Atypical manifestations of acute coronary syndrome --- throat discomfort: a multi-center observational study

Abstract

To present the clinical characteristics and the misdiagnosis rate of acute coronary syndrome manifested primarily as throat discomfort, we conducted a multicentric and retrospective study in the cardiology and otorhinolaryngology departments. Records of patients with primary complaint of throat discomfort, absence of chest pain at onset, and an ultimate diagnosis of acute coronary syndrome, as well as patients with pharyngitis (as controls) were collected from May 2015 to April 2016. The patients’ main manifestations were compared. Logistic regression results showed that chest tightness, dyspnea, perspiring, and exertional throat symptoms were significantly associated with acute coronary syndrome, with odds ratios of 8.3 (95% CI 2.2–31.5), 10.9 (95% CI 1.8–66.9), 25.4 (95% CI 3.6–179.9), and 81.2 (95% CI 13.0–506.7). A total of 25 (56.82%) out of 44 acute coronary syndrome patients, who were first admitted to the otorhinolaryngology department, were misdiagnosed, with a 12% (3/25) mortality rate. Throat discomfort can be the principal manifestation of acute coronary syndrome. Such patients exhibit high misdiagnosis and mortality rates. Exertional throat symptoms, chest tightness, perspiring, and dyspnea were important indicators of acute coronary syndrome in patients whose main complaint was throat discomfort. The awareness of this condition will result in prompt diagnosis and reduce morbidity and mortality.

Keywords

acute coronary syndrome (ACS) / throat discomfort (TD) / throat pain / cardiology departments / non-cardiologic physicians

1 Introduction

Cardiovascular disease has become the leading cause of morbidity and mortality worldwide [1,2]. Acute coronary syndrome (ACS), which includes acute myocardial infarction (AMI) and unstable angina, requires immediate attention and intervention [3]. However, some ACS patients, who do not experience chest pain, are misdiagnosed and inadequately treated [4]. Prompt treatment upon the onset of AMI symptoms decreases mortality, morbidity, and health care costs while increasing quality of life [5]. Moreover, the atypical presentation of ACS is a significant independent predictor of in-hospital mortality [6].

Chest pain is the most frequent symptom in patients with acute coronary artery disease (CAD) [7]. However, acute CAD can be manifested as chest discomfort (e.g., tightness, heaviness, squeezing, and pressure) without chest pain [8]. Approximately 25% of AMI cases were discovered during routine electrocardiograph (ECG) [9], and half of these cases are “silent” without any symptoms. In addition, Canto et al. reported that 33% of the patients diagnosed with MI did not present chest pain in the hospital [8]. The atypical presentations of AMI include back, epigastrium, throat, and jaw pain [4,6,10]. These patients may therefore visit a non-cardiac physician, including a gastroenterologist, otolaryngologist, or dentist on the first onset. AMI with throat distress may first be observed at the otolaryngologist’s office. Typical AMI presenting as throat distress has been reported [10–13], and the clinical characteristics of such patients based on large-scale studies are lacking. In the present study, we will first present a multi-center study of 101 ACS patients whose symptoms manifested primarily as throat discomfort (ACS-TD) and focus on their clinical characteristics and misdiagnosis rate.

2 Materials and methods

This research was conducted in accordance with the ethical standards of the Internal Review Board of Eye Ear Nose and Throat (Eye & ENT) Hospital, Fudan University in Shanghai. A retrospective study of medical records from the cardiology and ENT departments at six tertiary hospitals (Department of Otorhinolaryngology in the Eye & ENT Hospital, Fudan University; Affiliated Hospital of Jiangsu University and The Second People’s Hospital of Wuxi, Nanjing Medical University; Department of Cardiology in Zhongshan Hospital, Fudan University; Shanghai Tenth People’s Hospital, School of Medicine, Tongji University; and The First Affiliated Hospital of Nanjing Medical University) was conducted from May 2015 to April 2016. The population of interest (ACS-TD group) included patients who appeared at the above cardiology or ENT departments during the study period with a chief complaint of throat discomfort without obvious chest pain at their first presentation and turned out to be ACS. The control (TD) group also include an equal number of patients who experienced throat discomfort that turned out to be pharyngitis diagnosed according to the criteria of Shulman et al. and Chiappini et al. [14,15]. Patients in the TD group were included by sequence during the study period to exclude possible bias. One and a half years after the study period, these patients had no diagnosis of ACS known from their follow-up. All included patients had full knowledge of the information needed. Records of these patients were reviewed for basic demographic information, clinical characteristics of the chief complaint, local findings, symptom profile, risk factors, ECG information and coronary imaging data, and treatment information. In patients with non-painful throat discomfort, if the discomfort of the throat could not be described, we noted “throat distress.” The throat discomfort was classified into sore throat and non-painful throat discomfort (including throat distress that could not be clearly described, throat burning, foreign body sensation, throat tightness, constricting or choking of throat, throat itch, dry throat, and sense of phlegm). In the present study, the severity of the throat symptoms was also studied. For the grading of the severity of the throat symptoms, we referred to previous studies associated with pain [16]. Graded pain forms were collected from all patients, with 0–10 points on a numerical scale. The severity of the throat symptoms was determined based on the degree of interference with patients’ function, with ratings of 1–4 corresponding to mild degree, 5–6 to moderate degree, and 7–10 to severe degree. In addition, an exertional throat symptom was defined as throat discomfort associated with activity, including fast walking, running, biking, climbing stairs, heavy lifting, and exercise in cold weather, which could increase myocardial oxygen consumption. The history of cardiovascular disease encompasses prior myocardial infarction (MI), prior percutaneous transluminal coronary intervention (PCI), and any prior CAD. However, their history of previous cardiac events occurred at least 1.5 years before this attack.

The AMI diagnostic criteria were consistent with the guidelines of AMI in the Joint European Society of Cardiology (ESC) of 2017 [17] and ACS diagnostic criteria used in 2015 version by the ESC [18].

Statistical analysis was performed using the χ² test for categorical variables and the t-test for continuous variables in Stata 10.0 (the StataCorp, College Station, TX, USA). To evaluate the association between ACS and main symptoms of patients, we carried out logistic regression. Statistical significance level was defined at P<0.05.

3 Results

3.1 Patient recruitment

From May 2015 to April 2016, 101 patients were included in the ACS-TD group, and 101 were included in the TD group. Among the ACS-TD patients, 44 (43.56%) were first evaluated by an otolaryngologist, and 57 (56.44%) were initially treated by a cardiologist. Among the 44 ACS-TD patients first presented at the ENT department, 25 patients received pharyngitis therapy without any relief of throat symptoms with a misdiagnosis rate of 56.82% (25/44). All the 101 TD patients were first evaluated by an otolaryngologist and received pharyngitis therapy.

3.2 Basic information of ACS-TD and TD groups

For the ACS-TD group, with an average age of 58.1 (33–81) years, 38 (37.62%) patients were female and 63 (62.38%) male. The ACS-TD group had more male than female patients. For the TD group with a mean age of 55.9 (36–77) years, 41 (40.59%) patients were female and 60 (59.41%) male. No significant difference was observed in age (P = 0.121) or gender (P = 0.665) between the two groups (Table 1).

3.3 Clinical characteristics of throat symptom, concomitant symptoms, exertional throat symptom, and the association between ACS and main symptoms and local examination

3.3.1 Manifestation of throat discomfort

Clearly stated pharyngeal pain was present in 48 (47.52%) patients in the ACS-TD group (Table 2). Non-painful pharyngeal symptoms included vaguely stated distress (n = 32; 31.68%), tightness (n = 17; 16.83%), choking sensation (n = 9; 8.91%), and itching in throat (n = 1; 0.99%).

The control TD group presented more often with foreign body sensation (33.66% vs. 0.00%, P<0.001), throat itch (11.88% vs. 0.99%, P<0.01), dry throat (12.87% vs. 0.00%, P<0.001), and sense of phlegm (7.92% vs. 0.00%, P<0.01) and less often with vaguely stated distress (8.91% vs. 31.68%, P<0.001), tightness (4.95% vs. 16.83%, P<0.01), and compressing sensation (0.00% vs. 8.91%, P<0.01) in the throat compared with the ACS-TD group. The percentage of patients with pharyngeal pain was similar to that in the ACS-TD group (45.54% vs. 47.52%, Table 2). In addition, the distribution of the degree of throat symptoms was similar between the two groups (P>0.05).

In addition, we divided ACS patients into two sub-groups, namely, the AMI (acute coronary infarction, n = 59) and unstable angina (UA, n = 42) groups. The throat symptoms were compared between the groups. Results showed significant differences for throat pain (55.9%, n = 33 in AMI subgroup vs. 35.7%, n = 15 in UA subgroup, P = 0.045) and throat tightness (10.2%, n = 6 in AMI subgroup vs. 26.3%, n = 11 in UA subgroup, P = 0.034), but not for other throat symptoms.

3.3.2 Concomitant symptoms

In the ACS-TD group, 25 (24.75%) patients manifested throat discomfort without other concomitant symptoms. Among these patients, 11 (10.89%) patients complained about throat pain solely, 5 (4.95%) patients complained about throat tightness sensation solely, 6 (5.94%) patients complained about throat distress solely, 2 (1.98%) patients complained about both throat pain and tightness or choking.

The 76 other patients in the ACS-TD group complained about other non-specific concomitant symptoms. Among these conditions, chest tightness (n = 47, 46.53%), dyspnea (n = 14, 13.86%), and perspiration (n = 34, 33.66%) presented most frequently. In the TD group, 90 (89.10%) cases had only throat discomfort, and the 11 (10.89%) other patients complained about other atypical symptoms, such as chest tightness (n = 5, 4.95%), dyspnea (n = 5, 4.95%), and perspiration (n = 2, 1.98%), which presented most frequently. These main three concomitant symptoms were distributed differently in the ACS-TD group and TD groups, with statistical significance (P<0.05, Table 3).

Other rare presentations accompanied by throat discomfort were pain elsewhere (tooth, shoulder, and neck), neck distress, nausea, vomiting, dizziness, weakness, fatigue, palpitations, blackouts, and syncope, with an overall occurrence rate of 7.92% (eight cases) in the ACS-TD group and 0.99% (one case) in the TD group, with significant difference (P = 0.017, Table 3).

3.3.3 Exertional throat symptoms

Exertional throat symptoms were observed in 57.42% (58 cases) of the ACS-TD group and 1.98% (2 cases) in the TD group, with significant difference (P<0.001).

3.3.4 Logistic regression models for the analysis of the associations between main symptoms and ACS

We conducted logistic regression models to analyze the associations between the main symptoms and ACS. Chest tightness, dyspnea, perspiration, and exertional throat symptoms were positively and significantly associated with ACS with odds ratios (ORs) of 8.3 (95% CI 2.2−31.5), 10.9 (95% CI 1.8−66.9), 25.4 (95% CI 3.6−179.9), and 81.2 (95% CI 13.0−506.7), as shown in Table 4. Logistic regression was also performed for the diagnosis and number of symptoms, and the results showed that the number of the four symptoms listed above was significantly correlated with ACS (P<0.001, OR= 19.3). The risk of ACS diagnosis increased by 18-fold for each additional symptom compared with the control group. Age, gender, and the severity of throat symptoms had no significant effects on the incidence of ACS.

3.3.5 Local examinations

All ACS-TD patients mainly complained of throat discomfort. However, on local laryngology examination, no patients showed obvious acute inflammation. Among the three death cases, all patients suffered from severe throat symptoms without distinctive local acute inflammation, and this phenomenon was not consistent with their symptoms. For TD patients, throat symptoms presented with varying degrees of pharyngeal inflammation on local examination.

3.4 Risk factors

In the present study, the common risk factors were extracted from the medical histories of the ACS-TD patients, including prior cardiovascular disease (as stated in the section of “Materials and methods”), hypertension, smoking, and diabetes. Regarding the risk factors for cardiovascular disease, patients in the ACS-TD group more often experienced hypertension (67.32% vs. 21.78%, P<0.001) and less often had smoking (30.69% vs. 20.79%, P = 0.108) and diabetes (16.83% vs. 7.92%, P = 0.054) compared with the patients in TD group (Table 3). In addition, a history of chronic laryngitis was significantly less likely observed in the ACS-TD patients compared with the TD patients (9.90% vs. 32.67%, P<0.001).

3.5 Electrocardiogram (ECG) information, treatment, misdiagnosis, and mortality rate

3.5.1 ECG information

Among the 101 ACS-TD patients, 59 (58.42%) patients were diagnosed with AMI with 38 (37.62%) cases of ST-elevation (STE) infarction and 21 (20.79%) cases of non-ST-elevated myocardial (NSTE). The most common infarct location was the inferior wall (20 cases), followed by the anterior wall (14 cases), high lateral wall (2 cases), and extensive anterior wall (2 cases). Among the 21 cases with NSTE infarction, two cases showed normal ECG, three cases with non-fatal arrhythmia, and 16 cases of others which included mild abnormity of ST and/or T, of which neither belong to classical AMI nor any arrhythmias.

3.5.2 Treatment, misdiagnosis, and mortality rate

For treatment, pharyngitis medicine did not work in all 29 ACS-TD patients (29/29, 100%) and in 13.86% (14/101) TD patients (P<0.001). A total of 92 out of 101 (91.09%) ACS-TD patients underwent successful stent implantation. The six other ACS-TD patients received coronary angiography and medical therapy, in which three patients refused stent implantation. 98 of the ACS-TD patients recovered, whereas three AMI patients died after unsuccessful cardiopulmonary resuscitation. For the three cases of death, all patients were first admitted to the ENT department and were misdiagnosed.

3.6 Referred and unreferred ACS patients first admitted to the ENT department and their results

A total of 44 ACS-TD patients were first treated by the otolaryngology team rather than by the cardiology team. Among these patients, 19 patients were immediately referred for further cardiac evaluation, while the 25 remaining patients (25/44, 56.82%) received pharyngitis treatment with a diagnosis of “chronic pharyngitis” and were inappropriately discharged from the ENT department.

By comparing the information between the two subgroups of ACS-TD patients, namely, the unreferred (n = 25) and the other patients (n = 76) that include 19 cases referred from the ENT department and 57 cases first admitted to the cardiology department, significant differences were found for symptoms of throat pain and distress and history of pharyngitis (Table 5). The number of patients (20 cases, 80%) who complained of throat pain in the unreferred group was significantly higher than those in the referred group (28 cases, 36.84%, P<0.001). None of the patients in the unreferred group complained of throat distress, and this figure is significantly less than that in the referred groups (32 cases, 42.11%, P<0.001). Eight (32.00%) out of 25 unreferred patients and two (2.63%) referred patients had a history of pharyngitis, with significant difference (P<0.001). No significant difference was found in the demography, other throat symptoms, cardiac symptoms, and other past medical history between unreferred and referred patients (P>0.05).

4 Discussion

AMI remains the leading cause of death worldwide [19]. The AMI mortality is 67.6 deaths/100 000 inhabitants [20]. An estimated 1.1 million people in the US experience AMI each year [21]. The atypical presentation of AMI without chest pain is more common than imagined and is associated with increased mortality, which is nearly two or three times higher in patients presenting without chest pain [8]. In the emergency department, approximately 2.1%–2.3% of the ACS patients are mistakenly discharged, mostly because of atypical symptom presentation [22]. Failure to recognize an atypical presentation of ACS can be fatal. The misdiagnosis rate of ACS was high in the present study (i.e., 56.82%) compared with the above-cited literature being worthy of increased attention.

Craniofacial pain may be the only symptom of cardiac ischemia (6%) or sole manifestation of AMI (3%) [23]. The most common site of pain reported in this region is the throat, followed by the jaw, neck, teeth, and ear [24]. However, throat pain has rarely been studied. In the present study, 25 (24.75%) patients manifested throat discomfort without other concomitant symptoms. Among these symptoms, a special throat symptom, i.e., throat tightness or choking sensation as the only manifestation, presented on five (4.95%) ACS patients, which had not been reported. Symptom recognition at onset is paramount to the successful management and early treatment and improvement of the care quality of such patients. To our knowledge, this analysis represents the largest observational study that compares the detailed characteristics, treatments, and outcomes of ACS patients presenting primarily with throat symptoms and those of common pharyngitis.

All ACS-TD patients in the present study complained mainly of throat symptoms, and the main complaint of throat discomfort was not alleviated by conventional drugs for pharyngitis, but all symptoms were alleviated by cardiac treatment, including cardiac medications and stent implantation apart from the three death cases. In Schelbert et al.’s study, pressure and burning were the two pain quality descriptors frequently used by patients when describing the facial pain from cardiac origin [25]. In the present study, however, throat burning was not an indicator for distinguishing ACS from TD. A total of 25 (24.75%) patients manifested throat discomfort without other concomitant symptoms. Among these symptoms, a special throat symptom called throat tightness or choking sensation is the only manifestation presented on five (4.95%) ACS patients, and this condition has not been reported. The symptoms of throat distress, tightness, and compressing sensation were highly suggestive of ACS other than TD.

In the current analysis, the most frequent concomitant symptoms with throat discomfort in ACS patients was chest tightness (46.53%), followed by perspiration (33.66%) and dyspnea (13.86%). These symptoms along with exertional throat symptoms (57.42%) were significantly associated with the risk of ACS, thus supporting previous reports on the symptoms linked with ACS. For example, a study by Milner et al. found a relationship between perspiration and dyspnea and ACS [26]. Moreover, chest pressure is a significant predictor for the diagnosis of ACS [27]. Further throat pain on exertion indicates cardiac events [11]. These symptoms could not reasonably be explained by ordinary pharyngitis but rather by cardiovascular disease [28]. Moreover, these symptoms along with other rare cardiac symptoms of ACS (Table 3) were probably not well-appreciated by non-cardiac physicians. The lack of chest pain at the onset of the disease and ignoring or misinterpreting other concurrent symptoms could lead to misdiagnosis.

Based on the analysis of the referred and unreferred ACS-TD patients, who presented at the ENT department initially (Table 5), patients with a history of pharyngitis were more likely to be misdiagnosed with chronic pharyngitis rather than referred to the cardiology department. Although a history of pharyngitis was presented more in the TD group than in the ACS-TD groups with significant difference (P<0.001), the history of previous pharyngitis causes misdiagnosis of ACS patients with such history. However, regarding that the distribution of the degree or severity of throat symptoms was similar between the two groups, the severity of the throat symptoms is not an indicator for distinguishing ACS from TD, but could be the reason for unreferred cases, delaying the correct diagnosis.

Regarding the local examination of ACS patients, no obvious acute inflammation existed during their local examinations, consistent with previous reports [10–13]. For the infarction site of ACS patients in the present study, throat discomfort of cardiac origin was mostly associated with inferior wall ischemia, and this condition was the same as those in previous reports regarding craniofacial pain of cardiac origin [29]. This condition is associated with the function of vagal nerve [29]. The vagus and sympathetic nerve supplies both the heart and throat. The terminal end of the cervical sympathetic ganglion is located at the pharynx. When ACS occurs, pain or discomfort may be experienced in the throat, manifested as radiating or referred pain.

Overall, our study provided new methods for the prompt screening out of the possible at-risk patients of ACS by clinical manifestation. Notably, the presentation of chest tightness, perspiration, and dyspnea in patients who complain of throat discomfort and patients with exertional throat symptoms should lead to exploration of possible cardiac problems. This information should be noted by cardiac physicians, as well as non-cardiac doctors, especially ENT doctors. Further examinations, including ECG, myocardial enzyme detection, and laboratory microbiologic testing [15,17,18] could help distinguish ACS from common pharyngitis.

The study is naturally limited by its retrospective nature. Further prospective studies enrolling all patients with throat pain could potentially elucidate the prevalence of cardiac causes of throat pain. A potential ramification of our study for clinical practice is to educate patients and clinicians of the ACS presentation as throat discomfort. Physicians should have a high index of suspicion in patients with throat discomfort associated with ACS features. ECG and cardiac testing can be of help in such cases where alternate diagnoses are suspected.

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