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Biomedical subjects

A Farb

Publications and source records attributed to A Farb.

At least 19 recordsLinked to original sources
PubMed2001

Late arterial responses (6 and 12 months) after (32)P beta-emitting stent placement: sustained intimal suppression with incomplete healing.

BACKGROUND: Three-month studies of stent-delivered brachytherapy in the rabbit model show reduced neointimal growth. However, intimal healing is delayed, raising the possibility that intimal inhibition is merely delayed rather than prevented. The purpose of this study was to explore the long-term histological changes after placement of beta-emitting radioactive stents in normal rabbit iliac arteries. METHODS AND RESULTS: Three-millimeter beta-emitting (32)P stents (6, 24, and 48 microCi) were placed in normal rabbit iliac arteries with nonradioactive stents as controls. Animals were euthanatized at 6 and 12 months, and histological assessment, morphometry, and analysis of endothelialization were performed. Morphometric measurements demonstrated a >50% reduction in intimal growth and percent lumen stenosis within 24- and 48-microCi stents versus control nonradioactive stents at both 6 and 12 months. However, the 24- and 48-microCi stents also showed delayed healing of the intimal surface, characterized by persistent fibrin thrombus with nonconfluent areas of matrix, incomplete endothelialization, and increased intimal cellular proliferation. Stent edge stenosis was present at 12 months in the 24- and 48-microCi stent groups, characterized by both intimal thickening and negative arterial remodeling. CONCLUSIONS: Inhibition of intimal growth is maintained 6 and 12 months after (32)P beta-emitting stent placement. However, delayed arterial healing, incomplete endothelialization, and edge effects are present.

Animals↗
PubMed2001

Healed plaque ruptures and sudden coronary death: evidence that subclinical rupture has a role in plaque progression.

BACKGROUND: Subclinical episodes of plaque disruption followed by healing are considered a mechanism of increased plaque burden. Detailed pathological studies of healed ruptures, however, are lacking. METHODS AND RESULTS: We identified acute and healed ruptures from 142 men who died of sudden coronary death and performed morphometric measurements of plaque burden, luminal stenosis, and smooth muscle cell phenotype. Healed ruptures were found in 61% of hearts and were associated with healed myocardial infarction, increased heart weight, dyslipidemia, and diabetes. Multiple healed rupture sites with layering were frequently found in segments with acute and healed rupture; the percent area luminal narrowing increased with increased numbers of healed sites of previous rupture. The underlying percent luminal narrowing for acute ruptures (mean 79+/-15%) exceeded that for healed ruptures (mean 66+/-14%, P:=0.0001), and the area within the internal elastic lamina was significantly less in healed ruptures than in acute ruptures, when segments were grouped by distance from the ostium. Healed ruptures favored the accumulation of immature smooth muscle cells at repair sites, with a cellular proliferation index of 0.40+/-0.09%, significantly higher than the index at the sites of rupture (P:=0.008). CONCLUSIONS: These data provide evidence that silent plaque rupture is a form of wound healing that results in increased percent stenosis. Healed ruptures occur in arteries with less cross-sectional area luminal narrowing than acute ruptures and are a frequent finding in men who die suddenly with severe coronary atherosclerosis.

Cell Differentiation↗
PubMed2001

Coronary atherosclerosis in unheralded sudden coronary death under age 50: histo-pathologic comparison with 'healthy' subjects dying out of hospital.

AIM: sudden coronary death (SCD) in older individuals is generally associated with extensive coronary atherosclerosis, although it may be the first manifestation of ischaemic heart disease. In younger age-groups, SCD may occur in the presence of less severe disease. We sought to (1) examine the extent of coronary atherosclerosis in young victims of SCD compared with age- and sex-matched controls, (2) analyse the composition of atherosclerotic plaques in these patients, (3) identify the predominant mechanism of SCD, and (4) evaluate the possibility of detecting this mechanism on the basis of morphologic plaque features, in particular presence and amount of lipid accumulation and calcific deposits. METHODS AND RESULTS: coronary arteries were obtained at autopsy from 28 victims of SCD under age 50 with no prior clinical manifestation of ischaemic heart disease (IHD) and no myocardial scar formation and from 16 age- and sex-matched subjects dying of noncardiac causes out of hospital. Sections of all available major coronary arteries were cut in 5-mm intervals to yield a total of 1357 histologic sections, which were analysed using digitised planimetry. Victims of SCD had significantly more major coronary arteries per subject with luminal area narrowing > or = 75% than controls (on average, 2.1 vs. 0.2). Plaque area per histologic section was 5.1 +/- 2.1 mm(2) in SCD cases and 2.0 +/- 0.9 mm(2) in controls (P < 0.001). The major constituent of all plaques was fibrous tissue. Lipid core area per section was 0.49 +/- 0.59 mm(2) in SCD cases and 0.004 +/- 0.01 mm(2) in controls (P < 0.001), and calcified plaque area was 0.18 +/- 0.19 mm(2) in SCD cases and 0.02 +/- 0.05 mm(2) in controls (P < 0.001), both defining significant differences between SCD cases and controls. Arterial thrombosis, most often with underlying plaque rupture was the mechanism of SCD in > 80% of the cases. Considering histologic sections with > or = 50 and with > or = 75% area stenosis, plaque rupture was independently predicted by lipid core area. Calcific deposits were a frequent feature of plaque rupture but were only associated with it in univariate analysis. CONCLUSIONS: the extent and severity of coronary atherosclerosis in young victims of SCD as the first manifestation of IHD was substantially greater than in age-and sex-matched controls and comparable with that previously reported in SCD cases with a broader age range. Lipid core and calcified plaque areas provided for excellent separation between the two groups, which may have implications for identifying persons at increased risk for SCD by non invasive visualisation and assessment of the coronary arteries.

Adult↗
PubMed2001

Effect of menopause on plaque morphologic characteristics in coronary atherosclerosis.

BACKGROUND: Coronary artery disease in women appears 10 to 15 years later than in men. To test the hypothesis that the effects of estrogen may manifest themselves as histologic differences in coronary plaques, we examined the hearts of premenopausal and postmenopausal women who died suddenly from coronary artery disease. METHODS: We studied 51 cases of sudden coronary death and 47 deaths in women who died from noncoronary causes. Coronary deaths were classified on the basis of histologic features. The number of acute plaque ruptures, healed plaque ruptures, vulnerable plaques, and acute plaque erosions were compared between groups. Postmortem values of serum total cholesterol, HDL cholesterol, and thiocyanate were measured, and menopausal status was confirmed by calculating body mass index. RESULTS: Women older than 50 years of age were much more likely to have a ruptured plaque than were younger, premenopausal women. Plaque rupture was significantly associated with elevated total cholesterol level. In the 51 women who died of coronary disease, the mean number of vulnerable plaques increased significantly as women advanced into the postmenopausal years. CONCLUSIONS: Our data suggest that estrogen has an anti-inflammatory effect on atherosclerotic plaques, resulting in plaque stabilization. Plaque erosion, the major substrate for thrombosis in premenopausal women, does not appear to be inhibited by estrogen. Because plaque progression may result both from repeated rupture and repeated erosion, a better understanding of the effect of estrogen on atherosclerosis may yield insights into the nature of coronary artery disease.

Cadaver↗
PubMed2000

Neointimal responses 3 months after (32)P beta-emitting stent placement.

PURPOSE: Studies have shown a potential benefit of brachytherapy in preventing restenosis. However, the effects of intravascular radiation on arterial healing have not been well-established. The purpose of this study was to explore the histologic changes following placement of beta-emitting radioactive stents in arteries focusing on intimal responses and endothelialization. METHODS AND MATERIALS: 3.0-mm beta-emitting (32)P stents (6-microCi and 24-microCi) were placed in rabbit iliac arteries with nonradioactive stents serving as controls. Animals were euthanized at 3 months and histologic assessment, morphometry, and analysis of endothelialization were performed. RESULTS: The lumen areas of 24-microCi stents (4.24 +/- 0.22 mm(2), p < 0.0007) and 6-microCi stents (4.23 +/- 0.49 mm(2), p < 0.01) were larger than control stents (3.64 +/- 0.44 mm(2)). The mean lumen percent stenosis was 11. 4 +/- 3.0% in the 24-microCi stents (p < 0.007 vs. 6-microCi stents and p < 0.0001 vs. control stents), 18.7 +/- 6.4% in the 6-microCi stents (p < 0.02 vs. control stents), and 25.0 +/- 4.9% in control stents. Neointimal area was least in the 24-microCi stent (54.2% smaller than controls and 42.7% smaller than 6-microCi); the neointimal area of the 6-microCi stents was 20.0% less than controls. The control stent neointima consisted of smooth muscle cells in a proteoglycan and collagen matrix. In contrast, the intima of radioactive stents showed persistent fibrin thrombus with nonconfluent areas of matrix. Actin-positive intimal cell density was reduced with radioactive stenting, but intimal cell proliferation was increased. Evans blue staining, an indicator of increased endothelial permeability, was present on 86 +/- 9% of the stented segment of 6-microCi stents vs. 10 +/- 11% in controls (p < 0.0001). Scanning electron microscopy demonstrated endothelialization of 97 +/- 8% of the intimal surface of control stents; in contrast, the midportion of the 6-microCi stents remained nonendothelialized, and only 33 +/- 15% (p < 0.0001) of the entire stent surface was endothelialized. CONCLUSIONS: (32)P beta-emitting stents reduce neointimal growth, but healing is incomplete with poor endothelialization at 3 months. Longer-term studies with complete arterial healing are needed to determine whether there is sustained neointimal inhibition by stent-delivered brachytherapy.

Animals↗
PubMed2000

A comparison of the Framingham risk index, coronary artery calcification, and culprit plaque morphology in sudden cardiac death.

BACKGROUND: Neither clinical prediction models nor noninvasive imaging tests that detect coronary artery calcification identify all patients who experience acute coronary events. Variations in culprit plaque morphology may account for these inaccuracies. METHODS AND RESULTS: We compared the 10-year Framingham risk index, histologic coronary calcification, and culprit plaque morphology in 79 consecutive adults with sudden cardiac death. There was a modest relationship between the Framingham risk index and the extent of histologic coronary calcification (r=0.35, P=0.002). Agreement in risk classification between the histologic calcification score and the Framingham risk index occurred in 50 of 79 cases (63.3%, P=0. 039). Either a focus of coronary artery calcification >/=40 micromol/L (62% of cases) or a Framingham risk index score >/= average risk for age (62% of cases) were present in 66 of 79 (83.5%) cases. Cases with plaque erosion (n=22) had significantly less coronary calcification (P=0.003) and lower Framingham risk index (P=0.001) scores than stable (n=27) or ruptured (n=30) plaques. Fourteen of 22 (63.6%) cases of plaque erosion were classified as low risk by both the Framingham risk index and the histologic calcification score. CONCLUSIONS: The prediction of sudden cardiac death using the Framingham risk index and the measurement of coronary calcification are distinct methods of assessing risk for sudden cardiac death. Excessive reliance on either method alone will produce errors in risk classification, particularly for patients at risk of plaque erosion, but their combination may be complementary.

Adult↗
PubMed2000

The 90-day coronary vascular response to (90)Y-beta particle-emitting stents in the canine model.

PURPOSE: Long-term preclinical studies using continuous, low-dose-rate vascular brachytherapy with (32)P beta-emitting stents have yielded largely disappointing results. In contrast, a shorter half-life, higher dose-rate (90)Y beta-emitting stent more closely mimics the delivery dose rate characteristics of clinically effective beta- and gamma-wire and balloon brachytherapy devices. We evaluated the dose response characteristics of a (90)Y beta-emitting stent in the canine coronary injury model and hypothesized that this device would reduce neointimal formation. METHODS: Seventy-seven (90)Y beta-emitting coronary stents (15 mm BXTM, 3.0- and 3.5-mm diameter) were implanted in 26 normal dogs (20-25 kg) using a randomized, blinded study design. Stent activity included nonradioactive controls (n = 24), 4.5 microCi (n = 15), 8 microCi (n = 12), 16 microCi (n = 18), and 32 microCi (n = 8). Histologic endpoints were assessed at 3 months. RESULTS: Luminal stenosis and neointimal area were similar in control stents and low-activity (4.5 and 8 microCi) (90)Y stents. Higher activity stents (16 and 32 microCi) were associated with significant adverse effects. Frequent total occlusions (5 of 18 stents, 28%; p = 0.008) and a 40% increase in neointimal area (p = 0.024 vs. control) occurred in the 16 microCi group. Incomplete neointimal healing and a trend for reduced neointimal cell density were evident only in the 16- and 32-microCi group. CONCLUSION: Despite unique characteristics (2.7 day half-life and a higher dose rate) of (90)Y beta-emitting coronary stents, they have an adverse effect on neointimal formation, including frequent total occlusions at high activity levels. Incomplete healing, present 90 days (33 half-lives) after stent placement, indicates prolonged recovery from radiation injury.

Animals↗
PubMed2000

Pathologic validation of a new method to quantify coronary calcific deposits in vivo using intravascular ultrasound.

Current methods of calcium quantification by intravascular ultrasound (IVUS) measure the arc of calcium using the cross-sectional image at the lesion and at the reference site while neglecting calcium elsewhere. Calcium at these sites may not adequately represent the extent of total epicardial coronary calcium. We devised a new method to quantify calcium as a percentage of the coronary luminal surface. This study examines whether this new method accurately reflects coronary calcium determined by histology. Seventeen postmortem coronary arteries were pressure-fixed and imaged by IVUS using a motorized pullback device. Total plaque-luminal circumferential length and calcified plaque-luminal circumferential length were measured from serial cross-sectional IVUS images every 1 mm. With use of Simpson's method, the total plaque and calcified plaque surface area was then calculated. Histologic sections were stained with hematoxylin-eosin and Movat pentachrome at 3-mm intervals. Calcium was independently quantified by planimetry under light microscopy. Histologic analysis (n = 253 sections) revealed a wide range of calcium (0 to 47 mm2; mean 12 +/- 16 mm3). The IVUS-derived calcified plaque surface area was 17 +/- 23 mm2), which represented 3.1 +/- 4.1% (range 0% to 13.9%) of the total plaque surface area. The histologic and IVUS quantification of calcium by this method was strongly related (r = 0.84, p <0.0001), which was an improvement over current 2-dimensional measures of calcium arc (r = 0.41, p = 0.18). Calculation of calcified plaque surface area from sequential IVUS images appears to accurately reflect the degree of total coronary calcification.

Aged↗
PubMed2000

Coronary calcification: insights from sudden coronary death victims.

We studied 108 cases of sudden coronary death at autopsy. Any calcification was present in 55% of men and women under 40 years; all hearts showed some calcification by age 50 in men, and by age 60 in women. The only risk factor independently associated with increased calcification was diabetes mellitus, in women only. The degree of calcification was greatest for acute and healed plaque ruptures, and the least for plaque erosion. Calcification in coronary atherosclerosis appears to be delayed in women, is greatest in women diabetics, and is associated with one type of plaque instability, namely plaque rupture.

Adult↗
PubMed2000

Localization of apoptotic macrophages at the site of plaque rupture in sudden coronary death.

Although apoptosis is a well-recognized phenomenon in chronic atherosclerotic disease, its role in sudden coronary death, in particular, acute plaque rupture is unknown. Culprit lesions from 40 cases of sudden coronary death were evaluated. Cases were divided into two mechanisms of death: ruptured plaques with acute thrombosis (n = 25) and stable plaques with and without healed myocardial infarction (n = 15). Apoptotic cells were identified by staining of fragmented DNA and confirmed in select cases by gold conjugate labeling combined with ultrastructural analysis. Additional studies were performed to examine the expression and activation of two inducers of apoptosis, caspases-1 and -3. Ruptured plaques showed extensive macrophage infiltration of the fibrous cap, in particular at rupture sites contrary to stable lesions, which contained fewer inflammatory cells. Among the culprit lesions, the overall incidence of apoptosis in fibrous caps was significantly greater in ruptured plaques (P < 0.001) and was predominantly localized to the CD68-positive macrophages. Furthermore, apoptosis at plaque rupture sites was more frequent than in areas of intact fibrous cap (P = 0. 028). Plaque rupture sites demonstrated a strong immunoreactivity to caspase-1 within the apoptotic macrophages; staining for caspase-3 was weak. Immunoblot analysis of ruptured plaques demonstrated caspase-1 up-regulation and the presence of its active p20 subunit whereas stable lesions showed only the precursor; nonatherosclerotic control segments were negative for both precursor and active enzyme. These findings demonstrate extensive apoptosis of macrophages limited to the site of plaque rupture. The proteolytic cleavage of caspase-1 in ruptured plaques suggests activation of this apoptotic precursor. Whether macrophage apoptosis is essential to acute plaque rupture or is a response to the rupture itself remains to be determined.

Apoptosis↗
PubMed1999

Long-term coronary vascular response to (32)P beta-particle-emitting stents in a canine model.

BACKGROUND: The arterial placement of (32)P beta-particle-emitting stents in various experimental animal models results in discordant effects on neointimal formation. We studied the vascular effects of beta-particle-emitting stents in normal canine coronary arteries because compared with pigs and rabbits, the canine model may more closely mimic the vascular response of humans. METHODS AND RESULTS: Thirty stents (control nonradioactive, n=10; low-activity (32)P, 3.5 to 6.0 microCi, n=11; high-activity (32)P, 6.5 to 14.4 microCi, n=8) were implanted in normal canine coronary arteries through the use of a single balloon inflation at nominal pressure. Histological analysis after 15 weeks included the measurement of neointimal and adventitial area and thickness. Neointimal fibrin area was measured with the use of computer-assisted color segmentation on Movat pentachrome sections. Luminal stenosis was significantly increased in (32)P stents compared with control stents (44.6+/-16.8% versus 32.7+/-10.8%; P=0.05) and was highest in the high-activity group (45.5+/-24.3%). No evidence of an "edge effect" was seen in adjacent, nonstented coronary segments. All (32)P stents showed incomplete vascular healing as indicated by a dose-dependent increase in fibrin area with increasing stent activity. Arterial radiation resulted in a decrease in adventitial size, which was maximal for high-activity (32)P stents, indicating an inhibitory effect on the adventitial response to injury. CONCLUSIONS: (32)P beta-particle-emitting stents have adverse vascular effects at 15 weeks in the canine normal coronary artery model. Vascular brachytherapy with this device causes increased neointimal formation and prominent, dose-dependent lack of healing.

Animals↗
PubMed1999

Plaque rupture and sudden death related to exertion in men with coronary artery disease.

CONTEXT: Exertion has been reported to acutely increase the risk of sudden coronary death, but the underlying mechanisms are unclear. OBJECTIVE: To determine the frequency of plaque rupture in sudden deaths related to exertion compared with sudden deaths not related to exertion. DESIGN: Autopsy survey. Coronary arteries were perfusion fixed and segments with more than 50% luminal narrowing were examined histologically. Ruptured plaques were defined as intraplaque hemorrhage with disruption of the fibrous cap and luminal thrombus. Exertion before death was determined by the investigator of the death. SETTING: Medical examiner's office. PATIENTS: A total of 141 men with severe coronary artery disease who died suddenly, including 116 whose deaths occurred at rest (mean [SD] age, 51 [11] years) and 25 who died during strenuous activity or emotional stress (age, 49 [9] years). MAIN OUTCOME MEASURES: The frequency and morphology of plaque rupture was compared in men dying at rest vs those dying during exertion. Independent association of risk factors (total cholesterol, high-density lipoprotein cholesterol, glycosylated hemoglobin, cigarette smoking) in addition to acute exertion with plaque rupture were determined. RESULTS: The mean (SD) number of vulnerable plaques in the coronary arteries of men in the exertional-death group was 1.6 (1.5) and in the at-rest group was 0.9 (1.2) (P=.03). The culprit plaque in men dying during exertion was plaque rupture in 17 (68%) of 25 vs 27 (23%) of 116 men dying at rest (P<.001). Hemorrhage into the plaque occurred in 18 (72%) of 25 men in the exertional-death group and 47 (41%) of 116 men in the rest group (P=.007). Histological evidence of acute myocardial infarction was present in 0 of 25 in the exertion group and in 15 (13%) of 116 in the rest group. Men dying during exertion had a significantly higher mean (SD) total cholesterol-high-density lipoprotein cholesterol ratio (8.2 [3.0]) than those dying at rest (6.2 [ 2.7]; P=.002), and the majority (21/25) were not conditioned. In multivariate analysis, both exertion (P=.002) and total cholesterol-high-density lipoprotein cholesterol ratio (P=.002) were associated with acute plaque rupture, independent of age and other cardiac risk factors. CONCLUSION: In men with severe coronary artery disease, sudden death related to exertion was associated with acute plaque rupture.

Autopsy↗
PubMed1999

Histopathology of postpercutaneous transluminal coronary angioplasty remodeling in human coronary arteries.

BACKGROUND: We studied the histomorphometric correlates of long-term successful coronary balloon angioplasty (percutaneous transluminal coronary angioplasty [PTCA]). Restenosis after PTCA may occur secondary to the failure of compensatory arterial enlargement or post-PTCA arterial constriction. The histopathology of this process in human subjects remains poorly defined. METHODS: Forty-two coronary segments from 41 patients treated with PTCA 60 +/- 58 weeks before death were studied. The histomorphometric findings at the PTCA site were compared with those obtained at a proximal reference site. RESULTS: Histologic long-term success was seen in 18 (43%) of 42 arteries. Histologically successful PTCA arteries (PTCA site lumen of >/=50% of the reference lumen) demonstrated a larger acute lumen, smaller plaque size (normalized to the internal elastic lamina area), and thinner adventitia compared with histologic failures. Relative to the reference sites, histologically successful PTCA showed expansion of the external elastic lamina. In contrast, histologic failures showed a reduced external elastic lamina area, suggesting constrictive remodeling. Neointimal area correlated with the extent of internal elastic lamina disruption, but neither variable was related to histologic PTCA success or failure. CONCLUSIONS: These data provide histomorphometric confirmation of the hypothesis that constrictive remodeling, not neointimal formation, determines the long-term outcome of PTCA.

Angioplasty, Balloon, Coronary↗