Prevalence & Significance
A condition that afflicts the large and medium-sized arteries of almost every human, at least in societies in which cholesterol-rich foodstuffs are abundant and cheap, is atherosclerosis. This condition begins in childhood and, in the absence of accelerating factors, develops slowly until it is widespread in old age. However, it is accelerated by a wide variety of genetic and environmental factors (see later discussion). It is characterized by localized fibrous thickenings of the arterial wall associated with lipid-infiltrated plaques that may eventually calcify. Old plaques are also prone to ulceration and rupture, triggering the formation of thrombi that obstruct flow. Therefore, atherosclerosis leads to vascular insufficiency in the limbs, abnormalities of the renal circulation, and dilations (aneurysms) and even rupture of the aorta and other large arteries. It also leads to common severe and life-threatening diseases of the heart and brain because of formation of intravascular clots at the site of the plaques.
In the United States and most other developed countries, it has been calculated that atherosclerosis is the underlying cause of about 50% of all deaths. Almost all patients with myocardial infarction—and most of those with stroke resulting from cerebral thrombosis—have atherosclerosis. The incidence of ischemic heart disease and strokes has been declining in the United States since 1963, but atherosclerosis is still very common. Thus, atherosclerosis underlies and is fundamentally responsible for a large portion of the clinical problems seen by physicians caring for adult patients.
The initial event in atherosclerosis is infiltration of low-density lipoproteins (LDLs) into the subendothelial region. The endothelium is subject to shear stress, the tendency to be pulled along or deformed by flowing blood. This is most marked at points where the arteries branch, and this is where the lipids accumulate to the greatest degree.
The LDLs are oxidized or altered in other ways. Thus, altered LDLs activate various components of innate immune system including macrophages, natural antibodies, and innate effector proteins such as C-reactive protein and complement. Altered LDLs are recognized by a family of scavenger receptors expressed on macrophages that cooperate with toll-like receptors to stimulate inflammation and drive atherogenesis. The scavenger receptors mediate uptake of the oxidized LDL into macrophages and the formation of foam cells (Figure 11–15). The foam cells form fatty streaks. The streaks appear in the aorta in the first decade of life, in the coronary arteries in the second decade, and in the cerebral arteries in the third and fourth decades.
Formation of a fatty streak in an artery. After vascular injury, monocytes bind to the endothelium, then cross it to the subendothelial space, and become activated tissue microphages. The macrophages take up oxidized low-density lipoproteins (LDL), becoming foam cells. T cells release cytokines, which also activate macrophages. In addition, the cytokines cause smooth muscle cells to proliferate. Under the influence of growth factors, the smooth muscle cells then move to the subendothelial space where they produce collagen and take up LDL, adding to the population of foam cells. (Redrawn, with permission, from Hajjar DP et al. Atherosclerosis. Am Scientist. 1995;83:460.)
Oxidized LDLs have a number of deleterious effects, including stimulation of release of proinflammatory cytokines (such as macrophage migration inhibitory factor and type I interferon) and inhibition of NO production. Vascular smooth muscle cells in the vicinity of foam cells are stimulated and move from the media to the intima, where they proliferate, lay down collagen and other matrix molecules, and contribute to the bulk of the lesion. Smooth muscle cells also take up oxidized LDL and become foam cells. Lipids accumulate both intracellularly and extracellularly.
The intercellular “soup” in the plaques contains a variety of cell-damaging substances, including ozone. In addition, the “loading” of macrophages with cholesterol can be lipotoxic to the endoplasmic reticulum, resulting in macrophage apoptosis and plaque necrosis. Cholesterol crystals associated with necrotized macrophages further stimulate inflammation and lead to the recruitment of neutrophils. As the atherosclerotic lesions age, T cells of the immune system and monocytes are attracted to them, creating a vicious cycle of necrosis and inflammation.
As plaques mature, a fibrous cap forms over them. The plaques with defective or broken caps are most prone to rupture. The lesions alone may distort vessels to the point that they are occluded, but it is usually rupture or ulceration of plaques that triggers thrombosis, blocking blood flow.
Atherosclerotic lesions have been shown to have many of the characteristics of a low-grade infection. A number of investigators have searched for bacteria in plaques, and in a significant number Chlamydophila pneumoniae—an organism usually associated with respiratory infection—has been found. However, other organisms have also been found, and it is too early to say whether the chlamydiae are causative agents or merely coincidental tenants in the lesions.
A characteristic of atherosclerosis that is currently receiving considerable attention is its association with deficient release of NO and defective vasodilation. As noted, oxidized LDLs inhibit NO production. If acetylcholine is infused via catheter into normal coronary arteries, the vessels dilate; however, if it is infused when atherosclerosis is present, the vessels constrict. This indicates that endothelial secretion of NO is defective.
Interestingly, recent experimental evidence indicates that the activation of the vasculature endothelial receptor for endothelin B both stimulates eNOS and exerts antiproliferative effects on vascular smooth muscle cells. It has been speculated that the disrupted signaling via this receptor can be an additional contributing factor in pathophysiology of atherosclerosis.
Relation to Dietary Cholesterol & Other Lipids
Transforming a monocyte into a lipid-ingesting macrophage involves the appearance on its surface of a unique type of oxidized LDL receptor, the scavenger receptor, and monocytes are stimulated to produce these receptors by the action of macrophage colony-stimulating factor secreted by endothelial cells and vascular smooth muscle cells. When oxidized LDL-receptor complexes are formed, they are internalized and the receptors recycle to the membrane while the lipid is stored.
Obviously, accumulation of lipid in foam cells is a key event in the progression of atherosclerotic lesions, and it is well established that lowering plasma cholesterol slows the progress of atherosclerosis. The main pathways for the metabolism of ingested lipids are summarized in Figure 11–16. Because lipids are relatively insoluble, they are transported as special lipoprotein particles that increase their solubility. Dietary cholesterol and triglycerides are packaged in the protein-coated chylomicrons in intestinal epithelial cells. Under the influence of lipoprotein lipase, these particles release triglycerides to fat depots and muscles, and the resulting chylomicron remnants are taken up by the liver. The liver also synthesizes cholesterol and packages it with specific proteins to form very-low-density lipoproteins (VLDLs). These lipoprotein particles enter the circulation and under the influence of lipoprotein lipase donate triglycerides to tissues. In this way, they become cholesterol-rich intermediate-density lipoproteins (IDLs) and low-density lipoproteins (LDLs). The LDL supply cholesterol to the tissues. They provide all cells with the cholesterol for production of cell membranes and other uses. They also provide most of the cholesterol that is the precursor for all steroid hormones. As noted, oxidized LDLs are taken up by macrophages and smooth muscle cells in atherosclerotic lesions. On the other hand, high-density lipoproteins (HDLs) take cholesterol from peripheral cells and transport it to the liver where it is metabolized, keeping plasma and tissue cholesterol low. For this reason, it is referred to as “good cholesterol” as opposed to LDL cholesterol, which is “bad cholesterol.” Efforts are being made to increase HDL by pharmaceutical means in the treatment of atherosclerosis.
Simplified diagram of lipoprotein systems for transporting lipids in humans. In the exogenous system, chylomicrons rich in triglycerides of dietary origin are converted to chylomicron remnants rich in cholesteryl esters by the action of lipoprotein lipase. In the endogenous system, very low-density lipoproteins (VLDL) rich in triglycerides are secreted by the liver and converted to intermediate-density lipoproteins (IDL) and then to low-density lipoproteins (LDL) rich in cholesteryl esters. Some of the LDL enter the subendothelial space of arteries, are oxidized, and then taken up by macrophages, which become foam cells. LCAT, lecithin-cholesterol acyltransferase. The letters on the chylomicrons, chylomicron remnants, VLDL, IDL, and LDL identify the primary apoproteins found in them.
Because atherosclerosis is an abnormality of arterial blood vessels, it can affect almost any organ in the body. Calcified atherosclerotic plaques are occasionally detected on x-ray film, and angiographic visualization of deformed arterial walls is possible. In general, however, atherosclerosis is asymptomatic until one of its complications develops.
In coronary arteries, atherosclerotic narrowing that reduces the lumen of a coronary artery more than 75% causes angina pectoris, the chest pain that results when pain-producing substances accumulate in the myocardium. Typically, the pain comes on during exertion and disappears with rest, as the substances are washed out by the blood. When atherosclerotic lesions cause clotting and occlusion of a coronary artery, the myocardium supplied by the artery dies (myocardial infarction). Myocardial infarction is also discussed in Chapter 10.
In the cerebral circulation, arterial blockage at the site of atherosclerotic plaques causes thrombotic strokes. Strokes are discussed in Chapter 7. In the abdominal aorta, extensive atherosclerosis can lead to aneurysmal dilation and rupture of the vessel. In the renal vessels, localized constriction of one or both renal arteries causes renovascular hypertension (see later discussion). In the circulation to the legs, vascular insufficiency causes intermittent claudication (fatigue and usually pain on walking that is relieved by rest). If the circulation of a limb is severely compromised, the skin can ulcerate, producing lesions that are slow to heal. Frank gangrene of the extremities may also occur. Less frequently, clot formation and obstruction may occur in vessels supplying the intestines or other parts of the body.
As noted, the progression of atherosclerosis is accelerated by a wide variety of genetic and environmental factors (risk factors). These are summarized in Table 11–2. Obviously, treating the accelerating conditions that are treatable and avoiding those that are avoidable should reduce the incidence of myocardial infarctions, strokes, and other complications of atherosclerosis.
Table 11–2Conditions that accelerate the progression of atherosclerosis and the mechanisms responsible. ||Download (.pdf) Table 11–2 Conditions that accelerate the progression of atherosclerosis and the mechanisms responsible.
|Condition ||Mechanism |
|Male gender (and females after menopause) ||Lack of LDL-lowering effect of estrogens; estrogens probably act by increasing the number of LDL receptors in the liver. |
|Family history of ischemic heart disease, stroke ||Probably multiple genetic mechanisms. |
|Primary hyperlipidemia ||Inherited disorders causing lipoprotein lipase deficiency (type I), defective LDL receptors (type IIa), abnormal apoprotein E (type III), deficiency of apoprotein C (type V), or unknown cause (types IIb and IV). |
|Secondary hyperlipidemia1 ||Increased circulating triglycerides produced by diuretics, β-adrenergic blocking drugs, excess alcohol intake. |
|Cigarette smoking ||Probably carbon monoxide-induced hypoxic injury to endothelial cells. |
|Hypertension ||Increased shear stress, with damage to endothelium. |
|Diabetes mellitus (types 1 and 2) ||Decreased hepatic removal of LDL from the circulation; increased glycosylation of collagen, which increases LDL binding to blood vessel walls. |
|Obesity, particularly abdominal obesity ||Unsettled, but obesity is associated with type 2 diabetes, hypertriglyceridemia, hypercholesterolemia, and hypertension, all of which are risk factors in their own right. Moreover, it is becoming clear that fat tissue is very active in releasing a number of endocrine and paracrine factors (including TNF) that can alter the endothelial function and increase the inflammatory state of an individual. |
|Nephrotic syndrome ||Increased hepatic production of lipids and lipoprotein(a). |
|Hypothyroidism ||Decreased formation of LDL receptors in the liver. |
|High lipoprotein(a) ||Unsettled. |
|Elevated plasma homocysteine ||Unsettled. Probably increased homocysteine provides more H2O2 and other reactive oxygen molecules that foster formation of oxidized LDL. |
Estrogen increases cholesterol removal by the liver, and the progression of atherosclerosis is less rapid in premenopausal women than in men. In addition, epidemiologic evidence shows that estrogen replacement therapy protects the cardiovascular system in postmenopausal women. On the other hand, large doses of estrogens increase the incidence of blood clots, and even small doses produce a slight increase in clotting. In addition, in several studies, estrogen treatment of postmenopausal women failed to prevent second heart attacks. The reason for the discrepancies between the epidemiologic and experimental data is currently unsettled.
The effect of increased plasma levels of homocysteine and related molecules such as homocystine and homocysteine thiolactone, a condition sometimes called hyperhomocystinemia, deserves emphasis. These increases are associated with accelerated atherosclerosis, and the magnitude of the plasma elevation is positively correlated with the severity of the atherosclerosis. Markedly elevated levels resulting from documented mutations of relevant genes are rare, but mild elevations occur in 7% of the general population. The mechanism responsible for the accelerated vascular damage is unsettled, but homocysteine is a significant source of H2O2 and other reactive forms of oxygen, and this may accelerate the oxidation of LDL.
Homocysteine is an intermediate in the synthesis of methionine. It is metabolized by enzymes that are dependent on vitamin B6, vitamin B12, and folic acid. Supplementation of the diet with these vitamins reduces plasma homocysteine, usually to normal. Determining whether such supplements also reduce the incidence of the accelerated atherosclerosis will require prolonged, careful clinical trials, and the results of such studies to date are inconclusive.
Evidence is now overwhelming that lowering plasma cholesterol and triglyceride levels and increasing plasma HDL levels slows, and in some cases reverses, the atherosclerotic process. The desired decrease in lipids can sometimes be achieved with dietary restriction of cholesterol, saturated and trans fat alone, even though dietary restriction initiates a compensatory increase in cholesterol synthesis in the body. When dietary treatment is not adequate, reducing conversion of mevalonate to cholesterol with statins, drugs that inhibit hepatic 3-methylglutaryl coenzyme A (HMG-CoA) reductase, the enzyme which catalyzes this reaction, is beneficial. The currently available HMG-CoA reductase inhibitors include atorvastatin, lovastatin, pitavastatin, pravastatin, simvastatin, fluvastatin, and rosuvastatin.
In cases in which there is severe hypercholesterolemia because of congenitally defective LDL receptors, gene therapy may be an option. However, despite promising preliminary results, gene therapy in humans appears to be unachievable until better means for gene transfer are developed. Other approaches to slowing or preventing development of atherosclerosis by molecular biologic techniques are under development.
Antioxidant treatment with agents such as α-tocopherol, vitamin E, and β-carotene has been used to inhibit oxidation of LDL, and this reduces the incidence of atherosclerotic changes in experimental animals. However, the results of antioxidant treatment in humans have generally been disappointing or negative.
Men who smoke a pack of cigarettes a day have a 70% increase in death rate from ischemic heart disease compared with nonsmokers, and there is also an increase in women. Smoking cessation lessens the risk of death and of myocardial infarction. The deleterious effects of smoking include endothelial damage caused by carbon monoxide–induced hypoxia. Other factors may also be involved. Thus, stopping smoking is a major way to slow the progress of atherosclerosis.
Because of the increased shear stress imposed on the endothelium by an elevated blood pressure, hypertension is another important modifiable risk factor for atherosclerosis. Lowering blood pressure has its greatest effect in reducing the incidence of stroke, but there are beneficial effects on ischemic heart disease as well. With modern methods of treatment, blood pressure in hypertensives can generally be reduced to normal or near-normal values, and the decrease in strokes, myocardial infarctions, and renal failure produced by such treatment is clear testimony to the value of reducing or eliminating this risk factor.
In diabetics, there are microvascular complications and macrovascular complications (see Table 18–6). The latter are primarily related to atherosclerosis. There is a twofold increase in the incidence of myocardial infarction compared with nondiabetics; severe circulatory deficiency in the legs with gangrene is relatively common; there are more thrombotic strokes; and renal failure is a serious problem (see Chapter 18). It is interesting in this regard that rigorous control of blood pressure in diabetics has been shown to be more efficacious in reducing cardiovascular complications than rigorous control of blood glucose.
The nephrotic syndrome and hypothyroidism also accelerate the progression of atherosclerosis and are treatable conditions.
Although local inflammation clearly plays a direct role in the pathogenesis of atherosclerosis, the possibility that indirect mechanisms associated with autoimmune diseases, infections (including gum disease and gastric infections), or exposure to various pollutants contribute to (or even initiate) atherosclerosis remains controversial.
What is the most common cause of death in the United States among individuals older than 45 years?
What is the hypothesized mechanism of atherosclerotic plaque formation?
What are some ways in which atherosclerotic plaques can cause cardiovascular disease?
Name five treatable risk factors that accelerate the progression of atherosclerosis.
Hypertension is not a single disease but a syndrome with multiple causes. In most instances, the cause remains unknown, and the cases are lumped together under the term essential hypertension (Table 11–3). However, mechanisms are continuously being discovered that explain hypertension in new subsets of the formerly monolithic category of essential hypertension, and the percentage of cases in the essential category continues to decline. Essential hypertension is often called primary hypertension, and hypertension in which the cause is known is called secondary hypertension, although this separation seems somewhat artificial. This chapter discusses the pathogenesis of hypertension and its complications in general terms and then discusses the specific causes of the currently defined subgroups and the unique features, if any, that each adds to the general findings in patients with high blood pressure.
Table 11–3Primary and secondary causes of hypertension.
Current guidelines of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure define normal blood pressure as systolic pressure of less than 120 mm Hg and diastolic pressure of less than 80 mm Hg. Hypertension is defined as an arterial pressure greater than 140/90 mm Hg in adults on at least three consecutive visits to the doctor’s office. People whose blood pressure is between normal and 140/90 mm Hg are considered to have pre-hypertension and people whose blood pressure falls in this category should appropriately modify their lifestyle to lower their blood pressure to below 120/80 mm Hg. As noted (Figure 11–7), systolic pressure normally rises throughout life, and diastolic pressure rises until age 50–60 years but then falls, so that pulse pressure continues to increase. In the past, emphasis has been on treating individuals with elevated diastolic pressure. However, it now appears that, particularly in elderly individuals, treating systolic hypertension is equally important or even more so in reducing the cardiovascular complications of hypertension. Moreover, some studies indicate that overly aggressive treatment (particularly of diastolic hypertension) may be associated with adverse cardiac events (primarily myocardial infarctions) in patients with coronary artery disease or chronic heart failure. The explanation may be that because the coronary arteries fill during diastole, in individuals with coronary artery disease or heart failure, adequate cardiac muscle perfusion is dependent on a somewhat higher diastolic blood pressure.
The most common cause of hypertension is increased peripheral vascular resistance. However, because blood pressure equals total peripheral resistance times cardiac output, prolonged increases in cardiac output can also cause hypertension. These are seen, for example, in hyperthyroidism and beriberi. In addition, increased blood volume causes hypertension, especially in individuals with mineralocorticoid excess or renal failure (see later discussion); and increased blood viscosity, if it is marked, can increase arterial pressure.
Hypertension by itself does not cause symptoms. Headaches, fatigue, and dizziness are sometimes ascribed to hypertension, but nonspecific symptoms such as these are no more common in hypertensives than they are in normotensive controls. Instead, the condition is discovered during routine screening or when patients seek medical advice for its complications. These complications are serious and potentially fatal. They include myocardial infarction, heart failure, thrombotic and hemorrhagic strokes, hypertensive encephalopathy, and renal failure (Figure 11–17). This is why hypertension is called “the silent killer.”
Pathogenesis of the complications produced by arterial hypertension. LVH, left ventricular hypertrophy. (Redrawn, with permission, from Deshmukh R et al. Chapter 13 in Lilly LS et al, eds. Pathophysiology of Heart Disease: A Collaborative Project of Medical Students and Faculty, 3rd ed. Williams & Wilkins, 2003.)
Physical findings are also absent in early hypertension, and observable changes are generally found only in advanced severe cases. These may include hypertensive retinopathy (ie, narrowed arterioles seen on funduscopic examination) and, in more severe cases, retinal hemorrhages and exudates along with swelling of the optic nerve head (papilledema). Prolonged pumping against an elevated peripheral resistance causes left ventricular hypertrophy, which can be detected by echocardiography, and cardiac enlargement, which can be detected on physical examination. It is important to listen with the stethoscope over the kidneys because in renal hypertension (see later discussion) narrowing of the renal arteries may cause bruits. These bruits are usually continuous throughout the cardiac cycle. It has been recommended that the blood pressure response to rising from the sitting to the standing position be determined. A blood pressure rise on standing sometimes occurs in essential hypertension presumably because of a hyperactive sympathetic response to the erect posture. This rise is usually absent in other forms of hypertension. Most individuals with essential hypertension (60%) have normal plasma renin activity, and 10% have high plasma renin activity. However, 30% have low plasma renin activity. Renin secretion may be reduced by an expanded blood volume in some of these patients, but in others the cause is unsettled, and low-renin essential hypertension has not yet been separated from the rest of essential hypertension as a distinct entity.
In many patients with hypertension, the condition is benign and progresses slowly; in others, it progresses rapidly. Actuarial data indicate that on average untreated hypertension reduces life expectancy by 10–20 years. Atherosclerosis is accelerated, and this in turn leads to ischemic heart disease with angina pectoris and myocardial infarctions (Chapter 10), thrombotic strokes and cerebral hemorrhages (Chapter 7), and renal failure (Chapter 16). Another complication of severe hypertension is hypertensive encephalopathy, in which there is confusion, disordered consciousness, and seizures. This condition, which requires vigorous treatment, is probably due to arteriolar spasm and cerebral edema.
In all forms of hypertension regardless of cause, the condition can suddenly accelerate and enter the malignant phase. In malignant hypertension, there is widespread fibrinoid necrosis of the media with intimal fibrosis in arterioles, narrowing them and leading to progressive severe retinopathy, heart failure, and renal failure. If untreated, malignant hypertension is usually fatal in 1 year.
A discussion of disease treatment is beyond the scope of this book. However, it should be noted that in all forms of hypertension modern treatment with β-adrenergic blocking drugs, inhibitors of the renin-angiotensin system, Ca2+ channel inhibitors, and diuretics reduce blood pressure, usually to normal levels. In addition, these treatments delay or prevent complications and lengthen life expectancy. However, they are not curative and must be continued indefinitely. Thus, essential hypertension is like diabetes mellitus: It can be controlled but not cured. If a cause of hypertension can be identified, its treatment may result in a cure. Consequently, it is important to identify such cases.
Congenital narrowing of the aorta usually occurs just distal to the origin of the left subclavian artery. Peripheral resistance is increased above the constriction. Therefore, blood pressure is elevated in the arms, head, and chest but lowered in the legs. However, because the constriction is proximal to the renal arteries, renin secretion is increased in most cases of coarctation as a result of the reduction in arterial pressure in the renal arteries. This tends to increase blood pressure throughout the body. Elimination of the constriction by resecting the narrowed segment of the aorta usually cures the condition.
Through selective inbreeding, Dahl was able to develop two strains of rats: salt-sensitive rats that showed an increase in blood pressure when fed a high-salt diet and salt-resistant rats that did not. The genetic mechanisms responsible for these strain differences are currently under investigation. There may be a similar division of humans into salt-sensitive and salt-resistant groups, although obviously the lines between the groups are less distinct. As shown in Table 11–4, about 30% of whites with normal renal function and normal blood pressure are salt sensitive compared with 55% of whites with essential hypertension. For unknown reasons, a larger percentage of black hypertensives are salt sensitive. These figures have obvious significance in terms of recommendations about salt intake in hypertension.
Table 11–4Salt sensitivity in humans. ||Download (.pdf) Table 11–4 Salt sensitivity in humans.
| ||Percentage of Individuals |
| ||Normal ||Hypertensive |
| || || |
| ||30 ||55 |
| ||70 ||45 |
| || || |
| ||32 ||73 |
| ||68 ||27 |
It should be emphasized that the figures just cited refer to individuals with normal renal function and normal (or reduced) secretion of mineralocorticoid hormones. When renal function is reduced, mineralocorticoid secretion is increased, or the effects of mineralocorticoids are enhanced, there is abnormal retention of salt and water, and hypertension is produced on this basis (see later discussion).
Although the genetic mechanisms responsible for the differences in salt sensitivity are still unknown, recent studies have shed new light on our understanding of salt-mediated hypertension. Salt appears to activate three pathways that may lead to vascular smooth muscle contraction: 1) salt stimulates a subset of G proteins (G12-13) that are responsible for the activation of myosin light chain kinase, which phosphorylates myosin to initiate contraction; 2) salt stimulates the Rho/Rho kinase pathway, which inhibits myosin light chain phosphatase to prevent smooth muscle relaxation; 3) short-term increases in dietary salt intake stimulate release of endogenous ouabain (whose effect on the vascular smooth muscle parallels the effects of the cardiac glycoside) to inhibit Na+-K+ ATPase with a consequent decrease in Na+-Ca+ exchanger activity, ultimately elevating intracellular calcium levels and increasing smooth muscle tone. Experimental evidence suggests that individual differences in these signaling pathways may indeed contribute to salt-related hypertension.
Finally, animal studies point at new possible mechanisms for salt-sensitive hypertension, including aldosterone-independent activation of mineralocorticoid receptors, as well as sympathetically mediated activation of sodium reabsorption in the distal renal tubule.
Goldblatt’s observation that renal artery constriction increased blood pressure in experimental animals was rapidly followed by demonstration of the same event in humans. However, disappointment followed when it was found that renal hypertension resulting from constriction of one or both renal arteries accounted for only a very small percentage of cases of clinical hypertension. The narrowing can be due to atherosclerosis, fibroelastic overgrowth of the wall of the renal artery, or external pressure on the vessel. The initial constriction decreases renal arteriolar pressure, and this leads to increased renin secretion. The renin-angiotensin system is discussed in Chapters 16 and 21. However, in many cases, some other mechanism takes over chronically to maintain the hypertension. The nature of this other mechanism is unknown.
Ureteral obstruction can cause hypertension in animals and probably in humans by increasing renal interstitial pressure and thus decreasing the pressure gradient across the renin-secreting juxtaglomerular cells.
Acute and chronic glomerulonephritis and other forms of diffuse kidney disease can cause hypertension when loss of the ability to excrete salt is severe enough that Na+ and water are retained and blood volume is expanded.
Hormonal Disorders (see Chapters 12 & 21)
A remarkable number of adrenal abnormalities cause hypertension. These include mainly conditions in which mineralocorticoids are secreted in excess, but excess secretion of cortisol also causes hypertension, as does excess secretion of catecholamines by tumors of the adrenal medulla. These disorders are covered in detail in Chapters 12 and 21.
One particular contributing factor to hypertension in women is estrogen. Secretion of angiotensinogen from the liver is under endocrine control and is uniquely stimulated by estrogens. Consequently, it is increased in women taking contraceptive pills containing large amounts of estrogens. When circulating angiotensinogen is increased, more angiotensin II is formed and blood pressure rises. The normal compensation for this response is decreased secretion of renin because angiotensin II feeds back directly on the juxtaglomerular cells to reduce renin secretion. However, in some women, the compensation is incomplete and the estrogens cause a significant increase in blood pressure. Some of the women with the condition have underlying essential hypertension, which is triggered by the estrogens, but in others the hypertension is cured by stopping estrogen treatment.
In view of the fact that Na+ retention resulting from mineralocorticoid excess causes hypertension, it may seem surprising that a natriuretic hormone is also a suspected cause of hypertension. ANP and other natriuretic peptides of cardiac origin cause sodium loss in the urine and generally lower blood pressure. However, there is, in addition, a digitalis-like natriuretic substance in the circulation. Its source seems to be the adrenals, although it has also been claimed that it is secreted by the hypothalamus. This substance, which may be naturally occurring ouabain, inhibits Na+-K+ ATPase. This results in loss of Na+ in the urine, but Ca2+ accumulates in cells because of the decrease in Na+ gradient across the cell membrane. The increase in intracellular Ca2+ causes vascular smooth muscle to contract. Consequently, blood pressure is increased. However, the physiologic and pathophysiologic significance of this natriuretic hormone remains unsettled, and hypersecretion of it cannot as yet be considered a proved cause of clinical hypertension.
The nervous system plays a key role in maintaining blood pressure in normal individuals (see prior discussion). Clonidine and other drugs lower blood pressure by acting on the brain to decrease sympathetic discharge, and several of the most effective treatments for chronic hypertension act peripherally to reduce the effect of vasomotor sympathetic discharge to the blood vessels and heart. These and other observations suggest that clinical hypertension could be caused by CNS abnormalities. Interruption of the afferent input from the baroreceptors to the CNS in experimental animals causes increased blood pressure. However, emphasis has been placed on the variability of the blood pressure in such animals rather than on any consistent elevation of mean arterial pressure. There is some evidence that chronic pressure on the rostral ventrolateral medulla (Figure 11–13) caused by minor anatomic abnormalities can cause hypertension in humans. However, this evidence is controversial, and as yet it cannot be said that this is an established cause of hypertension.
An intriguing observation in experimental animals is that administration of drugs that inhibit the production of NO increase blood pressure. Furthermore, there is a sustained elevation in blood pressure in knockout mice in which the genetic expression of the endothelial form of NOS has been disrupted. These observations suggest that there is a chronic blood pressure-lowering effect of NO and raise the possibility that inhibition of the production or effects of NO could be a cause of hypertension in humans.
Facilitation of Na+-H+ Exchange
In approximately 50% of patients with essential hypertension, the function of a ubiquitous pH-regulating Na+-H+ exchanger in cell membranes is enhanced. Evidence indicates that this is associated with a polymorphism in the gene for one of the β subunits of a G protein that facilitates the function of the G protein. However, the overall significance of this abnormality remains to be determined.
Relation to Insulin Resistance
There is a higher incidence of insulin resistance, hyperinsulinemia, hyperlipidemia, and obesity in patients with essential hypertension and in their normotensive relatives than in the general population or in patients with hypertension from known causes. This combination of abnormalities is sometimes called the metabolic syndrome (previously syndrome X). There has been speculation that insulin resistance causes increased insulin secretion and that the resulting hyperinsulinemia stimulates the sympathetic nervous system, causing hypertension. However, correlation does not prove cause and effect, and patients with insulin-secreting pancreatic tumors (insulinomas) do not have an increased incidence of hypertension. Furthermore, in dogs and normal humans, prolonged infusions of insulin have a slight vasodilator rather than a vasoconstrictor effect, and in a careful study of obese patients with essential hypertension, prolonged infusion of insulin caused a small decrease rather than an increase in blood pressure. Thus, although the cause of the insulin resistance, hyperinsulinemia, obesity, and hyperlipidemia in hypertension remains unsettled, it seems unlikely that increased insulin resistance is a major cause of essential hypertension.
Describe five physical findings in long-standing or severe hypertension.
Name 10 known causes of hypertension and a means by which each could be identified as the cause of hypertension in a patient.
What is the effect on blood pressure of disrupting the gene for the endothelial cell form of NOS in mice?
The term “shock” is used to denote various conditions, including the response to the passage of electric current through the body; the state that follows immediately after interruption of the spinal cord; and the stunned reaction to bad news. In the current context, it refers to an abnormality of the circulatory system in which there is inadequate tissue perfusion because of a relatively or absolutely inadequate cardiac output. The causes are divided into four groups: inadequate volume of blood to fill the vascular system (hypovolemic shock); increased size of the vascular system produced by vasodilation in the presence of a normal blood volume (distributive, vasogenic, or low-resistance shock); inadequate output of the heart as a result of myocardial abnormalities (cardiogenic shock); and inadequate cardiac output as a result of obstruction of blood flow in the lungs or heart (obstructive shock). Examples of the conditions or diseases that can cause each type are set forth in Table 11–5.
Table 11–5Types of shock, with examples of conditions or diseases that can cause each type. ||Download (.pdf) Table 11–5 Types of shock, with examples of conditions or diseases that can cause each type.
Hypovolemic shock is characterized by hypotension; a rapid, thready pulse; cold, pale, clammy skin; intense thirst; rapid respiration; and restlessness or, alternatively, torpor. Urine volume is markedly decreased. However, none of these findings are invariably present. Hypovolemic shock is commonly subdivided into categories on the basis of cause. The use of terms such as hemorrhagic shock, traumatic shock, surgical shock, and burn shock is of some benefit because although there are similarities between these various forms of shock, there are important features that are unique to each.
In hypovolemic and other forms of shock, inadequate perfusion of the tissues leads to increased anaerobic glycolysis, with production of large amounts of lactic acid. In severe cases, the blood lactate level rises from a normal value of about 1 mmol/L to 9 mmol/L or more. The resulting lactic acidosis depresses the myocardium, decreases peripheral vascular responsiveness to catecholamines, and may be severe enough to cause coma.
Multiple compensatory reactions come into play to defend extracellular fluid volume (Table 11–6). The large number of reactions that have evolved indicates the importance of maintaining blood volume for survival.
Table 11–6Compensatory reactions activated by hypovolemia. ||Download (.pdf) Table 11–6 Compensatory reactions activated by hypovolemia.
Tachypnea → Increased thoracic pumping
Restlessness → Increased skeletal muscle pumping (in some cases)
Increased movement of interstitial fluid into capillaries
Increased secretion of vasopressin
Increased secretion of glucocorticoids
Increased secretion of renin and aldosterone
Increased secretion of erythropoietin
Increased plasma protein synthesis
A decrease in pulse pressure or mean arterial pressure decreases the number of impulses ascending to the brain from the arterial baroreceptors, resulting in increased vasomotor discharge. The resulting vasoconstriction is generalized, sparing only the vessels of the brain and the heart. The coronary vessels are dilated because of the increased myocardial metabolism secondary to an increase in heart rate. Vasoconstriction in the skin accounts for the coolness and pallor, and vasoconstriction in the kidneys accounts for the shutdown in renal function.
The immediate cardiac response to hypovolemia is tachycardia. With more extensive loss of volume, tachycardia can be replaced by bradycardia, whereas with very severe hypovolemia, tachycardia reappears. Bradycardia may be due to unmasking of a vagally mediated depressor reflex, perhaps related to limiting blood loss.
Vasoconstriction in the kidney reduces glomerular filtration. This reduces water loss, but it reaches a point at which nitrogenous products of metabolism accumulate in the blood (prerenal azotemia). If hypotension is prolonged, there may be severe renal tubular damage, leading to acute kidney injury.
The fall in blood pressure and the decreased O2-carrying power of the blood caused by the loss of red cells results in stimulation of the carotid and aortic chemoreceptors. This not only stimulates respiration but increases vasoconstrictor discharge. In severe hypovolemia, the pressure is so low that there is no longer any discharge from the carotid and aortic baroreceptors. This occurs when the mean blood pressure is about 70 mm Hg. Under these circumstances, if the afferent discharge from the chemoreceptors via the carotid sinus and vagus nerves is stopped, there is a paradoxic further fall in blood pressure rather than a rise.
Hypovolemia causes a marked increase in the circulating levels of the pressor hormones angiotensin II, epinephrine, norepinephrine, and vasopressin. ACTH secretion is also increased, and angiotensin II and ACTH both cause an acute increase in aldosterone secretion. The resulting retention of Na+ and water helps reexpand blood volume.
Forms of Hypovolemic Shock
Hemorrhagic shock is probably the most carefully studied form of shock because it is easily produced in experimental animals. With moderate hemorrhage (5–15 mL/kg body weight), pulse pressure is reduced but mean arterial pressure may remain normal. With more severe hemorrhage, blood pressure always falls.
After hemorrhage, the plasma protein lost in shed blood is gradually replaced by hepatic synthesis, and the concentration of plasma proteins returns to normal in 3–4 days. The increase in circulating erythropoietin increases red blood cell formation, but it takes 4–8 weeks to restore red cell counts to normal.
Traumatic shock develops when there is severe damage to muscle and bone. This is the type of shock seen in battle casualties and automobile accident victims. Bleeding into the injured areas is the principal cause of such shock. The amount of blood that can be lost into a site of injury that appears relatively minor is remarkable; the thigh muscles can accommodate 1 L of extravasated blood, for example, with an increase in the diameter of the thigh of only 1 cm.
Breakdown of skeletal muscle is a serious additional problem when shock is accompanied by extensive crushing of muscle (crush syndrome). When pressure on tissues is relieved and they are once again perfused with blood, free radicals are generated, which cause further tissue destruction (reperfusion-induced injury). Increased Ca2+ in damaged cells can reach toxic levels. Large amounts of K+ enter the circulation. Myoglobin and other products from reperfused tissue can accumulate in kidneys in which glomerular filtration is already reduced by hypotension, and the tubules can become clogged, causing anuria.
Surgical shock is due to combinations, in various proportions, of external hemorrhage, bleeding into injured tissues, and dehydration.
In burn shock, there is loss of plasma from burn surfaces and the hematocrit rises rather than falls, producing severe hemoconcentration. There are, in addition, complex metabolic changes. For these reasons, plus the problems of easy infection of burned areas and kidney damage, the mortality rate when third-degree burns cover more than 75% of the body is close to 100%.
In distributive shock, most of the symptoms and signs described previously are present. However, vasodilation causes the skin to be warm rather than cold and clammy. Anaphylactic shock is a good example of distributive shock. In this condition, an accelerated allergic reaction causes release of large amounts of histamine, producing marked vasodilation. Blood pressure falls because the size of the vascular system exceeds the amount of blood in it even though blood volume is normal.
A second type of distributive shock is neurogenic shock, in which a sudden loss of sympathetic autonomic activity (as seen in head and spinal cord injuries) results in vasodilation and pooling of blood in the veins. The resulting decrease in venous return reduces cardiac output and frequently produces fainting, or syncope, a sudden transient loss of consciousness. More benign and much more common form is postural syncope, which occurs on rising from a sitting or lying position. This is common in patients taking drugs that block sympathetic discharge or its effects on the blood vessels. Falling to the horizontal position restores blood flow to the brain, and consciousness is regained. Pressure on the carotid sinus produced, for example, by a tight collar can cause sufficient bradycardia and hypotension to cause fainting (carotid sinus syncope). Fainting caused by a variety of activities has been given appropriate names such as micturition syncope, cough syncope, deglutition syncope, and effort syncope.
Syncope resulting from neurogenic shock is usually benign. However, it must be distinguished from syncope resulting from other causes and, therefore, merits investigation.
Another form of distributive shock is septic shock. This condition is discussed in detail in Chapter 4. It is now the most common cause of death in ICUs in the United States. It is a complex condition that includes elements of hypovolemic shock resulting from loss of plasma into the tissues (“third spacing”) and cardiogenic shock resulting from toxins that depress the myocardium. It is associated with excess production of NO, and therapy with drugs that scavenge NO may be beneficial.
Streptococcal toxic shock syndrome is a particularly severe form of septic shock in which group A streptococci infect deep tissues; the M protein on the surface of those bacteria has an antiphagocytic effect. It also is released into the circulation, where it aggregates with fibrinogen.
About 25% of syncopal episodes are of cardiac origin and are due either to transient obstruction of blood flow through the heart or to sudden decreases in cardiac output caused by various cardiac arrhythmias. In addition, fainting is the presenting symptom in 7% of patients with myocardial infarctions.
Cardiogenic shock results whenever the pumping function of the heart is impaired to the point that blood flow to tissues is no longer adequate to meet resting metabolic demands; most commonly, it is due to extensive infarction of the left ventricle. The incidence of shock in patients with myocardial infarction is about 10%, and the mortality rate is 60–90%.
However, cardiogenic shock can also be caused by other diseases (heart failure, arrhythmias) that severely compromise normal ventricular function. The symptoms are those of hypovolemic shock plus congestion of the lungs and viscera resulting from failure of the heart to put out all the venous blood returned to it. Consequently, the condition is sometimes called “congested shock.”
The picture of congested shock is also seen in obstructive shock. Causes include massive pulmonary emboli, tension pneumothorax with kinking of the great veins, and bleeding into the pericardium with external pressure on the heart (cardiac tamponade). In the latter two conditions, prompt surgery is required to prevent death. Pulsus paradoxus occurs in cardiac tamponade. Normally, blood pressure falls about 5 mm Hg during inspiration. In pulsus paradoxus, this response is exaggerated, and blood pressure falls 10 mm Hg or more as a result of increased pressure of the fluid in the pericardial sac on the external surface of the heart. However, pulsus paradoxus also occurs with labored respiration in severe asthma, emphysema, and upper airway obstruction.
Some patients with hypovolemia or septic shock die soon after the onset of the condition, and others recover as compensatory mechanisms gradually restore the circulation to normal. In an intermediate group of patients, shock persists for hours and gradually progresses. It eventually reaches a state in which there is no longer any response to vasopressor drugs and in which, even if the blood volume is returned to normal, cardiac output remains depressed. This condition is known as refractory shock. It used to be called irreversible shock, and patients still die despite vigorous treatment. However, more and more patients are saved as understanding of the pathophysiologic mechanisms increases and treatment is improved. Therefore, “refractory shock” seems to be a more appropriate term.
Various factors appear to make shock refractory. Precapillary sphincters are constricted for several hours but then relax while postcapillary venules remain constricted. Therefore, blood flows into the capillaries and remains there. Various positive feedback mechanisms contribute to the refractory state. For example, cerebral ischemia depresses vasomotor and cardiac discharge, causing blood pressure to fall and making the shock worse. This, in turn, causes a further reduction in cerebral blood flow. In addition, myocardial blood flow is reduced in severe shock. Myocardial failure makes the pumping action of the heart less effective and consequently makes the shock worse and further lowers myocardial blood flow.
A complication of shock that has a very high mortality rate is pulmonary damage with production of acute respiratory distress syndrome. The cause appears to be capillary endothelial cell damage and damage to alveolar epithelial cells with the release of cytokines (see Chapter 9).
What are the four major pathophysiologic forms of shock?
Name three pathophysiologic consequences of lactic acidosis in shock.
Describe five specific forms of hypovolemic shock.
Name three specific forms of distributive shock and distinguish them from hypovolemic shock.
Name three factors that tend to make shock refractory.