Cardiovascular Pharmacology: Heart Anatomy and Electrical Activity

The Heart

The heart contains 4 chambers (2 atria and 2 ventricles). The atria receive venous blood while the ventricles eject blood into arteries. Blood flow within the heart is facilitated by 2 pairs of one-way valves. The heart lies at the centre of the thoracic cavity in the area between the lungs and is enclosed by the pericardium.

Heart Chambers

The heart has 4 chambers:

Right atrium This chamber receives oxygen-depleted, CO2-enriched venous blood from the systemic circulation via the superior vena carva (drains head, neck, arms and thoracic organs) and inferior vena cava (which drains organs below diaphragm)

Right ventricle This chamber receives blood from the right atrium via a 3 flap atrioventricular (AV) valve (tricuspid valve) and pumps blood through the open semilunar (pulmonary) valve into the pulmonary trunk and then on to the pulmonary arteries to supply the pulmonary circulation. Its wall is moderately thick and muscular.

Left atrium This chamber receives freshly oxygenated blood from the pulmonary veins.

Left ventricle This chamber receives blood from the left atrium via a 2 flap AV valve (bicuspid or mitral valve). It is thick-walled and muscular as it must overcome the peripheral vascular resistance to pump blood through the open semilunar (aortic) valve into the aorta and then around systemic circulation.

Atria have a small extension, the auricle and have thin, flaccid walls which are separated by the interatrial septum. Ventricles are separated by the interventricular septum and have internal ridges and folds known as trabeculae carneae. The chambers are demarcated on the surface by grooves known as sulci.

Circulation Overview

A note on the circulation The cardiovascular system is comprised of the heart and blood vessels. There are 2 major divisions: the pulmonary circuit and the systemic circuit. The circulatory system consists of the cardiovascular system, blood and lymphatic system. Great vessels are represented by large diameter arteries and veins, close to the heart.

Heart Valves and Wall

Heart, valves and the heart wall Atrioventricular valves are one-way valves embedded in the fibrous skeleton. The fibrous skeleton is a dense meshwork of connective tissue (collagenous and elastic fibres) bound up with the myocardium. It has 4 major functions:

• electrical insulation of atria from ventricular myocardium, which reduces number of electrical conduction routes through heart
• structural support, e.g. forms supportive rings (annuli fibrosi) around valves and openings of great vessels
• provides a framework for muscle to pull against
• affords elastic recoil that helps refilling of heart in diastole

AV valves open due to rising atrial pressure but close during ventricular contraction to prevent backflow of blood into the aorta. Evertion or prolapse of the valves is prevented by the papillary muscles. These are muscles within the ventricles attached to AV valve flaps or cusps by tendons (chordae tendinae). These contract during ventricular contraction and prevent evertion of the valve.

Semilunar valves are one-way valves located at the origin of the pulmonary artery (pulmonary valve) and aorta (aortic valve) and prevent the backflow of blood into the ventricles from the pulmonary and systemic circulation.

The Pericardium

The pericardium is a double-walled sac enclosing the heart. It consists of a fibrous layer of connective tissue and a thin smooth serous layer. This serous layer forms the visceral pericardium or epicardium covering the heart's surface. The space between the epicardium and parietal pericardium is the pericardial cavity containing pericardial fluid. This lubricates the membranes and allows the heart to beat without friction. The pericardium also serves to isolate the heart from other organs, allows room for the heart to expand and resists excessive expansion.

2The heart wall The heart wall has 3 layers:

• Epicardium = outer serous membrane layer
• Myocardium = thickest layer comprising cardiac muscle functioning as a syncytium; associated with fibrous skeleton
• Endocardium = endothelial covering of inner surfaces of chambers and valves; continuous with endothelium of blood vessels

Heart Sounds

Heart sounds are represented by 'lubb-dupp' sounds, associated with closing of first the AV valves and then the semilunar valves. There may be a third sound associated with diastolic ventricular refilling, sometimes heard in children. Heart murmurs are abnormal heart sounds due to valvular insufficiency or incompetence leading to backflow or reflux of blood. Common causes are:

• valvular stenosis, where valve cusps become scarred and stiff; associated with rheumatic fever
• mitral valve prolapse, with cusps everted in systole (this is congenital)
• septal defects, which allow the shunting of blood between atria or between ventricles

Foetal Heart Blood Flow

Blood flow in foetal heart A large fraction of right atrial blood is shunted to the left atrium via the foramen ovale. The majority of blood pumped by the right ventricle enters the aorta from the pulmonary trunk via the ductus arteriosus.

Myocardial Circulation

The myocardial circulation

• 5% of cardiac output goes to heart via coronary circulation; some of this blood derived from aortic backflow during diastole
• aorta gives off right + left coronary arteries
• left artery branches to become anterior interventricular artery and circumflex artery (supplies left atrium + posterior left ventricle)
• right artery branches to become marginal interventricular artery (supplies right atrium and lateral ventricles) and posterior interventricular artery (supplies posterior ventricles)
• ischaemia = deficient blood supply; results when blood flow impaired by e.g. vasoconstriction, thrombosis or atherosclerosis; leads to anginal pain; heart is very vulnerable to ischaemic injury due to large oxygen demand and lack of anaerobic respiration
• myocardial infarction = death of cardiac tissue due to ischaemia
• coronary circulation shows anastomosis (joining of vessels) at certain points; helps protect against ischaemia
• venous drainage is provided by great anterior and middle posterior cardiac veins feeding into coronary sinus in right atrium
• coronary circulation is compromised in systole (vessels compressed);
• coronary flow occurs only during diastole

Myocardial Metabolism

Myocardial metabolism Essentially 100% aerobic normally but adaptable with respect to energy substrates: 60% fatty acids 35% glucose 5% ketones, lactic acid, amino acids heart does not fatigue

Cardiac Cycle

Cardiac cycle = repeating contraction + relaxation: At 75 bpm, cycle takes 0.8s (diastole = 0.5s + systole =0.3s) Atria contract 0.1s before ventricles

3Cardiac cycle phases

1. Quiescent period
   • None of chambers contracting
   • Blood flows into atria + directly into ventricles through open atrioventricular valves
2. Atrial systole
   • Atria depolarise (P wave of ECG) and contract
   • Additional blood forced into ventricles
   • At end of phase, end-diastolic volume (EDV) = about 130 ml blood
   • 70% of EDV enters passively during quiescent phase;
   • Last 30% added by atrial systole
3. Isovolumetric contraction
   • Atria relax + remain in diastole for rest ofcycle
   • Ventricles depolarise (QRS wave of ECG) and contract
   • Ventricular pressure rises rapidly
   • Atrioventricular valves close (= 1st heart sound)
   • Contraction continues without change in volume while semilunar valves closed (due to pressure gradients favouring valve closure)
4. Ventricular ejection
   • Ejection begins when ventricular pressure exceeds aortic pressure (80 mm Hg) and pulmonary pressure (10 mm Hg), forcing semilunar valves open
   • Ejection is rapid at first then proceeds more slowly (reducedejection)
   • Ventricular pressure peaks at 120 m Hg on left side and 25 mm Hg on right side
   • Not all blood expelled, only about 70 ml = stroke volume (about 54% of EDV = ejection fraction)
   • Remaining blood at end = end-systolic volume (ESV), about 60 ml
   • Ejection fraction reaches 90% in exercise
5. Isovolumetric relaxation
   • Ventricles repolarise (T wave) in early diastole
   • Briefly in diastole, there is backflow of blood in aorta and pulmonary trunk; but this closes semilunar valves (= 2nd heart sound), causing slight pressure rebound = dicrotic notch of the aortic pressure curve
   • Relaxation continues without change in volume since semilunar valves are closed and atrioventricular valves are not yet open
6. Ventricular filling
   • Diastolic ventricular pressure continues to drop
   • until it less than atrial pressure when atrioventricular valves open admitting blood
   • Ventricles expand as they fill with blood (= 3rd heart sound, if it occurs) Expansion may be facilitated by elastic recoil of fibrous skeleton + result of bloodfilling
   • Blood filling occurs in 3 subphases:
     • Rapid phase of ventricular refilling (blood sucked in)
     • Diastasis (slower filling, P wave occurs at end of diastasis)
     • Atrial systole (completes filling process)

   Phase 6 therefore merges with phases 1 + overlaps with phase 2

Cardiac Electrical Activity

Cardiac electrical and mechanical activity The heart has specialised cardiac cells that form the pacemaker region + conductive tissue necessary for myogenic or automatic contractile activity (i.e. contractions are initiated from within muscle itself rather than in response to neuronal stimulation). The electrocardiogram corresponds to electrical events in the heart:

• P wave = atrial depolarisation
• QRS complex = ventricular depolarisation
• T wave = ventricular repolarisation

4Impulse generation + conduction

• Action potentials produced in sinoatrial node (SAN) of right atrium (other areas can generate action potentials but SAN normally dominates)

SAN Action Potential Phases

Phases of the SAN action potential (SLOW RESPONSE)

Phase 4: gradual spontaneous depolarisation = pacemaker potential or prepotential

• decays from-60 mV to threshold of -40 mV due to
• decaying K+ permeability (less K+ efflux through potassium channels)
• slow inward non-selective leak of cations (Na++ Ca2+) + slow influx of Ca2+ via T-type and to some extent L-type calcium channels

Phase 0: relatively more rapid depolarisation due to

• Ca2+ entry through voltage-operated channels (VOC) for calcium (L-type) (slow calciumchannels)

Phase 3: repolarisation due to

• K+ efflux

SAN Action Potential Summary

SUMMARY OF SAN ACTIONPOTENTIALS

• SAN = dominant pacemaker region in right atrium generating action potentials
• resting potential (-60 mV) unstable
• relatively more inside positive than myocytes (-90 mV)
• shows spontaneous depolarisation towards end of diastole = pacemaker potential / prepotential
• pacemaker potential generated by:
  • decaying K+ permeability
  • inward influx of cations (Na+ +Ca2+)
• when threshold reached (@-40 mV), relatively more rapid influx of Ca2+ through voltage-operated calcium channels (L-type) (action potential is slower to develop (=SLOW RESPONSE) + has smaller amplitude compared with atrial + ventricular myocytes)
• repolarisation via K+ efflux through potassium channels
• slope of pacemaker potential normally determines SAN firing frequency + heart rate (modulated by autonomic nervous system)
• automatic, inherent SAN firing frequency normally suppressed by vagal drive to give 0.8 Hz (= 75 beats/min (sinus rhythm))
• if SAN not operating, another pacemaker region takes over = ectopic focus e.g. atrioventricular node (AVN)

Myocyte Action Potential Phases

Phases of the myocyte action potential (FAST RESPONSE)

Phase 0: very rapid depolarisation (1-2 ms) to around +15 mV, activated when membrane potential moves from -90 mV to threshold (around -65 mV)

• due to inward voltage-activated Na+ current via fast sodium channels (Na VOC) (blocked by e.g.tetrodotoxin)

Phase 1: partial repolarisation due to

• activation of transient outward K+current + inactivation of fast sodium channels
• takes membrane potential to around 0 mV

Phase 2: plateau

• Ca2+ entry through voltage-operated calcium channels (L-type)
• Ca2+ influx approximately balances K+ efflux, therefore membrane potential (around 0 mV) exhibits very slow decay (to around -20 mV) so is reasonably sustained
• facilitated by inward-going rectification = K+ permeability decreases during plateau phase of depolarisation + prevents premature rapid repolarisation)
• Plateau phase pronounced in ventricular myocytes represents extension of the action potential allowing Ca2+ entry for contraction

Phase 3: final repolarisation

• increased K+ efflux = delayed outward-going rectification + inactivation of calcium channels

Phase 4: resting potential (polarisation)

Myocyte Action Potential Summary

SUMMARY OF MYOCYTE ACTION POTENTIALS

• stimulated by depolarising impulses originating in SAN
• at threshold depolarisation rapid Na+ influx through voltage-operated sodium channels
• leads to further rapid depolarisation + reversal of polarity = action potential spike
• membrane potential falls immediately afterwards due to transient low-level K+ efflux through potassium channels = initial repolarisation