Harald Tillmanns

A New Promoter Polymorphism in the Gene of Lipopolysaccharide Receptor CD14 Is Associated With Expired Myocardial Infarction in Patients With Low Atherosclerotic Risk Profile

Recent findings suggest that inflammation plays a role in atherosclerosis and its acute complications. Cellular response in infections with Gram-negative bacteria is mediated by bacterial lipopolysaccharide (LPS), which activates monocytes to expression of cytokines, growth factors, and procoagulatory factors via LPS receptor CD14. Endothelial cells and smooth muscle cells are stimulated by a complex of LPS and soluble CD14. In this study, LPS receptor CD14 was analyzed to find genetic variants and check them for an association with coronary artery disease or myocardial infarction (MI). When screening the CD14 gene by single-strand conformation polymorphism analysis, a promoter polymorphism was detected and confirmed as a T-to-C exchange at position -159. We determined the genotypes of 2228 men who had undergone coronary angiography for diagnostic purposes. Within the total study group there was no significant association of either genotype with MI or coronary artery disease. However, in a subgroup with low coronary risk (normotensive nonsmokers), a relative risk for MI in probands homozygous for the T allele could be evaluated (OR, 1.6; 95% CI, 1.0 to 2.4; P<0.05). The association was even stronger in low-risk patients older than 62 years (OR, 3.8; 95% CI, 1.6 to 9.0; P<0.01). In conclusion, we describe a new CD14 promoter polymorphism that is associated with MI, especially in older patients with a low atherosclerotic risk profile.

Intracoronary thrombolysis in acute myocardial infarction: Duration of ischemia as a major determinant of late results after recanalization

To define the effect of duration of myocardial ischemia on the late results after successful thrombolysis in patients with acute transmural myocardial infarction, data on 39 patients treated with intracoronary infusion of streptokinase were analyzed. Patients with successful recanalization of infarct vessel and a time lag between onset of symptoms and reperfusion less than 4 hours were assembled in group A1 (n = 15), and patients with successful recanalization but a time lag of more than 4 hours (n = 17) in group A2. Group B consisted of 7 patients with unsuccessful thrombolysis. Coronary anatomy, left ventricular volume, ejection fraction, and regional ejection fraction of infarct area were determined before and 4 weeks after thrombolysis with cineangiography. Serum creatine kinase activity was serially measured. Before intervention, the groups were comparable with regard to age, Killip class, localization of infarction, incidence of previous infarction, Gensini score of coronary anatomy, left ventricular volume, ejection fraction, regional ejection fraction of infarct area, and serum creatine kinase activity. Four weeks after the intervention, patients in group A1 had a higher ejection fraction (59%) and regional ejection fraction of infarct area (39%) than patients in group A2 (ejection fraction: 49%, p less than 0.05; regional ejection fraction: 26%, p less than 0.05) and group B (ejection fraction: 44%, p less than 0.05; regional ejection fraction: 25%, p = 0.05). Peak serum creatine kinase activity measured during the acute illness was lower in group A1 (764 U/liter) than in group A2 (1,580 U/liter, p less than 0.05) and group B (2,106 U/liter, p less than 0.05). Thus, contraction of infarct area was improved and enzymatic estimate of infarct size was reduced after early as compared with late reperfusion in patients with acute myocardial infarction.

Activation and decreased deformability of neutrophils after intermittent claudication.

This study investigated local alterations in neutrophil activation and deformability after intermittent claudication. In 17 patients with one-sided peripheral arterial occlusive disease, neutrophil count, proportion of activated neutrophils (by nitro blue tetrazolium test), and neutrophil filterability as a measure of passive deformability were assessed in the femoral arterial and venous blood of the diseased leg and in the femoral venous blood of the healthy leg (n = 10). The values were obtained at rest, immediately after claudication, and 10 minutes after claudication induced by repetitive toe stands. Immediately after exercise, the arterial and venous blood differences in the diseased leg were 1) neutrophil count, 9% (95% confidence interval [CI], 5-14%; relative increase in the venous blood compared with arterial blood); 2) the proportion of activated neutrophils, 26% (CI, 10-42%); and 3) the neutrophil filterability, -10% (CI, -4% to -15%). At rest and 10 minutes after exercise, neutrophil parameters did not differ significantly between the femoral arterial and venous blood. Furthermore, no arterial and venous blood differences in the neutrophil parameters were found in the healthy leg. In addition to local changes, systemic changes occurred immediately after exercise. In the femoral arterial blood, the total neutrophil count had risen by 13% (CI, 8-18%), the proportion of activated neutrophils had risen by 41% (CI, 25-58%), and average neutrophil rigidity had risen 17% (CI, 11-22%) compared with the values obtained before exercise. At 10 minutes after exercise, all neutrophil parameters were still elevated. We conclude that even short periods of ischemia, as in intermittent claudication, cause local alterations in neutrophil function and distribution.

Gene Polymorphism but not Catalytic Activity of Angiotensin I–Converting Enzyme Is Associated With Coronary Artery Disease and Myocardial Infarction in Low-Risk Patients

BACKGROUND An insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene has been postulated to be associated with an increased risk of coronary artery disease (CAD) and myocardial infarction (MI). METHODS AND RESULTS In the present study, the effects of I/D gene polymorphism and of ACE activity on CAD and MI were investigated in 920 individuals who underwent coronary angiography for diagnostic purposes. In the total population and in all CAD and MI groups, a strong association was observed between the gene polymorphism and ACE activities; DD genotypes had approximately twofold higher ACE activities than II genotypes. Although classic risk and protective factors of CAD and MI were identified, associations of ACE genotype and of ACE activity to CAD and MI were not detected in the total population. Among subjects defined to be at lower risk of MI by low body mass index and low cigarette consumption, however, an association of the DD genotype with MI was found. Exclusion of individuals with triglyceride levels > 140 mg/dL and cholesterol levels > 180 mg/dL revealed an association of the DD genotype with CAD. An association of the ACE activity with CAD or MI could not be demonstrated in any of the low-risk populations. CONCLUSIONS Increased ACE activity obviously is not a risk factor of CAD or MI. The importance of the deletion polymorphism for the development of CAD and MI may be restricted to individuals without classic risk factors.

Time-Course Analysis on the Differentiation of Bone Marrow-Derived Progenitor Cells Into Smooth Muscle Cells During Neointima Formation

Objective—Bone marrow-derived progenitor cells have been implicated to contribute to neointima formation, but the time course and extent of their accumulation and differentiation into vascular cells and, most importantly, the long-term contribution of bone marrow-derived progenitor cells to the vascular lesion remain undefined. Methods and Results—Wire-induced injury of the femoral artery was performed on chimeric C57BL/6 mice transplanted with bone marrow from transgenic mice expressing enhanced green fluorescence protein, and vessels were harvested at 3 days, 1, 2, 3, 4, 6, and 16 weeks after dilatation (n=8 animals per time point). Using high-resolution microscopy, we unexpectedly found that the expression of smooth muscle cell or endothelial cell markers in enhanced green fluorescence protein positive cells was a very rare event. Indeed, most of the enhanced green fluorescence protein positive cells that accumulated during the acute inflammatory response were identified as monocytes/macrophages, and their number declined at later time points. In contrast, a substantial fraction of highly proliferative stem cell antigen-1 and CD34+ but enhanced green fluorescence protein negative and thus locally derived cells were detected in the adventitia. Conclusion—These data provide evidence that the differentiation of bone marrow-derived progenitor cells into smooth muscle cell or endothelial cell lineages seems to be an exceedingly rare event. Moreover, the contribution of bone marrow-derived cells to the cellular compartment of the neointima is limited to a transient period of the inflammatory response.

Residual 201Tl Activity in Irreversible Defects as a Marker of Myocardial Viability Clinicopathological Study

BACKGROUND The objective of the present study was to characterize the relation between the residual 201Tl activity in irreversible perfusion defects and the extent of irreversible myocardial damage indicated by the volume fraction of myocardial interstitial fibrosis in patients with chronic coronary artery disease. METHODS AND RESULTS Stress planar 201Tl scintigraphy with tracer reinjection at rest was performed in 37 patients with > or = 75% stenosis of the left anterior descending coronary artery, and anteroseptal 201Tl activity was quantified by computer-assisted placement of regions of interest from the serial myocardial images. During coronary artery bypass grafting (performed within 6 +/- 3 weeks after scintigraphy), two transmural biopsy specimens were taken from the anterior wall of the left ventricle and the amount of interstitial fibrosis was assessed by use of light microscopic morphometry. A wide spectrum of interstitial fibrosis was obtained, ranging from 15 vol% to 60 vol%. Interstitial fibrosis was similar in patients with reversible (n = 11) or irreversible (n = 15) tracer defects in conventional stress-redistribution images. However, interstitial fibrosis was significantly lower in patients who had enhanced regional 201Tl activity after tracer reinjection compared with those who did not have enhancement of tracer activity after reinjection (28 +/- 8 vol%, n = 7, versus 41 +/- 12 vol%, n = 8; P = .031). The correlation between relative poststenotic 201Tl activity and interstitial fibrosis after tracer reinjection was significantly improved compared with conventional redistribution images (r = -.622 versus r = -.851, n = 15; P < .01). CONCLUSIONS The present data demonstrate that the level of regional 201Tl activity in redistribution and, in particular, reinjection images is significantly related to the mass of preserved viable myocytes in poststenotic left ventricular myocardium. Therefore, the residual 201Tl activity provides information about viability within irreversible perfusion defects and may itself serve as marker of myocardial viability.

Effect of Successful Thrombolytic Therapy on Right Ventricular Function in Acute Inferior Wall Myocardial Infarction

In 19 patients undergoing intracoronary fibrinolytic therapy for acute myocardial infarction, the site of coronary obstruction was in the proximal right coronary artery. Time between onset of symptoms and hospitalization was less than 4 hours. These patients were studied prospectively by radionuclide techniques immediately after admission, 48 hours and 4 weeks after AMI. Right and left ventricular (RV and LV) ejection fractions (EF) were calculated from gated blood pool scintigrams and the size of the LV perfusion defect was assessed by thallium-201 scintigraphy. Before the intervention, RV performance was significantly lower (RVEF 29 +/- 8%) than normal (53 +/- 7%). The size of the LV perfusion defect was relatively small (less than 25% of LV circumference), and as a consequence, LV pump function was only marginally impaired (LVEF 54 +/- 11%). Recanalization of the infarct artery was achieved in 12 patients (group A); in 7 patients the infarct artery remained occluded (group B). Early after the intervention (48 hours), RV performance in group A recovered significantly (RVEF: 30 +/- 9% vs 39 +/- 7%, p less than 0.01), and further improvement was noted at 4 weeks (RVEF 43 +/- 5%, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Pressure measurements in the terminal vascular bed of the epimyocardium of rats and cats.

In order to measure pulsatile pressures in microvessels of the left ventricular myocardium, we developed a method that extends the use of the resistance servo-nulling technique to the beating mammalian heart. In 9 cats and 25 rate, we studied the terminal vascular bed of the ventricular epimyocardium by incident light in vivo microscopy, using a highly sensitive television camera tape system. Following intravenous administration of fluorescent dextrans, microvascular diameters and flow patterns could be observed continuously. Intrahuninal pressures in the microvascular bed of the cat and rat heart were determined by micropuncture and a micropipet servo-nulling sy stem. In contrast to larger coronary arterioles (diameters 160–300 μm), smaller arterioles with diameters <100 μm showed a considerable pressure drop between ascending aorta and the site of pressure recording. In venules of the epimyocardium, the pressure curve exhibited a late systolic peak, occurring just before aortic valve closure. Maximal coronary arteriolar dilatation by dipyridamole (0.5 mg/kg body weight, iv) provoked only a slight increase in systolic coronary venular pressure (controls 25 ± 3 mm Hg, dipyridamole 27 ± 6 mm Hg). On the other hand, positive inotropic intervention by intravenous infusion of dobutamine (6 μg/kg per min), as well as the application of norepinepht-ine, resulted in a marked rise of systolic coronary venular pressure. These data suggest that the contractile state of the myocardium and left ventricular afterload are the major determinants of systolic coronary venular pressure.

Uptake and turnover of L-(13N)-glutamate in the normal human heart and in patients with coronary artery disease

L-(13N)-glutamate (4–8 mCi) was administered IV to 27 patients with coronary artery disease and to 12 control subjects.Quantitative whole body imaging of the 13N label was performed in 31 individuals at different time intervals following the injection. Initial uptake of the total myocardium was estimated to be 5.0±0.88% of the dose. Standardized areas of reduced size on the projection plane contained 2.38±0.41% of the total dose in control subjects and 2.67±0.49% in coronary patients. Subsequent imaging exhibited significant differences in the dynamic behavior of both groups: 13N activity loss within 10 min was 3.2±4.2% of the initial value in control subjects and 16.0±9.8% in coronary patients. In individual cases a high myocardial accumulation of the 13N label was observed in regions of reduced 201Tl uptake. The findings are explained by an augmented extraction efficiency in cases of flow reduction.Glutamate utilization may be involved in metabolic adaptations of the myocardium to chronic or repetitive ischemia and may be worthy of further investigation by positron emission tomography.

The Stromelysin-1 5A/6A Promoter Polymorphism Is a Disease Marker for the Extent of Coronary Heart Disease

Background. Matrix metalloproteinases, such as stromelysin-1, are implicated in the pathogenesis of coronary artery disease (CAD) and acute myocardial infarction (MI). A 5A/6A promoter polymorphism can regulate the transcription of the stromelysin-1 gene in an allele-specific manner. Evidence has been presented that the 6A allele is associated with the progression of coronary heart disease (CHD). In contrast, the 5A allele may be linked to the risk of MI. Results. To analyse the relation of the 5A/6A polymorphism with the risk and severity of CHD and the risk of MI, a case-control study of 515 healthy controls and 1848 participants who underwent coronary angiography for diagnostic purposes was conducted. In the total sample, the mean CHD scores—according to Gensini—were different between 5A/6A genotypes: 5A5A homozygotes had the lowest, 6A6A genotypes the highest and 5A6A heterozygotes intermediate scores. These differences were even more pronounced when the participants were restricted to individuals with a high coronary risk profile (high apoB levels, high Lp(a) levels, high glucose levels, combinations of either high apoB and Lp(a) levels or high apoB, Lp(a) and glucose plasma levels). Mean values were used as cut points for high-risk populations, respectively. In contrast, the 5A allele was not associated with the risk of CHD or MI. Even when angiographically controlled individuals without MI were compared with MI patients in subpopulations of participants with no, single, double and triple vessel disease, the frequencies of the 5A/6A and/or the 5A5A genotypes were not higher in each subgroup, respectively. Conclusions. The present results do not confirm an association of the 5A allele with the risk of MI, observed in another investigation, but strengthen the hypothesis of earlier studies that the 6A allele is a disease marker for progression of coronary heart disease. Further investigations should evaluate whether 6A allele carriers and especially 6A homozygotes might benefit from a more aggressive therapy against CHD progression.