Antianginal Drugs & newer
targets for myocardial infarction
PC-630

Anatomy of heart
Ischemic heart diseases:
(i) Angina
(ii) Myocardial infarction

Angina Pectoris
• Angina pectoris is the principle symptom of
ischemic heart disease
• The condition is characterized by sudden, severe
substernal pain or pressure
• The primary cause of angina is an imbalance
between myocardial oxygen demand and oxygen
supplied by coronary vessels
– This imbalance may be due to:
» a decrease in myocardial oxygen delivery
» an increase in myocardial oxygen demand
» or both

Types of angina
q (1)Stable angina
q (2)Unstable angina
q (3)Variant angina
The pathologic physiological mechanism of
angina: an imbalance between the myocardial
oxygen supply and demand

Pathophysiology

Pathophysiology: Molecular level

Factors Affecting
Myocardial Oxygen Delivery
• Coronary artery blood flow is the primary
determinant of oxygen delivery to the myocardium
– Myocardial oxygen extraction from the blood is nearly
complete, even at rest
• Coronary blood flow is essentially negligible during
systole and is therefore determined by:
– Perfusion pressure during diastole (aortic diastolic
pressure)
– Duration of diastole
– Coronary vascular resistance
» Coronary vascular resistance is determined by numerous
factors including:
• Atherscelorosis
• Intracoronary thrombi
• Metabolic products that vasodilate coronary
arterioles
• Autonomic activity
• Extravascular compression

Factors Affecting
Myocardial Oxygen Demand
• The major determinants of myocardial oxygen
consumption include:
– Ventricular wall stress
» Both preload (end-diastolic pressure) and afterload
(end-systolic pressure) affect ventricular wall stress
– Heart rate
– Inotropic state (contractility)
– Myocardial metabolism (glucose vs fatty acids)
• A commonly used non-invasive index of myocardial
oxygen demand is the “double product”:
– [Heart rate] X [Systolic blood pressure]
– Also known as the rate-pressure product

Stable angina occurs when
myocardial ischaemia is
caused by fixed
atherosclerotic narrowing of
one or more epicardial
coronary arteries. In some
circumstances, the angina is
associated with a coronary
spasm and metabolic
dysfunction.
Vasospastic angina occurs
when myocardial ischaemia
is caused by a coronary
artery spasm with or without
endothelial dysfunction.
Microvascular angina refers
to the absence of an
obstructed epicardial
coronary artery. Myocardial
ischaemia in this case can be
caused by microvascular
and/or endothelial
dysfunction and
inflammation.

Stable Angina
• Stable angina is also known as:
– Exertional angina
– Typical or classic angina
– Angina of effort
– Atherosclerotic angina
• The underlying pathology is usually atherosclerosis
(reduced oxygen delivery) giving rise to ischemia
under conditions where the work load on the heart
increases (increased oxygen demand)
• Anginal episodes can be precipitated by exercise,
cold, stress, emotion, or eating
• Therapeutic goals: Increase myocardial blood flow
by dilating coronary arteries and arterioles
(increase oxygen delivery), decrease cardiac load
(preload and afterload; decrease oxygen demand),
decrease heart rate (decrease oxygen demand),
[alter myocardial metabolism?]

Unstable Angina
• Unstable angina is also known as:
– Preinfarction angina
– Crescendo angina
– Angina at rest
• Associated with a change in the character, frequency,
and duration of angina in patients with stable angina,
and episodes of angina at rest
• Caused by recurrent episodes of small platelet clots
at the site of a ruptured atherosclerotic plaque which
can also precipitate local vasospasm
• May be associated with myocardial infarction
• Therapeutic rationale: Inhibit platelet aggregation
and thrombus formation (increase oxygen delivery),
decrease cardiac load (decrease oxygen demand), and
vasodilate coronary arteries (increase oxygen delivery)

Vasospastic Angina
• Vasospastic angina is also referred to as:
– Variant angina
– Prinzmetal's angina
• Caused by transient vasospasm of the coronary
vessels
• Usually associated with underlying atheromas
• Chest pain may develop at rest
• Therapeutic rationale: Decrease vasospasm of
coronary vessels (calcium channel blockers are
efficacious in >70% of patients; increase oxygen
delivery)

History of Antianginal Drugs
• Amyl nitrate and nitroglycerin were found to provide
transient relief of angina in the mid-to late 1800s
• Subsequently many other vasodilators were
introduced for the treatment of angina, but double-
blinded clinical trials showed many were no better
than placebo
– Some of the classic studies of the placebo effect
were carried out in patients with angina
• Beta-adrenergic blockers and calcium channel
blockers were developed during the early 1960’s and
are now also widely used in the prophylactic therapy
of angina
• pFox inhibitors, the first new drugs for angina in
more than 20 years, are approved by the FDA
recently

The mechanism of antianginal drugs
v(1)Decease myocardial oxygen consumption
v(2) Increase myocardial blood and oxygen
supply
v(3) antiplatelet, antithrombosis

Management with stable coronary
artery disease

Management of coronary artery disease

Management of coronary artery disease

Management of coronary artery disease

The schematic shows useful combinations (green lines), combinations that are not
recommended (red lines), possible combinations (blue solid lines), and drugs with similar
actions (blue dashed lines).

Pharmacology of Antianginal Agents
Three major classes of agents are used individually or in
combination to treat angina:
• Organic nitrates
– Vasodilate coronary arteries
– Reduce preload and aferload
• Calcium channel blockers
– Vasodilate coronary arteries
– Reduce afterload
– The non-dihydropyridines (verapamil and diltiazem) also
decrease heart rate and contractility
• Beta-adrenergic blockers
– Decrease heart rate and contractility
– Decrease afterload 2° to a decrease in cardiac output
– Improve myocardial perfusion 2° to a decrease in heart rate
• *All of these may also reduce platelet aggregation
• A new class of drugs, pFox inhibitors, are in the final stages of
approval for chronic angina
– Reduce myocardial oxygen consumption by shifting
metabolism from fatty acid to glucose metabolism
– No hemodynamic effects

Organic Nitrates / Nitrovasodilators
• All of these agents are enzymatically converted to
nitric oxide (NO) in the target tissues
– NO is a very short-lived endogenous mediator of
smooth muscle contraction and neurotransmission
• Veins and larger arteries appear to have greater
enzymatic capacity than resistance vessels, resulting
in greater effects in these vessels
• NO activates a cytosolic form of guanylate cyclase
in smooth muscle
– Activated guanylate cyclase catalyzes the
formation of cGMP which activates cGMP-
dependent protein kinase
– Activation of this kinase results in
phosphorylation of several proteins that reduce
intracellular calcium and hyperpolarize the
plasma membrane causing relaxation

Mechanism of Action of Nitrovasodilators
Nitric Oxide
activates
converts
Guanylate Cyclase*
GTP
cGMP
activates
cGMP-dependent protein kinase
Activation of PKG results in phosphorylation
of several proteins that reduce intracellular calcium
causing smooth muscle relaxation
Nitrates become denitrated by glutathione S-transferase
to release

MLCK
MLCK-P
cGMP
MLCK-P
NO-induced vasorelaxation

Pharmacological action
v(1) decrease myocardiac oxygen consumption
Dilate venous decrease blood returning to
heart decrease ventricular end-diastolic volume
and pressure
(large dose) dilate arterial decrease
peripheral resistance decrease afterload
v(2) increase blood supply to ischemia area
v(3) redistribution of coronary blood flow
v(4) Inhibition of platelet aggregation, increase the
release of PGI2

Clinical uses
v(1) all types of angina
v(2) acute myocardia infarction
v(3) CHF
§ isosorbide dinitrate used in prophylaxis attack and
CHF after myocardia infarction

Effects of Nitrovasodilators
• Peripheral vasodilation:
– Dilation of veins predominates over that of arterioles
• Increased coronary blood flow:
– Large epicardial coronary arteries are dilated without
impairing autoregulation in small coronary vessels
– Collateral flow may be increased
– Decreased preload improves subendocardial perfusion
– Dilation of coronary arteries can paradoxically result in
aggravation of angina - a phenomenon known as
“coronary steal”
• Inhibition of platelet function:
– May contribute to their effectiveness in the treatment
of unstable angina

• Hepatic first-pass metabolism is high and oral
bioavailability is low for nitroglycerin (GTN) and
isosorbide dinitrate (ISDN)
– Sublingual or transdermal administration of these
agents avoids the first-pass effect
• Isosorbide mononitrate (ISMN) is not subject to first-
pass metabolism and is 100% available after oral
administration
• Hepatic blood flow and disease can affect the
pharmacokinetics of GTN and ISDN
GTN ISDN ISMN
Half-life (min) 3 10 280
Plasma clearance (L/min) 50 4 0.1
Apparent volume of distribution (L/kg) 3 4 0.6
Oral bioavailability (%) < 1 20 100
Property
Pharmacokinetic Properties of
Organic Nitrates

Routes of Administration
• Amyl nitrate is a gas at room temperatures and can
be administered by inhalation
– Rapid onset, short duration (3-5 min)
• GTN and ISDN have a rapid onset of action (1-3 min)
when administered sublingually, but the short
duration of action (20-30 min) is not suitable for
maintenance therapy
• IV nitrogylcerin can be used to treat severe
recurrent unstable angina
• Slowly absorbed preparations of nitrovasodilators
(oral, buccal, transdermal) can be used to provide
prolonged prophylaxis against angina (3-10 hrs), but
can lead to tolerance (tachyphylaxis)

Tolerance and Dependence with
Nitrovasodilators
• Continuous or frequent exposure to nitrovasodilators can
lead to the development of complete tolerance
– Transdermal GTN may provide therapeutic levels of drug for 24
hours or more, but efficacy only lasts 8-10 hrs
– Nitrate-free periods of at least 8 hrs (e.g.- overnight) are
recommended to avoid or reduce tachyphylaxis
• The mechanism of tolerance is not completely understood
but appears to relate to the enzymes involved in
converting the nitrates to NO, or to the enzyme that
produces cGMP
• Industrial (occupational) exposure to organic nitrates has
been associated with “Monday disease” and physical
dependence manifest by variant angina occurring 1-2 days
after withdrawal
– Has resulted in myocardial infarction in some patients

Adverse Effects of Nitrovasodilators
• The major acute adverse effects of
nitrovasodilators are due to excessive vasodilation
– Orthostatic hypotension
– Tachycardia
– Severe throbbing headache
– Dizziness
– Flushing
– Syncope
• Organic nitrates are contraindicated in patients
with elevated intracranial pressure
• Sildenafil (Viagra) and other PDE-5 inhibitors can
potentiate the actions of nitrovasodilators
because they inhibit the breakdown of cGMP
(they should not be taken within 6 hours of
taking a nitrovasodilator)

Chemistry of Ca++ Channel Blockers
• Five major classes of Ca++ channel blockers are
known with diverse chemical structures:
– Benzothiazepines: Diltiazem
– Dihydropyridines: Nicardipine, nifedipine,
nimodipine, amlodipine, and many others
» There are also dihydropyridine Ca++-channel
activators (Bay K 8644, S 202 791)
– Phenylalkylamines: Verapamil
– Diarylaminopropylamine ethers: Bepridil
– Benzimidazole-substituted tetralines:
Mibefradil

Calcium antagonists
Mechanism of antiangina
• (1) dilate coronary arterial
• (2) reduction in peripheral vascular resistance
• (3) negative chronotropic and inotropic, decrease
myocardiac oxygen consumpation
• (4) protect cardiac myocytes
• (5) antiatherosclrosis

Clinical used
Variant angina, Stable angina, Unstable angina

Effects on Vascular Smooth Muscle
• Ca++ channel blockers inhibit L-type and/or T-type
voltage-dependent Ca++ channels
• Little or no effect on receptor-operated channels or
on release of Ca++ from SR
• “Vascular selectivity” is seen with the Ca++ channel
blockers
– Decreased intracellular Ca++ in arterial smooth muscle
results in relaxation (vasodilatation) -> decreased cardiac
afterload (aortic pressure)
– Little or no effect of Ca++-channel blockers on venous beds
-> no effect on cardiac preload (ventricular filling pressure)
– Specific dihydropyridines may exhibit greater potencies in
some vascular beds (e.g.- nimodipine more selective for
cerebral blood vessels, nicardipine for coronary vessels)
– Little or no effect on nonvascular smooth muscle

Effects on Cardiac Cells
• Magnitude and pattern of cardiac effects depends
on the class of Ca++channel blocker
• Negative inotropic effect (myocardial L-type
channels)
– Reduced inward movement of Ca++ during action
potential plateau phase
– Dihydropyridines have very modest negative inotropic
effect
– Mibefradil (T-type) has no negative inotropic effect
• Negative chronotropic/dromotropic effects (L-
and T-type channels)
– Verapamil, diltiazem, and mibefradil depress SA node
and AV conduction
– Dihydropyridines have minimal direct effects on SA node
and AV conduction (but they can cause reflex
tachycardia)

Relative Cardiovascular Effects of
Calcium Channel Blockers
(adapted from Goodman & Gilman, 9th ed.)
Verapamil ++++ ++++ +++++ +++++
Diltiazem +++ ++ +++++ ++++
Nifedipine +++++ + + 0
Nicardipine +++++ 0 + 0
Compound Coronary
vasodilation
Suppression
of cardiac
contractility
Suppression
of
SA node
Suppression
of
AV node

Desired Therapeutic Effects of Calcium
Channel Blockers for Angina
• Improve oxygen delivery to ischemic myocardium
– Vasodilate coronary arteries
– May inhibit platelet aggregation
– Particularly useful in treating vasospastic
angina
• Reduce myocardial oxygen consumption
– Decrease afterload (no effect on preload)
– Non-dihydropyridines also lower heart rate and
decrease contractility
– (* Dihydropyridines may aggravate angina in
some patients due to reflex increases in heart
rate and contractility)

Ca++ Channel Blockers: Toxicities
• Adverse effects are typically direct extensions of their
therapeutic effects and are relatively rare
– Major adverse effects:
» Depression of contractility and exacerbation of heart failure
» AV block, bradycardia, and cardiac arrest
– Minor adverse effects
» Hypotension, dizziness, edema, flushing
• Patients with ventricular dysfunction, SA node or AV
conduction disturbances, WPW syndrome, and systolic
blood pressures below 90 mm Hg should not be treated
with verapamil or diltiazem
• Immediate-release forms of dihydropyridines may increase
mortality in patients with myocardial ischemia
• Bepridil is associated with several serious toxicities
including DILQT syndrome (which can lead to the
ventricular proarrhythmia, torsades de pointes)

Ca++ Channel Blockers: Drug
Interactions
• b-blockers in combination with verapamil, diltiazem, or
bepridil
– Bradycardia, AV block, depression of inotropic state
• Some channel blockers (verapamil, diltiazem) can cause
an increase in plasma digoxin levels
– AV block can also occur with concurrent treatment
with channel blockers and digitalis
• Quinidine in combination with some calcium channel
blockers
– Results in decreased clearance of both and an
increased risk of bradycardia and AV nodal block
• Bepridil in combination with other drugs that are
known to cause DILQT syndrome (e.g. quinidine,
sotalol)

b-Adrenergic Blockers in the
Treatment of Angina
• Though most beta-blockers do not cause coronary
vasodilation like the nitrovasodilators or calcium
channel blockers, beta-blockers are important in the
treatment of angina because of their effects on the
heart
• Desired effects of beta-blockers
– Reduce myocardial oxygen consumption by
reducing contractility and heart rate
»Reducing cardiac output also reduces
afterload
»Some b-blockers can cause vasodilation
directly
– Improve myocardial perfusion by slowing heart
rate (more time spent in diastole)

β-adrenoceptor blocking drugs
The mechanism of antiangina
(1) decrease myocardial oxygen consumpation block β-
adrenoceptor inhibit myocardial contractility and
heart rate
(2) improve blood and oxygen supply to ischamia area
(3) lower heart rate, prolong diastolic perfusion time,
increase endocardium flow
(4) promote oxygen to dissociate from HbO2

qcilinical uses
v stable and unstable angina
v myocardial infarction

Adverse Effects and Contraindications
for b-Blockers
• May exacerbate heart failure
• Contraindicated in variant angina
• Contraindicated in patients with asthma
• Should be used with caution in patients with
diabetes since hypoglycemia-induced tachycardia can
be blunted or blocked
• May depress contractility and heart rate and
produce AV block in patients receiving non-
dihydropyridine calcium channel blockers (i.e.
verapamil and diltiazem)

Partial Fatty Acid Oxidation (pFox) Inhibitors
• Ranolazine (Ranexa) is approved by the FDA for the treatment
of chronic angina in 2006, acute coronary syndromes (ACS) ,
and long-term prevention of ACS
– First new antianginal drug in more than 25 years
• Acts by partially inhibiting fatty acid oxidation in the
myocardium, thus shifting metabolism to glucose which requires
less oxygen to metabolize
• No hemodynamic effects
• MARISA and CARISA clinical trials have studied more than
3300 angina patients and healthy volunteers, shown
effectiveness in chronic angina
• QT prolongation and testicular toxicity are the among the
possible toxicities so far

§ Ranolazine reduces calcium overload in the ischemic cardiomyocyte
through inhibition of the late sodium current (I Na)
§ Ranolazine is considered as an effective choice as add on
antianginal therapy on background of BBs, CCBs or nitrates and also
can be uses as first line in patients with absolute or relative
contraindication for BBs, CCBs or nitrates
§ Cost is the major prohibitive factor in some countries for its wider
use at this time.
Ranolazine

Trimetazidine
Trimetazidine improves cellular tolerance to ischemia by inhibiting
mitochondrial long chain 3-keto acyl-CoA-thiolase (LC3-KAT), a key
enzyme in fatty acid oxidation.
It thus reducing fatty acid metabolism and increases glucose metabolism
in heart
Since oxidation of fatty acid requires more O2, shift back to glucose
utilization reduce O2 demand.
Trimetazidine is thus labelled as pFOX (fatty acid oxidation pathway)
inhibitor.
In patients not adequately controlled by long-acting nitrate/BB/CCB,
addition of trimetazidine, further reduces anginal attacks and
increases exercise tolerence

• Use of more than one class of antianginal agent can reduce
specific undesirable effects of single agent therapy
Nitrates Alone
Reflex Increase
Decrease
Decrease
Reflex increase
Decrease
Beta-Blockers or
Ca Channel Blockers
Alone
Decrease*
Decrease
Increase
Decrease*
Increase
Nitrates Plus
Beta-Blockers or
Ca Channel Blockers
Decrease
Decrease
None or decrease
None
None
Undesireable effects are shown in italics
* Dihydropyridines may cause the opposite effect due to a reflex increase
in sympathetic tone
Heart Rate
Afterload
Preload
Contractility
Ejection time
Effect
Combination Therapy of Angina

Antianginal Combination Therapies
• Good Ones:
– A dihydropyridine calcium channel blocker and a beta-
blocker (coronary vasodilation, decreased afterload, lower
heart rate, suppression of reflex tachycardia)
– A nitrovasodilator and a beta-blocker (coronary vasodilation,
decreased preload, lower heart rate, suppression of reflex
tachycardia)
– A nitrovasodilator and a non-dihydropyridine calcium channel
blocker (coronary vasodilation, decreased preload and
afterload, lower heart rate, suppression of reflex
tachycardia)
– A nitrovasodilator, a dihydropyridine calcium channel
blocker, and a beta-blocker (coronary vasodilation,
decreased preload and afterload, lower heart rate,
suppression of reflex tachycardia)
• Bad Ones:
– A beta-blocker and non-dihydropyridine calcium channel
blocker (bradycardia, AV block, depressed LV function)

Additional Considerations in Treating Angina
• Modify risk factors associated with atherosclerosis (smoking,
hypertension, hyperlidemia)
– Statins can reduce coronary artery disease in some patients
• Patients with stable angina who are refractory to drug therapy
may require surgical revascularization (bypass) or angioplasty
– Patients with vasospastic angina are not good candidates for
these surgical procedures
• Unstable angina is an acute coronary syndrome that may require
maximally tolerated doses of conventional antianginal drugs, and
additional drugs including:
– Antiplatelet drugs (aspirin, platelet glycoprotein IIB/IIIA
inhibitors, and/or platelet ADP antagonists)
– Thrombolytic drugs (tissue plasminogen activator, streptokinase,
or similar fibrinolytic agent)
– Heparinoid anticoagulants including heparin or low molecular
weight heparins
– Surgical revascularization or angioplasty is often required in
these patients

Nitrate Resistance
Rapid and excessive elevation of plasma and tissue levels of
various vasoconstrictor substances (norepinephrine, epinephrine,
angiotensin II, endothelin and arginine vasopressin) remain a
possible mechanism for nitrate resistance.

Nicorandil
Nicorandil is an anti-angina medication that has the dual properties of
a nitrate and ATP-sensitive K+ channel agonist.
In humans, the nitrate action of nicorandil dilates the large coronary
arteries at low plasma concentrations.
At high plasma concentrations nicorandil reduces coronary vascular
resistance, which is associated with increased ATP-sensitive K+ channel
(KATP) opening.
However, the effect of nicorandil as a vasodilator is mainly attributed to
its nitrate property. Nicorandil is effective in cases where nitrates, such
as nitroglycerine, are not effective.
Due to its KATP channel agonist action in mitochondria, Nicorandil causes
pharmacological preconditioning and provides cardioprotective effects
against ischemia.

Side effect of Nicorandil
Common: Flushing, palpitations, weakness and
vomiting.
More recently, perianal, ileal and peristomal
ulceration has been reported as a side effect.

Ivabradine
o Ivabradine is a direct sinus node inhibitor and only drug in this
group
o It reduces heart rate by inhibiting the so-called funny channel (f
channel) in sinus node.
o Funny cationic channels open during early part of slow diastolic
(phase 4) depolarization. Thus the resulting inward current (If)
determines the slope of Phase 4 depolarization.
o Heart rate reduction decreases cardiac oxygen demand and
prolongation of diastole tends to improve myocardial perfusion (O2
supply).
o Ivabradine has been found to improve exercise tolerance in stable
angina and reduce angina frequency.

New hope or Experimental drugs for Angina
Mildronate
o Mildronate is a fatty acid oxidation inhibitor.
o In animal models, mildronate reduced myocardial infarct size.
o In one prospective randomized control trial of 512 patients with stable
angina, mildronate (1000 and 3000mg) improved total exercise time versus
placebo.
Perhexiline
o Perhexiline is a fatty acid oxidation inhibitor that has been studied for
angina in the past and shown to improve exercise and tachycardia (atrial
pacing) induced angina.
o It was introduced in France in the early 1970s and was remarkable
effective at preventing angina.
o But it showed peripheral neuropathy and hepatotoxicity in some group of
patients.

New hope or Experimental drugs for Angina
Molsidomine
o Molsidomine is metabolized in the liver to the active metabolite
linsidomine. It is an unstable compound that further metabolized to
releases NO.
o It reduced the level of soluble ICAM-1 (which is a marker for the
severity of atherosclerosis).
o It causes vasorelaxation of coronary arteries and thereby reduces
angina.
Phosphodiesterase inhibitors
o Phosphodiesterase inhibitors were designed initially to be a therapy for
angina. however, the effects were notpromising.
o However, there is growing evidence of improved coronary flow with other
phosphodiesterase inhibitors like Trapidil, dipyridamole and cilostazol.

New hope or Experimental drugs for Angina
Amiodarone/Dronedarone
o Amiodarone, approved as an anti-arrhythmic agent, was initially
introduced as an antianginal therapy.
o In elderly patients with treatment resistance angina, Amiodorane (50-
100mg) is effective when used with their current antianginal drugs.
o Dronedarone, which is an iodine-free derivative of amiodarone, with a
lesser side effect profile, reduced first cardiovascular hospitalization due
to coronary artery disease.
Fasudil
o Fasudil is a class of rho kinase inhibitors, and the only one currently
approved (Japan and China) for the treatment of cerebral vasospasm.
o Rho kinase inhibitors result in vascular smooth muscle relaxation through
manipulation of the Rho-associated protein kinase (ROCK) pathway, thus
they reduce blood pressure.
o This agent has not been tested as an angina therapy.

Newer or Experimental drugs for Angina
Allopurinol/febuxostat
o The exact mechanism of this anti-ischemic effect of allopurinol is unclear,
but xanthine oxidase inhibition by Allopurinol can reduce oxidative stress.
o Febuxostat is a potent non-purine selective inhibitor of xanthine oxidase and
show antioxidative effect similar to Allopuriol.
o But one human study is required to find its effect as anti-angina.
Testosterone
o Testosterone results in coronary artery dilation and increases coronary
blood flow in humans. The mechanism appears to be related to ion channels
on vascular smooth muscles.
o Several small studies have reported the beneficial anti-ischemic effect of
testosterone delivered via transdermal, intramuscular, and oral therapy.
o However, cardiovascular safety need to be looked as testosterone can
increase red blood cells, which increases thrombosis risk.

Adenovirus containing vascular
endothelial growth factor (Ad-VEGF121)
Reference:
Advancements in Pharmacotherapy for Angina. Expert Opin Pharmacother.
2017, April 18 (5):457-469
§ Intramyocardial delivery of an adenoviral vector encoding for an
angiogenic factor as therapy in refractory angina patients was the
Randomized Evaluation of VEGF for Angiogenesis (REVASC).
§ AdVEGF121 significantly increased exercise time to 1 mm ST-
segment depression, with improvements in various quality of life
measures.

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