Hypocalcemia-Induced QT Interval Prolongation

• Hypocalcemia is a rare and somewhat controversial cause of prolonged QT interval.

• Prolonged QT interval is a risk factor for sudden cardiac death and life-threatening ventricular arrhythmias.

• Corrected QT interval (QTc) is significantly prolonged in hypocalcemia and correlates with level of hypocalcemia.

• Hypocalcemia induces QTc prolongation probably through a calcium-dependent inactivation (CDI) of the L-type calcium channel (LTCC) and can lead to early after depolarization-induced serious ventricular arrhythmias.

• Calmodulin (CaM)-dependent mechanisms play a role in CDI of the LTCC so that CaM gene polymorphisms can underlie QTc prolongation.

• Furosemide is a possible cause of hypocalcemia-induced QTc prolongation.

• Hypocalcemia-induced QTc prolongation may be under-recognized, and its complex pathophysiology should alert clinicians to the potential for serious ventricular arrhythmias.

Hypocalcemia is a rare but known cause of a prolonged QT interval, an indicator of abnormal repolarization of the ventricular myocardium [1‒3]. A prolonged QT interval is a known complication of various drugs and is a risk factor for sudden cardiac death and Torsades de Pointes, a form of life-threatening polymorphic ventricular tachycardia [1, 2]. A recent systematic review found a positive correlation between corrected QT interval (QTc) and corrected total serum calcium levels but acknowledged that the available evidence is scarce [4]. Indeed there have been questions about the validity of the relationship between low-serum calcium and QT prolongation [5]. In that recent meta-analysis, there was insufficient information on the nature of the QT-heart-rate correction formula used in each study [4]. Furthermore, the construction of a linear regression model utilizing the mean from each study (rather than actual values) for QTc and serum calcium, measured with different methods in different labs, limits the strength of the conclusion about the relationship of hypocalcemia to QTc. This case provides an opportunity to examine newer concepts for the understanding of the mechanisms by which hypocalcemia might induce QT prolongation.

An 87-year-old man with a history of transcatheter aortic valve replacement, pulmonary hypertension, diastolic dysfunction with preserved systolic function, and myelofibrosis requiring regular blood transfusions presents to clinic for a follow-up assessment. A 12-lead ECG showed a prolonged QT interval (Fig. 1). Investigations for electrolyte abnormalities found hypocalcemia. He denied cardiac symptoms. Blood work revealed a total serum calcium of 1.63 mmol/L, phosphate 1.49 (normal 0.80–1.45), magnesium 0.84 mmol/L, sodium of 137 mmol/L, potassium of 4.6 mmol/L, albumin of 38 g/L, TSH of 1.94 mIU/L, GGT of 67 IU/L, ALP of 79 IU/L, creatinine of 115 μmol/L, eGFR of 49 mL/min, HgbA1c of 5.5%, venous pH 7.39, pCO₂ venous 44, bicarbonate excess 26 mmol/L, and lactate 1.5. As ionized calcium was not initially available, corrected serum calcium was calculated to a value of 1.7 mmol/L based on serum albumin level: parathyroid hormone (intact) 16.5 (normal 1.5–7.6). Along with findings of 1st-degree AV block, his ECG also revealed a prolonged QT interval of 508 ms. This was corrected for his heart rate of 62 bpm with several different heart-rate correction formulae, including the Bazett formula (QTcBZT) which demonstrated a QTc of 516 ms. A QTcBZT over 450 ms is prolonged for a man and using the Rabkin-spline heart-rate correction formula, the QTc was 507 ms which places it in the 99th percentile of the population [6]. His medications included ruxolitinib 5 mg daily, zopiclone 5 mg at night, furosemide 60 mg daily, and bisoprolol 2.5 mg daily. Although no definitive cause was identified for the hypocalcemia, it was assumed that the hypocalcemia resulted in the prolonged QT interval. The patient was treated with calcium carbonate, after which his serum calcium was almost normalized, and QT interval was shortened considerably on the ECG monitor. There were no ventricular arrhythmias, but an accelerated junctional rhythm was detected. His treatment entailed reduction of the furosemide dosage and prescription of oral calcium carbonate. Twenty-two days later, his serum calcium was 1.81 mmol/L. His QT was 472 ms for a heart-rate corrected QTCBZT of 468 ms and a Rabkin-spline heart-rate corrected QTc of 463 ms (Fig. 2).

This case presents some novel clinical data in its demonstration of a link between QTc prolongation and serum calcium with shortening of the QTc with partial restoration of serum calcium. Hypocalcemia does not commonly present in isolation, and it is important to identify the etiology of disturbed calcium homeostasis, including hormonal, acid-base, renal, and iatrogenic causes. There were no clearly identifiable causes in this case including no evidence of a hypoparathyroid state. Pseudohypoparathyroidism was considered but this entity is an extremely rare inherited (genetic) disorder usually evident in childhood and is associated with skeletal abnormalities and elevated TSH [7]. An elevated PTH, however, raises the possibility of an acquired form of pseudohypoparathyroidism which is also rare. While no 25-hydroxyvitamin-D levels were drawn, vitamin D deficiency should be considered with hypocalcemia in the setting of elevated PTH given relatively preserved renal function [8]. Another possibility included furosemide-induced hypocalcemia, and in this case, the dose of furosemide was reduced [9]. Furosemide acts to block the Na-K-2Cl cotransporter in the thick ascending loop of Henle, limiting passive reabsorption of cations such as calcium resulting in increased renal calcium excretion.

Phase 2 of the ventricular action potential is the membrane potential plateau mediated by the competitive balance of calcium influx (I_CaL) through the L-type calcium channel (LTCC) and potassium efflux through the rectifying potassium currents (I_Ks and I_Kr) [10]. Prolongation of these open channel states may induce early after-depolarizations where new action potentials may reach threshold levels to induce serious ventricular arrhythmias [11].

It may initially appear counterintuitive as to how hypocalcemia might induce prolongation of repolarization. One may consider that lower extracellular calcium would produce a weaker inward current relative to the competing repolarizing outward potassium currents, which would suggest a shortened repolarization phase as a result of an imbalance of ion movement in favor of the repolarizing current. Paradoxically, the opposite is true. Inactivation of the LTCC in ventricular myocytes depends on voltage-dependent inactivation and calcium-dependent inactivation (CDI) [12]. CDI is the predominant mechanism in LTCC, as shown in studies replacing Ca²⁺ with Ba²⁺ [13]. Usage of Ba²⁺, a divalent cation that preserves effects on voltage-dependent inactivation (electrochemically similar to Ca²⁺) but not CDI (molecularly different) resulted in significantly slower inactivation of LTCC [13‒15]. The LTCC’s dependence on CDI for inactivation is further demonstrated in congenital long QT syndrome 8 (LQTS8) or Timothy syndrome, where mutations of the CACNA1c gene resulted in defects in the CDI of LQTS8 channels and subsequent marked QT prolongation [10, 16].

The process of CDI is modulated by the intracellular Ca²⁺-binding protein calmodulin (CaM) [17]. In the open channel state of the LTCC, the I–II linker polypeptide loop from the α_1C subunit of the LTCC that will otherwise block Ca²⁺ entry (inactivation) is inhibited by the EF hand from undergoing the necessary conformational changes [18]. The EF-hand is a motif that consists of an α-helix “E,” a loop that may bind calcium, and a second α-helix “F” which are found in a large number of proteins [19]. A mechanism proposed by Kim et al. [20] suggests that upon depolarization and the influx of Ca²⁺, Ca²⁺ binds to CaM forming a Ca²⁺/CaM complex, which undergoes conformational change when Ca²⁺ reaches critical intracellular concentration; the EF hand is subsequently disinhibited and allows the I–II linker loop to begin the inactivation process by covering the channel pore, completing phase 2 of the ventricular myocyte action potential. The importance of CaM in the role of arrhythmogenesis cannot be underscored enough, as recent studies have identified multiple mutations in genes encoding CaM, notably CALM1, CALM2, and CALM3, all of which are redundant human genes encoding for an identical CaM protein, and are associated with congenital LQTS [21]. These mutations were mostly identified in pediatric patients presenting with life-threatening arrhythmias and markedly prolonged QT intervals. A study by Limpitikul et al. [22] on CaM mutants in adult guinea-pig ventricular myocytes found that CaM mutants increased action potential duration and strongly suppressed CDI inactivation of LTCC mediated by the Ca²⁺/CaM complex. This was supported by a similar study showing CaM mutations resulting in defective CDI of specifically LTCC and not the L-type sodium current [23].

In summary, hypocalcemia likely produces QTc prolongation primarily through a CDI mechanism on the LTCC. Lower extracellular calcium leads to a decreased I_CaL, subsequently causing intracellular calcium to take longer to reach the critical threshold to induce CDI of the LTCC [15]. The resulting prolonged repolarization of the ventricular myocyte can lead to early after-depolarizations and ensuing life-threatening ventricular arrhythmias [24]. Genetic polymorphisms in Ca²⁺-binding protein CaM which can prolong QT underscore the role for disturbances of myocardial calcium handling in arrhythmogenesis [22, 23]. Hypocalcemia is an under-recognized cause of QT prolongation and should be taken into careful consideration in patients presenting with incidental findings of a prolonged QT interval.

According to our University (University of British Columbia Office of Research Ethics) policy “4.4.2” case reports, individual case reports do not meet the definition of research; they are considered to be a medical/educational activity. As such they do not require Institutional approval. Informing the patient is recommended. In this case, the patient died 6 months after this case study and could not provide consent. Attempts to locate his family have been unsuccessful. The need for consent from the patient’s next of kin for publication of the details of the patient’s medical case was waived by University of British Columbia Office of Research Ethics.

The authors have no conflicts of interest to disclose.

There was no funding for this project.

J.K.K.T. wrote the first draft and made revisions. S.W.R. conceptualized the manuscript and made revisions.