Spontaneous coronary artery dissection associated with cocaine use: a case report and brief review.

Isolated, spontaneous dissection of the coronary arteries in the absence of trauma is an unusual but well-documented occurrence. Fewer than 50 cases have been reported in males in the English language literature, and only one case, nonfatal, was associated with cocaine use. We present the second overall and the first fatal case of cocaine-associated spontaneous coronary artery dissection and a brief review of the literature on coronary dissection and the cardiovascular effects of cocaine use. The mechanism of cocaine's toxicity on the heart and vasculature is complex, multifactorial, and predominantly related to cocaine's adrenergic properties. The increased arterial blood pressure from cocaine's inotropic and chronotropic effects combined with its direct vasoconstrictive effect leads to increased shear forces on the coronary endothelium. This elevated stress may be responsible for the formation of an intimal tear and the subsequent dissection of the coronary artery. If the dissected portion of the arterial wall is displaced enough to significantly occlude the true lumen, infarction can result. In light of this possibility, coronary artery dissection must be considered in young patients presenting with symptoms of cardiac ischemia and a history of cocaine use.

31P-magnetic resonance spectroscopy studies of cardiac transplant patients at rest.

Studies in animal models and patients have suggested that 31P-magnetic resonance spectroscopy (MRS) may be useful in diagnosing transplant rejection, but such studies often are confounded by the late inclusion of patients after transplantation. The present study examined the utility of 31P-MRS in the diagnosis of acute allograft rejection during the first posttransplant month. Thirteen recent heart transplant recipients underwent 57 resting 31P-MRS studies within 24 hr of a biopsy. Subjects lay supine with a 10-cm surface coil placed over the heart. A 1-dimensionsal chemical shift imaging protocol was used to collect spectral information. Spectra from the heart were weighted for distance from the coil and summed before analysis. ANOVA and Duncan's multiple range test were used to analyze the data comparing phosphocreatine (PCr)/ATP ratios with biopsy scores. Transplant patients had significantly lower myocardial PCr/ATP ratios when compared with a normal control group (1.27 +/- 0.27 versus 1.61 +/- 0.22, p < 0.001). However, when the patient group was classified by biopsy score, the expected order of score, 0 > 1 > 2 > 3, was not obtained. Rather, the order was 2 > 0 > 1 > 3. Although the difference between scores 2 and 3 was significant (1.46 versus 1.14, alpha = 0.05 level), the lower three groups were statistically indistinguishable. In addition, the PCr/ ATP ratios were not predictive of future biopsies. Although significantly lower than normal control subjects, resting myocardial PCr/ATP ratios of transplant subjects are not useful in assessing thelevel of rejection. It is suggested that the measurement may be more predictive in mildly exercised myocardium.

Myofibrillar protein structure and assembly during idiopathic dilated cardiomyopathy.

A neutral protease, mekratin, active in human hearts at end stage idiopathic dilated cardiomyopathy (IDC), mediates the breakdown of cardiac myosin LC2. Myosin purified from IDC heart tissue forms unusually short synthetic thick filaments. Therefore, determination of filament length and mekratin distribution in IDC heart muscle were initiated. Native thick filaments were prepared directly from control and IDC tissues and analyzed. Also, paraffin-embedded tissue sections were stained with a fluorescently-labeled anti-protease antibody to establish its distribution in myocardial tissues. Control sections had only very weak, background levels of fluorescence whereas IDC sections stained intensely throughout, indicating a wide ranging distribution of the protease within the myocyte cytoplasm. SDS-PAGE revealed LC2 to be present in stoichiometric amounts in control but greatly reduced in IDC heart muscle. Native thick filaments from control myocardium were structurally stable. They had a median length of 1.65 microm with well-defined bare zones and displayed the 43 nm helical periodicity typical of the relaxed arrangement of myosin heads close to the filaments' shafts. In contrast, native IDC filaments were less stable, and had a median length of 0.9 microm. These filaments were highly disordered: they had no surface periodicity and myosin heads were positioned away from the filaments' shafts. The shorter, less stable, aperiodic thick filaments from IDC hearts appear to result from depletion of LC2 caused by increased activity of mekratin in the IDC myocardium.

Calcium regulation in the human myocardium affected by dilated cardiomyopathy: a structural basis for impaired Ca2+-sensitivity.

Calcium regulation in the human heart is impaired during idiopathic dilated cardiomyopathy (IDC). Here, we analyze the structural basis for impairment in the regulatory mechanism. Regulation of contractility was monitored by MgATPase and Ca2+-binding assays as a function of calcium. Myofibrillar proteolysis and expression of troponin T isoforms were established by gel electrophoresis and by Western blots. Myofibrillar ATPase assays in low salt however, revealed a drastic lowering of calcium sensitivity in IDC myofibrils as indicated by reductions in both activation by high calcium and in EGTA-mediated inhibition of MgATPase. Structural changes in myofilament proteins were found in most IDC hearts, specifically proteolysis of myosin light chain 2 (LC2), troponin T and I (TnT and TnI), and sometimes a large isoform shift in TnT. IDC did not induce mutations in LC2 and troponin C (TnC), as established by cDNA sequence data from IDC cases, thus, calcium binding to IDC myofibrils was unaffected. Reassociation of IDC myofibrils with native LC2 raised MgATPase activation at high Ca2+ to control levels, while repletion with intact, canine TnI/TnT restored inhibition at low Ca2+. A model, identifying possible steps in the steric blocking mechanism of regulation, is proposed to explain IDC-induced changes in Ca2+-regulation. Moreover, shifts in TnT isoforms may imply either a genetic or a compensatory factor in the development and pathogenesis of some forms of IDC.

Cloning of the cDNA and nucleotide sequence of a skeletal muscle protease from myopathic hamsters.

A neutral protease with an estimated Mr of about 26 kD and responsible for cleavage ofmyosin LC2 was isolated from hamster skeletal muscle. Complementary DNAs were generated by RT-PCR using total hamster muscle RNA and degenerate oligonucleotide primers based on the sequences of two internal peptides. The nucleotide sequences of the resultant cDNAs were subsequently determined and the complete amino acid sequence of the protease deduced. Although the hamster protein shared 63-85% identity in nucleotide and amino acid sequences with rat and mouse mast cell proteases, it had a higher degree of specificity for myosin LC2 than mast cell proteases which also digested myosin LC1 and myosin heavy chains. As a result, the hamster protease was designated mekratin because of its unique enzymatic specificities to distinguish it from other mast cell proteases. A polyclonal antibody was raised specific to the hamster muscle and human cardiac muscle mekratins without apparent cross-reaction with rat mast cell proteases. We have earlier demonstrated the presence in excess of a neutral protease that specifically cleaves LC2 in human hearts obtained at end stage idiopathic dilated cardiomyopathy (IDC). Western analyses revealed that heart tissue from patients with IDC contained 5-10 fold more mekratin than control samples. Furthermore, the level of the protease in human IDC tissues was similar to that seen in myopathic hamster skeletal muscle. No bands were recognized by the antibody when IDC myofibrils were probed due to the removal of soluble proteins during sample preparation. Thus, these results strongly suggest that the anti-mekratin antibody will provide positive identification of IDC in many cases and diagnosis by exclusion may be replaced.

Structure and function of myocardial fibrillar collagen.

The extracellular collagen matrix of the myocardium plays an important role in maintaining muscle fiber and cardiac alignment and ventricular shape and size. It also influences tissue and ventricle stiffness. This network consists of an organized hierarchy of collagen that is intimately associated with individual and groups of myocyte and muscle fibers, as well as the coronary vasculature. In renovascular and genetic hypertension, the hypertrophic response of the myocardium includes an increase in collagen concentration, thickening of existing fibrillar collagen, and addition of newly synthesized collagen to all of the matrix components. The consequences of this remodeling are a stiffer myocardium and left ventricular diastolic dysfunction. With removal of less than half of the normal amount of collagen the opposite occurs. That is, the ventricle dilates and there is an increase in ventricular compliance. Thus an abnormal accumulation of collagen is a major distinguishing factor between physiologic and pathologic hypertrophy while an abrupt decrease in collagen concentration results in a ventricular remodeling similar to that of a heart in failure.

1H NMR measurement of triacylglycerol accumulation in the post-ischemic canine heart after transient increase of plasma lipids.

This study tests the hypothesis that increased levels of plasma lipids can accelerate accumulation of myocardial triacylglycerols in post-ischemic but viable myocardium. Two groups of dogs underwent 90 min of left anterior descending coronary artery (LAD) occlusion followed by 240 min of reperfusion. The first group of saline-treated dogs (n = 7) had physiological levels of plasma lipids during reperfusion: a second group treated with Liposyn and heparin (n = 5) experienced increased plasma lipids during reperfusion. The transmural content of triacylglycerols was determined during ischemia and reperfusion using 1H NMR one-dimensional chemical shift imaging (1D CSI), and at the end of reperfusion using Oil Red-O staining and chemical assay. TTC staining was used to identify the extent of irreversibly injured myocardium. Subepicardial and plasma triacylglycerol content, measured both by 1D CSI and chemically, did not change during reperfusion in saline-treated dogs. Infusing dogs with Liposyn and heparin for 90 min during reperfusion transiently elevated their plasma triacylglycerols, which returned to normal levels following Liposyn wash-out. During Liposyn wash-out, myocardial triacylglycerols measured by 1D CSI preferentially increased in the subepicardium of area-at-risk myocardium (P < 0.05). Triacylglycerol content, measured chemically, also increased in area-at-risk compared to non-ischemic subepicardium (P < 0.001). Significant endocardial damage occurred in both groups, but elevated levels of plasma lipids did not increase the size of the area-at-risk. Therefore, elevated plasma lipids caused a preferential accumulation of triacylglycerols in area-at-risk myocardium during reperfusion without exacerbating irreversible ischemic injury. These results are consistent with either inhibited fatty acid oxidation or mis-matched fatty acid extraction and oxidation in area-at-risk myocardium.

1H NMR spectroscopic imaging of myocardial triglycerides in excised dog hearts subjected to 24 hours of coronary occlusion.

BACKGROUND: Myocardial ischemic insult causes depression of fatty-acid beta-oxidation and increased fatty-acid esterification with triglyceride (TG) accumulation. This accumulation has been demonstrated to occur in the territory with diminished blood flow surrounding an infarct, ie, the region at risk. To evaluate whether the extent of TG accumulation in the canine heart after 24 hours of ischemia could be detected, we applied myocardial 1H nuclear magnetic resonance (NMR) spectroscopic imaging (SI). METHODS AND RESULTS: Seven adult mongrel dogs underwent 24 hours of left anterior descending coronary artery occlusion. Postmortem, the hearts were excised and the size and location of the infarct were determined. With a Philips 1.5-T clinical NMR imaging/spectroscopic system, two-dimensional (2D) 1H NMR SI was performed. TG 1H NMR chemical shift images were reconstructed from the frequency domain spectra by numerical integration. A statistically significant (P < .05) increase in TG signal intensity was demonstrated in the region at risk compared with the nonischemic control region. There was an intermediate quantity of TG in the infarct region. Biochemical determination of tissue TG content (milligrams per gram wet weight) in the control, at-risk, and infarct regions confirmed the 1H NMR measurements. Histological evaluation with oil red O staining also demonstrated graded TG accumulation in myocytes. The highest TG levels were found in the at-risk region and the lowest levels in the control region. CONCLUSIONS: By use of 2D 1H NMR SI, the present study confirms and extends previous work that demonstrates preferential accumulation of TG in the reversibly injured myocardium after 24 hours of coronary occlusion. This study provides an important step toward the clinical application of TG imaging. When TG imaging is ultimately possible, resultant data would have diagnostic, prognostic, and therapeutic implications.

Fibroblast growth factor-induced motor end plate regeneration in atrophic muscle.

OBJECTIVE: To determine whether fibroblast growth factor 1 implanted with viable nerve into atrophic muscle will stimulate formation of functional, acetylcholine producing motor end plates. DESIGN: Twelve male Lewis rats underwent predenervation of the hamstring muscle 8 weeks before implantation of the nerve at a site distant from the original motor end plate. Six animals underwent implantation of the tagged nerve ending into atrophic muscle with 50 microgram of fibroblast growth factor 1 in a fibrin adhesive carrier (group 1). Three animals underwent implantation with nerve, fibrin adhesive, and no fibroblast growth factor 1 (group 2); and three animals underwent implantation with fibroblast growth factor 1 and fibrin adhesive with no nerve (group 3). Animals were killed 9 weeks after implantation and nerve and muscle specimens were harvested. MAIN OUTCOME MEASURES: Histoenzymologic methods for acetylcholinesterase and silver impregnation of nerve fibers were performed 9 weeks after fibroblast growth factor 1-fibrin adhesive implantation. Variables included the number of motor end plates per highpower field and motor end plate length. RESULTS: Robust axonal sprouting and formation of multiple motor end plates were found arborized in serial fashion equidistant around the implanted nerve ending. Rare extrasynaptic staining occurred. End plate lengths were significantly shorter in the fibroblast growth factor 1-treated muscles (group 1) than in the specimens without fibroblast growth factor 1 (group 2) (31.2 vs 58.5 micron; P>001, paired t test). The arborization of motor end plates, rare extrasynaptic staining, and shorter end plate lengths seen in group 1 were all consistent with mature motor end plates. Controls (group 3) displayed limited motor end plate formation and extensive extrasynaptic staining typical of denervation. CONCLUSION: This study presents encouraging evidence that fibroblast growth factor 1 with fibrin adhesive carrier can facilitate the reinnervation of atrophied muscle by enhancing the formation or revitalization of motor end plates. Future studies will address muscle function and use of different carrier materials.

Human cardiac myosin light chains: sequence comparisons between myosin LC1 and LC2 from normal and idiopathic dilated cardiomyopathic hearts.

The primary structures of light chains isolated from the human myocardium with idiopathic dilated cardiomyopathy (IDC) were determined and compared with the sequence structures of myosin light chains obtained from control human heart myosin. Sequences were determined by chemical analysis and the identity of N-terminal residues established by mass spectrometry. The N-terminal residues in essential (ELC) and regulatory (RLC) light chains were blocked and were identified to be trimethyl alanine. The amino acid sequences of ELC and RLC from control human myosin revealed a high degree of homology with those purified from rat and chicken cardiac myosin. Comparison with a published partial chemical sequence of the human heart myosin light chains revealed significant variations. However, there was very good agreement with published sequences obtained by molecular biological techniques. Sequences of the light chains from cardiomyopathic myosin revealed no difference in the primary structures when compared with control human heart myosin light chains indicating IDC had no influence on, nor was caused by, altered myosin light chain gene expression.

Cryopreservation of coronary endothelium and endothelial-mediated responses.

Limited availability of functionally viable biological tissues for graft transplantation and scientific research necessitates the development of an effective storage method for preserving existing tissue samples. In this report we briefly reviewed recent attempts in the cryopreservation of coronary endothelium and endothelial-mediated vasoregulatory function. In contrast to partial preservation of vascular smooth muscle cell function, cryostorage of coronary arteries in dimethyl sulfoxide and fetal calf serum resulted in a near complete preservation of the endothelium and its vasoregulatory function. This protection was observed in both animal and human epicardial conduit coronary arteries, as well as in dog intramyocardial resistance arteries. The apparent better preservation of the latter resistance arteries, with a luminal diameter less than 50 microns, is consistent with earlier findings that cryopreservation efficacy improves with fewer and less packing of cells. To further investigate the cryopreservation of endothelial function, we cryostored canine cardiac valves and evaluated the vasorelaxant effects of valvular endothelium-derived vasoactive factors using a bioassay system. As was observed with intact coronary arteries, a near complete preservation of valvular endothelium and its production of vasoactive factors was noted following the freeze and thaw procedures. Thus, these results demonstrate that cryopreservation may provide a useful and efficient storage method for the conservation of limited supplies of biological vascular tissues for graft transplantation and scientific research.

Enhanced peripheral nerve regeneration by acidic fibroblast growth factor.

Transection of peripheral nerves may cause permanent denervation with paralysis and disability in humans and represents a challenging problem in microsurgery. Physiologic repair at increasing intervals after the acute phase of injury results in progressively worse recovery, emphasizing the importance of rapid and timely reinnervation to optimize endorgan viability. Despite recent advances in microsurgical techniques, imperfect reinnervation results in partial return of neuromuscular function, even in the mildest neuropraxias. Axonal repair of mature neurons involves a complex interaction of molecular events, suggesting that the presence of specific neuronotropic factors might enhance the regeneration process. Recombinant human fibroblast growth factor (FGF-1) has been shown to induce both rapid angiogenesis and neurogenesis through a synthetic conduit across a 15-mm surgical gap in the peripheral nerve of the rat. Evidence of newly formed neural structures was confirmed postoperatively by histological examination in a temporal fashion over a 24-week interval. Functional motor recovery of regenerated nerves was evaluated by determining the amplitude and latency of compound muscle action potentials in treated animals. Electrophysiology studies demonstrated consistent return of motor function in 43 and 57% of animals harboring an FGF-1 conduit at 8- and 24-week intervals, respectively. None of the control animals exhibited restoration of motor function. Collectively, these data suggest that FGF may serve as an important mediator of controlled growth during peripheral nerve regeneration.

Cardiac dilatation associated with collagen alterations.

There is a complex collagen network in the heart. Various components have been identified and generally on the basis of form and position some functions have been ascribed to one or another of these components. Since the various components all appear to be connected in a hierarchial network of some type assigning function is not difficult but demonstrating a given function is somewhat hazardous. We have demonstrated that two I.V. infusions of disulfide reagents one week apart activates a collagenolytic system that results in near complete loss of the collagen struts that interconnect myocytes, the collagen struts that connect capillaries to all adjacent myocytes and the weave complex that surrounds groups of myocytes. Increases in pre load or afterload result in responses indicating that the disulfide treated animals generate pressure equal to or greater than the control hearts, thus, the treatment has no affect on either myocyte contractility or force delivery to the ventricle. However, static pressure volume measurements in the disulfide treated animals are shifted far to the right indicating marked dilatation of the ventricle and increase in distensibility. This indicates that the weave complex contributes to the initial rectilinear portion of the pressure volume curve.

Rejection after cardiac transplantation. A time-related risk factor analysis.

BACKGROUND: The determinants of early and repeated episodes of acute rejection after cardiac transplantation remain elusive. METHODS AND RESULTS: To gain insight into this phenomenon, a multivariate analysis for repeated events was applied to 229 patients receiving 249 transplanted hearts between 1981 and July 1, 1991 (595 rejection episodes). The mean frequency of rejection per patient after initial cardiac transplantation was 1.2 at 3 months, 1.8 at 1 year, and 2.8 at 5 years. The pattern of rejection was characterized by an early period of higher risk (greatest during the first month) followed by a low constant risk that continued throughout the period of follow-up (maximum, 9.5 years). By multivariate analysis, risk factors were identified for the likelihood of subsequent rejection after a previous rejection episode (or time of transplantation). Triple-drug immunosuppression plus induction therapy yielded a higher risk of early subsequent rejection compared with other baseline immunotherapy protocols, but it also provided the greatest freedom (95%) from rejection-related death during the first year. Risk factors in the constant phase of hazard included younger age at transplant, female donor and/or recipient, longer donor ischemic time, greater HLA donor-recipient mismatch, and an increased number of previous rejection episodes. CONCLUSIONS: Immunologic and other patient-specific characteristics as well as rejection history predict the likelihood of future rejection events. The value of any antirejection protocol must be evaluated both in terms of rejection episodes and rejection-related deaths. Future analyses may identify specific high- and low-risk patient subsets for rejection, which may provide a more rational basis for altering the amount of chronic immunosuppressive therapy.

Light chain 2 profile and activity of human ventricular myosin during dilated cardiomyopathy. Identification of a causal agent for impaired myocardial function.

BACKGROUND: A number of parameters reflecting the effects of idiopathic dilated cardiomyopathy (IDC) on the structure and function of myosin from the human myocardium were analyzed. METHODS AND RESULTS: The content of the regulatory light chain, LC2, was reduced in myopathic heart myosin in contrast to the controls in which it was present in stoichiometric amounts relative to the essential light chain, LC1. In IDC hearts, the absence or significant reduction in amount of LC2 was related to the presence of an active protease, which was isolated and purified about 130-fold. The protease exhibited a significant degree of specificity: It cleaved LC2 almost totally (but not the heavy chains) in human control heart myosin but only partially cleaved LC2 in canine heart or in rabbit skeletal muscle myosins. The protease was present at a very low level or was inactive in control heart tissue. When the LC1/LC2 molar ratio was calculated, it was found to be 1:1.0 in control heart myosin and remained constant in various samples analyzed, whereas in myopathic myosin from different individuals, this ratio varied from 1:0.1 to 1:0.69. The rates of ATP binding to control and myopathic myosins were similar, whereas the Vm of actin-activated ATPase of myopathic myosin was about 25% less than that of the control. However, ATP binding and its hydrolysis by control S1, i.e., the myosin head, were faster by a factor of 2 than that of the myopathic S1. In addition, control myosin synthetic thick filament length as well as turbidity in solution, measured by light scattering, were twice as large as those of the myopathic heart myosin. These effects induced by myopathy in both filament assembly and turbidity were reversed upon reassociation of IDC myosin with LC2. CONCLUSIONS: The changes in myosin structure and function were linked to a protease-mediated cleavage of LC2 in myosin; a possible role for the protease in the degenerative effects of idiopathic dilated cardiomyopathy is thus defined.

Human coronary vascular smooth muscle and endothelium-dependent responses after storage at -75 degrees C.

In the present study, we investigated whether an established method of cryostorage at -75 degrees C in the presence of dimethyl sulfoxide (Me2SO) and fetal calf serum (FCS) could preserve the vascular and endothelial responses of isolated human coronary arteries. A total of 123 ring segments (4-5 mm in length) of epicardial coronary arteries were isolated within 1 to 2 h from hearts of four patients receiving a cardiac transplant. Thirty-nine coronary ring segments were studied immediately upon cleaning of surrounding tissues, while 84 similarly cleaned segments were stored at -75 degrees C for 7 to 10 days prior to in vitro reactivity studies. In the freshly isolated coronary arteries, addition of prostaglandin F2 alpha, endothelin (ET-1), or acetylcholine consistently produced a dose-dependent contraction, reaching a maximum contractile force of 9.6 +/- 0.7, 4.5 +/- 0.5, and 3.1 +/- 0.5 g (M +/- SEM), respectively, while histamine, thrombin and substance P consistently produced an endothelium-dependent relaxation (EDR) with a maximum of -89 +/- 2.8, -85 +/- 5.0, and -72 +/- 3.5%, respectively. Isoproterenol produced an endothelium-independent relaxation (-82 +/- 4.5%). Cryostorage of human coronary arteries at -75 degrees C without cryoprotectant resulted in a complete loss of the contractile response. In contrast, addition of Me2SO and FCS in the cryostorage medium significantly preserved the contractile responses, although they were decreased (1.9 +/- 0.3, 1.5 +/- 0.3, and 0.6 +/- 0.1 g to PGF2 alpha, ET-1, and acetylcholine, respectively) when compared to the fresh controls. The maximum EDR to histamine, thrombin, and substance P in the cryostored coronaries were also reduced to -40 +/- 5.6, -21 +/- 3.3, and -47 +/- 4.7%, respectively, and the isoproterenol-induced relaxation was reduced to -62 +/- 4.1%. These results suggest that although the cryostorage method described in the present report provided only limited preservation of human coronary arteries, significant vascular smooth muscle and endothelial-dependent functions were retained. Thus, it is possible that further refinement of the present cryostorage methodology may provide better preservation of functionally viable human blood vessels.

Influence of the cardiac myosin hinge region on contractile activity.

The participation of cardiac myosin hinge in contractility was investigated by in vitro motility and ATPase assays and by measurements of sarcomere shortening. The effect on contractile activity was analyzed using an antibody directed against a 20-amino acid peptide within the hinge region of myosin. This antibody bound specifically at the hinge at a distance of 55 nm from the S1/S2 junction, was specific to human, dog, and rat cardiac myosins, did not crossreact with gizzard or skeletal myosin, and had no effect on ATPase activity of purified S1 and myofibrils. However, it completely suppressed the movement of actin filaments in in vitro motility assays and reduced active shortening of sarcomeres of skinned cardiac myocytes by half. Suppression of motion by the anti-hinge antibody may reflect a mechanical constraint imposed by the antibody upon the mobility of the S2 region of myosin. The results suggest that the steps in the mechanochemical energy transduction can be separately influenced through S2.

Cutaneous silica granuloma. A rare entity or rarely diagnosed? Report of two cases with review of the literature.

Cutaneous silica granuloma is a poorly understood, uncommon condition that may mimic cutaneous sarcoidosis. We describe two cases of this entity and their characteristic latency period (between the time of silica exposure to the time of clinical onset of granuloma). We also review the histologic and energy dispersive x-ray analysis data, which prove the diagnosis. This condition should be recognized as an occupational dermatosis as well as the result of past incidental cuts or abrasions, which result in the development of granulomas, many in old wound scars. Differentiation from cutaneous sarcoidosis is possible with polarized light microscopy and energy-dispersive x-ray analysis.

Endothelium-dependent responses in long-term human coronary artery bypass grafts.

In the present study, responses of long-term human coronary artery bypass grafts (CABGs) to known endothelium-dependent vasodilators, acetylcholine, calcium ionophore A23187, thrombin, and histamine, as well as authentic nitric oxide, the putative endothelium-derived relaxing factor, were studied. Sixteen CAGBs were isolated within 1-2 hours from hearts of 14 patients receiving a cardiac transplant. A total of 109 ring segments were prepared from these CABGs and studied in vitro. The duration of the CABGs ranged from 7 months to 12 years. Addition of acetylcholine (0.01-10 microM), calcium ionophore A23187 (0.01-1.0 microM), thrombin (0.01-1.0 unit/ml), and histamine (0.01-1.0 microM) consistently produced a dose- and endothelium-dependent relaxation, reaching a maximum of -35.3 +/- 3.3%, -45.3 +/- 5.5%, -26.9 +/- 4.8%, and -17.8 +/- 2.5% (mean +/- SEM), respectively. No significant difference was observed among the CABGs with different duration of transplantation, whereas the relaxant responses of different segments along the entire length of a CABG were markedly different. These latter differences in the endothelium-dependent responses appear to correlate inversely with the development of intimal proliferative lesions in these CABGs. Addition of nitric oxide (0.01-10 microM) produced a potent dose- and endothelium-independent relaxation, which was also slightly depressed in CABGs with severe intimal proliferation. These results demonstrate that long-term transplanted human saphenous vein grafts retain their endothelium-dependent responses and that development of severe intimal proliferative lesions, rather than the duration of the grafts, result in marked alterations in the reactivity of these transplanted CABGs.