A comparison of acute phase proteins and traditional risk factors as markers of combined plaque and intima-media thickness and plaque density in carotid and femoral arteries.

OBJECTIVES: To test the hypothesis that some acute phase proteins may be better independent predictors of objective measures of arterial wall impairment than traditional risk factors. DESIGN: Cross-sectional study. MATERIALS AND METHODS: C-reactive protein (CRP), fibrinogen, C3 complement and traditional risk factors were measured in 288 men aged 55-64 years, randomly chosen from the local registry lists. By ultrasound assessment of the bifurcations of carotid and femoral arteries, maximum combined plaque/intima-media thickness (CPIMTmax) and mean plaque density (MPD, in a grey scale from 0 to 255) were also measured. RESULTS: In multivariate analysis only traditional risk factors remained associated with the overall CPIMTmax: smoking (r = 0.35, p < 0.0001), cholesterol (r = 0.23, p = 0.0001), age (r = 0.22, p = 0.0002), glucose (r = 0.18, p = 0.002) and systolic blood pressure (r = 0.13, p = 0.02). However, with regard to carotid disease only, fibrinogen was the strongest covariate of CPIMT (r = 0.18, p = 0.002). The overall MPD was independently associated with CRP (r = 0.25, p = 0.0008), physical activity (r = 0.19, p = 0.009), triglycerides (r = -0.18, p = 0.02) and body mass index (r = 0.15, p = 0.04). CRP was mainly associated with femoral MPD, while triglycerides were the major (inverse) covariate of carotid MPD. CONCLUSIONS: Traditional risk factors are the main determinants of CPIMTmax, although fibrinogen seems to play a role in carotids. CRP was associated with high density femoral plaques. Finally, no acute phase protein was independently associated with low density, potentially vulnerable, plaques.

Different associations of C-reactive protein, fibrinogen and C3 with traditional risk factors in middle-aged men.

BACKGROUND: Some acute phase proteins are associated with both ischemic events and traditional risk factors. Since they are strongly interrelated, each of them partly reflects the characteristics of other proteins. This study was carried out to ascertain the specific preferential associations of some acute phase proteins with traditional risk factors for atherosclerotic disease. METHODS: High-sensitivity C-reactive protein, fibrinogen and C3-complement were assessed in 288 unselected men aged 55-64 years. Three multiple linear regression analyses were performed, in which each of the three acute phase proteins was considered the dependent variable of both traditional risk factors and the other two proteins. RESULTS: The three acute phase proteins strongly correlated with each other. Moreover, C-reactive protein was independently associated with triglycerides (P<0.0001), age (P=0.0130), body mass index (P=0.0179), and acute (P=0.0280) and chronic (P=0.0582) inflammations (R2=0.17). Fibrinogen was associated with alcohol consumption (inversely, P=0.0001) and smoking (P=0.0598) (R2=0.06). Finally, C3 was associated with insulin (P<0.0001), cholesterol (P=0.0001), sedentarity (P=0.0028), glucose (P=0.0077), and systolic blood pressure (P=0.0124) (R2=0.28). CONCLUSIONS: When simultaneously studied in multivariate analysis, acute phase proteins have different preferential associations with traditional risk factors, a probable consequence of their involvement in different cellular activations and metabolic processes.

Conditional risk factors in men with previous myocardial infarction: relevance of C3 and homocysteine.

OBJECTIVE: To establish which traditional and conditional risk factors were effectively treated, and which remained active, in patients with previous myocardial infarction (PMI). METHODS AND RESULTS: In 47 PMI patients recently submitted to cardiological assessment and in 42 controls (50-70 years old men), traditional risk factors (total cholesterol, high-density lipoprotein cholesterol, blood glucose, blood pressure, cigarette smoking and body mass index) and the following variables were measured: fibrinogen, plasminogen activator inhibitor-1 (PAI-1), lipoprotein(a) [Lp(a)], total homocysteine, plasma folates, vitamin B12, high sensitivity C-reactive protein and C3 complement. Most patients were taking beta-blockers, ACE inhibitors and statins. Accordingly, patients had lower blood pressure and cholesterol values than controls. Moreover, they consumed less alcohol and coffee and did not differ from controls in cigarette smoking and body mass index. Conversely, patients had higher levels of homocysteine, fibrinogen, C3 complement and Lp(a), although of these factors only C3 and homocysteine remained significantly associated with PMI in multivariate analysis. C-reactive protein, PAI-1 and especially C3 often correlated with traditional risk factors in controls, but these correlations tended to disappear or reverse in PMI patients. Fibrinogen inversely correlated with alcohol consumption. Homocysteine correlated (inversely) with plasma folates only. Lp(a) did not correlate with any variable. CONCLUSIONS: Forty-seven patients with previous myocardial infarction displayed an excellent control of traditional risk factors, but they had higher mean C3 and homocysteine levels than the control group.

Short term effect of atorvastatin and vitamin E on serum levels of C3, a sensitive marker of the risk of myocardial infarction in men.

C3 complement is produced in response to macrophage activation and is a reliable marker of the risk of myocardial infarction in men. This study was designed to ascertain whether the treatment with atorvastatin, a powerful cholesterol lowering drug, and/or vitamin E, a natural antioxidant, may induce a short term decrease in serum C3 in subjects with persistently elevated levels. From an initial random sample of 1100 men aged 55-64 years, 140 subjects with 3 consecutive C3 measurements in the high tertile (>1.19 g/l) were selected. Those with total cholesterol <5.56 mmol/l were double blindly randomized in groups 1 (placebo, N = 28, G1) and 2 (vitamin E 600 IU/day, N= 30, G2). The subjects with total cholesterol values >5.56 mmol/l were randomized in groups 3 (placebo, N= 30, G3), 4 (atorvastatin 10 mg/day, N = 27, G4) and 5 (atorvastatin 10 mg/day + vitamin E 600 IU/day, N = 25, G5). After 3 months C3 levels were substantially unchanged in the first 4 groups, while in G5 a very significant decrement occurred: -0.070 g/l (5.2%); 95% CI 0.043-0.098; p <0.0001. "Normal" levels of C3 (< 1.19 g/l) were reached by 28% of G5 subjects. In G2 and G5 vitamin E levels increased by 60 and 36%, while in G4 they decreased by 23% (p < 0.0001), paralleling cholesterol and triglyceride fall. In all groups a progressive decrease in HDL cholesterol occurred (-17%, p < 0.0001). In conclusion, treatment with atorvastatin plus vitamin E for three months can lower persistently elevated C3 levels.

Relationship of serum C3 to fasting insulin, risk factors and previous ischaemic events in middle-aged men.

AIMS: Serum C3 is a powerful indicator of the risk of myocardial infarction, which correlates with body mass index, serum lipids and blood pressure. This study was performed to ascertain whether such correlations may be explained by an association of C3 with fasting insulin, and to assess comparatively the relationships of C3 and traditional risk factors to previous myocardial infarction. METHODS AND RESULTS: The fasting levels of C3, insulin, and the main risk factors were evaluated in 1090 unselected men aged 55-64 years, including 129 cases of previous ischaemic events (51 myocardial infarctions). In multivariate analysis C3 was associated with insulin (r=0.27, P<0.0001), cholesterol (r=0.18, P<0.0001), body mass index (r=0.13, P<0.0001), glucose (r=0.12, P=0.0001), systolic blood pressure (r=0.10, P<0.001), triglycerides (r=0.09, P<0.01) and HDL-cholesterol (r=-0.06, P<0.05). These variables explained 31% of the total C3 variance. Alcohol consumption and physical activity correlated inversely with C3, while no correlation was found with smoking and family history of myocardial infarction. C3 was associated with previous myocardial infarction and stroke, but not with angina pectoris and peripheral arterial disease. In logistic regression the variables associated with previous myocardial infarction were C3 (P=0.011), family history of myocardial infarction (P=0.018), ex-smoker status (P=0.020), age (P=0.025), glucose (P=0.028) and HDL-cholesterol (P=0.051, inverse relationship). CONCLUSIONS: The association of C3 with myocardial infarction persists retrospectively, and is more significant than any other association of traditional risk factors with previous myocardial infarction. Of the many variables associated with C3, fasting insulin is its main covariate, which suggests that C3 is a marker of a pro-atherogenic metabolic imbalance partly coinciding with insulin resistance.

The shape of enzymatic curves during acute myocardial infarction: relationship to the progression of necrosis and implications for thrombolysis.

BACKGROUND: During acute myocardial infarction, the ascending branch of creatine kinase curves has a sigmoidal course whose inflection point marks the maximum rate of enzymatic increase in serum. This study was performed to assess the relationship between these morphologic characteristics of creatine kinase curves and the progression of myocardial necrosis. METHODS AND RESULTS: In isolated rat hearts exposed to different degrees of ischemia (coronary flow of 0.6 or 0.2 ml/g/min), the total quantity of creatine kinase released in the effluent had a sigmoidal course similar to the ascending branch of the curves from patients with acute myocardial infarction. Other rat hearts were frozen (which causes maximum damage to cell structures), thawed and then perfused. The resulting enzymatic curves had a downward concave ascending trend, similar to the portion beyond the inflection point of sigmoidal curves (the rate of creatine kinase release was maximum at the onset of perfusion and then decreased progressively). Finally, in some experiments ischemic rat hearts were further damaged by the perfusion, at different times, with highly concentrated catecholamines and without oxygen and substrates. This damaging perfusate was able to increase the rate of creatine kinase release (p = 0.0001) only when it was started before the inflection point of enzymatic curves. In 25 creatine kinase curves from patients with acute myocardial infarction (19 men and 6 women, age range 42 to 68 years), who were not treated with thrombolysis, the time of inflection varied from 1 to 12 hours from the onset of symptoms, with a maximum frequency between the 7th and the 8th hour. CONCLUSIONS: Based on these data, a biological model with 3 compartments has been suggested to explain the shape of creatine kinase curves, according to which the inflection point would occur after the completion of myocardial necrosis. The variability of the time of inflection might account for the cases of beneficial late thrombolysis reported in literature.

Relationship between serum C3 levels and traditional risk factors for myocardial infarction.

OBJECTIVE: Serum C3, a complement component produced by macrophages, the liver and the adipose tissue, is associated with the risk of myocardial infarction in men. This study was performed to ascertain the relationships between serum C3 and traditional risk factors in an unselected population sample. METHODS AND RESULTS: A random population of 1,068 subjects (537 men and 531 women, 23 to 90 years old) was examined for risk factor assessment. Serum C3 was measured by nephelometry. C3 was independently associated with body mass index (P < 0.0005, especially in women), LDL-cholesterol (P = 0.0014 in men and 0.0215 in women), systolic blood pressure (P < 0.05) and, in women, with triglycerides (P = 0.0133) and blood glucose (P = 0.0383), as assessed by multivariate analysis (multiple linear regression). The overall R2 were 0.07 and 0.21 for men and women, respectively. Women over 50 years of age had significantly higher C3 levels, LDL-cholesterol and body mass index than younger women. The correlation of C3 with LDL-cholesterol was present after the age of 40 in men, and 2 decades later in women. CONCLUSIONS: These data show that serum C3 correlates with a cluster of conventional risk factors for myocardial infarction resembling insulin resistance. Such correlations may be either independent of, or mediated by the development of coronary atherosclerosis.

Mechanism of isoproterenol-induced angina pectoris in patients with obstructive hypertrophic cardiomyopathy and normal coronary arteries.

In 14 patients with obstructive hypertrophic cardiomyopathy and angiographically normal coronary arteries, 8 with angina (group B) and 6 without (group A), the effects of intravenous isoproterenol, 2 to 4 micrograms/min, followed by intravenous propranolol, 0.2 mg/kg, were studied. An intraventricular systolic gradient less than 50 mm Hg, high-quality echocardiograms and cineangiograms and high-fidelity pressure tracings were selection criteria. Hemodynamic and metabolic variables were assessed during basal conditions, after 5 minutes of isoproterenol infusion or at angina and ST-segment depression, and 5 and 10 minutes after intravenous propranolol infusion. Isoproterenol increased the intraventricular systolic gradient more significantly in group B than in group A (102.4 +/- 8.3 vs 52.2 +/- 8.2, p less than 0.0001). Group B also had higher left ventricular end-diastolic pressure (32.5 +/- 3.9 vs 20.2 +/- 5.7), lower mean arterial pressure (69.7 +/- 3.5 vs 84.7 +/- 4.8) and a smaller increase in coronary sinus flow (176.1 +/- 9.2 vs 261.5 +/- 33.9, all p less than 0.0001), concomitant with lactate release and ST-segment depression. Propranolol promptly reversed hemodynamic and metabolic changes caused by isoproterenol, except for a further coronary sinus flow increase (from 176.1 +/- 9.2 to 219 +/- 14.2 ml/min, p less than 0.001), and heart rate decrease below basal values (57.8 +/- 7.5 vs 79.9 +/- 9.8 beats/min, p less than 0.001) in group B.(ABSTRACT TRUNCATED AT 250 WORDS)

Lactate release during the recovery period of pacing-induced angina in assessment of myocardial ischaemia.

Myocardial lactate (L) metabolism was tested in 27 stable angina patients during atrial pacing (AP) and in the recovery period (R) from AP-induced angina pectoris. The recovery period was assessed in order to evaluate the changes in the rate of L release and detect possible relationships with the severity of ischaemic damage. The following variables were assessed: coronary sinus blood flow (CSBF), left ventricular end-diastolic pressure (LVEDP), lactate extraction ratio (L%), lactate extraction or release rate (LR) and myocardial oxygen consumption (MVO2) at the onset of AP (AP1), during angina (AP2), and 30 s, 2 and 4 min (R1, R2 and R3) after AP ceased. At Ap2, negative L% and LR values (-39.37 +/- 43.3, -3.2 +/- 2.9) were found, in spite of a rise in CSBF (+86%, P less than 0.001). Furthermore, LVEDP showed its maximal increase in AP2 (+27%, P less than 0.001). Compared to AP2, L% resulted unchanged in R1, while LR showed a mild decrease (from -3.2 +/- 2.9 to +2.06 +/- 2.93). Lactate production was converted to extraction in R3 only. Since lactate production and release are progressively reduced with increasing severity of ischaemic damage, AP2 coronary sinus lactate release should largely arise from the less damaged areas (i.e. the outer myocardial layers) and the contribution of the more damaged areas (i.e. the inner myocardial layers) should be more limited. After AP ceases, the mild ischaemic areas should recover more rapidly than the severely ischaemic areas, where the damage only declines, leading to a temporary increase in lactate production and release.(ABSTRACT TRUNCATED AT 250 WORDS)

Catecholamine release in coronary sinus during vasospastic angina induced by ergonovine.

In seven patients with spontaneous angina and three control subjects, aortic and coronary sinus norepinephrine and epinephrine were assessed. Samples were taken in basal conditions and during ergonovine test in coronary sinus and aorta. The behaviour of some hemodynamic parameters as heart rate, blood pressure, left ventricular end diastolic pressure and coronary sinus flow was also studied. Resting myocardial norepinephrine and epinephrine flux was similar for both groups. In ischemic patients ergonovine induced a coronary spasm accompanied by an evident reduction of coronary sinus flow and a slight increase in arterial epinephrine and norepinephrine concentrations. However, a significant decrease in the net myocardial norepinephrine and epinephrine release was evidenced. After ergonovine, not significant changes in norepinephrine and epinephrine concentration and release resulted in control subjects. The increase in peripheral catecholamine concentrations found in ischemic patients during ergonovine test could represent a reflex activation of sympathetic activity induced by an ischemia dependent ventricular mechanical disfunction. The decrease in myocardial catecholamine release during angina could be justified by sequestration of epinephrine and norepinephrine in ischemic areas induced by vasospasm or reflex inhibition of cardiac sympathetic tone.

[Importance of metabolic disorders and endocardial viability ratio in the prognosis of open-heart operations. Experimental study of the pig heart protected by potassium cardioplegia in hypothermia]. / Importanza delle turbe metaboliche e del subendocardial viability ratio nella prognosi di interventi a cuore aperto. Studio sperimentale sul cuore di maiale protetto con cardioplegia potassica in ipotermia.

The aim of this study was to investigate the protective efficacy of potassium cardioplegia in general moderate hypothermia, in five pigs, after 90 minutes of myocardial ischemia induced by extracorporeal circulation (ECC) and aortic clamping. The behaviour of subendocardial supply demand ratio (DPTI/TTI), of CSBF (coronary sinus blood flow) and numerous hemodynamic parameters was evaluated in addition to lactate myocardial metabolism changes, at rest, after 90 minutes of total ECC and during a 60 minutes reperfusion period. The reperfusion period included two phases: during the first (15-20 minutes) the animals were in ECC with unclamped aorta; spontaneous circulation was instituted during the second one (40 minutes). A marked increase in CSBF was observed at aortic clamp removal during the first phase (post ischemic reactive hyperemia). Coronary sinus lactate release was also noted, probably due to wash-out of previously sequestered acid metabolites during aortic clamping (90 minutes). At the onset of the second phase a depressed left ventricular performance and low DPTI/TTI values were shown. A rapid return (20 minutes) to normal values of this parameter was then noted. DPTI/TTI normalization results strictly correlated to the progressive improvement in myocardial performance. Hypothermic potassium cardioplegia seems therefore to prevent the irreversible myocardial damage and favour a fast recovery of cardiac function.

Hemodynamic and metabolic effects of nitroglycerin ointment in pacing-induced angina pectoris.

Hemodynamic and metabolic effects of nitroglycerin ointment (40 mg nitroglycerin) were tested on 15 patients with clinical evidence of stable angina. Basal value (B) and atrial pacing (AP)-dependent changes were evaluated before and 30 min after ointment administration. After treatment tension time index (TTI) basal value showed a 19% reduction (p less than 0.05). Compared to the control a lesser AP-dependent increase was also noted (27%, compared to 45%; p less than 0.005). According to TTI reduction, MVO2 showed an evident decrease both in basal conditions and during AP (21% and 29.6%, respectively). On the contrary, diastolic pressure time index (DPTI) does not result significantly influenced by the treatment. Consequently, DPTI/TTI ratio increase is largely the result of TTI reduction, which is well correlated to myocardial oxygen demand. Coronary sinus blood flow decrease (16% and 27% under basal conditions and during AP, respectively) confirms that the therapeutic efficacy of the ointment does not result from an increase in myocardial oxygen supply. Finally, during AP nitroglycerin ointment resulted in a significant decrease in myocardial lactate release (L% mean value ranges from-17.5% to 3.4%; p less than 0.001). Such an improvement probably reflects a primary influence of the drug on the extracoronary vascular bed.