Quantum thermodynamics of systems with anomalous dissipative coupling.

The standard system-plus-reservoir approach used in the study of dissipative systems can be meaningfully generalized to a dissipative coupling involving the momentum, instead of the coordinate: the corresponding equation of motion differs from the Langevin equation, so this is called anomalous dissipation. It occurs for systems where such coupling can indeed be derived from the physical analysis of the degrees of freedom that can be treated as a dissipation bath. Starting from the influence functional corresponding to anomalous dissipation, it is shown how to derive the effective classical potential that gives the quantum thermal averages for the dissipative system in terms of classical-like calculations; the generalization to many degrees of freedom is given. The formalism is applied to a single particle in a double well and to the discrete phi(4) model. At variance with the standard case, the fluctuations of the coordinate are enhanced by anomalous dissipative coupling.

Hexarelin protects H9c2 cardiomyocytes from doxorubicin-induced cell death.

Growth hormone secretagogues (GHSs) are synthetic peptidyl and nonpeptidyl molecules that possess strong growth hormone-releasing activity acting on specific pituitary and hypothalamic receptor subtypes. Differently from nonpeptidyl GHSs, peptidyl molecules such as hexarelin, a hexapeptide, possess specific high-affinity binding sites in animal and human heart and, after prolonged treatment, protect rats in vivo from ischemia-induced myocardial damage. To verify the hypothesis that peptidyl GHSs protect heart cells from cell death, we have investigated the cellular effects of hexarelin on H9c2 cardiomyocytes, a fetal cardiomyocyte-derived cell line, and on Hend, an endothelial cell line derived from transformed murine heart endothelium. We show that (i)H9c2 cardiomyocytes show specific binding for 125I-Tyr-Ala-hexarelin, which is inhibited by peptidyl GHSs such as Tyr-Ala-hexarelin and hexarelin but not by the nonpeptidyl GHS MK-0677, (ii) hexarelin promotes survival of H9c2 cardiomyocytes induced to die by doxorubicin, and (iii) that hexarelin inhibits apoptosis, as measured by DNA fragmentation, induced in both H9c2 myocytes and endothelial cells. In conclusion, our findings show that peptidyl GHSs such as hexarelin act as survival factors for cardiomyocytes and endothelium-derived cells in culture. These findings suggest that the inhibitory activity of hexarelin on cardiomyocytes and endothelial cell death could explain, at least partially, its cardioprotective effect against ischemia recorded in rats in vivo.

Patients with dilated cardiomyopathy show reduction of the somatotroph responsiveness to GHRH both alone and combined with arginine.

OBJECTIVE: Altered function of the GH/IGF-I axis in patients with dilated cardiomyopathy (DCM) has been reported. In fact, DCM patients show reduction of IGF-I levels, which could reflect slight peripheral GH resistance or, alternatively, reduced somatotroph secretion. Spontaneous GH secretion has been reported to be altered by some but not by other authors, whereas the GH response to GHRH, but not that to GH-releasing peptides, seems reduced in DCM patients. On the other hand, it is well known that the GH response to GHRH in humans is markedly potentiated by arginine (ARG), which probably acts via inhibition of hypothalamic somatostatin release; in fact the GHRH+ARG test is known as one of the most reliable to evaluate the maximal secretory capacity of somatotroph cells. METHODS: In order to further clarify the somatotroph function in DCM, in well-nourished patients with DCM (34 male, 4 female; age (mean+/-s.e. m.) 57.8+/-1.1 years; body mass index (BMI) 24.6+/-0.6kg/m(2); left ventricular ejection fraction 23.2+/-1.6%; New York Heart Association classification I/1, II/17, III/18, IV/2) we studied the GH response to GHRH (1.0 microgram/kg i.v.) alone or combined with ARG (0.5g/kg i.v.). The results in DCM patients were compared with those in age-matched control subjects (CS) (39 male, 7 female; age 58.9+/-1.0 years; BMI 23.2+/-0.3kg/m(2)). RESULTS: Mean IGF-I levels in DCM patients were lower than in CS (144.3+/-6.9 vs 175.1+/-8. 4 microgram/l, P<0.05) whereas basal GH levels were similar in both groups (1.7+/-0.3 vs 1.7+/-0.3 microgram/l). The GH response to GHRH in DCM patients was lower (P<0.05) than that in CS (GH peak 6.5+/-1.2 vs 10.7+/-2.1 microgram/l). In both groups the GH response to GHRH+ARG was higher (P<0.001) than that to GHRH alone. However, the GH response to GHRH+ARG in DCM patients remained clearly lower (P<0.01) than that in CS (18.3+/-3.2 vs 34.1+/-4.6 microgram/l). The GH response to GHRH alone and combined with ARG was not associated with the severity of the disease. CONCLUSION: DCM patients show blunted GH responses to GHRH both alone and combined with ARG. Evidence that ARG does not restore the GH response to GHRH in DCM patients makes it unlikely that the somatotroph hyporesponsiveness to the neurohormone reflects hyperactivity of hypothalamic somatostatinergic neurons.

Neonatal and adult human heart tissues from normal subjects and patients with ischemic, dilated or hypertrophic cardiomyopathy express insulin-like growth factor binding protein-3 (IGFBP-3).

In the human fetus IGFBP-3 mRNA expression is most abundant in the skin, muscle and heart but circulating IGFBP-3 levels show age-related variations. In human heart tissues from controls and patients with either ischemic, dilated or hypertrophic cardiomyopathy (no.: 20, age-range from fetuses to elderly subjects) we determined the expression of cardiac IGFBP-3 mRNA by reverse transcriptase polymerase chain reaction (RT-PCR) and the protein by Western blotting. The same parameters were also determined in human livers. We detected IGFBP-3 mRNA in neonatal and adult as well as in fetal human heart tissues in both ventricles. Western blotting revealed the presence of IGFBP-3 in all the examined cardiac tissues. IGFBP-3 appeared to be more abundant in the heart than in the liver and in the failing hearts from patients with ischemic heart disease than in those with hypertrophic cardiomyopathy. Thus both normal and pathological human heart tissues express IGFBP-3 across lifespan and IGFBP-3 could play IGF-dependent and/or -independent actions at the myocardial level.

Activity of GH/IGF-I axis in patients with dilated cardiomyopathy.

OBJECTIVE: There is evidence showing that GH and IGF-I have specific receptors in the heart and that these hormones are able to promote cardiac remodelling and inotropism. It has been reported that patients with dilated cardiomyopathy (DCM) benefit from treatment with rhGH showing a striking increase in cardiac contractility. However, until now, the activity of GH/IGF-I axis in DCM has never been clearly assessed. PATIENTS: To clarify this point, we enrolled 39 patients with idiopathic or post-ischaemic DCM (36 M/3 F; age (mean +/- S.D.) 55.3 +/- 9.0 years; BMI: 25.3 +/- 3.2 kg/m2; New York Heart Association class (NYHA) I/2, II/19, III/15, IV/3) and 42 age-matched controls (CS, 38 M/4 F; age 56.0 +/- 7.8 years; BMI: 24.9 +/- 1.5 kg/m2). DCM patients were characterized by a left-ventricular diastolic diameter of 73.8 +/- 8.3 mm, a shortening fraction of 15.9 +/- 6.4% and a left ventricular ejection fraction of 25.1 +/- 8.7%. In all subjects clinical and biochemical indices of renal and hepatic function as well as nutritional parameters were in the normal range. MEASUREMENTS: In both groups we studied: a) IGF-I levels in basal conditions and after administration of low rhGH doses for 4 days (5.0 or 10.0 mu/kg/day x 4 days); b) the acute GH-response to GHRH (1.0 mu/kg i.v.) or hexarelin (HEX, 2.0 mu/kg i.v.), a peptidyl GH secretagogue (GHRP); c) mean GH concentration (mGHc) over 10 h sampling (every 20 min) from 2200 h to 0800 h. RESULTS: Basal IGF-I levels in DCM were lower (P = 0.000039) than in CS (135.2 +/- 46.8 vs. 193.7 +/- 63.7 mu/l), whereas, basal IGFBP-3 and GHBP2 levels in DCM and CS were similar (2.5 +/- 1.3 vs. 2.6 +/- 0.5 mg/l and 25.3 +/- 3.6 vs. 28.3 +/- 5.0%; P = 0.95 and P = 0.085, respectively). After 4 days of 5.0 mu/kg/day rhGH administration, IGF-I levels in DCM (215.4 +/- 82.0 mu/l; P = 0.0023 vs. baseline) remained lower (P = 0.027) than those in CS (280.0 +/- 80.7 mu/l; P = 0.000080 vs. baseline). After 10.0 mu/kg/day for 4 days, IGF-I levels in DCM (297.2 +/- 109.2 mu/l; P = 0.0033 vs. baseline) were similar (P = 0.76) to those in CS (310.9 +/- 81.7 mu/l; P = 0.000060 vs. baseline). The GH response to GHRH in DCM was lower (P = 0.0022) than that in CS (hAUC0-120: 192.0 +/- 177.3 vs. 345.3 +/- 191.1 mu/l/h) whereas that to HEX in DCM and CS was similar (611.0 +/- 437.5 vs. 535.4 +/- 302.8 mu/l/h; P = 0.95). Within the DCM group, basal and rhGH-stimulated IGF-levels as wel as the GH response to GHRH or HEX were not different among NYHA classes and did not show any correlation with ECHO parameters. The mGHc in DCM (1.0 +/- 0.5 mu/l) was similar (P = 0.57) to that in CS (0.9 = 0.7 mu/l). CONCLUSIONS: Our present data demonstrate that in dilated cardiomyopathy patients with severe left ventricular dysfunction basal IGF-I levels are reduced whereas the IGF-I response to low rhGH doses is preserved. These findings suggest a normal peripheral GH sensitivity in dilated cardiomyopathy. On the other hand, though nocturnal mean GH concentration in dilated cardiomyopathy patients is similar to that in normal subjects, the somatotroph responsiveness to GHRH, but not that to hexarelin, is reduced. Thus, subtle alterations in the activity of GH/IGF-I axis are present in dilated cardiomyopathy.

Thermodynamics of quantum dissipative many-body systems.

We consider quantum nonlinear many-body systems with dissipation described within the Caldeira-Leggett model, i.e., by a nonlocal action in the path integral for the density matrix. Approximate classical-like formulas for thermodynamic quantities are derived for the case of many degrees of freedom, with general kinetic and dissipative quadratic forms. The underlying scheme is the pure-quantum self-consistent harmonic approximation (PQSCHA), equivalent to the variational approach by the Feynman-Jensen inequality with a suitable quadratic nonlocal trial action. A low-coupling approximation permits us to get manageable PQSCHA expressions for quantum thermal averages with a classical Boltzmann factor involving an effective potential and an inner Gaussian average that describes the fluctuations originating from the interplay of quanticity and dissipation. The application of the PQSCHA to a quantum phi(4) chain with Drude-like dissipation shows nontrivial effects of dissipation, depending upon its strength and bandwidth.

Diagnostic accuracy of predicting coronary artery disease related to patients' characteristics.

Patients' demographic and clinical characteristics may affect diagnostic accuracy of cardiologists. We asked a group of experienced cardiologists from three institutions to estimate the pretest probability of coronary artery disease in 257 patients referred for diagnostic coronary angiography and with no history of previous myocardial infarction nor valvular heart disease. Physicians pretest estimates were compared with the diagnostic findings of coronary angiography. We tested the influence of five variables on the accuracy of the pretest estimates: age, sex, chest pain characteristics, rest electrocardiogram and electrocardiographic exercise test result. Cardiologists tended to overestimate the presence of coronary artery disease and this tendency was particularly remarkable in the group of patients showing a negative exercise test. Pretest diagnostic accuracy was 0.72 when the test result was negative and 0.85 when the test result was positive (95% confidence interval of the difference 0.03 to 0.23; p < 0.001). The diagnosis of coronary artery disease was also more accurate for male than for female patients (0.81 vs 0.70; 95% confidence interval of the difference 0.02 to 0.21; p < 0.02). Characteristics of chest pain, age and rest electrocardiogram did not affect the level of pretest diagnostic accuracy. Cardiologists should be cognizant of correctly interpreting a negative exercise test and the clinical data of female patients; in both cases, they should move circumspect of the diagnosis of coronary artery disease.

Value of exercise stress test, radionuclide angiography and coronary angiography in predicting new coronary events in asymptomatic patients after a first episode of myocardial infarction.

One-hundred-and-fifty-five consecutive symptom-free patients underwent maximal treadmill exercise testing, rest and stress radionuclide angiography at least two months after an uncomplicated acute myocardial infarction; of these, 90 underwent coronary angiography. All patients were followed-up for a mean of 32 +/- 13 months regarding the prediction of hard (death and reinfarction) and soft (angina and coronary surgery) coronary events. The specificity, sensitivity, positive and negative predictive value of exercise stress test were 47%, 76% and 41% for any coronary events; none of the patients who incurred a hard coronary event showed ischemia during electrocardiographic exercise tests. Sensitivity, specificity and positive predictive value for failure to increase the ejection fraction of at least 5% were 60%, 45% and 30% for any coronary event and 25%, 49% and 2% for any hard coronary event. The presence of multivessel disease at coronary angiography showed a sensitivity of 62% for any coronary event and of 67% for hard coronary events; specificities were 66% and 57%, and predictive values were 52% and 10%, respectively. It is concluded that electrocardiographic exercise testing, radionuclide angiography and coronary angiography are not helpful two months after an episode of uncomplicated myocardial infarction in order to identify patients who will suffer a new coronary event.

[The midterm clinical results of myocardial revascularization with the internal mammary artery]. / Risultati clinici a medio termine della rivascolarizzazione miocardica con arteria mammaria interna.

After a 3-year (1985-1988) experience of myocardial revascularization using internal mammary artery (AMI) grafts and after having excluded (1986) an higher operative mortality and morbidity, clinical medium-term results have been analysed. The first 144 patients discharged alive after AMI bypass surgery in 1985 were clinically evaluated, with a mean interval of 21 months from surgery (range: 5-29 months). Exercise electrocardiographic test was performed by 100 patients, and angiography repeated in 15. Actuarial survival function was estimated by Cutler-Ederer method: 2-year actuarial survival was 99.3 +/- 0.7% (94 +/- 1.8%, when operative deaths were included). Non fatal myocardial infarction occurred in 3 patients and, at follow-up, 26 were symptomatic for angina: 2 patients underwent re-operation and 2 angioplasty. Two years after AMI bypass surgery, actuarial estimate of ischemic event-free patients was 70.9 +/- 4.5% (67.7 +/- 4.5%, when operative deaths were included): 73 out of 100 exercise tests were negative for both angina and ischemia, although only 43 patients, reached maximal work load; 9 were positive for both angina and ischemia and 18 for ischemia only. All patients who underwent angiographic evaluation (15 patients, 11 of whom because of angina relapse) had AMI grafts open, while in only 4 patients all the implanted grafts were open.

Results of total correction of tetralogy of Fallot performed in adults.

Today, total correction of tetralogy of Fallot is rarely performed in adults. In a 10-year period, 40 patients aged 20 to 67 years underwent intracardiac repair in our institution. Twenty-eight of them had had a palliative procedure 11 to 30 years earlier. Preoperatively, 23 patients were in New York Heart Association (NYHA) Functional Class II, 14 were in Class III, and 3 were in Class IV. Operative mortality was 2.5% (1/40). Follow-up ranged from 1 year to 11 years (average, 3 years). One patient died of a noncardiac cause 4 years after operation. Residual cardiac defects were observed in 4 patients. Postoperatively, 30 patients were in NYHA Functional Class I, 8 were in Class II, and 1 was in Class III. Major ventricular arrhythmias were recorded in 7 (35%) of 20 patients. Radionuclide angiography demonstrated impaired right ventricular function in 8 patients. Left ventricular impairment was present in 2. Total correction of tetralogy of Fallot can be performed safely in adults with low mortality and good functional improvement. The incidence of residual cardiac defects is low. The long-term importance of impaired ventricular function and arrhythmias remains to be ascertained.

[Comparison of two-dimensional echocardiography, angiocardioscintigraphy and cineventriculography in the study of left ventricular wall motion in ischemic cardiopathy]. / Confronto tra ecocardiografia bidimensionale, angiocardioscintigrafia e cineventricolografia nello studio della motilità di parete del ventricolo sinistro nella cardiopatia ischemica.

Thirty-two patients with non acute myocardial infarction (inferior in twenty, anterior in ten, anterior and inferior in two) were studied with contrast left ventriculography, two-dimensional echocardiography and radionuclide angiography to assess left ventricular wall motion. We adopted the CASS criteria for the standard left ventriculography, and the Mayo Clinic classification for the echocardiographic study. Radionuclide angiography studies were obtained in left anterior oblique view; the images were evaluated with the use of Walsh-Hadamard transform; the left ventricle was divided in basal and apical septal, apical, posterolateral, posterobasal and two central segments. We tried to correlate the findings of the three techniques both for single segments and larger regions made of contiguous segments. Left ventricular angiography and two-dimensional echocardiography showed a fair concordance for both anterobasal and posterolateral left ventricular wall, whereas for the septal, apical and posterolateral regions contrast and radionuclide angiography had the best correlation. Compared to left ventricular angiography two-dimensional echocardiography shows better sensitivity than radionuclide angiography; the latter is more specific in defining left ventricular wall motion. The two non invasive techniques are therefore helpful in the evaluation of wall motion and their role is complementary.

Use of radionuclide angiography and an electrocardiographic stress test to diagnose multivessel disease after a first episode of uncomplicated myocardial infarction.

Sixty consecutive patients who were symptom free 2-12 months after an uncomplicated acute myocardial infarction underwent maximal treadmill exercise testing, radionuclide angiography before and during submaximal bicycle stress test, and coronary angiography. The results of the non-invasive procedures were compared with those of coronary angiography. The sensitivity and specificity of electrocardiogram stress test for detection of multivessel disease were 40% and 77% respectively. Failure of left ventricular ejection fraction to increase at least 5% with exercise identified 20 of the 25 patients with multivessel disease (sensitivity 80%) and 23 of the 35 patients with no additional coronary artery stenosis (specificity 66%). In patients with anterior Q waves the sensitivity was 78% and the specificity 50%, whereas in the presence of inferior Q waves these values were 81% and 87% respectively. Loss of left ventricle synchronicity during effort, as indicated by failure of the standard deviation of the phases to decrease during exercise, demonstrated a radionuclide angiography sensitivity of 80% (77% for anterior myocardial infarction and 81% for inferior myocardial infarction) and a specificity of 50% (33% for anterior myocardial infarction and 64% for inferior myocardial infarction). When the test was considered to be positive if either the ejection fraction or the standard deviation of the phases criteria were positive, the sensitivity was 100% and specificity 46% (30% for anterior myocardial infarction and 65% for inferior myocardial infarction). It is concluded that in patients who are free from angina 2-12 months after an episode of uncomplicated myocardial infarction, a simple exercise electrocardiogram cannot be relied upon to detect residual ischaemia. An abnormal ejection fraction response or an increased standard deviation of the phases during exercise nuclear angiography or both identified all the patients with multivessel disease. None of the patients in whom radionuclide angiographic criteria were negative had multivessel disease.

[Evaluation of calcium metabolism and pituitary gonadotropin secretion during treatment with nifedipine]. / Valutazione del metabolismo del calcio e della secrezione gonadotropinica ipofisaria durante trattamento con nifedipinia.

The clinical use of calcium antagonist drugs in cardiology theoretically may interfere with the endocrine secretions. Actually the calcium ion appears to be primarily involved in the stimulus-secretion and excitation-contraction coupling. This paper is to evaluate the influence, in vivo, of nifedipine on calcium metabolism, FSH and LH secretions. The level of plasmatic calcium, parathyroid hormone (PTH), and FSH, LH secretion were observed in seven patients under cronic nifedipine treatment. The plasmic level of the hormones under investigation was tested with radioimmunoassay method. Neither calcium nor hormone levels had significant variations during the 28 days control period. From our data we can infer that long term treatment with nifedipine has no influence on calcium metabolism nor on gonadotropic hormones secretions, even though such an influence has been demonstrated in "in vivo" studies.