Navigating Chest Pain Mysteries

CardioNerds (Drs. Daniel Ambinder and Eunice Dugan) are joined by Namrita Ashokprabhu, incoming medical student, along with Drs. Yulith Roca Alvarez and Mehmet Yildiz from The Christ Hospital. Expert insights provided by Dr. Odayme Quesada. Audio editing by CardioNerds intern Christiana Dangas. This episode explores how cardiac MRI and coronary function testing revealed coronary vasospasm in a case of MINOCA.

Cardiac MRI is crucial in evaluating myocardial infarction with nonobstructive coronary arteries (MINOCA) and diagnosing myocarditis, but findings must be interpreted within clinical context. A 58-year-old man with hypertension, hyperlipidemia, diabetes, a family history of cardiovascular disease, and smoking history presented with sudden chest pain, non-ST-elevation on EKG, and elevated troponin I (0.64 µg/L). Cardiac angiography revealed nonobstructive coronary disease, including a 40% stenosis in the LAD, consistent with MINOCA. Eight weeks later, another event (troponin I 1.18 µg/L) led to cardiac MRI findings suggesting myocarditis. Further history revealed episodic chest pain and coronary vasospasm, confirmed by coronary functional angiography showing severe vasoconstriction, resolved with nitroglycerin. Management included calcium channel blockers and long-acting nitrates, reducing symptoms. Coronary vasospasm is a frequent MINOCA cause and can mimic myocarditis on CMRI. Invasive coronary functional testing, including acetylcholine provocation testing, is indicated in suspicious cases. 

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

Notes – Coronary Vasospasm

1. What are the potential underlying causes of MINOCA (Myocardial Infarction with Non-Obstructive Coronary Arteries)? 

• Plaque Rupture: Plaque disruption, which includes plaque rupture, erosion, and calcified nodules, occurs as lipids accumulate in coronary arteries, leading to inflammation, necrosis, fibrosis, and calcification. Plaque rupture exposes the plaque to the lumen, causing thrombosis and thromboembolism, while plaque erosion results from thrombus formation without rupture and is more common in women and smokers. Intravascular imaging, such as IVUS and OCT, can detect plaque rupture and erosion, with studies showing plaque disruption as a frequent cause of MINOCA, particularly in women, though the true prevalence may be underestimated due to limited imaging coverage. 

• Coronary Vasospasm: Coronary vasospasm is characterized by nitrate-responsive chest pain, transient ischemic EKG changes, and >90% vasoconstriction during provocative testing with acetylcholine or ergonovine, due to hyper-reactivity in vascular smooth muscle. It is a common cause of MINOCA, with approximately half of MINOCA patients testing positive in provocative tests, and Asians are at a significantly higher risk than Whites. Smoking is a known risk factor for vasospasm. In contrast, traditional risk factors like sex, hypertension, and diabetes do not increase the risk, and vasospasm is associated with a 2.5–13% long-term risk of major adverse cardiovascular events (MACE). 

• Spontaneous Coronary Artery Dissection: Spontaneous coronary artery dissection (SCAD) involves the formation of a false lumen in epicardial coronary arteries without atherosclerosis, caused by either an inside-out tear or outside-in intramural hemorrhage. SCAD is classified into four types based on angiographic features, with coronary angiography being the primary diagnostic tool. However, in uncertain cases, advanced imaging like IVUS or OCT may be used cautiously. While the true prevalence is unclear due to missed diagnoses, SCAD is more common in women and is considered a cause of MINOCA when it results in non-obstructive lesions, with various predisposing factors including genetics, fibromuscular dysplasia, and emotional stress.  

• Coronary Embolism/Thrombosis: Coronary embolism, often underdiagnosed, can be classified based on thrombus origin as direct, paradoxical, or iatrogenic, with atrial fibrillation being the most common cause. A Japanese study found that only 2.9% of AMI patients were related to coronary embolism, and 73% of these cases were due to atrial fibrillation, with recurrent thromboembolic events occurring in 10% of patients during follow-up. Risk factors for coronary thromboembolism include hereditary thrombophilia, with 14% of MINOCA patients having hereditary thrombophilia, and an extensive evaluation, including a hypercoagulable workup and screening for atrial fibrillation or patent foramen ovale, is crucial to determine the underlying cause. 

• Coronary Microvascular Dysfunction: The role of microvascular dysfunction in MINOCA remains uncertain due to limited data, though it is characterized by impaired vasodilation, increased vasoconstriction, and abnormal microcirculation remodeling, which affects coronary flow reserve without epicardial disease. Microvascular dysfunction is often underdiagnosed because it requires invasive functional testing, and studies in patients with ischemia but no obstructive coronary disease (INOCA) show a prevalence of up to 41%. A small study of MINOCA patients found that 25% had low myocardial perfusion reserve, suggesting potential involvement, but further research is needed to establish its role as a cause of MINOCA. 

• MINOCA mimickers: 

• Myocarditis: Myocarditis, often caused by viral infections, can also result from bacterial infections, toxic substances, or autoimmune disorders, and is more common in younger patients, though it can affect all ages. Fulminant myocarditis, though rare, can lead to life-threatening cardiogenic shock, and is diagnosed through CMR showing diffuse myocardial edema on T2 and myocardial biopsy. A meta-analysis found that one-third of MINOCA patients had myocarditis, particularly younger patients and those with elevated C-reactive protein levels. 

• Non-ischemic Cardiomyopathy: Non-ischemic cardiomyopathy encompasses conditions like dilated, hypertrophic, restrictive, and arrhythmogenic cardiomyopathy, with dilated cardiomyopathy being the most common. A longitudinal study found that 25% of MINOCA patients had non-ischemic cardiomyopathy, which was associated with the highest mortality compared to other MINOCA mechanisms. Stress CMR has also identified underlying microvascular dysfunction in patients with dilated cardiomyopathy. 

• Takotsubo Cardiomyopathy: Takotsubo cardiomyopathy, or stress-induced cardiomyopathy, is characterized by reversible wall motion abnormalities without obstructive CAD. It is often triggered by emotional or physical stress and is associated with a catecholamine surge. The condition is more common in postmenopausal women and has four main anatomical variants, with apical ballooning being the most common. Diagnosis typically involves coronary angiography, ventriculography, and CMRI to rule out other causes of AMI, with risks of cardiogenic shock and death comparable to those of AMI patients with CAD. 

2. What are the key diagnostic tests to evaluate MINOCA, and how are they applied in this case? 

• Coronary Intravascular Imaging: Coronary intravascular imaging with IVUS and OCT is essential for diagnosing plaque disruption in MINOCA and should be performed during coronary angiography of all three major epicardial arteries. IVUS identifies plaque disruption in up to 40% of MINOCA cases, while OCT detects the culprit lesion in about 50%. These imaging techniques are also valuable for evaluating SCAD in cases of diagnostic uncertainty. 

• Cardiac Imaging: Transthoracic echocardiography is valuable for assessing cardiac function after MINOCA, diagnosing Takotsubo and non-ischemic cardiomyopathy, and monitoring recovery of left ventricular function. Transesophageal echocardiography may be considered when coronary embolism is suspected. CMR is recommended for uncertain MINOCA diagnoses, providing accurate results in 74–87% of cases. It can differentiate between ischemic and non-ischemic MI, diagnose myocarditis, and detect coronary microvascular dysfunction through perfusion imaging. CMR’s diagnostic accuracy improves when performed closer to the event and also serves as a prognostic tool for long-term cardiovascular outcomes. 

• Invasive Coronary Functional Testing: Provocative spasm testing with intracoronary acetylcholine helps diagnose coronary vasospasm (epicardial or microvascular) and endothelial-dependent microvascular dysfunction, with a low complication rate (0.5%). In MINOCA patients, spasm testing is positive in about half, with epicardial spasm in 65% and microvascular spasm in 35%. CFR assessed by doppler flow velocity or thermodilution (with values <2.0) and IMR (>25) are used to assess microvascular dysfunction, though CFR is more sensitive. While coronary microvascular dysfunction is linked to worse outcomes in INOCA, its prognostic impact in MINOCA is less clear. However, low CFR has been associated with increased mortality across various patient populations. 

3. How is MINOCA treated based on its underlying etiology? 

• Plaque Rupture: Patients with plaque disruption should be treated with aspirin and high-intensity statin therapy. Additionally, for those with plaque disruption who do not require stenting, dual antiplatelet therapy with ticagrelor for up to 1 month may be considered, given the low revascularization rates at 1 year (5.7%) and 4 years (21.1%) follow-up.  

• Coronary Vasospasm: Long-acting calcium channel blockers (both dihydropyridine and non-dihydropyridine) are commonly used in MINOCA patients with epicardial coronary vasospasm. They relax vascular smooth muscle by inhibiting calcium ion influx. For patients with refractory angina, nitrates may be added to calcium channel blockers to enhance smooth muscle relaxation through increased nitric oxide availability.  

• SCAD: Conservative management is preferred over PCI in SCAD patients, as most dissections heal without intervention and PCI carries higher complication risks. PCI is reserved for STEMI, cardiogenic shock, or persistent ischemia. The use of antithrombotic agents during acute SCAD is debated, and secondary prevention (aspirin, beta-blockers, statins, and ACE inhibitors) should be tailored to individual risk factors. 

• CMD: Treatment options for coronary microvascular dysfunction are limited and mainly based on data from INOCA patients. Statins and renin-angiotensin system inhibitors have been shown to improve coronary flow reserve (CFR). Antianginal therapies such as beta-blockers, calcium channel blockers, and ranolazine are commonly used for patients with chest pain. 

• MINOCA Mimickers: 

• Takotsubo Cardiomyopathy: Management of MINOCA mimickers mainly involves supportive care and guideline-directed medical therapy for heart failure, though evidence is limited. Most patients with Takotsubo cardiomyopathy recover normal cardiac function spontaneously, while those with left ventricular dysfunction are treated with beta-blockers and renin-angiotensin system inhibitors. In cases of progressive circulatory failure, mechanical circulatory support may be needed. 

• Myocarditis: Myocarditis typically resolves within 2–4 weeks, but patients with arrhythmias or persistent cardiac dysfunction should receive guideline-directed therapy. Physical activity should be avoided in the acute phase for up to 6 months. Ongoing trials on antiviral and immunosuppressive treatments may offer targeted therapies in the future. 

References – Coronary Vasospasm

1. Tamis-Holland JE, Jneid H, Reynolds HR, et al. Contemporary diagnosis and management of patients with myocardial infarction in the absence of obstructive coronary artery disease: a scientific statement from the American Heart Association. Circulation. 2019;139:e891–908. doi:10.1161/CIR.0000000000000670  

2. Reynolds HR, Maehara A, Kwong RY, et al. Coronary optical coherence tomography and cardiac magnetic resonance imaging to determine underlying causes of myocardial infarction with nonobstructive coronary arteries in women. Circulation. 2021;143:624–40. doi:10.1161/CIRCULATIONAHA.120.052008  

3. di Fusco SA, Rossini R, Zilio F, et al. Spontaneous coronary artery dissection: overview of pathophysiology. Trends Cardiovasc Med. 2022;32:92–100. doi:10.1016/j.tcm.2021.01.002  

4. Zilio F, Muraglia S, Morat F, et al. Sex differences in clinical and angiographic characteristics in spontaneous coronary artery dissection. Future Cardiol. 2021;17:669–75. doi:10.2217/fca-2020-0124  

5. Omerovic E, Citro R, Bossone E, et al. Pathophysiology of takotsubo syndrome – a joint scientific statement from the heart failure association takotsubo syndrome study group and myocardial function working group of the European society of cardiology – part 2: vascular pathophysiology, gender and sex hormones, genetics, chronic cardiovascular problems and clinical implications. Eur J Heart Fail. 2022;24:274–86. doi:10.1002/ejhf.2368  

6. Agdamag AC, Patel H, Chandra S, et al. Sex differences in takotsubo syndrome: a narrative review. J Womens Health. 2020;29:1122–30. doi:10.1089/jwh.2019.7741  

7. Bentzon JF, Otsuka F, Virmani R, Falk E. Mechanisms of plaque formation and rupture. Circ Res. 2014;114:1852–66. doi:10.1161/CIRCRESAHA.114.302721  

8. Virmani R, Burke AP, Farb A, Kolodgie FD. Pathology of the vulnerable plaque. J Am Coll Cardiol. 2006;47:C13–8. doi:10.1016/j.jacc.2005.10.065  

9. Montone RA, Niccoli G, Fracassi F, et al. Patients with acute myocardial infarction and non-obstructive coronary arteries: safety and prognostic relevance of invasive coronary provocative tests. Eur Heart J. 2017;39:91–8. doi:10.1093/eurheartj/ehx667  

10. Raphael CE, Heit JA, Reeder GS, et al. Coronary embolus: an underappreciated cause of acute coronary syndromes. JACC Cardiovasc Interv. 2018;11:172–80. doi:10.1016/j.jcin.2017.08.057  

11. Tschöpe C, Ammirati E, Bozkurt B, et al. Myocarditis and inflammatory cardiomyopathy: current evidence and future directions. Nat Rev Cardiol. 2021;18:169–93. doi:10.1038/s41569-020-00435-x  

12. Tornvall P, Gerbaud E, Behaghel A, et al. Myocarditis or “true” infarction by cardiac magnetic resonance in patients with a clinical diagnosis of myocardial infarction without obstructive coronary disease: a meta-analysis of individual patient data. Atherosclerosis. 2015;241:87–91. doi:10.1016/j.atherosclerosis.2015.04.816  

13. Lintingre P-F, Nivet H, Clément-Guinaudeau S, et al. High-resolution late gadolinium enhancement magnetic resonance for the diagnosis of myocardial infarction with nonobstructed coronary arteries. JACC Cardiovasc Imaging. 2020;13:1135–48. doi:10.1016/j.jcmg.2019.11.020  

14. AlBadri A, Bairey Merz CN, Johnson BD, et al. Impact of abnormal coronary reactivity on long-term clinical outcomes in women. J Am Coll Cardiol. 2019;73:684–93. doi:10.1016/j.jacc.2018.11.040  

15. Kelshiker MA, Seligman H, Howard JP, et al. Coronary flow reserve and cardiovascular outcomes: a systematic review and meta-analysis. Eur Heart J. 2022;43:1582–93. doi:10.1093/EURHEARTJ/EHAB775  

16. Slavich M, Patel RS. Coronary artery spasm: current knowledge and residual uncertainties. IJC Heart Vasculat. 2016;10:47–53. doi:10.1016/j.ijcha.2016.01.003  

17. Samuels B, Shah S, Widmer R, et al. Comprehensive management of ANOCA, Part 1—definition, patient population, and diagnosis: JACC state-of-the-art review. JACC. 2023;82(12):1245–63. doi:10.1016/j.jacc.2023.06.043  

18. Smilowitz N, Prasad M, Widmer R, et al. Comprehensive management of ANOCA, Part 2—program development, treatment, and research initiatives: JACC state-of-the-art review. JACC. 2023;82(12):1264–79. doi:10.1016/j.jacc.2023.06.044  

19. Quesada O, Ashokprabhu ND, Tapp DN, et al. Utilizing invasive coronary functional testing in a coronary microvascular and vasomotor dysfunction program: methods and considerations. Catheter Cardiovasc Interv. 2024;104(7):1327–36. doi:10.1002/ccd.31282  

20. Yildiz M, Ashokprabhu N, Shewale A, et al. Myocardial infarction with non-obstructive coronary arteries (MINOCA). Front Cardiovasc Med. 2022;9:1032436. doi:10.3389/fcvm.2022.1032436