Coronary Microvascular Disease (CMD)

Authors: Kayla Romero, Claire Tian

Revised: Dina Abbas, Helia Mansouri Dana

Overview

Characterized by the narrowing of the coronary microcirculation, Coronary Microvascular Disease (CMD) is prevalent in patients with cardiovascular risk factors and atherosclerosis (Camici et al, 2014). Studies have shown that 60% of patients who undergo coronary angiography  that do not exhibit  significant stenosis may possess CMD (Chen  et al., 2016). 

There is no significant difference between sexes (51% men versus 54% women), as it is highly prevalent in patients suspected of coronary artery disease that are undergoing positron emission tomography (PET) (Chen et al., 2016). Roughly one third of patients with angina suffer from CMD, along with an increased risk of premature death (Sinha, Rahman, &  Perera, 2020).  

Recent advances in medicinal and technological research has enabled experts to gain a deeper insight on the most effective treatment methods; most notably, performing physiological tests have been shown to yield better results than simply empirical treatment of CMD (Sinha, Rahman, &  Perera, 2020). However, proper classification of this illness along with its corresponding treatment strategies still remain fairly limited to current knowledge, and have yet to be further examined (Sinha, Rahman, &  Perera, 2020). 

 

Etiology

CMD stems from the failure of adequate dilation of the coronary arteries, during which the oxygen demand is not properly sustained (Vancheri et al., 2020). Patients with CMD have coronary microvasculature which  have undergone structural changes commonly associated with atherosclerosis (Vancheriet al., 2020). Narrowing of pre-arterioles and intramural arterioles as well as capillary refraction are only a fractional component of the structural changes observed in CMD (Vancheri et al., 2020). Endothelial dysfunction, lack of vasodilator response and coronary spasms  are also contributing factors to this condition (Chen et al., 2016). 

 

Symptoms 

  • Angina or chest pain that worsens throughout the day or during strenuous activities
  • Shortness of breath, dyspnea on exertion
  • Lack of energy or fatigue 
  • Dizziness, fatigue (from lack of adequate blood) (Chen et al., 2016)

 

Risk Factors 

  • Similar to risk factors associated with cardiovascular disease:
    • Smoking
    • Diabetes Mellitus
    • Aging
    • Hypertension
    • Hyperlipidemia
    • Hypercholesterolemia
    • Inflammatory conditions (i.e. Systemic Lupus Erythematosus) (Chen et. al., 2016; Löffler & Bourque, 2016)

 

COVID-19 in patients with CMD

Patients having contracted COVID-19 are more susceptible to the health complications associated with CMD since the SARS-Cov 2 virus triggers additional autoimmune and inflammatory responses which may then exacerbate CMD conditions (Drakos et al., 2021). The presence of any viral infection tends to perturb the signal transduction pathways of the muscle cells, which stimulates atypical cytokine behaviour (Drakos et al., 2021). The dysregulation of cytokines, leads to inflammation which is undoubtedly responsible for many of the commonly experienced CMD symptoms, such as chest pain (Yin, et al., 2021).

It has further been shown that during the premature stages of host infection by the SARS-Cov 2 virus, interleukins — specifically IL-6 levels — are conspicuously increased, which contributes to the hyperinflammatory stage (Yin, et al., 2021). However, the level of killer T cells appears to decrease (Yin, et al., 2021). 

So far, treatment for CMD in patients additionally battling COVID-19 have involved the use of hydroxychloroquine and other steroid drugs, along with antivirals; though, further studies are required to determine whether or not they are effective in ameliorating the stresses of myocardial complications (Guzik et al., 2020). 

For more information, please refer to our article about COVID-19:

COVID-19 (SARS-CoV-2 Coronavirus)

 

Diagnosis

Clinical Features

Patients with CMD commonly have  angina, dyspnea on exertion, a gradual decrease in exercise tolerance and possibly heart failure (Löffler & Bourque, 2016; Marinescue et al., 2015). Patients will exhibit decreased response to oral medications such as nitrates intended to treat angina (Sinha, Rahman, &  Perera, 2020). 

According to Sinha, Rahman, &  Perera (2020) a diagnostic criteria to assess the presence of CMD includes: the presence and functional imaging evidence of myocardial ischaemia, impaired coronary microvascular function and the absence of obstructive epicardial coronary artery disease.The gold standard of clinically assessing CMD would be determining coronary flow reserve and myocardial perfusion reserve through invasive and non-invasive procedures such as stress PET and cardiovascular magnetic resonance (CMR) imaging (Marinescue et al., 2015). 

Pathological Features

Currently there are no techniques available to directly visualize coronary microvasculature (Chen, et al., 2016); however, there have been various imaging techniques used to facilitate the diagnosis of CMD (Chen, et al., 2016). CMR is often employed to determine myocardial perfusion and is helpful in deciphering the  prognosis in patients with ischemic heart disease (Chen, et al., 2016). It has been observed that CMD patients have a decreased response in vasodilators in the subendocardial region using CMR (Chen, Wei, AlBadri, et al., 2016). Additionally, PET has  been utilized to assess myocardial blood flow via  radioactive tracers. Exercise Stress Testing has also been suggested for detection of myocardial ischemia (Chen, et al., 2016).  

 

Treatment

Pharmacological

The use of angiotensin-converting enzyme (ACE) inhibitors, low-dose aspirin, beta-blockers, adenosine receptors, Ranolazine, and short-acting nitrates can be considered as treatment options for  CMD and the associated underlying cardiovascular disease risk factors (Marinescue, Loffler, Ouellette, et al., 2015). Supplementary to ACE inhibitors, albeit a less common treatment, beta-blockers may also be used (Chen et al., 2016). Beta-blockers aim to decrease oxygen consumption while the diastolic filling time is expanded (Chen et al., 2016). 

Ranolazine has also been shown to ameliorate the physiological stresses in CMD patients, by working to reduce the body’s calcium levels, leading to relaxation of the ventricular muscles (Chen, et al., 2016).  The management of antianginal, antiplatelet, anti-ischemic and antiatherosclerotic medication and the use of various other medications for other symptoms may prove effective in controlling underlying risk factors (Taqueti & Carli, 2018). The recent developments and breakthroughs still require testing and standardization trials to ascertain their success in treatment (Chen, et al., 2016).

 

Non-pharmacological

There are no well-known and fully defined non-pharmaceutical treatments for CMD (Taqueti & Di Carli, 2018). Controlling diabetes and hypertension in patients with CMD can result in improving their CFR and endothelial function by lowering their blood pressure and administering insulin sensitizer(Jadhav et al,2006, Chen, et al., 2016). 

Modifications in lifestyle such as diet, regular physical activity, weight loss and non-smoking habits have also been recommended,  in addition to consuming fruits, vegetables and high-fiber diets can improve CFR as well (Anand ET AL,2008, Stampfer MJ et al, 2000, Parikh P et al, 2005,Chen, et al., 2016). Furthermore, non-pharmacological methods focus on alleviating the symptoms of CMD rather than targeting the root cause of this disease (Chen,  et al., 2016). For instance, spinal cord stimulation helps to gradually build up exercise tolerance that may have been hindered during the initial stages of CMD; and cognitive behavioural therapy emphasizes relief of agonizing symptoms as well as how often they occur (Chen, et al., 2016). Generally, prevention via eating a healthy diet coupled with frequent exercise/activity along with daily adequate sleep is most effective to evade CMD and its health complications (Chen,  et al., 2016). 

 

Articles on Misdiagnosis

Brainin, P., Frestad, D., & Prescott, E. (2018). The prognostic value of coronary endothelial and microvascular dysfunction in subjects with normal or non-obstructive coronary artery disease: A systematic review and meta-analysis. International Journal of Cardiology, 254, 1–9. https://doi.org/10.1016/j.ijcard.2017.10.052

Lee, B.-K., Lim, H.-S., Fearon, W. F., Yong, A., Yamada, R., Tanaka, S., Lee, D. P., Yeung, A. C., & Tremmel, J. A. (2015). Invasive Evaluation of Patients with Angina in the Absence of Obstructive Coronary Artery Disease. Circulation, 131(12), 1054–1060. https://doi.org/10.1161/CIRCULATIONAHA.114.012636

Taqueti, V. R., & Di Carli, M. F. (2018). Coronary microvascular disease pathogenic mechanisms and therapeutic options: JACC state-of-the-art review. Journal of the American College of Cardiology, 72(21), 2625-2641. https://doi.org/10.1016/j.jacc.2018.09.042 

Velde, N. van der, Huurman, R., Yamasaki, Y., Kardys, I., Galema, T. W., Budde, R. P., Zijlstra, F., Krestin, G. P., Schinkel, A. F., Michels, M., & Hirsch, A. (2020). Frequency and Significance of Coronary Artery Disease and Myocardial Bridging in Patients With Hypertrophic Cardiomyopathy. American Journal of Cardiology, 125(9), 1404–1412. https://doi.org/10.1016/j.amjcard.2020.02.002

 

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Chen, C., Wei, J., AlBadri, A., Zarrini, P., & Merz, C. N. B. (2016). Coronary microvascular dysfunction―epidemiology, pathogenesis, prognosis, diagnosis, risk factors and therapy. Circulation Journal, 81(1), 3-11. https://doi.org/10.1253/circj.cj-16-1002 

Drakos, S., Chatzantonis, G., Bietenbeck, M., Evers, G., Schulze, A.B., Mohr, M., Fonfara, H., Meier, C., & Yilmaz, A. (2021). A cardiovascular magnetic resonance imaging-based pilot study to assess coronary microvascular disease in COVID-19 patients. Sci Rep, 11(1), 1-8. https://www.nature.com/articles/s41598-021-95277-z 

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