QT-RR relationship in healthy subjects exhibits substantial  intersubject variability and high intrasubject stability

Batchvarov, Velislav N.; Ghuran, Azad; Smetana, Peter; Hnatkova, Katerina; Harries, Monica; Dilaveris, Polychronis; Camm, A. John; Malik, Marek

doi:10.1152/ajpheart.00860.2001

Cited by 190 publications

(143 citation statements)

References 35 publications

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“…Although there are considerable differences in the slope of the linear QT/RR model between subjects, there is, at least in healthy individuals, a relatively high within-subject stability. 39 In our study, the baseline slopes in LV hypertrophy were similar to what has been found in hypertrophic cardiomyopathy by Savelieva et al 12 Each individual served as his/her own control, and the changes in the QT/RR slopes were consistent with the changes in QT (and JT). The effect of irbesartan was thus towards a normalization of the relation between repolarization and the RR interval (or heart rate), while the opposite was observed when atenolol was given to patients with eccentric LV hypertrophy (see Figure 3).…”

Section: Reverse-use Dependence: Qt/rr Slopesupporting

confidence: 87%

Cardiac repolarization and its relation to ventricular geometry and rate in reverse remodelling during antihypertensive therapy with irbesartan or atenolol: results from the SILVHIA study

et al. 2007

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Hypertensive left ventricular (LV) hypertrophy is associated with a substantial risk for malignant arrhythmias and sudden death. According to recent results, antihypertensive therapy with the angiotensin II type 1 receptor blocker irbesartan reverses both structural and electrical remodelling. However, the relation between the LV geometric pattern (concentric vs eccentric) and electrical reverse remodelling has not been characterized, neither has the relation between repolarization and rate (QT/RR and JT/RR relation), which presumably reflects the propensity for bradycardia-dependent ventricular arrhythmia. In this study, repeat echocardiographic and electrocardiographic measurements were performed in hypertensive patients with LV hypertrophy, randomized to double-blind therapy with irbesartan (n ¼ 44) or the b 1 -adrenoceptor blocker atenolol (n ¼ 48) for 48 weeks; 53 patients had concentric and 39 eccentric LV hypertrophy. In addition, 37 matched hypertensive subjects without LV hypertrophy and no current therapy served as controls. Irbesartan induced structural and electrophysiological reverse remodelling, independent of LV geometry. In contrast, atenolol had similar beneficial effect only in patients with concentric LV hypertrophy, while the response in those with eccentric hypertrophy was unfavourable with both prolonged repolarization time and an increased QT/RR slope (suggesting reverse-use dependence). In conclusion, there is a significant geometry-related difference in the reverse remodelling processes induced by irbesartan and atenolol. Echocardiographic characterization of the geometry in hypertension-induced LV hypertrophy might become an important step in the selection of optimal antihypertensive therapy.

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Section: Reverse-use Dependence: Qt/rr Slopesupporting

confidence: 87%

Cardiac repolarization and its relation to ventricular geometry and rate in reverse remodelling during antihypertensive therapy with irbesartan or atenolol: results from the SILVHIA study

et al. 2007

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“…On the other hand, the slope of linear regression for each animal by Fridericia's formula was significantly gentler than that by Bazett's formula, and no significant difference from that by individual correction was seen. The individual correction, a method to correct QT interval by determining a correction coefficient for each animal, has recently been regarded as important for accurate evaluation of QTc-interval changes in humans (24,25). The correction coefficient for QT interval, which was determined for each animal, in the individual correction method was similar to that in Fridericia's formula (coefficient β = 0.33).…”

Section: Discussionmentioning

confidence: 99%

QT PRODACT: Usability of Miniature Pigs in Safety Pharmacology Studies: Assessment for Drug-Induced QT Interval Prolongation

Kano

Toyoshi

Iwasaki³

et al. 2005

J Pharmacol Sci

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Abstract. To investigate whether miniature pigs are useful for evaluating the potential of drugs for drug-induced prolongation of the QT interval, we performed an in vivo QT assay using conscious and unrestricted miniature pigs. Compared with the vehicle average baseline values, haloperidol at 3 and 10 mg / kg, p.o. prolonged the QTcF interval (Fridericia's formula) by 8% -16%. The plasma concentration of haloperidol at which QT interval was prolonged (C max = 42.9 ng / mL) was almost equal to that in humans. dl-Propranolol at 3, 10, and 30 mg / kg, p.o. caused no alterations in QT interval. dl-Propranolol at 3, 10, and 30 mg / kg, at which plasma concentrations were lower than in humans treated with dl-propranolol at the therapeutic dose level, shortened QTcF interval by 7% -12%. dl-Sotalol at 10 mg / kg, p.o. prolonged QTcF interval by 7%. From the above results, we considered that the miniature pig can be used for prediction of drug-induced prolongation of QT interval in humans, and thus, it is one of the useful animal species for assessing electrocardiograms in safety pharmacology studies.

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“…These pairs of recordings were separated by 25 days. (That is, in each subject, 4 recordings were obtained on days 1,3,26, and 28.) Study subjects were not permitted to sleep while the Holter recordings were obtained, and extra care was taken to ensure the adherence to this requirement.…”

Section: Methodsmentioning

confidence: 99%

“…The intracellular mechanism underlying the repolarization dependency and thus the pattern of the QT/RR relationship are not completely understood and have been subject of both animal and modeling experiments of ionic currents (11,19,22). Why the QT/RR relationship and adaptation exhibits substantial intersubject differences with intrasubject stability (3,27) is not known. Further studies of the phenomenon require appropriate tools for the description of the relationship.…”

mentioning

confidence: 99%

QT/RR curvatures in healthy subjects: sex differences and covariates

Malik

Hnatkova²,

Kowalski

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Data of a large clinical study were used to investigate how much are the QT/RR patterns in healthy subjects curved and whether these curvatures differ between women and men. Daytime drug-free 12-lead Holter recordings were repeated 4 times in each of 176 female healthy subjects and 176 male healthy subjects aged 32.7 Ϯ 9.1 yr. In each of the subjects, up to 1,440 carefully verified QT interval measurements were obtained with QT/RR hysteresis-corrected RR intervals. Individual subject data were used to fit the following regression equation: QT ϭ ϩ (␦/␥)(1 Ϫ RR ␥ ) ϩ ε, where QT and RR are QT and RR measurements (in s), is regression intercept, ␦ is the QT/RR slope, ␥ is the QT/RR curvature and provides the lowest regression residual, and ε represents normally distributed zero-centered errors. The bootstrap technique showed the intrasubject reproducibility of QT/RR slopes and curvatures. In women and men, QT/RR curvatures were 0.544 Ϯ 0.661 and 0.797 Ϯ 0.706, respectively (P ϭ 0.0006). The corresponding QT/RR slopes were 0.158 Ϯ 0.030 and 0.139 Ϯ 0.023, respectively (P Ͻ 0.0001). QT/RR curvatures were related to QT/RR slopes but not to individually corrected mean QTc intervals or individual QT/RR hysteresis profiles. The individual heart rate correction formula derived from the curvilinear regression provided a significantly lower intrasubject variability of QTc interval than individual optimisation of linear or log-linear QT/RR heart rate corrections. The QT/RR curvature can be reliable measured and expressed numerically. The corresponding heart rate correction formula provides more compact data than the previously proposed approaches. There are substantial sex differences in QT/RR patterns. Women have a QT/RR pattern that is not only steeper than men but also more curved.QT/RR curvature profile; intrasubject stability; intersubject differences; QT heart rate correction THE DEPENDENCY of the duration of ventricular repolarization on the underlying heart rate is well known. It is also known that it is related to a similar dependency of action potential durations (7) that shows regional differences within the ventricular myocardium (23). Similarly, delayed adaptation of action potential durations after abrupt changes in stimulation rates are well known (8). The intracellular mechanism underlying the repolarization dependency and thus the pattern of the QT/RR relationship are not completely understood and have been subject of both animal and modeling experiments of ionic currents (11,19,22). Why the QT/RR relationship and adaptation exhibits substantial intersubject differences with intrasubject stability (3, 27) is not known. Further studies of the phenomenon require appropriate tools for the description of the relationship.A number of studies (5, 6, 10, 16) assessed the slope of the QT/RR relationship in long-term Holter recordings and investigated its meaning as a clinical characteristic. The majority of these studies investigated the relationship by means of linear regression between simultaneously measured QT a...

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QT-RR relationship in healthy subjects exhibits substantial intersubject variability and high intrasubject stability

Cited by 190 publications

References 35 publications

Cardiac repolarization and its relation to ventricular geometry and rate in reverse remodelling during antihypertensive therapy with irbesartan or atenolol: results from the SILVHIA study

Cardiac repolarization and its relation to ventricular geometry and rate in reverse remodelling during antihypertensive therapy with irbesartan or atenolol: results from the SILVHIA study

QT PRODACT: Usability of Miniature Pigs in Safety Pharmacology Studies: Assessment for Drug-Induced QT Interval Prolongation

QT/RR curvatures in healthy subjects: sex differences and covariates

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