Azerbaijan National Academy of Sciences

Heart muscle growth, commonly referred to as cardiac hypertrophy, is a compensatory response that matches organ size to the systemic demands of the body. Hypertrophy can be a detrimental or beneficial adaptation, depending on the type of growth that occurs. In pathologic hypertrophy, heart muscle mass increases (wall thickness) without a corresponding improvement in function. Pathologic hypertrophy is generally irreversible and readily transitions to heart failure (HF), making this maladaptive process a leading cause of morbidity and mortality1. Given the prominence in disease etiology, the biochemical and molecular characteristics of pathologic hypertrophy have been intensely studied and documented2,3.

Physiologic cardiac hypertrophy is a form of beneficial remodeling, characterized by a modest increase in heart mass with improved contractile function that is reversible. Both pregnancy and endurance exercise provide well-documented means to engage this form of organ growth, a response that can also directly antagonize pathologic hypertrophy and the progression to HF4,5. Akt- and MAPK-mediated signaling cascades appear to be consistent molecular signatures of physiologic hypertrophy, yet there is a paucity of definitive information regarding systemic factors that may initiate or propagate this healthy remodeling event6,7,8,9,10. Insulin-like growth factor has been examined as a probable physiologic hypertrophy agonist11,12,13, yet the pleiotrophic effects of this hormone may preclude its use as a bona fide cardiac restoration agent.

Cardiotrophin 1 (CT1) was originally identified as a promising hypertrophic agonist in vitro14,15, however its expression has been more recently linked to myocardial pathology, systemic elevated blood pressure, and cardiac failure in both animals and humans16,17,18,19. Despite these observational data implicating CT1 in certain cardiovascular diseases, this cytokine is known to bind and engage gp130 receptor complexes, a known pro-survival signal for cardiomyocytes20,21,22. Therefore, we reasoned that elevated expression of CT1 in human cardiac pathologies may simply reflect a compensatory response, which attempts to curtail disease progression through the biologic remodeling activity of CT1.

Here, we demonstrate that human CT1 protein (hCT1) engages a fully reversible form of myocardial growth, and that hCT1 attenuates the ongoing pathology and loss-of-function in an aggressive and unremitting model of right heart failure (RHF). hCT1 promotes cardiomyocyte growth in part by inducing a limited activation of an otherwise pathologic hypertrophy signal, as mediated by the caspase 3 protease. In addition, hCT1 engages a cardiomyocyte-derived vascular growth signal to ensure that the modest heart muscle growth is temporally matched with a supporting angiogenic response. Moreover, 2 weeks administration of hCT1 in vivo produced cardiac remodeling that was similar to that induced by exercise and, in a model of progressive RHF due to severe pulmonary arterial hypertension, improved cardiac function and reversed right ventricle (RV) dilatation. These data suggest that hCT1 fulfills the criteria as a beneficial remodeling agent, with a capacity to curtail or limit an intractable form of HF.