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.

2

3

Atherosclerosisliterally 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.

4

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 formation5

6

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

7

Etiology and Pathophysiology 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

lipid-ladenmacrophage

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

10

Constitutional risk factors in IHD: - Age - Gender - Genetics

Modifiable risk factors in IHD: - hyperlipidemia - hypertension - cigarette smoking - diabetes mellitus

11

Additional risk factors: - Inflammation - Hyperhomocystinemia - Metabolic syndrome - Lipoprotein (a) levels - Factors affecting hemostasis - Other factors

12

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.

14

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.

15

- 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).

16

17

18

Consequences of AtherosclerosisThe 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

19

20

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.

21

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

22

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)

23

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

24

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.

25

Hyperlipidemia

26

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 synthesisLipids 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

27

28

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.

29

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). 30

31

ChylomicronVLDLLDLHDL

Density (g/mL)

<0.940.94–1.0061.006–1.0631.063–1.210

Composition (%) 

Protein1–26–1018–2245–55

Triglyceride85–9550–654–82–7

Cholesterol3–720–3051–5818–25

Phospholipid3–615–2018–2426–32

Physiologic origin

IntestineIntestine 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 layerTurbidClearClear

Electrophoretic mobility

OriginPre-betaBetaAlpha

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

32

Background & Pathophysiology

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 cellsIncreased 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

33

Background & PathophysiologyLDL also excreted in bile

joins enterohepatic pooleliminated in stool

LDL can be oxidized in subendothelial space of arteriesOxidized LDL in artery walls provokes inflammatory

responseMonocytes recruited & transformed into macrophages

results in cholesterol laden foam cell accumulationFoam cells: beginning of arterial fatty streakIf processes continue: angina, stroke, MI, peripheral

artery disease, arrhythmias, death

34

35

36

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(.

EtiologyThere 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

3838

EtiologyPrimary lipoprotein disorders: 6 categories

used for phenotypical description of dyslipidemia

39

TypeLipoprotein ElevationEffect on lipid profile

IChylomicrons↑↑TG, ↑cholesterol

IIaLDL↑cholesterol

IIbLDL + VLDL↑cholesterol, ↑TG

IIIIDL (LDL1)↑cholesterol, ↑TG

IVVLDL↑TG, moderate ↑cholesterol

VVLDL + Chylomicrons↑↑TG, ↑cholesterol

Fredrickson-Levy-Lees Classification

Lipid PhenotypePlasma Lipids [mmol/L (mg/dL)]

Lipoprotein Elevated 

Pheno-type 

Clinical Signs

Isolated hypercholesterolemia 

Familial hypercholesterol-emia (LDL receptors)

Heterozygotes TC = 7–13 (275–500)

LDLIIaUsually develop xanthomas in adulthood and vascular disease at 30–50 years

Homozygotes TC >13 (>500)

LDLIIaUsually develop xanthomas in adulthood and vascular disease in childhood

Familial defective Apo B-100

Heterozygotes TC = 7–13 (275–500)

LDLIIa 

Polygenic hypercholesterol-emia (genetic/lifestyle)

TC = 6.5–9 (250–350)

LDLIIaUsually asymptomatic until vascular disease develops; no xanthomas

Isolated hypertriglyceridemia 

Familial hypertriglyceridemia

TG = 2.8–8.5 (250–750)

VLDLIVAsymptomatic; may be associated with increased risk of vascular disease

Familial LPL deficiency

TG >8.5 (>750)Chylomicrons, VLDL

I, VMay be asymptomatic; may be associated with pancreatitis, abdominal pain, hepatosplenomegaly

Familial Apo C-II deficiency

TG >8.5 (>750)Chylomicrons, VLDL

I, VAs above

41

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, LDLIIbUsually asymptomatic until vascular disease develops; familial form may present as isolated high TG or isolated high LDL cholesterol

Dysbetalipo-proteinemia

(Apo E)

TG = 2.8–8.5 (250–750); TC = 6.5–13 (250–500)

VLDL, IDL; LDL normal

IIIUsually asymptomatic until vascular disease develops; may have palmar or tuboeruptive xanthomas

42

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

DisorderMetabolic DefectLipid Effect

Main Lipid Parameter

Diagnostic Features

Polygenic hypercholesterolemia

↓LDL clearance↑LDL-CLDL-C: 130–250 mg/dLTG: 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-CLDL-C: 250–450 mg/dL

Family history of CHD, tendon xanthomas

Familial defective apoB-100

Defective ApoB on LDL and VLDL

↑LDL-CLDL-C: 250–450 mg/dL

Family history of CHD, tendon xanthomas

Dysbetalipoprotein-emia (type III hyperlipidemia)

ApoE2:E2 phenotype, ↓VLDL remnant clearance

↑Remnant VLDL, ↑IDL

LDL-C: 300–600 mg/dLTGs: 400–800 mg/dL

Palmar xanthomas, tuberoeruptive xanthomas

Familial combined hyperlipidemia

↑ApoB and VLDL production

↑CH, TG, or bothLDL-C: 250–350 mg/dLTGs: 200–800 mg/dL

Family history, CHDFamily history, Hyperlipidemia

Familial hyperapobetalipo-proteinemia

↑ApoB production

↑ApoBApoB: >125 mg/dL

None distinctive

Hypoalphalipoprotein-emia

↑HDL catabolism

↓HDL-CHDL-C: <40 mg/dL

None distinctive

XanthomasXanthomas 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 .

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

a. selective elevation in the plasma level of LDL, b. deposition of LDL-derived cholesterol in tendons (xanthomas) and

arteries (atheromas), c. 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 hyperlipidemiacharacterized 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.

Lipoprotein Abnormalities: 2˚ Causes Hypercholesterolemia

hypothyroidismobstructive liver diseasenephrotic syndromeanorexia nervosaacute intermittent porphyria

Medicationsprogestinsthiazide diureticsglucocorticoidsβ-blockersisotretinoinprotease

inhibitorscyclosporinemirtazipinesirolimus

Lipoprotein Abnormalities: 2˚ Causes Hypertriglyceridemia

obesityDMlipodystrophyglycogen storage diseaseileal bypass surgerysepsisPregnancymonocolonal gammopathy:

multiple myeloma, lymphoma

acute hepatitissystemic lupus erythematous

• Medications• alcohol• estrogens• isotretinoin• β-blockers• glucocorticoids• bile acid resins• Thiazides• asparaginase• interferons• azole antifungals• mirtazipine• anabolic steroids• sirolimus

54

Hypocholesterolemiamalnutritionmalabsorptionmyeloproliferative

diseaseschronic infectious

diseases acquired immune

deficiency syndrome tuberculosis

monoclonal gammopathy

chronic liver disease

5555

Lipoprotein Abnormalities: 2˚ Causes Low high-density

lipoproteinmalnutrition

obesityMedications

non-ISA β-blockersanabolic steroids

isotretinoin progestins

Metabolic syndrome

57

Any 3 or more of the following are needed for diagnosis

Total cholesterol 

<200Desirable

200–239Borderline high

240High

LDL cholesterol 

<100Optimal

100–129Near or above optimal

130–159Borderline high

160–189High

190Very high

HDL cholesterol 

<40Low

60 mg/dLHigh

Triglycerides 

<150Normal

150–199Borderline high

200–499High

500Very high All values are mg/dL58

Major risk factorsa – exclusive of LDL-C – that modify the LDL goals

AgeMen: > 45 yearsWomen: > 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 smokingWithin the past month

Hypertension (140/90 mm Hg or taking antihypertensive medication)

Low HDL cholesterol (<40 mg/dL)b

59

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 & CutpointsRisk CategoryLDL 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(<100 mg/dL;

consider drug options)a

Moderately high risk: 2+ risk factors (10-year risk >10%–20%)

<130(optional

goal <100)

>130>130(100–129: consider

drug options)

Moderate risk: 2+ risk factors (10-year risk <10%)

<130>130>160

Lower risk: 0–1 risk factorb

 

<160>160>190(160–189: LDL-

lowering drug optional)

60

Risk is estimated from Framingham risk scoreaSome 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.

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Calculation of LDL-cThe 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

63

64

HypertensionPersistent 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

65Chobanian 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 DamageBrain: stroke, transient ischemic attack,

dementiaEyes: retinopathy Heart: left ventricular hypertrophy, anginaKidney: chronic kidney disease Peripheral Vasculature: peripheral arterial

disease

66

67

EtiologyEssential hypertension:

> 90% of caseshereditary component

Secondary hypertension:< 10% of casescommon causes: chronic kidney disease,

renovascular diseaseother causes: Rx drugs, street drugs, natural

products, food, industrial chemicals

68

Causes of 2˚ HypertensionDiseases

chronic kidney diseaseCushing's syndromecoarctation of the aortaobstructive sleep apneaparathyroid diseasepheochromocytomaprimary aldosteronismrenovascular diseasethyroid disease

69

Causes of 2˚ HypertensionPrescription drugs:  

prednisone, fludrocortisone, triamcinoloneamphetamines/anorexiants: phendimetrazine,

phentermine, sibutramineantivascular endothelin growth factor agentsestrogens: usually oral contraceptivescalcineurin inhibitors: cyclosporine, tacrolimusdecongestants: phenylpropanolamine & analogserythropoiesis stimulating agents: erythropoietin,

darbepoietin

70

Causes of 2˚ HypertensionPrescription drugs:

NSAIDs, COX-2 inhibitorsvenlafaxine bupropionbromocriptinebuspironecarbamazepineclozapineketaminemetoclopramide

71

Causes of 2˚ HypertensionSituations:

β-blocker or centrally acting α-agonists when abruptly discontinued

β-blocker without α-blocker first when treating pheochromocytoma

Food substances:  sodiumethanol licorice

72

cocainecocaine withdrawalephedra alkaloids

(e.g., ma-huang)“herbal ecstasy” phenylpropanolamin

e analogsnicotine withdrawal

anabolic steroidsnarcotic withdrawalmethylphenidatephencyclidineketamineergot-containing

herbal productsSt. John's wort

73

Street drugs, other natural products  :

Causes of 2˚ Hypertension

Mechanisms of PathogenesisIncreased cardiac output (CO):

increased preload: increased fluid volume excess sodium intake renal sodium retention

venous constriction: excess RAAS stimulation sympathetic nervous system overactivity

74

Mechanisms of PathogenesisIncreased peripheral resistance (PR):

functional vascular constriction: excess RAAS stimulation sympathetic nervous system overactivity genetic alterations of cell membranes endothelial-derived factors

structural vascular hypertrophy: excess RAAS stimulation sympathetic nervous system overactivity genetic alterations of cell membranes endothelial-derived factors hyperinsulinemia due to obesity, metabolic syndrome

75

Arterial Blood PressureSphygmomanometry: 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

76

Arterial Pressure Determinants

77

Adult Classification Classification

Systolic Blood Pressure (mmHg)

Diastolic Blood Pressure (mmHg)

NormalLess than 120andLess than 80

Prehypertension120-139or80-89

Stage 1 hypertension

140-159or90-99

Stage 2 hypertension

> 160or> 100

78Chobanian 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 FailureProgressive 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

79

Epidemiology ~5.7 million Americans had HF in 2006670,000 more cases diagnosed each year Incidence, prevalence, & hospitalization rates

of heart failure are increasingAnnual hospital discharges > 1 millionDirect & indirect costs for 2009 ~$37.2 billionOverall 5-year survival rate ~50%

80Lloyd-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 .

EpidemiologyFactors affecting prognosis:

agegenderLVEFrenal functionblood pressureHF etiologydrug or device therapy

81

Etiology Can result from any disorder that affects the

hearts ability to contract &/or relaxClassic familiar form: impaired systolic function

(i.e. reduced LVEF)Studies suggest up to 50% heart failure patients

have preserved LVEF with presumed diastolic dysfunctionusually elderly, female, obese, HTN, atrial

fibrillation, DMFrequently, patients have coexisting systolic &

diastolic dysfunction82

HF Causes Coronary artery disease: most common cause

~70% of casesIschemic heart disease &/or HTN contribute

to development of HFSystolic dysfunction (decreased contractility)

reduction in muscle mass (e.g. myocardial infarction)

dilated cardiomyopathiesventricular 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) 83

HF CausesDiastolic 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 stenosispericardial disease

pericarditis, pericardial tamponade

84

85

PathophysiologyCO: volume of blood ejected per unit time

(L/min)CO = HR x SVMAP = CO x SVRIn normal LV function, increasing SVR has

little effect on SVpreload: 1˚ mechanism affecting CO

As LV dysfunction increases, the negative inverse relationship between SV & SVR becomes more important

86

87

88

Compensatory Mechanisms in HFThe 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

89

Compensatory Responses in HF

90

Compensatory Response

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 COShunt blood from nonessential organs to brain and heart

Increased MVO2

Increased afterload decreases stroke volume and further activates the compensatory responses

Tachycardia and increased contractility (because of SNS activation)

Helps maintain COIncreased MVO2

Shortened diastolic filling timeβ1-receptor downregulation, decreased receptor sensitivityPrecipitation of ventricular arrhythmiasIncreased risk of myocardial cell death

Ventricular hypertrophy and remodeling

Helps maintain COReduces myocardial wall stressDecreases MVO2

Diastolic dysfunctionSystolic dysfunctionIncreased risk of myocardial cell deathIncreased risk of myocardial ischemiaIncreased arrhythmia riskFibrosis

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com

91

Compensatory Responses in HFTachycardia & 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 92

93

94

Compensatory Responses in HFVasoconstriction & increased afterload

helps redistribute blood flow away from nonessential organs to coronary & cerebral blood vessels; increases afterload

increased afterload leads to decreased COVentricular hypertrophy & remodeling

key component of pathology progressionremodeling affects the heart at molecular &

cellular levelsmajor focus for therapeutic interventions

therapies that reverse modeling, decrease mortality, slow disease progression

95

96

HF Models Older paradigms

cardiorenal model problem viewed as excess Na+ & H2O diuretics main therapy

cardiocirculatory model problem viewed as impaired CO main therapies are positive inotropes, vasodilators

97

Current paradigm: neurohormonal model initiating event leads to decreased CObecomes 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

98

Neurohormonal HF Model

NeurohormonesAngiotensin 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

99

NeurohormonesNorepinephrine effects

tachycardiavasoconstrictionincreased contractilityβ1-receptor down regulationincreased risk of arrhythmiasmyocardial cell loss

contributes to hypertrophy, remodeling

100

NorepinephrineSNS 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

101

Neurohormones

NeurohormonesAldosterone

enhances Na+ retentionproduces interstitial cardiac fibrosis: decreases

systolic & diastolic functioncauses other target organ fibrosis, vascular

remodeling, proinflammatory state, oxidative stress

increases risk of arrhythmiasaldosterone antagonists reduce mortality

102

NeurohormonesNatriuretic 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

103

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

therapyrecombinant human BNP (nesiritide)

short-term hemodynamic & symptom improvement in acute HF

104

Neurohormones

NeurohormonesArginine 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

105

NeurohormonesArginine 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

106

Autocrine/Paracrine FactorsOther 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

107

Autocrine/Paracrine FactorsOther 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 treatment108

HF ExacerbationPreviously compensated patients may

develop worsening symptoms that require hospitalization

Factors that exacerbate or may precipitate HF negative inotropic effectsdirect cardiotoxicityincreased Na+ &/or H2O retentionsymptoms of volume overload with

hypoperfusion in severe cases

109

HF ExacerbationCauses

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 medicationsMost causes are preventable

110

Drugs That Exacerbate HFNegative inotropic

effectantiarrhythmics β-blockerscalcium channel

blockers verapamil diltiazem

itraconazoleterbenafine

Cardiotoxicdoxorubicindaunomycincyclophosphamidetrastuzumabimatinibethanolamphetamines

cocaine methamphetamine

111

Na+ & H2O retentionnonsteroidal anti-inflammatory drugscyclooxygenase-2 inhibitorsrosiglitazone, pioglitazoneglucocorticoidsandrogens, estrogenssalicylates (high dose)Na+ containing drugs

carbenicillin disodium ticarcillin disodium

112

Drugs That Exacerbate HF

Vascular injury and thrombosis

Coagulation CascadeTraditionally, 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.

Ischemic Heart DiseaseCaused by epicardial vessel atherosclerosis

which leads to coronary heart diseasePresentation:

acute coronary syndromechronic stable exertional angina pectorisischemia without clinical symptomsheart failure, arrhythmiascerebrovascular diseaseperipheral vascular disease

115

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 deathsCommon initial presentation:

women: anginamen: myocardial infarction

116Rosamond 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 .

AnginaClassified by symptom severity, disability,

specific activity scaleNumber of vessels obstructed important

determinate of outcomeRisk factors for increased mortality:

heart failuresmokingleft main or left main equivalent CADdiabetesprior MI

117

Grading of Angina Pectoris by the Canadian Cardiovascular Society Classification System

ClassDescription of StageClass IOrdinary physical activity does not cause angina, such as walking,

climbing stairs. Angina occurs with strenuous, rapid, or prolonged exertion at work or recreation.

Class IISlight 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 IIIMarked 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 IVInability to carry on any physical activity without discomfort—anginal symptoms may be present at rest.

118DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com

Etiology/PathophysiologyCoronary 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

119

Etiology/PathophysiologyDeterminants of myocardial oxygen demand

(MVO2)HRcontractilityintramyocardial wall tension during systole

(most important)Determinants of ischemia:

resistance in vessels delivering blood to myocardium

MVO2

120

Etiology/PathophysiologyCoronary blood flow

inversely related to arteriolar resistancedirectly related to coronary driving pressure

Extent of functional obstruction important limitation of coronary blood flowsevere stenosis (> 70%)

ischemia & symptoms at rest

121

122

Etiology/PathophysiologyChanges in O2 balance lead to rapid changes

in coronary blood flowMediators that affect O2 balance:

adenosineother nucleotidesnitric oxideprostaglandinsCO2

H+

123

Etiology/PathophysiologyExtrinsic factors

alterations in intramyocardial wall tension throughout the cardiac cycle

phasic systolic vascular bed compressionfactors that favor reduction in blood flow

Intrinsic factorsmyogenic control

Bayliss effectneural components

parasympathetic nervous system, sympathetic nervoussystem, coronary reflexes

124

Etiology/PathophysiologyFactors limiting coronary perfusion:

coronary reserve diminished at ~85% obstruction

critical stenosis occurs when obstructing lesion encroaches on the luminal diameter & exceeds 70%

125

FeatureHigh 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)

HistoryAccelerating 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 ischemiaNew or worsening MR murmurS3 or new/worsening ralesHypotension, bradycardia, tachycardiaAge > 75 y

     

     

ECGAngina at rest with transient ST-segment changes > 0.05 mVBundle-branch block, new or presumed new

T-wave inversions > 0.2 mVPathologic 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 126

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: http://www.accesspharmacy.com

Short-Term Risk of Death or Nonfatal Myocardial Infarction in Patients with Unstable Angina

NORMAL & ABNORMAL CARDIACCONDUCTION & 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 SystemUnder 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 20-30 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

Electrocardiogram (ECG)

P wave = atrial depolarization QRS complex = phase 0 of ventricular AP

(ventricular depolarization) T wave = phase 3 repolarization of ventriclesAtrial repolarization is not displayed on ECG,

because it occurs during ventricular depolarization & is obscured by QRS complex

PR interval (N= 0.12-0.2 sec) = time of conduction of impulses from atria to ventricles through AV node

QRS duration (N= 0.08-0.12) = 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 complexnormal QTc interval in adults is 0.36-0.44 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

(1)Abnormal impulse formation; (2)abnormal impulse conduction; or (3) both

Mechanisms of Arrhythmias (cont’d)

1. Abnormal Impulse InitiationMay 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)

Mechanisms of Arrhythmias (cont’d)

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

↑ activity of parasympathetic nervous system →↓ automaticity

Mechanisms of Arrhythmias (cont’d)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

Mechanisms of Arrhythmias (cont’d)Reasons for prolonged refractoriness &/or

slowed impulse conduction velocity in cardiac tissues:myocardial ischemia myocardial infarction, theleft atrial or LV hypertrophy HF due to LV dysfunction