last authored: 2014, Brian Beairsto, Brenden Bechamp, Julianne Zandberg
Introduction
The primary function of the heart is to pump blood throughout the body with enough pressure to ensure adequate perfusion of organs. This is accomplished through the contraction of the ventricles against closed valves until enough pressure is generated to expel blood out into the pulmonary and systemic vasculature.
real time MRI, courtesy of Zhang and colleagues
The heart pumps in a pulsatile fashion. A complete cardiac cycle involves the contraction of the two atria followed by the contraction of the two ventricles. In every cardiac cycle, the amount of blood ejected from the left ventricle can be measured as the stroke volume (SV). Cardiac output (CO) is the measure of how effectively the heart is working, and is the product of SV and heart rate (HR).
This module will discuss the function of the heart as a pump and the mechanisms through which it maintains adequate blood flow to the body.
Systole, Diastole & Cardiac Cycle
Systole is the contraction of the left and right ventricles, resulting in blood flow to the body and lungs, respectively. Diastole includes the contraction of the atria and the filling of the ventricles. The cardiac cycle breaks systole and diastole down into five phases during one heartbeat. It describes changes in pressure, volume, and flow through the heart in each phase. Systole is comprised of isovolumetric ventricular contraction and ventricular ejection. Diastole is comprised of isovolumetric ventricular relaxation, early diastole (rapid inflow & diastasis), and late diastole (atrial systole).
Wiggers diagram, used with permission, Daniel Chang
The cardiac cycle diagram above illustrates pressure and volume changes in response to systole and diastole. Labels are present to indicate each stage of the cycle as well as valve activity.
Isovolumetric Ventricular Contraction
Electrical activation of the ventricles (represented by the QRS complex) causes ventricular contraction to begin. Ventricular pressure rapidly rises above the pressure in the atria, forcing the atrioventricular (AV) valves closed and preventing blood from traveling back into the atria. The pressure is not yet great enough in this phase to open the pulmonary or aortic valves. Therefore, no changes in flow or volume occur here.
Ventricular Ejection
Ventricular pressure continues to rise as the ventricles contract. Once the ventricular pressure has risen to a level which exceeds that in the aorta, the aortic semilunar valve opens. Consequently, blood flows out of the ventricles into the aorta, thereby decreasing ventricular volume gradually to end systolic volume (ESV). The end of this phase marks the end of systole.
Isovolumetric Ventricular Relaxation
The ventricular muscle relaxes immediately following ventricular repolarization (signified by the T-wave). Consequently, pressure in the ventricles falls to a level lower than in the aorta, and pulmonary artery, resulting in closure of the semilunar aortic and pulmonary valves. The closure of these valves marks the beginning of diastole. Ventricular relaxation will continue until pressure drops below the level in the atria. Notice that all valves are closed in this phase, and no volume changes occur.
Early Diastole
When the atrial pressure exceeds ventricular pressure, the AV valves will open, allowing blood from the peripheral and pulmonary circulation to flow into the ventricles. This filling occurs passively (without contraction) and accounts for approximately 70% of blood entering the ventricles.
Late Diastole
Atrial contraction is responsible for the last 30% of ventricular filling. Shortly after the P wave, the atria contract and squeezing blood into the ventricles. The completion of this phase marks the end of diastole. The volume of blood contained in the ventricles at this time is appropriately termed end diastolic volume (EDV).
One complete cardiac cycle accounts for all of the mechanical activity that occurs during one heartbeat. The duration of systole remains constant from beat to beat, while the length of diastole varies with heart rate. Ventricular systole lasts about 0.3 seconds, while the remaining 0.4 seconds of the cardiac cycle represent diastole.
Heart sounds
S1 and S2 are normally heard during systole. S1 is the sound produced by the closing of the atrioventricular valves and S2 is the sound produced by the closing of the semilunar valves.
S3 and S4 are abnormal heart sounds. Occasionally, S3 may occur in young or highly active populations, in which case is suggestive of rapid ventricular filling. However, in most older populations, S3 is indicative of a significant problem, such as heart failure or severe valve regurgitation. S4 occurs when the atria must contract with increased force in order to expel blood into a noncompliant ventricle, which indicates an underlying pathology.
Stroke Volume and Cardiac Output
Stroke volume is a measure of the blood volume pumped out of the left ventricle in one heartbeat. It is calculated by subtracting end systolic volume (ESV; the amount of blood remaining just after ventricular contraction) from end diastolic volume (EDV; the amount of blood in the ventricles just before contraction).
SV = EDV – ESV.
Stroke volume is approximately 70 ml in an average healthy male. Stroke volume can also be expressed using the ejection fraction: the percentage of blood ejected from the ventricle, i.e. 70ml/120ml. It is normally 55-75%.
Stroke volume is used as a measure of the mechanical function of the heart. It is increased by contractility and preload and decreased by afterload. Preload is the degree of stretch on the heart, caused by the return of venous blood from the systemic circulation. Its measure can be approximated by the volume of blood in the ventricle at the end of diastole (End Diastolic Volume or EDV). Afterload is the ventricular wall tension during contraction, equalling the peripheral resistance that the heart must overcome. It is approximated by systolic pressure. Clinically, when systolic pressure is too high, it is referred to as hypertension. The higher the systolic pressure, the more difficult it is for the heart to maintain stroke volume. The ease with which the heart can eject blood from the ventricles is described by stroke work. Increased pressure demands increased stroke work to maintain proper stroke volume.
Stroke Work = SV x P
The product of stroke volume and heart rate determines cardiac output (CO; sometimes called Q). It is defined as the amount of blood pumped by the heart per minute.
CO = SV x HR
Regulation of Cardiac Output
The function of the heart as a pump is to supply the body with constant blood flow. As cardiac output is dependant on both heart rate and stroke volume, either can be manipulated to effect change in blood supply. Heart rate can be changed over a large range of values when compared to stroke volume, which varies over a smaller range.
Regulation of Heart Rate
main article: electrical control of the heart
Heart rate is primarily controlled by the fibres of the autonomic nervous system, which act on the nodes of the heart. The nodes are made up of groups of cells known as pacemaker cells, meaning that they are able to generate their own electrical signal. The primary signal is generated by the sinoatrial (SA) node, located in the right atrium. Unregulated, the SA node generates impulses at a rate of approximately 100 per minute.
Sympathetic nerve fibres change this through the release of neurotransmitters. When norepinephrine acts on the SA node, the rate of depolarization is increased, causing the threshold to be reached more quickly and increasing heart rate.
Parasympathetic nerve fibres release the neurotransmitter acetylcholine (ACh) onto the SA node, slowing heart rate by two mechanisms. First, parasympathetic stimulation will decrease the rate of spontaneous depolarization. The same stimulation will also cause hyperpolarization of the SA node cells. Both of these effects work to delay the time it takes to reach threshold, thereby decreasing heart rate.
Source – author content (?)
As seen in the image above, sympathetic stimulation (red line) of the SA node will compress the cycle and raise heart rate. Alternatively, parasympathetic stimulation of the SA node (green line) will stretch the cycle and lower heart rate.
Both sympathetic and parasympathetic signals are active in a resting state, competing to raise and lower heart rate, respectively. If both are removed, heart rate will rise from a normal resting value of approximately 70 beats/min to 100 beats/min. This demonstrates that at rest, parasympathetic stimulation is dominant. Alternatively, during a stressor such as exercise, parasympathetic activity is withdrawn and sympathetic stimulation is activated to cause an increase in heart rate, and ultimately cardiac output.
Regulation of Stroke Volume
In addition to HR, the stroke volume can be manipulated to generate a desired cardiac output. The contractile state (inotropy) is an important property of the heart because it cannot modulate its force generation through motor nerve activity or motor unit recruitment. Increasing the contractility of the heart will cause the muscle fibres to shorten more rapidly, increasing force generation and subsequently, allowing it to pump out a greater volume of blood with each cardiac cycle. This effect is independent of the preload.
Increasing beta adrenergic stimulation (nor-epinephrine) and catecholamine circulation (epinephrine) are the main ways the body increases inotropy. It can be increased exogenously through administration of positive inotropic drugs. Conversely, the inotropy can be decreased through parasympathetic vagal efferent nerves. It should be noted that the vagal efferents have the greatest effect on the atria and their effect on the ventricles is small. Decreasing contractility causes a reduction in SV and an increase in the amount of blood left in the heart after systole (end systolic volume or ESV). Clinically, decreased inotropy is seen in patients with heart failure.
The Frank-Starling Mechanism
Frank-Starling curve, used with permission, BitzBLitz
The Frank-Starling Mechanism states that the heart will pump all blood returned to it, within physiological limits. Accordingly, as the graph at left shows, increasing EDV (listed as LVEDP, or left ventricular end diastolic pressure) will result in increased stroke volume. This is true during normal periods, during times of increased contractility, or during heart failure (decreased contractility).
If EDV, or preload, is increased, the Frank-Starling mechanism will increase stroke volume such that ESV remains the same, resulting in a preserved ejection fraction. A greater EDV stretches the myocytes, which increases Troponin-C affinity for calcium and subsequently increases the force of contraction, to a maximum determined by sarcomere length. This is known as the length-tension relationship.
However, if afterload is increased while preload remains the same, smaller stroke volumes and increased ESVs will ensue, as the heart is not pumping with adequate pressure to expel the same amount of blood during systole. There is a linear relationship between afterload and ESV termed end-systolic pressure-volume relation (ESPVR). This is governed by the force-velocity relationship of cardiac muscle. As afterload increases, the shortening velocity of the myocyte decreases, reducing the SV.
The ESPVR line can be shifted upward or downward depending on the contractile state of the heart. Increasing contractility results in increased stroke volume and decreased ESV, shifting the ESPVR line upwards at a given preload. Decreased contractility causes a reduction in SV and therefore an increase in ESV. This will lead to an increase in EDV in the next cardiac cycle and subsequently, the Frank-Starling Mechanism will lead to elevation of the stroke volume as much as possible. In patients with heart failure, the Frank-Starling Mechanism is not enough to counteract the increase in EDV, and pulmonary and peripheral edema occurs as blood pools within the lungs and systemic circulation
Cellular Mechanisms of Contraction
The ventricular myocardium is composed of individual striated muscle cells called myocytes. Each fibre contains rod-like structures called myofibrils that run the length of the fibre and are composed of sarcomeres located in series with one another. Each sarcomere, the functional unit of contraction, contains overlapping actin (thin) and myosin (thick) filaments. Each myosin molecule possesses a globular portion at its end that forms bridges with the actin filaments and serves as the site of ATP hydrolysis.
The actin filament is composed of two chains of actin wrapped around a molecule of tropomyosin. The thin filament also contains a complex of regulatory troponin proteins (I, C, and T) that serve to block the myosin binding sites when cytoplasmic calcium is in low concentrations and the muscle is in its relaxed state.
Depolarization of the myocyte opens L-type calcium channels in the sarcolemma, facilitating an inward flux of extracellular calcium. The absolute quantity of extracellular calcium entering the cell is insufficient to cause myofibril contraction on its own. Instead, L-type channels are in close opposition to ryanodine receptors on the sarcoplasmic reticulum (SR). Calcium binding to these receptors results in massive release of calcium stored from the sarcoplasmic reticulum – a process termed the calcium-induced calcium release (CICR).
Cardiac muscle sarcolemma, courtesy of OpenStax College
Actin and Myosin cycling, courtesy of OpenStax College
Calcium ions released from the SR diffuse towards the myofibrils and bind to Troponin C. This inhibits Troponin I, leading to a conformational change in tropomyosin.
The active site on the actin filament is now exposed, allowing myosin cross-bridges to bind and form an active complex.
When ADP dissociates from the cross-bridge, muscle contraction occurs. The actin filaments slide along the myosin filaments with repetitive interactions between the myosin heads and the actin filaments, a process termed cross-bridge cycling. The cross-bridge dissociates and returns to its resting state when a new molecule of ATP binds to the myosin head.
ATP is formed from substrate oxidation in the mitochondria of the myocytes. Its high-energy phosphate stores are the source of energy for almost all the mechanical work of contraction.
With the inactivation of L-type channels during repolarization, calcium influx falls and calcium is actively pumped back into the SR and out if the cell. Troponin I is no longer inhibited and the troponin complex once again blocks the active site on the myosin molecules.
The concentration of intracellular calcium is the major determinant of the force of cardiac contractility. More calcium allows for greater actin-myosin interaction, producing a stronger contraction. Positive inotropic drugs (increase the contractility of the heart) typically act by increasing the concentration of calcium in cytoplasm of the myocyte.
Beta-adrenergic stimulation of the heart activates the G protein system, which in turn stimulates adenylate cyclase and the production of cAMP. This leads to phosphorylation pathways which increase L-type channel influx and SR release of calcium into the cytoplasm.
Beta-adrenergic stimulation also increases cardiomyocyte relaxation via the SR protein phospholamban. cAMP leads to phosphorylation of phospholamban, which reverses its inhibition of the SR calcium ATPase, allowing calcium to be pumped back into the SR.