We were able to demonstrate that LVDD and proinflammatory cytokines are associated in subjects with normal left ventricular systolic function. In particular increased plasma levels TNF-α and IL-6 seem to be correlated with impaired LVDD and more advanced left ventricular diastolic dysfunction. These data provide clinically important information on systemic immune abnormalities in subjects with LVDD. The Framingham Heart Study was the first to demonstrate an increased risk of heart failure in patients with diabetes . Since then, additional studies, including SOLVD  and HOPE , have identified diabetes as a major risk factor for the development of heart failure. Conversely, the presence of heart failure was identified as a possible risk factor for diabetes . Several studies have demonstrated evidence for preclinical left ventricular diastolic dysfunction (LVDD) as the first manifestation of myocardial involvement in diabetic patients . Although myocardial changes can be detected with echocardiography, even before the onset of hemodynamic abnormalities in subjects with normal conventional echocardiography, LVDD is often not diagnosed in clinical practice. On the other hand, there is increasing evidence that inflammation is involved in the pathophysiology of heart failure and diabetes [6–9]. Inflammation has become one of the central themes in the pathogenesis of systolic heart disease over the past decade. So far there have been few data on participation of inflammatory factors in the development of diastolic dysfunction.
It has been demonstrated that IL-6 shows cardiodepressive properties . In patients with systolic heart failure, IL-6 and TNF-α are associated with functional NYHA class . Furthermore, IL-6 and TNF-α have been shown to be independent predictors of mortality in heart failure . On the other hand, a recent study which followed patients with symptomatic systolic heart failure, E/Em ratio was associated with an increased risk of death or heart transplantation. A E/Em ratio > 17 had a mortality of approximately 40% vs. 5% in those with an E/Em ratio of less than 17 (p < 0,001) . From at al. demonstrated that there is an association between duration of DM and LVDD and that an increasing E/Em ratio is associated with all-cause mortality in diabetic patients . In this study, duration of DM ≥ 4 years was correlated with significant LV diastolic dysfunction and LVDD was predictive of all-cause mortality independent of hypertension and CAD. Recently Mogelvang et colleagues showed that in the general population, LVDD by TDI is a powerful and independent predictor of death, even in the subgroup with normal conventional echocardiography . Focusing on the elderly subjects, who are prone for diabetes and its complications, diastolic dysfunction is an independent predictor of cardiovascular events . Therefore, we speculate that the association of elevated proinflammatory cytokines with LVDD might put the patients at higher risk for the progression of symptomatic diabetic cardiomyopathy.
Proinflammatory cytokines are capable of modulating cardiovascular function by various mechanisms. It is now known that virtually every nucleated cell type in the myocardium, including the cardiac myocyte, is able to secrete proinflammatory cytokines in response to various myocardial damage or stressors. The expression of these cytokines can occur in absence of systemic immune activation.
They partly act in a negative inotropic manner and cause changes in turnover of the extracellular matrix resulting in myocardial fibrosis. The proinflammatory cytokine TNF-α induces cardiodepressive effects and causes apoptosis . The development of progressive cardiomyocyte apoptosis plays a critical role on the left ventricular geometry and the adverse cardiac remodeling that occurs in the setting of sustained inflammation.
There are some limitations in the present study. The consensus paper of the ESC  deals with the term diastolic heart failure, referring to subjects with heart failure. In our study, diastolic dysfunction was defined in asymptomatic patients using TDI techniques. Nevertheless, TDI is the most sensitive and widely available echocardiographic tool for the assessment of LV diastolic function . Furthermore, the fact that Em- velocity and E/Em are highly correlated with age might impair their predictive abilities in high risk population like ours in which age had an impact on the risk of cardiovascular and diabetes- related complications.
Moreover, we did not measure LA volume index and pulmonary vein velocities. These additional echo data might have been of interest especially in the cohort with E/Em ratio 8-14.