QT Interval in Adult with Chronic Hypokalemia due to Gitelman Syndrome

Patients with Gitelman syndrome present with an inherited salt-losing tubulopathy induced by loss-of-function mutations in the SLC12A3 gene encoding the apically expressed thiazide-sensitive NaCl cotransporter of the distal convoluted tubule. Patients usually have electrolyte disorders, including severe and chronic hypokalemia with metabolic alkalosis, hypomagnesemia, hypocalciuria, and secondary hyperaldosteronism (1). A prolonged QT interval on electrocardiogram (ECG) is thus expected; however, the true frequency of prolonged QT intervals and its change over time are unknown in Gitelman syndrome.

This study was a post hoc analysis of an open-label, randomized, crossover clinical trial titled the GITAB study (2). ECGs were available at the end of four washout periods and three experimental treatment periods with potassium-sparing drugs or nonsteroidal anti-inflammatory drugs (eplerenone, indomethacin, or amiloride in random order). Patients of GITAB were matched to healthy normotensive subjects according to age and sex at a 1:1 ratio. Healthy subjects were on an unrestricted potassium, magnesium, and sodium diet and selected from another patient-control study (3). Both studies were approved by the regional ethics committee (Comité de Protection des Personnes Paris-Ile de France III, France) and adhered to the Declaration of Helsinki. All patients gave written informed consent before participating in the study. QT intervals of patients with Gitelman syndrome were compared with those of age- and sex-matched controls (n=32 in each group). QT intervals were manually measured in each lead from the onset of the QRS complex to the end of the T wave. If the T wave and U wave were superimposed or could not be accurately discriminated, the downslope of the T wave was extended by drawing a tangent to the steepest proportion of the downslope until it crossed the TP segment. QTs were corrected (corrected QT [QTc]) according to the Framingham [QTc=QT+154×(1−(60/heart rate)), with heart rate in beats per minute] and the Fridericia formulae (QTc=QT/√³RR, with RR in milliseconds). A prolonged QT interval was defined as >450 ms in men and >460 ms in women (4). Of the 256 planned ECGs, 231 were available and analyzed for patients with Gitelman syndrome.

Mean age of both patients with Gitelman syndrome and control subjects was 40.3 years, and each subgroup included 50% women. There were no significant differences in terms of body mass index and BP levels between groups. Patients with Gitelman syndrome had significantly lower plasma potassium levels (2.7±0.5 versus 4.1±0.3 mmol/L, P<0.001), lower magnesium levels (0.54±0.10 versus 0.78±0.05 mmol/L, P<0.001), and higher plasma calcium levels (2.33±0.09 versus 2.24±0.08 mmol/L, P=0.001) when compared with controls.

At inclusion and according to both formulae, the mean QT duration was 430 ms in 32 patients with Gitelman syndrome, and 9% of them had a prolonged QTc interval. When compared with controls, mean QTc intervals in patients with Gitelman syndrome were longer according to both the Fridericia formula (men +29 ms; 95% confidence interval [95% CI], 18 to 40; women +26 ms; 95% CI, 12 to 40; P<0.001 for both) and the Framingham formula (men +31 ms; 95% CI, 18 to 44; women +27 ms; 95% CI, 13 to 41; P<0.001 for both). There was a threefold increase in frequency concerning the presence of U waves in patients with Gitelman syndrome compared with controls (84% versus 25%; P=0.001 for both sexes).

For all patients with Gitelman syndrome, between-visit change in QTc intervals was <30 ms between two consecutive off-medication and on-supplementation (magnesium and potassium) follow-up visits (Figure 1). Between-patient variability in QTc interval was <6% using either the Fridericia or the Framingham formula. Mean QTc interval in patients with Gitelman syndrome was not significantly different depending on indomethacin, eplerenone, and amiloride use when applying either the Fridericia or the Framingham formula (QTc changes <10 ms; P≥0.10 for all comparisons).

Figure 1.

Measurement and variations of corrected QT (QTc) interval during the washout visits according to sex. QT interval corrected using the Fridericia formula in men (A). QT interval corrected using the Fridericia formula in women (B). QT interval corrected using the Framingham formula in men (C). QT interval corrected using the Framingham formula in women (D). Black dotted lines indicate the threshold for prolonged QT interval according to sex.

This study found that <10% of patients with Gitelman syndrome had a prolonged QTc interval. Despite maintaining plasma potassium and magnesium concentrations stable by using the standardized oral potassium and magnesium supplementation recommended by guidelines (5), this frequency varies marginally when including all consecutive visits. These results are in contrast with previous studies reporting a higher frequency of prolonged QTc interval in Gitelman syndrome, ranging from 40% to 90%. This could be explained by the use of the Bazett formula by previous studies, the reference method to assess QTc at the time, which can overestimate the true QTc interval, particularly in subjects with elevated heart rate, such as patients with Gitelman syndrome (4). However, this study included only a small sample size mainly due to the rarity of the disease, and the results presented herein thus need to be confirmed by further studies. Finally, these results demonstrated a wide interindividual variability of QTc and a low frequency of prolonged QT in patients with Gitelman syndrome, suggesting a low risk of torsade de pointes in stable conditions. Moreover, repeated ECGs are probably not necessary due to low intraindividual variability, but ECG evaluation may still be recommended in acute clinical settings that may induce electrolyte disorders.

Disclosures

All authors have nothing to disclose.

Funding

The study was funded by French Ministry of Health and the Assistance Publique des Hôpitaux de Paris grant PHRC AOM08193. This work was supported by Contrat de Recherche Clinique from the Assistance Publique des Hôpitaux de Paris grant CRC10128.