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Related Learing objectives

• 27. Cardiac muscle: structural and functional characterization, regulation of contractile force

• 28. Cardiac cycle.

• 29. Factors determining the cardiac output. The Frank-Starling law of the heart.

• 30. Cardiac muscle: cellular electrophysiology. Electrocardiography (ECG)

• 31. Cardiac work and metabolism. The coronary circulation

Gabriella Kékesi Pharm.D. Ph.D.

HeartI. Anatomy

II. Origin and spread of cardiac excitation

III. Heart muscle

IV. Mechanical events of the cardiac cycle

V. Integrated control of cardiac output

VI. ECG

VII. Coronary circulation

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Size and location

• 250-350 g

• 150 mm x 110 mm – about the size of a fist

• located anterior to the vertebral column and posterior to the sternum

• Pericardium (double-walled sac): fibrous and visceral (epicardium) pericardium

• Wall of the heart: myocardium, endocardium

• Septum cordis

• Heart valves between the chambers – Atrium (superior - receiving), ventriculus (inferior -discharging)

• Pulmonary circuit, systemic circuit, coronary circulation

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A heart valve normally allows blood flow in only one direction through the heart. The four valves determine the pathway of blood flow through the heart. A heart valve opens or closes incumbent upon differential blood pressure on each

side.

Heart innervation

Automation Autonomous nervous system Chonotropic, dromotropic, inotropic, bathmotropic, lusytropic effects

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• Involuntary striated muscle found in the myocardium• The cardiac syncytium is a network of cardiomyocytes connected to each other by intercalated discs that enable the rapid transmission of electrical impulses through the network, enabling the syncytium to act in a coordinated contraction of the myocardium: an atrial syncytium and a ventricular syncytium

Cardiac muscle

HeartI. Anatomy

II. Origin and spread of cardiac excitation

III. Heart muscle

IV. Mechanical events of the cardiac cycle

V. Integrated control of cardiac output

VI. ECG

VII. Coronary circulation

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1. Sinoatrial node2. Atrioventricular node3. Bundle of His4. Left bundle branch5. Left anterior fascicle

6. Left posterior fascicle7. Left ventricle8. Ventricular septum9. Right ventricle10. Right bundle branch

Intrinsic conduction system of the heart

The sinoatrial node, often known as the cardiac pacemaker, is located in the upper wall of the right atrium and is responsible for the wave of electrical stimulation that initiates atrial contraction by creating an action potential.

AV node, situated in the lower right atrium. The delay at the AV node allows enough time for all of the blood in the atria to fill their respective ventricles. the AV node can also act as a pacemaker; this is usually not the case because their rate of spontaneous firing is considerably lower than that of the pacemaker cells in the SA node and hence is overridden.

Conducted through the bundles of His and back up the Purkinje fibers, leading to a contraction of the ventricles.

SA- and AV-nodes (nodal tissue)

• Pacemaker potential, dischargespontaneously

• Fluctuating membrane potential(prepotential)

• Fast voltage-dependent sodium channelsare inactive

• AP– SLOW depolarization

– If; vd. Ca2+ channels (T and L types); multile K+ channels

– Small amplitude

– Slowly propagation

Atrial and ventricular fibers + bundleof His, Purkinje-system

• AP– RAPID and sharp depolarization

– vd Na+ and Ca2+ (L) channels; K+ channels

– Plateau

– High amplitude

– Fast propagation

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Dissection of the cardiac action potential. Top: The action potential of a cardiac muscle fiber can be broken down into several phases: 0, depolarization; 1, initial rapid repolarization; 2, plateau phase; 3, late rapid repolarization; 4, baseline.Bottom: Diagrammatic summary of Na+, Ca2+, and cumulative K+ currents during the action potential. As is convention, inward currents are downward, and outward currents are upward.

Conduction rate in cardiac tissue

tissue Conduction rate (m/s)

SA node <0.01

Atrial pathway 1.0-1.2

AV node 0.02-0.05

Bundle of His 1.2-2.0

Purkinje system 2.0-4.0

Ventricular muscle 0.3-1.0

SA node discharge most rapidly, spontaneously (100/min)

Latent pacemakers

AV node – slow conduction rate –delay (0.1s)

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Left: Anatomical depiction of the human heart with additional focus on areas of the conductionsystem. Right: Typical transmembrane action potentials for the SA and AV nodes, other parts of the conduction system, and the atrial and ventricular muscles are shown along with the correlation to the extracellularly recorded electrical activity, that is, the electrocardiogram (ECG). The action potentials and ECG are plotted on the same time axis but with different zero points on the vertical scale. LAF, left anterior fascicle.

neuron Striatedmuscle

Smoothmuscle

Myocardialfiber

Resting potential (mV) -80-90 -80-90 -40-60 -80-90

Time of action potential 0.2-2 1-5 20-300 300

Delay (ms) 1-4 50 0

Time of contraction (ms) 10-100 200-3000 300

Mechanism of actionpotential

Na+ influx Na+ influx Ca++ influx Na+ and Ca++

influx

innervation somatic autonomic autonomic

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HeartI. Anatomy

II. Origin and spread of cardiac excitation

III. Heart muscle

IV. Mechanical events of the cardiac cycle

V. Integrated control of cardiac output

VI. ECG

VII. Coronary circulation

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1. As with skeletal muscle, the action potential in a heart cell will initiate contraction of that cell.

2. action potential duration is much longer than in skeletal muscles.

Skeletal muscle vs cardiac muscle

In the absolute refractory period (ARP), the cardiac myocytecannot be excited, whereas in the relative refractory period(RRP) minimal excitation can occur.

3. the contraction in the heart muscle occurs during the action potential, as shown infigure A (while in skeletal muscles the contraction occurs after the action potential).

4. The refractory period of the cardiac action potential is much longer

5. Therefore, in the heart, the contraction is finished before a second action potential can be generated, as shown in figure B.

6. Thus, the contractions in the heart can not summate (as they can in skeletal muscles; temporal summation).

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1. In skeletal muscle the resting length is quite close to the optimal length of muscle contraction2. The passive tension in cardiac muscle rises more steeply than in skeletal muscle3. The active length -tension curve of cardiac muscle shows that small changes in sarcomere length

produces large changes in tension due to:a) better overlap between the myofilamentsb) enhanced sensitivity of the myofilaments to Ca → At a longer muscle fibre length more

troponin C molecules are bound to Ca resulting in greater crossbridge cycling.

4. cardiac muscle normally operates only on the ascending limb of the curve

Regulation of contractile force

1. Initial sarcomer length – Frank-Starling law of the heart – „heterometric” regulation

2. SY nervous system – „homometric” regulation (β1)

1. The increase of extracellular calcium concentration (Caffeine: SR Ca++ release)

2. Na-K-pump inhibition (cardiac glycosides)

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HeartI. Anatomy

II. Origin and spread of cardiac excitation

III. Heart muscle

IV. Mechanical events of the cardiac cycle

V. Integrated control of cardiac output

VI. ECG

VII. Coronary circulation

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Divisions of the cardiac cycle: A) systole and B) diastole. The phases of the cycle are identical in both halves of the heart. The direction in which the pressure difference favors flow is denoted by an arrow; note, however, that flow will not actually occur if valve prevents it.

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Volume-pressure curve of the left ventricle

Stages of the cardiac cycle

Phases Time(ms)

Semilunarvalves

Atrioventricularvalves

pressure volume

DIASTOLE530 ms

Proto-diastole

40 Start to close closed ↓ No change

IsovolumetricRelaxation

80 closed closed ↓ No change

Isotonicrelaxation

Rapid filling

100 closed opened No change

↑

Slowfilling

210 closed opened No change

↑

Atrialsystole

100 closed opened small↑

↑

SYSTOLE270 ms

Isovolumetriccontraction

50 closed closed ↑ No change

ejection rapid ejection

90 opened closed small↑ ↓

Slowejection

130 opened closed no change

↓

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10-7. ábra . A jobb pitvari nyomásingadozások és a vena jugularis externa térfogatingadozásai a szívciklus alatt. Little, R. C., Little, W. C. (1989): Physiology of the Heart and Circulation. 4. kiadás, Year Book Medical Publ. Chicago ILL alapján. A felső (színes) görbén a v. jugularis externán regisztrált térfogatváltozás (vénapulzus), az alsó (fekete) görbén a jobb pitvar nyomásingadozásai láthatók. A függőleges szaggatott vonalak jelzik, hogy a vénapulzus később következik be, mint az azt létrehozó pitvari nyomásváltozás

(anulus fibrosus felfelé mozdul, mely növeli a

pitvari nyomást)

Heart sounds

Stethoscope„lub” S1: vibration induced by the suddenclosure of the atrioventricular valves atthe start of the ventricular systole

„dup” S2: shorter, high pitched, closure of the aortic and pulmonary valves just afterthe end of ventricular systole

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Echocardiography

• Standard two-dimensional, three-dimensional, and Doppler ultrasound to create images of the heart

• Non-invasive

• Indications:

– Geometry of the heart

– Detection of volume-changes

– SV determination

– Valves

• End-diatolic volume (EDV): 110-160 ml

• End-systolic vloume (ESV): 40-80 ml

• Stoke volume (SV): 70 ml (physical exercise: 140 ml)

• Ejection fraction=SV/EDV (0.5-0.7)

• Left ventricle:– Systole: 110 mmHg diastole: 6-8 mmHg

• Left atrium: 6-8 mmHg

• Right ventricle: – Systole: 24 mmHg diastole: 0-2 mmHg

• Right atrium: 0-2 mmHg

• Heart rate: 70/min (physical exercise: 180)

• Cardiac output: 5.5 L/min (Physical exercise: 24 L/min)

• cardiac index=CO/body surface area 3,2 l/minxm2

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HeartI. Anatomy

II. Origin and spread of cardiac excitation

III. Heart muscle

IV. Mechanical events of the cardiac cycle

V. Integrated control of cardiac output

VI. ECG

VII. Coronary circulation

Cardiac output• CO=Heart rate x SV

• SV=EDV-ESV

• Cardiac index: CO/body surface area (male, at rest, lying: 3.2 L/m2)

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Starling heart-lung preparation to determinecardiac output (CO)Intact pulmonary circulationLV-RA connection with a tube

No innervationChange periheral resistance (afterload)Change venous return (preload)

Intact coronary circulation

CO meas.

Peripheralresistance

Venousreturn(tank)

Volumeregister

Effect of sympathetic (noradrenergic) and vagal (cholinergic) stimulation on themembrane potential of the SA node. Note the reduced slope of the prepotential after vagal stimulation and the increasedspontaneous discharge after sympathetic stimulation.

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PRELOAD

• The degree to which the myocardium is stretched before it contracts (venousreturn)– Blood volume

– Venous resistance – decrease thevenous reservoires

– Intrathoracic pressure „respiratorypump”

– Skeletal muscle contraction (muscularactvity) – „muscle pump”

– Sucktion force of the heart• Direct flow into the ventricle during

diastolic filling

• Anulus fibrosus moves downwardduring systole, thus decreases atrialpressure

AFTERLOAD

• Resistance against which blood is expelled(contraction or dilatation)

Interactions between the components that regulate cardiac output and arterial pressure. Solid arrows indicate increases, and the dashed arrow indicates a decrease.

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Frank-Starling law

„Energy of contraction is proportional to the initiallength of the cardiac muscle fiber”

Length – extent of the preload proportional to theEDV

Heterometric regulation of cardiac output (vs homeometric SY regulaion)

reason: calcium sensitivity of the contractilefilaments of myocytes depends on the initiallength of the fiber

The effect of the autonomic nervous system on theheart

Sympathetic (SY)

• positive chronotropic (Firing rate) – Β1 receptor – cAMP – Ica increase

– Speeds If

• Positive inotropic (Contraction force) and lusitropic– NA- Β1 receptor – cAMP – Ica increase

– SR Ca-pump activity increase

• Positive dromotropic (conductivity rate)– Ca++-channel phosphorilation, ICa++-increase

– Delay in the AV node is shortened

• Positive bathmotropic (excitability)

Parasympathetic (PSY)

• negative chronotropic– ACh – M2 - cAMP level decrease – decreases If

and slows the opening of the Ca++ channels

– ACh-sensitive K+-channel (M2) – slope of prepotential is decreased because of hyperpolarization

• Negative dromotropic– ACh-sensitive K+-channel (M2) – slope of

prepotential is decreased because of hyperpolarization

– Delay in the AV node is lengthened

• Negative bathmotropic

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Hormonal effects on heart

Thyroid gland (permissive role): positiv inotropic and chronotropic effect

Increased number and sensitivity of 1 receptors

Insulin, glucagon, growth hormone: positiv inotropic effect

HeartI. Anatomy

II. Origin and spread of cardiac excitation

III. Heart muscle

IV. Mechanical events of the cardiac cycle

V. Integrated control of cardiac output

VI. ECG

VII. Coronary circulation

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• interpretation of the electrical activity of the heart over a period of time, as detected by electrodes attached to the outer surface of the skin and recorded by a device external to the body

• ECG is used to measure – the rate and regularity of heartbeats (tachy/bradycardia; arrhythmias)

– the size and position of the chambers (hypertrophy, atrophy)

– the presence of any damage to the heart (infarction)

– the effects of drugs or devices used to regulate the heart, such as a pacemaker

• Calibration (speed of recordings, amplitude)– 25 mm/s (1mm=0.04s); 10 mm=1 mV (1mm=0.1 mV)

• Unipolar vs bipolar electrodes

• Limb leads and precordial leads

ECG - electrocardiogram

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The correlation of the electrical activity of the heart and the ECG recordingsSpread of cardiac excitation

Limb leads and augmented limb leads

Einthoven(standard) Limb leads

Goldberger(augmented)

Limb leads

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Precordial leads

V1

In the fourth intercostal space (between ribs 4 and 5) just to the right of the sternum (breastbone).

V2

In the fourth intercostal space (between ribs 4 and 5) just to the left of the sternum.

V3 Between leads V2 and V4.

V4

In the fifth intercostal space (between ribs 5 and 6) in the mid-clavicular line.

V5

Horizontally even with V4, in the left anterior axillary line.

V6

Horizontally even with V4 and V5 in the midaxillary line.

Directions of ECG leads in 3 dimensionsHorizontal and frontal plane

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Depolarization moving toward an active electrode in a volume conductor (body) produces a positive deflection, whereas depolarization moving in the opposite direction produces a negative deflection.

By convention, an upward deflection is written when the active electrode becomes positive relative to the indifferent electrode, and a downward deflection is written when the active electrode becomes negative.

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P wave: atrial depolarization; <100msPQ (PR) segment: atrial plateau phasePQ (PR) interval: Atrial depolarization and conduction through AV node; 120-200 msQRS duration:80-120 ms; Ventricular depolarization and atrial repolarizationQT interval: Ventricular depolarization plus ventricular repolarization; 320-390 ms(heart rate)ST segment: Ventricular plateau phaseT wave: Ventricular repolarization

12 leads routine ECG

• Limb leads (I, II and III)

• Augmented limb leads (aVR, aVL, aVF)

• Chest (Precordial) leads (V1-V6)

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Clinical relevance of ECG

• The heart's electrical axis (cardiac vector) is the general direction of the ventricular depolarization wavefront (or mean electrical vector). The QRS axis can be determined by looking for the limb lead or augmented limb lead with the greatest positive amplitude of its R wave.

Left: Einthoven's triangle. Perpendiculars dropped from the midpoints of the sides of the equilateral triangle intersect at the center of electrical activity. RA, right arm; LA, left arm; LL, left leg. Center: Calculation of mean QRS vector. In each lead, distances equal to the height of the R wave minus the height of the largest negative deflection in the QRS complex are measured off from the midpoint of the side of the triangle representing that lead. An arrow drawn from the center of electrical activity to the point of intersection of perpendiculars extended from the distances measured off on the sides represents the magnitude and direction of the mean QRS vector. Right: Reference axes for determining the direction of the vector.

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• The normal QRS axis is generally down and to the left, following the anatomical orientation of the heart within the chest.

• An abnormal axis suggests – a change in the physical shape and orientation of the heart, or

– a defect in its conduction system that causes the ventricles to depolarize in an abnormal way.

Normal −30° to 90° Normal

Left axisdeviation

−30° to −90°May indicate left ventricular hypertrophy, left anterior fascicular block

Right axisdeviation

+90° to +180°May indicate right ventricular hypertrophy, left posterior fascicular block

Ional effects on the ECG

EC calcium level 2,5 mmol/L • Increased: enhanced myocardial contractility, relaxes less during

diastole, heart eventually stops in systole – calcium rigor

• Decreased: decreased contraction force

EC kalium level 4 mmol/L• hyperkalemia: heart stops in diastole(reason: resting membrane

potential decreases=> muscle fiber becomes unexcitable –decreased poropagation and contraction => heart failure)

• hypokalemia: ventricular extrasystole => heart failure

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HeartI. Anatomy

II. Origin and spread of cardiac excitation

III. Heart muscle

IV. Mechanical events of the cardiac cycle

V. Integrated control of cardiac output

VI. ECG

VII. Coronary circulation

VII. Coronary circulationCoronarographyEpicardial and subendocardial coronary arteriesFuncionally end arteries - very small anatomical anastomoses, which lack functionHigh capillarizationVenous blood - Sinus coronarius – Right atria

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Coronarography

1. aerob organ

High oxygen extraction: AVDO2: 114 mL/L (venous blood O2 saturation is 25%!!)

Oxygen consumption in rest: 12%

2. Continuous blood supply is required:

In rest: 180–240 mL/min (60–80 mL × 100 g–1 × min–1: 5% of CO).

During physical activity: up to 900–1200 mL/min (300–400 mL × 100 g–1 × min–1)

4-5 % of CO in rest and physical activity as well!

3. Nutrition

Small glycogen store; 60% FFA and triglycerides, 35% carbohydrates, 5% amino acids and keton bodies

To increase oxygen supply only by increasing the coronary circulation!!!

Oxigen consumption and metabolicrequirements of the cardiac muscle

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Regulation of coronary circulation

• High miogenic tone; no SY vasoconstrictor tone in rest!

• Autoregulation (60-140 mmHg): same flow through the coronary circulation is maintained over a range of pressures

• 1. Metabolic regulation

– pO2↓, adenosine, pCO2↑, H+↑

– Endotel-derived factors: NO – retrograde vasodilation

• 2. Neural

– Direct: α1, β2

– Indirect (β1 – positive heart effects – increased metabolism – vasodilation)

• 3. Extravascularis compression (cardiac cycle – 75% during dyastole)

• 4. Hormonal (thyroid gland, vasopressin)

Coronary circulation and thecardiac cycle

• Transmural pressure of coronaryarteries:

– Hydrostatic pressure vs compression

– LV: systole – compression of subendocardial arteries

– RV: it could be increased duringsystole

3-3. ábra. Coronay flow during the cardiac cycle.

Aorta pressure(mmHg)

Left coronaryflow

(mL/min)

Right coronaryflow

(mL/min)