THE AUSTRALIAN NATIONAL UNIVERSITY

1. THE AUSTRALIAN NATIONAL UNIVERSITY Special CirculationsChristian StrickerAssociate Professor for Systems PhysiologyANUMS/JCSMR - ANUChristian.Stricker@anu.edu.auhttp://stricker.jcsmr.anu.edu.au/Specirc.pptx

3. Aims The students should • realise that different vascular beds utilise different mechanisms for regulation of blood flow; • understand why coronary flow is largely during diastole; • be familiar with mechanisms resulting in coronary vaso-dilation as a consequence of increased cardiac work; • recognise why subendocardial vessels are prone to ischaemic damage; • be cognisant of factors regulating cerebral blood flow including autoregulation; and • know why cerebral vessels are different to many other vessels.

4. Contents • Coronary arteries • Anatomy • Pressures in LCA and RCA • Autoregulation of perfusion • Metabolic factors determining perfusion • Substrate utilisation • Stenosis and flow • Cerebral vessels • Anatomy • Autoregulation • Metabolic factors determining perfusion

5. Coronary Perfusion

6. Coronary Arteries Modified from Boron & Boulpaep(2009), 2nd ed. Despopoulos & Silbernagl2003, 5th ed. • Coronary arteries originate from aorta, behind valve cusps. • In general RCA (~1/7 of total): RV and RA; LCA: LV and LA. • Collateral network gives rise to high density of capillaries. • Veins drain into coronary sinus; from septum directly into ventricles (Thebesian veins → physiological shunt; see later).

7. Coronary Blood Flow • LCA: Flow drops to ≤ 0 at start of isovolumetric phase. Maximal flow during early diastole: LV/A perfused largely “only” during diastole. • RCA: Flow variable and maintained. Maximal flow at end of fast ejection part: RV/A perfused during systole & diastole. • Phasic blood flow: varies with cardiac cycle. • LV is much more critical in its blood supply than RV: • Flow in LCA larger than that in RCA (~ 6 - 7 x). Modified from Boron & Boulpaep(2009), 2. ed.

8. Wall Tension & Perfusion Patton et al. (1989), 21. ed. Despopoulos & Silbernagl2003, 5th ed. • Mechanical compression of LCA (transmural): dependent on wall position. • Subepicardial vessels little affected: better perfusion. • Subendocardialvessels compressed during systole: flow stops temporarily – i.e. flow limited during systole → these vessel beds are prone to hypoxia. • Systolic perfusion of RCA possible due to smaller cavity pressure (25 torr; limited “squeeze” on vessels).

9. Autoregulation of Perfusion • Immediate response. • Blood flow ± constant over pressure range between 60 – 180 torr. • Change in arteriolar resistance: pre-capillary sphincters. • Mechanism(s) (?): • myogenic: most likely • metabolic: ? • neuronal: works without. • Below autoregulation range, flow is dependent on resistance. Berne & Levy, 2008, 6. ed.

10. Neural Control of Perfusion • Ventricular fibrillation → removal of transmuraltension → blood flow↑→ ↑. • Over time, R↑ (autoregulation): flow↓ → homeostatic response. • Stimulation of sympathetic ganglion (stellate): R↑ initially • α1 receptors: constriction; but • compensated via R↓ later (metabolic hyperaemia, slow). • Metabolic self-regulation more powerful than neuronal response. Berne & Levy, 2008, 6. ed.

11. Cardiac Work & Blood Flow • Cardiac work linearly increases blood flow. • Same result if heart is denervated (minimal role of neuronal control; allows for transplantation). • Myocardial O2 balance: • O2 blood content & blood flow against • metabolic demand: • if quotient ↓: vasodilation. • if quotient ↑: vasoconstriction. • What are molecular mechansims? Berne & Levy, 2008, 6. ed.

12. Modulation of Coronary Resistance Berne & Levy, 2008, 6. ed. • Autonomic control minimal. • Metabolic control via KATP, NO, adenosine, H+, K+, and .

13. Key Metabolic Factors • ATP (energy availablility) via KATP channels • ATP production↓ activates KATP channels. • When activated, KATP hyperpolarises VSMC → Ca2+ influx↓→ vasodilation. • KATPchannels also activated on cardiomyocytes→ AP width↓ → Ca2+ entry↓→ limits energy expenditure. • Adenosine • transiently released from myocardial cells (short effect). • activates adenosine receptors and also activates KATP channels → vasodilation. • enhances release of NO → vasodilation. • NO (nitrous oxide; from endothelial cells) • relaxes smooth muscle cells.

14. Substrate Utilisation Despopoulos & Silbernagl2003, 5. ed. • At rest, glucose, fatty acids and lactate serve equally to provide energy. • During exercise, lactate from muscle is increasingly important in energy production. • Most increase via perfusion↑. But O2 consumption↑ slightly more than perfusion↑: O2 extraction↑ (but only little).

15. Coronary Stenosis and Flow • O2 extraction is close to maximal → flow limited. • Narrowing >~80% only causes significant flow↓ at rest. • Accentuated under exercise (exercise testing). • Effect of stenosis: P↓ & autoregulation↓ → flow↓. • Compensatory vasodilation in post-stenotic bed. • Acute consequence: hypoxia/ischaemia (infarct). • Chronic consequence: build-up of cap. collaterals. Patton et al. (1989), 21. ed.

16. Vasomotion and Stenosis • Atherosclerotic plaques hinder vasomotion. • Vasodilation→R↓in each vascular arm→ flow↑ in healthy vascular beds. • However, as R = const.around sclerotic plaques, relative R↑ locally → flow↓over plaque:haemodynamic steal. • Risk in exercise testing.

17. Cerebral Circulation Cerebral blood flow (CBF) Brain is the least tolerant organ to hypoxaemia/ischaemia.

18. Cerebral Vessels • Total flow: 15% of CO for an organ that is 2% of BW. • Largest flow via carotid art. • Collateral paths via circle of Willis. • Direction of flow can change under pathological conditions. • Fixed volume (cranium) → tight volume control. • Autonomic nervous fibres accompany vessels into the cranium. Modified from Boron & Boulpaep(2009), 2. ed.

19. Neural Control of CBF • Sympathetic: constriction (cervical sympath. fibres; α1-effect) • Parasympathetic: dilation via greater superf. petrosal nerve (VII); dense net around cerebral arteries (see above; black deposits stain acetylcholinesterase). • Neuronal control exists, but its functional impact under normal condition is quite small. Vasquez & Purves (1979), Pflügers Arch. 379:157

20. Autoregulation of CBF • Between mean arterial pressures 60 – 160 torr, CBF ± constant (solid line). • at low pressures: dangerous drop in CBF; risk of syncope. • at high pressures: risk of oedema due to filtration↑ → intracranial P↑. • Myogenic response (partial) • In hypertension, right shift: risk of syncope↑ at start of therapy. • Intracranial P↑ → BP↑ (tumor; Cushing phenomenon) via ischaemicstimulation of vasomotor centre: homeostatic flow maintenance. Patton et al. (1989), 21. ed.

21. Local Control of CBF Guyton & Hall (2006), 11. ed. • Regional neural activity↑ due to metabolism↑ causes local hyperaemia. • Exploited in fMRI (functional studies). • Primary mediators unknown: NO, adenosine, K+ (?). • Secondary mediators: ↑, ↓.

22. Blood Flow and • CBF very sensitive to changes in local : • vasodilation with ↑. • vasoconstriction with ↓ • Very rapid response. • Mechanism: perivascular pH changes caused by CO2. • However, acidosis in vessel does not CBF↑ because of blood-brain barrier. • Affected by BP: CO2sensitivi-ty↓ with BP↓, and vice versa. • Hypercapnia abolishes auto-regulation (see resp. control). Guyton & Hall (2006), 11. ed.

23. Blood Flow and Patton et al. (1989), 21. ed. • Little effect of on CBF under normal conditions; but with • mild hypoxia (45 torr): doubling of CBF; severe hypoxia (20 – 30 torr): maximal vasodilation (high altitude oedema…). • Hyperbaric hyperoxia: CBF↓ slightly (of little value…). • Metabolic or neural mechanism (?).

24. Take-Home Messages • Coronary perfusion is largest during diastole. • Autoregulation renders flow independent of aortic pressure. • Metabolic effect more powerful than neuronal. • ATP, NO and adenosine play a crucial role in metabolically regulating cardiac perfusion. • Only large stenosis (>80%) causes a significant flow limitation at rest. • Cerebral vascular bed is special because it has a parasympathetic innervation. • Metabolism is the most important determinant of resistance. • Regulation happens at local level to limit volume changes. • is the most important determinant of CBF.

25. MCQ Helmut Fringer, a 28 year-old medical student, has an assessment of his coronary circulation under strenuous exercise. Which of the following statements best describes the coronary circulation during exercise? • Increased O2 supply is mainly achieved via increased O2 extraction than an increase in blood flow. • Increased cardiac sympathetic fibre activity raises coronary perfusion. • Increased ATP availability contributes to vasodilation. • Blood flow is increased by release of acetylcholine. • Autoregulation is suppressed.

26. That’s it folks…

27. MCQ Helmut Fringer, a 28 year-old medical student, has an assessment of his coronary circulation under strenuous exercise. Which of the following statements best describes the coronary circulation during exercise? • Increased O2 supply is mainly achieved via increased O2 extraction than an increase in blood flow. • Increased cardiac sympathetic fibre activity raises coronary perfusion. • Increased ATP availability contributes to vasodilation. • Blood flow is increased by release of acetylcholine. • Autoregulation is suppressed.