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					Division of Neuroscience and Biomedical Systems
          Senior Honours Option
         Cardiovascular Science
       Course Information Document
                2005/2006
Option co-ordinator: Prof Mandy MacLean

Lecturers
   Professor Godfrey Smith     (West Medical Building, 415b G.Smith@bio)
   Dr. David Miller            (West Medical Building, 415 D.Miller@bio)
   Dr. Niall MacFarlane        (West Medical Building, 354 N.MacFarlane@bio)
   Professor Mandy MacLean     (West Medical Building, Rm 417 M.MacLean@bio)
   Professor Billy Martin      (West Medical Building, Rm 422 W.Martin@bio)
   Professor Anna Dominiczak   (Dept Medicine and Therapeutics ANNA.DOMINICZAK@clinmed)
   Dr M McBride                (Dept Medicine and Therapeutics, mwmb1c@clinmed.gla.ac.uk)
   Professor Stuart Cobbe      (Dept Medical Cardiology, Royal Infirmary stuart.cobbe@clinmed)
   Professor JC McGrath        (West Medical Building, Rm 422 imcgrath@bio)
   Dr. Craig Daly              (West Medical Building, Rm 440 C.Daly@bio)
   Dr. John McCarron           (West Medical Building, Rm 350 J.McCarron@bio)
   Dr. Francis Burton          (West Medical Building, Rm 409 F.L.Burton@bio)
   Professor W. Ferrell        (Centre for Rheumatic Dis., Glasgow Royal Infirmary, w.ferrell@bio)




Cardiovascular Science                                                                                3
TIMETABLE



Week 1
Mon 9th Jan   Cardiac & smooth muscle myofilament structure and function. WMB, Rm 222, 10-
1pm, Godfrey Smith and Dave Miller


Fri 13th Jan   Calcium signalling in cardiac and smooth muscle. WMB Rm 222 2-5pm Godfrey
Smith and John McCarron


Week 2
Mon 16th Jan The mechanical and cellular basis for myocardial contractility abnormalities in heart
failure., 2-5pm, WMB Rm 222, Francis Burton & Niall MacFarlane.


Fri 20th Jan    Regulation of vascular tone by nitric oxide, WMB, Rm 222, 10am-1pm W Martin


Week 3
Mon 23rd Jan Genetic Determinants of Cardiovascular Disease., WMB Rm 222 2-5pm. Professor
Anna Dominiczak/M McBride


Fri 27th Jan    Literature Review Session, WMB, Rm 222, 10am-1pm G Smith et al.


Week 4
Mon 30th Jan    Vascular Structure and Function., WMB Rm 222, 2-5pm C Daly & JC McGrath
Fri 3rd Feb     Pulmonary circulation in health and disease WMB, Rm 222, 10am-1pm MR
MacLean


Week 5
Mon 6th Feb     Non-invasive assessment of human vascular function. Seminar Room 2A, Queen
Elizabeth Building, Glasgow Royal Infirmary, 10am-1pm.


Fri 10th Feb   Clinical techniques to study myocardial haemodynamics and disease. WMB Rm 222,
2-5pm. Professor S Cobbe.Feb
WMB: West medical building




Cardiovascular Science                                                                               4
Structure of the course
The course consists largely of lecture/tutorials. Lectures/tutorials take place on Mondays and Fridays during
the first 5 weeks of the second term.

Background material
No formal background information or reading is required for the course.

Other information
Students are encouraged to ask questions or to clear up points of mis-understanding during the lectures We
encourage active participation in the course and if you wish to ask specific points at other times in the first
instance go and see the lecturer involved or Prof MacLean.
If you wish to discuss any points which relate to either the content or the organisation of the course please see
Prof M MacLean. All of the course will be considered as being suitable for examination. This will include
information and concepts discussed in the specific references provided.




Cardiovascular Science                                                                                              5
Course synopsis and learning Objectives
    General synopsis. The course will deal with all aspects of cardiovascular science. Both basic scientists and
    clinicians, drawn from the Division of Neuroscience and Biomedical Systems, Department of Medical
    Cardiology, Royal Infirmary and Department of Medicine and Therapeutics will contribute. The course
    will range from the cellular basis for the heart beat to the role of neurotransmitters in the control of blood
    pressure. The topics covered include cardiac muscle: structure and contractile properties at the molecular
    level - the relation between structure and function. Calcium events, myofilament mechanisms and cellular
    signalling in smooth and cardiac muscle cells. Clinical relevance of pathological changes in cell signalling
    and contractile function. The epidemiology of heart failure and genetic determinants of cardiovascular
    disease. Nerve transmission and endothelial function in the systemic vasculature - vascular structure and
    hypertension. Pulmonary vasculature and pulmonary hypertension. Structure and function of the feto-
    placental circulation. The pharmacology of nitric oxide and endothelial function.
    Cardiac & smooth muscle myofilament structure and function.
    By the end of these lectures you should be able to:
        List the separate elements of the contractile proteins of smooth and striated muscle.
        Describe the cross-bridge cycle events and energetics.
        Differentiate the role of calcium in the control of smooth muscle and cardiac muscle myofilament
         activity.
    Calcium signalling in cardiac and smooth muscle
    By the end of these lectures you should be able to:
        List the current theories for excitation-contraction coupling in cardiac and smooth muscle.
        Understand the factors involved in the control of the sarcoplasmic reticulum of cardiac and smooth
         muscle.
    The mechanical and cellular basis for myocardial contractility abnormalities in heart failure.
    By the end of these lectures you should be able to:
        List the known molecular subcellular changes that occur in hypertrophic cardiac muscle.
        Discuss how subcellular changes may contribute towards arrhythmia’s and contractile dysfunction.
    Clinical techniques to study myocardial haemodynamics and disease.
    By the end of these lectures you should be able to:
        Understand the changes in global myocardial function in disease.
        Understand the assessment of cardiac function by invasive and non-invasive techniques.
    References for above: to be announced


    Genetic Determinants of Cardiovascular Disease
    The students will first participate in an interactive seminar/tutorial with slides explaining the genetic
    glossary and major strategies using examples taken from our own published data. This will be followed
    by a series of practical small group sessions in the laboratories at the Western Infirmary where basic
    molecular genetic techniques (PCR, gel electrophoresis, DNA sequencing) and statistical analysis in
    quantitative genetics (MAPMAKER Linkage programme) will be presented by postdoctoral research
    assistants and lecturers.
    By the end of this session you should be able to:
        Understand major research strategies in genetics of complex, multifactorial polygenic disorders using
         examples of hypertension and other cardiovascular phenotypes.
        Describe a reductionist approach and the rationale for the use of model organisms in genetic studies.
        Understand molecular genetic and statistical methods for gene mapping in cardiovascular disease.
        Describe how to get from a quantitative trait locus to positional cloning of the gene of interest?
    References:

    Dominiczak AF et al (2000) Gene and hypertension- from gene mapping in experimental models
    to vascular gene transfer strategies, Hypertension 35:164-172.
    Jeffs B et al (2000) Applicability of a speed congenic strategy to dissect blood pressure
    quantitaive trait loci on rat chromosome 2, Hypertension 35:179-187.



Cardiovascular Science                                                                                               6
    Jacon HJ & Kwitek AE (2002) Rat Genetics: attaching physiology and Pharmacology to the
    genome, Nature Rev Genet 3:33-42.
        McBride et al (2003) Microarray analysis of rat chromosome 2 congenic strains, Hypertension 41:847-853.


    Regulation of vascular tone by nitric oxide
    Three isoforms of nitric oxide synthase (NOS) exist in nature. Two are constitutively expressed, in the
    vascular endothelium (eNOS) and central and peripheral nitrergic nerves (nNOS). The third is not
    normally expressed but can be induced (iNOS) following exposure to immunological stimuli, including
    bacterial endotoxin and certain cytokines. The role played by each of the isoforms of NOS in the control of
    vascular tone in health and disease will be explored.
    By the end of these lectures you should be able to:
          Describe the location and functions of the different isoforms of NOS in the cardiovascular system.
    References:
    Hobbs, A.J., Higgs, A. & Moncada, S. (1999). Inhibition of nitric oxide synthase as a potential therapeutic
    target. Ann. Rev. Pharmacol. Toxicol., 39, 191-220.
    Calver, A., Collier, J. & Vallance, P. (1993). Nitric oxide and cardiovascular control. Experimental Physiol.,
    78, 303-326.
    Moncada, S., Palmer, R.M.J. & Higgs, E.A. (1991). Nitric oxide: physiology, pathophysiology and
    pharmacology. Pharmacol. Rev., 43, 109-142.
    Jiang, F., Li, C.G. & Rand, M.J. (1997). Mechanisms of electrical field stimulation-induced vasodilatation in
    the guinea-pig basilar artery: the role of the endothelium. J. Autonomic Pharmacol., 17, 71-76.
    Radomski, M.W., Palmer, R.M.J. & Moncada, S. (1990). Glucocorticoids inhibit the expression of an
    inducible, but not the constitutive, nitric oxide synthase in vascular endothelial cells. Proc. Natl. Acad. Sci.
    USA., 87, 10043-10047.
    Schini, V.B., Durante, W., Elizondo, E., Scott-Burden, T., Junquero, D.C., Schafer, A.I. & Vanhoutte, P.M.
    (1992). The induction of nitric oxide synthase activity is inhibited by TGF-b1, PDGFAB and PDGFBB in
    vascular smooth muscle cells. Eur. J. Pharmacol., 216, 379-383.
    Wright, C.E., Rees, D.D. & Moncada, S. (1992). Protective and pathological roles of nitric oxide in
    endotoxin shock. Cardiovasc. Res., 26, 48-57.


    Pulmonary circulation in health and disease
    The pulmonary circulation differs from the systemic circulation both structurally and functionally, being of
    low resistance, highly compliant, less muscularised and normally vasodilated. It constricts to hypoxia
    whilst systemic arteries vasodilate. Chronic hypoxic insults or left ventricular dysfunction can lead to
    persistent vasoconstriction and pulmonary hypertension. This involves vascular remodelling and
    vasoconstriction. The normal pulmonary circulation and the changes that occur in pulmonary
    hypertension will be discussed along with novel therapeutic approaches to the treatment of pulmonary
    hypertension.
    By the end of these lectures you should be able to:
          Describe the pulmonary circulation, structure and function
          Describe the effects of hypoxia
          Understand the functional and structural changes that occur in pulmonary hypertension
          Describe current therapeutic strategies for pulmonary hypertension
    References:
    Gaine SP et al., (1998). Primary Pulmonary Hypertension. Lancet, 352(9129), 719-25.
    Fishman AP (1998). Etiology and pathogenesis of primary pulmonary hypertension: a perspective. Chest,
    114 (3 Suppl), 242S-247S.
    Voelkel NF (1997). Appetite suppressants and pulmonary hypertension. Thorax, 52, S63-7 (suppl 3).
    Brenner O. Pathology of vessels of the pulmonary circulation. Arch Int Med 1935; 56: 211-237.
    Heath D, Edwards JE. The pathology of hypertensive pulmonary vascular disease. A description of six
    grades of structural changes in the pulmonary arteries with special reference to congenital cardiac septal
    defects. Circulation 1958; 18: 533-547.




Cardiovascular Science                                                                                                 7
    Vascular Structure and Function
    i) Vascular structure and the alterations caused by hypertension e.g. smooth muscle remodelling (i.e.
    hypertrophy, hyperplasia, eutrophic remodelling). Various animal models of experimental hypertension will
    also be discussed. C Daly
    ii) Vascular adrenergic mechanisms will be discussed: basic adrenergic pharmacology of resistance vessels and
    structural studies using confocal microscopy will be described as will the various experimental methods used
    to study the function of resistance and systemic vessels. C.Daly
    iii) The vascular adventitia has been identified (recently) as playing a potentially very important role in arterial
    structure and function. Recent evidence will be reviewed. C. Deighan


    By the end of these lectures/tutorials you should be able to:
       Describe in detail vascular structure and autonomic control
       Describe cellular changes associated with vascular remodelling in hypertension
       Discuss animal models used in the studies of hypertension
       Understand vascular adrenergic mechanisms, i.e. their receptors and control
       Describe the basic concepts behind confocal microscopy and its application to the study of vascular beds.
       Discuss the importance of the vascular adventitia.


    References:


    B. Folkow; Hypertension (1990), 16; 89-101.
    Mulvany MJ et al., Vascular Remodeling [letter]. Hypertension (1996), 28:505-506.
    Arribas et al (1997) J. Hypertension 15: 1685-1693.
    Gutterman, D. D. (1999) Am. J. Physiol. 277:H1265-H1272
    Sartore S. et al (2001) Circ. Res. 89: 1111-1121
    Okamoto K, Aoki K (1963).. Jpn. Circ. J. 27, 282-293.
    Yukio Yamori (1994). Handbook of Hypertension. Vol 16 Experimental and Genetic Models of Hypertension.
    346-364



    Non-invasive assessment of human vascular function

    Progressive impairment in endothelial function is observed in patients with early coronary atherosclerosis.
    Endothelial dysfunction results in abnormal vascular reactivity, which in turn increases the haemodynamic
    stress on atherosclerotic plaques and increases the likelihood of plaque rupture and thrombosis. Endothelial
    dysfunction is not limited to the coronary circulation but is also detected in the peripheral circulation
    proportionate to the degree of dysfunction occurring in the coronary arteries. Moreover, there is recent
    evidence that endothelial function measures are predictive of future cardiovascular events. Assessment of
    large vessel function, particularly arterial stiffness, has also proven to have predictive value. There is
    therefore interest in developing non-invasive methods for assessing vascular function as an indicator of
    cardiovascular risk and some of the commonly used methods will be discussed.

    By the end of this lecture you should be able to:

       Describe non-invasive methods used to assess function of conduit and resistance vessels

       Distinguish between endothelial and non-endothelial dependent vasodilator mechanisms

    References:
    Correti MC, Plotnick GD & Vogel RA. (1995) Technical aspects of evaluating brachial artery vasodilatation
    using high-frequency ultrasound. Am. J. Physiol. 268: H1397-404.




Cardiovascular Science                                                                                                     8
    Petrie JR, Udea S, Morris AD, Murray LS, Elliot HL & Connell JM. (1998). How reproducible is bilateral
    forearm plethysmography? Brit J. Clin Pharmacol 45: 131-9.

    Morris SJ & Shore AC. (1996). Skin blood flow responses to the iontophoresis of Acetylcholine and sodium
    nitroprusside in man: possible mechanisms. J. Physiol 496: 531-42.

    Oliver JJ & Webb DJ. (2003). Noninvasive assessment of arterial stiffness and risk of atherosclerotic events.
    Arterioscler Thromb Vasc Biol 23:554-566.


Assessment


1). Essays and literature reviews will be set during the course. These will be assessed and feedback
provided. These will contribute to assessment of course performance.
2) Examination The examination will require answers to 3 questions from a total of 8 provided.
The examination period will be 3 hours.




Cardiovascular Science                                                                                              9

				
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