Diffuse intimal thickening of coronary arteries in slow coronary flow

Intravascular ultrasound imaging can detect intimal thickening and is suitable for detection of early atherosclerosis, which cannot be detected by conventional angiography. The aim of the present study was to investigate the epicardial coronary morphology and intracoronary pressure in relation to slow coronary flow (SCF). The study population consisted of 19 patients with SCF [11 (57.9%) females; 55.95 +/- 9.42 years]. Proximal, middle, distal and mean total vessel area, lumen area, intima + media area (IMA), percent IMA, and maximal intima + media (I + M) thickness were calculated and compared to healthy subjects. Proximal, middle, distal and mean I + M thickness, IMA, and % IMA of patients with SCF were found to be significantly higher than those of control subjects. Longitudinally extended massive calcification throughout the epicardial arteries was found in 13 (68.49%) patients with SCF and regional calcification was found in 6 (31.6%) patients with SCF. Proximal and distal pressure gradients of patients with SCF were determined to be 15.84 +/- 12.11 mmHg in the intracoronary pressure measurements. Fractional flow reserve values were significantly lower than the normal population (0.83 +/- 0.13, P < 0.0001). This study indicates that patients with SCF have diffuse intimal thickening, widespread calcification along the vessel wall and atheroma which does not cause luminal irregularities in coronary angiography, and a pressure gradient between proximal and distal segments of epicardial coronary arteries with SCF. Based on these results, we believe that SCF may be a form of diffuse atherosclerosis involving both the microvascular system and epicardial coronary arteries.     

Infection-associated intimal thickening in the coronary arteries of children

OBJECTIVES: based on autopsy material from children this study investigated the possible relationship of clinically evident infection prior to death with intimal thickening of the coronary arteries. BACKGROUND: viral infections are suggested to be associated with intimal thickening in the coronary arteries both in animals and man. METHODS: the coronary arteries were examined in 175 autopsied children 0-15 years of age (median 7 days). Semi-serial cross sections of the coronary arteries were screened for maximal intimal thickening at 0.2 mm intervals. The length of the internal elastic lamina, the areas of arterial media and intima were measured from cross-sections. Irregular linings of the arteries were mathematically transformed to circles. The percentage of intimal and musculoelastic layer area to luminal area encircled by arterial media was calculated. RESULTS: intimal thickening increased with age but was also associated with the presence of infectious disease at death. Already in the newborn children, who died shortly after the birth, the percentage of intimal and musculoelastic layer area to luminal area encircled by arterial media was big, maximally 55%. In the left coronary artery the mean percentages were 32 and 21% in the groups with viral and bacterial infections, respectively as compared to 16% in the group with no evidence of infection. CONCLUSION: infections in general and viral infections in particular, seem to be associated with intimal thickening, which may predispose coronary arteries to atherosclerosis. Atherogenesis might have a rapid dynamic component.     

Vitamin C attenuates abnormal vasomotor reactivity in spasm coronary arteries in patients with coronary spastic angina

Objectives. This study sought to examine effect of vitamin C, an antioxidant, on the abnormal vasomotor reactivity in spasm coronary arteries.Background. Oxygen free radicals generated in the arterial walls have been shown to cause endothelial vasomotor dysfunction.Methods. Responses of the epicardial arterial diameters of the left coronary arteries to the intracoronary infusion of acetylcholine (ACh) (10 and 50 μg/min) were measured by quantitative coronary angiography before and during combined intracoronary infusion of vitamin C (10 mg/min) or saline as a placebo in 32 patients with coronary spastic angina and in 34 control subjects.Results. Vitamin C infusion suppressed the constrictor response of the epicardial diameter to ACh in spasm coronary arteries but had no significant effect in the control coronary arteries (percent change in distal diameter in response to 10 μg/min of ACh [constriction (−), dilation (+), mean ± SEM] before vitamin C: −8.2 ± 2.9% in spasm arteries, +8.4 ± 2.9%1 in control arteries; during vitamin C: +0.2 ± 3.8%1 in spasm arteries, +7.2 ± 1.3%1 in control arteries [1p < 0.01 vs. spasm arteries before vitamin C]). The coronary sinus–arterial difference in plasma thiobarbituric acid reactive substances during ACh infusion, an indicator of lipid peroxidation in coronary circulation, was higher in patients with coronary spastic angina than in control subjects (p < 0.01) but was suppressed in patients with coronary spastic angina to comparable levels in control subjects by combined infusion of vitamin C. Saline infusion had no effect.Conclusions. The results indicate that vitamin C attenuates vasomotor dysfunction in epicardial coronary arteries in patients with coronary spastic angina. Oxygen free radicals may at least in part play a role in the abnormal coronary vasomotor reactivity in response to ACh in spasm coronary arteries.     

Plasma fibrinogen level is related to intimal pathology in coronary spastic angina

Fibrinogen promotes atherosclerosis and thrombosis. To evaluate the possibility that plasma fibrinogen levels represent a marker of atherosclerosis or are a predictor of cardiac events in coronary spastic angina, we studied the relation between plasma fibrinogen values and coronary angioscopic findings. We measured plasma fibrinogen in 20 patients with coronary spastic angina, 19 patients with chronic stable angina and 22 control subjects. Percutaneous angioscopic examination was performed in the patients with coronary spastic angina at the site of vasospasm induced by acetylcholine and in those with chronic stable angina at the site of organic coronary stenosis. Fibrinogen levels were significantly higher in those with coronary spastic angina (308.4±83.0 mg/dl) and chronic stable angina (289.4±69.3 mg/dl) than in the controls (239.5±49.9 mg/dl) (p<0.01, coronary spastic angina vs control;p<0.05 chronic stable angina vs control). Angioscopy showed intimal injuries (hemorrhage, flap, thrombus and/or ulcer) in 9 of the 20 (45%) coronary spastic angina patients, and flap or ulcer in 2 of the 19 (11%) chronic stable angina patients. Hemorrhage and/or thrombus were shown in 6 of the 20 coronary spastic angina patients. In the coronary spastic angina group fibrinogen levels were significantly higher (p<0.05) in those with than without hemorrhage and/or thrombus (365.3±97.4 mg/dl vs. 238.9±65.4 mg/dl). These results suggest that elevated fibrinogen levels in patients with coronary spastic angina are associated with atherosclerosis and thrombus formation.     

Intimal thickening of human femoral arteries with special regard to elastin, Part 1. Diffuse intimal thickening due to growth and age

In infants, human femoral arteries display seam-like internal elastic lamina (IEL) covered with endothelium on the luminal side and with smooth muscle cells (SMC) on the medial side. At birth the growth of IEL is finished, correlated with a loss of microfibrils (MF) at the periphery. With the onset of the postnatal vessel growth the joints of IEL seem to be mechanically widened until they have the appearance of gaps with progressing age. After the age of 40 years there are often rod-like crystallites in the IEL, probably composed of cholesterol esters. A small first consecutive lamina (CL) can be seen already in childhood; it enlarges until the 3rd decade of life and is interpreted as a substitute to the "fragmented" IEL. After the 5th decade of life the first CL is arranged within the intima at a certain distance from the IEL and consisting of loosely arranged elastic fibrils. In very old arteries (beyond the 8th decade of life) gaps are rarely seen in the first CL. In individuals over the age of 30 years, the space between IEL and the first CL is occupied by smooth muscle cells (SMC) which are tightly packed. Additional CLs above the first CL can be found in elderly individuals, there CL obviously contribute to the intimal thickening. The ultrastructure of the elastic elements of the vessel wall and their possible function are discussed.     

Limitations of medical therapy in patients with pure coronary spastic angina

OBJECTIVES: To assess the efficacy of medication for the treatment of pure coronary spastic angina, 71 consecutive patients with this diagnosis who had undergone coronary arteriography in a hospital with a follow-up of at least 2 years were studied. Methods and results: All 71 patients without significant organic stenosis were treated with long-acting calcium antagonists. The disappearance of chest pain attacks while receiving medical therapy was observed in 27 patients (38%), whereas the remaining 44 patients (62%) had chest pain attacks. Of special interest, 30 patients had more than one attack per month irrespective of the administration of calcium antagonists or isosorbide dinitrate. Medical treatment showed a good response in female patients (63% vs 31%, respectively; p < 0.05) and those with ST-segment elevation during selective spasm provocation tests (63% vs 30%, respectively; p < 0.05). In contrast, patients with a longer history of chest pain attacks before hospital admission and those with diffuse spasms (77% vs 34%, respectively; p < 0.01) had poor responses to medical treatment. In this study, neither sudden death nor acute myocardial infarction was observed during the follow-up periods. CONCLUSION: The limitations of medical therapy, including the administration of long-acting calcium antagonists, were observed in 30 of 71 patients (42%) with pure coronary spastic angina. Medical treatment was effective in only 38% of patients with pure coronary spastic angina in Japan.     

An aldose redutase inhibitor prevents the intimal thickening in coronary arteries of galactose-fed beagle dogs

Aims/hypothesis. Although increased polyol pathway activity has been implicated in the pathogenesis of diabetic microangiopathy, the relation with diabetic macroangiopathy remains unclear. Galactose feeding is known to stimulate the polyol pathway and to develop abnormalites similar to those in diabetic microangiopathy. Our study was conducted to investigate whether an activation of polyol pathway by long-term treatment with galactose produced morphological changes in coronary arteries of dogs and the effect of an aldose reductase inhibitor, epalrestat, was also studied.¶Methods. Dogs received either normal chow or chow containing 30 % galactose with or without epalrestat given orally (20 or 50 mg · kg^–1). After 44 months, morphometric analyses of coronary arteries were carried out and the galactitol contents in aortas were measured.¶Results. The ratio of areas of the intimal layer to those of the medial layer, an indicator of intimal thickening, was statistically significantly increased in galactose-fed dogs compared with control dogs. Galactose-fed dogs had a remarkable accumulation of galactitol in their aortas. These morphological and biochemical deficits were reduced by treatment with epalrestat.¶Conclusion/interpretation. This report morphologically shows diabetes-like macrovascular abnormalities in galactosaemic animals, suggesting that polyol pathway hyperactivity is closely related to the development of diabetic macroangiopathy, which could be prevented by aldose reductase inhibition. [Diabetologia (1999) 42: 1404–1409]     

Inflammation of the coronary arteries in patients with unstable angina

During surgery, 21 patients undergoing coronary artery bypass for unstable angina were found to have "red lines" overlying one or more coronary arteries. Adventitial biopsies showed vascular distention and inflammatory cells. The group was followed for an average of 54 months (14 to 68 months). There were no operative deaths. Recurrent myocardial ischemia developed in 38.1% (8/21); recurrent angina developed in 23.8% (5/21) and are being treated medically; myocardial infarction occurred in 9.5% (2/21); and reoperation was required in 4.8% (1/21). There was also one late death from a brain tumor. We suggest that the presence of adventitial inflammation may represent an aggressive, variant form of atherosclerosis and a less favorable clinical prognosis.     

Clinical characteristics of female patients with coronary spastic angina: comparison with male patients

There are many patients with vasospastic angina who have minor atherosclerosis, and in Japan the majority of them are male. No data exist concerning sex differences in patients with coronary spastic angina, so the present study sought to clarify the clinical characteristics between male and female patients with vasospastic angina. Between April 1991 and June 1998, 204 consecutive patients were diagnosed with vasospastic angina and of these, 26 (12.7%) were female. An acetylcholine test was performed with incremental doses of 20, 50, and 80 microg injected into the right coronary artery and 20, 50, and 100 microg into the left coronary artery. Ergonovine was injected in a total dose of 40 microg into the right coronary artery and 64 microg into the left coronary artery. Coronary spasm was defined as 99% or more luminal narrowing accompanied by ischemic changes on ECG. Compared with male patients, female patients had less organic stenosis (12 vs 33%, p<0.05), less history of smoking (15 vs 85%, p<0.01), and fewer focal spasms (31 vs 64%, p<0.01). There were no other differences between the 2 groups. In conclusion, Japanese female patients with vasospastic angina had the characteristics of diffuse provoked spasm, less organic stenosis, and less history of smoking, but only 1 in 10 of all patients with vasospastic angina are female.     

Increased autoantibodies against oxidized low-density lipoprotein in coronary circulation in patients with coronary spastic angina

Oxidized low-density lipoproteins are important in the progression of atherosclerosis. Autoantibodies against malondialdehyde-modified low-density lipoproteins have been reported to be predictive of the progression of atherosclerosis. This study sought to examine whether plasma levels of autoantibodies against oxidized low-density lipoprotein increase in the coronary circulation in patients with coronary spastic angina. The authors examined plasma antioxidized low-density lipoprotein antibody levels (activity unit values (AcU)/mL) simultaneously in the coronary sinus and the aortic root in 20 patients with coronary spastic angina, 23 patients with stable exertional angina, and 15 control subjects by measuring plasma levels of immunoglobulin G (IgG) autoantibodies against malondialdehyde-modified low-density lipoproteins by enzyme-linked immunosorbent assay. The plasma antioxidized low-density lipoprotein antibody levels (AcU/mL) in the coronary sinus increased in coronary spastic angina (38 +/- 16) compared with stable exertional angina (23 +/- 7) and control subjects (20 +/- 6) (p < or = 0.0001). The levels (AcU/mL) in the aortic root also increased in coronary spastic angina (33 +/- 12) compared with stable exertional angina (23 +/- 7) and control subjects (20 +/- 6) (p < 0.005). Furthermore, the coronary sinus-arterial differences of the levels (AcU/mL) were also higher in coronary spastic angina (5 +/- 9) than in stable exertional angina (0 +/- 6) and healthy subjects (-1 +/- 5) (p < 0.05). The generation of malondialdehyde-modified low-density lipoproteins is reported to be associated with atherothrombosis. These findings suggest that elevated levels of autoantibodies against malondialdehyde-modified oxidized low-density lipoproteins in coronary circulation are associated with the development of atherothrombosis from the progression of atherosclerosis rather than with the extent of coronary atherosclerosis in patients with coronary spastic angina.     

Verapamil in effort-induced angina pectoris in patients with normal coronary arteries

Summary: Two patients with classical effort-induced angina pectoris associated with abnormal ST-segment depression on graded exercise testing and normal coronary arteriograms are described. Both patients deteriorated during treatment with propranolol, and became asymptomatic during treatment with verapamil with normal graded exercise tests. Verapamil may thus improve an inadequate vasodilatatory response of the coronary vascular bed to effort.     

Long-term prognosis of spastic angina with normal or irregular coronary arteries. Apropos of 48 cases

Forty-eight consecutive patients (37 men, 11 women, mean age 49 +/- 8 years) were followed up regularly for a mean period of 7 years. All presented with spontaneous angina, documented coronary spasm and no stenosis greater than 50 p. 100 at coronary arteriography. The first attack of pain had taken place 3 days to 9 years previously; exertion angina was also present in 47 p. 100 of the cases and severe arrhythmia in 17 p. 100. Treatment was based on calcium antagonists in doses and combinations that varied with the course of the disease. The follow-up period lasted from 16 to 122 months (mean 85 +/- 24 months). 3 patients are now known to be alive but were lost sight of after 12 to 21 months. Major cardiac complications were 1 death (2 p. 100) and 3 cases of myocardial infarction (6.6 p. 100). None of the patients died suddenly. 70 p. 100 of the remaining 41 patients became asymptomatic; angina persisted in 15 p. 100 and 14 p. 100 had episodes of severe angina but with remissions of at least one year. No predictive factor of functional deterioration or major cardiac complications could be elicited. The long-term prognosis of vasospastic angina in patients with little or no coronary stenosis is favourable, but there is a very small risk of myocardial infarction or death.     

Macrophages, macrophage foam cells, and eccentric intimal thickening in the coronary arteries of young children

We surveyed the incidence and location of macrophages and macrophage foam cells in the coronary artery intima of 63 children that died in the first 5 years of life. We related the data on macrophages and macrophage foam cells to intimal smooth muscle cells and to measurements of intima:media area and thickness. All morphometric data were obtained from coronary arteries that were fixed by perfusion with glutaraldehyde under pressure, embedded in Maraglas, and cut into 1-micron cross-sections, and 65-nm fine sections. Coronary artery intima was always thicker (eccentric thickening) at bifurcations in the half of the circumference opposite to the flow divider. This was true for both male and female children. The remaining part of the coronary artery intima was less thick (diffuse thickening). Both types of intimal thickening were composed of an inner layer in which glycosaminoglycan ground substance predominated and a deeper musculoelastic layer. Fifty-nine children (94%) had intimal macrophages. Twenty children also had macrophage foam cells. Of 33 children aged to 8 months, 15 (45%) had macrophage foam cells. Of the 30 children older than 8 months, 5 (17%) had macrophage foam cells. Macrophages and macrophage foam cells occurred in the GAG-rich layer of the intima as isolated cells. In 5 infants macrophage foam cells occurred also as clusters of many cells. Macrophages were more numerous in cases that also had macrophage foam cells. Macrophages were 6 times, and macrophage foam cells 5 times more numerous in eccentric intimal thickening than in diffuse intimal thickening.     

Elastic recoil and intimal thickening after coronary stenting

In this study, the long-term elastic recoil of the stents and the intimal thickening over the stents were evaluated separately. Twenty-nine patients who received a Wiktor coronary stent were angiographically followed-up at 2 weeks, 3 months, and 6 months. The elastic recoil of the stent was evaluated by the changes in minimum stent diameter. The intimal thickness was evaluated by the difference between minimum stent diameter and minimum lumen diameter. Minimum stent diameter showed no significant change up to 6 months. The significant increase (P < 0.05) of the intimal thickness was detected only between 2 weeks and 3 months. In conclusion, the Wiktor stent prevented the elastic recoil up to 6 months, and was covered by the neointima which increased its thickness mainly between 2 weeks and 3 months after stenting. It was suggested that stent restenosis was not caused by the elastic recoil, but by the intimal thickening.     

Diffuse periairway thickening in patients with Mikulicz disease

A 70-year-old woman presented with dry mouth, bilateral swelling of the eyelids, and abnormal taste and smell sensations that had persisted for 3 years. She was diagnosed with Mikulicz disease and presented with dyspnea on exertion afterwards. Chest computed tomography and magnetic resonance imaging showed wall thickening of the trachea and bilateral bronchus. Transbronchial needle aspiration showed lymphoproliferative lesion in the tracheobronchus. The patient was treated with corticosteroid, which improved all of her clinical symptoms, computed tomography, and magnetic resonance findings. In this case, we presented a rare condition of coexistent Mikulicz disease with tracheobroncial wall thickening caused by lymphoproliferation without lesions in small airways or lung.     

Endothelium-dependent dilator response to substance P in patients with coronary spastic angina.

OBJECTIVE. This study was designed to examine whether patients with coronary spastic angina have an impaired coronary artery dilator response to substance P, an endothelium-dependent vasodilator. BACKGROUND. Impairment of the endothelium-dependent vasodilator response has been suggested to be involved in the pathogenesis of coronary spasm. METHODS. In 11 patients with coronary spastic angina and 11 control patients, substance P was infused into the coronary artery at 20 pmol/min for 5 min. Incremental doses of acetylcholine were then injected into the coronary artery. The effects of these drugs and nitroglycerin on the coronary artery diameter were quantitatively analyzed. RESULTS. Heart rate, systolic blood pressure and rate-pressure product did not change after substance P infusion. In 12 coronary arteries of the patients with coronary spastic angina, spasm was induced with acetylcholine. At the site of coronary spasm documented, the lumen diameter, which was 1.6 +/- 0.5 mm at baseline, increased to 2.1 +/- 0.7 mm after substance P infusion (p less than 0.01). It decreased to 0.2 +/- 0.3 mm during acetylcholine-induced spasm (p less than 0.001) and increased to 2.3 +/- 0.8 mm after nitroglycerin administration (p less than 0.001 vs. baseline and p = NS vs. after substance P infusion). Of the 12 arteries with spasm, 5 were angiographically normal and the other 7 were minimally or moderately atherosclerotic: the diameter change after substance P was +28 +/- 20% and +30 +/- 22%, respectively (p = NS). In control patients, the diameter of the middle portion of the left anterior descending artery, which was 2.0 +/- 0.4 mm at baseline, increased to 2.5 +/- 0.4 mm after substance P infusion (p less than 0.001). The diameter changes after substance P infusion were not different between the patients with coronary spastic angina and control patients. CONCLUSIONS. Substance P dilated the artery with spasm of the patients with coronary spastic angina to a degree similar to that in control patients, indicating the preserved endothelium-dependent dilator response at the site of coronary spasm by way of substance P receptor.     

Increased oxidative stress with elevated serum thioredoxin level in patients with coronary spastic angina

BACKGROUND: Increased oxidative stress has been implicated in the pathogenesis of coronary vasospasm. Thioredoxin (TRX) is a redox-active protein that is known to be induced by oxidative stress. HYPOTHESIS: The serum TRX level may be high in patients with coronary vasospasm. METHODS: The serum TRX level was determined using an enzyme-linked immunosorbent assay in 21 patients with the active stage of coronary spastic angina (CSA), in 18 patients with the inactive stage of CSA (iCSA), in 24 control subjects without coronary artery disease (Control), and in 20 patients with stable effort angina (SEA). RESULTS: Serum TRX levels (mean +/- standard deviation ng/ml) were significantly higher in CSA (64 +/- 44) than in iCSA (28 +/- 26), in Control (34 +/- 15), and in SEA (36 +/- 16). In contrast, serum alpha-tocopherol levels (mg/g lipids) were significantly lower in CSA (2.8 +/- 0.7) than in Control (4.0 +/- 1.2) and in SEA (3.2 +/- 0.4). Current smoking was significantly more prevalent in CSA (76%) than in any of the other groups. No significant correlation was found between the serum level of TRX and alpha-tocopherol in the study subjects. In nine patients with CSA, the serum TRX level decreased (93 +/- 41 --> 41 +/- 35 ng/ml) and the alpha-tocopherol level increased (2.7 +/- 0.6 --> 3.2 +/- 0.7 mg/g lipids) significantly under medication with calcium entry blockers after an at least 3-month angina-free period. CONCLUSIONS: Patients with coronary spastic angina had a higher serum TRX level associated with a lower serum level of antioxidant vitamin E, with redox equilibrium appearing to be related to the disease activity of coronary vasospasm in these patients. Oxidative stress may be related to the genesis of coronary vasospasm.