Venlafaxine-Associated Takotsubo Cardiomyopathy Complicated by Cardiogenic Shock and Left Ventricular Outflow Tract Obstruction: A Case Report and Literature Review

Abbreviations

ECG, Electrocardiography

IABP, Intra-aortic balloon pump

LVEDP, Left ventricular end-diastolic pressure

LVEF, Left ventricular ejection fraction

LVOTO, Left ventricular outflow tract obstruction

SNRI, Serotonin-norepinephrine reuptake inhibitor

STEMI, ST-segment elevation myocardial infarction

TCM, Takotsubo cardiomyopathy

INTRODUCTION

Takotsubo cardiomyopathy (TCM), also known as stress-induced cardiomyopathy, is a transient cardiac syndrome characterized by regional wall motion abnormalities in the absence of obstructive coronary artery disease.¹ It predominantly affects postmenopausal women and is often triggered by emotional or physical stress.¹ Although antidepressants such as venlafaxine — a serotonin-norepinephrine reuptake inhibitor (SNRI) — are rarely reported as precipitating factors, their sympathomimetic properties may contribute to TCM under certain conditions.^2-4

CASE PRESENTATION

A 77-year-old woman with a history of hypertension, type 2 diabetes mellitus, and depression — managed with venlafaxine 75 mg twice daily, which she had been taking for more than one year without recent dose adjustments — presented to a local hospital with acute chest tightness, diaphoresis, and mild dyspnea that began in the evening following her birthday celebration, during which she experienced heightened emotional excitement. Electrocardiography (ECG) demonstrated anterior ST-segment elevation myocardial infarction (STEMI) with elevated troponin I. She received loading doses of aspirin and ticagrelor and was transferred to a tertiary care center.

Upon arrival, she was hypotensive (blood pressure 89/56 mmHg) with a heart rate of 80 beats per minute. Physical examination revealed no jugular venous distension and a regular heart rhythm without murmur. Repeat ECG demonstrated ST-segment elevations in leads II, III, aVF, and V2-V6 with a prolonged QTc interval of 498 ms. Laboratory results showed elevated troponin T (1074 ng/L; normal < 14 ng/L), NT-proBNP (6394 pg/mL; normal < 125 pg/mL), and lactate (3.71 mmol/L; normal < 2.2 mmol/L). Chest radiography revealed bilateral pulmonary congestion. Transthoracic echocardiography demonstrated left ventricular systolic dysfunction with an ejection fraction (LVEF) of 30% and apical dyskinesia, with no significant valvular abnormality or left ventricular outflow tract obstruction (LVOTO). Emergency coronary angiography showed no significant coronary artery stenosis. Left ventricular end-diastolic pressure (LVEDP) was elevated at 21 mmHg, and no significant LVOTO was observed at the time (LV systolic pressure 107 mmHg, aortic systolic pressure 93 mmHg). Left ventriculography confirmed apical dyskinesia (Figure 1A and 1B). A diagnosis of TCM was made, likely triggered by emotional stress, venlafaxine, and potential recreational drug exposure, although toxicology screening was negative.

Figure 1.

(A&B) Left ventriculogram on Day 0 showed apical dyskinesia and basal hyperkinesia, which was compatible with the diagnosis of Takotsubo cardiomyopathy.

Later that evening, the patient developed acute respiratory distress with orthopnea, tachypnea (40 breaths/min), paradoxical breathing, and use of accessory muscles. Examination revealed diffuse wheezing, scant sputum, and cold, pale extremities. Repeat ECGs showed persistent ST-segment elevations. Echocardiography revealed worsening contractility without pericardial effusion. Laboratory testing demonstrated progressive lactic acidosis (5.73 mmol/L) and worsening hypoxemia. Hemodynamic monitoring with a Swan-Ganz catheter revealed cardiogenic shock: low cardiac index (1.19 L/min/m²), low cardiac power output (0.26 W), high pulmonary capillary wedge pressure (18 mmHg), and high systemic vascular resistance index (3842 dyn·s/cm⁵·m²), despite norepinephrine infusion (0.104 μg/kg/min). Dobutamine (up to 9.653 μg/kg/min) was added, and intra-aortic balloon pump (IABP) support was initiated.

On hospital Day 1, echocardiography revealed new-onset LVOTO with a peak intraventricular gradient of 97.4 mmHg. Urgent cardiac catheterization confirmed a significant pressure gradient (LV systolic pressure 168 mmHg, aortic systolic pressure 118 mmHg) and elevated LVEDP (36 mmHg). Given the progression to cardiogenic shock with LVOTO, IABP was removed, and an Impella CP® device was placed for mechanical circulatory support. Dobutamine was discontinued. Serial echocardiograms and hemodynamic assessments over the subsequent days revealed progressive improvement in LV function (Figure 2). The Impella CP® was successfully weaned and removed on Day 5.

Figure 2.

Hemodynamic data (Day 1-Day 5). Initial low cardiac index, low cardiac power output and high systemic vascular resistance index were compatible with cardiogenic shock.

The patient was extubated on Day 9, transferred to the general ward on Day 13, and discharged on Day 32. Venlafaxine was discontinued upon admission and subsequently replaced with sertraline after the patient’s condition stabilized. Cardiac magnetic resonance imaging on Day 23 confirmed the diagnosis of TCM, showing mid-to-apical hypokinesia without delayed gadolinium enhancement. Follow-up echocardiography on Day 83 revealed full recovery of systolic function (LVEF 69%) and no regional wall motion abnormality. A 24-hour urine collection on Day 1 revealed elevated norepinephrine (146 μg/24 h) and vanillylmandelic acid (8.1 mg/24 h), likely due to exogenous norepinephrine. Other catecholamines were within normal limits. The Naranjo Adverse Drug Reaction Probability Scale score was 3, suggesting a possible association with venlafaxine.

DISCUSSION

This case illustrates the hallmark features of TCM: an identifiable emotional stressor, chest pain, ECG changes mimicking STEMI, unobstructed coronary arteries, and reversible left ventricular dysfunction.¹ The clinical course was further complicated by cardiogenic shock and emergent LVOTO, requiring advanced mechanical circulatory support and careful reassessment of inotropic therapy.

The management of TCM is largely supportive. While LVOTO is a recognized complication, its natural course and progression in TCM remain inadequately defined.^1,5 In our patient, the initial pressure gradient between the left ventricle and the aorta was modest (14 mmHg) but increased in parallel with clinical deterioration. The use of catecholamines and IABP support during cardiogenic shock proved ineffective and may have exacerbated the degree of LVOTO. This case highlights the importance of serial re-evaluation of the LVOT pressure gradient during the clinical course, as it may significantly influence decisions regarding mechanical circulatory support. Notably, the elevated 24-hour urinary norepinephrine detected in our patient may have been secondary to the norepinephrine infusion initiated on Day 1 for hemodynamic support. These biochemical abnormalities should be interpreted with caution, as exogenous catecholamine administration — and the inotropes themselves — may not only explain the elevated levels but also worsen LVOTO. Furthermore, serial norepinephrine measurements were not obtained after venlafaxine discontinuation; therefore, we cannot definitively establish a temporal relationship between drug withdrawal, normalization of catecholamines and recovery of cardiac function. While venlafaxine may have contributed to the development of TCM through increased sympathetic activity, the causal relationship cannot be established with certainty in our case. The Naranjo score of 3 indicates only a possible association, underscoring the need for cautious interpretation. Further studies and pharmacovigilance reports are warranted to better define the potential link between venlafaxine and TCM.

The chronic use of venlafaxine may have contributed to TCM via enhanced sympathetic activity. Venlafaxine increases synaptic serotonin and norepinephrine, thereby elevating sympathetic tone, heart rate, and blood pressure — factors that can precipitate myocardial dysfunction.³ Identified risk factors for venlafaxine-associated TCM include female sex (especially postmenopausal),⁶ high-dose or rapidly titrated venlafaxine,⁷ and concurrent use of other sympathomimetics.⁶ Genetic factors such as CYP2D6 polymorphisms may also increase susceptibility.⁸

Case reports have described TCM in the context of both therapeutic and overdose venlafaxine use.^2-4,7,9,10 In several cases, additional emotional or physical stressors — such as chronic obstructive pulmonary disease exacerbations, or suicide attempts — were present and may have acted as contributing factors.^3,7,9 Most patients exhibited a marked reduction in LVEF during the acute phase,^2-4,9 with one case reporting LVEF below 10%.⁷ Regional wall motion abnormalities were consistently observed, predominantly involving the apical or mid-ventricular segments, aligning with the classic TCM phenotype.^2-4,7,9,10 While some patients required advanced hemodynamic support (e.g., IABP, or extracorporeal life support),^7,9 all cases demonstrated full recovery of cardiac function following drug discontinuation and supportive management. These findings support a potential causal link between venlafaxine exposure and TCM, emphasizing the importance of clinical awareness when evaluating patients on venlafaxine who present with acute cardiac symptoms.

LEARNING POINTS

• Long-term SNRI use can act as a potential risk factor for TCM.

• This case suggests an association between chronic venlafaxine use and TCM, supporting that cessation of venlafaxine treatment may be warranted after TCM onset.

• Re-evaluation of the LVOT pressure gradient and hemodynamic parameters during the clinical course is important, as it may influence the selection of appropriate mechanical circulatory support strategies.

DECLARATION OF CONFLICT OF INTEREST

All the authors declare no conflict of interest.