Differences in extent of mechano-induced QT-changes in SQTS, WT and LQTS rabbit models

Abstract Background Electro-mechanical (EMC) and mechano-electrical coupling (MEC) are essential for normal cardiac function. Alterations in these can result in increased arrhythmia formation. In “electrical” cardiac diseases, long-QT and short-QT syndrome, regional mechanical function is altered via EMC. Purpose In this study, we aimed to investigate how acute changes in mechanics may impact on electrical function (MEC) in these diseases. Methods To determine how acute changes in preload impact on QT duration, adult rabbits of both sexes were given a 6ml/kg BW bolus of 0.9% NaCl IV and 12-lead-ECGs were assessed first in wildtype (WT) and acquired drug-induced (E4031 to block IKr) LQT2 (“aLQT2”) rabbits, and in a second step in transgenic short-QT type 1 (“SQT1”, KCNH2-N588K) and WT littermate control rabbits (“WT-LMC”). Results At baseline, aLQT2 rabbits demonstrated a markedly prolonged heart-rate corrected QTc duration compared to WT (p<0.0001; n=13), with increased QT-dispersion (QTMax-Min [ms], WT 21.4±5.7 vs. aLQT2 25.8±5.8; p=0.003; n=13) and increased short-term variability of QT (STVQT [ms], WT 3.5±1.0 vs. aLQT2 5.3±1.7; p=0.02; n=13), markers for regional and temporal heterogeneity of repolarization, respectively. SQT1 rabbits (n=8) demonstrated a shorter QTc duration compared to WT-LMC (n=10; p=0.04), with no differences in QT-dispersion and STVQT between the two groups. Increased preload acutely prolonged QT and heart-rate corrected QTc in all groups (despite a slight increase in heart-rate by an average of 25 beats/min): in WT [ms] 171.6±11.6 to 213.3±20.3 (p<0.0001) vs. aLQT2 208.9±19.6 to 271.0±37.5 (p<0.0001; n=13 each), and in WT-LMC 171.3±4.8 to 199.2±5.4 (p<0.0001; n=10) vs. SQT1 156.0±4.7 to 177.3±3.5 (p=0.0004; n=8). Importantly, the extent of mechano-induced electrical changes differed among genotypes, with less pronounced QTc prolongation in SQT1 compared to WT-LMC (delta QTc [ms], SQT1 21.2±3.4 (n=8) vs. WT-LMC 27.9±2.8 (n=10; p=0.15)), and a more pronounced QTc prolongation in aLQT2 compared to WT (delta QTc [ms], WT 41.6±14.9 vs. aLQT2 62.1±32.1; p=0.006; n=13 each). Moreover, QT-dispersion was increased significantly upon global mechanical change only in aLQTS (QTMax-Min [ms], 25.8±5.5 to 32.7±12.3; p=0.03; n=13). Conclusion Acute changes in mechanical function result in electrical changes via MEC in SQT1, WT and aLQT2 rabbits. The extent of these changes, however, depends on the underlying QTc duration, with the least pronounced QTc prolongation in SQT1 rabbits, with the shortest QTc, and the most pronounced QTc prolongation in aLQT2 rabbits, with the longest QTc. The most pronounced MEC effects on global QT duration as well as on regional QT dispersion in aLQT2 indicate that acute MEC effects may play an additional role in LQTS-related arrhythmogenesis. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): German Research Foundation (DFG) andSwiss National Science Foundation (SNF)

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Electro-mechanical and mechano-electrical interactions in healthy and drug-induced LQTS rabbit hearts

EP Europace ◽

10.1093/europace/euab116.578 ◽

2021 ◽

Vol 23 (Supplement_3) ◽

Author(s):

R Lewetag ◽

T Hornyik ◽

S Jacobi ◽

R Moss ◽

N Pilia ◽

...

Keyword(s):

Longitudinal Velocity ◽

Electrical Coupling ◽

Qt Dispersion ◽

Cardiac Repolarization ◽

Mechanical Function ◽

Regional Heterogeneity ◽

Drug Induced ◽

Longitudinal Contraction ◽

German Research Foundation

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): German Research Foundation Background Electrical and mechanical heterogeneities and their interactions (electro-mechanical and mechano-electrical coupling; EMC / MEC) are essential for normal cardiac function. Alterations in these can result in increased arrhythmia formation. Purpose With this study, we aim to investigate EMC and MEC under physiological and pathological conditions to better understand their roles in arrhythmia development. Methods Multi-channel ECG and TPM-MRI were used to measure regional differences in EMC in healthy ("control") and IKr-blocker E-4031 induced acute LQTS ("E-4031") rabbit hearts in vivo. MEC was studied in both groups by acutely changing mechanical function (increased preload by 6 ml/kg BW bolus of NaCl). Results In acute LQTS hearts (E-4031 10µg/kg bolus + 1µg/(kg*min) iv), cardiac repolarization was markedly prolonged compared to healthy controls, (p < 0.0001; n = 13), with increased QT-dispersion (Max-Min), a marker for regional heterogeneity of repolarization (p < 0.01; n = 13). Changing electrical function by E-4031 resulted in changes of mechanical features (EMC): in acute LQTS hearts, diastolic longitudinal velocity (Vz) was reduced in all basal (p = 0.003; n = 19) and 4/6 mid segments (p = 0.006; n = 19). Longitudinal diastolic TTP was prolonged significantly in 5/6 basal and 4/6 mid segments by E-4031. These alterations led to an increased apicobasal heterogeneity of longitudinal contraction duration (basal-apical Vz_dia_TTP [ms] 2.9 ± 10.6 vs. 21.1 ± 21.3; p = 0.01; n = 9). Increased preload acutely prolonged QTc in both "control" and "E-4031" hearts (‘control’ 156.6 ± 11.6 to 198.3 ± 20.3; p < 0.0001 vs. ‘E-4031’ 193.9 ± 19.6 to 256.0 ± 37.5; p < 0.0001; n = 13) (MEC). This effect was more pronounced in "E-4031" acute LQTS hearts than in healthy hearts (Figure 1; delta QTc [ms] ‘control’ 41.6 ± 14.9 vs. ‘E4031’ 62.1 ± 32.1; p < 0.006, n = 13). QT-dispersion (Max-Min) was increased significantly upon mechanical change only in "E-4031" (‘E-4031’ 25.8 ± 5.5 to 32.7 ± 12.3; p < 0.03, n = 13). Conclusion E-4031-induced changes in electrical function resulted in marked alterations in mechanical features via EMC. Similarly, acute changes in mechanical function (increased preload) resulted in electrical changes via MEC. Importantly, QT-prolonging effects of acutely increased preload, as well as its effects on regional heterogeneity of repolarization, were more pronounced in E-4031-induced acute LQTS hearts, indicating that cardiac repolarization in LQTS may be more susceptible to acute MEC effects than in healthy hearts. Acute MEC effects may thus play an additional role in LQT-related arrhythmogenesis. Abstract Figure.

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Pharmacogenomics of anesthetic drugs in transgenic LQT1 and LQT2 rabbits reveal genotype-specific differential effects on cardiac repolarization

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00680.2008 ◽

2008 ◽

Vol 295 (6) ◽

pp. H2264-H2272 ◽

Cited By ~ 59

Author(s):

Katja E. Odening ◽

Omar Hyder ◽

Leonard Chaves ◽

Lorraine Schofield ◽

Michael Brunner ◽

...

Keyword(s):

Heart Rate ◽

Polymorphic Ventricular Tachycardia ◽

In Vivo Model ◽

Delayed Rectifier ◽

Cardiac Repolarization ◽

Drug Induced ◽

Littermate Control ◽

Anesthetic Agents ◽

Anesthetic Drugs ◽

Repolarization Reserve

Anesthetic agents prolong cardiac repolarization by blocking ion currents. However, the clinical relevance of this blockade in subjects with reduced repolarization reserve is unknown. We have generated transgenic long QT syndromes type 1 (LQT1) and type 2 (LQT2) rabbits that lack slow delayed rectifier K+ currents ( IKs) or rapidly activating K+ currents ( IKr) and used them as a model system to detect the channel-blocking properties of anesthetic agents. Therefore, LQT1, LQT2, and littermate control (LMC) rabbits were administered isoflurane, thiopental, midazolam, propofol, or ketamine, and surface ECGs were analyzed. Genotype-specific heart rate correction formulas were used to determine the expected QT interval at a given heart rate. The QT index (QTi) was calculated as percentage of the observed QT/expected QT. Isoflurane, a drug that blocks IKs, prolonged the QTi only in LQT2 and LMC but not in LQT1 rabbits. Midazolam, which blocks inward rectifier K+ current ( IK1), prolonged the QTi in both LQT1 and LQT2 but not in LMC. Thiopental, which blocks both IKs and IK1, increased the QTi in LQT2 and LMC more than in LQT1. By contrast, ketamine, which does not block IKr, IKs, or IK1, did not alter the QTi in any group. Finally, anesthesia with isoflurane or propofol resulted in lethal polymorphic ventricular tachycardia (pVT) in three out of nine LQT2 rabbits. Transgenic LQT1 and LQT2 rabbits could serve as an in vivo model in which to examine the pharmacogenomics of drug-induced QT prolongation of anesthetic agents and their proarrhythmic potential. Transgenic LQT2 rabbits developed pVT under isoflurane and propofol, underlining the proarrhythmic risk of IKs blockers in subjects with reduced IKr.

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Differences Between Study-Specific and Subject-Specific Heart Rate Corrections of the QT Interval in Investigations of Drug Induced QTc Prolongation

Pacing and Clinical Electrophysiology ◽

10.1111/j.1540-8159.2004.00530.x ◽

2004 ◽

Vol 27 (6p1) ◽

pp. 791-800 ◽

Cited By ~ 48

Author(s):

MAREK MALIK ◽

KATERINA HNATKOVA ◽

VELISLAV BATCHVAROV

Keyword(s):

Heart Rate ◽

Qt Interval ◽

Qtc Prolongation ◽

Drug Induced ◽

Subject Specific

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813 Left ventricular versus biventricular pacing. Acute changes in the footprint and heart rate variability

EP Europace ◽

10.1016/s1099-5129(05)80553-7 ◽

2005 ◽

Vol 7 ◽

pp. 188-188

Keyword(s):

Heart Rate ◽

Heart Rate Variability ◽

Biventricular Pacing ◽

Left Ventricular ◽

Acute Changes

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An explainable algorithm for detecting drug-induced QT-prolongation at risk of torsades de pointes (TdP) regardless of heart rate and T-wave morphology

Computers in Biology and Medicine ◽

10.1016/j.compbiomed.2021.104281 ◽

2021 ◽

Vol 131 ◽

pp. 104281

Author(s):

Alaa Alahmadi ◽

Alan Davies ◽

Jennifer Royle ◽

Leanna Goodwin ◽

Katharine Cresswell ◽

...

Keyword(s):

At Risk ◽

Heart Rate ◽

Torsades De Pointes ◽

Qt Prolongation ◽

Drug Induced ◽

T Wave ◽

Wave Morphology

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Safety and effectiveness of drug therapy for the acutely agitated patient (Part I)

Italian Journal of Medicine ◽

10.4081/itjm.2010.127 ◽

2013 ◽

pp. 127-136

Author(s):

Gianluca Airoldi

Keyword(s):

Heart Rate ◽

Qt Interval ◽

Physical Restraint ◽

Safety Data ◽

Surrogate Marker ◽

Diagnostic Procedures ◽

Torsades De Pointes ◽

Long Qt ◽

Drug Induced ◽

Qt Interval Prolongation

Acute agitation occurs in a variety of medical and psychiatric conditions, and the management of agitated, abusive, or violent patients is a common problem in the emergency department. Rapid control of potentially dangerous behaviors by physical restraint and pharmacologic tranquillization is crucial to ensure the safety of the patient and health-care personnel and to allow diagnostic procedures and treatment of the underlying condition. The purpose of this article (the first in a 2-part series) is to review the extensive safety data published on the antipsychotic medications currently available for managing situations of this type, including older neuroleptics like haloperidol, chlorpromazine, and pimozide as well as a number of the newer atypical antipsychotics (olanzapine, risperidone, ziprasidone). Particular attention is focused on the ability of these drugs to lengthen the QT interval in surface electrocardiograms. This adverse effect is of major concern, especially in light of the reported relation between QT interval and the risk of sudden death. In patients with the congenital long-QT syndrome, a long QT interval is associated with a fatal paroxysmal ventricular arrhythmia knownas torsades de pointes. Therefore, careful evaluation of the QT-prolonging properties and arrhythmogenic potential of antipsychotic drugs is urgently needed. Clinical assessment of drug-induced QT-interval prolongation is strictly dependent on the quality of electrocardiographic data and the appropriateness of electrocardiographic analyses. Unfortunately, measurement imprecision and natural variability preclude a simple use of the actually measured QT interval as a surrogate marker of drug-induced proarrhythmia. Because the QT interval changes with heart rate, a rate-corrected QT interval (QTc) is commonly used when evaluating a drug’s effect. In clinical settings, themost widely used formulas for rate-correction are those of Bazett (QTc=QT/RR^0.5) and Fridericia (QTc=QT/RR^0.33), both of which standardize themeasuredQTinterval to an RRinterval of 1 s (heart rate of 60 bpm).However, QT variability can also be influenced by other factors that are more difficult to measure, including body fat, meals, psycho-physical distress, and circadian and seasonal fluctuations.

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ICH E14-Compatible Holter Bin Method and its Equivalence to Individual Heart Rate Correction in the Assessment of Drug-Induced QT Changes

Journal of Cardiovascular Electrophysiology ◽

10.1111/jce.12450 ◽

2014 ◽

Vol 25 (11) ◽

pp. 1232-1241 ◽

Cited By ~ 5

Author(s):

MAREK MALIK ◽

KATERINA HNATKOVA ◽

DONNA KOWALSKI ◽

JAMES J. KEIRNS ◽

E. MARCEL VAN GELDEREN

Keyword(s):

Heart Rate ◽

Drug Induced ◽

Ich E14 ◽

Heart Rate Correction ◽

Bin Method

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Ramadan and blood pressure: importance of chronotherapy

European Journal of Preventive Cardiology ◽

10.1093/eurjpc/zwab061.154 ◽

2021 ◽

Vol 28 (Supplement_1) ◽

Author(s):

MA Bejar ◽

I Zairi ◽

I Ben Mrad ◽

B Besbes ◽

K Mzoughi ◽

...

Keyword(s):

Blood Pressure ◽

Heart Rate ◽

Dual Therapy ◽

Average Heart Rate ◽

Hypertensive Patients ◽

Mean Values ◽

Funding Sources ◽

Cardiology Department ◽

Group 2 ◽

And Gender

Abstract Funding Acknowledgements Type of funding sources: None. Background During Ramadan, alterations in the daily patterns of sleep, activities and medication timing might contribute to changes in blood pressure (BP) and heart rate among hypertensive patients. The aim of this study was to examine the effect of medication timing during Ramadan on blood pressure and heart rate in hypertensive subjects taking their treatment once daily. Methods The study prospectively recruited 44 hypertensive patients between April and June 2019, followed up at the cardiology department of our Hospital. A 24-hour pressure monitoring was carried out during two periods: prior to Ramadan and during the last ten days of Ramadan. Results We studied 29 women and 15 men, mean age was 58.7 years. 34% of the patients were diabetics and 16% had coronaropathy. 46% of the patients were on monotherapy, 43% on dual therapy and 11% on a triple antihypertensive therapy. During Ramadan, 57% of the patients took their treatment during the dinner (group1), whereas 43% took their treatment during the Shour (group 2). Average 24hour blood pressure in the whole group was 129 ± 18/74 ± 10 mmHg before Ramadan and 129 ± 19/74 ± 10 mmHg during Ramadan (p > 0.05). Daytime and nighttime mean values of systolic and diastolic blood pressure as well as mean values of heart rate were not different between both periods regardless of age and gender. However, during Ramadan, those who took their treatment after dinner had significant higher values of 24 hour systolic BP, awake systolic and diastolic BP, asleep systolic and diastolic BP than those who took their treatment with the shour (p < 0.05). Conclusion In this study, there were no significant changes in systolic and diastolic blood pressures as well as heart rate during the 2 periods. However, during Ramadan, a slight superiority of taking the treatment with the shour is observed. Average values of BP and heart rate Group 1 Group 2 p 24 hour SBP (mmHg) 134 ± 23 122 ± 6 0.017 24 hour DBP (mmHg) 76 ± 12 70 ± 5 0.052 Awake SBP (mmHg) 138 ± 23 125 ± 6 0.012 Awake DBP (mmHg) 79 ± 12 73 ± 5 0.044 Asleep SBP (mmHg) 127 ± 26 114 ± 12 0.030 Asleep DBP (mmHg) 71 ± 13 65 ± 7 0.045 24 hour average heart rate (bpm) 71 ± 7 70 ± 6 0.524 Awake average heart rate (bpm) 76 ± 7 74 ± 7 0.322 Asleep average heart rate (bpm) 65 ± 7 65 ± 7 0.931 Average values of blood pressure and heart rate in both groups Abstract Figure. 24hour course of blood pressure

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