Atherosclerosis: Open Access
Open Access

Coronary microvascular dysfunction; Tumour; Necrosis; Atherosclerosis; Inflammation

Introduction

Contrary to initial theories suggesting a nonthreatening disease progression [1,2], ischemic cardiac pain in the context of non-obstructed epicardial coronary arteries has been recognised as a clinical entity of increased cardiovascular risk when compared to control subjects [3,4]. Coronary microvascular dysfunction (CMVD) is the primary cause of peripheral ischemia in those who have “normal” epicardial coronary arteries. However, there is no definitive data on the pathogenesis, diagnosis, or therapy of CMVD. Resulting in inappropriate dilatation and an inability to supply the needed oxygen needs. Diabetes mellitus and arterial hypertension, both known cardiovascular risk factors, are implicated in this process due to their detrimental vascular consequences. Patients with CMVD may eventually develop heart failure with intact ejection fraction, with a varied prognosis due to a lack of disease-specific therapy [4]. Chronic low-grade inflammation is probably a factor in coronary artery disease. Importantly, recent trials of individuals with proven coronary artery disease (CAD) receiving either broad-based or specific anti-inflammatory medication have showed favourable cardiovascular outcomes [5-7]. Recent data shows that an inflammatory backdrop is also involved in the development of CMVD [8]. As a result, we discuss the most recent data on CMVD epidemiology and diagnostic approaches, as well as hypothesise on the impact of inflammation and the possible treatment implications of immunomodulatory drugs. The evaluation of coronary blood flow velocity and coronary blood flow following vasodilating drugs are major factors of coronary flow reserve (CFR), a measure of epicardial and microcirculatory blood flow. A lower CFR score indicates CMVD in the absence of epicardial artery blockage. Individual corrections for age and systolic blood pressure should always be applied. However, scientific research is presently focusing on noninvasive CMVD evaluation approaches. To begin, echocardiography has been employed in CMVD evaluation since 1998, when Wei et al. used intravenous infusion of airfilled albumin microbubbles to quantify myocardial blood flow (MBF) in an epicardial coronary artery. The use of ultrasound-destructible microbubbles allowed for a more accurate calculation of MBF by assessing their mean velocity (rate of reappearance after destruction in the setting of a constant intravenous infusion) and microvascular cross-sectional area (microbubble concentration in the myocardium) [9]. Aside from contrast echocardiography, Doppler echocardiographic measurement of coronary flow velocity reserve (ratio of coronary flow velocity under stress to rest at the proximal left anterior descending coronary artery) was reported to match adequately with invasive techniques [10,11]. Furthermore, its predictive effectiveness in highrisk people with known or suspected CAD was revealed [12]. Although echocardiography is appealing owing to the nature of the technique (bedside, low cost, and limited patient-related risk), it is operatordependent and has not been validated, and patient-related variables such as obesity or lung disease may impair measurement quality. Cardiac CT angiography (CCTA) appears to be another promising strategy in the assessment of CMVD, because it provides information regarding coronary architecture and myocardial perfusion in a single study [13]. MBF may be measured using electrocardiographically gated CT perfusion pictures at rest and during stress with vasodilators [14]. Furthermore, mathematical models modelling maximum hyperemia can be used to compute fractional flow reserve and MBF [15]. However, the increased radiation dose, along with a greater risk of contrast-induced acute kidney damage, should always be considered, particularly in those with underlying renal disease [16]. Surprisingly, recent advances in the identification of coronary inflammation using perivascular fat imaging in CT have received scholarly attention and may be applicable in the setting of CMVD [17]. The fat attenuation index (FAI), a recently developed imaging marker, was found to be higher in areas of severe atherosclerosis as well as in areas with a fractional flow reserve (FFR) of 0.75 or less [18,19], highlighting the existing burden of inflammation, which is a distinguishing feature of vulnerable plaques. A recent study involving 41 stable patients with high risk plaques demonstrated a correlation between FAI values and the gold standard method of perivascular inflammation imaging, PET-CT with 18F-NaF uptake [20]. Because a higher FAI value indicates a more hemodynamically severe stenosis, measurement of the pericoronary adipose tissue may be of additive discriminative relevance in highly stenotic atherosclerotic plaques and improve their evaluation by CCTA. FAI may also be useful in the setting of an acute myocardial infarction, with greater FAI values surrounding culprit lesions compared to nonculprit lesions. The FAI surrounding the culprit lesion was lower than baseline during the follow-up measurement, with values equivalent to those reported around stable atherosclerotic areas [17,21,22].

According to this discovery, FAI has a strong discriminate capacity (AUROC = 0.70) in detecting acute changes in the inflammatory load of pericoronary fat [21]. Oikonomou et al. [23] have characterised the fat radiomic profile (FRP) of stable pericoronary fat alterations in contrast to follow-up CCTA imaging. Several pharmaceutical therapies, such as aspirin, statins, or biologic therapy with anti-inflammatory medications, might be implicated in the alterations in pericoronary fat observed by FAI. The incremental predictive value of perivascular adipose tissue attenuation might become an essential imaging alternative for additional characterisation of residual cardiovascular risk, which existing scoring systems or inflammatory biomarkers may not appropriately quantify. The existence of persistent inflammation in the coronary artery bed and its identification are thought to help in more precise risk categorization and, as a result, the implementation of an appropriate treatment approach, which may include antiinflammatory medications. The use of statins and aspirin may alter this residual risk, and FAI is no longer predictive of incident cardiovascular risk in such situations [24]. FRP and its characteristics, on the other hand, are a non-modifiable cardiovascular risk factor that is unaffected by pharmacological therapy. FAI, in addition to being an appealing alternative imaging tool for detecting arterial inflammation, may also be less costly and expose the patient to less radiation. However, its relationship with the presence of CMVD has not been investigated, and further study is needed in this area to better clarify FAI’s involvement in the evaluation of CMVD. Cardiovascular Positron Emission Tomography (PET) has probably been the most thoroughly researched noninvasive technique of estimating MBF [25]. Despite constraints in terms of cost and availability of cyclotrons, myocardial perfusion reserve has been linked to unfavourable outcomes, including heart failure with maintained ejection fraction, in addition to its significance in CMVD diagnosis. Finally, advancements in cardiac MRI techniques have made imaging of microcirculation possible by using contrast media diffusion from the microvasculature into the interstitium during the first pass. To estimate MBF, integrated techniques such as the Fermi model have been developed, which, along with the microvascular perfusion resistance index, are good markers of CMVD. Furthermore, global CFR assessment using cardiac MRI is possible, providing additional prognostic information. The prevalence of imaging artefacts and the restricted usage of gadolinium in chronic renal disease patients are two of cardiac MRI’s limitations. Several studies have been conducted to assess the function of biomarkers in CMVD Schroder et al. examined 92 biomarkers in women with CMVD and found that, while a component of six anti-inflammatory biomarkers was related with CMVD even after controlling for established risk variables, it did not give extra predictive value. Serum soluble CD40 ligand and high sensitivity C reactive protein (CRP) have been related with CMVD in this context, underlining the inflammatory mechanism that mediates this entity. Safdar et al. has established the efficacy of renalase, a measure of endothelial function and inflammation, in patients with CMVD-related angina.

Role of Inflammation

Evidence from studies in autoimmune rheumatic disorders has highlighted the relationship between the pro-inflammatory state and endothelial dysfunction exhibited in CMVD as reduced nitric oxide (NO) bioavailability along with a high generation of reactive oxygen species (ROS). CMVD can be caused by a number of physiological mechanisms that cause either defective dilatation or increased constriction of coronary micro vessels. Following endothelial failure, inflammation and immune system dysregulation are driving forces that accelerate the atherosclerotic process, impacting the microvasculature. CMVD causes varying degrees of disruption to normal coronary physiology. Structure anomalies in patients with hypertrophic cardiomyopathy and arterial hypertension are responsible for the development of CMVD. Microvascular dysfunction in patients with non-obstructive coronary disease can be caused by a number of factors, including increased heart rate, decreased diastolic time, decreased driving blood pressure, and left ventricular inotropism, all of which must be considered when assessing microvascular function. Finally, the pulsative pattern of the heart, as well as intramyocardial and intraventricular pressures, have a linear effect on coronary blood flow. As a result, changes in the diastolic phase of the cardiac cycle influenced myocardial perfusion.

Conclusion

Chronic low-grade inflammation plays a significant role in the development of coronary atherosclerosis and is implicated in coronary microvascular dysfunction (CMVD). CMVD, characterized by structural and functional abnormalities in the coronary microvasculature, leads to inadequate dilation and an inability to meet myocardial oxygen demands. It is associated with various clinical manifestations, ranging from asymptomatic to stable angina, acute coronary syndrome, heart failure, and sudden cardiac death. The identification and understanding of CMVD have been challenging, but recent advancements in non-invasive screening approaches have shown promise. The evaluation of coronary flow reserve (CFR), which measures epicardial and microcirculatory blood flow, is a key component in diagnosing CMVD. Non-invasive techniques such as contrast echocardiography and Doppler echocardiography have been used for CMVD assessment, but they are operator-dependent and have limitations. Cardiac CT angiography (CCTA) has emerged as a promising strategy, providing information on coronary architecture and myocardial perfusion in a single study. Additionally, CCTA has shown potential in identifying coronary inflammation through perivascular fat imaging, offering a new avenue for CMVD evaluation.

Other non-invasive techniques, including cardiovascular positron emission tomography (PET) and cardiac MRI, have also been explored for assessing CMVD. Biomarkers, such as soluble CD40 ligand and high sensitivity C-reactive protein (CRP), have shown associations with CMVD, highlighting the role of inflammation in this condition. Understanding the underlying inflammatory mechanisms and immune system dysregulation in CMVD is crucial for developing effective treatment approaches. Recent studies have investigated the potential of anti-inflammatory agents, such as statins and immunomodulators, including anakinra, tocilizumab, and tumor necrosis factoralpha inhibitors, as additional or alternative treatments to reduce cardiovascular events in atherosclerotic heart disease with CMVD. Further research is needed to establish the efficacy of these therapies and to elucidate the relationship between inflammation, CMVD, and cardiovascular outcomes.

Coronary microvascular dysfunction, a common occurrence in cardiology practise, is caused by endothelial dysfunction, whereas systemic inflammation appears to be a key contributing component due to the cluster of comorbidities present. Recent pharmacological advancements in anti-inflammatory treatment may become critical in reducing the remaining cardiovascular risk in CAD with microvascular dysfunction. In summary, CMVD represents a significant clinical entity associated with increased cardiovascular risk. Advances in noninvasive screening approaches and the understanding of inflammation’s role in CMVD provide opportunities for improved diagnosis and targeted therapies. Continued research efforts are essential to enhance our understanding of CMVD pathophysiology, refine diagnostic techniques, and develop effective treatment strategies to reduce the burden of cardiovascular disease in patients with CMVD.

Acknowledgement

Not applicable.

Conflict of Interest

Author declares no conflict of interest.

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