Microvascular Angina and Microvascular Dysfunction – Emerging Insights and Interventions

Microvascular Angina and Microvascular Dysfunction – Emerging Insights and Interventions

Ayman Helal, MD

Interventional Cardiologist, Kettering General Hospital, UK

Introduction

Microvascular angina (MVA) is a type of angina characterized by chest pain in the absence of significant coronary artery stenosis. Unlike traditional angina, which is caused by large vessel obstruction, MVA is associated with dysfunction in the small vessels of the heart, also known as the coronary microcirculation. This condition falls under the broader category of ischemic heart disease, which can significantly impact patient quality of life and poses challenges in both diagnosis and management [1]. Recent research has shed light on the pathophysiology of MVA, emphasizing the role of microvascular dysfunction and exploring innovative interventional strategies to manage this condition.

Pathophysiology of Microvascular Angina

Coronary microvascular dysfunction (CMD) is the underlying mechanism of MVA. It involves impaired vasodilation and increased resistance within the coronary microcirculation, leading to inadequate myocardial perfusion. This dysfunction can occur at various levels, including the endothelium and smooth muscle cells, and may be influenced by factors such as endothelial dysfunction, increased oxidative stress, and inflammation. These abnormalities lead to impaired vasodilation, increased vascular resistance, and ultimately, inadequate myocardial perfusion during stress or even at rest. Additionally, CMD is often seen in patients with other forms of ischemic heart disease, such as myocardial infarction with non-obstructive coronary arteries (MINOCA) and heart failure with preserved ejection fraction (HFpEF), further complicating diagnosis and management [2]. The assessment of microvascular function is crucial for diagnosing MVA, as traditional angiography may not reveal any significant blockages in the epicardial coronary arteries.

Diagnosis of Microvascular Angina

Diagnosing MVA and CMD poses a significant challenge due to the absence of visible obstructions in coronary angiography. Traditional diagnostic approaches, which focus on identifying significant epicardial stenosis, often fail to detect microvascular disease. As a result, many patients with CMD are misdiagnosed or labelled as having non-cardiac chest pain, leading to suboptimal management.

Non-invasive testing, including  Positron emission tomography (PET), echocardiography, and cardiac magnetic resonance (CMR) may be considered for the detection of CMD, but they only provide surrogates of flow. In addition, perfusion assessment lacks the sensitivity to diagnose the relative contributions of epicardial and microvascular disease to myocardial blood flow reduction. Therefore, it is not always possible to distinguish ischemia because of obstructive coronary artery disease from CMD. The aforementioned limitation also means it is currently not possible to assess micro-vascular resistance (MVR). These caveats emphasize the need for invasive evaluation of coronary arteries and microvasculature to derive definitive conclusions on the causes of angina and nonobstructive coronary artery disease (ANOCA) [3].

Emerging diagnostic tools, however, are changing the landscape. Invasive methods, such as coronary flow reserve (CFR) measurement and the index of microcirculatory resistance (IMR), provide valuable insights into microvascular function (Fig. 1). CFR and IMR are both validated techniques that provide a robust assessment of coronary microvascular function. CFR reflects the combined contribution of both epicardial and microvascular flow, while IMR specifically targets the microvasculature, making it particularly useful in diagnosing CMD.  CFR assesses the ratio of maximum achievable blood flow to resting blood flow in the coronary arteries, offering an indication of the functional capacity of both the epicardial arteries and the microcirculation. IMR, on the other hand, directly measures the resistance within the coronary microcirculation, giving a specific assessment of microvascular health. A normal CFR value is typically greater than 2.0, indicating that the coronary circulation can adequately increase blood flow to meet the metabolic demands of the myocardium during stress. A reduced CFR suggests microvascular dysfunction and is indicative of MVA [4]. The Index of Microcirculatory Resistance (IMR) is another important metric used to assess microvascular function. Unlike CFR, which reflects both epicardial and microvascular function, IMR specifically targets the microcirculation. IMR is measured using a pressure-temperature sensor-tipped guidewire during coronary angiography [5].

Fig.1: The Assessment of Coronary Microvascular Dysfunction Parameters by Continuous Thermodilution in Angina and No Obstructive Coronary Artery Disease [3]. The top gives an overview of the main classification of coronary artery disease and the place of coronary vascular dysfunction. The bottom is a simplified overview of the continuous thermodilution method and the calculation of the different measurements is given. ∗Depending on the size of the left anterior descending coronary artery, 15-25 mL/min can be used to induce hyperemia. FFR = fractional flow reserve; hyp = hyperemic; MRR = microvascular resistance reserve; Pd = distal coronary pressure; Q = absolute flow; Qi = infusion flow; R = absolute resistance; rest = resting; T = mixing temperature; Ti = infusion temperature.

Step-by-Step Process of CFR and IMR Measurement

1. Setup: The process starts with coaxial guide catheter engagement avoiding any pressure damping and flushing thoroughly. Then, advance wire sensor 2/3rds distally to the LAD, unless there is a specific territory of interest, then administer GTN. The pressure wire measures the distal coronary artery pressure (Pd), and the guiding catheter measures the aortic pressure (Pa).
2. Baseline Mean Transit Time at Rest (Tmn_rest): Flush/purge pre-Tmn_rest to clear any blood and contrast, inject brisk 3ml x 3 saline injections at room temperature, repeat measurement of Tmn_rest and address outliers (± 0.25s) before proceeding.

3. Hyperemic Mean Transit Time (Tmn_hyp): Hyperaemia is induced using adenosine, typically administered intravenously. The goal is to achieve maximum vasodilation in the coronary arteries. Confirm hyperaemia by decrease in pressure, patient symptoms and FFR drop. Flush/purge pre-Tmn_hyp to clear any blood and contrast, then re-inject brisk 3ml x 3 saline injections at room temperature, repeat measurement of Tmn_hyp and address outliers (± 0.15s) before proceeding,

1. CFR Measurement: CFR is calculated as the ratio of hyperaemic to resting blood flow. In practice, this is measured as the ratio of the mean hyperaemic flow velocity to the mean resting flow velocity using a Doppler wire or the ratio of hyperaemic to baseline distal coronary pressure using a pressure wire.
2. IMR Measurement: To measure IMR, the coronary pressure wire is again used, but this time, the focus is on the distal coronary pressure during hyperaemia. The IMR is calculated by multiplying the hyperaemic mean transit time (obtained through thermodilution) by the distal coronary pressure (Pd) at peak hyperaemia.
3. Interpretation: A CFR value below 2.5 (CFR of 2.0-2.4 is a gray zone) and an IMR value of 25 or above are typically indicative of CMD. These thresholds help clinicians diagnose CMD and differentiate it from other forms of coronary artery disease [4,5].

Recent Research and the Role of Coronary Intervention

Recent studies have advanced our understanding of microvascular angina and its treatment. Traditionally, MVA has been managed with anti-anginal medications such as beta-blockers, calcium channel blockers and nitrates. However, these therapies do not address the underlying microvascular dysfunction [6].

Coronary Sinus Reducer: An Interventional Option

One promising interventional approach is the Coronary Sinus Reducer (CSR), a device designed to alleviate symptoms in patients with refractory angina, including those with MVA. The CSR offers a novel and minimally invasive option for patients with CMD who are refractory to medical therapy. While it does not address the microvascular dysfunction directly, its ability to improve symptoms provides a valuable addition to the treatment arsenal for CMD. The CSR is a balloon-expandable, hourglass-shaped stent implanted in the coronary sinus (Fig. 2). It creates a controlled narrowing that increases pressure in the coronary venous system, which in turn improves myocardial perfusion by redistributing blood flow from non-ischemic to ischemic areas of the myocardium. [6].

Fig. 2: Coronary Sinus Reducer System [6].

Evidence Supporting CSR: Clinical trials have demonstrated that CSR significantly reduces angina symptoms and improves quality of life in patients with refractory angina, including those with microvascular dysfunction. The COSIRA (Coronary Sinus Reducer for Treatment of Refractory Angina) trial is one of the key studies that highlighted the efficacy of CSR in this patient population. This trial demonstrated that the coronary sinus reducer significantly improved symptoms and quality of life in patients with refractory angina, including those with CMD. The study found that patients who received the reducer were more likely to experience a reduction in angina severity and an improvement in exercise tolerance compared to those who received a sham procedure [7].

Steps for Coronary Sinus Reducer Implantation:

1. Access and Cannulation: The procedure begins with venous access, typically via the femoral or jugular vein. A guiding catheter is advanced to cannulate the coronary sinus under fluoroscopic guidance.
2. Device Placement: The coronary sinus reducer, which is a stent-like device, is delivered to the desired location within the coronary sinus. Its position is confirmed with contrast injection.
3. Deployment: The reducer is deployed by inflating a balloon within the device, causing it to expand and oppose the walls of the coronary sinus.
4. Post-Procedural Care: After deployment, the device remains in place, creating a controlled narrowing that increases coronary sinus pressure. This increased pressure is hypothesized to enhance perfusion to ischemic myocardial areas.
5. Follow-Up: Patients typically undergo follow-up to monitor symptoms, exercise capacity, and any potential complications. Improvement in angina symptoms is usually assessed after a few months post-implantation  [7].

Conclusion

Microvascular angina, driven by microvascular dysfunction, presents a significant clinical challenge due to the limitations of traditional diagnostic and therapeutic approaches. Recent advancements in the understanding of MVA have led to the development of novel diagnostic tools such as CFR and IMR, which provide valuable insights into coronary microcirculatory function. Additionally, the emergence of the Coronary Sinus Reducer as an interventional treatment offers a therapeutic avenue for patients with refractory angina. Continued research and clinical trials are essential to further refine these strategies and improve outcomes for patients with microvascular angina.

References

1. Crea F, Lanza GA. New therapeutic developments in the management of microvascular angina. J Clin Med. 2020;9(8):2528.
2. Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med. 2007;356(8):830-840.
3. Jansen TPJ, Konst RE, Elias-Smale SE, et al.  Assessing Microvascular Dysfunction in Angina With Unobstructed Coronary Arteries: JACC Review Topic of the Week, Journal of the American College of Cardiology. 2021; 78(14): 1471-1479.
4. Gould KL, Johnson NP, Berry C, et al. Physiological assessment of coronary artery disease in the cardiac catheterization laboratory: a scientific statement from the American Heart Association. Circulation. 2013;127(22):2271-2308.
5. Fearon WF, Low AF, Yong AS, et al. Prognostic value of the index of microcirculatory resistance measured after primary percutaneous coronary intervention. Circulation. 2013;127(24):2436-2441.
6. Verheye S, Jolicoeur EM, Behan MW, et al. Efficacy of a device to narrow the coronary sinus in refractory angina. N Engl J Med. 2015;372(6):519-527.
7. Banai S, Ben Muvhar S, Parikh KH, et al. Coronary Sinus Reducer Implantation for the Treatment of Refractory Angina: A Clinical Guide. EuroIntervention. 2020;15(14):1191-1199.