Cardiac Mechanics Laboratory

Key Research Areas

• Cardiomyopathy
• Congenital Heart disease
• Ischemic heart disease

Research Overview

For over a decade researchers in the Cardiac Mechanics Laboratory directed by Prof Michael Feneley have studied how heart cells grow in disease and how effectively the heart contracts and relaxes under these conditions. The team is trying to understand the genetic and biochemical processes of cardiac hypertrophy. Cardiac hypertrophy happens naturally in pregnancy and with exercise, but untreated abnormal enlargement of the heart muscle often leads to heart failure. Chronic high blood pressure is the most common factor leading to cardiac hypertrophy and is due to lifestyle, diet, genetics or interplay between these.

Professor Chris Hayward will be working closely with Prof Feneley in the laboratory with a focus on mechanical heart assist devices. Heart failure often results in heart transplantation and assist devices maybe used in that setting. Heart failure has an enormous social cost and the economic burden on our healthcare system is substantial as patients often suffer an increasing number of illnesses and need rising rates of hospital care.

The Cardiovascular Mechanics Program includes a small animal physiology core laboratory, and a clinical research program. There are 4 key projects underway in the Cardiac Mechanics Laboratory, led by Professor Michael Feneley;

1. The biochemical pathways that lead to pathological growth of heart muscle (hypertrophy) are not yet fully understood. We are investigating a key molecule calcineurin and how its activation plays a role in the induction of left ventricular hypertrophy in response to long term high blood pressure, but only when kidney function is abnormal causing the renin-angiotensin system to be activated.
2. With Prof Boris Martinac several studies are being undertaken examining hypertrophy when the renin system is normal, but blood pressure is high. This is the most common cause of hypertension and is often caused by constrictions in major blood vessels due to age related hardening of the artery walls or atherosclerosis. The focus of this research is the connection between mechanical stretch receptors found on the surface of heart cells and the triggering of the biochemical and genetic cascade leading to hypertrophy. Several candidate receptors including TRPC’s, TRPM’s and most recently Peizo are being characterised in various models of human condition which lead to hypertrophy.
3. In a collaborative study with Diane Fatkin, zebrafish hearts are genetically modified to have copies of human mutations known to cause heart disease. Her focus is on Titin, a very large protein that is integral to the contractile apparatus of heart cells. Accurate measurements to confirm the disease in such tiny hearts (less than 5mm) while beating in anaesthetised fish has been made possible following the establishment of methods using high frequency ultrasound by Dr Louis Wang. He completed his PhD in the Institute under Diane and Michael’s supervision.
4. Determining the existence and role of an adrenergic receptor (AR), the a1D-AR receptor in the muscle cells of the heart previously thought not to be present. Whole heart work so far indicates its existence and an interaction with another AR the b2, which is targeted by many hypertension drugs due to its dominant role in controlling blood pressure.

Laboratory Members

Scott Kesteven, Senior Research Officer

A/Prof Mayooran Namasivayam, Clinician Scientist

1. Modified N-linked glycosylation status predicts trafficking defective human Piezo1 channel mutations. Li JV, Ng CA, Cheng D, Zhou Z, Yao M, Guo Y, Yu ZY, Ramaswamy Y, Ju LA, Kuchel PW, Feneley MP, Fatkin D, Cox CD. Commun Biol. 2021 Sep 6;4(1):1038.
2. Ventricular-Vascular Coupling Ratio Is the Ejection Fraction in Disguise. Namasivayam M, Hayward CS, Muller DWM, Jabbour A, Feneley MP. J Am Soc Echocardiogr. 2019 Jun;32(6):791.
3. The Ca2+-activated cation channel TRPM4 is a positive regulator of pressure overload-induced cardiac hypertrophy. Guo Y, Yu ZY, Wu J, Gong H, Kesteven S, Iismaa SE, Chan AY, Holman S, Pinto S, Pironet A, Cox CD, Graham RM, Vennekens R, Feneley MP, Martinac B. Elife. 2021 Jun 30;10:e66582.
4. Cardiac Gq Receptors and Calcineurin Activation Are Not Required for the Hypertrophic Response to Mechanical Left Ventricular Pressure Overload. Yu ZY, Gong H, Wu J, Dai Y, Kesteven SH, Fatkin D, Martinac B, Graham RM, Feneley MP. Front Cell Dev Biol. 2021 Feb 15;9:639509.
5. Pressure overload by suprarenal aortic constriction in mice leads to left ventricular hypertrophy without c-Kit expression in cardiomyocytes. Nicks AM, Kesteven SH, Li M, Wu J, Chan AY, Naqvi N, Husain A, Feneley MP, Smith NJ, Iismaa SE, Graham RM. Sci Rep. 2020 Sep 18;10(1):15318.
6. A-Band Titin Truncation in Zebrafish Causes Dilated Cardiomyopathy and Hemodynamic Stress Intolerance. Huttner IG, Wang LW, Santiago CF, Horvat C, Johnson R, Cheng D, von Frieling-Salewsky M, Hillcoat K, Bemand TJ, Trivedi G, Braet F, Hesselson D, Alford K, Hayward CS, Seidman JG, Seidman CE, Feneley MP, Linke WA, Fatkin D. Circ Genom Precis Med. 2018 Aug;11(8):e002135.
7. High-Frequency Echocardiography - Transformative Clinical and Research Applications in Humans, Mice, and Zebrafish. Wang LW, Kesteven SH, Huttner IG, Feneley MP, Fatkin D. Circ J. 2018 Feb 23;82(3):620-628.
8. Endocardial TRPC-6 Channels Act as Atrial Mechanosensors and Load-Dependent Modulators of Endocardial/Myocardial Cross-Talk. Nikolova-Krstevski V, Wagner S, Yu ZY, Cox CD, Cvetkovska J, Hill AP, Huttner IG, Benson V, Werdich AA, MacRae C, Feneley MP, Friedrich O, Martinac B, Fatkin D. JACC Basic Transl Sci. 2017 Oct 30;2(5):575-590.
9. Cardiac hypertrophy limits infarct expansion after myocardial infarction in mice. Iismaa SE, Li M, Kesteven S, Wu J, Chan AY, Holman SR, Calvert JW, Haq AU, Nicks AM, Naqvi N, Husain A, Feneley MP, Graham RM. Sci Rep. 2018 Apr 17;8(1):6114.