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Two new formulations, respectively denominated INT_M1 and INT_M2, of an integrated mathematical model to describe the glycemic and insulinemic responses to a 75g oral glucose tolerance test (OGTT) are proposed and compared. The INT_M1 assumes a single compartment for the intestine and the derivative of a power exponential function for the gastric emptying rate, while, in the INT_M2, a nonlinear three-compartment system model is adopted to produce a more realistic, multiphase gastric emptying rate. Both models were implemented in a Matlab-based, two-step procedure for estimation of seven adjustable coefficients characterizing the gastric emptying rate and the incretin, insulin and glucose kinetics. Model behaviour was tested vs. mean plasma glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucose and insulin measurements from two different laboratories, where glycemic profiles observed during a 75g OGTT were matched in healthy subjects (HC1- and HC2-group, respectively) by means of an isoglycemic intravenous glucose (I-IVG) infusion. Under the hypothesis of an additive effect of GLP-1 and GIP on insulin potentiation, our results demonstrated a substantial equivalence of the two models in matching the data. Model parameter estimates showed to be suitable markers of differences observed in the OGTT and matched I-IVG responses from the HC1-group compared to the HC2-group. Model implementation in our two-step parameter estimation procedure enhances the possibility of a prospective application for individualization of the incretin effect in a single subject, when his/her data are plugged in. [ABSTRACT FROM AUTHOR]

The possible dependence of T-wave alternans (TWA) on T-wave amplitude was investigated in 3 orthogonal leads (X, Y, Z) 20-min resting ECG recordings and in the derived vector magnitude (VM) from 176 healthy (H) subjects and 200 coronary-artery-disease (CAD) patients. After application of our adaptive-match-filter based method for parameterization of TWA in terms of its amplitude (TWA_A) and product-magnitude (TWA_PM, defined as the product of TWA_A times TWA duration), and once a TW_A parameter was defined for T-wave amplitude quantification, the existence of intra- and inter-subjects relationships of TWA_A and TWA_PM vs. TW_A was tested. Compared to the H-population, the CAD-population showed a significant (P <0.05) increase of TWA_A (62±38μV vs. 54±25μV) and TWA_PM (4029±2974beatμV vs. 3107±1976beatμV) and a significant decrease of TW_A (298±194μV vs. 467±246μV). These repolarization changes, however, occurred with no significant intra- or inter-subjects relationships of TWA_A and TWA_PM vs. TW_A. Thus, in our CAD and H populations there was no evidence of TWA dependence on T-wave amplitude. [ABSTRACT FROM AUTHOR]

Abstract: Physiological relevance of parameters of three arterial models, denominated W4P, W4S and IVW, was assessed by computation of parameter-related generalized sensitivity functions (GSFs), which allow the definition of heart-cycle time intervals where the information content of experimental data, useful for estimation of each model parameter, is concentrated. The W4P and W4S are derived from the three-element windkessel by connecting an inductance, L, in parallel or in series, respectively, with aortic characteristic impedance, R c . In the IVW, L is placed in series at the input of a viscoelastic windkessel, incorporating a Voigt cell (a resistor, R d , in series with a capacitor, C). Pressure and flow measured in the ascending aorta of five ferrets and five dogs were used to estimate all model parameters, by fitting to pressure. For each model structure, parameter-related GSFs were generated. Focusing on controversial L, R c and R d physical meaning, our GSF analysis yielded the conclusion that, in both the W4S and the IVW, but not in the W4P, the L-term is suitable to represent the inertial properties of blood motion. Moreover, the meaning of aortic characteristic impedance ascribed to R c is questionable; while R d is likely to account for viscous losses of arterial wall motion. [Copyright &y& Elsevier]

Abstract: Background and purpose: Left ventricular ejection fraction lacks specificity to predict sudden cardiac death in heart failure. T-wave alternans (TWA; beat-to-beat T-wave instability, often measured during exercise) is deemed a promising noninvasive predictor of major cardiac arrhythmic event. Recently, it was demonstrated that TWA during recovery from exercise has additional predictive value. Another mechanism that potentially contributes to arrhythmogeneity is exercise-recovery hysteresis in action potential morphology distribution, which becomes apparent in the spatial ventricular gradient (SVG). In the current study, we investigated the performance of TWA amplitude (TWAA) during a complete exercise test and of exercise-recovery SVG hysteresis (SVGH) as predictors for lethal arrhythmias in a population of heart failure patients with cardioverter-defibrillators (ICDs) implanted for primary prevention. Methods: We performed a case-control study with 34 primary prevention ICD patients, wherein 17 patients (cases) and 17 patients (controls) had no ventricular arrhythmia during follow-up. We computed, in electrocardiograms recorded during exercise tests, TWAA (maximum over the complete test) and the exercise-recovery hysteresis in the SVG. Statistical analyses were done by using the Student t test, Spearman rank correlation analysis, receiver operating characteristics analysis, and Kaplan-Meier analysis. Significant level was set at 5%. Results: Both SVGH and TWAA differed significantly (P < .05) between cases (mean ± SD, SVGH: −18% ± 26%, TWAA: 80 ± 46 μV) and controls (SVGH: 5% ± 26%, TWAA: 49 ± 20 μV). Values of TWAA and SVGH showed no significant correlation in cases (r = −0.16, P = .56) and in controls (r = −0.28, P = .27). Receiver operating characteristics of SVGH (area under the curve = 0.734, P = .020) revealed that SVGH less than 14.8% discriminated cases and controls with 94.1% sensitivity and 41.2% specificity; hazard ratio was 3.34 (1.17-9.55). Receiver operating characteristics of TWA (area under the curve = 0.699, P = .048) revealed that TWAA greater than 32.5 μV discriminated cases and controls with 93.8% sensitivity and 23.5% specificity; hazard ratio was 2.07 (0.54-7.91). Discussion and conclusion: Spatial ventricular gradient hysteresis bears predictive potential for arrhythmias in heart failure patients with an ICD for primary prevention, whereas TWA analysis seems to have lesser predictive value in our pilot group. Spatial ventricular gradient hysteresis is relatively robust for noise, and, as it rests on different electrophysiologic properties than TWA, it may convey additional information. Hence, joint analysis of TWA and SVGH may, possibly, improve the noninvasive identification of high-risk patients. Further research, in a large group of patients, is required and currently carried out by our group. [Copyright &y& Elsevier]

Abstract: Relationship between insulin action and secretion was analyzed in 10 hypertensive patients (H group; 5 male, 5 female; 56.9 ± 2.5 years) compared with 10 normotensive subjects (N group; 5 male, 5 female; 51.7 ± 3.7 years; P > .05) matched for age, sex, and body mass index. All participants (normoglycemic, nonobese, and not affected by metabolic syndrome) underwent a 5-hour, 22-sample, oral (75 g) glucose tolerance test. Insulin sensitivity was quantified by quantitative insulin sensitivity check index and an insulin sensitivity index computed by minimal-model–based “integral equation.” β-Cell responsivity indexes (dynamic, Φd; static, Φs; and global, Φoral) were estimated by C-peptide oral minimal model. Compared with the N group, our H group featured no significant difference (P > .05) in fasting glycemia, significant (P < .02) increase in plasma insulin (93%) and C-peptide (53%) concentrations, and significant (P < .01) reduction in both quantitative insulin sensitivity check index (10%) and insulin sensitivity index (68%). No significant variations of mean Φd, Φs, and Φoral were observed across the 2 groups in response to glucose challenge. Thus, insulin sensitivity deterioration in hypertension was not mirrored by a reciprocal change in β-cell responsivity. Nevertheless, our H group featured a 143% (P < .005) increase in the area under the curve of circulating insulin and a 34% (P < .01) reduction in the ratio between the area under C-peptide curve and the area under the curve of circulating insulin. These results support the hypothesis that decreased insulin clearance in hypertensive patients, not affected by metabolic syndrome, is a further regulatory mechanism, in addition to increased insulin secretion, to compensate for insulin resistance. [Copyright &y& Elsevier]

Abstract: ECG deviations from the isoelectric line (baseline wandering) may affect a reliable detection of T-wave alternans (TWA), a phenomenon associated with increased risk of death. The present study was designed to demonstrate, making use of simulated ECG time series, that baseline wandering might cause erroneous TWA detection from TWA-free ECG tracings, or prevent correct TWA detection whenever TWA was present. Our simulated time series were obtained from a real ECG complex (0.75s recording, sampled at 200Hz) repeated 170 times. TWA was simulated by varying T-wave amplitude (10, 50, 100 and 500μV) in a time window of 160ms centered around the T-wave apex. TWA fundamental frequency was 0.67Hz. Baseline fluctuations were simulated by sinusoidal waves of 0.1mV amplitude and frequency of 0.30, 0.67 and 1.50Hz, respectively. The presence of baseline oscillations at lower (0.30Hz) and higher (1.50Hz) frequency than TWA own frequency prevented TWA detection when TWA amplitude was lower or equal to that of baseline oscillations. TWA detection improved after removal of baseline oscillations by application of a third-order spline interpolation, only for frequencies lower than TWA frequency. For baseline oscillations at greater frequency than heart rate, however, spline interpolation became harmful. An improvement over the spline interpolation was obtained by a new heart-rate adapting match filter with a narrow bandwidth around TWA frequency, which allowed detection of TWA almost independently of baseline frequency components when these were different from TWA own frequency. [Copyright &y& Elsevier]

Abstract: Four methods reported in the literature for evaluation of insulin sensitivity indexes from oral glucose tolerance tests (OGTTs) were analyzed and compared in order to test their ability to discriminate the insulin-resistant state in hypertension. To this aim, 15 normoglycemic subjects, not affected by metabolic syndrome, underwent a 22-sample, 300-minute OGTT. Eight subjects were normotensive (mean age, 47.0 ± 4.2 years) and 7 were hypertensive (mean age, 53.6 ± 1.6 years). The following insulin sensitivity indexes were computed and compared: (a) 2 indexes, ISIE22/300 and ISIE8/180, provided by an integral equation (IE) method applied to the full OGTT and to a reduced 8-sample, 180-minute data subset, respectively; (b) 2 indexes, ISOGIS180 and ISOGIS120, computed by the oral glucose, insulin sensitivity (OGIS) method, which only requires 3 blood samples taken within 180 and 120 minutes, respectively; (c) an index, ISISI, which considers fasting and mean insulinemia and glycemia measured during a 5-sample, 120-minute OGTT; and (d) an index, ISMCR, which considers body mass index and requires 2 blood samples taken within 120 minutes. Except the ISOGIS180, all other indexes were able to detect a significant reduction (unpaired Student t test, P < .05) of insulin sensitivity in our hypertensive group compared with the normotensive group. Failure of ISOGIS180 was explained by the fact that this index did not capture the information portrayed by the peak of insulinemia in hypertensive patients, which occurred around the 90th minute. Intraclass correlation coefficients higher than 0.89 demonstrated a substantial agreement between ISIE22/300 and ISIE8/180 indexes. These are the only indexes characterized by units of measure consistent with the definition of insulin sensitivity as the ability of insulin to enhance glucose effectiveness. [Copyright &y& Elsevier]

Abstract: An association between heterogeneity of repolarization alternans (RA) and cardiac electrical instability has been reported. Characterization of RA in health and identification of physiological RA heterogeneity may help discrimination of abnormal RA cases more likely associated to arrhythmic events. Thus, aim of the present study was the identification of a physiological RA region in terms of mean temporal location (MRAD) with respect to the T apex, and mean amplitude (MRAA), by application of our heart-rate adaptive match filter method to clinical ECG recordings from 51 control healthy (CH) subjects and 43 acute myocardial infarction (AMI) patients. Results indicate that RA occurring within the first half of the T wave is dominant in both CH and AMI populations (74.5% and 53.5% of cases, respectively; P <0.05). Definition of physiological RA region in the MRAD vs. MRAA plane (−83ms≤MRAD≤23ms, 0≤MRAA≤30μV) provided 0% and 32.6% abnormal RA cases among the CH subjects and AMI patients, respectively. We conclude that myocardial infarction may associate with an RA occurring early (MRAD<−83ms) or late (MRAD>23ms) along the JT segment, in addition or in alternative to an abnormally high RA amplitude (MRAA>30μV). [Copyright &y& Elsevier]

Abstract: The aim was to investigate the effect of interferences surviving preprocessing (residual noise, baseline wanderings, respiration modulation, replaced beats, missed beats and T-waves misalignment) on automatic identification of T-wave alternans (TWA), an ECG index of risk for sudden cardiac death. The procedures denominated fast-Fourier-transform spectral method (FFTSM), complex-demodulation method (CDM), modified-moving-average method (MMAM), Laplacian-likelihood-ratio method (LLRM), and adaptive-match-filter method (AMFM) were applied to interferences-corrupted synthetic ECG tracings and Holter ECG recordings from control-healthy subjects (CH-group; n =25) and acute-myocardial-infarction patients (AMI group; n =25). The presence of interferences in simulated data caused detection of false-positive TWA by all techniques but the FFTSM and AMFM. Clinical applications evidenced a discrepancy in that the FFTSM and LLRM detected no more than one TWA case in each population, whereas the CDM, MMAM, and AMFM detected TWA in all CH-subjects and AMI-patients, with significantly lower TWA amplitude in the former group. Because the AMFM is not prone to false-positive TWA detections, the latter finding suggests TWA as a phenomenon having continuously changing amplitude from physiological to pathological conditions. Only occasional detection of TWA by the FFTSM and LLRM in clinics can be ascribed to their limited ability in identifying TWA in the presence of interferences surviving preprocessing. [ABSTRACT FROM AUTHOR]

Abstract: Enhanced modified moving average method (EMMAM) and correlation method (CM) for microvolt TWA identification are compared by aid of simulated ECG tracings (cases of absence of TWA and presence of stationary or time-varying TWA) and ECG recordings from healthy subjects (H-group) and patients who survived an acute myocardial infarction (AMI-group). The two competing methods were found to be equivalent when analyzing clean ECGs affected by stationary TWA. Non-stationary TWA is correctly tracked by the CM, whereas it is identified as stationary by the EMMAM. Moreover, the EMMAM suffers for its tendency to identify as TWA noise and other kinds of repolarization variability. Such limitation is most likely the cause of its false-positive TWA production. Finally, only the CM incorporates a local threshold criterion in the TWA detection algorithm which allows better discrimination between H and AMI groups, who are well known to be at increased risk to develop TWA. [Copyright &y& Elsevier]

Abstract: Role of hepatic insulin degradation in modulating insulin delivery to peripheral circulation, in insulin-resistant hypertensive patients, is not yet fully understood. This issue was investigated here by a novel application to hypertension of a previously proposed minimal modelling of insulin and C-peptide data, using population values for insulin and C-peptide kinetics parameters. Data, from frequently sampled intravenous glucose tolerance test (FSIGTT), were analysed in ten normoglycemic, hypertensive patients (H-group), compared with eight normoglycemic, normotensive subjects (N-group), matched for age, gender and body mass index. Minimal modelling of C-peptide and insulin data provided β-cell responsiveness to glucose perturbation (first, Φ 1, second, Φ 2, and basal, Φ b , phase), insulin secretion rate, ISR(t) and total pre-hepatic insulin secretion, TIS, as well as insulin delivery rate, IDR(t), and total insulin delivery, TID, into plasma, over 5-h test. Instantaneous normalized hepatic insulin degradation rate was computed as HIDR(t)=1−[IDR(t)/ISR(t)]. In our H-group, insulin sensitivity, S I , assessed by minimal model of glucose kinetics, showed a 56% reduction, which confirmed deterioration of insulin action in hypertension. This was associated with significant increase in Φ 1 (105%), TIS (55%) and TID (62%). No significant alterations were observed in other characteristic parameters of secretion and hepatic degradation of insulin, such that no significant difference was observed in HIDR(t) between our H and N groups. In conclusion, an increase of first phase and total insulin secretion occurring, in our H-group, in the presence of no alteration of hepatic insulin degradation, resulted in up-regulation of total insulin delivered to plasma (TID) for insulin-resistance compensation. [Copyright &y& Elsevier]

Abstract: Microvolt T-wave alternans (TWA), consisting of every-other-beat changes in ECG T-wave morphology, is an index of susceptibility to malignant ventricular arrhythmias, requiring automatic techniques to be identified. Five of these, namely, fast-Fourier-transform spectral method (FFTSM), complex-demodulation method (CDM), modified-moving-average method (MMAM), Laplacian-likelihood-ratio method (LLRM) and adaptive-match-filter method (AMFM), were applied here to simulated and sample clinical data. The aim was to compare individual methods ability to properly identify stationary and time-varying TWA, avoiding false-positive detections. The MMAM provided false-positive TWA when applied to simulated ECGs affected by amplitude variability, but TWA. Stationary TWA was properly quantified by the MMAM and, occasionally, underestimated by all other methods. The AMFM properly identified time-varying TWA. By contrast, the FFTSM detected not-stationary TWA as stationary, the MMAM introduced a time-delay in the estimated TWA-amplitude signal, while the CDM and LLRM were reliable only in the presence of slow-varying TWA. Altogether, the AMFM accomplished the best compromise between the needs to avoid false-positive TWA and to detect and characterize true-positive TWA. Results of our simulation approach were useful to explain different TWA levels measured by each competing methods applied to sample Holter ECGs from healthy subjects and coronary artery disease patients. [Copyright &y& Elsevier]