*Article* **Importance of Increased Arterial Resistance in Risk Prediction in Patients with Cardiovascular Risk Factors and Degenerative Aortic Stenosis**

**Jakub Baran 1, Paweł Kleczy ´nski 1, Łukasz Niewiara 1,2, Jakub Podolec 1, Rafał Badacz 1, Andrzej Gackowski 3,4, Piotr Pieni ˛azek ˙ 1,5, Jacek Legutko 1, Krzysztof Zmudka ˙ 1, Tadeusz Przewłocki 1,5 and Anna Kabłak-Ziembicka 1,4,\***


**Abstract:** Background: Cardiovascular disease is a leading cause of heart failure (HF) and major adverse cardiac and cerebral events (MACCE). Objective: To evaluate impact of vascular resistance on HF and MACCE incidence in subjects with cardiovascular risk factors (CRF) and degenerative aortic valve stenosis (DAS). Methods: From January 2016 to December 2018, in 404 patients with cardiovascular disease, including 267 patients with moderate-to-severe DAS and 137 patients with CRF, mean values of resistive index (RI) and pulsatile index (PI) were obtained from carotid and vertebral arteries. Patients were followed-up for 2.5 years, for primary outcome of HF and MACCE episodes. Results: RI and PI values in patients with DAS compared to CRF were significantly higher, with optimal cut-offs discriminating arterial resistance of ≥0.7 for RI (sensitivity: 80.5%, specificity: 78.8%) and ≥1.3 for PI (sensitivity: 81.3%, specificity: 79.6%). Age, female gender, diabetes, and DAS were all independently associated with increased resistance. During the follow-up period, 68 (16.8%) episodes of HF-MACCE occurred. High RI (odds ratio 1.25, 95% CI 1.13–1.37) and PI (odds ratio 1.21, 95% CI 1.10–1.34) were associated with risk of HF-MACCE. Conclusions: An accurate assessment of vascular resistance may be used for HF-MACCE risk stratification in patients with DAS.

**Keywords:** cardiovascular risk factors; heart failure; major cardiac and cerebral ischemic events; degenerative aortic stenosis; risk stratification; vascular resistance

#### **1. Introduction**

With ageing, a reduction in the elastin content and an increase in the collagen content lead to increased arterial stiffness and elevated central as well as peripheral arterial blood pressure [1]. Similarly, chronic low-grade inflammation or metabolic disorders, e.g., glycation of vessel wall proteins, contribute to the stiffening process of large arteries [2–4]. Arterial stiffness is a well-known predictor of all-cause mortality, including cardiovascular mortality [5].

Degenerative aortic valve stenosis (DAS) is another condition in which prevalence increases with age [6]. DAS progression, similar to arterial stiffening, is accelerated by common cardiovascular risk factors (CRF) and ageing [6–8].

**Citation:** Baran, J.; Kleczy ´nski, P.; Niewiara, Ł.; Podolec, J.; Badacz, R.; Gackowski, A.; Pieni ˛azek, P.; Legutko, ˙ J.; Zmudka, K.; Przewłocki, T.; et al. ˙ Importance of Increased Arterial Resistance in Risk Prediction in Patients with Cardiovascular Risk Factors and Degenerative Aortic Stenosis. *J. Clin. Med.* **2021**, *10*, 2109. https://doi.org/10.3390/jcm10102109

Academic Editor: Vanessa Bianconi

Received: 20 April 2021 Accepted: 11 May 2021 Published: 13 May 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Ultrasonography can easily and non-invasively provide information on vascular resistance indices (resistive index; RI and pulsatile index; PI), that are surrogate markers of arterial stiffness. Peripheral flow parameters can be particularly important in patients with DAS, in whom severely reduced left-ventricle outflow has an impact on the altered vascular system flow pattern [9].

Although both chronological and vascular ageing processes progress in time, they are often not parallel [10]. In patients with CRF, cardiac, and/or arterial disease, vascular ageing outruns the normal ageing process [1,10].

Patients with increased arterial stiffness tend to develop cardiovascular events at a younger age and with a higher mortality rate [1]. However, there are scarce data available as to whether DAS relates to vascular resistance at a higher extent as compared to the ageing process and CRF, and more importantly, whether vascular resistance can contribute to heart failure (HF) episodes and major adverse cardiac and cerebral events (MACCE) in patients with DAS.

We aimed to evaluate impact of vascular resistance on HF and MACCE events in subjects with cardiovascular risk factors and degenerative aortic valve stenosis.

#### **2. Materials and Methods**

#### *2.1. Study Population and Cardiovascular Risk Factors*

In this single-center prospective study, from January 2016 to December 2018, 517 consecutive patients with either CRF or DAS were assessed. A flowchart of this study is presented in Figure 1.

**Figure 1.** Study flowchart. CRF, cardiovascular risk factors; DAS, degenerative aortic valve stenosis; HF, heart failure; MACCE, major adverse cardiac and cerebral events; PI, pulsatile index; RI, resistive index.

CRF group was enrolled from patients with suspected or known stable coronary artery disease, with preserved LVEF ≥ 50% admitted to our department for coronary angiography.

Subjects with DAS were eligible if (1) aortic valve area was less than 1.5 cm2; they (2) had left ventricular ejection fraction (LVEF) ≥ 50%; and (3) underwent coronary angiography.

The exclusion criteria for both study and control groups included: significant stenosis of any carotid or vertebral artery (exceeding 50% lumen reduction), persistent atrial fibrillation or other severe arrhythmia, significant concomitant valve diseases, ongoing or recent myocardial infarction (<3 months), ischemic stroke or TIA, hemodynamic instability: NYHA class IV or acute heart failure, LVEF < 50%, aortic dissection, and lack of informed consent.

Finally, in 404 study patients, including 267 patients with moderate-to-severe DAS and 137 patients with CRF, distribution of RI and PI registered at carotid and vertebral arteries was evaluated. Patients were followed-up for mean 2.5 years, with primary outcome of HF and MACCE episodes.

The prevalence of CRF, including age, gender, hypertension, diabetes and dyslipidemia, and coronary artery disease was evaluated in both groups. Cardiovascular risk factors were defined as: hypertension (treated, or newly recognized, based on average on three measurements; SBP ≥ 140 mm Hg and/or DBP ≥ 90 mm Hg), diabetes mellitus (treated or newly recognized > 11 mmol/l (200 mg/d) in oral glucose tolerance test, hyperlipidemia (treated or newly recognized—total cholesterol > 4.9 mmol/L (190 mg/dL) and/or LDL > 3.0 mmol/L (115 mg/dL) and/or HDL men < 1.0 mmol/L (40 mg/dL), HDL women < 1.2 mmol/L (46 mg/dL) and/or triglycerides > 1.7 mmol/L (150 mg/dL) [11]. Coronary artery disease was defined as presence on coronary angiography of at least one main coronary artery lumen reduction exceeding 50%.

The study protocol was consistent with the requirements of the Helsinki Declaration, and approved by the local Institutional Ethics Committee. All subjects gave informed consent for participation in the study.

#### *2.2. Echocardiography, Carotid and Vertebral Artery Ultrasonography*

All patients underwent a complete echocardiographic study in compliance with the guidelines of the European Association of Cardiovascular Imaging [12]. Peak and the mean gradient across aortic valve, aortic valve area (AVA), LVEF were assessed in all subjects.

High-resolution B-Mode, color Doppler, and pulse Doppler ultrasonography of both carotid and vertebral arteries were performed with an ultrasound machine (TOSHIBA APLIO 450) equipped with a linear-array 5–10 MHz transducer in a patient lying in supine position with head tilted slightly backward. Exam was performed by two experienced sonographers who were blinded to subjects' clinical, echocardiographic, and angiographic characteristics.

Vascular resistance parameters were expressed as averaged RI and PI values calculated bilaterally from internal carotid and vertebral arteries. For this purpose, the peak-systolic (PSV) and the end-diastolic velocities (EDV), as well as vessel diameters were measured within 1.0 to 1.5 cm proximal segment of the internal carotid artery (ICA), and proximal V2 segment of vertebral artery, with a calculation of the pulsatile (PI) and resistive (RI) indexes in each evaluated segment, according to the following equations:

Resistive Index (RI) = PSV – EDV/PSV

Pulsatile Index (PI) = PSV – EDV/[(PSV + 2 × EDV)/3]

The averaged value of RI and PI from four arterial segments was taken into further statistical analysis.

#### *2.3. Outcome Data, Follow-Up, and Adverse Cardiovascular Events*

During mean observation period of 2.5 years, the incidences of HF episodes and MACCE were recorded.

MACCE was defined as fatal or non-fatal ischemic stroke, myocardial infarction, acute heart failure episode, or cardiovascular death (i.e., any sudden or unexpected death unless proven as non-cardiovascular on autopsy). HF episode was defined as new-onset acute HF incidence or any exacerbation of chronic heart failure requiring in-hospital stay and administration of intravenous medications such as diuretics, dopamine, adrenaline, or dobutamine.

Final visit was conducted through the telephone contact with a patient or pointed family member. For patients lost to follow-up (*n* = 4), the data on patient vital status were obtained from the national health registry.

#### *2.4. Statistical Analysis*

Data are presented as mean ± standard deviation for continuous variables and as proportions for categorical variables. Differences between mean values were verified using the T-Student, analysis of variance (ANOVA) test, and frequencies were compared by the chi-2 test for independence, as appropriate. The normal distribution of studied variables was determined by the Shapiro–Wilk test. The Spearman's rank-order correlation was performed for correlation between RI and PI. A receiver-operating characteristic (ROC) analysis was performed to determine the optimal cut-off values (common point of the most distant y = x line with ROC curve) for vascular resistance as potentially associated with DAS. The area under the curve (AUC), cut-offs sensitivity and specificity were calculated. The C statistic with comparison of AUCs was performed for evaluation of models with and without DAS to assess the probability of obtaining arterial stiffness parameters above thresholds. The analysis of risk factors associated with increased PI and RI values was performed with univariate regression analysis. We included age, gender, diabetes mellitus, hypertension, hyperlipidemia, coronary artery disease, LVEF, and DAS as factors potentially associated with vascular resistance. After identification of parameters potentially associated with increased vascular resistance, the multivariable logistic backward regression analysis was used to calculate odds ratio (OR) and 95% confidence interval (95% CI). We used Z-scores to standardize the raw values of age to a normal distribution. We also assessed incidence of HF-MACCE events in groups classified by high versus low PI and RI using univariate logistic regression analysis, followed by the multivariable regression models, with the PI ≥ 1.3 and the RI ≥ 0.7 as referent in all study participants. A 2-sided value of *p* < 0.05 was considered statistically significant. Statistical analyses were performed with Statistica version 13.3 software (TIBCO Software, Palo Alto, CA, USA) and with R Studio 3.6.3 [13].

#### **3. Results**

#### *3.1. Patient Characteristics*

The baseline characteristics of the patients are summarized in Table 1. Patients with DAS in comparison to patients with CRFs were significantly older (74.5 vs. 70.0 years, *p* = 0.001) and more often had hyperlipidemia (95.9 vs. 79.6%, *p* < 0.001), while history of myocardial infarction was more frequent in CRF group (31.4 vs. 20.2%, *p* = 0.002). Gender distribution, prevalence of hypertension, diabetes mellitus, and significant coronary artery disease did not differ between the CRF and DAS groups. On echocardiography, baseline LVEF was similar in both study groups, while peak and systolic aortic gradients were significantly higher in DAS vs. CRF groups.


**Table 1.** Baseline groups characteristics.

CRF, cardiovascular risk factors; DAS, degenerative aortic stenosis.

#### *3.2. Study Groups and Arterial Stiffness Findings*

The RI values were significantly positively correlated with the PI values (r = 0.99, *p* < 0.001).

The RI and PI values in both carotid and vertebral arteries differed significantly between patients with DAS vs. CRF (Table 1). Moreover, mean values of the RI (0.73 ± 0.06 vs. 0.64 ± 0.05, *p* < 0.001) and the PI (1.45 ± 0.23 vs. 1.14 ± 0.16, *p* < 0.001) were significantly higher in patients with DAS, compared to CRF (Table 1).

In line, in patients with moderate (*n* = 32) vs. severe (*n* = 235) DAS, mean values of RI (0.70 ± 0.06 vs. 0.74 ± 0.06; *p* = 0.001) and PI (1.34 ± 0.21 vs. 1.47 ± 0.23; *p* = 0.002) differed significantly.

The optimal cut-off values obtained from ROC analysis best discriminating vascular resistance in CRF vs. DAS patients were RI of 0.7 or higher (sensitivity of 80.5%, specificity of 78.8%) and PI value of 1.3 or higher (sensitivity of 81.3%, specificity of 79.6%).

Univariate regression backward analysis, followed by the multivariate regression analysis, showed associations with the RI ≥ 0.7 and the PI ≥ 1.3 for age, female gender, diabetes, and DAS (Table 2). There was also association between increased arterial stiffness and hyperlipidemia and hypertension in univariate analysis (Table 2).

In multivariable logistic regression backward analysis, DAS confirmed its independent association with high RI and high PI in the multivariate analysis, both in unadjusted and Z-score age-adjusted analysis (Table 2).


**Table 2.** Factors associated with increased arterial resistance.

Adding DAS to the model with CRF resulted in a higher predicted probability of the RI ≥ 0.7 (AUC: 0.843 vs. 0.754, *p* = 0.014) and the PI ≥ 1.3 (AUC: 0.891 vs. 0.789; *p* = 0.002) (Figure 2A,B).

**Figure 2.** Comparison of area under the curve (AUC) for multivariate models to detect increased Resistive Index (panel (**A**)) and Pulsatile Index (panel (**B**)). Baseline models AUCs for CRF are presented as dashed lines, AUCs for degenerative aortic stenosis are presented as solid lines. Abbreviations: AUC—area under the curve; PI—Pulsatile Index; RI—Resistive Index.

#### *3.3. Vascular Resistance Properties and the Outcomes*

During follow-up period, 68 (16.8%) episodes of HF-MACCE occurred, including 16 (11.7%) in CRF group and 52 (19.5%) in DAS group, *p* = 0.047.

HF-MACCEs were observed in 9 out of 172 patients with RI values below 0.7, as compared to 59 of 232 with RI ≥ 0.7 (5.2% vs. 25.4%, *p* < 0.001), whereas in 9 of 161 patients with PI < 1.3 vs. 59 of 245 patients with PI ≥ 1.3 (5.6% vs. 24.1%, *p* < 0.001).

In both study groups, patients who had HF-MACCE were older, and had higher prevalence of high RI and PI values.

Age, female gender, diabetes, hypertension, DAS, RI ≥ 0.7, and PI ≥ 1.3 showed association with HF-MACCE in univariable analysis (Table 3). In multivariable analysis, high RI (OR, 1.25; 95% CI 1.13–1.37) and PI (OR, 1.21; 95% CI 1.10–1.34), similar to age were independently associated with risk of HF-MACCE.

**Table 3.** Univariate and multivariate logistic regression analysis of factors associated with heart failure episodes (HF) and major adverse cardiac and cerebral events (MACCE).


#### **4. Discussion**

In the present study, in a subset of patients with moderate-to-severe DAS, similar to patients with CRF, we showed associations between increased carotid arterial resistance, defined as the PI ≥ 1.3 and the RI ≥ 0.7 with heart failure exacerbation episodes and adverse cardiovascular events in mid-term observational period. Therefore, high carotid PI and RI values could be used as surrogate markers of poor cardiovascular prognosis in patients with advanced DAS. The advantage of our concept is that carotid stiffness parameters are easily obtainable non-invasively and are reproducible [14].

Furthermore, ultrasonographic assessment of vascular resistance was also used in former studies, in the setting of large arteries disease or renovascular disease, as the prognostic marker of the outcome [15,16]. Lately, arterial stiffness was also used for risk assessment in patients with COVID infection [17].

Our study demonstrated that about three quarters of patients with DAS and cardiovascular risk factors had high RI and PI values, compared to ~ 20% of patients with CRF only. This high distribution of increased arterial stiffness parameters in DAS, as compared to CRF patients, corresponds to ~21–25% relative risk increase of HF-MACCE in mean 2.5-years follow-up period, compared to patients with lower PI and RI values.

We found that moderate-to-severe DAS independently relates to higher vascular resistance, likewise age, female gender, and diabetes. In a study by Yan et al., hypertension (HR 1.71; 95% CI: 1.66–1.76), diabetes (HR: 1.49; 95% CI: 1.44–1.54), and dyslipidemia (HR: 1.17; 95% CI: 1.14–1.21) were all significantly associated with increased risk of developing severe DAS [6]. There was a positive relationship between the severity, number and duration of cardiac risk factors, and risk of DAS [6]. Moreover, gender plays an important role in DAS pathogenesis, development and progression of valvular calcification processes, fibrosis, and hemodynamic severity, left ventricle hypertrophy, and cardiovascular outcomes in men and women [18,19]. Patients with DAS are often older and have more cardiovascular risk factors, systemic hypertension and atherosclerosis, which all show association with increased aortic stiffness and cognitive decline [20–23].

In contrast to overwhelming studies in favor of an independent role for arterial stiffness in predicting cardiovascular events in healthy elderly and diseased hypertensive, diabetic, or end stage renal disease subjects [24,25], studies concerning potential application of vascular resistance parameters in patients with advanced DAS are innumerous [26,27].

In one research study enrolling 103 asymptomatic patients with moderate-to-severe DAS, arterial stiffness assessed with femoral-carotid pulse wave velocity (PWV) method, showed significantly lower event-free survival in patients with PWV ≥10 m/s compared to those with lower PWV [26]. In line, the Simvastatin and Ezetimibe in Aortic Stenosis study during median 4.3 years observation period demonstrated a higher cardiovascular morbidity rate (hazard ratio 2.13; 95% CI 1.34–3.40) in patients with initially mild-to-moderate DAS and echocardiographically established low systemic arterial compliance [27].

There is some uncertainty about sequence of developing aortic valve calcifications, exposure to atherosclerosis risk factors, and arterial stiffening [1,28]. More recent data demonstrated that increasing arterial stiffness initiates systemic hypertension; thus, it is a cause, not an effect. However, once induced, hypertension leads to further arterial stiffening [28]. In addition, arterial stiffening reflects the vascular ageing process, and the latter one is at least as important as chronological age in cardiovascular events and mortality prediction [29,30].

In fact, the results of our study demonstrate that both chronological and vascular age were the only independent risk predictors of HF-MACCE in multivariate analysis.

It is important to realize that DAS is not only a disease of the valve (or heart), but this is a disease of the whole vascular system, and the latter contributes to adverse events. A decrease in elasticity is associated with a multitude of complications, including increased stress on the left ventricle, a gradual increase in blood pressure and, eventually, even end-organ damage through the transmission of harmful pulsation into the microcirculation. Thus, the increase in pulsatility associated with loss of elastic recoil in large blood vessels has detrimental effects on global cardiovascular health [9].

Biological vascular age should be used to select individuals for early prevention of cardiovascular complications with intensification of pharmacotherapy and earlier intervention on the valve [30–32].

Hypothetically, the risk prediction models may help clinicians develop personalized treatments, i.e., in patients with PI ≥ 1.3 or RI ≥ 0.7, early intervention on DAS could be considered. The treatment of choice could perhaps be transcatheter aortic valve implantation in such a subset of patients, as surgical aortic valve replacement may lead to further significant increase in PWV [31,32].

#### **5. Conclusions**

Patients with DAS have greater vascular resistance compared to controls with cardiovascular risk factors. Moreover, RI ≥ 0.7 and PI ≥ 1.3 may be used for cardiovascular risk stratification.

#### **6. Study Limitations**

Our study has obvious limitations, as it consisted of a single-center observational design. Secondly, in general, DAS patients are elderly, which caused difficulties when matching with a control group. For this reason, age-adjustment in multivariate analyses was performed.

**Author Contributions:** Conceptualization, J.B., A.G., T.P. and A.K.-Z.; data curation, Ł.N., R.B., A.G., P.P., J.L., K.Z. and A.K.-Z.; formal analysis, J.P., A.G. and P.P.; funding acquisition, J.P. and ˙ A.K.-Z.; investigation, P.K., Ł.N., R.B., P.P. and A.K.-Z.; methodology, J.B., Ł.N., R.B., T.P. and A.K.-Z.; project administration, K.Z.; resources, J.B. and T.P.; software, J.B. and Ł.N.; supervision, A.K.-Z.; ˙ validation, A.G., J.L. and K.Z.; visualization, J.B., Ł.N. and R.B.; writing—original draft, J.B., P.K. and ˙ J.P.; writing—review and editing, J.L., K.Z., T.P. and A.K.-Z. All authors have read and agreed to the ˙ published version of the manuscript.

**Funding:** This research was funded by grants from the Jagiellonian University (grant numbers: N41/DBS/000038 and N41/DBS/000437).

**Institutional Review Board Statement:** The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Ethics Committee of the Jagiellonian University (KBET/118/B/2014 and KBET/1072.6120.148.2018).

**Informed Consent Statement:** Informed consent was obtained from all subjects involved in the study.

**Data Availability Statement:** The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


### *Review* **OCT Findings in MINOCA**

#### **Krzysztof Bryniarski 1, Pawel Gasior 2, Jacek Legutko 1, Dawid Makowicz 3, Anna Kedziora 4, Piotr Szolc 1, Leszek Bryniarski 5, Pawel Kleczynski <sup>1</sup> and Ik-Kyung Jang 6,7,\***


**Abstract:** Myocardial infarction with non-obstructive coronary artery disease (MINOCA) is a working diagnosis for patients presenting with acute myocardial infarction without obstructive coronary artery disease on coronary angiography. It is a heterogenous entity with a number of possible etiologies that can be determined through the use of appropriate diagnostic algorithms. Common causes of a MINOCA may include plaque disruption, spontaneous coronary artery dissection, coronary artery spasm, and coronary thromboembolism. Optical coherence tomography (OCT) is an intravascular imaging modality which allows the differentiation of coronary tissue morphological characteristics including the identification of thin cap fibroatheroma and the differentiation between plaque rupture or erosion, due to its high resolution. In this narrative review we will discuss the role of OCT in patients presenting with MINOCA. In this group of patients OCT has been shown to reveal abnormal findings in almost half of the cases. Moreover, combining OCT with cardiac magnetic resonance (CMR) was shown to allow the identification of most of the underlying mechanisms of MINOCA. Hence, it is recommended that both OCT and CMR can be used in patients with a working diagnosis of MINOCA. Well-designed prospective studies are needed in order to gain a better understanding of this condition and to provide optimal management while reducing morbidity and mortality in that subset patients.

**Keywords:** cardiovascular disease; acute myocardial infarction; intravascular imaging

#### **1. Introduction**

Atherosclerotic cardiovascular disease is one of the leading causes of death around the world [1,2]. Advances in the understanding of the underlying pathobiology, diagnosis, and treatment of atherosclerosis have been made during the past century. This progress has significantly lowered the mortality rate in patients presenting with acute myocardial infarction (AMI) with obstructive coronary artery disease (CAD). However, in recent years challenges in the diagnosis and treatment of patients who presented with symptoms of AMI but did not have obstructive CAD have been recognized.

First reports of AMI without obstructive CAD go back 80 years [3,4]. This phenomenon was observed in the late 1970s by one of the pioneers in the field of interventional

**Citation:** Bryniarski, K.; Gasior, P.; Legutko, J.; Makowicz, D.; Kedziora, A.; Szolc, P.; Bryniarski, L.; Kleczynski, P.; Jang, I.-K. OCT Findings in MINOCA. *J. Clin. Med.* **2021**, *10*, 2759. https://doi.org/ 10.3390/jcm10132759

Academic Editor: Anna Kabłak-Ziembicka

Received: 9 April 2021 Accepted: 17 June 2021 Published: 23 June 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

cardiology—DeWood. In his studies, he performed coronary angiography in patients presenting with ST elevation myocardial infarction (STEMI) and non-ST elevation myocardial infarction (NSTEMI) [5,6]. Surprisingly, about 10% of patients presenting with AMI had no significant CAD on coronary angiography. His initial observations were later confirmed in several large AMI registries in which 13% of patients presenting with AMI did not have obstructive CAD [7,8].

Important questions were raised regarding the underlying pathophysiological mechanism and treatment of this presentation. This led to the creation of new terminology for this phenomenon, myocardial infarction with non-obstructive coronary artery disease (MINOCA). The first position papers regarding MINOCA were published by the European Society of Cardiology (ESC) in 2018, followed by the American Heart Association in 2019 [9,10]. According to both position papers, the diagnosis of MINOCA should be made immediately upon coronary angiography in a patient presenting with features consistent with AMI [11]. Although chest pain and elevated troponin levels are not specific for AMI, MINOCA is an umbrella term for several different conditions, thus should only be a working diagnosis requiring further evaluation. MINOCA can be confirmed only after the investigation of other underlying causes of elevated troponin levels. Ascertaining the pathophysiological mechanism and prognostic markers in order to provide proper management strategies is vital in patients with a diagnosis of MINOCA. In this narrative review we will discuss the role of optical coherence tomography (OCT) in patients presenting with MINOCA.

#### **2. Discussion**

#### *2.1. MINOCA: Is It a Serious Condition?*

Significantly, patients presenting with MINOCA have comparable, or only a slightly lower, incidence of major adverse cardiac events (MACE) during follow-up as compared to those presenting with AMI, despite their younger age and less comorbidities [12,13].

Kang et al. showed that the 12-month MACE rate in patients with MINOCA was comparable to patients with AMI with single or double vessel CAD (7.8% vs. 12.2%; *p* = 0.359) (Table 1) [14]. Ishi et al. observed that MINOCA was associated with a high risk of in-hospital mortality compared with MI with obstructive CAD [15]. In a study which included 4793 consecutive patients presenting with STEMI, patients without obstructive CAD had a long-term risk of death similar to, or higher than, patients with obstructive CAD, although their causes of death were less often cardiovascular [16]. Lindahl et al., in a retrospective study involving almost 10,000 patients, observed a 13% mortality rate for MINOCA patients during four-year follow-up [17]. Gasior et al., in a retrospective study of over 6000 patients, demonstrated higher mortality at 12-month follow-up in the MINOCA group when compared to the MI-CAD group (10.94% vs. 9.54%, *p* < 0.001), with no statistical difference in mortality at three-year follow up [18].

Contrary to those findings, Pasupathy et al. in a metaanalysis including 28 publications, demonstrated that patients with MINOCA had lower one-year all-cause mortality [12]. However, it should be emphasized that even though patients with AMI had a higher one-year mortality rate at 6.7%, the mortality of patients with MINOCA was still high (4.7%). Considering that patients with stable chest pain (without previous AMI) and non-obstructed coronary arteries had 0.2% one-year mortality, the mortality in MINOCA patients was markedly elevated [22].

It is of the utmost importance to optimize the management of patients with MINOCA based on the underlying mechanism. Montone et al. observed that patients with vasospastic angina who had a reduction in their dosing of calcium channel blockers (CCB) had increased mortality during follow-up compared to those who continued to take high doses of CCB [23,24]. Of note, more than one third of patients with MINOCA did not receive an optimal cardioprotective pharmacotherapy [25,26].


**Table 1.** Selected studies with outcomes of patients with myocardial infarction with non-obstructive coronary artery disease.

CA indicates coronary artery; CAS, coronary artery stenosis; CVD, cardiovascular disease; LM, left main; MACE, major adverse cardiovascular events; NA, not available; PCI, percutaneous coronary intervention; SAQ, Seattle Angina Questionnaire; STEMI, ST-elevation myocardial infarction; and QOL, quality of life. A, <sup>B</sup> and <sup>C</sup> stand for different groups. When not indicated, results of patients with myocardial infarction with non-obstructive coronary artery disease are given first.

#### *2.2. Etiology of MINOCA*

Myocardial infarction with non-obstructive coronary artery disease is a heterogenous entity with many possible etiologies that need to be clarified by proper diagnostics algorithm. Over the past several years, a few algorithms were developed in order to optimize the care of MINOCA patients [9,11,27]. Rigorous algorithms are crucial for effective treatment for certain conditions (for example, vasospasm) but may not be effective for another group of patients with MINOCA caused by a different mechanism (for example, plaque rupture) [11]. Common causes of a MINOCA working diagnosis may include plaque disruption, spontaneous coronary artery dissection (SCAD), coronary artery spasm, coronary thromboembolism, Takotsubo cardiomyopathy, and myocarditis. Importantly, due to the low resolution of coronary angiography, plaque disruption may occur in areas of coronary arteries which appear normal on the angiogram [28]. A large thrombus may result in severe narrowing or occlusion of the artery visible on angiogram, whereas smaller thrombi may either result in insignificant stenosis not visible on the angiogram or embolization to distal segments. Information regarding the exact pathogenic mechanism responsible for MINOCA, plaque vulnerability, or plaque burden cannot be obtained from angiography alone [29,30]. Spontaneous coronary artery dissection is another diagnosis which cannot be completely ruled out with angiography alone [31]. Two intravascular imaging modalities have been proposed to surpass the limitations of angiography: intravascular ultrasound (IVUS) and optical coherence tomography (OCT). IVUS studies showed that plaque rupture or ulceration may be identified in about 40% patients presenting with MINOCA [32,33]. Optical coherence tomography with a resolution of 10–20μm allows the visualization of intraluminal and superficial coronary artery structures in detail [34]. It has the ability to differentiate tissue morphological characteristics including the detection of lipid-rich, calcified, and fibrous plaques, thin cap fibroatheroma, and the differentiation between plaque rupture and erosion, red and white thrombi, as well as the identification of even small spontaneous dissections (Figure 1) [35,36]. It can function as a type of optical biopsy and is a powerful imaging technology for medical diagnostics. Unlike conventional histopathology, which requires removal of a tissue specimen and processing for microscopic examination, OCT can provide images of the vascular wall in situ and in real time. Its higher resolution undoubtedly can confirm findings such as plaque erosion or calcified nodule which may cause AMI and usually are not visible on both conventional angiography and IVUS.

**Figure 1.** Optical coherence tomography images from patients with MINOCA. Spontaneous dissection (**a**,**b**), plaque erosion (**c**), plaque rupture (**d**), thin-cap fibroatheroma (**e**), small white thrombi (**f**), and calcified nodule erosion (**g**,**h**). Figures from authors' library.

Howbeit, it should be emphasized that OCT also has several drawbacks [37]. First, its greater resolution as compared to IVUS comes with a lower penetration depth. In the case of large arteries such as the left main, visualization of the whole coronary artery may not be possible. Moreover, when performing pullback in ostial lesions incomplete blood clearance may lead to suboptimal image quality. Second, the need for contrast agents to clear blood may increase risk of contrast-induced nephropathy. Third, OCT images cannot penetrate lipid plaque and red thrombi.

According to a recent metaanalysis, up to 33% of patients with the diagnosis of MINOCA may have myocarditis [38]. In a recent prospective study, cardiac magnetic resonance (CMR) showed evidence of myocarditis in 25% of patients presenting with MINOCA, an MI in 25%, and cardiomyopathy in 25% [39]. Recent studies demonstrated the value of combined CMR and OCT imaging in MINOCA patients. Moreover, it should be stressed that finding one cause of MINOCA does not necessarily mean that others have been excluded. Several studies have emphasized the importance of coronary artery vasospasm in Takotsubo cardiomyopathy and myocarditis [40,41]. An OCT study including 23 patients found that those with Takotsubo cardiomyopathy have high plaque vulnerability [42].

#### *2.3. OCT in MINOCA*

Coronary thrombosis is the most frequent final event leading to an acute coronary syndrome in patients with AMI with obstructive coronary disease. Plaque rupture, plaque erosion, and calcified plaque are believed to be the most common underlying mechanisms contributing to AMI with the former being the most frequent in both autopsy and in vivo studies [43,44].

While angiographic images of haziness or minor filling may suggest plaque disruption, it can be definitively diagnosed using intracoronary imaging, with OCT being the preferable modality due to its higher resolution. However, IVUS may be considered as an alternative to OCT to a lesser extent [45]. One of the first OCT studies in MINOCA patients showed

that plaque disruption or thrombi were visible in 39% of 38 patients included in the study [46] (Table 2). Notably, during hospitalization 82% patients underwent CMR. In a detailed assessment of infarct-related arteries (i.e., those where infarct-related artery was identified on the basis of the association between coronary artery distribution and myocardial segments with late gadolinium-enhancement of ischemic origin), the authors found that 40% had plaque rupture and 30% had plaque erosion. Importantly, 30% of lesions had plaque disruption without thrombus. The latter might have resulted, as stated by the authors, either by resolution of thrombi from the initial antithrombotic therapy or by distal embolization during advancement of the OCT catheter. It could have also been an incidental finding after silent plaque rupture which occurred in the near past [47]. Findings by Opolski et al. led to the modification of the initial treatment in six patients. One of the main limitations of this study was the relatively small number of patients recruited which could present bias. Moreover, only 21% of the patients had three-vessel OCT.

**Table 2.** Myocardial infarction with non-obstructive coronary artery disease selected studies with use of optical coherence tomography.


CMR indicates cardiac magnetic resonance; OCT, optical coherence tomography; SCAD, spontaneous coronary artery dissection; and TCFA, thin cap fibroatheroma. \* T1-weighted imaging.

> In a small study by Mas-Lladó et al. involving 27 patients with MINOCA who had mostly one-vessel OCT, an abnormal image was found in 78% of patients [48]. Patients predominantly had either plaque erosion (41%) or plaque rupture (30%).

> In a more recent study presented by Gerabaud et al. 40 patients with MINOCA underwent both OCT and CMR [50]. Optical coherence tomography provided a diagnosis of AMI in 80% of patients including 35% with plaque rupture, 30% with plaque erosion, 7.5% with lone thrombus, 5% with SCAD, and 2.5% with calcified nodule. Acute myocardial infarction was evident in CMR in 77.5% of patients. Over half the patients (57.5%) had a substrate and/or diagnosis supported by both modalities, 22.5% of patients had a mechanism specified only by OCT, and 20% of patients had a clear diagnosis only by CMR. One of the major findings of this study was that combination of both CMR and OCT provided a much higher yield in diagnosing MINOCA as compared to using only one of the mentioned modalities. The limitations of this study were similar to the study of Opolski et al.—the small number of patients and the low number of patients with three-vessel OCT (12.5%). Moreover, OCT was not always done at the index procedure, and an older CMR imaging protocol was used.

> Reynolds et al. presented the biggest study to date, involving 145 women with a diagnosis of MINOCA [49]. In this study CMR was interpretable in 116 patients. Over half of the patients had three-vessel OCT (59.3%) and a possible culprit lesion was identified in 46.2% of patients. Plaque rupture, intra-plaque cavity, or a layered plaque phenotype were evident in 39% of patients, whereas thrombus without plaque rupture was found in 3.5% of patients and one patient had SCAD. Moreover, 2.1% of patients had intimal

bumping suggestive of coronary artery spasm. Combining both OCT and CMR allowed the identification of the cause of MINOCA in 84.5% of patients. A lesion visible on OCT could be identified in 42% of patients with CMR-detected infarction and in 79% of patients with CMR-detected regional injury. Hypothetically, patients who had CMR evidence of infarction or regional injury without abnormalities identified by OCT could suffer from coronary spasm or thromboembolism as the mechanism of MI. Importantly, 40% of patients without abnormal CMR had an OCT identified culprit lesion—this finding underlines the importance of OCT in the diagnosis of MINOCA and strengthens the guidelines which suggest multimodality imaging in patients with MINOCA. Reynolds et al. confirmed previous findings that multi imaging modalities, including both OCT and CMR, should be used in patients with MINOCA—the identification of the etiology of MINOCA may have potential to guide optimal medical therapy; however, new studies are warranted. Limitations of this study were the lack of three-vessel OCT in all patients and the inclusion of layered plaque phenotype and intra-plaque cavity as causes of MINOCA. Layered plaque phenotype is a consequence and not an etiology of plaque destabilization. The process of lesion progression to a layered plaque phenotype may take from weeks to months. Moreover, a recent OCT study reported that a layered plaque phenotype may be found in more than 50% of patients with stable angina [51]. To our knowledge, there was only one case report for the OCT finding of intraplaque hemorrhage. It should be emphasized that there is a difference in methodology used for OCT interpretation between the presented studies. Some studies include lone thrombus which in these authors' opinion may not always be easy to distinguish from plaque erosion. Also, other definitions were introduced, such as layered plaque phenotype. This may cause differences in incidence of OCT findings between different studies.

Although pathogenesis of SCAD remains unclear there is some evidence that it is related to connective/collagen tissue alterations. In-hospital mortality of patients with SCAD is similar to those with obstructive CAD. On angiogram, SCAD may be missed or misdiagnosed as vasospasm due to low resolution of the image, even though there may be a life-threatening condition [52]. In the recent OCT and CMR study, the incidence of SCAD was up to 5%. It is therefore crucial to perform both OCT and CMR in patients with a working diagnosis of MINOCA [53].

Coronary artery spasm reflects a vascular smooth muscle hyper-reactivity to endogenous vasospastic substance, but may also occur in the context of exogenous vasospastic agents [11,54]. Prevalence of coronary artery spasm in patients with MINOCA may vary between 3% and 95% [55]. Moreover, previous studies have shown that about one quarter of the patients with MINOCA have evidence of microvascular spasm [56]. In a recent study, Montone et al. showed that out of 80 enrolled patients presenting with MINOCA, a provocative test was positive in almost half of the patients [23]. Furthermore, a thrombus was found by OCT in 28.8% of patients presenting with vasospastic angina [57]. In patients presenting with vasospasm-induced AMI intimal tear, intra luminal thrombi and plaque erosion were significantly more frequent compared to patients with chronic stable vasospastic angina [58]. Thus, OCT may be a useful modality when assessing MINOCA patients suspected for coronary artery spasm. Coronary artery spasm on OCT is characterized by intimal bumping with a larger medial area and medial thickness [59].

Most of the current studies support the necessity of OCT in the diagnosis of patients presenting with MINOCA. Proper management of every patient with suspected myocardial infarction should include several different imaging modalities. A proposed approach to the proper diagnosis of patients with MINOCA is presented in Figure 2. In the authors' opinion, the first step starts with proper analysis of trans thoracic echocardiography (TTE) performed before angiography. Next, during coronary angiography when MINOCA is identified, angiography of the left ventricle (LV) could be of help for assessment of regional wall abnormalities. A combination of both TTE and LV angiography could be used to identify Takotsubo cardiomyopathy or myocarditis. OCT can be used to evaluate coronary arteries based on findings in the electrocardiogram, TTE, or LV angiography. If

no abnormalities, such as plaque disruption or SCAD, are found on OCT, CMR should be performed [60]. Finally, other tests such as the intracoronary acetylcholine provocation test could be considered for further evaluation of MINOCA patients in order to identify abnormalities, such as coronary artery spasm or microvascular dysfunction.

**Figure 2.** Proposed approach to myocardial infarction with non-obstructive coronary artery disease diagnosis. Flowchart is explained in the text. ACS indicates acute coronary syndrome; ARDS, acute respiratory distress syndrome; CMR, cardiac magnetic resonance; ESRD, end stage renal disease; MINOCA, myocardial infarction with non-obstructive coronary artery disease; OCT, optical coherence tomography; SCAD, spontaneous coronary artery dissection; and TEE, trans esophageal echocardiography.

#### **3. Conclusions**

Although AMI and non-obstructive coronary artery disease have been known for more than five decades, our knowledge is limited and many challenges still remain. Current studies show the importance of using OCT and CMR in patients with a working diagnosis of MINOCA. Moreover, when no abnormal findings are present on OCT, other tests should be performed in order to assess the coronary flow reserve (CFR) and microcirculatory resistance (iMR). Although recent studies shed light on the pathogenesis of MINOCA, well-designed prospective studies are needed in order to gain a better understanding of this condition and to provide optimal management while reducing morbidity and mortality in patients with MINOCA.

**Author Contributions:** Conceptualization, I.-K.J. and K.B.; methodology, I.-K.J., K.B., J.L., L.B., A.K., D.M., P.S., P.G. and P.K.; resources, K.B., P.S., D.M., A.K. and P.G.; data curation, K.B., P.G., P.S. and P.K.; writing—original draft preparation, K.B.; writing—review and editing, K.B., I.-K.J., D.M., P.G., P.S., J.L. and P.K.; visualization, K.B. and I.-K.J.; supervision, P.K., J.L. and I.-K.J.; project administration, K.B. and I.-K.J.; All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Conflicts of Interest:** Jang's research was supported by the Allan Gray Fellowship Fund and by Michael and Kathryn Park. Jang has received educational grants from Abbott Vascular and a consulting fee from Svelte Medical Systems Inc. (NJ, USA) and Mitobridge Inc. (MA, USA).

#### **References**

