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Biomedical subjects

A Farb

Publications and source records attributed to A Farb.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1999

Pathology of bailout coronary stenting in human beings.

OBJECTIVES: The aim of this study was to perform detailed postmortem analysis of bailout coronary stenting to gain insights into the mechanism of success or failure of the procedure. Bailout stenting is increasingly used for acute or threatened arterial closure after angioplasty. Few pathologic data from bailout stenting have been reported. METHODS AND RESULTS: The coronary arteries from 6 cases of bailout stenting were analyzed at autopsy. All stents were placed for extensive coronary dissection or abrupt vessel closure after balloon angioplasty. Twenty stents (11 Palmaz-Schatz and 9 Gianturco-Roubin stents) were placed in 8 coronary arteries, ranging from 1 to 5 stents per artery. After stenting, angiography showed good coronary flow in 3 of 6 cases. All patients died secondary to acute myocardial infarction. Histologically, in all cases, the stents were well opposed to the coronary artery wall, with a focally widely patent lumen by compression of the dissection plane. However, in 4 of 6 cases, there was residual dissection present in the nonstented portion of the arteries proximal, proximal to, and between stents or distal to the stented segment, resulting in focal luminal compression or obstruction. In 2 cases, bailout stenting effectively covered the dissection and prevented luminal compression. CONCLUSIONS: Bailout stenting for dissection after balloon angioplasty restores lumen patency in the stented segment. Residual dissection in nonstented segments adversely affects outcome and supports the need for continued development of new stents with increased trackability and tapering designs to more effectively treat major coronary dissections.

Adult↗
PubMed1999

Arterial remodeling in the left coronary system: the role of high-density lipoprotein cholesterol.

OBJECTIVES: We sought to evaluate the plaque and patient variables related to arterial remodeling responses of early, de novo atherosclerotic lesions involving the left coronary artery. BACKGROUND: Coronary artery remodeling is a lesion-specific process involving either enlargement or shrinkage of atherosclerotic coronary arteries. There are little histologic data available correlating plaque morphologic and patient clinical characteristics with the degree and type of arterial remodeling in early atherosclerosis. METHODS: We studied 736 serial arterial sections from the left coronary system of 97 autopsy cases (mean age 33 +/- 11 years) by correlating the arterial remodeling response to plaque with demographic, serologic and histologic variables. Using the most proximal section as a reference, and considering the expected degree of internal elastic lamina tapering, remodeling was classified as positive (including neutral remodeling or compensatory enlargement) or negative. RESULTS: Remodeling was classified as positive in 84.3% (compensatory in 30.6%) and negative in 15.7% of sections with an overall mean luminal stenosis of 10.4 +/- 9.9%. In the lesions with the greatest arterial cross-sectional narrowing from each case, compensatory enlargement was associated with higher high-density lipoprotein (HDL) cholesterol (59.4 +/- 27.2 mg/dl) compared with either neutral (49.3 +/- 15.5 mg/dl) or negative remodeling (30.4 +/- 5.2 mg/dl; p = 0.019). In subjects with advanced atherosclerosis (maximum American Heart Association histologic grade 5 atherosclerosis), there was a modest linear relationship between higher HDL cholesterol and the propensity for positive remodeling (r2 = 0.37; p = 0.025). On multivariate analysis, only HDL cholesterol was related to the arterial remodeling response. CONCLUSIONS: Negative arterial remodeling occurs in early atherosclerosis. Higher HDL cholesterol may favor positive remodeling.

Adolescent↗
PubMed1999

Pathology of in-stent restenosis.

The process of in-stent restenosis parallels wound healing responses. Stent deployment results in early thrombus deposition and acute inflammation, granulation tissue development, and ultimately smooth muscle cell proliferation and extracellular matrix synthesis. The severity of arterial injury during stent placement correlates with increased inflammation and late neointimal growth. These pathological findings provide useful targets for therapies aimed at reducing the incidence of in-stent restenosis.

Animals↗
PubMed1999

Plaque rupture and plaque erosion.

There are multiple substrates for coronary thrombosis overlying an atherosclerotic plaque. The most common, plaque rupture, consists of an interruption of a thin fibrous cap overlying a lipid rich core. Plaque rupture is a result of macrophage infiltration and matrix degradation, is often seen in calcified plaques, and is highly associated with hypercholesterolemia. A less common substrate, plaque erosion, is not associated with elevated cholesterol and is the prime cause of coronary thrombosis in premenopausal women. The characteristic histologic features are abundant surface smooth muscle cells and proteoglycans, and a small or absent lipid rich core. The mechanisms of plaque erosion are unclear, and there are no consistent risk factors, although patients are often smokers.

Adult↗
PubMed1999

Pathology of Transmyocardial Angiogenesis and Arteriogenesis.

Transmyocardial laser revascularization (TMLR) is increasingly used for improving myocardial perfusion in patients with diffuse coronary artery disease and refractory ischemia. The efficacy of TMLR, however, is in doubt because no definite increase in blood flow or longevity has been demonstrated. Although histologic results after TMLR show some neocapillary formation, the relative amount of angiogenesis is similar to what occurs naturally after myocardial infarction. Hence, it is suspected that these few capillaries would be sufficient to maintain a viable myocardium. Alternatively, the creation of collateral vessel "arteriogenesis" rather than capillary formation alone may improve the clinical outcome. Comprehensive experimental studies seem to indicate the feasibility of producing new collaterals. This method of vascularization is dependent upon specific cytokines or enzymes that induce proliferation of native arterial endothelial cells and smooth muscle cells. It is critical that we develop a better understanding of which factors regulate arteriogenesis, and concentrate on methods to document its existence in the clinical and experimental setting.

Journal Article↗
PubMed1998

Effect of risk factors on the mechanism of acute thrombosis and sudden coronary death in women.

BACKGROUND: Traditional risk factors have been linked to atherosclerotic heart disease in women. However, the effect of risk factors and menopausal status on the mechanism of sudden coronary death is unknown. METHODS AND RESULTS: We examined 51 cases of sudden coronary death and 15 hearts from women who died of trauma. Coronary deaths were divided into four mechanisms of death: ruptured plaque with acute thrombus (n = 8), eroded plaque with acute thrombus (n = 18), stable plaque with healed infarct (n = 18), and stable plaque without infarction (n = 7). Vulnerable plaques prone to rupture were defined as those with a thin, fibrous cap infiltrated by macrophages and were quantitated in coronary deaths and control subjects. Total cholesterol (TC), HDL cholesterol, glycosylated hemoglobin, cigarette smoking, and hypertension were determined in each case. Compared with control subjects, women with plaque ruptures had elevated TC (270 +/- 55 versus 194 +/- 44 mg/dL, P = 0.002), and those with erosions were more likely to be smokers (78% versus 33%, P = 0.01). Women with stable plaque and healed infarct had elevated glycosylated hemoglobin (10.2 +/- 5.0% versus 6.4 +/- 0.4% in control subjects, P = 0.001) and were more likely to be hypertensive (50% versus 15% in control subjects, P = 0.03). By multivariate analysis, cigarette smoking was associated with plaque erosion (P = 0.03, odds ratio [OR] 21), glycoslyated hemoglobin with stable plaque and healed infarct (P = 0.03, OR 41), TC with plaque rupture (P = 0.02, OR 7), and hypertension with stable plaque with healed infarct (P = 0.02, OR 15). Seven of 8 plaque ruptures occurred in women > 50 years of age versus 3 of 18 erosions (P = 0.001). In cases of coronary death, vulnerable plaques were associated with elevated cholesterol (P = 0.002) and age > 50 years (P = 0.002), independent of other risk factors. CONCLUSIONS: In women, traditional risk factors have distinct effects on the mechanisms of sudden coronary death, which vary by menopausal status. Effective risk factor modification may therefore differ between younger and older women and may be targeting different mechanisms of plaque instability.

Acute Disease↗
PubMed1998

Arrhythmogenic right ventricular cardiomyopathy and fatty replacement of the right ventricular myocardium: are they different diseases?

BACKGROUND: The relationship between arrhythmogenic right ventricular cardiomyopathy (ARVC) and pure fat replacement of the right ventricle is unclear. METHODS AND RESULTS: Myocardial thickness, epicardial fat thickness, percent fibrosis, and intramyocardial fat infiltration were measured in 16 sections each from 25 hearts with typical (fibrofatty) ARVC, 7 hearts with fat replacement of the right ventricle without fibrosis (FaRV), and 18 control hearts from patients who died of noncardiac causes. Patients with fibrofatty ARVC were younger than those with FaRV (31+/-14 versus 44+/-13 years, P=.02), more likely to have a history of arrhythmias or a family history of premature sudden death (56% versus 0%, P=.01), more likely male (80% versus 29%, P=.02), and less likely to have coexisting conditions that might have predisposed to sudden death (12% versus 86%, P<.001). Fibrofatty ARVC was characterized by right ventricular myocardial thinning, fat infiltration of the anterobasal and posterolateral apical right ventricle, subepicardial left ventricular fibrofatty replacements (64%), myocyte atrophy (96%), and lymphocytic myocarditis (80%). FaRV showed normal or increased myocardial thickness, a diffuse increase in intramyocardial and epicardial fat, little inflammation, and an absence of myocardial atrophy. Intramyocardial fat was frequently seen in normal hearts, especially in the anteroapical region, but was less extensive than in fibrofatty ARVC and FaRV. CONCLUSIONS: ARVC is a familial arrhythmogenic disease characterized by fibrofatty replacement of myocytes with scattered foci of inflammation. Fat infiltration per se is probably a different process that should not be considered synonymous with ARVC.

Adipose Tissue↗
PubMed1998

Progressive vascular remodeling and reduced neointimal formation after placement of a thermoelastic self-expanding nitinol stent in an experimental model.

Despite the improvements afforded by intracoronary stenting, restenosis remains a significant problem. The optimal physical properties of a stent have not been defined. We compared the vascular response to a thermoelastic self-expanding nitinol stent with a balloon-expandable tubular slotted stainless steel stent in normal porcine coronary arteries. Twenty-two stents (11 nitinol and 11 tubular slotted) were implanted in 11 miniature swine. The nitinol stents were deployed using the intrinsic thermal properties of the metal, without adjunctive balloon dilation. The tubular slotted stents were implanted using a noncompliant balloon with a mean inflation pressure of 12 atm. Intravascular ultrasound (IVUS) and histology were used to evaluate the vascular response to the stents. The mean cross-sectional area (CSA) of the nitinol stents (mm2) as measured by IVUS increased from 8.13 +/- 1.09 at implant to 9.10 +/- 0.99 after 28 days (P = 0.038), while the mean CSA of the tubular slotted stents was unchanged (7.84 +/- 1.39 mm2 vs. 7.10 +/- 1.07 mm2, P = 0.25). On histology at 3 days, the tubular slotted stents had more inflammatory cells adjacent to the stent wires (5.7 +/- 1.5 cells/0.1 mm2) than the nitinol (3.9 +/- 1.3 cells/0.1 mm2, P = 0.016). The tubular slotted also had increased thrombus thickness (83 +/- 85 microm) than the nitinol stents (43 +/- 25 microm, P = 0.0014). After 28 days, the vessel injury score was similar for the nitinol (0.6 +/- 0.3) and the tubular slotted (0.5 +/- 0.1, P = 0.73) designs. The mean neointimal area (0.97 +/- 0.46 mm2 vs. 1.96 +/- 0.34 mm2, P = 0.002) and percent area stenosis (15 +/- 7 vs. 33 +/- 7, P = 0.003) were significantly lower in the nitinol than in the tubular slotted stents, respectively. We conclude that a thermoelastic nitinol stent exerts a more favorable effect on vascular remodeling, with less neointimal formation, than a balloon-expandable design. Progressive intrinsic stent expansion after implant does not appear to stimulate neointimal formation and, therefore, may provide a mechanical solution to prevent in-stent restenosis.

Alloys↗
PubMed1998

Atheromatous plaque reflects serum total cholesterol levels: a comparative morphologic study of endarterectomy coronary atherosclerotic plaques removed from patients from the southern part of India and Caucasians from Ottawa, Canada.

BACKGROUND: Natives of South India have a very high incidence of coronary artery disease, despite low calorie and fat intake. HYPOTHESIS: This study was undertaken to determine whether morphologic features of atheromatous plaque reflect the serum total cholesterol. METHODS: Fifty-three endarterectomy specimens from patients (mean age 47 +/- 9 years, mean cholesterol 203 +/- 47 mg/dl) obtained from one cardiac surgeon working in a single institution in South India were evaluated. Morphologic findings were compared with 40 endoarterectomy specimens obtained from age-matched Caucasians from Ottawa, Canada, with a reported mean cholesterol of 262 +/- 47 mg/dl. Morphometric measurements of the vessel size, percent stenosis, and the various components of the atherosclerotic plaque were determined by computerized planimetry. RESULTS: The vessel size was smaller in the Indian than in the Canadian population (4.6 +/- 2.9 vs. 5.6 +/- 3.0 mm2, p = 0.07), the plaque area was less (4.3 +/- 2.3 vs. 5.3 +/- 2.8 mm2, p = 0.055) and the calculated percent stenosis was significantly less (93 vs. 96%, p = 0.028). Of all the parameters evaluated, only necrotic core in the Indian population (7.1 +/- 10.9% vs. Canadian 16.7 +/- 19.7%, p < 0.001) and proteoglycan deposition (7.9 +/- 11.2% vs. Canadian 3.7 +/- 5.3%, p < 0.023) were significantly different. Despite the Indians having low total cholesterol, there was greater diffuse double and triple-vessel disease and at a younger age than in the Caucasians. CONCLUSIONS: From our data, it appears that the mechanism of development of atherosclerotic disease in the Indians may be different because they have smaller vessels, smaller necrotic core, and greater proteoglycan deposition. Other etiologies, especially those related to a high carbohydrate diet (which is typical for South Indians), should be considered.

Adult↗
PubMed1998

Hamartoma of mature cardiac myocytes.

The clinical and pathological findings of three patients with hamartomas of mature cardiac myocytes resembling localized hypertrophic cardiomyopathy are presented. Hypertrophic cardiomyopathy is manifest by a poorly demarcated area of cardiac hypertrophy, microscopically demonstrating myofiber disarray and intramural coronary thickening. Localized, nonencapsulated masses of hypertrophied cardiac myocytes in locations other than the left ventricle or ventricular septum have not been reported. The clinical and pathological data of three patients with localized hamartomas were retrospectively retrieved. The patients were 9, 22, and 28 years old, respectively; none had a known family history of heart disease or cardiomyopathy. Two patients had cardiac arrhythmias: one patient died suddenly, and one patient had the Wolff-Parkinson-White syndrome. The third patient was asymptomatic. Two patients treated surgically had single masses in the right atrium and right ventricle, respectively. The patient who died suddenly had multiple discrete masses throughout the atrial and ventricular myocardium, including the left ventricular free wall. None of the three patients had septal asymmetry suggestive of hypertrophic cardiomyopathy. Histologically, there were discrete but unencapsulated nodules of marked myocyte hypertrophy with disorganization, focal scarring, and thickened intramural arteries. There was no myocyte vacuolization suggestive of cardiac rhabdomyoma. Ultrastructurally, the myocytes showed abundant and disorganized myofilaments and normal intercellular junctions. Hamartoma of mature cardiac myocytes is a previously undescribed cardiac tumor that shares some features of hypertrophic cardiomyopathy and rhabdomyoma, but is currently best considered a separate entity.

Adult↗