Preload

• Amount of blood loaded into left ventricle

• Also how much stretch is on fibers prior to contraction
• Some books say “length” instead of “stretch”
• More preload = more cardiac output
• More preload = more work the heart must do
• ↑O2 required
Preload
Important Terms

• LVEDV
• Volume of blood in the left ventricle when filled
• LVEDP
• Pressure in the left ventricle when filled
Afterload

• Forces resisting flow out of left ventricle

• Heart must squeeze to increase pressure
• Needs to open aortic valve → push blood into
aorta
• This is harder to do if:
• Blood pressure is high
• Aortic valve is stiff
• Something in the way: HCM, sub-aortic membrane
To INCREASE Afterload

1. Raise mean blood pressure

2. Obstruct outflow of left ventricle
• Aortic stenosis, HCM
To DECREASE Afterload

1. Lower the mean blood pressure

2. Treat aortic valve disease, HCM
• More afterload = more work
• More oxygen required
Contractility

• How hard the heart muscle squeezes

• Ejection fraction = index of contractility
• Major regulator: sympathetic nervous system
• Also increases heart rate
To INCREASE Contractility

• Sympathetic nervous system activity

• Sympathetic innervation to heart
• Circulating catecholamines (epinephrine,
norepinephrine)
• ↑ calcium release from sarcoplasmic reticulum
• Triggers: stress, exercise
• Sympathomimetic drugs
• Dopamine, dobutamine, epinephrine, norepinephrine
• Digoxin
• Inhibits Na-K pump → ↑ calcium in myocytes
To DECREASE Contractility

• Sympathetic system blocking drugs

• Beta blockers
• Calcium channel blockers
• Verapamil, diltiazem
• Less calcium for muscle contraction
• Heart failure
• Disease of myocytes
 ARTERIOSCLEROSIS

• Arteriosclerosis literally means “hardening of the arteries”; it is a generic

term reflecting arterial wall thickening and loss of elasticity. Four distinct
types are recognized, each with different clinical and pathologic causes and
consequences:
• Arteriolosclerosis affects small arteries and arterioles and may cause
downstream ischemic injury. The two variants, hyaline and hyperplastic
arteriolosclerosis, were discussed earlier in relation to hypertension.
• Mönckeberg medial sclerosis is characterized by the presence of calcific
deposits in muscular arteries, usually centered on the internal elastic lamina,
and typically in individuals older than 50 years of age. The lesions do not
encroach on the vessel lumen and usually are not clinically significant.
• Fibromuscular intimal hyperplasia is a non-atherosclerotic process that
occurs in muscular arteries larger than arterioles. This is predominantly an
SMC- and ECM-rich lesion driven by inflammation or by mechanical injury.
Such a healing response can cause substantial stenosis of the vessel; indeed
such intimal hyperplasia underlies in-stent restenosis and is the major long-
term limitation of solid organ transplants.
• Atherosclerosis, from Greek root words for “gruel” and “hardening,” is the
most frequent and clinically important pattern and is the subject of the next
section.
Atherosclerosi
s
Atherosclerosi
s
Vocabulary

• Arteriosclerosis
• Hardening of arteries
• Hyaline
• Hyperplastic
• Atherosclerosis
• Form of arteriosclerosis
• Most common type
Atherosclerosis

• Plaque accumulation in arterial walls

• Chronic inflammatory process
• Involves macrophages, T-cells
• Accumulation of lipoproteins especially LDL
• Underlying cause of many diseases
• Myocardial infarction
• Stroke
• Peripheral vascular disease

A. Rad et al./Wikipedia
 Nephron/Wikipedia

OpenStax College/Wikipedia
Arterial Structure

• Intima
• Single layer of endothelial
cells
• Basement membrane
• Media
• Smooth muscle cells
• Elastin
• Adventicia Bruce Blaus/Wikipedia

• Connective tissue
• Vasa vasorum (blood supply to artery
wall)
• Nerve fibers
Type of Arteries

• Elastic
• Large amounts of elastin in media layer
• Expansion in systole, contraction in diastole
• Aorta, carotid arteries, iliac arteries
• Muscular
• Layers of smooth muscle cells
• Vasoconstriction/vasodilation to modify blood flow
• Arterioles: smallest muscular vessels (most flow
resistance)
Atherosclerosis

• Large elastic arteries

• Aorta, carotid arteries, iliac arteries
• Medium-sized muscular arteries
• Coronary, popliteal

Luke Guthman/Wikipedia
Atherosclerosis
Pathogenesis

• Endothelial injury or dysfunction

• Details incompletely understood
• Believed to be related to risk factors
• Cigarette smoke
• High blood pressure
• High cholesterol
Atherosclerosis
Pathogenesis

• Branch points and vessel origins (ostia)

• Common sites of plaque
• Turbulent flow → endothelial stress
Atherosclerosis
Pathogenesis

• Lipids
• LDL accumulation in intima
• Oxidized by free radicals
• Oxidized LDL scavenged by macrophages
• Cannot be degraded
• Macrophages become foam cells

Public Domain
Atherosclerosis
Pathogenesis

• Chronic inflammation
• LDL oxidized from free radicals
• Damages endothelium, smooth
muscle
• Macrophages release cytokines
Atherosclerosis
Pathogenesis

• Smooth muscle cells proliferate in intima

• Lay down extracellular matrix
• Key growth factor: PDFG
• Platelet-derived growth factor

OpenStax College/Wikipedia
Atheroma Growth

• Fatty streaks
• Macrophages filled with lipids
• Form line (steak) along vessel
lumen
• Do not impair blood flow
• Can be seen in children, adolescents
• Not all progress

Npatchett/Wikipedia
Atheroma Growth

• Atherosclerotic plaques
• Intima thickens
• Lipids accumulate
• Usually patchy along vessel wall
• Rarely involve entire vessel wall
• Usually eccentric

Npatchett/Wikipedia
Npatchett/Wikipedia
BASIC PRINCIPLES
A. Literally, "hard arteries;" due to thickening
of the blood vessel wall
B. Three pathologic patterns-atherosclerosis,
arteriolosclerosis, and Monckeberg
medial calcific sclerosis
Atherosclerosis Complications

• Ischemia
• Plaque rupture
• Exposes thrombogenic substances
• Clot formation
• May cause acute vessel closure (STEMI)
• Thrombus may embolize (stroke from carotid
plaque)
Atherosclerosis Complications

• Hemorrhage into plaque

• Lesions: proliferating small vessels (“neovascularization”)
• Contained rupture may suddenly expand lesion
• Aneurysm
• Lesions may damage underlying media
• Plaque associated with abdominal aortic aneurysms

Public Domain
Dystrophic Calcification

• Commonly seen in atheroma

• Result of chronic inflammation
• Basis for “coronary CT scans”
Infarction

• Area of ischemic necrosis

• Two types: white and red
• White infarcts
• Occlusion of arterial supply to a solid
organ
• Common in heart, kidneys, spleen
• Limited blood seepage from healthy tissue
• Tissue becomes pale (white)
White Infarct
Renal Infarction

Ryan Johnson/Flikr
Red Infarcts
Hemorrhagic Infarct

• Blood enters ischemic tissue

• Blockage of venous drainage
• Testicular torsion
• Tissues with dual circulation
• Blood flow from 2nd supply floods ischemic area
• Classic location: Lung (diffuse blood supply)
• Small intestine
• Flow re-established to necrotic area
• Angioplasty restores flow in coronary artery
Red Infarct
Lung Infarction

Yale Rosen/Wikipedia
Cardiac
Ischemia
Cardiac Ischemia

• Caused by coronary atherosclerosis

• O2 SUPPLY << O2 DEMAND = ISCHEMIA
• Typical symptoms
• Chest pain (angina)
• Dyspnea
• Diaphoresis

Freestocks.org
 Stable Angina
Stable angina, effort-induced angina, classic or typical angina
Classic angina is the most common form of angina and, therefore, is also called
typical angina pectoris.

It is usually characterized by a short-lasting burning, heavy, or squeezing feeling in

the chest. Some ischemic episodes may present “atypically”—with extreme
fatigue, nausea, or diaphoresis—while others may not be associated with any
symptoms (silent angina). Atypical presentations are more common in women,
diabetic patients, and the elderly.

• Stable atherosclerotic plaque

• No plaque ulceration
• No thrombus
• Must occlude ~75% of lumen to cause symptoms

NO SYMPTOMS

SYMPTOMS WITH EXERTION

(EXERTIONAL
ANGINA)
Acute Coronary Syndromes

• Plaque rupture → thrombus

formation
• Subtotal occlusion
• Unstable angina
• Non-ST elevation myocardial infarction
• Total occlusion (100%)
• ST-elevation myocardial infarction (STEMI)

Subtotal Occlusion Total Occlusion

Sudden Death

• Common complication of CAD

• Plaque rupture → arrhythmias
• CAD is most common cause of sudden death adults
• Younger patients: Hypertrophic cardiomyopathy (HCM)
Risk Factors

• Major risk is prior coronary disease

• Coronary risk equivalents
• Diabetes
• Peripheral artery disease
• Chronic kidney disease
Risk Factors

• Hypertension
• Hyperlipidemia
• Family History (1° relative, M<50, F<60)
• Smoking
• Obesity, sedentary lifestyle
Extent of Ischemia

• Transmural ischemia
• Occurs with complete 100% flow obstruction (STEMI)
• Subendocardial ischemia
• Occurs with flow obstruction but some distal blood
flow
• Stable angina, unstable angina, NSTEMI

Subendocardial Ischemia Transmural Ischemia

Subendocardial Ischemia

Subendocardial Ischemia

Subtotal Occlusion

Limited distal flow

Transmural
Ischemia
Transmural Ischemia
Complete Occlusion
NSTEMI and
Unstable Angina
NSTEMI
Non-ST-Elevation Myocardial
Infarction

• Atherosclerotic plaque rupture

• Thrombus formation
• Subtotal (<100%) vessel occlusion
• Ischemic chest pain
Subendocardial Ischemia

Subendocardial Ischemia

Subtotal Occlusion

Limited distal flow

NSTEMI
ECG Changes

• ST depressions
• T-wave inversions
Cardiac Biomarkers

• Biomarkers spill into blood with cardiac injury

• Most common marker used: Troponin I or T
• Increase 2-4 hours after MI
• Stay elevated for weeks
• CK-MB also used
• Increase 4-6 hours after MI
• Normalize within 2-3 days
Cardiac Biomarkers

• Several types of CK
• MM – Skeletal muscle
• MB – Cardiac
• BB – Brain
• Most tissues have some of all three
• Ratio of MB to total CK can be used in ischemia
• Helpful when total CK also up due to muscle damage
Cardiac Biomarkers

• Some AST found in cardiac cells

• Abdominal pain with isolated ↑ AST could be MI

Bodyparts3D/Wikimedia Commons
Treatment of NSTEMI

• Thrombotic and ischemic syndrome (like STEMI)

• Unlike STEMI: No “ticking clock”
• Subtotal occlusion
• Some blood flow to distal myocardium
• No emergency angioplasty
• No benefit to thrombolysis
• Aspirin
• Beta blocker
• Heparin
• Angioplasty (non-emergent)
Typical NSTEMI Course

• Presents to ER with chest pain

• Biomarkers elevated
• Medical Therapy
• Aspirin
• Metoprolol
• Heparin drip
• Admitted to cardiac floor
• Hospital day 2 → angiography
• 90% blockage of LAD → Stent
Unstable Angina

• Atherosclerotic plaque rupture

• Thrombus formation
• Subtotal (<100%) vessel occlusion
• Ischemic chest pain
• Normal biomarkers
Unstable Angina

• Diagnosis largely based on patient history

• Chest pain increasing in frequency/intensity
• Chest pain at rest
• ECG may show ST depressions or T wave inversions
• Treatment is same as for NSTEMI
• Condition often called “UA/NSTEMI”
Stable
Angina
Stable Angina

• Ischemic chest pain with exertion

• Relieved by rest
• Stable pattern over time
• Stable coronary atherosclerotic plaque
• No plaque rupture/thrombus
Stable Angina

• Symptoms generally absent until ~75% occlusion

• Distal arteriolar dilation → normal flow if <75%
Stable Angina

• Diagnosis: cardiac stress test

• Increases demand for O2

Wikipedia/Public Domain
Stable Angina

• NOT a thrombotic problem

• No role for heparin or antithrombotic drugs
• In US usually treated with revascularization
• Most common indication PCI, CABG is stable angina
• Recent clinical trials suggest medical therapy may work just
as well as PCI/CABG in some patients
Stable Angina: Typical Case

• 65-year old man with chest pain while walking

• Relieved with rest
• Presents to ED
• EKG normal
• Biomarkers normal
• Stress test
• Walks on treadmill→ chest pain, EKG changes
• Cardiac catheterization performed
• 90% LAD artery blockage
• Stent placed → angina resolved
 Medical Therapy for Ischemia
Drug Strategies in Stable and Vasospastic
Angina
Drug strategies in stable and vasospastic angina
involve:
• ↓ oxygen requirement by ↓ TPR, CO, or both
(nitrates, CCBs, and beta blockers).

• ↑ oxygen delivery by ↓ vasospasm (nitrates and

CCBs). O2 Demand

O2 Supply
↓O2 Demand
↑O2 Supply ↓ Heart rate
Dilate coronary arteries ↓ Contractility
Increase diastole ↓ Afterload
↓ Preload
Nitrates
• Converted to nitric oxide → vasodilation
• Predominant mechanism is venous dilation
• Bigger veins hold more blood
• Takes blood away from left ventricle
• Lowers preload (LVEDV)
• Also arterial vasodilation (art<< veins)
• Increase coronary perfusion
• Some peripheral vasodilation

Nitroglycerine
Nitrates
• ↓ preload → ↓ cardiac output
• Sympathetic nervous system activation
• Increased heart rate/contractility
• Increases O2 demand
• Opposite of what we want to do for angina
Nitrates

• Rare patients with complex CAD → angina

• In most patients, preload reducing effects dominate
• Nitrates alone often improve angina
• Co-administer beta-blocker or Ca channel blocker
• Blunts “reflex” effect

Clinical Correlate
Drugs that decrease mortality in patients
with stable angina include aspirin,
nitroglycerin, and beta blockers.
Nitroglycerin is the preferred drug for
acute management of both stable
(decreased oxygen consumption) and
vasospastic (direct coronary vasodilation)
angina.
Nitrates
Forms

• Nitroglycerin Tablets/Spray
• Rapid action ~5 minutes
• Take during angina attack, before
exercise
• Isosorbide Dinitrate
• Effects last ~6hrs
• Isosorbide Mononitrate
• Once daily drug
• Topical Nitroglycerin
• Topical cream, patches
Nitrates
Adverse Effects

• Headache (meningeal vasodilation)

• Flushing
• Hypotension
• Angina
• Reflex sympathetic activation

phee/Pixabay/Public Domain
Nitrate Tolerance

• Drug stops working after frequent use

• Avoid continuous us for more than 24 hours
• Does not occur with daily isosorbide mononitrate

Jpeterson101/Wikipedia
Nitrate Withdrawal

• Nitrate withdrawal (rebound) after discontinuation

• Occurs when using large doses of long-acting nitrates
• Angina frequency will increase

Freestocks.org
Monday Disease

• Workers in nitroglycerin manufacturing facilities

• Regular exposure to NTG in the workplace
• Leads to the development of tolerance
• Over the weekend workers lose the tolerance
• "Monday morning headache" phenomenon
• Re-exposed on Monday
• Prominent vasodilation
• Tachycardia, dizziness, and a headache
Beta Blockers

• Slow heart rate and decrease contractility

• Increase preload (LVEDV)
• Slower heart rate = more filling time
• Increase O2 demand
• Blunts some beneficial effect
• Reduced blood pressure (↓ afterload)
• Net effect = less O2 demand
Beta Blockers

• For angina, generally use cardioselective (β1) drugs

• Metoprolol, atenolol
• Some beta blockers are partial agonists
• Pindolol, Acebutolol
• Don’t use in angina
Calcium Channel Blockers

• Three major classes of calcium antagonists

• dihydropyridines (nifedipine)
• phenylalkylamines (verapamil)
• benzothiazepines (diltiazem)
• Vasodilators and negative inotropes
Calcium Channel Blockers

• Nifedipine: vasodilator
• Lower blood pressure
• Reduce afterload
• Dilate coronary arteries
• May cause reflex tachycardia
• Verapamil/diltiazem: negative inotropes
• Similar to beta blockers
• Reduced heart rate/contractility
• Can precipitate acute heart failure if LVEF very
low
Antianginal Therapy
Nitrates/Beta Blockers

Nitrates +
Nitrates Beta blockers Beta blockers
Supply
Coronary vasodilation Increase -- Increase
Duration diastole ↓ reflex Increase --

Demand
Preload Decrease Increase Decrease
Afterload Decrease Decrease Decrease
Contractility ↑ reflex Decrease --/↓
Heart Rate ↑ reflex Decrease --/↓
Antianginal Therapy
Calcium Channel Blockers

Verapamil Diltiazem Nifedipine

Supply
Coronary vasodilation -- -- Increase
Duration diastole Increase Increase ↓ reflex

Demand
Preload Increase Increase --
Afterload Decrease Decrease Decrease
Contractility Decrease Decrease ↑ reflex
Heart Rate Decrease Decrease ↑ reflex
Ranolazine

• Inhibits late sodium current

• Reduces calcium overload → high wall
tension
• Reduces wall tension and O2 demand
Late Na influx

Na Na Ca
Ranolazine

• Constipation, dizziness, headache

• QT prolongation (blockade of K channels)

Ranolazine
• Ischemia causes increased sodium
which prevents calcium exit through
Na+/Ca++ exchanger pump
• Ranolazine blocks late inward Na+
current in cardiac myocytes, thereby
decreasing calcium accumulation
• Results in decreased end diastolic
pressure and improvement of dia- stolic
coronary flow
• Side effects include constipation and Prolong QT
nausea; increased QT makes the drug
contraindicated in patients with long
QT syndrome or taking drugs which
increase QT.
Variant (Prinzmetal) Angina

• Ischemia from vasospasm

• Not caused by atherosclerotic narrowing
• Often artery is “clean” with no stenosis
• May also occur near sites of mild
atherosclerosis
• Spontaneous episodes of angina
• Transient myocardial ischemia
• ST-segment elevation on ECG
Variant (Prinzmetal) Angina

• Episodes usually at rest

• Midnight to early morning
• Sometimes symptoms improve with exertion
• Associated with smoking
Variant (Prinzmetal) Angina
Diagnosis

• Usually based on history

• Intracoronary ergonovine
• Acts on smooth muscle serotonergic (5-HT2)
receptors
• Can be administered during angiography
• Vasospasm visualized on angiogram
• Intracoronary acetylcholine
• Acts on endothelial muscarinic receptors
• Healthy endothelium → vasodilation via nitric oxide
• Endothelial dysfunction → vasoconstriction
• Vasospasm visualized on angiogram
Variant (Prinzmetal) Angina
Treatment

• Quit smoking
• Calcium channel blockers, nitrates
• Vasodilators
• Dilate coronary arteries, oppose spasm
• Avoid propranolol
• Non selective blocker
• Can cause unopposed alpha
stimulation
• Symptoms may worsen

Pixabay/Public Domain
Vasospastic (prinzmetal) angina