9.1 Ventricular Performance
The ability of the heart to eject blood during a heartbeat is a function of three factors: the amount of cardiac filling (preload), the strength of contraction (contractility), and the pressure against which it ejects blood (afterload).
– Systole is the period when the ventricle is contracting, and ejection occurs.
– Diastole is the period when the ventricle is relaxing, and filling occurs.
Preload
Up to a point, the heart pumps more when it is filled more during diastole. This is often labeled Starling’s law of the heart, or the Frank–Starling mechanism. The amount of filling is called preload. It is a reflection of forces in the vasculature acting to fill the ventricle. The amount of preload can be expressed in several ways, for example, end-diastolic volume, end-diastolic pressure, or stretch (sarcomere length).
– It will be low in cases of hypovolemia (low blood volume) or low systemic venous tone.
– It will be high in cases of fluid retention, many cases of heart failure, or excessive venous sympathetic stimulation.
– If the right ventricle is impaired but not the left, right ventricular preload will tend to be high, and left ventricular preload will tend to be low.
Contractility
Contractility (also called inotropism) expresses the ability of the heart to contract at a given preload. Greater contractility manifests as greater systolic pressure or greater systolic ejection. At the cellular level, contractility reflects the amount of Ca2+ released from the sarcoplasmic reticulum with each heartbeat. The supply of Ca2+ in the sarcoplasmic reticulum is increased (positive inotropy) by anything that stimulates more Ca2+ to enter the cell through Ca2+channels, or that stimulates Ca2+ ATPase (sarco/endoplasmic reticulum Ca2+ ATPase [SERCA] pump) to take up Ca2+ from the cytosolic space. Both effects increase the amount of Ca2+ stored in the sarcoplasmic reticulum between beats.
– Positive inotropic effectors (i.e., those that cause an increase in contractility) include agents that cause a faster heart rate (more beats per minute allow more Ca2+ to enter per minut e), for example, sympathetic stimulation via β1-adrenergic receptors, drugs that are β1-adrenergic receptor agonists, and cardiac glycosides (e.g., digoxin).
– Negative inotropic effectors (i.e., those that cause a decrease in contractility) include para-sympathetic stimulation via muscarinic (M2) receptors and β-adrenergic receptor antagonists (β-blockers).
Digoxin
Digoxin is a cardiac glycoside that was once one of the first-line agents used in the treatment of heart failure. Its use is now reserved for cases when symptoms are not fully treated by standard therapies or in cases of severe heart failure while standard therapies are initiated. The therapeutic and toxic effects of digoxin are attributable to inhibition of Na+−K+ ATPase (the digitalis receptor) located on the outside of the myocardial cell membrane. When the pump is inhibited, Na+ accumulates intracellularly. The decreased Na+ gradient that results from this affects Na+−Ca2+ exchange, and Ca2+ accumulates intracellularly. Consequently, more Ca2+ (stored in the sarcoplasmic reticulum) is available for release and interaction with the contractile proteins in these cells during the excitation–contraction coupling process. At therapeutic doses of digoxin, there is an increase in contractile force. Toxicity to digoxin also relates to inhibition of Na+−K+ ATPase. Inhibition of the Na+−K+ pump affects the K+ gradient; this may lead to a significant reduction of intracellular K+, predisposing the heart to arrhythmias. Likewise, high levels of Ca2+ intracellularly may contribute to serious arrhythmias.
“Cardioselective” β blockers
Blockage of β1-adrenergic receptors in the heart reduces heart rate and contractility and delays atrioventricular (AV) conduction. Blockage of β2 receptors causes arteriolar vasoconstriction (including the coronary arteries) and bronchoconstriction, so agents that act selectively on β1 receptors (e.g., atenolol) are used to treat cardiovascular disease. These so-called cardioselective β1 blockers are used to reduce myocardial oxygen (O2) demand in angina and myocardial infarction (MI), to control hypertension, to depress AV nodal conduction in atrial fibrillation and atrial flutter, and to prevent ventricular fibrillation during the first 2 years following a myocardial Infraction (MI).
Afterload
Afterload is the pressure that the ventricle works against to eject blood during systole. At rest, it is primarily a function of total peripheral resistance (TPR), i.e., it requires greater systolic pressure to eject blood in the face of high peripheral resistance. Afterload also depends on the output of the heart because pressure in the peripheral circulation is a function of the amount of blood ejected. For example, during exercise, peripheral resistance is low, which by itself would decrease afterload, but afterload is actually somewhat elevated because the heart is ejecting so much blood that mean arterial pressure is increased. High afterloads increase the work of the heart, and therapy for hypertension includes drugs that reduce TPR. A stenosed (narrowed) aortic valve can greatly increase afterload because the left ventricle has to generate a much higher pressure to eject through the restriction.
9.2 Cardiac Output
Cardiac output is the amount of blood pumped by either ventricle each minute. It is expressed as follows:
Cardiac output = stroke volume × heart rate,
where stroke volume is the volume of blood ejected from the ventricles during each contraction. It is expressed as follows:
Stroke volume = end-diastolic volume – end-systolic volume
Ejection fraction is the percentage of ventricular end-diastolic volume that is ejected during a given contraction. It is expressed as follows:
Ejection fraction = stroke volume/end-diastolic volume
Stroke work is the work that the heart does during each heartbeat. Cardiac work is the work done by the heart each minute. For the left ventricle, these are expressed as follows:
Stroke work = aortic pressure × stroke volume
Cardiac work = stroke work × heart rate
Heart failure
Heart failure is a pathophysiological state when cardiac output is insufficient to allow adequate perfusion and oxygenation of tissues. There are several etiological factors, including intrinsic disease of the heart muscle (e.g., ischemia, myocardial infraction [MI], cardiomyopathy, and myocarditis), chronic elevated preload (e.g., mitral regurgitation and fluid overload due to chronic renal disease), chronic elevated afterload (e.g., aortic stenosis and hypertension), disorders of cardiac filling (e.g., cardiac tamponade and pericarditis), congenital cardiac malformations, arrhythmias, diabetes, severe anemia, hyperthyroidism, and amyloidosis. Treatment is with the following drugs (in order of use): diuretics, angiotensin-converting enzyme (ACE) inhibitors, β-blockers, positive inotropic drugs (e.g., digoxin), and nitrates.
Cardiac muscle metabolism
Cardiac muscle requires an abundant supply of O2-rich blood, as it depends almost exclusively on aerobic metabolism to supply the adenosine triphosphate (ATP) for its contractions. Other tissues can vary their extraction of O2 from blood and survive with anaerobic metabolism. Cardiac tissue has a very high fractional extraction of O2 and can only increase its uptake of O2 by increasing coronary blood flow. At rest, the heart uses oxidation of fatty acids for its ATP, and only small quantities of glucose are used. When cardiac workload is increased, cardiac muscle removes lactic acid from coronary blood and oxidizes it directly.
Measuring of Cardiac Output
Cardiac output can be assessed by a variety of methods. Although now superseded by newer techniques, the simplest method conceptually is built around the Fick principle. In this method, the O2 content of systemic arterial blood (from the pulmonary vein) and mixed venous blood (from the pulmonary artery) is measured. The difference between the two is the amount of O2 taken up per unit volume of blood that passes through the lungs and heart. The rate of pulmonary O2 uptake is also measured by spirometry. When the arteriovenous difference is divided into the rate of O2 uptake, the result is cardiac output. The formal expression is
CO = Vo2/(ao2 – vo2)
where CO is cardiac output (L/min), Vo2 is the rate of O2 uptake (mL O2/min), ao2 is systemic arterial blood O2 content (mL O2/L), and vo2 is mixed venous blood O2 content. (mL O2/L).
Example: A patient consumes O2 at a rate of 230 mL/min. Systemic arterial blood contains 180 mL O2/L, and mixed venous blood contains 130 mL O2/L. What is his cardiac output?
Current methods for measuring cardiac output include the thermodilution technique, where a bolus of cold saline of known quantity and temperature is injected into the right atrium, where it mixes with warm blood and slightly cools it. Downstream, in the pulmonary artery, a transducer measures the amount of cooling. The less cooling, the greater the volume of warm blood mixed with the saline. Mathematical analysis then calculates cardiac output. A noninvasive method uses echocardiography to estimate chamber volumes and calculate cardiac output.
Autonomic Nervous System Regulation of Heart Rate, Conduction Velocity, and Contractility
The autonomic innervation of the heart is shown in Fig. 9.1.
Heart Rate and Conduction Velocity
– The parasympathetic nervous system decreases heart rate and conduction velocity.
– It decreases heart rate by slightly hyperpolarizing pacemaker cells, decreasing the rate of diastolic depolarization in sinoatrial (SA) nodal cells and by increasing K+ conductance in phase 4 of the action potential.
– It decreases AV node conduction velocity by decreasing the inflow of Ca2+ and increasing the outflow of K+.
– The sympathetic system increases heart rate and conduction velocity.
– It increases heart rate by increasing the rate of diastolic depolarization in SA nodal cells by increasing Ca2+ or Na+ conductance in phase 4 of the action potential.
– It increases AV node conduction velocity by increasing the inflow of Ca2+.
Contractility
– Parasympathetic action slows the heart rate, but it has little influence on contractility.
– Sympathetic (β-adrenergic) stimulation raises both heart rate and contractility. Key sites of sympathetic action include surface membrane Ca2+ channels and the SERCA pump.
– Phosphorylation of Ca2+ channels via cyclic adenosine monophosphate (cAMP) and protein kinase A allows more Ca2+ to enter the myocytes during phase 2 of the action potential.
– Phosphorylation of the protein phospholamban on the sarcoplasmic reticulum stimulates the SERCA pump to pump faster, thereby storing more Ca2+, which is then released on subsequent beats. The increased pumping also decreases the period when Ca2+ is available to bind to troponin, thereby shortening the period of systole. This results in contractions that are more forceful and shorter in duration.
Fig. 9.1 
Autonomic innervation of the heart.
Postganglionic parasympathetic fibers (blue) and sympathetic fibers (red) innervate the sinoatrial (SA) node and the atrioventricular (AV) node. This allows both divisions of the autonomic nervous system to modulate heart rate and conduction velocity. Postganglionic sympathetic fibers also innervate ventricular muscle, allowing it to modulate contractility.
From Atlas of Anatomy, © Thieme 2008, Illustration by Markus Voll.
Table 9.1 summarizes the effects of the autonomic nervous system (ANS) on heart rate, conduction velocity, and contractility.
9.3 The Cardiac Cycle
The cardiac cycle is the set of repetitive events where the ventricles sequentially fill, contract, eject blood, and relax. The right and left ventricles do this in parallel and almost simultaneously. The cardiac cycle generates signals that can be detected and interpreted to determine the functional state of the heart. The most common of these signals used clinically are the electrocardiogram (ECG) and heart sounds. The ECG provides information about excitation of the myocardium, a process that is required to signal contraction. Heart sounds indicate the closure of valves and detect unusual blood flow patterns, such as turbulent flow (murmurs).
The sequence of events that comprise the cycle for the left ventricle is broadly divided into periods of systole and diastole. These are then further subdivided into phases. Figure 9.2 illustrates the events that occur at each phase of the cardiac cycle.
Systole
Phase I
– Ventricular systole begins immediately after ventricular excitation (indicated by the QRS complex on the ECG).
– The rise in pressure causes closing of the mitral valve (and in the right ventricle, closing of the tricuspid valve). The sudden change in momentum of moving blood upon valve closure creates the first heart sound. Normally, the two valves close nearly simultaneously and are heard as one sound, but splitting into two may occur in some pathologies.
– As pressure rises before the aortic valve opens, there is a short period of isovolumetric contraction. The ventricle changes shape, but not volume, because both valves are closed.
Phase IIa
– When chamber pressure exceeds aortic pressure, the aortic valve opens, and a period of rapid ejection begins. Ventricular volume falls, but pressure continues to rise because active contractile force in the myocytes is still increasing and because the decreasing chamber radius allows wall tension to generate more pressure (as described by Laplace’s law where pressure is inversely proportional to radius).
Phase IIb
– Pressure reaches a peak and starts to decline. Only a small amount of blood continues to be ejected. The ventricle does not empty completely but retains at least 30 to 50% of the enddiastolic volume.
– Usually two-thirds of the stroke volume is ejected during the first third of systole.
–The T wave of the ECG occurs, indicating ventricular repolarization.
Fig. 9.2 Cardiac cycle.
The cardiac cycle consists of systole (contraction) and diastole (relaxation). The electrocardiogram (ECG) measures the electrical activity of the heart. The pressures in the aorta, left ventricle and atrium, and right atrium (central venous pressure) vary according to the contraction stage. The left ventricular volume and aortic flow show the amount of blood pumped into systemic circulation. The four heart sounds are observed at specific stages in the cardiac cycle. The duration of systole is less variable than the duration of diastole, which varies considerably. (ESV, end-systolic volume)
Diastole
Phase III
– Pressure falls rapidly and the aortic valve closes, beginning a period of isovolumetric relaxation. Normally, the pulmonary valve closes at almost the same time. The sudden change in momentum of moving blood creates the second heart sound.
Phase IV (a and b)
– The mitral valve opens, and the left ventricle begins filling rapidly, then more slowly. Usually two-thirds of the filling occurs during the first third of diastole. This is the longest phase of the cardiac cycle, and the most variable. Its duration is greatly shortened at high heart rates and extended at very slow heart rates.
Phase IVc
– The atria contract at the very end of ventricular diastole, producing the P wave of the ECG. Some additional blood flows into the ventricle. The additional volume is not significant at rest but takes on a more important role at high heart rates when the period of diastolic filling is much shorter.
Murmurs
Murmurs are sounds produced by turbulent blood flow through heart valves. Stenosis is narrowing of a heart valve. It produces a murmur at the stage of the cardiac cycle when the valve is normally open. Regurgitation is when blood flows back across a valve when the valve is normally closed. It occurs at the corresponding part of the cardiac cycle. Murmurs may be more easily distinguished from one another by proper use of the stethoscope (bell vs diaphragm), by the position where the murmur is most audible, and how it is affected by inspiration, expiration, exercise, and the Valsalva maneuver.
Depicting the Cardiac Cycle: Graphing Pressure–Volume Loops
A useful way to display the events of the cardiac cycle is via a plot of chamber pressure versus chamber volume, known as a pressure–volume loop (Fig. 9.3).
– The difference between end-diastolic and end-systolic volumes is the stroke volume.
– The vertical portions of the loop (constant volume) represent the periods of isovolumetric contraction and isovolumetric relaxation.
Fig. 9.3 Pressure–volume loop.
A pressure–volume loop shows the relation between ventricular pressure and volume during a complete cardiac cycle. Valves open or close at the corners of the loop. As the stroke volume is ejected, ventricular pressure continues to rise to a peak, then falls until the aortic valve closes. The area within the loop is the stroke work.
