increased LV mass, in addition to systolic blood pressure. Of note, our study is the first to show that excess VAT is more important than glycemic control, insulin resistance, renal function and other clinical factors in abnormal cardiac structure and function in T2DM.
Many previous studies have demonstrated a high prevalence of LV diastolic dysfunction and hypertrophy in patients with T2DM [5
]. However, few studies have included a control group [15
]. Diastolic dysfunction progresses with age even in a healthy population, and diastolic dysfunction is a common phenomenon in healthy individuals over 60 years old [18
]. Thus, it is important to compare diabetics with age-matched control subjects when evaluating the prevalence of diastolic dysfunction. In this study, a higher prevalence of diastolic dysfunction, in addition to increased LV mass, was found in T2DM compared with control subjects. The 23% prevalence of diastolic dysfunction in the control subjects was probably due to aging.
Myocardial injury in T2DM has a complicated pathophysiology [1
], and many factors, such as hyperinsulinemia [10
], increased fatty acid [11
], inflammation [12
], renal function [13
] and myocardial steatosis [14
], have been postulated to be involved in its development. However, most previous clinical studies of diabetic cardiac dysfunction examined only glycemic control and other common cardiovascular risk factors, such as hypertension or obesity [5
]. Furthermore, some recent review articles that performed meta-analysis of multiple trials reported that intensive glycemic control does not inevitably result in a reduction of cardiovascular events and mortality [31
]. Thus, we hypothesized that some factors other than glycemic control may play an important role in the development of abnormal cardiac structure and function in T2DM. In this study, we investigated the association between echocardiographic pmeters in T2DM and several common risk factors, as well as factors that have not been examined before in the clinical setting. Importantly, excess VAT in our study, but not glycemic control, was found to be independently associated with diabetic diastolic dysfunction, in addition to gender, age and hypertension. Visceral fat accumulation might be a potential therapeutic target to improve cardiac dysfunction in T2DM rather than glycemic control.
Visceral adipose tissue is an important functional organ which abundantly secretes adipocytokines [33
]. In the lean state, small adipocytes efficiently store fatty acids as triglyceride and have the ability to inhibit the inflammatory state. In particular, high levels of adiponectin in the lean state have anti-inflammatory effects [34
]. On the other hand, increased visceral adipose tissue secrete various inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-8 and MCP-1. These adipocytokines are assumed to contribute to changes in cardiac structure and function [22
Increased inflammatory cytokines such as IL-6, IL-8 and MCP-1 have been shown to be significant indicators of a greater degree of heart failure with preserved EF [35
]. High plasma levels of TNF-α and IL-6 might cause cardiac diastolic dysfunction by decreasing diastolic calcium reuptake in myocytes [36
]. Studies in vitro showed that cardiac-restricted overexpression of TNF-α induces myocardial fibrosis and diastolic dysfunction [37
]. Furthermore, low plasma adiponectin had an association with early diastolic dysfunction in patients with heart failure [24
]. Taken together, these studies suggest that visceral fat accumulation may influence diastolic function through changes in inflammatory and anti-inflammatory adipocytokines. Furthermore, dysfunctional adipose tissue produces angiotensinogen and angiotensin II, which induces systemic hypertension [34
]. In this study, 49% of patients in the diabetes mellitus group had hypertension. Although activation of the renin-angiotensin system in diabetes mellitus per se is associated with increased oxidative damage and cardiomyocyte apoptosis and necrosis in the diabetic heart [38
], hypertension due to visceral adiposity may also influence diastolic function in T2DM. On the other hand, hsCRP, an inflammatory maker, was not directly related to cardiac dysfunction in the present study, whereas we found a significant correlation between hsCRP and VAT (r
<0.001). HsCRP can reflect inflammatory processes in various organs and is not only the mechanism by which VAT causes diastolic dysfunction. Presumably other inflammatory cytokines and anti-inflammatory cytokines relate to visceral fat accumulation and are also significant determinant factors for cardiac dysfunction in T2DM.
Age-related decline in LV diastolic function even in a healthy population has been widely reported using conventional and tissue Doppler methods [18
]. Gender differences in diastolic function have also been reported previously [19
]. Epidemiological and clinical studies have consistently demonstrated that elderly women in the general population were most likely to have diastolic heart failure [39
]. Menopausal hormone status has been suggested to be one of the factors to account for gender differences in diastolic dysfunction [40
], although the precise mechanism has not been clarified.
As for LV hypertrophy, the waist/hip and VAT/SAT ratios were found to be independent determinants in addition to systolic blood pressure. The waist/hip ratio, an indicator of obesity, was reported to be a predictor of cardiovascular mortality [41
]. Abnormal fat distribution expressed as the VAT/SAT ratio was associated with the development of insulin resistance and atherosclerosis [42
]. In this study, we could not determine the reason why the waist/hip and VAT/SAT ratios, but not the absolute amount of VAT, were independently related to increased LV mass. However, there is no doubt that visceral fat and obesity play some roles in the development of LV hypertrophy based on mechanisms similar to those of diastolic dysfunction in T2DM.
While we included asymptomatic patients without overt cardiovascular disease, we did not completely exclude latent patients with coronary artery disease using stress testing or coronary angiography. We did not measure serum adipocytokine levels and could not evaluate adipose dysfunction. Further investigation is required to determine the direct association between VAT and the level of adipocytokine dysfunction in diabetic cardiomyopathy. We included patients with the comorbidity of hypertension in this study. Hypertension caused by activation of the renin-angiotensin system in diabetes mellitus plays an important role in the development of cardiac dysfunction in T2DM. In addition, patients with T2DM have high prevalence of hypertension in the real clinical setting and are more subject to LV hypertrophy caused by hypertension than those without diabetes [43
]. These characteristics are important aspects of cardiac dysfunction in T2DM. Instead, we performed multiple regression analysis using clinical factors including history of hypertension and blood pressure to evaluate the independent determinants of LV mass and diastolic dysfunction, and VAT or VAT/SAT ratio was an independent determinant of cardiac structure and function in our population after adjustment for history of hypertension and blood pressure. However, hypertension per se causes diastolic dysfunction and LV hypertrophy, and further investigation in normotensive patients with T2DM is desirable to more accurately assess the mechanisms of cardiac abnormalities in T2DM. Moreover, further investigation in comparison with patients with hypertension but without T2DM would provide new insights to this issue. Finally, we measured only LV ejection fraction as an indicator of systolic function in this study. Ernande et al [17
]. reported reduced systolic strain using speckle-tracking imaging in T2DM; therefore, further investigation of systolic dysfunction with speckle-tracking imaging would be of interest.