Heart failure.

With 670,000 new cases of heart failure diagnosed each year, heart failure is the fastest-growing clinical cardiac disease burden in the United States, affecting 2% of the population, accounting for 34% of cardiovascular-related deaths, and representing 1-2% (~$40 billion) of all health care expenditures [1-3]. 

Cardiac hypertrophy and heart failure. 

The progression of cardiac hypertrophy represents the principal risk factor for the development of heart failure and subsequent cardiac death [2]. Cardiac hypertrophy is classically considered to be an adaptive and compensatory response that increases the work output of cardiomyocytes and thus maintains cardiac function despite increased load. Increased resistance, created by hypertension or by the aortic constriction technique used in this study, initially compromises left ventricular (LV) function. Then subsequently the development of LV hypertrophy begins to restore systolic function, and concentric LV hypertrophy develops, which increases the LV mass. A decline in LV function accompanies LV chamber dilation and myocardial fibrosis, which results in eventual heart failure and death [7, 8]. 

TRPV1

TRPV1 (transient receptor potential cation channel, subfamily V, member 1)   is a nonselective cation channel that may be activated by a wide variety of exogenous and endogenous physical and chemical stimuli. The best-known activators of TRPV1 are capsaicin, the hot component in chili peppers, and high heat great than 43˚C. 

Chili • capsaicin

Chili • capsaicin

Progression of Heart Failure

Progression of Heart Failure

The activation of TRPV1 leads to painful, burning sensation. Its endogenous activators include: low pH (acidic conditions), the endocannabinoid anandamide, N-arachidonoyl-dopamine. TRPV1 receptors are found mainly in the nociceptive neurons of the peripheral nervous system, but they have also been described in many other tissues, including the central nervous system, and tissues of the heart, circulatory systems and immune system. Among them, cardiomyocytes, cardiac blood vessels, perivascular nerves, pulmonary artery smooth muscle cells, coronary endothelial cells, skeletal muscle, mast cells, and dendritic cells. TRPV1 it is well positioned to receive multiple stimulatory signals.

Using mice which lack functional TRPV1, we investigated the role TRPV1 plays in the progression of cardiac hypertrophy and heart failure. We show  that the TRPV1 knockout mice are protected from cardiac hypertrophy [6]. They maintain better heart function, and have less fibrosis and apoptosis in their hearts when they are artificially modeled for cardiac hypertrophy.

We were also successful in treating mice for heart failure using a TRPV1 blocker [9]. 
 

 

This project has exemplifies optimally efficient translational research, where significant in vivo biological data is combined with an existing and extensive pharmacopeia for a highly promising target, simply a path of least resistance for the development of a new therapy for hypertrophy and heart failure.  

Based on our data we have been able to generate a patent, which was awarded in July 2015, and is the basis for a new startup company -Makai Biotechnology.


References

1.Roger, V.L., et al., Heart disease and stroke statistics--2012 update: a report from the American Heart Association. Circulation, 2012. 125(1): p. e2-e220.
2.Roger, V.L., et al., Heart disease and stroke statistics--2011 update: a report from the American Heart Association. Circulation, 2011. 123(4): p. e18-e209.
3.Lloyd-Jones, D., et al., Executive summary: heart disease and stroke statistics--2010 update: a report from the American Heart Association. Circulation, 2010. 121(7): p. 948-54.
4.Valenzano, K.J., et al., N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a novel, orally effective vanilloid receptor 1 antagonist with analgesic properties: I. in vitro characterization and pharmacokinetic properties. J Pharmacol Exp Ther., 2003. 306(1): p. 377-86. Epub 2003 Apr 29.
5.Watabiki, T., et al., Amelioration of neuropathic pain by novel transient receptor potential vanilloid 1 antagonist AS1928370 in rats without hyperthermic effect. J Pharmacol Exp Ther, 2011. 336(3): p. 743-50.
6.Buckley, C.L. and A.J. Stokes, Mice lacking functional TRPV1 are protected from pressure overload cardiac hypertrophy. Channels (Austin), 2011. 5(4): p. 367-74.
7.Patten, R.D. and M.R. Hall-Porter, Small animal models of heart failure: development of novel therapies, past and present. Circ Heart Fail, 2009. 2(2): p. 138-44.
8.Lygate, C., Surgical models of hypertrophy and heart failure: Myocardial infarction and transverse aortic constriction. Drug Discovery Today: Disease Models, 2006. 3(3): p. 283-290.
9    Horton, J. S., Buckley, C. L. & Stokes, A. J. Successful TRPV1 antagonist treatment for cardiac hypertrophy and heart failure in mice. Channels (Austin, Tex.) 7, 17-22, doi:10.4161/chan.23006 (2013)