Correspondence *Department of Internal Medicine, Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY 10029, USA

Email eric.adler@msnyuhealth.org

The case

A 46-year-old female with no previously documented illnesses presented with 15 months of diarrhea, abdominal pain, and flushing after alcohol consumption. Abdominal CT showed multiple hepatic masses, and needle biopsy yielded tissue consistent with a neuroendocrine tumor of the carcinoid type. Octreotide imaging localized the primary tumor to the terminal ileum of the small intestine. Transthoracic echocardiography at that time showed no tricuspid or pulmonic valve thickening. The estimated right atrial pressure was 10 mmHg and estimated right ventricular systolic pressure was 26 mmHg. The patient underwent ileocolic resection followed by treatment with octreotide, adriamycin, gemcitabine and oxaliplatin, and yttrium-90 microsphere radioembolization of the hepatic metastases.

Five years later, she reported fatigue and gradually worsening dyspnea on exertion, over 6 months, accompanied by bilateral leg swelling, over 2 months. Physical examination showed normal breath sounds, no clubbing, a grade II/VI systolic murmur loudest at the left and right upper sternal borders, and 2 + pitting edema to both knees. While breathing room air, the arterial pH was 7.48, Pco₂ was 34 mmHg, and Po₂ was 59 mmHg, and bedside oxygen saturation was 85% while standing and 91% while supine. Hemodynamic data are summarized in Table 1. Transthoracic echocardiography showed a dilated right ventricle, thickening and mildly restricted movement of the tricuspid valve leaflets, 2 + insufficiency of the tricuspid, pulmonic and mitral valves, and an estimated right ventricular systolic pressure of 39 mmHg. Following intravenous injection of agitated saline, brisk right-to-left interatrial shunting was demonstrated, consistent with a patent foramen ovale (PFO). Transesophageal echocardiography confirmed the PFO, and identified thickening of the aortic and mitral valve leaflets, and ruptured chordae tendinea. Moderate mitral and aortic insufficiency was also observed, along with stenosis of the tricuspid valve (Figure 1).

Figure 1 Systolic transesophageal echocardiograms of the patient at presentation

(A) Moderate to severe mitral regurgitation is evident, along with (B) thickened tricuspid and mitral leaflets. (C) Bubbles are evident in both atria following administration of agitated saline, suggestive of a right-to-left shunt.

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Table 1 Summary of the patient's hemodynamic data at presentation

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Percutaneous closure of the PFO was undertaken to improve arterial oxygen saturation and relieve symptoms. During the procedure, contrast aortography demonstrated compression of the inferior vena cava by a secondary tumor, directing blood flow toward the PFO (Figure 2). The PFO was closed using a 25 mm Amplatzer^® device (AGA Medical Corporation, Golden Valley, MN) under intracardiac echocardiographic guidance. After closure, there was no visible residual intracardiac shunt, as demonstrated by echocardiography. Systemic arterial oxygen saturation increased from 85% to 95% a few hours after the procedure, and dyspnea resolved. At discharge 6 days after the procedure, the patient was able to walk slowly for 5 min—before the percutaneous closure, she had been able to walk only a couple of steps. Three months after the procedure, however, she developed acute dyspnea, and passed away in the emergency department of a local hospital before a definitive diagnosis was established. The family declined autopsy.

Figure 2 Aortogram during percutaneous closure of the PFO

Note the apparent compression of the vena cava and direction of blood flow toward the PFO. Abbreviations: IVC, inferior vena cava; PFO, patent foramen ovale.

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Discussion of diagnosis

Carcinoid tumors are rare, slow-growing neuroendocrine neoplasms, occurring in approximately 3 per 100,000 people per year.¹ The most common location of the primary tumor is the small intestine. About 30% of patients develop carcinoid syndrome—a secondary effect caused by the vasoactive substances 5-hydroxytryptamine (serotonin), 5-hydroxytryptophan, histamine, bradykinins, tachykinins and prostaglandins that are released from the tumor into the systemic circulation.^{1, 2} Symptoms of carcinoid syndrome include flushing, secretory diarrhea and bronchospasm. Two-thirds of patients with carcinoid syndrome subsequently develop carcinoid heart disease, which is fatal in 50% of cases.² In as many as 20% of patients with a carcinoid tumor, the first presentation is due to cardiac manifestations.³

Cardiac involvement is associated with a reduction in life expectancy from 4.6 to 1.6 years after diagnosis, and occurs most often in patients with hepatic metastasis, most likely because secreted products from these tumors are not degraded by the liver and can, therefore, affect the heart.² Plaques of fibroblasts or myofibroblasts and fibrous stroma characterize the histopathology of carcinoid heart disease. These plaques occur on the endocardial surfaces, including all four cardiac valves. Right atrial and ventricular enlargement is often present, along with thickened, shortened and retracted tricuspid valve leaflets associated with regurgitation, stenosis and incompetence.^{2, 4} The extent of valvular involvement is the main prognostic indicator in carcinoid heart disease, and evaluation relies heavily on assessment by two-dimensional echocardiography.⁵

Since factors released from the tumor are also metabolized in the lungs, carcinoid heart disease primarily affects the right side of the heart and usually presents clinically with manifestations of tricuspid or pulmonic valve dysfunction.⁶ Left-sided carcinoid heart disease is less common, and is usually associated with a PFO, pulmonary disease, extensive hepatic metastasis, or rarely, an ovarian mass.⁷ Delivery of substances that accelerate fibrosis to the left side of the heart through an intracardiac shunt might have a role in the etiology of this condition. Left-sided carcinoid heart disease is almost always seen in conjunction with right-sided disease and diagnosed before left ventricular dysfunction develops.⁴ Left-sided disease can affect the mitral and aortic valves, and presents with symptoms of left-sided heart failure such as fatigue and dyspnea. Although left-sided involvement is generally considered to be rare in carcinoid heart disease, a recent prospective study challenges this dogma. Of 41 patients with carcinoid heart disease, 13 (32%) developed left-sided carcinoid lesions detectable by echocardiography.⁸ We suspect that as medical treatment for carcinoid tumors improves, and patients live longer, the prevalence of clinically apparent left-sided carcinoid heart disease will increase as well.

The patient described in this report had initially presented with a carcinoid tumor in the small intestine, along with hepatic metastasis. Five years later, she had developed right ventricular dilation and valvular dysfunction that were characteristic of cardiac involvement of both the right and left sides of the heart, including pitting edema, progressive shortness of breath and fatigue. Echocardiography also demonstrated a PFO with substantial right-to-left shunting at rest. Of the approximately 30 cases of left-sided carcinoid heart disease reported in the literature, PFO was detected in roughly half (Table 2). Right-to-left shunting through a PFO most commonly results from increased right atrial pressure, as occurs during the Valsalva maneuver or in the setting of severe pulmonary hypertension (Eisenmenger's syndrome), but anatomic factors such as prominent remnant eustachian valves can also contribute.⁹ These factors were not apparent in this patient, but aortography demonstrated compression of the inferior vena cava by a secondary tumor, which could have had the effect of directing caval blood flow toward the PFO. Compression of this sort would increase the shunt, exposing the left side of the heart to toxic metabolites. We postulate that this mechanism was responsible for the left-sided cardiac involvement seen in this patient. To our knowledge, external compression of the vena cava by tumor mass leading to this effect has not been previously described.

Table 2 Recorded cases of left-sided carcinoid heart disease with right-to-left atrial shunts

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Since no autopsy was performed, however, both this mechanism and the actual diagnosis must be considered speculative. Had autopsy been carried out, it is likely that typical carcinoid plaques would have been seen on both sides of the heart, thereby confirming the diagnosis. Similarly, the exact cause of death cannot be established—possibilities include pulmonary embolism, an intra-abdominal complication of the carcinoid tumor, cardiac arrhythmia or, less likely, a complication of the percutaneous device.

Treatment and management

Management of patients with carcinoid heart disease requires the collaboration of cardiologists, oncologists and gastroenterologists, and referral to specialist centers should be considered in complex cases. Patients with stable disease should be monitored by echocardiography and exercise testing once or twice annually, to detect evidence of progressive cardiac involvement.³ Since the right side of the heart is more commonly affected, selection of treatment options has traditionally focused on right ventricular size and function, and the severity of tricuspid regurgitation.¹⁰ Valve replacement is considered the definitive treatment for valvular insufficiency or stenosis, and should be considered in those with symptomatic but well-controlled carcinoid heart disease, especially when symptoms of right-sided heart failure, exercise impairment due to valvular dysfunction, progressive right-sided heart enlargement, or right ventricular systolic dysfunction develop.^{3, 4, 8} The perioperative mortality associated with cardiac surgery in patients with carcinoid heart disease has improved over the past two decades from over 20% to below 10%, but remains high.¹¹

As a result of the small number of cases reported in the literature, no current guidelines specifically address the management of patients with left-sided carcinoid heart disease. In light of the possible increasing prevalence of this condition, however, it seems logical to examine patients with left-sided cardiac involvement by transesophageal echocardiography and to consider closing the shunt at the time of valve surgery.^{4, 7} Eleven cases of left-sided carcinoid heart disease associated with PFO, who underwent surgical closure with or without valve replacement, have been reported, with two postoperative deaths (Table 2).

In patients not undergoing surgery, the decision to close the PFO is more difficult. Percutaneous closure is a less invasive and painful procedure than conventional closure, and should be considered as a palliative approach when surgery is not feasible.¹² Complications are rare, but include cardiac perforation, thrombus formation, erosion of cardiac structures, and possible dislodgement of the PFO closure device.

In the present patient, the risks of cardiac surgery were felt to outweigh the potential benefits because of her deteriorating clinical status, extensive metastatic disease and significant hypoxemia. Percutaneous closure was, therefore, performed as a palliative treatment, and was deemed successful, as the patient displayed increased oxygen saturation and walking ability at discharge. Only two other case reports describe percutaneous transcatheter closure of PFO in patients with carcinoid heart disease.^{13, 14} These patients also showed improvement in clinical status after closure, and similar benefits have been observed in two other patients with carcinoid heart disease in whom percutaneous PFO closure has been performed at our institution (unpublished). Although the patient eventually succumbed to her disease, endovascular treatment seems to have provided a period of symptom relief, enhancing the quality of life.

Conclusions

Left-sided involvement of carcinoid heart disease is rare, but can have dramatic and deleterious effects on a patient's exercise capacity and well-being. Percutaneous closure of a PFO can provide symptomatic relief and an improved quality of life in situations where surgery is not viable, and should be considered as a palliative option in severe cases.

References

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Subject areas under which this article appears: Intervention | Valvular disease