Dr. Thomas Netticadan
Heart Failure Research Laboratory, Canadian Centre for Agri-food Research in Health and Medicine
Department of Physiology, University of Manitoba
Does size really matter ?? Is bigger better or worse ??
Heart failure is the leading cause of death in humans in North America and most other parts of the world. The development of heart failure can be secondary to diseases such as hypertension, ischemic heart disease, valvular heart disease, congenital heart disease, cardiomyopathy (due to diabetes or of genetic origin) or myocarditis. Irrespective of the primary cause, the heart counters this stress by a compensatory response termed as cardiac hypertrophy. Cardiac hypertrophy is the increase in heart size and may be beneficial to the stressed heart in the initial stages, however, sustained hypertrophy is detrimental and is responsible for the enlarged heart to fail (heart failure). Hypertrophy could arise due to (a) pressure overload and/or (b) volume overload. Pressure overload is known to occur in clinical situations such as hypertension and valvular heart disease (as in aortic valve stenosis) while volume overload occurs in valvular heart disease (as in mitral valve regurgitation), congenital heart disease as well as anemia. Both types of overloads also occur in ischemic heart disease.
An important goal of our laboratory is to understand the cellular mechanisms leading to heart failure. For this purpose we have developed and characterized experimental models mimicking situations of pressure and/or volume overload. These models include aortic banding in rats to induce pressure overload, aortocaval shunt in rats to create volume overload, and, coronary artery ligation in rats to create a combination of volume and pressure overloads. Our studies aim to elucidate the cellular mechanisms underlying the development and progression of cardiac hypertrophy induced by pressure or volume or a combination of both overloads. It will also lead to the identification of potential therapeutic targets.
Size-limiting with nutraceuticals
Current pharmacological treatments available for treating heart failure in humans are aimed at preventing cardiac hypertrophy by blocking the activation of prohypertrophic pathways. Blockade of the renin – angiotensin system or the beta-adrenergic signaling cascade have met with some degree of success, however, death due to hypertrophy and resultant heart failure in humans throughout the world is on the rise. Thus, it is of paramount importance to devise new strategies to prevent cardiac hypertrophy. In this regard, our laboratory is exploring the potential of nutraceuticals (compounds derived from foods) as antihypertrophic agents. We have recently discovered that resveratrol, an antioxidant found in grapes, completely prevented the progression of cardiac hypertrophy induced by pressure overload in rats – this was in part achieved via induction of nitric oxide synthases (enzymes which catalyze the production of nitric oxide) potent antihypertrophic molecules. We are also studying the effects of other nutraceuticals in (1) preventing the development of cardiac hypertrophy due to pressure or volume overload or a mixture of pressure and volume overload as well as (2) inhibiting the progression of cardiac hypertrophy. Our research will establish a potential role for nutraceuticals as agents in the treatment of cardiac hypertrophy and heart failure arising due to different diseases.
- Cantor EJ, Babick AP, Vasanji Z, Dhalla NS, Netticadan T. A comparative serial echocardiographic analysis of cardiac structure and function in rats subjected to pressure or volume overload. Journal of Molecular and Cellular Cardiology. 2005 May;38(5):777-786.
- Babick AP, Cantor EJ, Babick JT, Takeda N, Dhalla NS, Netticadan T. Cardiac contractile dysfunction in J2N-k cardiomyopathic hamsters is associated with impaired SR function and regulation. American Journal of Physiology (Cell Physiology). 2004 Nov;287(5):C1202-8.
- Singh RB, Chohan PK, Dhalla NS, Netticadan T. The sarcoplasmic reticulum proteins are targets for calpain action in the ischemic-reperfused heart. Journal of Molecular and Cellular Cardiology. 2004 Jul;37(1):101-10.
- Netticadan T, Temsah RM, Kent A, Elimban V, Dhalla NS. Depressed levels of Ca2+-cycling proteins may underlie sarcoplasmic reticulum dysfunction in the diabetic heart. Diabetes. 2001 Sep;50(9):2133-2138.
- protein kinase is altered in heart failure. Circulation Research. 2000 Mar 17;86(5):596-605.
For more information, please contact:
Dr. Thomas Netticadan
1. Movahed A, Yu L, Thandapilly SJ, Louis XL, Netticadan T. Resevratrol protects adult cardiomyocytes against oxidative stress mediated cell injury. Archives of Biochemistry and Biophysics 2012 May 23. [Epub ahead of print].
2. Louis XL, Thandapilly SJ, Mohankumar SK, Yu L, Taylor CG, Zahradka P, Netticadan T. Treatment with low-dose resveratrol reverses cardiac impairment in obese prone but not in obese resistant rats. Journal of Nutritional Biochemistry 2011 Nov 30. [Epub ahead of print].
3. Thandapilly SJ, Louis XL, Yang T, Stringer DM, Yu L, Zhang S, Wigle J, Kardami E, Zahradka P, Taylor C, Anderson HD, Netticadan T. Resveratrol prevents norepinephrine induced hypertrophy in adult cardiomyocytes, by activating NO-AMPK pathway. European Journal of Pharmacology 2011;668(1-2):217-224
4. Juric D, Yao X, Thandapilly S, Louis X, Cantor E, Chaze B, Wojciechowski P, Vasanji Z, Yang T, Wigle J, Netticadan T. Defects in ryanodine receptor are associated with systolic dysfunction in rats subjected to volume overload. Experimental Physiology 2010;95(8):869-879.
5. Wojciechowski P, Juric D, Louis XL, Thandapilly SJ, Yu L, Taylor C, Netticadan T. Resveratrol arrests and regresses the development of pressure overload but not volume overload induced cardiac hypertrophy in rats. Journal of Nutrition 2010;140(5):962-968.
6. Thandapilly SJ, Wojciechowski P, Behbahani J, Louis XL, Yu L, Juric D, Kopilas MA, Anderson HD, Netticadan T. Resveratrol attenuates cardiac hypertrophy and contractile dysfunction in spontaneously hypertensive rats without lowering blood pressure. American Journal of Hypertension 2010;23(2):192-196.
7. Juric D, Wojciechowski P, Das DK, Netticadan T. Prevention of cardiac hypertrophy and diastolic impairment in aortic banded rats treated with resveratrol. American Journal of Physiology 2007;292(5):H2138-H143.
Natural Sciences and Engineering Research Council – Hormonal mechanisms of gene regulation
Canadian Institutes of Health Research RPP – Modulation of vascular smooth muscle cell phenotype by angiotensin II
Agri-food Research Development Initiative (ARDI) – Effects of CLA isomers on reduction of insulin resistance (Awarded to C.G. Taylor and P. Zahradka)
Natural Sciences and Engineering Research Council – Strategic Grant – Evaluation of insulin-mimetic components of buckwheat (Awarded to C.G. Taylor, P. Zahradka and L. Murphy)
Pulse Canada – Pulse crops improve CV health by promoting adiopkine (Awarded to P. Zahradka, C.G. Taylor and R. Guzman)
Dairy Producers of Canada – Mechanism for modulation of insulin action and obesity by CLA (Awarded to C.G. Taylor and P. Zahradka)
Summer Student Support