Brugada syndrome is a rare sodium channelopathy that predisposes to an increased risk of malignant arrythmias and sudden cardiac death. Previous studies have reported that metabolic disturbances can uncover a Brugada ECG pattern. Given the risk of malignant arrhythmias, it is important to correctly diagnose and treat Brugada syndrome. We report a case of Brugada syndrome uncovered by hyperkalaemia precipitated in a patient with pseudohypoaldosteronism.
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Brugada syndrome (BrS) is an autosomal-dominant sodium channelopathy associated with an increased risk of ventricular fibrillation and sudden cardiac death (SCD) in a structurally normal heart.1–3 The most studied cause of BrS is due to loss-of-function variants in the SCN5A gene, which encodes for α-subunit of the NaV1.5 sodium channel. Previous studies have reported that metabolic disturbance such as hyperkalaemia, hypokalaemia and metabolic acidosis can uncover Brugada ECG patterns in patients with genetically confirmed BrS or with ventricular fibrillation.4 5 Pseudohypoaldosteronism type I (PHA1) with loss of function mutation in epithelial sodium channels (ENaC) is a rare autosomal recessive disorder leading to resistance to aldosterone and life-threatening salt-wasting and hyperkalaemia.6 7 This case reports BrS uncovered by hyperkalaemia precipitated in a patient with pseudohypoaldosteronism.
A female in her 30s with a history of PHA1 (diagnosed in infancy, loss of function of ENaC), hypersensitivity pneumonitis and eczema presented with several days of nausea and vomiting. She had been regularly followed in the outpatient nephrology clinic and medical treatment of pseudohypoaldosteronism included sodium citrate-citric acid three times a day, which she was unable to take due to poor oral intake in the days leading up to admission. She was afebrile and hemodynamically stable with mild sinus tachycardia. She had a positive SARS-CoV-2 PCR result. Labs revealed severe hyperkalaemia with blood potassium level of 7.9 mmol/L and hyponatraemia with blood sodium of 121 mEq/L. She was given calcium gluconate, insulin, sodium zirconium, albuterol and intravenous fluids including sodium bicarbonate drip.
12-lead ECG revealed pathognomonic features of type 1 Brugada pattern with >2 mm ‘coved type’ ST-segment elevations in the right precordial leads, which descended with upward convexity into inverted T waves (figure 1A). A transthoracic echocardiogram revealed a structurally normal heart. Repeat ECG at 14 hours with a blood potassium level of 4.8 mmol/L and blood sodium level of 124 mEq/L revealed normalisation of ECG abnormalities (figure 1B).
She did not develop any malignant ventricular arrythmias during hospitalisation. After resolution of her nausea and vomiting, she was discharged with sodium chloride 2 g three times a day, sodium citrate 45 mg three times a day and sodium zirconium 10 mg per day.
Outcome and follow-up
On further interviewing, she denied palpitations as well as a personal or family history of sudden cardiac arrest or unexpected death. She used cannabis socially but denied other recreational drugs. She described three episodes of possible syncope in her lifetime in her teens, mid-20s and 3 months prior to presentation in the setting of dehydration.
Given her syncope of unknown origin and resolution of ECG abnormalities with correction of electrolyte disturbance, the decision was made to proceed with the implantation of a cardiac loop recorder to further risk stratify the patient for need of implantable cardioverter-defibrillator (ICD) placement. Should ventricular arrhythmia with concerning features be detected on the loop recorder, ICD placement could be pursued to prevent the risk of SCD. She was also referred for BrS genetic testing. Prior to discharge, she was educated on prompt fever treatment, avoidance of drugs that may unmask Brugada and adherence to medical therapy for PHA1.
PHA1 is a rare (type 1A—autosomal dominant, type 1B—autosomal recessive) disorder characterised by generalised resistance to the actions of aldosterone. It involves loss of function mutations of non-voltage gated ENaC in the late distal tubules, the connecting tubules and collecting ducts of the kidneys. Other tissues, such as the colon and sweat glands, also express ENaC. It is clinically manifested in the newborn and leads to life-threatening salt-wasting and hyperkalaemia. Salt supplements of ≤45 g/day are required indefinitely, together with control of hyperkalaemia. Recurrent salt-wasting crises and severe hyperkalaemia can lead to life-threatening cardiac arrhythmias and cardiac arrest.6 7
BrS has an overall presence of 1:2000 and is most common in Asia followed by Europe and the USA.1 The clinical manifestations of BrS are syncope and cardiac arrest or SCD from ventricular fibrillation. BrS is caused by a loss of function of the voltage-gated sodium channels found in the heart muscle. SCN5A was the first described mutation and results in alteration of the alpha-subunit of the Nav1.5 ion channel, however, a variety of potential pathogenic variants have been described. Although BrS and PHA are caused by mutations that encode sodium channels, a common genetic mutation linking the two has not been described.8 9
Diagnostic recommendations for BrS have changed over the past three decades since its first description in 1992. The recently devised Shanghai scoring system recognises the limitation of induced (fever, drugs or electrolytes) type 1 ECG changes in isolation and uses additional information (such as clinical and family history and genetic results) to make a definitive diagnosis.10
The association of metabolic disturbances in uncovering Brugada ECG change in patients at risk is well-reported. Precipitating factors can unmask BrS and should be avoided, including drugs such as psychotropic or anaesthetic agents, and fever.11 In our patient, it is likely that untreated pseudohypoaldosteronism predisposed her to hyperkalaemia which contributed to type-1 BrS ECG pattern. Mechanistically, hyperkalaemia depolarises resting cardiac membrane potential which in turn leads to steady-state inactivation of sodium channels such that fewer sodium channels are available to be activated during the action potential upstroke. This will lead to an increase in voltage gradient between the epicardium and endocardium and dispersion of repolarisation within the right ventricular epicardium. ST-segment elevation in the right precordial leads is proposed to be caused by this mechanism.5 12 It is therefore important that hyperkalaemia is promptly treated in patients with BrS, as they are highly susceptible to the reduced cardiac excitability effects of hyperkalaemia that can lead to malignant arrythmias and cardiac arrest.13 There are several case reports of BrS in acute SARS-CoV-2 infection and thought to be secondary to fever induced by inflammatory response activation.14 15 SARS-CoV-2 as an unmasking factor was not likely in this patient as she was afebrile throughout her stay without antipyretics, and case reports implicating SARS-CoV-2 and BrS consistently report fever as the unmasking event.16 This case highlights the importance of recognising genetic disorders, like PHA, that predispose patients to electrolyte derangement and can unmask BrS.
Brugada syndrome (BrS) can be uncovered by hyperkalaemia.
Given its potential for lethal arrythmias, early detection, accurate diagnosis and treatment of BrS are critical.
This case highlights the importance of understanding how genetic disorders, like pseudohypoaldosteronism, precipitating hyperkalaemia can unmask BrS and potentially alter the risk for malignant arrythmias.
Patient consent for publication
PATIENT’S PERSPECTIVE N/A
Contributors SB, JT, HK and SS were responsible for drafting of the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms, and critical revision for important intellectual content. SB, JT, HK and SS gave final approval of the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.