Paradoxical prolongation of QT interval during exercise in patients with HCM: Cellular mechanisms and implications for diastolic function
Aims Ventricular cardiomyocytes from Hypertrophic Cardiomyopathy (HCM) patient hearts show prolonged action potential duration (APD), impaired intracellular Ca2+ homeostasis and abnormal electrical response to beta -adrenergic stimulation. We sought to determine whether this behavior is associated w...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Oxford University Press
2022
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| _version_ | 1826308319994707968 |
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| author | Coppini, R Beltrami, M Doste, R Bueno Orovio, A Ferrantini, C Vitale, G Manuel Pioner, J Santini, L Argirò, A Berteotti, M Mori, F Marchionni, N Stefàno, P Cerbai, E Poggesi, C Olivotto, I |
| author_facet | Coppini, R Beltrami, M Doste, R Bueno Orovio, A Ferrantini, C Vitale, G Manuel Pioner, J Santini, L Argirò, A Berteotti, M Mori, F Marchionni, N Stefàno, P Cerbai, E Poggesi, C Olivotto, I |
| author_sort | Coppini, R |
| collection | OXFORD |
| description | Aims
Ventricular cardiomyocytes from Hypertrophic Cardiomyopathy (HCM) patient hearts show prolonged action potential duration (APD), impaired intracellular Ca2+ homeostasis and abnormal electrical response to beta -adrenergic stimulation. We sought to determine whether this behavior is associated with abnormal changes of repolarization during exercise and worsening of diastolic function, ultimately explaining the intolerance to exercise experienced by some patients without obstruction.
Methods and Results
Non-obstructive HCM patients (178) and control subjects (81) underwent standard exercise testing, including exercise echocardiography. Ventricular myocytes were isolated from myocardial samples of 23 HCM and 8 non-failing non-hypertrophic surgical patients. The APD shortening in response to high frequencies was maintained in HCM myocytes, while β-adrenergic stimulation unexpectedly prolonged APDs, ultimately leading to a lesser shortening of APDs in response to exercise. In HCM vs. control subjects, we observed a lesser shortening of QT interval at peak exercise (QTc: +27 ± 52 ms in HCM, -4 ± 50 ms in controls, P < 0.0001). In patients showing a marked QTc prolongation (>30 ms), the excessive shortening of the electrical diastolic period was linked with a limited increase of heart-rate and deterioration of diastolic function at peak effort.
Conclusions
Abnormal balance of Ca2+- and K+-currents in HCM cardiomyocytes determines insufficient APD and Ca2+-transient shortening with exercise. In HCM patients, exercise-induced QTc prolongation was associated with impaired diastolic reserve, contributing to the reduced exercise tolerance. Our results support the idea that severe electrical cardiomyocyte abnormalities underlie exercise intolerance in a subgroup of HCM patients without obstruction.
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| first_indexed | 2024-03-07T07:16:16Z |
| format | Journal article |
| id | oxford-uuid:0f06d5b4-a9a0-4b35-b73b-e581a28d2167 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:16:16Z |
| publishDate | 2022 |
| publisher | Oxford University Press |
| record_format | dspace |
| spelling | oxford-uuid:0f06d5b4-a9a0-4b35-b73b-e581a28d21672022-08-26T07:27:17ZParadoxical prolongation of QT interval during exercise in patients with HCM: Cellular mechanisms and implications for diastolic functionJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:0f06d5b4-a9a0-4b35-b73b-e581a28d2167EnglishSymplectic ElementsOxford University Press2022Coppini, RBeltrami, MDoste, RBueno Orovio, AFerrantini, CVitale, GManuel Pioner, JSantini, LArgirò, ABerteotti, MMori, FMarchionni, NStefàno, PCerbai, EPoggesi, COlivotto, IAims Ventricular cardiomyocytes from Hypertrophic Cardiomyopathy (HCM) patient hearts show prolonged action potential duration (APD), impaired intracellular Ca2+ homeostasis and abnormal electrical response to beta -adrenergic stimulation. We sought to determine whether this behavior is associated with abnormal changes of repolarization during exercise and worsening of diastolic function, ultimately explaining the intolerance to exercise experienced by some patients without obstruction. Methods and Results Non-obstructive HCM patients (178) and control subjects (81) underwent standard exercise testing, including exercise echocardiography. Ventricular myocytes were isolated from myocardial samples of 23 HCM and 8 non-failing non-hypertrophic surgical patients. The APD shortening in response to high frequencies was maintained in HCM myocytes, while β-adrenergic stimulation unexpectedly prolonged APDs, ultimately leading to a lesser shortening of APDs in response to exercise. In HCM vs. control subjects, we observed a lesser shortening of QT interval at peak exercise (QTc: +27 ± 52 ms in HCM, -4 ± 50 ms in controls, P < 0.0001). In patients showing a marked QTc prolongation (>30 ms), the excessive shortening of the electrical diastolic period was linked with a limited increase of heart-rate and deterioration of diastolic function at peak effort. Conclusions Abnormal balance of Ca2+- and K+-currents in HCM cardiomyocytes determines insufficient APD and Ca2+-transient shortening with exercise. In HCM patients, exercise-induced QTc prolongation was associated with impaired diastolic reserve, contributing to the reduced exercise tolerance. Our results support the idea that severe electrical cardiomyocyte abnormalities underlie exercise intolerance in a subgroup of HCM patients without obstruction. |
| spellingShingle | Coppini, R Beltrami, M Doste, R Bueno Orovio, A Ferrantini, C Vitale, G Manuel Pioner, J Santini, L Argirò, A Berteotti, M Mori, F Marchionni, N Stefàno, P Cerbai, E Poggesi, C Olivotto, I Paradoxical prolongation of QT interval during exercise in patients with HCM: Cellular mechanisms and implications for diastolic function |
| title | Paradoxical prolongation of QT interval during exercise in patients with HCM: Cellular mechanisms and implications for diastolic function |
| title_full | Paradoxical prolongation of QT interval during exercise in patients with HCM: Cellular mechanisms and implications for diastolic function |
| title_fullStr | Paradoxical prolongation of QT interval during exercise in patients with HCM: Cellular mechanisms and implications for diastolic function |
| title_full_unstemmed | Paradoxical prolongation of QT interval during exercise in patients with HCM: Cellular mechanisms and implications for diastolic function |
| title_short | Paradoxical prolongation of QT interval during exercise in patients with HCM: Cellular mechanisms and implications for diastolic function |
| title_sort | paradoxical prolongation of qt interval during exercise in patients with hcm cellular mechanisms and implications for diastolic function |
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