Transcript Dr Ranjith MP Senior Resident Department of Cardiology Government Medical college Kozhikode Introduction Described as "A variant form of angina pectoris" by Dr.

Dr Ranjith MP
Senior Resident
Department of Cardiology
Government Medical college
Kozhikode
Introduction
Described as "A variant form of angina pectoris" by Dr. Myron
Prinzmetal in 1959
Prinzmetal or coronary vasospastic angina
Episodes of angina pectoris, usually at rest and often between
midnight and early morning, in association with ST-segment elevation
on the ECG
Episodes are triggered by coronary artery vasospasm in the absence
of high grade coronary artery stenosis
Population at Risk
 Associated with other vasospastic disorders like Raynauds, or migraine headaches
 Patients with cocaine abuse, smoking, insulin resistance, Food-born botulism,
Magnesium deficiency
 Hyperventilation can precipitate
 Younger patient population (age < 50)
 More common in women with normal coronaries (pure VA) and in men with organic
lesions (non-pure)
 More frequent in Japan compared to white (Japan: up to 29%,France: 12% US 4%)
Pathogenesis
Focal spasm of a major coronary artery
Transient myocardial ischemia causes angina any patients. MI may develop in
some
Vascular smooth muscle hyper-reactivity is thought to be central to the
pathogenesis of variant angina
Spasm occurs in the absence of any preceding increase in myocardial oxygen
demand & in normal or diseased vessels
Spasm is usually focal. Spasm in more than one site and diffuse spasm have
been described
Pathogenesis
Vascular smooth muscle hyper-reactivity is a key factor in the
pathogenesis of coronary artery spasm

Multiple receptors have been involved in this spasm including
acetylcholine, serotonin, histamine, noradrenaline, and dopamine

Receptor antagonists (eg, ketanserin and prazosin) do not inhibit spasm.
Inhibition of smooth muscle contractile mechanisms using other (nonreceptor) pathways (eg, nitrates, calcium channel blockers) is effective

Increased calcium sensitivity of the vascular myosin light chain mediated
by enhanced Rho kinase activity and enhanced phospholipase C activity
have been shown to have a role
Pathogenesis
Autonomic nervous system —imbalance of vagal and sympathetic
tone in triggering coronary spasm

Episodes of variant angina occur more often from midnight to early
morning (when vagal tone is higher)
Endothelial dysfunction —may be a predisposing factor
Associated microvascular dysfunction
Clinical presentation
Chronic pattern of recurrent episodes of chest pain
Episodes are predominantly at rest and that many occur from
midnight to early morning
Each episode of chest pain generally lasts 5 to 15 minutes
Physical examination- no findings characteristic for VA. However,
during an episode, tachycardia, hypertension, diaphoresis, and a
gallop rhythm may be present
Investigations
12 lead ECG is usually normal between anginal episodes
During an acute episode- ST elevation in multiple leads
The ST-segment returns to baseline rapidly upon resolution of symptoms.
Occasionally, a transient period of T wave inversion may be seen
Other reported ECG abnormalities include a tall and broad R wave,
disappearance of the S wave, a taller T wave, and negative U waves
Ambulatory ECG monitoring – help in the diagnosis, assess the efficacy of
therapy
Investigations
Role of stress testing

Angina and no ST-segment elevation should undergo stress testing

Most will have a normal noninvasive stress test

Exercise-induced spasm with ST-segment elevation- 10 to 30%

Stress echocardiography with ergonovine provocation has been used to
diagnose variant angina, not recommend now
Role of coronary arteriography

In patients with suspected variant angina based on the history and an ECG
severe fixed obstruction needs to be excluded

Reasonable to refer a patient with a strong history consistent with VA if
episodes of pain did not occur during ambulatory monitoring.
Investigations
Three provocative tests- done only when the diagnosis of VA is
suspected, but not firmly established
1.
Ergonovine
2.
Acetylcholine

3.
Associated with a low frequency of serious complications (0.6 %)
It is preferred to either ergonovine or hyperventilation, by some
Hyperventilation

A high specificity (100 percent) & a sensitivity of 55 to 95%
Differential diagnosis
Fixed obstructive coronary artery disease
Early repolarization - generally occurs in patients without classic
angina pectoris and in whom the ST-elevation is chronic
Acute pericarditis & stress-induced cardiomyopathy - characterized
by pain that has been present for hours or days before presentation
Differential diagnosis
 Pericarditis - sharp pain that is affected by position or breathing & abnormal
echocardiography
 STEMI - pain and ST-elevation are usually present for > 15 minutes
 Cardiac syndrome X - ST depression on ECG during episodes
 GERD with esophageal spasm
Treatment
Reduces the frequency of symptomatic episodes and appears to
decrease the frequency of serious complications
Smoking cessation - significant decrease in the frequency of episodes
Sublingual nitroglycerin decrease the duration of symptoms and
ischemia
Treatment
Nitrates and calcium channel blockers (nifedipine, diltiazem, and
verapamil) are effective and both prevent vasoconstriction and
promote vasodilation in the coronary vasculature
There are no studies comparing one therapy to another
In one study the use of a calcium channel blocker therapy was an
independent predictor of myocardial infarct-free survival in VA patients
Guanethidine and clonidine - not well studied in this setting
Treatment
Rho kinase inhibitors – Fasudil, shown to inhibit acetylcholine-induced
spasm
Statins - Effective in preventing coronary spasm and may exert their
benefits via endothelial nitric oxide or direct effects on the vascular
smooth muscle

Fluvastatin 30 mg daily was evaluated in a trial of 64 patients .After six
months ACh-induced coronary artery spasm was significantly lower in
fluvastatin group compared to those who did not (48 Vs 79 %)
Magnesium – In a study of 22 patients, those administered IV Mg (n =
14) compared with placebo (n = 8) exhibited coronary vasodilation
Treatment
Percutaneous coronary intervention - may be helpful if significant
obstructive CAD is present and thought to be a potential trigger for
focal spasm
In a study of 45 patients with documented vasospastic angina and a
severe stenosis who underwent balloon only angioplasty or stenting.
After a seven-month follow-up, no restenosis was observed and
repeat provocative testing with intracoronary acetylcholine did not
induce spasm at the site of the initial stenosis; however, spasm at a
different site in the dilated vessel and/or in another vessel occurred in
77 percent of patients and multivessel spasm occurred in 62 percent
Effective medical therapy, such as calcium channel blockers, should
be continued after percutaneous revascularization
Treatment
Concerns about specific drugs

Nonselective beta blockers, such as propranolol should be avoided

Aspirin should be used with caution and at low doses

All medications of the triptan class should be avoided

5-Fluorouracil induce coronary artery spasm
Complications
Myocardial infarction and life-threatening arrhythmias may occur in
approximately 25 percent of untreated patients
Myocardial infarction - usually due to concurrent obstructive CAD

With variant angina alone, coronary vasospasm may trigger thrombus
formation

Lipoprotein(a) may play a role in this setting. It interferes with fibrinolysis
by competing with plasminogen binding to molecules and cells
Complications
 Arrhythmias - may be life-threatening

The type of arrhythmia is determined in part by the vessel & territory involved

Heart block - RCA, VT- LAD

The optimal approach to patients with variant angina & SCD is unknown. In an
observational study of 23 patients with VA in whom an ICD was placed for a
documented ventricular arrhythmia, all patients were alive during a median follow-up
of 2.1 yrs (4 VF & 1 pulseless electrical activity)

Patients with high risk features such as obstructive CAD, large ST elevations, focal
proximal epicardial coronary artery spasm, increased vasospastic and arrhythmic
activity, and multivessel coronary artery spasm who are on maximal or submaximal
doses of Ca channel blockers ICD is a better choice
Prognosis
Infarct-free survival at 10 - over 80 percent
 Independent predictors of infarct-free survival include


Extent and severity of CAD

SVD has 99 and 94% survival at 1 and 5 year

MVD has 87 and 77% survival at 1 and 5 year
Use of calcium channel blockers


Patients with a positive initial response to CCB are twice as likely to have an event
free clinical course compared to those with a poor response initially
Arrhythmic complication
Summary
Variant angina is characterized by spontaneous episodes of angina in
association with ST elevation on the ECG. The cause is a transient,
abrupt, and marked reduction in the luminal diameter of an epicardial
coronary artery due to spasm, leading to transient myocardial ischemia
Arrhythmias and MI are potentially life-threatening complications
Patients without obstructive CAD have a good long-term prognosis
Management includes cessation of smoking and pharmacologic therapy
Introduction
First described by Kemp in 1973
It has three characteristic features
1.
Angina or angina-like chest pain with exertion
2.
ST segment depression on treadmill exercise testing
3.
Normal coronary arteriography, with no spontaneous or inducible epicardial
coronary artery spasm on ergonovine or acetylcholine provocation
Pathogenetic mechanisms
1.
Metabolic abnormalities
2.
Impairment of left ventricular function over time
3.
Impaired coronary flow reserve
4.
Abnormal pain perception
5.
Increased tone of microvasculature
6.
Endothelial dysfunction
7.
Increased sympathetic tone
8.
Potassium pump alteration
9.
Oestrogen deficiency in post-menopausal women
10.
Early coronary artery disease not detectable on angiography
Clinical characteristics
 More common in women than men
 Typically younger than those with angina due to CAD (mean age 49±9 Yrs. in
two series)
 Chest pain is similar to angina-like pain in 50%
 The pain may be precipitated by effort, but also occurs at rest
 Myocardial ischemia and/or coronary microvascular dysfunction is present in
20 to 50 percent of women with chest pain and normal coronary arteries
Clinical characteristics
 Duration of anginal-type chest pain is often prolonged. In a review of 99
patients the average duration of chest pain was more than 10 mts in 53 %,
and more than 30 minutes in 35%. Many did not respond to S/L nitrates
 A strong association between cardiac syndrome X and psychiatric disorders
such as panic anxiety is observed
 Rheumatologic disorders, such as fibromyalgia and costochondritis, and
noncardiac causes of chest pain, such as esophageal dysfunction, have
occasionally been reported in patients with cardiac syndrome X
Diagnosis
Diagnosis is by exclusion
Should be considered when a patient (often a postmenopausal or
perimenopausal woman) describes effort-related anginal pain that
lasts 10 minutes or longer after cessation of activity and that
responds inconsistently to sublingual nitrates
ECG - Transient ST segment depression with anginal pain
Exercise testing - Horizontal or downsloping ST segment depression
during exercise, as seen in patients with obstructive CAD
Diagnosis
Exercise thallium-201 myocardial scintigraphy - may demonstrate
regional myocardial perfusion defects during exercise
Some reports have demonstrated neither perfusion defects nor RWMA
after dobutamine or transesophageal atrial pacing, despite the frequent
provocation of chest pain . It is possible that ischemia is limited to the
subendocardium, which could explain the absence of RWMA
CMR perfusion imaging - detect regional differences in myocardial blood
flow

In a study , cardiac syndrome X patients with dobutamine stress induced myocardial
perfusion defects in LAD territory on CMR had a lower CFR to adenosine compared to
those without perfusion defects in LAD territory. This study is evidence of coronary
microcirculation dysfunction in patients with cardiac syndrome X
Diagnosis
CAG - A normal CAG is a necessary component of the diagnosis

Tissue level perfusion, as determined by myocardial blush grade on CAG,
was evaluated in a series of 55 patients and 44 controls . An abnormal
blush grade was significantly more common in pts with cardiac syndrome X
(58 Vs 20%)
IVUS - may detect intramural atheroma
Coronary sinus filling time - assess the transit time through coronary
microcirculation. A recent study published from our department
showed CSFT was significantly delayed in patients with angina and
normal coronaries compared to control group (Mean CSFT 4.25 ±
0.72 s & 3.46 ± 0.99, p = 0.001)
Prognosis
Cardiac syndrome X with stable angina have a excellent prognosis,
while those with ACS have an appreciable acute mortality although
lower than that in patients with angiographic coronary disease
In CASS registry of over 4000 patients with normal or near normal
CAG the 7yr survival rate was 96 % in those with normal CAG & 92%
in mild disease
Only a minority of patients show evidence of progressive disease on
repeat CAG

In a series of 138 patients with chest pain and normal CAG at baseline,
CAG was repeated in 24 during a 5yr follow-up because of UA. Only 2
patients had progression to significant stenosis
Risk stratification
MRS handgrip stress testing - measurement of myocardial highenergy phosphates after hand-grip exercise. Among women without
CAD, abnormal MRS consistent with myocardial ischemia predicted
cardiovascular outcome

In a study at 3yr follow up, the frequency of cardiovascular events
(primarily hospitalization for unstable angina) was 13 percent in the 60
women with no obstructive CHD and normal MRS, 43 percent in the 14
women with no obstructive CHD and an abnormal MRS, and 48 percent in
a reference population of 352 women with CHD
Risk stratification
Stress testing - can detect patients at increased risk

In a study of 457 patients, 359 with normal CAG, and the remainder with
less than 50% stenosis. Dipyridamole stress echocardiography was
abnormal in 43 patients (9 %). At a median follow-up of 7.1 years, these
patients had a significantly higher rates of overall mortality (18 Vs 7 %) and
cardiac mortality (7.0 Vs 2.7%) compared to those with a normal stress
test
Treatment
Different therapeutic strategies have been proposed depending upon the
prevailing pathogenic mechanism, comorbidity, and clinical presentation
Beta blockers - Most effective in reducing the frequency and severity of
angina and in improving exercise tolerance. No definite RCTs available
Calcium channel blockers - Not effective or less predictably effective
Nitrates -Improvement with sublingual nitrates in about 40 percent of
patients
Treatment
ACE inhibitors and statins – A RCT in which 45 patients with cardiac
syndrome X were assigned to treatment with either ramipril (10 mg
OD) plus atorvastatin (40 mg OD) or placebo . After six months,
patients treated with atorvastatin and ramipril had significant
improvements in brachial artery flow-mediated vasodilation (a
marker of endothelial function), exercise duration, and angina
frequency compared to placebo
Imipramine - Low dose imipramine, may be effective in some patient
Treatment
Hormone therapy - May be beneficial in postmenopausal women. In a
double-blind controlled trial of 25 such women, hormone therapy
significantly reduced the frequency of anginal episodes (3.7 versus 7.3
episodes per 10 days with placebo) . Estrogen may act by improving
endothelium-dependent coronary vasomotion
The Women's Health Initiative, mostly of primary prevention, and the
HERS trials of secondary prevention showed that estrogen-progestin
replacement had no cardioprotective effect and may have produced
harm, increasing the risk of coronary disease, stroke, venous
thromboembolism, and breast cancer
Treatment
 Physical training - compared to no intervention, exercise training improved exercise
capacity by 34 % & delayed onset of pain during exercise by 100 %
 Alpha blockers - studies have shown no effect on exercise-induced angina
 Aminophylline - adenosine receptor antagonist. In a trial of oral aminophylline, the
time to the development of chest pain on exercise testing was prolonged & the
number of chest pain episodes over a 3wk interval were reduced, but the
development of ST segment depression was not diminished
 Spinal cord stimulation - successful in the treatment of refractory angina due to
coronary heart disease
Summary
Cardiac syndrome X is defined as angina-like chest pain with exertion,
positive ECG response (ST segment depression) on treadmill exercise
testing and normal CAG with no spontaneous or inducible epicardial
coronary artery spasm on ergonovine or acetylcholine provocation
Incidence is more common in women
Most patients with cardiac syndrome X and stable symptoms have an
excellent prognosis
Therapy is tailored to individual patient. Reassurance is key
Beta blockers seem to be effective in decreasing frequency and
severity of symptoms
 Sublingual nitroglycerin may also help symptoms in some patients
but calcium channel blockers are not very effective
MCQ -1
 False statement about variant angina?
A. ECG shows transient ST elevation
B. Patient may have obstructive CAD
C. Usually preceded by heavy excursion
D. Usually occurs in early night and early morning
MCQ - 2
 Population at risk for variant angina include all except
A. Patients with cocaine abuse & smoking
B. Insulin resistance
C. Food-born botulism
D. Calcium deficiency
MCQ - 3
 Provocative tests not used in diagnosis of variant angina
 Ergonovine
 Acetylcholine
 Hyperthermia
 Hyperventilation
MCQ - 4
 Statin trial in variant angina is with ………………………
A. Rosuvatatin
B. Fluvastatin
C. Simvastatin
D. Prasuvastatin
MCQ - 5
 False statement about variant angina
A. Infarct-free survival at 10 is over 80 percent
B. Independent predictors of infarct-free survival include extent and severity
of CAD
C. Trials have shown nitrates are better than calcium channel blockers in
preventing recurrence of chest pain
D. Use of calcium channel blockers is an independent predictors of infarct-free
survival
MCQ - 6
 Characteristic features of microvascular angina include all except
A. Angina or angina-like chest pain with exertion
B. ST segment elevation on treadmill exercise testing
C. Normal coronary arteriography
D. No spontaneous or inducible epicardial coronary artery spasm on
ergonovine or acetylcholine provocation
MCQ - 7
 False statement about microvascular angina is
A. More common in women than men
B. Typically younger than those with angina due to CAD
C. Chest pain is similar to angina-like pain in >70% of cases
D. The pain may be precipitated by effort
MCQ - 8
 False statement about microvascular angina is
A. Myocardial ischemia and/or coronary microvascular dysfunction is present
in >70% of cases
B. Duration of anginal-type chest pain may be more than 30 minutes
C. A strong association between psychiatric disorders such as panic anxiety
D. Exercise testing shows horizontal or downsloping ST segment depression
MCQ - 9
 False statement about treatment of variant angina
A. Beta blockers are effective in reducing the frequency and severity of angina
B. Calcium channel blockers are equally effective as Beta blockers
C. Improvement with sublingual nitrates in about 40 percent of patients
D. Alpha blockers - studies have shown no effect on exercise-induced angina
MCQ - 10
 All the following treatment modalities have good benefit risk ratio in
microvascular angina except
A. ACE inhibitors
B. Imipramine
C. Hormone therapy
D. Statins
MCQ -1
 False statement about variant angina?
A. ECG shows transient ST elevation
B. Patient may have obstructive CAD
C. Usually preceded by heavy excursion
D. Usually occurs in early night and early morning
MCQ - 2
 Population at risk for variant angina include all except
A. Patients with cocaine abuse & smoking
B. Insulin resistance
C. Food-born botulism
D. Calcium deficiency
MCQ - 3
 Provocative tests not used in diagnosis of variant angina
 Ergonovine
 Acetylcholine
 Hyperthermia
 Hyperventilation
MCQ - 4
 Statin trial in variant angina is with ………………………
A. Rosuvatatin
B. Fluvastatin
C. Simvastatin
D. Prasuvastatin
MCQ - 5
 False statement about variant angina
A. Infarct-free survival at 10 is over 80 percent
B. Independent predictors of infarct-free survival include extent and severity
of CAD
C. Trials have shown nitrates are better than calcium channel blockers in
preventing recurrence of chest pain
D. Use of calcium channel blockers is an independent predictors of infarct-free
survival
MCQ - 6
 Characteristic features of microvascular angina include all except
A. Angina or angina-like chest pain with exertion
B. ST segment elevation on treadmill exercise testing
C. Normal coronary arteriography
D. No spontaneous or inducible epicardial coronary artery spasm on
ergonovine or acetylcholine provocation
MCQ - 7
 False statement about microvascular angina is
A. More common in women than men
B. Typically younger than those with angina due to CAD
C. Chest pain is similar to angina-like pain in >70% of cases
D. The pain may be precipitated by effort
MCQ - 8
 False statement about microvascular angina is
A. Myocardial ischemia and/or coronary microvascular dysfunction is present
in >70% of cases
B. Duration of anginal-type chest pain may be more than 30 minutes
C. A strong association between psychiatric disorders such as panic anxiety
D. Exercise testing shows horizontal or downsloping ST segment depression
MCQ - 9
 False statement about treatment of variant angina
A. Beta blockers are effective in reducing the frequency and severity of angina
B. Calcium channel blockers are equally effective as Beta blockers
C. Improvement with sublingual nitrates in about 40 percent of patients
D. Alpha blockers - studies have shown no effect on exercise-induced angina
MCQ - 10
 All the following treatment modalities have good benefit risk ratio in
microvascular angina except
A. ACE inhibitors
B. Imipramine
C. Hormone therapy
D. Statins