Pathophysiology of Cardiovascular Diseases

Pathophysiology of Cardiovascular Diseases

Vascular disorders are responsible for more morbidity and mortality than any other category of human disease. Although the most clinically significant lesions typically involve arteries, venous diseases also occur. Vascular pathology results in disease via two principal mechanisms: (1) Narrowing (stenosis) or complete obstruction of vessel lumens, either progressively (e.g., by atherosclerosis) or precipitously (e.g., by thrombosis or embolism). (2) weakening of vessel walls, leading to dilation or rupture.

Atherosclerosis literally means “hardening of the arteries”; it is a generic term reflecting arterial wall thickening and loss of elasticity. There are three general patterns: - Arteriolosclerosis affects small arteries and arterioles, and may cause downstream ischemic injury. - Mönckeberg medial sclerosis is characterized by calcific deposits in muscular arteries in persons typically older than age 50. - Atherosclerosis, from Greek root words for “gruel” and “hardening,” is the most frequent and clinically important pattern. Mönckeberg medial sclerosis is characterized by calcific deposits in muscular arteries in persons typically older than age 50. The deposits may undergo metaplastic change into bone. Nevertheless, the lesions do not encroach on the vessel lumen and are usually not clinically significant.

Atherosclerosis is characterized by intimal lesions called atheromas (also called atheromatous or atherosclerotic plaques) that protrude into vessel lumens. An atheromatous plaque consists of a raised lesion with a soft, yellow, grumous core of lipid (mainly cholesterol and cholesterol esters) covered by a white fibrous cap. Atherosclerotic plaques can: - obstruct blood flow - rupture leading to thrombosis - weaken the underlying media and thereby lead to aneurysm formation

The major components of a well-developed intimal atheromatous plaque overlying an intact media.

Etiology and Pathophysiology
lipid-laden macrophage Chronic stable angina Relationship between atherosclerotic plaque encroachment in the coronary lumen (coronary blood flow) and the resulting influence of myocardial supply and demand Atherosclerosis Atherosclerotic plaque development Plaque rupture Platelet activation/aggregation Thrombus formation – incomplete/complete

Coronary artery disease (CAD) and ischemic heart disease (IHD) are important manifestations of the atherosclerosis. The prevalence and severity of atherosclerosis and IHD are related to two groups of risk factors: 1. Constitutional (non-modifiable) 2. Acquired (modifiable) or related to behaviours that are potentially amenable to intervention

Constitutional risk factors in IHD: - Age - Gender - Genetics
Modifiable risk factors in IHD: - hyperlipidemia - hypertension - cigarette smoking - diabetes mellitus • Age is a dominant influence. Although atherosclerosis is typically progressive, it usually does not become clinically manifest until middle age or later (see below). Between ages 40 and 60 the incidence of myocardial infarction increases fivefold. Death rates from IHD rise with each decade even into advanced age. • Gender. Other factors being equal, premenopausal women are relatively protected against atherosclerosis and its consequences compared to age-matched men. Thus, myocardial infarction and other complications of atherosclerosis are uncommon in premenopausal women in the absence of risk factors such as diabetes, hyperlipidemia, or severe hypertension. After menopause, however, the incidence of atherosclerosis-related diseases increases and at older ages actually exceeds that of men. Although a favorable influence of estrogen has long been proposed to explain the protective effect, some clinical trials have failed to demonstrate any utility of hormonal therapy for vascular disease prevention. As discussed in greater detail in Chapter 9, the atheroprotective effect of estrogens is related to the age at which the therapy is initiated. In younger postmenopausal women, there is a reduction in coronary atherosclerosis with estrogen therapy. The effect is unclear in older women. In addition to atherosclerosis, gender also affects a number of parameters that can influence outcomes of IHD; thus, women show differences in hemostasis, infarct healing, and myocardial remodeling.[29] • Genetics. Family history is the most significant independent risk factor for atherosclerosis. Many mendelian disorders associated with atherosclerosis, such as familial hypercholesterolemia (Chapter 5), have been characterized. Nevertheless, these genetic diseases account for only a small percentage of cases. The well-established familial predisposition to atherosclerosis and IHD is usually multifactorial, relating to inheritance of various genetic polymorphisms, and familial clustering of other established risk factors, such as hypertension or diabetes Modifiable risk factors in IHD. These include hyperlipidemia, hypertension, cigarette smoking, and diabetes. • Hyperlipidemia—and more specifically hypercholesterolemia—is a major risk factor for atherosclerosis; even in the absence of other factors, hypercholesterolemia is sufficient to stimulate lesion development.[28] The major component of serum cholesterol associated with increased risk is low-density lipoprotein (LDL) cholesterol (“bad cholesterol”); LDL cholesterol is the form of cholesterol that is delivered to peripheral tissues. In contrast, high-density lipoprotein (HDL, “good cholesterol”) mobilizes cholesterol from tissue and transports it to the liver for excretion in the bile. Consequently, higher levels of HDL correlate with reduced risk. • Understandably, dietary and pharmacologic approaches that lower LDL or total serum cholesterol, and/or raise serum HDL, are of considerable interest. High dietary intake of cholesterol and saturated fats (present in egg yolks, animal fats, and butter, for example) raises plasma cholesterol levels. Conversely, diets low in cholesterol and/or with higher ratios of polyunsaturated fats lower plasma cholesterol levels. Omega-3 fatty acids (abundant in fish oils) are beneficial, whereas trans-unsaturated fats produced by artificial hydrogenation of polyunsaturated oils (used in baked goods and margarine) adversely affect cholesterol profiles. Exercise and moderate consumption of ethanol raise HDL levels, whereas obesity and smoking lower it.[28] Statins are a class of drugs that lower circulating cholesterol levels by inhibiting hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in hepatic cholesterol biosynthesis.[31] • Hypertension (see above) is another major risk factor for atherosclerosis; both systolic and diastolic levels are important. On its own, hypertension increases the risk of IHD by approximately 60% (see Fig. 11-7). Hypertension is the most important cause of left ventricular hypertrophy and hence the latter is also related to IHD. • Cigarette smoking is a well-established risk factor in men and probably accounts for the increasing incidence and severity of atherosclerosis in women. Prolonged (years) smoking of one pack of cigarettes or more daily doubles the death rate from IHD. Smoking cessation reduces the risk substantially. • Diabetes mellitus induces hypercholesterolemia (Chapter 24) and markedly increases the risk of atherosclerosis. Other factors being equal, the incidence of myocardial infarction is twice as high in diabetics as in nondiabetics. There is also an increased risk of strokes and a 100-fold increased risk of atherosclerosis-induced gangrene of the lower extremities.

Additional risk factors: - Inflammation - Hyperhomocystinemia
- Metabolic syndrome - Lipoprotein (a) levels - Factors affecting hemostasis - Other factors • Inflammation. Inflammation is present during all stages of atherogenesis and is intimately linked with atherosclerotic plaque formation and rupture (see below). With increasing recognition that inflammation plays a significant causal role in IHD, assessment of systemic inflammation has become important in overall risk stratification. While a number of circulating markers of inflammation correlate with IHD risk, C-reactive protein (CRP) has emerged as one of the simplest and most sensitive.[33] CRP is an acute-phase reactant synthesized primarily by the liver. It is downstream of a number of inflammatory triggers and plays a role in the innate immune response by opsonizing bacteria and activating complement. When CRP is secreted from cells within the atherosclerotic intima, it can activate local endothelial cells and induce a prothrombotic state and also increase the adhesiveness of endothelium for leukocytes. Most importantly, it strongly and independently predicts the risk of myocardial infarction, stroke, peripheral arterial disease, and sudden cardiac death, even among apparently healthy individuals (Fig. 11-8). Indeed, CRP levels have recently been incorporated into risk stratification algorithms.[34] Interestingly, although there is as yet no direct evidence that lowering CRP directly reduces cardiovascular risk, smoking cessation, weight loss, and exercise all reduce CRP; moreover, statins reduce CRP levels largely independent of their effects on LDL cholesterol. • Hyperhomocystinemia. Clinical and epidemiologic studies show a strong relationship between total serum homocysteine levels and coronary artery disease, peripheral vascular disease, stroke, and venous thrombosis.[35] Elevated homocysteine levels can be caused by low folate and vitamin B12 intake, although the jury is still out on whether supplemental folate and vitamin B12 ingestion can reduce the incidence of cardiovascular disease. Homocystinuria, due to rare inborn errors of metabolism, results in elevated circulating homocysteine (>100 μmol/L) and premature vascular disease. • Metabolic syndrome. The metabolic syndrome is characterized by a number of abnormalities that are associated with insulin resistance.[36] Besides glucose intolerance, patients exhibit hypertension and central obesity; indeed, abnormal adipose tissue signaling has been proposed to drive the syndrome. Dyslipidemia leads to endothelial cell dysfunction secondary to increased oxidative stress; there is also a systemic proinflammatory state that further predisposes to vascular thrombosis. Regardless of the etiology, metabolic syndrome clearly plays into many of the known risk factors for atherosclerosis. • Lipoprotein (a) is an altered form of LDL that contains the apolipoprotein B-100 portion of LDL linked to apolipoprotein A. Lipoprotein (a) levels are associated with coronary and cerebrovascular disease risk, independent of total cholesterol or LDL levels.[37] • Factors affecting hemostasis. Several markers of hemostatic and/or fibrinolytic function (e.g., elevated plasminogen activator inhibitor 1) are predictors of risk for major atherosclerotic events, including myocardial infarction and stroke. Thrombin, through both its procoagulant and proinflammatory effects, as well as platelet-derived factors both are increasingly recognized as major contributors to local vascular pathology.[38],39 • Other factors. Factors associated with a less pronounced and/or difficult-to-quantitate risk include lack of exercise; competitive, stressful life style (“type A” personality); and obesity (which is often associated with hypertension, diabetes, hypertriglyceridemia, and decreased HDL).

Pathogenesis of Atherosclerosis
Historically, there have been two dominant hypotheses to explain the progress of the disease: - one emphasizes intimal cellular proliferation. - the other focuses on the repetitive formation and organization of thrombi. Recently, the response-to-injury hypothesis which views atherosclerosis as a chronic inflammatory and healing response of the arterial wall to endothelial injury was adopted.

Atherosclerosis is produced by the following pathogenic events:
- Endothelial injury, which causes (among other things) increased vascular permeability, leukocyte adhesion, and thrombosis. - Accumulation of lipoproteins (mainly LDL and its oxidized forms) in the vessel wall. - Monocyte adhesion to the endothelium, followed by migration into the intima and transformation into macrophages and foam cells. - Platelet adhesion.

- Factor release from activated platelets, macrophages, and vascular wall cells, inducing smooth muscle cell recruitment, either from the media or from circulating precursors. - Smooth muscle cell proliferation and ECM production. - Lipid accumulation both extracellularly and within cells (macrophages and smooth muscle cells).

Consequences of Atherosclerosis
The aorta, carotid, and iliac arteries (large elastic arteries) and coronary and popliteal (medium-sized muscular arteries) are targets for atherosclerosis. Heart attack, stroke, aneurysm and gangrene in the legs are potential consequences of the disease. The principal outcomes depend on: - The size of the involved vessels - The relative stability of the plaque itself - The degree of degeneration of the underlying arterial wall

1. Atherosclerotic stenosis
Compromised blood flow WILL lead to ischemic injury secondary to critical occlusion of a small vessel. Total circumference expansion due to outward remodelling of vessel media is an adaptive mechanism before an injury commences. At 70% fixed occlusion, clinical symptoms surface (Stable angina). The effects of vascular occlusion ultimately depend on arterial supply and the metabolic demand of the affected tissue.

2. Acute plaque change Plaque rupture is promptly followed by partial or complete vascular thrombosis resulting in acute tissue infarction (e.g., myocardial or cerebral infarction). Plaque changes fall into three general categories: - Rupture/fissuring, exposing highly thrombogenic plaque constituents - Erosion/ulceration, exposing the thrombogenic subendothelial basement membrane to blood - Hemorrhage into the atheroma, expanding its volume

- Intrinsic factors (e.g., plaque structure and composition)
The events that trigger abrupt changes in plaque configuration are complex and include: - Intrinsic factors (e.g., plaque structure and composition) - Extrinsic factors (e.g., blood pressure, platelet reactivity) INTRINSIC FACTORS: it is also established that the fibrous cap undergoes continuous remodeling that may make the plaque susceptible to acute alterations. Collagen represents the major structural component of the fibrous cap, and accounts for its mechanical strength and stability. Thus, the balance of collagen synthesis versus degradation affects cap stability. Collagen in atherosclerotic plaque is produced primarily by smooth muscle cells, so that loss of these cellular elements results in a weaker cap. Moreover, collagen turnover is controlled by matrix metalloproteinases (MMPs), enzymes elaborated largely by macrophages within the atheromatous plaque; conversely, tissue inhibitors of metalloproteinases (TIMPs), produced by endothelial cells, smooth muscle cells, and macrophages, modulate MMP activity. In general, plaque inflammation results in a net increase in collagen degradation and reduces collagen synthesis, thereby destabilizing the mechanical integrity of the fibrous cap (see below). Interestingly, statins may have a beneficial therapeutic effect not only by reducing circulating cholesterol levels but also by stabilizing plaques through a reduction in plaque inflammation. EXTRINSIC FACTORS: Influences extrinsic to plaques are also important. Thus, adrenergic stimulation can increase systemic blood pressure or induce local vasoconstriction, thereby increasing the physical stresses on a given plaque. Indeed, the adrenergic stimulation associated with waking and rising can cause blood pressure spikes (followed by heightened platelet reactivity) that have been causally linked to the pronounced circadian periodicity for the peak time of onset of acute myocardial infarction (between 6 AM and 12 noon).[52] Intense emotional stress can also contribute to plaque disruption; this is most dramatically illustrated by the uptick in the incidence of sudden death associated with disasters such as earthquakes and the September 11, 2001 attacks.

Mural thrombus in a coronary artery can also embolize
3. Thrombosis Thrombosis (partial/total) associated with a disrupted plaque is critical to the pathogenesis of the acute coronary syndromes. Thrombus superimposed on a disrupted partially stenotic plaque converts it to a total occlusion. In other coronary syndromes luminal obstruction by thrombosis is usually incomplete and will disappear with time. Mural thrombus in a coronary artery can also embolize - Mural thrombus in a coronary artery can also embolize. Indeed, small fragments of thrombotic material in the distal intra-myocardial circulation or microinfarcts can be found at autopsy in patients after sudden death or in rapidly accelerating anginal syndromes. Finally, thrombus is a potent activator of multiple growth-related signals in smooth muscle cells, which can contribute to the growth of atherosclerotic lesions.

4. Vasoconstriction Vasoconstriction at sites of atheroma is stimulated by: (1) circulating adrenergic agonists (2) locally released platelet contents (3) impaired secretion of endothelial cell relaxing factors (nitric oxide) relative to contracting factors (endothelin) as a result of endothelial cell dysfunction (4) mediators released from perivascular inflammatory cells.

Hyperlipidemia Hypercholesterolemia additive to nonlipid CHD risk factors: cigarette smoking, HTN, DM, low HDL, electrocardiographic abnormalities Presence of CHD, prior MI increases MI risk 5 to 7 times LDL level: significant predictor of morbidity/mortality ~50% of MIs and > 70% of CHD deaths occur in patients with known CHD

Background & Pathophysiology
Cholesterol: essential for cell membrane formation & hormone synthesis Lipids not present in free form in plasma; circulate as lipoproteins (complexes of lipids and proteins) 3 major classes of plasma lipoproteins: VLDL carries ~10 to 15 % of total serum cholesterol; carried in circulation as TG; VLDL = TG/5 LDL carries 60 to 70% of total serum cholesterol; IDL is also included in this group (LDL1) HDL carries 20 to 30% of total serum cholesterol; reverse transportation of cholesterol

Cholesterol, triglycerides, and phospholipids are the major lipids in the body. They are transported as complexes of lipid and proteins known as lipoproteins. Plasma lipoproteins are spherical particles with surfaces that consist largely of phospholipid, free cholesterol, and protein and cores composed mostly of triglyceride and cholesterol ester The figure shows a diagrammatic representation of the structure of low-density lipoprotein (LDL), the LDL receptor, and the binding of LDL to the receptor via apolipoprotein B-100.

The second way cells obtain cholesterol is by extracting it from the systemic circulation. The source of this cholesterol is the liver, where it is synthesized and secreted into the systemic circulation. Because cholesterol and other fatty substances are insoluble in water, they are formed into complexes (particles) in the hepatocyte and gut before being secreted into the aqueous medium of the blood. These particles contain an oily inner lipid core made up of cholesterol esters and TG and an outer hydrophilic coat made up of phospholipids and unesterified cholesterol. The outer coat also contains at least one protein, which provides the ligand for interaction with receptors on cell surfaces. The presence of a central lipid core and an outer protein gives rise to the name of these particles, lipoproteins. The three major lipoproteins found in the blood of fasting (10–12 hours) patients are very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL).2 These particles vary in size, composition, and accompanying proteins

Apoproteins These proteins have three functions:
provide structure to the lipoprotein, activate enzyme systems, bind with cell receptors The five most clinically relevant apolipoproteins are A-I, A-II, B-100, C, and E the B and E proteins are ligands for LDL receptors the blood concentration of apolipoprotein B-100 is an indication of the total number of VLDL and LDL particles in the circulation. An increased number of lipoprotein particles (i.e., an increased apolipoprotein B-100 concentration) is a strong predictor of CHD risk. Apo C-II is a cofactor for lipoprotein lipase Apo C-III downregulates lipoprotein lipase activity and interferes with the hepatic uptake of VLDL remnant particles (may emerge as an important marker of atherosclerosis and provide a way for clinicians to identify patients requiring aggressive treatment.) A-I protein activates LCAT, which catalyzes the esterification of free cholesterol in HDL particles. Levels of apolipoprotein A-I have a stronger inverse correlation with CHD risk than apolipoprotein A-II levels. HDL particles that contain only A-I apolipoproteins (LpA-I) are associated with a lower CHD risk than are HDL particles containing both A-I and A-II (LpA-I, A-II). A-I — Structural protein for HDL; activator of lecithin-cholesterol acyltransferase (LCAT). A-II — Structural protein for HDL; activator of hepatic lipase. A-IV — Activator of lipoprotein lipase (LPL) and LCAT. B-100 — Structural protein for VLDL, IDL, LDL, and Lp(a); ligand for the LDL receptor; required for assembly and secretion of VLDL. B-48 — Contains 48 percent of B-100; required for assembly and secretion of chylomicrons; does not bind to LDL receptor. C-I — Activator of LCAT. C-II — Essential cofactor for LPL. C-III — Interferes with apo-E mediated clearance of triglyceride-enriched lipoproteins by cellular receptors [3]; inhibits triglyceride hydrolysis by lipoprotein lipase and hepatic lipase [4]; interferes with normal endothelial function [5]. D — May be a cofactor for cholesteryl ester transfer protein (CETP). E — Ligand for hepatic chylomicron and VLDL remnant receptor, leading to clearance of these lipoproteins from the circulation; ligand for LDL receptor. There are three different apo E alleles in humans: E2, which has cysteine residues at positions 112 and 158; E3, which occurs in 60 to 80 percent of Caucasians and has cysteine at position 112 and arginine at position 158; and E4, which has arginine residues at positions 112 and 158 [6]. These alleles encode for a combination of apo E isoforms that are inherited in a codominant fashion. Compared to apo E3, apo E2 has reduced affinity and apo E4 has enhanced affinity for the LDL (apo B/E) receptor. These isoforms are important clinically because apo E2 is associated with familial dysbetalipoproteinemia (due to less efficient clearance of VLDL and chylomicrons) and apo E4 is associated with an increased risk of hypercholesterolemia and coronary heart disease. (CHD) (see "Primary disorders of LDL-cholesterol metabolism", section on 'Polygenic hypercholesterolemia' and "Approach to the patient with hypertriglyceridemia", section on 'Familial dysbetalipoproteinemia'). Apo(a) — Structural protein for Lp(a); inhibitor of plasminogen activation on Lp(a).

These proteins have three functions:
provide structure to the lipoprotein, activate enzyme systems, bind with cell receptors The five most clinically relevant apolipoproteins are A-I, A-II, B-100, C, and E the B and E proteins are ligands for LDL receptors Apo C-II is a cofactor for lipoprotein lipase Apo C-III downregulates lipoprotein lipase activity and interferes with the hepatic uptake of VLDL remnant particles (may emerge as an important marker of atherosclerosis and provide a way for clinicians to identify patients requiring aggressive treatment.) the blood concentration of apolipoprotein B-100 is an indication of the total number of VLDL and LDL particles in the circulation. An increased number of lipoprotein particles (i.e., an increased apolipoprotein B-100 concentration) is a strong predictor of CHD risk. A-I protein activates LCAT, which catalyzes the esterification of free cholesterol in HDL particles. Levels of apolipoprotein A-I have a stronger inverse correlation with CHD risk than apolipoprotein A-II levels. HDL particles that contain only A-I apolipoproteins (LpA-I) are associated with a lower CHD risk than are HDL particles containing both A-I and A-II (LpA-I, A-II).

Chylomicron VLDL LDL HDL Density (g/mL) <0.94 0.94–1.006 1.006–1.063 1.063–1.210 Composition (%) Protein 1–2 6–10 18–22 45–55 Triglyceride 85–95 50–65 4–8 2–7 Cholesterol 3–7 20–30 51–58 18–25 Phospholipid 3–6 15–20 18–24 26–32 Physiologic origin Intestine Intestine and liver Product of VLDL catabolism Liver and intestine Physiologic function Transport dietary CH and TG to liver Transport endogenous TG and CH Transport endogenous CH to cells Transport CH from cells to liver Plasma appearance Cream layer Turbid Clear Electrophoretic mobility Origin Pre-beta Beta Alpha Apolipoproteins A-IV, B-48, C-I, C-II, C-III B-100, C-I, C-II, C-III, E B-100, A-I, A-II, A-IV

VLDL secreted from the liver converted to IDL then LDL Plasma LDL taken up by receptors on liver, adrenal, & peripheral cells recognize LDL apolipoprotein B-100 LDL internalized & degraded by these cells Increased intracellular cholesterol levels inhibits HMG-CoA reductase & decreases LDL receptor synthesis Decreases in LDL receptors: plasma LDL not as readily taken up & broken down by cells

LDL also excreted in bile joins enterohepatic pool eliminated in stool LDL can be oxidized in subendothelial space of arteries Oxidized LDL in artery walls provokes inflammatory response Monocytes recruited & transformed into macrophages results in cholesterol laden foam cell accumulation Foam cells: beginning of arterial fatty streak If processes continue: angina, stroke, MI, peripheral artery disease, arrhythmias, death

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 (LPL). 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 LDLs enter the subendothelial space of arteries, are oxidized, and then are taken up by macrophages, which become foam cells. The letters on the chylomicrons, chylomicron remnants, VLDL, IDL, and LDL identify the primary apoproteins (ApoB, ApoC, ApoE) found in them. (LDLR, low-density lipoprotein receptor.)

Biosynthetic pathway for cholesterol
Biosynthetic pathway for cholesterol. The rate-limiting enzyme in this pathway is 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase). (CETP, cholesterol ester transfer protein; HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; LPL, lipoprotein lipase; VLDL, very-low-density lipoprotein.) Very-Low-Density Lipoproteins Very-low density lipoprotein particles are formed in the liver. They normally contain 15% to 20% of the total blood cholesterol concentration and most of the total blood TG concentration. The concentration of cholesterol in these particles is approximately one fifth of the total TG concentration; thus, if the total TG concentration is known, the VLDL-cholesterol (VLDL-C) level can be estimated by dividing total TG by 5. VLDL particles are large and appear to play only a small role in the pathogenesis of atherosclerosis VLDL Remnants As VLDL particles flow through capillaries, some of their TG content is removed through the action of the enzyme lipoprotein lipase. Drugs that enhance the activity of lipoprotein lipase (i.e., fibrates) increase the delipidization process and lower blood TG levels. The removed TG is converted to fatty acids and stored as an energy source in adipose tissue. As TG are removed, the VLDL particle becomes progressively smaller and relatively more cholesterol rich. The particles formed through this process include small VLDL particles (called remnant VLDL), intermediate-density lipoproteins (IDL), and LDL. Approximately 50% of the remnant VLDL and IDL particles are removed from the systemic circulation by receptors on the surface of the liver (receptors called LDL or B-E receptors); the other 50% are converted into LDL particles. Low-Density Lipoproteins Low-density lipoprotein particles carry 60% to 70% of the total blood cholesterol and make the greatest contribution to the development of atherosclerosis. This is why LDL-C is the primary target of cholesterol-lowering therapy. Approximately half of the LDL particles are removed from the systemic circulation by the liver; the other half may be taken up by peripheral cells or deposited in the intimal space of coronary, carotid, and other peripheral arteries, where atherosclerosis can develop. The probability that atherosclerosis will develop is directly related to the concentration of LDL-C in the systemic circulation and the length of time this level of exposure persists (the cumulative risk of CHD in men and women increases with age). High-Density Lipoproteins High-density lipoprotein particles transport cholesterol from peripheral cells back to the liver, a process called reverse cholesterol transport. In contrast to LDL, high HDL-C concentrations are desirable because cholesterol is being removed from vascular tissue and is not available to contribute to atherogenesis. In peripheral cells, the adenosine triphosphate binding cassette transporter A-1 (ABCA-1 transporter) and adenosine triphosphate binding cassette transporter G-1 (ABCG-1) facilitates the efflux of both cholesterol and phospholipids. Through mechanisms that have not been defined fully, HDL particles acquire this cholesterol and either transport it directly to the liver through interaction with an HDL receptor on the hepatocyte (the scavenger receptor, SR-B1) or transfer it to circulating remnant VLDL and LDL particles through the action of cholesterol ester transfer protein (CETP) in exchange for TG making the HDL particle less cholesterol rich. If the latter occurs, the cholesterol can be returned to the liver for clearance from the circulation or delivered back to peripheral cells. Patients have been described who have a deficiency of CETP; they often have a high plasma concentration of HDL-C and a low incidence of CHD. Drugs are being developed and tested that inhibit this protein. Recent trials, however, have not looked promising for this class of drugs. Non-HDL Cholesterol Non-HDL cholesterol (non-HDL-C) refers to the combined amount of cholesterol carried by VLDL and LDL particles (the cholesterol carried by IDL particles is reported as part of LDL cholesterol). As indicated, most often an elevated LDL-C is encountered, but in about 30% of cases, VLDL-C is also elevated. In these cases, it is helpful to know how much cholesterol is being carried by all of these particles. Non-HDL-C is determined by subtracting the HDL-cholesterol (HDL-C) level from the total cholesterol level. Chylomicrons Unlike the lipoproteins that transport cholesterol from the liver to peripheral cells and back (endogenous system), chylomicrons transport fatty acids and cholesterol derived from the diet or synthesized in the intestines from the gut to the liver (exogenous system). Chylomicrons are large, TG-rich lipoproteins. As they pass through capillary beds on the way to the liver, some of the TG content is removed through the action of lipoprotein lipase in a manner similar to that described for TG removal from VLDL particles. In the rare individual who has a lipoprotein lipase deficiency, this removal process is faulty and TG levels in the blood become very high (e.g., 1,000 to 5,000 mg/dL). Following a fatty meal, the number of chylomicron particles (and therefore the concentration of TG) is high. If the patient fasts for 10 to 12 hours, however, chylomicrons will have time to be removed from the blood. TG concentrations obtained during fasting reflect TG that is produced by the liver and carried in VLDL and other remnant particles (unless the patient has a rare chylomicron clearance disorder). This is why patients are asked to fast before a lipoprotein profile is obtained. A blood sample that is rich in chylomicrons (and to a lesser extent VLDL particles) appears turbid; the higher the TG level, the more turbid the sample. If the sample from a patient with hyperchylomicronemia is refrigerated, chylomicrons will float to the top and form a frothy white layer, whereas smaller VLDL stay suspended below.

Intracellular cholesterol is stored in an esterified form
Intracellular cholesterol is stored in an esterified form. Free cholesterol is converted to this ester form through the action of the enzyme acetyl CoA acetyl transferase (ACAT). Two forms of ACAT have been identified. ACAT1 is present in many tissues, including inflammatory cells, whereas ACAT2 is present in intestinal mucosa cells and hepatocytes

Etiology There are two major ways in which dyslipidemias are classified: Phenotype, or the presentation in the body (including the specific type of lipid that is increased) Etiology, or the reason for the condition (genetic (primary), or secondary to another condition.) This classification can be problematic, because most conditions involve the intersection of genetics and lifestyle issues. However, there are a few well defined genetic conditions that are usually easy to identify. Current laboratory values can not define underlying abnormality Secondary dyslipidemias and should be initially managed by correcting underlying abnormality when possible Atherogenic Dyslipidemia Atherogenic dyslipidemia is found in about 25% of patients who have a lipid disorder. It is characterized by a moderate TG elevation (150 to 500 mg/dL; indicative of the increased presence of VLDL remnant particles), a low HDL-C level (<40 mg/dL); and a moderately high LDL-C level (including increased concentrations of small-dense LDL particles). Most commonly, these patients are either overweight or obese with increased waist circumference, hypertensive, and insulin resistant with or without diabetes and are said to have the metabolic syndrome. Patients with atherogenic dyslipidemia can often be effectively managed with weight reduction and increased physical activity. If needed, drugs that enhance the removal of remnant VLDL and small dense LDL particles (i.e., statins) and that lower TG levels (i.e., niacin or fibrates) are effective in the management of these cases. 38

Etiology Primary lipoprotein disorders: 6 categories
used for phenotypical description of dyslipidemia Fredrickson-Levy-Lees Classification Type Lipoprotein Elevation Effect on lipid profile I Chylomicrons ↑↑TG, ↑cholesterol IIa LDL ↑cholesterol IIb LDL + VLDL ↑cholesterol, ↑TG III IDL (LDL1) IV VLDL ↑TG, moderate ↑cholesterol V VLDL + Chylomicrons Lipid Hyperlipidemia: lipids Hypercholesterolemia: cholesterol. Familial hypercholesterolemia is a specific form of hypercholesterolemia due to a defect on chromosome 19 Hyperglyceridemia: glycerides Hypertriglyceridemia: triglycerides Hypolipidemia Hypocholesterolemia: cholesterol Lipoprotein Hyperlipoproteinemia: lipoproteins (usually LDL unless otherwise specified) Hyperchylomicronemia: chylomicrons Hypolipoproteinemia: lipoproteins Abetalipoproteinemia: beta lipoproteins Tangier disease: high density lipoprotein Both Combined hyperlipidemia: both LDL and triglycerides

Increases Decreases Lipid Hyperlipidemia: lipids Hypercholesterolemia: cholesterol. Familial hypercholesterolemia is a specific form of hypercholesterolemia due to a defect on chromosome 19 Hyperglyceridemia: glycerides Hypertriglyceridemia: triglycerides Hypolipidemia Hypocholesterolemia: cholesterol Lipoprotein Hyperlipoproteinemia: lipoproteins (usually LDL unless otherwise specified) Hyperchylomicronemia: chylomicrons Hypolipoproteinemia: lipoproteins Abetalipoproteinemia: beta lipoproteins Tangier disease: high density lipoprotein Both Combined hyperlipidemia: both LDL and triglycerides

Plasma Lipids [mmol/L (mg/dL)] Lipoprotein Elevated Pheno-type
Lipid Phenotype Plasma Lipids [mmol/L (mg/dL)] Lipoprotein Elevated Pheno-type Clinical Signs Isolated hypercholesterolemia Familial hypercholesterol-emia (LDL receptors) Heterozygotes TC = 7–13 (275–500) LDL IIa Usually develop xanthomas in adulthood and vascular disease at 30–50 years Homozygotes TC >13 (>500) Usually develop xanthomas in adulthood and vascular disease in childhood Familial defective Apo B-100 Polygenic hypercholesterol-emia (genetic/lifestyle) TC = 6.5–9 (250–350) Usually asymptomatic until vascular disease develops; no xanthomas Isolated hypertriglyceridemia Familial hypertriglyceridemia TG = 2.8–8.5 (250–750) VLDL IV Asymptomatic; may be associated with increased risk of vascular disease Familial LPL deficiency TG >8.5 (>750) Chylomicrons, VLDL I, V May be asymptomatic; may be associated with pancreatitis, abdominal pain, hepatosplenomegaly Familial Apo C-II deficiency As above Polygenic Hypercholesterolemia Polygenic hypercholesterolemia, the most prevalent form of dyslipidemia, which is found in more than 25% of the U.S. population, is caused by a combination of environmental (e.g., poor nutrition, sedentary lifestyle) and genetic factors (thus, the term “polygenic”). Saturated fatty acids in the diet of these patients can reduce LDL receptor activity, thus reducing the clearance of LDL particles from the systemic circulation. As a result, patients with polygenic hypercholesterolemia have mild to moderate LDL-C elevations (usually in the range of 130 to 250 mg/dL), but no unique physical findings are seen. Family history of premature CHD is present in approximately 20% of cases. These patients are effectively managed with dietary restriction in saturated fats and cholesterol and by drugs that lower LDL-C levels (i.e., statins, bile acid sequestrants, niacin, and ezetimibe).

*cholesterol may be elevated in other lipoprotein disorders
Lipid Phenotype Plasma Lipid Levels [mmol/L (mg/dL)] Lipoprotein Elevated Pheno-type Clinical Signs Hypertriglyceridemia and hypercholesterolemia Combined hyperlipidemia TG = 2.8–8.5 (250–750); TC = 6.5–13 (250–500) VLDL, LDL IIb Usually asymptomatic until vascular disease develops; familial form may present as isolated high TG or isolated high LDL cholesterol Dysbetalipo-proteinemia (Apo E) VLDL, IDL; LDL normal III Usually asymptomatic until vascular disease develops; may have palmar or tuboeruptive xanthomas Note: Elevated cholesterol is not necessarily familial hypercholesterolemia (type IIa) *cholesterol may be elevated in other lipoprotein disorders *lipoprotein pattern does not describe underlying genetic defect

Disorder Metabolic Defect Lipid Effect Main Lipid Parameter Diagnostic Features Polygenic hypercholesterolemia ↓LDL clearance ↑LDL-C LDL-C: 130–250 mg/dL TG: 150–500 mg/dL None distinctive Atherogenic dyslipidemia ↑VLDL secretion, ↑C-III synthesis ↓LPL activity ↓VLDL removal ↑TG ↑Remnant VLDL ↓HDL ↑Small, dense LDL HDL-C: <40 mg/dL Frequently accompanied by central obesity or diabetes Familial hypercholesterolemia (heterozygous) Dysfunctional or absent LDL receptors LDL-C: 250–450 mg/dL Family history of CHD, tendon xanthomas Familial defective apoB-100 Defective ApoB on LDL and VLDL Dysbetalipoprotein-emia (type III hyperlipidemia) ApoE2:E2 phenotype, ↓VLDL remnant clearance ↑Remnant VLDL, ↑IDL LDL-C: 300–600 mg/dL TGs: 400–800 mg/dL Palmar xanthomas, tuberoeruptive xanthomas Familial combined hyperlipidemia ↑ApoB and VLDL production ↑CH, TG, or both LDL-C: 250–350 mg/dL TGs: 200–800 mg/dL Family history, CHD Family history, Hyperlipidemia Familial hyperapobetalipo-proteinemia ↑ApoB production ↑ApoB ApoB: >125 mg/dL Hypoalphalipoprotein-emia ↑HDL catabolism ↓HDL-C

Xanthomas Xanthomas are plaques or nodules consisting of abnormal lipid deposition and foam cells. They do not represent a disease but rather are symptoms of different lipoprotein disorders or arise without an underlying metabolic effect. Clinically, xanthomas can be classified as: eruptive, tuberoeruptive or tuberous, tendinous, or planar. Planar xanthomas include: xanthelasma palpebrarum/xanthelasma, xanthoma striatum palmare, intertriginous xanthomas. There are characteristic clinical phenotypes associated with specific metabolic defects

Eruptive skin xanthomata characteristic of severe chylomicronemia.
Tuberoeruptive and tuberous xanthomata typical of familial dysbetalipoproteinemia. A. Knee B. Palm. Eruptive skin xanthomata characteristic of severe chylomicronemia. Eruptive xanthomata are multiple, reddish-yellow papules that appear suddenly and are arranged in crops on the extensor surface of the extremities and the buttocks (Figs and 135-2). Tuberous xanthomata are nodules that are frequently localized to the extensor surfaces of the elbows, knees, knuckles, and buttocks (Fig ). Tendinous xanthomata are firm subcutaneous nodules found in fascia, ligaments, Achilles tendons, or extensor tendons of the hands, knees, and elbows (Fig ). Planar xanthomata are yellow macules, soft papules, or plaques found commonly on the upper eyelids (xanthelasma palpebrarum), the palms (xanthoma striatum palmare) (Fig ), and in intertriginous areas. Tendon xanthomata typical of heterozygous familial hypercholesterolemia. Similar xanthomata occur in patients with familial defective apolipoprotein B-100, cerebrotendinous xanthomatosis, and sitosterolemia. Xanthoma striatum palmare characteristic of familial dysbetalipoproteinemia.

Forms of xanthomas and other lipid deposits frequently seen in familial hypercholesterolemia homozygotes. A. Arcus corneae. B, C, E, and F. Cutaneous planar xanthomas, which usually have a bright orange hue. D and G. Tuberous xanthomas on the elbows. H. Tendon and tuberous xanthomas.

Familial hypercholesterolemia
characterized by selective elevation in the plasma level of LDL, deposition of LDL-derived cholesterol in tendons (xanthomas) and arteries (atheromas), inheritance as an autosomal dominant trait with homozygotes more severely affected than heterozygotes. The primary defect in familial hypercholesterolemia is the inability to bind LDL to the LDL receptor or, rarely, a defect of internalizing the LDL receptor complex into the cell after normal binding. Homozygotes have essentially no functional LDL receptors. This leads to lack of LDL degradation by cells and unregulated biosynthesis of cholesterol, with total cholesterol and LDL-C inversely proportional to the deficit in LDL receptors. Heterozygotes have only about half the normal number of LDL receptors, total cholesterol levels in the range from 300 to 600 mg/dL.

Familial LPL deficiency
LPL is normally released from vascular endothelium or by heparin and hydrolyzes chylomicrons and VLDL Familial LPL deficiency is a rare, autosomal recessive trait Diagnosis is based on low or absent enzyme activity with normal human plasma or apolipoprotein C-II, a cofactor of the enzyme. Type I lipoprotein pattern characterized by massive accumulation of chylomicrons and corresponding increase in plasma triglycerides. VLDL concentration is normal. Presenting manifestations include repeated attacks of pancreatitis and abdominal pain, eruptive cutaneous xanthomatosis, and hepatosplenomegaly beginning in childhood. Symptom severity is proportional to dietary fat intake and consequently to the elevation of chylomicrons. Accelerated atherosclerosis is not associated with the disease. type V (VLDL and chylomicrons). Abdominal pain, pancreatitis, eruptive xanthomas, and peripheral polyneuropathy Symptoms may occur in childhood, but usually the disorder is expressed at a later age. The risk of atherosclerosis is increased with the disorder. Patients commonly are obese, hyperuricemic, and diabetic, and alcohol intake, exogenous estrogens, and renal insufficiency tend to be exacerbating factors.

Dysbetalipoproteinemia
familial type III hyperlipoproteinemia (also called, broad-band, or β-VLDL) Patients develop the following clinical features after age 20 years: xanthoma striata palmaris (yellow discolorations of the palmar and digital creases); tuberous or tuberoeruptive xanthomas (bulbous cutaneous xanthomas); severe atherosclerosis involving the coronary arteries, internal carotids, and abdominal aorta. A defective structure of apolipoprotein E does not allow normal hepatic surface receptor binding of remnant particles derived from chylomicrons and VLDL (known as IDL). Aggravating factors such as obesity, diabetes, and pregnancy may promote overproduction of apolipoprotein B–containing lipoproteins. Although homozygosity for the defective allele (E2/E2) is common (1:100), only 1 in 10,000 express the full-blown picture, and interaction with other genetic or environmental factors, or both, is needed to produce clinical disease.

Familial combined hyperlipidemia
characterized by elevations in total cholesterol and triglycerides, decreased HDL, increased apolipoprotein B, and small, dense LDL. It is associated with premature CHD and may be difficult to diagnose because lipid levels do not consistently display the same pattern.

Type IV hyperlipoproteinemia
Two genetic patterns: familial hypertriglyceridemia, which does not carry a great risk for premature CAD, familial combined hyperlipidemia, which is associated with increased risk for cardiovascular disease. Type IV hyperlipoproteinemia is common and occurs in adults, primarily in patients who are obese, diabetic, and hyperuricemic and do not have xanthomas. It may be secondary to alcohol ingestion and can be aggravated by stress, progestins, oral contraceptives, thiazides, or β-blockers.

Other lipoprotein disorders
Rare forms of lipoprotein disorders include hypobetalipoproteinemia, abetalipoproteinemia, Tangier disease, LCAT deficiency (fish eye disease), cerebrotendinous xanthomatosis, sitosterolemia. Most of these rare lipoprotein disorders do not result in premature atherosclerosis, with the exceptions of familial LCAT deficiency, cerebrotendinous xanthomatosis, and sitosterolemia with xanthomatosis. Treatment consists of dietary restriction of plant sterols (sitosterolemia with xanthomatosis) and chenodeoxycholic acid (cerebrotendinous xanthomatosis), or, potentially, blood transfusion (LCAT deficiency).

Lipoprotein Abnormalities: 2˚ Causes
Hypercholesterolemia hypothyroidism obstructive liver disease nephrotic syndrome anorexia nervosa acute intermittent porphyria Medications progestins thiazide diuretics glucocorticoids β-blockers isotretinoin protease inhibitors cyclosporine mirtazipine sirolimus

Hypertriglyceridemia obesity DM lipodystrophy glycogen storage disease ileal bypass surgery sepsis Pregnancy monocolonal gammopathy: multiple myeloma, lymphoma acute hepatitis systemic lupus erythematous Medications alcohol estrogens isotretinoin β-blockers glucocorticoids bile acid resins Thiazides asparaginase interferons azole antifungals mirtazipine anabolic steroids sirolimus 54

Hypocholesterolemia malnutrition malabsorption myeloproliferative diseases chronic infectious diseases acquired immune deficiency syndrome tuberculosis monoclonal gammopathy chronic liver disease Low high-density lipoprotein malnutrition obesity Medications non-ISA β-blockers anabolic steroids isotretinoin progestins The myeloproliferative diseases ("MPD"s) are a group of diseases of the bone marrow in which excess cells are produced. They are related to, and may evolve into, myelodysplastic syndrome and acute myeloid leukemia, although the myeloproliferative diseases on the whole have a much better prognosis than these conditions 55

Effect on Plasma Lipids
Comments Cholesterol (%) Triglycerides (%) HDL-C (%) Diuretics Thiazides ↑5–7% initially ↑0–3% later ↑30–50 ↑1 Effects transient; monitor for long-term effects Loop No change ↓ to 15 β-blockers Nonselective Selective α-Blocking No change No change No change or ↓ ↑20—50 ↑15–30 No change ↓10–15 ↓5–10 No change Selective β-blockers have greater effects than nonselective; β-blockers with ISA or α-blocking effects are lipid neutral α-Agonists and antagonists (e.g., prazosin and clonidine) ↓0–10% ↓ 0–20 ↑0–15 In general, drugs that affect α-receptors ↓cholesterol and ↑HDL-C Oral contraceptives α-Monophasics ↑5–20 ↑10–45 ↑15 to ↓15 Effects caused by reduced lipolytic activity and/or ↑VLDL synthesis; mainly caused by progestin component; estrogen alone protective α-Triphasics ↑10–15 ↑5–10 Glucocorticoids ↑15–20 Ethanol ↑up to 50 ↑ Marked elevations can occur in patients who are hypertriglyceridemic Isotretinoin ↑50–60 ↓10–15 Changes may reverse 8 wk after stopping drug Cyclosporine

Metabolic syndrome Any 3 or more of the following are needed for diagnosis

Total cholesterol <200 Desirable 200–239 Borderline high 240 High
LDL cholesterol <100 Optimal 100–129 Near or above optimal 130–159 160–189 190 Very high HDL cholesterol <40 Low 60 mg/dL Triglycerides <150 Normal 150–199 200–499 500 Levels of Cholesterol and triglycerides increase throughout life until about the fifth decade for men and the sixth decade for women. Past these ages, total cholesterol and LDL plateau and fall slightly. Because the ratio of cholesterol to TG in LDL is 1:5, VLDL-C is estimated by dividing the total TG level by 5. All values are mg/dL

Major risk factorsa – exclusive of LDL-C – that modify the LDL goals
Age Men: > 45 years Women: > 55 years or premature menopause without estrogen replacement therapy Family history of premature CHD (definite myocardial infarction or sudden death before age 55 years in father or other male first-degree relative, or before age 65 years in mother or other female first-degree relative) Cigarette smoking Within the past month Hypertension (140/90 mm Hg or taking antihypertensive medication) Low HDL cholesterol (<40 mg/dL)b aDiabetes regarded as coronary heart disease (CHD) risk equivalent. bHDL cholesterol >60 mg/dL counts as "negative" risk factor; its presence removes one risk factor from the total count. Metabolic syndrome is considered as CHD risk equivalent

Goals & Cutpoints Risk Category LDL Goal (mg/dL)
LDL Level at Which to Initiate TLC (mg/dL) LDL Level at Which to Consider Drug Therapy High risk: CHD or CHD risk equivalents (10-year risk >20%) <100 (optional goal: <70) >100 (<100 mg/dL; consider drug options)a Moderately high risk: 2+ risk factors (10-year risk >10%–20%) <130 (optional goal <100) >130 (100–129: consider drug options) Moderate risk: 2+ risk factors (10-year risk <10%) >160 Lower risk: 0–1 risk factorb <160 >190 (160–189: LDL-lowering drug optional) Risk is estimated from Framingham risk score aSome authorities recommend use of LDL-lowering drugs in this category if LDL cholesterol <100 mg/dL cannot be achieved by therapeutic lifestyle changes (TLC). Others prefer to use drugs that primarily modify triglycerides and high-density lipoprotein, e.g., nicotinic acid or fibrates. Clinical judgment also may call for deferring drug therapy in this subcategory. bAlmost all people with 0–1 risk factor have a 10-year risk <10%; thus,10-year risk assessment in people with 0–1 risk factor is not necessary.

Patient Assessment Lab - definitions
The ACCURACY of a measurement system is the degree of closeness of measurements of a quantity to its actual (true) value. The PRECISION of a measurement system, also called reproducibility or repeatability, is the degree to which repeated measurements under unchanged conditions show the same results. SENSITIVITY (also called recall rate in some fields) measures the proportion of actual positives which are correctly identified as such (e.g. the percentage of sick people who are correctly identified as having the condition). SPECIFICITY measures the proportion of negatives which are correctly identified (e.g. the percentage of healthy people who are correctly identified as not having the condition). VALIDITY refers to the degree to which evidence and theory support the interpretations of test scores entailed by proposed uses of tests.

Calculation of LDL-c The majority of labs, including the insurance labs, do not directly measure the LDL portion of the lipid profile. On the other hand, total cholesterol, HDL and triglycerides are directly measured with values determined for each of these three tests. LDL is usually not measured directly due to the expense and time required to perform the analysis. Therefore, to estimate LDL, labs use the “FRIEDEWALD FORMULA” which is (in mg/dl): VLDL

Hypertension Persistent elevation of arterial blood pressure (BP)
National Guideline 7th Report of the Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) ~72 million Americans (31%) have BP > 140/90 mmHg Most patients asymptomatic Cardiovascular morbidity & mortality risk directly correlated with BP; antihypertensive drug therapy reduces cardiovascular & mortality risk Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6):1206–1252.

Target-Organ Damage Brain: stroke, transient ischemic attack, dementia
Eyes: retinopathy Heart: left ventricular hypertrophy, angina Kidney: chronic kidney disease Peripheral Vasculature: peripheral arterial disease

Etiology Essential hypertension: Secondary hypertension:
> 90% of cases hereditary component Secondary hypertension: < 10% of cases common causes: chronic kidney disease, renovascular disease other causes: Rx drugs, street drugs, natural products, food, industrial chemicals

Causes of 2˚ Hypertension
Diseases chronic kidney disease Cushing's syndrome coarctation of the aorta obstructive sleep apnea parathyroid disease pheochromocytoma primary aldosteronism renovascular disease thyroid disease

Prescription drugs: prednisone, fludrocortisone, triamcinolone amphetamines/anorexiants: phendimetrazine, phentermine, sibutramine antivascular endothelin growth factor agents estrogens: usually oral contraceptives calcineurin inhibitors: cyclosporine, tacrolimus decongestants: phenylpropanolamine & analogs erythropoiesis stimulating agents: erythropoietin, darbepoietin

Prescription drugs: NSAIDs, COX-2 inhibitors venlafaxine bupropion bromocriptine buspirone carbamazepine clozapine ketamine metoclopramide

Situations: β-blocker or centrally acting α-agonists when abruptly discontinued β-blocker without α-blocker first when treating pheochromocytoma Food substances: sodium ethanol licorice

Street drugs, other natural products: cocaine cocaine withdrawal ephedra alkaloids (e.g., ma-huang) “herbal ecstasy” phenylpropanolamine analogs nicotine withdrawal anabolic steroids narcotic withdrawal methylphenidate phencyclidine ketamine ergot-containing herbal products St. John's wort

Mechanisms of Pathogenesis
Increased cardiac output (CO): increased preload: increased fluid volume excess sodium intake renal sodium retention venous constriction: excess RAAS stimulation sympathetic nervous system overactivity

Mechanisms of Pathogenesis
Increased peripheral resistance (PR): functional vascular constriction: excess RAAS stimulation sympathetic nervous system overactivity genetic alterations of cell membranes endothelial-derived factors structural vascular hypertrophy: hyperinsulinemia due to obesity, metabolic syndrome

Arterial Blood Pressure
Sphygmomanometry: indirect BP measurement MAP = 1/3 (SBP) + 2/3 (DBP) BP = CO x TPR MAP: Mean Arterial Pressure SBP: Systolic Blood Pressure DBP: Diastolic Blood Pressure BP: Blood Pressure CO: Cardiac Output TPR: Total Peripheral Resistance

Arterial Pressure Determinants

Systolic Blood Pressure (mmHg) Diastolic Blood Pressure (mmHg)
Adult Classification Classification Systolic Blood Pressure (mmHg) Diastolic Blood Pressure (mmHg) Normal Less than 120 and Less than 80 Prehypertension or 80-89 Stage 1 hypertension 90-99 Stage 2 hypertension > 160 > 100 Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6):1206–1252.

Heart Failure Progressive clinical syndrome
Results from the heart’s inability to pump sufficient blood to meet the body’s metabolic needs Can occur from any disorder damaging the pericardium, heart valves, myocardium, or ventricle function Outdated term “congestive heart failure” inaccurate because patients may present without congestion

Epidemiology ~5.7 million Americans had HF in 2006
670,000 more cases diagnosed each year Incidence, prevalence, & hospitalization rates of heart failure are increasing Annual hospital discharges > 1 million Direct & indirect costs for 2009 ~$37.2 billion Overall 5-year survival rate ~50% Lloyd-Jones D, Adams R, Carnethon M, et al. Heart disease and stroke statistics—2009 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2009;117:e21–e181.

Epidemiology Factors affecting prognosis: age gender LVEF
renal function blood pressure HF etiology drug or device therapy

Etiology Can result from any disorder that affects the hearts ability to contract &/or relax Classic familiar form: impaired systolic function (i.e. reduced LVEF) Studies suggest up to 50% heart failure patients have preserved LVEF with presumed diastolic dysfunction usually elderly, female, obese, HTN, atrial fibrillation, DM Frequently, patients have coexisting systolic & diastolic dysfunction

HF Causes Coronary artery disease: most common cause
~70% of cases Ischemic heart disease &/or HTN contribute to development of HF Systolic dysfunction (decreased contractility) reduction in muscle mass (e.g. myocardial infarction) dilated cardiomyopathies ventricular hypertrophy pressure overload (e.g. systemic or pulmonary hypertension, aortic or pulmonic valve stenosis) volume overload (e.g. valvular regurgitation, shunts, high out-put states)

HF Causes Diastolic dysfunction
restricted ventricular filling, increased ventricular stiffness ventricular hypertrophy, hypertrophic cardiomyopathy infiltrative myocardial diseases: amyloidosis, sarcoidosis, endomyocardial fibrosis myocardial ischemia & infarction mitral or tricuspid valve stenosis pericardial disease pericarditis, pericardial tamponade

Pathophysiology CO: volume of blood ejected per unit time (L/min)
CO = HR x SV MAP = CO x SVR In normal LV function, increasing SVR has little effect on SV preload: 1˚ mechanism affecting CO As LV dysfunction increases, the negative inverse relationship between SV & SVR becomes more important

Compensatory Mechanisms in HF
The heart’s decrease in pumping capacity results in compensatory responses to maintain CO Responses are intended to be short term after acute reductions in BP or renal perfusion Persistent decline in CO in HF results in long term activation of compensatory responses leading to functional, structural, biochemical, molecular changes

Compensatory Responses in HF
Beneficial Effects of Compensation Detrimental Effects of Compensation Increased preload (through Na+ & water retention) Optimize stroke-volume via Frank-Starling mechanism Pulmonary and systemic congestion and edema formation Increased MVO2 Vasoconstriction Maintain BP in face of reduced CO Shunt blood from nonessential organs to brain and heart Increased afterload decreases stroke volume and further activates the compensatory responses Tachycardia and increased contractility (because of SNS activation) Helps maintain CO Shortened diastolic filling time β1-receptor downregulation, decreased receptor sensitivity Precipitation of ventricular arrhythmias Increased risk of myocardial cell death Ventricular hypertrophy and remodeling Reduces myocardial wall stress Decreases MVO2 Diastolic dysfunction Systolic dysfunction Increased risk of myocardial ischemia Increased arrhythmia risk Fibrosis DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:

Tachycardia & increased contractility primarily results from NE release CO increases until diastolic filling is compromised (HR 170 to 200 bpm) Fluid retention & increased preload decreased CO leads to reduced perfusion of other organs including the kidneys activation of renal-angiotensin-aldosterone system (RAAS) Na+ & H2O retention increase preload to increase CO in chronic HF, increases in preload have smaller effects on SV than in normal hearts

Vasoconstriction & increased afterload helps redistribute blood flow away from nonessential organs to coronary & cerebral blood vessels; increases afterload increased afterload leads to decreased CO Ventricular hypertrophy & remodeling key component of pathology progression remodeling affects the heart at molecular & cellular levels major focus for therapeutic interventions therapies that reverse modeling, decrease mortality, slow disease progression

HF Models Older paradigms cardiorenal model cardiocirculatory model
problem viewed as excess Na+ & H2O diuretics main therapy cardiocirculatory model problem viewed as impaired CO main therapies are positive inotropes, vasodilators

Neurohormonal HF Model
Current paradigm: neurohormonal model initiating event leads to decreased CO becomes progressive systemic disease mediated by neurohormones & autocrine/paracrine factors not a full explanation: drug therapies that target neurohormonal imbalances slow progression but do not stop disease progression

Neurohormones Angiotensin II
increases SVR, heightens SNS activation, promotes Na+ retention maintains perfusion pressure in severe HF impaired renal function ACE inhibitor/ARB initiation cause transient renal impairment stimulates ventricular hypertrophy, remodeling, myocyte apoptosis, oxidative stress, inflammation, extracellular matrix alterations blocking angiotensin II with ACE-inhibitors or ARBs prolongs survival

Neurohormones Norepinephrine effects tachycardia vasoconstriction
increased contractility β1-receptor down regulation increased risk of arrhythmias myocardial cell loss contributes to hypertrophy, remodeling

Neurohormones Norepinephrine
SNS activation through β-agonists & phosphodiesterase inhibitors increases mortality in HF patients β-blockers, ACE inhibitors, digoxin decrease SNS activation beneficial in HF β-blockers & ACE inhibitors decrease mortality digoxin does not decrease mortality but improves symptoms

Neurohormones Aldosterone enhances Na+ retention
produces interstitial cardiac fibrosis: decreases systolic & diastolic function causes other target organ fibrosis, vascular remodeling, proinflammatory state, oxidative stress increases risk of arrhythmias aldosterone antagonists reduce mortality

Neurohormones Natriuretic Peptides Atrial natriuretic peptide (ANP)
B-type natriuretic peptide (BNP) C-type natriuretic peptide (CNP) elevated ANP & BNP in HF natriuresis diuresis vasodilation decreased aldosterone release decreased hypertrophy SNS & RAAS inhibition

Neurohormones Natriuretic Peptides increased BNP
increased mortality, risk of sudden death, symptoms, hospitalization BNP assays (either BNP or N-terminal pro-BNP) help with HF diagnosis controversial whether BNP should be used to guide therapy recombinant human BNP (nesiritide) short-term hemodynamic & symptom improvement in acute HF

Neurohormones Arginine Vasopressin
AVP: pituitary peptide hormone that regulates renal H2O & solute excretion to maintain fluid homeostasis increased AVP in HF causes increased free renal H2O reabsorption volume overload hyponatremia increased arterial vasoconstriction reduced CO stimulates cardiac remodeling

Neurohormones Arginine Vasopressin
tolvaptan blocks the V2 receptor; increases serum Na+ & urine output FDA approved for treatment of clinically significant hypervolemic & euvolemic hyponatremia including patients with HF, cirrhosis, & Syndrome of Inappropriate Antidiuretic Hormone (SIADH) no effect on HR, BP, renal function, other electrolytes AVP antagonists may be useful in volume overloaded patients with hyponatremia

Autocrine/Paracrine Factors
Other circulating mediators proinflammatory cytokines TNF-α, IL-6, IL-1β negative inotropic effects reduced β-receptor-mediated responses increased myocardial cell apoptosis stimulate remodeling anti-TNFα agents no improvement in outcomes during clinical trials

Autocrine/Paracrine Factors
Other circulating mediators endothelin peptides are potent vasoconstrictors endothelin-1 has direct cardiotoxic & antiarrhythmogenic effects, stimulating cardiac myocyte hypertrophy endothelin-receptor antagonists have shown no benefit inflammatory & endothelial dysfunction in HF generated interest in statins for possible pleiotriopic effects on going trials assessing mortality will clarify role of statins in HF treatment

HF Exacerbation Previously compensated patients may develop worsening symptoms that require hospitalization Factors that exacerbate or may precipitate HF negative inotropic effects direct cardiotoxicity increased Na+ &/or H2O retention symptoms of volume overload with hypoperfusion in severe cases

HF Exacerbation Causes Most causes are preventable
noncompliance with medications & dietary recommendations (Na+ & H2O restrictions) cardiac events: MI & ischemia, coronary artery disease, atrial fibrillation non-cardiac events: pulmonary infection, anemia inadequate/inappropriate medications Most causes are preventable

Drugs That Exacerbate HF
Negative inotropic effect antiarrhythmics β-blockers calcium channel blockers verapamil diltiazem itraconazole terbenafine Cardiotoxic doxorubicin daunomycin cyclophosphamide trastuzumab imatinib ethanol amphetamines cocaine methamphetamine

Drugs That Exacerbate HF
Na+ & H2O retention nonsteroidal anti-inflammatory drugs cyclooxygenase-2 inhibitors rosiglitazone, pioglitazone glucocorticoids androgens, estrogens salicylates (high dose) Na+ containing drugs carbenicillin disodium ticarcillin disodium

Vascular injury and thrombosis
Vascular injury and thrombosis. (ADP, adenosine diphosphate; CO, cyclooxygenase; GP Ib, glycoprotein Ib; GP IIb/IIa, glycoprotein IIb/IIa; HK, high-molecular-weight kininogen; PAF, platelet-activating factor; PAI-1, plasminogen activator inhibitor; PF-4, platelet factor-4; PGG/PGH, prostaglandins; PGI, prostacyclin; PLA, phospholipase A; TS, thromboxane synthetase; TXA2, thromboxane A2; t-PA, tissue plasmogen activator; u-PA, urokinase plasmogen activator; vWF, von Willebrand factor.)

Coagulation Cascade Traditionally, the coagulation cascade has been divided into three distinct parts: the intrinsic, the extrinsic, and the common pathways. There are numerous interactions between the three pathways. Under normal circumstances, the endothelial cells that form the intima of vessels maintain blood flow by producing a number of substances that inhibit platelet adherence, prevent the activation of the coagulation cascade, and facilitate fibrinolysis.18,19 Vascular injury can expose the subendothelium (see Fig. 21–3). Platelets readily adhere to the subendothelium, using glycoprotein Ib receptors found on their surfaces and facilitated by von Willebrand factor. This causes platelets to become activated, releasing a number of procoagulant substances into the local circulation that stimulate platelets to expose glycoprotein IIb/IIIa receptors. These receptors allow the platelets to adhere to one another, resulting in platelet aggregation. In addition, the damaged vascular tissue releases tissue factor, also known as tissue thromboplastin, which activates the extrinsic pathway of the coagulation cascade (see Fig. 21–4). The coagulation cascade is a stepwise series of enzymatic reactions that result in the formation of a fibrin mesh.18,19 Clotting factors circulate in the blood in inactive forms. Specific stimuli convert an inactive precursor into an active form that, in turn, converts the next precursor in the sequence. It was once believed that all clotting factors were proteolytic enzymes, known as zymogens. It is now known that factors V and VIII have no enzymatic activity themselves, but rather serve as cofactors that greatly accelerate the enzymatic activity of their respective partners. The final steps in the cascade are the conversion of prothrombin to thrombin and fibrinogen to fibrin. Thrombin plays a key role in the coagulation cascade; it is responsible not only for the production of fibrin, but also for the conversion of factors V and VIII to their active forms, creating a positive feedback loop that greatly accelerates the production of more thrombin. Additionally, thrombin enhances platelet aggregation through its interactions with the glycoprotein IIb/IIIa receptor. Traditionally, the coagulation cascade has been divided into three distinct parts: the intrinsic, extrinsic, and common pathways (see Fig. 21–4).18,19 This artificial division is somewhat misleading, as there are numerous interactions between the three pathways. The extrinsic pathway, sometimes referred to as the tissue factor pathway, appears to be the principal mechanism that triggers the coagulation cascade. Tissue factor, released from the subendothelium, forms a complex with factor VIIa. The factor VIIa–tissue factor complex activates factor X in the common pathway and factor IX in the intrinsic pathway. The intrinsic pathway plays a key role in the propagation of clot formation. The activation and inhibition of factor X in the common pathway is a key step in the regulation of clot formation. With its cofactor, factor Va, factor Xa converts prothrombin (II) to thrombin (IIa), which then cleaves fibrinogen to form fibrin monomers. Finally, as the fibrin monomers reach a critical concentration, they begin to precipitate and polymerize to form fibrin strands. Factor XIIIa covalently bonds these strands to one another.

Ischemic Heart Disease
Caused by epicardial vessel atherosclerosis which leads to coronary heart disease Presentation: acute coronary syndrome chronic stable exertional angina pectoris ischemia without clinical symptoms heart failure, arrhythmias cerebrovascular disease peripheral vascular disease

Epidemiology ~79 million American adults: > 1 type of cardiovascular disease (CVD) ~2,400 Americans die of CVD each day average of 1 death every 33 seconds In 2004, CHD was responsible for 52% of CVD deaths Common initial presentation: women: angina men: myocardial infarction Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics—2007 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007;115:69–171.

Angina Classified by symptom severity, disability, specific activity scale Number of vessels obstructed important determinate of outcome Risk factors for increased mortality: heart failure smoking left main or left main equivalent CAD diabetes prior MI

Grading of Angina Pectoris by the Canadian Cardiovascular Society Classification System
Description of Stage Class I Ordinary physical activity does not cause angina, such as walking, climbing stairs. Angina occurs with strenuous, rapid, or prolonged exertion at work or recreation. Class II Slight limitation or ordinary activity. Angina occurs on walking or climbing stairs rapidly, walking uphill, walking or stair climbing after meals, or in cold, or in wind, or under emotional stress, or only during the few hours after wakening. Walking more than 2 blocks on the level and climbing more than 1 flight of ordinary stairs at a normal pace and in normal condition. Class III Marked limitations of ordinary physical activity. Angina occurs on walking 1 to 2 blocks on the level and climbing 1 flight of stairs in normal conditions and at a normal pace. Class IV Inability to carry on any physical activity without discomfort—anginal symptoms may be present at rest. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:

Etiology/Pathophysiology
Coronary atherosclerotic plaque formation leads to imbalance between O2 supply & demand  myocardial ischemia Ischemia: lack of O2, decreased or no blood flow in myocardium Anoxia: absence of O2 to myocardium

Determinants of myocardial oxygen demand (MVO2) HR contractility intramyocardial wall tension during systole (most important) Determinants of ischemia: resistance in vessels delivering blood to myocardium MVO2

Coronary blood flow inversely related to arteriolar resistance directly related to coronary driving pressure Extent of functional obstruction important limitation of coronary blood flow severe stenosis (> 70%) ischemia & symptoms at rest 121

Changes in O2 balance lead to rapid changes in coronary blood flow Mediators that affect O2 balance: adenosine other nucleotides nitric oxide prostaglandins CO2 H+ 123

Extrinsic factors alterations in intramyocardial wall tension throughout the cardiac cycle phasic systolic vascular bed compression factors that favor reduction in blood flow Intrinsic factors myogenic control Bayliss effect neural components parasympathetic nervous system, sympathetic nervoussystem, coronary reflexes 124

Factors limiting coronary perfusion: coronary reserve diminished at ~85% obstruction critical stenosis occurs when obstructing lesion encroaches on the luminal diameter & exceeds 70% 125

Short-Term Risk of Death or Nonfatal Myocardial Infarction in Patients with Unstable Angina
Feature High Risk (At least 1 of the following features must be present) Intermediate Risk (No high-risk feature but must have 1 of the following) Low Risk (No high- or intermediate-risk feature but may have any of the following) History Accelerating tempo of ischemic symptoms in preceding 48 h Prior Ml, peripheral or cerebrovascular disease, or CABG, prior aspirin use Character of pain Prolonged ongoing (> 20 min), rest pain Prolonged (> 20 min), rest angina, now resolved, with moderate or high likelihood of CAD New-onset CCS class III or IV angina in the past 2 weeks without prolonged (> 20 min) rest pain but with moderate or high likelihood of CAD Clinical findings Pulmonary edema, most likely caused by ischemia New or worsening MR murmur S3 or new/worsening rales Hypotension, bradycardia, tachycardia Age > 75 y ECG Angina at rest with transient ST-segment changes > 0.05 mV Bundle-branch block, new or presumed new T-wave inversions > 0.2 mV Pathologic Q waves Normal or unchanged ECG during an episode of chest discomfort Cardiac markers Markedly elevated (e.g., TnT or TnI > 0.1 ng/mL) Slightly elevated (e.g., TnT > 0.01 but < 0.1 ng/mL) Normal CABG, coronary artery bypass grafting; CAD, coronary artery disease; CCS, Canadian Cardiovascular Society; ECG, electrocardiogram; Ml, myocardial infarction; MR, mitral regurgitation; Tnl, troponin; TnT, troponin T. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:

NORMAL & ABNORMAL CARDIAC CONDUCTION & ELECTROPHYSIOLOGY
mechanical activity of heart (contraction of the atria & ventricles) occurs as a result of its electrical activity. Electrical depolarization of the atria results in atrial contraction, & ventricular depolarization is followed by ventricular contraction.

The Cardiac Conduction System
Under normal circumstances, SA node serves as pacemaker of heart (because of greater automaticity) & generates the electrical impulses → atrial ventricular depolarization if the SA node fails to generate depolarizations at rate faster than that of AV node → AV node may take over as pacemaker. if the SA node & AV node fail to generate depolarizations at a rate > 30-40/min. → ventricular tissue may take over as the pacemaker.

The Ventricular Action Potential
Myocyte resting membrane potential is usually –70- –90 mV, due to the action of the sodium-potassium ATPase pump (maintains high extracellular Na+ concentrations & low extracellular K+ concentrations. During each AP cycle, potential of membrane ↑ to a threshold potential, usually –60- –80 mV → fast Na+ channels open → Na+ rapidly enters the cell. → vertical upstroke of AP → potential reaches mV. = phase 0 (ventricular depolarization) → fast Na+ channels become inactivated → ventricular repolarization begins

The Ventricular Action Potential (cont’d)
phases 1-4 of AP represent ventricular repolarization Phase 1 repolarization: efflux of K+ ions Phase 2 repolarization: K+ continues to exit the cell, but the membrane potential is balanced by an influx of Ca++ & Na+ ions, transported through slow Ca++ & slow Na+ channels → plateau Phase 3: efflux of K+ greatly exceeds Ca++ & Na+ influx → major component of ventricular repolarization Phase 4: Na+ ions are actively pumped out via Na+-K+ ATPase pump→ restoration of membrane potential to its resting value

The ventricular AP

Electrocardiogram (ECG)
P wave = atrial depolarization QRS complex = phase 0 of ventricular AP (ventricular depolarization) T wave = phase 3 repolarization of ventricles Atrial repolarization is not displayed on ECG, because it occurs during ventricular depolarization & is obscured by QRS complex PR interval (N= sec) = time of conduction of impulses from atria to ventricles through AV node QRS duration (N= ) = time required for ventricular depolarization

ECG (cont’d) QT interval (from beginning of Q wave to end of T wave) = time required for ventricular repolarization the faster the heart rate, the shorter the QT interval, & vice versa. → QT interval is corrected for heart rate using Bazett’s equation: QTc is the QT interval corrected for rate, RR is interval from onset of one QRS complex to onset of the next QRS complex normal QTc interval in adults is seconds.

Refractory Periods a period of time during which cells and fibers cannot be depolarized again is referred to as the absolute refractory period - corresponds to phases 1, 2, & ~half of phase 3 repolarization on AP = period from Q wave to ~ first half of T wave on ECG if there is a premature stimulus for electrical impulse, this impulse cannot be conducted, because the tissue is absolutely refractory following absolute refractory period there is relative refractory period =latter half of phase 3 repolarization on AP= latter half of T wave on ECG if new (premature) electrical stimulus is initiated during relative refractory period, it can be conducted abnormally, potentially in arrhythmia

Mechanisms of Cardiac Arrhythmias
Abnormal impulse formation; abnormal impulse conduction; or both

Mechanisms of Arrhythmias (cont’d)
1. Abnormal Impulse Initiation May result from abnormal ↑ automaticity of SA node →↑ rate of generation of impulses & sinus tachycardia. If rate of initiation of spontaneous impulses by other cardiac fibers becomes abnormally automatic & exceeds that of the SA node → other types of tachyarrhythmias: premature atrial contractions, precipitation of atrial tachycardia or atrial fibrillation (AF) Abnormal automaticity in the ventricles → ventricular premature depolarizations (VPDs) or may precipitate ventricular tachycardia (VT) or ventricular fibrillation (VF)

↑ activity of sympathetic nervous system →↑ automaticity of SA node or other automatic cardiac fibers ↑ activity of parasympathetic nervous system →↓ automaticity

2. Abnormal Impulse Conduction: “reentry.” is often result of abnormal automaticity → mechanism is both abnormal impulse formation (automaticity) & abnormal impulse conduction (reentry) 3 conditions must be present: (1) at least 2 pathways down which an electrical impulse may travel (2) a “unidirectional block” in one of the conduction pathways (is sometimes a result of prolonged refractoriness in this pathway) (3) slowing of the velocity of impulse conduction down the other conduction pathway

Reentry (1a) 2 pathways for impulse conduction, with bidirectional block in 1 pathway (shaded area) → non-viable reentrant loop (1b) 2 pathways for impulse conduction; slowing of conduction down 1 pathway, with no change in refractory period down the other pathway → unidirectional block. The retrograde impulse may reenter the area of unidirectional block → tachyarrhythmia (2a) 2 pathways for impulse conduction; lack of unidirectional block → potential reentrant pathway is non-viable (2b) 2 pathways for impulse conduction; refractory period is prolonged down 1 pathway, with no change in conduction down the other pathway → unidirectional block. The retrograde impulse may reenter the area of unidirectional block → tachyarrhythmia Under normal circumstances, when a premature impulse is initiated, it cannot be conducted in either direction down either pathway because the tissue is in its absolute refractory period from the previous beat. A premature impulse may be conducted down both pathways if it is only slightly premature and arrives after the tissue is no longer refractory. However, when refractoriness is prolonged down one of the pathways, a precisely timed premature beat may be conducted down one pathway, but cannot be conducted in either direction in the pathway with prolonged refractoriness because the tissue is still in its absolute refractory period When the velocity of impulse conduction in the other pathway is slowed, the impulse traveling forward down the other pathway still cannot be conducted. However, because the impulse in the other pathway is traveling so slowly, by the time it circles around and travels upward down the other pathway, that pathway is no longer in its absolute refractory period, and now the impulse may travel upward in that pathway. → electrical impulse “reenters” a previously stimulated pathway in the wrong direction → circular movement of electrical impulses → exciting each cell around it → if the impulse is traveling at a rate faster than the intrinsic rate of the SA node → tachycardia

Reasons for prolonged refractoriness &/or slowed impulse conduction velocity in cardiac tissues: myocardial ischemia myocardial infarction, the left atrial or LV hypertrophy HF due to LV dysfunction

Pathophysiology of Cardiovascular Diseases

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