Jennifer A. Snyder, MPAS, PA-C

A 55-year-old white man with controlled hypertension and hypercholesterolemia awoke with mild chest discomfort that he believed was mild gastroesophageal reflux. He denied radiation of pain to the shoulders, arms, back, or neck; dyspnea; palpitations; diaphoresis; nausea/vomiting; cough; or fever, during the first 30 hours of discomfort. There was no change in discomfort with deep breath, palpation of the chest, or administration of antacids. Minimal, short-lived improvement was noted with belching.

The patient had no trouble sleeping in the prone position and did not notice an increase in discomfort or unusual difficulty during his daily vigorous 30-minute aerobic workout. In fact, his symptoms seemed to improve or disappear during exercise. The patient denied any recent illness or exposure to sick people, had not traveled outside the United States, and had not been exposed to radiation of the chest wall. At the end of the second day of discomfort, the patient noted irregular palpitations with mild shortness of breath and was transported to the hospital for evaluation. He denied being a cigarette smoker or illicit drug user.

The patient had no history of MI or diabetes. The patient’s father had an MI in his 80s, and two uncles died suddenly in their 50s of “massive heart attacks.” His mother, who had died of sepsis of uncertain etiology approximately 10 days earlier, also had hypertension and hypercholesterolemia but no history of coronary artery disease (CAD). Both of the patient’s adult daughters had been diagnosed with celiac disease in the preceding three years. His elder daughter had also been diagnosed with type 1 diabetes within the past two years.

On examination, the patient was afebrile, with a blood pressure of 143/87 mm Hg; pulse, 53 beats/min; and respiratory rate, 17 breaths/min. The patient’s weight was 204 lb and his height, 75 in (BMI, 25.5). The patient was in no apparent distress. Head, eyes, ears, nose, and throat were unremarkable. There was no significant jugular venous distention. The carotid pulses were full, and no bruits were appreciated. S₁ and S₂ sounds were within normal limits. No murmurs or S₃ or S₄ gallops were appreciated. The chest was clear on auscultation. Results of the abdominal exam were negative, no edema was noted in the extremities, and pulses were symmetrical.

ECG demonstrated subtle ST-segment elevation in leads I and aVL with a prominent R wave in lead V₁. This pattern was interpreted as consistent with an acute inferolateral MI. A baseline ECG, previously obtained by the patient’s internist, had been interpreted as normal.

Peak troponin level was 55 ng/mL (normal, < 0.03 ng/mL); total creatine kinase (CK), 807 U/L (reference range, 20 to 259 U/L); and mass CK-MB fraction, 44 ng/mL (0.1 to 6.6 ng/mL). Total cholesterol was 105 mg/dL, with both LDL- and HDL-cholesterol fractions at 46 mg/dL. A complete blood count without differential revealed a total white blood cell count of 53,000/µL. Hemoglobin and hematocrit were both low (12.3 g/dL and 34.5%, respectively). All indices were within normal limits, as was the platelet count. Glucose, blood urea nitrogen, creatinine, potassium chloride bicarbonate, and calcium were all within normal limits. The sodium level was slightly low (132 mEq/L). Emergency catheterization revealed an ejection fraction of 45% (reference range, 55% to 70%), with mild-to-moderate diffuse hypokinesis but normal coronary arteries.

The patient was diagnosed with myocarditis, likely of viral origin.

DISCUSSION

Although the incidence of myocarditis in the US is difficult to assess, autopsy reports implicate it in 8.6% to 12% of cases of sudden cardiac death in young adults,^1,2 and a large prospective series implicated myocarditis in 9% of cases of dilated cardiomyopathy.³ Myocarditis is considered to be at one extreme of a spectrum of perimyocardial processes that result in inflammation of the myocardium (see figure), pericardium, or both.⁴

The underlying pathology involves an acute injury to the myocyte. This activates the innate and humoral immune systems, resulting in severe inflammation. The immune reaction eventually subsides, and the myocardium recovers. In certain patients, however, myocardial inflammation persists, resulting in ongoing myocyte damage, relentless symptomatic heart failure, or even death.⁵

Although a variety of diagnostic criteria have been developed and employed, the diagnosis of myocarditis is often one of exclusion. First proposed in 1986, the Dallas criteria—a histopathologic classification for myocarditis diagnosis—are based on endomyocardial biopsy, with inflammatory cellular infiltrate (with or without associated myocyte necrosis) visible on conventionally stained myocardial tissue sections.⁵ However, this method poses significant practical limitations, including low sensitivity (43% to 64%) and complication and death rates of 6% and 0.4%, ­respectively.^5,6

An empiric diagnosis of myocarditis is often based on a combination of clinical findings including altered ECG, increase in myocardial enzymes, and lack of significant CAD.⁶ The recommended diagnostic cardiac magnetic resonance (CMR) imaging criteria for clinically suspected myocardial inflammation (ie, the Lake Louise Criteria) include at least two of the following:⁷

• Regional or global myocardial signal intensity increase in T2-weighted images.

• Increased global myocardial early gadolinium enhancement ratio between myocardium and skeletal muscle in gadolinium-enhanced T1-weighted images.

• At least one focal lesion with nonischemic regional distribution in inversion recovery–prepared gadolinium-enhanced T1-weighted images (“late gadolinium enhancement”).

Because of its reported high sensitivity and specificity (100% and 90%, respectively), CMR was used in the case patient to confirm the diagnosis of myocarditis.⁸ Specifically, CMR with contrast demonstrated normal left ventricular cavity size and mild reduction in overall left ventricular systolic function, with a visually estimated left ventricular ejection fraction of 45% to 50%. Regional hypokinesis of the mid-inferior wall and apical inferior septum was noted. Delayed contrast imaging demonstrated extensive non-CAD scarring and fibrosis, involving the basal anterior wall, basal inferior wall, and basal and midlateral wall in a pattern consistent with acute myocarditis.

Just as there is variability in the specific criteria by which the diagnosis of myocarditis can be made, the array of clinical findings with which it can manifest range from fatigue and other nonspecific symptoms to fulminant congestive heart failure and sudden death.⁶ Often, but not always, a viral prodrome precedes the onset of “cardiac symptoms” (eg, chest pain, dyspnea, palpitations, or syncope).⁵ This patient’s multiple risk factors for CAD and a suggestive, albeit atypical, history of chest discomfort, palpitations, and shortness of breath helped to focus the clinicians’ evaluation on the heart.

Potential Causes

Once a diagnosis of myocarditis is rendered, the next challenge is distinguishing its specific source from a plethora of potential etiologies, including infection, toxic exposure, or hypersensitivity/autoimmune reaction. Viral infections (mostly herpes, parvovirus, and cytomegalovirus) are thought to cause most cases of myocarditis in developed countries.^5,9

Viral myocarditis results when viruses enter cardiac myocytes and incite a cytotoxic effect with activation of the immune response, including expression of interferon , natural killer cells, and release of nitric oxide. The majority of patients recover, but some develop an adaptive immune response, which further causes cardiac damage. In this response, antibodies to viral and to some cardiac proteins are produced, and effector T lymphocytes proliferate. Viral genome or inflammatory mechanisms may persist, contributing to ventricular dysfunction leading to heart failure and arrhythmias.¹⁰

Celiac disease is a chronic gastroenterologic disease caused by an immune response to a gluten protein. Damage to the brush border of the small intestine results in an inability to absorb fat, protein, vitamins, and minerals. Intermittent diarrhea, abdominal pain, and bloating are most commonly reported, but celiac disease may also manifest less obviously with iron deficiency anemia, joint pain, muscle cramps, osteoporosis, and neuropathy.¹¹ Iron deficiency anemia that is refractory to iron replacement may offer insight into diagnosing myocarditis due to celiac disease.¹² Although studies have found that more than 4% of patients with myocarditis also had celiac disease, none had the classic GI symptoms of celiac disease.¹²

Takotsubo cardiomyopathy is a transient left ventricular apical ballooning syndrome of unknown etiology. (For more information, see Fasolino T. Takotsubo cardiomyopathy: a clinical overview). Patients who have experienced emotional or physiologic stress and postmenopausal women appear to be at greatest risk. The clinical symptoms mimic MI, including chest pain with ST-segment elevation in the precordial leads on ECG¹³ and minor elevation of the cardiac enzyme and biomarker levels.¹⁴ However, patients experiencing this stress cardiomyopathy lack evidence of atherosclerotic CAD.¹⁵ An echocardiogram or CMR imaging reveals characteristic wall motion hypokinesis, akinesis, or dyskinesis of the left ventricular apex and mid-ventricle that help to differentiate it from other forms of myocarditis.^15,16 Patient prognosis is favorable, with 95% of patients experiencing a full recovery; left ventricular dysfunction usually begins to improve in a few weeks.^13,14

Sarcoidosis is a systemic disease resulting in noncaseating granulomas in multiple organs.¹⁷ Initial presentation typically includes bilateral hilar adenopathy, pulmonary reticular opacities, and/or skin, joint, or eye lesions.¹⁸ Patients with cardiac sarcoidosis most commonly present with conduction disturbances and ventricular arrhythmias.¹⁷ Although frequently absent, clinical symptoms may include palpitations, syncope, dizziness, or chest pain and clinical heart failure.^17,18 It is difficult to distinguish cardiac sarcoidosis from other forms of myocarditis unless signs of systemic sarcoidosis are evident. A patient with suspected cardiac sarcoidosis should have an ECG to detect subclinical conduction abnormalities.¹⁷ The patient should wear a Holter monitor for 24 hours to screen for cardiac involvement, and echocardiography should be performed to define cardiac abnormalities.¹⁹

Giant-cell myocarditis (GCM) is a rare, rapidly progressive, and frequently fatal myocardial disease. Based on endomyocardial or surgical biopsy, GCM is histologically defined by multinucleated giant cells, a lymphocytic inflammatory infiltrate, and myocyte necrosis. It is often found in association with various immune-related systemic disorders.²⁰ Patients present with heart failure, ventricular arrhythmias, and atrioventricular block that fails to improve with standard therapy.²¹

Treatment and Management

The typical management of acute myocarditis includes supportive care for left ventricular dysfunction and arrhythmia control.²² Many of the standard heart failure therapies—β-blockers, ACE inhibitors, angiotensin receptor blockers, and aldosterone antagonists—are efficacious; several, at least in animal models, appear to exert anti-inflammatory as well as the standard cardiovascular effects.²³

Caution is advised regarding the selection of specific therapies. For example, in one study, metoprolol produced deleterious effects in acute murine Coxsackie virus myocarditis; inflammation, necrosis, and mortality significantly increased in the treatment group, compared with the placebo group.²³

Information on the effects of particular therapies for specific etiologies of myocarditis are limited, but some evidence supports immunosuppressive and immune-modulating therapies for chronic, virus-negative inflammatory cardiomyopathy. Immunosuppressive therapy is also beneficial for acute GCM and sarcoidosis.²³ For patients with myocarditis associated with celiac disease, a gluten-free diet alone or in combination with immunosuppressive agents can significantly improve clinical outcomes.¹²

OUTCOME FOR THE CASE PATIENT

Because the patient was already taking a statin and an ACE inhibitor for hypercholesterolemia and hypertension, respectively, as well as one baby aspirin per day, only a β-blocker was added to his discharge medication regimen.

Three months after hospital discharge, the patient underwent repeat CMR imaging. The ejection fraction had markedly improved to the 55%-to-60% range, although extensive midmyocardial-to-epicardial scarring in a multifocal pattern, primarily involving the basilar anterior and anterolateral wall, was still present, as was a small focus of an active (albeit healing) process in the inferior wall. Clinically, the patient was doing reasonably well and was vigorously exercising daily without dizziness, syncope, chest discomfort, or shortness of breath.

However, within several weeks of discharge, the patient reported having one two-hour episode of frequent palpitations at rest. Since that episode, palpitations have occurred infrequently. A 48-hour Holter monitor was ordered to better evaluate the palpitations and showed only rare premature ventricular contractions and isolated premature atrial contractions; no complex ectopy was noted. A follow-up stress echocardiogram was scheduled for 12 months, assuming the patient was free of clinical signs and symptoms of heart failure and arrhythmias at that time.

CONCLUSION

Myocarditis can manifest with a broad spectrum of signs and symptoms that may make its identification difficult, especially if a cardiac source is not initially considered in the differential diagnosis. However, for patients who present with elevated biomarkers and normal coronary artery anatomy, the identification of myocarditis is relatively easy; the difficulty in this circumstance relates to the identification of the specific etiology of the myocarditis.

The long-term prognosis for myocarditis is frequently good and the treatment straightforward, using medications that are modeled after standard heart failure therapy. However, depending on the etiology, specific treatment may be advisable—or required—in order to improve outcomes.

References

1. Fabre A, Sheppard MN. Sudden adult death syndrome and other ­nonischaemic causes of sudden cardiac death: a UK experience. Heart. 2006;92:316-320.

2. Doolan A, Semsarian C, Langlois N. Causes of sudden cardiac death in young Australians. Med J Aust. 2004;180:110-112.

3. Felker GM, Hu W, Hare JM, Hruban RH, et al. The spectrum of dilated cardiomyopathy: the Johns Hopkins experience with 1,278 patients. Medicine (Baltimore). 1999;78:270-283.

4. Leitman M, Tyomkin V, Peleg E, et al. Left ventricular function in acute inflammatory peri-myocardial diseases—new insights and long-term follow-up. Cardiovasc Ultrasound. 2012;10:42.

5. Blauwet LA, Cooper LT. Myocarditis. Prog Cardiovasc Dis. 2010;52:274-288.

6. Testani JM, Kolansky DM, Litt H, Gerstenfeld EP. Focal myocarditis mimicking acute ST-elevation myocardial infarction: diagnosis using cardiac magnetic resonance imaging. Tex Heart Inst J. 2006;33:256-259.

7. Friedrich MG, Sechtem U, Schulz-Menger J, et al. Cardiovascular magnetic resonance in myocarditis: a JACC white paper. J Am Coll Cardiol. 2009;53: 1475-1487.

8. Olimulder MA, van Es J, Galjee MA. The importance of cardiac MRI as a diagnostic tool in viral myocarditis-induced cardiomyopathy. Neth Heart J. 2009;17:481-486.

9. Mavrogeni S, Bratis K, Markussis V, et al. The diagnostic role of cardiac magnetic resonance imaging in detecting myocardial inflammation in systemic lupus erythematosus. Differentiation from viral myocarditis. Lupus. 2013;22:34-43.

10. Schultz JC, Hilliard AA, Cooper LT, Rihal CS. Diagnosis and treatment of viral myocarditis. Mayo Clin Proc. 2009;84:1001-1009.

11. Schuppan D, Dieterich W. Pathogenesis, epidemiology, and clinical manifestations of celiac disease in adults (2013). www.uptodate.com/contents/pathogenesis-epidemiology-and-clinical-manifestations-of-celiac-disease-in-adults. Accessed November 14, 2013.

12. Frustaci A, Cuoco L, Chimenti C, et al. Celiac disease associated with autoimmune myocarditis. Circulation. 2002;105:2611-2618.

13. Thakar S, Chandra P, Hollander G, Lichstein E. Electrocardiographic changes in Takotsubo cardiomyopathy. Pacing Clin Electrophysiol. 2011;34:
1278-1282.

14. Fefer P, Chelvanathan A, Dick A, et al. Takotsubo cardiomyopathy and left ventricular outflow tract obstruction. J Interv Cardiol. 2009;22:444-452.

15. Stensaeth KH, Fossum E, Hoffmann P, et al. Takotsubo cardiomyopathy in acute coronary syndrome; clinical features and contribution of cardiac ­magnetic resonance during the acute and convalescent phase. Scand Cardio­vasc J. 2011;45:77-85.

16. Omerovic E. How to think about stress-induced cardiomyopathy?—Think “out of the box”! Scand Cardiovasc J. 2011;45:67-71.

17. McKenna WJ. Cardiac sarcoidosis (2013). www.uptodate.com/contents/cardiac-sarcoidosis. Accessed November 14, 2013.

18. King TE Jr. Clinical manifestations and diagnosis of sarcoidosis (2013). www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-sarcoidosis. Accessed November 14, 2013.

19. Bussinguer M, Danielian A, Sharma O. Cardiac sarcoidosis: diagnosis and management. Curr Treat Options Cardiovasc Med. 2012;14:652-664.

20. Cooper LT Jr, Berry GJ, Shabetai R; Multicenter Giant Cell Myocarditis Study Group Investigators. Idiopathic giant-cell myocarditis—natural history and treatment. N Engl J Med. 1997;336(26):1860-1866.

21. Kandolin R, Lehtonen J, Salmenkivi K, et al. Diagnosis, treatment, and outcome of giant-cell myocarditis in the era of combined immunosuppression. Circ Heart Fail. 2013;6:15-22.

22. Htwe TH, Khardori NM. Cardiac emergencies: infective endocarditis, pericarditis, and myocarditis. Med Clin North Am. 2012;96:1149-1169.

23. Kindermann I, Barth C, Mahfoud F, et al. Update on myocarditis. J Am Coll Cardiol. 2012;59:779-792.

A 55-year-old white man with controlled hypertension and hypercholesterolemia awoke with mild chest discomfort that he believed was mild gastroesophageal reflux. He denied radiation of pain to the shoulders, arms, back, or neck; dyspnea; palpitations; diaphoresis; nausea/vomiting; cough; or fever, during the first 30 hours of discomfort. There was no change in discomfort with deep breath, palpation of the chest, or administration of antacids. Minimal, short-lived improvement was noted with belching.

The patient had no trouble sleeping in the prone position and did not notice an increase in discomfort or unusual difficulty during his daily vigorous 30-minute aerobic workout. In fact, his symptoms seemed to improve or disappear during exercise. The patient denied any recent illness or exposure to sick people, had not traveled outside the United States, and had not been exposed to radiation of the chest wall. At the end of the second day of discomfort, the patient noted irregular palpitations with mild shortness of breath and was transported to the hospital for evaluation. He denied being a cigarette smoker or illicit drug user.

The patient had no history of MI or diabetes. The patient’s father had an MI in his 80s, and two uncles died suddenly in their 50s of “massive heart attacks.” His mother, who had died of sepsis of uncertain etiology approximately 10 days earlier, also had hypertension and hypercholesterolemia but no history of coronary artery disease (CAD). Both of the patient’s adult daughters had been diagnosed with celiac disease in the preceding three years. His elder daughter had also been diagnosed with type 1 diabetes within the past two years.

On examination, the patient was afebrile, with a blood pressure of 143/87 mm Hg; pulse, 53 beats/min; and respiratory rate, 17 breaths/min. The patient’s weight was 204 lb and his height, 75 in (BMI, 25.5). The patient was in no apparent distress. Head, eyes, ears, nose, and throat were unremarkable. There was no significant jugular venous distention. The carotid pulses were full, and no bruits were appreciated. S₁ and S₂ sounds were within normal limits. No murmurs or S₃ or S₄ gallops were appreciated. The chest was clear on auscultation. Results of the abdominal exam were negative, no edema was noted in the extremities, and pulses were symmetrical.

ECG demonstrated subtle ST-segment elevation in leads I and aVL with a prominent R wave in lead V₁. This pattern was interpreted as consistent with an acute inferolateral MI. A baseline ECG, previously obtained by the patient’s internist, had been interpreted as normal.

Peak troponin level was 55 ng/mL (normal, < 0.03 ng/mL); total creatine kinase (CK), 807 U/L (reference range, 20 to 259 U/L); and mass CK-MB fraction, 44 ng/mL (0.1 to 6.6 ng/mL). Total cholesterol was 105 mg/dL, with both LDL- and HDL-cholesterol fractions at 46 mg/dL. A complete blood count without differential revealed a total white blood cell count of 53,000/µL. Hemoglobin and hematocrit were both low (12.3 g/dL and 34.5%, respectively). All indices were within normal limits, as was the platelet count. Glucose, blood urea nitrogen, creatinine, potassium chloride bicarbonate, and calcium were all within normal limits. The sodium level was slightly low (132 mEq/L). Emergency catheterization revealed an ejection fraction of 45% (reference range, 55% to 70%), with mild-to-moderate diffuse hypokinesis but normal coronary arteries.

The patient was diagnosed with myocarditis, likely of viral origin.

DISCUSSION

Although the incidence of myocarditis in the US is difficult to assess, autopsy reports implicate it in 8.6% to 12% of cases of sudden cardiac death in young adults,^1,2 and a large prospective series implicated myocarditis in 9% of cases of dilated cardiomyopathy.³ Myocarditis is considered to be at one extreme of a spectrum of perimyocardial processes that result in inflammation of the myocardium (see figure), pericardium, or both.⁴

The underlying pathology involves an acute injury to the myocyte. This activates the innate and humoral immune systems, resulting in severe inflammation. The immune reaction eventually subsides, and the myocardium recovers. In certain patients, however, myocardial inflammation persists, resulting in ongoing myocyte damage, relentless symptomatic heart failure, or even death.⁵

Although a variety of diagnostic criteria have been developed and employed, the diagnosis of myocarditis is often one of exclusion. First proposed in 1986, the Dallas criteria—a histopathologic classification for myocarditis diagnosis—are based on endomyocardial biopsy, with inflammatory cellular infiltrate (with or without associated myocyte necrosis) visible on conventionally stained myocardial tissue sections.⁵ However, this method poses significant practical limitations, including low sensitivity (43% to 64%) and complication and death rates of 6% and 0.4%, ­respectively.^5,6

An empiric diagnosis of myocarditis is often based on a combination of clinical findings including altered ECG, increase in myocardial enzymes, and lack of significant CAD.⁶ The recommended diagnostic cardiac magnetic resonance (CMR) imaging criteria for clinically suspected myocardial inflammation (ie, the Lake Louise Criteria) include at least two of the following:⁷

• Regional or global myocardial signal intensity increase in T2-weighted images.

• Increased global myocardial early gadolinium enhancement ratio between myocardium and skeletal muscle in gadolinium-enhanced T1-weighted images.

• At least one focal lesion with nonischemic regional distribution in inversion recovery–prepared gadolinium-enhanced T1-weighted images (“late gadolinium enhancement”).

Because of its reported high sensitivity and specificity (100% and 90%, respectively), CMR was used in the case patient to confirm the diagnosis of myocarditis.⁸ Specifically, CMR with contrast demonstrated normal left ventricular cavity size and mild reduction in overall left ventricular systolic function, with a visually estimated left ventricular ejection fraction of 45% to 50%. Regional hypokinesis of the mid-inferior wall and apical inferior septum was noted. Delayed contrast imaging demonstrated extensive non-CAD scarring and fibrosis, involving the basal anterior wall, basal inferior wall, and basal and midlateral wall in a pattern consistent with acute myocarditis.

Just as there is variability in the specific criteria by which the diagnosis of myocarditis can be made, the array of clinical findings with which it can manifest range from fatigue and other nonspecific symptoms to fulminant congestive heart failure and sudden death.⁶ Often, but not always, a viral prodrome precedes the onset of “cardiac symptoms” (eg, chest pain, dyspnea, palpitations, or syncope).⁵ This patient’s multiple risk factors for CAD and a suggestive, albeit atypical, history of chest discomfort, palpitations, and shortness of breath helped to focus the clinicians’ evaluation on the heart.

Potential Causes

Once a diagnosis of myocarditis is rendered, the next challenge is distinguishing its specific source from a plethora of potential etiologies, including infection, toxic exposure, or hypersensitivity/autoimmune reaction. Viral infections (mostly herpes, parvovirus, and cytomegalovirus) are thought to cause most cases of myocarditis in developed countries.^5,9

Viral myocarditis results when viruses enter cardiac myocytes and incite a cytotoxic effect with activation of the immune response, including expression of interferon , natural killer cells, and release of nitric oxide. The majority of patients recover, but some develop an adaptive immune response, which further causes cardiac damage. In this response, antibodies to viral and to some cardiac proteins are produced, and effector T lymphocytes proliferate. Viral genome or inflammatory mechanisms may persist, contributing to ventricular dysfunction leading to heart failure and arrhythmias.¹⁰

Celiac disease is a chronic gastroenterologic disease caused by an immune response to a gluten protein. Damage to the brush border of the small intestine results in an inability to absorb fat, protein, vitamins, and minerals. Intermittent diarrhea, abdominal pain, and bloating are most commonly reported, but celiac disease may also manifest less obviously with iron deficiency anemia, joint pain, muscle cramps, osteoporosis, and neuropathy.¹¹ Iron deficiency anemia that is refractory to iron replacement may offer insight into diagnosing myocarditis due to celiac disease.¹² Although studies have found that more than 4% of patients with myocarditis also had celiac disease, none had the classic GI symptoms of celiac disease.¹²

Takotsubo cardiomyopathy is a transient left ventricular apical ballooning syndrome of unknown etiology. (For more information, see Fasolino T. Takotsubo cardiomyopathy: a clinical overview). Patients who have experienced emotional or physiologic stress and postmenopausal women appear to be at greatest risk. The clinical symptoms mimic MI, including chest pain with ST-segment elevation in the precordial leads on ECG¹³ and minor elevation of the cardiac enzyme and biomarker levels.¹⁴ However, patients experiencing this stress cardiomyopathy lack evidence of atherosclerotic CAD.¹⁵ An echocardiogram or CMR imaging reveals characteristic wall motion hypokinesis, akinesis, or dyskinesis of the left ventricular apex and mid-ventricle that help to differentiate it from other forms of myocarditis.^15,16 Patient prognosis is favorable, with 95% of patients experiencing a full recovery; left ventricular dysfunction usually begins to improve in a few weeks.^13,14

Sarcoidosis is a systemic disease resulting in noncaseating granulomas in multiple organs.¹⁷ Initial presentation typically includes bilateral hilar adenopathy, pulmonary reticular opacities, and/or skin, joint, or eye lesions.¹⁸ Patients with cardiac sarcoidosis most commonly present with conduction disturbances and ventricular arrhythmias.¹⁷ Although frequently absent, clinical symptoms may include palpitations, syncope, dizziness, or chest pain and clinical heart failure.^17,18 It is difficult to distinguish cardiac sarcoidosis from other forms of myocarditis unless signs of systemic sarcoidosis are evident. A patient with suspected cardiac sarcoidosis should have an ECG to detect subclinical conduction abnormalities.¹⁷ The patient should wear a Holter monitor for 24 hours to screen for cardiac involvement, and echocardiography should be performed to define cardiac abnormalities.¹⁹

Giant-cell myocarditis (GCM) is a rare, rapidly progressive, and frequently fatal myocardial disease. Based on endomyocardial or surgical biopsy, GCM is histologically defined by multinucleated giant cells, a lymphocytic inflammatory infiltrate, and myocyte necrosis. It is often found in association with various immune-related systemic disorders.²⁰ Patients present with heart failure, ventricular arrhythmias, and atrioventricular block that fails to improve with standard therapy.²¹

Treatment and Management

The typical management of acute myocarditis includes supportive care for left ventricular dysfunction and arrhythmia control.²² Many of the standard heart failure therapies—β-blockers, ACE inhibitors, angiotensin receptor blockers, and aldosterone antagonists—are efficacious; several, at least in animal models, appear to exert anti-inflammatory as well as the standard cardiovascular effects.²³

Caution is advised regarding the selection of specific therapies. For example, in one study, metoprolol produced deleterious effects in acute murine Coxsackie virus myocarditis; inflammation, necrosis, and mortality significantly increased in the treatment group, compared with the placebo group.²³

Information on the effects of particular therapies for specific etiologies of myocarditis are limited, but some evidence supports immunosuppressive and immune-modulating therapies for chronic, virus-negative inflammatory cardiomyopathy. Immunosuppressive therapy is also beneficial for acute GCM and sarcoidosis.²³ For patients with myocarditis associated with celiac disease, a gluten-free diet alone or in combination with immunosuppressive agents can significantly improve clinical outcomes.¹²

OUTCOME FOR THE CASE PATIENT

Because the patient was already taking a statin and an ACE inhibitor for hypercholesterolemia and hypertension, respectively, as well as one baby aspirin per day, only a β-blocker was added to his discharge medication regimen.

Three months after hospital discharge, the patient underwent repeat CMR imaging. The ejection fraction had markedly improved to the 55%-to-60% range, although extensive midmyocardial-to-epicardial scarring in a multifocal pattern, primarily involving the basilar anterior and anterolateral wall, was still present, as was a small focus of an active (albeit healing) process in the inferior wall. Clinically, the patient was doing reasonably well and was vigorously exercising daily without dizziness, syncope, chest discomfort, or shortness of breath.

However, within several weeks of discharge, the patient reported having one two-hour episode of frequent palpitations at rest. Since that episode, palpitations have occurred infrequently. A 48-hour Holter monitor was ordered to better evaluate the palpitations and showed only rare premature ventricular contractions and isolated premature atrial contractions; no complex ectopy was noted. A follow-up stress echocardiogram was scheduled for 12 months, assuming the patient was free of clinical signs and symptoms of heart failure and arrhythmias at that time.

CONCLUSION

Myocarditis can manifest with a broad spectrum of signs and symptoms that may make its identification difficult, especially if a cardiac source is not initially considered in the differential diagnosis. However, for patients who present with elevated biomarkers and normal coronary artery anatomy, the identification of myocarditis is relatively easy; the difficulty in this circumstance relates to the identification of the specific etiology of the myocarditis.

The long-term prognosis for myocarditis is frequently good and the treatment straightforward, using medications that are modeled after standard heart failure therapy. However, depending on the etiology, specific treatment may be advisable—or required—in order to improve outcomes.

References

1. Fabre A, Sheppard MN. Sudden adult death syndrome and other ­nonischaemic causes of sudden cardiac death: a UK experience. Heart. 2006;92:316-320.

2. Doolan A, Semsarian C, Langlois N. Causes of sudden cardiac death in young Australians. Med J Aust. 2004;180:110-112.

3. Felker GM, Hu W, Hare JM, Hruban RH, et al. The spectrum of dilated cardiomyopathy: the Johns Hopkins experience with 1,278 patients. Medicine (Baltimore). 1999;78:270-283.

4. Leitman M, Tyomkin V, Peleg E, et al. Left ventricular function in acute inflammatory peri-myocardial diseases—new insights and long-term follow-up. Cardiovasc Ultrasound. 2012;10:42.

5. Blauwet LA, Cooper LT. Myocarditis. Prog Cardiovasc Dis. 2010;52:274-288.

6. Testani JM, Kolansky DM, Litt H, Gerstenfeld EP. Focal myocarditis mimicking acute ST-elevation myocardial infarction: diagnosis using cardiac magnetic resonance imaging. Tex Heart Inst J. 2006;33:256-259.

7. Friedrich MG, Sechtem U, Schulz-Menger J, et al. Cardiovascular magnetic resonance in myocarditis: a JACC white paper. J Am Coll Cardiol. 2009;53: 1475-1487.

8. Olimulder MA, van Es J, Galjee MA. The importance of cardiac MRI as a diagnostic tool in viral myocarditis-induced cardiomyopathy. Neth Heart J. 2009;17:481-486.

9. Mavrogeni S, Bratis K, Markussis V, et al. The diagnostic role of cardiac magnetic resonance imaging in detecting myocardial inflammation in systemic lupus erythematosus. Differentiation from viral myocarditis. Lupus. 2013;22:34-43.

10. Schultz JC, Hilliard AA, Cooper LT, Rihal CS. Diagnosis and treatment of viral myocarditis. Mayo Clin Proc. 2009;84:1001-1009.

11. Schuppan D, Dieterich W. Pathogenesis, epidemiology, and clinical manifestations of celiac disease in adults (2013). www.uptodate.com/contents/pathogenesis-epidemiology-and-clinical-manifestations-of-celiac-disease-in-adults. Accessed November 14, 2013.

12. Frustaci A, Cuoco L, Chimenti C, et al. Celiac disease associated with autoimmune myocarditis. Circulation. 2002;105:2611-2618.

13. Thakar S, Chandra P, Hollander G, Lichstein E. Electrocardiographic changes in Takotsubo cardiomyopathy. Pacing Clin Electrophysiol. 2011;34:
1278-1282.

14. Fefer P, Chelvanathan A, Dick A, et al. Takotsubo cardiomyopathy and left ventricular outflow tract obstruction. J Interv Cardiol. 2009;22:444-452.

15. Stensaeth KH, Fossum E, Hoffmann P, et al. Takotsubo cardiomyopathy in acute coronary syndrome; clinical features and contribution of cardiac ­magnetic resonance during the acute and convalescent phase. Scand Cardio­vasc J. 2011;45:77-85.

16. Omerovic E. How to think about stress-induced cardiomyopathy?—Think “out of the box”! Scand Cardiovasc J. 2011;45:67-71.

17. McKenna WJ. Cardiac sarcoidosis (2013). www.uptodate.com/contents/cardiac-sarcoidosis. Accessed November 14, 2013.

18. King TE Jr. Clinical manifestations and diagnosis of sarcoidosis (2013). www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-sarcoidosis. Accessed November 14, 2013.

19. Bussinguer M, Danielian A, Sharma O. Cardiac sarcoidosis: diagnosis and management. Curr Treat Options Cardiovasc Med. 2012;14:652-664.

20. Cooper LT Jr, Berry GJ, Shabetai R; Multicenter Giant Cell Myocarditis Study Group Investigators. Idiopathic giant-cell myocarditis—natural history and treatment. N Engl J Med. 1997;336(26):1860-1866.

21. Kandolin R, Lehtonen J, Salmenkivi K, et al. Diagnosis, treatment, and outcome of giant-cell myocarditis in the era of combined immunosuppression. Circ Heart Fail. 2013;6:15-22.

22. Htwe TH, Khardori NM. Cardiac emergencies: infective endocarditis, pericarditis, and myocarditis. Med Clin North Am. 2012;96:1149-1169.

23. Kindermann I, Barth C, Mahfoud F, et al. Update on myocarditis. J Am Coll Cardiol. 2012;59:779-792.

A 55-year-old white man with controlled hypertension and hypercholesterolemia awoke with mild chest discomfort that he believed was mild gastroesophageal reflux. He denied radiation of pain to the shoulders, arms, back, or neck; dyspnea; palpitations; diaphoresis; nausea/vomiting; cough; or fever, during the first 30 hours of discomfort. There was no change in discomfort with deep breath, palpation of the chest, or administration of antacids. Minimal, short-lived improvement was noted with belching.

The patient had no trouble sleeping in the prone position and did not notice an increase in discomfort or unusual difficulty during his daily vigorous 30-minute aerobic workout. In fact, his symptoms seemed to improve or disappear during exercise. The patient denied any recent illness or exposure to sick people, had not traveled outside the United States, and had not been exposed to radiation of the chest wall. At the end of the second day of discomfort, the patient noted irregular palpitations with mild shortness of breath and was transported to the hospital for evaluation. He denied being a cigarette smoker or illicit drug user.

The patient had no history of MI or diabetes. The patient’s father had an MI in his 80s, and two uncles died suddenly in their 50s of “massive heart attacks.” His mother, who had died of sepsis of uncertain etiology approximately 10 days earlier, also had hypertension and hypercholesterolemia but no history of coronary artery disease (CAD). Both of the patient’s adult daughters had been diagnosed with celiac disease in the preceding three years. His elder daughter had also been diagnosed with type 1 diabetes within the past two years.

On examination, the patient was afebrile, with a blood pressure of 143/87 mm Hg; pulse, 53 beats/min; and respiratory rate, 17 breaths/min. The patient’s weight was 204 lb and his height, 75 in (BMI, 25.5). The patient was in no apparent distress. Head, eyes, ears, nose, and throat were unremarkable. There was no significant jugular venous distention. The carotid pulses were full, and no bruits were appreciated. S₁ and S₂ sounds were within normal limits. No murmurs or S₃ or S₄ gallops were appreciated. The chest was clear on auscultation. Results of the abdominal exam were negative, no edema was noted in the extremities, and pulses were symmetrical.

ECG demonstrated subtle ST-segment elevation in leads I and aVL with a prominent R wave in lead V₁. This pattern was interpreted as consistent with an acute inferolateral MI. A baseline ECG, previously obtained by the patient’s internist, had been interpreted as normal.

Peak troponin level was 55 ng/mL (normal, < 0.03 ng/mL); total creatine kinase (CK), 807 U/L (reference range, 20 to 259 U/L); and mass CK-MB fraction, 44 ng/mL (0.1 to 6.6 ng/mL). Total cholesterol was 105 mg/dL, with both LDL- and HDL-cholesterol fractions at 46 mg/dL. A complete blood count without differential revealed a total white blood cell count of 53,000/µL. Hemoglobin and hematocrit were both low (12.3 g/dL and 34.5%, respectively). All indices were within normal limits, as was the platelet count. Glucose, blood urea nitrogen, creatinine, potassium chloride bicarbonate, and calcium were all within normal limits. The sodium level was slightly low (132 mEq/L). Emergency catheterization revealed an ejection fraction of 45% (reference range, 55% to 70%), with mild-to-moderate diffuse hypokinesis but normal coronary arteries.

The patient was diagnosed with myocarditis, likely of viral origin.

DISCUSSION

Although the incidence of myocarditis in the US is difficult to assess, autopsy reports implicate it in 8.6% to 12% of cases of sudden cardiac death in young adults,^1,2 and a large prospective series implicated myocarditis in 9% of cases of dilated cardiomyopathy.³ Myocarditis is considered to be at one extreme of a spectrum of perimyocardial processes that result in inflammation of the myocardium (see figure), pericardium, or both.⁴

The underlying pathology involves an acute injury to the myocyte. This activates the innate and humoral immune systems, resulting in severe inflammation. The immune reaction eventually subsides, and the myocardium recovers. In certain patients, however, myocardial inflammation persists, resulting in ongoing myocyte damage, relentless symptomatic heart failure, or even death.⁵

Although a variety of diagnostic criteria have been developed and employed, the diagnosis of myocarditis is often one of exclusion. First proposed in 1986, the Dallas criteria—a histopathologic classification for myocarditis diagnosis—are based on endomyocardial biopsy, with inflammatory cellular infiltrate (with or without associated myocyte necrosis) visible on conventionally stained myocardial tissue sections.⁵ However, this method poses significant practical limitations, including low sensitivity (43% to 64%) and complication and death rates of 6% and 0.4%, ­respectively.^5,6

An empiric diagnosis of myocarditis is often based on a combination of clinical findings including altered ECG, increase in myocardial enzymes, and lack of significant CAD.⁶ The recommended diagnostic cardiac magnetic resonance (CMR) imaging criteria for clinically suspected myocardial inflammation (ie, the Lake Louise Criteria) include at least two of the following:⁷

• Regional or global myocardial signal intensity increase in T2-weighted images.

• Increased global myocardial early gadolinium enhancement ratio between myocardium and skeletal muscle in gadolinium-enhanced T1-weighted images.

• At least one focal lesion with nonischemic regional distribution in inversion recovery–prepared gadolinium-enhanced T1-weighted images (“late gadolinium enhancement”).

Because of its reported high sensitivity and specificity (100% and 90%, respectively), CMR was used in the case patient to confirm the diagnosis of myocarditis.⁸ Specifically, CMR with contrast demonstrated normal left ventricular cavity size and mild reduction in overall left ventricular systolic function, with a visually estimated left ventricular ejection fraction of 45% to 50%. Regional hypokinesis of the mid-inferior wall and apical inferior septum was noted. Delayed contrast imaging demonstrated extensive non-CAD scarring and fibrosis, involving the basal anterior wall, basal inferior wall, and basal and midlateral wall in a pattern consistent with acute myocarditis.

Just as there is variability in the specific criteria by which the diagnosis of myocarditis can be made, the array of clinical findings with which it can manifest range from fatigue and other nonspecific symptoms to fulminant congestive heart failure and sudden death.⁶ Often, but not always, a viral prodrome precedes the onset of “cardiac symptoms” (eg, chest pain, dyspnea, palpitations, or syncope).⁵ This patient’s multiple risk factors for CAD and a suggestive, albeit atypical, history of chest discomfort, palpitations, and shortness of breath helped to focus the clinicians’ evaluation on the heart.

Potential Causes

Once a diagnosis of myocarditis is rendered, the next challenge is distinguishing its specific source from a plethora of potential etiologies, including infection, toxic exposure, or hypersensitivity/autoimmune reaction. Viral infections (mostly herpes, parvovirus, and cytomegalovirus) are thought to cause most cases of myocarditis in developed countries.^5,9

Viral myocarditis results when viruses enter cardiac myocytes and incite a cytotoxic effect with activation of the immune response, including expression of interferon , natural killer cells, and release of nitric oxide. The majority of patients recover, but some develop an adaptive immune response, which further causes cardiac damage. In this response, antibodies to viral and to some cardiac proteins are produced, and effector T lymphocytes proliferate. Viral genome or inflammatory mechanisms may persist, contributing to ventricular dysfunction leading to heart failure and arrhythmias.¹⁰

Celiac disease is a chronic gastroenterologic disease caused by an immune response to a gluten protein. Damage to the brush border of the small intestine results in an inability to absorb fat, protein, vitamins, and minerals. Intermittent diarrhea, abdominal pain, and bloating are most commonly reported, but celiac disease may also manifest less obviously with iron deficiency anemia, joint pain, muscle cramps, osteoporosis, and neuropathy.¹¹ Iron deficiency anemia that is refractory to iron replacement may offer insight into diagnosing myocarditis due to celiac disease.¹² Although studies have found that more than 4% of patients with myocarditis also had celiac disease, none had the classic GI symptoms of celiac disease.¹²

Takotsubo cardiomyopathy is a transient left ventricular apical ballooning syndrome of unknown etiology. (For more information, see Fasolino T. Takotsubo cardiomyopathy: a clinical overview). Patients who have experienced emotional or physiologic stress and postmenopausal women appear to be at greatest risk. The clinical symptoms mimic MI, including chest pain with ST-segment elevation in the precordial leads on ECG¹³ and minor elevation of the cardiac enzyme and biomarker levels.¹⁴ However, patients experiencing this stress cardiomyopathy lack evidence of atherosclerotic CAD.¹⁵ An echocardiogram or CMR imaging reveals characteristic wall motion hypokinesis, akinesis, or dyskinesis of the left ventricular apex and mid-ventricle that help to differentiate it from other forms of myocarditis.^15,16 Patient prognosis is favorable, with 95% of patients experiencing a full recovery; left ventricular dysfunction usually begins to improve in a few weeks.^13,14

Sarcoidosis is a systemic disease resulting in noncaseating granulomas in multiple organs.¹⁷ Initial presentation typically includes bilateral hilar adenopathy, pulmonary reticular opacities, and/or skin, joint, or eye lesions.¹⁸ Patients with cardiac sarcoidosis most commonly present with conduction disturbances and ventricular arrhythmias.¹⁷ Although frequently absent, clinical symptoms may include palpitations, syncope, dizziness, or chest pain and clinical heart failure.^17,18 It is difficult to distinguish cardiac sarcoidosis from other forms of myocarditis unless signs of systemic sarcoidosis are evident. A patient with suspected cardiac sarcoidosis should have an ECG to detect subclinical conduction abnormalities.¹⁷ The patient should wear a Holter monitor for 24 hours to screen for cardiac involvement, and echocardiography should be performed to define cardiac abnormalities.¹⁹

Giant-cell myocarditis (GCM) is a rare, rapidly progressive, and frequently fatal myocardial disease. Based on endomyocardial or surgical biopsy, GCM is histologically defined by multinucleated giant cells, a lymphocytic inflammatory infiltrate, and myocyte necrosis. It is often found in association with various immune-related systemic disorders.²⁰ Patients present with heart failure, ventricular arrhythmias, and atrioventricular block that fails to improve with standard therapy.²¹

Treatment and Management

The typical management of acute myocarditis includes supportive care for left ventricular dysfunction and arrhythmia control.²² Many of the standard heart failure therapies—β-blockers, ACE inhibitors, angiotensin receptor blockers, and aldosterone antagonists—are efficacious; several, at least in animal models, appear to exert anti-inflammatory as well as the standard cardiovascular effects.²³

Caution is advised regarding the selection of specific therapies. For example, in one study, metoprolol produced deleterious effects in acute murine Coxsackie virus myocarditis; inflammation, necrosis, and mortality significantly increased in the treatment group, compared with the placebo group.²³

Information on the effects of particular therapies for specific etiologies of myocarditis are limited, but some evidence supports immunosuppressive and immune-modulating therapies for chronic, virus-negative inflammatory cardiomyopathy. Immunosuppressive therapy is also beneficial for acute GCM and sarcoidosis.²³ For patients with myocarditis associated with celiac disease, a gluten-free diet alone or in combination with immunosuppressive agents can significantly improve clinical outcomes.¹²

OUTCOME FOR THE CASE PATIENT

Because the patient was already taking a statin and an ACE inhibitor for hypercholesterolemia and hypertension, respectively, as well as one baby aspirin per day, only a β-blocker was added to his discharge medication regimen.

Three months after hospital discharge, the patient underwent repeat CMR imaging. The ejection fraction had markedly improved to the 55%-to-60% range, although extensive midmyocardial-to-epicardial scarring in a multifocal pattern, primarily involving the basilar anterior and anterolateral wall, was still present, as was a small focus of an active (albeit healing) process in the inferior wall. Clinically, the patient was doing reasonably well and was vigorously exercising daily without dizziness, syncope, chest discomfort, or shortness of breath.

However, within several weeks of discharge, the patient reported having one two-hour episode of frequent palpitations at rest. Since that episode, palpitations have occurred infrequently. A 48-hour Holter monitor was ordered to better evaluate the palpitations and showed only rare premature ventricular contractions and isolated premature atrial contractions; no complex ectopy was noted. A follow-up stress echocardiogram was scheduled for 12 months, assuming the patient was free of clinical signs and symptoms of heart failure and arrhythmias at that time.

CONCLUSION

Myocarditis can manifest with a broad spectrum of signs and symptoms that may make its identification difficult, especially if a cardiac source is not initially considered in the differential diagnosis. However, for patients who present with elevated biomarkers and normal coronary artery anatomy, the identification of myocarditis is relatively easy; the difficulty in this circumstance relates to the identification of the specific etiology of the myocarditis.

The long-term prognosis for myocarditis is frequently good and the treatment straightforward, using medications that are modeled after standard heart failure therapy. However, depending on the etiology, specific treatment may be advisable—or required—in order to improve outcomes.

References

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9. Mavrogeni S, Bratis K, Markussis V, et al. The diagnostic role of cardiac magnetic resonance imaging in detecting myocardial inflammation in systemic lupus erythematosus. Differentiation from viral myocarditis. Lupus. 2013;22:34-43.

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16. Omerovic E. How to think about stress-induced cardiomyopathy?—Think “out of the box”! Scand Cardiovasc J. 2011;45:67-71.

17. McKenna WJ. Cardiac sarcoidosis (2013). www.uptodate.com/contents/cardiac-sarcoidosis. Accessed November 14, 2013.

18. King TE Jr. Clinical manifestations and diagnosis of sarcoidosis (2013). www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-sarcoidosis. Accessed November 14, 2013.

19. Bussinguer M, Danielian A, Sharma O. Cardiac sarcoidosis: diagnosis and management. Curr Treat Options Cardiovasc Med. 2012;14:652-664.

20. Cooper LT Jr, Berry GJ, Shabetai R; Multicenter Giant Cell Myocarditis Study Group Investigators. Idiopathic giant-cell myocarditis—natural history and treatment. N Engl J Med. 1997;336(26):1860-1866.

21. Kandolin R, Lehtonen J, Salmenkivi K, et al. Diagnosis, treatment, and outcome of giant-cell myocarditis in the era of combined immunosuppression. Circ Heart Fail. 2013;6:15-22.

22. Htwe TH, Khardori NM. Cardiac emergencies: infective endocarditis, pericarditis, and myocarditis. Med Clin North Am. 2012;96:1149-1169.

23. Kindermann I, Barth C, Mahfoud F, et al. Update on myocarditis. J Am Coll Cardiol. 2012;59:779-792.