Prognostic factors of MINOCA and their possible mechanisms

Abstract

Objective

Despite not showing substantial stenosis of coronary arteries, Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA) presents with myocardial ischemia injury, thus having a grave prognosis and a high risk of long-term complications. This necessitates increased clinical attention and exploration of its root causes to prevent a similar crisis.

Methods

Research on MINOCA is limited, especially in terms of its clinical attributes, long-term outlook, risk stratification, and prognosis-linked cardiometabolic risk factors. This review aims to fill these gaps, providing an extensive overview of clinical trials and studies on MINOCA to separate the issue from the presence of non-obstructive coronary arteries in cardiac patients.

Results

It has been found that MINOCA patients still face a high risk of long-term adverse events. Due to social and physiological factors, the hospital mortality rate is higher among women, and they are also more susceptible to MINOCA. Cardiac metabolic risk factors, including disorder of glucose and lipid metabolism, as well as changes in serum CysC levels, have significant impacts on the occurrence and prognosis of MINOCA.

Conclusions

Further research is still needed to fully understand the complex biological mechanisms underlying the prognostic factors of MINOCA. A profound understanding of these factors could reveal potential targets for improving prognosis, thereby indicating new strategies for managing this cardiovascular condition.

1. Introduction

Coronary artery disease (CAD), the most common global cardiovascular disease, often leads to acute myocardial infarction (AMI)—a lethal cardiovascular disease (Barbara et al., 2019). AMI’s pathophysiology primarily involves the progression of coronary atherosclerotic plaques which induce coronary thrombosis, luminal obstruction, and myocardial ischemic necrosis (Desiderio et al., 2003, Nakamura et al., 2001). Despite most AMI patients having obstructive myocardial infarction (MI) during coronary angiography (CAG), 5–10 % are without coronary artery obstruction, a condition known as MI with non-obstructive coronary arteries (MINOCA) (Giancarla et al., 2019). MINOCA causes, categorized into epicardial and microvascular causes, diverse patient prognosis (Giancarla et al., 2019). The diagnosis of MINOCA requires AMI diagnostic criteria, absence of obstructive CAD, and exclusion of other diseases triggering elevated troponin or non-ischemic myocardial injury (Agewall et al., 2017, Tamis-Holland Jacqueline et al., 2019). Diagnostic cardiac imaging plays an emerging and crucial role in evaluating suspected or diagnosed MINOCA patients, aiming to accurately identify and treat the specific causes of MINOCA, thus improving the prognosis and quality of life for these patients (Montone Rocco et al., 2021). While considering MINOCA's prognosis more optimal than MI-CAD, recent studies indicate poor prognosis and high long-term adverse event risk, drawing attention in clinical practice (Evbayekha Endurance et al., 2022, Mehmet et al., 2022). The present review systemically analyzes baseline characteristics and cardiometabolic risk factors of MINOCA, aiding future clinical management and scientific research.

2. The overall prognosis of MINOCA

Beltrame et al (Beltrame, 2013) first proposed the concept of MINOCA in 2013. MINOCA is considered to be a heterogeneous group of disorders caused by a number of etiologies, of which atherosclerotic plaque rupture is the most common (Evbayekha Endurance et al., 2022). Other coronary lesions, such as coronary spasm, spontaneous dissection, embolism and microvascular dysfunction can also cause MINOCA, but these are less common. It is worth noting that the use of acetylcholine or coronary artery provocation tests has been effective in diagnosing MINOCA caused by coronary artery spasm, which has certain value in evaluating patient prognosis (Montone Rocco, 2021). Depending on the underlying cause, MINOCA lacks specific treatment and most patients are still treated with secondary prophylaxis for MI-CAD (Mehmet et al., 2022). In recent years, more studies have explored the clinical features and prognosis of MINOCA compared with MI-CAD, but there remains few studies concerning risk stratification and survival analysis of MINOCA. Recent studies have shown that patients with MINOCA have a younger age of onset, recent studies have shown that patients with MINOCA have a younger age (average 5–8 years) of onset than traditional cardiovascular diseases (Mehmet et al., 2022, Nordenskjöld Anna et al., 2019). It has previously been suggested that patients with MINOCA do not have significant coronary stenosis and that their prognosis is more optimal than that of patients with MI-CAD (Giancarla et al., 2019, Chao-Jie et al., 2020). A study found that the rates of in-hospital mortality or MI within 1 year in patients with MINOCA were lower than those in patients with MI-CAD (Bainey et al., 2018), which was consistent with the conclusion of another study in China (Abdu Fuad et al., 2019). A large-scale study also demonstrated that the rates of patients with MINOCA (18.7 vs. 27.6 %), mortality (12.3 vs. 16.7 %), hospitalization (1.3 vs. 6.1 %) and hospitalization for heart failure episode (5.9 vs. 9.3 %) were lower than that for patients with MI-CAD (all P < 0.001) (Dreyer Rachel et al., 2020).

However, a number of studies have shown that the risk of major adverse cardiovascular events (MACEs) in patients with MINOCA remains high and that their prognosis is not optimistic. According to a Swedish study, up to 23.9 % of patients with MINOCA developed a MACE within an average follow-up time of 4.1 years (Yeh et al., 2010). Safdar et al (Safdar et al., 2018) compared 2,690 patients in 103 hospitals and found that the 1-year all-cause mortality of patients with MINOCA was similar to that of patients with MI-CAD. This conclusion was contrary to the results of previous studies and has attracted attention. Coincidentally, a more recent study also cautions that MINOCA is not a benign condition and stated that its 3-year mortality rate reaches as high as 16 % (Zhang et al., 2022). Further research has found that some MINOCA patients, specifically those with spontaneous coronary artery dissection (Ciliberti et al., 2020), are at risk of sudden cardiac death. Andersson et al (Andersson et al., 2018) and Planer et al (Planer et al., 2014) confirmed in ST-elevation MI (STEMI) and non-ST elevation-acute coronary syndrome (NSTE-ACS) populations that the long-term mortality risk of patients with MINOCA or MI-CAD was not statistically different.

Notably, the conclusions of the aforementioned studies on the prognosis of MINOCA are not entirely consistent, which may be related to the different populations included in each study, the number of cases, the proportion of potential causes, the drug treatment and the follow-up time (Table 1). For example, among the studies that support the more optimal prognosis of MINOCA, the study by Bainey et al study (Nordenskjöld Anna et al., 2019) included individuals aged 59–63 years old. By contrast, a study that suggested that the prognosis of MINOCA was poor, included subjects aged 18–55 years old, which was younger than the former study (Yeh et al., 2010). According to previous study, an age of > 60 years old is a risk factor for MINOCA (Beltrame, 2013), which may explain the inconsistent conclusions of the aforementioned studies. Additionally, mechanisms undrlying MINOCA are multiple and completely different among them and possible differences in prognosis may be related to different mechanisms (Del et al., 2021). Recent studies have also found that the “one-size-fits-all” approach used for MICAD treatment may not be suitable for all MINOCA patients (Antonio et al., 2022). Therefore, personalized etiology-targeted therapy should be implemented to improve the prognosis of MINOCA based on different pathogenic mechanisms.

Table 1.

Related information from studies with different conclusions regarding the prognosis of myocardial infarction with non-obstructive coronary arteries.

First author, year	Conclusion	Type of research	Number of cases	Intervention measures	Follow-up time, months	(Refs.)
Nordenskjöld et al, 2019	Positive	Retrospective cohort study	9,092	–	-	(Montone Rocco, 2021)
He et al, 2020	Positive	Prospective cohort study	524	Exercise training program	36	(Nordenskjöld Anna et al., 2019)
Bainey et al, 2018	Positive	Prospective cohort study	35,928	Secondary prevention medication for myocardial infarction	72	(Chao-Jie et al., 2020)
Abdu et al, 2019	Positive	Prospective cohort study	2,029	–	12	(Bainey et al., 2018)
Dreyer et al, 2020	Positive	Retrospective cohort study	276,522	Coronary angiography	-	(Abdu Fuad et al., 2019)
Yeh et al, 2010	Negative	Prospective cohort study	46,086	–	96	(Dreyer Rachel et al., 2020)
Safdar et al, 2018	Negative	Prospective cohort study	2,690	–	12	(Yeh et al., 2010)
Zhang et al, 2022	Negative	Retrospective cohort study	165	–	-	(Safdar et al., 2018)
Andersson et al, 2018	Negative	Prospective cohort study	4,793	Coronary angiography	30	(Zhang et al., 2022)
Planer et al, 2014	Negative	Prospective cohort study	6,921	Coronary angiography	-	(Ciliberti et al., 2020)

3. Clinical features and prognosis of patients of different sexes with MINOCA

Sex differences in the predictors and prognosis of MINOCA. Epidemiological data indicate that the mortality rate of patients following AMI in the United States is increasing rapidly (increase 18.71 % from 2010) and sex differences are beginning to develop, as the in-hospital mortality rate following AMI in women is relatively higher than in men (Virani et al., 2020). Another study similarly demonstrated that women with AMI have a higher rate (11.1 % increase) of cardiovascular death per year than men (Bucholz et al., 2014). These studies indicate that the prognosis of patients of different sexes with AMI may be different. However, this topic is rarely reported and there is a lack of data from studies with long-term follow-up.

Recent study have shown that the mean age of MINOCA onset in women is significantly higher than that in men, revealing differences in patient characteristics between the sexes (Lisa et al., 2023). A multivariate regression analysis in another study also identified women and cancer as independent predictors of MINOCA. This appeared to identify the role of sex in the prognosis of MINOCA (Cobi et al., 2022). However, Mohammed et al (Abdul-Quddus et al., 2021) studied the differences in clinical features, predictors and outcomes in patients with MINOCA and found that, although the predicted risk factors for MACE were different in men and women [the multivariate predictors of MACE in the female group were age, hypertension and left ventricular ejection fraction (LVEF), while diabetes, smoking and LVEF were the multivariate predictors of MACE in the male group], the clinical outcomes were similar in both groups. In a meta-analysis involving 28,671 patients with MINOCA, MACE events were higher in women than in men, while there were no statistically significant differences in all-cause mortality, non-fatal MI and cardiovascular readmission rates between men and women (Rahul et al., 2022). The conclusions of the aforementioned studies are not entirely consistent, and this difference may be due to the different number of patients included in the studies and the different follow-up times.

Social factors of sex differences in MINOCA. As mentioned above, Females with MINOCA have a higher risk of developing MACE compared to males, but the overall mortality rate is similar for both genders (Andersson et al., 2018, Antonio et al., 2022). This is consistent with what researchers understand about AMI (Xu et al., 2015, Nauta et al., 2012), and this conclusion can be explained with similar reasons, there is a combined effect of both social and physiological factors. In terms of social factors, hospitalized female patients have more mental stress and depressive symptoms compared with men, which in turn leads to adverse health behaviors as well as poorer cardiovascular outcomes (Shively Carol et al., 2009). This may further result in a higher proportion of women with hypertension, diabetes and hyperlipidemia, a worse baseline clinical status in women and a significantly higher rate of Killip grade III in women compared with men (Hsue Priscilla et al., 2015). Moreover, compared with men, women have fewer clinical symptoms, and delayed or irregular treatment is more prominent (Orth-Gomér et al., 1998). In addition, women are less likely to receive standard secondary prophylaxis treatment (such as antiplatelet drugs, statins, β-blockers or angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers) in hospital than men, thus women are more likely to develop heart failure or cardiogenic shock after the onset of MINOCA, leading to a higher incidence of all-cause mortality and MACE than in men (Abdul-Quddus et al., 2021, Rahul et al., 2022, Xu et al., 2015, Nauta et al., 2012, Shively Carol et al., 2009, Hsue Priscilla et al., 2015, Orth-Gomér et al., 1998, Hui-Xin et al., 2006). These factors indicate why women have a higher risk of MACE than men.

Physiological factors of sex differences in MINOCA. Women live longer on average and have the cardioprotective effects of estrogen. Estrogen delays the progression of atherosclerosis, and the risk of pre-menopausal MINOCA is low (Planer et al., 2014). The biological effects of estrogen are realized through the estrogen receptors (ERs), including ERα, ERβ and G protein-coupled ER (GPER). These three types of ER are widely expressed in various tissues and organs throughout the body, including the heart and vascular walls (Nauta et al., 2012). After estrogen activates the related receptors, it can play a role via non-genomic pathways (Aryan et al., 2020). Estrogen at physiological concentration can act rapidly (in seconds or minutes) in non-genomic pathways, which is currently recognized as the main pathway type for estrogen to protect the cardiovascular system (Shively Carol et al., 2009). In this pathway, estrogen acts by changing the level of the classical secondary messenger (Cellular cytokine receptors ect) by activating the ER on the plasma membrane, leading to the rapid activation of various kinase pathways (Steagall et al., 2017, Feng et al., 2017).

Activation of the ER can protect the heart from MINOCA through two mechanisms: The acute therapeutic effect of ischemia reperfusion (I/R) and the preventive effect on I/R. In examining the acute therapeutic effect of I/R, an animal study reported that myocardial catalase and superoxide dismutase (SOD) activity and the phosphorylation of AKT were enhanced after rats were injected with estradiol (E2) or selective ERα agonists with reduced malondialdehyde content (Hsue Priscilla et al., 2015). Changes in the levels of these factors activates the MEK/ERK/GSK-3β axis through the GPER to reduce the sensitivity of the mitochondrial permeability transition pore (mPTP) to Ca²⁺ overload, resulting in a delayed opening of the mPTP (Orth-Gomér et al., 1998). This delayed opening protects the integrity of the structure of the mitochondria, while reducing LC3 I and LC3 II protein levels, and increasing the expression of p62 and PINK1. PINK1 inactivation of the Parkin pathway reduces mitophagy and ultimately results in reduced reactive oxygen species (ROS) production and MI area. This acute therapeutic effect against I/R can be antagonized by ER antagonists or nitric oxide synthase inhibitors (Planer et al., 2014). The mechanism of the acute therapeutic effect of the ER through I/R is outlined in Fig. 1A. As for the preventive effect on I/R, it was found that the left MI area of mice with coronary ischemia was reduced by E2 administration, accompanied by an increase in mitochondrial p38β and mitochondrial SOD (MnSOD) activity (Sivasinprasasn et al., 2019). E2 enhances MnSOD activity in cardiomyocytes via ERα and ERβ enhancing the activation of mitochondrial p38β, thereby inhibiting intracellular ROS production and reducing myocardial injury and infarct area during I/R (Luo et al., 2016). The mechanism of the preventative effect of the ER on I/R is outlined in Fig. 1B. Another study found that 4-week estrogen therapy administered to female rats 12 weeks after bilateral oophorectomy not only preserved the structural integrity of mitochondria, but also improved insulin resistance and dyslipidemia (Kilanowski-Doroh Isabella et al., 2023). A possible explanation for this is that long-term estrogen therapy activates PI3K and increases phosphorylation of the E2-binding subunits of aldehyde dehydrogenase 2 and α-ketoglutarate dehydrogenase, thereby reducing ROS production in mitochondria (Aryan et al., 2020). This suggests that estrogen prophylaxis may have a significant advantage in cardiac ischemia due to MINOCA.

Fig. 1.

(A) The acute therapeutic effect of the ER through I/R protects the heart from myocardial infarction with non-obstructive coronary arteries. (B) The preventive effect of the ER on I/R. α-KGDH, α-ketogluterate dehydrogenase; ALDH2, aldehyde dehydrogenase; E2, estradiol; ER, estrogen receptor; GPER, G protein-coupled estrogen receptor; I/R, ischemia reperfusion; MAD, malondialdehyde; mPTP, mitochondrial permeability transition pore; ROS, reactive oxygen species; (Mn)SOD, (mitochondrial) superoxide dismutase.

4. Effect of cardiometabolic risk factors on the prognosis -+of patients with MINOCA

Glucose metabolism disorder and MINOCA. Glucose metabolism disorders mainly refer to glucose, fructose, galactose and metabolic hormones or enzymes with abnormal structure, function or concentration. Clinically important glucose metabolism disorders mainly result in too high or low blood glucose concentrations (van Helden et al., 2020). Previous studies have confirmed the association between diabetes and CAD prognosis (Songzan et al., 2023, O'Sullivan Jack et al., 2023), but the effect of diabetes on cardiovascular outcomes in patients with MINOCA is unclear.

Diabetes often coexists with cardiovascular risk factors, such as obesity, hypertension and abnormal lipid metabolism, and mediates extensive macrovascular and microangiopathy complications throughout the body, which is speculated to play a key role in the occurrence and development of MINOCA (Steagall et al., 2017). A recent study by Abdu et al (Abdu Fuad et al., 2023) provided some basis for this speculation. In the study, 410 patients with MINOCA were analyzed and it was found that stress hyperglycemia was independently associated with poor long-term prognosis in patients with MINOCA. Another study also demonstrated that stress hyperglycemia measured at hospital admission is a strong predictor of adverse short and long-term outcomes for MINOCA (Pasquale et al., 2021). Recent studies suggest that type 2 diabetes is less common in patients with MINOCA than in patients with MI-CAD, but it remains an independent predictor of all-cause mortality over time (Choo et al., 2019, Nordenskjöld et al., 2018).

The conclusions of the aforementioned studies are similar to what is known about MI-CAD. In patients with MI-CAD, the damage caused by diabetes mainly originates from promotion of the vascular inflammatory response, promotion of oxidative stress, mediation of vascular endothelial damage and smooth muscle cell proliferation (Luying et al., 2023). These factors can interact in a chain that ultimately leads to atherosclerotic plaque formation and progression, inducing plaque rupture and thrombosis and leading to myocardial damage and necrosis (Marlene et al., 2022). However, these mechanisms are somewhat different for MINOCA. In epicardial MINOCA, coronary artery spasm is the main cause of disease (O'Sullivan Jack et al., 2023, Abdu Fuad et al., 2023). There are two main factors that induce coronary artery spasm: Hyperresponsiveness of vascular smooth muscle cells (VSMCs) to local or multiple attacks and the transient stimulation of VSMCs by vasoconstrictors (Hiroaki, 2014). It is currently suggested that the increase of vascular endothelial inflammatory factors caused by glucose metabolism disorders is a notable factor in the hyperresponsiveness of VSMCs. Elevated blood glucose levels can activate the protein kinase C (PKC) pathway, leading to a decrease in endothelial nitric oxide production and an increase in prostaglandin synthesis, causing endothelial dysfunction (Pasquale et al., 2021). In addition, PKC can also regulate the activity of other protein kinases, such as PI3K/AKT and MAPK, damaging endothelial function and increasing vasoconstriction (Bye Bailey et al., 2023). When endothelial cells are stimulated by inflammation, pro-inflammatory factors increase glucose uptake and glycolysis. Lactate-induced NF-κB activation plays a major role in this process (Paula et al., 2023). Pro-inflammatory factors can also activate mechanotransducers, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) (Driskill Jordan and Duojia, 2023). Similar to NF-κB, YAP/TAZ signaling also promotes endothelial cell glycolysis. Thus, inflammation and endothelial cell glucose metabolism appear to have a causal relationship, mutually promoting a cycle of disordered glucose metabolism (Fig. 2). However, the main trigger for stimulating VSMC hyperresponsiveness is increased Rho kinase activity (Tedy et al., 2022). Abnormal elevation of blood glucose can induce increased Rho kinase activity and further stimulate spasm in VSMCs. In clinical practice, active diabetes screening and early intervention can aid in the early prevention and prognosis of CAD.

Fig. 2.

Mechanism of endothelial dysfunction caused by disordered glucose metabolism in myocardial infarction with non-obstructive coronary arteries. NO, nitric oxide; PKC, protein kinase C; TAZ, transcriptional coactivator with PDZ-binding motif; YAP, Yes-associated protein.

Another mechanism of epicardial etiology in MINOCA is the presence of off-center plaques that develop centrifugally due to positive vascular remodeling (Fangdi et al., 2022). However, these lesions tend to have features of fragile plaques, such as large lipid pools and thin fibrous caps (Montone Rocco et al., 2021), which can induce plaque rupture, resulting in transient local thrombosis and spontaneous fibrinolysis, causing distal coronary thromboembolism and MINOCA. Although there have been no studies concerning glucose metabolism and plaque morphology, diabetes is a risk factor for intravascular plaque formation, which may also greatly increase the incidence of MINOCA (van Helden et al., 2020, Songzan et al., 2023). Moreover, abnormal blood sugar levels can directly damage the vascular endothelium to cause arterial spasm or atherosclerotic plaque formation, mediated by non-enzymatic glycosylation of low-density lipoprotein cholesterol (LDL-C), other apolipoproteins and blood clotting factors like Apolipoprotein B, Fibrinogen, Factor V and Factor VII (Elias et al., 2023).

The common causes of microvascular MINOCA include Takotsubo syndrome (TS), MI-like myocarditis, microvasospasm and coronary embolism (Paula et al., 2023). TS accounts for 1.2–2.2 % of coronary artery spasm incidences and its pathogenesis remains unknown (Roshanzamir and Showkathali, 2013). Patients with TS are characterized by the onset of recent physical or psychological pressure, and often exhibit visible ST segment elevation, T wave inversion (Abhishek, 2017). However, a recent study have found that glucose and lipid metabolism pathways are dysregulated in TS, and glycolysis and decreased levels of β oxidation metabolites are responsible for the above changes (Nadine et al., 2022). In microvasospasm pathogenesis, abnormally elevated blood glucose levels and abnormal glucose tolerance leads to the activation of PKC, the production of advanced glycation end products and ROS, upregulation of growth factors and inflammatory factors and a loss of insulin signaling, which contribute to microangiopathy (Poznyak Anastasia et al., 2022).

Lipid metabolism disorder and MINOCA. Unlike conventional MI-CAD, dyslipidemia is less frequently observed in patients with MINOCA (Evbayekha Endurance et al., 2022). However, relevant studies have shown that dyslipidemia still plays an important role in the pathogenesis and prognosis of MINOCA (Elias et al., 2023, Roshanzamir and Showkathali, 2013, Abhishek, 2017). In a study of 196 individuals, independent predictors of risk of MACE in patients with MINOCA included high LDL-C levels (Lin et al., 2023). Another study found that elevated residual cholesterol is an independent risk factor for adverse prognosis in MINOCA (Side et al., 2022). A recent study have also demonstrated that lipoprotein (a) [Lp(a)] level is an independent predictor of MINOCA ischemic events or death (Andrea et al., 2023).

Comparison of lipid metabolism abnormalities in the pathogenesis of MINOCA and MI-CAD. Excess cholesterol accumulates in the blood vessel wall, leading to plaque formation, and lipid metabolism disorders and hyperlipidemia are the main risk factors for this. MINOCA and MI-CAD can both be caused by MI due to plaque problems. Plaque problems include plaque rupture, plaque erosion and calcified nodules, of which plaque rupture is the most common cause (Zhi et al., 2023). Plaque rupture is typically associated with thin-fiber cap atherosclerotic plaques, which can induce thrombosis and, in some cases, transient vascular occlusion due to spontaneous thrombolysis. In plaque rupture, CAG (Nimrat and Onur, 2022) typical reveals few thrombus fragments without significant vascular embolism. Plaque erosion refers to histologically visible vascular endothelial thromboses in unruptured coronary arteries, and it may be associated with apoptosis of endothelial cells and loss of endothelial-extracellular matrix connections (Evbayekha Endurance et al., 2022). Calcified nodules are a type of vulnerable plaque that mostly occur in the elderly. CAG examination displays granular nodules protruding from the lumen with a red thrombus attached to the surface (Poznyak Anastasia et al., 2022). The incidence of plaque rupture and plaque erosion in patients with MINOCA can be > 40 % (Agewall et al., 2017).

The role of lipid metabolism in the pathogenesis of MINOCA and MI-CAD differs. The causal relationship between dyslipidemia, hypercholesterolemia, hypertriglyceridemia and coronary atherosclerosis is well established (O'Sullivan Jack et al., 2023). Dysregulated lipid metabolism is a major risk factor for coronary atherosclerosis, in which LDL-C is positively associated with cardiovascular disease onset. In a study by Wang et al (Nelson et al., 2020), it was demonstrated that, for every 1 mmol/l decrease in blood LDL-C levels, the risk of coronary heart disease was decreased by 55 %. However, for patients with MINOCA, the prevalence of hyperlipidemia was lower than that observed or not significantly different to the whole MI-CAD cohort (O'Sullivan Jack et al., 2023). Moreover, a study by Larsen et al (Larsen Alf et al., 2014) found no significant difference in hypercholesterolemia incidence between patients with MINOCA or MI-CAD. However, in a large study including 322,523 patients, blood cholesterol levels in patients with MINOCA were lower than those in patients with MI-CAD (Smilowitz Nathaniel et al., 2017). In a study in China, it was concluded that LDL-C was negatively associated with MINOCA onset, and the levels of LDL-C in the MINOCA group was lower in the univariate analysis compared with the MI-CAD group, which was statistically significant (Abdu Fuad et al., 2019).

However, further studies found that the independent risk factors for adverse cardiac events were not the same in the STE and NSTE populations of patients with MINOCA, with higher LDL-C levels observed in patients NSTE (Lin et al., 2023). Xu et al (Xu et al., 2020) also demonstrated that total cholesterol was only a predictor of NSTE MINOCA disease onset, not STE. A meta-analysis indicated that reducing LDL-C levels was effective in reducing the incidence of cardiovascular disease and stroke, while higher LDL-C levels were an independent risk factor for MACE in the STE MINOCA group (Baigent et al., 2010). The administration of statins to patients with MINOCA reduces LDL-C levels and stabilizes and controls coronary plaque progression with a beneficial prognostic impact (Choo et al., 2019). Another study has found that the different mechanisms of MINOCA negate any benefits of patients taking DAPT (Dual Antiplatelet Therapy) or statin medications (Stefanescu et al., 2017). These contradictory findings leave the role of statin drugs in the treatment of MINOCA inconclusive. Current research also tends to suggest that MINOCA patients are not the primary focus of secondary prevention measures, thus resulting in a higher risk of recurrent myocardial infarction (Nordenskjöld et al., 2019).These studies suggest that cholesterol levels may play different roles in patients with STE or NSTE MINOCA. A Previous study have reported higher short-term mortality rates in patients with STEMI and higher long-term mortality rates in patients with NSTEMI, which was also observed in the MINOCA population (Nordenskjöld et al., 2018). It can therefore be inferred that abnormal cholesterol metabolism may have an effect on long-term mortality in patients with MINOCA, but this conclusion needs further validation.

Association of Lp(a) and MINOCA prognosis. Lp(a) is a plasma lipoprotein formed by the covalent association of lipoprotein B100 and lipoprotein A (Yaxin et al., 2023). Epidemiological data indicate that 20–30 % of the global population has elevated Lp(a) levels, which significantly increases the risk of cardiovascular events, including in young individuals with no other risk factors (Michael et al., 2023). Further studies have confirmed a correlation between Lp(a) levels and the prognosis of patients with coronary heart disease, with higher Lp(a) levels being associated with poorer prognosis (Xu et al., 2020, Baigent et al., 2010, Choo et al., 2019). The role of Lp(a) in increasing residual cardiovascular risk is independent of LDL-C and other risk factors (Xu et al., 2020). However, the significance of Lp(a) in MINOCA has only recently been recognized, and research in this area remains limited. In a 2021 prospective study of 1,179 patients with MINCOA, Gao et al (Side et al., 2021) were the first to evaluate the impact of Lp(a) levels on the long-term prognosis of patients with MINOCA treated with statins, and suggested that improving Lp(a) levels may enhance the prognosis of this population. However, another study suggested that elevated Lp(a) was an independent predictor of poor prognosis in patients with MINOCA, with the role of statins in improving prognosis lacking sufficient evidence (Andrea et al., 2023).

The relationship between elevated Lp(a) levels and increased cardiovascular risk is not fully understood, but several mechanisms have been proposed that primarily involve pro-inflammatory and pro-thrombotic effects. Given its structural similarity to LDL particles, Lp(a) can enhance foam cell formation, generate ROS and promote smooth muscle cell proliferation, thereby promoting atherosclerosis (Stefanescu et al., 2017). Additionally, Lp(a) can be recognized by inflammatory cells and trigger inflammatory pathways. Lp(a) also competes with plasminogen for binding sites, inhibiting fibrinolysis and promoting thrombus formation (Halima et al., 2023). A recent prospective multicenter study involving 1,042 patients with AMI found that patients with MINOCA were younger, more likely to be female, had a lower incidence of diabetes and Lp(a) > 9 mg/dl and had higher high-density lipoprotein cholesterol (HDL-c) levels (Andrea et al., 2023). In conclusion, in patients with AMI, the absence of high Lp(a) and HDL-c levels are independent predictors of the absence of CAD, and high Lp(a) levels are also independent predictors of ischemic events or death. Despite these findings, the pathophysiological mechanisms of MINOCA remain a topic of debate.

Serum cystatin C (CysC) levels may affect the prognosis of MINOCA. CysC, an endogenous tissue cysteine protease inhibitor, primarily functions to maintain the balance between proteases and inhibitors (Nordenskjöld et al., 2018). Inflammatory cytokines that are related to atherosclerosis formation promote the production of tissue proteases, and elevated CysC levels can disrupt this balance (Yaxin et al., 2023). This disruption can lead to increased degradation of the arterial elastic lamina and extracellular matrix, promoting the formation and progression of coronary atherosclerosis (Yaxin et al., 2023). Elevated serum CysC levels have been closely linked with stable CAD, ACS, NSTEMI and STEMI (Azadeh et al., 2023, Lena et al., 2023). In 2021, Lu et al (Ya-Wen et al., 2021) found that CysC could be used to assess the severity of coronary lesions in patients with CAD, with higher CysC levels being an independent risk factor for CAD progression. Another study found a positive correlation between serum CysC levels and the degree of coronary lesions in patients with MINOCA, with high CysC levels being an independent risk factor for adverse events in these patients (Brolin Elin et al., 2018).

A number of clinical studies have found a positive correlation between serum CysC and CRP (Nordenskjöld et al., 2019, Nordenskjöld et al., 2018, Yaxin et al., 2023). In addition, in a previous tudy, a significant correlation between serum CysC and TNF was noted (Cheng et al., 2009). A study by Leung et al (Leung-Tack et al., 1990) found that serum CysC and its fragments could promote the phagocytosis and chemotaxis of neutrophils, exacerbating the inflammatory response. The most crucial aspect in the development of cardiovascular diseases is the remodeling of the extracellular matrix. Under normal circumstances, serum CysC maintains a dynamic balance with tissue proteases (Kavindi et al., 2023). When an inflammatory response occurs, VSMCs excessively secrete tissue proteases under the stimulation of inflammatory factors (Marycarmen et al., 2023). This leads to an increase in mitochondrial outer membrane permeability in vascular endothelial cells, and the mitochondria release apoptosis-inducing factors that promote cell apoptosis, leading to vascular endothelial damage. Then, platelets adhere to the damaged endothelium and various inflammatory factors in the blood form a positive feedback loop, further accelerating the development of atherosclerosis (Fig. 3) (Yiwei et al., 2023). As tissue proteases disrupt the vascular environment, the concentration of serum CysC also increases (Andrea et al., 2023). High concentrations of serum CysC can inhibit the solubilizing effect of tissue proteases, reducing tissue protein degradation, protecting arterial endothelium and preventing damage from inflammatory reactions (Andrea et al., 2023). This halts further damage to the vascular intima and inhibits the progression of atherosclerosis. However, although serum CysC secretion increases during inflammation, it remains relatively deficient compared with the increase in tissue protease secretion at arterial injury sites (Yaxin et al., 2023, Michael et al., 2023, Side et al., 2021). When serum CysC is relatively insufficient, tissue proteases remain upregulated, causing degradation of the extracellular matrix and collagen accumulation, and leading to extracellular matrix remodeling (Michael et al., 2023, Side et al., 2021). Additionally, many researchers have proposed new explanations the involvement mechanism of CysC in MINOCA: i) Vascular endothelial cell damage and dysfunction: During the sulfhydryl oxidation process, serum CysC produces a series of free radicals (such as superoxide anions, hydrogen peroxide and hydroxyl radicals) causing protein damage, enzyme release, receptor activity and functional impairment (Ward Nathan, 2023). Free radicals also promote the oxidation of LDLs, forming foam cells. The accumulation of foam cells forms lipid stripes and lipid plaques, accelerating the progression of atherosclerosis and narrowing the arterial lumen (Lei et al., 2023). ii) Serum CysC can directly induce the proliferation and migration of VSMCs and interfere with VSMC function through signal transduction pathways (Azadeh et al., 2023). iii) High serum CysC levels can alter coagulation factor functions, promoting platelet adhesion and aggregation, which leads to thrombosis (Lena et al., 2023). iv) Vascular contraction dysfunction: Nitric oxide is a potent endothelium-derived vasodilator and has strong antiplatelet properties (Ya-Wen et al., 2021). Damage to vascular endothelial cells by serum CysC can reduce nitric oxide production, causing vascular contraction, further endothelial damage, platelet aggregation, plaque formation and cascading positive feedback responses, accelerating atherosclerotic plaque formation and progression (Sylwia et al., 2022). v) Elevated serum CysC can also act through the CD40 pathway, an immune-inflammatory regulatory pathway. CD40 ligand induces the expression of matrix metalloproteinases in plaque macrophages and VSMCs, leading to plaque rupture (Klas and Arne, 2004).

Fig. 3.

Mechanism by which CysC promotes atherosclerosis development. CysC, cystatin C.

5. Conclusion

MINOCA, accounting for 5–10 % of AMI cases, poses a high risk of long-term adverse events despite past assumptions of a better prognosis than obstructive MI-CAD. Particularly susceptible are women, due to societal and physiological aspects. The onset and prognosis significantly relate to cardiometabolic risk factors including glucose, lipid metabolic disorders, and varying serum CysC levels. Factors affecting prognosis are summarized in Table 2. Current research, although limited, suggests that these complex prognostic factors may provide targets for enhancing MINOCA treatment outcomes. Further exploration could uncover novel approaches to this cardiovascular condition.

Table 2.

Summary of factors and mechanisms affecting MINOCA prognosis.

A, Sex factors
Factors affecting prognosis	Related mechanisms	Impact on MINOCA prognosis	(Refs.)
Social	–	Female patients with MINOCA have more psychological stress and depressive symptoms than men, which in turn leads to poorer health behaviors and cardiovascular outcomes.	(Planer et al., 2014, Virani et al., 2020, Lisa et al., 2023, Cobi et al., 2022, Abdul-Quddus et al., 2021, Rahul et al., 2022, Xu et al., 2015, Nauta et al., 2012, Shively Carol et al., 2009)
Physiological	MEK/ERK/GSK-3β, PI3K/ALDH2/α-KGDH and p38β/MnSOD	Estrogen achieves acute therapeutic effects and preventive effects on I/R by activating the ER, thereby protecting the heart.	(Hsue Priscilla et al., 2015, Orth-Gomér et al., 1998, Hui-Xin et al., 2006, Planer et al., 2014, Aryan et al., 2020, Steagall et al., 2017, Feng et al., 2017)
B, Cardiometabolic factors
Factors affecting prognosis	Related mechanisms	Impact on MINOCA prognosis	[Refs.]
Glucose metabolism disorder	PI3K/AKT, PKC/MAPK and PKC/YAP/TAZ	Disordered glucose metabolism promotes increased secretion of inflammatory factors, leading to endothelial dysfunction. Meanwhile, the increased levels of inflammatory factors further contribute to impaired glucose uptake and metabolism in blood vessels, forming a cycle of disordered glucose metabolism.	(van Helden et al., 2020, Songzan et al., 2023, O'Sullivan Jack et al., 2023, Abdu Fuad et al., 2023, Pasquale et al., 2021, Choo et al., 2019, Nordenskjöld et al., 2018, Luying et al., 2023, Marlene et al., 2022, Hiroaki, 2014, Bye Bailey et al., 2023, Paula et al., 2023, Driskill Jordan and Duojia, 2023, Tedy et al., 2022, Fangdi et al., 2022, Elias et al., 2023, Roshanzamir and Showkathali, 2013)
Lipid metabolism disorder	Lack of research temporarily.	The role of cholesterol in the pathogenesis of MINOCA is controversial; total cholesterol is a predictor of pathogenesis in patients with NSTE MINOCA; a high LDL-C level is an independent risk factor for MACE in STE MINOCA; reducing Lp[a] levels improves survival in patients with MINOCA.	(Abdu Fuad et al., 2023, Pasquale et al., 2021, Choo et al., 2019, Nordenskjöld et al., 2018, Luying et al., 2023, Marlene et al., 2022, Hiroaki, 2014, Bye Bailey et al., 2023, Paula et al., 2023, Driskill Jordan and Duojia, 2023, Tedy et al., 2022, Fangdi et al., 2022, Elias et al., 2023, Roshanzamir and Showkathali, 2013, Abhishek, 2017, Nadine et al., 2022, Poznyak Anastasia et al., 2022, Lin et al., 2023, Side et al., 2022, Andrea et al., 2023, Zhi et al., 2023, Nimrat and Onur, 2022, Agewall et al., 2017, Nelson et al., 2020, Larsen Alf et al., 2014, Smilowitz Nathaniel et al., 2017, Abdu Fuad et al., 2019, Xu et al., 2020, Baigent et al., 2010, Choo et al., 2019, Stefanescu et al., 2017, Nordenskjöld et al., 2019, Yaxin et al., 2023)
CysC metabolic disturbance	Promotion of inflammatory response, promotion of free radical generation, promotion of proliferation and migration of vascular smooth muscle cells, alteration of coagulation factor function, reduction in NO production and activation of CD40 ligand.	High levels of CysC are an independent risk factor for adverse events in patients with MINOCA.	(Azadeh et al., 2023, Lena et al., 2023, Ya-Wen et al., 2021, Brolin Elin et al., 2018, Cheng et al., 2009, Leung-Tack et al., 1990, Kavindi et al., 2023, Marycarmen et al., 2023, Yiwei et al., 2023, Ward Nathan, 2023)

α-KGDH, α-ketogluterate dehydrogenase; ALDH2, aldehyde dehydrogenase; CysC, cystatin C; ER, estrogen receptor; I/R, ischemia reperfusion; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein (a); MACE, major adverse cardiovascular event; MINOCA, myocardial infarction with non-obstructive coronary arteries; MnSOD, mitochondrial SOD; NO, nitric oxide; (N)STE, (non-)ST elevation; PKC, protein kinase C; TAZ, transcriptional coactivator with PDZ-binding motif; YAP, Yes-associated protein.

CRediT authorship contribution statement

Mowei Kong: Writing – original draft. Zhenying Pei: Writing – review & editing, Conceptualization. Yuyu Xie: Writing – review & editing. Yu Gao: Writing – original draft. Jun Li: . Guoxiang He: .

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability

No data was used for the research described in the article.