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AIM: The aim of this thesis is to assess, in LQTS and according to genotype, the myocardial electromechanical (EM) function response to exercise, its relation to symptoms and its response to b-blocker therapy. To achieve this aim, we conducted 4 studies with the following specific objectives: 

i. To study the ventricular repolarization (QTc interval) behaviour during stress and its potential haemodynamic effects, as reflected in left ventricular filling and stroke volume response to exercise.

ii. To access the exercise response of electromechanical coupling, expressed by the electromechnical window (EMW), and its relation to symptoms.

iii. To access for potential mechanical disturbances during stress by studying the myocardial contraction response to exercise, its effects on myocardial diastolic function and their relation to co-existent ventricular repolarization disturbances.

iv. To investigate the myocardial behaviour during early relaxation an most particularly the longitudinal apico-basal relaxation sequence, its synamic response to exercise and any potentia contribution to the development of symptoms.

v. To investigate the effect of b-blocker therapy on the above electromechanical parameters at rest and during exercise. 

METHODS: Forty seven (age 45±15yrs, 25 female, 20 symptomatic) LQTS mutation carriers and 35 healthy individuals (matched for age and sex) underwent an exercise test (Bruce protocol). ECG and doppler and speckle-tracking echo parameters were recorded at rest, peak exercise and recovery. 

RESULTS: We found that abnormal ventricular repolarization in LQTS carriers was related to marked LV mechanical dispersion and to abnormally reversed LV end-systolic electromechanical relationship and longitudinal early relaxation sequence. These phenomena worsened at peak exercise, especially in LQT1 carriers, and were related to impaired LV daistolic function and attenuated stroke volume response to exercise. Such abnormal electromechanical responses to exercise were more pronounces in LQTS subjects with previous adverse cardiac events and could better identigy these subjects than QTc interval alone. These disturbances were also less pronounced in LQTS carriers treated with b-blockers. 

CONCLUSION: Incorporating stress-echocardiograhic evaluation of electromechanical parameters in the routine assessment of LQTS individuals may help better stratification, symptom interpretation and management. 

Background: Recent echocardiography studies in inherited long QT syndrome (LQTS) have shown left ventricular (LV) myocardial relaxation disturbances to follow markedly prolonged and dispersed mechanical contraction. Aim: We used speckle-tracking echocardiography to assess disturbances in LV myocardial relaxation sequence during exercise and their relationship to symptoms. Methods: Forty seven LQTS patients (45 ± 15 years, 25 female and 20 symptomatic, LVEF: 65 ± 6%) and 35 controls underwent exercise echocardiogram using Bruce protocol. ECG and echo parameters were recorded at rest, peak exercise (p.e.) and recovery. Results: Between patients and controls there were no differences in age, gender, HR or LVEF. At p.e, patients had longer time to LV longitudinal ESR (tESR) at all three LV segments; basal (p < 0.0001), mid- cavity (p = 0.03) and apical (p = 0.03) whereas at rest such difference was noted only at base (p = 0.0007). Patients showed reversed apico-basal relaxation sequence (ΔtESRbase–apex) with early relaxation onset occurring later at base than at apex, both at rest (49 ± 43 vs. –29 ± 19 ms, p < 0.0001) and at p.e. (46 ± 38 vs. –40 ± 22 ms, p < 0.0001), particularly in symptomatic patients (69 ± 44 vs. 32 ± 26, p < 0.0007). ΔtESRbase–apex correlated with longer QTc interval, lower ESR and attenuated LV stroke volume. Conclusion: LQTS patients show reversed longitudinal relaxation sequence, which worsens with exercise, particularly in those with previous cardiac events.

Background: Electromechanical heterogeneities due to marked dispersion of ventricular repolarisation and mechanical function have been associated with symptoms in long QT syndrome (LQTS) patients.

Aim: To examine the exercise response of longitudinal LV systolic and diastolic myocardial function and synchronicity in LQTS patients and its relationship with symptoms; Methods: Forty seven (age 45 ± 15 yrs, 25 female, 20 symptomatic) LQTS patients and 35 healthy individuals underwent an exercise test (Bruce protocol). ECG and echo parameters were recorded at rest, peak exercise (p.e.), and recovery.

Results: LQTS patients had prolonged and markedly dispersed myocardial contraction, delayed early relaxation phase, and significantly decreased filling time at all exercise phases. Unlike controls, these electromechanical disturbances deteriorated further with exercise, during which additional decrease of the LV diastolic myocardial function and attenuated LV stroke volume were noted. Such abnormal responses to exercise were seen to a greater degree in symptomatic patients and in the LQT1 subgroup and improved with B-blocker therapy. Worsening myocardial contraction dispersion at p.e. was the strongest discriminator for previous clinical events, and its discriminating power excelled further by adding early relaxation delay.

Conclusions: Electromechanical disturbances were shown to worsen during exercise in LQTS patients and were more pronounced in those with previous arrhythmic events.

Background; Electromechanical (EM) coupling heterogeneity is significant in long QT syndrome (LQTS), particularly in symptomatic patients; EM window (EMW) has been proposed as an indicator of interaction and a better predictor of arrhythmia than QTc. Hypothesis To investigate the dynamic response of EMW to exercise in LQTS and its predictive value of arrhythmia.

Methods: Forty-seven LQTS carriers (45 +/- 15 years, 20 with arrhythmic events), and 35 controls underwent exercise echocardiogram. EMW was measured as the time difference between aortic valve closure on Doppler and the end of QT interval on the superimposed electrocardiogram (ECG). Measurements were obtained at rest, peak exercise (PE) and 4 minutes into recovery.

Results: Patients did not differ in age, gender, heart rate, or left ventricular ejection fraction but had a negative resting EMW compared with controls (-42 +/- 22 vs 17 +/- 5 ms, P < 0.0001). EMW became more negative at PE (-89 +/- 43 vs 16 +/- 7 ms, P = 0.0001) and recovery (-65 +/- 39 vs 16 +/- 6 ms, P = 0.001) in patients, particularly the symptomatic, but remained unchanged in controls. PE EMW was a stronger predictor of arrhythmic events than QTc (AUC:0.765 vs 0.569, P < 0.001). B-blockers did not affect EMW at rest but was less negative at PE (BB: -66 +/- 21 vs no-BB: -113 +/- 25 ms, P < 0.001). LQT1 patients had worse PE EMW negativity than LQT2.

Conclusion: LQTS patients have significantly negative EMW, which worsens with exercise. These changes are more pronounced in patients with documented arrhythmic events and decrease with B-blocker therapy. Thus, EMW assessment during exercise may help improve risk stratification and management of LQTS patients.

BACKGROUND: Long QT syndrome (LQTS) carriers are characterized by abnormal ventricular repolarization, prolonged systole, and mechanical dispersion. Prolonged left ventricular (LV) systole has been shown to result in disproportionate shortening of LV filling in other conditions. The aim of this study was to assess LV filling, diastolic function, and stroke volume (SV) response to dynamic exercise, in a group of LQTS carriers.

METHODS: Forty-seven LQTS carriers (45 ± 15 years, 20 symptomatic) and 35 healthy individuals underwent bicycle stress echocardiogram. Electrocardiographic and echocardiographic measurements were obtained at rest, peak exercise, and 4 minutes into recovery.

RESULTS: Long QT syndrome carriers and controls did not differ in age, gender, heart rate, QRS duration, or LV ejection fraction. At rest, LQTS carriers had longer QTc and shorter filling time (FT). At peak exercise, QTc increased and remained longer than controls at recovery. A negative correlation was found between QTc and FT (r = -.398, P = .001) with greater fall in FT in LQTS carriers than in controls at peak exercise (-23% ± 10 vs +2% ± 3, P < .0001). FT correlated with SV (r = +.27, P = .001), which increased more in controls than in LQTS carriers (+32% ± 4 vs +2% ± 1, P < .05). These differences were more pronounced in symptomatic LQTS carriers who had shorter FT and smaller SV at peak exercise and during recovery compared to asymptomatics (P < .05).

CONCLUSIONS: Long QT syndrome carriers have longer QTc, but also shorter FT. These disturbances worsen at peak exercise (particularly in symptomatics) compromising LV filling and SV, hence a potential pathomechanism for adverse events.

BACKGROUND: Ethnic differences in prevalence and severity of coronary artery disease are well established and are usually attributed to risk factors variation. This study investigates the differences in coronary artery narrowing and coronary calcification between two age- and gender-matched cohorts of South Asian and Caucasian symptomatic angina patients.

METHODS: We identified 101 symptomatic angina patients of South Asian origin who had undergone CT angiography and calcium scoring, and compared them with 101 age and gender matched Caucasian patients.

RESULTS: South Asians had a greater mean number of arterial segments with both obstructive and non-obstructive plaque than Caucasians (p=0.006 and p=0.0003, respectively) and higher prevalence of triple-vessel disease (p=0.0004). Similarly, South Asians had a higher mean CAC score (p<0.0001) and the percentage of South Asians with CAC>0 and in all categories of CAC score 100-1000 were also higher, as was the number of arterial segments with calcified and non-calcified plaque. These results were more marked in patients aged >50 but in those ≤50, Caucasians showed a higher mean number of diseased segments (p=0.019), with non-obstructive plaque (p=0.02), possibly suggesting that Caucasians are likely to have more diffuse atherosclerosis at an earlier age. CAC prevalence and severity in this age-group were not significantly different between South Asians and Caucasians.

CONCLUSION: Despite similar conventional risk factors for CAD, symptomatic South Asians seem to have more aggressive and diffuse arterial calcification compared to Caucasians. These differences are more profound above the age of 50, suggesting potential genetic or other risk factors yet to be determined.