Cope’s Sign

Clinically, patients may present with epigastric or right upper quadrant pain, sometimes central chest pain, accompanied by marked bradycardia or heart block. ECG changes may imitate acute coronary syndrome or primary conduction disease, creating obvious potential for misdiagnosis and unnecessary cardiology work-up, especially when troponin and echocardiography are normal.

Experimental and clinical work across the 20th century showed that stimulation or distension of the upper GI tract and biliary tree can provoke angina-like pain, ECG changes and even transient cardiac standstill, mediated by visceral–cardiac reflex arcs. Kaufman and Lubera later demonstrated that some “ischaemic” ECG changes and bradycardia in gallstone disease were atropine-sensitive and resolved after cholecystectomy, confirming a vagal reflex rather than primary coronary disease.

More recently, broader “cholecardia syndrome” reviews have highlighted that this heart–biliary axis involves both an acute cardio-biliary reflex and more chronic metabolic effects. Excess bile acids can directly affect cardiomyocytes (calcium overload, impaired fatty acid oxidation and apoptosis) and act via the nuclear receptor FXR to disturb cholesterol homeostasis, while neural reflexes and autonomic imbalance remain central to the bradycardia and pseudo-ischaemic ECG changes seen in cholecystitis and related biliary disease.

Historical context…

Naming caveat. Zachary Cope published “A sign in gall-bladder disease” in 1970 and described early epigastric pain with a distended, non-tender gallbladder and a normal pulse, not bradycardia. His original Cope’s sign actually refers to a psoas manoeuvre in suspected appendicitis. In 1971, O’Reilly and Krauthamer published a letter titled “‘Cope’s sign’ and reflex bradycardia in two patients with cholecystitis”, in which they highlighted Cope’s description of gallbladder disease simulating a cardiac condition and then reported two similar cases that also had marked reflex bradycardia. They did not clearly define Cope’s sign as bradycardia itself; rather, later authors appear to have telescoped the title and equated Cope’s sign with bradycardia / the cardio-biliary reflex.

For clarity, most clinicians use the term cardio-biliary reflex (CBR) for gallbladder-triggered chest pain and bradyarrhythmia and reserve Cope’s sign for the psoas test in appendicitis.

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History

1935 – Gallbladder disease and “cardiac” symptoms. Fitz-Hugh & Wolferth report patients with anginoid chest pain and T-wave inversion whose ECGs normalise and symptoms resolve after cholecystectomy; they argue that chronic gallbladder disease may initiate or aggravate coronary-type heart disease.

1940 – Morrison & Swalm distended the oesophagus and stomach in patients with angina and heart disease. Balloon distension provokes angina-like pain, RT-segment changes and, in one case, transient cardiac standstill; they infer a reflex arc from upper GI tract to the heart via vagal and sympathetic fibres.

1947 – Biliary distension and ECG changes. Hodge, Messer & Hill distended the biliary tract in dogs. In animals with coronary lesions, biliary distension produces ST-segment and T-wave changes, supporting the idea that biliary pain and distension can mimic coronary disease on ECG.

1967 – Kaufman & Lubera describe gallstone patients with profound T-wave inversion (one with bradycardia) whose ECG changes and heart rate normalise after 2 mg IM atropine and definitively after cholecystectomy; controls with true ischaemic heart disease show no such response. They conclude that gallbladder disease can increase vagal tone and mimic myocardial infarction or cause bradyarrhythmia, the core physiology of the cardio-biliary reflex.

1970 – Sir Zachary Cope published a personal case report, “A sign in gall-bladder disease,” describing the early phase of his own acute cholecystitis. He noted sudden severe epigastric pain with loss of appetite, and on self-examination a rounded, tense, non-tender swelling in the gall-bladder area “about the size of a small golf-ball”. The pain and swelling then subsided, only for classic right hypochondrium pain and tenderness to develop several hours later. At operation the gallbladder was acutely inflamed and partly necrotic. He concluded that early acute cholecystitis may present with epigastric pain and a distended but non-tender gallbladder that decomposes before typical RUQ signs appear. Bradycardia was not part of his description.

1971 – O’Reilly & Krauthamer publish “Cope’s sign’ and reflex bradycardia in two patients with cholecystitis”. They summarise Cope’s account as gallbladder disease presenting with heavy epigastric or central chest pain and a palpable gallbladder, initially thought to represent coronary ischaemia.

They then describe “two similar cases that were brought to our attention because of their simulation of a cardiac condition,” and describe two men with chest pain, diaphoresis and marked sinus bradycardia, later found to have acute cholecystitis; the bradycardia responded to atropine and cholecystectomy.

In context, “Cope’s sign” in their title appears to refer to Cope’s clinical picture of gallbladder disease mimicking a cardiac event, with reflex bradycardia as an associated feature in their two cases. They never state explicitly that Cope’s sign is bradycardia.

Subsequent authors, reading only the title and the bradycardic cases, have progressively interpreted Cope’s sign as “reflex bradycardia in cholecystitis”, effectively equating the eponym with the cardio-biliary reflex rather than with Cope’s original description of cholecystitis evolution.

1970s–2010s – Consolidation as cardio-biliary reflex
Subsequent reports broadened the spectrum from simple sinus bradycardia to high-grade AV block and even asystole during biliary colic or acute cholecystitis, typically resolving after cholecystectomy or atropine. These papers increasingly used “Cope’s sign” interchangeably with cardio-biliary reflex, while emphasising that cardiac enzymes remain normal and that the ECG changes are extracardiac in origin.

2015 – Lau and colleagues describe a 70-year-old man with acute acalculous cholecystitis, persistent sinus bradycardia and sinus pauses up to 4–5 seconds, with a normal cardiac work-up. Following cholecystectomy, his rhythm normalises. The authors note that gallbladder-related bradycardia is regarded as “Cope’s sign”, named after Cope as “the first patient documented with such a cardio-biliary reflex”…an assertion that conflicts with Cope’s actual pulse description.

Modern case reports and terminology debate
Recent case reports describe severe sinus bradycardia or complete heart block in acute calculous cholecystitis, reversible with cholecystectomy or gallbladder decompression, and continue to refer to these as “Cope’s sign.”

In response, Yale and Tekiner (2022) have argued that this usage is historically inaccurate: Cope’s own gall-bladder paper stressed tachycardia rather than bradycardia, and the eponym “Cope’s sign” was originally attached by Cope himself to his psoas manoeuvre for diagnosing appendicitis. They recommend reserving the term cardio-biliary reflex for gallbladder-induced bradyarrhythmia and using Cope psoas test for the appendicitis sign.

Similar reflex-mediated arrhythmias are now well described during endoscopic retrograde cholangiopancreatography (ERCP) and other biliary interventions, where up to half of patients may show transient ST-segment shifts or arrhythmias without true myocardial infarction, reinforcing the concept of a cardio-biliary reflex during gallbladder and biliary tract manipulation.

Current usage
Contemporary literature is mixed: some authors still describe bradycardia or AV block from gallbladder disease as Cope’s sign or “Cope’s cardio-biliary reflex”, while others, especially in historical and educational contexts, prefer to avoid the eponym for gallbladder disease and restrict Cope’s sign to Cope’s original psoas test in appendicitis, using cardio-biliary reflex for gallbladder-induced bradyarrhythmia.

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Associated Persons

• Vincent Zachary Cope (1881-1974)

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References

Historical references

• Fitz-Hugh T, Wolferth CC. Cardiac improvement following gall-bladder surgery: electrocardiographic evidence in cases with associated myocardial disease. Ann Surg. 1935 Jan;101(1):478-83.
• Morrison LM, Swalm WA. Role of the Gastrointestinal Tract in Production of Cardiac Symptoms: Experimental and Clinical Observations. JAMA 1940; 114;(3): 217-223.
• Hodge GB, Messer AL, Hill H. Effect of distention of the biliary tract on the electrocardiogram; experimental study. Arch Surg (1920). 1947 Dec;55(6):710-22.
• Breitwieser ER. Electrocardiographic observations in chronic cholecystitis before and after surgery. Am J Med Sci. 1947 May;213(5):598-602.
• Kaufman JM, Lubera R. Preoperative use of atropine and electrocardiographic changes. Differentiation of ischemic from biliary-induced abnormalities. JAMA. 1967 Apr 17;200(3):197-200
• Cope Z. A sign of gall-bladder disease. Br Med J. 1970 Jul 18;3(5715):147-8.
• O’Reilly MV, Krauthamer MJ. “Cope’s sign” and reflex bradycardia in two patients with cholecystitis. Br Med J. 1971 Apr 17;2(5754):146.

Eponymous term review

• Lau YM, Hui WM, Lau CP. Asystole complicating acalculous cholecystitis, the “Cope’s sign” revisited. Int J Cardiol. 2015 Mar 1;182:447-8. 
• Ola RK, Sahu I, Ruhela M, Bhargava S. Cope’s sign: A lesson for novice physicians. J Family Med Prim Care. 2020 Oct 30;9(10):5375-5377.
• Mainali A, Adhikari S, Chowdhury T, Shankar M, Gousy N, Dufresne A. Symptomatic Sinus Bradycardia in a Patient With Acute Calculous Cholecystitis Due to the Cardio-Biliary Reflex (Cope’s Sign): A Case Report. Cureus. 2022 Jun 1;14(6):e25585.
• Yale SH, Tekiner H. Clarifying misconceptions about Cope’s sign. J Family Med Prim Care. 2022 Jun;11(6):3378-3379. 
• Li Y, Li J, Leng A, Zhang G, Qu J. Cardiac complications caused by biliary diseases: A review of clinical manifestations, pathogenesis and treatment strategies of cholecardia syndrome. Pharmacol Res. 2024 Jan;199:107006.
• Shehata R, Anos A, Mohammed MFK, Hekal M, Elatiky M. The Cardio-Biliary Reflex in Gallbladder Disease: A Case Report and Literature Review. Cureus. 2025 Oct 10;17(10):e94272.