Novel insight into the natural history of short QT syndrome

Abstract

Objectives: This study intends to gain further insights into the natural history, the yield of familial and genetic screening, and the arrhythmogenic mechanisms in the largest cohort of short QT syndrome (SQTS) patients described so far.

Background: SQTS is a rare genetic disorder associated with life-threatening arrhythmias, and its natural history is incompletely ascertained.

Methods: Seventy-three SQTS patients (84% male; age, 26 ± 15 years; corrected QT interval, 329 ± 22 ms) were studied, and 62 were followed for 60 ± 41 months (median, 56 months).

Results: Cardiac arrest (CA) was the most frequent presenting symptom (40% of probands; range, <1 month to 41 years). The rate of CA was 4% in the first year of life and 1.3% per year between 20 and 40 years; the probability of a first occurrence of CA by 40 years of age was 41%. Despite the male predominance, female patients had a risk profile superimposable to that of men (p = 0.49). The yield of genetic screening was low (14%), despite familial disease being present in 44% of kindreds. A history of CA was the only predictor of recurrences at follow-up (p < 0.0000001). Two patterns of onset of ventricular fibrillation were observed and were reproducible in patients with multiple occurrences of CA. Arrhythmias occurred mainly at rest.

Conclusions: SQTS is highly lethal; CA is often the first manifestation of the disease with a peak incidence in the first year of life. Survivors of CA have a high CA recurrence rate; therefore, implantation of a defibrillator is strongly recommended in this group of patients.

Keywords: genetics; short QT syndrome; sudden cardiac death; ventricular arrhythmias.

Figure 1

Patients Grouped According to QTc Interval and the Most Severe Symptom Experienced Each bar represents the number of patients with QTc values falling into each 10-ms interval (lower number inclusive). There was no significant correlation between QTc interval and symptoms (n = 73, p = 0.35). QTc = corrected QT.

Figure 2

Cardiac Arrest-Free Survival Kaplan-Meier analysis: blue line represents main study cohort (n = 73); green line represents main study cohort plus the 18 young victims of sudden death without an electrocardiogram (ECG) (N = 91). pts = patients.

Figure 3

Characteristics of Genotype-Positive Families Each row refers to a kindred. Columns from left to right show gene and mutation identified; ECG of probands; the family tree; QTc interval duration; symptoms at enrollment, and events at follow-up for each mutation carrier, as numbered in the family tree. In the pedigree column, affected subjects are indicated by the solid symbols, unaffected subjects by open symbols, and sudden death victims by the grey symbols. + = mutation carrier; − = mutation noncarrier; → = probands; ☐ = male patients; ◯ = female patients. The asterisk indicates a novel mutation. AF = atrial fibrillation; CA = cardiac arrest; ECG = electrocardiogram; ICD = implantable cardioverter-defibrillator; NSVT = nonsustained ventricular tachycardia; QTc = corrected QT interval.

Figure 4

CA-Free Survival at Follow-up by CA Occurrence Before Enrollment Kaplan-Meier analysis: red and blue lines, respectively, represent patients with (n = 14) and without (n = 48) cardiac arrest (CA) before enrollment. Patients with CA before enrollment were more likely to experience CA during follow-up (p < 0.0000001).

Figure 5

Onset of VF in Short QT Syndrome (A) Baseline QTc interval reported along with the coupling interval (CI) of the ventricular ectopic beat (VEB) initiating ventricular fibrillation (VF) (column 1). Tracings of VEBs (column 2) with the same CI as the initiating beat of VF (column 3) are shown. VEBs occurred immediately before VF onset in Patients #1, #3, and #4. VF was initiated by VEBs with a short CI in Patients #1 to #3. (B) Patient #2 had multiple polymorphic nonsustained ventricular tachycardia episodes (first 3 rows) as a prelude to VF (fourth row) during an arrhythmic storm. Episodes are initiated by the same VEB (CI = 250 ms). ICD = implantable cardioverter-defibrillator.

Figure 6

Multiple Episodes of VF in 2 Patients (A) Patient #1. Telemetry tracings (rows 1 to 3) from an arrhythmic storm and an ICD tracing (row 4) of an unrelated episode of VF. Arrhythmias (in the absence of amiodarone) were initiated by the same short-coupled (CI = 230 ms) ventricular extrasystolic beats. (B) Patient #2. Two successive episodes of VF within the same arrhythmic storm initiated by the same long-coupled ventricular extrasystolic beats (CI = 350 ms). Abbreviations as in Figure 5.