Progression of coronary artery disease in young male post-infarction patients is linked to disturbances of carbohydrate and lipoprotein metabolism and to impaired fibrinolytic function.

AIMS: To assess determinants of coronary artery disease progression in men with previous myocardial infarction. METHODS AND RESULTS: A total of 102 unselected non-diabetic Swedish men (age 40.4 +/- 3.6, range 23-44 years) entered the study 3-6 months after a first myocardial infarction. The programme included metabolic and haemostatic investigations and routine coronary angiography at baseline, followed by re-angiography 5 years later. Of the original cohort, 76 patients underwent a second angiogram. Separate semiquantitative scoring systems were used for diffuse coronary atherosclerosis and distinct stenoses in 15 proximal coronary segments. Smoking, global severity of coronary atherosclerosis and presence of multi-vessel disease at baseline (P < 0.001) characterized patients with severe progression of both diffuse and focal lesions. Higher plasma levels of low density lipoprotein cholesterol (P < 0.01) and low density lipoprotein triglycerides (P < 0.05), a lower plasma high density lipoprotein2 cholesterol level (P < 0.05) and higher plasma plasminogen activator inhibitor-1 activity (P < 0.05), together with a high baseline stenosis score (P < 0.001) characterized patients with severe progression of coronary atherosclerosis. On the other hand, more pronounced fasting and post-prandial glycaemia (P < 0.05), together with higher plasma plasminogen activator inhibitor-1 activity (P < 0.01) characterized severe progressors with respect to coronary stenosis. Multivariate analysis identified the presence of multi-vessel disease as an independent predictor of progression of both coronary atherosclerosis (P = 0.008) and stenoses (P = 0.007), whereas a high low density lipoprotein triglyceride level (P < 0.01) was independently related to progression of coronary atherosclerosis and a high fasting glucose level (P = 0.02) to progression of coronary stenoses. CONCLUSION: Disturbances in carbohydrate and lipoprotein metabolism and impaired fibrinolytic function are associated with progression of coronary artery disease in young male post-infarction patients.

High-density lipoprotein: relations to metabolic parameters and severity of coronary artery disease.

The regulation of plasma high-density lipoprotein (HDL) cholesterol level by the joint influence of plasma lipoprotein lipids, lipoprotein lipase (LPL), hepatic lipase (HL), cholesteryl ester transfer protein (CETP), oral glucose tolerance, and postload plasma insulin and proinsulin levels was investigated in young postinfarction patients and healthy population-based control subjects. In addition, the association between HDL cholesterol and the number and severity of coronary stenoses previously reported in this cohort of young postinfarction patients was further investigated by analyzing the determinants and angiographic relations of HDL subclasses measured by gradient gel electrophoresis. The following parameters showed significant univariate relations with HDL cholesterol level in the patient group: very-low-density lipoprotein (VLDL) cholesterol and triglyceride, low-density lipoprotein (LDL) triglyceride, and postload plasma insulin concentrations, preheparin plasma LPL mass, and postheparin plasma HL activity. In the control group, significant correlations with HDL cholesterol concentration in addition to those noted among the patients were found for body mass index (BMI), LDL cholesterol level, postload plasma intact proinsulin concentration, and LPL activity in postheparin plasma. In contrast to the patients, no significant relations were noted for postload plasma insulin level and preheparin plasma LPL mass. Multiple stepwise regression analysis showed that 42% of the variability of HDL cholesterol in the patients could be accounted for by VLDL cholesterol concentration (29%), LDL triglyceride level (7%), and postheparin plasma HL activity (8%), whereas the corresponding figure in controls was 35% (VLDL cholesterol concentration [9%] and postheparin plasma HL activity [26%]. The strength of the relationships of HDL cholesterol and HDL subclasses to the coronary stenosis score was similar and statistically significant (r = .25 to .36). When the metabolic parameters that correlated with HDL cholesterol and HDL subclass concentrations in univariate analysis were used as covariates, all relations to the coronary stenosis score disappeared. This clearly indicates that the influence of triglyceride-rich lipoproteins and lipolytic enzymes needs to be considered when assessing the association between HDL cholesterol and coronary artery disease (CAD).

Insulin, intact and split proinsulin, and coronary artery disease in young men.

BACKGROUND: Glucose intolerance and hyperinsulinemia are common disturbances in nondiabetic men with premature coronary artery disease (CAD). To investigate the relation between insulin-like molecules and severity of coronary atherosclerosis, 62 consecutive nondiabetic men presenting with a first myocardial infarction before the age of 45 were studied along with 41 healthy, age-matched, male, population-based control subjects. METHODS AND RESULTS: Specific two-site immunoradiometric assays were used to distinguish intact proinsulin, (des 31,32) proinsulin, and "true" insulin in fasting plasma and during an oral glucose tolerance test (OGTT). Global coronary atherosclerosis and number and severity of distinct stenoses were determined in the patients in 15 proximal coronary arterial segments by use of separate semiquantitative classification systems. The patients had a two- to threefold increase in insulin and insulin propeptide concentrations in the fasting state as well as during the OGTT. Severity of coronary atherosclerosis correlated significantly (P < .05 to P < .01) with basal proinsulin (r = .40) and the proinsulin area under the curve (AUC) (r = .34), basal insulin (r = .31), basal C peptide (r = .30), and the glucose AUC (r = .30). In multiple stepwise regression analysis including insulin-like molecules, major plasma lipoproteins, and lipoprotein subfractions, basal proinsulin (increase in R2 = .09) and dense LDL triglycerides (increase in R2 = .10) predicted 19% of the variation of the global coronary atherosclerosis score after adjustment for age, body mass index, fasting insulin concentration, and VLDL triglycerides. CONCLUSIONS: This study shows that young, nondiabetic, male survivors of myocardial infarction are truly hyperinsulinemic during an OGTT and suggests a close association between proinsulin and coronary atherosclerosis.

Relation of plasma levels and composition of apolipoprotein B-containing lipoproteins to angiographically defined coronary artery disease in young patients with myocardial infarction.

BACKGROUND: Hypertriglyceridemia is a common metabolic disturbance in men < 45 years old with myocardial infarction. To further investigate the relation between triglyceride-rich lipoproteins and severity of coronary atherosclerosis in this subset of postinfarction patients, apolipoprotein B-containing lipoproteins of 64 consecutive patients were subfractionated in connection with coronary angiography. METHODS AND RESULTS: Density-gradient ultracentrifugation of plasma and coronary angiography were performed 4 to 6 months after the myocardial infarction. Global coronary atherosclerosis and the number and severity of distinct stenoses were evaluated by semiquantitative analysis of 15 proximal coronary segments. The majority of the patients (60%) were hypertriglyceridemic and had higher coronary scores than normotriglyceridemic patients. Of the major plasma lipoproteins, triglycerides and cholesterol in the low-density lipoprotein (LDL) fraction were associated with global coronary atherosclerosis, whereas LDL triglycerides and high-density lipoprotein (HDL) cholesterol correlated directly and inversely, respectively, with the coronary stenosis score. Plasma apolipoprotein B correlated with both coronary scores. The plasma concentrations of lipid and protein in the very-low-density lipoprotein (VLDL) subfractions (VLDL1 through VLDL3) and intermediate-density lipoprotein (IDL) did not correlate with either of the coronary scores, whereas the concentration of triglycerides in dense LDL (density > 1.040 kg/L) was strongly associated with both coronary scores. Compositional analysis of the smallest VLDL particles (VLDL3) and IDL revealed a correlation between the number of cholesteryl ester molecules in small VLDL and global coronary atherosclerosis in hypertriglyceridemic patients. CONCLUSIONS: Global coronary atherosclerosis and distinct stenoses in young postinfarction patients are associated with the number of apolipoprotein B-containing particles in plasma and the concentration of LDL triglyceride. Specifically, dense triglyceride-rich LDL particles and, in hypertriglyceridemic patients, small cholesteryl ester-rich VLDL particles relate to coronary artery disease severity.

Coronary angiographic changes during 2 years after myocardial infarction largely undetected by repeated tomographic thallium-201 scintigraphy and not reflected by clinical symptoms.

Repeated coronary angiographies and single photon emission computed tomographies (SPECT) were performed at 9 and 33 months after myocardial infarction (MI) in 47 young men. Coronary lesions were classified in eight grades with respect to the reduction of the luminal diameter. The progression and regression of two steps or more in lesions of grade 2 or more, the recanalization of coronary thrombosis and an increase in collaterals were recorded. Patients were divided into three groups with regard to (A) deterioration, (B) improvement and (C) no changes in the three major coronary regions, respectively. Overall, 23 patients (49%) showed changes between the first and the second investigation. A simplified method using summarized short-axis slices for evaluation of the thallium-201 SPECT showed a significant difference in change of regional myocardial uptake of thallium-201 between groups A and B (P = 0.047) but not between the groups A and C, in lateral myocardial regions. No significant differences were found between any of the groups in respect of the anterior or inferior myocardial regions. These findings were not explained by changes in clinical status, maximum heart rate or workload, or by changes in medication. Our results suggest that substantial changes in coronary morphology can take place during the 2 years following MI without consistent changes in clinical symptoms or regional myocardial perfusion.

Association between high levels of growth factors in plasma and progression of coronary atherosclerosis.

Although intimal proliferation of smooth muscle cells (SMC) is recognized as one of the key mechanisms in the development of atherosclerosis, our knowledge of the role of circulating growth factors for SMC in this process is limited. In the present study the plasma levels of platelet-derived growth factor (PDGF), beta-thromboglobulin (beta-TG), platelet factor 4 (PF 4) and total growth factor activity were determined in a group of 30 young postinfarction patients who had participated in an angiographic study of mechanisms associated with progression of coronary atherosclerosis. Significant correlations were found between the total growth factor activity in plasma and progression (r = 0.42, P < 0.05), as well as severity (r = 0.52, P < 0.01), of global coronary atherosclerosis. Attempts to identify the nature of the total growth factor activity indicated that less than 20% could be attributed to PDGF, the major serum mitogen for SMC. PDGF levels determined by radioimmunoassay were not related to progression or severity of global coronary atherosclerosis, but showed a significant association with the number and severity of distinct stenoses (r = 0.40, P < 0.05). Due to the retrospective design of this study, it is not possible to conclude whether there is a causal relationship between circulating growth factors and development of coronary atherosclerosis.

Susceptibility to low-density lipoprotein oxidation and coronary atherosclerosis in man.

Animal studies indicate a possible role for lipid oxidation in the development of atherosclerosis. We set out to investigate whether there was a relation between the ability of low-density lipoprotein (LDL) to resist oxidation in vitro and the severity of coronary atherosclerosis in man. 35 unselected young (mean [SD] age 39.9 [4.2] years) male survivors of myocardial infarction underwent angiography, and LDL was isolated from their plasma by density gradient ultracentrifugation. In-vitro LDL susceptibility to oxidation was assessed by determination of the lag phase for the formation of conjugated dienes in the presence of copper ions. An inverse relation was found between lag phase and quantitative estimates of global coronary atherosclerosis (r = -0.45; p less than 0.02). Multivariate analysis indicated that the lag phase for oxidative modification of LDL and LDL cholesterol concentration correlated independently with severity of coronary atherosclerosis. The lag phase for oxidation of LDL was also related to the triglyceride content of the LDL fraction (r = -0.55; p less than 0.002). The finding that susceptibility to LDL oxidation is associated with severity of coronary atherosclerosis may indicate that lipid oxidation promotes premature coronary atherosclerosis and that individuals with an LDL enriched in triglycerides are at particular risk.

Minimum heart rate and coronary atherosclerosis: independent relations to global severity and rate of progression of angiographic lesions in men with myocardial infarction at a young age.

The relations of hemodynamic factors, plasma fibrinogen concentration, serum lipoprotein levels, and clinical risk indicators to coronary atherosclerosis were studied in 56 men who had survived a first myocardial infarction before the age of 45 years and who subsequently underwent two coronary angiographies with an intervening time interval of 4 to 7 years. Presence, severity, and rate of progression of both diffuse lesions and distinct stenoses were determined by means of separate classification systems in 15 proximal coronary arterial segments. High minimum heart rate measured during a 24-hour period in connection with the reangiography was associated with progression of both diffuse lesions and distinct stenoses. High minimum heart rate also correlated positively with angiographic scores of global severity of diffuse atherosclerosis and stenoses. Progression of disease was predicted independently by minimum heart rate and low-density lipoprotein/high-density lipoprotein ratio, whereas lipoprotein A, fibrinogen levels, hypertension, smoking, and beta-adrenergic receptor blockade treatment did not discriminate between patients with and without progression.

High density lipoproteins and coronary atherosclerosis. A strong inverse relation with the largest particles is confined to normotriglyceridemic patients.

The relations of high density lipoprotein (HDL) subclasses to severity and rate of progression of coronary atherosclerosis were investigated in 60 men who had survived a myocardial infarction before the age of 45 years and who had subsequently undergone two coronary angiographies, with an intervening time interval of 4-7 years between angiographies. Five HDL subclasses with different particle sizes were determined by gradient gel electrophoresis, and the major serum lipoprotein classes were separated by preparative ultracentrifugation in connection with the second angiography. Highly significant inverse correlations were found between the plasma levels of the largest HDL particles, the HDL2b subclass, and both disease severity as observed on the second coronary angiogram (r = -0.53, p less than 0.001) and progression of coronary lesions between angiographies (r = -0.38, p less than 0.01). Grouping the patients according to the presence or absence of very low density lipoprotein (VLDL) triglyceride elevation revealed striking differences in the relations of HDL subspecies to coronary atherosclerosis between normotriglyceridemic and hypertriglyceridemic subjects. There were strong inverse correlations between the plasma HDL2b concentration and both severity of lesions (r = -0.72, p less than 0.001) and rate of lesion progression (r = -0.58, p less than 0.01) in the normotriglyceridemic patients, whereas this relation was absent in subjects with hypertriglyceridemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood volume after coronary artery bypass grafting.

Patients with stable angina pectoris are reported to have a markedly reduced blood volume (BV). In the present study, average BV was still 19% less than that predicted in 77 men examined 5 years after coronary artery bypass grafting. Beneficial effects of the operation such as relieved angina, absence of medication, complete revascularization status at repeat angiography, and restored physical fitness were not found to be associated with a normalization of the BV. No significant correlation was found between BV and body weight, heart volume, exercise capacity, ejection fraction or left ventricular end-diastolic pressure. The reduced BV in patients with angina pectoris after successful revascularization and the absence of correlation with physiological variables indicate a persisting disturbed regulation mechanism.

Polar presentation of coronary angiography and thallium-201 single photon emission computed tomography. A method for comparing anatomic and pathologic findings in coronary angiography with isotope distribution in thallium-201 myocardial SPECT.

Individual results of coronary angiography were compared with tomographic myocardial scintigraphy (SPECT) in 99 patients. Coronary angiography findings were transferred to polar maps. Borders between arteries were assigned angles in a coordinate system constructed as a compass-rose. Areas perfused by different arteries were described by sectors. Findings were visually compared with the perfusion defects in a polar presentation of thallium-201 SPECT also described by angles. The mean values and SD for the angles representing arterial borders and perfusion defects were presented. The left ventricular myocardium was perfused by 3 coronary arteries in 92/99 patients. Dominant left artery was present in 7/99 patients; 79 perfusion defects were related to 118 arterial sectors 84 per cent had totally or partially matched stenotic arteries. Inter-individual differences in distribution of coronary arteries influence the localization of perfusion defects in myocardial SPECT and can be estimated with this polar presentation method.

Coronary endarterectomy--angiographic and clinical results.

Of 75 patients who underwent coronary endarterectomy, 16% had left main stem stenosis, 4% one-vessel, 27% two-vessel and 53% three-vessel disease. On average 2.9 grafts per patient were inserted, in conjunction with 82 manual endarterectomies (38 right coronary, 35 left anterior descending, 9 circumflex branches). In 68/75 cases (91%) the endarterectomy was not preplanned and in 39 cases (52%) greater than or equal to 3 cm of the atherosclerotic core was removed. All four early deaths (5%) followed endarterectomy of LAD. Acute perioperative myocardial infarction was confirmed in 19% and probable in further 8%. At angiography 1-139 (median 25) months postoperatively, all three internal mammary artery grafts and 19/34 saphenous vein grafts (56%) to endarterectomized vessels were patent, though in 4 of the 19, the coronary artery was occluded distal to the anastomosis. In addition 17/18 conventional internal mammary artery (94%) and 48/59 conventional saphenous vein grafts (81%) were patent. The vein graft patency rate was not significantly influenced by postoperative anticoagulant therapy, but was significantly increased among patients with relief of angina: 44% reported freedom from angina and 92% at least some relief after a median of 3 years. The 5-year and 10-year survival rates were 85% and 68%. Despite the increased risk, endarterectomy can be recommended for severely diseased major coronary arteries.

Angiographic studies of internal mammary artery grafts 11 years after coronary artery bypass grafting.

Of 99 consecutive patients with 101 internal mammary artery grafts, 91 of 97 hospital survivors (94%) underwent angiography 2 weeks after operation, 84 of 96 survivors (88%) after 1 year, 66 of 88 survivors (75%) after 5 years, and 37 of 69 survivors (54%) after 11 years (range 10 to 13 years). Thirty-five of the 37 patients who consented to a fourth postoperative angiographic study (95%, confidence limits 86% to 100%) still reported relieved angina 11 years after the operation, and seven patients (19%, confidence limits 5% to 33%) were completely free of symptoms. Angiographic findings in 30 patients with symptoms of angina were progression of the coronary artery disease in 22, (73%, confidence limits 56% to 91%), occluded or stenosed grafts in nine (30%, confidence limits 12% to 48%), and nonbypassed obstructions in six patients (20%, confidence limits 4% to 36%). The cumulative 11-year patency rate was 88%, confidence limits 81% to 95%, for internal mammary artery grafts and 61%, confidence limits 45% to 76% for saphenous vein grafts. Six of 18 saphenous vein grafts (33%, confidence limits 19% to 58%) occluded in the interval between 5 and 11 years after operation, and gross wall irregularities were observed in six of the 12 patent saphenous vein grafts. Unligated side branches and stenosis of the internal mammary artery did not prevent long-term graft patency. Internal mammary artery graft failures were related to technical errors during the operation and occurred when the internal mammary artery was used to bypass a low-grade coronary artery stenosis. In one patient, regression of a coronary artery stenosis was associated with a marked decrease in luminal size of the internal mammary artery graft before the 5-year follow-up. This single internal mammary artery graft became occluded in the interval between 5 and 11 years after the operation. Eleven of 36 internal mammary artery grafts (31%, confidence limits 14% to 47%) increased 15% to 40% in luminal diameter as a result of increased myocardial blood demand before the 11-year follow-up.

Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction.

Measurements of haemostatic function and metabolic and angiographic indices of risk were included in a prospective cohort study of variables predictive of recurrences within 3 years in 109 unselected men with a first myocardial infarction (MI) before the age of 45. In the course of follow-up, 16 patients had at least one reinfarction (fatal recurrences in 9 and nonfatal in 7) and 1 died suddenly. High plasma concentrations of the fast-acting plasminogen activator inhibitor were independently related to reinfarction along with dyslipoproteinaemia involving VLDL and HDL, poor left ventricular performance, and multiple-vessel coronary artery disease. Besides being independently associated with reinfarction in the present population, high triglyceride levels were possibly connected with a predisposition to thrombosis through a coexisting high level of plasminogen activator inhibitor. The data indicate that reduced fibrinolytic capacity due to increased plasma levels of the plasminogen activator inhibitor predisposes to reinfarction in a complex interplay with atherogenic factors, multiple coronary lesions, and compromised left ventricular function.

Delayed left ventricular free wall rupture complicating coronary artery bypass surgery. A case report.

Rupture of the left ventricular free wall is a not uncommon life-threatening complication of acute myocardial infarction and after prosthetic mitral valve replacement. To our knowledge, no case of left ventricular rupture after coronary artery bypass surgery has been reported. A case is now described in which coronary artery bypass grafting was complicated by delayed rupture, which was successfully repaired. Different etiologic factors are discussed, but the cause considered most likely was trauma from elevation of and traction on the heart in exposure of its posterior aspect.

Does post-exercise ST depression reflect local ischemia or some global effect in the left ventricle?

As exercise-induced ST depressions are most frequent and marked in lead V5 independent of which single coronary artery is obstructed, some other mechanisms of ST depressions than local ischemia should be searched for. Left ventricular hemodynamics during exercise was studied in two groups of patients with severe effort angina, 19 with and 12 without ST depression after exercise (STAE). During supine exercise until angina, stroke index became significantly lower (37 vs. 52 ml/m2) and left ventricular end-diastolic pressure (LVEDP) significantly higher (40 vs. 30 mmHg) in the STAE group. The best discriminator was the early diastolic pressure (LVeDP) (22 vs. 11 mmHg), which is interpreted as a sign of a more ischemic ventricle in the STAE group. The sum of STAE in all leads is correlated to LVeDP but not to LVEDP during exercise. The link between the significant ischemia in various locations and STAE appearing most frequently and markedly in V5 seems to be some global mechanism as the occurrence of STAE and the height of the R wave were positively correlated in the various leads. As STAE in coronary heart disease shows similar configuration and distribution as in aortic valvular stenosis and digoxin medication of healthy subjects, a possible link could be the compensatory increase in contractility in non-ischemic parts of the ventricle.

Comparative study of echo- and angiocardiographically determined regional left ventricular wall motion in recent myocardial infarction.

We have studied regional left ventricular (LV) wall motion with M-mode, cross-sectional (2D) echocardiography and LV angiography in 50 patients with a recent myocardial infarction. Regional LV wall motion was evaluated according to a 9-segment model. 2D echocardiography permitted information from all, M-mode echocardiography from 8 and angiocardiography from 6 segments. Wall motion was visually classified according to a 5-grade scale. Systolic mean wall velocity (V mean) and its deviation from normal values was calculated from M-mode registrations. 2D echo- and angiocardiography were evaluated in 35 patients and M-mode echo- and angiocardiography in 37. Total agreement in segmental wall motion was seen in 61% when comparing 2D echo- with angiocardiography, and a further 35% showed 1-grade and 4% a 2-grade difference. Corresponding values for comparisons between M-mode echo- and angiocardiography were 59%, 32% and 9%, respectively. Discrepant wall motion grading from the 2D echo- and angiocardiography comparison was seen in 94 of 243 (38%) segments. Approximately one quarter of the discrepancies were either due to minor differences in evaluation or due to wall motion scoring. Discrepancies were seen in 83 of 202 (41%) segments when M-mode echo- and angiocardiography were compared. In 42 (21%) these were attributed to obvious M-mode errors and in 8 (4%) to left ventricular angiography. In 20 further segments, nonidentical subsegmental evaluations were the probable cause of discrepancies, and in 8 (10%) ischaemia during the angiocardiography. Five segmental discrepancies remained unexplained.

ST depression and left ventricular haemodynamics during exercise in patients with angina pectoris.

The mechanism of ischaemic ST depression and the cause of its low sensitivity to coronary artery stenosis are not well understood. Of 30 patients with severe stable effort angina, 19 (63%) showed ischaemic ST depressions after exercise (the STAE group) and 11 did not. The highest load during the symptom-limited exercise test and the heart rate on that load did not differ between the two groups. The clinical characteristics and angiographic findings were also similar, but the findings at heart catheterization differed during exercise (in supine). Although the load was similar, the stroke index was significantly lower (38 vs. 53 ml/m2 BSA) and the left ventricular end-diastolic pressure rose to a significantly higher value in the STAE group (40 vs. 32 mmHg). When STAE occurred, they were exclusively or concomitantly present in chest lead 5. These findings suggest that ischaemic STAE may not reflect regional ischaemia but the consequent left ventricular dysfunction. The mechanism may, for example, be that a sufficiently elevated left ventricular diastolic pressure causes a global subendocardial ischaemia.

Prediction of left main coronary artery stenosis by exercise electrocardiography.

The possibilities of predicting left main coronary artery stenosis (LMCAS) by the T wave pattern in exercise ECG were studied in a consecutive series of patients with stable angina pectoris and were compared to the predictive ability of ST criteria. After exclusion of patients with interfering diagnoses and digitalis treatment, 146 patients remained; 16 of them had LMCAS. Appearance or increase of a biphasic or negative T wave in leads V2-6 2 min after exercise detected 63% of the LMCAS, and the predictive value of a positive test was 36%. The sensitivity of the ST criteria was only 38% and the predictive value 26%. The observer concordance was 98% for the T wave and 84% for the ST criteria. These T wave criteria are at least as sensitive and predictive as the ST criteria and easier to apply.