Download Pathophysiology Diseases of blood vessels

 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
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.
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 formation
5
The major components of a well-developed intimal atheromatous plaque overlying
an intact media.
6
7
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
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 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
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
 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
26
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
27
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.
28
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
Chylomicron
VLDL
LDL
HDL
<0.94
0.94–1.006
1.006–1.063
1.063–1.210
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
Transport CH
endogenous CH from cells to
to cells
liver
Plasma
appearance
Cream layer
Turbid
Clear
Clear
Electrophoretic
mobility
Origin
Pre-beta
Beta
Alpha
B-100, C-I, C-II,
C-III, E
B-100,
A-I, A-II, A-IV
Density (g/mL)
Composition (%)
Apolipoproteins A-IV, B-48, C-I,
C-II, C-III
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 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
33
Background & Pathophysiology
 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
34
35
Biosynthetic pathway for cholesterol.
The rate-limiting enzyme in this
pathway is 3-hydroxy-3methylglutaryl 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.)
36
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
38
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)
↑cholesterol, ↑TG
IV
VLDL
↑TG, moderate ↑cholesterol
V
VLDL + Chylomicrons
↑↑TG, ↑cholesterol
39
Lipid Phenotype
Plasma Lipids
[mmol/L (mg/dL)]
Lipoprotein
Elevated
Pheno- Clinical Signs
type
Heterozygotes
TC = 7–13 (275–500)
LDL
IIa
Usually develop xanthomas
in adulthood and vascular
disease at 30–50 years
(LDL receptors)
Homozygotes
TC >13 (>500)
LDL
IIa
Usually develop xanthomas
in adulthood and vascular
disease in childhood
Familial defective
Apo B-100
Heterozygotes
TC = 7–13 (275–500)
LDL
IIa
Polygenic
hypercholesterolemia (genetic/lifestyle)
TC = 6.5–9 (250–
350)
LDL
IIa
Usually asymptomatic until
vascular disease develops;
no xanthomas
Isolated hypercholesterolemia
Familial
hypercholesterolemia
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
TG >8.5 (>750)
Chylomicrons,
VLDL
I, V
As above
41
Lipid Phenotype
Plasma Lipid Levels
[mmol/L (mg/dL)]
Lipoprotein
Elevated
Phenotype
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
Dysbetalipoproteinemia
TG = 2.8–8.5 (250–750);
TC = 6.5–13 (250–500)
VLDL, IDL;
LDL normal
III
Usually asymptomatic
until vascular disease
develops; may have
palmar or tuboeruptive
xanthomas
(Apo E)
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
42
Main Lipid
Parameter
Diagnostic
Features
Disorder
Metabolic Defect
Lipid Effect
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
LDL-C: 250–450
mg/dL
Family history of
CHD, tendon
xanthomas
Familial defective
apoB-100
Defective ApoB on
LDL and VLDL
↑LDL-C
LDL-C: 250–450
mg/dL
Family history of
CHD, tendon
xanthomas
Dysbetalipoproteinemia (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
hyperapobetalipoproteinemia
↑ApoB production
↑ApoB
ApoB: >125 mg/dL
None distinctive
Hypoalphalipoproteinemia
↑HDL catabolism
↓HDL-C
HDL-C: <40 mg/dL
None distinctive
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
Tuberoeruptive and
tuberous xanthomata
typical of familial
dysbetalipoproteinemia. A.
Knee B. Palm.
Eruptive skin
xanthomata
characteristic of severe
chylomicronemia.
Tendon xanthomata typical of
heterozygous familial
hypercholesterolemia. Similar
xanthomata occur in patients with
familial defective apolipoprotein B100, 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 CII, 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.
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
Lipoprotein Abnormalities: 2˚ Causes
 Hypertriglyceridemia
 obesity
 DM
 lipodystrophy
 glycogen storage disease
• Medications
• alcohol
• estrogens
• isotretinoin
• β-blockers
• glucocorticoids
 ileal bypass surgery
• bile acid resins
 sepsis
• asparaginase
 Pregnancy
 monocolonal gammopathy:
multiple myeloma, lymphoma
 acute hepatitis
 systemic lupus erythematous
• Thiazides
• interferons
• azole antifungals
• mirtazipine
• anabolic steroids
• sirolimus
54
Lipoprotein Abnormalities: 2˚ Causes
 Hypocholesterolemia
 malnutrition
 malabsorption
 myeloproliferative
diseases
 chronic infectious
diseases


acquired immune
deficiency syndrome
tuberculosis
Low high-density 
lipoprotein
malnutrition 
obesity 
Medications 
non-ISA β-blockers 
anabolic steroids 
isotretinoin 
progestins 
 monoclonal gammopathy
 chronic liver disease
55
55
Metabolic syndrome
Any 3 or more of the following are needed for diagnosis
57
Total cholesterol
<200
200–239
240
LDL cholesterol
<100
100–129
130–159
160–189
190
HDL cholesterol
<40
60 mg/dL
Triglycerides
<150
150–199
200–499
500
Desirable
Borderline high
High
Optimal
Near or above optimal
Borderline high
High
Very high
Low
High
Normal
Borderline high
High
Very high
All values are mg/dL
58
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
59
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
(<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)
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.
60
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.
61
62
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
63
64
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.
65
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
66
67
Etiology
 Essential 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
68
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
69
Causes of 2˚ Hypertension
 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
70
Causes of 2˚ Hypertension
 Prescription drugs:
 NSAIDs, COX-2 inhibitors
 venlafaxine
 bupropion
 bromocriptine
 buspirone
 carbamazepine
 clozapine
 ketamine
 metoclopramide
71
Causes of 2˚ Hypertension
 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
72
Causes of 2˚ Hypertension
Street drugs, other natural products: 
 cocaine
 anabolic steroids
 cocaine withdrawal
 narcotic withdrawal
 ephedra alkaloids
 methylphenidate
(e.g., ma-huang)
 “herbal ecstasy”
 phenylpropanolamine
analogs
 nicotine withdrawal
 phencyclidine
 ketamine
 ergot-containing herbal
products
 St. John's wort
73
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
74
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:





excess RAAS stimulation
sympathetic nervous system overactivity
genetic alterations of cell membranes
endothelial-derived factors
hyperinsulinemia due to obesity, metabolic syndrome
75
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
76
Arterial Pressure Determinants
77
Adult Classification
Classification
Normal
Systolic Blood
Pressure (mmHg)
Diastolic Blood
Pressure (mmHg)
Less than 120
and
Less than 80
Prehypertension
120-139
or
80-89
Stage 1 hypertension
140-159
or
90-99
Stage 2 hypertension
> 160
or
> 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.
78
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
79
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
80
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
81
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
82
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 output states)
83
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
84
85
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
86
87
88
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
89
Compensatory Responses in HF
Compensatory
Response
Beneficial Effects of
Compensation
Detrimental Effects of
Compensation
Increased preload Optimize stroke-volume via Frank(through Na+ &
Starling mechanism
water retention)
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 MVO2
Increased afterload decreases stroke
volume and further activates the
compensatory responses
Tachycardia and
increased
contractility
(because of SNS
activation)
Helps maintain CO
Increased MVO2
Shortened diastolic filling time
β1-receptor downregulation, decreased
receptor sensitivity
Precipitation of ventricular arrhythmias
Increased risk of myocardial cell death
Ventricular
hypertrophy and
remodeling
Helps maintain CO
Reduces myocardial wall stress
Decreases MVO2
Diastolic dysfunction
Systolic dysfunction
Increased risk of myocardial cell death
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:
http://www.accesspharmacy.com
90
91
Compensatory Responses in HF
 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
92
93
94
Compensatory Responses in HF
 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
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
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
98
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
99
Neurohormones
 Norepinephrine effects
 tachycardia
 vasoconstriction
 increased contractility
 β1-receptor down regulation
 increased risk of arrhythmias
 myocardial cell loss

contributes to hypertrophy, remodeling
100
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
101
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
102
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
103
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
104
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
105
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
106
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
107
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
108
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
109
HF Exacerbation
 Causes
 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
110
Drugs That Exacerbate HF
 Negative inotropic effect  Cardiotoxic
 antiarrhythmics
 doxorubicin
 β-blockers
 daunomycin
 calcium channel blockers
 cyclophosphamide
 verapamil
 trastuzumab
 diltiazem
 imatinib
 itraconazole
 ethanol
 terbenafine
 amphetamines


cocaine
methamphetamine
111
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
112
Vascular
injury and
thrombosis
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.
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
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 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.
116
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
117
Grading of Angina Pectoris by the Canadian
Cardiovascular Society Classification System
Class
Class I
Class II
Class III
Class IV
Description of Stage
Ordinary physical activity does not cause angina, such as walking,
climbing stairs. Angina occurs with strenuous, rapid, or prolonged
exertion at work or recreation.
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.
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.
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:
http://www.accesspharmacy.com
118
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
119
Etiology/Pathophysiology
 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
120
Etiology/Pathophysiology
 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
122
Etiology/Pathophysiology
 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
Etiology/Pathophysiology
 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
Etiology/Pathophysiology
 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)
Accelerating tempo of ischemic
symptoms in preceding 48 h
Intermediate Risk (No
high-risk feature but must
have 1 of the following)
History
Prior Ml, peripheral or
cerebrovascular disease, or
CABG, prior aspirin use
Character of pain Prolonged ongoing (> 20 min), Prolonged (> 20 min), rest
rest pain
angina, now resolved, with
moderate or high likelihood
of CAD
Low Risk (No high- or
intermediate-risk feature but
may have any of the following)
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- T-wave inversions > 0.2 mV Normal or unchanged ECG
segment changes > 0.05 mV
Pathologic Q waves
during an episode of chest
Bundle-branch block, new or
discomfort
presumed new
Cardiac markers Markedly elevated (e.g., TnT or Slightly elevated (e.g., TnT > Normal
TnI > 0.1 ng/mL)
0.01 but < 0.1 ng/mL)
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: 126
http://www.accesspharmacy.com
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 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
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= 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 complex
 normal 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 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)
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
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
Mechanisms of Arrhythmias
(cont’d)
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