Cones of skin occur where hypertrophic scar occurs.

Hypertrophic scarring is devastating for the patient, however the pathophysiology and treatment remain unknown after decades of research. The process follows deep dermal injury, occurs only on certain body parts, does not occur in the early fetus or in animals, and is a localized event. This suggests that an anatomic structure in human, deep dermis may be involved. The dermis is a matrix perforated by cones containing many structures including skin appendages and fat domes. We hypothesized that studying the cones might reveal a structure related to scarring. We examined tangential wounds from various body parts on human cadavers along with skin histology from various human body parts, the early fetus, partial thickness burns, hypertrophic scars, and two other species-rats and rabbits. We found that the cones may in fact be the structure. They exist where hypertrophic scar occurs-cheek, neck, chest, abdomen, back, buttock, arm, forearm, dorsal hand, thigh, leg, dorsal foot, helix and ear lobe. They do not exist where hypertrophic scar does not occur-scalp, forehead, concha, eyelid, palm, early fetus, and in rat, or rabbit. It also became apparent that the cones have been omitted from most considerations of skin histology. We suggest that the cones need to be studied in relation to hypertrophic scarring and restored to skin diagrams.

Fatal parvovirus myocarditis in a 5-year-old girl.

Infection with parvovirus B19 is common in children and typically causes mild illness. We report here the case of a 5-year-old girl who died suddenly, 2 weeks after the clinical diagnosis of a parvoviral infection (erythema infectiosum). Microscopic examination of the heart showed severe myocarditis with extensive T-cell and macrophage infiltration. Cultures, serology, and molecular analyses of serum for enteroviridae, adenovirus, influenza, varicella zoster, cytomegalovirus, and herpes simplex viruses were negative. Quantitative polymerase chain reaction (PCR) analysis for parvovirus B19 in peripheral blood, however, showed active infection (91,000 genomes/mL serum; 2.4 genomes/mononuclear cell). Despite the presence of myocarditis, immunostaining for parvoviral surface antigens was negative in the heart. Quantitative PCR analysis of paraffin sections showed that myocardial parvoviral content was significantly less than that of the normal appearing kidney and within the range predicted simply by tissue blood content. Thus, parvovirus B19 infection can be complicated by fatal myocarditis. Because the virus does not appear to have infected the heart, per se, we speculate that myocarditis arose from immunological cross-reaction to epitopes shared between the virus and the myocardium. HUM PATHOL 32:342-345.

Detection and characterization of atherosclerotic fibrous caps with T2-weighted MR.

PURPOSE: We assessed the performance of T2-weighted MR imaging in detecting atherosclerotic fibrous caps and in depicting their integrity. METHODS: Twenty atherosclerotic lesions removed by carotid endarterectomy were imaged on a 1.5-T system using T2-weighted spin-echo sequences. The MR images were reviewed independently by four blinded interpreters for fibrous caps and ruptures. The results obtained from the observers were then graded against histologic findings by using receiver-operating characteristic (ROC) curve analysis. RESULTS: The area under the ROC curve for fibrous cap detection was 0.80, indicating that T2-weighted MR imaging was a good but not definitively diagnostic test for detecting ex vivo fibrous caps. The ROC curve for fibrous cap characterization yielded an area of 0.75, indicating that T2-weighted MR imaging was a fair but not highly diagnostic test for depicting fibrous cap integrity. A definite reading for detection of fibrous caps or rupture was fairly specific (90% and 98%, respectively) but not very sensitive (37% and 12%, respectively). CONCLUSIONS: T2-weighted MR imaging of ex vivo atherosclerotic plaques aided in the detection and evaluation of fibrous caps. In both cases, MR imaging proved more useful for ruling out disease than for confirming its presence.

Apolipoproteins B, (a), and E accumulate in the morphologically early lesion of 'degenerative' valvular aortic stenosis.

Nonrheumatic aortic stenosis of trileaflet aortic valves has been considered to be a "degenerative" process, but the early lesion of aortic stenosis contains the chronic inflammatory cells, macrophages and T lymphocytes. Because lipoprotein deposition is prominent in atherosclerosis, another chronic inflammatory process, this study examined whether lipoproteins accumulate in aortic valve lesions. Immunohistochemical studies were performed to detect apolipoprotein (apo) B, apo(a), apoE, macrophages, and alpha-actin-expressing cells on 18 trileaflet aortic valves that ranged from normal to stenotic. All three apolipoproteins were detected in early through end-stage lesions of aortic stenosis but not in histologically normal regions. Comparison with oil red O staining suggested that most of the extracellular neutral lipid in these valves was associated with either plasma-derived or locally produced apolipoproteins. Thus, in early through end-stage aortic valve lesions, apolipoproteins accumulate and are associated with the majority of extracellular valve lipid. These results are consistent with the hypothesis that lipoprotein accumulation in the aortic valve contributes to pathogenesis of aortic stenosis.

Anatomical findings in patients having had a chronically indwelling coronary sinus defibrillation lead.

The purpose of this report is to review the gross and histological cardiac anatomical findings in patients with chronically indwelling coronary sinus leads at the time of autopsy or cardiac transplantation. Transvenous cardioverter defibrillators offer effective protection against sudden death. The use of a coronary sinus electrode has been shown in some patients to decrease the defibrillation threshold. The anatomical consequences of chronically indwelling coronary sinus cardioversion/defibrillation electrodes in patients having transvenous implantable cardioverter defibrillators is unknown. The hearts of seven patients with chronically indwelling coronary sinus electrodes were evaluated following autopsy (n = 2) or cardiac transplantation (n = 5). The coronary sinus electrode in each case was a 6.5 French silicone lead with a 5-cm long defibrillation coil (Medtronic CS lead model 6933) that was positioned as distally as possible within the coronary sinus at the time of implantable cardioverter defibrillator surgery. The seven hearts examined were derived from patients whose age ranged between 49 and 69 (mean 56 +/- 7 years). Six had coronary artery disease and one had idiopathic dilated cardiomyopathy. The time from implant to death or cardiac transplantation was 8 +/- 6 months, range 1-18 months. In all seven patients, there was no evidence of any significant damage from the presence of the coronary sinus lead. The only finding in each case was the scattered presence of a thin white fibrous sheath over the lead that intermittently adhered to the coronary sinus endothelium and, in the two patients transplanted 1-3 months after implantable cardioverter defibrillator insertion, a mild inflammation reaction adjacent to the leads in the coronary sinus endothelium. There was no evidence of coronary sinus occlusion, adjacent coronary artery injury, coronary sinus perforation, coronary sinus burn, or myocardial injury adjacent to the lead. Cause of death was due to end-stage congestive heart failure and thrombotic stroke, respectively, in the two patients examined at autopsy. Coronary sinus defibrillation leads can be used safely without harmful anatomical effect.

Osteopontin is expressed in human aortic valvular lesions.

BACKGROUND: Nonrheumatic stenosis of trileaflet aortic valves, in which calcification is a prominent feature, has been termed a "degenerative" condition, but it has been demonstrated recently that chronic inflammation is a characteristic feature of the developing lesion of aortic stenosis. This observation raised the possibility that calcification in the aortic valve might be actively regulated. Thus, the present study investigated whether osteopontin, a protein implicated in the regulation of both normal and dystrophic calcification, could be detected in lesions of valvular aortic stenosis. METHODS AND RESULTS: Morphological and immunohistochemical studies were performed on 14 human aortic valves, representing a range of pathology from normal to clinically stenotic. The extent of calcification and macrophage accumulation and their relation to the presence of osteopontin protein were characterized. Highly statistically significant associations were found between the degree of osteopontin expression and the degrees of both calcification and macrophage accumulation in early through late lesions of aortic stenosis. Further, in situ hybridization localized osteopontin mRNA to a subset of lesion macrophages. CONCLUSIONS: These results suggest that, rather than representing a degenerative and unmodifiable process, calcification in aortic stenosis may be, in part, an actively regulated process with the potential for control either through modification of inflammation or synthesis of proteins such as osteopontin, which may modulate calcification in this tissue.

University of Wisconsin solution provides superior myocardial preservation compared with Stanford cardioplegic solution.

The efficacy of the University of Wisconsin solution to safely prolong preservation times for kidney, pancreas, and liver transplantation is established, but its efficacy in enhancing myocardial preservation is not yet clear. We studied the effects of Stanford cardioplegic solution and the University of Wisconsin solution both in preserving the myocardium and in protecting it from the effects of reperfusion injury after 6 hours of preservation. In 28 rat hearts we measured changes in high-energy phosphate content (with magnetic resonance spectroscopy) and histologic changes (edema, endothelial changes, myocyte architecture) during preservation and changes in high-energy phosphate content, histologic status, and performance (aortic systolic and diastolic pressure, heart rate, rhythm) in Langendorff and working hearts during reperfusion. No significant differences in the kinetics of high-energy phosphate changes were noted between the two cardioplegic solutions during preservation. However, at the end of 6 hours of preservation, hearts in the Stanford cardioplegic solution group were more edematous (p < 0.01) than those in the University of Wisconsin group. During reperfusion, no significant differences in the kinetics of high-energy phosphates were noted between the two cardioplegic solutions. None of the hearts in the University of Wisconsin solution group developed ventricular fibrillation at the start of reperfusion, but all hearts in the Stanford group did so. Once sinus rhythm was established no significant differences in developed pressure or heart rate were found between the two solutions. After 2.5 hours of reperfusion, hearts in the Stanford group were more edematous (p < 0.002) and had a greater disruption of myocyte architecture (p < 0.002) and greater arteriolar endothelial injury (p < 0.004). In conclusion, the University of Wisconsin solution better protects the myocardium in this rat model than does Stanford solution. The mechanism for this beneficial effect of the University of Wisconsin solution appears to be due to its better preservation of the microvasculature rather than differences in preservation of high-energy phosphates.

Characterization of the early lesion of 'degenerative' valvular aortic stenosis. Histological and immunohistochemical studies.

BACKGROUND: Nonrheumatic stenosis of trileaflet aortic valves, often termed senile or calcific valvular aortic stenosis, is considered a "degenerative" process, but little is known about the cellular or molecular factors that mediate its development. METHODS AND RESULTS: To characterize the developing aortic valvular lesion, we performed histological and immunohistochemical studies on Formalin-fixed and methanol-Carnoy's-fixed paraffin-embedded aortic valve leaflets or on frozen sections obtained at autopsy from 27 adults (age, 46 to 82 years) with normal leaflets (n = 6), mild macroscopic leaflet thickening (n = 15), or clinical aortic stenosis (n = 6). Focal areas of thickening ("early lesions") were characterized by (1) subendothelial thickening on the aortic side of the leaflet, between the basement membrane (PAS-positive) and elastic lamina (Verhoeff-van Gieson), (2) the presence of large amounts of intracellular and extracellular neutral lipids (oil red O) and fine, stippled mineralization (von Kossa), and (3) disruption of the basement membrane overlying the lesion. Regions of the fibrosa adjacent to these lesions were characterized by thickening and by protein, lipid, and calcium accumulation. Control valves showed none of these abnormalities. Immunohistochemical studies were performed using monoclonal antibodies directed against macrophages (anti-CD68 or HAM-56), and contractile proteins of smooth muscle cells or myofibroblasts (anti-alpha-actin and HHF-35) or rabbit polyclonal antiserum against T lymphocytes (anti-CD3). In normal valves, scattered macrophages were present in the fibrosa and ventricularis, and occasional muscle actin-positive cells were detected in the proximal portion of the ventricularis near the leaflet base, but no T lymphocytes were found. In contrast, early lesions were characterized by the presence of an inflammatory infiltrate composed of non-foam cell and foam cell macrophages, occasional T cells, and rare alpha-actin-positive cells. In stenotic aortic valves, a similar but more advanced lesion was seen. CONCLUSIONS: The early lesion of "degenerative" aortic stenosis is an active inflammatory process with some similarities (lipid deposition, macrophage and T-cell infiltration, and basement membrane disruption) and some dissimilarities (presence of prominent mineralization and small numbers of smooth muscle cells) to atherosclerosis.

E-selectin expression in human cardiac grafts with cellular rejection.

BACKGROUND: E-selectin expression has recently been documented to occur with lymphocytic infiltration in the skin and synovium. The question of whether E-selectin is expressed in the context of cardiac graft rejection was addressed in this study. METHODS AND RESULTS: One hundred ninety-five human posttransplant cardiac biopsy specimens were immunoreacted with antibodies to E-selectin and VCAM-1, and endothelial expression of both adhesion molecules was recorded as present or absent. Cardiac graft rejection was graded in blinded fashion. The frequency of E-selectin expression was 11% in biopsies without rejection, 36% in mild rejection, and 58% in moderate rejection, a significant correlation (P < .001). VCAM-1 expression was present in 11% of biopsies with no rejection, 37% with mild rejection, and 85% with moderate rejection, corroborating the previously reported strong correlation between VCAM-1 expression and graft rejection (P < .0001). In 71% of specimens, E-selectin expression coincided with VCAM-1 expression. In the remaining 29% of specimens in which E-selectin and VCAM-1 expression were not both present, isolated E-selectin expression was found more frequently in biopsies with early, increasing rejection, whereas isolated VCAM-1 expression was found more frequently in specimens with established moderate rejection and later, resolving rejection. CONCLUSIONS: E-selectin is expressed in cardiac allograft rejection and may play a role in recruitment of lymphocytes into the graft. Rejection trend analysis suggests that E-selectin expression may be prominent early in the course of rejection.

Effect of cyclosporine on the uptake of monoclonal antibody to cardiac myosin.

Monoclonal antibody to cardiac myosin labeled with indium-111 diethylenetriamine pentaacetic acid holds promise as a noninvasive marker of cardiac graft rejection. Uptake of antibody has correlated with histologic evidence of rejection in nonimmunosuppressed animals. Whether this correlation will apply with immunosuppression has important clinical implications. Fifty-two heterotopic heart transplantations were performed between isogeneic and nonisogeneic strains of rats. Cyclosporine-treated (15 mg/kg day subcutaneously for 9 days) and untreated control animals were killed on day 9, 48 hours after injection of radiolabeled antibody. Donor and recipient hearts were submitted for scintillation scanning and histologic analysis. In untreated animals, antibody uptake was significantly greater in nonisogeneic than in isogeneic donor hearts, correlating with a significantly higher rejection score and increased myocyte necrosis in the former. Between isogeneic groups, cyclosporine-treated donor hearts had significantly higher antibody uptake and donor/native antibody uptake ratios than did untreated isogeneic hearts. There was, however, no significant difference in the histologic degree of rejection or myocyte necrosis between isogeneic groups. Between cyclosporine-treated and untreated nonisogeneic animals, donor heart antibody uptake and donor-native heart antibody uptake ratios were not significantly different. Nonetheless, the histologic grade of rejection and presence of myocyte necrosis was significantly greater in untreated than in treated nonisogeneic hearts. There were no abnormalities in the native hearts. In this model, cyclosporine treatment correlates with an increased uptake of antimyosin antibody in both isogeneic and nonisogeneic donor hearts, out of proportion to histologic evidence of rejection or myocyte necrosis. This effect may lead to false-positive results in clinical tests utilizing antimyosin antibody uptake as a marker of rejection in the presence of cyclosporine therapy.

Panlobular emphysema in young intravenous Ritalin abusers.

We studied a distinctive group of young intravenous Ritalin abusers with profound obstructive lung disease. Clinically, they seemed to have severe emphysema, but the pathologic basis of their symptoms had not been investigated previously. Seven patients have died and been autopsied: in four, the lungs were fixed, inflated, dried, and examined in detail radiologically, grossly, microscopically, and by electron probe X-ray microanalysis. All seven patients had severe panlobular (panacinar) emphysema that tended to be more severe in the lower lung zones and that was associated with microscopic talc granulomas. Vascular involvement by talc granulomas was variable, but significant interstitial fibrosis was not present. Five patients were tested for alpha-1-antitrypsin deficiency and found to be normal, as were six similar living patients. These findings indicate that some intravenous drug abusers develop emphysema that clinically, radiologically, and pathologically resembles that caused by alpha-1-antitrypsin deficiency but which must have a different pathogenesis. Talc from the Ritalin tablets may be important, but the mechanism remains to be elucidated.

Radio-frequency ablation: effect of voltage and pulse duration on canine myocardium.

The purpose of this investigation was to examine in vivo the relationship of radio-frequency (RF) pulse voltage and duration on the volume of tissue injury. RF 500-kHz pulses of 20-, 40-, and 60-V amplitude (RMS) were applied to the epicardium of 18 dogs for pulsing periods of 5-20 s. Systematic and quantitative tissue analysis was then performed after 30 days. No chronic lesions were evident on microscopic examination for 20-V RF pulse applications up to 15 s. Application of 20-V pulses for 20 s produced small lesions having a volume of 2.4 +/- 0.7 mm3. At 40 V, the volume of tissue injury ranged from 39.1 +/- 10.3 mm3 for 5 s of pulse application to 128.8 +/- 24.8 mm3 for 20 s of pulse application. Over the first 15 s of 40-V pulse application, the volume of tissue injury increased as pulse application time increased. There was no further increase in tissue injury for 40-V pulsing durations greater than 15 s. At 60 V, volumes of tissue injury ranged from 122.7 +/- 33.5 mm3 at 5 s to 313.6 +/- 73.7 mm3 at 20 s. Lesion size increased significantly for pulse durations of up to 10 s. Thereafter, 60-V pulses yielded little increase in tissue injury. In addition, persistent 60-V pulsing for periods greater than 9 s duration resulted in arcing and tissue vaporization in 28% of the applications. Thus RF energy is limited in its ability to create safe and effective tissue injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Detection of cardiac allograft rejection and myocyte necrosis by monoclonal antibody to cardiac myosin.

Indium 111-labeled monoclonal antibody to cardiac myosin was examined for efficacy in the detection of cardiac graft rejection and rejection-related myocyte necrosis. Heterotopic heart transplants were performed in isogenic and allogenic groups of rats (n = 56). At selected intervals posttransplant, uptake of injected antibody in the donor and native hearts was determined by gamma scintillation scanning. Indium uptake was compared to histologic results graded for the severity of rejection and the presence of myocyte necrosis. The donor heart uptake of labeled antibody was significantly greater in both moderate rejection and severe rejection than in lesser degrees of rejection (P = 0.05). The donor/native heart antibody uptake ratio (AUR) in both severe and moderate rejection were significantly different from no or mild rejection (P = 0.05). In pooled grafts without myocyte necrosis, both the absolute donor heart antibody uptake and the donor/native heart AUR were significantly greater in grafts with moderate or severe rejection than in those with no or mild rejection (P less than 0.001). Among grafts with moderate or severe rejection, those with myocyte necrosis had greater donor heart antibody uptakes and greater donor/native heart AUR than grafts without myocyte necrosis (P less than 0.001). The grade of rejection and the presence of histologic myocyte necrosis appear to be closely related but independent variables, both of which influence antibody uptake. It is concluded that monoclonal antibody to cardiac myosin may be a useful noninvasive tool that could distinguish moderate or severe rejection from lesser degrees of rejection and that could detect the presence of myocyte necrosis.

Effect of voltage and charge of electrical ablation pulses on canine myocardium.

Multiple paired lesions produced by a train of high-voltage low-charge rectangular pulses (20 A, 30 microsecond) and a train of low-voltage high-charge rectangular pulses (2 A, 300 microsecond) were made to the left ventricular epicardium of 23 dogs to determine the relative influence of voltage and charge delivery on injury of canine myocardium. Both pulsing methods contained equal amounts of energy (15 J) delivered over equal periods of time (100 ms), and both pulsing methods were nonarcing and therefore nonbarotraumatic. The volume of cardiac tissue injury resulting from both types of pulses was then evaluated from planimetered serial histological sections after 1, 10, and 30 days. Over the 30-day period, lesion size progressively decreased to 56% of its original value for the high-voltage low-charge pulse. In contrast, lesion size from the low-voltage high-charge pulse remained relatively constant, decreasing only 12% of its original value. These results indicate that when energy delivery is held constant, voltage, not charge, is the dominant mediator of cell injury. Also, cells subjected to high voltages appear to recover partially over time with significantly less constancy of tissue injury than that seen with low-voltage high-charge pulses.

The coronary arteries in cases of cardiac and noncardiac sudden death.

Thirty-four cardiac and 22 sudden noncardiac deaths in men were examined with an injection, radiographic, and dissection autopsy technique to obtain as many coronary narrowings as possible for study. The narrowest sites in each of the major coronary vessels (LAD, LCX, and RCA) from each subject were identified histologically for analysis. The parameters studied were size of lumen, estimated as percentage of vessel cross-section, vs. the age of subject and the grades of chronic inflammatory cell infiltrate, of neovascularization, of intimal haemorrhage, and of pultaceous cholesterol-rich deposit in the wall. Genstat statistical analysis revealed that the significant explanatory variables for the reduction in arterial lumen were active inflammation and cardiac cause of death. Neither age nor cholesterol-rich deposits had significant explanatory power. A pathogenic role for inflammation may well be possible and efforts will be made in the future to investigate its etiology.

Validation of a computerized QRS criterion for estimating myocardial infarction size and correlation with quantitative morphologic measurements.

This replication study describes the relation of myocardial infarction (MI) size, measured at autopsy, to initial and late QRS abnormalities, measured by computerized spatial vectorcardiography. Thirty-one patients with MIs of differing ages and left ventricular locations and 24 patients with no evidence of heart disease were studied. The percent volume of MI was significantly estimated by the initial QRS abnormalities (r = 0.94, p less than 0.00001). The 2 regression equations from the previous training set and from this present test set were compared to verify validity of the criterion, the integral of magnitudes of spatial vectors during initial abnormal depolarization to estimate MI size. There was not a significant difference between the 2 intercepts, the 2 slopes, the 2 straight-line regressions or the 2 correlation coefficients. The additional information obtained from late QRS abnormalities contributed little to improve estimation of size of multiple MIs of differing ages and left ventricular locations, but accurately predicted (r = 0.87) the size in single inferobasal MI. The results indicate that vectorcardiographic measurements of early activation abnormalities is a valid criterion to estimate MI size.

Estimation of inferobasal myocardial infarct size by late activation abnormalities of the QRS complex.

This report describes the relation of myocardial infarct (MI) size in the left ventricular inferobasal wall, measured at necropsy, to late activation abnormalities of the QRS complex, measured by computerized spatial vectorcardiography. Fifteen patients with single inferobasal MIs and 10 patients with no evidence of heart disease were studied. The percentage of MI in the inferobasal wall was significantly related to the vectorcardiographic abnormalities noted late (i.e., 31 +/- 13 ms before the end of the QRS waveform) (r = 0.96, p less than 0.00001). The integral of the vector magnitudes during late abnormal activation significantly predicted the amount of MI in the basal inferior wall (r = 0.88) and in the basal inferior wall plus the outer, subepicardial half of the transmural middle inferior, lateral and inferoseptal walls (r = 0.91). The additional information obtained from late activation of the QRS complex contributed more significance to the estimation of the left ventricular inferobasal MI size than the abnormalities commonly noted during early activation (i.e., during the Q wave).

Selective myocardial cell necrosis in nonhuman primates.

A retrospective study was performed to describe the histologic stages of selective myocardial cell necrosis (SMCN) in nonhuman primates, and to compare the incidence of SMCN in two groups of nonhuman primates. Myocardial tissues taken at the time of autopsy from 50 primates at an experimental center were compared with similar tissues from 50 primates housed in a breeding colony. SMCN was confirmed in 20% of the experimental primates and 30% of the breeding primates, proportions that were not significantly different. The incidence and histologic characteristics of SMCN in nonhuman primates were similar to those described in humans, and resembled the lesion produced in experimental primates by administration of catecholamines of by hypokalemia.