Coronary Microvascular Dysfunction and Atrial Cardiomyopathy: Risk Factors: History
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Contributor:
Irina Afrăsânie
,
Iulian Theodor Matei
,
Sabina Andreea Leancă
,
Adriana Chetran
,
Alexandru Dan Costache
,
Vlad-Adrian Afrăsânie
,
Bianca-Ana Dmour
,
Daniela Crișu
,
Minerva Codruța Bădescu
,
Lăcrămioara Ionela Șerban
,
Irina Iuliana Costache

Ischemia with nonobstructive coronary artery disease (INOCA) is increasingly recognized as a significant cause of angina, myocardial remodeling, and eventually heart failure (HF). Coronary microvascular dysfunction (CMD) is a major endotype of INOCA, and it is caused by structural and functional alterations of the coronary microcirculation. At the same time, atrial cardiomyopathy (ACM) defined by structural, functional, and electrical atrial remodeling has a major clinical impact due to its manifestations: atrial fibrillation (AF), atrial thrombosis, stroke, and HF symptoms. Both these pathologies share similar risk factors and have a high comorbidity burden. CMD causing INOCA and ACM frequently coexist. 

  • coronary microvascular dysfunction
  • atrial cardiomyopathy
  • heart

1. Introduction

Both coronary microvascular dysfunction (CMD) and atrial cardiomyopathy (ACM) share similar risk factors, suggesting a possible common pathophysiological pathway causing these pathogenies. Traditional cardiovascular risk factors and emerging entities with deleterious cardiovascular effects such as obstructive sleep apnea (OSA) and dysfunctional epicardial adipose tissue (EAT) promote endothelial dysfunction (ED), which contributes to CMD and ACM development, reinforcing their possible association [1][2].

2. Traditional Cardiovascular Risk Factors

Aging is associated with significant atrial remodeling, due to increased atrial fibrosis. Atrial dilatation is more severe in the elderly, and atrial fibrillation (AF) incidence increases with age [1]. Moreover, increasing age was found to be associated with CMD and epicardial vasospasm as a consequence of abnormal coronary function induced by vascular senescence [3].
Smoking significantly increases the risk of AF by up to 33%, and it is also associated with Ischemia with nonobstructive coronary artery disease (INOCA) endotypes [4][5]. The negative effect of smoking is initiated by induced ED. Smoking compounds decrease endothelial nitric oxide (NO) synthesis and induce endothelial cell activation, further causing platelet adhesion and inflammatory cell recruitment. In addition, smoking increases the production of reactive oxygen species (ROS) which directly cause endothelial cell disruption and apoptosis [6].
Obesity is a comorbidity with major deleterious systemic effects. Adipose tissue is an active metabolic organ that secretes proinflammatory cytokines, creating a low-grade systemic inflammatory environment. Chronic vascular inflammation promotes ED, which alters the coronary arterial vasomotor response, causing CMD [7]. In addition, atrial ED and inflammation in the atrial coronary microcirculation promote atrial structural and electrical remodeling and induce an atrial prothrombotic state, leading to ACM manifestations [1]. Left atrium (LA) size increases proportionally to body surface area and obesity significantly augments the risk of developing AF [4][8].
Arterial hypertension is the underlying cause of at least 1 in 5 cases of incident AF, being the most prevalent modifiable risk factor for AF [4]. Increased blood pressure leads to progressive dilatation and mechanical dysfunction of the LA, and it promotes the development of an atrial arrhythmic substrate. Renin–angiotensin–aldosterone system (RAAS) activation signals proinflammatory and profibrotic pathways which cause atrial myocyte hypertrophy and atrial collagen deposition, maintaining the adverse atrial remodeling process [1]. At the same time, RAAS activation causes vascular remodeling, being a major contributor to CMD development. Angiotensin II triggers smooth muscle cell proliferation and hypertrophy, which decreases the vascular arterial lumen and can potentially lead to coronary capillary rarefaction. Moreover, angiotensin II mediates vascular inflammation and ED, contributing to coronary functional dysregulation due to decreased levels of vasodilators and abnormal response to vasoconstrictor stimuli [9].
Diabetes mellitus (DM) is another major risk factor for both CMD and ACM. Persistent hyperglycemic stress causes mitochondrial dysfunction with increased oxidative stress production, and activation of the advanced glycation end product (AGE)–AGE receptor (RAGE) system [1]. These molecular abnormalities signal profibrotic pathways in the atria, alter impulse conduction, and increase susceptibility for AF development, with a 35% higher risk of AF occurrence in diabetic patients compared to the healthy population [4]. Similarly, high oxidative levels and activation of the AGE–RAGE interaction reduce NO synthesis and cause systemic endothelial damage, including in the coronary microvasculature. Consequently, CMD is a frequent encounter in diabetic patients, and it includes both structural and functional microvascular alterations. In addition to anginal symptoms, coronary ED also mediates myocardial inflammation and fibrosis, leading to ventricular dysfunction [10].

3. Emerging Cardiovascular Risk Factors

3.1. Obstructive Sleep Apnea

OSA is a sleep disorder characterized by multiple nocturnal pauses in breathing due to airway collapse, followed by reoxygenation. OSA is associated with multiple cardiovascular consequences, and ED appears to mediate this pathogenic link [11]. After the apneic episode resumes, reoxygenation is accompanied by a strong sympathetic drive, which impairs the endothelial function, with increased systemic inflammation and oxidative stress, reduced bioavailability of NO, and activation of prothrombotic pathways [12]. The link between OSA and systemic ED was evidenced by several studies showing impaired values of brachial  flow-mediated vasodilatation (FMD) in patients with OSA, which occur even in the absence of other risk factors for ED such as hypertension or DM [11].
In addition, it appears that OSA might contribute to the development of CMD in patients with nonobstructive CAD, most probably due to repeated episodes of hypoxemia–reoxygenation, which resemble the ischemia–reperfusion injury. In line with this, a meta-analysis showed that OSA was significantly associated with lower coronary flow reserve (CFR) [13]. Another study demonstrated that OSA was present in more than half of the included patients with microvascular angina and normal epicardial coronary arteries; in addition, severe OSA was associated with significantly lower values of  coronary flow reserve (CFR) [14].
At the atrial level, OSA triggers a true myopathic process, with electrophysiological changes caused by intermittent hypoxemia and hypercapnia, increases in intrathoracic pressure, and sympathovagal activation, which significantly augment the risk of AF [12]. In fact, in The Sleep Heart Health Study, patients with OSA had a prevalence of nocturnal AF of 4.8%, compared to 0.9% in patients without OSA [15]. Similarly, OSA has a high prevalence in AF patients, with reported rates from 21% to 74%, and it increases the risk of AF recurrence after arrhythmia ablation and cardioversion [16][17]. Ultimately, the proarrhythmic changes are accompanied by structural remodeling, characterized by atrial enlargement and dysfunction, which subsequently contribute to ventricular diastolic impairment and manifestations of HF [18].

3.2. Epicardial Adipose Tissue—A New Cardiovascular Risk Factor?

EAT is the visceral fat deposit of the heart and it is located beneath the epicardium and in direct contact with the myocardium. It is typically located in the atrioventricular and interventricular grooves, and it can surround the entire myocardial surface when the amount of fat increases. It is also arranged along the epicardial coronary branches, and it can extend into the myocardium as it follows the coronary adventitia. There is no anatomical structure separating the myocardium from the EAT; thereby, these structures share the same microcirculation, which enables cellular and molecular interactions at this level [19].
EAT is an organ with a higher metabolic activity compared to subcutaneous fat, and under abnormal conditions, it directly exerts multiple cardiac deleterious effects. Metabolic disorders such as obesity and DM induce systemic inflammation which signals epicardial adipocyte proliferation and dysfunction. Subsequently, defective adipocytes secrete proinflammatory cytokines such as IL-6, IL-1β, and IL-8 which promote myocardial inflammation, cardiomyocyte dysfunction, and fibrosis, by paracrine and endocrine signaling [20]. All these processes lead to a metabolic-inflammatory phenotype of ventricular myopathy, characterized by reduced ventricular distensibility, leading to  HF with preserved ejection fraction (HFpEF) [10]. In addition, increased EAT local production of vasoactive compounds such as angiotensinogen modulates coronary vascular tone and acts in conjunction with the increased inflammatory reaction to promote functional CMD, capillary rarefaction, and atherogenesis [19][21]. Indeed, it has been demonstrated that pericoronary adipose tissue is correlated with the development and severity of coronary atherosclerotic plaques, which suggests that EAT might play a role in the initiation and progression of coronary atherosclerosis, possibly through induced coronary ED and sustained inflammation [22]. Moreover, several studies showed that in patients with INOCA, EAT thickness is independently associated with reduced CFR, implying that EAT might be involved in the development of CMD [23][24].
A large amount of published data shows a strong association between EAT and AF, which might be explained by the development of an inflammatory atrial myopathy [10][20][21]. Surrounding atrial EAT induces changes in the local atrial environment by persistent inflammation and oxidative stress, modifying ion currents and promoting the development of an atrial arrhythmic substrate with increased AF burden. Additionally, direct fatty infiltration of atrial myocardium by extensions of EAT and atrial fibrosis modulated by bioactive adipokines further contribute to atrial structural remodeling, which in turn maintains arrhythmogenesis [19]. Several studies showed that EAT volume is associated with the prevalence of AF and with its severity, having higher values in persistent or permanent AF compared to paroxysmal AF or sinus rhythm [25][26]. Moreover, periatrial EAT is significantly increased in patients with AF, and it is associated with arrhythmic recurrence after AF ablation, suggesting the direct effect of EAT on the electrophysiologic properties of the adjacent atrial myocardium [27][28].

This entry is adapted from the peer-reviewed paper 10.3390/life13020443

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