Markers of inflammation, thrombosis and endothelial activation correlate with carotid IMT regression in stable coronary disease after atorvastatin treatment.

BACKGROUND AND AIMS: MIAMI is a prospective multicenter clinical study designed to investigate the relationship between changes in carotid intima-media thickness (C-IMT) and changes in circulating markers of inflammation, thrombosis and endothelial activation in stable coronary patients treated for 20+/-3.7 months with 20mg/day atorvastatin. METHODS AND RESULTS: Eighty-five subjects had their C-IMT, blood lipids and soluble markers measured at baseline, at the 12th month and at the end of the study. Almost all soluble markers decreased upon treatment except for high-sensitivity C-reactive protein (hs-CRP), interleukin-18 (IL-18), tissue factor pathway inhibitor-free (TFPI-free) and soluble vascular cell adhesion molecules-1 (sVCAM-1) which did not change significantly, and interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and soluble CD40 ligand (sCD40L) which increased. sCD40L, fibrinogen, tissue factor pathway inhibitor-total (TFPI-total), soluble intercellular adhesion molecules-1 (sICAM-1), sE-selectin, interleukin-8 (IL-8) and von Willebrand factor (vWF) changed significantly even after application of the Bonferroni correction for multiple comparisons. Changes in lipids did not correlate with C-IMT regression either when considered singly or when combined in a lipid score. Changes in soluble markers correlated poorly with C-IMT regression when analyzed singly, but strongly when combined in relevant composite scores (inflammation/coagulation score, endothelial activation score, soluble markers score and total score). CONCLUSION: In patients with stable coronary artery disease treated with moderate doses of atorvastatin, carotid IMT regression correlated with changes of inflammation, thrombosis and endothelial activation profiles.

E-selectin and TFPI are associated with carotid intima-media thickness in stable IHD patients: the baseline findings of the MIAMI study.

OBJECTIVE: MIAMI was a prospective multicenter clinical study designed to investigate the relationship between changes in carotid intima-media thickness (C-IMT) and those in the levels of circulating markers of inflammation, thrombosis and endothelial dysfunction. The study was performed in a group of stable coronary patients treated for two years with a moderate dosage of atorvastatin (20mg/day). In this paper the cross-sectional relationship between C-IMT and the same circulating markers of inflammation, thrombosis and endothelial dysfunction measured at baseline was investigated. METHODS: Eighty-five subjects that had not used statins for at least two months were enrolled in the study. At time of enrollment, the levels of vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), E-selectin, interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-alpha, high-sensitivity C-reactive protein (hs-CRP), tissue factor (TF), tissue factor pathway inhibitor (TFPI), von Willebrand factor (vWF), fibrinogen, total cholesterol (TC), high-density lipoprotein (HDL) and low-density lipoprotein (LDL), and triglycerides were measured, in parallel with C-IMT assessment. RESULTS: In cross-sectional analyses, markers of endothelial perturbation (i.e. E-selectin) and TFPI were more strongly correlated with arherosclerotic burden than markers of inflammation. The baseline picture in this study indicates that E-selectin and TFPI are linked with atherosclerotic burden.

IPO-V2: a prospective, multicenter, randomized, comparative clinical investigation of the effects of sulodexide in preventing cardiovascular accidents in the first year after acute myocardial infarction.

OBJECTIVES: This study was conducted to assess the efficacy of sulodexide, a glycosaminoglycan compound with antithrombotic properties, in preventing death and thromboembolic events after acute myocardial infarction. BACKGROUND: Antithrombotic therapy has been found to play an important role in the prevention of cardiovascular events and death after acute myocardial infarction. Glycosaminoglycan-containing compounds, including sulodexide, show profibrinolytic and antithrombotic properties that render them suitable for use in patients after infarction. METHODS: A total of 3,986 patients who had recovered from acute myocardial infarction were randomized to receive either the standard therapy routinely administered at each study center, excluding antiplatelet and anticoagulant drugs (control group, 1,970 patients), or the standard therapy plus sulodexide (treated group, 2,016 patients). Between 7 and 10 days after the episode of acute myocardial infarction, sulodexide was administered as a single daily 600-lipoprotein-lipase-releasing unit (LRU) intramuscular injection for the 1st month, followed by oral capsules of 500 LRU twice daily. Patients were evaluated for > or = 12 months. RESULTS: At the end of the study, 140 deaths (7.1%) were recorded in the control group and 97 (4.8%) in the sulodexide group (32% risk reduction, p = 0.0022, chi-square test). A total of 90 patients (4.6%) in the control group had a further infarction, compared with 66 (3.3%) in the sulodexide group (28% risk reduction, p = 0.035). Furthermore, a reduction in left ventricular thrombus formation (evaluated by echocardiography) was observed in the sulodexide group (n = 12; 0.6%), compared with values in the control group (n = 25; 1.3%) (53% risk reduction, p = 0.027). Sulodexide was well tolerated and devoid of significant adverse events. All significant results were confirmed by "actual treatment" analyses. CONCLUSIONS: The study provides evidence that long-term therapy with sulodexide started early after an episode of acute myocardial infarction is associated with reductions in total mortality, rate of reinfarction and mural thrombus formation.

Echocardiographic follow-up in patients with mild to moderate mitral stenosis: is a yearly examination justified?

The result of this study showed that echocardiographic and Doppler parameters in patients with mild to moderate mitral stenosis did not undergo any major changes over a relatively long observation period, reflecting the substantial stability of the valve disease process. Thus, unless such patients experience clinical deterioration, a yearly echocardiographic examination appears to be unjustified.

Plasma lipids during extracorporeal circulation.

Total lipids, lipid classes, and per cent composition of fatty acids were investigated in plasma and stored subcutaneous fats of 19 subjects undergoing extracorporeal circulation (ECC). The tests were made before and 3, 20, 40, and 60 minutes after ECC was started. Hemodilution caused a general fall in total lipids and lipid classes. Evaluation of the lipid classes as percentages of the total lipids assumed to be 100 per cent allow the lipid variation due to hemodilution to be disregarded. A linear correlation between an increase in free fatty acids (FFA) and a decrease in triglycerides can thus be observed. This has been attributed to action of the lipase lipoproteic (LLP) activity stimulated by heparin, which is usually employed in ECC hemodilution. The hypothesis that FFA's are mobilized from stored subcutaneous fats was discounted.

Haemodynamics at rest and under effort in chronic arteriovenous fistulae (AVFs).

Latero-lateral femoro-femoral arteriovenous fistulae (AVFs) were surgically created in mongrel dogs. After 7-9 months during which the dogs were trained on a treadmill, devices suitable for recording arterial pressure and aortic and coronary flow were chronically implanted. Haemodynamic parameters of the dogs were controlled either at rest or after effort, keeping AVFs open or manually closed. The results, when statistically processed, showed that haemodynamic changes induced by occlusion of AVFs at rest and under effort are similar from a qualitative point of view, but considerably more marked after muscular exercise. Under effort the shunt index calculated rose to a higher extent than cardiac output. The decrease in heart rate after AVFs occlusion was significantly correlated with flow in the fistulae. However, the Nicoladoni-Branham phenomenon ought to be used for indirect evaluation of the shunt flow.

Pharmacokinetics of deslanatoside C-3H administered parenterally to the guinea-pig, rabbit and dog.

The pharmacokinetics of Deslanatoside C-3H, a short-acting polar cardiac glycoside, were investigated in the guinea-pig, rabbit and dog, after parenteral administration. Deslanatoside C was on average 20% plasma protein-bound and had a red blood celle/plasma partition ratio of 1/9. Tissue uptake of Deslanatoside C observed in the guinea-pig seems on average to be higher than in rabbits. Among the various organs and fluids tested, the highest levels were encountered in the urine, bile and kidneys of both the guinea-pig and rabbit. The main excretory route of this glycoside was via the urine, although significant amounts were excreted via the bile in all the three species tested. Cumulative urinary excretion 24 hr after i.v. injection was 50% (75% of which in unchanged form) in the guinea-pig, 46.5% (86% of which in unchanged form) in the rabbit, and 42.9%(84% of which in unchanged form) in the dog. Among the cardiac glycosides, Deslantoside C seems to possess the highest urinary excretion rate, which has in fact also recently been confirmed in human subjects.

[Echocardiography in Ebstein's anomaly (author's transl)]. / L'ecocardiografia nella malattia di Ebstein.

Results about an echocardiographic study of 20 patients with Ebstein's anomaly diagnosed by cardiac catheterization and angiography, are referred. In 8 patients an echocardiogram and phonocardiogram were recorded and in five patients an echocontrast examination was performed. The echocardiographic features constantly recorded in Ebstein's anomaly are represented by anterior chamber dilatation, interventricular septum paradoxical movement, anterior tricuspid leaflet wide excursion, decreased diastolic closure rate and delayed closure of tricuspid valve compared to mitral valve. The reduced left ventricular dimension and frequent incidence of "hammock-like" shape of mitral valve during systole and reduced diastolic closure rate of anterior mitral leaflet are pointed out. Possible causes of anterior chamber dilatation, of interventricular septum paradoxical motion and delayed tricuspid closure are discussed. According to the previous study no echocardiographic pattern is surely diagnostic of the disease by itself; a delayed tricuspidal closure (more than 70 msec) when associated to an anterior tricuspid leaflet wide excursion and decreased E-F slope, is of particular value for diagnosis.

Effects of ibopamine on systemic, pulmonary and regional hemodynamics. Experimental investigations in anesthetized dogs.

The effects of a new orally effective dopamine-like derivative, ibopamine (SB-7505), the 3,4-diisobutyryl ester of N-methyldopamine, on the cardiovascular system were investigated in anesthetized dogs. Ibopamine increased dose-dependently stroke volume index, cardiac index, left ventricular pressure, its first derivative: dP/dt, peak velocity left ventricular ejection and renal blood flow. After beta-blockade the positive inotropic effect of ibopamine is inhibited. Total peripheral resistance and renal vascular resistance decreased after ibopamine. Urine output was increased dose-dependently, reaching 115% after ibopamine 8 mg/kg intraduodenally. Coronary and femoral flows and resistance did not change after administration of 4 and 8 mg/kg. Only very high doses (24 mg/kg) caused an increase in flow and resistance. Mesenteric flow decreased transiently and then returned to the previous level or increased considerably over the basal figures when a high dose was used. No significant changes or fall in heart rate were observed with doses up to 16 mg/kg and no significant changes in pulmonary resistance were noted. The data obtained from the present investigation show, however, that oral ibopamine is capable of producing most of the effects induced by intravenously given dopamine in anesthetized dogs. Ibopamine's cardiac and renal effects may open new prospects for the long-term treatment of chronic heart failure in human subjects.

Haemodynamic, radionuclide ventriculography and ergometric evaluation of captopril treatment in congestive heart failure.

Eight patients with NYHA Class II congestive heart failure were studied before and after captopril with right heart catheterization, cycloergometric stress tests and radionuclide 99Tc cineventriculography. Acute administration of captopril increased stroke volume and cardiac index and reduced left ventricular filling pressure. Similar changes though less marked were seen after 30 days of captopril therapy. Functional aerobic capacity and left ventricular performance improved over 15 and 30 days of captopril respectively. We therefore suggest that captopril can be effective also in patients with moderate congestive heart failure.

Effects of ibopamine on heart performance: a radionuclide ventriculography study in patients with idiopathic dilatative cardiomyopathy.

The effects of ibopamine (SB-7505, Ib), a new orally active 3,4-diisobutyryl ester of N-methyldopamine, were studied in 8 patients aged between 34-56 years with idiopathic dilatative cardiomyopathy (II-III New York Heart Association Class) diagnosed by means of right and left heart catheterization and selective coronary angiography. Equilibrium radionuclide ventriculography (RVG) was performed in baseline conditions and 1, 2, and 3 h after the administration of a single oral dose of 200-300 mg of Ib. After 2 h Ib increased cardiac output (CO) (+16%, p less than 0.05), stroke volume (SV) (+12%, p less than 0.05) and ejection fraction (EF) (+10%, p less than 0.01). Patients were then randomly treated with placebo or Ib 100 mg t.i.d. according to a double-blind cross-over design for two periods of 15 days each. At the end of each period a RVG was repeated in baseline conditions and 1, 2, and 3 h thereafter. The mean values of the four determinations where higher after Ib than after placebo (CO: +10.1%, p less than 0.01; SV: +14.1%, p less than 0.01; EF: +10.8%, p less than 0.05). Patients subsequently started a long-term treatment with Ib 100 mg t.i.d.; after 6 months patients underwent RVG 3 h after the last dose of Ib: compared with the values recorded at the same time after the short-term treatment. CO further increased by 17% (NS), SV by 22% (p less than 0.05) and EF by 24% (p less than 0.05). The treatment was well tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical evaluation of probucol in hypercholesteremia: individual lipoprotein responses and inhibitory effect on carotid atherosclerosis progression.

Probucol treatment has been evaluated in 140 patients with hypercholesterolemia attending a single Lipid Clinic, in an attempt to identify the relations between lipid/lipoprotein responses and patient characteristics. Probucol was administered as a single drug at the standard dose (0.5 g tablets b.i.d.) for at least 6 months. One-hundred (71%) patients displayed a reduction of low-density lipoprotein cholesterol (LDL-C), which was significantly correlated with the baseline LDL-C level (r = 0.64; p < 0.0001). Most of the patients (90%) also responded with a reduction of high-density lipoprotein cholesterol (HDL-C); the HDL-C reduction was also directly related to baseline HDL cholesterolemia (r = 0.67, p < 0.0001). A highly significant correlation was found between the individual LDL-C and HDL-C responses. Eleven patients who continued with probucol treatment had a B-mode ultrasonographic investigation performed at baseline and after 24 months. No changes in carotid mean and maximal intimal-medial thickness were recorded, in contrast to an increase (i.e., indicative of atherosclerosis progression) in matched patients with hypercholesterolemia receiving other lipid-lowering regimens. Our report underlines that probucol can still provide a valuable option for the treatment for hypercholesterolemia, being particularly effective in patients with a combined increase of LDL-C and HDL-C levels.

[Echocardiographic and polygraphic study of acute/effects of Ibopamine on cardiac performance]. / Studio ecocardiografico e poligrafico degli effetti acuti della Ibopamina sulla performance cardiaca.

The effects of Ibopamine, a new orally active dopaminergic agent, on cardiac performance were studied both in a group of healthy volunteers and in a group of patients with congestive heart failure (CHF), using non-invasive methods, such as echocardiography and polygraphy. Randomly, and in double-blind fashion, the healthy volunteers received single doses of Ibopamine 50, 100 and 150 mg orally every 3 days. The CHF patients, also randomly and in double-blind fashion, were given single doses of either placebo or Ibopamine 100 or 150 mg every 2 days. Echocardiographic and polygraphic data were recorded in baseline conditions and 3, 6 and 8 hours after the drug administration. The heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured at the same time. The following parameters were considered: echocardiography: left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), interventricular septum excursion (IVSE), left ventricular posterior wall excursion (LVPWE), per cent fractional fiber shortening (%FS); polygraphy: electromechanical systole (Q-A2), total ejection time (ET), pre-ejection period (PEP), ET/PEP ratio. In CHF patients, body weight and 24-h diuresis were also measured daily. Neither of the two groups showed significant changes in HR, SBP and DBP with any drug dose. A shortening of ET (-2.2%, p less than 0.01) and Q-A2 (-2.8%, p less than 0.001) was found in the group of normal subjects with a dose of 50 mg.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic and metabolic changes induced by temporary clamping of the thoracic aorta.

Numerous authors reported a significant deterioration of heart function induced by aortic cross-clamping. Nevertheless, the aorta has been clamped during various surgical procedures without any complication. We studied the hemodynamic and metabolic variations induced by 20 min thoracic aorta cross-clamping in 6 open-chest dogs. During clamping the most striking modifications were an increase in coronary blood flow of over 65%, an increase in cardiac work of over 77% and an increase in total peripheral resistances of over 68% compared to base values. No significant variations were found in the heart rate and cardiac index. Metabolic parameters, such as O2 consumption and lactate consumption increased significantly during the clamping period. The increase in lactate consumption and the progressive and continuous improvement in oxygenation indexes (lactate/pyruvate, redox potential, excess of lactate) proved the absence of any myocardial anoxia during this period. Within 15--30 min after declamping all hemodynamic and metabolic parameters reverted to values close to basal values. These data strongly suggest that the mammalian heart can tolerate this procedure satisfactorily for a limited period of time. In clinical settings, one should consider the base conditions of the cardiovascular system before transposing these conclusions.

[Value of echocardiography in the diagnosis of dissecting aneurysm of the aorta]. / Validita' dell'ecocardiografia nella diagnosi di aneurisma dissecante dell'aorta.

A revision of 1300 echocardiograms of adults showed 14 patients whose echocardiographic diagnosis of aortic root dissecting aneurism (D.A.). Of these, 8 didn't have any anamnestic, clinical or instrumental evidence of D.A. In the other 6, admitted to our department with a suspected D.A., echocardiography proved to be useful in confirming such diagnosis in 4, in excluding it in 1, but gave a false positive diagnosis of D.A. in the sixth, affected by a diffuse carcinomatosis with pleuropericardial blood effusion. From the examination of the present experience, the Authors deem echocardiography is a useful diagnostic tool in the screening of D.A. when the following conditions are fulfilled: 1) presence of all the major criteria of Nanda and Gramiak, especially the aortic root anterior wall dilatation beyond 16 mm; 2) an almost suggestive story and clinical evidence of D.A. The usefulness of an echocardiographic pattern recently described as diagnostic of D.A. (loss of continuity between the borders of the anterior aortic wall with interventricular septum, and/or posterior aortic wall with mitral anulus) was confirmed: it was detected in 3 of the 4 D.A. patients but in none of the others. The presence of a false positive and the possibility of technical artifacts nevertheless induce caution in the interpretation of the echocardiographic pattern alone.

Renal effect of SB 7505: a double-blind study.

Two groups of 20 patients with no evidence of cardiovascular, hepatic, renal or gastrointestinal failure were treated orally for five days with placebo or SB 7505 100 mg/day. No change was observed in heart rate or blood pressure. Urine output, the excretion of Na, K and Cl, and creatinine clearance were significantly increased.

[Role of ambulatory ECG in the diagnostic work of a cardiology division]. / Ruolo dell'ECG dinamico nell'iter diagnostico in una Divisione di Cardiologia.

Holter monitoring may be effected during hospitalization either for clinical research or for high-risk patients or after surgical treatments. In the other cases, if possible, it should be better to effect ambulatory electrocardiographic monitoring in patients engaged in their normal daily activity nevertheless reducing hospital costs. Last year, in our department we effected 2420 Holter monitoring, of which 44% for patients hospitalized in our department, 11% hospitalized in other divisions, 44% for ambulatory patients. Holter monitoring was effected in the 35% of patients to detect arrhythmias, in the 29% for the evaluation of the effect of antiarrhythmic therapy; the 28% of Holter monitoring was recorded for patients recovering from acute infarction. Holter monitoring, associated to the other cardiological screening tests, has a very important rule for diagnosis of arrhythmias or myocardial ischemia, prognostic evaluation of cardiopathic patients (ischemic heart disease, cardiomyopathies, valvular and congenital heart disease), verification of the effects of therapy (PTCA, surgical and antiarrhythmic treatment).

[The mitral prolapse syndrome. Observation of 100 cases (author's transl)]. / La sindrome del prolasso della mitrale. Osservazioni su 100 casi

100 patients with mitral prolapse syndrome (MPS) were studied with electrocardiogram, phonocardiogram, thorax radiography and echocardiogram. In 44 of the patients, the effort test and dynamic electrocardiogram were performed; 25 underwent hemodynamic examination, and 10 underwent selective coronarography. The most frequent symptomatologies were palpitations and vertigo; the most-registered electrocardiographic alterations were ventricular extrasystoles and altered electrical repolarization in the inferior seat. The symptomatic patients with rhythm disturbances showed reduced work capacity (RWC) with aggravation of the effort arrhythmias. The phonocardiogram showed variability of the phonoauscultatory reports, not only from patient to patient, but also in the same patient. The apicocardiogram presented a characteristic systolic re-entry which coincided with the non-ejective click. In all cases, the echocardiogram demonstrated a systolic movement backwards from the mitralic strips with different aspects. The endocavitary pressures in the studied cases were normal or only slightly altered. The left ventriculography frequently demonstrated assynergic areas, and constantly, eversion of the posterior mitralic strips in the left atrium. In most of the cases, the selective coronarography showed the absence of the ventricular atrial tract of the circumflex. The sustained role of the mixomatous degeneration in the pathogenetic mechanism of the MPS must be emphasized. The beta-blockers were the most effective drugs against arrhythmias, which in some cases showed themselves impervious to any medicinal treatment. MPS is considered a very diffuse disease which can run its course without detection or which can be accompanied by serious rhythm disturbances that can threaten the patient's life. The importance of echocardiography in the diagnosis of MPS is emphasized. The SPM patient showed undergo a series of wave tests which reveal malignant potentialities, so that the best therapeutic principles, both for the treatment and prevention of the arrhythmias, can be applied.

Acute clinical tolerance of creatinol O-phosphate.

Acute clinical tolerance to N-methyl-N-(beta-hydroxyethyl) guanidine O-phosphate (creatinol O-phosphate, COP) was investigated in volunteer human subjects without heart or renal disease and without other serious illness. COP was administered i.v. at three different dosages, 1020 mg (group A), 2040 mg (group B) and 3060 mg (group C), in comparison with a placebo (group D). Arterial pressure, heart rate, ECG pattern and a complete blood analysis showed no change at any COP dosage, with the exception of blood phosphate, which increased in groups B and C. Cumulative urinary excretion of phosphate and creatinine and diuresis increased, whereas other urine parameters did not change. The phosphate and creatinine increases derived from the COP molecule and the increase in diuresis from a simple osmotic process required to dilute the phosphate in the tubular fluid. All these alterations were statistically significant and dose-related with COP and had been expected. COP proved to be a very well tolerated drug without any evident side effect.