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Biomedical subjects

R Virmani

Publications and source records attributed to R Virmani.

At least 73 records · Page 4Linked to original sources
PubMed1999

Apoptosis in human atherosclerotic plaques.

Intimal cell death has been a recognized feature of advanced atherosclerotic disease. With the advent of DNA in situ end labelling and/or ultrastructural techniques, recent findings suggest that cells of an atheroma undergo programmed cell death or apoptosis. The pathophysiologic relevance of apoptosis in atherosclerotic disease is debatable. Apoptotic cell death may influence lesion progression and thus reduce overall plaque burden. Alternatively, apoptosis may prove a means of quenching the inflammation, converting cellular-rich lesions to so-called 'stable' fibrous hypocellular plaques or conversely weaken the fibrous cap causing plaque rupture, a major cause of acute coronary syndromes. Apoptotic cells within plaques are typically macrophages, smooth muscle cells and T-cells and the frequency of death varies in the different regions of the lesion. The precise signalling pathways of apoptosis in plaques are unknown. There is however, some evidence that production of immune cytokines may promote apoptosis through activation of the Fas ligand-mediated death pathway. Genetic signals that regulate apoptosis in the atheroma, at least in smooth muscle cells, may involve the tumour suppressor genes p105RB and p53. Further studies as to the relevance of apoptosis in acute coronary syndromes and potential mechanisms are emerging.

Journal Article↗
PubMed1999

Sudden death after a cold drink: case report.

We report a case of sudden cardiac death in a 12-year-old boy after rapid ingestion of a frozen slurry drink. The cause of death was determined to be a cardiac arrhythmia secondary to a previously undiagnosed cardiac rhabdomyoma with associated myocardial scarring. Ingestion of cold liquids has been associated with syncope, but not sudden cardiac death. In this case, bradycardia induced by cold-induced vasovagal reflex may have precipitated the terminal arrhythmia. Ingestion of cold liquids should be considered a potential trigger for fatal cardiac arrhythmias in patients with underlying heart disease.

Arrhythmias, Cardiac↗
PubMed1999

Granulomatous 'foreign body reactions' contribute to exaggerated in-stent restenosis.

BACKGROUND: Results of previous studies with stents coated with 'biocompatible' polymers showed that severe inflammatory reaction and subsequent in-stent restenosis may occur. OBJECTIVE: To evaluate the contribution of granulomatous reaction from uncoated stents to formation of in-stent neointimal hyperplasia. METHODS: Uncoated stainless-steel stents were implanted into 21 porcine coronary arteries without oversizing and harvested after 2 months (n = 6) or 6 months (n = 7). We compared the stents with granulomatous reaction with those without foreign-body reaction. RESULTS: Granulomatous reactions occurred in five 21 stents and resulted in there being significantly greater in-stent neointimal hyperplasia than there was with stents without foreign-body reaction (angiographic diameter stenosis 45 +/- 36 versus 16 +/- 16%, area of neointimal 3.30 +/- 1.4 versus 1.22 +/- 0.4 mm2, thickness of neointima 0.46 +/- 0.29 versus 0.11 +/- 0.09 mm, stenosed area 56 +/- 24 versus 20 +/- 7%, P < 0.01 for each comparison). This increase in amount of neointima was accompanied by significantly greater proliferating cell nuclear antibody staining (15 +/- 5 versus 3 +/- 2%, P < 0.05) in the presence of a granuloma near the stent struts. CONCLUSIONS: A localized granulomatous reaction is associated with a significant increase in amount of stent neointima and proliferation of cells. Thus, permanent stent implants may provoke granulomatous vascular reactions that may affect late-healing responses and clinical outcomes.

Animals↗
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 erosion is a major substrate for coronary thrombosis in acute myocardial infarction.

OBJECTIVE: To evaluate the prevalence of plaque erosion as a substrate for coronary thrombosis. DESIGN: Pathological study in patients with acute myocardial infarction not treated with thrombolysis or coronary interventional procedures. PATIENTS: 298 consecutive patients (189 men, mean (SD) age 66 (11) years; 109 women, 74 (8) years) dying in hospital between 1984 and 1996 from acute myocardial infarction, diagnosed by ECG changes and rise in cardiac enzymes. MAIN OUTCOME MEASURES: Histopathological determination of plaque erosion as substrate for acute thrombosis; location and histological type of coronary thrombosis; acute and healed myocardial infarcts; ventricular rupture. RESULTS: Acute coronary thrombi were found in 291 hearts (98%); in 74 cases (25%; 40/107 women (37.4%) and 34/184 men (18.5%); p = 0.0004), the plaque substrate for thrombosis was erosion. Healed infarcts were found in 37.5% of men v 22% of women (p = 0.01). Heart rupture was more common in women than in men (22% v 10.5%, p = 0.01). The distribution of infarcts, thrombus location, heart rupture, and healed infarcts was similar in cases of plaque rupture and plaque erosion. CONCLUSIONS: Plaque erosion is an important substrate for coronary thrombosis in patients dying of acute myocardial infarction. Its prevalence is significantly higher in women than in men.

Aged↗
PubMed1999

Sudden death in right ventricular dysplasia with minimal gross abnormalities.

Arrhythmogenic right ventricular cardiomyopathy is emerging as a relatively common cause of exercise-induced sudden death in the young. The diagnostic criteria at autopsy are, however, not fully established, leading to both over- and underdiagnosis. We report a young man and a young woman dying suddenly of right ventricular dysplasia during exercise, in whom the gross autopsy findings in the right ventricle were minimal or even absent. However, the histologic features in both right and left ventricles were typical of the disease, and consisted of fibrofatty infiltrates with typical myocyte degeneration of the right ventricle and subepicardial regions of the left ventricle. These cases illustrate that microscopic findings are diagnostic and may be present in the absence of gross findings. Marked fat replacement is not essential for the diagnosis of right ventricular dysplasia, and the right ventricle should be extensively sampled histologically in all cases of sudden unexpected death, especially those that are exercise related.

Adult↗
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

Stent design favorably influences the vascular response in normal porcine coronary arteries.

OBJECTIVES: The purpose of this study was to compare the arterial response following implantation of a stainless-steel, balloon-expandable, tubular slotted stent with that of a novel computer-designed, multi-cellular stent in normal porcine coronary arteries. BACKGROUND: Intracoronary stent placement has evolved into the primary strategy for percutaneous revascularization of symptomatic coronary arterial lesions. Presently there is intense interest in developing new stent designs to improve stent delivery and biocompatability. METHODS: Computer-assisted design was utilized to develop a balloon-expandable stent with symmetric expansion properties, uniform arterial wall coverage, longitudinal flexibility and radial strength. Quantitative coronary angiography and histological assessment of the stented arteries was used to evaluate the acute and chronic vascular responses to a stainless-steel, balloon-expandable, tubular slotted stent as compared to the computer-designed BX stent in the normolipemic swine. RESULTS: Forty stents (24 BX, 16 tubular slotted) were implanted in 19 miniature swine at a mean inflation pressure of 9 atm using identical delivery systems. Eight of the BX and none of the tubular slotted stents were post-dilated with a non-compliant balloon at 12-14 atm. The mean stent-to-artery ratio was similar for the BX (1.03 +/- 0.06) and tubular slotted (1.04 +/- 0.11; p = 0.59) designs. Protrusion or asymmetric radial flaring of a strut at the stent margin was present in 1 of 23 BX stents (4.3%) and 10 of 15 tubular slotted stents (66.7%; p < 0.0001). The mean arterial injury score was significantly less for the BX stent (0.2 +/- 0.2) as compared with the tubular slotted stents (0.4 +/- 0.4; p = 0.025). At 3 days, thrombus area was similar for the BX and tubular slotted designs (0.42 +/- 0.16 mm2 versus 0.44 +/- 0.18 mm2, respectively; p = 0.88). The mean neointimal area was significantly less for the BX at 2 months (1.09 +/- 0.25 mm2 versus 2.93 +/- 2.26 mm2 in the tubular slotted stent) and at 6 months (1.10 +/- 0.26 mm2 versus 2.07 +/- 0.65 mm2 in the tubular slotted stent; p = 0.01), resulting in approximately 50% less in-stent stenosis. CONCLUSIONS: The arterial response to a balloon-expandable stent can be favorably influenced by computer-assisted modification of design in an experimental model. Further study is warranted to determine the impact of stent design upon clinical in-stent restenosis.

Angioplasty, Balloon, Coronary↗
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

Overexpression of transforming growth factor beta1 in arterial endothelium causes hyperplasia, apoptosis, and cartilaginous metaplasia.

Uninjured rat arteries transduced with an adenoviral vector expressing an active form of transforming growth factor beta1 (TGF-beta1) developed a cellular and matrix-rich neointima, with cartilaginous metaplasia of the vascular media. Explant cultures of transduced arteries showed that secretion of active TGF-beta1 ceased by 4 weeks, the time of maximal intimal thickening. Between 4 and 8 weeks, the cartilaginous metaplasia resolved and the intimal lesions regressed almost completely, in large part because of massive apoptosis. Thus, locally expressed TGF-beta1 promotes intimal growth and appears to cause transdifferentiation of vascular smooth muscle cells into chondrocytes. Moreover, TGF-beta1 withdrawal is associated with regression of vascular lesions. These data suggest an unexpected plasticity of the adult vascular smooth muscle cell phenotype and provide an etiology for cartilaginous metaplasia of the arterial wall. Our observations may help to reconcile divergent views of the role of TGF-beta1 in vascular disease.

Animals↗
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

Interaction of genetic deficiency of endothelial nitric oxide, gender, and pregnancy in vascular response to injury in mice.

To begin to dissect atherogenesis as a complex genetic disorder affected by genetic makeup and environment, we have (a) generated a reproducible mouse model of neointimal growth; (b) evaluated the effect of disruption of a single gene, endothelial nitric oxide synthase, believed to be central to intimal growth, and (c) examined the modifying effects of gender and pregnancy upon the vascular response. Cuff placement around the femoral artery causes reproducible intimal growth. We assessed the response to injury by quantitative morphometry, measuring the intimal to medial (I/M) volume ratio. In wild-type mice, cuff placement causes pronounced intimal proliferation without affecting the media, resulting in I/M ratios of 31% (SV129 males) and 27% (C57BL/6 males). eNOS mutant male mice have a much greater degree of intimal growth (I/M ratio of 70%). Female mice show less intimal response than do males, although eNOS mutant female mice still have more response than do wild-type females. Most dramatic, however, is the effect of pregnancy, which essentially abolishes the intimal response to injury, even overriding the effect of eNOS mutation. We conclude that eNOS deficiency is a genetic predisposition to intimal proliferation that is enhanced by male gender, and that may be overridden by pregnancy.

Animals↗
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↗