Machine learning classification of OARSI-scored human articular cartilage using magnetic resonance imaging.

OBJECTIVE: The purpose of this study is to evaluate the ability of machine learning to discriminate between magnetic resonance images (MRI) of normal and pathological human articular cartilage obtained under standard clinical conditions. METHOD: An approach to MRI classification of cartilage degradation is proposed using pattern recognition and multivariable regression in which image features from MRIs of histologically scored human articular cartilage plugs were computed using weighted neighbor distance using compound hierarchy of algorithms representing morphology (WND-CHRM). The WND-CHRM method was first applied to several clinically available MRI scan types to perform binary classification of normal and osteoarthritic osteochondral plugs based on the Osteoarthritis Research Society International (OARSI) histological system. In addition, the image features computed from WND-CHRM were used to develop a multiple linear least-squares regression model for classification and prediction of an OARSI score for each cartilage plug. RESULTS: The binary classification of normal and osteoarthritic plugs yielded results of limited quality with accuracies between 36% and 70%. However, multiple linear least-squares regression successfully predicted OARSI scores and classified plugs with accuracies as high as 86%. The present results improve upon the previously-reported accuracy of classification using average MRI signal intensities and parameter values. CONCLUSION: MRI features detected by WND-CHRM reflect cartilage degradation status as assessed by OARSI histologic grading. WND-CHRM is therefore of potential use in the clinical detection and grading of osteoarthritis.

aEEG in preterm infants.

Over the last decade, the survival of premature babies has improved dramatically. Such infants, especially those with extremely low birth weight, are still affected by dangerous complications occurring during the neonatal period that often cause brain damage. Intraventricular-intraparenchymal haemorrhage (IVH-IPH), periventricular leukomalacia (PVL), seizures, meningitis and hypoxic-ischaemic encephalopathy are the most common complications. Such problems require more specialized monitoring of brain function during this critical period. In recent years, many studies on very premature infants have shown that aEEG has a high predictive value for both short-term and long-term outcome. In fact, it has been proven that some types of background activity patterns, the absence of a sleep-wake cycle, and seizure activity are related to the onset of early complications such as IVH-IPH and PVL. Most recent studies have shown that an aEEG performed in the early hours or during the first days of life can predict the neurobehavioural development of preterm infants at 2 years and 3 years (Bayley Scale). In particular our study demonstrates that loss of sleep-wake cycling, shown by aEEG, has a high positive predictive value for the development of posthaemorrhagic hydrocephalus (PPH) in preterm infants with IVH; therefore, the study of cerebral background activity and in particular of sleep-wake cycling can be used as an early prognostic tool in patients at risk of PPH.

A novel angiopoietin-derived peptide displays anti-angiogenic activity and inhibits tumour-induced and retinal neovascularization.

BACKGROUND AND PURPOSE: Pathological angiogenesis is associated with various human diseases, such as cancer, autoimmune diseases and retinopathy. The angiopoietin (Ang)-Tie2 system plays critical roles in several steps of angiogenic remodelling. Here, we have investigated the anti-angiogenic effect of a novel angiopoietin-derived peptide. EXPERIMENTAL APPROACH: Using computational methods, we identified peptides from helical segments within angiopoietins, which were predicted to inhibit their activity. These peptides were tested using biochemical methods and models of angiogenesis. The peptide with best efficacy, A11, was selected for further characterization as an anti-angiogenic compound. KEY RESULTS: The potent anti-angiogenic activity of A11 was demonstrated in a multicellular assay of angiogenesis and in the chorioallantoic membrane model. A11 bound to angiopoietins and reduced the binding of Ang-2 to Tie2. A11 was also significantly reduced vascular density in a model of tumour-induced angiogenesis. Its ability to inhibit Ang-2 but not Ang-1-induced endothelial cell migration, and to down-regulate Tie2 levels in tumour microvessels, suggests that A11 targets the Ang-Tie2 pathway. In a rat model of oxygen-induced retinopathy, A11 strongly inhibited retinal angiogenesis. Moreover, combination of A11 with an anti-VEGF antibody showed a trend for further inhibition of angiogenesis, suggesting an additive effect. CONCLUSIONS AND IMPLICATIONS: Our results indicate that A11 is a potent anti-angiogenic compound, through modulation of the Ang-Tie2 system, underlining its potential as a therapeutic agent for the treatment of ocular and tumour neovascularization, as well as other pathological conditions that are dependent on angiogenesis.

Prognostic role of B-type natriuretic peptide in patients with diabetes and acute decompensated heart failure.

BACKGROUND: Several studies have reported the prognostic value of natriuretic peptides, but their predictive value in patients with diabetes mellitus is unknown. The aim of the study was to test the hypothesis that measurement of brain natriuretic peptide (BNP) levels in ambulatory patients with congestive heart failure (CHF) and diabetes can predict the occurrence of cardiovascular events at 6-month follow-up. METHODS: We enrolled 145 consecutive patient with diabetes [age 72 +/- 9 years, hypertension (21%), ischaemic heart disease (52%), atrial fibrillation (22%), preserved left ventricular function (29%)] seen in the outpatient heart failure clinic after an acute episode of cardiac failure. RESULTS: The median (25th/75th interquartile range) BNP concentrations at discharge were 186 (75-348) pg/ml. At 6-month clinical follow-up 10/145 (7%) subjects had died and 31/145 (21%) had been readmitted because of cardiac decompensation. BNP values of 200 and 500 pg/ml were found to have the best compromise between sensitivity (88 and 46%, respectively) and specificity (71 and 89%, respectively) for predicting events at 6 months. Multivariate Cox regression analysis identified only two parameters as predictors of events: serum creatinine [hazard ratio (HR) = 3.3; P = 0.02], and BNP plasma level BNP cut-off values (HR = 3.8; P = 0.03 for 201-499 pg/ml and HR = 7.7; P = 0.001 for > or = 500 pg/ml). CONCLUSION: These results suggest that BNP and serum creatinine are strong predictors of clinical events in patients with diabetes and CHF. In these patients, clinical outcome might be stratified by plasma BNP levels.

Relationship between B-type natriuretic peptide levels and ventilatory response during cardiopulmonary exercise test in patients with chronic heart failure.

AIM: Aim of the study was to evaluate if brain natriuretic peptide (BNP) levels, a cardiac neurohormone well correlated with prognosis in chronic heart failure (CHF), are associated with enhanced ventilatory response to exercise, in ambulatory patients with intermediate peak oxygen uptake (PVO2). METHODS: Resting BNP was measured in 129 consecutive stable CHF patients with mild to moderate heart failure (90% New York Heart Association (NYHA) class II or III) and intermediate (10-18 mL/kg/min) PVO2, assessed during cardiopulmonary exercise test. Mean (SD) left ventricular ejection fraction (EF) and pulmonary systolic pressure (PAP) were 41 +/- 3% and 47 +/- 14 mmHg, respectively. The enhanced ventilatory response to exercise (EVR) was assessed as a slope of the relation between minute ventilation and carbon dioxide production (VE/VCO2 slope) > 35. RESULTS: Thirty-three over 129 patients (26%) had EVR. Mean BNP plasma level was 394 +/- 347 pg/mL. A significant correlation between BNP and EVR (r = 0.310; p < 0.01), was observed. In the logistic multivariate model, a BNP plasma level > 100 pg/mL had an independent predictive value for EVR (95% IC 1.68 to 10.5, Odds Ratio 4.23, p = 0.02). We found a significant correlation between BNP and PAP (r = 0.390; p < 0.001), and between PAP and EVR (r = 0.511; p < 0.01). CONCLUSIONS: In CHF patients with intermediate PVO2, plasma BNP is clearly related to the enhanced ventilatory response to exercise. In this subset, BNP levels could represent an effective alternative tool for the clinical assessment in patients with unreliable cardiopulmonary exercise test.

Influence of contractile reserve and inducible ischaemia on left ventricular remodelling after acute myocardial infarction.

OBJECTIVE: To assess the relative influence of contractile reserve and inducible ischaemia on subsequent left ventricular volume changes after myocardial infarction. DESIGN: Left ventricular end diastolic and end systolic index volumes were calculated prospectively at discharge and at six months in 143 patients referred for early postinfarction dobutamine stress echocardiography. On the basis of their responses to this test, patients were divided into three groups: scar (n = 48; group 1); contractile reserve (n = 36; group 2); inducible ischaemia (n = 59; group 3). RESULTS: At six months, the left ventricular end diastolic index volume decreased in group 2 (mean (SD), -3.9 (9.4) ml/m2) and increased in both group 1 (+2.8 (10.6) ml/m2, p = 0.009 v group 2) and group 3 (+7.5 (11.4) ml/m2, p < 0.0001 v group 2). The end systolic index volume decreased in group 2 (-4.9 (7.3) ml/m2) and increased in both group 1 (+1.3 (8.3) ml/m2, p = 0.0015 v group 2) and group 3 (+2.8 (8.9) ml/m2, p = 0.0002 v group 2). In multivariate analysis, the contractile reserve (hazard ratio 0.19, 95% confidence interval (CI) 0.14 to 0.47), inducible ischaemia (5.86, 95% CI 1.54 to 29.7), and end systolic index volume at discharge (1.04, 95% CI 0.99 to 1.11) were independent predictors of an increase in end diastolic index volume of > or = 15 ml/m2 at six months. CONCLUSIONS: Contractile reserve and inducible ischaemia, as detected by early dobutamine stress echocardiography, identify patients with differences in long term left ventricular remodelling after acute myocardial infarction.

Unfavourable left ventricular remodelling in patients with dobutamine-inducible ischaemia after acute myocardial infarction.

AIMS: Aim of the study was to assess the role of early inducible ischaemia for determining left ventricular remodelling in patients with acute myocardial infarction. METHODS AND RESULTS: In 179 consecutive patients with first myocardial infarction the occurrence of new wall motion abnormalities during dobutamine stress echocardiography at discharge was related to the left ventricular volume changes at 6 months. Left ventricular end-diastolic and end-systolic index volumes (mL/m(2)) were echocardiographically detected at discharge and at 6 months and the relative changes were calculated. The study population consisted of 105 patients without and 74 patients with inducible ischaemia; of these, 46 patients had > or =4 ischaemic segments. At 6 months, the end-diastolic index volume increased in patients with inducible ischaemia compared to patients without (+7.5+/-11.2 vs -0.1+/-10.2 mL/m(2); P=0.0049) and final mean end-diastolic volume was greater in patients with inducible ischaemia than without (70.8+/-16.0 vs 61.1+/-17.0 mL/m(2); P=0.0012). The end-systolic volume increased at 6 months in patients with inducible ischaemia and it decreased in patients without (+2.8+/-8.6 vs -1.4+/-7.8 mL/m(2); P=0.021). At the multivariate analysis, inducible ischaemia in > or =4 segments (odds ratio=6.43), the wall motion score index at the peak of dobutamine infusion (odds ratio=1.14) and the end-systolic index volume at discharge (odds ratio=1.06) were independent predictors of subsequent left ventricular end-diastolic index volume increase > or =15 mL/m(2). CONCLUSION: In patients with first myocardial infarction the presence and the severity of inducible ischaemia, as detected by dobutamine stress echocardiography at discharge, indicates an unfavourable left ventricular remodelling.

Effect of early treatment with captopril and metoprolol singly and together on postinfarction left ventricular remodeling.

BACKGROUND: beta-Blockers improve clinical outcome after acute myocardial infarction (AMI), but few data are available on their effectiveness in preventing left ventricular remodeling. The aim of the study was to assess the relative effects of captopril, metoprolol, and their combination on left ventricular remodeling after uncomplicated AMI. METHODS: Two hundred fifty consecutive patients with a first AMI were randomly allocated to receive for 6 months captopril (up to 75 mg/d, group 1), metoprolol (up to 200 mg/d, group 2), or both (group 3) starting within 24 hours from symptom onset. Of these, 130 patients (group 1, 46; group 2, 47; group 3, 37) completed the study; all patients underwent 2-dimensional echocardiography at baseline and after 2 weeks and 3 and 6 months from AMI. RESULTS: At 6 months, in comparison with baseline values, left ventricular end-diastolic area index (LVEDI) significantly increased in group 3 (P =.013) and wall motion score index significantly decreased in group 1 (P =.038). At any follow-up evaluation, the covariance analysis showed significantly greater interval changes in LVEDI in group 3 than in group 1 (P =.0077 at 2 weeks, P =.0108 at 3 months, and P = 0.0155 at 6 months). No significant differences were observed between group 1 and group 2 and between group 2 and group 3. CONCLUSIONS: After uncomplicated first AMI, early and long-term treatment with captopril alone attenuates left ventricular remodeling better than its combination with metoprolol. In the head-to-head captopril versus metoprolol therapy strategy comparison, captopril alone seems more effective in reducing postinfarction enlargement, but a definite difference was not demonstrated.

Prognostic value of pharmacologic stress echocardiography in patients with left bundle branch block.

PURPOSE: Although coronary artery disease is a frequent cause of left bundle branch block, the prognostic value of myocardial ischemia in patients with this conduction abnormality has not been defined. We investigated the value of pharmacologic stress echocardiography in risk stratification of patients with left bundle branch block. PATIENTS AND METHODS: Three hundred eighty-seven patients [230 men and 157 women, mean (+/- SD) age, 64 +/- 9 years] with complete left bundle branch block on the resting electrocardiogram underwent dobutamine (n = 217) or dipyridamole (n = 170) stress echocardiography to evaluate suspected or known coronary artery disease. A summary wall motion score (on a one to four scale) was calculated. The primary end points were cardiac death and nonfatal myocardial infarction. RESULTS: A positive echocardiographic result (evidence of ischemia) was detected in 109 (28%) patients. During a mean follow-up of 29 +/- 26 months, there were 21 cardiac deaths and 20 myocardial infarctions, 63 patients underwent coronary revascularization, and 1 patient received a heart transplant. In a multivariate analysis, four clinical and echocardiographic variables were associated with increased risk of cardiac death: resting wall motion score index [hazard ratio (HR) = 7.5 per unit; 95% confidence interval (CI), 2.8 to 20; P = 0.001], previous myocardial infarction (HR = 2.9; 95% CI, 1.1 to 7.3; P = 0.02), diabetes (HR = 2.7; 95% CI, 1.1 to 6.6; P = 0.03), and the change in wall motion score index from rest to peak stress (HR = 3.0 per unit; 95% CI, 1.0 to 8.6; P = 0.04). The 5-year survival was 77% in the ischemic group and 92% in the nonischemic group (P = 0.02). Four variables were associated with increased risk of cardiac death or infarction: previous myocardial infarction (HR = 3.4; 95% CI, 1.7 to 6.8; P = 0.0005), diabetes (HR = 2.4; 95% CI, 1.2 to 4.6; P = 0.01), resting wall motion score index (HR = 2.2 per unit; 95% CI, 1.1 to 4.1; P = 0.02), and positive echocardiographic result (HR = 2.2; 95% CI, 1.1 to 4.5; P = 0.03). The 5-year infarction-free survival was 60% in the ischemic group and 87% in the nonischemic group (P < 0.0001). Stress echocardiography significantly improved risk stratification in patients without previous myocardial infarction (P = 0.0001), but not in those with previous myocardial infarction (P = 0.08). In particular, it provided additional value over clinical and resting echocardiographic findings in predicting cardiac events among patients without previous infarction. CONCLUSIONS: Myocardial ischemia during pharmacologic stress echocardiography is a strong prognostic predictor in patients with left bundle branch block, particularly in those without previous myocardial infarction.

Safety, feasibility, and prognostic implications of pharmacologic stress echocardiography in 1482 patients evaluated in an ambulatory setting.

BACKGROUND: The outpatient prognostic assessment of coronary artery disease (CAD) by exercise electrocardiography has limitations, including the feasibility of the test and its low positive predictive value in several clinical conditions. In the current study we investigated the safety, feasibility, and prognostic value of pharmacologic stress echocardiography in a large cohort of ambulatory patients. METHODS: The study group was made of 1482 ambulatory patients (969 men, aged 60 +/- 10 years) who underwent stress echocardiography with either dipyridamole (n = 846) or dobutamine (n = 636) for evaluation of suspected or known stable CAD. The pretest likelihood of CAD was intermediate (<70%) in 709 patients and high (> or =70%) in 773 patients. RESULTS: There was no complication during the dipyridamole test, whereas 2 ischemia-dependent, sustained ventricular tachycardias occurred during the dobutamine test. Limiting side effects were observed in 2% of dipyridamole and in 3% of dobutamine stresses. The echocardiogram was positive in 459 patients. During a mean follow-up of 28 +/- 24 months, 58 patients died, 33 had a nonfatal myocardial infarction, and 158 underwent early (< or =3 months) and 64 late (>3 months) revascularization. Multivariate predictors of hard events (death, infarction) were positive echocardiographic results (hazard ratio [HR] 2.9) and resting wall motion score index (WMSI) (HR 2.3). In considering major events (death, infarction, late revascularization) as end points, positive echocardiographic result (HR 4.3), scar (HR 2.2), and resting WMSI (HR 1.7) were independent prognostic predictors. The 5-year survival rates for the ischemic and nonischemic groups were, respectively, 80% and 91% (HR 3.6, 95% confidence interval [CI] 3.8-8.4; P <.0001) considering hard cardiac events and 65% and 88% (HR 2.6, 95% CI 2.1-5.9; P <.0001) considering major events. Multivariate predictors of major events were positive echocardiographic results (HR 8.2) and male sex (HR 2.5) for the intermediate-risk group and positive echocardiographic results (HR 2.9), resting WMSI (HR 1.8), and prior Q-wave myocardial infarction (HR 1.8) for the high-risk group. CONCLUSIONS: Pharmacologic stress echocardiography is safe, highly feasible, and effective in prognostic assessment of ambulatory patients when both a general population and groups selected on the basis of pretest likelihood of CAD are analyzed. It represents a valid complementary tool to exercise electrocardiography for prognostic purposes in outpatients.

Incremental prognostic value of stress echocardiography as an adjunct to exercise electrocardiography after uncomplicated myocardial infarction.

OBJECTIVE: To assess the prognostic value of stress echocardiography as an adjunct to exercise electrocardiography in patients with uncomplicated acute myocardial infarction. DESIGN: 496 patients underwent a maximum exercise ECG and pharmacological stress echocardiography (406 dobutamine and 90 dipyridamole) within 15 days of uncomplicated acute myocardial infarction and were followed for a mean of 25 months (range 1-74 months) for reinfarction, unstable angina, and cardiac death. Patients undergoing revascularisation were omitted. RESULTS: Exercise ECG was positive in 162 patients (32.6%) and low threshold positive (< 100 W) in 91 (18%). Stress echocardiography was positive in 239 patients (48%) (194 with dobutamine and 45 with dipyridamole stress). The agreement between the two tests was 63% (kappa = 0.24, 95% confidence interval 0.15 to 0.33). Sixty nine spontaneous events occurred (14 cardiac deaths, 26 reinfarctions, and 29 with unstable angina requiring hospital admission), and 126 patients underwent revascularisation (39 coronary angioplasty and 87 bypass surgery). By receiver operating characteristic curve analysis, stress echocardiography provided incremental prognostic information compared with clinical data. A low threshold positive exercise ECG was associated with a worse outcome, but there was a fivefold increase in risk in patients with positive stress echocardiography who also had a high threshold (> 100 W) positive exercise ECG. Event-free survival of patients with both tests positive was significantly less than in patients with only one positive test or with both tests negative. CONCLUSIONS: Stress echocardiography provides additional prognostic information after uncomplicated acute myocardial infarction, but the greatest gain is found in patients with a high threshold positive exercise ECG.

Prognostic interaction between viability and residual myocardial ischemia by dobutamine stress echocardiography in patients with acute myocardial infarction and mildly impaired left ventricular function.

Dobutamine stress echocardiography (DSE) accurately detects viable myocardium and residual ischemia in patients with acute myocardial infarction (AMI). The prognostic interaction of viability and ischemia has not been completely clarified in these patients. This study assesses the long-term effect of viability, ischemia, or their combination on survival in patients with AMI and mildly impaired left ventricular (LV) function. Four hundred eleven patients (age 57 +/- 9 years) underwent predischarge DSE (up to 40 microg/kg/min plus atropine if needed) after uncomplicated AMI and were prospectively followed for 23 months (range 1 to 78). According to DSE findings, patients were divided into 4 groups: viability only, ischemia only, combination of viability and ischemia, and scar. Adverse outcome occurred in 64 patients: 34 patients had hard events (9 cardiac deaths, 25 nonfatal AMI) and 30 patients had unstable angina requiring hospitalization. The combination of viability and ischemia, diabetes mellitus, and non-Q-wave AMI were significant predictors of all events at univariate and multivariate analysis. The same variables were also univariate predictors of hard events, but multivariate analysis indicated only the combination of viability and ischemia and diabetes as independent predictors. The event-free survival of patients with combined viability and ischemia was significantly lower (hazard ratio 3 [95% confidence interval 1.8 to 11]) compared with patients with ischemia only. Thus, viability and ischemia show a significant adverse prognostic interaction in patients with AMI and preserved LV function.

Triarylpyrazoles with basic side chains: development of pyrazole-based estrogen receptor antagonists.

Recently, we developed a novel triaryl-substituted pyrazole ligand system that has high affinity for the estrogen receptor (ER) (Fink, B. E.: Mortenson, D. S.: Stauffer, S. R.; Aron, Z. D.: Katzenellenbogen, J. A. Chem. Biol. 1999, 6, 205). Subsequent work has shown that some analogues in this series are very selective for the ERalpha subtype in terms of binding affinity and agonist potency (Stauffer, S. R.: Coletta, C. J.: Tedesco. R.: Sun, J.: Katzenellenbogen, J. A. J. Med. Chem. 2000, submitted). We now investigate how this pyrazole ER agonist system might be converted into an antagonist or a selective estrogen receptor modifier (SERM) by incorporating a basic or polar side chain like those typically found in antiestrogens and known to be essential determinants of their mixed agonist/antagonist character. We selected an N-piperidinyl-ethyl chain as a first attempt, and introduced it at the four possible sites of substitution on the pyrazole core structure to determine the orientation that the pyrazole might adopt in the ER ligand binding pocket. Of these four, the C(5) piperidinyl-ethoxy-substituted pyrazole 5 had by far the highest affinity. Also, it bound to the ER subtype alpha (ERalpha) with 20-fold higher affinity than to ERbeta. In cell-based transcription assays, pyrazole 5 was an antagonist on both ERalpha and ERbeta, and it was also more potent on ERalpha. Based on structure-binding affinity relationships and on molecular modeling studies of these pyrazoles in a crystal structure of the ERalpha-raloxifene complex, we propose that pyrazoles having a basic substituent on the C(5) phenyl group adopt a binding mode that is different from that of the pyrazole agonists that lack this group. The most favorable orientation appears to be one which places the N(1) phenol in the A-ring binding pocket so that the basic side chain can adopt an orientation similar to that of the basic side chain of raloxifene.

Estrogen pyrazoles: defining the pyrazole core structure and the orientation of substituents in the ligand binding pocket of the estrogen receptor.

Previously, we reported that certain tetrasubstituted 1,3,5-triaryl-4-alkyl-pyrazoles bind to the estrogen receptor (ER) with high affinity (Fink, B. E.; Mortenson, D. S.; Stauffer, S. R.; Aron, Z. D.; Katzenellenbogen, J. A. Chem. Biol. 1999, 6, 205-219; Stauffer, S. R.; Katzenellenbogen, J. A. J. Comb/. Chem. 2000, 2. 318 329; Stauffer, S. R.: Coletta, C. J.: Sun, J.; Tedesco, R., Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med. Chem. 2000, submitted). To investigate how cyclic permutation of the two nitrogen atoms of a pyrazole might affect ER binding affinity, we prepared a new pyrazole core isomer, namely a 1,3,4-triaryl-5-alkyl-pyrazole (2), to compare it with our original pyrazole (1). We also prepared several peripherally matched core pyrazole isomer sets to investigate whether the two pyrazole series share a common binding orientation. Our efficient, regioselective synthetic route to these pyrazoles relies on the acylation of a hydrazone anion, followed by cyclization, halogenation, and Suzuki coupling. We found that the ER accommodates 1,3,4-triaryl-pyrazoles of the isomeric series only somewhat less well than the original 1,3,5-triaryl series, and it appears that both series share a common binding mode. This preferred orientation for the 1,3,5-triaryl-4-alkyl-pyrazoles is supported by binding affinity measurements of analogues in which the phenolic hydroxyl groups were systematically removed from each of the three aryl groups, and the orientation is consistent, as well, with molecular modeling studies. These studies provide additional insight into the design of heterocyclic core structures for the development of high affinity ER ligands by combinatorial methods.

[The effect of cardiovascular rehabilitation on the variability of the RR cycle after a first uncomplicated acute myocardial infarct]. / Effetto della riabilitazione cardiovascolare sulla variabilità del ciclo RR dopo un primo infarto miocardico acuto non complicato.

BACKGROUND: The aim of this study was to verify the changes in the autonomic balance by means of heart rate variability assessment in patients with myocardial infarction referred for cardiac rehabilitation. METHODS: We studied 122 patients (79 males, 43 females, mean age 56 +/- 5 years), with a first uncomplicated myocardial infarction (anterior 48, thrombolysis 72), Killip class 1, preserved left ventricular function (ejection fraction 49 +/- 6%). All patients were free of inducible residual ischemia. Four weeks after myocardial infarction, patients were randomized into two groups; Group 1 (n = 58) referred for an 8 week cardiac rehabilitation program (scheduled: 24 sessions); Group 2 (n = 64): normal daily physical activity. During a 24-hour Holter ECG monitoring the following parameters were calculated in pharmacological wash-out at randomization (T0) and at the end of cardiac rehabilitation/control period (T1): mean value of RR intervals (RR), its standard deviation (SDNN), pNN50, rMSSD in the time domain; low frequency (LF) and high frequency (HF) value and the LF/HF ratio in the frequency domain. T1-T0 changes in percent values (delta %) were considered and compared between the two groups. RESULTS: Thirty-one patients were excluded from the study either for insufficient adhesion to the cardiac rehabilitation program (< 13 sessions, 22 patients) or recurrent ischemia (3 Group 1 patients and 3 Group 2 patients) and non-assessable 24-hour Holter ECG monitoring (3 patients). Thirty-one Group 1 patients and 60 Group 2 patients completed the study with a first and a second 24-hour Holter ECG monitoring performed at 30 +/- 3 days and 60 +/- 4 days respectively. At the same time an ergospirometric test was performed to evaluate cardiopulmonary function by means of exercise time, maximum oxygen consumption, anaerobic threshold, exercise time at the anaerobic threshold, and maximum oxygen consumption at the anaerobic threshold. Twenty-eight Group 1 patients and 44 Group 2 patients completed the study with a first and a second ergospirometric test. Baseline heart rate variability parameters were comparable in the two groups. During the observation period only in Group 1 patients heart rate variability parameters changed significantly: RR (Group 1 = +18.3 +/- 21.3; Group 2 = +4.2 +/- 5.2, p = 0.000), pNN50 (Group 1 = 45.0 +/- 38.9; Group 2 = +24.2 +/- 34.7, p = 0.011), HF (Group 1 = +81.6 +/- 124; Group 2 = -28.7 +/- 75.4, p = 0.014) and LF/HF ratio (Group 1 = -26.0 +/- 16.1; Group 2 = -4.9 +/- 6.1, p = 0.062). There were no significant differences in SDNN, rMSSD and LF. A linear correlation between delta LF/HF ratio and baseline LF/HF ratio values was found in Group 1 (r = 0.489, p = 0.006), whereas no correlation was found between this parameter and age, ejection fraction, creatine phosphokinase, and infarct localization. Group 1 patients had a significant improvement in exercise tolerance compared to Group 2 patients. CONCLUSIONS: A cardiac rehabilitation program positively modifies the sympatho-vagal balance in patients with uncomplicated myocardial infarction, increasing the parasympathetic tone and exercise tolerance.

Pyrazole ligands: structure-affinity/activity relationships and estrogen receptor-alpha-selective agonists.

We have found that certain tetrasubstituted pyrazoles are high-affinity ligands for the estrogen receptor (ER) (Fink et al. Chem. Biol. 1999, 6, 205-219) and that one pyrazole is considerably more potent as an agonist on the ERalpha than on the ERbeta subtype (Sun et al. Endocrinology 1999, 140, 800-804). To investigate what substituent pattern provides optimal ER binding affinity and the greatest enhancement of potency as an ERalpha-selective agonist, we prepared a number of tetrasubstituted pyrazole analogues with defined variations at certain substituent positions. Analysis of their binding affinity pattern shows that a C(4)-propyl substituent is optimal and that a p-hydroxyl group on the N(1)-phenyl group also enhances affinity and selectivity for ERalpha. The best compound in this series, a propylpyrazole triol (PPT, compound 4g), binds to ERalpha with high affinity (ca. 50% that of estradiol), and it has a 410-fold binding affinity preference for ERalpha. It also activates gene transcription only through ERalpha. Thus, this compound represents the first ERalpha-specific agonist. We investigated the molecular basis for the exceptional ERalpha binding affinity and potency selectivity of pyrazole 4g by a further study of structure-affinity relationships in this series and by molecular modeling. These investigations suggest that the pyrazole triols prefer to bind to ERalpha with their C(3)-phenol in the estradiol A-ring binding pocket and that binding selectivity results from differences in the interaction of the pyrazole core and C(4)-propyl group with portions of the receptor where ERalpha has a smaller residue than ERbeta. These ER subtype-specific interactions and the ER subtype-selective ligands that can be derived from them should prove useful in defining those biological activities in estrogen target cells that can be selectively activated through ERalpha.

Coronary flow reserve of normal left anterior descending artery in patients with ischemic heart disease: A transesophageal Doppler study.

The aim of this study was to investigate the flow reserve of a normal left anterior descending coronary artery (LAD) in patients with coronary artery disease (CAD) of other epicardial vessels by Doppler transesophageal echocardiography (TEE). Thirty-one consecutive patients (age 59 +/- 8 years; 23 men) referred for TEE were considered. Eighteen patients had CAD and a 70% or greater LAD stenosis (group 1); 13 patients had right and/or circumflex CAD (>/=70% stenosis) and normal or minimally diseased LAD (group 2). Ten patients (age 54 +/- 11 years) with normal coronary arteries constituted group 3. Baseline and adenosine (0.160 microg/kg per minute intravenously over 60 minutes) flow velocities in the LAD were measured by pulsed Doppler examination during TEE. Peak and mean systolic and diastolic flow velocities were calculated. Adenosine/baseline peak and mean velocity ratios were used for evaluating blood flow reserve in the LAD. Heart rate and arterial pressure values were similar in the 3 groups at baseline and during adenosine infusion. Baseline and adenosine-related flow velocities were comparable in the 3 groups. Peak and mean diastolic velocity ratios were lower in groups 1 and 2 compared with group 3 (peak velocity ratio 1.68 +/- 0.81 and 1.93 +/- 0.35 vs 2.62 +/- 0.32, P <. 05; mean velocity ratio 1.71 +/- 0.86 and 2.01 +/- 0.41 vs 2.84 +/- 0.74, P <.05), whereas no differences were found between groups 1 and 2. No significant differences were found in systolic flow velocity ratios among the 3 groups. Patients with ischemic heart disease have a reduced diastolic flow velocity reserve in the LAD independent from the presence of significant LAD stenosis. Thus the adenosine TEE-Doppler study should be considered a screening test for CAD rather than for LAD disease.