Coronary vasospasms and other cardiac manifestations in Eosinophilic Granulomatosis with Polyangiitis: Clinical impact and frequency in a monocentre study of 103 patients

Abstract

Background

Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic necrotising vasculitis characterised by tissue and blood hypereosinophilia. Cardiac involvement has previously been identified as the most significant predictor of mortality.

Objective

To identify and characterise previously untreated patients with EGPA and their cardiac manifestations at disease onset.

Methods

A retrospective monocentre study was conducted on 103 patients. Upon patient presentation, detailed multidisciplinary physical evaluations and laboratory diagnostics were performed. Cardiac events were defined as EGPA-related abnormalities in ECG, echocardiography, cardiac MRI, invasive coronary angiography or cardiac histopathology.

Results

Cardiac manifestations were diagnosed in 36 of 103 patients with EGPA (35%). Patients with EGPA with cardiac involvement (EGPA-CI) exhibited typical symptoms of EGPA concomitant with elevated cardiac biomarkers. Pericarditis (77%), cardiomyopathy with cardiac failure (55%) and definite myocarditis (36%) were the most common diagnoses, which in some cases resulted in cardiogenic shock (14%) or cardiac arrest (6%). Vasospastic coronary arteries causing myocardial infarctions were identified as a life-threatening cardiac manifestation in 8% of patients with EGPA-CI. Overall, patients with EGPA-CI presented with significantly higher disease activity and worse prognosis, with elevated median eosinophilic count and C-reactive protein levels.

Conclusions

Cardiac involvement is a common initial manifestation of EGPA and is associated with elevated systemic disease activity. In addition to pericarditis and myocarditis, coronary vasospasms were identified as a rare and severe manifestation of EGPA that may mimic myocardial infarction. Consequently, at the early stage of disease, patients may present with advanced cardiac impairment, emphasising the necessity of prompt diagnostic and therapeutic intervention to positively affect prognosis.

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic autoimmune disease with necrotising vasculitis affecting small-to-medium-sized blood vessels. Cardiac involvement is considered a predictor of disease mortality but remains understudied.

WHAT THIS STUDY ADDS

• This study on untreated patients with EPGA identifies coronary vasospasms as a rare, likely underdiagnosed, severe feature of the disease. The data indicate that at the time of EGPA diagnosis, patients often present with advanced cardiomyopathy and heart failure.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• Our study emphasises the need for thorough cardiac evaluation of patients with EGPA already at disease onset. Patients with cardiac manifestations need rapid diagnostic and therapeutic measures to prevent further organ damage.

Introduction

Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic autoimmune disease with necrotising vasculitis affecting small-to-medium-sized blood vessels.¹ It is further characterised by blood eosinophilia, eosinophilic infiltration of tissues and granuloma formation.^{2 3} With an estimated incidence of approximately 1–5 per million, EGPA is the rarest form of anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAVs). Although any organ can be affected, patients with EGPA often present with symptoms of upper and lower airway manifestations - such as nasal polyps, sinusitis, asthma, pulmonary infiltrates, skin lesions and neuropathy.⁴

An often under-recognised, yet common manifestation, is cardiac involvement in EGPA. It is considered the most significant predictor of mortality, occurring more frequently in ANCA-negative patients with EGPA.⁵,⁹ Nevertheless, the diagnosis of cardiac involvement in EGPA is often challenging, as symptoms may be subclinical, non-specific or mistaken for other cardiac conditions. Based on previous studies, clinical presentations predominantly include pericarditis, myocarditis and endocarditis, which can subsequently lead to life-threatening heart failure and arrhythmias.^{10 11} Using these parameters, it has repeatedly been estimated that up to 50% of patients with EGPA may experience cardiac manifestations of varying severity during the course of their disease.¹² To improve the detection of underlying cardiac disease, diagnostic algorithms have recently been proposed; however, definitive guidelines are still lacking.¹²,¹⁴ Furthermore, specific data on cardiovascular symptoms and manifestations in untreated patients at the time of disease onset are sparse and vary due to the low incidence, possible delay of diagnosis and heterogeneous patient populations.

In this study, we retrospectively interrogated data from 103 patients with EGPA at the time of diagnosis and characterised cardiac manifestations defined as the presence of pericarditis, myocarditis or cardiomyopathy with cardiac failure. Using this approach, we identified a total of 36 patients with a comprehensive spectrum of cardiac disease. Importantly, among patients presenting with cardiac involvement and the working diagnosis of myocardial infarction with non-obstructive coronary arteries (MINOCA), we identified three young patients with coronary vasospasms. This suggests that vasospasms are a rare, likely underdiagnosed, but potentially grave feature of patients with EGPA, which can cause severe organ damage if not addressed by additional diagnostic considerations and therapeutic measures.

Methods

This is a retrospective monocentre study of a total of 103 patients with EGPA who were treated at the Vasculitis Centre of the Department of Rheumatology and Clinical Immunology at the Medical Centre of the University of Freiburg between 2005 and 2024. All patients included in the study were diagnosed with EGPA, fulfilling the American College of Rheumatology (ACR) 1990 criteria¹⁵ or the 2022 ACR and European Alliance of Associations of Rheumatology (EULAR) criteria for eosinophilic granulomatosis with polyangiitis¹⁶ and the 2012 revised international Chapel Hill Consensus Conference Nomenclature of Vasculitides.¹

All clinical, laboratory and radiological data were retrieved retrospectively using the hospital’s electronic patient records. They included an assessment of patients’ medical history prior to their first visit at the Medical Centre and available documentation on previous physical examinations, pre-existing conditions and medical therapies. Baseline characteristics, including age, gender, symptoms, organ manifestations, disease activity (Birmingham Vasculitis Activity Score (BVAS)) and prognosis (1996 five-factor score (FFS)) scores and therapeutic regimens, were gathered.^{7 17}

Disease manifestations

Patients were routinely evaluated by a multidisciplinary medical team. In the process of their diagnostic evaluation for EGPA, general symptoms (fever, weight loss, myalgia and arthralgia), cutaneous (oedema, nodules, purpura, urticaria and livedo), ear/nose/throat (rhinorrhoea, bloody rhinorrhoea, nasal crusts, sinusitis and otitis), pulmonary (asthma, nodular infiltration, pulmonary infiltrates, pleuritis, alveolar haemorrhage and acute respiratory distress syndrome), digestive (abdominal pain, haematemesis, rectal bleeding, cholecystitis and ischaemic colitis), renal (proteinuria, haematuria, serum creatinine and glomerular nephropathy) and neurological (mononeuritis multiplex, polyneuropathy, non-ischaemic central nervous system manifestations, ischaemic stroke or cerebral infarctions) manifestations were assessed and complemented by routine laboratory markers. Additionally, more specific tests, including indirect immunofluorescence and/or ELISA for proteinase 3 (PR3) ANCA or myeloperoxidase (MPO) ANCA and immunoglobulin E (IgE), were performed. Other causes of blood eosinophilia (eg, parasites, haematological diseases or solid cancer and drugs) were excluded by systematic diagnostics whenever necessary.

Cardiac evaluation

Patients were evaluated for cardiac manifestations and potential risk factors (diabetes, hypertension, dyslipidaemia, obesity, active smoking and familial predisposition) during their initial presentation based on symptoms (dyspnoea, chest pain or pressure, palpitations and syncope), ECG and laboratory testing results, including myocardial markers (creatine kinase (CK), creatine kinase-myocardial band (CK-MB), lactate dehydrogenase (LDH), myoglobin, troponin I/T and pro-B-type natriuretic peptide (pro-BNP)). With cardiac involvement being likely, echocardiography, cardiac catheterisation, cardiac MRI (CMR) or endomyocardial biopsy (EMB) were performed, contingent on the individual case and medical decision-making processes by the treating healthcare professionals.

Irregular ECGs were categorised based on repolarisation (including ST-segment elevation or depression, T-wave inversion, loss or poor progression of R-wave and pathological Q-wave), rhythm (including supraventricular and ventricular tachycardia and atrial fibrillation) or conduction (including atrioventricular block and intraventricular block) abnormalities. Transthoracic echocardiographies (TTE) were analysed regarding systolic dysfunction (left ventricular ejection fraction (LVEF) <50%), wall motion abnormalities, pericardial effusions and ventricular thrombi. CMR was evaluated for pericardial effusion, gadolinium enhancement, left ventricular dysfunction, dilated left ventricle and myocardial oedema. Invasive coronary angiographies were performed to detect coronary stenosis, vasospasms or wall irregularities.

A cardiac manifestation of EGPA was defined as the presence of pericarditis, myocarditis, cardiomyopathy with cardiac failure or coronary vasospasms. These diagnoses were made in accordance with the relevant clinical practice guidelines.⁵¹⁸,²⁰ Any other probable cause of heart disease other than EGPA was not attributable to any patient in our cohort at disease onset but would have led to exclusion from the cardiac analysis if identified.

Statistical analysis

Statistical analyses were performed using GraphPad Prism V.10.3.1. Absolute numbers and percentages were used for categorical variables describing the study population and compared by Fisher’s exact test. Continuous variables were expressed as medians (with IQRs). Their analyses were evaluated using Student’s t-test. Differences in survival between groups were assessed by the log-rank test. Statistical significance: p < 0.05 (*), p < 0.01 (**), p < 0.001 (***), p < 0.0001 (****). n.s., not significant.

Results

General patient characteristics

A total of 103 patients with diagnosed EGPA were included in this study (table 1). The median age at onset of disease was 53.7 years. No significant sex bias was observed. Asthma bronchiale preceded EPGA diagnosis in most cases by a median of 3 years and was present in 96 (93%) patients. Other clinical features included pulmonary infiltrates (64%) and neurological manifestations such as polyneuropathy (40%), mononeuritis multiplex (31%) or cerebral infarctions (13%). With four exceptions, patients with EGPA exhibited paranasal sinus involvement (96%), presenting with rhinosinusitis and/or nasal polyposis. Cutaneous manifestations were observed in 22 patients (21%), while 14 patients (14%) reported gastrointestinal symptoms. Glomerular nephropathy, accompanied by relevant haematuria and proteinuria, was less prevalent, occurring only in 7% of patients. ANCA were detectable in up to 23 patients (22%), with specificity against MPO in 20 patients and against PR3 in three patients. In 85 patients (83%), the diagnosis was confirmed histologically by biopsy showing signs of eosinophilic vasculitis and/or tissue infiltration.

Table 1. Demographic and clinical features of EGPA study population.

	Total EGPA patients (n=103)	EGPA-nCI (n=67)	EGPA-CI (n=36)	P value
Demographics
Female/male	49/54	29/38	20/16	n.s.
Age at diagnosis, years	54 (40–59)	54 (43–60)	53 (31–59)	n.s.
Classification criteria
ACR 1990 criteria fulfilled	92/103 (89)	60/67 (90)	32/36 (89)	n.s.
ACR/EULAR 2022 criteria fulfilled	98/103 (95)	63/67 (94)	35/36 (97)	n.s.
Organ manifestation
Blood eosinophilia >1000/µL	80/95 (84)	48/61 (79)	32/34 (94)	n.s.
Extravascular tissue eosinophilia	85/103 (83)	56/67 (84)	29/36 (81)	n.s.
Eosinophilic asthma	96/103 (93)	63/67 (94)	33/36 (92)	n.s.
Duration of asthma before diagnosis, years	3 (2–9)	2.5 (1–8)	3 (2–9)	n.s.
Pulmonary infiltrates	66/103 (64)	44/67 (66)	22/36 (61)	n.s.
Paranasal sinus abnormality	99/103 (96)	66/67 (99)	33/36 (92)	n.s.
Neurological manifestation	54/103 (52)	32/67 (48)	22/36 (61)	n.s.
Mononeuritis multiplex	32/103 (31)	19/67 (28)	13/36 (36)	n.s.
Glomerular nephropathy	7/103 (7)	5/67 (7)	2/36 (6)	n.s.
Gastrointestinal manifestation	14/103 (14)	6/67 (9)	8/36 (22)	n.s.
Cutaneous manifestation	22/103 (21)	18/67 (27)	4/36 (11)	n.s.
Laboratory results
p-ANCA+ pattern in IIF	18/103 (17)	12/67 (18)	6/36 (17)	n.s.
c-ANCA+ pattern in IIF	8/103 (8)	7/67 (10)	1/36 (3)	n.s.
Anti-Myeloperoxidase+	20/103 (19)	13/67 (19)	7/36 (19)	n.s.
Anti-Proteinase-3+	3/103 (3)	2/67 (3)	1/36 (3)	n.s.
C-reactive protein, mg/L	36 (7–80)	10 (3–68)	68 (36–91)	*
Eosinophil granulocyte cell count, µL	3777 (1337–5697)	2685 (1105–6068)	5682 (2894–9845)	**
Eosinophil granulocytes, %	29 (17–43)	22 (12–38)	40 (24–50)	***
Clinical scores
Birmingham Vasculitis Activity Score at diagnosis	15 (11–20)	12 (9–18)	18 (15–24)	****
Five Factor Score 1996 at diagnosis	0 (0–1)	0 (0–2)	1 (1-2)	****
Therapy
Pulses of methylprednisolone	73/103 (71)	39/67 (58)	34/36 (95)	****
Prednisone dose at baseline, mg/day	50 (40–60)	50 (35–60)	60 (50–70)	****
Induction therapy with cyclophosphamide	40/103 (39)	19/67 (28)	21/36 (58)	**
Induction therapy with rituximab	7/103 (7)	3/67 (4)	4/36 (11)	n.s.
EGPA-specific survival
1-year survival	100	100	100	n.s.
5-year survival	97.6 (90.6–99.4)	100	96.4 (77.3–99.6)	n.s.
10-year survival	95.5 (85.9–98.6)	100	90.8 (66.7–97.7)	0.064

Categorical variables are expressed in number and (percentage), while continuous variables are expressed as median and (IQR). Cause-specific survival proportions are expressed in percentage with (95% CIs) at 1, 5 and 10 years after diagnosis.

*p<0.05, **p<0.01, ***p<0.001 and ****p<0.0001.

ACR, American College of Rheumatology; ANCA, anti-neutrophil cytoplasmic antibodies; EGPA, eosinophilic granulomatosis with polyangiitis; EGPA-CI, EGPA with cardiac involvement; EGPA-nCI, EGPA without cardiac involvement; EULAR, European Alliance of Associations for Rheumatology; IIF, indirect immunofluorescence; n.s., not significant.

Cardiac symptoms and risk factors

Cardiac manifestations were diagnosed in 36 of 103 patients with EGPA (35%) at disease onset (table 2). Chest pain or pressure (61%), dyspnoea (67%) and angina pectoris (28%) were the most frequent clinical presentations in 30 symptomatic patients (83%). The other six patients (17%) did not report any signs of cardiac discomfort and were therefore considered cardiac asymptomatic. Six patients (17%) had a previous diagnosis of hypertension, four (11%) were treated for dyslipidaemia, two patients (6%) reported active tobacco use, and 15 patients (42%) had a previous history of smoking. Only three patients fulfilled the WHO criteria of obesity (8%). Five patients (16%) had direct family members with a history of cardiovascular disease. None of the patients included in our cardiac cohort reported either relevant previous cardiac events or interventions nor a history of malignancies and use of cardiotoxic medication.

Table 2. Cardiac features in patients with EGPA with cardiac involvement.

Cardiac manifestations		n/N (%)
Clinical symptoms
Symptomatic patients		30/36 (83)
Dyspnoea		24/36 (67)
Chest discomfort		22/36 (61)
Classic angina pectoris		10/36 (28)
Palpitations		2/36 (6)
Syncope		2/36 (6)
Laboratory results
LDH >225 U/L	437 (260–627) U/L	29/33 (88)
CK >190 U/L	237 (128–631) U/L	20/32 (63)
CK-MB >24 U/L	42 (33–63) U/L	20/20 (100)
Myoglobin >51 ng/mL	92 (53–184) ng/mL	12/17 (71)
Troponin I >100 ng/L	18170 (13 200–34820) ng/L	6/6 (100)
Troponin T >14 ng/L	699 (57–2060) ng/L	21/23 (91)
Pro-BNP >125 pg/mL	3500 (1177–9813) pg/mL	19/20 (95)
Cardiovascular risk factors
Diabetes mellitus		0/36 (0)
Hypertension		6/36 (17)
Dyslipidaemia		4/36 (11)
Obesity		3/36 (8)
Active smoking		2/36 (6)
Familial predisposition		5/31 (16)
Cardiac diagnostics
ECG	Repolarisation abnormalities*	14/33 (42)
	Rhythm abnormalities†	9/33 (27)
	Conduction abnormalities‡	3/33 (9)
Echocardiography	Left ventricular dysfunction	21/35 (60)
	Left ventricular ejection fraction, ≤45%	19/35 (54)
	Wall motion abnormalities	20/35 (57)
	Pericardial effusion	28/35 (80)
	Valve disorder	16/35 (46)
	Intraventricular thrombus	5/35 (14)
Exclusion of coronary artery disease by cardiac catheterisation		24/24 (100)
Pathological CMR findings		15/15 (100)
Eosinophilia in endomyocardial biopsy		8/10 (80)
Cardiac diagnosis
Pericarditis		27/35 (77)
Clinically suspected myocarditis		24/36 (66)
Definite myocarditis by endomyocardial biopsy and/or CMR		13/36 (36)
Coronary vasospasms		3/36 (8)
Myocardial infarction with non-obstructive coronary arteries		6/36 (16)
Cardiomyopathy with cardiac failure		20/36 (55)
Cardiogenic shock		5/36 (14)
Cardiac arrest		2/36 (6)

Categorical variables are expressed in number and (percentage), while continuous variables are expressed as median and (IQR).

^*Includes ST-segment elevation or depression, T-wave inversion and loss or poor progression of R-wave and pathological Q-wave.

^†Includes atrial fibrillation, supraventricular or ventricular tachycardia.

^‡Includes atrioventricular block and intraventricular block.

CK, creatine kinase; CK-MB, creatine kinase-myocardial band; CMR, cardiac magnetic resonance imaging; EGPA, eosinophilic granulomatosis with polyangiitis; EMB, endomyocardial biopsy; LDH, lactate dehydrogenase; Pro-BNP, pro-B-type natriuretic peptide.

Patients with cardiac involvement

Patients with cardiac involvement (EGPA-CI) were comparable in age (median age 53.3 years; 31–59) to those without cardiac involvement (EGPA-nCI, median age 53.8 years; 43–60). A higher prevalence of cardiac manifestations was observed in females (55.5% vs 43.3%), though this did not reach statistical significance. Patients with EGPA-CI showed significantly higher disease activity measured by BVAS (18 vs 12, p<0.0001) and had a worse prognosis by FFS (1 vs 0, p<0.0001). Median eosinophilic granulocyte count (5682/µL, 2894–9845/µL) and median C-reactive protein (CRP) serum concentration (68 mg/L, 36–91 mg/L) were both significantly higher in patients with EGPA-CI compared with patients with EGPA-nCI with a median of 2685 eosinophils/µL (1105–6068, p<0.001) and a median CRP of 10 mg/L (3–68 mg/L, p<0.05). ANCA positivity (19.4% vs 23.9%) and extracardiac organ manifestations were similarly distributed in both groups (table 1). With respect to treatment, use of methylprednisolone pulses (95% vs 58%, p<0.0001), cyclophosphamide (53% vs 26%, p<0.01) and rituximab (11% vs 4%) for remission induction was more frequent, and higher daily median dosages of prednisone were applied as part of the treatment regimen (60 mg vs 50 mg, p<0.0001) for patients with EGPA-CI.

Cardiac manifestations at disease onset

Pericarditis was the most common cardiac abnormality documented at disease onset, occurring in 77% of the cases (figure 1). Accordingly, pericardial effusions were detectable by echocardiography in 28 of 35 patients (80%). Myocarditis was clinically suspected in 24 of 36 patients (66%) and was proven in 13 cases (36%) in which EMB and/or CMR were additionally performed. Classic cardiac laboratory biomarkers (LDH, CK, CK-MB, myoglobin, troponin and pro-BNP) were usually increased in our patients with EGPA-CI (table 2). Specifically, elevated troponin (93%), CK-MB (100%) and pro-BNP (95%) were consistently indicative of cardiac involvement. ECGs revealed repolarisation, rhythm and conduction abnormalities. An intraventricular thrombus was detected in five patients (14%). Valve disorders were observed frequently (46%), but were functionally minor in most cases. The majority of patients with EGPA-CI presented with significantly decreased LVEF (54%) and wall motion abnormalities (57%) as demonstrated by echocardiography. In contrast, no regional contractile dysfunction or impaired LVEF was identified in 40 of 63 patients with EGPA-nCI, where echocardiography was performed. Many patients developed left ventricular dysfunction (60%), some requiring temporary advanced life support in cardiogenic shock (14%). With suspected myocardial infarction, with ST-elevation (STEMI) and non-ST-elevation (NSTEMI), upon clinical presentation, obstructive coronary artery disease was ruled out in all 24 cases of patients who required cardiac catheterisation. Most patients with elevated troponin but unexplained cardiac cause underwent further evaluation with EMB and/or CMR. All 10 EMBs revealed myocardial damage, with eight cases providing evidence of eosinophilia. Pathological findings consistent with suspected myocardial EGPA were reported in the CMR of 15 patients. Four CMR examinations that were initiated as part of a recently implemented standard at our Vasculitis Centre returned with negative results, ruling out cardiac manifestation in newly diagnosed patients with EGPA.

Figure 1. Frequency of cardiac manifestations in patients with EGPA and cardiac involvement. CMR, cardiac MRI; EGPA, eosinophilic granulomatosis with polyangiitis; MINOCA, myocardial infarction with non-obstructive coronary arteries.

Coronary vasospasms

With the working diagnosis of MINOCA, vasospasms of the coronaries were identified as the most likely cause of suspected infarction in three of the patients with EGPA-CI. These patients with vasospastic cardiac involvement (EGPA-vCI) were younger (median age 27.9 years, 27.6–33.9) than other patients with EGPA-CI (53.7 years, 39.8–60.8 years, p<0.05), ANCA-negative and were conspicuous by the clinical severity of disease. Without exception, patients with EGPA-vCI initially presented with STEMI (figure 2a), the highest troponin levels of the cohort and other strikingly elevated myocardial biomarkers. Echocardiography showed an early global decrease in myocardial contractility. Emergency coronary angiography revealed multiple major stenoses of left and right coronaries due to vasospasms that were either completely resolved after application of nitroglycerin or spontaneously regressive over time (figure 2b). To prevent further complications, additional intracoronary acetylcholine provocation tests were usually not performed. CMR revealed ischaemic patterns of transmural late gadolinium enhancement (LGE), not confined to the vascular territory of a single coronary artery, due to systemic involvement of EGPA (figure 2c).

Figure 2. Clinical presentation of patients with EGPA and coronary vasospasms. (a) Initial emergency 12-lead ECG of a patient with EGPA showing ST segment elevation in leads II, III, avF and depression in I, avL, V2, V5 and V6. (b) Coronary angiography on the day of admission with severe vasospasms of the right and left coronary arteries (white arrows). (c) Cardiac MRI demonstrating transmural late gadolinium enhancement in the inferior and apicoseptal regions from cardiac base to apex (white arrows). EGPA, eosinophilic granulomatosis with polyangiitis.

Further immediate management of EGPA-vCI proved to be particularly challenging in these cases. One patient required implantation of an extracorporeal life-support system due to cardiogenic shock. Despite immediate high-dose steroids and cyclophosphamide, the patient developed new episodes of angina pectoris and relapsing coronary vasospasms in the first 4 weeks after disease onset, as well as alveolar haemorrhage. With an intensified therapy regimen including rituximab, stabilisation of the disease was accomplished. Severe cardiomyopathy with an ejection fraction of 20% made a temporary wearable cardioverter defibrillator and subsequent implantation of a subcutaneous implantable cardioverter-defibrillator device stringently necessary. Two patients received three drug-eluting stents because of recurring angina and vasospasms at a referral hospital shortly before being transferred and diagnosed with EGPA. The use of high-dose steroids, cyclophosphamide and biologicals achieved a stable course of disease in these cases.

Relapse and survival rate with cardiac manifestation

Patients were followed up for a median time period of 8.7 years (4.3–16.7). In the EGPA-nCI cohort, only one patient died after 2.5 years due to an unrelated cause. Three fatalities were recorded among patients with EGPA-CI, all of which were associated with progressive heart failure. None of the deaths occurred in the initial acute phase of disease but after a period of approximately 4, 10 and 19 years from the initial onset of disease. The 10-year survival rate, even in cases of severe heart manifestation, was greater than 90% (table 1). Relapses were identified in 23 of the 36 patients with EGPA-CI (64%) over a median follow-up period of 9 years (4.5–16.7). The first event occurred after a median period of 12.6 months (5.2–61.7), while 27% of relapses within the EGPA-CI group involved renewed cardiac involvement. The median eosinophilic granulocyte count at the time of cardiac relapse was 910/µL (630–1390), and the median relative eosinophilia was 11.8% (8–15.9).

Discussion

Cardiac manifestations have been known to be the most relevant life-limiting factors in EGPA for decades. However, in the absence of a precise definition of eosinophilic heart disease, as well as limited accessibility to new diagnostic approaches such as CMR, past studies have rarely focused on cardiovascular involvement in detail. As a result, the existing research evaluating cardiac manifestations over the last decades is highly heterogeneous in terms of design and methodology. Previous analyses have predominantly focused on patients with established EGPA who were in either complete or partial remission and undergoing immunosuppressive therapy.^{11 13 14 21} This resulted in a documented prevalence as low as 17%. Notably, previous postmortem studies and more recent CMR screening studies revealed that cardiac involvement is frequently underestimated, with 60%–92% of patients with EGPA affected.^{12 22} Given these discrepancies and the previously reported potential for life-threatening cardiac events to occur early in the course of disease, this study was designed to investigate eosinophilic-mediated cardiac disease in patients with previously undiagnosed and untreated EGPA. The objective was to gain a deeper understanding of the cardiac manifestations and elucidate implications for future diagnostic and possibly therapeutic recommendations.

The comprehensive analysis of our single-centre cohort, which is characterised by a high rate of 83% histopathologically confirmed patients with EGPA, enabled us to identify a cardiac manifestation in 35% of newly diagnosed EGPA. This is in line with recent data from a Chinese cohort describing 36.4% of patients with EGPA affected, using a similar approach.²³ Both groups of our cohort, patients with and without cardiac involvement, otherwise demonstrated the typical extracardiac organ manifestations of EGPA. Except for a reduced incidence of dermatological manifestations but more gastrointestinal symptoms in patients with EGPA-CI, no other relevant clinical differences were observed.

Cardiac involvement has historically been associated with the absence of ANCA, which itself has been linked to an overall unfavourable prognosis and multiorgan involvement.^{24 25} Consequently, the ANCA positivity rate among our patients with EGPA-CI was only 19.4%. The overall low frequency of ANCA positivity in our cohort, which is lower than the usually assumed rate of approximately 30%–40%, may be reflective of the cohort’s average high severity of disease, also supported by high systemic inflammation, including elevated serum CRP levels.²⁶ Furthermore, the proportion of patients with histopathologically proven EGPA was high. We observed in our cohort that patients with EGPA-CI showed a significantly elevated eosinophilic blood count, which was discussed as a potential discriminator to identify cardiac involvement.²³ The significantly elevated BVAS and high FFS observed in patients with EGPA-CI were also a testament to the high disease activity and poor prognosis associated with this condition.

Although the majority of our patients with EGPA-CI, who were marginally younger in age and more often female, reported dyspnoea, chest discomfort or classic angina pectoris, it is noteworthy that 17% were asymptomatic in this regard. In addition, classic cardiovascular risk factors were often absent. The fact that their cardiac manifestations could have certainly been overlooked highlights the necessity of a multifaceted diagnostic approach. In order to identify each affected patient and to avoid undue delays in diagnosis and treatment, we suggest it is essential to use a comprehensive set of parameters, including not only clinical but also laboratory, imaging and, if reasonable and necessary, histopathological data.

Laboratory markers indicative of myocardial necrosis, including troponin and myoglobin, were strikingly increased in our EGPA-CI cohort, underscoring their potential as biomarkers for the early detection of cardiac involvement in EGPA.¹³ Similarly, the utilisation of pro-BNP as an indicator of potential cardiomyopathy can be supported, as previously suggested.¹² EGPA-related cardiomyopathy has been described as a major cause and independent predictor of disease-related death. Prior research has shown that up to 40% of patients with EGPA may present with some level of cardiomyopathy at their initial clinical encounter.²¹ In more than 50% of our patients with untreated EGPA-CI, the LVEF was already markedly reduced, and cardiac wall motion abnormalities were evident. In line with our observation of intraventricular thrombi in five patients (14%), a recognised feature of cardiac EGPA manifestation and increased levels of biomarkers suggestive of myocardial injury, cardiovascular thromboembolic events appear to represent an important yet often underappreciated complication of EGPA. A large multicentre cohort demonstrated a more than twofold increased risk of both arterial and venous events, particularly within the first 2 years surrounding diagnosis, largely independent of traditional cardiovascular risk factors.²⁷ Similarly, a population-based study in AAV, including a subgroup of patients with EGPA, confirmed excess risks of cardiovascular disease and venous thromboembolism, supporting the concept of accelerated, inflammation-driven atherothrombosis.²⁸ Taken together, these findings suggest that initial management of EGPA should not only focus on controlling primary disease activity but also incorporate heightened vigilance for arterial and venous thromboembolic events, especially during the first 2 years after onset. This highlights the critical importance of early diagnostics to correctly assess EGPA disease activity, particularly in cases with cardiac involvement. Transthoracic echocardiography is a readily available and standard technique in emergency rooms and hospital wards, providing rapid and informative cardiologic imaging. As such, it should be used as a routine baseline screening method in patients newly diagnosed with EGPA.

Due to its high sensitivity, CMR has become another pivotal technique for assessing cardiac involvement in EGPA. For trained radiologists, it facilitates the differentiation between active and chronic myocardial injuries that are undetectable by ECG or TTE.²⁹ The most common finding in AAV, especially in EGPA, is subendocardial LGE, indicating tissue injury and fibrosis.³⁰ Additionally, the regional distribution pattern facilitates the differentiation from other aetiologies. Our data suggest that acute and chronic changes caused by myocarditis in EGPA are more frequently characterised by LGE found in subendocardial and transmural regions of the heart. The distribution of the lesions is not consistent with the typical characteristics of a culprit coronary artery in myocardial infarction, as it is not confined to a specific coronary artery territory but rather is patchy.³¹ Particularly, the employment of specific T2 mapping techniques has the potential to allow quantitative tissue characterisation of active disease inflammation versus myocardial scar. These parameters could possibly be used as biomarkers during the clinical course of the disease.³² Expectedly, all patients with EGPA-CI who underwent CMR showed radiological evidence of myocardial injury or ischaemia. A recent prospective study using CMR as a screening method revealed that cardiac involvement is present in approximately a third of patients with EGPA with stable disease.³³ This finding reinforces the importance of not only monitoring the clinical activity of cardiac disease in patients with EGPA but also the need to implement standardised screening examinations, even in those who appear to be responding to immunosuppressive therapy. Consequently, CMR could serve as a new future gold standard, superseding the myocardial biopsy procedure, which is less sensitive and carries a higher risk of complications.

The combination of all described diagnostic techniques enabled us to identify pericarditis, histologically or radiologically proven myocarditis, and cardiomyopathy with acute heart failure as the most common cardiac manifestations in newly diagnosed patients with EGPA. Nevertheless, the major challenge in diagnosing cardiac manifestations in EGPA at disease onset is the presentation with non-specific cardiac symptoms and their possible misinterpretation. Understandably, based on their symptoms and acute ECG abnormalities, two-thirds of our patients with EGPA underwent acute cardiac catheterisation, often before completion of full blood work. However, coronary artery disease was ruled out in each of these cases, resulting in some patients initially being left without a definite underlying cause of MINOCA.

Interestingly, among our cohort of 36 patients with EGPA-CI, we observed at least three patients who developed epicardial coronary vasospasms, which initially resembled classic type 1 myocardial infarctions. Coronary vasospasms have recently been more frequently documented as manifestations of EGPA in single case reports.³⁴,³⁶ However, their prevalence has not been widely recognised in larger cohorts. A recent French multicentre study investigated vasospasms in eosinophilic diseases, finding that 35% of patients affected were patients with EGPA with otherwise low cardiovascular risk.³⁷ However, the authors of the study indicated that their patients with EGPA did not present with any other features of systemic vasculitis and had low inflammatory markers. This is in stark contrast to the characteristics observed in our cohort. All three patients with EGPA-vCI developed coronary vasospasms concomitant with other hallmark vasculitic organ manifestations, including alveolar haemorrhage, as well as blood eosinophilia and elevated CRP levels. These discrepancies may be attributed to the fact that the patients in our centre exhibited active systemic disease and were not undergoing any immunosuppressive treatment. None of the known direct triggers for coronary vasospasms, including allergens, drugs or tumours, were identified.

The exact mechanism underlying coronary vasospasms in the context of EGPA, therefore, remains to be elucidated. It seems reasonable to hypothesise that the previously reported infiltration of eosinophils into the adventitia and periadventitial soft tissue of epicardial coronaries, along with the potential release of vasoactive substances, including leukotrienes, may be involved in the pathogenesis of coronary vasospasms in EGPA.^{38 39} Nevertheless, further research is required to distinguish the mechanisms underlying this phenomenon in EGPA from those observed in other diseases with coronary vasospasms, such as Kounis syndrome or isolated eosinophilic coronary periarteritis.^{38 40}

In light of our findings, we conclude that eosinophilia-associated epicardial coronary vasospasms are possibly not merely a local cardiac phenomenon. We would rather argue that they can also present as a manifestation of systemic vasculitis and need an acute level of awareness. From a clinical perspective, it is imperative to be vigilant in identifying eosinophilia-mediated vasospasms, as they have the potential to result in myocardial infarctions and subsequently lead to sudden cardiac failure or death. In such cases, urgent clinical monitoring and intensified therapeutic interventions, not only rigorous immunosuppressive therapy regimens but also extracorporeal life support, may be necessary. Additionally, the early diagnosis of EGPA and the prompt administration of adequate immunosuppressive therapy in the context of prolonged coronary vasospasms may prevent unnecessary measures such as the implantation of stents or repeated coronary angiographies at high frequency despite missing cardiac risk factors.

As awareness of cardiac manifestations in EGPA has evolved, it is reasonable to hypothesise that long-term patient survival of patients with EGPA-CI is improving. Although progressive heart disease remained the primary cause of mortality in this study, the 10-year survival rate in the EGPA-CI cohort exceeded 90%, despite the presence of severe cardiac manifestations. In addition to the contributions of therapeutic and technological advances, the observed outcome can be attributed to continuous monitoring and intensive medical care provided. Consequently, in the event of a new diagnosis of EGPA, it is recommended to conduct a comprehensive cardiovascular evaluation in a timely manner. This assessment should include the evaluation of cardiac biomarkers (CK/CK-MB, troponin and pro-BNP), ECG, TTE and CMR. A similar approach should be considered in relapses of disease or in any asymptomatic patient without a comparable screening in the past. Subsequent treatment decisions should take the pathological results of a cardiac workup into account, and the patient should be referred to a specialised centre with interdisciplinary expertise in the field of AAV. According to current international guidelines, any cardiac involvement is considered to be an organ- or life-threatening complication of EGPA.^{41 42} For this reason, the use of intravenous cyclophosphamide in combination with glucocorticoids is highly recommended for remission induction. Rituximab can be considered as an alternative or added therapy. In addition to quarterly or at least semiannually scheduled rheumatology follow-up visits, it is imperative to arrange recurring cardiology consultations and optimise heart treatment.

Limitations

It is important to consider certain limitations of this study. Due to its retrospective design and the fact that the decision to undertake diagnostic tests was made by the treating physician at the time, not all patients underwent the same diagnostic pathway. This results in missing data points and could have introduced selection bias. The standard of care and diagnostic modalities used at the respective time need to be considered. No standardised screening process was employed. The scope of the current study did not encompass a detailed multiyear follow-up, as this was not the primary objective.

Conclusion

Cardiac involvement is rather frequently evident in patients with newly diagnosed and active EGPA. At this stage of the disease, patients often present already with advanced cardiomyopathy and acute heart failure, requiring rapid diagnostic and therapeutic measures to prevent further acute organ damage and potential long-term organ complications. In addition to pericarditis, myocarditis and cardiomyopathy, we identified coronary vasospasms mimicking type 1 myocardial infarction as a previously underestimated manifestation of systemic vasculitis in EGPA with the potential to cause sudden cardiac failure. Overall, there is still an immediate need for an improved clinical definition and pathophysiological understanding of the different organ involvements in EGPA and its tailored treatment.

Data availability statement

Data are available upon reasonable request.