Patients with recently diagnosed T2DM but no evidence of cardiac dysfunction at rest by echocardiography exhibited an abnormally increased PCWP response during graded exercise compared with healthy subjects. At peak exercise, the elevated PCWP was inversely correlated with impaired myocardial perfusion. The finding of elevated PCWP, collected using invasive methods, suggests the presence of cardiac dysfunction during exercise in persons with recently diagnosed T2DM that may be related to impaired cardiac perfusion associated with T2DM. Importantly, the exaggerated PCWP responses were found in all diabetic subjects tested and occurred in subjects screened for, and who demonstrated, normal systolic and diastolic functions at rest.
Cardiac dysfunction and exercise intolerance have been widely described in patients with T2DM (2
). For example, previous studies using noninvasive measurements have suggested abnormal resting LV systolic and diastolic functions in patients with advanced diabetes (3
). Furthermore, two recent echocardiographic studies suggested a direct relationship between resting diastolic function and exercise capacity in subjects with the metabolic syndrome or diabetes compared with healthy controls (21
). Early invasive studies demonstrated elevated LV end-diastolic pressure and decreased LV filling rates in the resting state in patients with advanced diabetes (31
). However, in all of these studies, cardiac measures were made in the resting state and among patients with T2DM across a broad range of disease history and comorbidities. In contrast, using invasive methods, the current study evaluated cardiac function during exercise in patients with recently diagnosed T2DM who demonstrated no evidence of resting LV systolic dysfunction or diastolic dysfunction by echocardiography or perfusion defects by nuclear imaging. We found no differences in the HR, SV, or CO responses at peak exercise between groups. We also observed no significant differences in absolute
at peak exercise although
in milliliters per kilogram per minute was lower in persons with diabetes than controls as had been previously reported (27
). These subjects may differ from individuals previously studied by our group and others due to rigorous prestudy exclusion of cardiovascular disease by baseline echocardiogram. Although these data indicate that cardiac and systemic exercise performance was not significantly impaired in these recently diagnosed T2DM subjects, we observed a profound increase in PCWP with exercise in the subjects with T2DM that was not observed in healthy counterparts.
The accentuated PCWP response during exercise in people with T2DM, and in particular those with short disease duration, has not been previously reported. This finding is clinically significant in that it indicates an elevated filling pressure for a given amount of ventricular volume. Importantly, this condition is thought to precede the development of overt cardiac dysfunction and is commonly observed in patients with LV cardiac failure (15
There are a number of factors that could be related to the abnormal rise in exercise PCWP including LV systolic dysfunction, diastolic dysfunction, or an increase in SVR (cardiac afterload). In the current study, we found no evidence of resting LV systolic dysfunction either with echocardiography or nuclear imaging in the persons with T2DM as LV ejection fraction (LVEF) was normal and no different from that of control subjects. There was also no significant difference in the LVSW response to exercise between groups. CO was also similar at peak exercise in both groups. It is plausible that incomplete LV emptying because of reduced LVEF or contractility during exercise could lead to our observation of elevated PWCP; however, in light of the similar peak exercise cardiac functional measures, we interpret these data to suggest that LV systolic dysfunction is an unlikely or at least an incomplete explanation for the abnormal elevation in PCWP.
Alternatively, the abnormal PCWP response during exercise in diabetic subjects is consistent with a finding of diastolic dysfunction. Abnormal diastolic function of the left ventricle is associated with prolonged ventricular relaxation time, and thus, there would be an excessively elevated LV filling pressure, as seen using our invasive measure of PCWP. This pathophysiologic state results in alterations in ventricular filling that can also be analyzed by noninvasive techniques using tissue Doppler echocardiography. For example, Ha et al. (10
) used noninvasive measurement of ventricular tissue velocities during low to moderate exercise to describe blunted systolic and diastolic tissue velocities in T2DM subjects compared with control subjects. The significance of the study by Ha et al. was that resting tissue Doppler measurements were normal in the T2DM subjects, and tissue contractile abnormalities only developed with the onset of low- and moderate-intensity exercises. Our invasively obtained data are consistent with these echocardiographic findings in that we found no evidence of hemodynamic or cardiac dysfunction at rest in these T2DM subjects but that they demonstrated an abnormal increase in PCWP that began with the lowest work rate and continued to increase until peak exercise. Given the previous data suggesting a relationship between resting diastolic function and exercise capacity (21
), the present data would seem to support a functional role for abnormal diastolic function during exercise in persons with early diabetic disease. Although we did not obtain echocardiography measurements during exercise in the current study, our results provide invasive evidence for diastolic dysfunction during exercise in subjects with early diabetes and directly support the noninvasive findings of a prior study by Ha et al. (11
) in nondiabetic subjects with exertional dyspnea.
Other possible explanations for an accentuated rise in PCWP with exercise include decreased ventricular compliance and increased afterload related to an elevated MAP. We noted that MAP at peak exercise tended to be higher in T2DM than in control subjects; however, there was no correlation between this measure and PCWP at peak exercise. Furthermore, there were no differences in rest or peak SVR between persons with T2DM and controls, suggesting that vasodilatory reserve was not a major factor.
In contrast, our findings from the technetium Tc 99m sestamibi substudy suggested that myocardial perfusion obtained at peak exercise was reduced in T2DM compared with controls. This observation supports a model wherein subclinical hypoperfusion at the microvascular level may be one factor related to impaired cardiac function in T2DM. Recently, cardiac imaging with SPECT has been used for the noninvasive estimation of coronary flow reserve, a marker of myocardial vascular function (33
) and is comparable with invasive intracoronary measurements of blood flow (33
). Technetium-99m SPECT imaging has been demonstrated to be an accurate and simple way to noninvasively estimate coronary flow reserve with a good interobserver and intraobserver reproducibility (33
). Limitations of this technique include low-resolution–related factors, such as attenuation or partial volume average effects, which may be cancelled out by using the ratio of stress to rest counts. In the current study, we noted that the change in normalized MPI was associated with the PCWP response. It has been previously shown that T2DM subjects with established microvascular disease have been reported to have defects in stress-induced cardiac perfusion and a trend toward decreased diastolic function (17
) although this is not universally observed (21
). Given the small sample size of the current study, further studies with a larger number of patients will be needed to corroborate the finding of abnormal MPI in patients with “early-onset” diabetes and its relationship with decreased exercise capacity and LV diastolic abnormalities. Thus, these results pose a provocative question in terms of perfusion and potential metabolic mechanisms for our functional hemodynamic findings. Indeed, abnormalities in the T2DM myocardium (e.g., diabetic cardiomyopathy) may have their pathogenesis in several important processes including impaired calcium homeostasis, advanced glycation end-products, activation of the renin–angiotensin system, increased oxidative stress, mitochondrial dysfunction, and altered myocardial substrate metabolism (3
). It is likely that these changes are present early in the natural history of insulin resistance and may be manifest as alterations in cardiac function as demonstrated by the elevated PCWP responses in this study. Our study supports the notion that diabetes-related cardiomyopathy begins very early in the pathogenesis of insulin resistance and T2DM.
Other, noncardiac components of oxygen delivery or extraction could also cause impairment in exercise performance in T2DM including increased capillary basement membrane thickening, greater blood viscosity (19
), or skeletal muscle and mitochondrial abnormalities (14
). Future studies should explore the various etiologic factors possibly responsible for the exercise impairment observed in T2DM.
In contrast to prior studies, we found that the decrease in
in T2DM compared with controls was less than previously observed (2
). Our small sample size may have played a role, or alternatively, lack of differences may be due to patient selection bias compared with prior studies given that patients were volunteering for cardiac catheterization. In addition, patients were required to have normal cardiac function at rest by echocardiography. Given that patients were early in the course of T2DM by diagnosis, PCWP differences may have been the earliest sign of altered cardiac mechanics. Because only women were studied, these results may not be generalizable to men. Women were studied exclusively in this study for two reasons. First, we have observed that women with T2DM perform worse with regard to exercise tolerance than men with T2DM compared with their nondiabetic counterparts (28
). In addition, subject homogeneity likely facilitates ascertaining whether significant differences between diabetic and nondiabetic subjects exist.