A case of catecholamine-induced cardiomyopathy treated with extracorporeal membrane oxygenation

Abstract

A 55-year-old female patient was presented with severe dyspnea due to sudden onset of heart failure (ejection fraction (EF) <10%). Echocardiogram showed a takotsubo pattern with an akinetic apical segment. Coronary angiography did not reveal any obstructive disease. She became hypotensive which was refractory to conventional pressor agents. Catecholamine-induced cardiomyopathy was suspected after the CT scan of the abdomen showed a 4 cm necrotic right adrenal mass consistent with pheochromocytoma (PHEO). Venous arterial extracorporeal membrane oxygenation and α blockers were initiated. There was a rapid improvement in cardiac function with EF normalising in 1 week. Subsequently, β-blockers were added and right adrenalectomy was done 3 weeks after the admission. She did extremely well after surgery with her blood pressure normalising without the need for antihypertensive therapy. Genetic evaluation revealed no pathogenic mutations implicated in the development of PHEO.

Background

Pheochromocytomas (PHEO) are endocrine tumours of the chromaffin cells in the adrenal medulla while paragangliomas (PGL) arise from the chromaffin cells in the sympathetic and parasympathetic nerve ganglia.¹ Around 85% of tumours of chromaffin cell tumours are PHEO and 15% are PGL.² Catecholamine-induced cardiomyopathy (CICMP) is a rare and challenging complication of PHEO and PGL occurring in about 8%–11% of PHEO and PGL.³ CICMP can present in diverse ways depending on the type and amount of catecholamine which is oversecreted. Prompt recognition and management of CICMP are essential to reduce mortality and morbidity. Due to the relative rarity of this condition, there is a lack of evidence-based guidelines for the management of CICMP.⁴

Case presentation

A 55-year-old female patient with no significant medical history presented to the emergency room with sudden onset of dyspnea. She had no history of hypertension, palpitations, headaches or diaphoresis. She was noted to be tachycardic (180 beats/min) and hypertensive (170/120 mm Hg) and was started on diltiazem drip. She also developed frothing and became hypotensive. Emergent intubation was done for impending respiratory failure. ECG showed ST-segment elevations in I, aVL, V2 and V3. Bedside echocardiogram showed a left ventricular ejection fraction (EF) of 10% with dyskinesis of the apex and hypokinesis of the other segments. She was started on diuretics and norepinephrine drip for the management of pulmonary oedema and hypotension. Cardiac catheterisation did not reveal any significant coronary artery disease. Cardiogenic shock secondary to fulminant myocarditis was suspected and an intraaortic ballon pump was placed. She was transferred to our hospital for advanced heart failure therapies as the patient continued to be hypotensive.

Investigations

Laboratory assessment on admission showed metabolic acidosis with high lactate levels, elevated aspartate aminotransferase, alanine aminotransferase and acute kidney injury (table 1). The toxicology drug screen was negative. CT scan of the abdomen showed a 4 cm heterogenous enhancing right adrenal mass with areas of central hypoenhancement consistent with the appearance of a PHEO (figure 1). Biochemical assessment showed high levels of plasma metanephrines; however, it is to be noted that the patient had recently been on pressor agents (table 1).

Table 1.

Laboratory assessment on admission and after stopping ECMO

	Admission	After ECMO
Venous blood pH (7.35–7.45)	7.14	7.42
Plasma bicarbonate (22–39 mmol/L)	15	24
eGFR (>60 mL/min)	28	>60
AST (0–32 U/L)	181	47
ALT (0–33 U/L)	91	27
Lactate (0.7–2.1 mmol/L)	9	1.9
Troponin (<0.03 ng/mL)	2.01	0.48
Plasma normetanephrine (<0.9 nmol/L)	7.2
Plasma metanephrine (<0.5 nmol/L)	2.3
24 hours urinary metanephrines (<400 μg/24 hours)	4683
Plasma aldosterone (<28 ng/dL)	<1
Plasma renin activity (0.25–5.82 ng/mL/hour)	20.8

ALT, alanine aminotransferase; AST, aspartate aminotransferase; ECMO, extra corporeal membrane oxygenation; eGFR, estimated glomerular filtration rate.

Figure 1.

CT scan of the abdomen showing a 4 cm right adrenal mass.

Differential diagnosis

CICMP can mimic several cardiovascular disorders. It can present as hypertrophic cardiomyopathy which is similar to hypertrophic obstructive cardiomyopathy (HOCM) and are characterised by hypertrophy of the posterior wall and interventricular septum, as well as anterior motion of the mitral valve replacement; however, in CICMP, all these changes regress after surgical excision of the PHEO or PGL.^{5 6} CIMCP can present takotsubo or reverse takotsubo syndrome which are indistinguishable from primary takotsubo’s.⁷ CIMCP-induced myocarditis can be confused with viral myocarditis due to the similarity in presentations; however, in CIMCP, these changes are reversible with treatment of PHEO or PGL.⁸ Several radiological characteristics are useful to differentiate different radiological lesions.(table 2)⁹

Table 2.

Radiological characteristics of different adrenal lesions⁹

Adrenal adenoma	Pheochromocytoma	Adrenal carcinoma	Metastasis
Small, round/oval, homogenous, <3 cm	Round/oval, >3 cm, heterogeneous with cystic areas	Irregular, unclear margins, >4 cm, heterogeneous with mixed densities	Round/oval, unclear margins<3 cm, bilateral, heterogeneous with mixed densities
<10 HU	>10 HU	>10 HU	>10 HU
>50% washout in 10 min	<50% washout in 10 min	<50% washout in 10 min	<50% washout in 10 min
Isointense to liver in T2-weighed images	Hyperintense compared with liver in T2-weighed images	Hyperintense compared with liver in T2-weighed images	Hyperintense compared with liver in T2-weighed images
Rare necrosis, calcifications, haemorrhage	Necrosis, calcifications and haemorrhage common	Necrosis, calcifications and haemorrhage common	Necrosis, haemorrhage and calcification are not uncommon

Treatment

Dopamine drip was initiated in addition to the norepinephrine drip; however, the patient continued to remain hypotensive. Venous arterial extracorporeal membrane oxygenation (VAECMO) was started for resistant cardiogenic shock, and there was a marked improvement in the acidosis, liver enzymes and kidney function. Doxazosin therapy was initiated 1 day after the VAECMO was started and titrated to control blood pressure. The VAECMO flow rate was slowly weaned and stopped over 5 days. Subsequently, propranolol was added to control the heart rate with excellent response to both the agents.

Follow-up echocardiogram, a week after admission, showed significant improvement in cardiac function with an EF of >50%. Right adrenalectomy was done 3 weeks after the original admission. Pathology revealed a PHEO with no lymphovascular invasion.

Outcome and follow-up

On follow-up in the clinic 3 weeks after surgery, the patient’s blood pressure had normalised and was off antihypertensives. Genetic evaluation revealed no pathogenic mutations in RET, VHL, NF-1, SDH, MAX and TMEM127 genes.

Discussion

PHEO and PGL are rare chromaffin cell tumours with an incidence of 3–8 per 1 million per year. They are characterised by hypersecretion of one or more catecholamines (epinephrine, norepinephrine or dopamine). Clinically, they can present with hypertension, diaphoresis, palpitations, pallor, chest pain, hyperglycaemia and constipation.^{2 10}

Catecholamines are synthesised in the adrenal medulla, sympathetic ganglia and brain. They bind to α-adrenergic receptor and β-adrenergic receptor to mediate effects on the cardiovascular system. β1-adrenergic receptors are present in the sinoatrial node, atrioventricular node and cardiac myocytes, while β2-adrenergic receptors are located in the heart, vascular, uterine and airway smooth muscle. Activation of β1 receptors results in increases in heart rate and myocardial contractility, while activation of the β2 receptors results in myocardial relaxation. α-adrenergic receptors are present in the vascular smooth muscle, and their activation leads to vasoconstriction. Norepinephrine acts preferentially on α-adrenergic receptors to cause vasoconstriction leading to an increase in blood pressure. Epinephrine at low doses preferentially binds to β receptors leading to an increase in cardiac contractility (β1) but no increase in blood pressure due to β2-mediated vasodilation, while at higher doses, it binds to α receptors which override the β2-mediated vasodilation and cause vasoconstriction.^{11 12}

The pathogenesis of CICMP is secondary to chronic sustained elevation of catecholamines. Excess catecholamines initially cause excitation of β1-adrenergic receptors and an increase in myocardial oxygen demand. The mismatch between myocardial oxygen demand and delivery leads to the development of ischaemic areas in the heart. Sustained exposure to catecholamines can lead to desensitisation of β1-adrenergic receptors by activation of the β1 adrenoreceptor kinase leading to heart failure. Catecholamines also increase the influx of calcium into the cardiac myocytes; however, excess catecholamines can cause overloading of calcium in the mitochondria of the cardiac myocytes. This influx of calcium leads to increased oxidative stress leading to cell death.^13–16

CICMP can present with three different types of cardiomyopathies (table 3).

Table 3.

Features of different types of CICMP⁴

Hypertrophic cardiomyopathy	Takotsubo cardiomyopathy	Dilated cardiomyopathy
Chest pain, syncope, dyspnea and orthopnea	Substernal chest pain, dyspnea and syncope	Fatigue, weight gain, orthopnea and abdominal pain
ST-T wave changes, deep narrow Q waves and decreased R-waves	T wave inversion and ST segment elevation	ST-T wave changes, bundle branch block and arrhythmias
Concentric hypertrophy of posterior left ventricular wall and interventricular septum, systolic anterior motion of mitral valve and increased outflow gradient	Apical ballooning of apex with basal hyperkinesia,  reverse takotsubo’s- hyperkinetic apex with akinetic base	Eccentric hypertrophy of left and right ventricle
Cardiac angiography with no obstructive disease	Cardiac angiography with no obstructive disease	Cardiac angiography with no obstructive disease

CICMP, catecholamine-induced cardiomyopathy.

The development of the different types of cardiomyopathies is related to the differing adaptation responses of the cardiac myocytes to the excess catecholamines. Zhang et al studied 163 cases of CICMP (63 dilated cardiomyopathy, 38 takotsubo cardiomyopathies, 30 inverted cardiomyopathies, 10 of HOCM, 8 myocarditis and 14 unspecified). Hypertension was the presenting feature in 65%, while the classic PHEO triad (headaches, diaphoresis and palpitations) was present only in 4%. CICMP improved in 96% after surgical resection.¹⁷ Hassan et al analysed 80 cases of PHEO-induced takotsubo syndrome and compared them with a review of patients with the primary takotsubo syndrome. PHEO-induced takotsubo syndrome patients were about 20 years younger, had more frequent ST depression on ECG, and were more likely to have a cardiogenic shock as compared with patients with the primary takotsubo syndrome.¹⁸

The key to the management of CICMP is an early diagnosis. CICMP should be suspected in all cases of heart failure or cardiomyopathy with unclear aetiology, an acute coronary syndrome with non-obstructive coronaries and multiple organ failure without a clear aetiology. A preoperative echocardiogram is recommended in all cases of PHEO and PGL.⁴ Biochemical diagnosis of PHEO and PGL is made by finding high levels of plasma free metanephrines or total urinary metanephrines. However, it must be borne in mind that metanephrines may be elevated due to cardiogenic shock or administration of pressor agents. In such cases, PHEO is diagnosed radiologically by finding an adrenal mass with a density higher than 10 HU.²

Immediate stabilisation of blood pressure is essential in CICMP. α blockers are used to counter the vasoconstriction which is responsible for organ failure. The target blood pressure is less than 130/80 mm Hg and a heart rate of 70–80/min when sitting. In cases of wide fluctuations in blood pressure, boluses of intravenous phentolamine need to be administered, and after stabilisation of blood pressure, it can be transitioned to oral α blockers. β blockers are administered after α blockade has been established to prevent tachycardia. After stabilisation of cardiac function, resection of the PHEO or PGL is done which improves the CICMP.^{19 20}

Hypotension in CICMP could be secondary to systolic dysfunction or intravascular volume contraction due to chronic catecholamine exposure. Conventional pressor agents (norepinephrine, dopamine and epinephrine) may not be effective due to the downregulation of β-adrenergic receptors. Milrinone which acts through the calcium channel can be used. Refractory hypotension may necessitate the need for intraaortic balloon pump or VAECMO.⁴

VAECMO is a mechanical life support technique which offers both ventilator and haemodynamic support. Hekimian et al analysed 49 patients with CICMP with refractory cardiogenic shock needing ECMO. Most of the patients initially presented with hypertension before going into cardiogenic shock. All patients had severe cardiac dysfunction with EFs of 10%–15%. The median period of ECMO use was 4 days. Post-surgery, 93% of patients survived.²¹

Learning points.

• Catecholamine-induced cardiomyopathy (CICMP) is a rare complication seen in 8%–11% of pheochromocytomas (PHEO) and paragangliomas (PGL); however; early recognition and management is crucial as it can cause increased mortality and morbidity.

• The pathogenesis of CICMP involves the development of ischaemic areas in the myocardium due to an oxygen demand-supply mismatch, downregulation of β-adrenergic receptors and massive influx of calcium into the cardiac myocytes.

• CICMP needs to be suspected in cases of heart failure without a clear aetiology, an acute coronary syndrome with non-obstructed coronaries and multiple organ failure without any apparent cause.It can present as dilated cardiomyopathy, hypertrophic cardiomyopathy, refractory cardiogenic shock or sudden onset pulmonary oedema.

• As cardiogenic shock and intravascular volume contraction can both occur in pheocromocytomas, assessing  fluid status is important for guiding therapeutic interventions. Therefore using a central line to monitor central venous pressure is recommended.Cardiogenic shock may need to be treated with milrinone as common pressors are ineffective due to the downregulation of β receptors. Refractory cardiogenic shock may need management with intraaortic balloon pump or venous-arterial extra corporeal membrane oxygenation.

• α blockers are used to relieve the vasoconstriction and control blood pressure. Subsequently, β blockers are added to prevent tachycardia. After stabilisation of cardiovascular function and haemodynamic status, surgical resection of PHEO or PGL is done.Surgical resection can lead to a rapid improvement in cardiac function. About 93% of patients with CICMP who underwent surgical resection survived.