Integrative Cardiovascular Physiology
Professor Desmond Sheridan, Principal Investigator
The Academic Cardiology Unit is pursuing a number of research areas:
Contribution of platelets to the deleterious effects of myocardial ischaemia
We have reported that spontaneous platelet activation within ischaemic myocardium contributes to the electrophysiological disturbances associated with myocardial ischaemia leading to the development of ventricular fibrillation. We have also reported that this platelet activation is mediated via a platelet thromboxane receptor and is mitigated by substances released from the vascular endothelium (NO and PGI2). More recently we have shown that diadenosine polyphosphates released from activated platelets, have important vascular and cardiac electrophysiological effects.
Flores et al. Experimental Physiology 1999;84:253-274; Flores et al. Cardiovascular Research 1999;42:15-26; Flores et al. Platelets. 2000;11(7):415-7; Botchway et al. Clin Lab Haematol. 2000 Feb;22(1):21-8; Stavrou et al. J. Cardiovasc Pharmacol 2001; 37(5): 571-84; Stavrou et al. J Pharmacol Exp Ther 2001; 298(2): 531-8.
Electrophysiological disturbances associated with cardiac hypertrophy
We have reported that cardiac hypertrophy is associated with delayed myocardial conduction. This is accentuated during myocardial ischaemia creating conditions suitable for the development of re-entry. We have also reported that this impaired conduction is due in part to an increase in gap junction electrical impedance and is associated with a reduction in anisotropy. More recently we have demonstrated that myocyte intracellular pH is reduced in hypertrophy, a condition known to increase gap junction impedance. Other factors known to alter gap junction impedance, including alterations in ionic homeostasis and the connexin composition of gap junctions are currently being investigated.
Botchway et al. Cardiovasc Res. 2003; 60: 510-7; Wallis et al. Arch Physiol Biochem. 2001 Apr;109(2):117-26; Carey et al. J Cardiovasc Electrophysiol 2001 Jul;12(7):830-5; Gray et al. Pflugers Arch 2001 Apr;442(1):117-23; Cooklin et al Exp Physiol. 1998 Nov;83(6):763-70.
Disturbances in the coronary circulation in cardiac hypertrophy.
A reduction in coronary flow reserve is known to occur in cardiac hypertrophy. We have shown that these abnormalities are associated with a greater vulnerability to brief periods of ischaemia, with impaired metabolic recovery and have identified a number of causal factors:
- The systolic impediment to coronary flow is increased in hypertrophied hearts due to the increased muscle bulk and delayed myocardial relaxation.
- Coronary vascular conductance is reduced due to a morphological defect at the level of resistance arterioles. The density of resistance arterioles is reduced in hypertrophy and their wall thickness to lumen ratio is increased. These abnormalities result in a greater resistance to coronary perfusion per unit volume of myocardium in hypertrophy.
- Vasodilator responses of coronary resistance vessels are reduced in hypertrophy and this is true for both endogenous and exogenous stimuli.
Radvan et al Am. J. Of Cardiol. 1997:80,1621-1623; Kingsbury et al. J Mol Cell Cardiol. 2000 Mar;32(3):527-38; Kingsbury et al. Br J Pharmacol. 2001; 132; 1209-1216; Rajappan et al. Circulation. 2002 Jan 29;105(4):470-6; Rajappan et al. Circulation. 2003;107: 3170-5; Rajappan et al Eur J Cardiothorac Surg. 2003; 24: 59-65.
Disturbances in lung function in chronic heart failure
We have developed models and methods to investigate lung dysfunction in chronic heart failure. We have reported major adaptations in lungs in response to chronic heart failure including a reduced alveolar capillary water filtration, increased vascular resistance and vascular remodelling.
We are currently investigating alterations in gene expression of receptors for neurohormones and other potential mediators of these changes.
Huang et al. Cardiovasc Res. 2001 Jan;49(1):207-17; Kingsbury et al. Basic Res Cardiol. 2003; 98: 295-303.
Platelet activation and its contribution to outcomes during coronary intervention
We used flow cytometry to study platelet function in coronary sinus blood samples taken during coronary interventions in patients with acute and chronic coronary syndromes.
Our results have shown that the type of disease and other risk factors related to coronary disease, including platelet GPIIBIIIA genotype are important in the natural history of platelet activation following coronary intervention.
Siminiak et al. Exp. Clin.. Cardiol. 1996; 1, 87-93; Siminiak et al. Int. J. of Cardiology. 1997; 61, 113-118; Kalawski et al. Eur J Cardiothorac Surg. 1998 Sep;14(3):290-5; Siminiak et al. Heart Vessels. 1998;13(4):189-94; El-Gendi et al. Heart. 2002 Feb;87(2):158-9.
