Cardiovascular Physiology

Electrical Activity of the Heart 

MYOCARDIUM 

• Nodal cells 
  • Automaticity = intrinsic ability to depolarise  
  • SA node (R atrium) via anterior, middle (Wenckebach) and posterior (Thorel) tracts + Bachmann’s bundle (inter-atrial) ->  AV node ->  bundle of His ->  L and R bundle branch ->  Purkinje fibres  
  • SA node: 
    • Develops from R side of embryo, supplied by R vagus 
    • Intrinsic rate 60-80bpm  
  • AV node: 
    • Develops from L side, supplied by L vagus  
    • Has 0.1 second delay to allow atrial contraction prior to ventricles 
    • Fewer gap junctions and smaller diameter of fibres = slower conduction  
  • Sympathetic fibres from stellate ganglion 
  • NE fibres epicardial, vagal fibres are endocardial 
• Contractile cells 
  • Consist of contractile proteins (actin, myosin, troponin) + sarcoplasmic reticulum  

PROPERTIES OF CARDIAC MUSCLE 

Nodal cell

• Nil true resting MP 
• Pacemaker potential – 60mV  
• Na+ influx via “FUNNY” Na+ channels to -55 mV ->  
• Ca2+ influx via T-type Ca2+ channels to -40 mV ->  
• Aggressive Ca2+ influx via L-type Ca2+ channels to +40mV (depolarisation) 
• Many cations in cell – pass via GAP JUNCTIONS to other nodal cells or contractile cells to depolarise as a unit.  
• Na channels close at +40 mV ->   
• K+ efflux via voltage gated K+ channels (repolarisation) 
• GAP JUNCTION + DESMOSOME = INTERCALATED DISC. Keep cells close together to allow passage of ions.  

Contractile cell

• Resting MP – 90mV  
• Threshold MP – 70mV  
• Ion passage via Gap Junctions leads to TP = AP = spreads “syncytium”  
• Action potential phases: 
  • 0 Rapid depolarisation 
    • Na+ influx via VG Na+ channel 
  • 1 Initial rapid repolarisation 
    • Inactivation of Na+ channels 
    • Some Ca2+ influx via L-type Ca2+ channels 
    • K+ efflux  
  • 2 Plateau  
    • More Ca2+ influx > K efflux  
  • 3 Slow repolarisation 
    • Ca2+ channels close  
    • K+ efflux  
  • 4 Resting  
    • Slow K+ efflux  
• Sarcoplasmic reticulum: 
  • Calcium/ calmodulin binds RYR-2 R ->  opens channel and releases more Ca2+ into sarcoplasm ->  enables cross bridges between actin/ myosin ->  contraction.  
  • Ca2+ is transported back into SR via Ca2+ ATPase or out of cell via 3Na/2Ca exchange ->  relaxation. 

Sympathetic nervous system

• Stellate ganglion (C6-7) ->  fibres to epicardium, release NE/E onto B1 R: 
• Activates G stimulatory protein ->  formation of cAMP via adenylate cyclase ->  increases protein kinase A (pKa) ->  phosphorylates Ca2+ channel ->  increased activity.  
• NODAL CELLS =  
  • Increased Ca2+ influx = quicker AP = increased HR. 
  • Positive chronotrope. 
• CONTRACTILE CELL =  
  • Increased Ca2+ influx = RYR-2 releases more Ca2+ = increased cross bridging = increased contraction.  
  • Positive inotrope.

Parasympathetic nervous system

• Fibres from vagus nerve to endocardium, release Ach onto M2 muscarinic R: 
• Activates G inhibitory protein = 
• Alpha subunit inhibits adenylate cyclase ->  reduce cAMP and pKa, reduce Ca2+ influx. 
• Beta/Gamma subunits ->  open more K+ channels, increased K+ efflux = cell more negatively charged. Decrease AP and HR and hyperpolarise cell.  

DIGITALIS: Two actions 

1. Depresses AV nodal tissue ->  decreased HR and better cardiac filling  

2. Improves contractility via: 
   • Inhibits Na+/K+ ATPase ->  increased [Na+] intracellularly ->  impair 3Na/2Ca2+ exchanger due to gradient shift ->  increased intracellular Ca2+ thus stored in SR ->  better contraction 

ECG 

Basics: movement towards positive electrode = positive deflection

Lead II: 

P wave = atrial depolarisation, SA node ->  AV node  

PR interval = delay at AV node  

Q = first negative deflection, interventricular septum depolarisation (LBB depolarises septum and sends impulses to RBB, NET VECTOR = away from positive electrode 

R = ventricular depolarisation, as LV thicker than RV NET VECTOR = skewed to L side 

S = depolarisation upwards through ventricles, negative deflection 

ST segment = entire myocardium depolarised (positive) and has not yet repolarised 

T = negative charges moving away from positive electrode NET positive deflection 

Bipolar leads: I, II, III = coronal view  

Unipolar leads: V1 (4^th ICS parasternal) – V6 (5^th ICS MAL), aVL, aVR and aVF = transverse view  

Bundle of His Electrogram: 

A deflection – AV node activation ->  H spike – transmission through His ->  V – ventricular depolarisation  

ARRHYTHMIAS 

1. Sinus arrhythmia  

• Variable heart rate with phases of respiration 
• Normal phenomenon 
• Due to fluctuations in parasympathetic output to heart with respiration: 
  • Inspiration = vagal impulses from stretch R in lungs inhibit cardio-respiratory centre in medulla ->  reduced vagal tone to heart ->  HR increases 

2. Sick Sinus Syndrome  

• Bradycardia/ tachycardia syndrome  
• Age >50 secondary to degeneration of conduction system or after heart surgery 

3. Heart block 

• First degree: slowed conduction between atria and ventricles 
  • All atrial impulses reach ventricle 
  • Lengthened PR interval  
• Second degree 
  • Not all atrial impulses reach ventricle  
  • Mobitz I (Wenckebach)= progressive prolongation of PR interval culminating in dropped P wave  
    • Usually benign rhythm 
  • Mobitz II  = intermittent non conducted P waves with constant PR interval, 2:1 or 3:1 block 
    • More likely to be associated with haemodynamic instability and 3^rd degree heart block 
    • Mandates admission for monitoring and pacemaker insertion  
• Third degree: atrioventricular dissociation “Escape rhythm” 
  • Idioventricular rhythm = ventricles beat at low rate, independent of atria  
  • Block may be due to AV nodal disease (AV block at 45 bpm) or conducting system below AV node (infranodal block at 15-35 bpm) 
  • Heart block causes asystolic periods, causing cerebral ischaemia (syncope, dizziness) = Stokes- Adams syndrome  
  • Clinically: JVP cannon a waves due to RA contracting against closed tricuspid valve  
• LBBB/ RBBB 
  • Impulse travels down normal bundle then sweeps back through muscle to activate ventricle on blocked side  
  • QRS prolonged and abnormal morphology  
  • Left bundle branch fascicular block: 
    • Anterior – Left axis deviation  
    • Posterior – Right axis deviation  
• Bifascicular block = RBBB with LAFB (or less commonly LPFB)  
• Trifascicular block 
  • Complete = 3^rd degree HB 
  • Incomplete = 1^st deg HB + LAFB/LPFB + RBBB 

4. Ectopic Foci of Excitation = increased automaticity  

Irritable focus can discharge once (premature beat) or repetitively (rapid, regular tachycardia).  

• Re-entry tachycardia = transient block present (refractory period), impulse travels down other side and may travel retrograde direction (circus movement)  

• AVRT = involves anatomical re-entry circuit  
  • 200-300/min 
  • Often triggered by premature atrial or ventricular beats 
  • Divided into orthodromic (usually normal QRS unless pre-existing BBB) and antidromic (wide QRS, mistaken for VT) 

• AVNRT = most common cause of palpitations in patients with structurally normal hearts  
  • 140-280/min, regular  
  • Re-entrant pathway is within AV node involving fast and slow pathways 
  • P wave: 
    • Nil visible = slow-fast (80-90%) 
    • Visible after QRS = fast- slow (10%) 
    • Visible before WRS = slow- slow (1-5%)
  • Tx: vagal manoeuvres, adenosine  

• Atrial arrhythmias: SVT 
  • Paroxysmal atrial tachycardia – >100/min, due to single ectopic focus 
    • Paroxysmal or sustained 
    • Involving re-entrant activity/ increased automaticity  
    • Abnormal P wave morphology  
    • Causes = digoxin toxicity, atrial scarring, catecholamine excess, idiopathic 
  • Multifocal atrial tachycardia – 110-150/min, irregular rhythm arising from multiple ectopic foci 
    • Three different P wave morphologies  
    • Usually occurs in elderly patients with respiratory failure  
  • Atrial flutter – rate 200-350/min, caused by re-entry circuit within RA 
    • Sawtooth pattern, associated with 2:1 or greater AV block and loss of isoelectric baseline  
    • Anticlockwise re-entry 90% cases = inverted flutter waves II, III, aVF and positive flutter waves V1  
    • Can be detected via Lewis Lead system  
  • Atrial fibrillation – 300-500/min, atria and ventricles beat at irregular rate secondary to discharge of one or more ectopic foci (in pulmonary vein) 
    • Fast AF = 160-180/min 
    • AF with aberrancy: wide QRS  
      • Due to bundle branch block 
      • Due to accessory pathway (WPW)  
    • Can be difficult to differentiate VT and SVT with aberrancy 
  • Consequences: 
    • In paroxysmal atrial tachycardia/ flutter – ventricular rate so high that diastole is too short for adequate filling of ventricles ->  reduced CO ->  HF  
    • Stimulating vagal reflex discharge (oculocardiac reflex, carotid sinus massage) ->  ACh release depresses atrial conduction converts tachycardia to sinus rhythm  

• Ventricular arrhythmias  
  • VT – rapid regular ventricular depolarisations  
    • Extreme axis deviation “northwest axis” 
    • Fusion beats = sinus and ventricular beat coincide to produce hybrid complex  
    • Capture beats = SA node transiently ‘captures’ ventricles to produce normal QRS complex  
    • AV dissociation  
    • Positive or negative concordance in chest leads (V1-6) = entirely position (R) or negative (QS) complexes  
    • RSR complex with taller LEFT rabbit ear

• Torsades – form of VT with varying QRS morphologies  
• VF – irregular and ineffective ventricular contractions due to discharge of multiple ventricular foci or circus movement  
  • Can be produced by electric shock “R on T phenomena” as ventricles are incompletely repolarised  

5. Long QT Syndrome  

• QT interval prolongation ->  irregular cardiac repolarisation ->  increased risk of ventricular arrhythmias  
• Causes: Drugs, electrolyte abnormalities, MI, congenital (genetic mutations of K+ or Na+ channels) 

6. Accelerated AV conduction 

Wolff- Parkinson- White Syndrome  

• Additional aberrant muscular or nodal tissue connection (Bundle of Kent) between atria and ventricles 
• Bundle of Kent conducts more rapidly than AV node and one ventricle is excited early ->  short PR interval + slurred upstroke and prolonged QRS ->   

Lown– Ganong– Levine Syndrome  

• Aberrant bundle bypasses AV node and enters interventricular conducting system distal to AV node = short PR + normal QRS ->  paroxysmal SVT  

Condition	ECG sign
ARVD (arrhythmogenic RV dysplasia)	Epsilon wave = small positive deflection buried at end of QRS
Wolf Parkinson White	Delta wave = slurred upstroke in QRS associated with short PR interval
Brugada Syndrome	Coved ST segment V1-2 ~ Brugada sign (Type I) and is potentially diagnostic, must be associated with other clinical criteria  Other ECG signs for Types II/ III
Anterolateral STEMI	STE in precordial leads V1-6  STD in reciprocal inferior leads   V1-2 are septal leads  V3-4 are anterior  V5-6 are lateral I/aVL are high lateral
Inferior STEMI	STE II, III, aVF (III>II s/o RV) Reciprocal depression aVL  STE V1 or V4R suggests RV infarction
Posterior STEMI	STD in V1-3 -> request posterior ECG
L main occlusion	Coved STE in AVR and widespread STD
Proximal LAD occlusion	Biphasic T wave V1-V4 “Wellens”  OR deeply inverted T wave V1-V4
PE	Sinus tachycardia  RAD, RBBB  S1Q3T3  Non specific ST/ T wave changes	https://litfl.com/ecg-changes-in-pulmonary-embolism/

Treatment of arrhythmias  

• Drugs: 
  • Na+ channel blockers – slow influx Na+ and variably alter action potential duration
  • K+ channel blockers – prolong refractory period  
  • Ca2+ channel blockers – slow SA and AV conduction  
  • Beta blockers – reduce activation of Ca2+ channels  
• Ablation of aberrant pathway 

ECG in other diseases 

1. Myocardial infarction  

• Infarcted cells: 
  • Immediate = accelerated opening of K+ channels ->  abnormally rapid repolarisation 
  • Few minutes = resting membrane potential of infarcted fibres decreases due to loss of intracellular K+  
  • 30 minutes = slower depolarisation  

• Initially, infarcted area is positive relative to myocardium causing current to travel from infarcted tissue to normal tissue during isoelectric phase -> TP segment depression (seen as ST segment elevation on ECG)
• Days to weeks, dead muscle becomes electrically silent  
• Infarcted area becomes negative relative to normal myocardium, common changes: 
  • Q wave 
  • Failure of R wave progression 
  • Bundle branch blocks  

Complications: “CRASH PAD” = cardiac rupture, arrhythmia, shock, HTN/ HF, pericarditis/ PE, LV aneurysm, DVT  

2. Hyperkalaemia  

• Tall peaked T waves (altered repolarisation) ->  prolongation of QRS ->  sine waves ->  dropped P waves ->  ventricular arrhythmias  
• RMP decreases as extracellular K+ increases  
• Paralysis of atria, fibres become unexcitable and heart stops in diastole  

3. Hypokalaemia 

• Prolongation of PR interval ->  prominent U waves ->  late TWI  

4. Hypercalcaemia  

• Heart relaxes less during diastole and eventually stops in systole (calcium rigor) 

5. Hypocalcaemia  

• Prolongation QT interval  

Heart As a Pump 

Mechanical Events of the Cardiac Cycle 

Duration of cardiac cycle = 0.8 seconds  

• Systole = 0.27 seconds  
• Diastole = 0.53 seconds  
• Duration of systole is more fixed, at higher HR ->  diastole shortened ->  impede filling and reduce CO  
• Diastole events: 
  • Heart muscle rests 
  • Coronary blood flow to subendocardial portions of LV 
  • Ventricular filling  

Action potential = 0.25 seconds  

• Refractory periods due to Na+ channels go from inactivated ->  closed ->  open state 
  • Absolute refractory period ~ 0.2 seconds = Na+ channels inactivated and nil AP possible  
  • Relative refractory period ~ 0.05 seconds = second AP could be fired if stimulus great enough, due to some Na+ channels in closed state  
• Cardiac muscle cannot contract in response to second stimulus near end of initial contraction 
• Cannot be tetanized (summed contractions) like skeletal muscle ->  has shorter refractory periods  
• Theoretically, highest rate of ventricular contraction = 400/ min, however in adults AV node will only conduct ~ 230 impulses/ min due to refractory period  

Duration of isovolumetric ventricular contraction – difficult to measure, however: 

• Total electromechanical systole (QS2) = onset of QRS to second heart sound  
• Pre-ejection period (PEP) = difference between QS2 and LVET  
• LV ejection time (LVET) = beginning of carotid pressure rise to dicrotic notch  

Timing: two side of heart are asynchronous  

• RA systole precedes LA  
• LV systole precedes RV 
• RV ejection begins before LV (as pulmonary trunk pressure < aortic pressure) 
• Expiration: pulmonary and aortic valves close at same time  
• Inspiration: aortic valve closes slightly before pulmonary (lower impedance of pulmonary vascular tree) 

Arterial pulse  

• Blood forced into aorta (4m/s) in systole creates pressure wave = pulse  
  • Radial pulse 0.1s after peak of systolic ejection in aorta  
  • With age, arteries become more rigid and pulse moves faster  
• Strength determined by pulse pressure  
  • Weak “thready” in shock 
  • Strong with large SV  
  • Aortic insufficiency = force of systolic ejection enough to make head nod with each heart-beat = collapsing, Corrigan or water hammer pulse
• Dicrotic notch  = oscillation in falling phase of pulse wave ß vibrations of aortic valve snapping shut  

Atrial pressure changes and Jugular pulse 

• Atrial pressure: 
  • Rises during atrial systole and first part of isovolumetric contraction (AV valves bulge into atria)  
  • Falls as ventricles contract (AV valves pulled downwards) 
  • Rises as atria fill in early diastole (AV valves open) 
• 3 waves in JVP 
  • A = atrial systole (some blood regurgitates into venous system + inflow stops) 
  • C = bulging tricuspid valve into atria during isovolumetric contraction 
  • V = rise in pressure prior to tricuspid valve opening in diastole  
  • Superimposed on respiratory cycle as VR increases during expiration and decreases during inspiration (increase in negative intrathoracic volume) 

Heart Sounds  

• S1 “Lub” = AV valve closure @ start of ventricular systole  
• S2 “Dub” = SL valve closure @ end of ventricular systole  
  • May be split if interval between AV and PV (physiologic/ pathologic)  
• S3 = 1/3 way through diastole, due to rapid ventricular filling and vibrations due to inflow of blood  
• S4 = immediately before S1, due to high atrial pressure or stiff ventricle filling (LVH) 

Murmurs

Cardiac Output 

CO = HR x SV  

Normal ~ 70 x 70 = ~ 5L/min  

Normal EF ~ 65% 
Healthy person can increase SV by <200% and increase CO by 700%. 

Two determinants: 

1. HR  

• 60-80 bpm via SA node 
• Factors which increase: 
  • SNS via NE/E ->  b1 R + chronotrope 
  • T3, T4 ->  increased BMR ->  increased temperature 
  • Hyper Ca2+ 
  • Hypo K+ 
  • Low PO2/ high PCO2/ low pH via chemo R (secondary action on cardiac centre) 
  • Drugs  
  • Anxiety  
  • Atrial Bainbridge reflex = increased VR ->  atrial stretch ->  cardiac centre ->  increase HR  
• Factors which decrease: 
  • PNS via Ach ->  mu R – chronotrope  
  • Hypo Ca2+ 
  • Hyper K+  
  • Elite athletes due to high SV  
  • Drugs  
• Age (infants have higher HR ~ 120-140 bpm) 

2. SV 

• End diastolic volume (EDV) ~ 120 mL  
• End systolic volume ~50-70 mL  
• SV = EDV – ESV = 70mL/ beat  
• Dependent on 3 factors: 
  • Preload = degree of stretch in myocardium during filling  

Frank Starling Law: increased stretch allows more cross bridge connections and increased force of contraction 

Length of cardiac muscle fibres proportional to EDV  

Frank Starling Curve: relationship between SV and EDV  

• Heterometric regulation = CO regulated by changes in cardiac muscle fiber length  

• Homometric regulation = CO regulated by changes in contractility independent of length  

• Stroke volume increases with end-diastolic volume 
• The relationship is not linear and plateaus at high end-diastolic volumes 
• Increased contractility increases the stroke volume at any given end-diastolic volume 
• With poor contractility, stroke volume may begin to decrease with increasing end-diastolic volume 
• EDV via venous return  
  • Muscle and respiratory pump  
  • Venomotor tone 
  • Thoracic and abdominal pressure   
• Filling time (increase HR = decreased filling time) 
• Intrapericardial pressure (increased by inflammation/ fluid = limits filling) 
• Ventricular compliance (decreased by infiltrative disease/ stiffness due to MI) 

• Contractility  
  • SNS via NE/E ->  b1 R ->  increases intracellular Ca2+ ->  increase contractility 
  • Lactate depresses myocardium  
  • Hormones: T3/T4 increase expression of b1 R, glucagon increase cAMP 
  • Drugs: 
    • Increase = digitalis, dopamine, dobutamine, atropine  
    • Decrease = beta blockers, Ca2+ blockers  
  • Ions:  
    • Increase = Hyper Ca2+ 
    • Decrease = Hypo Ca2+, Hyper K+/ Na+/ H+  

• Afterload = amount of resistance which must be overcome for ventricles to eject blood  
  • Increase in setting of HTN, aortic plaques, aortic stenosis  

Methods of measurement  

• Doppler method on ECHO 
• Direct Fick method 
  • LV output = O2 consumption (mL/min)/ (Arterial – venous blood O2 content mL/L) 
  • LV output = 250 mL/min/ ((190- 140 mL/L) = 5L/min  
• Indicator dilution method  
  • Radioactive isotope injected into vein and samples of arterial blood measured  

CO in various conditions  

Oxygen consumption by heart  

• 9mL/100g/min at rest  
• Increase in afterload causes greater increase in oxygen consumption than increase in preload  
  • Angina is more common in aortic stenosis than aortic insufficiency  
• Transplanted heart (nil neural input) relies on increase in SV rather than HR to raise CO in setting of exercise  

Cardiac Function in Health and Disease 

Gravitational effects  

• Dependent on blood volume (high = minimal effect, low = marked effect) 
• Standing position: MAP in feet 180-200 mmHg and in head 60-75 mmHg 
• If no movement, 300-500mL blood pools in venous system ->  reduction in SV ->  cerebral ischaemia  
• Muscle pump aids venous return  
• Compensations occur via carotid/aortic bodies: 
  • Increase HR  
  • Increase renin and aldosterone  
  • Arteriolar constriction  
• Compensations in cerebral circulation:  
  • Reduced cerebral blood flow = reduced ICP = increase PCO2 
  • Dilation of cerebral vessels  

Postural Hypotension = standing causes fall in blood pressure 

Causes: 

• Primary autonomic failure  
  • Congenital deficiency of dopamine beta- hydroxylase (little/ no production of NE/E) 
• Sympatholytic drugs 
• Diabetes, syphilis ->  damage to SNS  
• Idiopathic  

Effects of Acceleration 

• Positive g force (long axis of body from head to foot) 
  • Blood “thrown” into lower part of body 
  • Reduced arterial pressure to head, CO maintained for a time as blood drawn from pulmonary reservoir  
  • At 5g + loss of consciousness 
  • Negated by anti-gravity suits = compress abdomen and legs with force proportionate to positive g = decreased venous pooling + increased VR  

• Negative g force (opposite) 
  • Increased cardiac output + rise in cerebral arterial pressure  
  • Intense congestion of head and neck vessels ->  ecchymosis around eyes, severe headache, mental confusion  
• Across body g = better tolerated, 11 g back-to-chest direction for 3 mins and 17 g chest-to-back direction for 4 mins (astronauts positioned this way) 

Effects of Zero Gravity  

• CVS function maintained for 14 months, on return disuse atrophy causing postural hypotension ->  re-adaptation in 7-14 weeks  
• Atrophy of skeletal muscle 
• Space motion sickness 
• Loss of plasma volume  
• Loss of bone mineral density  
• Loss of red cell mass  

Exercise

Shock = inadequate tissue perfusion  

Hypovolaemic (decreased blood volume) 

• Haemorrhage, trauma, surgery, burns, fluid loss via diarrhoea/ vomiting  
• Compensatory mechanisms: 
  • Vasoconstriction 
  • Tachycardia, tachypnoea (increase thoracic pump) 
  • Restlessness (muscle pump) 
  • Movement of interstitial fluid into capillaries 
  • Hormone secretion = NE/E, vasopressin, glucocorticoids, renin/ aldosterone, EPO 
  • Increased plasma protein synthesis  
  • Renal = constriction of afferent/ efferent, Na+ retention, uraemia/ ARF  
• Refractory shock (irreversible) secondary to: 
  • Severe cerebral ischaemia ->  depression vasomotor, cardiac areas of brain 
  • Myocardial depression and reduced coronary blood flow 
  • ARDS  

Distributive (marked vasodilation) 

• Fainting = autonomic activity causes vasodilation (vasovagal) 
• Anaphylaxis = Ag-Ab releases histamine from mast cells  
• Sepsis = endotoxins cause vasodilation/ cytokine and coagulant reactions ->  end organ dysfunction  

Cardiogenic (inadequate output by diseased heart) 

• MI, CCF, arrhythmia  

Obstructive (obstruction of blood flow) 

• Tension pneumothorax, PE, tamponade  

Hypertension = sustained elevation of arterial pressure 

• Causes: 
  • Essential (cause unknown) 
  • Renal  
  • Endocrine = primary aldosteronism, Cushing’s, Phaeochromocytoma  
  • Miscellaneous = Liddle’s (mutation in ENaCs), coarctation of aorta  
• Effects: 
  • Increase afterload ->  LVH (further increase myocardial oxygen demand) ->  decrease in coronary blood flow has more serious consequences  

Heart failure = pump failure and inability to distribute blood to meet tissue demands 

• Systolic = weak ventricular contraction causes reduced SV ->  increase in EDV and fall in EF  
  • Initial response is cardiac remodelling + Na+/water retention  
• Diastolic = elasticity of myocardium reduced ->  reduced diastolic filling  

• Symptoms  

• Treatment  
  • Improving cardiac contractility  
    • Beta blockers, digoxin  
    • Dobutamine/dopamine/adrenaline
  • Decreasing load on heart  
    • ACE I/ ARB (reduces afterload) 
    • Nitrates/ hydralazine (reduces preload) 
    • Diuretics  
  • Treat underlying cause e.g. revascularisation

Circulation 

Blood and Lymph Flow 

Angiogenesis = Proliferation of blood vessels 

• Vascular endothelial growth factor (VEGF) 

Biophysics 

Flow, pressure and resistance:  Flow (mL/second) = Pressure (mmHg) / Resistance (R units) 

In the vascular system, 

Pressure = mean intraluminal pressure at arterial end – mean pressure at venous end. 

Eg. Mean aortic pressure is 90 mmHg and LV output is 90 mL/second 

TPR = 90 mmHg/ 90 mL/s = 1 R unit. 

Methods for measuring blood flow: 

Doppler flow meters  

Plethysmography  

Laminar flow:  

• Within blood vessel, thin layer of blood is in contact with vessel wall ->  doesn’t move 
• Next layer has low velocity, increasing until centre of stream has highest velocity  
• Occur up to “critical velocity” after which, flow becomes turbulent  
• Streamline flow is silent, turbulent flow creates sound  
• Disturbed at branching of arteries  

Turbulent flow: 

• Probability related to diameter of vessel and viscosity of blood  
• Re = pDV/ n  
  • Re is Reynold number  
  • p is density of fluid  
  • D is diameter of tube (cm) 
  • V is velocity of flow (cm/second) 
  • n is viscosity of fluid  
  • Re <2000 = flow not turbulent  
  • Re >3000 = turbulent flow present  
• Examples: 
• Constriction of artery ->  increases velocity of blood flow ->  turbulence ->  sound heard  
  • Bruits heard over arteries with atherosclerotic plaques  
  • Sounds of Korotkoff when measuring BP 
• Occurs more frequently in anaemia as viscosity of blood is lower (producing systolic murmur) 

Shear stress and gene activation  

• Flowing blood creates force on endothelium that is parallel to long axis of vessel  
• Shear stress (y) is proportionate to viscosity (n) x shear rate (dy/dr = rate at which axial velocity increases from vessel wall toward lumen)  
  • y = n (dy/dr)  
• Changes in shear stress produce changes in gene expression in endothelial cells 
• Produce growth factors, integrins 

Average Velocity  

• Velocity = displacement per unit time (cm/s) 
• Flow = volume per unit time (cm³/s) 
• A = area of conduit 
  • V = Q/A and Q = VA  
• If flow stays constant, velocity inversely proportional to area  

• Examples: 

Average velocity of blood is high in aorta, declines steadily in smaller vessels and is lowest in capillaries (1000 times total area of aorta).  

Average arm to tongue circulation time is 15 seconds  

Poiseuille-Hagen Formula  

•  Relationship between flow in long narrow tube, viscosity of fluid and radius of tube 
•  Flow is proportional to the pressure difference between the two ends of the tube and inversely proportional to the viscosity and length 
• Simplified, R = 8nL/ pr⁴  
  • R resistance  
  • n viscosity  
  • L length of tube  
  • r radius of tube  
• Blood flow and resistance markedly affected by small changes in calibre of vessels  
• Change in radius alters resistance to 4^th power, therefore 2 fold increase in radius decreases resistance by factor of 16  
• Example: 
  • Flow through vessel is doubled by increased of only 19% in radius  
  • When radius is doubled, resistance is reduced to 6% previous value  
• Explains why organ blood flow is effectively regulated by small changes in calibre of arterioles and how arteriolar diameter have such pronounced effect on systemic arterial pressure  

Viscosity and Resistance  

• In vivo, deviates from prediction in Poiseuille Hagen  
• Whole blood is 3-4 times as viscous as water ->  depends on haematocrit (% blood volume occupied by RBC) 
• Large vessels = increased haematocrit/ n lead to increased R  
• Smaller vessels (arterioles, capillaries and venules) = viscosity change per unit change in haematocrit is much less  
  • Due to difference in nature of flow  
  • Net change is significantly smaller 
• Explains why small haematocrit changes have relatively little effect on TPR  
• Increased n ->  increased TPR and cardiac work 
  • Large haematocrit changes (eg. polycythaemia)  
  • Elevated Ig 
  • Spherocytosis 
• Decreased n ->  decreased TPR  
  • Anaemia = improved blood flow partially compensates for reduced ability to carry oxygen  

Critical closing pressure 

• Pressure in small tube reduced to point where flow ceases = collapse  

Law of Laplace  

• Relationship between distending pressure and tension  
• Tension in wall of cylinder = transmural pressure x radius/ wall thickness  
• T = Pr/ w 
  • Transmural pressure can be ignored as low tissue pressure in body 
  • P equated to pressure inside viscous  
  • w is very small, can be ignored in thin walled vessels  
• In a sphere, P = 2T/r  
• In a cylinder, P = T/r  

• Smaller radius of blood vessel, lower wall tension necessary to balance distending pressure  
• Small diameter of capillaries prevents them from rupturing according to Law of Laplace  
• Examples: 
  • Vessels =  
    • Aorta, tension at normal pressure is 170 000 dynes/ cm  
    • Vena cava, tension at normal pressure is 21 000 dynes/cm 
    • Capillaries, is 16 dynes/cm  
  • Heart =  
    • Radius of cardiac chamber increased (dilated), greater tension required in myocardium to produce any given pressure  
  • Lungs = 
    • Radii of alveoli become smaller during expiration and collapse is prevented due to surface tension lowering agent surfactant’ 

Bernoulli Principle  

• Greater velocity of flow in a vessel, lower lateral pressure distending its walls  

• When vessel is narrowed ->  velocity of flow in narrowed portion increases and distending pressure decreases  

Resistance and Capacitance Vessels 

• Large amount of blood can be added to venous system before veins are distended and venous pressure rises = capacitance vessels  
• Arterioles are site of peripheral resistance = resistance vessels  

• Circulating blood volume: 
  • 50% in veins 
  • 12% in heart cavities 
  • 18% in low pressure pulmonary system 
  • 2% aorta, 8% arteries, 1% arterioles and 5% in capillaries  

• Blood transfusion = 1% added to arterial system (high pressure) and remaining to pulmonary/ systemic veins and heart chambers OTHER THAN LEFT VENTRICLE (low pressure system) 

Blood Circulation 

Artertiolar

• Aorta – flow is phasic, greater in systole due to ability to recoil = “Windkessel” effect  
• Systolic/ diastolic pressure 
• Pulse pressure = difference between systolic and diastolic, usually ~50 mmHg  
• Mean pressure = average in cardiac cycle  
  • MAP = diastolic pressure + 1/3 pulse pressure  
  • MAP at end of arterioles ~ 30-38mmHg. 
• Effect of Gravity: 
  • Pressure in vessels below heart are increased ~ 0.77 mmHg/cm  
  • Eg. Upright human, MAP at heart level is 100 mmHg, MAP in: 
  • Head = 62 mmHg (50cm above heart thus, 100 – (0.77x 50) 
  • Foot = 180 mmHg 
• Measuring methods: 
  • Arterial line  
  • Auscultation method =  Riva-Rocci cuff inflated until brachial artery occluded (above SBP, no sounds heard) ->  cuff pressure slowly released causing spurt of blood with each heart beat (SBP > cuff pressure, sounds of Korotkoff due to turbulent blood flow) indicate SBP ->  lowering cuff pressure further leads to louder then muffled and dull sounds ->  disappear (artery no longer occluded). Cuff pressure when sounds disappear indicate DBP except, in adults post exercise/ children/ hyperthyroidism or aortic insufficiency where DBP is when muffled sounds are heard.  
  • Palpation method = inflating arm cuff and palpating radial pulse ~ 5mmHg inaccurate 

Capillary

• Contain 5% blood volume  
• Nail bed capillaries ~32 mmHg at arterial end and 15mmHg at venous end  
• Pulse pressure ~ 5mmHg at arteriolar end and 0 at venous end. 
• Large total cross sectional area. 
• Transit time ~1-2 seconds 
• Transport across wall: 
  • Junctions/ fenestrations 
  • Vesicular  
  • Diffusion 
    • Flow limited  
    • Diffusion limited  
  • Depends on balance of forces = Starling forces 
    • Hydrostatic  
    • Oncotic  
• Typical muscle capillary: Arteriolar end, fluid moves into interstitial space (H>O) and into capillary at venous end (H<O) 
• Renal glomeruli: 
  • Fluid moves out entire length 
• 24 L filtered daily and 85% reabsorbed/ 15% returned via lymphatics.  
• Resting tissues, capillaries are collapsed. 
• In active tissues, meta-arterioles and capillary sphincters dilate = overcome critical closing pressure of vessels and blood flows through capillaries.

Venous

• Pressure 12-18 mmHg 
• Affected by gravity = increased by 0.77 mmHg for each cm above RA  
• Velocity of blood in great veins ~ 10cm/ second  
• Aided by: 
  • Heartbeat 
    • Atrial pressure drops sharply during ventricular systole due to AV valves pulled downwards  
    • Blood sucked into atria from great veins ->  contributes to VR during rapid heart rates  
    • Slow heart rates ->  two period of peak flow during ventricular systole and early diastole  
• Increase negative thoracic pressure during inspiration: 
  • Intrapleural pressure falls  from -2.5 to -6 mmHg 
  • Drop in venous pressure 6mmHg (exp) to 2mmHg (insp) 
  • Aids venous return  
  • Rise in intra-abdominal pressure also squeezes blood toward heart  
• Skeletal muscle pump 
  • Contraction of muscles compresses veins  
• Venous pressure in the Head: 
  • Upright position, venous pressure above heart decreased by gravity  
  • Dural sinuses have rigid walls and cannot collapse = pressure is negative 
  • Example. During neurosurgical procedures, opening sinuses may result in air embolism (sucked in). 
• Measuring methods: CVL  

Lymphatics

• 2-4L over 24 hours  
• Two types: 
  • Initial = lack valves or smooth muscle, located in intestine or skeletal muscle. Fluid is massaged along and drains into collecting lymphatics
  • Collecting = contract in peristaltic fashion 
• Lymphagogues increase lymph flow. 
• Variable quantities of protein depending on tissues draining.  

Interstitial fluid 

• Increase volume and oedema due to: 
  • Increase filtration pressure  
    • Arteriolar dilation
    • Venular constriction 
    • Increased venous pressure  
      • CCF, incompetent valves, venous obstruction, increased total ECF, gravity) 
  • Decreased osmotic pressure gradient across capillary 
    • Decreased plasma protein level 
    • Accumulation of osmotically active substances in interstitial space 
  • Increased capillary permeability  
    • Substance P 
    • Histamine, kinins, lactate  
    • Hyperkalaemia, increased osmolality, increased temperature 
    • Hypoxia  
  • Inadequate lymph flow  
    • Obstruction 
      • Radical mastectomy and removal of axillary lymph nodes reduces lymph drainage 
      • Filariasis  

Cardiovascular Regulatory Mechanisms 

Local

• Autoregulation = intrinsic capacity to alter resistance to compensate for different perfusion pressures 
• Vasodilator metabolites 
  • decreased O2 
  • pH  
  • increased osmolality  
  • increased CO2  
  • increased temp  
  • hyperkalaemia  
  • histamine  
  • adenosine 
  • ANP 
  • lactate  
• Localised vasoconstriction 
  • platelet serotonin  
  • decreased temp  
• Substances secreted by endothelium: 
  • VASODILATOR 
    • Prostacyclin (via endothelial cells) 
    • NO (aka  endothelium derived relaxing factor) 
    • Synthesised by arginine, activated guanylyl cyclase to make cGMP  
    • Inactivated by Hb 
    • CO
    • Kinins  
  • VASOCONSTRICTION 
    • Thromboxane A2 (via PLT) 
    • Endothelin-1 
      • Not stored in secretory granules 
      • Stimulated by angiotensin II, growth factor, catecholamines, hypoxia, insulin, oxidized LDL, HDL, thrombin and shear stress 
      • Inhibited by NO, ANP, PGE2 and prostacyclin  

Hormonal

• Vasodilator
  • Epinephrine in skeletal muscle and liver  
  • CGRPa 
  • Substance P 
  • Histamine 
  • ANP 
  • VIP  
• Vasoconstriction
  • Epinephrine elsewhere 
  • Norepinephrine 
  • AVP 
  • Angiotensin II 
  • Circulating Na/K ATPase 
  • Neuropeptide Y 

Nervous system

• Vasoconstriction
  • Increased discharge of noradrenergic vasomotor nerves: 
  • Vasomotor area (medulla) ->  Intermediolateral gray column ->  preganglionic sympathetic neuron (Ach) ->  postganglionic sympathetic neuron (NE) onto heart and vessels. 
  • Stimulated by: 
    • CO2, hypoxia  
    • Cortex via hypothalamus (pain, sexual excitement) 
    • Pain (somatosympathetic reflex) 
    • Carotid/ aortic chemoR  
  • Inhibited by: 
    • Lung inflation 
    • Carotid/ aortic/ cardiopulmonary baroR 
    • Dorsal motor nucleus + nucleus ambiguous (medulla) ->  vagal nerve fibers  
• Vasodilator
  • Decreased discharge of noradrenergic vasomotor nerves  
  • Activation of cholinergic dilator fibers to skeletal muscle  

Baroreceptors 

= Stretch R in carotid sinus/ aortic arch, LA/RA/ pulmonary veins ->  monitor arterial circulation 

• Stimulated by distension causing discharge at increased rate  
• Afferent fibers pass via glossopharyngeal/ vagus nerve to medulla = inhibits tonic discharge of vasoconstrictor nerves and excites vagal innervation of heart  

• Vasodilation, reduced heart rate and blood pressure  
• Cutting carotid sinus nerves ->  neurogenic hypertension 

Chemoreceptors  

= Detect changes in PaO2/pH/PaCO2 in carotid body @ bifurcation of common carotid artery and aortic body 

• Responsible for increase in ventilation in response to hypoxemia  
• Cutting carotid bodies ->  loss of hypoxic ventilatory drive  

Valsalva Effect: Four phases 

1. Onset of straining and beginning of increased intrathoracic pressure  

BP rises initially as ITP added to aortic pressure. 

2. Persistent straining and maintenance of thoracic pressure  

BP falls as ITP compresses venous return and decreases CO. Inhibits baroR causing tachycardia and increase TPR. 

3. Release of breath holding and glottic pressure with sudden drop in intrathoracic pressure  

CO restored but peripheral vasoconstriction persists causing high BP.  

4. Sudden increase in cardiac output and aortic pressure which stimulates baroR causing bradycardia and drop BP to normal.  

Circulation through Special Regions 

Cerebral Circulation 

• Inflow to brain via common carotid and vertebrals forming Circle of Willis  
• Supply almost exclusive to each cerebral hemisphere  
• Venous drainage via deep veins and dural sinuses emptying into internal jugular  
• Anatomic features: 
  • Cerebral capillaries = non fenestrated with tight junctions and few vesicles. Mainly lipid soluble diffusion + carrier mediated transport.  
  • Surrounded by astrocytes, end feet applied to basal lamina of capillaries forming gaps  
  • Choroid epithelial cells connected via tight junctions  

• Innervation: 3 sets, first two on large arteries  
  • Post ganglionic sympathetic = cell bodies in superior cervical ganglia, endings contain epinephrine + neuropeptide C + 
  • Cholinergic neurons = originate in sphenopalatine ganglia  
  • Sensory nerves = distal arteries, cell bodies in trigeminal ganglia and contain substance P, neurokinin A, calcitonin gene related peptide (CGRP). Touching or pulling cerebral vessels causes pain.  
  • Role in blood flow regulation is topic of debate  

• CSF:  
  • Total 150mL, 550mL/day production rate  
  • Formed in choroid plexus 
    • Plasma filtration across choroidal epithelium  
    • Active secretion of water and ions  
    • Similar composition to brain ECF  
  • Flows through ventricles ->  foramens of Magendie and Luschka to subarachnoid space ->  absorbed through arachnoid villi into cerebral venous sinuses  
  • Lumbar CSF pressure = 70- 180 mmH20  
  • Accumulation leads to hydrocephalus   
  • Protects brain by permitting buoyancy/ cushioning to blows  
  • Pain caused by CSF deficiency (post LP) is due to increased traction on nerves/ vessels  
• Blood Brain Barrier: 
  • Formed by tight junctions between capillary endothelium and choroid epithelium = prevent proteins from entering and slow penetration of smaller molecules (eg. urea) 
  • Mainly carrier mediated and active transport systems  
  • Strives to maintain constancy of environment for neurons  
  • Substances: 
    • Water, CO2, O2 and lipid soluble steroid hormones enter passively 
    • H+ and HCO3- regulated transcellular route  
    • Glucose actively transported via GLUT 1 
    • Drugs and peptides can cross capillaries but are back transported from apical membranes of epithelial cells via P glycoprotein  
  • Circumventricular organs outside of BBB, all have fenestrated capillaries  
    • Posterior pituitary + median eminence of hypothalamus  
    • Area postrema  
    • Organum vasculosum of lamina terminalis (OVLT) 
    • Subfornical organ (SFO) 

• Cerebral blood flow regulation: 
  • Kety Method with inhaled N2O 
  • Fick Principle = blood flow to any organ can be measured by amount of given substance (Q) removed from blood stream by the organ per unit time/ (difference between concentration in arterial blood and venous blood) 
  • Cerebral blood flow = Q/ (A-V) 
  • 54 mL/100g/min in adults, flow for whole brain 756 mL/min  
• ICP 
  • Kellie-Monro Doctrine = volume of brain, blood and spinal fluid are relatively constant in rigid cranium  
  • Rise in venous pressure ->  decreases perfusion pressure and compresses cerebral vessels ->  decreases cerebral blood flow  
  • Helps compensate for changes in arterial pressure  
• Autoregulation to maintain arterial pressure 65-140 mmHg  
• Flow to various parts of brain  
  • Marked variation with changes in brain activity  
  • At rest, 69 mL/100g/min to gray matter versus 28 mL/100g/ min to white matter  
  • Awake at rest, flow greatest in premotor and frontal region  

• Metabolism and oxygen requirements  
  • Cerebral metabolic rate for O2 is ~20% of total body resting consumption 
  • Extremely sensitive to hypoxia, especially cortex and basal ganglia  
  • Glucose is 90% energy source  
  • Glutamate- glutamine conversion with ammonia = detoxifying mechanism  

Coronary Circulation 

• 2 coronaries arise from sinuses behind cusps of aortic valve at aortic root  
• Venous blood returned via coronary sinus and cardiac veins into RA  
• Arteriosinusoidal vessels, thebesian veins and arterioluminal vessels drain directly to chambers  
• Pressure gradients and flow: ~250mL/min  
  • Heart compresses blood vessels when it contracts 
  • Pressure in LV>aorta during systole ->  flow occurs to subendocardial portion of LV during diastole – can be reduced during tachycardia. More prone to ischaemia during systole. 
  • Pressure in RV<aorta during systole thus flow not reduced during systole under normal circumstances   
• Measured via coronary angiography + radionuclides  
• Variations in flow: 
  • Heart extracts 70-80% O2 from each unit of blood delivered  
  • Blood flow increased when metabolism of myocardium increased  
  • Caliber of coronary vessels affected by: 
    • Autoregulation 
    • Chemical vasodilators = hypoxia, increased CO2/ H+/ K+/ lactate/ PG/ adenine nucleotides/ adenosine  
    • Neural = vasoconstriction via vagal fibers and indirect vasodilation via NE on b R causing increased HR/force + release chemical vasodilators  

Last Updated on September 24, 2021 by Andrew Crofton