Case Report

Cardiogenic shock associated with reversible dilated cardiomyopathy during therapy with regular doses of venlafaxine

Abstract

We report a cardiac complication in a patient treated with regular doses of venlafaxine. A 49-year-old man with prior normal cardiac function and stable chronic Hepatitis C was treated for a major Depressive disorder with usual doses of venlafaxine during an 8-month period until the occurrence of a cardiogenic shock in a context of dilated cardiomyo- pathy. Three months after withdrawal of the drug, the left ventricular ejection fraction returned to normal values. Cardiomyopathy is a rare complication with high doses of venlafaxine that was not previously reported in patients free of prior cardiac disease and cardiomyopathy and treated with usual doses (initially 150 mg daily; after 3 months, 75 mg daily). An objective assessment revealed that venlafax- ine was probably implied in the subsequent development of cardiomyopathy when considering the Naranjo Probability Scale. Physicians who usually prescribe venlafaxine have to be briefed on such potential cardiac adverse effects even with usual doses.

heart failure is mainly due to high blood pressure, coronary heart disease, and valvular heart disease [1]. However, HF may also be induced by some adverse effects of drugs [2,3]. Several noncardiac drugs can induce a worsening of HF. Anticancer agents, immunomodulating drugs, antidiabetic drugs, Appetite suppressants, antimi- graine drugs, antipsychotic drugs, antiparkinsonian drugs, glucocorticoids, and antifungal drugs can account for this worsening [3]. Furthermore, such drugs also may affect hemodynamic conditions in patients with previous cardiac diseases.

Venlafaxine is an antidepressant drug metabolized by Cytochrome P450 (CYP). This drug is metabolized primarily by CYP2D6, which is subject to genetic polymorphism, to yield O-desmethylvenlafaxine and, to a lesser extent, by CYP3A4 to yield N-desmethylvenlafaxine [4]. Venlafaxine inhibits the neuronal reuptake of serotonin and norepinephr- ine and, to a minor degree, dopamine, with little or no anticholinergic, antihistaminic, or ?-adrenergic activity [5]. Venlafaxine blocks the cardiac fast inward sodium current in

a concentration-dependent manner, thereby promoting membrane-stabilizing effects [6].

Usually, the diagnosis of drug-induced disease may be difficult because clinical and biological symptoms are often nonspecific. Previous clinical trials have reported venlafax- ine adverse effects, including dose-dependent blood pressure elevation, cardiac rhythm or conduction disturbances, and orthostatic hypotension. When taken in overdose, venlafax- ine may cause serious cardiotoxicity [7].

We describe a case where Therapeutic doses of venlafaxine caused a severe cardiomyopathy associated with a cardio- genic shock. After withdrawal of the drug, this cardiomyo- pathy progressively improved over 3 months.

In December 2006, a 49-year-old white man was admitted to a cardiology unit for cardiogenic shock. His past medical history included chronic hepatitis treated with pegylated interferon from December 2004 to January 2006 and a major depressive disorder treated with venlafaxine since March 2006 (initially, 150 mg daily; 3 months later, 75 mg daily). This compliant patient was followed up by a psychiatrist who periodically continued the treatment. Cardiovascular risk factors included a history of hypertension (blood pressure, 150/90 mm Hg) that was treated with indapamide and has been well controlled since 2000. This patient was an active smoker. No obesity was revealed (body mass index, 24.7 kg/ m²), as well as no diabetes mellitus (glycated hemoglobin, 5.5%) or alcohol abuse (no history and no abnormality in hepatic enzymes). A cardiac assessment including an echocardiographic examination was performed after the withdrawal of pegylated interferon in January 2006 and ruled out a preexisting cardiomyopathy (left ventricular [LV] ejection fraction [LVEF] and end diastolic diameter [LVEDD] were 71% and 52 mm, respectively; Diastolic function was normal). Wall stiffness had normal values. No valvular disease (stenosis or regurgitation) was found.

A progressive dyspnea appeared 3 days before admission and was followed by orthopnea, New York Heart Associa- tion class IV, requiring admission to the cardiology unit. Upon admission, the physical examination revealed regular heart sounds, a tachycardia with 105 beats/min, and blood pressure of 80/55 mm Hg. No cardiac murmur was heard. Bilateral crackles over both lung fields and peripheral signs of shock were observed. Chest x-ray, known to have normal results before admission, showed a mild cardiomegaly and a bilateral pulmonary edema but no pleural effusion. An

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electrocardiogram (ECG) revealed a sinus tachycardia, an LV hypertrophy (Sokoloff index, 40 mm), and Negative T waves on leads V₅ through V₆ (Fig. 1A). Routine laboratory examinations did not show any blood electrolyte imbalance (sodium, 137 mmol/L; potassium, 3.6 mmol/L). Blood creatinine level was 102 umol/L (reference range, 80-115 umol/L), C-reactive protein level was 9 mg/L (reference value, b10 mg/L), and Fibrinogen level was 3.3 g/L (reference value, b4 g/L). There was no anemia (hemoglo- bin, 14.5 g/L), no abnormality in white blood cell count (7000/uL), and no lymphopenia. Upon admission, the Amino-Terminal Pro-B-Type Natruretic Peptide (NT- proBNP) level was increased (13 300 ng/L; reference value, b450 ng/L). Troponin Ic and Creatinine kinase values were 0.01 ug/L (reference value, b0.12 ug/L) and 90 U/L (reference value, b180 U/L), respectively.

A 2-dimensional echocardiography showed a diffuse impaired biventricular contraction with an LVEF of 16% (Fig. 1B). No LV hypertrophy, no LV dilation (LVEDD, 55 mm; index LVEDD, 48 mm/m²), no valvulopathy, and no pericardial effusion were shown. The cardiac index was 1.9 L

min^-1 m^-2. One week after admission, a coronary angio- graphy showed completely Normal coronary arteries.

The diagnosis of cardiogenic shock associated with severe cardiomyopathy was retained. Therapy begun with dobuta- mine (during a 7-day period), which was progressively associated with furosemide, perindopril, and spironolactone. Amiodarone was subsequently added when a sustained ventricular tachycardia occurred. Before treatment with amiodarone, thyroid hormones had normal values. Upon admission, venlafaxine was withdrawn. This patient remained hospitalized during a 3-week period.

The diagnosis of cardiomyopathy due to venlafaxine was proposed as some other causes of cardiomyopathy were ruled out. We excluded ischemic cardiomyopathy (coronary arteries were angiographically normal; no wall motion abnormalities on echocardiography), myopericarditis (no inflammatory syndrome; normal creatinine kinase value), valvular heart disease, toxic cardiomyopathy (alcohol abuse, anticancer drugs, interferon; however, this latter drug was withdrawn 1 year ago), and biochemical abnormalities, such as hypocalcemia.

Fig. 1 (A) Electrocardiogram upon admission (December 4, 2006): sinus rhythm with a LV hypertrophy and negative T waves on V₅ through V₆. (B) Echocardiography Parasternal long axis view upon the admission (December 4, 2006): LVEDD (55 mm) and LVEF (16%). (C) Electrocardiogram 3 months later (March 16, 2007): sinus rhythm with negative T waves on V₅ through V₆ and regression of the LV hypertrophy. (D) Echocardiography parasternal long axis view 3 months later (March 16, 2007): normalization of echocardiographic parameters (telediastolic diameter [53 mm] and LVEF [57%]).

An improvement in the patient’s condition subsequently appeared during the 3-week period. Three months after the withdrawal of venlafaxine, the patient was asymptomatic and returned to New York Heart Association class II. The physical examination results became normal, particularly blood pressure, and ECG abnormalities disappeared (Fig. 1C). A new echocardiography showed the improvement of LVEF to 57% (Fig. 1D). Treatment with a ?-blocker (nebivolol, 1.25 mg/d) was added. Values for ECG and LVEF returned to reference values (Table 1). A complete evaluation was performed with a radionuclide angiography (LVEF, 63%) and a stress test-VO₂ peak at 33 mL min^-1 kg^-1. The ambulatory ECG Holter recording was normal without significant atrial or ventricular premature beats or arrhythmias (only 2 auricular isolated ectopic beats). Amiodarone, which never introduced any modification in thyroid hormone levels, was also withdrawn, and no recurrence of any ventricular arrhythmia was found. Six months later, the patient remained free of signs and symptoms and then went back to his professional activities. No abnormality was found in the physical examination, ECG, chest x-ray, and echocardiography. Now with a 2-year aftercare, the patient remains asymptomatic without any cardiac disease.

This case report describes the positive development of a cardiogenic shock associated with reversible cardiomyopathy in a well-minded and compliant patient treated with therapeutic doses of venlafaxine and not with toxic doses.

Several noncardiac drugs are known to be associated with the development or worsening of HF. They include anticancer agents (anthracyclines, cyclophosphamide, and trastuzumab), immunomodulating drugs (interleukin 2, interferon ?-2, infliximab, and etanercept), antidiabetic drugs (rosiglitazone, pioglitazone, and troglitazone), appetite suppressants (fenfluramine, dexfenfluramine, and phentermine), antimigraine drugs (ergotamine and methysergide), antipsychotic drugs (clozapine), antipar-

Table 1 Data from the patient during the follow-up (month/day)

12/4th Day 0		1/16th Day 34	3/15th Day 93	4/17th a Day 125
LVEDD (mm)	55	51	53
LVEF (%)	18	44	57	63
Heart rate	108	71	66	52
(beats/min)
Cardiac index	1.9	2.6	4.0
(L min-1 m-1)
CRP (mg/L)	9	3	3	3
Fibrinogen (g/L)	3.5	3.2	3.3	3
NT-proBNP	13 300	1500	300	320
(ng/L)
CRP indicates C-reactive protein. a Parameters evaluated by radionuclide angiography.

kinsonian drugs (pergolide and cabergoline), antifungal drugs (itraconazole and amphotericin B), and glucocor- ticoids [3]. More recently, selective cyclooxygenase-2 inhibitors have been shown to cause heart disease, particularly in patients with previous cardiorenal dysfunction.

Prescriptions of venlafaxine have increased since its introduction in 1994. It may result in miscellaneous adverse effects that are generally self-limited. They include nausea, fatigue, headache, dizziness, and dry mouth and also might include cardiovascular adverse effects [8,9]. These various cardiovascular adverse effects reported with venlafaxine frequently include vascular headache, angina pectoris, and hypotension and, sometimes, hypertension and syncope. In healthy young adults, venlafaxine increases the QT interval (as defined by an increase of N20% in the QT duration when compared with resting ECG or QT duration N450 milliseconds), particularly at high doses greater than 200 mg/d [10,11]. In addition, a more severe cardiovascular toxicity has been reported after toxic doses of venlafaxine [12]. In the retrospective study by Howell et al focused on hemodynamic and ECG data, the most frequent major Cardiovascular adverse events among 235 consecutive cases were tachycardia (40%), corrected QT prolongation (defined by a corrected QT N450 milliseconds; 21.6%), and transient dose-dependent arrhythmias [7,11]. Moreover, an overdose of venlafaxine (3 g/d) was associated with the occurrence of atrial fibrillation with wide QRS complexes [13]. Furthermore, Mbaya et al [14] studied the Cardiovascular effects of high doses of venlafaxine (346.15 mg; range, 225-525 mg) in 5 patients with major depressive disorders and they did not find any association between dose of venlafaxine and heart rate, PR duration, QRS duration, and QT intervals. In this latter study including a small number of patients, only 1 had a moderate increased arterial pressure [14].

Regarding venlafaxine alone, cardiomyopathy has been rarely reported, only in some case reports. Relevant information was identified through a search in Medline (1994-2008) using the following key words: venlafaxine, cardiotoxicity, cardiomyopathy, and arrhythmias. More- over, we declared this secondary adverse effect to the “pharmacovigilance committee” of the Avicenne Hospital. In one case of overdose of venlafaxine, an LV dysfunction with a marked hypokinesia was observed [11]. In the second case report, Fangio et al [12] reported an Acute HF associated with venlafaxine poisoning in a patient who had a severe cardiomyopathy with global hypokinesia and an LVEF of 35% without dilated cardiomyopathy (LVEDD was normal). Cardiomyopathy returned to reference values after a 10-day period of drug cessation. More recently, Hojer et al [8] described a third case of a fatal cardiotoxicity induced by venlafaxine. In these 3 case reports, cardiomyopathy was due to an overdose of venlafaxine. However, in 2 other cases using usual doses of venlafaxine (initially, 75 mg daily; after 1 month, 37.5

mg daily), cardiomyopathy was observed with a reduced LVEF (38%) and interstitial pneumonia with an improve- ment after a 2-week period of drug cessation [15]. Thus, in our case report, we describe a cardiomyopathy with severe LV dysfunction without LV dilation.

For chronic hepatitis C, our patient had been treated with pegylated interferon during a 14-month period. This therapy was stopped 11 months before the admission. Interferon-related cardiotoxicity includes cardiac arrhyth- mias, dilated cardiomyopathy, ischemic heart disease, myocardial infarction, and sudden death [16]. These cardiac adverse effects were related neither to the daily nor to the cumulative total dose. In most patients, the cardiac toxicity was reversible after cessation of the drug [17]. Cardiomyopathy rarely appears with high doses of standard interferon, and only an isolated case of fatal cardiomyopathy was reported in a patient during treatment with a usual dose of pegylated interferon-? [18,19]. Moreover, cardiovascular adverse effects of interferon may occur even after the end of therapy, mostly consisting in arrhythmias and ischemic heart disease but not in cardiomyopathy [18-21]. Cardiomyopathy appears only during treatment. No clinical factors, including history of cardiovascular disease, were related to these cardiovascular adverse effects. Thus, in our patient, the treatment with interferon does not seem to be responsible for cardiomyo- pathy as it was shown by previous echocardiographies. We excluded a stress cardiomyopathy or Tako-Tsubo cardio- myopathy [22] because there was no association with a triggering emotional or physical stress. Furthermore, echocardiography and ventriculography did not reveal any akinesia of midsegments or hyperkinesia of LV baseline segments [23].

The mechanisms of action of venlafaxine on the heart are complex. Primarily, venlafaxine is metabolized by an isoenzyme of the CYP450 system (CYP2D6). In particular, CYP2D6 may manifest phenotypically as slow or rapid metabolizers. Administration of venlafaxine to poor metabolizers places them at risk of accumulation of the drug to toxic concentrations [24]. Thus, increased plasma concentrations of venlafaxine can be observed not only after an overdose of the drug but also because of the decrease in its clearance in some subjects [24]. Moreover, venlafaxine blocks the cardiac fast inward sodium current in a concentration-dependent manner, thereby promoting membrane-stabilizing effects [6,23,25]. In addition, venla- faxine has been identified as a potential contributor to an increased defibrillation threshold and atrial fibrillation, which can be treated by sodium bicarbonate that reverses the membrane-stabilizing activity [6,11,26,27].

In our patient, the relationship between treatment with venlafaxine and the subsequent development of cardiomyo- pathy is probable when applying the Naranjo Probability scale [28]. Naranjo et al used a questionnaire to determine the likelihood of an Adverse drug reaction actually due to the drug better than the result of other factors. Probability is

assigned via a score termed definite, probable, possible, or doubtful. So arguments for probable involvement of venlafaxine are the following:

• symptoms of dilated cardiomyopathy appeared 6 months after the introduction of the treatment;
• a preexisting cardiomyopathy was ruled out by a Cardiologist consultation and specific investigation with echocardiography performed after cessation of the interferon therapy and before introducing venlafaxine;
• 3 months after withdrawal of venlafaxine, the cardio- myopathy was completely reversible;
• other causes of cardiomyopathy have been ruled out;
• absence of other drugs that could interact with CYP2D6 or P-glycoprotein inhibitor; and
• absence of Serotonin syndrome.

This case highlights that drug-induced cardiac disease should be considered as a potential adverse effect of venlafaxine, sometimes resulting in the development of a severe cardiomyopathy. Our case reports the development of cardiac failure in a middle-aged man without relevant comorbidity or cardiac medical history. Physicians who prescribe antidepressant drugs should be aware of the potential risks associated with venlafaxine and a high prevalence of cardiovascular adverse events. Tachycardia and QT prolonga- tion are the most frequent adverse effects. These effects are more often dose dependent.

The prognosis of cardiomyopathy may be promising when the drug is withdrawn.

The follow-up of symptomatic cardiomyopathy in patients treated with usual doses of venlafaxine should include serial cardiac examinations and ECG completed by an echocardiography.

Acknowledgments

The authors are grateful to Dr Bernard Uzzan for help with the English manuscript.

Jean-Christophe Charniot MD, PhD

Noelle Vignat MD AP-HP Avicenne Hospital Department of Cardiology Universite Paris 13, UFR SMBH 125 Route de Stalingrad

93009 Bobigny Cedex, France E-mail address: [email protected]

Jean-Jacques Monsuez MD, PhD AP-HP, Rene Muret Hospital Department of Internal Medicine

Universite Paris 13 UFR SMBH, Bobigny, France

Rachid Kidouche MD Boryana Avramova MD Jean-Yves Artigou MD AP-HP Avicenne Hospital Department of Cardiology

Universite Paris 13, UFR SMBH 125 Route de Stalingrad 93009 Bobigny Cedex, France

Jean-Paul Albertini MD, ScD AP-HP Avicenne Hospital Department of Biochemistry Universite Paris 13, UFR SMBH 125 Route de Stalingrad

93009 Bobigny Cedex, France

doi:10.1016/j.ajem.2009.05.010

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