A New Approach for the Accurate Diagnosis of Non-Cardiac Chest Pain

Abstract

1. Chest pain does not originate solely from the heart; distinguishing between cardiac and non-cardiac chest pain is critical for patient safety and subsequent treatment strategy.

2. Among patients with non-cardiac chest pain, as many as 50–60% of cases can be traced to gastroesophageal reflux disease (GERD).

3. Pepsin, as a novel biomarker, with its unique advantages, has emerged as a powerful tool for diagnosing GERD, particularly for identifying reflux-related chest pain.

Chest Pain – A Symptom that Instantly Alarms

Chest pain is a symptom that can immediately tighten anyone’s nerves. The first terrifying thought in people’s minds is often: “Is something wrong with my heart?” This fear is deeply rooted in awareness of fatal cardiac events such as myocardial infarction. However, the clinical reality is more complex: the heart is far from the only source of chest pain. Accurate differentiation between cardiac and non-cardiac chest pain is not only essential for correct diagnosis but also determines patient outcomes and treatment strategies.

1. Cardiac Chest Pain: The Eye of the Storm

The most common culprits are coronary artery diseases, including angina pectoris, acute myocardial infarction, pericarditis, myocarditis, and aortic dissection—all capable of causing myocardial injury.

Such pain is typically intense, as if something heavy is pressing on the chest, accompanied by breathlessness, nausea, vomiting, or cold sweats. Electrocardiograms may reveal abnormalities such as ST-segment elevation/depression or T-wave inversion. Laboratory markers including troponin I/T, brain natriuretic peptide (BNP), or NT-proBNP assist in diagnosis.

2. Non-Cardiac Chest Pain: A Broad Stage of “Mimics”

Once cardiac causes are excluded, the search extends to a wide range of conditions:

• Gastrointestinal disorders: GERD is the most important cause, followed by esophageal spasm, hiatal hernia, esophagitis, and peptic ulcer.

• Pulmonary and pleural diseases: Pulmonary embolism (often with dyspnea and hemoptysis), pleuritis (sharp pain on breathing), pneumonia, pneumothorax, and lung cancer.

• Musculoskeletal causes: Costochondritis, rib fractures, chest wall muscle strain.

• Dermatologic causes: Herpes zoster (severe neuralgic pain preceding rash).

GERD – The “Master Mimic” of Non-Cardiac Chest Pain

Studies show that among patients presenting with chest pain in cardiology departments but later ruled out for heart disease, 50–60% were ultimately diagnosed with GERD. Why is GERD so adept at masquerading as cardiac pain?

1. Shared Neural Pathways – The Physiological Basis of Mimicry

Sensory nerve fibers from the distal esophagus and the heart overlap at the spinal cord level. When refluxate such as acid or pepsin irritates the esophageal mucosa, pain signals may be misinterpreted by the brain as originating from the heart. This neuroanatomical “miscommunication” explains why GERD-related pain is often mistaken for angina.

2. Clinical Presentation – Hard to Tell Apart

• Nature of pain: GERD-related chest pain is often described as burning (heartburn) or a squeezing/pressure sensation behind the sternum, closely resembling angina.

• Location & radiation: Typically retrosternal or subxiphoid, radiating to the neck, jaw, or back—mirroring angina distribution.

• Triggers: Worsens after meals, on bending over, or lying down—different from exertional angina, but nocturnal reflux pain can be misjudged as “decubitus angina.”

• Associated symptoms: Frequently accompanied by reflux symptoms such as regurgitation or heartburn, though in some patients chest pain may be the only manifestation.

3. Serious Consequences of Misdiagnosis

• Unnecessary invasive tests: Repeated coronary angiography.

• Ineffective medication use: Prolonged anti-anginal drug therapy, ineffective for GERD and associated with side effects.

• Delayed correct treatment: Untreated GERD can progress to esophagitis, Barrett’s esophagus (precancerous), or strictures.

• Resource and psychological burden: Wasted healthcare resources and heightened patient anxiety.

Therefore, when evaluating non-cardiac chest pain—especially with atypical symptoms or negative cardiac tests—GERD must be high on the differential list.

Pepsin – A “Molecular Probe” for GERD Diagnosis

Limitations of Traditional GERD Diagnostics:

• Endoscopy: Gold standard for erosive GERD, but 60–70% of reflux patients (NERD) show no visible mucosal changes.

• 24h pH monitoring: Traditional gold standard for acid reflux, but fails to detect weakly acidic (pH 4–7) or non-acid reflux (e.g., bile).

• Impedance–pH monitoring: Detects all reflux types, but invasive, costly, and poorly tolerated.

• Empirical PPI therapy: Simple and economical, but low specificity; other disorders may respond, and some GERD patients do not.

Pepsin as a Direct Marker of Reflux:

Pepsin is a digestive enzyme secreted by gastric chief cells from its precursor pepsinogen, activated in highly acidic gastric environments (pH 1.5–3.5).

• Key feature: Active pepsin should not normally exist in the esophagus, pharynx, oral cavity, or airways. Its presence there is direct molecular evidence of gastric reflux.

Clinical Application of Pepsin Testing:

• Sampling: Primarily via saliva, collected during symptomatic episodes or in the morning.

• Advantages:

• Direct evidence: Confirms reflux itself, unlike pH monitoring (acid only) or endoscopy (mucosal injury).

• Covers all reflux types: Acidic, weakly acidic, and non-acid reflux, as long as pepsin is present.

• Non-invasive and repeatable: Easy, painless collection, suitable for dynamic monitoring and treatment evaluation.

• Identifies extra-esophageal reflux: Pepsin in saliva provides strong evidence linking reflux to extra-esophageal symptoms such as chest pain, cough, laryngitis, or asthma.

• Guides personalized therapy: A positive result strengthens the case for targeted GERD treatment (PPI, lifestyle changes, or surgery), reducing misdirected cardiac therapy.

Conclusion: Clearing the Fog of Chest Pain with Pepsin

Chest pain is not a “heart-exclusive” alarm. Once life-threatening cardiac causes are excluded, investigating non-cardiac sources is essential. GERD, with its high prevalence and remarkable ability to mimic heart pain, is the leading suspect in such cases.

Traditional diagnostic tools often fall short, particularly in NERD and weakly acidic/non-acid reflux. The emergence of pepsin testing as a molecular probe provides a powerful, non-invasive, and highly specific method to capture direct evidence of reflux. It enhances both sensitivity and specificity in GERD diagnosis, especially in atypical chest pain, identifies diverse reflux events, and establishes causal links with extra-esophageal symptoms. Ultimately, pepsin testing helps clinicians deliver precise and effective treatment—bringing clarity to the diagnostic challenge of chest pain.