Chapter 11_ Cardiovascular Function in Pathological Situations | Cardiovascular Physiology: Mosby Physiology Monograph Series, 9e (Mosbys Physiology Monograph)

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Objectives

The student understands the primary disturbances, compensatory responses, decompensatory processes, and possible therapeutic interventions that pertain to various abnormal cardiovascular situations.

Defines circulatory shock.
Identifies the primary disturbances that can account for cardiogenic, hypovolemic, anaphylactic, septic, and neurogenic shock states.
Lists the compensatory processes that may arise during shock.
Identifies the decompensatory processes that may arise during shock and describes how these lead to irreversible shock states.
Indicates how coronary artery disease may lead to abnormal cardiac function.
Defines the term angina pectoris and describes the mechanisms that promote its development.
Indicates the mechanisms by which various therapeutic interventions may alleviate angina and myocardial ischemia in association with coronary artery disease.
Defines the term heart failure and differentiates between systolic and diastolic dysfunction.
Identifies the short-term and long-term compensatory processes that accompany heart failure.
Describes the advantages and disadvantages of the fluid accumulation that accompanies heart failure.
Defines arterial hypertension.
Identifies the various factors that may contribute to the development of primary hypertension.
Describes the role of the kidney in establishing and/or maintaining hypertension.

Cardiovascular Function in Pathological Situations: Introduction

In this last chapter, some of the pathological situations that can interfere with the homeostatic functions of the cardiovascular system will be introduced. It is not intended as an in-depth coverage of cardiovascular diseases but rather as an introductory presentation of how the physiological processes described previously are evoked and/or altered during various abnormal cardiovascular states. In each case there is generally a primary disturbance that evokes appropriate compensatory reflex responses. Often, however, pathological situations also lead to inappropriate "decompensatory processes" which tend to accelerate the deterioration of cardiovascular function. Therapeutic interventions may be required and are often designed to limit or reverse these decompensatory processes.

Circulatory Shock

A state of circulatory shock exists whenever there is a generalized, severe reduction in blood supply to the body tissues and the metabolic needs of the tissues are not met. Even with all cardiovascular compensatory mechanisms activated, arterial pressure is usually (though not always) low in shock.

Primary Disturbances

In general, the shock state is precipitated by either severely depressed myocardial functional ability or by grossly inadequate cardiac filling due to low mean circulatory filling pressure. The former situation is called cardiogenic shock and occurs whenever cardiac pumping ability is compromised (eg, severe arrhythmias, abrupt valve misfunction, coronary occlusions, and myocardial infarction). The latter situation can be caused by any of the conditions itemized below that decrease central venous volume and/or ventricular filling:

1. Hypovolemic shock accompanies significant hemorrhage (usually greater than 20% of blood volume), severe burns, chronic diarrhea, or prolonged vomiting. These situations can induce shock by depleting body fluids and thus circulating blood volume.

The occurrence of a pulmonary embolus (a clot mobilized from systemic veins lodging in a pulmonary vessel) may evoke a shock state that resembles hypovolemic shock in that left ventricular filling may be compromised. While small emboli have minor functional consequences, large emboli not only reduce cardiac output but interfere with adequate gas exchange in the lungs.

2. Anaphylactic shock occurs as a result of a severe allergic reaction to an antigen to which the patient has developed a sensitivity (eg, insect bites, antibiotics, certain foods). This immunological event, also called an "immediate hypersensitivity reaction," is mediated by several substances (such as histamine, prostaglandins, leukotrienes, bradykinin) that, by multiple mechanisms not well understood, results in substantial peripheral vasodilation and increases microvascular permeability.

3. Septic shock is caused by vasodilator effects of substances released into the circulating blood by infective agents. One of the most common is endotoxin, a lipopolysaccharide released from bacteria. This substance induces the formation of a nitric oxide synthase (called inducible nitric oxide synthase to distinguish it from the normally present constitutive nitric oxide synthase) in endothelial cells, vascular smooth muscle, and macrophages which then produce large amounts of the vasodilator nitric oxide.

4. Neurogenic shock is produced by loss of vascular tone due to inhibition of the normal tonic activity of the sympathetic vasoconstrictor nerves and often occurs with deep general anesthesia or in reflex response to deep pain associated with traumatic injuries. The transient vasovagal syncope that may be evoked by strong emotions is a mild form of neurogenic shock.

As shown in the top half of Figure 11 1, the common primary disturbances in all forms of shock are decreased cardiac output and decreased mean arterial pressure. Generally, the reduction in arterial pressure is substantial, and so therefore is the influence on the cardiovascular centers from reduced arterial baroreceptor discharge rate. In addition, in the case of hypovolemic, anaphylactic, and septic shock, diminished activity of the cardiopulmonary baroreceptors due to a decrease in central venous pressure and/or volume acts on the medullary cardiovascular centers to stimulate sympathetic output.¹ If arterial pressure falls below about 60 mmHg, brain blood flow begins to fall and this elicits the cerebral ischemic response. As indicated in Chapter 9, the cerebral ischemic response causes the most intense of all activation of the sympathetic nerves.

¹ In the case of cardiogenic shock, central venous pressure will increase; and in the case of neurogenic shock, central venous pressure cannot be predicted because both cardiac output and venous return are likely to be depressed. Thus, in these instances, it is not clear how the cardiopulmonary baroreceptors affect autonomic output.

Compensatory Mechanisms

In general, the various forms of shock elicit the compensatory responses in the autonomic nervous system that we would expect from a fall in blood pressure.² These are indicated in the bottom half of Figure 11 1. These compensatory responses to shock, however, may be much more intense than those that accompany more ordinary cardiovascular disturbances. Many of the commonly recognized symptoms of shock (eg, pallor, cold clammy skin, rapid heart rate, muscle weakness, venous constriction) are a result of greatly increased sympathetic nerve activity. When the immediate compensatory processes are inadequate, the individual may also show signs of abnormally low arterial pressure, such as dizziness, confusion, or loss of consciousness.

There are some additional compensatory processes that are initiated during the shock state:

1. Breathing is rapid and shallow, which promotes venous return to the heart by action of the respiratory pump.

2. The release of renin from the kidney as a result of sympathetic stimulation promotes the formation of the hormone angiotensin II, which is a potent vasoconstrictor and participates in the increase in total peripheral resistance even in mild shock states.

3. Circulating levels of epinephrine from the adrenal medulla increase in response to sympathetic stimulation and contribute to the vasoconstriction.

4. The increase in arteriolar constriction reduces capillary hydrostatic pressure. Because plasma oncotic pressure has not changed (at least initially), there is a net shift of fluid from the interstitial space into the vascular space.

5. Glycogenolysis in the liver induced by epinephrine and norepinephrine results in a release of glucose and a rise in blood (and interstitial) glucose levels and, more importantly, a rise in extracellular osmolarity by as much as 20 mOsm. This will induce a shift of fluid from the intracellular space into the extracellular (including intravascular) space.

The latter two processes result in a sort of "autotransfusion" that can move as much as 1 L of fluid into the vascular space in the first hour after the onset of the shock episode. This fluid shift accounts for the reduction in hematocrit that is commonly observed in hemorrhagic shock.

In addition to the immediate compensatory responses shown in Figure 11 1, fluid retention mechanisms are evoked by hypovolemic states that affect the situation in the long term. Recall that a decrease in activity of the cardiopulmonary baroreceptors causes production and release of the antidiuretic hormone (vasopressin) from the posterior pituitary. In addition to being a potent vasoconstrictor and contributing to the increase in total peripheral resistance in severe shock states, this hormone promotes water retention by the kidneys. Furthermore, activation of the renin-angiotensin-aldosterone pathway promotes renal sodium retention (via aldosterone) and the thirst sensation and drinking behavior (via angiotensin II). These processes contribute to the replenishment of extracellular fluid volume within a few days of the shock episode.

²Two primary exceptions to this statement include (1) neurogenic shock, where reflex responses may be absent or lead to further depression of blood pressure, and (2) certain instances of cardiogenic shock associated with inferoposterior myocardial infarctions, which elicit a reflex bradycardia and decrease sympathetic drive (the Bezold-Jarisch reflex).

Decompensatory Processes

Often the strong compensatory responses elicited during shock are capable of preventing drastic reductions in arterial pressure. However, because the compensatory mechanisms involve intense arteriolar vasoconstriction, perfusion of tissues other than the heart and brain may be inadequate despite nearly normal arterial pressure. For example, blood flow through organs such as the liver and kidneys may be reduced nearly to zero by intense sympathetic activation. The possibility of permanent renal or hepatic ischemic damage is a very real concern even in seemingly mild shock situations. Often, patients who have apparently recovered from a state of shock die several days later because of renal failure and uremia.

The immediate danger with shock is that it may enter the progressive stage, wherein the general cardiovascular situation progressively degenerates, or, worse yet, enter the irreversible stage, where no intervention can halt the ultimate collapse of cardiovascular function that results in death.

The mechanisms behind progressive and irreversible shock are not completely understood. However, it is clear from the mechanisms shown in Figure 11 2 that bodily homeostasis can progressively deteriorate with prolonged reductions in organ blood flow. These homeostatic disturbances in turn adversely affect various components of the cardiovascular system so that arterial pressure and organ blood flow are further reduced. Note that the events shown in Figure 11 2 are decompensatory mechanisms. Reduced arterial pressure leads to alterations that further reduce arterial pressure rather than correct it. These decompensatory mechanisms that are occurring at the tissue level to lower blood pressure are eventually further compounded by a reduction in sympathetic drive and a change from vasoconstriction to vasodilation with a further lowering of blood pressure. The factors that lead to this unexpected reduction in sympathetic drive from the medullary cardiovascular centers are not clearly understood. If the shock state is severe enough and/or has persisted long enough to enter the progressive stage, the self-reinforcing decompensatory mechanisms progressively drive arterial pressure down. Unless corrective measures are taken quickly, death will ultimately result.

Cardiac Disturbances

Coronary Artery Disease

Whenever coronary blood flow falls below that required to meet the metabolic needs of the heart, the myocardium is said to be ischemic and the pumping capability of the heart is impaired. The most common cause of myocardial ischemia is atherosclerotic disease of the large coronary arteries. In atherosclerotic disease, localized lipid deposits called plaques develop within the arterial walls. With severe disease these plaques may become calcified and so large that they physically narrow the lumen of arteries (producing a stenosis) and thus greatly and permanently increase the normally low vascular resistance of these large arteries. This extra resistance adds to the resistance of other coronary vascular segments and tends to reduce coronary flow. If the coronary artery stenosis is not too severe, local metabolic vasodilator mechanisms may reduce arteriolar resistance sufficiently to compensate for the abnormally large arterial resistance. Thus, an individual with coronary artery disease may have perfectly normal coronary blood flow when resting. A coronary artery stenosis of any significance will, however, limit the extent to which coronary flow can increase above its resting value by reducing maximum achievable coronary flow. This occurs because, even with very low arteriolar resistance, the overall vascular resistance of the coronary vascular bed is high if arterial resistance is high.

Coronary artery disease can jeopardize cardiac function in several ways. Ischemic muscle cells are electrically irritable and unstable and the danger of fibrillation is enhanced. During ischemia, the normal cardiac electrical excitation pathways may be altered and often ectopic pacemaker foci develop. Electrocardiographic manifestations of myocardial ischemia can be observed in individuals with coronary artery disease during exercise stress tests. In addition, there is some evidence that platelet aggregation and clotting function may be abnormal in atherosclerotic coronary arteries and the danger of thrombus or emboli formation is enhanced. It appears that certain platelet suppressants or anticoagulants such as aspirin may be beneficial in the treatment of this consequence of coronary artery disease. (Details of the blood clotting process are included in Appendix D.)

Myocardial ischemia not only impairs the pumping ability of the heart, but also produces intense, debilitating chest pain called angina pectoris. Anginal pain is often absent in individuals with coronary artery disease when they are resting but is induced during physical exertion or emotional excitement. Both of these situations elicit an increase in sympathetic tone that increases myocardial oxygen consumption. Myocardial ischemia and chest pain will result if coronary blood flow cannot keep pace with the increase in myocardial metabolism.

Primary treatment of coronary artery disease (and atherosclerosis, in general) should include attempts to lower blood lipids by dietary and pharmacological techniques that prevent (and possibly reverse) further development of the plaques. The interested student should consult medical biochemistry and pharmacology texts for a complete discussion of this very important topic.

Treatment of angina that is a result of coronary artery disease may involve several different pharmacological approaches. First, vasodilator drugs such as nitroglycerin may be used to acutely increase coronary blood flow. In addition to increasing myocardial oxygen delivery by dilating coronary vessels, nitrates may also reduce myocardial oxygen demand by dilating systemic veins and reducing the cardiac preload and by decreasing arterial resistance and reducing the cardiac afterload. Second, -adrenergic blocking agents such as propranolol may be used to block the effects of cardiac sympathetic nerves on heart rate and contractility. These agents limit myocardial oxygen consumption and prevent it from increasing above the level that the compromised coronary blood flow can sustain. Third, calcium channel blockers such as verapamil may be used to dilate coronary vessels. These drugs, which block entry of calcium into the vascular smooth muscle cell, interfere with normal excitation-contraction coupling. They have been found to be most useful for treating the angina caused by vasoconstrictive spasms of large coronary arteries (Prinzmetal's angina).

Invasive or surgical interventions are now commonly used to eliminate coronary artery stenosis. In some cases, x-ray techniques can be used to visualize a radiopaque, balloon-tipped catheter as it is threaded into the coronary artery to the occluded region. Rapid inflation of the balloon squeezes the plaque against the vessel wall and improves the patency of the vessel. This technique, called coronary angioplasty, may also be effective in opening occlusions produced by intravascular clots associated with acute myocardial infarction.³ A small tube-like device called a stent is often implanted inside the vessel at the angioplasty site. This rigid implant promotes continued patency of the vessel over a longer period than angioplasty alone. If angioplasty and stent placement is inappropriate or unsuccessful, coronary bypass surgery may be performed. The stenotic coronary artery segments are bypassed by implanting parallel low-resistance pathways formed either from natural (eg, saphenous vein or mammary artery) or artificial vessels.

³ Another method for treatment of acute myocardial infarction has been the intravascular injection of substances that dissolve blood clots such as streptokinase or tissue plasminogen activating factor. This method is most successful when given within a few hours of the infarction.

Chronic Heart Failure Systolic Dysfunction

Heart (or cardiac, or myocardial) failure is said to exist whenever ventricular function is depressed through myocardial damage, insufficient coronary flow, or any other condition that directly impairs the mechanical performance of heart muscle. By definition, systolic heart failure implies a lower than normal cardiac function curve, that is, a reduced cardiac output at any given filling pressure. Acute heart failure has already been discussed in the context of cardiogenic shock and as part of the decompensatory mechanisms operating in progressive and irreversible shock. Often, however, sustained cardiac "challenges" may induce a chronic state of heart failure. Such challenges might include (1) progressive coronary artery disease, (2) sustained elevation in cardiac afterload as that which accompanies arterial hypertension or aortic valve stenosis, or (3) reduced functional muscle mass following myocardial infarction. In some instances, external causes of cardiac failure cannot be identified and some primary myocyte abnormality is to blame. This situation is referred to as primary cardiomyopathy. Regardless of the precipitating cause, most forms of failure are associated eventually with a reduced myocyte function. Many specific structural, functional, and biochemical myocyte alterations accompany severe heart failure. Some of the more well-documented abnormalities include (1) reduced calcium sequestration by the sarcoplasmic reticulum and up-regulation of the sarcolemmal Na/Ca exchanger (leading to low intracellular calcium levels for excitation-contraction coupling), (2) low affinity of troponin for calcium (leading to reduced cross-bridge formation and contractile ability), (3) altered substrate metabolism from fatty acid to glucose oxidation, and (4) impaired respiratory chain activity (leading to impaired energy production).

The primary disturbance in systolic heart failure (acute or chronic) is depressed cardiac output and thus lowered arterial pressure. Consequently, all the compensatory responses important in shock (Figure 11 1) are also important in heart failure. In chronic heart failure, however, the cardiovascular disturbances may not be sufficient to produce a state of shock. Moreover, long-term compensatory mechanisms are especially important in chronic heart failure.

The circumstances of chronic heart failure are well illustrated by cardiac output and venous function curves such as those shown in Figure 11 3. The normal cardiac output and normal venous function curves intersect at point A in Figure 11 3. A cardiac output of 5 L/min at a central venous pressure of less than 2 mmHg is indicated by the normal operating point (A). With heart failure, the heart operates on a much lower than normal cardiac output curve. Thus, heart failure alone (uncompensated) shifts the cardiovascular operation from the normal point (A) to a new position, as illustrated by point B in Figure 11 3 ie, cardiac output falls below normal while central venous pressure rises above normal. The decreased cardiac output leads to decreased arterial pressure and reflex activation of the cardiovascular sympathetic nerves. Increased sympathetic nerve activity tends to (1) raise the cardiac function curve toward normal and (2) increase peripheral venous pressure through venous constriction and thus raise the venous function curve above normal. Cardiovascular operation will shift from point B to point C in Figure 11 3. Thus, the depressed cardiac output is substantially improved by the immediate consequences of increased sympathetic nerve activity. Note, however, that the cardiac output at point C is still below normal. The arterial pressure associated with cardiovascular operation at point C is likely to be near normal, however, because higher than normal total peripheral resistance will accompany higher than normal sympathetic nerve activity.

In the long term, cardiovascular operation cannot remain at point C in Figure 11 3. Operation at point C involves higher than normal sympathetic activity, and this will inevitably cause a gradual increase in blood volume by the mechanisms that were described in Chapter 9. Over several days, there is a progressive rise in the venous function curve as a result of increased blood volume and, consequently, increased mean circulatory filling pressure. Recall that this process involves a sympathetically induced release of renin from the kidney, which activates the renin-angiotensin-aldosterone system that promotes fluid retention. This will progressively shift the cardiovascular operating point from C to D to E as shown in Figure 11 3.

Note that increased fluid retention (C D E in Figure 11 3) causes a progressive increase in cardiac output toward normal and simultaneously allows a reduction in sympathetic nerve activity toward the normal value. Reduced sympathetic activity is beneficial for several reasons. First, decreased arteriolar constriction permits renal and splanchnic blood flow to return toward more normal values. Second, myocardial oxygen consumption may fall as sympathetic nerve activity falls, even though cardiac output tends to increase. Recall that increased heart rate and increased cardiac contractility greatly increase myocardial oxygen consumption. Reduced myocardial oxygen consumption is especially beneficial in situations where inadequate coronary blood flow is the cause of the heart failure. In any case, once a normal cardiac output has been achieved, the individual is said to be in a "compensated" state.⁴

Unfortunately, the consequences of fluid retention in cardiac failure are not all beneficial. Note in Figure 11 3 that fluid retention (C D E) will cause both peripheral and central venous pressures to be much higher than their normal values. Chronically high central venous pressure causes chronically increased end-diastolic volume (cardiac dilation). Up to a point, cardiac performance is improved by increased cardiac filling volume through Starling's law. Excessive cardiac dilation, however, can impair cardiac function because increased total wall tension is required to generate pressure within an enlarged ventricular chamber (T = P x r,Chapter 2).

The high venous pressure associated with fluid retention also adversely affects organ function because transcapillary fluid filtration, edema formation, and congestion are produced by a high venous pressure (hence the commonly used term congestive heart failure). Pulmonary edema with dyspnea (shortness of breath)⁵ and respiratory crisis often accompany left heart failure. Common signs of right heart failure include distended neck veins, ankle edema, and fluid accumulation in the abdomen (ascites) with liver congestion and dysfunction.⁶

In the example shown in Figure 11 3, the depression in the cardiac output curve because of heart failure is only moderately severe. Thus, it is possible, through moderate fluid retention, to achieve a normal cardiac output with essentially normal sympathetic activity (point E). The situation at point E is relatively stable because the stimuli for further fluid retention have been removed. If, however, the heart failure is more severe, the cardiac output curve may be so depressed that normal cardiac output cannot be achieved by any amount of fluid retention. In these cases fluid retention is extremely marked, as is the elevation in venous pressure, and the complications of congestion are very serious problems.

Another way of looking at the effects of cardiac failure is given in Figure 11 4. The left ventricular pressure volume loops describing the events of a cardiac cycle from a failing heart are displaced far to the right of those from normal hearts. The untreated patient described in this figure is in serious trouble with a reduced stroke volume and ejection fraction and high filling pressure. Furthermore, the slope of the line describing the end-systolic pressure volume relationship is shifted downward and is less steep, indicating the reduced contractility of the cardiac muscle. However, because of this flatter relationship, small reductions in cardiac afterload (ie, arterial blood pressure) will produce substantial increases in stroke volume and significantly help this patient.

As might be expected from the previous discussion, the most common symptoms of patients with congestive heart failure are associated with the inability to increase cardiac output (low exercise tolerance and fatigue) and with the compensatory fluid accumulation (congestion, shortness of breath, peripheral swelling). In severe cases, the ability of the cardiac cells to respond to increases in sympathetic stimulation is diminished by a reduction in the effective number (down-regulation) of the myocyte ₁-adrenergic receptors. This further reduces the ability of the myocytes to increase their contractility as well as the ability of the heart to increase its beating rate in response to sympathetic stimulation. Thus, low maximal heart rates contribute to the reduced exercise tolerance.

Treatment of the patient with congestive heart failure is a difficult challenge. Treatment of the precipitating condition is of course the ideal approach, but often this cannot be done effectively. The cardiac glycosides (eg, digitalis)⁷ have been used to improve cardiac contractility (ie, to shift the cardiac function curve upward, increasing contractile force of the myocyte at any given starting length).⁸ These drugs are unfortunately quite toxic and often have undesirable side effects.

Treatment of the congestive symptoms involves balancing the need for enhanced cardiac filling with the problems of too much fluid. Drugs that promote fluid loss (diuretics such as furosemide or thiazides) are extremely helpful as are the angiotensin-converting enzyme (ACE) inhibitors and the angiotensin II receptor blockers.⁹ A potent diuretic can quickly save a patient from drowning in the pulmonary exudate and reduce diastolic volume of the dilated heart to acceptable levels, but it can also lower blood pressure to dangerous levels.

⁴ The extracellular fluid volume remains expanded after reaching the compensated state even though sympathetic activity may have returned to near normal levels. Net fluid loss requires a period of less than normal sympathetic activity which does not occur. For reasons not well understood, the cardiopulmonary baroreceptor reflexes apparently become less responsive to the increased central venous pressure and volume associated with heart failure.

⁵ Patients often complain of difficulty breathing especially during the night (paroxysmal nocturnal dyspnea). Being recumbent promotes a fluid shift from the extremities into the central venous pool and lungs making the patient's pulmonary problems worse. Such patients often sleep more comfortably when propped up.

⁶ Plasma volume expansion combines with abnormal liver function to reduce the concentration of plasma proteins by as much as 30%. This reduction in plasma oncotic pressure contributes to the development of interstitial edema of congestive heart failure.

⁷ A "tea" made from the leaves of the foxglove plant (digitalis purpurea) was used for centuries as a common folk remedy for the treatment of "dropsy" (congestive heart failure with significant peripheral edema). With the formal recognition of its medicinal benefits in the late eighteenth century by the English physician Sir William Withering, digitalis became a valuable official pharmacological tool.

⁸ The mechanism of cardiac glycoside action is thought to involve the inhibition of the sodium/potassium adenosine triphosphatase (Na⁺/K⁺ ATPase) leading to increases in intracellular [Na⁺], which is then exchanged for extracellular calcium via the Na⁺/Ca²⁺ exchanger. This results in "loading" of the sarcoplasmic reticulum during diastole and increased calcium release for subsequent excitation-contraction coupling.

⁹ The ACE inhibitors are very helpful to the congestive heart failure patient for several reasons. By inhibiting the conversion of angiotensin I into its more active form, angiotensin II, peripheral vasoconstriction is reduced (which improves cardiac pumping by afterload reduction) and aldosterone levels are reduced (which promotes diuresis). In addition, ACE inhibitors also seem to prevent some of the apparently inappropriate myocyte and collagen growth that occurs with cardiac overload and failure.

Chronic Heart Failure Diastolic Dysfunction

Although systolic dysfunction is the primary cause of heart failure, some degree of diastolic dysfunction is also commonly present. Diastolic dysfunction implies a stiffened heart during diastole such that increases in cardiac filling pressure do not produce normal increases in end-diastolic volume. Some individuals (primarily elderly patients with hypertension and cardiac hypertrophy) who have symptoms of cardiac failure (exertional dyspnea, fluid retention, pulmonary edema, and high end-diastolic pressures) seem to have normal systolic function, but with normal or even reduced ventricular end-diastolic volumes despite increased cardiac filling pressure. Thus, the term diastolic heart failure has been used to describe this situation.

Potential causes of altered diastolic properties in heart failure include (1) delayed myocyte relaxation early in diastole due to slow cytosolic calcium removal processes, (2) inadequate ATP levels required to disconnect the myofilament cross-bridges rapidly, (3) residual, low-grade cross-bridge cycling during diastole due to calcium leaking from the sarcoplasmic reticulum, (4) increased myofibrillar passive stiffness due to alterations in the myofibrillar protein titin, and (5) decreased cardiac tissue passive compliance due to extracellular remodeling, collagen cross-linking, and other extracellular matrix protein alterations.

At this point, therapeutic interventions that directly influence diastolic properties are not well understood. Attempts to reduce interstitial fibrosis (with ACE inhibitors and/or angiotensin receptor antagonists) and to reduce diastolic calcium leak from the sarcoplasmic reticulum (with -adrenergic blockers) have had limited success.

Hypertension

Hypertension is defined as a chronic elevation of arterial blood pressure above 140/90 mmHg for adults. It is an extremely common cardiovascular problem, affecting more than 20% of the adult population of the western world. It has been established beyond doubt that hypertension increases the risk of coronary artery disease, myocardial infarction, heart failure, stroke, and many other serious cardiovascular problems. Moreover, it has been clearly demonstrated that the risk of serious cardiovascular incidents is reduced by proper treatment of hypertension.¹⁰

In approximately 90% of cases, the primary abnormality that produces high blood pressure is unknown. The term essential hypertension (or primary hypertension) is applied to this situation. In the remaining 10% of hypertensive patients, the cause can be traced to a variety of sources, including epinephrine-producing tumors (pheochromocytomas), aldosterone-producing tumors (in primary hyperaldosteronism), certain forms of renal disease (eg, renal artery stenosis, glomerular nephritis, toxemia of pregnancy), certain neurological disorders (eg, brain tumors which increase intracranial pressure), certain thyroid and parathyroid disorders, aortic coarctation, lead poisoning, drug side effects, abuse of certain drugs, or even unusual dietary habits. The high blood pressure that accompanies such known causes is referred to as secondary hypertension. Most often, however, the true cause of the hypertension remains a mystery, and it is only the symptom of high blood pressure that is treated.

¹⁰ Because recent findings have verified an increased risk of cardiovascular complications with even mildly elevated blood pressure, a new category designated prehypertension has been added to include blood pressures ranging from 120 139 mmHg systolic and 80 89 mmHg diastolic.

Facts About Essential Hypertension

In the midst of a bewildering amount of information about essential hypertension, a few universally accepted facts stand out:

1. Genetic factors contribute importantly to the development of hypertension. Familial tendencies for high blood pressure are well documented. In addition, hypertension is generally more common in males than in females and in blacks than in whites.

2. Environmental factors can influence the development of hypertension. High salt diets and/or certain forms of psychological stress may either aggravate or precipitate hypertension in genetically susceptible individuals.

3. Structural changes in the left heart and arterial vessels occur in response to hypertension. Early alterations include hypertrophy of muscle cells and thickening of the walls of the ventricle and resistance vessels. Late changes associated with deterioration of function include increases in connective tissue and loss of elasticity.

4. The established phase of hypertension is associated with an increase in total peripheral resistance. Cardiac output and/or blood volume may be elevated during the early developmental phase, but these variables are usually normal after the hypertension is established.

5. The increased total peripheral resistance associated with established hypertension may be due to (a) rarefaction (decrease in density) of microvessels, (b) the pronounced structural adaptations that occur in the peripheral vascular bed, (c) a continuously increased activity of the vascular smooth muscle cells,¹¹ (d) an increased sensitivity and reactivity of the vascular smooth muscle cells to external vasoconstrictor stimuli, and/or (e) diminished production and/or effect of endogenous vasodilator substances (eg, nitric oxide).

6. The chronic elevation in blood pressure does not appear to be due to a sustained elevation in sympathetic vasoconstrictor neural discharge nor is it due to a sustained elevation of any blood-borne vasoconstrictive factor. (Both neural and hormonal influences, however, may help initiate primary hypertension.)

7. Blood pressure-regulating reflexes (both the short-term arterial and cardiopulmonary baroreceptor reflexes and the long-term, renal-dependent, pressure-regulating reflexes) become adapted or "reset" to regulate blood pressure at a higher than normal level.

8. Disturbances in renal function contribute importantly to the development and maintenance of primary hypertension. Recall that the urinary output rate is influenced by arterial pressure, and, in the long term, arterial pressure can stabilize only at the level that makes urinary output rate equal to fluid intake rate. As shown by point N in Figure 11 5, this pressure is approximately 100 mmHg in a normal individual.

All forms of hypertension involve an alteration somewhere in the chain of events by which changes in arterial pressure produce changes in urinary output rate (see Figure 9 9) such that the renal function curve is shifted rightward as indicated in Figure 11 5. The important feature to note is that higher than normal arterial pressure is required to produce a normal urinary output rate in hypertension. While this condition is always present with hypertension, it is not clear whether it could be the common cause of hypertension or simply another one of the many adaptations to it.

Consider that the untreated hypertensive individual in Figure 11 5 would have a very low urinary output rate at the normal mean arterial pressure of 100 mmHg. Recall from Figure 9 8 that whenever the fluid intake rate exceeds the urinary output rate, fluid volume must rise and consequently so will cardiac output and mean arterial pressure. With a normal fluid intake rate, this untreated hypertensive patient will ultimately stabilize at point A (mean arterial pressure = 150 mmHg). Recall from Chapter 9 that the baroreceptors adapt within days so that they have a normal discharge rate at the prevailing average arterial pressure. Thus, once the hypertensive individual has been at point A for a week or more, even the baroreceptor mechanism will begin resisting acute changes from the 150-mmHg pressure level.

A most important fact to realize is that, although high blood pressure must always ultimately be sustained by either high cardiac output or high total peripheral resistance, neither need be the primary cause. A shift in the relationship between arterial pressure and urinary output rate, as illustrated in Figure 11 5, however, will always produce hypertension. The possibility that the kidneys actually "set" the blood pressure is supported by evidence accumulating from kidney transplant studies. In these studies, the blood pressure is shown to "follow" the kidney (ie, putting a hypertensive kidney in a normotensive individual produces a hypertensive individual whereas putting a normotensive kidney in a hypertensive individual produces a normotensive individual).

¹¹ Continuous activation of vascular smooth muscle might be evoked by autoregulatory responses to increased blood pressure, as discussed in Chapter 6. A total body autoregulation could produce an increase in total peripheral resistance so that total systemic flow (ie, cardiac output) would remain nearly normal in the presence of increased mean arterial pressure.

Therapeutic Strategies for Essential Hypertension Treatment

In certain hypertensive individuals, restricting salt intake produces a substantial reduction in blood pressure because of the reduced requirement for water retention to osmotically balance the salt load. In the example of Figure 11 5, this effect is illustrated by a shift from point A to point B. The efficacy of lowering salt intake to lower arterial pressure depends heavily on the slope of the renal function curve in the hypertensive individual. The arterial pressure of a normal individual, for example, is affected only slightly by changes in salt intake because the normal renal function curve is so steep.

A second common treatment of hypertension is diuretic therapy. Many diuretic drugs are available, but most have the effect of inhibiting renal tubular salt (and therefore fluid) reabsorption. The net effect of diuretic therapy, as shown in Figure 11 5, is that the urinary output rate for a given arterial pressure is increased; ie, diuretic therapy raises the renal function curve. The combined result of restricted fluid intake and diuretic therapy for the hypertensive individual of Figure 11 5 is illustrated by point C.

A third therapeutic intervention is treatment with -adrenergic blockers that inhibit sympathetic influences on the heart and renal renin release. This approach is most successful in hypertensive patients who have high circulating renin levels.

A fourth antihypertensive strategy is to block the effects of the renin-angiotensin system either with ACE inhibitors blocking the formation of the vasoconstrictor angiotensin II or with angiotensin II receptor blockers. Other pharmacological interventions may include use of -adrenergic receptor blockers, which prevent the vasoconstrictive effects of catecholamines, and calcium channel blockers, which act directly to decrease vascular smooth muscle tone.

Alterations in life style, including reduction of stress, decreases in caloric intake, limitation of the amount of saturated fats in the diet, and establishment of a regular exercise program, may help reduce blood pressure in certain individuals.

Key Concepts

Circulatory shock is defined as a generalized, severe reduction in tissue blood flow so that metabolic needs are not met.

The primary disturbances that can lead to shock can be categorized as those that directly interfere with pump function (cardiogenic shock) or those that interfere with ventricular filling (hypovolemia, pulmonary embolus, or sustained vascular dilation).

Shock is invariably accompanied by a compensatory increase in sympathetic activity aimed at maintaining arterial pressure via augmented cardiac output and vascular resistance.

Decompensatory processes precipitated by the shock state are generally caused by inadequate blood flow and loss of homeostasis and result in tissue damage with a progressive and irreversible fall in arterial pressure.

Coronary artery disease, usually associated with development of atherosclerotic plaques, results in a progressive compromise in coronary blood flow which becomes inadequate to meet the tissue's metabolic needs.

Systolic heart failure is defined as a reduction of cardiac muscle contractility and results in a depressed cardiac output at all preloads.

Compensatory fluid retention mechanisms are evoked in heart failure to improve cardiac filling, but when fluid retention is excessive, congestive complications arise (eg, pulmonary edema and abdominal ascites).

Diastolic dysfunction resulting from reduced cardiac compliance often accompanies (and may precipitate) heart failure.

Chronic elevation of arterial blood pressure due to unknown causes (essential or primary hypertension) is a common and serious condition influenced by genetic and environmental factors.

Study Questions

11 1. Clinical signs of hypovolemic shock often include pale and cold skin, dry mucous membranes, weak but rapid pulse, muscle weakness, and mental disorientation or unconsciousness. What are the physiological conditions that account for these signs?

11 2. Which of the following would be helpful to hemorrhagic shock victims?

a. Keep them on their feet

b. Warm them up

c. Give them fluids to drink

d. Maintain their blood pressure with catecholamine-type drugs

11 3. What happens to hematocrit

a. During hypovolemic shock resulting from prolonged diarrhea?

b. During acute cardiogenic shock?

c. During septic shock?

d. With chronic bleeding?

11 4. Left ventricular chamber enlargement with congestive heart failure increases the wall tension required to generate a given systolic pressure. True or false?

11 5 Why are diuretic drugs often helpful in treating patients in congestive heart failure?

11 6. What is the potential danger of vigorous diuretic therapy for the patient in heart failure?

11 7. Why does renal artery stenosis produce hypertension?

See answers.