Unsuspected echocardiographic abnormality in the long QT syndrome. Diagnostic, prognostic, and pathogenetic implications

BACKGROUND. The idiopathic long QT syndrome (LQTS) is characterized by electrocardiographic abnormalities and by a high incidence of lethal arrhythmias. The present case/control study demonstrates the frequent occurrence of unusual and specific ventricular wall motion abnormalities in LQTS and their association with history of syncope or cardiac arrest. These anomalies were present in 23 of 42 LQTS patients (55%) and in two of 42 healthy controls (5%, p less than 0.0001) matched for age, sex, height, and weight. METHODS AND RESULTS. Two new measurements were developed to assess quantitatively the abnormalities observed. The first, Th1/2, is an index of the rapidity of the early contraction phase; the second, TSTh, is an index of the presence of a slow movement in the late thickening phase. Th1/2 was smaller in LQTS patients (15.0 +/- 4.1 versus 19.9 +/- 3.9% of the cardiac cycle, p less than 0.001), indicating that they reach half-maximal systolic contraction more rapidly than controls. TSTh was greater in LQTS patients (9.37 +/- 6.82 versus 2.88 +/- 4.46%, p less than 0.001), indicating that they spend more time at a very low thickening rate. A peculiar double peak pattern of late thickening was present in 11 patients and in no controls. These abnormalities were more frequent in symptomatic than in asymptomatic patients (20 of 26, 77%, versus three of 16, 19%, p less than 0.005; relative risk, 2.75). They were not affected by beta-blockade or by left cardiac sympathetic denervation. The same echocardiographic abnormalities were produced by right stellectomy in nine of nine anesthetized dogs, were not dependent on cycle length, and were not modified by subsequent left stellectomy. CONCLUSIONS. This study demonstrates a previously unsuspected abnormality in the ventricular contraction pattern of LQTS patients and, for the first time, provides evidence that a noninvasively detected cardiac abnormality is associated with a higher risk for syncope/cardiac arrest. The experimental reproduction of this echocardiographic abnormality by right stellectomy indicates that this newly found clinical characteristic of LQTS does not contradict the "sympathetic imbalance" hypothesis.     

A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene

Short QT syndrome (SQTS) leads to an abbreviated QTc interval and predisposes patients to life-threatening arrhythmias. To date, two forms of the disease have been identified: SQT1, caused by a gain of function substitution in the HERG (I(Kr)) channel, and SQT2, caused by a gain of function substitution in the KvLQT1 (I(Ks)) channel. Here we identify a new variant, "SQT3", which has a unique ECG phenotype characterized by asymmetrical T waves, and a defect in the gene coding for the inwardly rectifying Kir2.1 (I(K1)) channel. The affected members of a single family had a G514A substitution in the KCNJ2 gene that resulted in a change from aspartic acid to asparagine at position 172 (D172N). Whole-cell patch-clamp studies of the heterologously expressed human D172N channel demonstrated a larger outward I(K1) than the wild-type (P<0.05) at potentials between -75 mV and -45 mV, with the peak current being shifted in the former with respect to the latter (WT, -75 mV; D172N, -65 mV). Coexpression of WT and mutant channels to mimic the heterozygous condition of the proband yielded an outward current that was intermediate between WT and D172N. In computer simulations using a human ventricular myocyte model the increased outward I(K1) greatly accelerated the final phase of repolarization, and shortened the action potential duration. Hence, unlike the known mutations in the two other SQTS forms (N588K in HERG and V307L in KvLQT1), simulations using the D172N and WT/D172N mutations fully accounted for the ECG phenotype of tall and asymmetrically shaped T waves. Although we were unable to test for inducibility of arrhythmia susceptibility due to lack of patients' consent, our computer simulations predict a steeper steady-state restitution curve for the D172N and WT/D172N mutation, compared with WT or to HERG or KvLQT1 mutations, which may predispose SQT3 patients to a greater risk of reentrant arrhythmias.     

Risk of congenital complete heart block in newborns of mothers with anti-Ro/SSA antibodies detected by counterimmunoelectrophoresis: a prospective study of 100 women

OBJECTIVE: To assess the true prevalence of congenital complete heart block (CCHB) in infants of anti-Ro/SSA-positive women known to have connective tissue disease (CTD) and, secondarily, to evaluate the prevalence of other electrocardiographic abnormalities in these newborns at birth. METHODS: A prospective study was conducted in 4 referral hospitals. One hundred anti-Ro/SSAA-positive mothers were followed up before they became pregnant and during the index pregnancy. Counterimmunoelectrophoresis and immunoblotting were used to test for antibodies to extractable nuclear antigens. RESULTS: Of the 100 women with anti-Ro/SSA antibodies, 2 had infants who developed CCHB in utero (2%). The CCHB was detected at 22 weeks and 20 weeks, respectively. One of the 2 mothers had primary Sj?gren's syndrome (SS), and the other had undifferentiated CTD (UCTD). No case of CCHB occurred among the infants of 53 mothers with systemic lupus erythematosus (SLE). No fetal death occurred due to CCHB. In 2 centers, electrocardiography was recorded in 24 unselected newborns, and 4 were found to have sinus bradycardia. CONCLUSION: The prevalence of CCHB in newborns of prospectively followed up women already known to be anti-Ro/SSA positive and with known CTD was 2%. This finding is useful with regard to preconception counseling of these women. The risk of delivering an infant with CCHB may be higher in mothers with primary SS or UCTD than in those with SLE. Additional electrocardiographic abnormalities such as sinus bradycardia and prolongation of the QT interval may be present in their children.     

Dynamic QT interval analysis in uraemic patients receiving chronic haemodialysis

OBJECTIVE: To analyse the duration of the QT interval and its relationship with heart rate changes in patients with uraemia, before and during haemodialysis. METHODS: QT and RR intervals were measured automatically using a dedicated algorithm with 24-h Holter recordings in 29 patients (15 women) receiving chronic haemodialysis. QT corrected for heart rate (QTc) and the slope of QT/RR linear regression were calculated. Arterial blood pressure (ABP) was measured before and during haemodialysis. Plasma concentrations of K+, Mg2+ and Ca2+ were assessed before and after haemodialysis. RESULTS: ABP decreased significantly from baseline (102.7 +/- 11.0 mmHg) during the first (100.6 +/- 8.8 mmHg, P < 0.05), second (95.6 +/- 10.6 mmHg, P < 0.05), and third (94.9 +/- 10.3 mmHg, P < 0.05) hours of haemodialysis. QTc was longer during haemodialysis than during a 4-h period of no dialysis (447 +/- 28 ms compared with 429 +/- 22 ms, P < 0.001), and increased progressively during haemodialysis, with the greatest value during the last hour of haemodialysis (454 +/- 32 ms compared with 426 +/- 22 ms, P < 0.001). QT/RR slopes and correlation coefficients were lower during haemodialysis than during the period of no dialysis (0.13 +/- 0.08 compared with 0.20 +/- 0.07, P < 0.001 and 0.48 +/- 0.30 compared with 0.81 +/- 0.20, respectively; P < 0.001), suggesting a reduced ability to adapt the QT interval in response to changes in heart rate. The effects of haemodialysis on QT interval and the QT/RR relationship were greater in women than in men. QTc variations during dialysis were not correlated with changes in ABP, but were inversely related to changes in Ca2+ concentration (r2 = 0.35; P = 0.001). CONCLUSIONS: In patients with uraemia, the haemodialysis session induces a progressive increase in QT interval and modifies its relationship with heart rate. These effects may predispose some individuals to ventricular arrhythmias at the end of and immediately after the haemodialysis session.     

Electrolyte concentration during haemodialysis and QT interval prolongation in uraemic patients.

AIMS: To assess the effect of different combinations of potassium and calcium concentrations on QT interval in the dialysis bath in uraemic patients. METHODS AND RESULTS: Sixteen haemodialysis (HD) patients underwent a 24 h Holter recording before and during HD sessions with six randomized combinations of electrolytes concentrations of the dialysis bath (K(+), 2 and 3 mmol/L; Ca(2+), 1.25, 1.5, and 1.75 mmol/L). The effect of different dialysis baths on QT interval was significant (P < 0.05). The longest mean QTc was observed with the lowest K(+) (2 mmol/L) and Ca(2+) concentrations (1.25 mmol/L), whereas the shortest mean QTc was observed with the highest K(+) (3 mmol/L) and Ca(2+) concentrations (1.75 mmol/L). QTc was >440 ms in 9 of 16 patients (56%) at the lowest Ca(2+) and K(+) concentrations, and in 3 of 16 patients (18%) at the highest electrolytes level. Changes in QTc during the HD sessions were inversely correlated with that in total Ca and Ca(2+) plasma concentrations (P < 0.0001). CONCLUSION: Changes in ventricular repolarization duration associated with HD largely depend on the concentrations of Ca(2+) and K(+) in the dialysis bath. These findings may have important implications for the choice of the electrolytes concentration of the dialysis bath during the HD session.     

Effects of exercise training on heart rate and QT interval in healthy young individuals: are there gender differences?

AIMS: The aim of the present study was to assess the effects of exercise training on heart rate, QT interval, and on the relation between ventricular repolarization and heart rate in men and women. METHODS AND RESULTS: A 24 h Holter recording was obtained in 80 healthy subjects (40 males) who differed for the degree of physical activity. Trained individuals showed a lower heart rate and a higher heart rate variability than sedentary subjects, independent of the gender difference in basal heart rate. Mean 24 h QTc was similar in trained and non-trained men, while a significant difference was observed between trained and non-trained women. Exercise training reduced the QT/RR slope in both genders. This effect on the QT/RR relation was more marked in women; in fact, the gender difference in the ventricular repolarization duration at low heart rate observed in sedentary subjects was no longer present among trained individuals. CONCLUSION: The results of this study suggest that the cardiovascular response to exercise training may be different in men and women. Women may benefit more from interventions aimed to increase physical activity as a tool for prevention of cardiovascular morbidity and mortality.     

Electrocardiographic abnormalities in infants born from mothers with autoimmune diseases--a multicentre prospective study

OBJECTIVES: To assess the prevalence of congenital heart block (CHB) and electrocardiographic (ECG) abnormalities in infants of anti-Ro/SSA-positive women. METHODS: Sixty anti-Ro-positive and 36 anti-Ro-negative patients were prospectively followed before/during pregnancy and underwent weekly fetal echocardiography from 18th to 26th weeks of gestational age. Infants' ECG and/or ECG-Holter were performed at 1, 3, 6 and 12 months. ECG of 200 consecutive neonates were used as a healthy control group. RESULTS: One of 61 fetuses of anti-Ro-positive mothers developed CHB (20th week); another anti-Ro-positive baby developed second degree atrioventricular (AV) block (30th week). The prevalence of transient first degree AV block detected post-natally was significantly higher in the anti-Ro-positive group, in comparison with healthy controls (P = 0.002). No differences in corrected QT (QTc) interval prolongation prevalence (>/=440 ms) was observed between the anti-Ro-positive and -negative groups, but both were significantly higher than that of the control population (P < 0.001). ECG-Holter showed QTc prolongation in 59% of infants of anti-Ro-positive and in 60% of infants of anti-Ro-negative mothers. Holter QTc was >/=470 ms in four infants of anti-Ro-positive group and two of anti-Ro-negative group. Known acquired causes of QTc prolongation were excluded. CONCLUSIONS: This prospective study confirms the low occurrence of CHB in newborns from anti-Ro-positive mothers. ECG abnormalities (first degree AV block and QTc interval prolongation) are frequent in infants of mothers with autoimmune diseases, independently of maternal disease, autoantibody profile and treatment during pregnancy.