2019 Research Forum

An Unusual Case of Paraquat-Induced Rhabdomyolysis & Hepatic Injury Presenting with Takotsubo Cardiomyopathy Sara Jaka MD R1, Jessica McFarland MS IV, Emily Gunz MS IV, Tasneem Khan MS III, Leila Moosavi MD R3, Carlos D’Assumpcao MD R1, Tana Parker MD, Fowrooz Joolhar MD, Arash Heidari MD, Tiffany Win MD

Discussion

Introduction

Case Presentation Takotsubo cardiomyopathy (TM) is a syndrome of reversible left ventricular (LV) systolic dysfunction commonly characterized by LV apical ballooning and mid and apical segment hypokinesis without evidence of obstructive coronary artery disease. We present a case of reversible TM in a patient with rhabdomyolysis and transaminitis secondary to Paraquat exposure. A 45-year old Hispanic female with diabetes, hypertension, and dyslipidemia presented to the hospital with a chief complaint of one month of bilateral upper and lower extremity weakness. On presentation she was diaphoretic but denying chest pain or shortness of breath. EKG showed Q waves in the inferior and anterior leads, but no ST elevations. Troponins were elevated to 2.57 prompting NSTEMI workup. Transthoracic echo (TTE) showed an LVEF of 20- 25% with akinetic mid and distal segments and apical ballooning highly suggestive for TM. We started the patient on guideline-directed medical therapy with an ace-inhibitor and beta-blocker. Left and right heart catheterization showed absence of obstructive coronary artery disease. Critical lab values were a CK of 14848, LDH of 1414, aldolase 169, ALT of 748 and AST 651. An intensive workup for rheumatologic, infectious, and autoimmune causes of her myopathy were unremarkable. EMG studies were consistent with active myopathy, MRI brain was unremarkable, and MRI pelvis showed diffuse muscular edema bilaterally through proximal thighs. Daily during the course of the admission, the patient expressed that her muscle weakness was slowly improving. Further history taking elucidated that her muscle weakness began around the time she started working in a new grape field where Paraquat had been sprayed one month prior, as confirmed by the local spraying company. Patient also reports having drank water from a tub filled with hose water there. Electron microscopy of muscle biopsy from the right gluteus muscle was inconclusive. TTE repeated 6 days after admission showed an LVEF of 50-55% and no regional wall motion abnormalities coinciding with the patient’s improved clinical picture. Patient was discharged and followed in cardiology clinic one week later where she demonstrated complete resolution of muscle weakness.

Takotsubo cardiomyopathy is referred to as “broken heart syndrome” for its association with severe and acute stressors. Diagnosis of TM requires EKG, cardiac enzymes, and angiography due to the conflated clinical picture of most patients who present with presumed acute coronary syndrome. EKG changes can show ST elevations in the acute phase, T wave inversions in the late phase, and QT prolongation, or Q waves in the subacute phase. Cardiac enzymes are often elevated, albeit with lower levels than in ACS, and resolve sooner. These patients often undergo angiography given there is no reliable way to differentiate TCM and ACS with EKG and cardiac markers alone, and will show clear coronary arteries or minimal stenosis. Coronary angiogram and TTE will show mid-ventricular dysfunction, apical hypokinesis, or apical ballooning with akinesis with mean EF ranging from 20-49%. Management of TM is similar to cardiomyopathy with LV systolic dysfunction: beta-blockers, ace-inhibitors, and diuretics. The pathophysiology behind TM is best explained by a theory known as the beta-2 adrenoreceptor/inhibitory G protein theory. This theory states that increased adrenaline during acute stress or illness leads to hyperstimulation of beta-2 adrenoreceptors which predominantly saturate the apical regions of the heart. Beta-2 receptor stimulation activates inhibitory G proteins leading to reduced cAMP levels and, ultimately, contractile dysfunction and hypokinesis more pronounced at the cardiac apex. We believe paraquat toxicity initiated the cascade of rhabdomyolysis and hepatic injury for our patient. When paraquat is ingested, it concentrates intracellularly where it undergoes redox cycling producing paraquat- radicals. The super oxide radicals are reactive and cause direct cellular damage. Large volume ingestion is most commonly associated with respiratory failure. Chronic low dose exposure, however, is more likely to affect the liver, heart, and kidneys. Paraquat targets the biliary excretory pathways in the liver causing cholangiocellular injury of bile ducts in the portal areas. Paraquat-induced myopathy can also occur after prolonged exposure. The toxin causes degeneration of muscle fibers correlating with increased plasma CK levels. Although the patient was exposed to numerous herbicides working in the field, paraquat is the only agent known to cause hepatic, myocardial, renal and skeletal muscle injury.

FIGURE 2: T2-weighted MRI pelvis showing diffuse bilateral muscle edema without atrophy.

FIGURE 3: EKG from 1) admission and 2) clinic. 1) Q waves in inferior and anterior leads. 2) diffuse T wave inversions.

Conclusions

• Paraquat, a non-selective contact herbicide, can lead to severe systemic toxicity. This case illustrates that reversible cardiomyopathy can develop in the setting of paraquat-induced rhabdomyolysis and hepatic injury. • Obtaining a detailed history of occupational and toxic exposures plays a critical role in identifying an accurate diagnosis and reversible cause of what can be a fatal disease. • Early recognition of this rare presentation is crucial as disease progression can lead to severe multi-organ failure. Discontinuation early on of paraquat exposure can lead to excellent outcomes, as in this case.

References

1. Gianni M, Dentali F, Grandi AM, et al. Apical ballooning syndrome or Takotsubo cardiomyopathy: a systematic review. Eur Heart J . 2006; 27: 1523-1529 2. Inoue M, Shimizu M, Ino H, et al. Differentiation between patients with Takotsubo cardiomyopathy and those with anterior acute myocardial infarction. Circ K. 2005; 69:89-94 3. Bybee KA, Kara T, Prasad A, et al. Systematic review: transient left ventricular apical ballooning: a syndrome that mimics ST-segment elevation MI. Ann Intern Med. 2004; 141:858-865. 4. Redfors B, Shao Y, Ali A, Omerovic E. Current hyotheses regarding the pathophysiology behind the takotsubo syndrome. Int J Cardiol 2014; 177:771-9 5. Lyon AR, Rees PS, Prasad S, et al. Stress cardiomyopathy: a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning. Nat Clin Pract Cardiovasc Med 2008; 5:22-9 6. Yalta K, Yilmaztepe M, et al. Left Ventricular Dysfunction in the Setting of Takotsubo Cardiomyopathy: A review of Clinical Patterns and Practical Implications. Cardiac Failure Review . 2018;4:14-20 7. Suntres ZE. Roles of antioxidants in paraquat toxicity. Toxicology . 2002. 180:65-77 8. Fenoglio J Jr, McAllister H Jr, Mullick F. Drug related myocarditis. Hum Pathology . 1981. 10:900-7 9. Tabata N, Morita M, et al. Paraquat myopathy: report on two suicide cases. Forensic Science International . Vol 100 Issues 1-2, Mar 1999. 117-126

Bilal Saeed MD, University of Toledo Medical Center, Satoshi Kurisu MD, Hiroshima City Hospital.

normal base contraction with apical ballooning during systole

tako-tsubo: octopus trap

FIGURE 1: Coronary angiography showing clear and patent left anterior descending, left circumflex, and right coronary arteries.

69