Diseases That Increase Transmural Dispersion of Repolarization
Beyond COVID-19, the primary diseases that increase transmural dispersion of repolarization (TDR) include congenital long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), end-stage renal disease, and Kawasaki disease with myocarditis.
Inherited Ion Channelopathies
The most well-established conditions are the inherited cardiac channelopathies, which share a common final pathway of amplified TDR leading to sudden cardiac death 1:
Long QT Syndrome (LQTS)
- LQTS increases TDR through preferential prolongation of action potential duration in M cells 2
- LQT2 demonstrates greater TDR than LQT1, with median TPE intervals of 112±5 ms versus 91±2 ms respectively 3
- The mechanism involves selective action potential prolongation in the mid-myocardial layer, creating increased transmural repolarization gradients that set up conditions for reentry and torsades de pointes 2
- LQT1 patients show abrupt TDR increases at heart rates corresponding to RR intervals of 600-900 ms, while LQT2 patients demonstrate this across a much wider range (600-1400 ms) 3
Short QT Syndrome (SQTS)
- SQTS patients have significantly elevated TPE/QT ratios (0.28±0.03) compared to controls (0.21±0.02) 4
- The increased TDR results from preferential abbreviation of action potential duration in either endocardium or epicardium 1
- These patients also demonstrate reduced autonomic control of TDR, with lesser capacity to change TPE intervals from steady-state to maximal values 4
Brugada Syndrome
- TDR amplification occurs through selective abbreviation of action potential duration specifically in right ventricular epicardium 1
Catecholaminergic Polymorphic VT (CPVT)
- The unique mechanism involves reversal of the direction of activation of the ventricular wall, which is responsible for increased TDR 1
Acquired Conditions
End-Stage Renal Disease
- Both regional and transmyocardial dispersion of ventricular repolarization are significantly increased in end-stage renal disease 5
- QT dispersion is markedly elevated (46±17 ms versus 26±16 ms in controls, P<0.001) 5
- Corrected maximum Tp-Te intervals are prolonged (114±23 ms versus 103±23 ms in controls, P=0.023) 5
- This increased dispersion likely contributes to the high cardiac mortality rate in dialysis patients, as approximately half die from cardiac causes with ventricular arrhythmias as common terminal events 5
Kawasaki Disease with Myocarditis
- Inflammation in acute Kawasaki disease aggravates heterogeneity of ventricular repolarization, even when myocarditis is asymptomatic 6
- Tp-e/QT ratio correlates positively with inflammatory markers (CRP level and body temperature) 6
- Patients with transient coronary artery lesions show significantly higher Tp-e/QT ratios compared to those without coronary involvement 6
Clinical Implications and Mechanisms
The common pathophysiological thread across these conditions is that increased transmural repolarization gradients create the substrate for reentry circuits 2. The trigger for life-threatening arrhythmias typically involves a premature ventricular contraction arising from early afterdepolarizations during the abnormally prolonged repolarization phase 2.
Important Caveats:
- Not all QT prolongation carries equal arrhythmic risk—heterogeneity of repolarization (increased TDR) appears necessary in addition to QT prolongation to produce arrhythmogenic responses 2
- Drug-induced LQTS also increases TDR through inhibition of IKr current, though genetic susceptibility plays a role in individual responses 2
- The TPE/QT ratio >0.28 may indicate increased arrhythmia risk across various conditions 4