Acute coronary syndrome with coronary arteries without obstructive lesions.
Diagnostic therapeutic controversy?
MIGUEL LÓPEZ-HIDALGO, CELESTE CORNEJO RIVAS, ANTONIO EBLEN-ZAJJUR
Ciudad Hospitalaria Dr. “Enrique Tejera”, Valencia, Venezuela.
Facultad de Ciencias de la Salud, Universidad de Carabobo, Valencia, Venezuela.
Facultades de Ingeniería, Biología y Medicina, Pontificia Universidad Católica de Chile, Chile. E-mail
Recibido 02-ABR-18, ACEPTADO despues de revisión el 17-MAYO-2018.
There are no conflicts of interest to disclose.
Acute coronary syndrome (ACS) without obstructive angiographic lesions has a prevalence of 10 to 15%. Different pathophysiologic mechanisms have been proposed. There is a paucity of data in our country regarding this entity. Aim: To determine the prevalence, clinical characteristics, and assess major outcomes of ACS with angiographically normal coronary arteries, in a cardiovascular reference center within a period of two years. Methods: Retrospective case-control study of patients with ACS that were submitted to coronary angiography and divided into patients with coronary artery disease (CAD, n=44) and those without obstructive coronary lesions (NCAD, n=20). Statistical analysis was performed establishing a p <0.05 as significant, X2 was used for categorical and student t test for continuous variables. Results: From a total of 64 patients, 31% had NCAD, in this group 80% were females and had higher prevalence of family history of early coronary artery disease, NCAD vs CAD: 20% vs 2.2% (p=0.01). There was no significant difference in individual cardiovascular outcomes between groups in 2 years. In 70% of cases the pathophysiological mechanism was not assessed, not detecting the basic etiology. Conclusions: Prevalence of ACS without obstructive angiographic lesions represents a significant proportion of patients, with predominance of female gender and family history of early coronary artery disease with no significant difference of individual cardiovascular outcomes between groups.
In acute coronary syndrome (ACS), 10-15% of patients present coronary arteries with no obstructive angiographic lesions, which is significant in the mid and long term [1,2].
In ACS, different pathophysiological mechanisms are described; the one most accepted and most frequent currently is the atherothrombotic mechanism by destabilization of an atheroma plaque in the vessel wall. Among the causes for coronary origin are concealed atherosclerotic disease, which does not appear in coronary angiography, because the method only allows for a panoramic view of the coronary lumen, and no plaques are detected with external growth (expansive remodeling according to Glagov’s model), which are potentially vulnerable plaques, in which arterial lumen may look normal in coronary angiography.
It is known that most acute coronary episodes have their origin in the rupture of a vulnerable plaque, with no significant stenosis leading to thrombosis, and for this reason a significant proportion of cases of ACS with no obstructive lesions are due to the fact that when the angiography is made, the thrombus responsible for acute ischemia has already disappeared from the occlusive segment where the vulnerable unstable plaque was; whether by endogenous thrombolysis or by distal embolization with the thrombus fragments occluding microcirculation, leaving the epicardial coronary artery with a normal angiographic appearance, or in some cases, a small bump in the lumen can be observed in coronary angiograph, of less than 20%, or even parietal irregularities [1,3,4].
Until recently, myocardial ischemia in patients with coronary arteries with no obstructive lesions was known just as cardiac syndrome X. In the last 15 years, different pathophysiological mechanisms have been discovered, which are related to these cases; within them, the most significant ones are microvascular disease, which has become very important ; vasospasm of epicardial coronary arteries, coronary artery ectasia, phenomenon of slow flow or coronary slow flow phenomenon by its clinical features ; hypercoagulability disorders [4,6], broken-heart or Takotsubo syndrome, coronary arteries of anomalous origin and trajectory, intramyocardial bridging, use of illegal drugs stimulating to the central nervous system, such as cocaine, amphetamines and their new varieties that generate general endothelial dysfunction with epicardial coronary spasm; and more recently, synthetic cannabis that generates distal coronary obstruction [1,5,7,8].
However, a proper diagnosis is not always made for these entities, due to a lack of protocols for a differential diagnosis and/or by the complexity of its analysis, requiring special, expensive studies, not available in many centers, among them noninvasive studies such as: positron-emission tomography, that evaluates ischemia at cellular level; cardiac magnetic resonance, that evaluates ischemia and myocardial necrosis at tissue level; multislice tomography angiography; and invasive coronary tests such as intravascular ultrasound (IVUS) and analysis of fractional flow reserve (FFR).
Consequently, when the base mechanism is ignored, a great diagnostic mystery is generated, and at the time of making decisions, many patients do not receive a treatment adjusted to each etiology, with subsequent repercussions .
Currently, both acute and chronic myocardial ischemia, with coronary arteries with no lesions caused by pathophysiological mechanisms or nosological entities of recent description, are a very important area of investigation as many aspects are ignored, and there are few randomized clinical trials to define both diagnostic and therapeutic guidelines [4,5,10,11].
In our area, there are very few studies about it. Because of the aspects mentioned above, a study was made, the primary goal of which was to detect the prevalence and clinical profile of patients with acute coronary syndrome, who underwent cardiac catheterization and the results of which were coronary arteries with no angiographic obstructive lesions, with patients who went to a public reference service of cardiology, for a term of 2 years (January 2015 to January 2017). Likewise, the secondary goal was to determine major cardiovascular events recorded over this term, compared to patients with obstructive CAD.
Retrospective study of cases and monitoring, the primary objective of which was to analyze the prevalence and clinical profile (given the most frequently associated cardiovascular risk factors and demographic relationship) of ACS in patients with coronary arteries with no obstructive lesions, who were admitted into the Cardiology Service of the Ciudad Hospitalaria “Dr. Enrique Tejera”, Valencia, Venezuela, and as secondary aim major outcomes, in comparison (as reference) to patients with obstructive CAD.
The sample was constituted by adults with ACS, in whom consecutive coronary angiography was performed. They were divided into two groups; those with coronary arteries with no obstructive lesions (NCAD), defined as patients with coronary angiographies with normal angiographic appearance, no stenotic lesions, or with minimum lesions, like parietal irregularities, or with stenosis <30% (criteria similar to other studies) ; and those with atherosclerotic CAD or significant angiographic obstructive lesions, greater or equal to 50% (CAD), which were compared to the subsequent analysis of their clinical profile and major cardiovascular outcomes (mixed and individual) caused by: myocardial infarction, recurrent angina, heart failure, need for revascularization and death.
Patients older than 18 years old, of any gender, who were admitted in the coronary care unit of the Cardiology Service in the CHET, with diagnosis of ACS, in whom coronary angiography was conducted.
From the study, patients with any of the following conditions were excluded: cardiogenic shock, treatment with thrombolytic agents before angiography, pericarditis, acute aortic syndrome, heart valve disease, dilated heart disease, chest trauma, autoimmune diseases.
Clinical data were collected from the medical histories of the cardiology service; the statistical analysis was made with the EPI-INFO v7 free-access software. For continuous variables, the comparison was made with student’s t test (after confirming Gaussianity); and for categorical variables, the X2 test was used, assuming a statistical significance of p<0.05.
The study was approved by the research and ethics committee of our institution.
A total of 64 patients were evaluated; 44 (69%) of whom belonged to the NCAD arm, and 20 (31%) to the CAD arm. The distribution by gender in the global sample was balanced, with 48% being males and 51% being females. However, the female gender was predominant in the NCAD arm in comparison to the CAD arm (80% vs 38.6%; p=0.001; Figure 1). The average age of the global sample was 61±11 years, with no significant difference between both groups. As to the risk factors, systemic hypertension in this population was very high (81%), followed by smoking (44%), diabetes mellitus (28%) and dyslipidemia (22%); with no significant differences between both groups (Figure 2). Even when the presence of systemic hypertension was similar in both groups, systolic hypertension (sHTN) in admission was higher in NCAD patients (Table 1) p=0.01.
Figure 1. Percentage distribution of patients with ACS according to gender
CAD: Group with obstructive lesions; GS: Global sample; NCAD: Group with no obstructive lesions.
Figure 2. Distribution of cardiovascular risk factors of patients with ACS. CAD: Obstructive coronary disease; GS: General sample; NCAD: Nonobstructive lesions; DM: Diabetes mellitus; DLP: Dyslipidemia; HTN: Hypertension; FH: Family history of early CAD; SED: Sedentarism; SMK: Smoking. *P<0.01
Table 1. Baseline characteristics of the patients studied:
Age, average±SD (years)
Female, n (%)
Family hist. early CAD, n (%)
Diabetes Mellitus, n (%)
Hypertension, n (%)
Dyslipidemia, n (%)
Sedentarism, n (%)
Smoking, n (%)
SBP mmHg, average ±SD
DBP mmHg, average ±SD
HR bpm, average ±SD Type of event: STE-ACS, n (%)
TIMI risk, score, average±SD NSTE-ACS, n (%)
- NSTEMI, n (%)
- Unstable Angina, n (%)
TIMI, risk score, average±SD
Time to cath, average±SD (days)
GS: Global sample; CAD: Group with obstructive coronary artery disease; NCAD: Group with no obstructive coronary lesions; SD: Standard deviation; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; STEMI: ST-elevation myocardial infarction; TIMI risk score for STEMI and NSTEMI; NSTEMI: non-ST elevation myocardial infarction; Time to cath: Period from arrival to the ER until performance to catheterization; MCE: Composite major cardiovascular events (angina, readmission by angina, need to revascularize, heart failure and death). *P<0.05 by significance with X2 test
The most frequent diagnosis in admission in the sample of the patients studied was 94% of non-ST elevation acute coronary syndrome (NSTE-ACS), a greater proportion (61%) was for non-ST elevation myocardial infarction (NSTEMI) with risk of cardiovascular events in the short term, estimated according to the TIMI score of risk, with an average value of 3.4±1.4 points. In the NCAD group, the predominant clinical entity was also NSTE-ACS with 80%, distributed in unstable angina vs NSTEMI: 62.5% vs 37.5%, p=0.005. Likewise, a significant number of patients with composite cardiovascular events became evident (myocardial infarction, recurrent angina, heart failure requiring revascularization, and death); with 55% in the NCAD arm vs 30% in the CAD arm (p=0.05) in the 2-year evaluation (Table 1, Figure 3). When analyzing the individual outcomes, there was no statistical difference between the groups, with recurrent angina being the most frequent one, p=0.26 (Table 3, Figure 4).
Figure 3. Composite cardiovascular events; accumulated frequency in 2 years. CAD: Patients with obstructive lesions; GS: Global sample; NCAD: Patients with no obstructive lesions; MCE: Accumulated major cardiovascular events (recurrent angina, MI, HF, revascularization and death). *p=0.05
Tabla 3. Major individual cardiovascular events in a period of 2 years
CAD: Group with obstructive angiographic lesions; NCAD: Group with no obstructive lesions.
Figure 4. Individual major cardiovascular events in 2 years. CAD: Obstructive coronary disease; GS: Global sample; NCAD: No obstructive lesions;
R angina: Recurrent angina; Re-IM: Re-infarction; HF: Heart failure; Revasc: New revascularization.
On the other hand, in terms of treatment, it was possible to observe that the use of beta blockers was greater in the CAD arm in comparison to NCAD (72.7% vs 35%; p=0.002). The same happened with the use of convertase enzyme inhibitors (61.3% vs 30%; p=0.01), nitrates (58.1% vs 5%; p=0.008), statins (81.8% vs 50%; p=0.006). In the case of treatment with ARBs, their use was greater in the NCAD group vs CAD (11% vs 60%; p=0.004). The use of calcium channel blockers was similar in both groups (18% vs 20%; p=0.23).
In this study, the clinical and follow-up characteristics were evaluated in 64 patients with ACS, performing comparisons between the patients with and without angiographic coronary lesions. In the NCAD group, a predominance of the female gender became evident, which is in agreement with previous reports [12134,15,16,17]. A family history of early CAD presented a higher magnitude in terms of prevalence in patients from the NCAD group, an aspect mentioned and quite controversial in some studies . However, the results of this study support the familial and genetic relationship present in the cases of the NCAD group.
Cortell A et al, in 2009 , in a prognostic study of NSTE-ACS, 76% of patients who were admitted by NSTEMI, performed catheterization before 48 hours with the main goal of evaluating major cardiovascular events in the group of patients with coronary arteries with no obstructive lesions, in a 3-year follow-up; and identifying associated risk factors. The finding was that 13% of these patients had coronary arteries with no obstructive lesions (in this study the value was 18%). Cortell A et al, in the group of patients with no significant obstructive lesions, showed an extreme predominance in the female gender, similar to the findings in our study. Other variables of interest, such as the absence of diabetes and a lower rate of ST downsloping in ECG, were elements indicating a greater likelihood of coronary angiography with no obstructive lesions in NSTE-ACS; finding in this subgroup of patients a decrease in the probability of death or infarction of 30% .
The results of this investigation in relation to the clinical profile of patients with ACS with no obstructive lesions (NCAD-ACS) agree to a large extent, with previous reports by presenting a higher prevalence of NSTE-ACS and occurring predominantly in women, with a tendency of less prevalence of diabetes and with an incidence of 2 years of lower rate of mortality in the group with no obstructive lesions.
As to the pathophysiological mechanisms based on the findings proper, we could propose that many cases were by microvascular disease (or microcirculation spasm); as most of the patients with NSTE-ACS of the NCAD group had unstable angina 62.5%; and many with NSTEMI (37.5%) could be related to spontaneous thrombolysis or distal embolization.
In the large CRUSADE trial with 55,514 patients with NSTE-ACS, in which the difference in genders was compared in NSTE-ACS with coronary arteries with no lesions, in whom angiography was performed, they found 10% (5,538 patients) with non-obstructive CAD; and from these, 15.1% were women and 6.8% men. The CRUSADE concluded that NSTEMI with normal coronary angiographies is twice more common in women, and regardless of gender, the clinical profile is similar to those with CAD, and outcomes are more favorable in those without obstructive lesions in both genders .
In the population studied there was 31% of patients with ACS and no obstructive lesions. This greater prevalence could be due to a bias in selection, as this was a retrospective study of a subgroup of patients with ACS that for reasons of institutional and/or personal feasibility could undergo coronary angiography, which was not of protocol by definition.
As to the profile of risk of patients according to the type of ACS, the patients with NSTE-ACS did not have significant differences between the CAD and the NCAD groups, having in both groups an average value of 3 points in the TIMI risk score, representing an intermediate risk of events (equivalent to 3% of probability of composite events of MI, need for revascularization, or death in 15 days). Likewise, for 6 patients with NSTE-ACS, there were no significant differences in the TIMI risk score for both groups (Table 1), which is in agreement with other studies .
In recent studies, in diabetic patients with ACS and stable angina, who had coronary arteries angiographically with no lesions, but with a very thin caliber, IVUS showed diffuse atheromatosis with progressive, concentric and uniform thinning of vessel lumen. They appeared to be coronary arteries with a very thin constitution in terms of caliber and with no lesions, but in fact it was diffuse CAD, which could not have been differentiated otherwise .
Coronary artery spasms are a true challenge, as in many patients at the time of angiography, the spasm causing the event was not present, and often such diagnosis is dismissed, unless ergonovine or acetylcholine spasm challenge is made, that is hardly done in hemodynamic labs nowadays, thus remaining as a diagnostic mystery in most of these cases [10,19,20,21].
It is remarkable that in this investigation, the patients in the NCAD group received less treatment with nitrates (Table 2), although in the mechanisms involved there are vasospastic syndromes, where the use of nitrates, calcium channel blockers are advised, and to avoid the use of beta blockers, particularly nonselective ones, as they foster vasospasms.
Table 2. Treatment received during hospitalization
When the clinical outcomes recorded in 2 years are analyzed, a greater tendency to accumulated cardiovascular events (angina, MI, new revascularizations, HF and death) resulted in the NCAD group, unlike what is reported in literature. But, when analyzing individual major cardiovascular events, it is observed that indeed there were no statistically significant differences between both groups (Table 3). We should take into account that for the analysis of outcomes, a significant limitation is the retrospective character of the study, and the fact that not all patients in the acute phase performed their control and follow-up evaluations in the same institution.
Different studies reveal that microvascular angina with coronary arteries with no significant obstructive lesions is responsible for 25% of ACS in women and 10% in men [1,10,18,19,20,22]. In the acute cases, the differential diagnosis should rule out transient thrombosis, where the thrombus disappears quickly, whether by spontaneous thrombolysis or by embolization, epicardial coronary spasm, or the presence of two specific clinical syndromes such as: angina by microvascular spasm and cardiomyopathy related to stress or Takotsubo disease.
The diagnosis requires evidence of typical symptoms of coronary origin with dynamic changes in the ST-T segment in ECG, and sometimes increase in biomarkers of myocardial necrosis, in the presence of coronary angiography with no obstructive lesions, with dyskinesia effect of the apical ballooning type in the left ventricle. Whether in ventriculography or in echocardiogram, evidence of microvascular disease is obtained by the evaluation of vasoconstriction and vasodilation response to stimulation, and the exclusion of epicardial coronary vasospasm and transient intracoronary thrombus. The former is achieved through challenge tests, and the latter is assumed by exclusion . Both microvascular angina syndrome and Takotsubo cardiomyopathy are proposed as being caused by microvascular spasm, by diffuse spasm or by severe microvascular spasm with total occlusion of the vessels for a relatively short or moderate period in a myocardial segment, with greater frequency in the antero-apical wall and spontaneous solution [16,7,23,24].
Niccoli’s group poses four mechanisms involved in the pathogenesis of coronary microvascular obstruction: 1) ischemia lesion; 2) reperfusion lesion; 3) distal embolization; and 4) individual susceptibility, both genetic and by persistent coagulation . It would be interesting to go deeper into genetic susceptibility, since in this study it was possible to observe that patients in the NCAD group presented a greater statistically significant prevalence of family history of early CAD.
Within the pathophysiological mechanisms proposed, there are factors modulating coronary microvascular obstruction: genetic variability, diabetes, acute hyperglycemia, hypercholesterolemia, and lack of previous conditioning. Genetic factors can modulate adenosine release, which normally plays an important role in homeostasis, that at myocardial level protects from an excessive load, decreasing contractility and simultaneously causing vasodilation at microvascular level, improving the contribution of tissue oxygen, main humor factor of regulation of coronary functional reserve. In ischemia scenarios, such concentrations may vary according to the requirements and alterations in this mechanism, with deficiency in adenosine production or release, which may lead to ischemia in absence of obstructive epicardial CAD. This finding is currently called coronary microvascular spasm, main mechanism of coronary microvascular disease (CMD) [1,22,25].
Between the pathophysiological mechanisms to explain coronary pain, an interesting hypothesis is presented, described as “sensitive heart”, backed by several studies with small samples of patients with pain suggesting coronary involvement, and positive stress tests, but with no sound evidence of myocardial ischemia in other tests such as stress echo. In this same line, cerebral perfusion studies were conducted with positron emission tomography, showing perfusion alteration in the cortical activation region of the right hemisphere of the frontal operculum/insula, which in turn creates altered patterns of afferent viscera signals that may produce an abnormal perception of pain during cardiac stress in absence of ischemia , which adds to the controversy on this topic, thus increasing the interest on investigating this area.
In this study, the different pathophysiological mechanisms related to ACS were not evaluated as we didn’t have tests such as: noninvasive tests of the multislice tomography angiography and cardiac magnetic resonance type, and invasive tests of coronary vasospasm challenge, IVUS and coronary fractional flow reserve (FFR), necessary to clarify them .
In this medical care center, for the first time we attempted to characterize the group of patients admitted into the cardiology service with diagnosis of ACS and angiograms showing normal coronary arteries or with no significant obstructive lesions, finding a similar behavior in some aspects in many of the published studies and reviews [1,13,14].
In patients with ACS and coronary arteries with no lesions, it was thought for a long time that they had a benign prognosis. Currently, the most recent evidence has shown that this is not so, and many present a significant recurrence of angina and readmissions, in some comparable to obstructive CAD of 1 vessel, with incidence of MI and minor mortality .
Between the limitations of the study, we may point out the fact that 56% of angiographies were performed during the first week of admission of the patient, in average at 12±8 days. ACS are caused in 69% of cases by vulnerable plaques with non-significant stenosis and in 3% of the cases by significant plaques with stenosis, even in STEMI. At 24 hours, in 80% of cases thrombi are no longer visualized by coronary angiography. On the other hand, 0% of thrombi embolize at microcirculation, all of this creating a selection bias according to the time of the angiography, and close to 60% to 70% of patients with STEMI present significant stenosis in angiography by atheromatous plaques, subsequent to thrombus lysis, either by therapeutic or spontaneous thrombolysis [14,16,22]. The size of the sample was limited due to our center not having an invasive cardiology lab, and for which patients have to be moved to other centers, entailing costs hard to cover for patients of public institutions. In the institution there is no availability of noninvasive or invasive methods, essential to determine the pathophysiological mechanism, ergo the underlying pathology.
In many cases, even with all the technological resources available, the group of patients with acute ischemic events that have no significant obstructive angiographic lesions, were not investigated in terms of the underlying pathological mechanism by vasospasm challenge tests, thus presenting a diagnostic dilemma by attributing most of cases to microvascular disease, as this diagnosis is made by exclusion, so its clinical management is controversial. There are no large randomized studies in this subset of patients that would evaluate different therapeutic strategies [1,22,23]; so a preventive treatment should be chosen, similarly to patients with intermediate to high coronary risk factors, preferentially with the use of beta blockers of calcium channels and nitrates, avoiding beta blockers, and assuming the possibility of undocumented vasospastic syndrome, to thus decrease the rate of recurrence.
It is necessary to perform randomized prospective studies with proper sizes of sample, to obtain more trustworthy data and to be able to prepare diagnostic and therapeutic protocols based on a higher level of evidence.
In this study, patients with ACS with no significant angiographic stenosis are characterized by greater prevalence of women, of family history of early CAD and presence of intermediary risk for new cardiovascular events (TIMI risk score: 3 points). Except family history of early CAD, many of these findings match previous reports in literature, so greater trials are required to evaluate possible genetic aspects involved.
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