Fever induced Brugada electrocardiographic pattern converted to the early repolarization pattern after fever abatement in an elderly man

Brugada syndrome (BrS) is one of inherited arrhythmia syndromes characterized by ST-segment elevation in the right precordial leads and is associated with increased risk of ventricular fibrillation (VF) and sudden cardiac death (SCD) in the absence of a structural heart disease. Fever is a known trigger for Brugada ECG pattern (BrP).^[1] Relevant studies showed that BrS patients with a fever induced type 1 (F-type 1) BrP have a worse prognosis due to the higher risk of future arrhythmic events.^[2] However, the prognosis of asymptomatic subjects with F-type 1 BrP remains to be elucidated, especially in the elderly. Recent studies have found that in elderly patients, F-type 1 BrP led to VF or even syncope.^[3,4,5] Thus, more clinical attention should be given rise on cases of elderly asymptomatic patients with F-type 1 BrP.

Here we described a case of an elderly patient without BrS diagnosis who showed F-type 1 BrP, and then converted to the early repolarization pattern (ERP) after fever abatement. ERP, which was previously believed to be benign, has recently been shown to be a marker for arrhythmogenic potential. It is unclear whether the overlap of F-type 1 BrP and ERP increases the risk of malignant arrhythmia in elderly patients.

An 86-year-old man presented to the fever clinic with 3 h of high fever. The patient had a history of a cold one day prior. His fever was accompanied by chills and lethargy, and with no generalized myalgia, abdominal pain, or diarrhea. Medical history was significant for resected pancreatic ductal adenocarcinoma, chronic kidney disease stage 3a and hypertension.

On examination, the patient was febrile (temperature, 39.0°C), with a heart rate of 90 beats/min and a blood pressure of 107/65 mmHg. The remainder of his examination was normal. Electrocardiography (ECG) on admission revealed normal sinus rhythm and coved ST-segment elevation of 3 mm, followed by negative T-wave in right precordial leads (Figure 1A), consistent with type-1 BrP. The abdominal computer tomography showed that subcapsular low-density lesion in the anterior lower segment of the right lobe of the liver. Laboratory measures were unremarkable except for neutrophilia, the elevated serum C-reactive protein and procalcitonin. Klebsiella pneumoniae was later cultured from the blood. The oropharyngeal real-time reverse transcriptase-polymerase chain reaction test for SARS-CoV-2 and influenza A/B were negative. The patient was admitted with a diagnose of liver abscess and Klebsiella pneumoniae bloodstream infection and was treated with antibiotics, fluids, and antipyretics. He gradually defervesced. Repeated ECG showed ERP--low amplitude J-wave in inferior and lateral leads (Figure 1B). No Brugada wave was simultaneously recorded in the third intercostal space (Figure 1C). Next day, his ECG showed resolution of the ST-segment elevation in right precordial leads, as well as J waves in lateral leads (Figure 2A). On the third day, a repeated ECG showed the disappearance of the J waves in the inferior leads (Figure 2B). The patient’s echocardiogram was normal. No myocardial abnormality was found on magnetic resonance imaging. No ventricular arrhythmia (VA) was detected in dynamic electrocardiogram. He did not take any medicine that could cause Brugada-like ECG.

Figure 1.

ECG recordings.

(A): Initial ECG on arrival while the patient was febrile. Leads V₁ and V₂ showed a type 1 Brugada pattern with 3 mm of coved ST segment elevation followed by an inverted T wave (arrows). (B): 8 hours later after the patient had defervesced, showed the early repolarization pattern followed by ascending/upsloping ST-segment elevation in the inferior and lateral leads (arrows), instead of the type 1 Brugada pattern. (C): No Brugada wave was recorded in the third intercostal space after abatement of fever.

Figure 2.

Another two ECGs recorded on the next day (A) and the third day (B).

Panel A showed disappearing of the ST-segment elevation in right precordial leads, as well as J waves in lateral leads. Panel B showed disappearing of the J waves in inferior leads.

Genetic analysis showed the patient did not carry any pathogenic or likely pathogenic mutations related to BrS. But he carried four rare variants (Table 1). The varSEAK software predicted that variations in the SCN5A gene might not affect splicing; the latter two might cause changes in amino acids, but the amino acids at these positions were highly conserved in vertebrates. The four variants were determined to be of uncertain significance due to a lack of family and functional evidence.

Table 1. Genetic testing results of the patient.

Gene	Transcript number	Exon	Nucleotide change	Amino acid change	Variant Type	ACMG in InterVar[6]
RYR2	NM_001035	6	c.310A > T	p.Thr104Ser	Missense	Uncertain_significance
TMEM43	NM_024334	4	c.346C > T	p.Arg116Trp	Missense	Uncertain_significance
SCN5A	NM_000335	27	c.4540-75T > G	-	Missense	NA
SCN5A	NM_000335	16	c.2787+29nsACACACACACACACACACAC	-	Indel	NA

The patient denied previous history of syncope, agonal respiration, or palpitations. Family history was significant for unexplained sudden death -his father at the age of 44. The patient was diagnosed as possible BrS with a Shanghai BrS Score of 3 points. Given that the risk of sudden death in senior BrS patients is relatively low,^[7] defibrillator implantation was not recommended. Instead, lifestyle modifications were advised including avoiding and promptly treating fevers, and consulting with a pharmacist prior to using new medications. Recommended screening of family members was refused. No VA occurred during 10 months of follow-up.

BrP and ERP are two ECG patterns characterized by J waves. The overlap of ERP and BrP has been reported mainly in young men, and the inferolateral ERP has been identified as a potential high-risk marker for VA. The patient with F-type 1 BrP we report is 86 years old, the oldest reported to date. After resolution of the fever, his ECG changed from type 1 BrP to ERP in the inferolateral leads. The patient had no symptoms associated with BrS. However, he had a family history of sudden unexplained death. Genetic testing identified four rare variants of uncertain clinical significance and no pathogenic/likely pathogenic variants were identified. Primary prevention of cardiac events in such an asymptomatic patient of advanced age is an important issue for clinical decision making.

Clinical data on the prognosis of older adults with F-type 1 BrP are scarce and inconsistent. Some evidence suggested that the clinical phenotype of type 1 BrP may be age-dependent, with a lower incidence of VA in patients older than 60 years.^[7] However, others have reported that, unfortunately, 0.13% of BrS patients may develop major arrhythmic events (MAE) by the age of 70.^[8] Further studies are needed to develop a better multi-factor risk stratification score, which should take into account the patient’s age.

For asymptomatic patients, there is no clear evidence or marker to distinguish whether the fever-induced Brugada-like ECG is BrS or BrP. Yalta, et al.^[9] considered that fever-induced conversion from a baseline type-2 or type-3 ECG pattern to a type-1 ECG pattern most likely suggests an unmasked BrS. On the other hand, fever-induced conversion from a normal baseline ECG pattern to type-2 or type-3 ECG pattern most likely suggests a BrP. However, fever-induced conversion from a normal baseline ECG pattern to a type-1 ECG pattern might suggest either BrP or unmasked BrS. This type therefore has a greater prognostic uncertainty and may miss the diagnosis of BrS, with a greater risk of VA. The patient in this case falls into the last category, with the possibility of BrP or unmasked BrS.

The ERP is a common finding in BrS. ERP was reported in 12.8% BrS patients.^[10] BrS patients with ERP had an increased risk of MAE compared to patients without ERP. And patients with inferolateral (global) ERP had a higher risk compared to those with only inferior or lateral location. The elderly asymptomatic patient we reported here had an ECG pattern that switched from type 1 BrP to inferolateral ERP after fever subsidence. For his age of 86, the risk of MAE is very low according the latest meta-analysis.^[8] On the other hand, F-type 1 BrP, global ERP and J waves with dynamic amplitude are high-risk features of VA, whereas a low-amplitude J wave with a rapidly rising ST segment is a low-risk feature according to the consensus on J wave syndrome.^[11] This case highlights that J-wave syndrome is a complex clinical entity with variable presentations. The current ability to assess VA risk in patients with J-wave syndrome needs to be improved.

The diversity of manifestations of this clinical entity has been shown to be associated with the complexity of genetic variants. A recent review by Antzelevitch, et al.^[12] showed that families with rare SCN5A variants tend to have disseminated disease and low disease epistasis. The observation of phenotypically positive genotype-negative individuals in these families suggested that BrS may be a more complex genetic disease than a Mendelian disease. It has also been suggested that the susceptibility of BrS patients to VA may not be due to a single mutation, but rather the result of multiple BrS susceptibility variants acting in concert through one or more pathways. This patient was tested for four rare genetic variants. The clinical significance of these variants as judged by the predictive software is currently unknown due to a lack of functional evidence. However, he has a family history of sudden death in a first-degree relative at the age of 44, so more evidence is needed to assess the clinical significance of these rare variants.

The ECG manifestations of ERP and BrP are diverse. Current research supports both as manifestations of the same mechanism in different conditions. Experimental evidence indicates that the electrocardiographic J wave is the expression of a transmural voltage gradient of the action potential (AP) notch due to a prominent transient outward current (Ito) in the ventricular epicardium but not endocardium.^[13] Although J-wave diversity is largely determined by the characteristics of Ito, it is also influenced by ventricular conduction, pathophysiological conditions that alter the balance between Ito and other ionic currents. Because of the temperature-dependent nature of some ion channel activity, the J-wave changes as the body temperature changes.

Undiagnosed BrS has been estimated to have a mortality rate of up to 10% per year.^[14] There are several triggers, especially fever, that can unmask a BrP. In the current COVID-19 outbreak, fever is the most common symptom. Elderly patients have many underlying diseases and low immunity. Once they have a fever, the risk of arrhythmia is higher than in adults and the prognosis is worse. Because BrS is a rare disease, most emergency physicians and geriatricians have a poor understanding of its ECG characteristics. Physicians should be aware of these ECG findings to facilitate emergency or urgent cardiology follow-up, depending on the patient's clinical risk factors.

CONCLUSION

The prognosis of F-type 1 BrP in elderly asymptomatic patients remains unclear. These patients should receive rapid cooling, detailed ECG monitoring and close follow-up. Individualised treatment should be recommended according to the patient's clinical condition.

CONFLICT OF INTEREST

None.

SUPPLEMENTARY DATA

Supplementary data to this article can be found online.