Diabetes is associated with the premature development of large vessel arterial stiffness 1. Increased arterial stiffness is known to be associated with cardiac and kidney dysfunction and is a powerful risk factor for early mortality 2. In comparison to the well-established changes in compliance that occur at the large vessel level in diabetes, much less is known about the changes in compliance of the cardiovascular system at the end-organ level.

Early in the course of diabetes, progressive cardiac fibrosis and hypertrophy lead impaired relaxation and a stiff left ventricle. We have previously found 'diastolic dysfunction' in over half of all unselected patients with type 2 diabetes attending a diabetes clinic at a tertiary care center 34. Furthermore, recent epidemiological studies show that diastolic dysfunction is an independent risk factor for cardiac death 5. We have also shown that increased resistance of the intrarenal arteries is associated with a reduced glomerular filtration rate (GFR), an independent predictor of cardiac mortality 678.

These findings led us to hypothesize that reduced compliance of the intrarenal arteries that is associated with diabetic kidney disease, is mirrored by changes in the diabetic heart, which are manifested by worsening markers of diastolic function. The aim of this study was therefore to search for a link between compliance of the intrarenal arteries and compliance of the left ventricular wall in individuals with type 2 diabetes.

The clinical and biochemical characteristics of the study population are shown in Table 1. Many clinic subjects were obese (57%), had hypertension (81%) or established cardiovascular disease (36%). Over half of all patients in this cohort had chronic kidney disease (CKD) including elevated AER levels (>20 μg/min) in 45% and 22% with an iGFR < 60 ml/mim/1.73 m².

Subjects were further stratified according to results of their TTE examination. Thirty five percent of participants had normal cardiac function on TTE examination (n = 59). However, the majority of diabetic subjects (65%) had abnormal cardiac function (n = 108), including 66 individuals with diastolic dysfunction alone (40%), 30 with concurrent diastolic and systolic dysfunction (18%) and in a small number of individuals (n = 12) isolated systolic dysfunction was the only finding (7%). Subjects with diastolic dysfunction were generally older, had a greater frequency of hypertension and renal impairment than those with a normal TTE examination. As expected, subjects with concurrent systolic dysfunction had a greater prevalence of past CVD (Table 1).

The mean renal RI was 0.69 ± 0.01 in the total cohort with 48% of subjects with type 2 diabetes having an elevated RI beyond the normal range (> 0.7). As shown in Figure 1, renal RI values were significantly higher in with (any) diastolic dysfunction (0.72 ± 0.06) compared with those who had a normal TTE examination (0.66 ± 0.06, p < 0.01). Moreover, the finding of an elevated RI level (> 0.7) was twice as common in individuals with (any) diastolic dysfunction compared with those who had a normal TTE examination (59% vs 25%, p < 0.001). Less than 18% of all those with elevated RI levels (> 0.7) in this cohort had normal cardiac function. As shown in Table 1, RI levels were elevated to a similar extent in subjects with diastolic dysfunction alone (0.72 ± 0.06) and in those with concurrent diastolic and systolic dysfunction (0.71 ± 0.06) when compared those who had a normal TTE examination (0.66 ± 0.06, both p < 0.01).

As shown in figure 2, renal RI values were correlated with markers of diastolic dysfunction including the E/Vp ratio (r = 0.41, p < 0.001) and left atrial area (r = 0.36, p < 0.001). Renal RI values were also associated with the E/A ratio (r = 0.36, p < 0.001) and the E/E' ratio (r = 0.31, p < 0.001). The association between renal RI levels and all of the above markers of diastolic dysfunction remained significant (all p <0.001) after correcting for multiple clinical and biochemical variables including age, duration of diabetes, BMI, blood pressure, albumin excretion rate, iGFR levels, use of blockers of the renin-angiotensin system, as well as adjusting for parameters of systolic function. While renal RI values were weakly correlated with parameters of systolic function (e.g fractional shortening and ejection fraction, both p = 0.05), these associations were eliminated after adjusting for age.

This study shows that resistance of the intrarenal arteries is closely linked with abnormal cardiac function in patients with type 2 diabetes. In particular, there was a continuous relationship between increasing resistance of the intrarenal arteries and established indices of left ventricular filling pressure and diastolic function. These associations were independent of systolic function, hypertension, the presence and severity of chronic kidney disease, the use of renin-angiotensin inhibitors and other potentially confounding variables.

These data support the hypothesis of a common pathway to diabetic complications, which promotes stiffening and progressive dysfunction in both the heart and major vessels. Such common contributory factors may include oxidative stress, insulin resistance, inflammation, the accumulation of advanced glycation end products (AGEs), activation of the rennin angiotensin system (RAS), arterial calcification and endothelial (dys)function. However, it is likely that a parallel increase in the resistance of the intrarenal arteries and indices of diastolic dysfunction also partly reflects a generalized reduction in vascular compliance associated with arteriosclerosis in a range of vascular beds. In support of this suggestion, both the intra-renal RI and parameters of diastolic dysfunction have been shown to be associated with systemic pulse wave velocity, arterial compliance, and systemic vascular damage in both diabetic and non-diabetic subjects 1415.

This study demonstrates that worsening indices of diastolic function in subjects with type 2 diabetes parallels increases in resistance of the intrarenal vessels. These findings are consistent with the hypothesis that both the development of vascular and myocardial stiffening in diabetes are manifestations of common pathophysiological mechanisms. It is possible that these processes also contribute to the link between renal dysfunction and cardiovascular outcomes in subjects with type 2 diabetes 78.

TTE: transthoracic echocardiogram; RI: resistance index; iGFR: isotopic glomerular filtration rate (measured by the plasma disappearance of ^99mTc-DTPA employing the Brochner-Mortensen correction); E: early mitral flow velocity; E': early diastolic velocity of the mitral annulus; A: late mitral flow velocity; Vp: flow propagation velocity; BMI: body mass index; BP: blood pressure; RAS: renin angiotensin system; CHD: coronary heart disease; AER: albumin excretion rate; CRP: C-reactive protein; HbA_1c: glycated haemoglobin.

The authors declare that they have no competing interests.

RJM drafted the paper. RJM, SP, TJS, PGM, MCT, GJ, LMB & PMS were involved in the study design, coordination and data acquisition. MCT performed the statistical analysis of the data presented. LMB & PMS coordinated and interpreted the TTE studies whilst PGM & HH coordinated and interpreted the renal arterial RI studies. All authors approved the final version of the manuscript.