Cardiovascular disease is a major cause of morbidity and mortality in patients with chronic kidney disease (CKD).1 Although patients requiring dialysis are at greatest risk, the disease processes appear to begin much earlier in the course of CKD with a graded inverse relationship between the risk of cardiovascular events and renal function.2 It is more likely that patients with early CKD will die of cardiovascular disease than develop end-stage kidney disease.3 This relationship between cardiovascular disease and CKD has major public health implications as CKD is a common finding.1 To date, most studies have examined myocardial and vascular disease in patients with late-stage CKD 4^–6 and there are few data on cardiovascular abnormalities in early-stage CKD when preventive treatment may be most effective. The hypothesis of this study was that increased stiffness of the large arteries might be (a) detectable early in the natural history of CKD and (b) associated with adverse changes in ventricular systolic and diastolic function. We used MRI and echocardiography to examine ventricular and arterial function in patients with early CKD and compared the findings with those of age- and sex-matched controls.

PATIENTS AND METHODS

Study subjects

One hundred and seventeen patients were recruited from renal clinics at our institution during 2005–7. Patients were included if aged 18–80 years, with stage 2 (glomerular filtration rate (GFR) 60–89 ml/min/1.73 m² and evidence of kidney damage for ⩾3 months) or stage 3 CKD (GFR 30–59 ml/min/1.73 m²).7 GFR was estimated (eGFR) using the four-variable Modification of Diet in Renal Disease formula.8 All patients were receiving established treatment with an ACE inhibitor (70%) or angiotensin II receptor blocker (32%), or both. Other treatments included statins (40%) and calcium channel blockers (27%). Exclusion criteria included a history of angina, myocardial infarction, heart failure, cerebral or peripheral vascular disease; the presence of atrial fibrillation, valvular disease, uncontrolled hypertension (mean daytime 24-hour ambulatory blood pressure monitoring >130/85 mm Hg), diabetes mellitus and anaemia. Patients were matched for age and sex with 40 healthy controls with no evidence of CKD as defined by K/DOQI guidelines.1 The protocol was approved by the South Birmingham Local Research Ethics Committee and patients gave written consent.

Data collection

A cardiovascular assessment including 12-lead electrocardiogram was performed at entry. Brachial blood pressure was recorded in the non-dominant arm using a validated oscillometric sphygmomanometer (Dinamap ProCare GE).

Cardiovascular magnetic resonance imaging

Cardiovascular magnetic resonance (CMR) imaging was performed on a 1.5 T scanner (Siemens Sonata Symphony, Erlangen, Germany). Serial contiguous short-axis cines were piloted from the vertical long axis/horizontal long axis of the right and left ventricle (ECG-gated, True-FISP; temporal resolution 40–50 ms, TR 3.2 ms, TE 1.6 ms, FA 60°, slice thickness 7 mm) in accordance with previously validated methodologies.9

Analysis was performed offline (Argus Software Siemens, Erlangen, Germany) by a single blinded observer. Arterial distensibility (×10⁻³/mm Hg) were assessed in the ascending aorta at the level of the pulmonary artery and calculated using standard formulae:

Distensibility =  (Δaortic area)/(aortic area min × ΔP)

where Δaortic area  =  (maximum aortic area – minimum aortic area), ΔP is the average of three brachial pulse pressure measurements performed during CMR.6 10

Echocardiography

Echocardiography was performed using second harmonic imaging on a Vivid 7 machine (GE Vingmed Ultrasound, Horten, Norway). All variables were measured in triplicate and averaged.11 Pulsed-wave tissue Doppler (TDI) was performed from apical four-, two- and three-chamber views as previously described.12 The ratio of mitral inflow early diastolic velocity and mitral annular early diastolic TDI velocity (E/Em) was used to estimate left atrial pressure.

Arterial–vascular interaction

Measurements were made in accordance with previously validated methodologies.13^–15 In brief:

• End-systolic pressure was estimated as systolic pressure (recorded at the time of echocardiography by sphygmomanometry) × 0.9.13

• Effective arterial elastance (Ea) and effective arterial elastance index (EaI) were estimated as end-systolic pressure/stroke volume (Doppler derived) and normalised to body surface area (EaI).14 EaI correlates with measures of arterial load derived from aortic impedance data and reflects the elastance of the arterial system.

• End-systolic elastance (Ees) was estimated using blood pressure, stroke volume, pre-ejection and total systolic times.13

• End-diastolic elastance (Eed) was estimated from the ratio of mitral inflow early diastolic velocity and mitral annular early diastolic TDI velocity (E/Em) divided by the volume of filling during diastole.15

Statistical analysis

Statistical analyses were performed using SPSS software (SPSS for Windows, version 14.0). Data in text and tables are presented as mean (SD) unless stated otherwise. The Kolmogorov–Smirnov test was used to test for normal distribution of data and log transformed as necessary Categorical variables were compared by the Pearson χ² test. Continuous variables were compared between groups using one-way analysis of variance, with Tukey post hoc test. Pearson correlation coefficients were used to measure associations between continuous variables. The general linear model was used to investigate association between indices of cardiovascular function with adjustment for age and gender. Intraoperator variability between echocardiographic (4%) and MRI measurements (2.5%) was assessed as previously described.16

RESULTS

Subjects

There were no significant differences in demographic data between patients with CKD and controls. (table 1). The most common causes of CKD were glomerulonephritis 55%, vasculitis 13%, polycystic kidney disease 8% and systemic lupus erythematosus 7%. Seventy per cent of patients had a history of hypertension controlled with an average of 2.1 antihypertensive agents. There was no difference in blood pressure between the groups (table 1).

Cardiovascular magnetic resonance imaging

No difference was found between patients and controls in mean left ventricular (LV) volumes or ventricular ejection fraction measured using CMR (table 2). Mean LV mass was greater in patients with CKD than in controls. Almost a third of patients with CKD had LV hypertrophy (LVH) as defined by an LV mass greater than age, gender and body surface area corrected limits.9 The mean LV mass and proportion of patients with LVH did not differ significantly between stage 2 and 3 CKD. Aortic distensibility (fig 1) was reduced in both stage 2 and stage 3 CKD compared with controls (p<0.01). There was a significant positive correlation between aortic distensibility and eGFR (r = 0.349, p<0.01). LV mass was inversely correlated with aortic distensibility (r = −0.284, p<0.001).

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Figure 1 Aortic distensibility measured on cardiovascular magnetic resonance at the level of the main pulmonary artery in healthy controls and patients with chronic kidney disease (CKD). Data are mean (SD) (horizontal bar) for continuous variables. One-way analysis of variance. F = 16.6. *p<0.05, **p<0.01 vs controls; †p<0.05, ††p<0.01 CKD 2 vs CKD 3.

Echocardiography

There was no difference in systolic function between patients with CKD and controls. Ejection fraction and longitudinal systolic tissue Doppler velocities in patients with CKD were within normal limits.17 (table 3, fig 2A). Diastolic parameters including early myocardial relaxation (basal Em, fig 2B), E/Em ratio, M-mode colour flow propagation, and pulmonary venous a-wave duration were abnormal in CKD compared with controls (table 3). Left atrial volumes were greater in patients with CKD than in controls. Right and left ventricular Tei indexes were increased in CKD (table 3).

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Figure 2 Bar graphs of pulsed tissue Doppler myocardial velocities (A) systolic (Sm) and (B) early mitral filling (Em). E/Em, ratio of pulse Doppler transmitral early filling velocity (E) and pulse tissue Doppler early filling myocardial velocity recorded from lateral mitral annulus (Em). Data are mean (SEM) for continuous variables. p Values derive from one-way analysis of variance *p<0.05 **p<0.01 vs controls.

Arterial–ventricular interaction

Arterial elastance (Ea), arterial elastance index (EaI), LV end-systolic elastance (Ees), LV end-diastolic elastance (Eed) were all greater in CKD than in controls (table 4). In patients with CKD stage 3, the systemic vascular resistance index and pulse pressure were increased compared with controls, indicating that both mean resistive and pulsatile load were increased. There were no differences between systemic vascular resistance index, pulse pressure and heart rate between patients with stage 2 CKD and controls, indicating that differences in EaI between these subjects principally reflected altered pulsatile load and hence the oscillatory arterial properties (stiffness). Examination of patients and controls showed that EaI and Ees were significantly correlated (Pearson’s r = 0.692, p<0.001) (fig 3). The arterial–ventricular coupling ratio (Ees/Ea) was maintained in both patients and controls, although the absolute values for both of Ea and Ees were increased in CKD. Arterial elastance (r = −0.282, p<0.05), Ees (r = −0.137, p<0.05) and Eed (r = −0.347, p<0.01) were all inversely correlated with eGFR.

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Figure 3 The positive association of arterial elastance index (EaI) with end-systolic elastance (Ees) in controls and patients with chronic kidney disease (CKD), measured by echocardiography. Ees is increased with EaI (Pearson correlation coefficient r = 0.692). Ea is a significant predictor of Ees in a regression model (r² = 0.47, p<0.001).

Effect of drugs and biochemical variables

Haemoglobin, calcium, phosphate and parathyroid hormone were within normal range in all subjects. There was no detectable association between cardiac and vascular stiffness measures on CMR and echocardiography with these biochemical variables by univariate analysis. There was also no correlation between any marker of vascular function with any antihypertensive agents or statin.

DISCUSSION

We have demonstrated major abnormalities of both arterial and LV function and their interaction in patients with early CKD. Most similar studies to date have examined patients with end-stage kidney disease and have used other measures of arterial stiffness such as pulse-wave analysis and pulse-wave velocity (PWV).18 These provide valuable information on wave reflection and regional vascular stiffness in the aorta and iliac vessels (carotid–femoral PWV) but are an indirect measure of central aortic stiffness and are dependent on the assumptions of a circulatory model.4 In contrast, we have employed MRI, which allows direct measurement of the change in ascending aortic dimensions in response to pressure fluctuation and hence represents the true load imposed on the left ventricle and central large artery walls. Measurement of arterial and systolic elastance by echocardiography is an indirect but validated technique13^–15 which provides information on both arterial and ventricular stiffness, allowing the assessment of vascular ventricular coupling, a major determinant of cardiovascular performance.19

Although we cannot exclude the influence of hypertension on our results, this was not a study of patients with hypertension and incidental renal dysfunction. All patients were recruited from a specialist renal clinic and had established renal disease, proven by biopsy in 60% of cases. Blood pressure was optimally controlled before recruitment. Cardiovascular abnormalities, including reduced aortic compliance on CMR, have been demonstrated in patients with end-stage CKD,6 20^–22 but our study suggests that significant damage is already present in stage 2 disease, often before a rise in serum creatinine has occurred. Perhaps most importantly, aortic distensibility was reduced and the arterial elastance index, a measure of net ventricular after load, increased in our patients compared with controls. Thus, it appears that an increased oscillatory load occurs early in the course of CKD, at least in part as a result of changes in the aortic wall. Changes in aortic distensibility of a similar magnitude have recently been reported in patients with type 2 diabetes.23

It is established that arterial stiffness is a strong predictor of cardiovascular morbidity and mortality in end-stage CKD and appears to be independent of other prognostic factors including age, LVH and blood pressure.18 Our findings of increased arterial stiffness and reduced aortic distensibility in patients with early CKD are consistent with previous studies using PWV, which demonstrated a graded increase in arterial stiffness with advancing stage of CKD.24^–26 There is evidence that this increased arterial stiffness is not merely a response to hypertension. Briet et al showed that aortic stiffness determined by PWV was greater in CKD than in hypertensive controls with normal renal function.24 Mourad et al demonstrated a positive correlation between creatinine clearance and carotid compliance measured by Doppler ultrasound in young hypertensive subjects independent of age and blood pressure.25 Possible causes of aortic stiffness in early CKD apart from hypertension include an increase in aortic wall calcium, endothelial dysfunction, elastin fragmentation and vascular inflammation.27

Our results also show abnormalities of cardiac structure and function in early CKD. Mean LV mass in the early CKD group was not increased but the high prevalence of LVH in both stage 2 and stage 3 CKD suggests that a hypertrophic response occurs early, although not invariably, in the course of renal disease. The association between LV mass index and aortic distensibility is consistent with an important role for aortic stiffness as a driver of LVH in early renal disease. Systolic ventricular function, assessed using echocardiography and CMR, was preserved in early CKD while abnormalities of diastolic function were evident. LV relaxation was delayed and maximal ventricular end-diastolic stiffness increased. Consistent with impaired diastolic function, left atrial volumes and left ventricular end-diastolic pressure were increased. The increase in Ees suggests that resting LV contractility is enhanced in early CKD in order to maintain the arterial–ventricular coupling ratio and cardiac performance. There is now good evidence that the “price” of this compensatory response is an increase in LV stiffness and haemodynamic instability.19 Cardiac reserve is reduced and during exercise the increase in both Ees and Ea causes an excessive rise in systolic pressure, increasing cardiac work and metabolic demand.28

These abnormalities of both arterial and ventricular function are strikingly similar to those reported in patients with heart failure with normal ejection fraction (HFnIEF).29^–32 Kawaguchi et al showed higher Ea and Ees in subjects with HFnIEF than in controls and similar adverse effects on diastolic function.29 Patients with HFnIEF often have impaired renal function and it will be of great importance to determine whether this is a cause or effect of the HFnIEF disease process.30 The ultrastructural changes responsible for these abnormalities of ventricular function in CKD have not been studied but we speculate that, as in HFnIEF, there may be abnormalities of myocardial collagen and perhaps changes in titin isoform expression.33 Research in this area and on the impact of the increased LV stiffness on effort tolerance and haemodynamic stability in patients with CKD is required. Patients with HFnIEF have a poor prognosis and the implications for patients with early CKD are profound. It will also be of importance to determine whether the abnormalities we have described can be reversed by renal transplantation.34

Limitations

These are observational data and the relationships between eGFR and abnormalities of vascular and cardiac function cannot prove causality. The lack of a treated hypertensive control group means that we cannot exclude the possibility of a major influence of hypertension on the functional abnormalities we have found in early CKD. There are also ultrastructural changes present in the arteries and myocardium of patients with CKD that may have functional consequences but could not be assessed in this clinical study.35 36 The measurements of elastance were derived by non-invasive methodology rather than from invasive ventricular pressure–volume relations, although these methods are well validated against invasive techniques.14 15 37 We used brachial artery pressure in the calculation of aortic distensibility and elastance as this is in accord with validated methods.6 13 15 We accept, however, that central aortic pressure is the pressure “seen” by the aorta and left ventricle. The use of derived central aortic pressure (applanation tonometry) in the calculation of aortic distensibility and in elastance values did not affect the significance of the results.

CONCLUSION

Early CKD is characterised by increased arterial stiffness, LV systolic stiffness, impaired early relaxation, and increased end-diastolic stiffness. Arterial–ventricular coupling is preserved. These changes resemble closely those described in HFnIEF and may have implications for myocardial performance and prognosis. Measures to prevent these changes should be considered in patients with early-stage CKD.