Now You See It, Now You Don’t?
Information about a real patient is presented in stages (boldface type) to an expert (Dr Omid Salehian) who responds to the information, sharing his reasoning with the reader (regular type). A discussion by the authors follows.
A 52-year-old woman is referred by her family physician to a general internist’s clinic for assessment of a 3-month history of exertional dyspnea. She also reports a nonproductive nocturnal cough, night sweats, and an 18-lb weight loss over the preceding 3 months. The patient denies any history of chest pain, palpitations, presyncope, or syncope.
The patient has a history of chronic obstructive pulmonary disease for which she was admitted to hospital 3 times in the last several months. Each time, she received a course of antibiotics and oral glucocorticoids, with no relief of her dyspnea. She reports no prior cardiac history, history of malignancies, or venous thromboembolic disease. Her home medications include salbutamol and tiotropium. She is a current smoker, with a 40–pack-year history, and denies alcohol intake or recreational drug use.
Dr Salehian: Exertional dyspnea is a common complaint in patients presenting to emergency departments, general practitioners, internists, respirologists, and cardiologists. It has a very broad differential and could be attributable to a problem with the cardiovascular, respiratory, central nervous, or endocrine system. Furthermore, many patients with neoplastic or autoimmune disorders can present with dyspnea. The presence of constitutional symptoms and weight loss in a middle-aged smoker is definitely concerning. Malignancy involving the lung, breast, or gastrointestinal system should be at the top of the differential diagnosis. One must also consider the possibility of hematologic malignancies such as lymphoma. Chronic systemic infections such as subacute bacterial endocarditis should be considered in the differential diagnosis. Collagen vascular disorders such as systemic lupus erythematosus or vasculitides could also have a similar presentation.
Patient presentation (continued): On physical examination, she appears cachectic, weighing 51 kg at a height of 148 cm. Her blood pressure is 142/80 mm Hg and heart rate is 104 bpm; she has a regular respiratory rate of 24 breaths per minute and oxygen saturation of 93% on room air. Her temperature is 37.8°C. She is in mild respiratory distress, speaking in short sentences. Jugular venous pressure is 7 cm above the sternal angle with a positive abdominojugular reflux. Her carotid pulse is of normal volume and contour with no audible bruits. The apical impulse is normal in location and size. Auscultation reveals a normal S1 and S2 with a soft diastolic murmur heard best at the apex. No extra heart sounds are audible. There are coarse inspiratory crackles bilaterally at the lung bases. There is no pedal edema, and peripheral pulses are all palpable. There are no rashes, swollen joints, or palpable lymph nodes.
On laboratory investigations, her total white blood cell count is 13 500 with 90% neutrophils, hemoglobin of 6.5 g/dL, and platelet count of 506×103/mm3. Her serum electrolytes are normal, and her serum creatinine is 0.49 mg/dL.
Twelve-lead ECG(Figure 1) demonstrates sinus rhythm with left atrial enlargement. Chest x-ray(Figure 2) demonstrates evidence of hyperinflation with bilateral interstitial opacities and linear atelectasis in the left mid lung zone. There are findings suggestive of left atrial enlargement. Other cardiac chambers appear to be of normal size.
Dr Salehian: The physical examination is consistent with pulmonary edema with elevation in right-sided pressures. The absence of a third heart sound (S3) indicates that pulmonary edema is unlikely to be attributable to left ventricular dysfunction, although one must acknowledge the difficulties in hearing extra heart sounds in tachycardic patients. The associated apical diastolic murmur points toward mitral stenosis as the underlying cause of the pulmonary edema. Rheumatic disease is the most common cause of mitral stenosis and classically has an audible opening snap heard at the apex. This sound may be difficult to appreciate in the presence of tachycardia. However, the absence of an opening snap in the context of clinical findings of mitral stenosis and pulmonary edema should lead one to consider alternative reasons for mitral stenosis such as severe degenerative mitral valve disease, congenital mitral inflow obstruction such as supravalvular stenosing ring, or cor triatriatum. Finally, tumor obstruction of the mitral inflow seen with left atrial tumors such as myxomas should be considered.
The initial laboratory investigations revealing severe anemia, leukocytosis, and mild thrombocytosis are also concerning. Chronic infection or inflammation can explain these findings and should remain part of the differential diagnosis. The ECG and chest x-ray further support the clinical suspicion of mitral inflow obstruction and the presence of interstitial pulmonary edema. A transthoracic echocardiogram would be the investigation of choice at this stage to confirm the clinical suspicion of mitral inflow obstruction and to ascertain its origin.
Patient presentation (continued): A transthoracic echocardiogram(Figure 3 and Movies I–III in the online-only Data Supplement) demonstrates a large, mobile left atrial mass attached to the interatrial septum measuring 2.5×4.8 cm. There is evidence of “pseudo–mitral stenosis” caused by obstruction of the mitral valve orifice by the left atrial mass during diastole. The mean gradient across the mitral valve is 12 mm Hg at a heart rate of 100 bpm. Left ventricular systolic function is preserved with no obvious regional wall motion abnormalities. There is moderate pulmonary hypertension with an estimated right ventricular systolic pressure of 55 mm Hg.
Dr Salehian: The transthoracic echocardiographic findings are consistent with the clinical suspicion of hemodynamically significant mitral inflow obstruction secondary to a left atrial mass, leading to pulmonary edema. Although the differential diagnosis of a left atrial mass causing obstruction of mitral inflow is relatively narrow and includes thrombus and left atrial tumors, the location of the mass in the left atrium and its attachment to the interatrial septum are pathognomonic for a cardiac myxoma, the most common primary benign cardiac tumor. If the site of tumor attachment is not clearly identified on transthoracic echocardiogram, a transesophageal echocardiogram (TEE) should be considered to establish the presence of septal attachment and assessment of the pulmonary veins. Tumor invasion of the left atrium through the pulmonary veins has been well described with lung malignancies. A TEE will also be helpful to evaluate for the presence of additional intracardiac masses and to evaluate the mitral valve to assist in surgical planning. Patients with cardiac myxomas may have 1 or more of the following: symptoms related to intracardiac obstruction, symptoms related to systemic embolization, and constitutional symptoms, weight loss, and anemia resulting from the proinflammatory cytokines produced by the tumor.
Patient presentation (continued): The patient is diagnosed with a large left atrial myxoma, and arrangements are made to transfer the patient to a tertiary care center for consideration of cardiac surgery for tumor resection. Given the patient’s age and the presence of cardiovascular risk factors, cardiac catheterization(Figure 4 and Movie IV in the online-only Data Supplement) is performed to rule out significant coronary artery disease. This demonstrates the presence of significant multivessel coronary artery disease involving all 3 major arteries. An operative date for tumor resection and concomitant aortocoronary bypass is set for the following week.
Twenty-four hours after the cardiac catheterization, the patient’s bedside nurse notes the development of acute confusion and drowsiness, and a code blue is called. On physical examination, her left pupil is dilated, and there is dense left-sided hemiparesis of the upper and lower extremities. Urgent noncontrast computed tomography (CT) of the head(Figure 5A) does not demonstrate any acute intracranial abnormalities. Neurology is consulted for the management of an acute ischemic stroke and recommends urgent administration of tissue-type plasminogen activator (tPA), which is initiated within 1.5 hours of symptom onset.
Dr Salehian: Tumor resection of cardiac myxomas is the mainstay of management to relieve the symptoms associated with mechanical obstruction, to decrease the likelihood of embolization, and to eliminate the risk of sudden death associated with large tumors. Preoperative assessment of coronary arteries can be performed with invasive coronary angiography or CT angiography and is generally recommended in older patients and those with multiple coronary artery risk factors. The aortic valve should not be crossed during catheterization of the left side of the heart (especially if multipurpose catheters are used) to minimize the potential for embolization of tumor particles as large tumors enter the left ventricular cavity with every cardiac cycle.
The development of neurological signs, her decreased level of consciousness, and her confusion are of great concern. With the knowledge of the underlying left atrial tumor, the likelihood that the acute neurological deterioration is related to tumor embolization is extremely high. However, other potential causes should also be entertained such as atheroembolism from the aorta or carotid arteries, especially after invasive angiography. Central nervous system infections and vascular abnormalities such as dissection of the aorta or an arch vessel are less likely but should also be considered. Re-establishment of cerebral perfusion in a timely manner is the cornerstone of acute stroke management. Use of recombinant tPA in the management of acute embolic stroke within the first 4.5 hours has shown significant benefit in the reduction of morbidity and disability associated with strokes.1 However, in this case, the likely cause of cerebral ischemia is quite different from the majority of embolic strokes; hence, the use of tPA is less well established. There are, however, case reports of successful reperfusion after tPA administration in patients with embolic complications of cardiac tumors. Depending on the availability of resources and expertise, transarterial embolectomy should be considered in the setting of possible tumor-related emboli.2,3
Patient presentation (continued): Thirty minutes after tPA administration, repeat physical examination demonstrates cool, bilateral lower extremities with absent femoral, popliteal, and pedal pulses. Her neurological examination remains unchanged. Urgent CT of the abdomen with intravenous contrast demonstrates abrupt occlusion of the infrarenal abdominal aorta extending to both common iliac arteries(Figure 6 and Movie V in the online-only Data Supplement). Vascular surgery is consulted, and the patient is taken immediately to the operating room for emergent embolectomy of the abdominal aortic mass. Intraoperatively, the patient is also found to have a cold, pulseless right upper extremity. Further embolectomy of the right brachial artery is performed. Pathological examination of the emboli is consistent with fragments of a cardiac myxoma at both sites(Figure 7).
Repeat echocardiogram(Figure 8 and Movies VI and VII in the online-only Data Supplement) performed the same day reveals a significant reduction in the size of the previously identified left atrial mass, now measuring 1.1×2.0 cm. There is now evidence of moderate, global left ventricular systolic dysfunction that was not seen on the echocardiogram performed 1 week earlier.
Dr Salehian: Development of cool extremities and absent pulses highly suggests arterial embolization of the tumor. The absence of bilateral femoral pulses implies that the level of obstruction is proximal to the iliac bifurcation, indicating that the mass is large. CT angiography confirms the suspicion of aortic obstruction. One must weigh the time it takes to perform and interpret CT angiography against the risk of ongoing ischemia and need for urgent surgical revascularization. In most institutions, CT angiography can be performed without delay and provides valuable information for surgical planning.
Aortic obstruction at this level has a number of detrimental effects. There is an immediate rise in left ventricular afterload after aortic obstruction, which can result in hemodynamic instability and hypoperfusion of vascular beds, including the coronary artery tree, leading to global myocardial ischemia. In addition, severe limb ischemia and subsequent lactate production may result in decreased myocardial contractility. Hence, acute surgical relief of the obstruction in these patients is indicated. On the basis of the distribution of multiple emboli to different vascular territories, it appears that the tumor has dispersed into multiple pieces. Occasionally, such tumors can also embolize to coronary arteries, causing acute infarction and further compromising the patient’s hemodynamic status.4 An ECG would be helpful to exclude myocardial ischemia in this case, although the most likely cause of global left ventricular dysfunction is the acute increase in afterload and lactic acidosis resulting from muscle ischemia.
Patient presentation (continued): The patient is admitted to the intensive care unit after her aortic embolectomy. Her neurological status deteriorates further, with worsening radiographic evidence of cerebral edema(Figure 5B). The neurosurgery team is consulted, and she undergoes right-sided decompressive craniectomy and insertion of a right external ventricular pressure monitor for the management of elevated intracranial pressure. She remains hospitalized for 6 weeks after her acute stroke. She has persistent dense left-sided hemiplegia with hemi-neglect. Given the significant operative risk related to her cerebral event and relatively small residual mass with presumed lower risk of recurrent embolization, the decision is made not to proceed with cardiac surgery for removal of the residual left atrial myxoma. Continued clinical and imaging surveillance every 6 months was considered a reasonable alternative. Given that she did not have symptoms associated with her coronary artery disease, aggressive medical management was deemed sufficient at this time with a possible role for percutaneous coronary intervention in the future if needed. Ultimately, she was transferred to a rehabilitation unit closer to her hometown with local cardiology and neurology follow-up arranged.
Cardiogenic embolism accounts for 20% to 30% of ischemic strokes and has been shown to be associated with greater disability and higher mortality than nonembolic cerebrovascular events.5 Ischemic stroke in young patients (age <45 years) or recurrent systemic embolic events should prompt investigation for a cardiac source of embolism. Atrial fibrillation is the most common cause of cardioembolic stroke; however, less common causes such as cardiac tumors, left ventricular thrombi, rheumatic heart disease, and mechanical prosthetic valves are important to consider (Table).
All patients with a suspected cardiac source of embolism should undergo transthoracic echocardiography examination as part of the initial evaluation. However, studies have consistently demonstrated the superiority of TEE in this clinical setting, with a diagnostic yield of 40% to 50% in patients with no clear cause of stroke identified on clinical assessment.6 TEE is often required to visualize left atrial or atrial appendage thrombi, a patent foramen ovale, or valvular vegetations not visualized on transthoracic echocardiography.7
Cardiac tumors are a rare but important cause of cardioembolic stroke, and among these, myxomas and papillary fibroelastomas are the most common. Papillary fibroelastomas are benign, typically solitary, cardiac tumors attached to the endocardial surface. Unlike valvular vegetations, fibroelastomas are typically attached by a pedicle to the “downstream: side of valvular surfaces (ie, the aortic side of the aortic valve). Surgical excision is considered to be curative and is indicated in symptomatic patients with previous embolic events. In asymptomatic patients, surgical excision is reserved for patients deemed to be at high risk of embolic events. Careful evaluation of tumor size (>1 cm), mobility, and the presence of a stalk is recommended with TEE imaging to determine which asymptomatic patients may benefit from prophylactic surgical excision.8
Cardiac myxomas are benign neoplasms that are found in the left atrium >70% of the time and are typically attached to the fossa ovalis of the interatrial septum. Only a small proportion of patients present with the classic triad of fever, valvular obstruction, and systemic embolism. A delay in diagnosis is the rule, given that constitutional symptoms are a predominant feature in symptomatic patients.9,10 This often leads to workup for chronic infection, connective tissue disorders, or underlying malignancy. Echocardiography is the imaging modality of choice for both diagnosis and evaluation of the embolic potential of cardiac myxomas.11 Myxomas are characterized into 2 types. Type 1 myxomas have an irregular or villous surface and a long stalk and are associated with a higher risk of embolization compared with type 2 myxomas, which have a smooth surface and soft consistency.11,12 Histologically, >40% of cardiac myxomas have evidence of surface thrombi, an important predictor of embolic potential.13,14 Despite the proposed mechanism that cerebral infarcts may result from embolization of surface thrombi alone, routine use of anticoagulation is not recommended. There are published reports of perioperative use of vitamin K antagonists and aspirin in patients undergoing surgical resection, but there are few data available to support the use of medical therapy in these patients. Moreover, case series of patients with neurological complications of cardiac myxomas have demonstrated histological confirmation of tumor fragments (myxoid material) rather than thrombus alone in the cerebral vessels,13 suggesting that mechanistically anticoagulation is unlikely to be effective in reducing embolic potential.
The management of embolic complications of cardiac myxomas presents a significant challenge. There are reports of successful reperfusion after thrombolytic therapy in the setting of acute ischemic stroke.14,15 The risk of hemorrhagic transformation in patients with tumor embolization, however, is not well understood. Case series have demonstrated an association between cardiac myxomas and cerebral aneurysm formation, although the exact mechanism is not well elucidated.16,17 Given the theoretical increase in intracranial hemorrhage risk, alternative approaches to the management of cerebral ischemia should be considered. Mechanical aspiration of the tumor from the cerebral arteries by transcatheter techniques has been successfully reported in the management of ischemic strokes secondary to cardiac myxomas and papillary fibroelastomas.2 Endovascular mechanical treatment also provides the advantage of histological examination for definitive diagnosis. Although this technique provides theoretical advantages over thrombolytic therapy, lack of widespread availability and expertise limits its use.
Surgical resection is the treatment of choice in most cases of cardiac myxomas and should be expedited in those cases with a high-risk morphological appearance. Overall operative risk is considered to be low. Recurrence after surgical excision is rare in sporadic cases (<3%) but is reported in up to 20% of familial cases.18,19 Carney complex is a rare autosomal-dominant condition that was first described in 1995 and is characterized by the presence of cardiac myxomas, spotty hyperpigmentation, and endocrine hyperactivity.20 More than 700 cases of Carney complex have been described worldwide. More than two thirds of cases are linked to the PRKAR1A gene mutation.21,22 Patients with cardiac myxomas as part of the Carney complex are known to be at high risk of tumor recurrence after surgical excision. Therefore, careful postoperative clinical follow-up and serial imaging are of upmost importance in this population. Transthoracic echocardiography surveillance is recommended every 6 to 12 months after surgical excision. Consideration should also be given to screening first-degree relatives in whom PRKAR1A mutations are identified.21
Cardiac myxomas are a rare but important cause of cardioembolic stroke and systemic embolism. Surgical resection to reduce the risk of embolic complications, valvular obstruction, and congestive heart failure remains the cornerstone of management and should be expedited once the diagnosis is established. In most cases, surgery is considered to be curative, although careful follow-up is important to monitor for recurrence, particularly in familial cases.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.115.015652/-/DC1.
- © 2015 American Heart Association, Inc.
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