We presented the clinical profile and 4-year follow-up of 72 adult (≥ 40 years) subjects with short QT interval in one of the southern sectors of the PERSIAN cohort. Findings were as following: (1) the prevalence of short QT interval in our normal adult population was 1.65% (n = 72, SQTS-susceptible group) with varying degrees of SQTS probability, which was within the range obtained by Japanese , U.S.  and Finnish  cohorts (0.37 to 2.88% at 360msec cut-off). Also, 4 subjects had QTc < 330ms; (2) up to 27.78% of subjects in SQTS-susceptible group had symptoms, including AF (16.67%), palpitations (6.94%), unexplained syncope (4.17%), and SCD (1.39%), respectively; (3) at least, 2 subjects with high-probability SQTS and 3 with intermediate-probability SQTS identified according to Gollob’s criteria; (4) based on the European Society of Cardiology criteria, an underestimated crude prevalence of 0.18% was calculated for SQTS in our cohort; (5) bradycardia and early repolarization recognized in ECGs of 33.33% and 9.72% of SQTS-susceptible group; (6) SQTS-susceptible group had a significantly lower mean heart rate; (7) infantile SCD was found in 11.11% of the first- and second-degree relatives of SQTS-susceptible group, reflected that family screening for SQTS must carry out to avoid SCDs in mostly-asymptomatic subjects; (8) A significant male predominance observed in SQTS-susceptible group; (9) one suspicious case of Brugada syndrome was identified.
Similar to in-line studies [14,16], we found a male predominance in short QT interval group, supporting that QT interval is generally longer in females [20-22]. Although we could not assess this male predominance for SQTS, several studies have shown that the same is true for SQTS, which support the role of sex-specific parameters like sex hormones (especially testosterone level during puberty) modulation of potassium currents, genes located on the X chromosome, membrane ion channel availability, and intracellular signal transduction in pathogenesis of SQTS [10,14,23-25].
In a recently published pooled analysis on 145 SQTS patients, 42.76% of patients were symptomatic (SCD: 33.79%, syncope: 21.38%, palpitation: 15.17%, and AF: 13.79%) . We found that more than approximately one quarter of subjects with short QT interval had symptoms, comprising AF, palpitation, unexplained syncope, and SCD, respectively. In Miyamoto et al.  cohort, the rate of AF was lower than our study (9.1% vs. 16.67%). Obviously, this is significantly higher than the 2.8% reported for adults in Iran  and 2% in the general population in the world , showing the presence of the same mechanism of an accelerated repolarization, shorter refractory period, and decreased action potential in the atrium. Several reports on childhood slow rate AF diagnosed with SQTS support this [30-33].
Early repolarization usually accounts for as a benign ECG finding in normal population with a heterogenous prevalence, range 1-13% [34-40]. However, early repolarization might be associated with an increased risk of arrhythmic events like idiopathic ventricular fibrillation and the short QT interval [37,40]. That is, an uneven increase of early repolarization with a significant male precedence has been reported in short QT interval cases (6.1-30%) [14,39,40] and SQTS patients (65%) ; nevertheless, this finding was reached up to 11.11% in SQTS-susceptible group of our study, predominantly involving inferolateral leads that was in agreement with previous reports [30,40]. The proposed common underlying mechanism for early repolarization is a reduction in inward repolarizing currents by loss of function mutations and/or an increase in outward repolarizing currents by gain-of-function mutations. It decreases the action potential duration (short QT interval), and increases the risk of reentrant mechanisms that can lead to AF and VF [27,41,42]. Noticeably, early repolarization is found in both short QT interval patients with mutations  and without mutations in the known genes , reflecting a variable genetic background for the association between short QT interval and early repolarization. By and large, the role of early repolarization, particularly inferior/inferolateral early repolarization, in risk stratification of cardiac events in individuals with short QT interval or SQTS is still unanswered, and studies on the association between long-term outcomes and presence of early repolarization in different QT interval groups are warranted.
The overlapping syndromes, concomitant Brugada-like (atypical) and SQTS, in a single patient with the same mutation and positive family history of SCD are reported in less reported variants including voltage-dependent calcium channel subunits (CACNA2D1, CACNA1C, CACNB2)  and sodium channel protein (SCN5A) . We identified a suspicious symptomatic (AF) case of Brugada-like ECG with short QT interval. This less understood varying genotype–phenotype relationship is believed to modulate by external factors (such as medication, fever, or electrolyte disorder)  and genetic modifiers (such as ethnicity) .
Another finding was bradycardia in one third of SQTS-susceptible group as well as a lower mean heart rate. One explanation might be the indecisive performance of correction formula. Whatsoever, some common physiologic effects i.e., ion channel gain or loss-of-function, hormonal effects or autonomic nervous system alterations (co-existence of lower heart rate and lower blood pressure in Anttonen et al. , study) may incorporate in short QT interval, repolarization and attenuated sinus node activity.
In our cohort, infantile SCD was found in 11.11% of the first- and second-degree relatives of short QT interval group. Giustetto et al. , showered that approximately half of SQTS patients have history of familial SCDs. In addition, SCDs in a close relative diagnose late in half of the families . Furthermore, while most of cases never experience symptoms, SQTS can be highly malignant with a highest mortality rate preceding productive age . As a result, SQTS represents as a “self-extinguishing” and “neglected” disease; that is, first- and second-degree relatives of an index patient must be screened and clinically assessed to avoid SCDs [7,48].
Our study has limitations: (1) The calculated number of SQTS patients was a case for underestimation in our study. First, our cohort did not include subjects younger than 40 years, which rise the chance of underestimation. Previous studies have shown that SQTS might be more prevalent at the two age extremes, partially explained by two distinct underlying mechanisms [14,15]. Furthermore, the arrhythmogenic and malignant forms of SQTS are more likely to cause infantile SCDs and SCDs during 20 to 40 years of age , and it appears that a short QT interval in a normal middle-aged subject may be considered as a benign condition . This fact might be linked to the low rate of SCDs and symptomatic patients as well as lack of cases with extremely short QT interval (< 300ms) and documented ventricular tachyarrhythmias in our cohort. Albeit, it should be noticed that in a SQTS cohort SCD did not occur in any of the patients during follow-up . Second, Although Gollob’s diagnostic criteria relies on four items, we could not evaluate subjects for two items of both scoring criteria (items 3 and 4); (2) Due to the limited resources, we could not perform gene study and assess SQTS among first degree relatives of intermediate to high probability SQTS cases and symptomatic subjects with short QT interval. This could be a potential source of bias because these scenarios increase the chance of identifying more cases for such a disease that shows a robust familial clustering and most of cases diagnose incidentally, till being symptomatic or developing life-threatening events; (3) Although QT interval is gender-dependent, lower limit of QT interval is not described for males and females, separately. Hence, using a single cut-off value might exert bias in case finding, as this is expected to be longer in females than males. We partially dealt with this issue by using a higher cutoff value (370ms). In addition, owing to the nature of our cohort- a normal adults’ population- we applied Bazett correction formula, which is shown to yield a consistent result at the range of heart rates encountered in healthy adults at rest .