Angina Printzmetal

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350 AMERICAN JOURNAL OF CRITICAL CARE,July 2004, Volume 13, No. 4

CARDIOLOGY CASEBOOKA regular feature of the American Journal of Critical Care, Cardiology Casebook is intended to enhance practitioners knowledge

and critical thinking. Stylized case studies are accompanied by self-assessment quizzes. We welcome letters to the editors regarding

this feature.

PRINZMETALS ANGINABy Kathryn Buchanan Keller,RN, PhD, and Louis Lemberg,MD.From Florida Atlantic University ChristineE. Lynn College of Nursing, Boca Raton, Florida (KBK) and the Division of Cardiology, Department ofMedicine, University of Miami School of Medicine, Miami, Fla (LL).

A75-year-old female, retired private duty

nurse, has been complaining for the past 10

days of unprovoked classical attacks of

angina 2 to 3 a day usually in the mornings. The

angina occurs at rest and may last 5 to 10 minutes. On

careful questioning she admitted to similar attacksduring the previous 2 years, which were disregarded

because they were infrequent (every 4 to 6 weeks)

and shorter in duration. However, the attacks were

also unprovoked and unrelated to any specific activity,

emotional upset, or food intake. Family history

revealed her father and mother died at age 72 and 78,

respectively, of causes unknown, and her only sibling,

a brother, died at age 74 of an acute myocardial

infarction. Past medical history revealed symptomatic

osteoarthritis of her large extremity joints. Periodicallyshe obtained relief with two 325 mg aspirin tablets 3

to 4 times daily and lately had a greater dependency

on aspirin. In addition, she was taking a multivitamin

daily.

On physical examination, the patient was normal

in weight 56 kg (125 lb), 1 m 65 (5 ft 5 in) in height

and moderately active. Blood pressure was 120/75

mm Hg in the right arm, and pulse was 76/min and

regular. The lungs were normal on auscultation. The

heart rate was 76/min; S1 and S2 were normal. A

grade II aortic systolic murmur was heard over thesecond right intercostal interspace, consistent with

aortic valve sclerosis. The point of maximal cardiac

impulse was in the fifth intercostal interspace at the

midclavicular line. Peripheral vascular examination

was unremarkable. A complete blood count and uri-

nalysis were normal. Blood chemistries revealed nor-mal liver and renal function. A lipid profile revealed:

cholesterol 4.78 mmol/L (185 mg/dL), triglycerides

1.35 mmol/L (120 mg/dL), high-density lipoprotein

cholesterol 1.19 mmol/L (46 mg/dL), low-density

lipoprotein cholesterol 2.46 mmol/L (95 mg/dL),very-low-density lipoprotein cholesterol 0.31 mmol/L

(l2 mg/dL). A high-sensitivity C-reactive protein was

normal. A resting electrocardiogram (ECG) revealed

a cardiac rate of 72/min, regular sinus rhythm, andwas considered within normal limits (Figure 1). Since

the patient was asymptomatic and by history her new

symptoms were unrelated to anything specific and

were in fact unprovoked, a 48-hour Holter ECG moni-

tor was applied in an effort to document any ECG

changes that may appear associated with her symp-toms. A review of the Holter monitoring recording a

few days later revealed 2 episodes of unprovoked

angina accompanied by marked ST-segment elevation

in the monitored leads that lasted 7 minutes. Occa-

sional ventricular premature beats were noted during

the attacks. The ST segments returned to normal after

8 to 9 minutes in both episodes (Figure 2).

QUESTIONS1. Which one of the following is the diagnosis in

this case?a. atherosclerotic heart disease

b. congenital anomalous angina of the left

coronary artery from the right or non-

coronary aortic sinus of valsalva

c. myocardial bridges

d. Prinzmetals variant angina (PVA)

e. hypoplastic coronary arteries

2. Which of the following statement(s) is/are cor-

rect?a. the occurrence of coronary spasm is

referred to as PVA

b. coronary vessel spasm is always associ-

ated with ST-segment elevation

c. PVA is a rare clinical phenomenon and

has a benign courseTo purchase reprints, contact Louis Lemberg, MD, University of Miami Schoolof Medicine, Division of Cardiology (D-39), PO Box 016960, Miami, FL 33101.


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AMERICAN JOURNAL OF CRITICAL CARE,July 2004, Volume 13, No. 4 351

Figure 1 Routine resting electrocardiogram is within normal limits.

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III aVF

aVL

aVR

Hewlett Packard 4755AV

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V2

V3 V6

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V5

V4

RHYTHM STRIP: II25 mm/s; 1 cm/mV

LOC 00000-0000

Figure 2 The clock times are given in hours, minutes and seconds. Arrows point to the ST-segment elevations. Note the regressionof J point elevation. Ventricular premature beats appear just before ventricular repolarization returns to normal. The subjectsdiary indicated that the acute electrocardiographic changes appeared at the time of the angina.

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e. PVA is unprovoked angina caused by

coronary vasospasm occurring at rest,

producing ST-segment elevations

Myron Prinzmetal first described a variant form

of angina in his classic 1959 publication in the Ameri-

can Journal of Medicine.1 The term variant anginaor PVA is a distinct clinical entity characterized by

episodes of chest pain occurring at rest, associated

with ST-segment elevation and caused by coronary

vasospasm. Coronary vasospasm, however, is not syn-

onymous with PVA, since the clinical spectrum of

vasospasm also includes angina associated with ST

depression and exertional angina. Variant angina rep-

resents only 1 aspect of a continuous spectrum ofacute myocardial ischemia caused by coronary vaso-

spasm.2 PVA, once thought to be infrequent, is cur-

rently recognized more often and is a significant

determinant of cardiac morbidity and mortality. Con-

tinuous 24-hour Holter ECG monitoring of patientswith PVA revealed serious cardiac arrhythmias in

approximately 50% of cases. These included complex

ventricular ectopic beats, ventricular tachycardia, ven-

tricular fibrillation, asystole, and second- and third-

degree atrioventricular block.3 There was no relationshipbetween the severity of coronary artery disease and

the occurrence of these serious arrhythmias. In PVA,

these arrhythmias are generally associated with

marked ST-segment elevation of 4 mm or more.4 Brad-

yarrhythmias are associated with acute ST elevations

in the inferior leads, whereas ventricular arrhythmias

can be seen with acute ST elevations in the anterior

leads.3 There is a high risk for SCD when ventricular

arrhythmias occur during acute ST elevations; theventricular arrhythmias during resolution of the ST

elevations (accelerated idioventricular beats) arebenign and a sign of reperfusion.4,5 In a study of 114

patients with variant angina followed for 26 months,

SCD occurred in 42% of those who experienced seri-

ous arrhythmias during their anginal episodes com-

pared with an incidence of 6% in those without

serious arrhythmias.4 Multivessel spasm increases the

risk of SCD.6

3. b. cigarette smoking is a risk factor for PVA

c. PVA can be triggered by the use of cocaine

d. PVA can be associated with Raynaudsphenomenon

e. autonomic dysfunction has been impli-

cated in the etiology of PVA

f. anginal attacks may vary with the men-

strual cycle


d. PVA may initiate serious cardiac arrhyth-

mias that can lead to sudden cardiac death

(SCD)

e. PVA is unprovoked angina caused by

coronary vasospasm occurring at rest,

producing ST-segment elevations

3. Which of the following statement(s) is/are cor-

rect?a. patients with PVA typically have the same

risk factors as patients with coronary

artery disease

b. cigarette smoking is a risk factor for PVA

c. PVA can be triggered by the use of cocaine

d. PVA can be associated with Raynauds

phenomenon

e. autonomic dysfunction has been impli-

cated in the etiology of PVA

f. angina attacks may vary with the men-

strual cycle

4. The diagnosis of PVA is verified by which of

the following procedures?

a. echocardiography

b. magnetic resonance imaging of coronary

arteries

c. 24-hour Holter ECG monitoring

d. event recorder

e. ergonovine stimulation

f. loop recorder

5. Which of the following is not/are not helpful in

the diagnosis of PVA?

a. 24-hour Holter ECG monitoringb. thallium-201 ECG exercise stress test

c. coronary angiography

d. ergonovine stimulation

e. event recorder

6. Which of the following medications should be

used in the treatment of patients with PVA?

a. nitratesb. calcium channel blockers

c. -adrenoreceptor blockersd. -blockerse. aspirin

ANSWERS1. d. PVA

2. d. PVA may initiate serious cardiac arrhyth-

mias that can lead to SCD


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The classical clinical manifestation of PVA is

chest pain at rest associated with ST-segment eleva-

tion. PVA tends to occur in younger females who,

except for cigarette smoking, may not exhibit theusual clinical cardiac risk factors.7 The anginal attacks

in PVA tend to have a circadian rhythm and generally

occur in the early morning hours.1,8 These attacks canbe triggered by alcohol, drinking iced drinks, rapid

eye movement sleep, ergonovine, atrial pacing,

cocaine, nicotine, acetylcholine, and hyperventilation.9

PVA has been associated with other vasospastic disor-

ders such as migraine headaches and Raynauds phe-

nomena.10

The pathogenesis of coronary spasm is not well

understood. Factors implicated include the activationof the autonomic nervous system (-adrenergic recep-tors) and endothelial dysfunction. Vasospasm can be

precipitated by acetylcholine and meta-choline and

prevented by atropine and-receptor blockers, eg,

prazosin or clonidine; these factors implicate involve-ment of the parasympathetic nervous system and-adrenergic vascular receptors.11-13 Autonomic nervous

system involvement is further supported by the obser-

vation that surgical sympathetic denervation has been

effective in treating patients who are refractory tomedical treatment.14,15 The role of endothelial dysfunc-

tion in PVA has been reported in a prospective study

of premenopausal women with variant angina in

which endothelial dysfunction and the frequency of

anginal attacks varied with the menstrual cycle and

estradiol levels.16 Anginal episodes were most frequent

with the lowest estradiol levels and least frequent with

the highest levels.16 Other studies have shown that the

coronary artery that is vasospastic in PVA reveals dif-fuse intimal thickening.17 This may be a response to

repeated spasms.

4. c. 24-hour Holter ECG monitoring

e. ergonovine stimulation

f. loop recorder

A 24- or 48-hour Holter recording can be very

definitive in the diagnosis, but is dependent on attacks

of PVA. A loop recorder is an effective diagnostic

tool. The ECG recordings are stored at either a 7, 14,

21, or 42 minute event. Stored data can be retrieved at

any time.18

Loop recorders can operate for 1 yearbefore battery failure.

The most sensitive test for coronary artery spasm

is coronary stimulation by ergonovine, which has a

greater than 90% sensitivity and specificity for the

diagnosis of PVA. This test is recommended when

recurrent episodes of ischemic chest pain occur at rest

without the classic ECG manifestations of PVA (ie,

ST-segment elevation) and normal or minimally

abnormal coronary angiograms.

5. b. thallium-201 ECG exercise stress test

c. coronary angiographye. event recorder

Exercise stress testing is of little use in the diag-

nosis of PVA because the basic pathophysiology in

PVA is a decrease in oxygen supply as a result of

vasospasm: this is in sharp contrast to the increase in

demand with exercise that occurs in the pathophysiol-

ogy of occlusive coronary artery disease. Coronaryangiography in PVA often demonstrates normal coro-

nary vessels or minimal coronary artery disease (in

the elderly). An event recorder is patient reliant, and

as a result the recording may lack the onset or resolu-

tion of the ECG recording during the angina in PVA.An event recorder is therefore not recommended for

the diagnosis of PVA.

6. a. nitrates

b. calcium channel blockers

c. -adrenoreceptor blockers

The nitrates and/or the calcium channel blockers

(nifedipine, diltiazem, or verapamil) are the mainstay

of treatment for PVA. Calcium channel blockers and

nitrates prevent vasoconstriction and promote vasodila-

tion. Prazosine is a selected-adrenoreceptor blockerand is an alternative therapy in PVA. Long-term sur-

vival is excellent. -Blockers can exacerbate vasospasmin coronary vasospastic states and propranolol is

known to prolong the attacks of PVA. -Adrenergicblockade of vasodilatory -adrenergic receptors con-vert the effects of sympathetic stimulation into a pure

-adrenergic vasoconstrictor response. Thus the useof non-selective -blockers should be avoided.19 Aspirinin small doses (81 mg to 325 mg) block thromboxin

A2, a powerful vasoconstrictor, allowing the full

vasodilating and platelet-inhibiting effects of prosta-

cyclin. Aspirin in large doses inhibits prostacyclin

production.20 Excessive aspirin intake (325 mg tablets

4-8 daily) can aggravate coronary artery vasospasm in

PVA by blocking cyclooxygenase, which results insuppression of prostaglandin production.

SUMMARYPrinzmetals angina, often referred to as variant

angina, is a temporary increase in coronary vascular

AMERICAN JOURNAL OF CRITICAL CARE,July 2004, Volume 13, No. 4 353


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tone (vasospasm) causing a marked, but transient

reduction in luminal diameter. This coronary vasospas-

tic state is usually focal at a single site and can occur

in either a normal or diseased vessel. Patients are pre-dominantly younger women who may not have the

classical cardiovascular risk factors (except for cigarette

use). PVA has been associated with vasospastic disor-ders such as Raynauds phenomenon and migraine

headaches. Arrhythmias are common and may be life

threatening especially when the effects of vasospasm

are seen in those ECG leads that reflect the potential

variations of the epicardial surface of the left ventri-

cle. Endothelial dysfunction has been considered as

primarily responsible for PVA. The diagnosis is made

by observing transient ST-segment elevation duringthe attack of angina. Since PVA is not a demand-

induced symptom, but rather a supply (vasospastic)

abnormality, exercise treadmill stress testing is of no

value in the diagnosis of PVA. The most sensitive and

specific test for PVA is the administration of ergonovine

intravenously. Fifty micrograms at 5-minute intervals

is given until a positive result or a maximum dose of

400 g has been administered. When positive, the

symptoms and associated ST-segment elevation

should be present. Nitroglycerin rapidly reverses the

effects of ergonovine if refractory spasm occurs.Medical therapy classically employs vasodilator

drugs, which include nitrates and calcium channel

blockers. The prognosis is good when there is no sig-

nificant coronary artery stenosis. Treatment of associ-

ated coronary atherosclerosis in elderly patients with

PVA is advised. When PVA is associated with coro-

nary atherosclerosis, the prognosis is determined by

the severity of the underlying disease. -Blockers andlarge doses of aspirin are contraindicated in PVA.

ACKNOWLEDGMENTSupported in part by a grant from the Applebaum Foundation in loving memory ofMr. Joseph Applebaum.

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Angina Printzmetal