Polymorphism in the fractalkine receptor CX3CR1 as a genetic risk factor for coronary artery disease.

Coronary atherosclerosis is a major cause of death in industrialized countries. Monocytes, which play a key role in atherosclerosis, migrate into the vessel wall, presumably guided by specific chemoattractant and adhesion molecules. A compelling candidate for this role is the chemokine receptor CX3CR1, which is expressed on monocytes and acts as either a chemotactic receptor or an adhesion molecule, depending on whether its ligand, fractalkine, is presented free or membrane bound. A common variant of CX3CR1 was recently identified, encoded by the alleles I249 and M280, which form a common I(249)M(280) haplotype. When CX3CR1 genotypes were analyzed in 151 patients with acute coronary syndromes and in 249 healthy controls, CX3CR1 I249 heterozygosity was associated with a markedly reduced risk of acute coronary events, independent of established acquired coronary risk factors (eg, smoking, diabetes). The adjusted odds ratio for this allele was 0.43 (95% confidence interval, 0.26-0.72; P =.001). Consistent with this, functional analysis of peripheral blood mononuclear cells showed that CX3CR1 I249 heterozygosity was associated with a significant decrease in the number of fractalkine binding sites per cell. The results show that CX3CR1 I249 is an independent genetic risk factor for coronary artery disease and that CX3CR1 may be involved in the pathogenesis of atherosclerotic disease. (Blood. 2001;97:1925-1928)

A new T-287C polymorphism in the 5' regulatory region of the tissue factor pathway inhibitor gene. Association study of the T-287C and C-399T polymorphisms with coronary artery disease and plasma TFPI levels.

Tissue factor pathway inhibitor (TFPI) is an important regulator of the extrinsic blood coagulation pathway. We screened the untranslated 5' region of the TFPI gene for polymorphisms and investigated their possible involvement in arterial thrombosis. The allele frequencies of a new polymorphism, located 287 base pairs upstream of the transcription start site (T-287C), and that of the previously described C-399T polymorphism, were similar in cases and controls. In controls, the -287C allele was associated with significantly higher levels of total TFPI antigen, arguing for an effect of this polymorphism on TFPI gene expression. In controls, the C-399T polymorphism did not alter TFPI levels. In the cases, however, decreased total and post-heparin free TFPI levels and increased F1+2 levels were significantly associated with the -399T allele. These findings suggest that the T-287C and C-399T polymorphisms are not associated with an increased risk of coronary heart disease, a result which should be confirmed by a larger study. However, their influence on outcome, or a link with subtypes of acute coronary syndromes, cannot be excluded.

Reperfusion syndrome: relationship of coronary blood flow reserve to left ventricular function and infarct size.

OBJECTIVES: We tested the hypothesis that the reperfusion syndrome (RS), defined as an additional elevation of the ST segment upon reperfusion, may be a marker of microcirculatory reperfusion injury during acute myocardial infarction (AMI). BACKGROUND: The pathophysiology of the RS is unknown, and its prognostic implications are controversial. METHODS: Twenty-one patients with an anterior AMI treated < or =12 h after onset by primary coronary angioplasty (PTCA) were studied. Coronary velocity reserve (CVR), an index of microcirculatory function, was measured using a Doppler guidewire. Left ventricular (LV) ejection fraction, infarct size (percent defect) and LV end-systolic volume index (LVESVi) were evaluated by radionuclide ventriculography, 201T1 single-photon emission computed tomography and contrast ventriculography, respectively. RESULTS: Baseline ST elevation and pain-to-TIMI 3 time were similar in patients with and without RS. Patients with RS (10/21) had a lower post-PTCA CVR than patients without RS (median [95% confidence interval]: 1.2 [1-1.3] vs. 1.6 [1.5-1.7], p < 0.005). Even though predischarge CVR was similar in the two groups, infarct size at six weeks (26 [21 to 37] vs. 14 [10-17]% 201T1 defect, p = 0.001) and predischarge LVESVi (45% [40 to 52] vs. 30% [29 to 38] mL/m2, p = 0.001) were larger, and LV ejection fraction at six weeks (40% [37 to 46] vs. 55% [50 to 60], p = 0.004) was lower in patients with RS than in patients without RS. CONCLUSIONS: Patients with RS during primary PTCA for an anterior AMI have a transiently lower CVR than patients without RS, but sustained LV dysfunction and larger infarct size, suggesting that RS is a marker of microcirculatory reperfusion injury.

Decreased no-reflow in patients with anterior myocardial infarction and pre-infarction angina.

AIMS: Pre-infarction angina is associated with better outcome after myocardial infarction. The aim of this study was to assess whether pre-infarction angina is associated with decreased no-reflow after coronary recanalization. METHODS AND RESULTS: Twenty-three patients underwent intracoronary myocardial contrast echocardiography during the acute phase of anterior myocardial infarction after successful recanalization, and before hospital discharge. Myocardial perfusion was graded semi-quantitatively in the area at risk (dyssynergic segments). Global left ventricular function was assessed by radionuclide angiography on days 8 and 42 and regional wall motion was assessed by 2D echocardiography on days 0 and 42. Fourteen patients had pre-infarction angina (angina less than 7 days before myocardial infarction) and nine did not. Baseline characteristics were similar in the two groups. The myocardial contrast echocardiography perfusion score in the area at risk after recanalization was higher in the patients with pre-infarction angina than in those without (0.72 +/- 0.19 vs 0.53 +/- 0.22, P=0.04), and the incidence of no-reflow (myocardial contrast echocardiography perfusion score < or =0.5) was lower (14% vs 56%, P=0.04). This difference persisted 8 +/- 2 days after myocardial infarction (0. 87 +/- 0.11 vs 0.69 +/- 0.26, P=0.04), and was associated with greater mid-term (day 42) improvement in left ventricular function in patients with pre-infarction angina than in those without, as assessed by changes in radionuclide left ventricular ejection fraction (+5.8 +/- 8.1% vs -3.3 +/- 4.6%, respectively;P=0.01) and by changes in regional wall motion score on 2D echocardiography (-0. 61 +/- 0.39 vs -0.24 +/- 0.17, respectively;P=0.04). CONCLUSION: Pre-infarction angina is associated with preservation of the microvasculature, reflected by reduced no-reflow. This may be a mechanism underlying greater recovery of left ventricular function in patients with pre-infarction angina.

[Applications of contrast echocardiography in the acute phase of myocardial infarction]. / Applications de l'échocardiographie de contraste à la phase aiguë de l'infarctus du myocarde.

The present interest in myocardial contrast echocardiography is related to the development of new contrast agents which can be used intravenously and the perfection of new echocardiographic technologies. Amongst the potential applications of this technique, the study of myocardial perfusion in the acute phase of myocardial infarction is one of the most promising as shown by the experience acquired over several years with intracoronary contrast echocardiography. It allows assessment of the extent of the zones at risk before recanalisation, the presence of collateral vessels and, above all, the quality of myocardial reperfusion. The demonstration of the absence of effective reperfusion of the myocardial microcirculation, or the phenomenon of no-reflow, is one of the main advantages of contrast echocardiography and has been identified as an important independent prognostic factor. This technique could therefore become essential in the evaluation of methods for reducing the extent of microvascular damage. Although many questions remain unanswered about the ideal methods of performing and analysing intravenous contrast echocardiography, the preliminary results confirm the potential of the technique in non-invasive evaluation of myocardial reperfusion in the acute phase of myocardial infarction.

Polymorphisms of the tissue factor pathway inhibitor (TFPI) gene in patients with acute coronary syndromes and in healthy subjects : impact of the V264M substitution on plasma levels of TFPI.

-Mutations of the gene encoding tissue factor pathway inhibitor (TFPI), an inhibitor of TF-induced activation of the coagulation cascade, were screened for in 130 patients and 142 healthy controls to determine whether these variants contribute to acute coronary syndromes or modify plasma TFPI levels. The following 3 new polymorphisms were identified: 384T-->C in exon IV, which does not change the corresponding amino acid (tyrosine 57); -33C-->T in intron 7 (the T/T, C/T, and C/C genotypes were found in approximately 50%, 40%, and 10% of subjects in both groups); and 874G-->A in exon IX (GTG-->ATG), which predicts a valine to methionine change (V264M) in the carboxy-terminus tail of TFPI. The V264M polymorphism was found in 9.2% of the cases and 4.9% of the controls; the associated odds ratio (OR) for acute coronary syndromes was 2.0 (95% confidence interval [CI], 0.7 to 5.1). The OR increased to 3.6 (95% CI, 0.8 to 15.7) and 3.2 (95% CI, 0.9 to 11.8) in nonsmokers and patients without other risk factors, respectively. The possible link between the V264M polymorphism and coronary heart disease was checked in a large case-control study of myocardial infarction (Etude Cas-Témoins de l'Infarctus du Myocarde [the ECTIM Study]). The results showed no link between the V264M polymorphism and coronary syndromes. Interestingly, however, 5 patients heterozygous for the V264M polymorphism had significantly lower plasma TFPI levels than did 13 patients with the most common genotype. Although our present results do not support an association between TFPI polymorphisms and acute coronary syndromes, the possibility that 1 of them, especially the exon IX polymorphism, is associated with subtypes of myocardial infarction or to evolutive particularities that were not assessed in this study, cannot be excluded and is currently being evaluated.

Early changes in myocardial perfusion patterns after myocardial infarction: relation with contractile reserve and functional recovery.

OBJECTIVES: The purpose of this study was to assess early temporal changes in myocardial perfusion pattern by myocardial contrast echocardiography (MCE) and their relation to myocardial viability in patients with reperfused acute myocardial infarction (AMI). BACKGROUND: Myocardial contrast echocardiography no-reflow is associated with poor contractile recovery after AMI. However, little is known regarding early reversibility of microvascular dysfunction and its relation to myocardial viability. METHODS: Intracoronary MCE was performed immediately after reflow and 9 days later in 28 patients with a first AMI and successful coronary recanalization (Thrombolysis in Myocardial Infarction trial grade 3 flow). Semiquantitative contrast score and wall motion score (WMS) were assessed in each initially asynergic segment at initial and repeat MCE study. Low dose dobutamine echocardiography (DE) was performed at day 10, and follow-up (FU) rest echocardiography was performed 6 weeks later. RESULTS: Among 200 initially asynergic segments, 49% exhibited no or heterogeneous contrast enhancement at initial MCE versus 24% at restudy (p < 0.001). Three groups of segments were defined according to early changes in contrast pattern: group A, "sustained no-reflow" (n = 17); group B, improved contrast score (n = 68), and group C, "sustained reflow" (n = 112). Group A segments showed no improvement in WMS at FU. In contrast, group B segments showed significant improvement in WMS at FU (p < 0.0001), and exhibited more frequently contractile reserve at DE (36% vs. 6%, p = 0.02) and contractile recovery at FU (34% vs. 7%, p = 0.03) than group A segments. Group C segments exhibited contractile reserve and contractile recovery in 47% and 51% of segments respectively. CONCLUSIONS: Improvement in MCE perfusion pattern may occur after initial no-reflow in the days following reperfused AMI and is associated with preservation of contractile reserve and gradual regional functional recovery.

Revascularization of patients with unstable coronary artery disease: the case for early intervention.

In unstable angina, there are data to suggest a substantial risk of recurrent ischemia, infarction, and death when early angiography and/or revascularization have been deferred. Conversely, it has been suggested that early angiography and revascularization are more dangerous than deferred procedures. Critical review of the literature, however, suggests that there is no specific risk inherent in early intervention, but rather that patients who cannot wait are at higher risk anyway. The most valuable data on the comparison of an "early invasive" and a "conservative" strategy in unstable angina come from the Thrombolysis in Myocardial Ischemia (TIMI) IIIB study. The results show no major difference in outcome between groups (despite a high intervention rate in the conservative group), but a shorter hospital stay, lower drug use, and fewer rehospitalizations in the group treated according to the early invasive strategy. These results have been interpreted as favoring early intervention, due to the potential for a shorter hospital stay (a major determinant of cost in many countries) because of the possibility of achieving complete diagnosis and treatment within several days of admission, with good results. In addition, since the inception of the TIMI IIIB study, there have been major improvements in the field of angioplasty, such as the increased use of stents and the availability of safe and effective glycoprotein (GP) IIb-IIIa inhibitors. Thus, the pathophysiology, the excellent results of early intervention, and the recent improvements in angioplasty and its medical and pharmacologic environment, provide a strong rationale for early intervention.

[Myocardial viability: results of myocardial revascularization during the acute phase of myocardial infarction]. / Viabilité myocardique: résultats de la revascularisation myocardique à la phase aiguë de l'infarctus.

Complete coronary reperfusion after thrombolysis or primary angioplasty is associated with limitation of infarct size and conservation of left ventricular function. The area of viable myocardium recovers its function secondarily, the amount of recovery being related to the precocity of reperfusion. Patients with a patent artery in the acute stage do not all recover segmental contraction to the same extent. There are considerable discrepancies between coronary patency and myocardial perfusion. Myocardial perfusion, measured in the acute phase by myocardial contrast echocardiography is the best predictor of preservation of function. This suggests that microvascular lesions are a sign of the extent and irreversibility of myocardial damage. Modern treatment of infarction should not only restore coronary patency but also ensure effective myocardial reperfusion. The factors which determine recovery of ventricular function after reperfusion during the acute phase, are, in addition to early and complete coronary recanalisation and effective myocardial reperfusion: short duration of ischaemia, small size of the area at risk, collateral circulation, ability of the myocardium to withstand ischaemia, limitation of reperfusion injury. Other factors (smoking, pre-infarction angina, the occluded artery or method of reperfusion) may play a role but the role of confounding factors is always difficult to exclude.

Complementarity of lung scintigraphy and D-dimer test in pulmonary embolism.

D-dimer assay (DDA), measuring fibrin degradation products, was compared with lung scintigraphy (LS) in a prospective unselected series of 83 consecutive patients referred owing to suspicion of pulmonary embolism (PE). This patient series was also used to compare several methods of performing and interpreting LS images. The final diagnosis was established independently by a separate panel with all available information except for the result of DDA. D-dimer was determined by ELISA (threshold value 500 ng/ml). LS, including perfusion (.Q) and pseudo-ventilation (Technegas) (.V), was classified according to PIOPED, (1) immediately by the physician on duty, and (2) retrospectively by a blinded panel. A positive (19) or negative (61) diagnosis of PE was achieved in 80 patients, the prevalence of PE being 24%. Only one false-negative was noted on DDA (sensitivity=95%) but there were 42 false-positives (specificity=31%), resulting in a positive predictive value of 30% and a negative predictive value of 95%. Emergency and retrospective interpretations of LS were close (kappa=0.4). In a minority of patients, PE may be excluded with reasonable certainty if DDA is normal, resulting in a significant saving in terms of time and money.

Comparison of the long-term prognostic value of peak exercise oxygen pulse and peak oxygen uptake in patients with chronic heart failure.

OBJECTIVE: To evaluate the ratio of peak oxygen consumption to peak heart rate (peak oxygen pulse) as a predictor of long term prognosis in chronic heart failure. PATIENTS AND SETTING: 178 consecutive heart failure patients recruited to the cardiology department of a tertiary referral centre between 1986 and 1993. DESIGN: Bicycle ergometry with measurement of respiratory exchange. Mean (SD) follow up was 32 (25) months. RESULTS: Patients who died had a lower peak oxygen consumption (16.0 (5.5) v 18.0 (5.5) ml/min/kg, p = 0.05), lower indexed peak oxygen consumption (52 (14) v 60 (16)%, p = 0.006) but similar peak oxygen pulse (8.4 (2.6) v 8.4 (3.0) ml/beat, NS). The following variables were associated with a good long term prognosis: New York Heart Association class II, non-ischaemic heart failure, peak oxygen consumption > or = 17 ml/min/kg, indexed peak oxygen consumption > 63%. Peak oxygen pulse did not have predictive value. Only indexed peak oxygen consumption remained an independent predictor of survival in multivariate analysis. CONCLUSIONS: Peak oxygen pulse has lower prognostic value than peak oxygen consumption, especially when the latter is indexed to predicted values.

[Mechanisms of cardiac failure]. / Mécanismes de l'insuffisance cardiaque.

Heart failure is defined as the inability of the heart to deliver a cardiac output sufficient for the needs of the periphery. The mechanisms responsible for ventricular failure always correspond for changes in ventricular filling that may have 2 origins: decrease in ventricular systolic function, leading the ventricle to operate on the vertical part of its pressure volume relationship; primary decrease in ventricular distensibility. An increase neurohormonal stimulation participates in sodium retention and in the preservation of blood pressure. The mechanisms leading to the progressive alteration of the haemodynamic status are not perfectly known, but a progressive increase in wall stress and myocyte loss are likely to occur.

[Secondary prevention after myocardial infarction; rôle of platelet antiaggregants and hypolipemic agents]. / Prévention secondaire de l'infarctus du myocarde; place des antiagrégants plaquettaires et des hypolipémiants.

The goals of secondary prevention after myocardial infarction are to avoid the complications of infarction itself, to prevent reinfarction, to detect and treat ischaemic episodes and to slow the progression of atherosclerosis. Antiplatelet therapy, especially with aspirin, has a clearcut beneficial effect decreasing cardiovascular mortality and of non-fatal reinfarction. A metaanalysis of ten trials has shown a 25% decrease in vascular events in the long-term, irrespective of age, gender, blood pressure blood glucose level, and dosage whether low (75 to 160 mg) or moderate (160 to 325 mg/day). Apart from the irreversible inhibition of cyclooxygenase, a beneficial effect on remodelling may be observed. Lipid lowering therapy has made significant advances since the introduction of the statimes. Compared with fibrates, statines have the advantage of reducing total mortality in addition to coronary mortality, whereas the fibrates, though reducing the latter, have been reported to increase total mortality and non-coronary mortality, but in a non-significant manner. Fibrates remain the drugs of choice for the treatment of pure hypertriglyceridaemia. The mechanisms of action of the statine are diverse: effects on endothelium-dependent relaxation, haemostasis, stabilisation of the atheromatous plaque and prevention of its rupture. The cost/effectiveness ratio of aspirin and statines is very high, the latter being much more cost-effective than, for example, the treatment of mild hypertension.

[Secondary prevention after myocardial infarction; role of beta blockaders]. / Prévention secondaire de l'infarctus du myocarde; place des bêtabloquants.

The betablockers are the most important drugs in the secondary prevention after myocardial infarction. Several studies have shown that, in patients without a contraindication to these drugs, betablockers reduce the mortality and recurrence of infarction by about 25%. The best results observed in the subgroup of patients with criteria of severity (previous myocardial infarction or cardiac failure, left ventricular dysfunction, arrhythmias, residual ischaemia, occluded artery or triple vessel disease) has been shown in the APSI and BHAT studies where the reduction in mortality was almost 50% in the subgroup of patients with cardiac failure. The duration of treatment and the role of betablockers with respect to ACE inhibitors are not as clearcut in 1996.