The moderating effect of fluid overload on the relationship between the augmentation index and left ventricular diastolic function in patients with CKD – Scientific Reports

The LVDD in pre-dialysis patients with CKD is associated with poor cardiovascular outcomes and increased all-cause mortality rates19,20. Among the known risk factors for LVDD, we evaluated the impact of the relationship between vascular stiffness and fluid overload on LVDD in patients with advanced-stage CKD21. The factors that are more strongly associated with LVDD may vary depending on the stages of CKD; however, vascular stiffness and fluid overload have been reported as significantly associated with the development of LVDD as kidney function declines.

CKD has been proposed as a model of early vascular aging since it is associated with arterial stiffness; this plays a role in the development of cardiovascular disease (CVD)22,23. In CKD, multifactorial pathophysiological mechanisms contribute to arterial remodeling and premature vascular aging, ultimately resulting in arterial hardening. Vascular calcification, especially as a part of CKD-MBD in patients with CKD or ESRD, is recognized as one of the main factors contributing to vascular stiffening24. The augmentation index (AIx), which represents the functional status of the central and peripheral arteries, is reported to be an independent predictor of all-cause and cardiovascular mortality in patients with ESRD14. This study evaluated vascular stiffness using rAIx75 derived from pressure waveform analysis.

Notably, several studies have investigated whether the association between arterial stiffness and echocardiographic markers of LVDD was significant in patients with various diseases and in the general population12,16,25,26. However, studies targeting patients with CKD are rare. Declining kidney function induces structural and functional vascular changes, significantly affecting central and peripheral hemodynamics. In CKD, uncontrolled fluid overload also leads to changes in the hemodynamics. Furthermore, all the factors mentioned above are ultimately associated with structural and functional changes in the myocardium. However, as mentioned earlier, there have been few attempts to analyze vascular stiffness, fluid overload, and LVDD within a single framework.

It is well known that arterial stiffening increases with advancing age27. With aging or in diseases, such as CKD, that promote vascular calcification and arterial stiffness, the central arteries become stiff earlier than the brachial arteries; this results in a larger forward wave amplitude, earlier arrival of reflected waves, and increased pulse pressure28. Consequently, cPP increases more and earlier than peripheral pulse pressure. That is why we used central blood pressure only as a covariate and not peripheral blood pressure. Besides age, several clinical factors have been reported as risk factors for vascular stiffening. In our study, other known risk factors were also as covariates. Factors associated with the occurrence of CKD-MBD and vascular calcification, such as vitamin D3, high-sensitivity C-reactive protein, and intact parathyroid hormone, showed no statistical significance in t-tests and Pearson correlations. Additionally, they did not yield statistical significance in stepwise linear regression analyses aimed at identifying potential determinants of LV diastolic function. As a result, these factors were not employed as covariates in our study.

In the general population, left ventricular hypertrophy (LVH) has been reported as one of the pathogenetic mechanisms of LVDD. In patients with CKD, both LVDD and LVH are common and closely related29. Although it remains unclear whether cardiac structural changes precede functional changes in CKD or vice versa, LVMI was also included as one of the confounders in this analysis. In patients with diabetes, structural and functional alterations occur in the cardiac tissue, leading to impaired LV diastolic function. Therefore, diabetes is independently associated with impaired LV diastolic function6. Furthermore, arterial stiffness and fluid imbalance contribute to LVDD in patients with diabetes and CKD17,25. Herein, diabetes was used as a covariate for all patients, and the differences in the interaction effect between the presence or absence of diabetes were investigated as a subgroup analysis.

Vascular stiffening associated with aging exhibits sexual dimorphism, with young women having lower stiffness than age-matched men. However, this sex difference reverses during normal aging30. Notably, numerous studies have previously reported the sex differences in the arterial changes associated with vascular stiffness15,31. Investigations have also explored the sex-specific association between arterial stiffness and LVDD, showing a significant correlation between LVDD and an arterial stiffness biomarker in women but not in men26. Sex-specific differences in long-term outcomes of HFpEF were observed, with ventricular-vascular stiffening being significant in women and heart rate playing a significant role in men32. These findings suggested that higher arterial stiffness in women may increase their susceptibility to developing HFpEF4,16. Patients with HFpEF and fluid overload generally experience worse prognoses than those with normal fluid volume33. Increased vascular stiffness and fluid overload may have coincidentally occurred together due to the nature of CKD, however, there are few studies simultaneously evaluating the interaction with the LVDD biomarker. In this study, we observed that rAIx75 and OH/ECW each had a positive correlation with the E/e´ ratio. Furthermore, a significant interaction between rAIx75 and OH/ECW was identified across all the patient groups. The positive B-coefficient for the interaction term, which was evident in all the patients, women, and the diabetes subgroup, indicated a tendency for the E/e´ ratio to increase gradually with elevated vascular stiffness and higher OH/ECW values. Interestingly, the results suggested a gradual deterioration of the diastolic function as arterial stiffness rises and fluid overload increases, which was particularly notable in women. The factor causing the differences between men and women does not appear to be fluid overload, but rather seems to be influenced by differences in vascular stiffness. Subsequently, we also consider that there is a difference in the interaction effect of OH/ECW. Additionally, the interaction between rAIx75 and OH/ECW remained marginally significant in the diabetes group after covariate correction, but not in the non-diabetic group. Our study suggested a potential vulnerability to the occurrence of LVDD or HFpEF, particularly in postmenopausal or elderly women with advanced-stage CKD. However, given that our study primarily comprised older women, conducting an analysis that stratifies between menstruating and postmenopausal women could potentially yield different results.

This study has several limitations. First, it should be noted that the formal definition of LVDD involves additional echocardiographic measurements beyond the E/e´ ratio34. However, in line with previous studies, a simplified and modified definition of LVDD (specifically, E/e´ ratio > 15) was used in this study. Second, the rAIx75 was employed as an indicator to assess arterial stiffness, whereas the aortic AIx was omitted. However, the rAIx75 demonstrated a robust correlation with aortic AIx35. Third, we did not simultaneously assess the severity of vascular calcification, which is directly and closely associated with aortic stiffness, using other evaluation methods, such as quantitative computerized tomography. Moreover, while sex-specific risk factors, including hormonal changes, have been suggested to contribute to the susceptibility to the development of LVDD and subsequent heart failure36, we did not assess the role of hormone variations. Therefore, at this point, generalizing our results to other early-stage patients, especially young women, is limited. Despite these limitations, the strengths of our study include that we conducted our study on a relatively homogenous group of patients with CKD5, based on the estimated glomerular filtration rate. Additionally, the assessment of vascular stiffness and volume status was simultaneously and objectively measured at the time of echocardiography. To the best of our knowledge, this is the first study to have attempted such analysis.

Considering these results, it is worth noting that fluid overload could be one of the aggravating factors of LVDD in patients with CKD5 who have increased arterial stiffness. It is advisable to perform simultaneous assessments of vascular stiffness, fluid balance, and LV function, particularly in the specific groups mentioned earlier (women and patients with diabetes). Therefore, implementing tailored treatment strategies targeting this risk factor may prevent cardiac structural and functional impairments. Furthermore, these findings may serve as evidence applicable to patients with chronic heart failure.