Association of central arterial blood pressure and left ventricular hypertrophy in patients with chronic kidney disease

In the general population, central arterial blood pressure has proved to be more closely related to left ventricular hypertrophy (LVH) than brachial arterial blood pressure. We aimed to investigate whether this relationship was true in patients with chronic kidney disease (CKD).


| INTRODUCTION
Chronic kidney disease (CKD) and its related complications are an important public health problem worldwide, and China is not an exception. According to a cross-sectional survey, the prevalence of CKD in this country is 10.8%. 1 KDIGO guideline divided CKD into five stages: stage 1 (GFR ≥90 ml/min/1.73 m 2 ), stage2 (GFR 60-89 ml/ min/1.73 m 2 ), stage 3a (GFR 45-59 ml/min/1.73 m 2 ), stage 3b (GFR 30-44 ml/min/1.73 m 2 ), stage 4 (GFR 15-29 ml/min/1.73 m 2 ) and stage 5 (GFR < 15 ml/min/1.73 m 2 ). 2 Cardiovascular mortality is considered the main cause of death in patients with CKD and is 2.6 times higher in such patients than in the general population. 3 In this regard, the National Kidney Foundation Kidney Disease Outcomes Quality

Initiative (NKF KDOQI) CKD Cardiovascular disease (CVD) Working
Group has issued a report emphasizing that CVD is a high-risk factor for death in CKD patients, and identified left ventricular hypertrophy (LVH) as the main intervention target. 4 LVH is an abnormal increase in left ventricular myocardial mass resulting from an increased afterload or diastolic overload 5 and it represents an independent predictor of cardiovascular events and mortality. 6 It is widely accepted that blood pressure, traditionally measured with a sphygmomanometer in the brachial artery (brachial arterial blood pressure [BABP]), is directly associated with CVD and LVH. However, current evidence has shown that central arterial blood pressure (CABP) may be a more accurate predictor of cardiovascular events 7,8 and LVH [9][10][11] than BABP in the general population. To our knowledge, there is no study focused on the relation between CABP and LVH in patients with CKD. The aim of this study is twofold: first, to investigate whether the CABP is a better predictor of LVH than BABP in this population, and second, to explore the risk factors for LVH.

| Study design and participants
In this cross-sectional study, we reviewed the medical records of the

| Echocardiography
All echocardiographic examinations were performed by trained ultrasound physicians, in accordance with the American Society of Echocardiography guidelines. 13 The left ventricular mass (LVM) was calculated using the formula: in which LVDd is the left ventricular internal dimension at end-diastole, LVPWd the left ventricular posterior wall thickness at end-diastole and IVSd the interventricular septum thickness at end-diastole. 14

| Differences between participants with and without LVH
Regarding blood pressure measurements, CSBP, CPP, BSBP, brachial pulse pressure (BPP), AIx, AIx@75, AP and PWV were all significantly elevated in patients with LVH in comparison to patients with normal LVMI (Table 2). Other variables such as the BMI, fasting blood glucose, BDBP and CDBP were not significantly different between groups.

| Correlation between LVH and blood pressure measurements
As central and brachial blood pressure increased, the incidence of LVH did so proportionately. The incidence of LVH in the highest quartile was approximately 50% higher than in the lowest quartile ( Figure 1A). Similarly, a direct relation between pulse pressure (both CPP and BPP) and LVH was noticed ( Figure 1B).
The multivariate logistic regression model was constructed using for-  Therefore, we found that BPP is not superior to CPP in the diagnosis of LVH.

| DISCUSSION
In summary, our study found that CPP has a strong association with LVH in CKD patients. LVH is a sign of subclinical organ damage, and is closely associated with an increase in cardiovascular morbidity and mortality in CKD patients. Although brachial measurement is the F I G U R E 2 Receiver operating characteristic curves for central and brachial pulse pressures for the prediction of LVH. BPP, brachial pulse pressure; CPP, central pulse pressure preferred method for assessing blood pressure due to its simplicity and universal applicability, many simple, non-invasive methods for measuring CABP are available as well. These include pulse recording through arteries (carotid artery, brachial artery and radial artery), pulse acquisition technology (pressure measurement and echo tracking), pulse wave calibration, and mathematical analysis (transfer function and wave analysis). 17,18 Due to the pulse wave amplification effect, the peripheral arterial pressure is always greater than the corresponding aortic pressure. However, these are not strictly and proportionately related, so a normal peripheral arterial blood pressure can coexist with an increased CABP. It has been found that the latter is more closely related to LVH pathophysiology than peripheral blood pressure. 19 Although non-invasive CABP measurement is widely used to predict cardiovascular outcomes in patients with coronary heart disease and hypertension, few studies including CKD patients were available to date. 20  Because the lower the eGFR of the patient, the worse the kidney function, the greater the risk of cardiovascular death. Therefore, we believe that the cardiovascular accidents of these patients deserve our attention.
We found that after adjusting for confounding factors, CPP remained independently associated with LVH (OR = 5.597, 95%CI: 2.363-13.259, p < .001). Clinical studies have shown that pulse pressure is an independent predictor of cardiovascular and all-cause mortality in the general population 24,25 and in patients with CKD. 26,27 CABP pressure wave includes two parts: a forward wave produced by ventricular ejection and a reflected wave resulting from peripheral blood vessels stiffness. When the pressure wave travels from the elastic aorta to a hardened brachial artery, the upper part of the pressure wave becomes narrower, the systolic peak becomes more prominent, the systolic and pulse pressure increases, and the left ventricular afterload raises. This process leads to LVH, left ventricular diastolic dysfunction and impaired coronary perfusion. 28 As the diameter of peripheral arteries decreases progressively, the stiffness increases; this changes the sum of wave reflections at specific points in the arterial tree, leading to an augmentation of pulse pressure and making the CPP lower than the BPP.
Anaemia is a common clinical manifestation of CKD, mainly due to insufficient secretion of erythropoietin. Previous studies have shown that long-term flow/volume overload can lead to increased cardiac work in patients with chronic anaemia, leading to progressive heart enlargement and LVH. 29 Decreased Hb levels trigger left ventricular remodelling and increase ejection fraction and peak oxygen consumption in exercise tests. 30 Park et al. 31 found that a decrease in Hb was significantly associated to LVH; this association was also present in non-anaemic participants. Their conclusions are consistent with the conclusions of our research.
Finally, some studies have reported that elevated serum phosphate levels are independently associated with LVH and an increased risk of CVD in CKD patients. 32 This is consistent with our conclusion.
Elevated phosphate levels may stimulate the transformation of vascular smooth muscle cells into cells with an osteoblast phenotype, increase intracellular calcium levels and induce arterial calcification. 33,34 Furthermore, hyperphosphatemia can increase the levels of circulating fibroblast growth factor-23, which may contribute to the development of LVH. 33,34 All in all, our research confirmed that CABP and BABP are strongly related to LVH in patients with CKD. Furthermore, we have found that CPP may be a better predictor of LVH than BPP in this CKD population. Anaemia and high levels of serum phosphate could lead to the development of LVH in CKD patients.
Our research has some limitations. First, our study is a single-centre, cross-sectional observational study, and a causal relationship between blood pressure and clinical outcomes cannot be proven.
Despite this limitation, our study is the first to propose a relation between CPP and LVH in CKD patients; future prospective cohort studies addressing the same clinical problem may confirm our results.
Second, as we restricted our analysis to patients with CKD, our results cannot be generalized to other populations. Finally, in our study, half of the subjects received antihypertensive drugs which may affect CABP measurements. Although we adjusted our analysis for the usage of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, calcium channel blockers and β-blockers, the effect of antihypertensive therapy on CABP deserves further investigation.

| CONCLUSION
In summary, our study found that an increased CPP and phosphate levels, and decreased haemoglobin levels are independent risk factors for LVH in CKD patients. In this population, the measurement of CPP may be more valuable than BPP for assessing the risk of LVH. Furthermore, in light of the current evidence, we speculate that CABP measurement in CKD patients might prove to be advantageous over BABP in terms of predicting hard outcomes such as CVD and mortality, and we make a call for further research in this area. Finally, proper treatment of elevated CPP and optimization of phosphate and haemoglobin levels may minimize the risk of LVH in CKD patients.