Diagnostic Potential of UCHL1 in Acute Decompensated Heart Failure

Heart failure (HF) is an important cause of morbidity and mortality among US Veterans. Epidemiologic data points to acute decompensated heart failure (ADHF) as a leading cause of hospitalizations in the VA system. The pathophysiologic mechanisms underlying the progressive deterioration of cardiac function remain poorly understood. Autophagy is an evolutionarily conserved pathway that targets cytoplasmic contents to the lysosome for degradation in the cell. In mammals, autophagy has been classified into three different types depending on the means by which the target is delivered into lysosomes for final degradation: (i) macroautophagy, (ii) microautophagy, (iii) chaperone-mediated autophagy (CMA). Both macroautophagy and CMA may participate in degradation of damage proteins; however, only macroautophagy could clear the damage organelles in the cells. Among them, macroautophagy (thereafter and other parts of this proposal referred to as autophagy) is the best characterized. It can be induced by nutrient deprivation and various stress conditions; in these circumstances, autophagy is essential for the maintenance of cell homeostasis by its promotion of the removal of damaged components including long-live and dysfunctional proteins and damaged organelles, such as mitochondria, as well as by its provision of energy and biomolecules to cells including cardiomyocytes. Thus, autophagy is increasingly recognized to play an important role in protecting the heart against various pathological stress-induced damage and dysfunction. In contrast, it has also been proposed that autophagy may be detrimental to the heart in some specific settings. However, the precise reason for such discrepancies is poorly understood. In particularly, the regulatory mechanisms for selective control of autophagy-mediated cardiac protection or dysfunction are unclear. The therapeutic approach targeting autophagy to cardiac disease and heart failure remains to be established.

An important regulatory process within the autophagy pathway is ubiquitination. Ubiquitination targets proteins for degradation. On the contrary, de-ubiquitinating proteins reverses this process. Studies have demonstrated deubiquitination to be linked to certain pathological processes, such as heart failure. Ubiquitin carboxyhydrolase L1 (UCHL1) has been identified by the co-investigator (Dr. Taixing Cui) in mouse models of pressure-overload cardiomyopathy. More data is required to identify UCHL1 as a significant marker in humans with HF.

Heart failure biomarkers play an important role in heart failure care. In general, despite significant overlaps, these biomarkers are loosely arranged into the following categories: 1) myocardial stress/injury, 2) neurohormonal activation, 3) remodeling and 4) comorbidities. None of current biomarkers alone or in combination may fulfil the need regarding screening, diagnosis, prognosis and therapy guidance. Therefore, it is important to find out novel biomarkers of cardiac disease and heart failure, especially those which reflect in important pathophysiologic pathway involved in heart failure disease process and help clinical judgement for understanding diagnosis, prognosis, or management of heart failure. As a result, the novel biomarkers will supplement traditional clinical and laboratory testing to improve understanding of the complex disease processes of heart failure and possibly achieve personalized care for heart failure patients. Human studies of circulating UCHL1 have identified it as a having diagnostic or prognostic value in this pathological settings. However, whether it is applicable to cardiovascular disease has not been studied. This gap will be filled in part by this proposal.

Aim: To explore the diagnostic and/or prognostic value of circulating exosomal UCH-L1 in VA HF patients. We will translate findings from animal models to bed side by a proof-of-principal study to demonstrate that circulating UCH-L1, particularly the exosomal UCH-L1 is higher during acute decompensation than when compensated in VA HF patients.