78-Year-Old Woman With Intermittent Chest Pain and Palpitations

Abstract

A 78-year-old woman presented to the emergency department with pressure-like chest pain, palpitations, and nausea that began the night before. She had experienced these symptoms intermittently over the past 6 months. These episodes often occurred at rest and, to some extent, with anxiety; lasted several hours; and then resolved spontaneously. The symptoms did not worsen with inspiration, exertion, or position. She had no shortness of breath, orthopnea, paroxysmal nocturnal dyspnea, or lower-extremity edema. One year before, she underwent an outpatient work-up for palpitations, which included 48-hour Holter monitor that revealed brief runs of supraventricular tachycardia and radionucleotide stress test that was normal. She was started on metoprolol but continued to have these episodes intermittently. Her medical history was notable for hypertension and osteoarthritis. She did not have a history of diabetes, hyperlipidemia, smoking, or family history of premature coronary artery disease. Upon arrival to the emergency department, her heart rate was 85 beats per minute and blood pressure was 124/57 mm Hg. She continued to have intermittent chest pressure, rated 7 out of 10, with some improvement with sublingual nitroglycerin. Physical examination revealed a regular rate and rhythm with no murmurs, rubs, or gallops. No jugular venous distension, rales, or lower extremity edema was noted. 12-lead electrocardiogram (ECG) showed normal sinus rhythm with no ST-segment or T-wave abnormalities. Her chest radiograph was read as normal. Initial laboratory evaluation revealed the following (reference ranges provided parenthetically): hemoglobin, 10.0 g/dL (12.0 to 15.5 g/dL); platelets, 256 x 109/L (157 to 371 x 109/L); leukocytes, 5.6 x 109/L (3.4 to 9.6 x 109/L); sodium, 142 mmol/L (135 to 145 mmol/L); creatinine, 1.03 mg/dL (0.59 to 1.04 mg/dL); 0-, 2-, and 12-hour high-sensitivity troponin T (hscTnT) was 10, 10, and 15 ng/L, respectively (<10 ng/L); sedimentation rate, 15 mm/1h (0 to 29 mm/1h); and D-dimer, 312 ng/mL FEU(< 500 ng/mL FEU).1.Which one of the following diagnoses is the most likely explanation for this patient’s presentation?a)Pulmonary embolusb)Pericarditisc)Paroxysmal atrial fibrillationd)Acute myocardial infarctione)Esophageal spasm Pulmonary embolus can effectively be ruled out, given that the patient’s chest pain was nonpleuritic, her oxygen saturation and heart rate were normal, she had no clinical risk factors for deep venous thrombosis, and her D-dimer was normal. Pericarditis is unlikely, as her chest pain was not positional, ECG was without diffuse ST elevation or PR depression, no friction rub was auscultated, and inflammatory markers were normal. ECG and telemetry monitoring during episodes of chest pain did not reveal paroxysmal atrial fibrillation, making that unlikely to be the source of her symptoms. The most likely cause of her symptoms is an acute myocardial infarction (MI). Her chest pain improved with sublingual nitroglycerin and laboratory results demonstrated a mild troponin elevation with a rising pattern with a value > 99th percentile upper reference limit. Esophageal spasm may also cause pressure-like chest pain that may improve with administration of nitroglycerin; however, it is not associated with elevated cardiac biomarkers. A transthoracic echocardiogram (TTE) was performed before the patient was seen on rounds and revealed an ejection fraction of 54% and akinesis of the ventricular septum most prominent at the base. In comparison, a TTE from 1 year before demonstrated no regional wall motion abnormalities and an ejection fraction of 60%.2.Which one of the following steps should be performed next?a)Coronary angiographyb)Stress electrocardiogram (ECG)c)Radionuclide stress myocardial perfusion imagingd)Computed tomography (CT) angiography of the coronary arteriese)Observe 12 hours for resolution Coronary angiography is the “gold standard” for evaluating epicardial coronary vessels and is the next best diagnostic test. Given the presence of a new regional wall motion abnormality and a compatible clinical history, concern for acute MI was predominant. Stress tests, including stress ECG and radionuclide stress imaging, would be contraindicated. Further, patients with elevated troponin suggestive of MI and new regional wall motion abnormality in an ischemic territory, as a group, benefit therapeutically from an invasive strategy.1Wallentin L. Lindholm D. Siegbahn A. et al.Biomarkers in relation to the effects of ticagrelor in comparison with clopidogrel in non-ST-elevation acute coronary syndrome patients managed with or without in-hospital revascularization: a substudy from the Prospective Randomized Platelet Inhibition and Patient Outcomes (PLATO) trial.Circulation. 2014; 129: 293-303PubMed Google Scholar Coronary CT angiography has limited utility in such patients, who, as a group, often require intervention. Observation can be considered in patients who present with suspicion of noncardiac chest pain with low pretest probability for coronary stenosis. In this case, it would not yield new information and would result in a delay in diagnosis and potential therapy. She underwent coronary angiography, which demonstrated no hemodynamically significant stenosis of the epicardial coronary vessels.3.Which one of the following steps would provide the most diagnostic information for evaluating the cause of her elevated hscTnT and regional dysfunction?a)Provocative coronary spasm testingb)Thrombophilia testingc)Cardiac magnetic resonance imaging (MRI) with intravenous (IV) contrast materiald)Endomyocardial biopsye)Urine drug screen Myocardial infarction with nonobstructive coronary arteries (MINOCA) is a working diagnosis that is defined by the presence of features consistent with acute MI, including a rise and/or fall in serial cardiac biomarkers with at least one value above the 99th percentile and corroborative clinical evidence of ischemia, and the lack of obstructive coronary artery disease on coronary angiography.2Thygesen K. Alpert J.S. Jaffe A.S. et al.Fourth Universal Definition of Myocardial Infarction (2018).J Am Coll Cardiol. 2018; 72: 2231-2264Crossref PubMed Scopus (1539) Google Scholar Our patient meets criteria based on her troponin elevation, new regional wall motion abnormality in an ischemic territory, and lack of coronary artery stenosis greater than 50%. Further evaluation is required in patients with MINOCA to elucidate potential underlying causes and effectively guide treatment. Epicardial coronary spasm and microvascular angina can lead to MINOCA and should be suspected in patients with histories of recurrent angina, as in our patient. Provocative coronary spasm testing with intracoronary acetylcholine or ergonovine in the catheterization lab and procedures to detect abnormal vasodilator reserve can be used to evaluate patients like this with nonobstructive coronary arteries. However, provocative testing requires sophisticated centers and protocols, especially if one wishes to interrogate the microvasculature as well as the epicardial coronary arteries. Genetic thrombophilia disorders may predispose to formation of thrombus in distal vessels and has been associated with MINOCA in previous studies.3Mansourati J. Da Costa A. Munier S. et al.Prevalence of factor V leiden in patients with myocardial infarction and normal coronary angiography.Thromb Haemost. 2000; 83: 822-825Crossref PubMed Scopus (92) Google Scholar Despite this, routine testing is not recommended in patients with MINOCA lacking personal or family histories suggestive of thrombophilic disorder. Cardiac MRI with IV contrast material is the test that would provide the most diagnostic information, as it would allow for evaluation of several possibilities for this presentation including myocardial ischemia and infarction, myocarditis, or structural myocardial diseases. In fact, previous studies using cardiac MRI to evaluate patients with presentations suggestive of MINOCA have demonstrated that myocarditis is actually the most common diagnosis.4Pasupathy S. Air T. Dreyer R.P. Tavella R. Beltrame J.F. Systematic review of patients presenting with suspected myocardial infarction and nonobstructive coronary arteries.Circulation. 2015; 131: 861-870Crossref PubMed Scopus (476) Google Scholar Although myocarditis is often thought to be a diffuse disease, it can be localized as well.5Caforio A.L.P. Malipiero G. Marcolongo R. Iliceto S. Myocarditis: a clinical overview.Curr Cardiol Rep. 2017; 19: 63Crossref PubMed Scopus (59) Google Scholar Endomyocardial biopsy can be used to aid in the diagnosis of myocarditis when other evaluations are inconclusive, but the only identified area of abnormality was in the septum which is a difficult area to biopsy. Random biopsies for myocarditis have a very low yield.5Caforio A.L.P. Malipiero G. Marcolongo R. Iliceto S. Myocarditis: a clinical overview.Curr Cardiol Rep. 2017; 19: 63Crossref PubMed Scopus (59) Google Scholar A urine drug screen may be of value in the diagnosis of drug-induced abnormalities in coronary vasomotion, but its diagnostic yield would be low in our patient, given her age and clinical history. Cardiac MRI with IV contrast material demonstrated a perfusion defect in the ventricular septum, most prominent in the basilar portion, consistent with the area of regional wall motion abnormality seen on TTE upon presentation. No wall motion abnormalities, delayed enhancement, or myocardial edema was seen on cardiac MRI.4.Based on the available clinical data, what is the most likely etiology of this patient’s presentation?a)Myocarditisb)Microvascular angina with MIc)Epicardial coronary vasospasmd)Coronary artery embolisme)Takotsubo cardiomyopathy Cardiac MRI enables detection of various features of myocarditis, including evidence of inflammatory hyperemia and edema or late gadolinium enhancement suggestive of myocyte necrosis and scar. These findings were not present on our patient’s cardiac MRI, making myocarditis less likely. Microvascular angina is a common cause of chest pain with nonobstructive coronary artery disease with a particularly high prevalence in women and is the best answer.6Kaski J.C. Rosano G.M. Collins P. Nihoyannopoulos P. Maseri A. Poole-Wilson P.A. Cardiac syndrome X: clinical characteristics and left ventricular function. Long-term follow-up study.J Am Coll Cardiol. 1995; 25: 807-814Crossref PubMed Scopus (408) Google Scholar Features of her presentation consistent with microvascular angina include the recurrent nature of her symptoms, the relationship to anxiety/stress, her improvement with sublingual nitroglycerin, and transient regional wall motion abnormality on TTE with concordant perfusion defect on cardiac MRI. Epicardial coronary vasospasm could also have explained her presentation and can be associated with transient perfusion defects on cardiac MRI but requires provocative coronary spasm testing to differentiate it definitively from microvascular dysfunction. However, given the high prevalence of microvascular angina in women and that vasospasm is more likely to present ischemic ECG changes, which were not present, microvascular angina is more likely. Coronary artery embolism is an uncommon cause of acute MI that can affect both epicardial and the microcirculation and may be difficult to detect angiographically. It should be suspected in patients with MINOCA and comorbidities associated with high risk for systemic embolism, such as prosthetic heart valves, infective endocarditis, atrial fibrillation, or dilated cardiomyopathy with apical thrombus. MRI may show myocardial edema or delayed enhancement suggestive of infarct or may be unremarkable, dependent on the size of the embolus. Our patient did not have any significant risk factors for coronary artery emboli, making this improbable to be the cause of her presentation. Takotsubo cardiomyopathy is a syndrome characterized by transient left ventricular dysfunction, most commonly associated with apical ballooning in the absence of significant coronary artery disease. Its pathogenesis is poorly understood, but postulated mechanisms include catecholamine excess, microvascular dysfunction, and/or coronary spasm. It is not included in MINOCA by the Universal Definition of MI.2Thygesen K. Alpert J.S. Jaffe A.S. et al.Fourth Universal Definition of Myocardial Infarction (2018).J Am Coll Cardiol. 2018; 72: 2231-2264Crossref PubMed Scopus (1539) Google Scholar Cardiac MRI showed no evidence of the type of left ventricular dysfunction suggestive of Takotsubo cardiomyopathy in our patient.5.In addition to sublingual nitroglycerin as needed, which one of the following is the most appropriate treatment at this time?a)Diltiazemb)Lisinoprilc)Sildenafild)Aspirine)Atorvastatin Of the available choices, diltiazem is the most appropriate treatment. Calcium channel blockers and beta blockers have been found to be effective in relieving microvascular angina in most studies and either can be used as first line treatment for microvascular angina.7Lanza G.A. Colonna G. Pasceri V. Maseri A. Atenolol versus amlodipine versus isosorbide-5-mononitrate on anginal symptoms in syndrome X.Am J Cardiol. 1999; 84: 854-856.A8Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar The benefit of angiotensin-converting enzyme (ACE) inhibitors, such as lisinopril, for microvascular angina is not well established, but they may be considered as adjunctive therapy to calcium channel blockers.8Masumoto A. Mohri M. Takeshita A. Three-year follow-up of the Japanese patients with microvascular angina attributable to coronary microvascular spasm.Int J Cardiol. 2001; 81: 151-156Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar Sildenafil is not a first-line therapy but may be used in patients with symptoms refractory to other therapies. There is no clear benefit of aspirin or statins for microvascular angina. Despite this, because of the increased cardiovascular mortality in this patient population and the thought that the substrate for MINOCA is usually atherosclerotic, they are both commonly used. The patient was started on diltiazem daily with sublingual nitroglycerin as needed and was discharged home from the hospital in stable condition. Myocardial infarction is defined as a clinical or pathologic event in the setting of myocardial ischemia, in which there is evidence of myocardial injury based on a rise or fall of troponin, along with supportive evidence including typical symptoms, ECG changes, or imaging findings of loss of viable myocardium or new regional wall motion abnormalities.2Thygesen K. Alpert J.S. Jaffe A.S. et al.Fourth Universal Definition of Myocardial Infarction (2018).J Am Coll Cardiol. 2018; 72: 2231-2264Crossref PubMed Scopus (1539) Google Scholar MINOCA is a heterogenous working diagnosis in patients presenting with evidence of acute MI and no hemodynamically significant obstruction seen on coronary angiography. Previous studies suggest that patients with MINOCA are younger (median age 59 vs 64; P<.001)9Gehrie E.R. Reynolds H.R. Chen A.Y. et al.Characterization and outcomes of women and men with non-ST-segment elevation myocardial infarction and nonobstructive coronary artery disease: results from the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA guidelines (CRUSADE) quality improvement initiative.Am Heart J. 2009; 158: 688-694Crossref PubMed Scopus (171) Google Scholar and more often women (43% vs 24%; P<.001)4Pasupathy S. Air T. Dreyer R.P. Tavella R. Beltrame J.F. Systematic review of patients presenting with suspected myocardial infarction and nonobstructive coronary arteries.Circulation. 2015; 131: 861-870Crossref PubMed Scopus (476) Google Scholar compared with patients who have MI and obstructive coronary artery disease. This may be a function of the populations studied, as it is likely that microvascular disease alone may influence a much larger group of patients.10Murthy V.L. Naya M. Taqueti V.R. et al.Effects of sex on coronary microvascular dysfunction and cardiac outcomes.Circulation. 2014; 129: 2518-2527Crossref PubMed Scopus (378) Google Scholar MINOCA has been reported in approximately 10% of patients presenting with clinical myocardial infarction, and obtaining an accurate diagnosis in these cases can be challenging.9Gehrie E.R. Reynolds H.R. Chen A.Y. et al.Characterization and outcomes of women and men with non-ST-segment elevation myocardial infarction and nonobstructive coronary artery disease: results from the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA guidelines (CRUSADE) quality improvement initiative.Am Heart J. 2009; 158: 688-694Crossref PubMed Scopus (171) Google Scholar The pathogenesis of MINOCA may be related to epicardial, microvascular, or structural myocardial dysfunction. Epicardial causes include coronary artery spasm as seen in “variant angina,” coronary artery dissection, or acute thromboses that form at the site of nonobstructive eccentric plaques that may be missed on coronary angiography or may resolve with anticoagulation prior to angiography. Microvascular causes include coronary microvascular endothelial dysfunction or, less frequently, thrombus secondary to coronary artery embolism or a thrombophilia that lodges in the microvasculature. Structural myocardial diseases—including myocarditis, Takotsubo cardiomyopathy, hypertrophic cardiomyopathy, or dilated cardiomyopathy—often present with features similar to MINOCA. Although microvascular disease may be a participant in these entities, and a portion of the literature considers them to be classified under MINOCA, they are not considered to be part of MINOCA by the Fourth Universal Definition of MI.2Thygesen K. Alpert J.S. Jaffe A.S. et al.Fourth Universal Definition of Myocardial Infarction (2018).J Am Coll Cardiol. 2018; 72: 2231-2264Crossref PubMed Scopus (1539) Google Scholar In addition, Type-II MI, or supply-demand ischemia, is another entity that may lead to MI in patients with nonobstructive coronary arteries and should be suspected in the appropriate clinical setting. A previous systematic review and pooled analysis of patients evaluated by cardiac MRI for presentations suggestive of MI with elevated troponin and normal angiograms demonstrated that only 24% of patients had features suggestive of small subendocardial infarctions as indicated by delayed subendocardial hyperenhancement. The remainder had findings of structural myocardial dysfunction, most often myocarditis, or no detectable abnormalities.4Pasupathy S. Air T. Dreyer R.P. Tavella R. Beltrame J.F. Systematic review of patients presenting with suspected myocardial infarction and nonobstructive coronary arteries.Circulation. 2015; 131: 861-870Crossref PubMed Scopus (476) Google Scholar Delineating the cause of MINOCA can be difficult and often requires advanced cardiac imaging or additional invasive tests. Cardiac MRI is becoming increasingly used to evaluate MINOCA, as it provides the ability to identify features suggestive of MI, myocarditis, or structural myocardial diseases. Sophisticated intracoronary imaging may be used to help identify evidence of nonobstructive plaque rupture not visible on angiography. Provocative spasm testing with vasospastic agents may also be considered in patients with histories suggestive of vasospasm, and inducible spasm has been reported in anywhere from 15% to 74% of patients with MINOCA.11Wang C.H. Kuo L.T. Hung M.J. Cherng W.J. Coronary vasospasm as a possible cause of elevated cardiac troponin I in patients with acute coronary syndrome and insignificant coronary artery disease.Am Heart J. 2002; 144: 275-281Crossref PubMed Google Scholar, 12Da Costa A. Isaaz K. Faure E. et al.Clinical characteristics, aetiological factors and long-term prognosis of myocardial infarction with an absolutely normal coronary angiogram: a 3-year follow-up study of 91 patients.Eur Heart J. 2001; 22: 1459-1465Crossref PubMed Scopus (165) Google Scholar Comprehensive evaluation of the coronary microvasculature, using pressure wires to evaluate coronary flow reserve and index of microvasculature resistance, may also be performed and is used in some centers. Often, further invasive testing is deferred if not immediately performed in the catheterization laboratory, as these are not required for diagnosis of coronary vasospasm or microvascular dysfunction and initiation of empiric treatment. It is worth noting that the etiology of the myocardial injury remains undetermined in nearly one-fourth of patients who are evaluated by cardiac MRI.4Pasupathy S. Air T. Dreyer R.P. Tavella R. Beltrame J.F. Systematic review of patients presenting with suspected myocardial infarction and nonobstructive coronary arteries.Circulation. 2015; 131: 861-870Crossref PubMed Scopus (476) Google Scholar Treatment for MINOCA is specific to its underlying cause. Owing to the heterogeneity of causes, studies evaluating the prognosis of MINOCA are of limited value. However, available data suggest that the prognosis is guarded. A meta-analysis of six studies comparing the 12-month mortality of patients with MINOCA to those with MI secondary to obstructive coronary atherosclerosis suggests that MINOCA is associated with lower mortality than MI and obstructive disease (3.5% vs 6.7%; P=.003) but greater mortality than those used as a control population.4Pasupathy S. Air T. Dreyer R.P. Tavella R. Beltrame J.F. Systematic review of patients presenting with suspected myocardial infarction and nonobstructive coronary arteries.Circulation. 2015; 131: 861-870Crossref PubMed Scopus (476) Google Scholar