Cardiovascular Physiology

Chapter 4 Cardiovascular Physiology

A. Cardiac cycle: composed of systole and diastole

• Systole is that part of the cardiac cycle in which the heart contracts and blood is ejected.

• In atrial systole, the atria pump blood into the relaxed ventricles, whereas in ventricular systole, the ventricles pump blood into the blood vessels.

• Blood pressure is greatest during systole and is referred to as the systolic blood pressure (SBP).

B. Heart valves

• Function to establish one-way flow of blood in the heart (Fig. 4-1)

C. Principal heart sounds

• Reflect valve closure and/or pathologic states

1. S₁: closure of AV valves

S₁: closure of AV valves;typically auscultated as a single sound

• Produced by closure of the AV valves in early systole as a result of the rapidly increasing ventricular pressure

• Heard loudest at the apex

• Has mitral (M₁) and tricuspid (T₁) components that do not vary with the respiratory cycle (i.e., S₁ split during inspiration or expiration is not normal)

• Mitral valve closes just before the tricuspid (0.01 second before).

• Closure of these valves is therefore interpreted as a single sound on auscultation.

Clinical note: In certain circumstances, S₁ may be accentuated. This occurs when the valve leaflets are “slammed” shut in early systole from a greater than normal distance because they have not had time to drift closer together. Three conditions that can result in an accentuated S₁ are a shortened PR interval, mild mitral stenosis, and high cardiac-output states or tachycardia.

2. S₂: closure of semilunar valves

S₂: normally “split” during inspiration

• Produced by closure of the semilunar valves in early diastole

• Diastolic pressures in the aorta and pulmonary artery exceed the pressures in the relaxing ventricles, causing the semilunar valves to close.

• Has aortic (A₂) and pulmonic (P₂) components (A2:P2), which vary with the respiratory cycle (Fig. 4-2)

• During inspiration, when intrathoracic pressures decrease, the reduced pulmonary artery pressure decreases the back pressure responsible for pulmonic valve closure, resulting in delayed closure of the pulmonic valve and a “split” S₂.

4-2 A, Relationship of splitting of S₂ to respiration in normal subjects. B, Reversed splitting of S₂ associated with delayed aortic closure, most commonly caused by left bundle branch block (LBBB). C, Fixed splitting of S₂ characteristic of severe pulmonary hypertension. A₂, Aortic valve closure; P₂, pulmonic valve closure; PA, pulmonic artery; S₁, first heart sound.

(From Fowler NO: Diagnosis of Heart Disease. New York: Springer-Verlag; 1991, p 31.)

S₂: best appreciated in the 2nd or 3rd left intercostal space

a. Furthermore, despite the increased preload, for unclear reasons the aortic valve closes earlier during inspiration.

b. S₂: can be best appreciated on auscultation at the 2nd or 3rd left intercostal space

Clinical note: Paradoxical or “reversed” splitting occurs when S₂ splitting occurs with expiration and disappears on inspiration. Moreover, in paradoxical splitting, the pulmonic valve closes before the aortic valve, such that P₂ precedes A₂. The most common cause is left bundle branch block (LBBB). In LBBB, depolarization of the left ventricle is impaired, resulting in delayed left ventricular contraction and aortic valve closure.

3. S₃: ventricular gallop

S₃: presence reflects volume-overloaded state

• An S₃ is sometimes heard in early to middle diastole, during rapid ventricular filling.

• Caused by a sudden limitation of ventricular expansion (some authors believe it is caused by sudden tensing of the chordae tendineae)

• May be normal in children and young adults but usually represents disease in older adults

• Typically caused by a volume-overloaded heart, as may be seen in congestive heart failure or advanced mitral regurgitation, in which the rate of early diastolic filling is increased

Clinical note: An S₃ is usually caused by volume overload in congestive heart failure. It can also be associated with valvular disease, such as advanced mitral regurgitation, in which the “regurgitated” blood increases the rate of ventricular filling during early diastole.

D. Ventricular pressure changes during the cardiac cycle (Fig. 4-3)

4-3 Ventricular pressure changes during the cardiac cycle.

S₁: due to closure of AV valves in early systole from ↑ ventricular pressure

S₂: due to closure of semilunar valves in early diastole because pulmonic/aortic pressures exceed intraventricular pressures

• During diastole, the ventricles gradually increase in volume, causing ventricular pressures to gradually increase (A).

• The slight “hump” before systole (B) represents atrial contraction in the final “topping off” phase of ventricular filling.

• When systole begins, the increasing ventricular pressures close the AV valves (C).

• Pressure continually builds until the ventricular pressure exceeds that of the aorta (left ventricle) or the pulmonary artery (right ventricle) (D).

• The aortic valve (left ventricle) or the pulmonic valve (right ventricle) then opens (E).

• Blood is ejected into the circulation (F).

• After the ventricles have finished contracting, they begin to relax, and intraventricular pressures decrease.

a. When the intraventricular pressure is less than the aortic pressure (left ventricle) or the pulmonary artery pressure (right ventricle), the aortic and pulmonic valves close (G).

• After closure of the semilunar valves, the ventricles continue to relax, and intraventricular pressures continue to decrease (H).

• Once intraventricular pressures are less than atrial pressures, the AV valves open (I), and the ventricular filling of diastole begins again.

• Note: The normal phonocardiogram in Figure 4-3 parallels the ventricular pressure curve.

a. S₁ occurs at the beginning of systole with AV valve closure (C), and S₂ occurs at the beginning of diastole with semilunar valve closure (G).

b. If an S₃ were present, it would occur in early diastole, because it is caused by rapid ventricular filling.

c. If an S₄ were present, it would occur in late diastole, because it is caused by atrial contraction against a stiff ventricle.

• Note: Rapid ventricular filling occurs in the early part of diastole, when the pressure gradients for blood flow between the pulmonary veins and left ventricle are greatest and the mitral valve is wide open.

II. Cardiac Performance

Cardiac performance: assessed by measuring cardiac output

• Cardiac performance is often assessed by measuring the cardiac output, which is the volume of blood pumped out of the heart each minute.

A. Cardiac output

1. Cardiac output (CO) is the product of heart rate (HR) and stroke volume (SV).

CO = HR × SV

2. HR is primarily under the influence of the autonomic nervous system.

3. In a healthy adult, the CO is approximately 5 L/minute:

4. CO can also be calculated by measuring whole body oxygen consumption.

• The Fick principle states that oxygen consumption by the body is a function of the amount of blood delivered to the tissues (cardiac output, CO) and the amount of O₂ extracted by the tissues (arteriovenous O₂ difference):

where [O₂]_a = arterial O₂ concentration (~200 mL O₂/L blood) and [O₂]_v = venous O₂ concentration (~150 mL O₂/L blood).

5. This equation can be rearranged to calculate the cardiac output:

where oxygen consumption is monitored by analysis of expired air, mixed venous blood is sampled by inserting a catheter into the pulmonary artery, and arterial blood is obtained from any peripheral artery.

6. For example, the CO for a healthy 70-kg man is calculated as follows:

• While this is an important physiologic concept, CO is rarely measured in this way.

B. Stroke volume

Stroke volume = EDV − ESV

1. Stroke volume (SV) is the volume of blood ejected from the ventricle during systole.

• SV is a major determinant of pulse pressure.

• SV is equal to the difference between end diastolic volume and end systolic volume

• In a typical adult, the SV is calculated as follows:

2. Ejection fraction

Ejection fraction = SV/EDV

• Ejection fraction (EF) is the percentage of blood in the ventricle at the end of diastole that is pumped into the circulation with each heartbeat.

a. In other words, it is the SV divided by the EDV.

• In a typical adult, the EF is calculated as follows:

Clinical note: If the heart muscle is not contracting efficiently (e.g., after a myocardial infarction), the EF may be decreased. If the ejection fraction is equal to or less than 40%, patients are said to have systolic heart failure. Multiple studies have shown that these patients benefit from taking angiotensin-converting-enzyme inhibitors (ACE inhibitors), which reduce pathologic ventricular remodeling in heart failure. Note that some patients may have a “preserved” ejection fraction on echocardiography but still have heart failure; in these cases, they would have diastolic heart failure.

3. Determinants of stroke volume

Stroke volume: dependent on preload, contractility, and afterload

• SV is determined by three principal factors: preload, contractility, and afterload.

• Preload

Preload: “load” placed on ventricle at start of systole; equivalent to EDV

a. Preload is the degree of tension or “load” on the ventricular muscle when it begins to contract.

b. This load is mainly determined by the volume of blood within the ventricle at the end of diastole (EDV), which in itself is primarily dependent on venous return.

c. An increased EDV causes an increased SV (Fig. 4-4).

d. Precisely why an increased EDV increases SV remains controversial, but there are two prominent theories.

4-4 Stroke volume versus preload. Atrial pressure at ventricular end diastole correlates with ventricular end diastolic volume and pressure and is often used as a surrogate marker of preload. Note that cardiac output increases from point A to point B as the preload increases.

Frank-Starling relationship: increased preload (to a point) results in increased CO

• The Frank-Starling relationship, also called the length-tension relationship of the heart theory, postulates that the increased ventricular wall tension associated with increased EDV stretches ventricular myocytes and results in a greater overlap of actin and myosin filaments.

(1) This greater overlap causes more forceful contractions and increases the SV.

Increased preload → ↑ stretching of sarcomeres → ↑ sensitivity to Ca²⁺

• The second theory postulates that the contractile apparatus of cardiac myocytes becomes more sensitive to cytoplasmic calcium (Ca²⁺) as the myocytes (and therefore sarcomeres) are stretched under conditions associated with increased preload.

(1) This concept is similar to the myogenic theory proposed to explain autoregulation of blood flow, to be discussed later.

• Contractility

Contractility: ↑ with digitalis, sympathetic stimulation; ↓ in heart failure

a. Contractility is a measure of the forcefulness of contraction at any given preload (i.e., independent of myocardial wall tension at EDV) (Fig. 4-5).

b. It is commonly referred to as the inotropic state of the heart.

c. Drugs (e.g., digitalis), sympathetic excitation, and heart disease may all affect contractility.

• Afterload

4-5 Stroke volume versus contractility. For any given end diastolic volume (A), addition of a positive inotropic agent (e.g., epinephrine) increases stroke volume and cardiac output by increasing contractility (B). Similarly, addition of a negative inotropic agent (e.g., antagonist of circulating epinephrine or norepinephrine) decreases stroke volume and cardiac output by decreasing contractility (C). Note that in heart failure, a new preload “set point” (D) is established to optimize cardiac output.

Afterload: ↑ in aortic stenosis and hypertension, ↓ with intra-aortic balloon pump

a. Afterload is the pressure or resistance against which the ventricles must pump blood, including systemic blood pressure and any obstruction to outflow from the ventricle, such as a stenotic (narrowed) aortic valve.

b. At a given preload and contractility, if afterload increases, SV will decrease (Fig. 4-6).

4. Mechanical characterization of contraction

• Wall tension

4-6 Determinants of stroke volume.

Laplace relationship: myocardial wall tension needs to ↑ in order to generate an ↑ intraventricular pressure to overcome an ↑ afterload

a. When pressure is increased inside a vessel, it causes a distending force.

b. The force that opposes this distention is the tension or stress in the vessel wall.

c. The Laplace equation relates these two forces:

where σ = wall tension, P = intraluminal pressure, r = intraluminal radius, and h = wall thickness.

d. Think of the ventricle as a very thick-walled vessel, and use the Laplace equation to determine that, if the ventricle must generate a greater intraventricular pressure to overcome an afterload, myocardial wall tension will increase.

Left ventricular hypertrophy: occurs by addition of sarcomeres in parallel

e. Left ventricular hypertrophy with the addition of sarcomeres in parallel (↑H) then occurs as a compensatory response to increased wall tension.

• Stroke work

Stroke work: ↑ with increasing SV or by maintaining constant SV in face of ↑ afterload

a. Stroke work is a measure of the mechanical work performed by the ventricle with each contraction.

b. Stroke work will increase in two scenarios: by increasing stroke volume against a constant afterload or by maintaining a given SV while afterload increases.

C. Venous return

1. Effect of venous return on cardiac output by influencing preload

Venous return: rate determined by pressure gradient between systemic veins and right atrium

• The rate of venous return is determined by the pressure gradient between the systemic veins and the right atrium.

• Increased venous return increases preload and CO (Fig. 4-7).

4-7 Relationship of preload to stroke volume. ESV, End systolic volume.

(From Lilly LS: Pathophysiology of Heart Disease, 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2003, Fig. 9-5A.)

Venous return is decreased at increased right atrial pressures.

• At increased right atrial pressures (e.g., pulmonary hypertension), venous return is reduced because the pressure gradient driving venous return is reduced.

• When right atrial pressure equals systemic venous pressure, there is no pressure gradient and therefore no flow.

Venoconstriction or intravenous volume infusion → ↑ systemic venous pressure → ↑ venous return and CO

Venodilation or loss of blood → ↓ systemic venous pressure → ↓ venous return and CO

• Contraction of the veins or infusion of volume increases the systemic venous pressure and therefore the driving force for venous return to the right side of the heart, increasing venous return (Fig. 4-8, point B) at a given right atrial pressure.

• Alternatively, loss of blood or dilation of the veins reduces systemic venous pressure and decreases venous return (see Fig. 4-8, point C).

4-8 Rate of venous return as a function of right atrial pressure.

Clinical note: Patients experiencing massive blood loss (e.g., trauma patients) are given large volumes of intravenous fluids to increase systemic venous pressure and to increase venous return, thereby increasing preload and CO.

• The situation becomes more complex when the CO curve is superimposed on the venous return curve (Fig. 4-9).

• Recall that as preload increases, CO increases by the Frank-Starling relationship.

2. Other determinants of venous return

• Respiratory pump

Respiratory pump: ↑ VR during inspiration due to ↓ intrathoracic and ↑ abdominal pressures

a. Venous return is facilitated during inspiration because of an increased venous pressure gradient associated with inspiration.

b. As the chest wall expands outward in inspiration, intrathoracic pressure decreases.

c. At the same time, abdominal pressure increases (partly because of the descending diaphragm).

d. The net result of these pressure changes is an increased pressure gradient driving increased venous return to the right atrium.

Clinical note: The presence of an inspiratory S₂ split on cardiac auscultation can be explained by increased venous return to the right atrium during inspiration, which increases the EDV and necessitates a longer systole to eject the additional blood into the pulmonary artery. Pulmonary vascular resistance also decreases somewhat during inspiration, which decreases the pulmonary back pressure needed to close the pulmonic valve. These two factors delay closure of the pulmonary valve during inspiration.

D. Ventricular pressure-volume loops

1. Cardiac function is commonly characterized graphically by pressure-volume loops.

2. There are four phases (Fig. 4-10).

• Phase III: ejection period

Phase III: ejection of blood after opening of aortic valve

a. This phase begins as pressures in the left ventricle exceed those in the aorta, causing the aortic valve to open.

b. Blood is then continually ejected until the pressures in the aorta exceed those in the ventricle, and the aortic valve closes.

E. Atrial pressure changes during the cardiac cycle (Fig. 4-11)

4-11 Atrial pressure curve. The a wave would be absent during atrial fibrillation.

a wave: atrial contraction → slight ↑ in atrial pressure

1. A slight pressure increase (a wave) is caused by atrial contraction.

c wave: isovolumic ventricular contraction and inward bulging of AV valves → large ↑ in atrial pressure

2. A large pressure increase (c wave) is caused by isovolumic ventricular contraction and inward bulging of the AV valves.

x descent: start of ventricular ejection → rapid ↓ in atrial pressure

3. A rapid reduction in pressure (x descent) is caused by initiation of the ventricular ejection phase; sometimes referred to as the vacuum effect.

v wave: atrial filling after closure of AV valves → gradual ↑ in atrial pressure

4. A gradual pressure increase (v wave) is caused by atrial filling after closure of the AV valves.

5. A gradual pressure decrease (y descent) is caused by ventricular filling after opening of the AV valves.

Clinical note: Measurement of atrial pressures can be helpful in determining the cause of various cardiac disorders. Elevated right atrial and pulmonary artery pressures can often be appreciated on examination by simply looking for jugular venous distention or by performing echocardiography. However, a more invasive procedure, using a pulmonary wedge device or Swan-Ganz catheter, is required to evaluate left atrial pressure. This catheter is inserted into a peripheral vein and threaded through the venous circulation until it becomes “wedged” in one of the small branches of the pulmonary artery. Equilibration of blood from the pulmonary veins then allows an indirect measurement of left atrial pressure.

F. Pathophysiology of the major valvular diseases

1. Aortic stenosis

Aortic stenosis: ↑ afterload, ↓ stroke volume, pulsus parvus et tardus

• The cross-sectional area of the aortic valve becomes pathologically decreased, causing substantial resistance to ejection of blood through the valve.

• This increase in resistance increases afterload, which decreases the SV and consequently decreases CO.

• Figure 4-12A shows a pressure-volume loop in a patient with aortic stenosis.

• Notice how an increased intraventricular pressure must be attained to overcome the significant afterload produced by the stenotic valve.

• The heart expends more energy developing increased pressures; therefore, less energy is available for the ejection phase, so the SV is decreased.

• Development of the pressure necessary to overcome the afterload also takes time, which means that it takes longer for a pulse to appear after closure of the AV valves (S₁).

• The combination of reduced SV (which reduces the pulse pressure) and delayed pulse from the increased afterload is responsible for the description of the pulse seen in aortic stenosis: pulsus parvus et tardus (weak and late) (see Fig. 4-12B).

4-12 Pressure-volume changes in aortic stenosis. Ao, Aorta; AV, atrioventricular; IVC, inferior vena cava; LA, left atrium; LV, left ventricle; LVH, left ventricular hypertrophy; MV, mitral valve; PA, pulmonary artery; PMI, point of maximal impulse; PV, pulmonary valve; RA, right atrium, RV, right ventricle; SV, stroke volume; SVC, superior vena cava; TV, tricuspid valve.

(B, From Goljan EF: Rapid Review Pathology, 3rd ed. Philadelphia: Mosby; 2010, Fig. 10-18.)

Pathology note: In some individuals, the aortic valve is congenitally bicuspid. These bicuspid valves are predisposed to early calcification and stenosis, often causing significant aortic stenosis in individuals in their late 40s or early 50s. More commonly, aortic stenosis in elderly people is caused by calcification of the normal tricuspid valve, a condition known as senile calcific aortic stenosis. Another cause of aortic stenosis is rheumatic fever, but this disease is becoming rare in developed nations because of the use of antibiotics.

Clinical note: A stenotic aortic valve increases the rate of blood flow through the aortic valve, producing turbulent flow and consequently a systolic ejection murmur (while blood is being ejected across the valve).

2. Aortic regurgitation (insufficiency)

Aortic regurgitation: ↓ effective SV, widened pulse pressure

• The aortic valve does not normally prevent backflow of blood into the left ventricle.

• In aortic regurgitation, a significant fraction of the blood ejected into the aorta with each heartbeat returns to the left ventricle (Fig. 4-13A). Naturally, this decreases the CO.

• The increased preload that occurs from blood regurgitating back into the ventricle increases the SV (although not necessarily the effective SV), which helps maintain a relatively normal systolic pressure.

4-13 A and B, Pathologic and clinical findings often seen with aortic regurgitation. Ao, Aorta; AV, atrioventricular; IVC, inferior vena cava; LA, left atrium; LV, left ventricle; LVH, left ventricular hypertrophy; MV, mitral valve; PA, pulmonary artery; PV, pulmonary valve; RA, right atrium, RV, right ventricle; SVC, superior vena cava; TV, tricuspid valve.

(A, From Damjanov I: Pathophysiology. Philadelphia: Saunders; 2008, Fig. 4-53; B, from Goljan EF: Rapid Review Pathology, 3rd ed. Philadelphia: Mosby; 2010, Fig. 10-19.)

Aortic regurgitation: increased SV and decreased diastolic pressure → Water Hammer pulse on exam

• However, diastolic pressure may be substantially reduced because of this “backward flow,” thus explaining the widened pulse pressure commonly seen in aortic regurgitation and the bounding and forceful pulses, the so called Water Hammer pulse (Fig. 4-13B).

Pathology note: Aortic regurgitation may involve several different pathogenetic mechanisms. The most common causes are connective tissue defects that weaken the supporting aortic and valvular structures (e.g., Marfan syndrome, Ehlers-Danlos syndrome) and inflammatory diseases of the heart and/or aorta (e.g., endocarditis, syphilitic aortitis).

3. Mitral stenosis

Mitral stenosis: rheumatic fever still most common cause

• In early diastole, the mitral valve opens and provides negligible resistance to blood flow from the left atrium to the left ventricle.

• In mitral stenosis (Fig. 4-14), the mitral valve becomes stenotic owing to abnormal structural changes.

• This results in a large diastolic pressure gradient between the left atrium and left ventricle.

• Resistance to blood flow across the mitral valve increases, and adequate ventricular filling can occur only at pathologically elevated atrial filling pressures.

4-14 Schematic of mitral stenosis illustrating some of the pathologic anatomic and hemodynamic changes that may occur. Ao, Aorta; AV, aortic valve; IVC, inferior vena cava; LA, left atrium; LV, left ventricle; LVH, left ventricular hypertrophy; MV, mitral valve; PA, pulmonary artery; PH, pulmonary hypertension; PV, pulmonary valve; RA, right atrium; RV, right ventricle; RVH, right ventricular hypertrophy; SVC, superior vena cava; TV, tricuspid valve.

(From Goljan EF: Rapid Review Pathology, 3rd ed. Philadelphia: Mosby; 2010, Fig. 10-14.)

Mitral stenosis: associated with large diastolic pressure difference between left atrium and ventricle

Pathology note: Rheumatic fever remains the most common cause of mitral stenosis. Symptoms of mitral stenosis (dyspnea, exercise intolerance) usually develop about 20 years after an acute episode of rheumatic fever.

Mitral stenosis: ↑ left atrial pressures →↑ hydrostatic pressures in pulmonary circulation → pulmonary edema

• As left atrial pressures become elevated, the hydrostatic pressures in the pulmonary veins and capillaries also become elevated, causing net transudation of fluid into the pulmonary interstitium.

• Initially, the pulmonary lymphatics can reabsorb this fluid and prevent pulmonary edema.

• Once the left atrial pressure exceeds 30 to 40 mm Hg, however, the compensatory capacity of the lymphatics is overwhelmed, and fluid begins to accumulate in the lungs.

Symptoms of pulmonary edema: dyspnea, reduced exercise capacity

• This fluid accumulation causes the symptoms of mitral stenosis, such as dyspnea and reduced exercise capacity.

Treatment of severe symptomatic mitral stenosis: mitral valve repair (commissurotomy), balloon valvuloplasty, or valve replacement

• If the degree of stenosis is severe, repair (mitral commissurotomy), percutaneous balloon valvuloplasty, or replacement of the mitral valve is necessary to prevent fatal progression of the disease.

4. Mitral regurgitation (insufficiency)

• In early systole, ventricular contraction is isovolumic when both the semilunar and AV valves are closed.

• This allows the entire left ventricular output to move “forward” into the aorta once the aortic valve opens.

Mitral regurgitation: mitral valve does not form good seal → blood flows into left atrium during early systole

• In mitral regurgitation, however, the mitral valve does not form a good “seal” and allows backward flow of blood into the left atrium during early systole.

• Figure 4-15 shows the hemodynamic changes in mitral regurgitation. Note that both the left atrium and left ventricle are enlarged.

• Symptoms of mitral regurgitation therefore may be associated with reduced forward flow CO, elevated left atrial pressures, and/or left ventricular volume overload because of the additional preload imposed on the left ventricle by the addition of the “regurgitated” blood to the normal venous return.

4-15 Mitral regurgitation with part A showing the pathologic changes associated with mitral regurgitation and part B highlighting the high-velocity flow into the left atrium during systole.

(A, From Damjanov I: Pathophysiology. Philadelphia: Saunders; 2008, Fig. 4-55; B, from Talley N, O’Connor S: Clinical Examination, 5th ed. Philadelphia: Elsevier; 2006, Fig. 3-40.)

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