Contemporary study of acute myocarditis in South Africa: CAMISA

Abstract

Aims

This study aims to determine the clinical presentations, aetiologies and outcomes of patients presenting with acute myocarditis (AM) in South Africa.

Methods

This is a prospective cohort study. Consecutive patients presenting to Tygerberg Hospital, Cape Town, South Africa, between August 2017 and November 2021 who fulfilled the European Society of Cardiology diagnostic criteria for clinically suspected myocarditis undergoing all recommended investigations, including cardiac MRI (CMR) and endomyocardial biopsy (EMB), were included.

Results

111 cases (mean age 41.2 years, 66.3% male) of clinically suspected myocarditis were recruited. AM was confirmed in 89: 44 (49.4%) on CMR only, 16 (18.0%) on EMB only and 29 (32.6%) on both CMR and EMB. 46 (51.7%) presented with infarct-like symptoms, 31 (34.8%) presented with heart failure (HF), 8 (9.0%) with sustained ventricular tachycardia (VT) and 4 (4.5%) with complete heart block (CHB). Viral pathogens were detected in 52 (58.4%) patients with AM, with Parvovirus B19 the most frequent in 39 (75.0%) as monoinfection and as coinfection in 4 (3 (5.8%) with Epstein-Barr virus (EBV) and 1 (1.9%) with EBV and human herpesvirus 6. The prespecified adverse outcome, defined as the occurrence of major adverse clinical events, including cardiac death, documented sustained VT, recurrence of AM and HF hospitalisation, occurred in 30.3%. Initial presentation with sustained VT (HR 5.36, 95% CI 1.76 to 16.33, p=0.003) or CHB (HR 5.67, 95% CI 1.38 to 23.26, p=0.016) was a significant predictor of adverse outcome on multivariate analysis.

Conclusion

We report data from the largest cohort of patients with AM outside of the developed world. It provides insight into the clinical presentation, aetiology, viral pathogens and outcomes of patients with AM locally. The findings in this cohort from Africa appear similar to the developed world.

WHAT IS ALREADY KNOWN ON THIS TOPIC

• The epidemiology of acute myocarditis (AM) in the developed world had been previously described. It predominantly affects young adult males, with viral infections the most common aetiology identified in North America and Europe, and similarly in South Africa. The clinical presentations and outcomes of patients with AM in South Africa, however, are currently unknown.

WHAT THIS STUDY ADDS

• In this study involving the largest known cohort of patients with AM emanating from Africa, we confirmed the heterogeneity in the clinical presentation, with most patients presenting with symptoms mimicking acute coronary syndrome or heart failure. Viral myocarditis appeared to be the most common form of myocarditis locally. The outcomes of local patients with confirmed myocarditis also did not appear to be completely benign, as the prespecified adverse outcome occurred in 30.3% of our cohort. Initial presentation with ventricular tachyarrhythmia or complete heart block was a significant predictor of poor outcomes.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• The findings of this study highlight the similarities between patients with AM in South Africa and the developed world. These findings also emphasised the importance of a high index of clinical suspicion and access to specialised investigations including cardiac MRI and endomyocardial biopsy in confirming the diagnosis, with early recognition pertinent due to potential adverse outcomes.

Introduction

Myocarditis is defined as an inflammatory disease of the heart muscle, diagnosed by established histological, immunological and immunohistochemical (IHC) criteria.¹ Its clinical diagnosis can be difficult and is often missed due to the heterogeneity of presentations, ranging from symptoms of chest pain and ECG changes mimicking acute myocardial infarction, to life-threatening arrhythmias or sudden cardiac death (SCD).¹ Furthermore, access to cardiac MRI (CMR) and endomyocardial biopsy (EMB), which are both required to make a definitive diagnosis, is severely limited in South Africa.

Although often undetermined, the aetiology of acute myocarditis (AM) is wide ranging and includes a variety of infectious agents, systemic diseases, drugs and toxins.¹ Viral infections are the most common cause of myocarditis in North America and Europe.²,⁶ Parvovirus B19 (PVB19) and human herpesvirus-6 (HHV6) have become the most commonly identified viruses on EMB specimens of patients with viral myocarditis over the past 20 years.²,⁷ However, their aetiological roles and clinical significance remain debated.²,⁷ The most common aetiology of myocarditis in Africa, and particularly South Africa, is unknown.

The prognosis of AM depends largely on the clinical presentation and underlying aetiology. Although often thought to be a benign and self-limiting condition, up to 30% of biopsy-proven myocarditis can progress to dilated cardiomyopathies.^{1 6 8} Factors associated with poor long-term outcome include heart failure (HF) presentation, left ventricular ejection fraction (LVEF) of less than 50% at diagnosis, presence of late gadolinium enhancement (LGE) on CMR and the presence of IHC evidence of inflammation or detection of viral genomes on EMB.⁸,¹² The outcomes of patients with AM in South Africa are currently unknown.

This prospective study aims to determine the clinical presentations, aetiologies and outcomes of patients presenting with AM in a tertiary centre in Cape Town, South Africa.

Methods

Population and study design

This is a single-centre prospective cohort study. Consecutive patients over the age of 18 years presenting to Tygerberg Hospital, Cape Town, South Africa between August 2017 and November 2021 who fulfilled the European Society of Cardiology’s (ESC) diagnostic criteria for clinically suspected myocarditis were enrolled.¹ All potential patients underwent the full panel of recommended investigations, including CMR and EMB.¹ In brief, myocarditis was clinically suspected if patients presented with symptoms compatible with myocarditis, such as chest pain or symptoms of HF, accompanied by at least one additional investigation supporting the diagnosis of myocarditis. This includes newly developed ECG changes such as ST-T wave changes, atrioventricular block (AVB) or ventricular tachycardia (VT), evidence of cardiomyocyte necrosis in the form of elevated cardiac troponins, global or regional dysfunction of the left or right ventricle on transthoracic echocardiography (TTE) or CMR and findings of oedema or a typical pattern of LGE on CMR. Myocarditis was also considered in patients who present with symptoms in keeping with an acute coronary syndrome (ACS) without evidence of obstructive epicardial coronary artery disease or recent plaque rupture on coronary angiography.

All patients underwent a full clinical evaluation. Routine laboratory studies were performed which included a full blood count, renal function, high sensitivity troponin T (hsTnT) and C-reactive protein. Additional laboratory studies were requested at the discretion of the attending physician. All patients also underwent a standard 12-lead ECG, TTE and CMR as per standardised protocols described below. Coronary angiography was performed to exclude any significant epicardial coronary artery disease, defined as >50% stenosis in a single coronary artery segment. Right ventricular EMB was performed on all patients.

As all patients who swabbed positive for COVID-19 during the first waves of the pandemic were not permitted in the MRI suite of our hospital and therefore could not undergo CMR during their initial admission, these patients were excluded from the current study.

All patients with confirmed AM were discharged on maximally tolerated doses of ACE inhibitors and β-blockers, as recommended by the ESC.¹ Additional medical therapy for patients with impaired LVEF and device therapy for those presenting with AVB or sustained VT were guided by the relevant ESC guidelines and at the discretion of the treating physician.^{13 14} Immunosuppressive therapy, if indicated, was administered in a similar regimen to that described in the Tailored Immunosuppression in Virus-Negative Inflammatory Cardiomyopathy (TIMIC) study,¹⁵ with high dose corticosteroids for 1 month followed by a tapered dose for 5 months and a steroid-sparing agent for 6 months. The first follow-up was scheduled for 3 months after discharge at our cardiology outpatient clinic and included a full clinical evaluation, recording of a 12-lead ECG and TTE. Subsequent follow-up visits were scheduled at 6 monthly intervals. To determine endpoint occurrence at the end of the study period, telephonic contact was attempted with all patients. If telephonic contact was not possible, individual patient’s records were sought from the electronic medical records systems of Tygerberg Hospital (Enterprise Content Management, OpenText, Waterloo, Canada), the Western Cape provincial health department (Electronic Continuity of Care Record, Health System Technologies, Cape Town, South Africa; Clinicom, Siemens Healthcare GmbH, Erlangen, Germany). Patients were deemed lost to follow-up if no physical or telephonic contact could be made and if no electronic medical records were found in the past 6 months. The vital status of patients lost to follow-up was confirmed by searching the national death registry.

Transthoracic echocardiography

Comprehensive functional and structural two-dimensional TTE were performed on all patients with Vivid S7 or Vivid E95 (GE Healthcare, Chicago, USA). Measurements were performed in accordance with the British Society of Echocardiography guidelines.¹⁶

Cardiac MRI

This was done in accordance with recommendations as set out in the Journal of the American College of Cardiology’s white paper on CMR in myocarditis and the 2018 update of CMR criteria for myocardial inflammation, as well as the Journal of Cardiovascular Magnetic Resonance’s 2013 CMR protocol update,¹⁷,¹⁹ and was previously described in detail.²⁰ All imaging was done at Tygerberg Hospital using a 1.5T field strength magnet (Magnetom Avanto; Siemens Healthcare GmbH, Erlangen, Germany). CMR analysis was carried out using commercially available software (CMR42, Circle CVI, Calgary, Canada).

CMR case definitions of AM and CMR parameter analysis were made according to either the original or updated Lake Louise criteria (LLC).¹⁷,¹⁹

Endomyocardial biopsy

Right ventricular septal biopsies via femoral access were performed on all patients. EMB procedures were limited to two experienced interventional cardiologists, each with more than 5 years of experience, and an interventional cardiology fellow with more than a year of experience under the supervision of the two experienced interventionists. All procedures were performed via femoral venous access. In order to ensure safety in a low volume centre, routine real-time dynamic TTE guidance with an in-house developed protocol was performed on all procedures in addition to fluoroscopic guidance.²¹ At least six specimens were taken from different sections of the septum to improve sensitivity. Three to four specimens were fixed in 4% buffered formalin for histological and IHC analysis, while the remaining samples were transported in 0.9% saline for viral genome detection by PCR.

Histopathological and immunohistochemical analysis

Specimens were assessed by a single anatomical pathologist at the National Health Laboratory Services. Light microscopy was performed on H&E stained slides, along with IHC testing using anti-CD3 (T lymphocytes), anti-CD163 (macrophages) and anti-HLA-DR to define the types of immune cells. Additional stains, including Congo red, were performed at the discretion of the pathologist. Myocarditis was diagnosed by either the Dallas histological criteria or the WHO/International Society and Federation of Cardiology IHC criteria.^{22 23}

Virological testing of samples

To investigate viruses associated with myocarditis, a combination of multiplex and singleplex PCR assays was used. EMB material was split into two, for nucleic acid extraction, respectively with the Qiagen RNA easy Mini kit, for RNA extraction, and QIAamp DNA Mini kit (Qiagen, Hilden, Germany), for DNA extraction.

To detect adenoviruses and influenza viruses, DNA and RNA were tested with the Anylplex II RV16 (V.1.1) assay (Seegene, Seoul, South Korea); this assay also included parainfluenza viruses, human coronaviruses (229E, NL63 and OC43), human enteroviruses, respiratory syncytial viruses and human bocavirus (limit of detection was 50 copies per reaction (packet insert)). Each assay run included positive and negative controls. Herpesviruses including human herpesvirus 1, 2, human cytomegalovirus, Epstein-Barr virus and HHV6 were tested for with the Seeplex Meningitis-V1 ACE Detection assay (V.2.0) (Seegene, Seoul, South Korea) from the DNA extract; limit of detection ranging from 10 to 50 copies per µL. In addition, DNA was tested with the PVB19 R-gene assay (bioMérieux, Marcy-l'Étoile, France) and to increase the sensitivity for human enteroviruses, RNA was tested using an in-house developed assay as previously described;²⁴ each run including a positive and negative control as part of validity criteria. All virological assays were performed in a diagnostic accredited laboratory, which included frequent proficiency testing as guided by the South African National Accreditation System.

Outcome

The prespecified adverse outcome was the occurrence of major adverse clinical events (MACEs), which included cardiac death, documented sustained VT, recurrence of AM and HF hospitalisation during the follow-up period. If more than one event occurred in a patient, the first event was used. Time to MACE was calculated from the date of first admission. Clinical event adjudication was based on a consensus reached by three cardiologists after review of physical or electronic patient records accessed from the relevant health facilities and information gathered from telephonic contact with patients and relatives.

Statistical analysis

Statistical analysis was performed using SPSS Statistics V.27.0 (International Business Machines, New York, USA). Normality of data was determined using the Kolmogorov-Smirnov test. Continuous variables were expressed as absolute numbers with associated percentages, mean and SD if normally distributed, or median and IQR if not normally distributed. Categorial variables were expressed as absolute numbers and percentages. Comparisons between groups were done by the use of the Kruskal-Wallis or Mann-Whitney U test for non-normally distributed continuous variables and Student t-test for normally distributed variables. The χ² and Fisher exact test were used for comparison of categorical variables. The Kaplan-Meier method was used to construct survival curves of patients grouped by prespecified variables which were then compared with the Mantel-Cox log-rank test. Cox proportional-hazards regression analysis was performed to assess associations between clinical variables and diagnostic findings with prespecified adverse outcome occurrence. After univariate screening, variables with a p value <0.05 were forced to enter a multivariate model to identify independent predictors of outcome defined by p value <0.05. Results are expressed with the HRs and their associated 95% CIs. A 2-tailed p value <0.05 was considered statistically significant.

Results

Between August 2017 and November 2021, 111 patients who presented to Tygerberg Hospital fulfilled the ESC diagnostic criteria for clinically suspected myocarditis.

AM was confirmed in 89 patients: 44 (49.4%) on CMR only, 16 (18.0%) on EMB only and 29 (32.6%) on both CMR and EMB. The mean age of the cohort of patients with AM was 41.2±13.5 years and 66.3% were male. 16 patients were HIV positive with a mean CD4 count of 320.3. The mean duration of symptoms prior to first presentation was 4.9±4.8 days. 55 patients (61.8%) were of mixed ancestry, 31 (34.8%) of black African descent and 3 (3.4%) Caucasian (online supplemental table 1). Viral genomes were detected by PCR on EMB specimens of 52 (58.4%) patients with confirmed AM. Four patients were diagnosed with cardiac sarcoidosis. One patient presented with refractory VT and cardiogenic shock with severely impaired left ventricular systolic function and fulfilled the diagnostic definition for fulminant myocarditis.²⁵ One patient was diagnosed with acute necrotising eosinophilic myocarditis (Figure 2), with no systemic cause of eosinophilia identified.

Viral pathogens were also detected in 12 (54.6%) of 22 patients without AM on CMR or EMB. One case of cardiac amyloidosis and one case of B-cell lymphoma were diagnosed histologically in this group, both were excluded from study analysis.

The baseline demographic data, clinical findings, laboratory investigations, echocardiographic findings and prevalence of viral genomes of patients with confirmed AM and those without are summarised and compared in table 1. Patients with confirmed myocarditis were significantly younger, had significantly higher hsTnT and smaller left ventricles on TTE at presentation.

Table 1. Baseline characteristics of patients with clinically suspected acute myocarditis (n=111).

	Confirmed myocarditis (n=89)	No myocarditis (n=22)	P value
Demographics
Age (year)	41.2±13.5	47.1±11.2	<0.05
Sex, male (n, %)	59 (66.4)	14 (63.6)	ns
HIV+ (n, %)	16 (18.0)	1 (4.6)	ns
Clinical presentation (n,%)
Acute coronary syndrome	46 (51.7)	8 (36.4)
Heart failure	31 (34.8)	9 (40.9)
Heart block	4 (4.5)	1 (4.6)
Ventricular tachycardia	8 (9.0)	4 (18.2)
Clinical findings
Tachycardia (n, %)	40 (44.9)	10 (45.5)	ns
Fever (n, %)	9 (10.1)	0 (0)	ns
Laboratory investigations
White cell count	10.68±4.78	9.90±4.22	ns
CRP (mg/L)	17.0 (IQR 6.0–58.0)	8.00 (IQR 3.0–42.0)	ns
hsTnT (ng/L)	466.0 (IQR 54.0–1095.0)	48.00 (IQR 10.0–145.0)	0.001
Echocardiographic measurements
LVEF (%)	39.8±14.2	34.9±12.7	ns
LVEDD (mm)	51.3±6.5	54.7±6.6	<0.05
TAPSE (mm)	16.39±4.6	16.3±4.9	ns
RV S’ (cm/s)	9.8±2.9	9.1±2.1	ns
GLS (%)	−10.3±4.9	−7.7±3.3	ns
Virus genomes detected (n,%)	52 (58.4)	12 (54.6)	ns
Parvovirus B19	39 (75.0)	11 (91.7)
Epstein-Barr virus	6 (11.5)	0 (0)
Human Herpesvirus 6	2 (3.9)	1 (8.3)
Human Bocavirus	1 (1.9)	0 (0)
Enterovirus	0 (0)	0 (0)
Adenovirus	0 (0)	0 (0)
PVB19/EBV	3 (5.8)	0 (0)
PVB19/EBV/HHV6	1 (1.9)	0 (0)

CRP, C-reactive protein; EBV, Epstein-Barr virus; GLS, global longitudinal strain; HHV6, Human Herpesvirus 6; hsTnT, high sensitivity troponin T; LVEDD, left ventricular end diastolic diameter; LVEF, left ventricular ejection fraction; ns, non-significant; PVB19, Parvovirus B19; RV S’, right ventricular systolic wave prime; TAPSE, tricuspid annular plane systolic excursion.

Clinical presentation

In patients with confirmed myocarditis, 46 (51.7%) presented with infarct-like (IL) symptoms. 31 (34.8%) presented with new onset HF, 8 (9.0%) with sustained VT and 4 (4.5%) with complete heart block (CHB). The baseline demographic data, clinical findings, findings of laboratory investigations, TTE, CMR and EMB of these four groups of patients are summarised and compared in table 2.

Table 2. Baseline characteristics of patients with confirmed acute myocarditis (n=89).

	Infarct-like(n=46)	Heart failure(n=31)	3° heart block(n=4)	VT(n=8)	P value
Demographics
Age (year)	40.4±14.2	39.1±11.1	56.8±14.2	41.2±14.3	ns
Sex, male (n, %)	35 (76.1)	17 (54.8)	3 (75.0)	4 (50.0)	ns
HIV+ (n, %)	6 (13.0)	10 (32.3)	0 (0)	0 (0)	ns
Clinical findings
Tachycardia (n, %)	14 (30.4)	18 (58.1)	–	–	<0.001
Fever (n, %)	3 (6.5)	5 (16.1)	1 (25.0)	0 (0)	ns
Laboratory investigations
White cell count	11.09±4.79	9.78±4.90	8.84±1.86	12.68±5.00	ns
CRP (mg/L)	21.0 (3.5–51.5)	17.00 (9.5–89.0)	17.5 (10.0–32.5)	3.5 (2.0–21.3)	ns
hsTnT (ng/L)	724.0 (348.0–1372.0)	48.5 (24.8–278.3)	914.0 (44.8–3060.5)	195.0 (84.0–382.0)	<0.001
Echocardiographic measurements
LVEF (%)	45.9±13.4	30.6±11.0	35.8±15.1	43.1±10.3	<0.001
LVEDD (mm)	48.8±6.0	53.9±6.9	54.0±4.9	53.8±3.1	0.001
TAPSE (mm)	18.1±4.1	14.1±4.1	15.5±6.8	16.7±4.4	<0.05
RV S’ (cm/s)	10.9±3.0	8.8±2.6	9.0±2.7	9.4±2.5	<0.05
GLS (%)	−13.4±4.5	−6.7±2.6	−10.9 ±	−14.8±1.6	0.001
CMR (Lake Louise Criteria) positive (n, %)	40 (87.0)	23 (74.2)	3 (75.0)	7 (87.5)	ns
EMB positive (n, %)	23 (50.0)	17 (54.8)	3 (75.0)	2 (25.0)	ns
Dallas Criteria (n, %)	8	5	1	1	ns
IHC Criteria (n, %)	15	12	2	1	ns
Viral genomes detected (n, %)	29 (63.0)	16 (51.6)	2 (50.0)	5 (62.5)	ns
Parvovirus B19 (n, %)	23 (50.0)	11 (35.5)	1 (25.0)	4 (50.0)	ns

CMR, cardiac MRI; CRP, C-reactive protein; EMB, endomyocardial biopsy; GLS, global longitudinal strain; hsTnT, high sensitivity troponin T; IHC, immunohistochemistry; LVEDD, left ventricular end diastolic diameter; LVEF, left ventricular ejection fraction; ns, non-significant; RV S’, right ventricular systolic wave prime; TAPSE, tricuspid annular plane systolic excursion; VT, ventricular tachycardia.

ECG findings

85 (95.5%) patients with confirmed myocarditis had abnormal ECG at presentation (table 3). The most common abnormal findings were T wave inversion (40.5%), sinus tachycardia (36.0%) and ST-segment elevation not in keeping with acute pericarditis (24.7%). Four (4.5%) patients had QRS duration of more than 120 ms at baseline (assessed after cardioversion and excluding those with CHB)—3 (3.3%) with bundle branch block and 1 (1.1%) with pre-excitation. Nine (10.1%) patients received fibrinolysis as they were deemed to fulfil the diagnostic criteria for ST-segment elevation myocardial infarction (STEMI) by their primary treating physician. Four of these patients were current smokers. One was an ex-smoker. Three had hypertension. One was both hypertensive and a current smoker.

Table 3. ECG findings of patients with confirmed myocarditis (n=89).

	N (%)
Normal	4 (4.5)
Sinus tachycardia	32 (36.0)
ST elevation (non-pericarditis)	22 (24.7)
Pericarditis	6 (6.7)
T wave inversion	36 (40.5)
Conduction abnormalities
Bundle branch block	3 (3.4)
Pre-excitation	1 (1.1)
Ventricular tachycardia	8 (9.0)
Heart block
1st degree	1 (1.1)
3rd degree	4 (4.5)

Management

Immunosuppressive therapy was administered to all four cases of cardiac sarcoidosis, one of eosinophilic myocarditis, one of fulminant myocarditis and three patients with biopsy-confirmed virus-negative AM. A single 7-day course of high-dose intravenous immunoglobulins was administered to each of the three cases of biopsy-confirmed PVB19 myocarditis noted above, along with the single case of biopsy-confirmed human bocavirus myocarditis. The PVB19 viral loads on EMB specimens of the three patients with PVB19 myocarditis were 116 copies/mL, 483 copies/mL and 592 copies/mL. Permanent pacemakers were implanted in all four patients with CHB. Implantable cardioverted defibrillators (ICD) were implanted in seven of eight (87.5%) patients presenting with sustained VT. The remaining patient who presented with sustained VT did not consent to ICD implantation.

Outcomes

After an average follow-up period of 24.1 months, the prespecified adverse outcome occurred in 27 of 89 (30.3%) patients. 10 (11.2%) patients were lost to follow-up, but all 10 were confirmed to be alive in the national death registry. Cardiac death occurred in 11 patients, documented sustained ventricular tachycardia in 7 patients and HF hospitalisation in 9 patients. No patients underwent cardiac transplantation or implantation of left ventricular assist devices. On univariate analysis, older age at diagnosis, initial presentation with VT or CHB, QRS duration of more than 120 ms and lower LVEF were found to be significant predictors of the primary endpoint. After adjustment for covariates, only initial presentation with VT or CHB remained significant predictors of the prespecified adverse outcome (figure 1 and table 4).

Figure 1. Unadjusted survival free from prespecified adverse outcome (composite of cardiac death, documented sustained VT and HF hospitalisations) according to clinical presentation. HB, heart block; HF, heart failure; IL, infarct-like; VT, ventricular tachycardia.

Table 4. Predictors of prespecified adverse outcome (composite of cardiac death, documented sustained ventricular tachycardia and heart failure hospitalisations).

Variable	Univariate analysis		Multivariate analysis
	HR (95% CI)	P value	HR (95% CI)	P value
Age (year)	1.03 (1.01 to 1.06)	0.02	1.03 (0.99 to 1.07)	0.11
Female sex	1.10 (0.49 to 2.45)	0.82	–	–
Race
Black African	Reference		–	–
Mixed ancestry	0.79 (0.34 to 1.81)	0.57	–	–
Caucasian	1.32 (0.61 to 2.82)	0.48	–	–
Clinical presentation
Infarct-like	Reference		Reference
Heart failure	1.53 (0.62 to 3.77)	0.36	1.20 (0.43 to 3.32)	0.73
Ventricular tachycardia	5.42 (1.83 to 16.06)	0.002	5.36 (1.76 to 16.33)	0.003
3° heart block	9.41 (2.46 to 36.05)	0.001	5.67 (1.38 to 23.26)	0.016
hsTnT <100 ng/L	2.02 (0.92 to 4.44)	0.18	–	–
HIV+	1.60 (0.70 to 3.68)	0.26	–	–
QRS >120 ms	3.96 (1.20 to 13.44)	0.02	2.39 (0.50 to 11.44)	0.28
LVEF	0.97 (0.93 to 1.00)	0.049	0.97 (0.94 to 1.01)	0.16
LVEDD	1.03 (0.98 to 1.09)	0.29	–	–
Late gadolinium enhancement
Presence	1.35 (0.41 to 4.50)	0.62	–	–
Diffuse	1.31 (0.39 to 4.35)	0.66	–	–
Endomyocardial biopsy positive	1.52 (0.69 to 3.32)	0.29	–	–
Presence of viral genomes	1.26 (0.57 to 2.74)	0.56	–	–

hsTnT, high sensitivity troponin T; LVEDD, left ventricular end diastolic diameter; LVEF, left ventricular ejection fraction.

Discussion

The findings of this study confirm the heterogeneity in the clinical presentation of a cohort of South African patients with AM, with patients presenting most commonly with symptoms mimicking ACS or symptoms of HF. Viral myocarditis appears to be the most common form of myocarditis locally. The outcomes of local patients with confirmed myocarditis also do not appear to be completely benign, as the prespecified adverse outcome occurred in 30.3% of our cohort.

The clinical diagnosis of AM can be difficult and is often missed due to wide-ranging presenting symptoms that often mimic common cardiovascular emergencies.¹ Most patients present either with ischaemic-type chest pain mimicking ACS or acute or subacute onset HF.¹⁹,^{12 26 27} Pericardial chest pain is not a common finding.²⁶ A smaller proportion of patients may present with life-threatening arrhythmias or SCD.¹⁹,^{12 26 27} Our study findings showed that local patients appeared to present similarly, with 51.7% of 89 patients presenting with IL symptoms, 34.8% presenting with symptoms of HF and 4.5% and 9.0% presenting with CHB and sustained VT, respectively. The fact that nine patients received fibrinolytic therapy after being deemed by their primary treating physicians to have met the diagnostic criteria for STEMI further reaffirms AM as the great mimicker.

The difficulty in diagnosis is further compounded by the lack of pathognomonic findings of myocarditis on bedside and laboratory investigations.¹ Although initial ECGs were abnormal in 95.5% of patients, the majority of abnormal findings were non-specific, with the most common being T wave inversion (40.45%), sinus tachycardia (35.96%) and ST segment elevation (24.72%). While hsTnT is a sensitive marker of myocyte injury, it is non-specific in the diagnosis of AM and may be negative in up to two-thirds of patients with biopsy-confirmed myocarditis.^{1 5 28 29} Similarly in our cohort, patients who presented with HF had a median hsTnT of 48 ng/L, which is below the threshold for clinical significance in our centre (100 ng/L), and significantly lower than those with IL presentation (724 ng/L), VT (914 ng/L) and CHB (195 ng/L).

The definitive diagnosis of AM requires access to CMR and EMB. CMR is the imaging modality of choice in the diagnosis of AM.¹ Its specificity and positive predictive values, when the LLC is met, are reported as high as 91%, although its sensitivity and negative predictive value are somewhat lower, at 67% and 69%, respectively.^{13 30 31} However, despite allowing for a provisional non-invasive diagnosis, CMR cannot determine the specific underlying aetiology of AM. EMB thus remains the gold standard for the diagnosis of AM, as it allows the direct microscopic visualisation of inflammatory infiltrates and cardiac myocyte necrosis.^{1 6} It also identifies the specific type of inflammatory infiltrate (lymphocytic, eosinophilic, giant cell) and can determine the underlying aetiology, which may be important in guiding therapy.^{1 6} Despite this, EMB has yet to gain widespread acceptance due to its perceived low diagnostic yield thought to be related to sampling error as a result of patchy involvement of the myocardium, and concerns regarding its invasive nature and safety. Our study findings showed that these two diagnostic modalities played complementary roles in confirming the diagnosis of AM. In our cohort, 16 cases would have been missed if EMB had not been performed. This argues for its more widespread use in patients with clinically suspected myocarditis, even in low volume centres, where procedural safety can be ensured with routine use of fluoroscopic and real-time echocardiographic guidance.²¹ Furthermore, although one patient was correctly diagnosed with AM on CMR, the subsequent performance of EMB allowed for histological subtyping and confirmation of eosinophilic myocarditis (figure 2), leading to the prompt institution of definitive therapy in a potentially life-threatening form of myocarditis.

Figure 2. A 31-year-old female presented with acute onset ischaemic-type chest pain and autonomic symptoms. hsTnT was significantly elevated at 2962 ng/L (n <14 ng/L). (A and B): Initial ECG showed anterolateral ST segment depression which subsequently evolved to diffuse T-wave inversion. (C and D): TTE showed marked concentric left ventricular hypertrophy with mildly reduced LV systolic function, estimated LVEF 40–45% and inferoposterolateral hypokinesia along with a small pericardial effusion. (E and F): Coronary angiogram showed no significant epicardial coronary artery disease or evidence of recent plaque rupture. (G): Short τ inversion recovery (STIR) sequence showing increased signal predominantly in the lateral wall (white arrows) in keeping with active myocardial oedema. (H): Near-transmural late gadolinium enhancement (LGE) in the corresponding distribution of increased STIR signal (white arrows). (I and J): Significant abnormalities on both T1 and T2 mapping most marked in the lateral wall of the left ventricle. (K): H&E stain of endomyocardial biopsy (EMB) specimen demonstrating an eosinophilic infiltration (white arrows) on the background of myocytolysis, confirmed the diagnosis of acute necrotising eosinophilic myocarditis. (L and M): Positive immunohistochemical staining for anti-CD3 (T lymphocytes) and anti-CD163 (macrophages) on EMB specimen. (N): Electron microscopy demonstrating eosinophil crystalloid granules (white arrows). hsTnT, high sensitivity troponin T; LV, left ventricle; LVEF, left ventricular ejection fraction; TTE, transthoracic echocardiography.

Viral infections are known to be the most common cause of myocarditis in North America and Europe.¹,⁴ The findings of our study showed that viral myocarditis also appears to be the most common form of myocarditis locally, with viral genomes isolated in EMB specimens of 58.4% of 89 patients with confirmed AM. The viral prevalence in our cohort appeared similar to those described in the recent literature of the developed world,¹,⁷¹⁰ with PVB19 being the most commonly detected virus in EMB specimens of patients with confirmed myocarditis. It has been postulated that patients with acute PVB19 tend to present with symptoms mimicking ACS as PVB19 infects the endothelial cells of myocardial vessels and not myocytes directly, leading to endothelial dysfunction and vasospasm.^{3 4 7} However, PVB19 was detected in similar proportions across clinical presentations in our cohort. Whether PVB19 is a true causal agent of myocarditis or a mere bystander remains debated, as it had been previously detected in hearts of 60–85% of postmortem subjects and individuals undergoing cardiac surgery without any evidence of myocarditis or cardiomyopathy in German cohorts.^{32 33} Similarly, PVB19 was also detected in EMB specimens of 11 patients of our cohort without evidence of AM on CMR or EMB. The local background prevalence of PVB19 thus requires further investigation to determine its clinical significance in our setting. Furthermore, the use of advanced techniques in the detection of cardiotropic viruses may help us further understand the local and international prevalence and clinical significance of these viruses in patients presenting with AM.³⁴

Although often thought of as a benign and self-limiting condition, previous studies have shown poor long-term outcomes in up to 30% of patients with AM.⁶,¹² Outcomes of our cohort of patients appeared comparable, with the prespecified adverse outcome occurring in 30.3% of patients after an average follow-up period of 24.1 months. In contrast, factors that have previously been shown to be predictors of poor outcome were not found to be of significance in our study.⁸,¹²²⁷ Although older age, lower LVEF and QRS duration >120 ms were found to be significant predictors of adverse outcome on univariate analysis in our cohort, only presentation with sustained VT or CHB remained significant predictors of poor outcome on multivariate analysis, with HRs of 5.36 and 5.67, respectively. Outcomes were similar between patients with IL and HF presentation despite significantly lower hsTnT and LVEF at diagnosis in patients presenting with HF. The timing of ICD implant in patients with AM presenting with VT remains controversial and debated. The ESC currently recommends that ICD implantation be postponed until the acute phase of myocarditis has resolved, with wearable cardioverter defibrillators (WCD) as a bridge to the decision of implantation.¹⁴ However, the exact duration of this acute phase is not well defined. Due to the unavailability of WCD locally, it is our routine practice to implant ICD for secondary prevention in patients presenting with VT prior to discharge. This strategy was further supported by the fact that five out of eight patients presenting with VT had subsequent episodes of documented VT following discharge.

Limitations

This study was performed in a single centre and its results may not be generalisable to other populations. Although this likely represents the largest cohort of patients with clinically suspected myocarditis who have all undergone EMB in Africa, the sample size remains relatively small. Our study period overlapped with the COVID-19 pandemic. All patients presenting to our centre during this period were screened for disease. Patients who swabbed positive were not allowed in the MRI suite and could therefore not undergo CMR. Furthermore, only procedures deemed emergencies and life-saving were performed in our catheterisation laboratory, and EMB was seldom performed. As a result, despite possible clinical suspicion of myocarditis in this group of patients, even with supporting evidence of myocardial injury in the form of ECG or echocardiographic abnormalities, or elevated hsTnT, we were unable to confirm the diagnosis of myocarditis definitively. We elected to exclude this group of patients and our study findings are therefore only generalisable to the population not affected by COVID-19. Despite our best efforts to trace every patient in our cohort in order to determine the occurrence of the primary endpoint by telephonic contact and by searching the electronic medical records systems of both our hospital and the provincial health department along with the national death registry, a significant proportion of the cohort was still lost to follow-up. The reason for this is likely twofold. First, Tygerberg Hospital covers a large geographical drainage area with some patients living several hundred kilometres away from the hospital. Due to the poor socioeconomic background of some of the patient population served, these long-distance journeys are not always financially viable. Some patients might therefore have sought medical attention at healthcare facilities closer to where they reside. However, the majority of these visits would likely have been logged on the provincial electronic medical records systems that we accessed. Second, access to both fixed-line and mobile telephones might have been limited in our patient population. The fact that our study was conducted in a tertiary centre might have led to referral bias, where only the sickest patients were referred, thus potentially leading to an inflated rate of adverse events. However, the rate of adverse outcomes in our study appeared to be in line with those previously reported in the developed world.⁶,¹² Lastly, the small sample size of our study and incomplete follow-up might have contributed to the lack of significance of traditional variables previously found to be associated with adverse outcomes.

Conclusion

We report data from the largest cohort of patients with clinically suspected myocarditis outside the developed world. It provides insight into the clinical presentation, aetiology and viral pathogens locally, which appears similar to the developed world. The outcome of local patients with confirmed myocarditis also appears comparable to those previously reported and highlights the importance of early clinical recognition and diagnosis of this group of patients to prevent poor outcomes.

Data availability statement

Data are available upon reasonable request.