Cystatin C and galectin-3 as therapeutic targets in heart failure

We have carefully read the Letter to the Editor by Pérez-Calvo and colleagues, regarding our article ‘Left atrial volume index in patients with heart failure and severely impaired left ventricular systolic function: the role of established echocardiographic parameters, circulating cystatin C and galectin-3’ and we thank the authors for offering important issues for further discussion.¹ The authors strongly disagree with our proposal that cystatin C (CysC) and galectin-3 (Gal-3) may be novel therapeutic targets in heart failure (HF), as we suggest in our recent article published in the journal.² In this study we showed that left atrial volume index was correlated with mitral regurgitant volume, plasma CysC and right ventricular systolic pressure in HF with severely impaired ejection fraction (HFrEF). Moreover, CysC was positively associated with circulating Gal-3, giving new insights to heart and kidney cross-talk. This indicates that multiple processes are involved in fibrosis, as both proteins are responsible for extracellular matrix (ECM) modulation.^3,4

In in vivo models of HF, CysC is produced in the ischaemic area of the myocardium and contributes to cardiac fibroblast-mediated accumulation of ECM proteins, such as collagen I/III and fibronectin, through inhibition of cathepsin B (CTSB).³ Elevated levels of CysC have been found not only in HFrEF, but also in HF with preserved ejection fraction, independently of renal function, for which CysC is a robust biomarker.^5–7 Inhibition of CTSB in an animal model of myocardial infarction improved systolic function, and reduced cardiomyocyte hypertrophy and fibrosis.⁸ Moreover, knockout and inhibition of CTSB attenuate myocardial hypertrophy, fibrosis and cardiomyocyte apoptosis caused by pressure overload.⁹ In a recent study, inhibition of CysC in hypertensive rats protected against cardiac hypertrophy.¹⁰ Thus, CTSB and CysC have been proposed as therapeutic targets in HF in these studies. Accordingly, we maintain that possible interactions of CysC and ECM should be further studied.

Similarly, knockout or pharmacological inhibition of Gal-3 reduced myocardial fibrogenesis and remodelling, and prevented progression to HF in a rat and two murine models.¹¹ Furthermore, a recent study has demonstrated that angiotensin II mediates myocardial inflammation, fibrosis and impairment through Gal-3.¹² Genetic deletion of Gal-3 in this study prevented myocardial fibrosis and preserved systolic function. Despite some discrepancies in the thoracic aortic constriction model, mainly attributed to differences in sex and experimental settings, the role of Gal-3 as mediator of cardiac dysfunction and remodelling has been pointed out in many experimental models, including that of myocarditis and pulmonary hypertension-induced right ventricular remodelling.^13–17 Moreover, the importance of circulating Gal-3 levels in identifying risk of all-cause mortality, cardiovascular mortality and HF has also been repeatedly demonstrated and recently supported by a large-scale meta-analysis.¹⁸ Based on all the above, Gal-3 has been fairly characterized as a biomarker and a biotarget in HF.^4,19 Last but not least, Gal-3 is not a good surrogate of kidney function, but is probably a causal factor for renal impairment.²⁰ This however warrants further research.

HF is a major public health issue, whose prevalence is expected to rise due to the aging of the population and improvement in treatment of coronary artery disease.²¹ Nevertheless, pharmacological improvements in HF treatment have come to a standstill in the last few years. To this end, inflammation and fibrosis are two significant processes in HF to which new therapeutic strategies should be addressed.²²