"I get a real buzz from collaborating
with other research organisations & 
seeing the results from clinical trials,"

- Professor Livia Hool

Professor Livia Hool

Head, Cardiovascular Electrophysiology Laboratory

Research Overview

Key Research Areas

  • Understanding sudden cardiac death during the “fight or flight” response
  • Mechanisms of mitochondrial dysfunction in the familial hypertrophic heart
  • Mechanisms of sudden cardiac death in familial hypertrophic cardiomyopathy
  • Preventing heart failure associated with muscular dystrophy 

Research Overview

Based in Western Australia, the Cardiovascular Electrophysiology Laboratory led by Professor Livia Hool, is concerned with understanding how alterations in calcium and energetics in the heart lead to sudden cardiac death and heart failure. The  main way that calcium moves into heart muscle cells is via a unique channel. The channel is essential to life and controls excitation and contraction in the heart. Scientists in this laboratory are currently designing and optimising treatments to help people suffering from ischemic and hypertrophic cardiomyopathy, as well as heart failure associated with muscular dystrophy.

Muscular dystrophy is a fatal muscle wasting disorder affecting 1 in 3,500 boys. The boys show signs of weakness as infants and are restricted to a wheelchair by the age of 12. Researchers in the Cardiovascular Electrophysiology Laboratory have collaborated with scientists from Murdoch University, to develop a drug therapy to help young boys suffering from muscular dystrophy. The drug was administered to a wheelchair-bound ten year old in the United States as part of a clinical trial and as a result of the therapy the boy was able to run in the Boston Children’s Marathon in June 2014.

research projects

There are 5 key projects underway in the Cardiovascular Electrophysiology Laboratory, based in Western Australia;

 1. Identifying the molecular mechanism for activation of the L-type Ca2+ channel during the “fight or flight” response

 Acute alterations in function of the L-type Ca2+ channel lead to sudden cardiac death. Chronic increases in function of the channel lead to the development of cardiac hypertrophy and failure. Sympathetic stimulation increases calcium influx through the L-type Ca2+ channel as a result of phosphorylation of the channel by PKA and is absolutely required to increase contractility during the “fight or flight” response. However the mechanism for this has remained controversial for 40 years because heterogeneous expression systems used to study responses have resulted in conflicting findings and the use of in vitro cell systems have confounded the findings. We have identified a novel serine required to activate the purified human Cav1.2 channel protein by PKA. We will “molecularly reconstruct” the channel from purified Cav1.2 protein and confirm the functional role of the serine on the native channel in vitro. Using CRISPR/Cas9 technology we will demonstrate that the site is essential for in vivo channel stimulation by β-adrenergic signalling.

2. Determining therapy to reverse hypertrophy in familial hypertrophic cardiomyopathy

Familial hypertrophic cardiomyopathy is the leading cause of death in healthy individuals under the age of 40 years with the exception of sudden infant death syndrome. There is currently no treatment that prevents the cardiomyopathy. We have identified a novel mechanism by which the L-type Ca2+ channel regulates mitochondrial function and energetics in the heart that occurs via cytoskeletal proteins. In familial hypertrophic cardiomyopathy the communication between the channel and the mitochondria is altered and the hearts are hypermetabolic. We have targeted the L-type Ca2+ channel with a peptide that prevents the hypermetabolic mitochondrial response. We are designing mutant peptides with increased affinity for the channel to reverse the cardiomyopathy. 

 3. Elucidating the mechanisms for induction of sudden cardiac death in familial hypertrophic cardiomyopathy

Patients with a mutation in a sarcomeric protein associated with familial hypertrophic cardiomyopathy have an increased risk of sudden cardiac death but the mechanisms for sudden death are poorly understood.  We use single cell electrophysiology and fluorescent techniques in myocytes from hearts of murine models of familial hypertrophic cardiomyopathy and iPSC-cardiomyocytes from patients with known mutations to determine mechanisms for arrhythmia. 

4. How is force transmitted from membrane to the mitochondria in a myocyte? 

The mechanisms for the development of hypertrophic cardiomyopathy at the level of the myocyte are not well understood. This project examines the effect of altering the stiffness of substrates on myocyte function in particular calcium regulation and mitochondrial function.  

5. Optimising gene therapy to prevent cardiomyopathy in Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy is a fatal X-linked disease that leads to progressive muscle weakness due to the absence of dystrophin. The cardiomyopathy is characterised by cytoskeletal protein disarray and reduced myocardial metabolic activity. Designing treatment that results in reversal of the cardiomyopathy has been challenging. We have demonstrated that the L-type calcium channel plays an important role in regulating normal cardiac metabolic activity due to a functional communication via the cytoskeletal network. Absence of the cytoskeletal protein dystrophin results in loss of communication between the channel and mitochondria in the murine model of Duchenne muscular dystrophy (mdx) reflected as a decrease in mitochondrial metabolic activity following activation of the channel. This occurs in pre-cardiomyopathic mdx mice, and persists through to the development of the mdx cardiomyopathy. As a novel approach we use activation of the L-type calcium channel to “report” mitochondrial function and assess efficacy of therapy. Previous studies demonstrated that short term phosphorodiamidate morpholino oligomer (PMO) therapy that induces skipping of dystrophin exon 23 and accumulation of functional dystrophin partially restored cardiac metabolic activity by the channel in mdx mice. We have now identified a dosing regimen of uncharged PMO’s that fully restores metabolic activity in the heart and reverses the cardiomyopathy. The PMO’s designed by collaborators at Murdoch University have been approved for therapy by FDA in Duchenne Muscular Dystrophy patients.

Laboratory Members & Collaborators

Laboratory members

Helena Viola, Research Associate

Henrietta Cserne Szappanos, Research Associate

Ashay Shah, PhD student

Warren Pavey,  PhD student

Barsha Saha  Honours Student

Jerome Randle-Rai, Honours Student

Davina Daudu, Honours Student

Laetitia Hughes, Honours Student


Christine and Jon Seidman, Harvard University

Yoram Rudy, Washington University 

Ken Roos, UCLA

Philip Thompson, Monash University

Christopher Semsarian, Centenary Institute

Aleksandra Filipovska, The Harry Perkins Institute for Medical Research

Evan Ingley, The Harry Perkins Institute for Medical Research

Swaminatha Iyer, UWA

Sue Fletcher and Steve Wilton, Murdoch University 

Yu Suk Choi, UWA

Publication Highlights

1. Muralidharan, P., Szappanos, H.C., Ingley, E. and Hool, L. (2016) “Evidence for redox sensing by a human cardiac calcium channel.” Nature Scientific Reports 6: 19067(1-14). First report to identify the reactive cysteine on the Cav1.2 protein and provide evidence of redox sensing by the channel clarifying controversies over whether the channel is an oxygen sensor.

2. Viola HM, Johnstone VPA, Cserne Szappanos H, Richman T, Toutsman T, Filipovska A, Semsarian C, Seidman J, Seidman C and Hool LC. The role of the L-type Ca2+ channel in altered metabolic activity in a murine model of familial hypertrophic cardiomyopathy JACC: Basic Translational Research VOL. 1, NO. 1-2, 2016

3. Richman TR, Spahr H, Ermer JA, Davies SMK, Viola HM, Bates KA, Papadimitriou J,  Hool LC, Rodger J, Larsson N-G, Rackham O  and Filipovska A. Loss of the RNA-binding protein TACO1 causes late-onset mitochondrial dysfunction in mice Nature Communications Jun 20;7:11884, 2016

4. Viola HM, Johnstone VPA, Cserne Szappanos H, Richman T, Toutsman T, Filipovska A, Semsarian C and Hool LC. The L-type Ca2+ channel facilitates abnormal metabolic activity in the cTnI-G203S mouse model of hypertrophic cardiomyopathy J Physiology (London) Jul 15;594(14):4051-70, 2016. Evidence that communication between the channel and mitochondria is disrupted in TnI mutant mice and L-type Ca2+ channel current is altered. 

5. Hardy N, Viola HM, Johnstone VPA, Clemons TD, Cserne Szappanos H, Singh R, Smith NM, Swaminathan Iyer K and Hool LC. Nanoparticle Mediated Dual-delivery Enables Simultaneous Action Against Myocardial Damage and Oxidative Stress in Cardiac Ischemia- Reperfusion Injury ACS Nano  9(1): 279-289, 2015. A pioneering example of dual drug delivery and parallel imaging in nanomedicine.

6. Viola HM, Adams A, Davies SKM, Fletcher S, Filipovska A and Hool LC. Impaired functional communication between the L-type calcium channel and mitochondria contributes to metabolic inhibition in the mdx heart Proceedings National Academy Sciences USA 111(28): E2905-E2914, 2014. Selected for F1000Prime recommended as being of special significance in the field. Evidence that communication between the channel and mitochondria is disrupted in mdx cardiomyopathy. Treatment with morpholino oligomers rescues metabolic inhibition

7. Clemons TD, Viola HM, House M, Swaminathan Iyer K and Hool L. A ‘TAT-less’ delivery of a peptide against activation of the L-type calcium channels in cardiac ischemia-reperfusion injury ACS Nano 7(3): 2212-2220, 2013. First example of nanoparticle mediated delivery of peptides to the heart outperforming the traditional cell penetrating peptide performance.

8. Gaur N, Rudy Y and Hool LC. Contributions of ion-channel currents to ventricular action potential changes and induction of early afterdepolarizations during acute hypoxia. Circulation Research 105(12): 1196-203, 2009

9. Viola HM, Arthur PG and Hool LC. Evidence for regulation of mitochondrial function by the L-type Ca2+ channel in ventricular myocytes Journal of Molecular and Cellular Cardiology   46:1016–1026, 2009. Selected for F1000Prime recommended as being of special significance in the field.

10. Hool, L.C. and Arthur, P.G. Decreasing cellular hydrogen peroxide with catalase mimics the effects of hypoxia on the sensitivity of the L-type Ca2+ channel to b-adrenergic receptor stimulation in cardiac myocytes. Circulation Research: 91:601-609, 2002

11. Hool, L.C. Hypoxia alters the sensitivity of the L-type Ca2+ channel to a-adrenergic receptor stimulation in the presence of b-adrenergic receptor stimulation. Circulation Research 88(10): 1036-1043, 2001.

12. Hool, L.C. Hypoxia increases the sensitivity of the L-type Ca2+ channel to b-adrenergic receptor stimulation via a C2 region-containing protein kinase C isoform. Circulation Research 87(12): 1164-1171, 2000