Cardiac hypertrophy after transplantation is associated with persistent expression of tumor necrosis factor-alpha.

BACKGROUND: The mechanisms that contribute to cardiac allograft hypertrophy are not known; however, the rapid progression and severity of hypertrophy suggest that nonhemodynamic factors may play a contributory role. Tumor necrosis factor-alpha (TNF-alpha) is a cytokine produced in cardiac allografts and capable of producing hypertrophy and fibrosis; therefore, we suggest that TNF-alpha may play a contributory role. Accordingly, the aims of our study were to define the role of systemic hypertension in the development of hypertrophy, characterize the histological determinants of hypertrophy, and characterize the expression of myocardial TNF-alpha after heart transplantation. METHODS AND RESULTS: To separate the effect of hypertension from immune injury in the development of cardiac allograft hypertrophy, we measured the gain in left ventricular mass by 2D echocardiography in heart transplant recipients and lung transplant recipients who developed similar rates of systemic hypertension. The gain in left ventricular mass was 73% in heart transplant recipients and 7% in lung transplant recipients (P<0.0001). By comparing myocardial samples obtained during the first week after transplant and at 1 year, we found that there was a significant increase in total collagen content (P<0.0001), collagen I (P<0.0001), collagen III (P<0.0001), and myocyte size (P<0.0001). These changes were associated with persistent myocardial TNF-alpha expression. CONCLUSIONS: We suggest that the contribution of hypertension to cardiac allograft hypertrophy is minimal and that persistent intracardiac expression of TNF-alpha may contribute to the development of cardiac allograft hypertrophy.

The locus of a novel gene responsible for arrhythmogenic right-ventricular dysplasia characterized by early onset and high penetrance maps to chromosome 10p12-p14.

Arrhythmogenic right-ventricular dysplasia (ARVD), a cardiomyopathy inherited as an autosomal-dominant disease, is characterized by fibro-fatty infiltration of the right-ventricular myocardium. Four loci for ARVD have been mapped in the Italian population, and recently the first locus was mapped in inhabitants of North America. None of the genes have been identified. We have now identified another North American family with early onset of ARVD and high penetrance. All of the children with the disease haplotype had pathological or clinical evidence of the disease at age <10 years. The family spans five generations, having 10 living and 2 dead affected individuals, with ARVD segregating as an autosomal-dominant disorder. Genetic linkage analysis excluded known loci, and a novel locus was identified on chromosome 10p12-p14. A peak two-point LOD score of 3.92 was obtained with marker D10S1664, at a recombination fraction of 0. Additional genotyping and haplotype analysis identified a shared region of 10.6 cM between marker D10S547 and D10S1653. Thus, a novel gene responsible for ARVD resides on the short arm of chromosome 10. This disease is intriguing, since it initiates exclusively in the right ventricle and exhibits pathological features of apoptosis. Chromosomal localization of the ARVD gene is the first step in identification of the genetic defect and the unraveling of the molecular basis responsible for the pathogenesis of the disease.

Relation of the contractile reserve of hibernating myocardium to myocardial structure in humans.

BACKGROUND: Although dobutamine echocardiography (DE) is widely used to assess myocardial viability in humans, little is known about the relation between contractile reserve and myocardial structure. METHODS AND RESULTS: We evaluated 20 patients with coronary disease (64+/-13 years old, ejection fraction 28+/-7.5%) with DE (up to 40 micrograms . kg(-1). min(-1)), rest-redistribution (201)Tl single photon emission CT, and quantitative angiography before bypass surgery. During surgery, patients underwent transmural myocardial biopsies (n=37) guided by transesophageal echocardiography to determine the extent of interstitial fibrosis and intracellular and interstitial proteins by histopathology and immunohistochemistry. Among the 37 segments biopsied, 16 recovered function as assessed 2 to 3 months later. Segments with postoperative functional recovery had more wall thickening at low-dose DE (28% versus 3%, P<0.001), higher thallium uptake (69% versus 48%, P=0.03), and less interstitial fibrosis (2% versus 28%, P<0.001). Quantitative angiographic parameters did not predict recovery of function. Segments with DE viability (contractile reserve and/or ischemia) had less fibrosis (2.7% versus 28%, P<0.001), less vimentin and fibronectin (both P<0.01), more glycogen (P=0.016), and higher thallium uptake (64% versus 35.5%, P<0.05) than those without viability. Viable segments by both DE and thallium had less fibrosis (1%) than those viable by 1 of the 2 techniques (9%) or not viable by both (28%, P=0.005). Thickening at low-dose DE correlated well with the extent of interstitial fibrosis (r=-0.83, P<0.01). CONCLUSIONS: Contractile reserve during DE correlates inversely with the extent of interstitial fibrosis and the amount of fibronectin and vimentin and directly with rest-redistribution thallium uptake.

Localization of a gene responsible for arrhythmogenic right ventricular dysplasia to chromosome 3p23.

BACKGROUND: Arrhythmogenic right ventricular dysplasia (ARVD), a familial cardiomyopathy occurring with a prevalence of 1 in 5000, is characterized by replacement of myocytes with fatty and fibrous tissue. Clinical manifestations include structural and functional abnormalities of the right ventricle and arrhythmias, leading to a sudden death rate of 2.5% per year. Four loci have been mapped, but no gene has been identified as yet. METHODS AND RESULTS: We identified a large family of >200 members with ARVD segregating as an autosomal dominant trait affecting 10 living individuals. The diagnosis of ARVD was based on international diagnostic criteria including history, physical examination, ECG, echocardiogram, right ventricular angiogram, endomyocardial biopsy, and 24-hour ambulatory ECG. Blood was collected for DNA from 149 family members. Analysis of 257 polymorphic microsatellite markers by genetic linkage excluded previously known loci for ARVD and identified a novel locus at 3p23. Analysis of an additional 20 markers further defined the region. A peak logarithm of the odds score of 6.91 was obtained with marker D3S3613 at theta=0% recombination. Haplotype analysis identified a shared region between markers D3S3610 and D3S3659 of 9. 3 cM. CONCLUSIONS: A novel locus for ARVD has been mapped to 3p23 and the region narrowed to 9.3 cM. Identification of the gene will allow genetic screening and a specific diagnosis for a disease with protean nonspecific findings. It should also provide insight fundamental to understanding cardiac chamber-specific gene expression and/or the mechanism of myocyte apoptosis observed in this disease.

Assessment of myocardial viability with 99mTc-sestamibi tomography before coronary bypass graft surgery: correlation with histopathology and postoperative improvement in cardiac function.

BACKGROUND: Assessment of myocardial viability by 99mTc-sestamibi remains controversial. Accordingly, we investigated the use of sestamibi as a marker of myocardial viability, defined by histopathology, and for predicting improvement of myocardial function after coronary artery bypass graft surgery (CABG). METHODS AND RESULTS: 99mTc-sestamibi perfusion tomography and radionuclide angiography were performed within 2 days before CABG in 21 patients with > or = 75% stenosis of the left anterior descending coronary artery and resting anterior wall dyssynergy. During CABG, transmural myocardial biopsies were obtained from the dyssynergic anterior wall and from normal myocardial segments to determine the extent of viable myocardium by histopathology. Improvement of regional left ventricular function was evaluated by radionuclide angiography at 6 to 8 weeks after CABG. There was a good correlation (r=.85, P<.001) between the quantified sestamibi activity and the extent of viable myocardium determined morphometrically. Among 21 biopsied dyssynergic myocardial segments, 11 improved their function after CABG and 10 failed to improve. Biopsied segments with improved postoperative function had significantly higher sestamibi activity (81+/-5% versus 49+/-16%, P<.0001) and significantly lower extent of interstitial fibrosis (7+/-4% versus 31+/-21%, P=.0002) than segments that failed to improve. A 55% threshold of 99mTc-sestamibi activity had positive and negative predictive values of 79% and 100%, respectively, for recovery of function after CABG in the biopsied segments. CONCLUSIONS: Myocardial 99mTc-sestamibi activity correlates well with the extent of viable myocardium and predicts improvement in regional function after CABG. This lends support to the use of sestamibi as a myocardial viability agent.

Mucopolysaccharidosis presenting as pediatric multiple aortic aneurysm: first reported case.

Within the pediatric population, the rare aortic aneurysm is most often brought on by congenital cardiovascular malformation or connective tissue disorder, trauma, inflammatory disease, or infection. Thus our 8-year-old patient who had multiple aortic aneurysms and evidence of mucopolysaccharidosis presented a doubly unique case. Three and one-half months after the patient underwent emergency aortic valve replacement, we performed resection and graft replacement of both her descending thoracic aorta and thoracoabdominal aorta. Histologic analysis of the aneurysm wall displayed severe medial degeneration with large deposits of acid mucopolysaccharides. Subsequent evaluation, although negative for connective tissue disorders, showed glycosaminoglycans, chondroitin sulfate, and heparan sulfate in the patient's urine. These findings are diagnostic for a heterogeneous group of storage diseases termed mucopolysaccharidoses, although testing of the patient's cultured fibroblasts failed to reveal any specific previously described enzymatic defect. After reviewing the literature, we believe that this is the first known successfully treated pediatric aortic aneurysm associated with mucopolysaccharidosis.

Pathologic correlates of aortic plaques, thrombi and mobile "aortic debris" imaged in vivo with transesophageal echocardiography.

OBJECTIVES: This study sought to evaluate the pathologic correlates of aortic atheromas, thrombi and mobile "aortic debris" imaged in vivo by transesophageal echocardiography (TEE). BACKGROUND: Atherosclerotic plaques with various complexity, thrombi and debris are frequently identified by TEE during imaging of the aorta. However, pathologic data to characterize these lesions imaged in vivo are lacking. METHODS: Intraoperative TEE was performed prospectively in 31 patients undergoing repair of aortic aneurysm or dissection. TEE was used to guide the surgeon to mark aortic areas of interest that were sent for pathologic examination. A four-point scoring system was used for both TEE and pathologic evaluation to grade the degree of involvement of the aortic wall with atheroma. Ultrasound video intensity of the aortic wall lesions was measured and compared with quantitative measures of wall composition at pathologic examination. The presence of thrombi and mobile aortic debris by TEE was noted and compared with pathologic findings. RESULTS: Histologic-TEE correlations were possible in 62 aortic segments. There was 73% exact agreement between TEE and pathologic grading. Discrepancies were mostly in the inability of TEE to detect superficial ulcerations. However, separation of normal aorta and minimal intimal thickening (grades I and II) from more complex atheromas (grades III and IV) was observed in 93%. For identification of thrombus, TEE had a sensitivity of 91% (29 of 32 segments) and a specificity of 90% (27 of 30 segments). Mobile aortic debris were identified in six aortic segments and were confirmed at pathologic examination to be thrombi. Ultrasound video intensity increased with worsening complexity of atheroma and related significantly to aortic plaque composition at pathologic evaluation (r = 0.80, p < 0.0001). Ultrasound intensity of thrombi and mobile debris was similar and was lower than that of complex atheromas. CONCLUSIONS: Thus, in the evaluation of aortic pathologic segments, TEE can assess aortic plaque complexity and identify thrombus formation, findings that may have important therapeutic implications.

Lipoprotein(a) in plasma, arterial wall, and thrombus from patients with aortic aneurysm.

The plasma concentration of lipoprotein(a) [Lp(a)] is highly correlated with the incidence of cardiovascular and peripheral vascular disease. A positive physiological role for Lp(a) has not yet been clearly identified, although elevated plasma levels in pregnant women, long-distance runners, subjects given growth hormone, patients after cardiovascular surgery, and patients with cancer, diabetes, or renal disease suggest its involvement in tissue synthesis and repair. The hypothesis that Lp(a) is involved in repair/reinforcement of the aorta was tested in 38 patients undergoing surgery for aortic aneurysm. In 29 patients 1 day before surgery, the mean plasma Lp(a) protein level was 10.7 mg/dl. At about 1, 2, and 8 weeks after surgery, the level was 14.1, 15.1, and 15.2 mg/dl, respectively. These levels are significantly higher than those of a comparable group of normal subjects (6.4 mg/dl; n = 274). Specimens of resected aortic aneurysm showed extensive medial degeneration, discontinuous elastic fibers, and deposition of mucopolysaccharides; these specimens were treated with a detergent-containing buffer to extract entrapped lipoproteins. The mean Lp(a) protein level in aortic wall extracts was 14.6 ng/mg tissue; these individual values were significantly associated with plasma Lp(a) levels before surgery (r2 = 0.31, p = 0.0003). The mean Lp(a) protein level in aortic thrombus extracts was substantially higher at 69.6 ng/mg tissue; these individual levels also were significantly associated with plasma Lp(a) concentrations before surgery (r2 = 0.68, p < 0.0001). The observations that: (i) plasma Lp(a) protein is about 1.7-fold higher in patients with aortic aneurysms than in normal subjects; and (ii) that Lp(a) protein in the aneurysmic thrombus is about 4.8-fold higher than in the aortic wall suggest that this lipoprotein plays a significant and direct role in thrombus formation and in reinforcement of the aneurysmic aortic wall.

Assessment of myocardial viability with 99mTc sestamibi in patients undergoing cardiac transplantation. A scintigraphic/pathological study.

BACKGROUND: 99mTc sestamibi and 201 Tl are tracers that allow equivalent detection of myocardial infarction. However, because sestamibi does not undergo as much time-dependent redistribution as does 201Tl, it has been considered suboptimal for the detection of myocardial viability. METHODS AND RESULTS: Fifteen consecutive patients with ischemic cardiomyopathy who underwent orthotopic cardiac transplantation received an intravenous injection of 99mTc sestamibi at 1 to 6 hours before transplantation. Rotational tomography of the excised, intact, native hearts was performed to quantify the extent of myocardial hypoperfusion. The hearts were then sliced and reimaged on a gamma camera, followed by pathological quantification of the extent and severity of scarred and normal myocardium. Samples of normally and abnormally perfused myocardium underwent gamma well counting to determine tissue radioactivity and were examined under light microscopy for delineation of myocardial structure after trichrome staining. The mean extent of scintigraphic scar quantified through the use of rotational tomography was 45 +/- 14% of the left ventricle and correlated closely with pathological scar size (r = .89), despite a slight overestimation. Scintigraphic scar size determined with planar imaging of the individual myocardial slices also correlated closely with pathological scar size (r = .88). A good correlation existed between tissue 99mTc sestamibi activity determined through well counting and histological evidence of myocardial viability (r = .89). Most hypokinetic and 40% of akinetic/dyskinetic myocardial segments contained scintigraphically and histologically normal myocardium. CONCLUSIONS: 99mTc sestamibi scintigraphy can be used to accurately quantify the extent of myocardial scarring. Furthermore, the relative sestamibi activity in perfusion defects, measured several hours after administration, is a good indicator of myocardial viability determined with microscopy.

Valvulitis involving a bioprosthetic valve in a patient with systemic lupus erythematosus.

A 37-year-old man with systemic lupus erythematosus, who underwent an aortic valve replacement with a Carpentier-Edwards porcine valve for severe aortic insufficiency, was admitted to the hospital with pulmonary edema. Transesophageal echocardiography revealed severe aortic insufficiency arising from partial dehiscence of the valve sewing ring, as well as centrally from the valve cusp. In addition, marked thickening of the mitral valve was observed with severe eccentric regurgitation. At surgery, valvulitis of the native mitral and bioprosthetic aortic valves was demonstrated, with a perforation of the porcine valve cusp. After replacement of both valves, the patient had a stormy postoperative course with recurrent communications between the left ventricle and atrium requiring multiple surgeries and eventually died. This case illustrates the severity of valvulopathy and ensuing complications that can affect patients with systemic lupus erythematosus and demonstrates that the valvulopathy can affect bioprosthetic valves, a finding that has significant implications as to the type of valve replacement in these patients.

Basic fibroblast growth factor reverses atherosclerotic impairment of human coronary angiogenesis-like responses in vitro.

The influence of atherosclerosis on vascular growth in humans was evaluated in an in vitro model of angiogenesis. Coronary artery intima-media explants from patients (n = 10) with coronary artery disease (CAD) (in all cases Stary type V lesions) and patients without CAD (n = 10) were cultured in a collagen matrix containing serum-free medium. Endothelial cell growth from explants was organized as capillary-like microtubes (CLM); the sum of their lengths was morphometrically quantitated as an index of angiogenesis. CLM growth was suppressed in CAD explants (n = 120), the index values at two weeks averaging only 20% +/- 3% of non-CAD explants (n = 120, P < 0.001). Addition of exogenous basic fibroblast growth factor (bFGF) (10 ng/ml) stimulated CLM growth substantially more in the CAD than in the non-CAD group, whereas bFGF-neutralizing antibodies nearly abolished growth in both. Endothelial cells isolated from non-CAD coronary arteries exhibited in culture typical endothelial characteristics, including cobblestone appearance, staining for von Willebrand factor, CLM formation on Matrigel substrate, and sensitivity to bFGF and to bFGF-neutralizing antibody. Inhibition of cell replication by oxidized low-density lipoprotein (OxLDL) was reversed by bFGF. We conclude that human atherosclerosis is associated with impairment of angiogenesis-like endothelial growth and that decreased bFGF availability contributes to the impairment.

Magnetic resonance imaging for assessment of tissue rejection after heterotopic heart transplantation.

Detection of myocardial rejection is difficult in patients with heterotopic heart transplantation because of the complex vascular anatomy present after transplant surgery. To determine whether magnetic resonance imaging might be useful for the assessment of heart rejection, eight patients with heterotopic heart transplantation were serially studied on 27 occasions. One patient had two donor hearts implanted, which allowed the study of 33 donor hearts. Data acquisition was gated to the ECG signal of the donor heart. Heavily T2-weighted (TE = 90 ms) velocity compensated spin-echo images were obtained through the midportion of the donor heart to assess tissue rejection. Donor heart function was qualitatively measured by acquiring multiphasic gradient echo images at the same level. A myocardial/skeletal muscle signal intensity ratio was calculated for the donor heart and compared to results of right ventricular biopsy obtained within 24 hours of imaging. A change in signal intensity ratio of 0.14 or more exceeded normal signal variation. All three episodes of rejection detected by biopsy were detected by magnetic resonance imaging. In three instances a significant change in the signal intensity ratio was associated with clinical evidence of rejection and a negative biopsy. Two instances were treated with a steroid bolus, and the signal returned to baseline. In three other instances a significant change in the magnetic resonance imaging signal occurred without clinical or biopsy evidence of rejection. Cardiac toxoplasmosis was present in one of these cases, and signal intensity returned to baseline after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Heart allograft involvement with Epstein-Barr virus-associated posttransplant lymphoproliferative disorder.

We describe a 60-year-old man who underwent heart transplant and died 5 months later. At autopsy, the patient was found to have posttransplant lymphoproliferative disorder (PTLD), which was not suspected ante mortem. The PTLD involved the lung, lymph nodes, spleen, and kidney and the intima of right coronary artery of the transplanted heart. Epstein-Barr virus infection was demonstrated on direct gel and dot blot after polymerase chain reaction amplification. In situ hybridization for Epstein-Barr virus DNA confirmed the presence of Epstein-Barr virus-infected lymphocytes in the intima of the right coronary artery of the cardiac allograft. To our knowledge, this case represents the first report of involvement of a heart allograft by PTLD in which Epstein-Barr virus infection of the atypical cells is documented. Although primary allograft involvement by PTLD has rarely been reported in heart transplant recipients, recognition that this may occur is important, since the lymphoid infiltrate of PTLD must be distinguished from the lymphoid infiltrate of acute rejection to avoid inappropriate therapy.

Sudden death caused by bradycardia and asystole in a heart transplant patient with coronary arteriopathy.

The mechanism of death as a result of allograft ischemic heart disease is not well characterized. Ventricular tachycardia and fibrillation may not be the terminal events they often are in the general population. We report observations in a 41-year-old man with cardiac allograft arteriopathy who died suddenly while wearing an ambulatory monitor. The lethal rhythm was a progressive bradycardia terminating in asystole. Autopsy revealed epicardial and small vessel intramyocardial, coronary arteriopathy, and only mild allograft rejection. It is our belief that ischemia caused the bradycardic sudden death. We would like to hypothesize that prophylactic permanent pacemaker implantation may prevent bradycardic sudden death and improve survival in heart transplant patients with coronary disease.

Inability of isolated soluble interleukin-2 receptor levels to predict biopsy rejection scores after heart transplantation.

Successful cardiac transplantation requires suppression of rejection, and endomyocardial biopsy is generally used to quantify this and guide immunotherapy. Biopsy, however, is an invasive, costly, cardiac catheterization with repetition limited. Since rejection requires lymphocyte activation, an alternative method of assessing rejection dynamics might be ELISA determination of soluble interleukin-2 receptor (sIL-2R) levels since induction of the interleukin-2 ligand and its receptor is required. Reports suggest that sIL-2R levels rise during kidney, liver, and heart-lung allograft rejection and heart recipients have an adverse prognosis if sIL-2R is elevated postoperatively. It is unclear, however, if serial measurements or single determinations are sufficient or if change from a baseline assessment is important. The purpose of this study was to determine if an isolated sIL-2R level after heart transplant predicted endomyocardial biopsy score at that moment. To do this, we prospectively followed 60 consecutive patients after orthotopic heart transplant and correlated 479 endomyocardial biopsy scores (McAllister scale 0-10) with matched sIL-2R levels. Regression analysis demonstrated minimal relationship between sIL-2R level and biopsy score (r =.11, r2 =.01, P=.009). When the maximum sIL-2R level for each individual patient was compared with the matched biopsy score, regression analysis revealed r=.04, r2=.001, P=.8. Likewise, when all biopsy scores and sIL-2R levels for each patient were meaned, analysis showed r=.14, r2=.02, P=.26. Thus in heart transplant patients, there is poor correlation between an isolated biopsy score and matched sIL-2R level. However, when mean +/- SEM sIL-2R was determined for severe rejection (score 7-10) and compared with sIL-2R for all other grades, it was significantly higher (1600 +/- 257 vs. 423 +/- 57 U/ml; P=.012). Still, the sensitivity, specificity, and predictive value of an sIL-2R level above 1000 U/ml predicting severe rejection was only 52%, 63%, and 8%. It would be difficult, therefore, to use a single sIL-2R determination after heart transplant to foretell the endomyocadial biopsy score. Serial measurements or quantification of a change in sIL-2R level from baseline might be more predictive of rejection severity.

Elevated soluble interleukin-2 receptor levels early after heart transplantation and long-term survival and development of coronary arteriopathy.

Rejection dynamics after heart transplantation might be characterized by soluble interleukin-2 receptor levels. To determine whether elevated levels early (measured by enzyme-linked immunosorbent assay once weekly the first 3 weeks at time of heart biopsy) after transplantation predict mortality and development of coronary disease, the means of these three determinations and the endomyocardial biopsy scores (McAllister scale 0-10) were compared for survivors and nonsurvivors and patients who had coronary arteriopathy develop and those who did not. Fifty-five patients alive 30 days after heart transplantation were prospectively followed up. Overall, 47 patients were male (85%), and the median age was 51 years. Mean +/- SD follow-up was 26 +/- 15 months (range, 1 to 54 months). There were 38 survivors (69%), and coronary arteriopathy developed in 15 patients (27%). Whereas mean +/- SD heart biopsy scores for the early weeks were similar between survivors and nonsurvivors (3.6 +/- 1.4 vs 4.4 +/- 1.6; p greater than 0.05), the difference in soluble interleukin-2 receptor levels was significant (703 +/- 362 U/ml vs 1793 +/- 1070 U/ml; p less than 0.001). A mean level less than 1000 U/ml in any given patient predicted long-term survival with a 76% sensitivity, 79% specificity, and 88% negative predictive value. Mean receptor levels for those patients in whom coronary arteriopathy did not develop were 880 +/- 846 U/ml and for those with this difficulty, 1410 +/- 590 U/ml (p = 0.001). Late morbidity and mortality after heart transplantation seem predicted by early elevation of plasma soluble interleukin-2 receptor levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitation and localization of apolipoproteins [a] and B in coronary artery bypass vein grafts resected at re-operation.

Lp[a] is a lipoprotein whose plasma concentration is highly correlated with cardiovascular disease. Its protein moiety, apoLp[a], consists of two large polypeptides, apo[a] and apo B. The possible contribution of Lp[a] to atherosclerosis in saphenous vein aortocoronary bypass grafts was studied in a population of patients undergoing coronary re-bypass surgery. The vein graft tissue levels of apoLp[a] were compared with graft duration, gross and light microscopic pathology, as well as plasma levels of apoLp[a]. The localization pattern of apo[a] and apo B in vein graft tissue was determined. In addition, the plasma levels of cholesterol, triglycerides, apoproteins (apo) A-I, A-II, and E were measured. In a representative subpopulation of 17 patients with a mean age of 63 years from whom grafts with a mean duration of 112 months were resected, the mean total plasma cholesterol level was 221 mg/dl, the mean high density lipoprotein cholesterol level was 31 mg/dl, and the mean plasma triglyceride level was 228 mg/dl. In normal saphenous veins, the level of apoLp[a] was below measurable limits (less than 2 ng/mg), and the level of apo B was very low (3.3 ng/mg). In resected grafts, the mean tissue level of apoLp[a] was 32 ng/mg, and that of apo B was 70 ng/mg, demonstrating the net accumulation of these apoproteins in veins from the time of their grafting into the arterial bed. The apoLp[a]/apo B ratio was determined in 77 tissue segments from 59 grafts (28 patients) and was found to be 0.313. This tissue ratio was significantly higher (p = 0.02) than the plasma apoLp[a]/apo B ratio from these patients, which was 0.132. Immunostaining showed co-localization of apo[a] and apo B in the neointima of grafts. The most abundant pathologic features observed in resected grafts were proliferated intima (43/52), thrombus (28/52), and atherosclerotic core regions (21/52). The level of tissue apo B correlated well with the abundance of core regions (r = 0.501), whereas the level of tissue apoLp[a] did not correlate as well with this feature (r = 0.233). Although apo[a] and apo B are almost absent from normal saphenous vein, these apoproteins (and presumably the lipoproteins Lp[a] and low density lipoprotein) accumulate in bypass vein grafts. The data support the view that these lipoproteins play a significant role in vein graft atherosclerosis.

Tissue distribution of atrial natriuretic factor in normal and pathologic human hearts.

The tissue distribution and possible neuroendocrine nature of atrial natriuretic factor (ANF) were studied, using the avidin-biotin-peroxidase technique and antibodies to ANF, chromogranin (Ch), and neuron-specific enolase (NSE). Tissues examined included: Group 1, formalin-fixed and fresh frozen atrial tissue from adjacent areas of the hearts from two heart-lung-transplant patients; Group 2, the entire atria and sampling of other areas from formalin-fixed hearts of five gunshot wound or automobile accident victims; and Group 3, formalin-fixed right auricular tissue from 19 open-heart-surgery patients. In each case of Group 3, the ANF score, expressed as the product of the percentage of stained areas by the staining intensity, was correlated with age, weight, height, blood pressure, ejection fraction, and degree of coronary arterial stenosis. It was found that: (a) ANF was limited to atrial myocytes; the staining was significantly stronger in the right atrium, diffuse and most intense in auricles and pectinate muscles, diffuse and strong in subendocardium, focal and weak in other areas; (b) although ANF has been reported to be a peptide hormone stored in dense-core granules, it does not seem to belong to the diffuse neuroendocrine system because Ch and NSE were consistently absent in cardiac myocytes; and (c) although the limited numbers of evaluable clinical parameters do not significantly correlate with ANF scores, a change in the pattern and intensity of ANF staining was noted in some cases of Group 3.

Treatment of symptomatic peripheral atherosclerotic disease with a rotational atherectomy device.

Narrowings 70 to 90% in diameter in 3 iliac, 4 superficial femoral and 2 popliteal arteries were crossed and atherectomized successfully in 6 patients using the Squibb Rotablator under angiographic guidance during surgical bypass procedures on these arteries. The Rotablator consists of a 1.25 to 4.5 mm diameter oblong burr with tiny diamond blades mounted on a flexible shaft, which tracks over a spring-tip guidewire and rotates at speeds greater than 120,000 rpm. All stenoses were reduced to less than or equal to 50% of the normal luminal diameter. No significant complications occurred. Of the 6 patients having the atherectomy procedure, 5 were reevaluated by duplex Doppler measurements 1.5 to 5.5 (mean 3.5) months after atherectomy and found to be patient with only mild residual flow disturbance. Repeat follow-up by angiography after a mean of 5.2 months, however, showed only 3 (37%) of the atherectomized segments in 3 patients to still be patent. All were symptomatically improved. Of the effluent particles analyzed, 90% were less than 8 microns in size, while only 5% reached 250 microns. With improvements in technique, the largest particles were 150 to 180 microns, constituting only 1.4% of effluent debris. Samples of the effluent from 2 patients were injected in vivo into the left coronary system of 2 pigs. There were no acute hemodynamic or electrocardiographic complications or pathologic evidence of muscle necrosis or vascular thrombosis 18 to 48 hours later. These preliminary results with respect to feasibility and safety of the Rotablator are promising.