Letter to the Editor: “Cardiometabolic Biomarkers and Their Temporal Patterns Predict Poor Outcome in Chronic Heart Failure (Bio-SHiFT Study)” Free

Although mortality from cardiovascular disease has been reduced by >60% over the past decades, heart failure (HF) represents a notable exception. A realistic explanation for such an ominous trend is the lack of a single pathophysiological paradigm of HF capable to entirely elucidate the disease progression. Indeed, the beneficial effects exerted by first-line drugs counteracting the classical neurohormonal model—rooted in overexpression of several molecular pathways (i.e., sympathetic nervous, renin-angiotensin-aldosterone, and cytokine systems)—are limited by the activation, during disease progression, of alternative escape pathways (e.g., myocardial chimases). For this reason, researchers are looking for additional pathophysiological mechanisms, with the aim of complementing the paradigm of neurohormonal hyperactivity.

In this context, growing evidence supports the hypothesis that an imbalance between catabolic and anabolic forces plays a pivotal role in HF, resulting in a multiple hormonal and metabolic deficiency syndrome (MHDS) (1). Several studies have demonstrated that MHDS is a common finding in HF (2, 3), with only few patients displaying no hormonal deficits. More important, each component of MHDS (e.g., GH/IGF-1 axes, thyroid hormones, androgens, and insulin resistance) is associated with an impairment of functional capacity and a poor outcome (4).

Taking all of this into account, the article published in the Journal of Clinical Endocrinology & Metabolism by Brankovic et al. (5) is very fascinating, providing further demonstration of the impairment of hormonal axes in HF. The authors indeed demonstrated, in a cohort of 263 patients with chronic HF from the Bio-SHiFT study, that the temporal patterns of IGF binding proteins (IGFBPs), particularly IGFBP-1, IGFBP-2, and IGFBP-7, predict adverse clinical outcomes, expressed as a composite end point of cardiac death, hospitalization for HF, cardiac transplantation, and left ventricular assist device implantation. In this population, patients who experienced the adverse end point had higher levels of the measured IGFBPs; in addition, the authors showed that not only IGFBP blood levels but also their slopes are predictors of reduced survival. Thus, because these proteins are also endowed with a bioactive role in signaling pathways, it seems reasonable to consider them not only as mere biomarkers but also as actors with a relevant role within the GH-IGF- IGFBP system. Furthermore, considering the novel evidence that GH may be safely and beneficially administered as a replacement therapy in patients with HF who have a coexisting impairment of the GH–IGF-1 axis (e.g., GH deficiency) (6), the hypothesis put forward by Brankovic et al. (5) that the IGFBP temporal pattern could in part explain the nonresponsiveness of some patients to GH treatment is thought provoking and needs further investigation.

Of note, the findings of this study are in line with previous reports, in which abnormalities of the GH–IGF-1 axis represent one of the strongest hormonal predictors of cardiovascular impairment and reduced survival in HF (2, 7).

This evidence supports the even more common theory that MHDS is not a mere epiphenomenon in HF, representing a novel and promising model of HF progression. In this scenario, definitive results will soon become available from the TOSCA (Trattamento Ormonale nello Scompenso CArdiaco: Hormone Therapy in Heart Failure) Registry, the most robust prospective observational trial on MHDS in the field of HF (8), hopefully shedding new light on the intricate relationships between hormones and HF.

Acknowledgments

Disclosure Summary: A.S. receives research grant support from Cardiopath. The remaining authors have nothing to disclose.

References