Pier Giorgio Rogasi

Association between time of increased fibrinopeptide A levels in plasma and episodes of spontaneous angina: A controlled prospective study

Thirty-seven patients affected by spontaneous angina and 15 comparable control subjects were enrolled in a 12-month prospective study to evaluate the relationship between blood clotting activation (assessed by fibrinopeptide A [FPA] plasma concentration) and the occurrence of myocardial ischemic attacks. FPA measurements and clinical examinations in patients were performed every 2 weeks. In control subjects blood sampling was performed every 4 weeks. Data from 28 patients who completed the study and from the 15 control subjects were analyzed. The clinical activity of angina was divided into three classes (asymptomatic, mildly symptomatic, and severely symptomatic) on the basis of the number and time-concentration of the ischemic attacks and ECG changes during the 15 days preceding each clinical examination. In all but one patient, a cyclic pattern of activity of coronary artery disease was observed. During follow-up studies, 624 FPA measurements were performed in patients and 173 in control subjects. Mean values were 4.68 +/- 4.53 and 1.32 +/- 0.60 ng/ml, respectively (p less than 0.001). FPA levels differed markedly in relation to the activity of angina. A relationship between FPA levels and activity of disease (r = 0.54, p less than 0.01) was found in time course. Bolus heparin administration (100 IU/kg) during the active phase of angina sharply but incompletely lowered FPA plasma levels, indicating thrombin formation both intravascularly and extravascularly. Present results indicate that a marked blood clotting activation occurs simultaneously with the outbursts of clinical activity of spontaneous angina.

Altered membrane fatty acid composition and increased thromboxane A2 generation in platelets from patients with diabetes.

Lipid composition of platelet membranes and thromboxane A2 (TxA2) generation by platelets were investigated in 42 diabetic patients (14 with macroangiopathic complications, 10 with microangiopathy and 18 without vascular complications) and in 42 clinically healthy subjects of similar age. All subjects were on a similar dietary regimen and the adherence to diet was checked by analysis of red blood cell lipids. Platelets from all groups of diabetic patients produced increased amounts of TxA2 than platelets from controls (at least p less than 0.01) and patients with macroangiopathy (p less than 0.01). Platelet cholesterol and total platelet phospholipids were higher in patients with macroangiopathy, while the relative percentage of the different phospholipid fractions in platelet membrane and their saturated and unsaturated fatty acids were similar in the different groups. Arachidonic acid (AA) content in phosphatidylcholine (PC) was found to be significantly higher in diabetic patients than in controls (at least p less than 0.005). Moreover patients with macroangiopathy had higher AA (p less than 0.001) and lower eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) levels in PC (p less than 0.001) than the other groups of patients and controls.

Altered lipid composition and thromboxane A2 formation in platelets from patients affected by IIa hyperlipoproteinemia

Platelets from patients with familial hypercholesterolemia (type IIa hyperlipoproteinemia), a condition associated with high prevalence of atherosclerosis and of its thrombotic complications, are known to be hyperresponsive to aggregating stimuli and to synthesize increased amounts of thromboxane A2 (TxA2) in comparison to platelets from normal subjects. In order to search if these functional alterations are linked to a different platelet lipid composition, we studied a group of young patients affected by IIa hyperlipoproteinemia and a group of suitable controls with similar dietary habits. Both cholesterol and phospholipid content of platelets were higher in patients than in controls with a significant increase of cholesterol/phospholipid molar ratio (at least p less than 0.05). The percent contents of the main platelet phospholipid fractions were not altered, while an increase in saturated fatty acids, both unesterified and esterified in different lipid fractions, was observed. Moreover, an increased TxA2 production by platelets and a significantly increased number of megathrombocytes occur in patients with respect to controls (p less than 0.001). Our results indicates that platelets from patients with IIa hyperlipoproteinemia have an altered lipid composition which could explain, at least in part, the enhanced platelet reactivity reported in these patients.

Increased thromboxane A2 generation and altered membrane fatty acid composition in platelets from patients with active angina pectoris.

Lipid composition of platelet membranes and thromboxane A2 (TxA2) generation by platelets were investigated in eighty-seven anginal patients (forty-two with resting angina in active phase and forty-five with effort stable angina or rest angina in inactive phase) and in forty-five clinically healthy subjects of similar age. All subjects were on the same dietary regimen and the adherence to diet was checked by analysis of red blood cell lipids. Platelets from active angina patients produced more TxA2 than platelets from both inactive patients and controls (p less than 0.001). Moreover patients with active angina had higher arachidonic acid (AA, p less than 0.001) and lower eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) levels in phosphatidylcholine (PC, p less than 0.001), than inactive patients and controls. AA and EPA changes in membrane PC significantly correlated with TxA2 production (p less than 0.001) but not with coronary pathoanatomy. Plasma lipids, content of cholesterol, total phospholipids (and their saturated and unsaturated fatty acids) and the different phospholipid fractions in platelet membrane were not different in the three groups. Present results indicate that in platelets from anginal patients phospholipid fatty acid composition is at least in part independent of plasma composition and that in active angina there are modifications leading to increased TxA2 formation and possibly contributing to the occurrence of ischemic attacks.

Abnormal cardiocoronary thromboxane A2 production in patients with unstable angina

Thromboxane B2 (TXB2), the stable metabolite of thromboxane A2 (TXA2), was measured in the coronary sinus and in aortic blood before and after cold pressor test (CPT) in 21 patients suffering from ischemic heart disease (7 affected by stable effort angina and 14 by unstable angina) and in 12 patients not suffering from myocardial ischemia (control group) during coronary angiography. Aspirin (10 mg/kg intravenously) was administered before catheterization in order to prevent platelet and leukocyte TXA2 formation. Control subjects and patients with effort angina had TXB2 resting levels lower than unstable angina patients without a transcardiac gradient which, on the contrary, was found in unstable angina patients. Only in these patients CPT resulted in a significant TXB2 increase more marked in the coronary sinus (from 50.0 +/- 18.9 pg/ml to 73.0 +/- 35.1 pg/ml, p less than 0.001) than in the aorta (from 33.4 +/- 17.1 pg/ml to 42.6 +/- 24.0 pg/ml, p less than 0.05), so that the transcardiac TXB2 gradient significantly increased. In all but two unstable angina patients, TXB2 elevation was not associated with a fall of cardiac lactate extraction. The resting and CPT-induced TXB2 gradients were unrelated to the presence and severity of coronary angiographic lesions. These results indicate that unstable angina patients show an abnormal cardiocoronary capacity to synthesize TXA2, which seems not to be elicited by the occurrence of myocardial ischemia.

Red blood cell lipid alterations in type II diabetes mellitus

Alterations in blood rheological properties have been reported in diabetes mellitus. Changes in lipid composition of red blood cell (RBC) membranes resulting in an impairment of RBC deformability may play a role in the altered blood rheological pattern. The aim of this study was to investigate the lipid composition of RBC membrane in a group of patients affected by type II diabetes (age 21-45 years), selected on the basis of the absence of complications and good metabolic control, and in a group of suitable control subjects. Saturated fatty acid amounts in the different phospholipid fractions were significantly higher in diabetics than in controls (p less than 0.05), whereas polyunsaturated fatty acids were decreased (p less than 0.05). Cholesterol/phospholipid molar ratio was not altered. On the contrary, sphingomyelin/phosphatidylcholine ratio was higher in diabetics than in controls (1.10 +/- 0.08 vs 0.96 +/- 0.10, p less than 0.01) due specially to high levels of sphingomyelin. These alterations could account for the impairement of RBC deformability frequently reported in diabetes mellitus, independently of metabolic control and the presence of severe atherosclerotic lesions.

Age related changes in platelet lipid composition.

Platelet lipid composition was investigated in 52 healthy subjects aged 20 to 68 years with similar dietary habits and living in a narrow geographic area in order to search possible changes referrable to aging. No significant variations were observed when platelet cholesterol, total phospholipids and different phospholipid fractions were considered, whereas cholesterol/phospholipid (C/PL) molar ratio significantly increased with aging (p less than 0.01). Moreover, a significant increase in 16:0 + 16:1 fatty acids was found in phosphatidylcholine (PC) and in sphingomyelin (SP) (r = 0.62, p less than 0.001 and r = 0.30, p less than 0.05 respectively) and a decrease in 18:2 n6 in the phospholipid fractions considered (at least p less than 0.05). These results indicate that modifications in platelet lipid composition occur with aging and that they could affect platelet functions so playing a role in the onset of atherosclerosis and in thrombotic phenomena occurring with increasing frequency in the elderly.

Decrease in frequency of anginal episodes by control of thrombin generation with low-dose heparin: A controlled cross-over randomized study

Increased thrombin generation is frequently associated with an increase in anginal activity. A cross-over, single-blind, completely randomized study was planned in order to evaluate whether the control of thrombin generation affected the increase in anginal activity. After discharge from the hospital, 24 patients (18 men and 6 women, aged 40 to 69 years) suffering from spontaneous angina were followed up to 12 months and were alternatively treated during two consecutive 6-month periods with calcium heparin, 12,500 IU by the subcutaneous route, or with placebo by the intramuscular route, in addition to the usual antianginal medications. Thrombin generation and clinical activity of angina were assessed every 15 days by measuring fibrinopeptide A (FPA) plasma levels and by grading in three classes (symptomless, mildly symptomatic, and severely symptomatic) the anginal activity on the basis of the number and the time concentration of the ischemic attacks and ECG changes. Low-dose heparin treatment significantly reduced both the FPA plasma level (from 4.1 +/- 3.7 to 2.3 +/- 1.8 ng/ml, p less than 0.001) and the clinical activity of angina. During heparin treatment, the frequency of the observations in the severely and mildly symptomatic classes decreased, respectively, by 53% and by 30%, whereas that in the symptomless class increased by 23% (p less than 0.001) in comparison with the period on placebo. Present results indicate that the control of thrombin generation obtained by low-dose heparin treatment favorably affects the degree of anginal activity in patients with spontaneous angina.

Enhanced peripheral vasoconstrictor response and increased thromboxane A2 synthesis after the cold pressor test in patients with angina at rest.

Peripheral vascular resistance (PVR) and thromboxane A2(TxA2) synthesis after the cold pressor test were investigated in different subsets of patients with angina (10 with stable effort angina, 36 with resting angina [24 in an active phase and 12 in an inactive phase], and five with Prinzmetals variant angina) and in 41 control subjects of equivalent age and risk factors. Left ventricular end-diastolic pressure, ejection fraction, extent of coronary angiographic lesions, and baseline PVR were not significantly different among the various patient groups. In all patient groups, except those with variant angina, the cold pressor test resulted in a higher increase in PVR than in the control subjects (p less than .001 for all groups). In patients with variant angina the vasoconstrictor response was increased only in proximity (about 1 hr) to ischemic attacks. In patients with active resting angina the vasoconstrictor response was on the average four times longer than that in patients with effort angina and with inactive resting angina (p less than .001). This exaggerated vasoconstrictor response was associated with elevated TxA2 resting levels in plasma and with increased TxA2 synthesis after the cold pressor test. A linear relationship was found between the area of the vascular response and the area of TxA2 production after the cold pressor test in patients with active resting angina (r = .87, p less than .001). The increased TxA2 synthesis and the inappropriate increase of peripheral vascular response to sympathetic stimulation revert back to normal in the inactive phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of oral treatment with pantethine on platelet and plasma phospholipids in IIa hyperlipoproteinemia.

In a single-blind, crossover, completely randomized study, the effects of oral treatment with pantethine or placebo on fatty acid composition of plasma and platelet phospholipids were investigated in 10 IIa hyperlipoproteinemic patients. A significant decrease of total cholesterol and total phospholipids was observed both in plasma and in platelets after a twenty-eight-day treatment. In plasma, pantethine induced a decrease of the ratio sphingomyelin/phosphatidylcholine. Moreover, a relative increase of n3-polyunsaturated fatty acids both in plasma and in platelet phospholipids and a decrease of arachidonic acid in plasma phospholipids were observed. These results indicate that pantethine can affect plasma and platelet lipid composition with possibly favorable influences on the determinants of cell membrane fluidity.