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J Electrocardiol. Author manuscript; available in PMC Sep 1, 2011.
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Short and Long QT Syndromes: does QT length really matter?

Introduction

The short QT syndrome (SQTS) is a recent inherited arrhythmia disorder associated with family history of sudden cardiac death, short refractory periods, and inducible ventricular fibrillation (VF) in absence of structural heart disease. Initially, sporadic cases of SQTS were reported by Gussak et al. in family-related and unrelated patients with idiopathic VF and history of sudden cardiac death 1. Subsequently, a clinical investigation of patients with idiopathic VF by Viskin et al. reported a significant subgroup of these patients (primarily males) exhibiting ECG tracings with very short QT intervals and peaked T-wave morphologies 2. Gaita et al. confirmed that short QT was associated with familial sudden death3, and genetic investigations revealed heterogeneous forms of the SQT syndrome 46. As of today, five mutations have been associated with abnormally short QT/QTc intervals. Three mutations are linked to gain function of the potassium channels IKr, IKs and IKl through the KCNH25, KCNQ14 and KCNJ26 genes, respectively. The two most recent mutations were identified in the CACNA1c and CACNA1b genes 7, and have been associated with loss of function of the L-type calcium channels. The inherited long QT syndromes (LQTS), on the other hand, have been studies for several decades 8. Long QT is associated with an increased propensity to arrhythmogenic syncope, polymorphic ventricular tachy- cardia (torsades de pointes), which itself may lead to ventricular fibrillation, and sudden cardiac death. At least 12 different gene mutations have been associated with the LQTS (LQT1 -12). The LQT1 and LQT2 are the most prevalent forms of the syndrome, representing an estimated 80–90% of the positively genotyped cases. Both LQT1 and LQT2 are associated with loss of function of voltage-gated potassium channels (IKs and IKr).9

In this essay, we will discuss arrhythmogenic mechanisms in the SQTS, in relation to the current arrhythmogenic mechanisms associated with the LQTS, for the mutations primarily involving repolarizing potassium currents. L-type calcium channels related reports were associated with moderately shortened QTc intervals (≤ 360 msec in males and ≤370 mec in females) and thus their association to a short QT syndrome (<300–320 msec) may be questionable.7

Arrhythmogenesis in the long QT syndromes

In the LQT1 and LQT2 syndromes, the fundamental arrhythmogenic triggering mechanisms are linked to the decreased outward potassium currents. The loss of function in potassium currents results in ventricular repolarization delay increasing the window of vulnerability to ar-rhythmia. It facilitates the triggering of early after-depolarization (EAD) through increased repolarization heterogeneity: global heterogeneity sets conditions for sustained arrhythmia while increased transmural dispersion of action potentials provides a substrate for reentry and prolongs the time window for calcium channels to remain open.

Triggers for LQT1 and LQT2 patients are associated with adrenergic activation, nonetheless, differences are observed. Clinical cases of cardiac events in LQT1 patients generally preceded by exercise or swimming. In LQT2, increased adrenergic tone plays an important role too, but cardiac events in these patients are mainly associated with emotional stress or exposure to auditory stimuli 1012 and suggest a somewhat different mechanism of arrhythmia generation. Consistently to genotyped specific mechanism, pause induced EADs have been shown to precede TdP for LQT2 but not LQT1 patients13. The slow component of the potassium repolarizing current (IK s) is strongly stimulated by activation of β-adrenergic receptors via increase in intracellular cAMP concentrations and activation of protein kinase A (PKA).14 The β-adrenergic stimulation increases IKs and results in rate dependent action potential shortening A decrease in IKs function due to mutations associated with LQT1 is expected to disrupt this rate dependent regulation. During exercise, delay of the repolarization at high heart rates combined with an increase in sympathetically activated calcium channel function may predispose to arrhythmias. For LQT2, increase calcium release that follows a pause in rhythm, combined with a prolonged repolarization due to decrease in IKr function, may contribute to EAD generation, beta-adrenergic activation of IKs may not be fast enough during acute emotional stress and auditory stimuli to compensate for the decreased mutant IKr currents. Local release of catecholamines and catecholamine-induced EADs have been reported in LQTS patients15, and may represent the primary arrhythmogenic mechanism in these LQTS type.

It is noteworthy that different mutations within the same gene (hERG or KCNQ1) can lead to different phenotypic expression and carry different level of risks. An increasing number of investigations support the concept that certain mutations, their location, and their topology, are more arrhythmogenic than others (pore, non-pore region 10, transmembrane or cytoplasmic domains).1618 These emerging investigations are likely to unravel further the arrhythmogenic mechanisms involved in these syndromes.

In the acquired and congenital forms of the long QT syndrome, there is a clear clinicalconsensus about the boundary for QTc interval duration (>500msec) above which the risk for ventricular arrhythmias is of concern. However, the definition of a lower boundary of QTc in the SQTS and its association with increased cardiac risk is less clear. The threshold for the lower boundary of QTc suggesting the syndrome was, in earlier work, described by the ratio of QT/QTp ≤ 80% 19, with QTp being the predicted QT based on Rautaharju’s formula 20. While in an earlier report, Viskin et al. proposed gender-specific thresholds of QTc: <360 msec in males and QTc <370 msec in females, based on 28 patients with idiopathic VF. Another example of a remarkable endeavor to define QTc shortening threshold for the SQTS is from Watanabe et al. This group conducted a large retrospective analysis of ECGs in a general hospital (Nigaata, Japan) from a database consisting of 86,068 ECGs acquired between 2003 and 2009. The patients without history of cardiac events or cardiovascular disease, or any medication were reviewed for short QTc interval. Forty four individuals were found with QTc <330 msec representing 0.3% of this population.21 This group was compared to a group of patients with QTc <360msec and documented ventricular fibrillation, resuscitated SDC and syncope, or SQTS genotyping. The electrocardiographic parameters such as QT apex, TpTe interval and QTc interval were compared between these two groups. The T-peak to T-end interval prolongation was the most significant parameter between these two groups, but not the QTc interval. Today, a QTc <320 msec is definitely accepted as an abnormal QTc value 20, yet the prevalence of a short QT interval in 12-lead standard resting ECGs of the general population is not systematically associated with cardiac risk. As reported by Anttonen et al. in a group of middle-aged randomly selected individuals from Finland (N=10,957), 0.1% of the studied population was associated with QTc <320 msec [21], and this short QT was not associated with life-threatening events. This lack of association between abnormally shorten QTc interval and cardiac events was confirmed by another large independent study from Japan 22, published shortly after, in which 26,350 ECGs were reviewed. Using a QTc <300 msec threshold, 0.03% of the population exhibited a short QT interval, and none of these individuals had the dangerous clinical symptoms of the SQTS. Consequently, the short QT interval in the SQTS seems to be a phenotypic expression lacking association with ar-rhythmia risks. Importantly, one would note the use of heart rate correction formula and the method used for measuring the QT interval may have non-negligible effect in the studies that have described the abnormal lower boundary for QTc interval in the SQTS.

Interestingly, an electrocardiographic pattern associated with the SQTS, and commonly reported, is the lack of an ST segment and the presence of peaked and tall T-waves. Unfortunately, none of the reports investigating short QT reported information related to T-wave amplitude or other morphological aspect of the T-wave. The late portion of the T-wave i.e. the T-peak to T-end interval (TpTe) is statistically prolonged in most SQTS reports; so the role of repolariza-tion heterogeneity (global or transmural) as the primary arrhythmogenic mechanism involved in the SQTS syndrome may carry more clinically relevant information than the QT/QTc interval duration. I will discuss two aspects: transmural dispersion associated with the shortening of the actions potentials and early repolarization patterns.

Wedge experiments supporting the role of transmural dispersion and TpTe interval prolongation as a surrogate marker of arrhythmogenic risks

Because of the limited number of reported cases with the SQT syndrome, the characteristics and the arrhythmogenic mechanisms of this syndrome are not well understood. Yet, interesting investigations have been reported in ventricular-wedge model developed by Extramiana and Anztelevitch in 2004.23 Their experiment demonstrated that heterogeneous distribution of action potential shortening within the left ventricle and associated with transmural dispersion facilitates the induction of polymorphic ventricular tachycardia. Interestingly, the shortening of the QT interval was not sufficient to trigger the arrhythmia: transmural dispersion was found to be an ar-rhythmogenic requirement. An additive β-adrenergic stimulation (isoproterenol) to their wedge experiment led to abbreviate further the QT interval and prolong more the TpTe interval duration. These experimental conditions led to systematic triggering of polymorphic ventricular tachycardia in their models.

The concept of increased transmural dispersion was evaluated in a couple of non-genotyped SQTS patients by Anttonen et al. using the Tpeak to Tend interval normalized by the QT interval (TpTe/QT). The study revealed an increased TpTe/QT ratio at lower heart rate in SQTS patient, yet these values were primarily driven by the QT interval shortening than TpTe interval prolongation. 24 As noted earlier, TpTe interval was significantly prolonged (p<0.001) in SQTS patients from a Japanese cohort of 37 patients compared to normal subject with short QTc (<330 msec).Therefore, there are both animal experiments and clinical investigations that have sought to confirm the concept of transmural dispersion as a primary arrhythmogenic mechanism in I Kr-related arrhythmia. The current findings did support this arrhythmogenic concept, yet one would caution that if this mechanism is demonstrated in the wedge experiment, clinical reports did not consistently described TpTe interval prolongation in SQT syndrome patients.

The prevalence of early repolarization pattern in short QT syndrome: reinforcing the role of transmural dispersion through J-point elevation manifested in leads with inferior or lat- erally directed positive poles

A very recent publication from Watanabe et al. reported a high prevalence of early repolarization in a large retrospective study involving 25 cases of SQTS patients. The review of the ECG tracings from this group evidenced a statistically significant higher occurrence of early repolarization (odds ratio equal to 5.6, p=0.001) in comparison to subject with short QT but no history of cardiac events. Early repolarization is a ECG finding associated with very different prognosis, it is defined as an elevation of the QRS–ST junction (J point) in leads other than V1 through V3 on 12-lead electrocardiography (elevation 0.1.mV or >0.2 mV in more than two leads). Tikkanen et al. investigated the relationship between the presence of ERP and long-term outcome in 10,864 middle-aged individuals 25. The association between an increased risk of death and the ERP was significant after adjustment for QTc and left ventricular hypertrophy. ERP independent predictive value from ar-rhythmic events was already reported in survivors of primary ventricular fibrillation 26 or patients with inducible VF 27. The genesis of the ERP remains to be elucidated, but the cellular basis for the J point was investigated in 1996 by Yan et al. whom described the heterogeneity of action potential domes as the main mechanism producing the manifesta- tion of the electrocardiographic J-wave. In parallel, the propagation of the action potential dome in a heterogeneous manner was associated with local reexcitation i.e. extrasystolic activity and phase 2 reentry. This mechanism was observed in canine epicardium exposed to K+ channel openers such.as pinacidil. Finally, Antzelevitch et al. proposed the concept of the “J-wave syndrome” 28 to encompass a spectrum of disorders associated with the genesis of J -wave. With three proposed types depending on the location of leads present- ing a J-wave, the arrhythmogenic substrate in several mutations of the SQTS could lead to increase of outward potassium currents and develop arrhythmia vulnerability according to the described mechanism.

Conclusion

To conclude, ventricular repolarization deficiency associated with perturbation of the repolarizing potassium current, and primarily its slow and rapid components (gain or loss of functions) is associated with profound effect on the electrical activity of the heart and predisposes the individual for life-threatening arrhythmias. There is no doubt that more mutations will be discovered for both the SQTS and LQTS. These syndromes represent rare but important conditions that will, over time, help to elucidate important factors involved in the triggering and maintaining of arrhythmias. It is important to stress that abnormal QT intervals are not always associated with an increased risk for cardiac events. Long QT is defined as QTc>470 in males and QTc>480 in females. Nonetheless, increased risk for arrhythmias is only associated with QTc>500ms in this population. In a similar manner, for SQT, although <320ms is considered abnormal, the correlation between QTc and risk has not yet been established. It ispossible that very short QTc (200–260) may be associated with an increase in cardiac risk, but nonetheless, for both syndromes there is a wide range of QTc that is considered abnormal, without a significant increase in risk. In particular, for this population, it is very important to look at additional markers to identify patients at risk. Transmural dispersions, apico-basal or lateral to posterior heterogeneity are likely to all contribute in a complex mechanism that can generate specific or non-specific ECG patterns. In this discussion, TpTe interval prolongation and early repolarization patterns/J wave are presented as interesting electrocardiographic manifestations of the short QT syndrome, yet these patterns remain to be further investigated. The availability of large database of ECGs from patients with this syndrome (such as the LQST ECG database of LQTS genotyped patients available in the Telemetric Holter ECG Warehouse32), or an international SQTS registry would help addressing this important clinical question. Finally, because the ECGs of patients with the SQTS are also described as “peaked T-wave with large amplitude”, one may consider extending the analysis of electrocardiographic phenotype to the morphology of the T-wave/T-loop, as it was done in the congenital and acquired form of the LQTS 2931.

As a final remark, the prolongation or the shortening of the QT interval revealed to be imperfect surrogate markers of an increased risk for arrhythmic events. The current concepts for the underlying arrhythmogenic mechanisms involved in the triggering of life-threatening arrhythmias for these syndromes do not systematically require the presence of abnormal duration of the QT/QTc interval.

Acknowledgments

Work described in this manuscript was partially funded by the National Health, Lung, Blood Institute through the 5U24HL096556-03 award.

Footnotes

Conflict of interest: the authors have not received any financial support from any source in the preparation of this document.

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Reference List

1. Gussak I, Brugada P, Brugada J, et al. Idiopathic short QT interval: a new clinical syndrome? Cardiology. 2000;94(2):99–102. [PubMed]
2. Viskin S, Zeltser D, Ish-Shalom M, et al. Is idiopathic ventricular fibrillation a short QT syndrome? Comparison of QT intervals of patients with idiopathic ventricular fibrillation and healthy controls. Heart Rhythm. 2004 November;1(5):587–91. [PubMed]
3. Gaita F, Giustetto C, Bianchi F, et al. Short QT Syndrome: a familial cause of sudden death. Circulation. 2003 August 26;108(8):965–70. [PubMed]
4. Bellocq C, van Ginneken AC, Bezzina CR, et al. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation. 2004 May 25;109(20):2394–7. [PubMed]
5. Brugada R, Hong K, Dumaine R, et al. Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation. 2004 January 6;109(1):30–5. [PubMed]
6. Priori SG, Pandit SV, Rivolta I, et al. A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circ Res. 2005 April 15;96(7):800–7. [PubMed]
7. Antzelevitch C, Pollevick GD, Cordeiro JM, et al. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation. 2007 January 30;115(4):442–9. [PMC free article] [PubMed]
8. Moss AJ, Schwartz PJ, Crampton RS, Locati E, Carleen E. The long QT syndrome: a prospective international study. Circulation. 1985 January;71(1):17–21. [PubMed]
9. Anderson CL, Delisle BP, Anson BD, et al. Most LQT2 mutations reduce Kv11.1 (hERG) current by a class 2 (trafficking-deficient) mechanism. Circulation. 2006 January 24;113(3):365–73. [PubMed]
10. Moss AJ, Zareba W, Kaufman ES, et al. Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go-go-related gene potassium channel. Circulation. 2002 February 19;105(7):794–9. [PubMed]
11. Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation. 2001 January 2;103(1):89–95. [PubMed]
12. Wilde AA, Jongbloed RJ, Doevendans PA, et al. Auditory stimuli as a trigger for ar-rhythmic events differentiate HERG-related (LQTS2) patients from KVLQT1-related patients (LQTS1) J Am Coll Cardiol. 1999 February;33(2):327–32. [PubMed]
13. Tan HL, Bardai A, Shimizu W, et al. Genotype-specific onset of arrhythmias in congenital long-QT syndrome: possible therapy implications. Circulation. 2006 November 14;114(20):2096–103. [PubMed]
14. Terrenoire C, Clancy CE, Cormier JW, Sampson KJ, Kass RS. Autonomic control of cardiac action potentials: role of potassium channel kinetics in response to sympathetic stimulation. Circ Res. 2005 March 18;96(5):e25–e34. [PubMed]
15. Shimizu W, Ohe T, Kurita T, et al. Early afterdepolarizations induced by isoproterenol in patients with congenital long QT syndrome. Circulation. 1991 November;84(5):1915–23. [PubMed]
16. Moss AJ, Shimizu W, Wilde AA, et al. Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. Circulation. 2007 May 15;115(19):2481–9. [PMC free article] [PubMed]
17. Nagaoka I, Shimizu W, Itoh H, et al. Mutation site dependent variability of cardiac events in Japanese LQT2 form of congenital long-QT syndrome. Circ J. 2008 May;72(5):694–9. [PubMed]
18. Shimizu W, Moss AJ, Wilde AA, et al. Genotype-phenotype aspects of type 2 long QT syndrome. J Am Coll Cardiol. 2009 November 24;54(22):2052–62. [PMC free article] [PubMed]
19. Giustetto C, Di MF, Wolpert C, et al. Short QT syndrome: clinical findings and diagnostic-therapeutic implications. Eur Heart J. 2006 October;27(20):2440–7. [PubMed]
20. Rautaharju PM, Zhou SH, Wong S, et al. Sex differences in the evolution of the electrocardiographic QT interval with age. Can J Cardiol. 1992 September;8(7):690–5. [PubMed]
21. Watanabe H, Makiyama T, Koyama T, et al. High prevalence of early repolarization in short QT syndrome. Heart Rhythm. 2010 May;7(5):647–52. [PubMed]
22. Funada A, Hayashi K, Ino H, et al. Assessment of QT intervals and prevalence of short QT syndrome in Japan. Clin Cardiol. 2008 June;31(6):270–4. [PubMed]
23. Extramiana F, Antzelevitch C. Amplified transmural dispersion of repolarization as the basis for arrhythmogenesis in a canine ventricular-wedge model of short-QT syndrome. Circulation. 2004 December 14;110(24):3661–6. [PubMed]
24. Anttonen O, Junttila MJ, Maury P, et al. Differences in twelve-lead electrocardiogram between symptomatic and asymptomatic subjects with short QT interval. Heart Rhythm. 2009 February;6(2):267–71. [PubMed]
25. Tikkanen JT, Anttonen O, Junttila MJ, et al. Long-term outcome associated with early re-polarization on electrocardiography. N Engl J Med. 2009 December 24;361(26):2529–37. [PubMed]
26. Rosso R, Kogan E, Belhassen B, et al. J-point elevation in survivors of primary ventricular fibrillation and matched control subjects: incidence and clinical significance. J Am Coll Cardiol. 2008 October 7;52(15):1231–8. [PubMed]
27. Takagi M, Aihara N, Takaki H, et al. Clinical characteristics of patients with spontaneous or inducible ventricular fibrillation without apparent heart disease presenting with J wave and ST segment elevation in inferior leads. J Cardiovasc Electrophysiol. 2000 August;11(8):844–8. [PubMed]
28. Antzelevitch C, Yan GX. J wave syndromes. Heart Rhythm. 2010 April;7(4):549–58. [PMC free article] [PubMed]
29. Couderc JP, Vaglio M, Xia X, et al. Impaired T-amplitude adaptation to heart rate characterizes I(Kr) inhibition in the congenital and acquired forms of the long QT syndrome. J Cardiovasc Electrophysiol. 2007 December;18(12):1299–305. [PubMed]
30. Couderc JP. Measurement and regulation of cardiac ventricular repolarization: from the QT interval to repolarization morphology. Philos Transact A Math Phys Eng Sci. 2009 April 13;367(1892):1283–99. [PMC free article] [PubMed]
31. Vaglio M, Couderc JP, McNitt S, Xia X, Moss AJ, Zareba W. A quantitative assessment of T-wave morphology in LQT1, LQT2, and healthy individuals based on Holter recording technology. Heart Rhythm. 2008 January;5(1):11–8. [PubMed]
32. Couderc JP. The Telemetric and Holter ECG Warehouse Initiative (THEW): a Data Repository for the Design, Implementation and Validation of ECG-related Technologies. Conf Proc IEEE Eng Med Biol Soc. 2010 In press. [PMC free article] [PubMed]
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