The discovery of (1R, 3R)-1-(3-chloro-5-fluorophenyl)-3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile, a potent and selective agonist of human transient receptor potential cation channel subfamily m member 5 (TRPM5) and evaluation of as a potential gastrointestinal prokinetic agent.

This publication details the discovery of a series of selective transient receptor potential cation channel subfamily M member 5 (TRPM5) agonists culminating with the identification of the lead compound (1R, 3R)-1-(3-chloro-5-fluorophenyl)-3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile (39). We describe herein our biological rationale for agonism of the target, the examination of the then current literature tool molecules, and finally the process of our discovery starting with a high throughput screening hit through lead development. We also detail the selectivity of the lead compound 39 versus related family members TRPA1, TRPV1, TRPV4, TRPM4 and TRPM8, the drug metabolism and pharmacokinetics (DMPK) profile and in vivo efficacy in a mouse model of gastrointestinal motility.

Glutamine depletion by crisantaspase hinders the growth of human hepatocellular carcinoma xenografts.

BACKGROUND: A subset of human hepatocellular carcinomas (HCC) exhibit mutations of ß-catenin gene CTNNB1 and overexpress Glutamine synthetase (GS). The CTNNB1-mutated HCC cell line HepG2 is sensitive to glutamine starvation induced in vitro with the antileukemic drug Crisantaspase and the GS inhibitor methionine-L-sulfoximine (MSO). METHODS: Immunodeficient mice with subcutaneous xenografts of the CTNNB1-mutated HCC cell lines HepG2 and HC-AFW1 were treated with Crisantaspase and/or MSO, and tumour growth was monitored. At the end of treatment, tumour weight and histology were assessed. Serum and tissue amino acids were determined by HPLC. Gene and protein expression were estimated with RT-PCR and western blot and GS activity with a colorimetric method. mTOR activity was evaluated from the phosphorylation of p70S6K1. RESULTS: Crisantaspase and MSO depleted serum glutamine, lowered glutamine in liver and tumour tissue, and inhibited liver GS activity. HepG2 tumour growth was significantly reduced by either Crisantaspase or MSO, and completely suppressed by the combined treatment. The combined treatment was also effective against xenografts of the HC-AFW1 cell line, which is Crisantaspase resistant in vitro. CONCLUSIONS: The combination of Crisantaspase and MSO reduces glutamine supply to CTNNB1-mutated HCC xenografts and hinders their growth.

Nature-inspired indolyl-2-azabicyclo[2.2.2]oct-7-ene derivatives as promising agents for the attenuation of withdrawal symptoms: synthesis of 20-desethyl-20-hydroxymethyl-11-demethoxyibogaine.

Microwave assisted Diels-Alder cycloaddition of 5-Br-N-benzylpyridinone (2) with methyl acrylate is described to gain an easy access to 7-bromo-2-benzyl-3-oxo-2-aza-5 or 6-carbomethoxy bicyclo[2.2.2]oct-7-enes (3)-(6). The preparation of the ibogaine analogue 20-desethyl-(20-endo)-hydroxymethyl-11-demethoxyibogaine (17) is described by stereoselective hydrogenation of the C(7)-C(8) double bond. Biological evaluation showed an interesting in vitro binding profile toward dopamine transporter, serotonin transporter and opioid receptor systems accompanied by an antiwithdrawal effect in mice for hydroxymethyl 7-indolyl-2-aza-bicyclo[2.2.2]oct-2-ene (14). The simplification of the ibogaine structure appears as a promising approach toward the design of compounds that could reduce the withdrawal symptoms.

Sodium sensitivity of blood pressure in long-term detoxified alcoholics.

To investigate whether sodium sensitivity of blood pressure participates in the relationship of arterial hypertension to chronic alcohol consumption, 30 alcoholics detoxified from 6 to 12 months and 30 teetotaler controls underwent a dietary sodium manipulation study. They received a daily 55 mmol sodium diet for 7 days, followed by a 260 mmol sodium diet for 7 days. Changes in 24-hour urinary sodium excretion between the end of each period were similar in alcoholics and controls (202+/-16 SEM mmol and 227+/-11, respectively). Plasma renin activity in alcoholics was lower than in controls at both low (2.4+/-0.4 ng angiotensin I/mLxh(-1) versus 3. 7+/-0.2, P<0.003) and high sodium intake (0.47+/-0.10 versus 0. 82+/-0.10, P<0.05), with smaller variations in alcoholics (-1.9+/-0. 3 versus -2.9+/-0.2, P<0.009). In alcoholics, alteration in sodium intake was followed by greater changes in both systolic and mean blood pressure (ambulatory blood pressure monitoring), which rose by 10.6+/-2.2 mm Hg and 7.3+/-1.5 versus 4.7+/-1.4 and 3.9+/-1.0 in controls, respectively (P<0.03 for systolic and P<0.05 for mean blood pressure). The ratio of changes in mean blood pressure to those in 24-hour urinary sodium excretion was higher in alcoholics (0.044+/- 0.011 mm Hgxmmol(-1) versus 0.018+/-0.0041, P<0.005). Our data show that in detoxified alcoholics, there is an abnormal response of both blood pressure and plasma renin activity to variations in salt intake similar to that in sodium-sensitive arterial hypertension. The precise relationship between the sodium sensitivity of blood pressure in detoxified alcoholics and the long-term influence of alcohol on blood pressure remains to be elucidated.

Can weight gain in healthy, nonobese volunteers be predicted by differences in baseline plasma insulin concentration?

In this study, we have evaluated the effect, over approximately 14 yr, of differences in baseline degree of hyperinsulinemia on weight gain in 647 healthy, nonobese factory workers. The subjects were divided into 4 quartiles, on the basis of their plasma insulin response to an oral glucose challenge, in 1981. At that time, the mean (+/-SD) plasma insulin concentration, 2 h after the glucose challenge, varied from 18+/-5 to 106+/-42 microU/mL. Despite this approximate 6-fold difference in plasma insulin response at baseline, the weight gain over the period of observation was similar in all quartiles, with mean (+/-SD) increments (kg) of 1.8+/-5.1, 1.6+/-5.3, 2.3+/-5.2, and 2.3+/-5.7, going from the lowest quartile to the highest quartile, in terms of insulin concentration. Furthermore, when the population was considered as a whole, there was no correlation between baseline degree of hyperinsulinemia and change in either absolute (r = 0.004) or percent (r = 0.003) weight gain. Finally, there was no difference in the number of individuals who gained more than 4.5 kg, as a function of their baseline insulin response. Consequently, we conclude that 6-fold differences in plasma insulin responses to glucose do not predict weight gain in a healthy, nonobese population.

Comparison of fasting plasma leptin concentrations in healthy subjects with high and low plasma insulin.

This study was initiated to evaluate the role of hyperinsulinemia in the regulation of fasting plasma leptin. We measured plasma leptin and insulin concentrations in 404 healthy nondiabetic subjects. For analytical purposes, the population was divided into quartiles on the basis of the lowest (quartile 1) and highest (quartile 4) plasma insulin response to oral glucose, and fasting plasma leptin values in these 2 dichotomous groups were compared. The total plasma integrated insulin response was 4-fold greater in quartile 4, associated with significantly higher (P < .001) fasting plasma leptin (12.60+/-0.85 v8.53+/-0.56 ng/mL). Fasting plasma leptin concentrations remained significantly higher in the hyperinsulinemic quartile when comparisons were made after subdividing the population on the basis of gender, body mass index (BMI), or waist to hip ratio (WHR). These results demonstrate that fasting plasma leptin concentrations are significantly higher in hyperinsulinemic individuals, and this difference is independent of either overall or central obesity.

Hyperinsulinemia in a normal population as a predictor of non-insulin-dependent diabetes mellitus, hypertension, and coronary heart disease: the Barilla factory revisited.

The study was initiated to evaluate the ability of hyperinsulinemia (as a surrogate measure of insulin resistance) to predict the development in a previously healthy population of three putative outcomes of this abnormality--glucose intolerance, hypertension, and coronary heart disease (CHD). The study involved defining the incidence at which these changes occurred between 1981 and 1993 to 1996 in 647 individuals who were free of any disease when initially studied. The study population consisted of approximately 90% of the subjects evaluated in 1981, divided into quartiles on the basis of the plasma insulin response to a glucose challenge as determined in 1981. The results indicated that the 25% of the population with the highest insulin response in 1981 had significant (P < .001) increases in the incidence of impaired glucose tolerance (IGT) or type 2 diabetes (eightfold), hypertension (twofold), or CHD (threefold). Furthermore, the ability of hyperinsulinemia to predict the three clinical endpoints was independent of differences in age, gender, or body mass index (BMI). Finally, if CHD is considered the clinical endpoint, multiple logistic regression analysis indicates that the values for plasma triglyceride (TG) and mean arterial blood pressure ([MAP] as measured in 1981) also predict the development of CHD. These results indicate that the untoward clinical effects of insulin resistance and/or compensatory hyperinsulinemia, glucose intolerance, hypertension, and CHD clearly can develop in less than 15 years.

Detection of early abnormalities of left ventricular function by hemodynamic, echo-tissue Doppler imaging, and mitral Doppler flow techniques in patients with coronary artery disease and normal ejection fraction.

We have investigated the possibility of detecting early abnormalities of left ventricular function at the initial phase of ischemic cardiomyopathy. Sixteen normotensive patients with coronary artery disease and normal left ventricular ejection fraction and 6 control patients were studied by invasive hemodynamic techniques in combination with transmitral Doppler flow or with echo-tissue Doppler imaging. The extent of the percentage of left ventricular longitudinal shortening and the systolic peak velocity at echo-tissue Doppler were significantly higher in the control patients than in patients with ischemic cardiomyopathy (P <.01). Left ventricular end-diastolic pressure was higher (P <.05), whereas mean values of isovolumic contraction and relaxation indexes (dP/dt/P: P <.05; +dP/dt: P <.05; -dP/dt: P <.01) were lower in patients with ischemic cardiomyopathy. Tau was significantly longer in ischemic patients (42.7 +/- 8.8 versus 34.5 +/- 3.7 ms, P <.05). In the control patients, the aortic valve closure to peak E interval by transmitral Doppler flow was significantly longer than that measured by echo-tissue Doppler (P <.001), whereas in patients with ischemic cardiomyopathy, this interval difference was still present and significantly shorter (P <.05). In patients with coronary artery disease and normal ejection fraction, minor and early abnormalities of left ventricular function related to isovolumic contraction and relaxation as well as to longitudinal shortening could be detected. In addition, a suction-like effect, detected during early filling evaluation with echo-tissue Doppler, is significantly decreased but not abolished during the early stages of coronary artery disease.

Effect of aging on left ventricular filling in untreated hypertensive patients.

The aim of this study was to evaluate the influence of age and other clinical and echocardiographic parameters on left ventricular filling in a group of 174 untreated patients with mild to moderate hypertension (aged 20-82 years; mean 51.2 years) and in 189 age-matched normotensive subjects. All subjects underwent an echocardiographic study with pulsed Doppler evaluation of left ventricular filling. Left ventricular dimensions and indexes of systolic function were similar and within normal limits in both groups. Left ventricular filling was altered in hypertensive subjects < 65 years with a decrease of peak early velocity (peak E), an increase of peak atrial velocity (peak A) and a reduced E/A ratio. However in subjects > or = 65 years, we did not observe any differences in transmitral flow velocity pattern between hypertensive and normotensive subjects. The stepwise regression analysis showed that age alone explains up to 8% of peak E variance, 14% of peak A and 26% of E/A ratio in hypertensives, while in normotensives it explains up to 18% of peak E variance, 50% of peak A and 61% of E/A ratio. The other variables entered into the regression slightly improved the predictive power. In conclusion, age is the major independent factor affecting left ventricular filling in both groups, even if its predictive power was smaller in the hypertensive group. The similarity of diastolic filling pattern in elderly hypertensive and normotensive subjects suggests that the 'aging factor' plays an important role in influencing left ventricular filling pattern so as to mask the effect of hypertension in the elderly patients.

Ejection phase indexes with apexcardiography. Comparison with echocardiographic and angiographic parameters.

The reliability of a new noninvasive method for evaluating ejection fraction and the mean velocity of circumferential fiber shortening by apexcardiography and carotid pulse tracing has been evaluated. Three groups of subjects were considered. Group 1: 30 normal subjects (mean age 43 years); Group 2: 34 patients with aortic valve disease (mean age 51 years); Group 3: 76 patients with coronary artery disease (mean age 50 years). The mechano-cardiographic tracing points were acquired by an ultrasonic digitizing system and compared with the same indexes measured from the ventriculogram. In 53 patients M-mode echocardiographic evaluations also were performed. The correlations between the apexcardiographic derived ejection phase indexes and the angiographic measurements were highly significant in all subjects and in each group of patients. The correlations between the ejection phase indexes determined by echocardiography and the same angiographic data were also significant, but the r-values were somewhat lower than those found between the apexcardiographic and angiographic parameters in the same patients. Our results have assessed the reliability of this new method and demonstrated that this noninvasive technique can be applied not only in coronary disease but also in aortic valve disease and in normal subjects. It can be concluded that the apexcardiographic evaluation of cardiac performance appears applicable to patients in whom a means of assessing and sequentially following ventricular function is indicated.

[Lipids in enteral nutrition: does an optimal ratio between omega-6 and omega-3 exist?]. / I lipidi in nutrizione enterale: esiste un rapporto ottimale omega-6/omega-3?

The ratio between PUFA omega-6 and omega-3 is 3:1 in the unweaned, 5:1 in the young man, 5-10:1 in the adult. The PUFA omega-6 prevail over omega-3 because of elongation and desaturation processes. Linoleic acid is the beginning of the omega-6 series, a-linolenic acid of the omega-3 series. Both acids give rise to PUFA which must be introduced with diet because the human race is not able to synthetize. They represent the 2-6% of total daily caloric intake and correspond about to 10 g every day according to LARN 1986-1987. During some diseases (after surgery, trauma, sepsis, etc.) their need increases until 25-50 g every day, so it is necessary a proper enteral nutrition (EN). For this reason the bromatological composition of diets for EN must respect the physiological ratio between omega-6 and omega-3 PUFA. The composition of 37 diets for EN was examined and it was found that 7 (18%) have a proper ratio between the two series of PUFA. Twenty-three (62%) do not signal any ratio, two have 6:1, two 4.5:1, in three the ratio is in favour of omega-3. Then the concentration of linoleic and alfa-linolenic acid was examined and it was found that 24 (64%) diets signal the concentration of linoleic acid, 10 (27%) of both acids, two have no data about and only one diet reports the concentration of alfa-linolenic acid. A more exact formulation of PUFA into the composition of EN diets is suggested because PUFA are now recognized to play an important role in the fields of inflammation and immunity.

[Arterial blood pressure in a population of Italian clerical workers. Correlation with other coronary risk factors]. / Pression artérielle dans une population d'employés italiens. Corrélation avec d'autres facteurs de risque coronarien.

Distribution of arterial blood pressure and prevalence of hypertension have been reported in 172 subjects (568 males and 144 females), derived from screening of a bank clerks population. 99 subjects were found to be hypertensive: 46 (46.4 p. 100) were aware of being hypertensive, 24 (24.3 p. 100) resulted to be under treatment and only in 5 subjects blood pressure values were effectively controlled. The relationships between arterial blood pressure and some recognized or suspected coronary risk factors were also determined by multiple regression analysis. Age, heart rate, body mass index, glycemia after loading, turned out the variables most correlated with blood pressure. The multiple regression analysis showed that overall evaluation of coronary risk factors explained up to 21 p. 100 of the systolic blood pressure variation and to 17 p. 100 of diastolic pressure in male subjects, while for women the obtained values were 34 p. 100 and 24 p. 100 respectively. After a critical evaluation of different parameters able to affect arterial blood pressure, the difficult approach to hypertension preventive and therapeutic problems was emphasized.

Airway barrier dysfunction induced by exposure to carbon nanotubes in vitro: which role for fiber length?

Although carbon nanotubes (CNTs) are increasingly used, their biological effects are only incompletely characterized. However, experimental evidence suggests that the intratracheal instillation of CNTs causes the formation of interstitial granulomas and progressive pulmonary fibrosis in rodents. Using human epithelial Calu-3 cells as a model of airway epithelium in vitro, we have recently reported that the exposure to commercial multi-walled CNTs (MWCNTs) causes a progressive decrease of the transepithelial electrical resistance (TEER), pointing to a CNT-dependent impairment of the epithelial barrier function. To characterize better this behavior, we compared the effects of two types of MWCNTs and single-walled CNTs (SWCNTs) of different lengths on the TEER of Calu-3 monolayers. All the materials were used at a dose of 100 microg/mL corresponding to an exposure of 73 microg/cm(2) of cell monolayer. Only the longer MWCNTs and SWCNTs cause a significant decrease in TEER. To elucidate the mechanism underlying the changes in barrier function, the expression of the junction proteins occludin and ZO-1 has been also assessed. No significant decrease in the mRNA for either protein is detectable after the exposure to any type of CNTs. It is concluded that the impairment of barrier function in Calu-3 monolayers is a peculiar effect of CNTs endowed with clear cut fiber properties and is not referable to marked changes in the expression of junction proteins.

[Exercise-induced R wave changes in normals and coronary patients. Computer analysis of CB5 lead (author's transl)]. / Comportamento dell'onda R durante sforzo in soggetti normali e coronaropatici. Analisi automatica della derivazione CB5.

Changes in R-wave amplitude (delta R) during treadmill test were studied in 84 coronary artery disease (CAD) patients and in 150 normal subjects. The evaluation of ECG recordings (CB5 lead) was carried out by a computer program. At maximal exercise, R-wave decreased by 2.1 +/- 2.8 mm in normal subjects, while in CAD patients mean delta R was significantly lower (0.4 +/- 1.7 mm). When the evaluation of delta R was performed at comparable heart rate and work load values, no significant differences were observed between normals and CAD patients. Using as criterion for a positive test an ischemic ST segment depression greater than or equal to 1.0 mm, the diagnostic sensitivity was 66.7%, while the specificity was 94.0%. When an increase or no change in R-wave was taken as evidence of an abnormal response, sensitivity and specificity values were 57.1% and 65.3% respectively. After a critical review of different parameters able to affect delta R, the difficult physiopathological evaluation and the poor diagnostic reliability of delta R were emphasized. The different heart rate and work load values attained by normals and CAD patients proved to be a further confounding factor in delta R comparison between the two groups.

Peak aortic blood acceleration: a possible indicator of initial left ventricular impairment in patients with coronary artery disease.

In 25 patients undergoing diagnostic cardiac catheterization, a catheter-tip electromagnetic velocity transducer was used to evaluate maximum velocity and acceleration of blood in the ascending aorta. All patients underwent a complete haemodynamic evaluation, including high-fidelity recording of intraventricular pressures and calculation of the derived indices, left ventriculography and coronary angiography. Nineteen patients with critical coronary stenoses were divided according to the presence of signs of left ventricular dysfunction, while the control group consisted of six subjects with chest pain, but without cardiac abnormalities detectable by cardiac catheterization. Maximum aortic acceleration was significantly lower in coronary patients (378 +/- 130 vs 562 +/- 82 in the control group P less than 0.01) and also in the selected subgroup of coronary patients with normal haemodynamic and angiographic indices of left ventricular systolic function (310 +/- 102 vs 562 +/- 82, P less than 0.01). No relationship could be observed between maximal blood acceleration and left ventricular peak systolic pressure, +dP/dt, left ventricular end-systolic volume index and ejection fraction. Our results suggest that maximal blood acceleration from the left ventricle may detect an initial myocardial impairment in patients with definite coronary artery disease but with normal conventional indices of left ventricular function. The clinical interest of this index, however, is limited by overlapping values in patients with and without coronary artery disease and the inability of a further separation of ischaemic patients in accordance with the severity of left ventricular impairment and the extension of coronary artery involvement.

Alcohol addiction: evaluation of alcohol abstinence after a year of psycho-medical-social treatment.

The aim of this study was to evaluate alcohol abstinence in alcoholics and their family relationships after a year of treatment. The 100 alcoholics recruited were divided into two groups: ALC, where treatment consisted of clinical control and meetings of with the family consulting together with their relatives at the Centre for Study and Treatment of Alcoholism and CAT, where treatment consisted of clinical control and weekly attendance together with their relatives at Alcoholics-in-Treatment-Clubs (CAT). The clinical condition of the sample was assessed by laboratory data. The subjects were given an MQ-Quant questionnaire, based on an artificial neural network (ANN) model, which analyses the communicative fatigue of their interactions. The same examination was applied after 1 year excluding patients relapsed and their relatives. Psycho-medical-social treatment by the attendance of alcoholics and their families into a Multifamily Community induces alcohol abstinence of about 79%. This percentage is greater than psycho-medical treatment carried out in the Centre of Alcoholism for ALC group (50%). We observed a significant difference between the communicative fatigue of the ALC group compared to the CAT group.

[Effects of digitalis on the left ventricular filling phase in the normal and ischemic heart. Angiographic study in man]. / Effetti della digitale sul riempimento ventricolare sinistro nel cuore normale ed ischemico. Studio angiografico nell'uomo.

The effects of digitalis on the left ventricular diastolic phase are very scant. In order to gain a better insight into this problem, we measured the hemodynamic effects of an intravenous injection of K-strophantidin (0.005 mg/kg in a bolus given within 5-10 min) during the diastolic phase in 9 normal male subjects and in 9 male patients with coronary artery disease (CAD), maintaining a normal overall ejection fraction despite of the presence of some hypokinetic segments. Administration of K-strophantidin decreased significantly in normal controls the left ventricular volumes at 1/3, 1/2, 2/3 of the diastolic phase, whereas it did not produce significant change in CAD patients. Digitalis decreased the first and increased the second filling peak of the volumetric variable dV/dt in the normal controls, but not in the CAD patients. In the latter group the 2 peaks before digitalis administration were similar. The effects of digitalis on the dV/dt measured during the second filling peak were significantly different in the 2 groups. The increments of pressure in middle and end diastole in CAD patients were significantly greater than those observed in normal controls. Results of the present study suggest that digitalis has a negative influence on the left ventricular filling phase both in normal and CAD subjects. In fact digitalis modifies in normals the pattern of the left ventricular filling phase whereas it induces an untoward increase in the middle and end diastolic pressure in CAD patients.

Early and subtle abnormalities of left ventricular function in clinically stable coronary artery disease patients with normal ejection fraction.

BACKGROUND: It has been reported that, in the initial phase of ischemic cardiomyopathy, the earliest alterations of left ventricular function are detected during the relaxation phase. The aim of this study was to look for precocious abnormalities in the early stage of ischemic cardiomyopathy in both left ventricular systolic and diastolic phases. METHODS AND RESULTS: Using simultaneous left ventricular catheterization and echo-Doppler techniques, we studied both systolic and diastolic function in 44 (37 males and 7 females, mean age 55.7+/-8) normotensive, clinically stable, coronary artery disease patients with normal left ventricular ejection fraction in comparison to 9 age- and sex-matched normal control subjects (7 males and 2 females, mean age 54.7+/-9). Mean values of E deceleration time, tau, left ventricular end-diastolic volume and pressure, and end-systolic volume and lowest diastolic pressure were significantly higher (from P<.05 to P<.01), whereas mean dP/dt/P values significantly lower (P<.05) in coronary artery disease patients than in controls. A strict relationship (P<.001) between dP/dt/P and tau, left ventricular lowest and end-diastolic pressure was found in all subjects studied. CONCLUSION: Early and subtle abnormalities in parameters of both systolic and diastolic function can be found in the majority of coronary artery disease patients with normal ejection fraction.

Tardokinesis in coronary artery disease: evidence with instantaneous analysis of left ventricular ejection.

Instantaneous measurements of ejection phase indices throughout the whole systole have been performed in 10 normal subjects (normal group), and in 8 coronary artery disease (CAD) patients (CAD group). All the patients of the CAD group were selected from 230 CAD patients because of their normal values in standard ejection phase indices (i.e. ejection fraction, EF; mean velocity of circumferential fiber shortening, VcfM; mean normalized systolic ejection rate, MNSER). An 'instantaneous' evaluation of the ventricular function, by means of a frame-by-frame analysis throughout the ejection period, allowed us to detect abnormalities of ventricular ejection in the early phase of systole in these CAD patients. In comparison with the control group, the CAD group presented similar peak values of dV/dt, dV/dt/EDV and Vcf, and a significantly longer time to peak values of these indices; EF curve analysis showed similar values at the end of systole in the two groups, but the mean curve of the CAD group was significantly lower in the first third of ejection when compared with that of control group. A segmental wall motion analysis in the early phase of systole showed a diffuse delayed ventricular wall motion (tardokinesis) related to abnormalities demonstrated by frame-by-frame analysis of ejection phase indices. Our results confirm that the CAD patients may have abnormalities of ventricular performance in the early phase of systole even when standard ejection phase indices are still within the normal range. In addition, the chronological appearance of these abnormalities during the whole systole has been clearly assessed; finally, these data confirm the importance of acceleration in blood ejection from the left ventricle as an index of ventricular function.