Ventricular arrhythmia and tachycardia-induced cardiomyopathy in Gitelman syndrome, hypokalaemia is not the only culpable

Abstract

Gitelman syndrome (GS) is an autosomal recessive tubulopathy recently implicated in cases with ventricular arrhythmias (VAs), the latter being considered linked to electrolytes’ imbalance. However, a direct causal relationship is considered to be an oversimplification for a complex molecular dysfunction. Recent work has suggested a degree of microvascular dysfunction in patients with GS that might be attributed as a mechanism of arrhythmia. We report a case of GS presenting with VAs complicated by cardiomyopathy. The high load of premature ventricular contractions that were attributed to the hypokalaemia has masked the presence of the left ventricular (LV) outflow tract tachycardia. Her LV systolic function recovered after successful electrophysiology ablation procedure. Atrioventricular nodal re-entry tachycardia was discovered incidentally during the study and was ablated successfully.

Background

Gitelman syndrome (GS) has been considered for long time to be a benign disease with electrolytes imbalances mainly inform of hypokalaemia and hypomagnesemia.¹ This disorder is hereditary in form of autosomal recessive gene defect affecting the kidney thiazide sensitive sodium chloride cotransporter.² Lately with accumulating body of evidence in the literature linking this disease to sudden cardiac death (SCD) and ventricular arrhythmias (VAs), the benign outlook of the disease has changed with more aggressive cardiac investigations and interventions.^3–7

We present a young patient with GS complaining of palpitation and dizziness that were attributed to VA. The initial management was to correct the electrolytes imbalances and suppress the VAs with medications. Later on, with persistence of VAs and development of left ventricular (LV) dysfunction, she was subjected to electrophysiology study (EP) that identified a LV out flow tachycardia and got ablated.

Case presentation

A 34-year-old female school teacher, a known case of GS presented to the cardiology outpatient department with history of palpitations and near syncope of 3 months’ duration. The palpitations were sensed as forceful beats and associated with dizziness. She denied history of loss of consciousness, chest pain or shortness of breath. Her medical history was significant for prolonged stay in the intensive care unit for postpartum sepsis and acute renal failure. She is a mother of two children and has no family history of SCD.

On examination, her heart rate was 82 beats/min (bpm) with irregular rhythm, blood pressure of 120/70 mm Hg and normal auscultatory findings.

Investigations

Her ECG showed normal sinus rhythm with premature ventricular contractions (PVCs) of left bundle branch block (LBBB) morphology. The corrected QT interval was 438 msec. Her initial transthoracic echocardiography (TTE) revealed normal LV dimensions with preserved systolic function and no significant valvular disease. Despite being on potassium and magnesium supplements, her serum potassium and magnesium were 3.6 mmol/L and 0.67 mmol/L, respectively. Her haemoglobin was 13 g/dL and thyroid stimulating hormone was 2.5 mIU/L. She had normal kidney function and liver function tests. Twenty-four-hour ambulatory ECG monitor (Holter) identified a PVCs load of 22% with 103 couplets, 13 runs of non-sustained ventricular tachycardia (NSVT) and 1 episode of torsades de pointes (figure 1).

Figure 1.

Strip rhythm from 24-hour ambulatory heart rate monitoring showing unifocal PVC with LBBB morphology, arrow pointing towards run of three PVC with heart rate of 161 bpm. bpm, Beats/min; LBBB, left bundle branch block; PVC, premature ventricular contraction.

Treatment

Based on the above findings, the VAs were attributed to her hypokalaemia and hypomagnesemia induced by the GS. Her drug regimen was intensified to maintain serum potassium and magnesium above 4 mmol/L and 0.8 mmol/L, respectively. She was prescribed spironolactone (50 mg two times per day) and beta blockers (metoprolol 25 mg two times per day).

Outcome and follow-up

In 1-month follow-up, she improved in her symptoms, with fewer palpitation attacks and no presyncope. In the repeated Holter, the PVCs load reduced to 10% with 50 episodes of couplets and no NSVT episodes. Therefore, it was decided to continue her medical therapy and up titrate the dose of metoprolol to 50 mg two times per day.

One year later, she presented again with history of exertional fatiguability and mild shortness of breath of New York Heart association class II. She was compliant with her medication and her electrolytes were maintained in the normal range.

Clinical examination showed sinus bradycardia of 50 bpm and blood pressure of 110/70 mm Hg. Repeated TTE revealed normal LV dimensions with borderline reduction in her systolic function and global hypokinesia. LV ejection fraction was 51%. Repeated Holter showed a PVCs load of 9% and 24 couplets. The average heart rate was 59 bpm. Cardiac MRI was done and showed no evidence of structural abnormalities or delayed enhancement pattern with gadolinium scan. Persistence of PVCs could be implicated in inducing LV dysfunction and hence she was sent for EP study and ablation.

EP study with three-dimensional mapping was used. The catheter was advanced retrograde into the aortic sinuses to map the LV outflow tract. High load of PVCs with LBBB morphology, inferior axis and R/S (equalisation of the R wave and S wave of the QRS complex) transition at V3/V4 was noticed. The earliest activation point was at the subaortic valve area below the non-coronary cusp. Radio frequency ablation was done till no PVCs of the same morphology were documented. During the procedure, the patient went into supra ventricular tachycardia of atrioventricular nodal re-entry tachycardia (AVNRT) type frequently. The ablation catheter was introduced to her right atrium and a slow pathway was ablated successfully (figure 2).

Figure 2.

Tracing from the electrophysiology study: (A) 12-lead ECG with speed of 100 mm/s showing PVC with LBBB with R/S transition at V4, (B) PVC of LBBB morphology originating from LV out flow tract, (C) ablation of PVC, (D) AVNRT that was detected during the ablation procedure. AVNRT, atrioventricular nodal re-entry tachycardia; LBBB, left bundle branch block; PVC, premature ventricular contraction.

Her postablation course was uneventful. Metoprolol therapy was stopped, and repeated Holter showed the disappearance of PVCs. TTE with strain imaging revealed normal LV function and a strain value of −19 (figure 3). The patient reported feeling normal in terms of functional capacity and the resolution of her palpitations. Follow-up visit 1 year later showed no recurrence of symptoms.

Figure 3.

Eyeball representation of the global longitudinal strain pattern, normal value obtained of −19.

Discussion

GS is an autosomal recessive disorder resulting from gene defects encoding the renal thiazide-sensitive sodium chloride cotransporter.² The biochemical alteration mimics chronic thiazide diuretic use with hypokalaemia, hypomagnesemia and metabolic alkalosis.¹ Although initially GS was thought to be benign from the cardiac point of view, the accumulated body of evidence suggests the contrary.^3–7

Derangements in electrolytes in the form of hypokalaemia and hypomagensemia are historically considered to be a potential cause for VAs related to prolongation of the QT interval and impairment of cardiac performance.^{8 9}

An analysis of 21 GS cases by Foglia et al revealed evidence of mild to moderate QT interval prolongation (446–509 ms) in almost 50% of the patients regardless of their serum potassium and magnesium levels.¹⁰ They failed to demonstrate any arrhythmia on 24 hours Holter, with normal resting TTE and exercise treadmill tests.¹⁰

Due to recent case reports of aborted SCD in cases of GS, the hypothesis of prolonged QT as a sole mechanism for arrhythmia was revisited with the work of Scognamiglio et al.^{5 7} They provided evidence of reduced myocardial perfusion and coronary microvascular defects during exercise that in combination with electrolytes’ derangements will create a nidus for arrhythmia.⁷

There are four reported cases in the literature linked GS to VAs (table 1).^3–6 Three patients presented with palpitations and evidence of VAs on 12-lead ECG, while one had an aborted SCD. Such presentation promoted further investigations that included EP studies. All of them were treated with electrolytes’ replacement, two patients were implanted with intracardiac defibrillator and one had an EP study and ablation (table 1).

Table 1.

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

Case no	Year published	Age	Gender	Type of arrhythmia	Mode of presentation	Diagnosis	Treatment	Outcome
1	2004	62	Female	NSVT PVCs	Palpitations	ECG, echocardiography, Holter, EP study	Radio frequency ablation	6 months follow-up no arrhythmia
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 replacements, amiodarone, ICD	No follow-up data
4	2010	27	Male	OTVT	Palpitation, presyncope	ECG, echocardiography, cardiac MRI, Holter	Electrolytes replacement, aldactone	Alive at 1-year follow-up

ECG, electrocardiography; EP, electrophysiology; ICD, intracardiac defibrillator; MRI, magnetic resonance imaging; NSVT, non-sustained ventricular tachycardia; OTVT, outflow ventricular tachycardia; PVCs, premature ventricular contractions; SCD, sudden cardiac death; VF, ventricular fibrillation; VT, ventricular tachycardia.

In our patient, the presentation of palpitations initiated the cardiac work up that revealed the presence of high load PVC. With the correction of potassium and magnesium levels, the PVC load was reduced but never disappeared despite her compliance to medication. The question remains whether the PVCs were secondary to GS per se or there is an underlying arrhythmogenic focus. PVCs in the long run with high load can cause cardiomyopathy related to the dyssynchrony of myocardial contraction. This was the indication to subject her to EP study and ablation, aiming for complete suppression of the PVCs.¹¹ Surprisingly, during the procedure, she had a supra ventricular tachycardia in the form of typical AVNRT, which was ablated. To the best of our knowledge, this is the first case of GS that combines supra ventricular and VAs with successful ablation.

Patient’s perspective.

I am an intermediate grade Arabic language teacher and I love to do my job with passion and to give my maximum efforts. The great challenge in teaching Arabic language is to explain the grammar but I used to do it with no hassle. I did not find it difficult till I experienced annoying episodes of palpitations and profound weakness during my classes. I was struggling to cope with my job for quite some time.

Due to my frequent sickness I have been assigned fewer classes and confined to ground floor as I could not climb the stairs. I felt so much depressed when I compared myself to my previous fitness. After getting myself treated I started to feel different.

Initially I didn’t feel confident enough to proceed with my original daily work assignments. But day by day I felt I am more energetic. I tested myself whether I can be able to walk for longer distance then to try climbing the stairs again. I regained the trust in myself and I feel so grateful for my family specially my husband and my daughters whom they provided me with great love and support.

I also feel so thankful for my doctors whom they worked so hard to get me back to my usual health and fitness and get me back healthy to my classes.

Learning points.

• Ventricular arrhythmia is reported in cases with Gitelman syndrome, which can lead to complications including cardiomyopathy and sudden cardiac death.

• Electrolytes imbalance in the form of hypokalaemia and hypomagensemia is not the only underlying mechanism of arrhythmia, microvascular dysfunction might play a role in the aetiology.⁷

• Extensive cardiac evaluation is required for patients with Gitelman syndrome and persistent or high burden of arrhythmia to delineate the aetiology and mechanism of arrhythmia.

• Advance treatment methods like intracardiac devices or electrophysiology study ablation might be necessary to arrest the progression of the disease.