Paradoxical prolongation of QT interval during exercise in patients with hypertrophic cardiomyopathy: cellular mechanisms and implications for diastolic function

Figures

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  Figure 1. Effects of simulated exercise in trabeculae, effects of high stimulation frequency alone. (A) Representative superimposed twitches elicited during stimulation at 1, 2, and 2 Hz in the presence of isoproterenol, in ventricular trabeculae from non-failing non-hypertrophic valve-disease patients (used as controls, traces on top) and hypertrophic cardiomyopathy patients (bottom). (B) Percentage change of twitch amplitude and twitch duration to 50% relaxation (For50%) while going from 1 to 2 Hz + isoproterenol in non-failing non-hypertrophic valve-disease and hypertrophic cardiomyopathy trabeculae. Diast. Tens. = percentage variation of diastolic tension (expressed as a fraction of the amplitude of a steady state twitch). Average force results from nine CTR trabeculae (5 patients) and 31 hypertrophic cardiomyopathy trabeculae (21 hypertrophic cardiomyopathy patients). (C) For50% in the presence of isoproterenol in hypertrophic cardiomyopathy and non-failing non-hypertrophic valve-disease trabeculae. Average force results from nine non-failing non-hypertrophic valve-disease trabeculae (5 patients) and 31 hypertrophic cardiomyopathy trabeculae (21 hypertrophic cardiomyopathy patients).…

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  Figure 2. Effects of β-adrenergic stimulation alone in cardiomyocytes and trabeculae from non-failing non-hypertrophic valve-disease and hypertrophic cardiomyopathy patients. (A) Representative superimposed action potential traces elicited during 0.5 Hz stimulation in non-failing non-hypertrophic valve-disease (left) and hypertrophic cardiomyopathy (right) cardiomyocytes, in the absence and presence of isoproterenol 10−7M. (B) Representative calcium transients, recorded as in (A). (C) Representative isometric force twitches at 0.5 Hz in intact trabeculae. (D) Percentage change of different parameters recorded in non-failing non-hypertrophic valve-disease and hypertrophic cardiomyopathy ventricular cardiomyocytes and trabeculae in response to isoproterenol. From left: APD90% = action potential duration at 90% of repolarization; CaT50% = calcium transient duration from stimulus to 50% of decay; CaTAMP = amplitude of calcium transients (peak systolic-resting diastolic [Ca]); For50% = force twitch duration from onset to 50% of twitch relaxation; Diast [Ca] = diastolic Ca concentration at steady state; ForAMP = amplitude of force twitches. Average cell data (Means ± SEM) from 14 control…

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  Figure 3. Mathematical modelling of the effects of the combination of beta-stimulation with high pacing frequency in control and hypertrophic cardiomyopathy cardiomyocytes. (A and B) Representative superimposed action potential traces (left), Ca2+-transient traces (centre), and active tension (right), elicited during stimulation at 1, at 2 Hz, or during a combination of 2 Hz pacing and β-adrenergic stimulation, in simulated CTR (A) and hypertrophic cardiomyopathy (B) myocytes. (C) Average percentage variation of physiological parameters (action potential duration at 90% repolarization, Ca-transient amplitude, Ca2+-transient time to 50% decay, active tension decay to 50% relaxation) upon combined increase of pacing rate from 1 to 2 Hz and β-adrenergic stimulation, as estimated from populations of CONTROL and hypertrophic cardiomyopathy models. (D) Average percentage variation of force amplitude upon combined 2 Hz pacing/β-stimulation. (C and D) Means ± SEM from 210 models. *P < 0.05, paired Student’s t-test.

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  Figure 4. Changes of QT interval during exercise. (A and B) Relationship between electrical diastolic time (time from the end of T wave to the start of QRS) at peak exercise, measured in ms, and the variation of corrected QT interval from rest to peak exercise, in hypertrophic cardiomyopathy patients (A) and in control subjects (B). Linear fitting is indicated in red. (C and D) Relationship between electrical diastolic interval at peak exercise and peak heart rate, in hypertrophic cardiomyopathy patients (C) and in control subjects (D). Linear fitting in red. Fitting parameters and statistics outcomes are indicated in each panel.

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  Figure 5. Diastolic function, heart rate, and QT variations. E/e′ ratio calculated at rest (A) and at peak exercise (B) in the 24 hypertrophic cardiomyopathy patients in whom QTc prolongs by more than 30 ms from rest to exercise (‘with exercise-induced QTc increase’) and in the remaining 21 patients with no change (‘without exercise-induced QTc increase’). (C) Percentage change of E/e′ during exercise in the two subgroup of hypertrophic cardiomyopathy patients. (D) Percentage of predicted peak heart rate in the two groups of hypertrophic cardiomyopathy patients. Each dot is a patient. Each box plot shows 20–80% range (box height), average value (empty square inside the box), median value (horizontal line inside the box), and standard deviation (black whiskers). Statistics: unpaired t-test.

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  Figure 6. Altered adrenergic response in hypertrophic cardiomyopathy myocytes. Scheme depicting the altered response of hypertrophic cardiomyopathy cardiomyocytes to beta-adrenergic stimulation. Β-adrenergic receptors activate adenylyl cyclase though Gs subunits, which in turn generate cyclic AMP. cyclic AMP activates protein kinase A, which phosphorylates a number of intracellular targets (green plus symbols), including calcium and potassium channels. In hypertrophic cardiomyopathy cells, at variance with controls, the net effect of β stimulation in hypertrophic cardiomyopathy cells is an increase of depolarizing currents driven by the heightened L-type Ca2+-current, ultimately resulting in a longer action potential.

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