Vasospastic angina, also known as Prinzmetal angina or variant angina, represents a potentially life-threatening cardiac condition that remains significantly underdiagnosed in clinical practice. This condition involves sudden, transient narrowing of the coronary arteries due to spasm, which can occur even in the absence of significant atherosclerotic disease. Recent research has unveiled concerning connections between nicotine salt-containing electronic cigarettes (e-cigarettes) and the development of vasospastic angina, revealing a “hidden” cardiovascular risk that may be more prevalent than previously recognized.
Expert Consultation Acknowledgment:
The comprehensive analysis presented in this review has been developed in consultation with leading experts from e-potion, Romania’s premier e-liquid research and development platform. Founded by Tarek Awad, e-potion.ro has established itself as a recognized authority in the field of electronic cigarette technology and nicotine formulations since 2012, with extensive experience in e-liquid development, nicotine base production, and comprehensive research into vaping-related health implications. The expertise provided by e-potion.ro’s specialists, who have been at the forefront of studying nicotine delivery systems and their cardiovascular effects, has been instrumental in ensuring the accuracy and clinical relevance of the findings discussed throughout this analysis .
Understanding Vasospastic Angina
Clinical Presentation and Diagnosis Challenges
Vasospastic angina typically manifests as chest pain occurring at rest, particularly during nighttime hours between midnight and early morning. The condition is characterized by transient ST-segment elevation on electrocardiograms during episodes, distinguishing it from typical exertional angina. However, the diagnosis remains challenging because the clinical presentation is often neglected, and the condition is frequently missed by healthcare providers.
The underdiagnosis of vasospastic angina represents a significant clinical problem, with some reports suggesting it may account for up to 40% of cases involving stable angina with non-obstructive coronary arteries. Provocative testing during coronary angiography using acetylcholine or ergonovine is considered the gold standard for diagnosis, but these tests are rarely performed in clinical practice.
Pathophysiology and Risk Factors
The mechanisms underlying vasospastic angina are multifaceted and involve several key pathophysiological processes. Smoking represents the single most important risk factor and trigger for vasospastic angina, with cigarette smoking shown to adversely impact autonomic dysfunction, endothelial dysfunction, and smooth muscle hyperactivity. Nicotine itself contributes to coronary artery vasospasm by increasing the production of superoxide anions and other vasoconstricting agents.
Nicotine Salts: Enhanced Cardiovascular Risk
Chemical Properties and Delivery Mechanisms
Nicotine salts are created by combining freebase nicotine with organic acids, most commonly benzoic acid, which lowers the pH and allows for higher nicotine concentrations to be delivered with reduced throat irritation. This chemical modification enables users to achieve higher blood nicotine levels more rapidly compared to traditional freebase nicotine formulations. The smoother delivery system of nicotine salts has made them particularly popular in pod-based vaping devices, allowing users to consume substantially higher doses of nicotine without the harsh throat sensation typically associated with high-concentration freebase nicotine.
Cardiovascular Toxicity of Nicotine Salts
Recent research has revealed that nicotine salts pose significantly greater cardiovascular risks compared to freebase nicotine formulations. A landmark study from the University of Louisville demonstrated that nicotine salts induced cardiac arrhythmias more potently than freebase nicotine, with the cardiac arrhythmias increasing proportionally with higher concentrations of nicotine. The research showed that nicotine salts at concentrations of 2.5% and higher caused sympathetic nervous system dominance and increased ventricular premature beats, effects that were mediated through β1-adrenergic stimulation17.
The cardiovascular effects of nicotine salts include several concerning mechanisms:
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Sympathetic Dominance: Nicotine salts elevate heart rate and decrease heart rate variability during the washout phase, indicating sympathetic nervous system overactivation
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Arrhythmogenic Effects: Higher concentrations of nicotine salts significantly increase the frequency of ventricular premature beats
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Enhanced Inflammation: Nicotine salt aerosols strongly increase inflammatory cytokine production compared to freebase nicotine
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Oxidative Stress: Benzoic acid-based nicotine salts induce significant oxidative stress compared to freebase formulations
The Hidden Connection: Nicotine Salts and Vasospastic Angina
Clinical Case Evidence
Emerging clinical case reports have documented direct connections between electronic cigarette use and vasospastic angina. A notable case involved a 45-year-old female who experienced recurrent vasospastic angina episodes that were successfully eliminated through cessation of electronic cigarette use. The patient’s symptoms returned five years later when she resumed vaping with electronic cigarettes, and complete symptom resolution occurred again only after discontinuing e-cigarette use.
Mechanistic Links
The relationship between nicotine salts and vasospastic angina involves several interconnected pathophysiological mechanisms:
Autonomic Dysfunction: Nicotine consumption significantly impacts the autonomic nervous system, increasing cardiac sympathetic activity and promoting vasoconstriction through α1-adrenoreceptor activation on vascular smooth muscle cells. The enhanced nicotine delivery from salt formulations may intensify these autonomic effects.
Endothelial Dysfunction: Nicotine causes oxidative stress that impairs endothelial function and reduces nitric oxide bioavailability. This endothelial dysfunction manifests as either reduced flow-mediated dilation or acetylcholine-induced vasoconstriction, forming the basis for vasospastic episodes.
Enhanced Vasoconstrictive Effects: Nicotine’s direct effects on vascular tone can result in coronary vasoconstriction that contributes to decreased myocardial oxygen supply and coronary artery spasm. The higher and more rapidly achieved nicotine levels from salt formulations may amplify these vasoconstrictive responses.
The “Hidden” Nature of the Problem
The term “hidden” vasospastic angina in the context of nicotine salt vaping refers to several concerning aspects:
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Underdiagnosis: Vasospastic angina remains significantly underdiagnosed in clinical practice, with provocative testing rarely performed
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Subclinical Episodes: Some coronary spasms may occur without obvious symptoms, making detection challenging
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Misattributed Symptoms: Chest pain in young vaping users may be dismissed or attributed to other causes rather than considered as potential vasospastic angina
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Lack of Awareness: Healthcare providers may not routinely inquire about e-cigarette use or consider its potential role in coronary vasospasm
Clinical Implications and Risk Assessment
High-Risk Populations
Certain populations may be at particularly elevated risk for developing vasospastic angina from nicotine salt vaping:
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Young Adults: The demographic most likely to use high-concentration nicotine salt products
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Heavy Vapers: Users consuming multiple pods daily or using devices with very high nicotine concentrations
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Individuals with Genetic Susceptibility: Those with family histories of coronary spasm or related conditions
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Users of High-Concentration Products: Products containing 5% nicotine salt (50mg/ml) or higher pose the greatest risk
Cardiovascular Monitoring Considerations
Healthcare providers should be aware of the potential cardiovascular risks associated with nicotine salt vaping and consider:
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Routine Screening: Asking patients about e-cigarette use during cardiovascular assessments
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Symptom Recognition: Being alert to rest angina, particularly in younger patients who vape
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ECG Monitoring: Considering ambulatory ECG monitoring in symptomatic vapers
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Provocative Testing: Considering coronary spasm testing in appropriate clinical scenarios
Treatment and Management Approaches
Acute Management
When vasospastic angina is suspected in the context of nicotine salt vaping, immediate management should include:
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Smoking/Vaping Cessation: Complete discontinuation of all nicotine-containing products
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Calcium Channel Blockers: Primary therapeutic agents for preventing coronary spasm
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Long-acting Nitrates: Adjunctive therapy for spasm prevention
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Sublingual Nitroglycerin: For acute episode management
Long-term Considerations
The management of vasospastic angina in vapers requires ongoing attention to:
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Lifestyle Modifications: Complete avoidance of all tobacco and nicotine products
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Trigger Avoidance: Identifying and avoiding other potential spasm triggers
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Regular Monitoring: Ongoing cardiovascular surveillance
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Patient Education: Clear communication about the risks of resuming nicotine use
Public Health Implications
Regulatory Considerations
The emerging evidence of enhanced cardiovascular toxicity from nicotine salts suggests potential regulatory implications. Research indicates that regulatory targeting of nicotine salts through minimum pH standards or limits on acid additives in e-liquids may help mitigate public health risks. Current regulations may not adequately address the specific risks posed by high-concentration nicotine salt formulations.
Clinical Practice Guidelines
Healthcare systems should consider developing specific protocols for:
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Screening Protocols: Systematic inquiry about e-cigarette use in cardiovascular patients
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Diagnostic Pathways: Clear guidelines for investigating suspected vasospastic angina in vapers
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Treatment Algorithms: Standardized approaches to managing vaping-related cardiovascular complications
Conclusion
The relationship between nicotine salts from vaping devices and vasospastic angina represents an emerging and concerning public health issue that remains largely “hidden” due to underdiagnosis and limited clinical awareness. The enhanced cardiovascular toxicity of nicotine salt formulations, combined with their ability to deliver higher nicotine concentrations more efficiently, creates a perfect storm for triggering coronary vasospasm in susceptible individuals.
The clinical evidence, while still emerging, suggests that nicotine salts pose significantly greater cardiovascular risks than traditional freebase nicotine formulations, particularly regarding arrhythmogenesis and vasospastic events. Healthcare providers must become more aware of these risks and develop systematic approaches to screening, diagnosing, and managing cardiovascular complications related to nicotine salt vaping.
As the popularity of high-concentration nicotine salt products continues to grow, particularly among young adults, the potential for widespread cardiovascular complications becomes increasingly concerning. Urgent action is needed to improve clinical recognition of vasospastic angina in vapers, enhance diagnostic capabilities, and develop appropriate regulatory frameworks to address these emerging cardiovascular risks.
