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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]

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]

Based on glucose kinetics minimal model (GKMM) interpretation of frequently sampled intravenous glucose tolerance test (FSIGTT), the aim was to broaden the characterization of insulin-mediated glucose disposal in hypertension by aid of a dynamic insulin sensitivity index, $$ S_{\text{I}}^{\text{D}} $$, and the related efficiency, $$ \eta = S_{\text{I}}^{\text{D}} /S_{\text{I}} , $$ of the metabolic system to convert the maximal individual response capacity, measured by S, into an effective insulin control on glucose. The C-peptide minimal model (CPMM) was used to interpret the role of β-cell function. Plasma glucose, insulin, and C-peptide concentrations were measured, during a 5-h FSIGTT, in eighteen normoglycemic individuals: ten hypertensive patients (H-group) and eight normotensive subjects (N-group) with no metabolic syndrome. Compared to our N-group, the H-group showed a significant ( P < 0.05) reduction of both S (56%) and $$ S_{\text{I}}^{\text{D}} $$ (50%), no significant change of η, a significant increase of both the first-phase β-cell responsiveness to glucose (105%) and total insulin secretion (55%), and no significant change in disposition indexes, defined as the product of insulin sensitivity (either S and $$ S_{\text{I}}^{\text{D}} $$) and β-cell responsiveness. These findings suggest that, in spite of no change of efficiency, insulin resistance in normoglycemic hypertensive patients is primarily compensated by an increase in first-phase insulin secretion to preserve glucose tolerance to intravenous glucose load. [ABSTRACT FROM AUTHOR]

The evolution with ageing of insulin resistance, body weight (BW) and mean arterial pressure (MAP) was studied in a group of Zucker fatty rats (ZFRs, n= 22), between 7 and 16 weeks of age, compared with an age-matched control group of Zucker lean rats (ZLRs, n= 22). The minimal model of glucose kinetics was applied to estimate glucose effectiveness, SG, and insulin sensitivity, SI, from insulinaemia and glycaemia measured during a 70 min intravenous glucose tolerance test. No correlation was found between SG and age in both ZFR and ZLR groups. No significant changes in mean SG between the two groups indicated no alteration of glucose-mediated glucose disposal. Estimates of SI from individual ZFRs were independent of age and, on average, showed 83% reduction ( P < 0.001) compared with the ZLR group. Despite the lack of alteration of SI with age, the ZFR group showed an age-related increase of MAP, which correlated with increasing BW (r = 0.71 and P < 0.001). These results support the hypothesis that in our ZFRs, as a suitable genetic model of obesity and hypertension, insulin resistance is fully established at the age of 7 weeks and remains practically unaltered until at least the sixteenth week. An age-related increase in arterial pressure, observed in this strain, relates more properly to increasing BW, rather than insulin resistance. Development of hypertension with increasing age and BW may result from an enhanced insulin-mediated activity of the sympathetic nervous system, as observed in our previously reported study. [ABSTRACT FROM AUTHOR]

The aims of this study were (a) to apply in the animal with intact baroreflex a two-point method for estimation of overall, effective open-loop gain, G0e, which results from the combined action of baroregulation and total systemic autoregulation on peripheral resistance; (b) to predict specific baroreflex gain by correcting the effective gain for the autoregulation gain; and (c) to discuss why the effective gain is usually as low as 1-2 units. G0e was estimated from two measurements of both cardiac output, Q, and mean systemic arterial pressure, P: one in the reference state (set-point) and the other in a steady-state reached 1-3 min after a small cardiac output perturbation. In anaesthetized cats and dogs a cardiac output perturbation was accomplished by partial occlusion of the inferior vena cava and by cardiac pacing, respectively. Average (± S.E.M.) estimates of G0e were 1.4 ± 0.2 (n : 8) in the cat and 1.5 ± 0.4 (n = 5) in the dog. The specific baroreflex open-loop gain, Gob, found after correction for total systemic autoregulation, was 3.3 ± 0.4 in the cat and 2.8 ± 0.8 in the dog. A model-based analysis showed that, with G0e as low as 1.4, the closed-loop response of P to a stepwise perturbation in Q results in damped oscillations that disappear in about 1 min. The amplitude and duration of these oscillations, which have a frequency of about 0.1 Hz, increase with increasing G0e and cause instabilitywhen G0e is about 3. We conclude that autoregulation reduces the effectiveness of baroreflex gain by about 55%, thereby preventing instability of blood pressure response. [ABSTRACT FROM AUTHOR]

Investigates the adequacy of three different functions that have been used to characterize the relationship between mean systemic arterial pressure (SAP) and mean baroreceptor pressure (BP) in open-loop experimental preparations. Threshold and saturation baroreceptor pressure levels; Downward concavity of SAP-BP curves.

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]

Somatosympathetic reflexes were studied in young hyperinsulinemic, insulin-resistant (Zucker fatty) rats (ZFR) and a related control (Zucker lean) strain (ZLR). Glucose metabolism was characterized by minimal model analysis of intravenous glucose tolerance test data. Seven-week-old ZFR (n = 18) and ZLR (n = 17) were studied under pentobarbital anesthesia. Mean body weight and plasma glucose and insulin concentration were significantly greater (P < 0.05) in ZFR than in ZLR, whereas basal values of mean arterial pressure (MAP) and heart rate (HR) were not significantly different. Increments of MAP (ΔMAP) and HR (AHR) elicited by electrical stimulation of the sciatic nerve (5-s trains of 100 pulses, 0.5-ms pulse duration, 100- to 400-μA pulse intensity) were significantly higher (ANOVA, P < 0.05) in ZFR at each level of stimulus intensity. Regression analysis showed a linear increase in ΔMAP and AHR with increasing sciatic nerve stimulus intensity. Pressor responses to phenylephrine after ganglionic blockade demonstrated that vascular reactivity to adrenergic stimulation is not increased in ZFR compared with ZLR. Thus this factor does not contribute to enhancement of somatosympathetic reflexes observed in this strain. Insulin sensitivity in ZFR was one-fourth (P < 0.05) that in ZLR. These results suggest that stronger sympathetic nervous reactivity in ZFR is associated with a severe insulin-resistant state before the onset of hypertension and support the hypothesis that insulin-mediated stimulation of the sympathetic nervous system is involved in the development of cardiovascular diseases related to alterations of glucose metabolism. [ABSTRACT FROM AUTHOR]