Decoding Gitelman syndrome in a structurally normal heart with polymorphic ventricular tachycardia: A case report

Key Teaching Points.

• •Early detection is the key: Early detection of electrolyte imbalances in the form of hypokalemia and hypomagnesemia in a structurally normal heart is essential to prevent potentially fatal polymorphic ventricular tachycardia.
• •Imaging is essential: PET scan is a must to rule out any possibility of cardiac sarcoidosis, tuberculosis, or amyloidosis.
• •Genetic testing: Genetic testing for the SLC12A3 gene mutation must be positive to confirm the diagnosis of Gitelman syndrome.
• •Prompt intervention improves outcomes: The management of these arrhythmic episodes requires urgent intervention, including synchronized cardioversion and aggressive electrolyte repletion.

Introduction

Gitelman syndrome (GS) is a rare autosomal recessive disorder characterized by a defect in the renal tubular reabsorption of electrolytes, leading to a spectrum of metabolic abnormalities, including hypokalemia, metabolic alkalosis, hypomagnesemia, and hypocalciuria.¹ Although GS is primarily a salt-wasting tubulopathy, its complex electrolyte disturbances can have significant cardiovascular implications. One such grave complication is the development of life-threatening polymorphic ventricular tachycardia (VT).² This case report describes a patient with GS who presented with recurrent episodes of syncope and palpitations caused by polymorphic VT. The patient’s arrhythmias were linked to severe electrolyte imbalances, specifically hypokalemia and hypomagnesemia, which were exacerbated during the hospitalization. The management of these arrhythmic episodes required urgent interventions, including synchronized cardioversion and aggressive electrolyte repletion. What distinguishes this case is the demonstration of the direct relationship between GS-induced electrolyte abnormalities and the onset of polymorphic VT. It highlights the critical importance of early detection and management of electrolyte imbalances in GS patients to prevent potentially fatal cardiac events.

Case presentation

We present the case of a 60-year-old woman who was referred to our emergency department from a peripheral hospital with a chief complaint of recurrent palpitations and syncope. Her medical history was unremarkable, and she was not on any diuretic therapy. On presentation, her vital signs were stable, but a previous electrocardiogram (ECG) showed polymorphic VT. Initial diagnostic workup included a complete blood count, comprehensive metabolic panel, arterial blood gas analysis, cardiac positron emission tomography (PET) scan, and echocardiography. Echocardiography demonstrated normal left ventricular function with no regional wall motion abnormalities, and cardiac PET scan was absolutely normal, ruling out any possibility of cardiac sarcoidosis, tuberculosis, or amyloidosis. During the stay in the emergency department, the patient experienced another episode of polymorphic VT with hemodynamic collapse, prompting immediate synchronized DC cardioversion of 200 J, which restored normal sinus rhythm. The initiation sequence of polymorphic VT in this case was the R-on-T phenomenon (Figure 1). Amiodarone was administered as a bolus (150 mg) followed by a continuous infusion of 1 mg/min for 6 hours and then 0.5 mg/min for next 18 hours.

Figure 1.

12-Lead ECGs showing recurrent episodes of R-on-T phenomenon (arrow) leading to polymorphic ventricular tachycardia. ECG = electrocardiogram.

Biochemical analysis indicated severe hypokalaemia with a serum potassium level of 2.7 mEq/L (normal range, 3.5–5.5 mEq/L) and hypomagnesemia with a serum magnesium level of 0.9 mg/dL (normal range, 1.7–2.2 mg/dL). Arterial blood gas analysis shows blood pH, 7.51; serum bicarbonate level, 31 mEq/L, along with hypokalemia and hypomagnesemia. Intravenous magnesium sulfate (4 g) was promptly administered and potassium chloride (10 mEq/h) infusion started. A repeat ECG showed sinus rhythm with a corrected QT interval (QTc) of 430 msec in normal range (Figure 2). Despite ongoing potassium infusion, the patient experienced 6 additional episodes of polymorphic VT over the next 24 hours, requiring 2 more DC cardioversions. Further investigations showed persistent hypokalemia despite continuous potassium supplementation. Thereafter, subsequent analysis of spot urine chemistries showed high potassium excretion (50.6 mmol/L; normal, <20 mmol/L), low urine calcium (6 mg/L; average value, 100–300 mg/24 h), and elevated urine chloride (55 mmol/L; normal, 20–40 mmol/L). Other investigations such as computed tomography of the abdomen were performed to rule out any adrenal mass and their results were normal. Elevated urine excretion of potassium, hypokalemia, hypomagnesemia, and hypocalciuria was suggestive of GS. Other possible causes of renal potassium loss, such as renal tubular acidosis, metabolic acidosis, hyperaldosteronism, and so forth, were ruled out.

Figure 2.

Digital 12-lead ECG showing sinus rhythm with normal QTc interval. ECG = electrocardiogram.

The patient was started on the potassium-sparing diuretic amiloride 5 mg daily and high-dose oral potassium supplementation. Genetic testing for the SLC12A3 gene mutation was positive to confirm the diagnosis of GS. The patient had no family history of sudden cardiac death, arrhythmias, or renal issues. The patient was born out of a nonconsanguineous marriage. Family members were advised to consider genetic counselling because of potential hereditary risks associated with GS. Subsequent 24-hour Holter monitoring showed only 1 episode of nonsustained VT and occasional ventricular premature complexes (<1%). After the initiation of amiloride and effective potassium repletion, the patient's potassium levels stabilized, and there were no further episodes of polymorphic VT.

Discussion

GS is a rare autosomal recessive disorder characterized by defects in renal tubular electrolyte reabsorption, primarily involving the Na–Cl co-transporter encoded by the SLC12A3 gene.¹ This leads to a distinct set of biochemical abnormalities, including hypokalemia, metabolic alkalosis, hypomagnesemia, and hypocalciuria. The syndrome’s clinical spectrum ranges from mild symptoms such as muscle weakness, dizziness, and ataxia to more severe manifestations such as ventricular arrhythmia (VA).³

In this case, the patient presented with recurrent episodes of polymorphic VT, a life-threatening arrhythmia. Despite initial management with magnesium and potassium supplementation, the patient continued to experience multiple polymorphic VT episodes, highlighting the challenge in stabilizing electrolyte imbalances in GS.

The diagnostic approach to GS involves clinical suspicion based on characteristic biochemical findings: chronic hypokalemia, metabolic alkalosis, elevated urinary chloride excretion, and reduced calcium excretion (Table 1).⁴ Genetic testing for biallelic mutations in the SLC12A3 gene confirms the diagnosis with high specificity. The long-term prognosis of GS is generally favorable, with rare progression to chronic kidney disease despite potential renal complications related to electrolyte abnormalities.

Table 1.

Diagnostic criteria for Gitelman syndrome

Criteria for suspecting a diagnosis of GS

•Chronic hypokalaemia (<3.5 mmol/L) with inappropriate renal potassium wasting (spot potassium-creatinine ratio >2.0 mmol/mmol [>18 mmol/g]) •Metabolic alkalosis •Hypomagnesemia (<0.7 mmol/L [<1.70 mg/dL]) with inappropriate renal magnesium wasting (fractional excretion of magnesium >4%) •Hypocalciuria (spot calcium-creatinine ratio <0.2 mmol/mmol [<0.07 mg/mg]) in adults •High plasma renin activity or levels •Fractional excretion of chloride >0.5% •Low or normal-low blood pressure •Normal renal ultrasound

Features against a diagnosis of GS

•Use of thiazide diuretics or laxatives •Family history of kidney disease transmitted in an autosomal dominant mode •Absence of hypokalaemia (unless renal failure); inconsistent hypokalemia in absence of substitutive therapy •Absence of metabolic alkalosis (unless coexisting bicarbonate loss or acid gain) •Low renin values •Urine: low urinary potassium excretion (spot potassium-creatinine ratio <2.0 mmol/mmol [<18 mmol/g]), hypercalciuria •Hypertension, manifestations of increased extracellular fluid volume •Renal ultrasound: nephrocalcinosis, nephrolithiasis, unilateral kidneys, cystic kidneys •Prenatal history of polyhydramnios, hyperechogenic kidneys •Presentation before age 3 years

Criteria for establishing a diagnosis of GS.

Identification of biallelic inactivating mutations in SLC12A3.

GS = Gitelman syndrome.

Six reported cases appear in the world literature that linked GS to VA (Table 2). Five patients presented with palpitations and evidence of VAs on 12-lead ECG, whereas 1 had an aborted sudden cardiac death. All of them were treated with electrolytes replacement, and 2 patients underwent automatic implantable cardioverter defibrillator implantation.^2,3,5, 6, 7, 8

Table 2.

Summary of relevant reported cases in literature associating Gitelman’s syndrome with ventricular arrhythmia

Case no.	Year published	Age	Sex	Type of arrhythmia	Mode of presentation	Diagnosis	Treatment	Outcome
1	2004	62	Female	NSVT PVCs	Palpitations	ECG, echocardiography, Holter, EP study	Radiofrequency ablation	6 months’ follow-up No arrythmia
2	2005	39	Female	Monomorphic VT	Presyncope	ECG, echocardiography, Holter, EP study	Electrolytes replacement, amiloride, captopril, lidocaine, amiodarone, ICD	No follow-up data
3	2007	40	Male	VT/VF	Aborted SCD	ECG, echocardiography, Holter, EP study	Electrolytes replacement, amiodarone, ICD	No follow-up data
4	2010	27	Male	OTVT	Palpitation, presyncope	ECG, echocardiography, Holter, EP study	Electrolytes replacement, aldactone	Alive at 1 year follow-up
5	2019	34	Female	NSVT, PVCs Torsade de pointes	Palpitation, presyncope	ECG, echocardiography, Holter, EP study	Electrolytes replacement, aldactone Beta blocker, radiofrequency ablation	1 year follow-up No arrythmia
6	2023	28	Female	Polymorphic VT	Presyncope	ECG, echocardiography	Electrolytes replacement	No follow-up data

ECG = electrocardiography; EP = electrophysiology; ICD = intracardiac defibrillator; NSVT = nonsustained ventricular tachycardia; OTVT = outflow tract ventricular tachycardia; PVCs = premature ventricular contractions; SCD = sudden cardiac death; VF = ventricular fibrillation; VT = ventricular tachycardia.

Foglia et al,⁹ in their analysis of 21 cases of GS, has shown that mild to moderate QTc prolongation (446–509 msec) is seen in almost 50% of cases irrespective of their potassium or magnesium levels, although their Holter and ECG did not reveal any evidence of ventricular ectopics or VT. Initially considered to be a benign condition but because of its association with fatal VA and evidence of aborted sudden cardiac death, it needs a more aggressive approach to pick up early electrolyte imbalances to prevent fatal complications.⁹ Scognamiglio et al¹⁰ also has shown evidence of coronary microvascular defects and reduced myocardial perfusion on exercise along with electrolyte imbalance acting as a nidus for VT, thus questioning its benign nature.¹⁰

The laboratory values in this patient were satisfying the criteria for the diagnosis of GS, such as elevated excretion of potassium and chloride and low excretion of calcium, and the genetic test confirmed the diagnosis. Newly diagnosed GS with severe electrolyte derangements was likely the cause of polymorphic arrhythmia in this patient.

Conclusion

This case underscores the critical role of recognizing GS as a potential cause of severe electrolyte derangements leading to life-threatening arrhythmias such as polymorphic VT. It emphasizes the need for vigilant monitoring, timely intervention with electrolyte replacement, and consideration of genetic testing in suspected cases to optimize patient outcomes.

Disclosures

None reported.