Cardiac hypertrophy biomarker

PREDICTIVE CARDIAC HYPERTROPHY BIOMARKERS IN NONCLINICAL STUDIES... 

Ideally, a biomarker of cardiac hypertrophy would be predictive, that is, its concentration in serum or plasma would be altered in advance of eventual increases in heart weight, and specific for the heart in both humans and animals commonly used in safety assessment. This would allow early detection of cardiac risk in short-duration toxicology studies (e.g., l days), serial monitoring in longer-duration toxicology studies, or pharmacology studies in order to enable the prediction of cardiac hypertrophy liabilities in humans. In practice, biomarkers are not always specific for a certain organ or... 

Matrix metalloproteinases (MMP), tissue inhibitors of metalloproteinase (TMP), and collagen propeptides (PIIINP) are also indicative of remodeling that occurs during cardiac hypertrophy, but are also nonspecific and consistent with more advanced hypertrophy than occurs in short-duration animal studies. A panel consisting of MMP-7, MMP-9, TIMP-1, PIIINP, and NTproBNP has shown promise in predicting the presence of cardiac hypertrophy in humans with hypertension and may prove useful in animal studies however, further research is needed (Zile et al., 2011). Osteoprotegerin (OPG), a member of the TNF receptor superfamily, has shown promise as a biomarker of cardiac hypertrophy however, little is known regarding the utihty of OPG in the context of nonclinical safety studies (Coutinho et al., 2011 Koyama et al., 2014). 

Numerous neuroendocrine biomarkers correlate with severity of cardiac dysfunction. Heart failure is associated with increase in peripheral vascular resistance due to increases in sympathetic tone, norepinephrine, renin, angiotensin II, arginine vasopressin, and endothelin-1. The increased venous pressure causes atrial distension that stimulates production and release of atrial and brain natriuretic peptides (ANP, BNP) from the atria and ventricles, respectively. ANP inhibits the renin-angiotensin-aldosterone system. In humans and mammals, BNP has been found to be an early biomarker of left ventricular hypertrophy developing with doxorubicin cardiotoxicity, congestive heart failure, or occult dilated cardiomyopathy (Erkus et al. 2006 Walker 2006 Oyama, Sisson, and Solter 2007). 

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