Klotho as a biomarker for coronary microvascular disease

Klotho was initially recognized as an anti-aging protein, with animal models of klotho-deficiency showing a progeria phenotype. Klotho is mainly produced by the healthy kidney, as a transmembrane protein that can be cleaved from the membrane into a soluble form (sKlotho), and is reduced in patients with chronic kidney disease(1). Both membrane bound and soluble Klotho exert their effects by acting as co-receptors for FGF receptors, thereby modulating their signalling function, particularly when activated by FGF23 (2). In the heart, FGF23 in the absence of sKlotho, induces a variety of processes, including endothelial dysfunction, cardiomyocytes hypertrophy and increased interstitial fibrosis (2). Indeed, lower sKlotho levels are associated with a variety of cardiovascular diseases including hypertension, atherosclerosis, atrial fibrillation and heart failure (3). Furthermore, lower circulating α-Klotho levels are associated with a reduced coronary flow reserve in healthy individuals(4).

A recently published study (5), therefore investigated whether lower sKlotho levels were associated with coronary microvascular dysfunction (CMD) in patients undergoing invasive coronary function testing to assess  the cause of angina pectoris and compared patients with and without CMD, matched for conventional risk factors. Even in the absence of kidney disease, sKlotho was lower in patients with CMD as compared to no-CMD, and the odds of low sKlotho in CMD was significant in a logistic regression model after adjusting for cardiovascular risk factors as well as BUN, as a marker for kidney disease. The correlation of low sKlotho with CMD remained present when only patients with low risk for cardiovascular disease (based on tradtional risk factors) were included in the analysis, suggesting that sKlotho can serve as a novel biomarker in this population.

As endothelial cells were shown to produce NO in the presence of sKlotho, and reactive oxygen species in its absence (2), reductions in sKlotho may not only serve as a biomarker, but may also be causal in development/ progression of CMD. Intriguingly, sKlotho levels also correlated with circulating endothelial progenitor cells (EPCs) with vascular repair properties. Given the observation that EPCs lose their reparative properties in the absence of Klotho, this is an interesting observation, that may hamper endogenous microvascular repair mechanisms, and further contribute to aggravate CMD.

Thus, future studies should include sKlotho as a determinant of coronary microvascular function and further identify the causal contribution of loss of sKlotho into progression of CMD.