Clinical Presentation and Laboratory Findings in Men Versus Women with Myocarditis

Abstract

Objectives:

Understanding sex differences in myocarditis is crucial to improve clinical care. We sought to investigate sex differences focusing on clinical presentation and laboratory parameters.

Methods:

From 2011 to 2018, 77 patients were diagnosed with myocarditis according to European Society of Cardiology (ESC) criteria with available clinical, laboratory, and cardiac magnetic resonance imaging data. First, we investigated sex differences of clinical and laboratory parameters in the entire cohort of 77 patients. Second, we focused on patients with acute myocarditis (n = 51) defined as recent symptom onset (≤10 days).

Results:

Myocarditis was present in 63 men (82%) and 14 women (18%). While men most frequently presented with chest pain (78%), a considerable amount of women presented with dyspnea as the only symptom (40%). Within the entire cohort, only creatinine kinase (CK) was higher in men versus women (364 ± 286 vs. 147 ± 148 U/L, p = 0.007), while in patients with acute myocarditis both CK and myoglobin (Mb) were higher in men versus women (CK: 327 ± 223 vs. 112 ± 65 U/L, p = 0.004 and Mb: 111 ± 126 vs. 25 ± 29 μg/L, p = 0.04). No sex differences were found for high-sensitivity troponin T, C-reactive protein, and NT-probrain natriuretic peptide.

Conclusions:

This is the first study reporting sex differences in clinical presentation and routine laboratory parameters in myocarditis. While clinical presentation appeared to be subtle in women with dyspnea being the only presenting symptom of myocarditis in a considerable part, men typically complained of chest pain. Similarly to observations in myocardial infarction, atypical symptoms and underdiagnosis may be a cause for under-representation of women in cohorts of myocarditis.

Introduction

Sex-specific differences have been increasingly recognized in cardiovascular medicine.^1

–5 In the field of molecular analysis and transcriptomics, various types of cardiomyopathies have been investigated,^6

–11 among which sex-specific differences have been identified on the gene expression level in patients with new-onset and end-stage heart failure.⁵ In the era of precision medicine, there is strong agreement within the scientific community that investigation of sex differences among cardiomyopathies is a necessity for improved clinical care¹² and improved therapies through deeper understanding of the pathophysiology.^3,13,14 Specifically, in the field of myocarditis, clinical studies have identified various differences in the incidence and trajectory of myocarditis in men versus women.^15,16 Overall, studies have repeatedly reported cohorts of myocarditis that contained a much greater percentage of men versus women affected by the disease.^15
–17 With regard to clinical trajectory, the Intervention in Myocarditis and Acute Cardiomyopathy (IMAC) Study-2 demonstrated that female sex was associated with lower risk of death and cardiac transplantation.¹ In line with that, animal studies have demonstrated that male mice develop more severe myocardial inflammation than females.^18,19 Similarly, in humans it has been shown by Cocker and colleagues that male patients with acute myocarditis presented with more severe disease on cardiac magnetic resonance (CMR) imaging.² Interestingly, men were found to develop more fibrosis than women on CMR.² Thus, one may speculate that this leads to greater proarrhythmogenic potential and as a consequence higher risk of sudden cardiac death. Furthermore, hypertrophy has been shown to be ∼30% more common in men than in women,²⁰ which has been suggested to be a consequence of higher testosterone levels inducing muscular growth in the heart.²¹ Given the fact that cardiac hypertrophy and, as a consequence, increased heart weight are more common in men, it appears plausible that cardiac enzymes released from cardiomyocytes during inflammation may reach higher serum levels in male sex. Also, since myocarditis commonly occurs in the context of a systemic inflammatory state with involvement of skeletal musculature (e.g., viral illness), markers of skeletal muscle breakdown may be elevated to higher levels in men. Furthermore, we sought to evaluate if sex-specific differences in clinical presentation occur among patients with myocarditis similar to the previously described Yentl syndrome in acute coronary syndrome.¹² Such a phenomenon may explain a strong under-representation of women among previously published cohorts of patients with myocarditis, which typically ranges from 20% to 30%.¹⁶ Our study sought to investigate sex differences in clinical presentation and laboratory parameters of patients with myocarditis.

Methods

Patient population

We performed a single-center retrospective chart review of patients, who presented to the University Hospital of Zurich with clinically suspected myocarditis and underwent CMR for further diagnostic evaluation. Patients with CMR findings suggestive of myocarditis detected from January 2011 to February 2018 were included in our study. Myocarditis was diagnosed based on European Society of Cardiology (ESC) diagnostic criteria.²² In addition, CMR findings such as signs of edema on T2-weighted images and positive late gadolinium enhancement (LGE) with diffuse midwall or epicardial patterns were regarded as suggestive of myocarditis.²³ Patients presenting with angina-like symptoms, elevation of high-sensitivity troponin T (TnT-hs), and exclusion of obstructive coronary artery disease (CAD) by coronary angiography were included in this analysis. Coronary angiography was performed by cardiac catheterization or computed tomography if pretest probability for CAD was very low. The Ethics Committee of the Kanton of Zurich approved the study.

Total population of acute and chronic myocarditis

First, we analyzed all patients presenting with myocarditis to our hospital between January 2011 and February 2018 with available clinical and laboratory data to identify sex-specific differences in demographics, comorbidities, clinical presentation, left ventricular ejection fraction (LVEF), and laboratory parameters.

Acute myocarditis

Then, we analyzed a subgroup of patients with acute myocarditis by restricting the analysis to patients with recent symptom onset (≤10 days), as described previously.¹⁵ Fulminant myocarditis was defined as new onset heart failure with hemodynamic instability, while new left ventricular dysfunction in hemodynamically stable patients was regarded as acute nonfulminant myocarditis.^24,25

Exclusion criteria were as follows: chronic or recurrent myocarditis, symptoms >10 days, and/or known myositis. Symptom onset was defined by the occurrence of at least one of the following complaints: chest pain, dyspnea, new-onset or worsening heart failure, ventricular tachycardia, syncope, or cardiac arrest.

As mentioned above, we investigated demographics, comorbidities, clinical presentation, LVEF, and laboratory parameters in the cohort restricted to acute myocarditis.

Laboratory parameters

As previously described,¹⁵ the following blood parameters were analyzed on the day of admission: TnT-hs, creatine kinase (CK), myoglobin (Mb), NT-probrain natriuretic peptide (NT-proBNP), C-reactive protein (CRP), leukocytes, and thrombocytes. Reference ranges in our core laboratory are defined as follows: TnT-hs: ≤14 ng/L; CK: 190 IU/L for men and 170 IU/L for women; Mb: 28–72 μg/L for men and 25–58 μg/L for women; NT-proBNP: <125 pg/mL; CRP: ≤5 mg/L; leukocytes: 3–9.6 G/L; and thrombocytes: 143–400 G/L.

CMR examination

Diagnosis of myocarditis was based on cine-CMR, T2-weighted imaging, and T1-weighted LGE images performed on a 1.5- or 3.0-Tesla scanner (SiemensSkyra, Erlangen, Germany or Philips Achieva, Best, The Netherlands) using an electrocardiography-gated breath-hold protocol.¹⁵

LGE short-axis images were generated 10 minutes after intravenous administration of a gadolinium-based contrast agent. Routine CMR reporting included evaluation of LVEF and wall motion abnormalities. Pericardial involvement was defined as pericardial thickening or effusion on CMR. Two experienced analysts of CMR interpreted all imaging data of this study under the oversight of the director of cardiac imaging in our division. Data analysis was performed in a blinded manner.

Statistical analysis

All statistical analyses were performed with SPSS (version 23 SPSS, Chicago, IL) and Stata (version Stata/SE 13.1, TX). Significance was defined as p-value <0.05. First, we analyzed sex-specific differences in clinical presentation within all patients presenting to our hospital with symptoms of myocarditis. Then, we restricted our analysis to patients with acute myocarditis, defined as symptom onset within ≤10 days. Numerical values were analyzed with Student's t-test, and chi-square was used for categorical values. To compare laboratory parameters including CK and Mb with sex-adjusted thresholds, the scale model standardization was used. Therefore, values of female patients were multiplied by the ratio of the upper limit of men and the upper limit of women. The first author had full access to all data in the study, and takes responsibility for its integrity and the data analysis.

Results

Patient characteristics of the total population of acute and chronic myocarditis

First, we investigated sex-specific differences in the overall population of patients with myocarditis. A total of 77 patients were diagnosed with myocarditis and met inclusion criteria for the first analysis. Baseline conditions of patients with acute and chronic myocarditis are illustrated in Table 1. The proportion of men was larger than the proportion of women (n = 63, 82% vs. n = 14, 18%). The mean age in men was 40 ± 16 years, while it was 40 ± 17 years in women (p = 0.86). The average BMI was almost identical in both groups: men 27 ± 4 kg/m² and women 27 ± 6 kg/m² (p = 0.69). Comorbidities such as nonobstructive CAD, arterial hypertension (aHTN), hyperlipidemia (HLD), diabetes mellitus, atrial fibrillation, atrial flutter, and heart failure were overall rare and did not differ between groups (Table 1).

Table 1.

Baseline Characteristics of Patients with Myocarditis Overall

CharacteristicsAll cases of myocarditis	Men (n = 63)	Women (n = 14)	p-Value
Mean age, years (±SD)	40 ± 16	40 ± 17	0.86
Mean BMI, (kg/m²) (±SD)	27 ± 4	27 ± 6	0.69
Nonobstructive CAD, n (%)	5 (8%)	1 (7%)	0.25
aHTN, n (%)	10 (16%)	1 (7%)	0.63
HLD, n (%)	5 (8%)	0 (0%)	NA
DM, n (%)	2 (3%)	0 (0%)	NA
Atrial fibrillation, n (%)	5 (8%)	1 (7%)	0.92
Atrial flutter, n (%)	1 (2%)	0 (0%)	NA
HF, n (%)	6 (17%)	4 (30%)	0.634
LVEF, mean (±SD)	51 (±13)	57 (±12)	0.14
TnT-hs, ng/L (±SD)	597 (±753)	255 (±436)	0.11
CK, U/L (±SD)	364 (±286)	147 (±148)	0.007^*
Mb, μg/L (±SD)	175 (±367)	33 (±38)	0.17
NT-proBNP, ng/L (±SD)	1148 (±2681)	1190 (±2253)	0.96
CRP, mg/L (±SD)	21 (±33)	8 (±6)	0.13
Lc, G/L (±SD)	9 (±4)	9 (±3)	0.73
Tc, G/L (±SD)	245 (±104)	260 (±89)	0.63

p-value <0.05

aHTN, arterial hypertension; BMI, body mass index; CAD, coronary artery disease; CK, creatine kinase; CRP, C-reactive protein; DM, diabetes mellitus; HLD, hyperlipidemia; Lc, leukocytes; LVEF, left ventricular ejection fraction; Mb, myoglobin; NT-pro BNP, NT-probrain natriuretic peptide; NA, not applicable; SD, standard deviation; Tc, thrombocytes; TnT-hs, high-sensitivity troponin T.

There were no significant differences in baseline parameters of men vs women, except for CK, which was higher in men (364 ± 286 vs 147 ± 148 U/l, p = 0.007) even after adjusting for sex specific reference ranges (364 ± 286 vs. 164 ± 44 U/l, p = 0.013). Other laboratory parameters including TnT-hs, myoglobin, CRP, NT-pro-BNP, leukocytes, and thrombocytes did not differ between men and women when analyzed in the cohort comprised of chronic and acute myocarditis (Table 1). Furthermore, LVEF was similar in men (51 ± 13%) vs women (57 ± 12%, p = 0.14).

Clinical parameters of acute myocarditis

Fifty-one patients were diagnosed with acute myocarditis during the years 2011–2018 and met inclusion criteria for this study. Baseline parameters of patients with acute myocarditis are illustrated in Table 2. The cohort consisted of 41 men (80%) and 10 women (20%). Men presented at a mean age of 41 ± 18 years, while the mean age in women was 40 ± 20 years (p = 0.93). Average BMI of both groups was >25 kg/m² with a trend for higher BMI in women although not reaching level of significance (28 vs. 26 kg/m²; p = 0.21). Similar to the combined cohort, comorbidities were overall rare in acute myocarditis, and did not differ between men and women (Table 2). Among patients with acute myocarditis, 6% were found to have nonobstructive CAD, 14% aHTN, 4% HLD, 2% diabetes, 6% atrial fibrillation, 2% atrial flutter, and 16% symptoms of heart failure.

Table 2.

Baseline Characteristics of Patients with Acute Myocarditis

CharacteristicsAcute myocarditis	Men (n = 41)	Women (n = 10)	p-Value
Mean age, years (±SD)	41 ± 18	40 ± 20	0.93
Mean BMI, (kg/m²) (±SD)	26 ± 3	28 ± 6	0.21
Nonobstructive CAD, % (n)	5 (2)	10 (1)	0.54
aHTN, % (n)	15 (6)	10 (1)	0.70
HLD, % (n)	5 (2)	0 (0)	NA
DM, % (n)	2 (1)	0 (0)	NA
Atrial fibrillation, % (n)	5 (2)	2 (1)	0.54
Atrial flutter, % (n)	2 (1)	0 (0)	NA
HF, % (n)	15 (6)	2 (2)	0.68
LVEF, mean (±SD)	52 (±12)	59 (±9)	0.14
TnT-hs, ng/L (±SD)	617 (±761)	187 (±187)	0.08
CK, U/L (±SD)	327 (±223)	112 (±65)	0.004^*
Gender-adjusted CK, U/L (±SD)	327 (±223)	123 (±72)	0.007^*
Mb, μg/L (±SD)	111 (±126)	25 (±29)	0.04^*
Gender-adjusted Mb, μg/L (±SD)	111 (±126)	30 (±34)	0.051
NT-proBNP, ng/L (±SD)	1228 (±3045)	339 (±418)	0.40
CRP, mg/L (±SD)	12 (±17)	10 (±5)	0.70
Lc, G/L (±SD)	9 (±4)	9 (±3)	1.0
Tc, G/L (±SD)	241 (±73)	268 (±103)	0.35

p-value <0.05.

With respect to clinical symptoms in acute myocarditis, more men presented with chest pain (n = 32, 78%) than dyspnea (n = 4, 10%). In addition, one patient presented with abdominal pain. In the female cohort, only six patients complained of chest pain (60%), whereas four complained of dyspnea (40%) (Table 3).

Table 3.

Symptoms of Patients with Acute Myocarditis

SymptomsAcute myocarditis	Men (n = 41)	Women (n = 10)	p-Value
Cardiac arrest, % (n)	7 (3)	10 (1)	0.78
Cardiogenic shock, % (n)	2 (1)	0 (0)	0.62
Chest pain, % (n)	78 (32)	60 (6)	0.24
Abdominal pain, % (n)	2 (1)	0 (0)	0.62
Dyspnea, % (n)	10 (4)	40 (4)	0.02^*

p-value <0.05.

One woman presented with cardiac arrest due to ventricular tachycardia. Among men, one (2.5%) participant was resuscitated for ventricular tachycardia, two (5%) for ventricular fibrillation, and one (2.5%) patient developed cardiogenic shock. Baseline LVEF did not differ between men and women (52% ± 12% vs. 59% ± 9%, p = 0.14). In total, fulminant myocarditis was present in one (10%) woman and four (10%) men among patients with acute myocarditis.

Sex-specific differences of cardiac biomarkers and inflammatory parameters in acute myocarditis

Myoglobin was elevated in men vs women (111 ± 126 vs 25 ± 29μg/l, p=0.04, Table 2). After adjusting for sex specific reference ranges, a non-significant trend remained (111 ± 126 vs. 30 ± 34 IU/l, p = 0.051). The sex specific difference of CK (327 ± 223 vs 112 ± 65 IU/l, p = 0.004; Table 2) remained after adjustment for sex specific reference ranges (327 ± 223 vs. 123 ± 72 U/l, p = 0.007). All other laboratory parameters investigated including TnT-hs, CRP, pro-BNP, leukocytes, and thrombocytes did not reveal any sex specific differences (Table 2).

Discussion

This is the first study to investigate sex-specific differences of clinical presentation, muscle enzymes, and inflammatory parameters in myocarditis. One of the major findings of this study was that the most common complaint in men at presentation was chest pain, while a considerable percentage of women presented with dyspnea—a somewhat atypical symptom of myocarditis. This finding raises concern that the observed under-representation of women in previously described clinical cohorts could be caused by underdiagnosis, as it had been observed previously in coronary syndrome.

Another important observation was that serum levels of CK and Mb are significantly higher in men as compared with women with acute myocarditis. CK serum levels were also found to be higher in the entire cohort that included chronic cases of myocarditis, while Mb levels did not differ. Surprisingly, other biomarkers and laboratory parameters such as TnT-hs, CRP, NT-proBNP, leukocytes, and platelet counts were similar in both groups.

CK is a muscle enzyme that catalyzes transfer of high-energy phosphate group from phosphocreatine to adenosine diphosphate generating triphosphate in mitochondria and cytosol. Given the strong presence of CK in the contractile proteins of myocytes, many factors leading to myocyte injury can lead to its elevation.²⁶ Since CK is known to be present in both cardiac and skeletal muscles, which tend to have higher mass in men as compared with women,^20,21 the finding of higher CK levels in men with acute myocarditis is biologically plausible. As the cardiac-specific TnT-hs did not differ, it is possible that CK might also be released from noncardiac muscle during active inflammation.

While sex-specific differences in CK have not been described in myocarditis as of today, various studies in the general population reported that CK levels are affected by sex. In that regard, Yen and colleagues have demonstrated in a study of 4,562 healthy asymptomatic Asians that CK levels were more frequently elevated in men than in women.²⁷ Similarly, Wong and colleagues have described sex-specific differences of CK levels in the general population.²⁸ Also in patients undergoing statin therapy, higher levels of CK have been observed in males as compared with females.²⁹

Mb, on the contrary, has not been investigated as comprehensively with respect to sex differences. Mb is a skeletal and cardiac muscle protein with the capability of binding and delivering oxygen to mitochondria.³⁰ It gets released within 3 hours of myocardial injury^31

–34 and eliminated with a half-time of 5.2 minutes.³⁵ In contrast, the elimination half-life of CK is ∼36 hours. This fact may have contributed at least partially to the observation that no sex-specific differences were observed for Mb when including chronic cases, while sex differences of CK remained significant. Similar to CK, Mb is expressed in both cardiac and skeletal muscles, which again makes it conceivable that levels of Mb were found to be higher in men given the larger muscle mass. Myocarditis has been shown to commonly present as systemic illness that may affect skeletal muscle.³⁶

Similar to prior reports, we identified a much greater proportion of men than women with myocarditis.^15,16 Comprehensive data from animal experiments suggest that testosterone may be a key player in the activation of the inflammatory processes in acute myocarditis, in particular by activating Th1 response. Another potential mediator of altered immune response in male patients could be higher levels of Interleukin (IL)-6 and IL-17A as commonly found in men, which have been associated with worse cardiac outcomes and could contribute to the development of heart failure in patients with myocarditis. These factors may explain the over-representation of men in this type of cardiomyopathy.^18,37
–39 While to the best of our knowledge no prior studies have specifically reported sex-specific differences in presenting symptoms of myocarditis, several studies in the field of heart failure reported sex-specific differences in left ventricular function. The Euro Heart Failure Survey program screened deaths and discharges from medical wards of 24 countries in the European Union between 2000 and 2001 to identify patients with known or suspected heart failure.⁴⁰ Among a total of 46,788 deaths and discharges, 11,327 (24%) were found to have suspected or confirmed heart failure.⁴⁰ Men were more likely to have moderately to severely decreased LVEF, whereas women were more likely to develop diastolic dysfunction.⁴⁰ In line with these findings, Bursi and her team found in 556 residents that patients with preserved LVEF were more likely to be female.⁴¹

Limitations

While there was a trend of higher TnT-hs levels in men, statistical significance was not reached. Sex differences in CK and Mb levels rather than TnT-hs could potentially be explained by a systemic inflammatory state in patients with myocarditis not only affecting the heart but also skeletal muscle. Since TnT-hs is an enzyme specific for the heart, which contributes only a small amount to the overall muscle mass of the human body, it seems plausible that sex differences of TnT-hs are less substantial than those of CK and Mb in a systemic inflammatory state.

Also CK elevation in general has to be interpreted with caution. Indeed, it has been suggested recently that the current reference range of CK (0–200 U/L), which is currently routinely used in most laboratories, may be too restrictive and lead to overdiagnosis of muscular disease.⁴² A study in 1,000 healthy young adults illustrated that by using these parameters, abnormal CK plasma levels were observed in 19% of men and 5% of women. Thus, the actual normal distribution of CK appears to be skewed toward higher values in the normal population and non-Gaussian, while most laboratories use the central 95% of observations in the white population as a reference range assuming a Gaussian distribution.⁴²

In addition, diagnosis of myocarditis was based on clinical and CMR findings rather than endomyocardial biopsy (EMB), which is currently considered the gold standard for definitive diagnosis. Indeed, our population consisted of mostly stable patients with preserved or mildly reduced LVEF in which EMB is not usually performed. In our center, we consider EMB in cases with new onset of heart failure, sustained ventricular tachycardia, or new onset of conduction defect such as atrioventricular heart block Mobitz second or third degree.⁴³ Due to the retrospective character of our study, the time period between symptom onset and CMR performed was not standardized. Moreover, there was no standardized protocol for diagnostic evaluation as multiple physicians were involved in patient care over a long period of time.

This study contains observational data demonstrating a different clinical presentation of men versus women with myocarditis and describing higher levels of CK and Mb in men. Possible causes for these findings have not been investigated. One may hypothesize that the immune response in men may lead to a more severe inflammatory reaction and as a consequence influence clinical presentation, myocyte necrosis, and increased cardiac biomarkers.

Conclusions

In summary, our data show for the first time that there are sex-specific differences in the clinical presentation of patients with myocarditis. A considerable amount of women with myocarditis presented with somewhat atypical symptoms, that is, dyspnea, while men developed primarily chest pain. A more subtle character of symptoms among women with myocarditis may be a contributing factor to under-representation of the female sex in previously published cohorts of myocarditis. With regard to laboratory parameters, CK and Mb were higher in men versus women with acute myocarditis. Raising awareness of these sex differences is crucial to optimize clinical practice and research studies.

Footnotes

Acknowledgments

We thank the staff of the University Hospital Zurich for their help with patient enrollment.

This work was supported through funding from the Forschungskredit of the University of Zurich FK-17-047, the Holcim Foundation (Holcim Stiftung zur Förderung der wissenschaftlichen Fortbildung, Switzerland), the Hartmann Müller Foundation, and the Walter and Gertrud Siegenthaler Foundation issued to Dr. Bettina Heidecker.

Author Disclosure Statement

No competing financial interests exist.

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