Imaging plays an important role in the diagnosis and prognosis of a patient with PH. Literature shows that imaging such as echocardiography and magnetic resonance is imperative in the future of translational research. Echocardiography of the rodent right ventricle proofs to be a difficult task due to limited acoustic window and different morphology compared to the left ventricle. It is however possible and is lately persistently used to measure hemodynamics and right heart parameters in studies with animal models of PH. At the Hatter Institute Gerald Maarman, a PhD student is currently doing his PhD project on cardioprotection against the cardiac damage associated with PH. Prof. Laurie Blauwet is currently helping Gerald find the optimal position to hold the Echo probe in order to obtain an apical four chamber view of the rat heart, the aortic valve and pulmonary artery in order to determine the right heart parameters.
Gerald J. Maarman (3rd year PhD student)
Supervisor: Assoc Prof. Sandrine Lecour ; Co-supervisor/s: Prof. Karen Sliwa
Year projected started: 2011
Projected year of completion: 2014
Overview of study:
Pulmonary arterial hypertension (PAH) is a devastating disorder that affects patients with diseases such as chronic obstructive pulmonary disease, schistosomiasis, systemic sclerosis and HIV/AIDS. The pathophysiology of PAH is not completely understood and this is the main reason why current PAH treatments have limited impact on patient survival and quality of life. Therefore, PAH remains a deadly disorder and constant research is being done to develop new and better treatments. My PhD project investigates novel treatments that can protect the heart against PAH-induced damage. One such treatment is a pharmacological agent called melatonin, which has been shown to be cardioprotective in hypertensive and ischemic heart disease. We aim to test whether melatonin can be cardioprotective in PAH. This project may prove melatonin to be a cheap and effective treatment against PAH.
Review paper: That comprehensively reviews the role of animal models in PAH
Review paper: That highlights novel cardioprotective approaches to protect the right ventricle in PAH
Progress made in the project thus far:
Techniques used/to be used in this project:
Lindizwe Dlamini (2nd year MSc student)
Supervisor: Assoc Prof. Sandrine Lecour ; Co-supervisor/s: Dr. Dee Blackhurst and Dr. Roisin Kelly
Year projected started: 2013
Main purpose of study: The purpose of this study is to establish whether the potential cardioprotective effect observed after chronic wine treatment in rats may be attributed to its melatonin content and/or its isomers. Additionally, describing the cardioprotective effects of melatonin isomers might be a stepping stone in developing a safe and inexpensive novel therapy to prevent and treat IHD.
Outcomes: Pending (Not applicable)
The objectives of the study:
Techniques used in project:
Lauren Nicholson ( MSc student)
Supervisor: AssocProf. Sandrine Lecour ; Co-supervisor/s: Prof. Karen Sliwa
Year projected started: 2012
Year projected ended: 2013
Introduction: Peripartum cardiomyopathy (PPCM) is a heart disease of unknown aetiology emerging in previously healthy women towards the end of pregnancy or first postpartum months1. Previous studies have suggested that oxidative stress contributes to the pathogenesis of PPCM2. Melatonin is a powerful endogenous antioxidant that can limit the damaging effect of oxidative stress3. Melatonin levels are known to be altered in sleep disruption, depression and other cardiac diseases.
Aims: The aim of this study was to determine if melatonin levels are disrupted in women with PPCM compared to healthy patients. We hypothesised that sleep disruption and depression may contribute to a disruption in their melatonin levels.
Methodology: Pregnant and postpartum healthy control (HC) , with (PPCM) or other cardiac diseases (CD) were recruited for the study. A sleep quality questionnaire and the Edinburgh postnatal depression scale (EPDS) was administered to all patients to compare their sleeping patterns and depression levels. Daytime and nocturnal salivary melatonin levels were also compared and the serum concentration of the stress hormone cortisol was measured. To evaluate stress and antioxidant capacity a thiobartubaric reactive substances (TBARS) and oxygen radical absorbance capacity (ORAC) assays were performed on the plasma of all women. Basic naturietic peptide (BNP) was measured in serum as a marker of heart failure.
Results: BNP levels were elevated in the postnatal PPCM compared to HC and CD women. The oxidative stress in the form of lipid peroxidation was also elevated in the postnatal PPCM group, there was no observable difference in the antioxidant capacity. The PPCM and CD groups both demonstrated increased EDPS scores and elevated serum cortisol compared to HC. The postnatal PPCM women also demonstrated delayed, fragmented, inefficient sleep. The PPCM women also demonstrated significantly higher (p<0.05) postpartum nocturnal melatonin (99.8±8.8) levels compared to HC (73.4±8.3) and CD (77.8±7.8).
Conclusion: The postnatal PPCM women demonstrated increased level of salivary nocturnal melatonin as well as increase EDPS scores and sleep disruption. Further studies are required to fully understand the mechanism of this increase as well as potential therapeutic targets.
Dr Sarah Pedretti (Postdoctoral Fellow)
Supervisor: Assoc Prof. Sandrine Lecour
Year project started: 2011
Main purpose of study:
A recent World Health Organization report warns of the escalating global burden of cardiovascular diseases (CVD), projecting that it will become the major worldwide cause of death and disability by 2020. In the Western Cape region of South Africa, ischemic disease is already the leading cause of death, often killing by acute myocardial infarction. Surprisingly, the African black population from the heart of Soweto study presents a high prevalence of risk factors for atherosclerotic disease including diabetes but overall, ischemic heart disease apparently remains fairly uncommon compared with the other South African ethnic groups. This relative protective effect may be related to the rarity of hypercholesterolemia in the African black population as they may have a higher level of high density lipoprotein (HDL) relative to low density lipoprotein (LDL) than non-black South Africans.
Interestingly, a variety of studies exploring the mechanism, suggest a protective effect of HDL against ischemic heart disease. Well known for its ability to limit the formation of atherosclerotic plaque by favoring the cholesterol transport back to the liver, HDL has other beneficial cardiac effects including anti-inflammatory and anti-oxidant effects. However, the cardioprotective components of HDL and its exact mechanisms of cardiovascular protection remain unclear.
We have identified sphingosine-1-phosphate (S1P), a major component of HDL, as a powerful cardioprotective sphingolipid that limits ischemia-reperfusion injury.
Our preliminary work suggests that this protective effect is mediated via the activation of a prosurvival signaling pathway that we have newly discovered in the heart and that we have named the Survivor Activating Factor Enhancement (SAFE) pathway.
Since I started on that project I have demonstrated that, in a model of isolated adult mouse cardiomyocytes subjected to simulated ischemia, HDL/S1P cardioprotection is mediated via the SAFE pathway and subsequent inhibition of mitochondrial permeability transition pore.
The principal objective of our study is to evaluate the role of S1P in the cardioprotective capacity of HDL to counteract myocardial injury induced by ischemia/reperfusion in vitro (isolated perfused hearts or isolated cardiomyocytes). We will also address the importance of the SAFE pathway in S1P/HDL induced cardioprotection.
Experiments will be performed in isolated mouse cardiomyocytes and perfused hearts that will be subjected to an ischemia/reperfusion insult.
We have 2 main research aims:
1. To delineate the role of Sphingosine Kinases (SphK) in S1P-induced protection in hearts subjected to ischemia/reperfusion
SphK are the enzymes that catalyse the formation of endogenous S1P.
Using an isolated perfused heart model, hearts extracted from wildtype mice will be subjected to an ischemia/reperfusion insult with/without S1P and inhibitors of SphK. Measurements of SphK activities and S1P content in isolated hearts will be used as an endpoint.
2. To evaluate the mechanisms involved in HDL/S1P-induced cardioprotection
The prosurvival transcription factor signal transducer and activator of transcription 3 (STAT3) and tumor necrosis factor α (TNFα) are the 2 main components of the SAFE pathway.
To delineate whether the SAFE pathway is activated by S1P in HDL-induced cardioprotection, cardiomyocytes extracted from STAT3 and TNFα deficient mice will be subjected to a simulated ischemia/reperfusion insult with/without reconstituted HDL containing various concentrations of S1P. Western blot analysis will also be performed as an endpoint.
Papers published from study:
M. Brulhart-Meynet, V. Braunersreuther, J. Brinck, F. Montecucco, K. Galan, G. Pelli, S. Pedretti, F. Mach, S. Lecour, R.W James, M.A Frias “Post-ischemic treatment with native and reconstituted HDL limit reperfusion injury”, Basic Research in Cardiology, in revision
R.F Kelly-Laubscher, J.C King, D. Hacking, S. Somers, S. Pedretti, G. Maarman and S. Lecour «Preconditioning with sphingosine-1-phosphate requires activation of signal transducer and activator of transcription-3», Acta Physiologica, in revision
M.A Frias, S. Pedretti, D. Hacking, S. Somers, L. Lacerda, L.H Opie,R.W James and S. Lecour «HDL protects against ischemia reperfusion injury by preserving mitochondrial integrity», Atherosclerosis, May 2013; 228 (1):110-6
M.A Frias, S. Lecour, R.W James and S. Pedretti «High density lipoprotein/sphingosine-1 phosphate-induced cardioprotection: Role of STAT3 as part of the SAFE pathway», JAK/STAT, April 2012; 1 (2)
Techniques used in project: