Assessment of the sensitivity of detecting drug-induced QTc changes using subject-specific rate correction.

AIMS: To quantify the sensitivity of QT heart-rate correction methods for detecting drug-induced QTc changes in thorough QT studies. METHODS: Twenty-four-hour Holter ECGs were analyzed in 66 normal subjects during placebo and moxifloxacin delivery (single oral dose). QT and RR time series were extracted. Three QTc computation methods were used: (1) Fridericia's formula, (2) Fridericia's formula with hysteresis reduction, and (3) a subject-specific approach with transfer function-based hysteresis reduction and three-parameter non-linear fitting of the QT-RR relation. QTc distributions after placebo and moxifloxacin delivery were compared in sliding time windows using receiver operating characteristic (ROC) curves. The area under the ROC curve (AUC) served as a measure to quantify the ability of each method to detect moxifloxacin-induced QTc prolongation. RESULTS: Moxifloxacin prolonged the QTc by 10.6 ± 6.6 ms at peak effect. The AUC was significantly larger after hysteresis reduction (0.87 ± 0.13 vs. 0.82 ± 0.12, p<0.01) at peak effect, indicating a better discriminating capability. Subject-specific correction further increased the AUC to 0.91 ± 0.11 (p<0.01 vs. Fridericia with hysteresis reduction). The performance of the subject-specific approach was the consequence of a substantially lower intra-subject QTc standard deviation (5.7 ± 1.1 ms vs. 8.8 ± 1.2 ms for Fridericia). CONCLUSION: The ROC curve provides a tool for quantitative comparison of QT heart rate correction methods in the context of detecting drug-induced QTc prolongation. Results support a broader use of subject-specific QT correction.

Evaluation of a subject-specific transfer-function-based nonlinear QT interval rate-correction method.

The QT interval in the electrocardiogram (ECG) is a measure of total duration of depolarization and repolarization. Correction for heart rate is necessary to provide a single intrinsic physiological value that can be compared between subjects and within the same subject under different conditions. Standard formulas for the corrected QT (QTc) do not fully reproduce the complexity of the dependence in the preceding interbeat intervals (RR) and inter-subject variability. In this paper, a subject-specific, nonlinear, transfer function-based correction method is formulated to compute the QTc from Holter ECG recordings. The model includes five parameters: three describing the static QT-RR relationship and two representing memory/hysteresis effects that intervene in the calculation of effective RR values. The parameter identification procedure is designed to minimize QTc fluctuations and enforce zero correlation between QTc and effective RR. Weighted regression is used to better handle unbalanced or skewed RR distributions. The proposed optimization approach provides a general mathematical framework for further extensions of the model. Validation, robustness evaluation and comparison with existing QT correction formulas is performed on ECG signals recorded during sinus rhythm, atrial pacing, tilt-table tests, stress tests and atrial flutter (29 subjects in total). The resulting average modeling error on the QTc is 4.9 ± 1.1 ms with a sampling interval of 2 ms, which outperforms correction formulas currently used. The results demonstrate the benefits of subject-specific rate correction and hysteresis reduction.

Extraction and analysis of T waves in electrocardiograms during atrial flutter.

Analysis of T waves in the ECG is an essential clinical tool for diagnosis, monitoring, and follow-up of patients with heart dysfunction. During atrial flutter, this analysis has been so far limited by the perturbation of flutter waves superimposed over the T wave. This paper presents a method based on missing data interpolation for eliminating flutter waves from the ECG during atrial flutter. To cope with the correlation between atrial and ventricular electrical activations, the CLEAN deconvolution algorithm was applied to reconstruct the spectrum of the atrial component of the ECG from signal segments corresponding to TQ intervals. The locations of these TQ intervals, where the atrial contribution is presumably dominant, were identified iteratively. The algorithm yields the extracted atrial and ventricular contributions to the ECG. Standard T-wave morphology parameters (T-wave amplitude, T peak-T end duration, QT interval) were measured. This technique was validated using synthetic signals, compared to average beat subtraction in a patient with a pacemaker, and tested on pseudo-orthogonal ECGs from patients in atrial flutter. Results demonstrated improvements in accuracy and robustness of T-wave analysis as compared to current clinical practice.

Modeling transport of interstitial potassium in regional myocardial ischemia: effect on the injury current.

Myocardial ischemia leads to an efflux of potassium ions from affected cells. The resulting depolarization of the resting membrane is one of the main features of ischemic myocardium. It has been shown experimentally that a part of the surplus interstitial potassium is transported out of the ischemic zone, even if no coronary blood flow is present in the affected area. We propose to model this transport mechanism mathematically with a diffusion equation. This model explains the measured spatial profiles of extracellular potential and potassium concentration. In addition, it allows a quantitative prediction of the transmembrane current that flows as a result of ischemia-induced depolarization. This current is thought to play a role in arrhythmogenicity, which is an important cause of mortality in acute myocardial infarction. Our model predicts that this current reaches its maximum exactly on the border of the hypoxic area. An important depolarizing current would be present just within the border, where hypoxia is accompanied by a resting membrane potential that is only slightly elevated, due to coupling with the adjacent normal tissue. Still, in the presence of potassium transport the predicted current density is not large enough to explain ectopic activation on the lateral border of the ischemia. This suggests that activation is more likely to occur at the endocardium, where the potassium gradient is steeper.

The role of extracellular potassium transport in computer models of the ischemic zone.

Ischemic heart disease is associated with large mortality and morbidity. Understanding of the relations between coronary artery occlusion, geometry of the ischemic region, physiology of ischemia, and the resulting changes in electrocardiogram (ECG) leads and catheter signals is important to support diagnosis and treatment. Computer models play an important role in understanding ischemia, by linking experimental to clinical results. In this paper we argue that the observed transport of extracellular potassium should be represented in such models. We used a diffusion equation to describe the transport mechanism. This model reproduced the measured spatial distribution of potassium, and its temporal development. We discuss the role of potassium transport next to other aspects of ischemia: the mechanism of changes in action potential and ECG, cellular coupling, anisotropic bidomain tissue conductivity, and the geometry of the ischemic zone.

Why do we need supercomputers to understand the electrocardiographic T wave?

OBJECTIVE: Propagation of depolarisation and repolarisation in myocardium results from an interplay of membrane potential, transmembrane current, and intercellular current. This process can be represented mathematically with a reaction-diffusion (RD) equation. Solving RD equations for a whole heart requires a supercomputer. Therefore, earlier models used predefined action potential (AP) shapes and fixed propagation velocities. We discuss why RD models are important when T waves are studied. METHODS: We simulated propagating AP with an RD model of the human heart, which included heterogeneity of membrane properties. Computed activation times served as input to a model that used predefined AP, and to a "hybrid model" that computed AP only during repolarisation. The hybrid model was tested with different spatial resolutions. Electrocardiograms (ECGs) were computed with all three models. RESULTS: Computed QRS complexes were practically identical in all models. T waves in the fixed-AP model had 20 to 40% larger amplitudes in leads V1-V3. The hybrid model produced the same T waves as the RD model at 0.25-mm resolution, but underestimated T-wave amplitude at lower resolutions. CONCLUSION: Fixed AP waveforms in a forward ECG model lead to exaggerated T waves. Hybrid models require the same high spatial resolution as RD models.

Understanding ST depression in the stress-test ECG.

OBJECTIVE: The electrocardiogram (ECG) obtained during stress testing often shows a typical pattern of primary ST depression. A similar pattern can occur in unstable angina. Current textbooks consider ST depression as a direct result of partial occlusion of a coronary artery. However, animal models could not reproduce this phenomenon. An alternative explanation for ST depression specific to stress testing involves global subendocardial ischemia. In this study, we evaluated both explanations with a realistic mathematical model of the human heart. METHODS: The ECG was simulated with an anisotropic reaction-diffusion model of the human heart and an inhomogeneous boundary-element model of the human torso. RESULTS: Limited subendocardial ischemic zones caused small ST depression in ECG leads not overlying the ischemic region. An ischemic zone of 50% transmural extent covering the entire left ventricular subendocardium caused an ST-depression pattern similar to that observed during stress test. CONCLUSION: In contrast to regional subendocardial ischemia, global subendocardial ischemia can explain ST depression in our model.

Effects of valsartan or amlodipine alone or in combination on plasma catecholamine levels at rest and during standing in hypertensive patients.

To compare the effects of valsartan and amlodipine alone or in combination on plasma norepinephrine (NE) at rest and standing for 10 minutes in patients with hypertension, 47 patients with a sitting diastolic blood pressure (BP) (DBP)>95 mm Hg and<110 mm Hg were randomized in a double-blind fashion to either valsartan or amlodipine. During the first 4 weeks of treatment, patients received a low dose of either valsartan (80 mg) or amlodipine (5 mg). The patients were force-titrated to the high dose of either drug (160 or 10 mg) for 4 weeks. After 8 weeks of therapy, those who still had a DBP>90 mm Hg (nonresponders) received combination therapy with the other drug, whereas patients with a DBP<90 mm Hg (responders) continued on monotherapy. Decreases in ambulatory BP and clinic systolic BP and DBP were significant (P<.05) after 8 weeks' therapy with no difference between the 2 groups. Amlodipine but not valsartan as monotherapy consistently increased NE levels at rest and enhanced NE levels during standing. Valsartan decreased basal NE in responders. Combination therapy with valsartan and amlodipine did not attenuate the rise in NE levels induced by amlodipine. This study indicates that therapy with amlodipine increases peripheral sympathetic basal tone and reactivity to standing in patients with hypertension, whereas valsartan does not. Combined therapy with amlodipine/valsartan did not attenuate the sympathetic activation induced by amlodipine. The hypotensive action of valsartan may be mediated in part by an inhibition of the sympathetic baroreflex in patients with hypertension.

The effect of lesion size and tissue remodeling on ST deviation in partial-thickness ischemia.

BACKGROUND: Myocardial ischemia causes ST segment elevation or depression in electrocardiograms and epicardial leads. ST depression in epicardium overlying the ischemic zone indicates that the ischemia is nontransmural. However, nontransmural ischemia does not always cause ST depression. Especially in animal models, ST depression is hard to reproduce. OBJECTIVE: The purpose of this study was to determine the circumstances in which ST depression could be expected. METHODS: We studied ischemia in a large-scale computer model of the human heart. A realistic representation of the ischemia-induced changes in resting membrane potential was used, which was based on diffusion of extracellular potassium. Ischemia diameter, transmural extent, and tissue conductivity were varied. RESULTS: Our simulations confirm earlier work showing that partial-thickness ischemia, like full-thickness ischemia, typically causes ST elevation in an anisotropic model of the ventricles. However, we identified three situations in which ST depression can occur in overlying leads. The first is a reduced anisotropy ratio of the intracellular conductivity, which may result from hypertrophy and gap-junctional remodeling, circumstances that are likely to accompany ischemia. Second, an increase of the extracellular anisotropy has the same effect. Third, ST depression was found, independent of the anisotropy ratios, in very large and thin ischemic regions, resembling those that may occur in left-main or multivessel disease. CONCLUSION: Both tissue remodeling and geometric factors can explain ST depression in overlying epicardial leads. We note at the same time that ST elevation is found in most circumstances, while depression occurs as a reciprocal effect, even in partial-thickness ischemia.

Progressive epicardial coronary blood flow reduction fails to produce ST-segment depression at normal heart rates.

ST-segment depression is commonly seen in patients with acute coronary syndromes. Most authors have attributed it to transient reductions in coronary blood flow due to nonocclusive thrombus formation on a disrupted atherosclerotic plaque and dynamic focal vasospasm at the site of coronary artery stenosis. However, ST-segment depression was never reproduced in classic animal models of coronary stenosis without the presence of tachycardia. We hypothesized that ST-segment depression occurring during acute coronary syndromes is not entirely explained by changes in epicardial coronary artery resistance and thus evaluated the effect of a slow, progressive epicardial coronary artery occlusion on the ECG and regional myocardial blood flow in anesthetized pigs. Slow, progressive occlusion over 72 min (SD 27) of the left anterior descending coronary artery in 20 anesthetized pigs led to a 90% decrease in coronary blood flow and the development of ST-segment elevation associated with homogeneous and transmural myocardial blood flow reductions, confirmed by microspheres and myocardial contrast echocardiography. ST-segment depression was not observed in any ECG lead before the development of ST-segment elevation. At normal heart rates, progressive epicardial stenosis of a coronary artery results in myocardial ischemia associated with homogeneous, transmural reduction in regional myocardial blood flow and ST-segment elevation, without preceding ST-segment depression. Thus, in coronary syndromes with ST-segment depression and predominant subendocardial ischemia, factors other than mere increases in epicardial coronary resistance must be invoked to explain the heterogeneous parietal distribution of flow and associated ECG changes.

ST elevation or depression in subendocardial ischemia?

ST-segment depression in epicardial electrograms can be a "reciprocal" effect of remote myocardial ischemia (MI), and can also be due to local partial-thickness or "subendocardial" MI. Experimental studies have shown either ST elevation or depression in leads overlying a subendocardial ischemic region. Those reporting elevation have shown depression over the lateral borders of the ischemia. Simulation studies with anisotropic models have explained the ST-elevation results. Presently, while experimentalists may have difficulty understanding the ST elevation, most model studies fail to explain ST depression in overlying leads during partial-thickness ischemia. We have simulated partial-thickness ischemia in a 3-dimensional model of the human heart. Our results show that the conductivity of the intracavitary blood, geometry of the ischemic region, and bidomain anisotropy ratios can all have a decisive influence on the sign of the ST deviation. We hypothesize that ST depression in leads overlying an ischemic zone is due to subendocardial ischemia in tissue where a redistribution of gap junctions has taken place.

Absence of clinically significant increase in pulmonary artery pressure after intravenous perflutren injection for myocardial perfusion imaging in pigs.

OBJECTIVE: We sought to evaluate the impact of a continuous intravenous infusion of perflutren on systemic pulmonary artery pressures at clinically relevant doses for myocardial perfusion imaging in pigs. METHODS: Five anesthetized, ventilated, open-chest pigs were administered perflutren intravenously at a rate of 0.0364 mL/kg/min over approximately 5 minutes. RESULTS: Optimal, sustained myocardial opacification was achieved in all animals. Perflutren produced transient, reversible increases in pulmonary artery pressures versus baseline: 10.6% (3.0 +/- 1.4 mm Hg; 95% confidence interval 1.7-4.2; P < .01) for systolic, 15.2% (2.5 +/- 1.4 mm Hg; 95% confidence interval 1.3-3.7; P < .05) for diastolic, and 11.6% (2.6 +/- 1.1 mm Hg; 95% confidence interval 1.68-3.65; P < .01) for mean pressures. Heart rate and systemic arterial pressures displayed nonsignificant increases during perflutren infusion compared with baseline. CONCLUSION: A continuous intravenous infusion of perflutren at a rate achieving optimal, sustained myocardial perfusion imaging in pigs induces a mild, transient, not clinically significant increase in pulmonary artery pressures without affecting heart rate or systemic arterial pressures.

Effect of the renin-angiotensin system or calcium channel blockade on the circadian variation of heart rate variability, blood pressure and circulating catecholamines in hypertensive patients.

OBJECTIVE: To determine the effects of 8 weeks of therapy with amlodipine, ramipril or telmisartan on the autonomic system over 24 h in hypertensives. METHODS: After a placebo run-in, 57 patients were included in a prospective randomized open-label design protocol for therapy with amlodipine (5 mg for 4 weeks followed by 10 mg for 4 weeks, n = 22), or ramipril (2.5 mg for 1 week, 5.0 mg for 3 weeks and 10 mg for 4 weeks, n = 17) or telmisartan (80 mg for 8 weeks, n = 18). Autonomic functions were assessed by norepinephrine (NE) and epinephrine (E), as well as by the spectral analysis of heart rate variability (HRV). RESULTS: The 24-h ambulatory blood pressure, plasma NE and HRV demonstrated the characteristic day-night circadian rhythm in hypertensives. Higher values for SBP and DBP and for NE levels, as well as for spectral analysis components - low frequency band (LF) and low frequency/high frequency (LF/HF) ratio - were found during the day, whereas the HF was higher during the night. In patients treated with amlodipine, the HF decreased significantly during the night, while the LF and the LF/HF ratio increased during the day in association with the rise in NE. The therapy with telmisartan did increase the HF during the night and the day, while ramipril did not influence all HRV components during the night but significantly increased the HF, and decreased the LF/HF ratio during the day. No changes were observed in plasma NE with telmisartan or ramipril, but a 50% increase in NE levels throughout the 24-h period was found in amlodipine-treated patients. CONCLUSION: These data suggest a sympathetic activation during the day and a decrease in parasympathetic activity during the night after therapy with amlodipine, correlated with increases in plasma NE. In contrast, the therapy with telmisartan significantly increased parasympathetic activity without changes in NE during the night and day. The therapy with ramipril increased the parasympathetic activity only during the day.

Distinction between myocardial ischemia and postural changes in continuous ECG monitoring based on ST-segment amplitude and vector orientation--preliminary results.

BACKGROUND: Myocardial ischemia, commonly defined as ST-segment elevation or depression on the electrocardiogram (ECG), is plagued by a large number of false positive events. OBJECTIVES: To present a new method that attempts to distinguish between 'highly probable ischemia' and positional changes. METHODS: Continuous three-lead orthogonal ECG monitoring was performed in three groups of subjects: 16 healthy volunteers undergoing a body position change protocol, 22 patients undergoing percutaneous transluminal coronary angioplasty (PTCA) and 17 patients with acute coronary syndromes (ACS). For each event (ischemic or postural), the change in ST-segment amplitude was calculated, as well as the angle between the ST-segment vector of the reference beat and the beats demonstrating ST-segment elevation or depression. Angles and ST-segment amplitude changes from well-documented ischemic events obtained from the PTCA patients and from the healthy volunteers in six different body positions were compared. RESULTS: Using both ST-segment amplitude and vector angle changes, ischemic events could be detected and differentiated from a postural change with a sensitivity of 91% and a specificity of 96%. Finally, the approach was blindly applied to continuous ECG recordings of ACS patients. The method allowed the classification of 37% of all ST-segment changes detected as highly probable ischemic events as opposed to only 7% using the standard 100 microV threshold. CONCLUSION: The current approach showed that highly probable ischemic events could be better distinguished from positional changes with objective criteria using ST-segment amplitude and vector orientation.