Why a Common Heart Drug Fails Millions with Microvascular Angina
For decades, nitrate medications have been the go-to treatment for angina pectoris – the characteristic chest pain caused by reduced blood flow to the heart muscle. These drugs, including nitroglycerin and isosorbide dinitrate, work by dramatically dilating blood vessels, rapidly relieving pain for millions of patients with obstructive coronary artery disease.
Yet, for a substantial subgroup of angina patients—those with microvascular angina—these same medications provide surprisingly little benefit. This puzzling phenomenon represents one of cardiology's most intriguing paradoxes.
Recent research has revealed that the answer lies not in the medications themselves, but in the fundamental differences between two distinct types of heart disease: traditional obstructive coronary artery disease and microvascular dysfunction 1 4 .
Identifying microvascular angina poses significant challenges for cardiologists. Standard tests like exercise stress tests (EST) often show clear signs of ischemia (such as ST-segment depression on ECG), yet subsequent angiograms reveal clean coronary arteries. This discrepancy historically led to frequent misdiagnosis and patient frustration 7 .
The UZ CLEAR study (2024) highlighted the diagnostic limitations of conventional testing, demonstrating that approximately 60% of patients with positive exercise stress tests but no obstructive CAD actually had underlying microvascular dysfunction when appropriately tested with both FFR (assessing large vessels) and IMR (assessing microvessels) 7 .
In 2013, Dr. Giulio Russo and team designed an experiment to evaluate nitrate effects on patients with microvascular angina versus traditional obstructive coronary disease 1 5 .
29 patients with confirmed microvascular angina and 24 with obstructive single-vessel coronary disease were recruited.
Each participant completed two exercise stress tests: one without medication and one after administration of 5mg sublingual isosorbide dinitrate.
Using sophisticated Doppler-echocardiography, the team measured coronary blood flow response to nitroglycerin.
No significant improvement in time to ischemia (308±160 vs. 284±136 seconds). 86% still developed significant ST-segment depression despite nitrate pretreatment 1 .
The Russo study provided compelling evidence that the microvasculature in MVA patients responds differently to nitrates than both the epicardial vessels in CAD patients and healthy microvessels 1 .
| Parameter | Healthy Microvessels | Microvessels in MVA | Epicardial Vessels in CAD |
|---|---|---|---|
| Primary regulation mechanism | Endothelium-dependent hyperpolarization | Impaired dilation | Nitric oxide-mediated dilation |
| Response to nitrates | Moderate dilation | Minimal dilation | Pronounced dilation |
| Response to acetylcholine | Normal dilation | Paradoxical constriction | Variable response |
| Oxidative stress level | Normal | Elevated | Moderate elevation |
Editorial commentary on the study by Beltrame and Horowitz proposed several intriguing explanations for this phenomenon 4 , including physiological differences, oxidative stress environment, molecular targets, and structural differences.
More recent studies have reinforced Russo's findings. A 2024 investigation published in the Journal of Clinical Medicine compared baseline and post-nitrate exercise testing in patients with angina but non-obstructed coronary arteries stratified by acetylcholine test results 3 .
First-line therapy, particularly nebivolol which has nitric oxide-potentiating effects.
Especially beneficial for patients with demonstrated microvascular spasm.
Shown to improve endothelial function and symptoms.
Ranolazine and ivabradine show promise in refractory cases.
The emerging understanding of microvascular angina and nitrate resistance represents a paradigm shift in cardiology – moving away from a one-size-fits-all approach toward personalized medicine.
The disappointing performance of nitrates in microvascular angina has ironically opened exciting new avenues for cardiovascular research and therapy development, offering hope for the millions of patients worldwide who continue to struggle with angina symptoms despite having "clear" coronary arteries.
The story of nitrate resistance in microvascular angina teaches us an important lesson about medical science: sometimes the most valuable discoveries come not from finding what works, but from understanding why standard approaches fail. The meticulous work of Russo and colleagues 1 5 has fundamentally changed how cardiologists approach angina management, leading to more targeted diagnostics and personalized therapies.
For patients with persistent angina symptoms despite negative angiograms, these findings validate their experience and offer hope for more effective future treatments.
The nitrate paradox thus represents not a dead end, but a gateway to deeper understanding of cardiovascular physiology and more effective, personalized care for some of cardiology's most challenging patients.