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49-Year-Old Woman With Chest Pain

      A 49-year-old woman came to the emergency department because of an episode of nocturnal chest pain. She described the pain as nonexertional retrosternal heaviness that extended to her right arm and was associated with nausea. The pain was not positional or pleuritic; it lasted approximately 5 minutes and resolved spontaneously. Her cardiac risk factors included a 35-pack-year history of smoking and a family history of premature coronary artery disease, hypertension, obesity, and hyperlipidemia. The patient walked 30 minutes daily at a moderate pace without experiencing any symptoms.
      The patient's medical history included cervical cancer treated with a total abdominal hysterectomy, migraines, and anxiety. Medications included conjugated estrogens and a multivitamin. On physical examination, she was moderately obese. Her blood pressure was 155/75 mm Hg, and the pulse rate was 80/min. Bilateral carotid murmurs with a parvus-tardus pattern were detected. A 3/6 crescendo-decrescendo systolic ejection murmur, loudest at the right upper sternal border with extension to both carotids, was evident.
      • 1.
        On the basis of the clinical information provided, which one of the following diagnoses is least likely in this patient?
        • a.
          Myocardial infarction (MI)
        • b.
          Aortic stenosis
        • c.
          Acute pericarditis
        • d.
          Unstable angina
        • e.
          Pulmonary embolus
      A diagnosis of MI is based on the triad of history, electrocardiogram, and enzymes—2 of the 3 are necessary for the diagnosis. The patient's substernal heaviness is 1 of the typical manifestations of acute MI. The pain commonly extends down the ulnar aspect of the left arm but frequently travels to the opposite arm. Nausea and vomiting occur in more than 50% of patients with inferior transmural MI, presumably because of activation of the vagal reflex or stimulation of left ventricular receptors.
      • Pasternak RC
      • Braunwald E
      • Sobel BE
      Acute myocardial infarction.
      A crescendo-decrescendo systolic murmur that extends to both carotid arteries along with a parvus-tardus pattern suggests aortic stenosis. The single most important physical finding indicating the severity of the disease process is the carotid upstroke. Carotid upstroke that is delayed (tardus) and diminished (parvus) is the physiological expression of a compromised outflow tract. Acute pericarditis classically manifests with sharp and pleuritic posterior precordial pain that extends to the left trapezoid ridge. Our patient's pain was not pleuritic and was unrelated to posture. Thus, acute pericarditis is the least likely diagnosis. The pattern of pain in unstable angina can be categorized as (1) new-onset (<2 months) angina, (2) chronic angina progressing to Canadian class III or IV, (3) post-MI angina, (4) non-Q wave MI angina, (5) variant angina, or (6) angina at rest. If this patient's pain is due to a cardiac problem, unstable angina is certainly 1 of the possibilities. The pain resulting from pulmonary embolism may resemble that of acute MI, and in massive embolism it is located substernally. This patient's risk factors for deep venous thrombosis are obesity, smoking, and estrogen replacement therapy.
      Laboratory evaluation revealed the following results (reference ranges shown parenthetically): hemoglobin, 13.2 g/dL (12.0-15.5 g/dL); creatine kinase, 122 U/L (38-176 U/L); glucose, 196 mg/dL (70-100 mg/dL); and aspar-tate aminotransferase, 14 U/L (12-31 U/L). Findings on chest radiography were unremarkable. An ECG was obtained in the emergency department.
      The patient was admitted to the hospital to rule out MI and for further diagnostic work-up of her chest discomfort. She was given aspirin, nitrate as needed, and oxygen and was observed. The next morning she experienced a recurrence of the chest pain, and a second ECG was obtained during the episode of pain (Figure 1).
      • 2.
        Based on the clinical picture of this patient and the ECG (Figure 1), which one of the following is the least appropriate treatment?
        • a.
          Aspirin
        • b.
          Thrombolytics
        • c.
          Heparin
        • d.
          Calcium channel blockers
        • e.
          Nitrates
      Figure thumbnail gr1
      Fig. 1Electrocardiogram obtained during an episode of chest pain.
      The ECG (Figure 1) revealed pronounced ST elevation in the inferior leads (II, III, and aVF) with reciprocal ST-segment depression in the anterior precordial leads (V1 through V3). This pattern of electrocardiographic changes is consistent with an acute injury or ischemia in the distribution of the right coronary artery. Antiplatelet therapy reduces the risk of vascular death by about one sixth and the risk of nonfatal MI by one third in patients with unstable angina or suspected acute MI and in those with a history of MI. Aspirin, the most commonly studied antiplatelet agent, is associated with a 25% reduction in vascular events. In light of our patient's chest pain and the ECG, aspirin is appropriate treatment. Randomized trials
      • Bar FW
      • Vermeer F
      • de Zwaan C
      • et al.
      Value of admission electrocardiogram in predicting outcome of thrombolytic therapy in acute myocardial infarction: a randomized trial conducted by The Netherlands Interimiversity Cardiology Institute.
      have shown that infarct size salvage in patients with inferior MI is greatest for those with high ST-segment elevation or pronounced contralateral ST-segment depression who receive thrombolytics within 4 hours of onset of symptoms. Our patient fulfills all the aforementioned criteria, and thus thrombolysis is reasonable treatment. Because of the recognition of thrombosis in the underlying patho-physiology of acute coronary syndromes, intravenous hep-arin is considered standard therapy for preventing the propagation of the clotting process.
      • Hirsh J
      • Raschke R
      • Warkentin TE
      • Dalen JE
      • Deykin D
      • Poller L
      Hcparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety.
      A meta-analysis of 24 trials with all types of calcium channel blockers in patients with MI showed a nonsignificant 4% increase in mortality
      • Hennckens CH
      • Albert CM
      • Godfricd SL
      • Caziano JM
      • Buring JE
      Adjunctive drug therapy of acute myocardial infarction—evidence from clinical trials.
      and revealed no evidence of benefit during or after an acute MI. Calcium channel blockers are not recommended as standard therapy during or after an MI. Nitrates decrease the consumption of oxygen by reducing ventricular preload and increase the supply of oxygen by reducing coronary vasospasm in patients who seek medical assessment within 24 hours of the onset of symptoms of acute MI,
      • Hennckens CH
      • Albert CM
      • Godfricd SL
      • Caziano JM
      • Buring JE
      Adjunctive drug therapy of acute myocardial infarction—evidence from clinical trials.
      and therefore they would be appropriate treatment.
      The patient's ECG returned to baseline spontaneously after 1 minute, and symptoms resolved. She was transferred to the coronary care unit and received aspirin, hep-arin, and sublingual nitroglycerin as needed. Her creatine kinase levels remained within the reference range. She continued to experience intermittent episodes of chest pain and was given an injection of technetium Tc 99m-labeled sestamibi during 1 of the subsequent episodes. However, no myocardial perfusion defects were evident.
      • 3.
        Which one of the following is false regarding the diagnostic procedure performed in our patient?
        • a.
          Normal images during chest pain strongly suggest that the pain is not due to myocardial ischemia
        • b.
          Healthy liver function is important to obtain the best images
        • c.
          Injection of radiolabeled sestamibi is the imaging procedure of choice in obese patients
        • d.
          Accumulation of radiolabeled sestamibi in the lungs indicates ventricular dysfunction and is a poor prognostic sign
        • e.
          Because the injection of radiolabeled sestamibi was given to the patient during an episode of pain, the best images can be obtained 1 to 2 hours after the injection
      Radiolabeled sestamibi is a new myocardial perfusion imaging agent. Once it accumulates within the myocardial cell, it is bound within the mitochondria in a relatively stable fashion. Myocardial perfusion defects accurately predict the presence of hemodynamically important CAD. Therefore, normal images during pain suggest that the pain is not due to cardiac ischemia but do not absolutely exclude ischemia.
      • Taillefer R
      • Primcau M
      • Costi P
      • Lambert R
      • Leveille J
      • Latour Y
      Technctium-99m-seslamibi myocardial perfusion imaging in detection of coronary artery disease: comparison between initial (1-hour) and delayed (3-hour) postexercise images.
      After injection of sestamibi, the uptake in the liver system is high, with subsequent excretion into the biliary tract. This excretion is critical for the clearest images. Liver disease impairs the liver's ability to excrete the sestamibi. Images obtained with use of radiolabeled sestamibi generally have better quality than those with thallium-labeled medium
      • Pasternak RC
      • Braunwald E
      • Sobel BE
      Acute myocardial infarction.
      ; they have substantially less low-radiation background scatter and are therefore clearer. Because clarity of images is an issue with morbidly obese patients, injection of radiolabeled sestamibi is considered the imaging procedure of choice. Normally, very little thallium accumulates in the lungs after exercise. Thallium uptake by the lungs signifies exercise-induced left ventricular dysfunction
      • Zaret BL
      • Wackers FJ
      Nuclear cardiology (first of two parts).
      ; however, this has not been shown with sestamibi. After injection, the lungs and the liver usually take up sestamibi, and its presence in these regions is not associated with ventricular dysfunction. Recently, investigators demonstrated that a small degree of redistribution occurs with sestamibi. Three hours after the injection of sestamibi during a stress test or episode of pain, normally perfused cells have a significantly faster clearance than the ischemie myocardial cells.
      • Taillefer R
      • Primcau M
      • Costi P
      • Lambert R
      • Leveille J
      • Latour Y
      Technctium-99m-seslamibi myocardial perfusion imaging in detection of coronary artery disease: comparison between initial (1-hour) and delayed (3-hour) postexercise images.
      Thus, imaging should be performed no later than 1 to 2 hours after the injection of sestamibi during a stress test or episode of chest pain.
      The patient subsequently underwent coronary angiog-raphy in conjunction with intravascular ultrasonography (IVUS). IVUS revealed no obstructive lesions, and the coronary arteries were otherwise normal. However, there was severe coronary vasoconstriction due to the catheter in the circumflex and right coronary arteries. The evening after catheterization, the patient had recurrent chest pain with ST elevation and nonsustained polymorphic ventricular tachycardia.
      • 4.
        Which one of the following is the most appropriate step in the further management of this patient?
        • a.
          Obtain another coronary angiogram with coronary provocation because the diagnosis ofvasospasm has not been confirmed
        • b.
          Perform an electrophysiologic study to determine the cause of ventricular tachycardia
        • c.
          Place an implantable defibrillator for the possibility of future episodes of ventricular tachycardia
        • d.
          Administer vasodilatory medications, ie, long-acting nitrates and calcium channel blockers
        • e.
          Administer sublingual nitroglycerine as needed for episodic chest pain
      Coronary vasospasm can be diagnosed on the basis of the triad of chest pain, ST elevation, and nonobstructive CAD. Spontaneous resolution of symptoms and return of ST segment to baseline further support this diagnosis. This patient not only experienced angina type chest pain with ST elevations but also had coronary vasospasm during angiography and IVUS. Therefore, the criteria for coronary vasospasm has been fulfilled, and angiographie provocation is unnecessary. Although she had a nonsustained ventricular tachycardia, she did not experience presyncopal or syncopal symptoms. Moreover, the tachycardia occurred in association with myocardial ischemia and resolved when the episode ended; thus, an electrophysiologic study is not warranted. The most likely cause of her ventricular tachycardia is ischemia-induced arrhythmia, and the therapeutic choice is treatment of the underlying cause. At this time, defibrillator placement is unnecessary. The treatment of choice for coronary vasospasm is vasodilatory agents such as long-acting nitrates and calcium channel blockers. Usually, 1 class of medications, eg, nitrates, is instituted, and a second class is added if the patient remains symptomatic. One of the main reasons to use long-acting nitrates and calcium channel blockers is to prevent the frequent recurrence of vasospastic spells. Sublingual nitrates may prove to be helpful in treating an acute episode, but they will not prevent future recurrence of these attacks.
      The patient was treated with extended-release iso-sorbide mononitrate, and diltiazem was added later. Because of an occasional recurrence of her symptoms, the dosages were increased, and eventually arginine hydro-chloride was added to her regimen. After a period of complete relief, she had occasional symptoms. The addition of quinapril diminished her symptoms considerably.
      • 5.
        Which one of the following statements about our patient's diagnosis is false?
        • a.
          Management and prevention of atherosclerosis have central roles in arresting the disease process
        • b.
          Placement of coronary artery stents has an established therapeutic role
        • c.
          In the absence of severe coronary artery stenosis, complications such as MI or death are rare
        • d.
          Results of acetylcholine challenge determine whether the disease process is due to endothelial dysfunction
        • e.
          ST-segment elevation observed during ischemie episodes does not indicate myocardial injury
      Investigators have suggested that all coronary arteries in patients with vasospasm are affected by endothelial injury or atherosclerosis even though these arteries may seem angiographically normal.
      • Lee SJ
      • Park SJ
      • Park SW
      • et al.
      Increased basal tone and hyper-responsiveness to acetylcholine and ergonovine in spasm-related coronary arteries in patients with variant angina.
      Such lesions predispose to coronary vasospasm regardless of the underlying pathophysiol-ogy. Thus, aggressive management of these lesions should be a key component of vasospasm treatment. Despite isolated case reports of stent placement as a means of managing patients with these frequently challenging conditions, no clinical trials have demonstrated efficacy with this approach. Promising results have been reported with stent placement in patients whose condition is refractory to medical treatment,
      • Kultursay H
      • Can L
      • Payzin S
      • et al.
      A rare indication for slcnting: persistent coronary artery spasm.
      but it is investigational and therefore has no established role in treatment. Most studies have demonstrated that patients without severe obstructive CAD have a good prognosis; this was supported by a recent study involving long-term follow-up of 277 patients without pronounced CAD who had confirmed vasospasm.
      • Bory M
      • Pierron F
      • Panagides D
      • Bonnet JL
      • Yvorra S
      • Desfossez L
      Coronary artery spasm in patients with normal or near normal coronary arteries: long-term follow-up of 277 patients.
      Coronary vasospasm elicited by methylergometrine maleate is mediated by serotonergic (5-hydroxytriptamine2) receptors. Methylergometrine-induced vasospasm is thought to be due to hyperreactivity of vascular smooth muscle cells or endothelial dysfunction. Paradoxical vasoconstriction induced by acetylcholine, however, is more specific for endothelial dysfunction, probably because acetylcholine causes endothelium-dependent relaxation through the release of nitric oxide.
      • Lee SJ
      • Park SJ
      • Park SW
      • et al.
      Increased basal tone and hyper-responsiveness to acetylcholine and ergonovine in spasm-related coronary arteries in patients with variant angina.
      This response seems to be lost in pathologic states, such as hypercholesterolemia, hypertension, and atherosclerosis. An ECG obtained during an angina attack in patients with vasospasm shows elevation and depression of the ST segment, which are not necessarily associated with myocardial injury.
      The patient is currently receiving a combination of long-acting and regular diltiazem, pravastatin, maximal dose of arginine, isosorbide mononitrate, quinapril, and sublingual nitroglycerine as needed. Her symptoms are well controlled with this regimen, although she has occasional recurrence of chest pains.

      DISCUSSION

      Strong evidence suggests that any process that injures en-dothelium, such as atherosclerosis, balloon injury, hypoxia, and reperfusion, can lead to coronary vasospasm.
      • Maxwell AJ
      • Cooke JP
      Regulation of vasomotor tone in comprehensive cardiovascular medicine.
      Our patient has 4 risk factors for coronary atherosclerosis: smoking, family history of CAD, hyperlipidemia, and hypertension. Three of these are modifiable, and aggressive treatment should be the cornerstone of her therapy. Smoking is believed to be a risk factor for coronary vasospasm in women. Caralis et al
      • Caralis DG
      • Dcligonul U
      • Kem MJ
      • Cohen JD
      Smoking is a risk factor for coronary spasm in young women.
      tested the hypothesis that an association exists between smoking and pure coronary vasospasm in premenopausal women. In that case-control study, 62% of patients and only 17.5% of control subjects were smokers. Our patient has a 35-pack-year history of smoking. Smoking is believed to impair endothelium-dependent va-sodilation. Activity of nitric oxide, an endothelium-dependent coronary vasodilator, is reduced in patients with coronary ischemie disease, and the same is probably true in those with coronary endothelial dysfunction.
      • Caralis DG
      • Dcligonul U
      • Kem MJ
      • Cohen JD
      Smoking is a risk factor for coronary spasm in young women.
      Hypercholesterolemia is believed to be an independent risk factor for coronary vasospasm. In addition to a reduction in nitric oxide activity, levels of endothelin 1, a coronary vasoconstrictor peptide, are shown to be increased in the plasma of patients with hypercholesterolemia.
      Whether endothelial dysfunction is primary in the initiation of hypertension or is merely an epiphenomenon is unclear. However, treatment of elevated blood pressure normalizes endothelium-dependent relaxation, a suggestion that the endothelial abnormality is secondary in the hypertensive process.
      • Maxwell AJ
      • Cooke JP
      Regulation of vasomotor tone in comprehensive cardiovascular medicine.
      In addition, platelet dysfunction seems to have a role in the pathogenesis of coronary vasospasm. In patients with variant angina, during attacks there is biochemical evidence of platelet activation manifested by elevated levels of thromboxane metabolites. Various modalities have been used to improve endothelium-dependent vasodilation. Recently, the Trial on Reversing Endothelial Dysfunction showed that administration of quinapril (an angiotensin-converting enzyme inhibitor) for 6 months in patients with documented CAD improved coronary va-somotor response to acetylcholine, indicating improvement in endothelial function.’
      • Purcell H
      Conference review: scientific session of the American College of Cardiology 1996.
      Moreover, administration of the nitric oxide precursor, arginine, can help restore endothelium-dependent vasodilation. Our patient's symptoms have been controlled with the aforementioned interventions. In addition to taking vasodilators, diltiazem, and long-acting nitrates, she is receiving treatment for dys-lipidemia, estrogen replacement therapy, quinapril, and arginine and is participating in smoking cessation programs. She may benefit more by the addition of an antiplatelet agent, probucol for its antioxidant properties, and fish oil for attenuation of atherosclerosis and improvement in endothelial-vasodilator function.

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        Increased basal tone and hyper-responsiveness to acetylcholine and ergonovine in spasm-related coronary arteries in patients with variant angina.
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        Regulation of vasomotor tone in comprehensive cardiovascular medicine.
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