Plasma indoxyl sulfate levels predict cardiovascular events in patients with mild chronic heart failure

Miki Imazu,Makoto Amaki,Hiroki Fukuda,Toshisuke Morita,Shin Ito,Masafumi Kitakaze,Takuya Hasegawa,Hideaki Kanzaki,Osamu Tsukamoto,Hiroyuki Takahama,Tatsuro Hitsumoto

doi:10.1038/s41598-020-73633-9

Abstract

Indoxyl sulfate (IS) is associated with either chronic kidney disease or renal failure, which may predict cardiovascular events via cardiorenal syndrome. The present study aimed to elucidate whether the plasma levels of IS can predict the occurrence of cardiovascular events in patients with chronic heart failure (CHF) and investigate which causes of CHF leading to cardiovascular events are highly influenced by plasma IS levels. We measured the plasma IS levels in 165 patients with CHF [valvular disease: 78, dilated cardiomyopathy: 29, hypertrophic cardiomyopathy (HCM): 25 and others: 33] admitted to our hospital in 2012, and we followed up these patients for more than 5 years (the median follow-up period: 5.3 years). We measured the plasma IS level in 165 patients with CHF, and Kaplan–Meier analyses showed that high plasma IS levels (≥ 0.79 µg/mL, the median value) could predict the occurrence of cardiovascular events, i.e., cardiovascular death or rehospitalization due to the worsening of CHF. The sub-analyses showed that the high IS level could predict cardiovascular events in patients with CHF due to HCM and that the plasma IS levels were closely associated with left ventricular (LV) dimension, LV systolic dysfunction, and plasma B-type natriuretic peptide levels, rather than LV diastolic dysfunction. Plasma IS level predicts cardiovascular events in patients with CHF, especially those with HCM along with cardiac dysfunction. Besides, IS may become a proper biomarker to predict cardiovascular events in patients with CHF.

Highlights

Indoxyl sulfate (IS) is associated with either chronic kidney disease or renal failure, which may predict cardiovascular events via cardiorenal syndrome
The major findings of this study were as follows: (1) the plasma IS levels in the patients with chronic heart failure (CHF) predicted the cardiovascular events of either cardiovascular death or rehospitalization due to the worsening of HF; (2) the plasma IS level appropriately predicted the cardiovascular events in patients with CHF accompanied by hypertrophic cardiomyopathy (HCM), whereas the other causes in the sub-analyses for the causes of CHF were not involved; and (3) the plasma IS level was closely associated with the left ventricular (LV) systolic function in CHF patients with HCM
It was essential to indicate whether CHF per se increases plasma IS level independent of eGFR or secondary renal dysfunction attributable to the pathophysiology of CHF may increase the plasma IS level

Summary

Introduction

Indoxyl sulfate (IS) is associated with either chronic kidney disease or renal failure, which may predict cardiovascular events via cardiorenal syndrome. We have previously reported the increase of plasma IS levels in CHF patients with preserved renal function as well as the removal of IS using AST-120, an adsorbent of uremic toxins in the gut, restoring the left ventricular (LV) systolic and diastolic function[8]. This clinical observation has been confirmed in a pacing-induced HF canine model; the plasma IS levels increase along with the progression of HF, and AST-120 improves LV d ysfunction[9]. Either of these deleterious sequelae may affect cardiomyocytes, cardiac fibroblasts, and cardiac endothelial c ells[14] and lead to cardiovascular dysfunction These results support the theory that plasma IS may become a novel biomarker for the prediction of cardiovascular events in patients with CHF. We retrospectively and consecutively enrolled patients with CHF who were hospitalized for the worsening of CHF, initial onset of acute HF (AHF), or precise examination in our hospital at 2012, and we followed up with these patients for more than 5 years

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Conclusion