a b s t r a c t

Background: sex differences in heart diseases, including acute coronary syndrome, congestive heart failure, and atrial fibrillation, have been studied extensively. However, data are lacking regarding sex differences in pericar- ditis and myopericarditis patients.

Objectives: The purpose of the study was to evaluate whether there are sex differences in pericarditis and myopericarditis patients as well.

Methods: We performed a retrospective, single-center observational study that included 200 consecutive patients hospitalized with idiopathic pericarditis or myopericarditis from January 2012 to April 2014. Patients were eval- uated for sex differences in prevalence, clinical presentation, Laboratory variables, and outcome. We excluded pa- tients with a known cause for pericarditis.

Results: Among 200 consecutive patients, 55 (27%) were female. Compared with men, women were significantly older (60 +- 19 years vs 46 +- 19 years, P b .001) and had a higher rate of chronic medical conditions. Myopericarditis was significantly more common among men (51% vs 25%, P = .001). Accordingly, men had sig- nificantly higher levels of peak troponin (6.8 +- 17 ng/mL vs 0.9 +- 2.6 ng/mL, P b .001), whereas women present- ed more frequently with pericardial effusion (68% vs 45%, P = .006). Interestingly, women had a significantly lower rate of hospitalization in the cardiology department (42% vs 63%, P = .015). Overall, there were no signif- icant differences in ejection fraction, type of treatment, complications, or in-hospital mortality.

Conclusions: Most patients admitted with acute idiopathic pericarditis are male. In addition, men have a higher prevalence of myocardial involvement. Significant sex differences exist in laboratory variables and in hospital management; however, the outcome is similar and favorable in both sexes.

(C) 2016

Introduction

Sex differences in heart diseases have been studied extensively. Numerous studies have shown that females diagnosed as having acute coronary syndrome or atrial fibrillation have adverse outcomes compared with males [1-3]. The increased risk is attributed to older age and higher prevalence of chronic conditions [4,5]. On the other hand, female sex is associated with better survival among patients with advanced heart failure [6].

? Conflict of interest: None on the part of any author.

?? Financial disclosure: None.

? Funding/support: None.

?? All authors take responsibility for all aspects of the reliability and freedom from bias of

the data presented and their discussed interpretation

* Corresponding author at: Department of Cardiology, Tel Aviv Medical Center, 6 Weizman St, Tel Aviv, Israel. Tel: +972 52 7360430; fax: +972 3 6962334.

E-mail address: michalpela@gmail.com (M. Laufer-Perl).

There are limited data regarding sex differences among pericarditis and myopericarditis patients. Previous research revealed conflicting re- sults regarding sex differences in the prevalence of pericarditis. Several studies found males to be at increased risk for acute pericarditis and myopericarditis [7-9], whereas other studies have reported no specific sex predisposition for pericarditis [10]. None of the studies addressed differences in clinical presentation, laboratory variables, diagnostic tests, and management.

The incidence of acute pericarditis is difficult to quantify because there are undoubtedly many Undiagnosed cases. It is a common disease, accounting for up to 5% of patients presenting to the emergency department with nonischemic chest pain [11,12]. Therefore, it is important to recognize whether there are sex differences in prevalence, clinical pre- sentation, and outcome, to improve the diagnosis and management of these patients.

The aim of the current study was to evaluate sex differences in prevalence, clinical presentation, laboratory variables, and outcomes among patients admitted with the diagnosis of pericarditis and myopericarditis.

http://dx.doi.org/10.1016/j.ajem.2016.10.039

0735-6757/(C) 2016

Methods

Study population

We performed a retrospective, single-center observational study at the Tel-Aviv Medical Center. The study population included all 264 consecutive patients 18 years or older who were admitted to our facility between January 2012 and April 2014, and who were discharged with the diagnosis of idiopathic pericarditis or myopericarditis (International Classification of Diseases codes 420, 422, 423, 429). We excluded patients with an Underlying etiology for pericarditis or myopericarditis, among them 21 patients with malignancy, 12 with autoimmune disease exacerbation, 1 with active tuberculosis infection, 5 with status post-myocardial infarction, and 25 with status postprocedural intervention, leaving a total of 200 patients in our cohort (Fig. 1).

The diagnosis of acute pericarditis was made according to the 2015 European guidelines [13], which require 2 of the following clinical criteria: pericarditic chest pain, pericardial rubs, new widespread ST- elevation or PR depression, or pericardial effusion (new or worsening). Additional supporting findings were evaluated as well, including inflammatory markers (white blood cells, C-reactive protein), chest x-ray, and echocardiography. A diagnosis of idiopathic pericarditis was made when no specific cause could be found with routine diagnostic testing, including immonulogy and viral panel [14]. The term myopericarditis indicates a primarily pericarditic syndrome with minor myocardial involvement, which describes most of combined pericarditis and myocarditis cases encountered in clinical practice [13]. The diagnosis of myopericarditis was established if the patient fulfilled the definite diagnosis of acute pericarditis and showed biochemical evidence of myonecrosis (abnormal levels of ultra-High-sensitive troponin N0.05 ng/mL or creatine kinase N174 U/L [7,13].

Sex differences were evaluated for prevalence, duration of hospital- ization, clinical presentation, laboratory results, electrocardiographic changes, echocardiography findings, in-hospital management (type of imaging, what department were they treated in), type of treatment, in-hospital complications, and in-hospital mortality.

The study was approved by the institutional ethics committee.

Table 1

Baseline characteristics

Variable	Male (n = 145)	Female (n = 55)	P
Age (y), mean +- SD	46 +- 19	60 +- 19	b.001
History of smoking, n (%)	46 (32)	13 (24)	.263
Hypertension, n (%)	29 (20)	19 (34)	.032
Hyperlipidemia, n (%)	24 (17)	17 (31)	.025
Diabetes mellitus, n (%)	12 (8)	10 (18)	.046
Ischemic heart disease, n (%)	14 (10)	5 (9)	.903
Congestive heart failure, n (%)	4 (3)	1 (2)	.699
Valvular disease, n (%)	2 (1)	0 (0)	.381
Permanent pacemaker, n (%)	3 (2)	1 (2)	.910
History of atrial fibrillation, n (%)	5 (3)	4 (7)	.244
History of Stroke, n (%)	6 (4)	3 (5)	.688
History of pericarditis, n (%)	10 (7)	3 (5)	.712

Statistical analysis

All data were summarized and displayed as mean +- SD for continuous variables and as number (percentage) of patients in each group for categor- ical variables. The P values for the categorical variables were calculated with the ?² test. Continuous variables were compared using the independent- sample t test or Mann-Whitney tests as appropriate and not an analysis of variance testing for which the Bonferroni correction is used. Therefore, we did not add the Bonferroni correction. We analyzed the whole cohort and then conducted a subgroup analysis only on troponin-positive patients (myopericarditis) for sex differences. A 2-tailed P value less than .05 was considered significant for all analyses. All analyses were performed with the SPSS software (SPSS Inc, Chicago, IL).

Results

Baseline Characteristics

The study population included 200 consecutive patients (Fig. 1), of whom 55 (27%) were female. Baseline characteristics of the patient population are presented in Table 1.

Fig. 1. Flowchart of the study design.

Table 2

Clinical presentation and diagnostic tests

Variable	Male	Female	P
	(n = 145)	(n = 55)
Myopericarditis, n (%)	74 (51)	14 (25)	.001
Chest pain, n (%)	131 (90)	45 (82)	.098
Dyspnea, n (%)	42 (29)	20 (36)	.312
Fever, n (%)	63 (43)	19 (35)	.253
PR depression in ECG, n (%)	32 (22)	10 (18)	.547
ST elevation in ECG, n (%)	72 (50)	12 (22)	b.001
Inverted T in ECG, n (%)	27 (19)	11 (20)	.824
Pleural effusion, n (%)	39 (27)	16 (29)	.777
Peak troponin (ng/mL), mean +- SD	6.8 +- 16.9 17	0.9 +- 2.4 2.6	b.001
Peak CPK (U\L), mean +- SD	275 +- 336	70 +- 58	b.001
Peak CRP (mg\L), mean +- SD	100 +- 74	111 +- 87	.423
Peak WBC (103/uL), mean +- SD	10 +- 4	11 +- 4	.500
Pericardial effusion, n (%)	62 (45)	34 (68)	.006
Ejection fraction b50, n (%)	22 (16)	5 (11)	.365
E/A, mean +- SD	1.4 +- 0.5	1.3 +- 0.6	.179
Deceleration time, mean +- SD	183 +- 55.3	191 +- 60.5	.422
E/e? average, mean +- SD	7.9 +- 2.7	11.8 +- 6.2	b.001
Performed CT coronary, n (%)	24 (17)	6 (11)	.318
Performed coronary angiography, n (%)	23 (16)	10 (18)	.693

Abbreviations: CPK, Creatine phosphokinase; CRP, C-reactive protein; CT, computed tomography; WBC, white blood cells.

Compared with male patients, female patients were significantly older (60 +- 19 years vs 46 +- 19 years, P b .001) and had a significantly higher rate of comorbidities (Table 1). There was no significant differences in the history of pericarditis (5% vs 7%, P = .71) between the sexes.

Clinical presentation

Myocardial involvement (myopericarditis) was significantly more common among men (51% vs 25%, P = .001; Table 2 and Fig. 2).

On presentation, there were no significant differences in Typical symptoms between women and men, including chest pain (82% vs 90%, P = .1), dyspnea (36% vs 29%, P = .31), or fever (35% vs 43%, P = .25). Regarding typical electrocardiographic changes, only ST elevation was significantly more common in men (50% vs 22%, P b .001; Fig. 2). Most patients were evaluated by echocardiography (184 patients; 92%), with only a minority of 16 patients (8 men [4%] and 8 women [14%]) not performing the examination due to reasons unknown to us. Based on the echocardiography, pericardial effusion was significantly more common among women (68% vs 45%, P =

.006), although there was no significant difference regarding the diag- nosis of tamponade. In addition, diastolic pattern abnormalities, based on mean E/e? average ratio (11.8 +- 6.2 vs 7.9 +- 2.7, P b .001), were more common among women. There were no significant differences be- tween women and men in performing computed tomography (11% vs 17%, P = .32) or coronary angiography (18% vs 16%, P = .69) evaluation.

Laboratory tests

Myopericarditis was more common among men, with significantly higher levels of peak troponin (6.8 +- 17 ng/mL vs 0.9 +- 2.6 ng/mL, P b .001) and peak creatine kinase (275 +- 336 U/L vs 70 +- 58 U/L,

P b .001; Table 2).

Treatment

Women were less likely to be hospitalized in the cardiology depart- ment (42% vs 63%, P = .015) and had a trend toward longer hospitaliza- tion (4.8 +- 3.84 days vs 3.8 +- 3.12 days, P = .08; Table 3). Overall, there were no significant differences between women and men regarding the medical treatment applied, including nonsteroidal anti-inflammatory drugs (53% vs 50%, P = .73), steroids (20% vs 17%, P = .581), and

colchicine (53% vs 58%, P = .475).

Outcome

Overall, there were no significant differences in the incidence of complications, including tamponade or the need for pericardiocentesis (Table 3). Importantly, there was no significant difference in the total in-hospital mortality (1% vs 0%, P = .53).

Subgroup myopericarditis

Among myopericarditis patients, men tend to be even younger (36 +- 14 vs 60 +- 26 years, P = .004) and presented more commonly

with chest pain (97% vs 86%, P = .06) and fever (50% vs 14%, P =

.014). Women still had a lower rate of hospitalization in the cardiology department (64% vs 89%, P = .016), although no significant differences were demonstrated in the medical treatment applied or in-hospital complication and mortality.

Fig. 2. Sex differences in clinical presentation.

Table 3

Treatment and outcome

Variable	Male (n = 145)	Female (n = 55)	P
Days of hospitalization, mean +- SD	3.8 +- 3.12	4.8 +- 3.84	.076
Hospitalization in cardiology	92 (63)	23 (42)	.015
department, n (%) NSAIDs therapy, n (%)	72 (50)	29 (53)	.731
Steroids therapy, n (%)	24 (17)	11 (20)	.581
Colchicine therapy, n (%)	84 (58)	29 (53)	.475
Tamponade, n (%)	9 (6)	3 (6)	.888
Pericardiocentesis, n (%)	9 (6)	5 (9)	.483
In-hospital mortality, n (%)	1 (1)	0 (0)	.536

Abbreviation: NSAIDs, nonsteroidal anti-inflammatory drugs.

Discussion

In the present work, performed in a cohort of consecutive pericardi- tis and myopericarditis patients, a male dominance was observed with a younger age and a higher prevalence of myocardial involvement. Although significant sex differences exist in hospital management, the outcome was similar and favorable in both sexes.

Sex differences in heart conditions, including acute coronary syndrome, atrial fibrillation, and congestive heart failure, are well studied and observed [15,16]. Nevertheless, few data are known regarding patients with acute idiopathic pericarditis.

Previous reports have shown that among patients with acute idiopathic pericarditis and myopericarditis, male sex was dominant, with a prevalence of 60% to 65% in most studies [7,17]. Our study was consistent with these findings, with an even higher male dominance

(73%). As reported in previous studies [17], we also found that women present at an older age compared with men and, accordingly, present with a higher prevalence of chronic diseases.

Our study showed that myocardial involvement was relatively frequent, appearing in 44% of the patients. Moreover, myopericarditis was more common among men, with a high dominance of 84%, as reported in previous studies [7,18].

The reasons for sex differences in the prevalence of pericarditis and myopericarditis are unknown. We considered 2 main hypotheses. The first is underdiagnosis among women. Pericarditis is a disease charac- terized by young age at presentation and is suspected in patients pre- senting with chest pain. Because acute coronary syndrome in the young population is more common among men [19], it is possible that women having chest pain seek medical attention less frequently, and even when doing so, it may be underdiagnosed by the medical staff due to unawareness to heart diseases among young women. A second possible explanation relates to sex hormone differences [8,20] (Fig. 3). In men, testosterone plays a major role in the development of myocar- ditis, by a combined mechanism of inhibition of anti-inflammatory cells [21], commitment to a Th1-type immune response [22], and by in- creasing viral binding to myocytes [21,23]. In women, progesterone ag- gravates cardiac inflammation [24], whereas estrogen has inhibitory effects of proinflammatory T cells [9]. Accordingly, Kyto et al [17] found that during the postmenopausal period, when estrogen levels are low, the incidence of PEricarditis is higher, which explains the higher mean age among women.

Unlike acute coronary syndrome [2], no differences were observed in the clinical presentation of the total study population. On the other hand, in the subgroup of myopericarditis patients, men presented

Fig. 3. Sex hormone differences as a mechanism for sex differences.

more frequently with chest pain and fever. Regarding the diagnostic tests that were performed, differences were shown in ECG, with a higher incidence of ST elevation among men. In addition, significant differences were found on echocardiography, with a higher incidence of pericardial effusion and diastolic dysfunction among women. The frequency of pericardial effusion might be related to sex hormone differences between the sexes, with progesterone aggravates cardiac inflammation and may cause the formation of pericardial inflamed effusion [24]. More researches are needed to better understand this mechanism. On the other hand, the frequency of diastolic dysfunction might be a consequence of an older age at presentation, combined with a greater prevalence among females in general [25].

Interestingly, we are the first to observe that women were hospital- ized less frequently in the cardiology department compared with men. This held true in the total study population (42% vs 63%, P = .015) and in the subgroup of myopericarditis (64% vs 89%, P = .016). This de- mands further investigation as to whether these differences in manage- ment are sex related, or whether they are derived from underdiagnosis of women by the medical staff or perhaps due to higher levels of tropo- nin in men, which usually influences the decision for hospitalization in a cardiology department.

Although there were differences regarding the department of hospitalization, there were no significant differences in the medical treatment. Most importantly, consistent with the study conducted by Imazio et al [7], the overall prognosis was excellent with only one case of in-hospital mortality.

Limitations

This was a single-center retrospective, observational study, and as such may have been subject to bias, although we included consecutive patients. Another limitation is the inclusion criteria of diagnosis of acute idiopathic pericarditis, which is based on a clinical algorithm that was not dictated by a specific protocol.

Conclusions

Our study is novel by comparing multiple variants in sex differences in clinical presentation, laboratory variables, and hospital management, among patients admitted with pericarditis and myopericarditis. Our study demonstrated that in line with other heart diseases, sex differences do exist in inflammatory Cardiac conditions, with a significantly higher prevalence and with increased myocardial involvement among men. Further studies are needed to evaluate the mechanism responsible for these differences.

Acknowledging these differences may improve the diagnosis and treatment of pericarditis and myocarditis among women.

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