THE CARDIOVASCULAR SYSTEM The Cardiovascular System (CVS) consists of blood (plasma and cells) blood vessels the

the heart The Lymphatic System (LS) consists of lymph and lymphocytes lymphatic vessels lymphoid tissues and organs Both systems are interconnected and interdependent as they exchange fluid and cells. The cardiovascular and lymphatic systems are often said to be components of a single circulatory system. The Cardiovascular System Arteries (efferent vessels) carry blood away from the heart Veins (afferent vessels) carry blood towards the heart arteries HEART veins venules arterioles tissue capillaries

It actually consists of two circuits, linked by the heart: Pulmonary circuit (9% total blood volume) Pulmonary arteries deoxygenated blood Right Ventricle Right Atrium Vena cava superior vena cava inferior vena cava peripheral capillary beds O2 Lungs CO2 Pulmonary veins oxygenated blood

Left Atrium HEART (7% total blood vol)Left Ventricle Ascending aorta Aortic arch Descending aorta

Systemic circuit (84% total blood volume; 64% in veins)

A more pictorial way of showing the two circuits or loops is

pulmonary loop

systemic loop

N.B. the systemic loop has two sub-circuits not shown here through the kidneys through the GI tract and the liver

THE HEART The heart is a muscular pumping organ Heart Wall has a three-layered structure (Martini Fig 18-4): epicardium a visceral pericardium is a serous membrane (mesothelium and underlying loose CT) covering the outer surface of the heart myocardium the muscular wall of the heart endocardium a simple squamous epithelium covering the inner surfaces of the heart and is continuous with the endothelium of the attached blood vessels

Heart Chambers (Martini Fig 18-6a Sectional Anatomy of the Heart) The hollow cavity of the heart is divided by internal fibrous and muscular walls into four chambers:

Right atrium receives low-02 blood from the systemic venous circulation ventricle alternately fills with blood from the right atrium and contracts to pump blood into the pulmonary arteries Left atrium receives oxygenated blood from the pulmonary veins ventricle alternately fills with blood from the left atrium and contracts to pump it into the aorta

Heart Valves (Martini Figs 18-6a; 18-18) Movement of blood in and out of the ventricles is controlled by two sets of non-return valves 1. Atrio-Ventricular valves (AV valves) Right tricuspid valve (3 flaps) Left bicuspid or mitral valve (2 flaps)

These valves are anchored to the ventrical walls by strong tendons (chordae tendinae) via papillary muscles. When the ventricles contract, the valve flaps are pushed together by the blood, thus closing off the atria. The chordate tendinae prevent the valve flaps being pushed further into the atria and opening again. 2. Semilunar valves (half-moon shaped flaps) Right pulmonary valve Left aortic valve

These valves each have three rather stronger flaps (not anchored in the chambers) which are pushed open by the pressure of contraction in their ventricle. When this stops, they are pushed together by the back-pressure of blood in the arteries and close, preventing blood re-entering the ventricles. A coordinated sequence of ventricular wall contractions results in blood moving through the heart as shown in the diagrams above (described in cardiac cycle section). Cardiac Muscle Cardiac muscle cells are of three types: contractile, stimulatory (pacemaker), or conducting; even though developmentally they are all fundamentally muscle cells:

Types of cardiac muscle cells in the myocardium: Cell type Myocardial muscle Pacemaker Conducting Location atria and ventricles SA node and AV node Bundle of His and branches Purkinje fibres; some nodal pathways in the atria Function force generation initiation and control of heart rate coordination of contraction across heart walls

Pacemaker and conducting cardiac muscle cells have very reduced amounts of contractile machinery (thick and thin filaments, etc). Cardiac muscle cells (cardiocytes; cardiomyocytes; cardiac myocytes) Cardiac muscle cells (Martini Fig 18-5) form branched fibres and adjacent cells are bound together by gap junctions and desmosomes at structures called intercalated discs. Intercalated discs convey the force of contraction from cell to cell and also propagate action potentials as the ions involved can diffuse from one cell to the next through the junctions. Cardiac muscle cells have sarcomeres (i.e. are striated) and contract by a similar sliding filament mechanism to that of skeletal muscle (see PTH121 notes), but with several very important modifications: 1. Cardiac muscle cells are relatively small and usually have a single central nucleus. 2. T-tubules are short and broad and encircle the sarcomeres at the Z-lines (no triads) 3. The sarcoplasmic reticulum lacks terminal cisternae and its tubules contact the cell membrane as well as the T-tubules. 4. Action potentials trigger the release of calcium ions (Ca2+) from the SR into the sarcoplasm and also increase the permeability of the sarcolemma to Ca2+ ions from the extracellular fluid. 5. Sarcomere contraction depends almost entirely on ATP from aerobic metabolism in mitochondria (cells have lipids and glycogen reserves as well as a high concentration of 02binding myoglobin molecules. Contraction of cardiac muscle cells Ventricular cardiac muscle cells: resting potential threshold potential -90mV -75mV

The stimulus normally is the excitation of an adjacent contractile cell in a portion of its cell membrane close to the intercalated disc so that the ions can pass through.

Development of the action potential for contraction (Martini Fig 18-15a): Step 1: Rapid depolarisation (fast Na+ channels) Fast voltage-regulated Na+ channels open rapidly but only for a few msecs Step 2: Plateau (slow Ca2+ channels) At +30mV the fast Na+ channels close and the intracellular Na+ starts to be ejected by active transport. But repolarisation does not occur because slow Ca2+ channels in sarcolemma open and Ca2+ ions enter from the extracellular fluid (ECF), roughly balancing the loss of activelytransported Na+. The membrane potential only gradually declines (i.e. the plateau phase; the main difference between action potentials in cardiac and skeletal muscle cells and is why a single cardiac muscle contraction lasts much longer) reaching 0mV after about 175 msec. The Ca2+ ions lead to myofibril contraction as in skeletal muscle. Step 3: Rapid repolarisation (slow K+ channels). 0mV is the threshold potential for the slow Ca2+ channels to close and for slow K+ channels to open. The input of positively-charged calcium thus stops and positively-charged potassium rushes out of the cell, causing rapid repolarisation and bringing the membrane potential back to the resting value again and closing the K+ channels. The refractory period in cardiac muscle cells Absolute refractory period: the cell membrane cannot respond to a stimulus as the Na+ channels are either already open or they are closed and inactivated (200 msec). This lasts through the plateau phase and into the start of the repolarisation phase. Relative refractory period: during the last 50 msec of the repolarisation phase the voltageregulated Na+ channels are closed but are not inactivated so a stronger than normal stimulus (i.e. larger amount of internal Na+ coming through the intercalating disc) will initiate another action potential. Effect of Ca2+ ion concentration on cardiac muscle contraction An action potential across cardiomyocyte membrane produces a contraction by increasing the concentration of Ca2+ around the myofibrils (thus stimulating the sliding filament mechanism) in two steps ECF Ca2+ enters cardiomyocyte during plateau phase (about 20% of that necessary for contraction) This triggers Ca2+ release by sarcoplasmic reticulum (providing remaining 80%)

Thus cardiac muscle contraction is very sensitive to changes in the ECF Ca2+ concentration. When the slow Ca2+ channels close, the intracellular Ca2+ causing the contraction is quickly lowered by a combination of absorption into the SR and pumping back into the ECF.

Conducting system of the heart The hearts own conducting system or nodal system regulates heartbeats without any external neural or hormonal stimulation (automaticity or autorhythmicity), though these can modify the rate or strength of the heartbeats. Anatomically, the system has three parts (Martini Fig 18-12) Sinoatrial (SA) node embedded in the posterior wall of the right atrium near the entrance of the superior vena cava. Atrioventricular (AV) node larger node which sits within the floor of the right atrium near the opening of the coronary sinus. The SA node is connected to the AV node by internal conducting pathways. AV bundle, bundle branches and Purkinje fibres the AV bundle runs down the interventricular septum of the heart and connects the atria to the ventricles. The two bundle branches extend to the apex (lowest point) of the ventricles, turn backwards and fan out as Purkinje fibres.

Spontaneous depolarisation (prepotential) in pacemaker cardiac muscle cells The action potentials causing heart muscle cells to contract are actually generated within the heart by the specialised pacemaker cardiac muscle cells of the SA and AV nodes. These cells cannot maintain a stable resting potential as their membranes are leaky, allowing ions to enter slowly. After each repolarisation, their membranes gradually depolarise again and the resting potential gradually drifts towards the threshold for another depolarisation:

Rate of action potential generation SA node 80-100 per minute AV node 40-60 per minute

As the SA node depolarises more rapidly, it determines the overall heart rate. If the SA node or the intermodal conducting pathways are damaged, the AV node determines the heart rate, but it is slower (40-60 pm). Impulse (AP) conduction through the heart

Step 1: SA nodal activity initiates atrial activation Step 2: Action potential conduction along the intermodal pathways is accompanied by spreading of the action potentials through the intercalating discs of the contractile cells of both atria. The action potential cannot spread to the ventricles because the fibrous skeleton separating the two types of chamber isolates the atrial from the ventricular myocardium. Step 3: The action potential reaches the AV node after about 50 millisecs but it takes another 100 msec to pass through the AV node and enter the AV bundle. This delay allows time for atrial contraction to be completed before ventricular contraction begins. Step 4: The impulse travels to the apex (lowest point) of the heart via the AV bundle and the bundle branches to the Purkinje fibres. It also passes via the moderator band to the papillary muscles of the right ventricle (which pull the chordate tendinae of the right AV valve). Step 5: Purkinje fibres conduct action potentials very rapidly. Within 75 msec the action potential has spread to all ventricular contractile muscle cells. Starting at the apex, the wave of ventricular contraction sweeps backwards towards the semilunar valves.

(see also Martini Fig 18-13)

The Cardiac Cycle (Martini Fig 18-16) This is the sequence of muscular events in the heart that follows from the sequence of electrical events outlined in the previous section as the action potential spreads through the hearts electrical conducting system. Systole (the last e is pronounced) = contraction of cardiac muscle cells in the heart chamber; diastole = relaxation. At a typical heart rate of 75 beats per minute, one cycle lasts for about 800 msec (0.8 sec). At the start of the cycle, all the heart muscle is relaxed and blood is being pushed into both atria and on into the ventricles by the blood pressure in the vena cava and the pulmonary veins, and the ventricles are about 70% full with both AV valves still open. Atrial systole (~100 msec). At this point the pressure in the atria begins to exceed the venous pressure so no more blood can enter. The atria contract towards the AV valves, pushing more

blood into the ventricles, filling the final 30% of available ventricular volume. The resistance to flow through the AV valves as less than back into the veins, so little backflow out of the heart occurs. Atrial diastole (remaining ~700 msec). Both atria are relaxed and blood again enters the atria from the vena cava and pulmonary veins. Ventricular systole (~270 msec). This occurs in two stages as determined by the effects of pressure changes on the valves isovolumetric contraction the increasing pressure within the ventricles as they contract pushes the AV valves closed so that blood cannot pass back into the atria again, but the pressure is not yet great enough to push open the semilunar valves against the arterial blood pressure. Hence the volume of the ventricles does not change as blood cannot yet flow out of them, but the ventricular pressure continues to rise. ventricular ejection continued isometric contraction by ventricular muscle brings the ventricular pressure above the aortic pressure and blood is pushed out through the semilunar valves into the aortic and pulmonary trunks. Ventricles continue to contract isotonically with little further increase in pressure. Ventricular diastole (remaining ~400 msec). Similarly occurs in two stages early ventricles relax and ventricular pressure falls below arterial, so back-flow of blood from arteries pushes the semi-lunar valves closed, but the ventricular pressure is still higher than the atrial pressure and the AV valves remain closed. late continued ventricular relaxation brings the ventricular pressure below the atrial, so that the AV valves are pushed open and blood can flow in from the atria once more. For a summary of the pressure changes in the heart chambers, see Martini Fig 18-17) Note that both ventricles will eject the same volume of blood at each systole (see week 2). Heart sounds (auscultation) (Martini Fig 18-18) The opening and closing of valves can be heard with a stethoscope placed in particular positions above the thoracic wall S1: first heart sound (loud lubb sound) the AV valves closing when ventricular pressure exceeds atrial pressure S2: second heart sound (slightly softer dupp sound) the semilunar valves closing as ventricular pressure drops below arterial S3 and S4 are murmurs arising from turbulent blood flow and are difficult to hear in healthy adults but are more obvious and often diagnostic in valve malfunctions.

Electrocardiogram (ECG)

As the action potentials pass through the heart, the electrical changes caused by depolarisation of the heart muscle cells can be detected by appropriately-placed surface electrodes. A typical normal pattern would be:

The initial depolarisation of the SA node cells is too small to detect, but the so-called P wave is caused by the wave of depolarisations sweeping over both atria and the QRS complex by ventricular depolarisation (much larger as the tissue mass is larger). The T wave is caused by ventricular repolarisation but the earlier atrial repolarisation signal is swamped by the much larger QRS complex. Changes is the size of voltage spikes or in the time of the P-R and Q-T intervals provide important diagnostic information. Autonomic nervous control of the heart The autonomic or involuntary nervous system (ANS; see later in module) has two divisions, the sympathetic (fight or flight) system and the parasympathetic (rest and repose) system. Atria including SA and AV nodes innervated by both, while the ventricles are mainly stimulated by sympathetic nerve fibres which outnumber the parasympathetic fibres. Stimulation of the parasympathetic vagus nerve dominates the heart rate of a healthy resting person by releasing the neurotransmitter acetylcholine (ACh) at synapses on the SA node. As the ACh concentration increases, chemically-regulated K+ channels are opened in the membrane, which repolarises even more (hyperpolarisation) and therefore takes longer to return to the threshold for the next action potential (Martini Fig 18-22b). Hence the heart rate decreases (bradycardia). Conversely, sympathetic nerves releasing noradrenaline (NE) at the nodes open Ca2+ channels which reduce repolarisation so that it takes less time for the node membranes to reach threshold for the next action potential and the heart rate increases (tachycardia; Martini Fig 18-22c). During cardiac reflexes, cardiac centres in the brain stem (Martini Fig 18-21) control the autonomic regulation of cardiac activity cardio-acceleratory centre controls sympathetic neurons which will stimulate the heart cardio-inhibitory centre controls the parasympathetic neurons which slow the heart rate Both cardiac centres are regulated by reflex pathways and by inputs from higher brain centres, in particular the hypothalamus. They respond to changes in blood pressure and O2 and CO2

blood gas levels in the arteries. If the blood pressure falls, arterial O2 will fall and CO2 will rise. This will reduce parasympathetic release of ACh and stimulate sympathetic release of NE, both of which result in an increase in heart rate until the blood pressure is brought back to normal (see week 3-4).