The present study examined the prognostic significance of coronary artery sclerosis with regard to in- and out-of-hospital complications, as well as long-term outcomes, including mortality, in a cohort of 373 troponin-positive patients with non-obstructive coronary arteries. Patients with coronary artery sclerosis demonstrated a higher burden of comorbidities and increased medication use, and experienced higher rates of both in-hospital and out-of-hospital events than those without CAD. Remarkably, our study covered a follow-up period exceeding 6 years, underscoring the reliability of our findings over a substantial timeframe, and allowing for a comprehensive analysis of long-term outcomes.

The observed higher mortality in patients with coronary sclerosis may be attributed to the elevated prevalence of cardiovascular risk factors, each contributing individually to increased mortality. Cardiovascular risk factors play a pivotal role in the development and progression of atherosclerosis, with diabetes mellitus and arterial hypertension standing out as significant contributors [12, 13]. These factors are closely associated with the occurrence of CAD [12, 13] and are associated with a sixfold increase in mortality [14]. Therefore, it was not surprising to find that diabetes mellitus and arterial hypertension were significantly more prevalent among patients with coronary sclerosis than those without CAD in our study. In addition, arterial hypertension was an independent predictor for in-hospital events and diabetes mellitus was an independent predictor for out-of-hospital events. Another cardiovascular risk factor linked to coronary sclerosis in our study was chronic kidney disease. Chronic kidney disease can result from other cardiovascular risk factors, including diabetes mellitus and arterial hypertension, making patients with chronic kidney disease more susceptible to developing CAD [13, 15, 16]. Additionally, chronic kidney disease contributes not only to the development of CAD but also to its progression [15].

Furthermore, in our study, patients with coronary sclerosis also exhibited a significantly higher prevalence of chronic obstructive pulmonary disease, primarily caused by long-term cigarette smoking. Smoking itself is a major risk factor for the development of CAD, making an association with coronary sclerosis in our study highly plausible [13, 17].

Moreover, age is considered a nonmodifiable risk factor for atherosclerosis [18]. Advancing age is associated with physiological changes such as arterial stiffening, endothelial dysfunction, and the gradual accumulation of atherosclerotic plaque within the coronary arteries [13]. Additionally, older age often coincides with the presence of other cardiovascular risk factors, such as hypertension, diabetes mellitus, and dyslipidemia, which further contribute to the susceptibility to CAD [18]. The higher rate of events in the coronary sclerosis group may therefore be attributed to the cumulative effect of these cardiovascular risk factors, combined with age-related changes in the coronary arteries.

A meta-analysis comprising 54 studies with a total of 35,039 patients experiencing angina without obstructive CAD assessed the composite primary outcome of all-cause death and nonfatal myocardial infarction [19]. After a median follow-up of 5 years, the pooled incidence of the primary outcome was 0.98/100 person-years, with significant heterogeneity among studies [19]. The primary outcome was associated with prevalent dyslipidemia, diabetes, and hypertension [19]. Notably, studies enrolling patients with less-than-obstructive CAD exhibited a higher incidence of the primary outcome than those including only patients with “entirely normal” coronary arteries [19]. The presence of coronary atherosclerosis has therefore been identified as a main determinant of major adverse events [19]. Additionally, patients in this category experienced a high incidence of recurrent hospitalization, angina recurrence, and repeated coronary angiography [19].

Besides the higher prevalence of cardiovascular risk factors in patients with MINOCA with coronary sclerosis relative to patients with MINOCA without CAD in our study, those with coronary sclerosis were also significantly more likely to have cardiac comorbidities such as atrial fibrillation and valvular disease. Atrial fibrillation and CAD often coexist in individuals, with each condition potentially influencing the development and progression of the other [20,21,22,23]. In addition, shared risk factors contribute to the strong association between atrial fibrillation and CAD [22]. Conditions such as hypertension, diabetes mellitus, and aging, all of which were associated with coronary sclerosis in our study, increase the likelihood of developing both disorders [22].

The association in our study between valvular regurgitation and coronary artery sclerosis further emphasizes the higher frequency of more complex cardiac diseases in this patient cohort [24].

The results of this study suggest that troponin-positive patients with non-obstructive coronary arteries but with coronary sclerosis present with significantly more cardiovascular risk factors and cardiac comorbidities than those without CAD. Considering the risk factors for the development and progression of coronary sclerosis or CAD, these are almost identical to the findings of our study and thus not surprising. However, studies which differentiate between patients with MINOCA with and without coronary sclerosis and analyze the clinical baseline characteristics of these patients are very limited, and hence the present study was nevertheless able to provide novel findings.

The baseline characteristics of the cohort already indicated that patients with coronary sclerosis had a higher prevalence of comorbidities, particularly cardiovascular conditions, than those without. The findings from the medication analysis further supported this observation. Notably, patients with coronary sclerosis exhibited a greater number of pre-existing cardiovascular disorders, influencing their medication intake at both admission and discharge. In contrast, individuals without CAD received additional medications for the secondary prevention of CAD, contributing to more comparable prescription rates overall at discharge.

According to the current guidelines of the European Society of Cardiology (ESC), the diagnosis of the underlying cause of the working diagnosis of MINOCA enables the initiation of appropriate treatment based on the final diagnosis. Secondary prevention therapies should be considered for those who have been diagnosed with atherosclerotic coronary artery disease and to control risk factors [1].

Previous studies have demonstrated that patients with MINOCA received secondary prophylactic medication less frequently than patients with myocardial infarction and obstructive CAD. However, data on patients with MINOCA with coronary sclerosis compared to patients with MINOCA without CAD are lacking. An observational study included 9466 consecutive patients with MINOCA from the SWEDEHEART registry [25]. After matching treated and untreated groups using a propensity score analysis, the study found that treatment with statins and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers was associated with a lower risk of major adverse cardiac events, while beta-blocker treatment showed a trend toward a positive effect [25]. However, dual antiplatelet therapy exhibited a neutral effect [25]. The results suggest long-term benefits of certain secondary prophylactic medications in patients with MINOCA [25]. However, the study did not differentiate between patients with and without coronary sclerosis. Dal Fabbro et al. conducted a retrospective study with 244 patients with MINOCA focusing on the impact of coronary sclerosis [25]. Significant differences in secondary prevention therapy were observed, with coronary sclerosis patients being more frequently prescribed acetylsalicylic acid, statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers than patients without CAD [26]. Similarly, our results revealed that there was a difference at discharge in the prescription of antiplatelet agents and angiotensin receptor blockers, but prescription rates of angiotensin-converting enzyme inhibitors converged from admission to discharge, with no significant difference between the two groups.

The extent to which the differences in secondary prophylactic medication affected the rate of events during follow-up cannot be assessed in this study. Patients with coronary sclerosis received secondary prophylactic medication more frequently and still suffered events more often, but they also had a significantly higher cardiovascular risk profile, which may have been the decisive factor. This observation would be supported by the predictor analysis, as cardiovascular risk factors and comorbidities were identified as independent predictors of a worse outcome, both in-hospital and out-of-hospital.

The retrospective design of the current study represents a major limitation. Moreover, the study cohort exhibits heterogeneity. The inclusion of patients with a working diagnosis of MINOCA is a potential confounding factor, given that variations in final diagnoses and treatments within this subgroup could impact the observed outcomes. It is plausible that some patients may have received a definitive diagnosis during or after hospitalization, such as myocarditis or Takotsubo syndrome, factors not considered in this analysis. Both the inclusion of Takotsubo cardiomyopathy patients and the partial lack of echocardiographic parameters due to the retrospective study design could explain why the mean ejection fraction of the study cohort was relatively low.

This study was conducted in a single center, which may have implications for the medications prescribed at discharge. The focus on a single center raises questions about the generalizability of our results to larger populations with MINOCA. In addition, the cohort is relatively small, complicating the detection of statistically significant differences and potentially limiting the power of some comparisons. Another notable limitation is the absence of a control group with obstructive CAD. The diagnosis of “coronary sclerosis” was made by experienced interventional cardiologists, but only visually, i.e., no quantitative coronary angiography, intravascular ultrasound, or optical coherence tomography was used as standard in each patient. Furthermore, exercise stress testing was not performed as standard in all patients, which could have provided a possible additional indication of coronary microvascular dysfunction as the cause of myocardial ischemia [27, 28].