The present study provides an integrated approach to the assessment of diabetic cardiac function in rats, using both noninvasive echocardiography and invasive hemodynamic evaluation; it provides important new insights into the pathophysiology of diabetic cardiomyopathy. The present data confirm our preliminary findings that STZ diabetes induces hyperglycemia, weight loss, and bradycardia. However, the major finding of this study is that rats with 30 days of STZ-induced-diabetes had impairment in cardiac structure and function as evidenced noninvasively by echocardiography and invasively by LV catheterization, and also that this LV dysfunction was exacerbated by volume overload.
Noninvasive evaluation of cardiac function
Echocardiographic measurements of cardiac function and structure in the present experiments demonstrated both LV systolic and diastolic dysfunction in 30-day diabetic rats. In fact, several investigators have shown abnormalities in LV systolic function, diastolic function, and complaints in humans [10–12] and rats [9, 14–16], by using a noninvasive method of evaluation. Joffe et al  observed diabetic cardiomyopathy, characterized by LV systolic and diastolic dysfunction, after two and a half months of STZ in rats. Akula et al  in a recent study used echocardiography to examine LV function in STZ rats over a definite course of time (2, 4, 8, and 12 weeks). They concluded that LV systolic and diastolic dysfunction was fully visible at 12 weeks of diabetes by this method, and that echocardiography is useful in diagnosing cardiac abnormalities in diabetic rats without the need for invasive histopathological procedures. In contrast with these authors, we observed systolic and diastolic dysfunction after 30 days of STZ-induced diabetes documented by reduced ejection fraction, fractional shortening, and E-wave and increased A-wave and EDT, as well as by reduced VCF and increased IVRT observed in diabetic animals compared with controls. Corroborating our data, Yu et al  observed significant deficits in myocardial morphology and functionality by using magnetic resonance imaging at 4 weeks of diabetes in STZ-induced diabetic mice. In another study, Mihm et al  showed reductions in HR and EDT after 3 days of STZ-induced diabetes, and these reductions progressed throughout the 56-day period. Furthermore, these authors observed that systolic dysfunction was detected only after 35 days of study.
LV cavity dilatation accompanied by no changes in wall thickness has been observed previously after 35 and 75 days [7, 14] and 12 weeks  of diabetes. Joffe et al  demonstrated not only LV cavity dilatation, but also increased LV mass after 75 days of STZ induction in rats, suggesting evidence of cardiomyopathy characterized by eccentric hypertrophy. In contrast, in the present study, we observed LV cavity dilatation accompanied by decreased thickness of the LV posterior wall and interventricular septum after 30 days of diabetes, suggesting a reduction in LV mass. Similarly, Dobrzynki et al  observed reduced heart weight and LV mass associated with cardiac and renal function damage after 21 days of STZ-induced diabetes in rats. In addition, our study is the first to describe the RWT reduction in diabetic rats, indicating a probable reduction in LV mass, as previously demonstrated .
MPI is a simple and nongeometric index that combines systolic and diastolic functions independently of heart rate, not requiring frequency based normalization . The importance of MPI in this study is that it is an HR-independent measure unlike transmitral flow velocities. MPI also has not been used previously to investigate cardiomyopathy in diabetic rats. In our evaluations, MPI was increased in diabetic rats, suggesting global cardiac dysfunction in these animals. This result appears to correlate well with invasive measurements of systolic and diastolic measurements in humans  and animals . Recently, MPI was validated in mice, and is strongly correlated with invasive measurements of the LV dP/dt max . MPI has a prognostic value after myocardial infarction , as well as in adults with amyloidosis  and dilated cardiomyopathy , and is not affected by mitral regurgitation .
Invasive evaluation of cardiac function
Dent et al  demonstrated that differences in diastolic function might be noninvasively quantified in diabetic hearts; however, these authors recognized that the lack of in vivo hemodynamic data was one limitation of their study. In our experiments, direct measurements of cardiac function corroborate diastolic and systolic LV function impairment observed after 30-day-induced diabetes by the echocardiographic approach. In vivo LV function evidenced reduced LVSP and +dP/dt max, reflecting a systolic dysfunction, increased LVEDP and attenuated -dP/dt max, showing diastolic dysfunction. These data associated with the impairment in MPI reported in the diabetic group in the present study corroborate the positive correlation between these ventricular indexes, as previously shown in mice . In fact, similar alterations in LVEDP, contractility, bradycardia, reduced cardiac output, and renal damage were evidenced after 21 days of STZ in rats. Reduction in HR in diabetic rats has been attributed to changes in sinoatrial node [1, 3, 26], although functional alterations in the cholinergic mechanism cannot be excluded as a causal factor. Joffe et al  showed the in vivo reduced peak of LV systolic pressure and increased LVEDP, as well as in vitro attenuation of LV +dP/dt max and -dP/dt max after 75 days of STZ-induced diabetes in rats. Another study in which in vivo LV cannulation was performed showed a decrease in LV +dP/dt max and -dP/dt max after 15 days of STZ injection in rats . Impairment in cardiovascular function in mice was also observed in diabetic-infarcted mice at the same time point . In a previous study by our group, we reported that the isolated hearts of 11-week STZ-induced diabetic rats did not have differences in LV isovolumetric systolic pressure, but had reduced contractility compared with isolated hearts in control rats .
In addition, our results show impairment in cardiac responses during and after volume overload in STZ-induced rats. A similar increase in LVEDP observed in control rats in the present experiments was previously demonstrated in the early stages of volume overload induced by A-V fistula in control rats . However, in contrast with that observed in control rats, the high values of recorded LVEDP in STZ-induced rats remained elevated after volume overload, which may be explained by cardiac changes produced by STZ. Despite the fact that LV cavity dilatation allows major blood compliance, the reduced fractional shortening, ejection fraction, and VCF observed in STZ-induced rats are probably associated with the increase in LVEDP during and after volume overload, because the volume of blood can not be completely ejected.
Studies that have examined both systolic and diastolic dysfunction in diabetes suggest that the latter is more susceptible to preclinical changes. Diastolic dysfunction is not just a defect in active relaxation, but also in passive stiffness of the left ventricle . The echocardiographic evidence of subclinical contractile dysfunction and diastolic filling abnormalities are predictive of subsequent chronic heart failure . Patients with diastolic heart failure have an increased mortality of 5–8% compared with the control group . Systolic dysfunction occurs late, often when patients have already developed significant diastolic dysfunction. However, the prognosis in patients with systolic dysfunction is an annual mortality of 15–20%, greater than mortality in patients with diastolic dysfunction . Thus, the early detection of diastolic and systolic dysfunction can prevent worsening of this condition.