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Global healthcare delivery systems are facing ever-increasing challenges on multiple fronts. The need to study and define successful models of care delivery systems has become increasingly important. The L V Prasad Eye Institute (LVPEI) has a distinctive eye care delivery system offering rich lessons at many operational levels. The system has been developed on the basis of LVPEI's foundational public eye health study, and follows a complexity-driven (dependent on disease complexity) clinical care system forming a five-tier pyramidal model - at the apex is the quaternary care centre at Hyderabad, followed by increasing numbers of tertiary, secondary or community, primary, and rural eye care centres, where the revenue from paying patients covers free-care via an economic cross-subsidy. This has achieved a level of scale, efficiency, social impact, and clinical and scientific innovation rarely seen in a single health system. Building on the foundational principles of this pyramidal care with a robust economic cross-subsidy model, LVPEI has seamlessly established successful professional, academic, and educational systems that combine innovation, scientific discovery, and the development of in-house technologies focused on improving service quality and clinical decision making. In this case study, we show that all elements of the LVPEI model are practical and may be applicable to academic medical centres in diverse healthcare settings; currently, this is being tested in Liberia, West Africa.

Background— Heart failure is a debilitating condition resulting in severe disability and death. In a subset of cases, clustered as idiopathic dilated cardiomyopathy (iDCM), the origin of heart failure is unknown. In the brain of patients with dementia, proteinaceous aggregates and abnormal oligomeric assemblies of β-amyloid impair cell function and lead to cell death. Methods and Results— We have similarly characterized fibrillar and oligomeric assemblies in the hearts of iDCM patients, pointing to abnormal protein aggregation as a determinant of iDCM. We also showed that oligomers alter myocyte Ca 2+ homeostasis. Additionally, we have identified 2 new sequence variants in the presenilin-1 ( PSEN1 ) gene promoter leading to reduced gene and protein expression. We also show that presenilin-1 coimmunoprecipitates with SERCA2a. Conclusions— On the basis of these findings, we propose that 2 mechanisms may link protein aggregation and cardiac function: oligomer-induced changes on Ca 2+ handling and a direct effect of PSEN1 sequence variants on excitation-contraction coupling protein function.

OBJECTIVES We report an in-depth postmortem morphologic analysis of atrial myocardium in human pulmonary veins (PVs) from patients with and without atrial fibrillation (AF). BACKGROUND Electrophysiologic studies established the critical role of PVs in the initiation of AF. To date, a paucity of data exists about PV morphology as an arrhythmogenic substrate. METHODS Longitudinal tissue-strips of PVs were excised and histologically analyzed from the distal part to just beyond the atriovenous junction in the left atrium from 20 patients, obtained at autopsy. Anatomical measurements, including diameters, lengths, and wall-thicknesses of PVs, obtained at autopsy, were made. RESULTS Histological analysis revealed extension of atrial myocardium into 89% of all PVs. Prevalence of myocardial extension was significantly higher in veins of 6 patients with compared with 14 patients without AF. Other significant differences in the histology of PVs between the two groups were a higher frequency of discontinuity and hypertrophy and a higher degree of fibrosis of the atrial myocardium in the PVs of patients with AF. A marked variation existed in anatomical dimensions of PVs, although no differences were observed between patients with or without AF. CONCLUSIONS Atrial myocardium was more often present in the PVs of patients with compared with patients without AF. In the first group, the atrial myocardium in the PVs was characterized by more severe discontinuity, hypertrophy, and fibrosis. A marked variation in anatomical dimensions of the PVs existed.

Presentation of Case A 27-year-old woman was admitted to the hospital because of syncope and two intracardiac masses. The patient had been well until about three years before admission, when she had an episode of numbness in the lower left area of the face, associated with weakness of the right arm and right leg; the numbness lasted 30 to 60 minutes and did not recur. Evaluation at that time included cranial computed tomographic (CT) scanning, which reportedly showed no abnormalities; a cardiac ultrasonographic study was not performed. She was well for the next year. During the two years before admission, . . .

Background To investigate the role of endothelial nitric oxide synthase (NOS3) in left ventricular (LV) remodeling after myocardial infarction (MI), the impact of left anterior descending coronary artery ligation on LV size and function was compared in 2- to 4-month-old wild-type (WT) and NOS3-deficient mice (NOS3 −/− ). Methods and Results Two days after MI, both strains of mice had a similar LV size, fractional shortening, and ejection fraction by echocardiography. Twenty-eight days after MI, both strains had dilated LVs with decreased fractional shortening and lower ejection fractions. Although the infarcted fraction of the LV was similar in both strains, LV end-diastolic internal diameter, end-diastolic volume, and mass were greater, but fractional shortening, ejection fraction, and the maximum rate of developed LV pressure (dP/dt max ) were lower in NOS3 −/− than in WT mice. Impairment of diastolic function, as measured by the time constant of isovolumic relaxation (τ) and the maximum rate of LV pressure decay (dP/dt min ), was more marked in NOS3 −/− than in WT mice. Mortality after MI was greater in NOS3 −/− than in WT mice. Long-term administration of hydralazine normalized blood pressure in NOS3 −/− mice, but it did not prevent the LV dilatation, impaired systolic and diastolic function, and increased LV mass that followed MI. In WT mice, capillary density and myocyte width in the nonischemic portion of the LV did not differ before and 28 days after MI, whereas in NOS3 −/− mice, capillary density decreased and myocyte width increased after MI, whether or not hydralazine was administered. Conclusions These results suggest that the presence of NOS3 limits LV dysfunction and remodeling in a murine model of MI by an afterload-independent mechanism, in part by decreasing myocyte hypertrophy in the remote myocardium.

Antiatherogenic effects of sex steroids in premenopausal women are not well defined. Therefore, we employed an established rabbit model for atherosclerosis to study the effects of exogenous estrogen and a progesterone analogue (P) on serum lipids and aortic plaque load. Serum cholesterol (C) and triglyceride (T) levels and atherosclerotic plaque loads were compared in 5 groups of male New Zealand White rabbits fed a 12-week, C-rich diet: 1 control group (CG) and 4 groups treated with estriol (E), haloperidol (H), low-dose 17-hydroxyprogesterone (LDP), or high-dose 17-hydroxyprogesterone (HDP). Serum P was measured in the LDP and HDP groups. Serial histologic sections (15 each of 27 ascending aortas) were studied by light microscopy and computerized morphometric analysis. Plaque load is defined as the ratio of intimal area to medial area (I/M). Exogenous E (p

Objective - A high-resolution coronary artery imaging modality has the potential to address important diagnostic and management problems in cardiology. Optical coherence tomography (OCT) is a promising new optical imaging technique with a resolution of approximately 10 μm. The purpose of this study was to use a new OCT catheter to demonstrate the feasibility of performing OCT imaging of normal coronary arteries, intimal dissections, and deployed stents in vivo. Methods and results - Normal coronary arteries, intimal dissections, and stents were imaged in five swine with OCT and compared with intravascular ultrasound (IVUS). In the normal coronary arteries, visualization of all of the layers of the vessel wall was achieved with a saline flush, including the intima which was not identified by IVUS. Following dissection, detailed layered structures including intimal flaps, intimal defects, and disruption of the medial wall were visualized by OCT. IVUS failed to show clear evidence of intimal and medial disruption. Finally, the microanatomic relationships between stents and the vessel walls were clearly identified only by OCT. Conclusions - In this preliminary experiment, we have demonstrated that in vivo OCT imaging of normal coronary arteries, intimal dissections, and deployed stents is feasible, and allows identification of clinically relevant coronary artery morphology with high-resolution and contrast.

Presentation of Case A 61-year-old man was admitted to the hospital because of a wide-complex tachycardia and dyspnea. The patient had been well until one month earlier, when he was assaulted and sustained an orbital fracture, associated with blurred vision. Soon thereafter, in the hope of improving his vision, he began to take dietary supplements identified as bilberry, Ginkgo biloba, alpha lipoic acid, omega-3 fish oil, lecithin, and S-adenosylmethionine, in addition to vitamins E, C, and B complex. Two days before admission, nausea, vomiting, diarrhea, and midepigastric pain developed several hours after dinner. On the following morning, he awoke . . .

Until recently, Japanese legislative guidelines dictated that undergraduate clinical training consisted of students' observations of clinicians' work. In 2006, Tokyo Medical and Dental University initiated a reform of their traditional undergraduate clinical curriculum. The reform integrated students into patient care teams, and included the implementation of a clinical faculty 'tutor'.This short communication describes a formative assessment of the reform work.In 2007, students, residents, and tutors were surveyed to determine their perceptions of students' integration into clinical activities, and patients' acceptance of students in their medical care. An external consultant observed students' patient care activities, and assessed the methods of and perceived barriers to clinical teaching.Surveys indicated that students were most engaged in history-taking, procedures, and case presentations. Observations revealed students' activities and teaching to be focused on students' case presentations. Perceived barriers to teaching included insufficient time and personnel. Respondents felt that patients were accepting students in their clinical care.This clinical reform effort includes an increase in students' interactions with patients through history-taking, and teaching through case presentations.

BACKGROUND Growth and development of the prostate are androgen-dependent. Keratinocyte growth factor (KGF), widely expressed by mesenchymal cells, is thought to act like an andromedin between stroma and epithelium of the prostate. Since KGF has recently emerged as an autocrine mediator in prostate cancer, we investigated the role KGF plays in the human prostate and its relationship to androgen receptor (AR). METHODS Normal (n = 13), benign hyperplastic (n = 5), and neoplastic (n = 14) human prostate tissues as well as cultured epithelial and stromal cells were analyzed using polymerase chain reaction (PCR), Western blot analysis, and immunohistochemistry. RESULTS Reverse transcriptase polymerase chain reaction and Western blotting showed KGF expression in stromal cultured cells of the normal prostate but not in epithelial cells. Using immunohistochemistry, KGF was found to be localized in fibroblasts and smooth muscle cells, independent of prostate disease. There was KGF expression in epithelial cells of BPH and prostate cancer. Human androgen receptor was uniformly expressed in the same secretory glandular cells that were positive for KGF in BPH and prostate cancer. CONCLUSIONS Our results provide evidence that KGF is a stromal-derived mediator, recently shown to act in a paracrine manner in normal prostate but now detected in epithelial cells in prostate cancer and BPH. These findings support the hypothesis that KGF might act as an autocrine factor in prostate cancer and BPH. Prostate 41:233–242, 1999. © 1999 Wiley-Liss, Inc.

Purpose: There is a lack of suitable in vitro models for the human prostate. To study stromal-epithelial interactions, we established stromal cells in cultures from benign and malignant prostate tissue that resemble more closely the in vivo conditions of the human prostate.Materials and Methods: Stromal cells were obtained from explant primary culture, established in DU145 cell conditioned medium and maintained in RPMI-fetal bovine serum (FBS) supplemented with insulin, transferrin and selenium (ITS). Proliferation studies to compare different media were performed using a3 [H]thymidine assay. Stromal cells were characterized by immunocytochemistry using epithelial and mesenchymal markers. Morphology was evaluated by electron microscopy, light and phase-contrast microscopy. Androgen receptor (AR) mRNA expression was measured by polymerase-chain-reaction (PCR). The response to different concentrations of dihydrotestosterone (DHT) and the antihormones flutamide and hydroxyflutamide was tested by3 [H]...

Presentation of Case A 17 1/2-year-old girl was admitted to the hospital because of a thoracoabdominal aneurysm. The patient had been born after a normal pregnancy and delivery, and her early growth, development, and health were normal. Four years before admission, she had begun to experience ocular irritation and a decrease in hearing, which progressed over a period of one month to almost total bilateral sensorineural deafness. She was initially treated with corticosteroids administered orally, but because of abdominal discomfort, the medication was subsequently injected. The ocular symptoms improved, but her hearing did not. Seven months before admission, a thoracoabdominal . . .

Presentation of Case An 11-year-old girl was admitted to the hospital because of fever, hypotension, and azotemia. The patient had been in excellent health until four days earlier, when fever, headache, sore throat, stiffness of the neck, abdominal pain, and an abdominal rash developed. The results of laboratory tests performed three days before admission and subsequently are presented in Table 1 and Table 2. A rapid test for streptococcal antigens was negative. Two days before admission, amoxicillin and diphenhydramine were administered. A throat culture yielded non–group A, β-hemolytic streptococci. The symptoms persisted, the urinary output was low, and menses began. One day before . . .

Segmental mediolytic arteriopathy, a rare, noninflammatory arterial disease, is fundamentally a variant of fibromuscular dysplasia. The characteristic angiographic findings of segmental mediolytic arteriopathy include the "string of beads" and microaneurysms which are indistinguishable from those of vasculitis, and the correct diagnosis can be made only after histopathologic evaluation of the arterial lesions. Thrombosis, arterial wall hemorrhage, and dissection are among the complications of segmental mediolytic arteriopathy. We describe herein a patient with segmental mediolytic arteriopathy who presented with hemoperitoneum. The patient underwent urgent surgical repair of a ruptured hepatic artery aneurysm. The postoperative visceral arteriography findings led to a clinical diagnosis of polyarteritis nodosa, and immunosuppressive therapy was initiated. This treatment was stopped as soon as the correct biopsy diagnosis of segmental mediolytic arteriopathy was obtained through outside consultation. The patient recovered without drug treatment and was spared the potentially life-threatening complications of immunosuppression.

Purpose : Near-infrared Raman spectroscopy provides an important new means of analyzing the chemical composition of the arterial wall. The objective of this study was to show that Raman spectroscopy can be used to evaluate the lipid and calcium salt contents of human peripheral arteries. The results extend a recently developed Raman-based method for analyzing the chemical composition of coronary arteries. Methods and Results : We studied 167 segments of carotid and femoral artery wall in various pathologic states. The Raman spectra from these samples was accurately modeled. The resulting chemical concentrations were compared with the amounts of cholesterol and calcium mineral determined at histologic evaluation by an experienced cardiovascular pathologist. Strong correlations between spectroscopic measurements and morphologic findings were demonstrated and validated the applicability of the method to peripheral arteries. Conclusions : Raman spectroscopy can provide reliable histochemical information about peripheral and coronary arteries. Such information may help identify rupture-prone plaques before the onset of symptoms and allow aggressive and directed intervention. Accurate knowledge of the chemical composition of a lesion may be useful in selecting the most appropriate treatment. (J Vasc Surg 1998;27:710-9.)

Intraluminal delivery of antisense oligonucleotides to c-myb was assessed following balloon angioplasty in swine peripheral arteries. Successful delivery and intramural persistence of oligonucleotide for over 24 h were demonstrated following angioplasty with hydrogel balloons coated with 32P-labeled antisense. Delivery of fluorescein-labeled antisense demonstrated further localization within the arterial media and intracellularly. Preliminary in vitro studies demonstrated the feasibility of inhibition of porcine lymphocyte proliferation using the murine antisense to c-myb. Twelve iliac or carotid arteries underwent angioplasty with antisense-coated balloons, while the contralateral vessels underwent angioplasty with the same-sized balloons coated with the complementary sense strand. Six to seven days later, dilated arterial segments were surgically isolated. In 10 of 12 vessel pairs, antisense-treated vessels demonstrated less cellular proliferation than did contralateral sense-treated vessels, as assessed by quantitative immunohistochemical staining of proliferating cell nuclear antigen, and smooth muscle cell proliferation was reduced 18% in antisense-treated vessels compared to the contralateral sense-treated vessels (PCNA-positive nuclear area: 7.7 ± 4.9% vs. 9.3 ± 5.2%, P < 0.04). Intraluminal delivery of antisense oligonucleotides to c-myb is feasible with a catheter-based system and may reduce smooth muscle cell proliferation following arterial injury. Cathet. Cardiovasc. Diagn. 41:232–240, 1997. © 1997 Wiley-Liss, Inc.

This article reviews the nature of novice and expert thinking and shows how pattern recognition is a key distinction between the two. The article also discusses the ladder that learners climb as they move from medical student to senior staff surgeon and suggests ways of viewing surgical trainees as they progress through the process so that learning activities can be adopted that best fit them.

Healthcare is becoming increasingly complex across the globe; technology, delivery models, economic requirements, demographics and the epidemiology of disease are changing at a rapid pace. Despite the multiple efforts in defining common competencies and standards that all healthcare professionals should meet, it has become clear that educational and training programs have to adjust to the needs of societies they serve, and that the institutions that design and deliver those programs need to be accountable to society for the products they produce. Academic institutions that educate healthcare professionals will have to interact differently with the many stakeholders needed to create effective and efficient, and culturally appropriate healthcare systems. Present day medical education has its roots in the European university which traditionally valued academic freedom, autonomy and independent research over serving society and the job market; future efforts will require a fundamental shift in the outlook and measures of success for academic institutions. The recent outcomes and competency movement is a first step in that direction but more will need to be done. Rather than being one participant, possibly a reluctant one, academia should become the catalyst for change, the hub for stakeholder interactions, and the breeding ground for the new healthcare workforce.

Recent efforts to identify the essential skills and competencies required for medical practice have resulted in an expansion of the educational outcomes for which medical schools are accountable. Teachers in the preclinical years, formerly focused on the transmission of biomedical principles and factual information, are now charged with presenting discipline-specific concepts with an emphasis on clinical relevance while advancing active learning, critical thinking, communication skills, and other professional competencies. Problem-based learning has been widely introduced to support these educational goals but other, less resource-intensive, discussion methodologies have not been extensively explored.To examine the feasibility of case-method teaching (CMT) during the preclinical curricula to integrate basic science concepts in the management of clinical problems.CMT sessions were conducted with students during the first- and second-year of hybrid curricula at two US medical schools.First- and second-year medical classes of 40-95 students prepared for and actively engaged in single session case discussions and were able to productively apply basic science principles in clinical problem-solving.CMT represents a feasible and resource-conservative pedagogical format to promote critical thinking and to integrate basic science principles during the preclinical curriculum.

Background:Fluoroscopy-guided catheter placement is limited in its ability to determine electrode-endocardial contact and involves radiation exposure. We hypothesized that (1) intracardiac echocardiography (ICE) would provide superior assessment of linear electrode contact compared to fluoroscopy and (2) slow temperature decay upon discontinuation of the radiofrequency current (time for temperature to fall 90% after a 10-second test application of the radiofrequency current T90) would indicate optimal electrode-myocardial contact. Methods:Sixty endocardial lesions were created in the atria and ventricles of six goats by simultaneous delivery of the radiofrequency current through two linear electrodes of a microcatheter with a central interelectrode thermocouple. Catheter placement was guided by fluoroscopy. A 7.5-MHz ICE transducer in the right atrium or ventricle assessed electrode contact. T90 and previously reported parameters of electrode contact and lesion formation were recorded. Histomorphometry was performed on the lesions. Results:T90 was 4.27 ± 4.98 seconds. Lesion depth significantly correlated with ICE assessment of electrode contact (r = 0.56, P = 0.001); T90 upon radiofrequency current offset (r = 0.48, P = 0.008), impedance fall upon radiofrequency current onset (r = 0.37, P = 0.008), bipolar pacing threshold preablation (r =−0.56, P = 0.001), bipolar electrogram amplitude preablation (r = 0.43, P = 0.02), but not with fluoroscopic assessment of the electrode contact (r = 0.18, n.s.). For the prediction of achieving a lesion depth of >2 mm, a T90 of >4.0 seconds yielded a specificity of 86% and a sensitivity of 52%, ICE yielded a specificity and sensitivity of 58% and 68%, respectively, while the specificity and sensitivity of fluoroscopy were 26% and 68%, respectively. Both ICE and T90 provide additional clinical relevance during guidance of cardiac microcatheter ablation.

Background— In classic Fabry patients, accelerated coronary atherosclerosis and left ventricular hypertrophy manifest in the fourth decade; however, signs of cardiovascular disease also are observed later in life in “cardiac variant” patients and symptomatic female heterozygotes. These disturbances are caused by globotriaosylceramide (GL-3) accumulation in the heart resulting from lysosomal α-galactosidase A deficiency. Methods and Results— We analyzed pretreatment and posttreatment endomyocardial biopsies from 58 Fabry patients enrolled in a 5-month, phase 3, double-blind, randomized, placebo-controlled trial, followed by a 54-month open-label extension study of recombinant human α-galactosidase A. Baseline evaluations revealed GL-3 deposits in interstitial capillary endothelial cells and large, laminated inclusions within cardiomyocytes. In this study, we evaluated microvascular GL-3 clearance; no clearance of GL-3 was observed in the cardiomyocytes during this trial. Five months of recombinant human α-galactosidase A treatment in the phase 3 trial resulted in complete microvascular clearance of GL-3 from 72% of treated patients compared with only 3% of placebo patients ( P Conclusions— The findings suggest that long-term treatment with recombinant human α-galactosidase A may halt the progression of vascular pathology and prevent the clinical manifestations of atherosclerotic disease. This histopathological study should be a useful guide for clinicians and pathologists who diagnose and follow Fabry patients.

The neodymium:YAG (yttrium-aluminum-garnet) laser can cause transmural coagulation necrosis of bladder tumor or bladder wall. Pathologic specimens of 18 patients prospectively treated with the neodymium: YAG laser before radical cystectomy were reviewed to compare the initial clinical stage of bladder tumor with the final pathologic stage and to assess the destructive tissue effects of neodymium: YAG laser therapy. Eleven of 18 patients were unchanged pathologically in stage of tumor or had tumor progression. Seven patients had a lower pathologic tumor stage; 3 of these patients had pathologic, Stage TO with no residual tumor, with the remainder of patients showing superficial disease. One asymptomatic small bowel injury was discovered at operation. Healing lesions showed marked granulation tissue, coagulation necrosis, and persistent ulceration.

Regression of Barrett's epithelium after antireflux operations remains a controversial topic. We evaluated the effect of antireflux procedures in patients with Barrett's esophagus on the regression of columnar epithelium and dysplasia and its potential protective effect on the subsequent development of carcinoma. Of the 241 patients with Barrett's esophagus treated at the Lahey Clinic from 1973 to 1989, 37 patients underwent an antireflux operation. Regression was defined at histological evidence of regenerating squamous mucosa that completely or partially replaced the columnar epithelium. Improvement in lower esophageal sphincter pressure to 12 mm Hg or greater occurred in 19 of 26 patients (73%) who had perioperative manometry. Symptomatic relief of esophagitis occurred in 34 of 37 patients (92%). Four patients had partial regression with regenerating squamous mucosa juxtaposed with areas of columnar epithelium. Carcinoma developed in 3 of 37 patients (8.1%). One patient had recurrence of severe symptoms of reflux esophagitis before development of carcinoma. Patients with Barrett' s esophagus who have undergone a successful antireflux operation with symptomatic relief and evidence of improvement in lower esophageal sphincter pressures rarely show regression of Barrett's mucosa and may still be at risk for development of carcinoma. Therefore, the indications for antireflux operation in Barrett's esophagus should remain the same as for other patients with gastroesophageal reflux, but yearly endoscopic and histological surveillance should be continued postoperatively.

We report the case of an 18-yr-old man with quiescent ulcerative colitis complicated by concomitant primary sclerosing cholangitis and rapidly progressive glomerulonephritis. Findings on immunofluorescence microscopy and electron microscopy suggested that glomerular injury occurred secondary to the deposition of circulating immune complexes. Renal disease responded to treatment with corticosteroids. A review of the literature found similar cases of glomerulonephritis and inflammatory bowel disease, but no previous association with sclerosing cholangitis has been recognized. The pertinent clinical, immunological, and pathophysiological aspects of this association are reviewed.

Background— The current understanding of the pathophysiology of coronary artery disease is based largely on postmortem studies. Optical coherence tomography (OCT) is a high-resolution (≈10 μm), catheter-based imaging modality capable of investigating detailed coronary plaque morphology in vivo. Methods and Results— Patients undergoing cardiac catheterization were enrolled and categorized according to their clinical presentation: recent acute myocardial infarction (AMI), acute coronary syndromes (ACS) constituting non-ST-segment elevation AMI and unstable angina, or stable angina pectoris (SAP). OCT imaging was performed with a 3.2F catheter. Two observers independently analyzed the images using the previously validated criteria for plaque characterization. Of 69 patients enrolled, 57 patients (20 with AMI, 20 with ACS, and 17 with SAP) had analyzable images. In the AMI, ACS, and SAP groups, lipid-rich plaque (defined by lipid occupying ≥2 quadrants of the cross-sectional area) was observed in 90%, 75%, and 59%, respectively ( P =0.09). The median value of the minimum thickness of the fibrous cap was 47.0, 53.8, and 102.6 μm, respectively ( P =0.034). The frequency of thin-cap fibroatheroma (defined by lipid-rich plaque with cap thickness ≤65 μm) was 72% in the AMI group, 50% in the ACS group, and 20% in the SAP group ( P =0.012). No procedure-related complications occurred. Conclusions— OCT is a safe and effective modality for characterizing coronary atherosclerotic plaques in vivo. Thin-cap fibroatheroma was more frequently observed in patients with AMI or ACS than SAP. This is the first study to compare detailed in vivo plaque morphology in patients with different clinical presentations.

Objectives This study was designed to determine in a dog model of coronary thrombosis whether short-term eptifibatide (Ep) combined with low-dose plasminogen activator (rt-PA) inhibits platelet recruitment at sites of endothelial damage after normalization of platelet function. Background Ep plus reduced-dose rt-PA has not previously been shown to render a recanalized coronary artery resistant to platelet recruitment after normalization of platelet function. Methods Inhibition of platelet recruitment was studied by scanning electron microscopy (SEM) in a canine model of left anterior descending (LAD) thrombosis. In phase I treatment groups were: 1) Ep (n = 6); 2) Ep + rt-PA (n = 6); 3) rt-PA (n = 6); and 4) placebo (n = 4). Coronary blood flow was monitored and LAD segments excised for SEM after 90-min infusion of study drug. In phase II, dogs were randomized to Ep alone (n = 5) or to Ep + rt-PA (n = 5). Coronary blood flow was monitored during and 120 min after cessation of drug when platelet function had returned to normal and LAD segments were excised. Results All animals except placebo showed reflow. In phase I, SEM showed an absence of platelet aggregates with Ep alone and with Ep + rt-PA, but not with rt-PA alone. In phase II, SEM showed an intimal surface devoid of mural thrombus and platelet aggregates only in Ep + rt-PA treated arteries. Ep-alone treated arteries showed new platelet aggregates at sites of residual mural thrombus. Conclusions Short-term infusion Ep plus low-dose rt-PA acutely neutralizes the ability of damaged endothelial surfaces to recruit new platelets by inhibiting platelet aggregation and eliminating residual mural thrombus.

To investigate the role of endothelial nitric oxide synthase (NOS3) in left ventricular (LV) remodeling induced by chronic pressure overload, the impact of transverse aortic constriction (TAC) on LV structure and function was compared in wild-type (WT) and NOS3-deficient (NOS3–/–) mice. Before TAC, LV wall thickness, mass, and fractional shortening were similar in the two mouse strains. Twenty-eight days after TAC, both WT and NOS3–/– mice had increased LV wall thickness and mass as well as decreased fractional shortening. Although the pressure gradient across the TAC was similar in both strains of mice 28 days after TAC, LV mass and posterior wall thickness were greater in NOS3–/– than in WT mice, whereas fractional shortening and the maximum rate of developed LV pressure were less. Diastolic function, as measured by the time constant of isovolumic relaxation and the maximum rate of LV pressure decay, was impaired to a greater extent in NOS3–/– than in WT mice. The degree of myocyte hypertrophy and LV fibrosis was greater in NOS3–/– than in WT mice at 28 days after TAC. Mortality was greater in NOS3–/– than in WT mice 28 days after TAC. Long-term administration of hydralazine normalized the blood pressure and prevented the LV dilation in NOS3–/– mice but did not prevent the LV hypertrophy, dysfunction, and fibrosis associated with NOS3 deficiency after TAC. These results suggest that the absence of NOS3 augments LV dysfunction and remodeling in a murine model of chronic pressure overload.

Background— Macrophage degradation of fibrous cap matrix is an important contributor to atherosclerotic plaque instability. An imaging technology capable of identifying macrophages in patients could provide valuable information for assessing plaque vulnerability. Optical coherence tomography (OCT) is a new intravascular imaging modality that allows cross-sectional imaging of tissue with a resolution of ≈10 μm. The aim of this study was to investigate the use of OCT for identifying macrophages in fibrous caps. Methods and Results— OCT images of 26 lipid-rich atherosclerotic arterial segments obtained at autopsy were correlated with histology. Cap macrophage density was quantified morphometrically by immunoperoxidase staining with CD68 and smooth muscle actin and compared with the standard deviation of the OCT signal intensity at corresponding locations. There was a high degree of positive correlation between OCT and histological measurements of fibrous cap macrophage density ( r =0.84, P r =−0.56, P 10% CD68 staining. Conclusions— The high contrast and resolution of OCT enables the quantification of macrophages within fibrous caps. The unique capabilities of OCT for fibrous cap characterization suggest that this technology may be well suited for identifying vulnerable plaques in patients.

Transmyocardial laser revascularization (TMLR) has potential benefit for patients with end-stage coronary artery disease and intractable angina not amenable to conventional revascularization techniques. Neovascularization has been proposed to occur around the laser channels. Our aim was to determine the feasibility of a novel nonlaser myocardial revascularization technique and its effect on angiogenesis in a nonischemic porcine model.In the first phase, six transmyocardial stainless steel coil implants (TMI) were deployed to the lateral wall of the left ventricle in each of 6 pigs. The animals were sacrificed at 8 and 12 weeks, with a single animal dying prematurely at 4 weeks, and the myocardium was assessed for new vessel growth. In the second phase, 8 implants were deployed in each of 12 pigs with regular fluoroscopic follow-up until sacrifice at 2 weeks to assess implant stability.The deployment procedure was safe and feasible with no complications evident. A significant increase in new vessels at implant sites with 5.43 +/- 3.67, 4.97 +/- 2.44, and 3.57 +/- 2.29 seen per high power field at 12, 8, and 4 weeks, respectively, compared to 1.00 +/- 1.06 (p0.0001) in control myocardium. There was no evidence of implant migration in Phase 2.TMIs can feasibly be deployed in the nonischemic pig model with a high success rate. The presence of angiogenesis at the implant site and the maintenance of this reaction for 3 months implies that TMI may offer an alternative to TMLR while providing a platform for delivery of angiogenic factors.

A 44-year-old woman with end-stage renal disease due to fibrillary/immunotactoid glomerulopathy presented with progressive symptoms of heart failure. An echocardiogram showed a dilated left ventricle with diffuse hypokinesis. An endomyocardial biopsy revealed patchy fibrosis. Immunofluorescence demonstrated interstitial staining with immunoglobulin G and complement component C3. Electron microscopy (Figure 1) revealed deposition of fibrils with diameters ranging from 8.0 to 12.4 nm that were negative on Congo red staining and …

Background To test whether deficiency in endothelial nitric oxide synthase (eNOS) affects atherosclerosis development, we compared lesion formation in apolipoprotein E (apoE)/eNOS-double knockout (DKO) and apoE-knockout (KO) control animals. Methods and Results After 16 weeks of “Western-type” diet, apoE/eNOS-DKO males and females showed significant increases in lesion area of 93.6% and 59.2% compared with apoE-KO mice. All apoE/eNOS-DKO animals studied developed peripheral coronary arteriosclerosis, associated with perivascular and myocardial fibrosis, whereas none of the apoE-KO mice did. Transthoracic echocardiography showed a significantly increased left ventricular wall thickness and decreased fractional shortening in DKO animals. Mean arterial pressure was increased in DKO mice and was comparable in degree to eNOS-KO animals. Male DKO animals developed atherosclerotic abdominal aneurysms and aortic dissection. Conclusions eNOS deficiency increases atherosclerosis in Western-type diet-fed apoE-KO animals and introduces coronary disease and an array of cardiovascular complications, including spontaneous aortic aneurysm and dissection. This phenotype constitutes the first murine model to demonstrate distal coronary arteriosclerosis associated with evidence of myocardial ischemia, infarction, and heart failure. Hypertrophy and reduced left ventricular function cannot be explained by increased blood pressure alone, because eNOS-KO animals do not develop these complications.

Cardiac hamartomas are a rare type of benign tumor affecting the heart. We describe a 33-year-old patient who presented with a wide complex tachycardia. Diagnostic imaging revealed a mass in the patient's left ventricular wall, near the apex of the heart. The mass was surgically resected and appeared benign. Its pathology was that of a hamartoma of mature cardiac myocytes. Postoperative electrophysiology evaluation showed no inducible focus and the patient remains alive and asymptomatic after 2 years of follow-up.

With a limited supply of donor hearts in the United States and a prevalent history of cocaine abuse among potential heart donors, the question of transplanting the hearts of cocaine users presents a dilemma to the surgeon. We report a patient who died of the acute right ventricular failure of a heart from a donor with a history of binge drinking and cocaine abuse and who had sustained traumatic brain death. The donor's serum was positive for cocaine prior to transplantation, and autopsy findings were consistent with cocaine cardiomyopathy. This case illustrates the importance of accurate donor history and toxicologic screen prior to heart transplantation and suggests that hearts of cocaine users should not be transplanted, especially in a setting of traumatic brain death.

In order to achieve a better long-term patency result and solve the problem of tensile strength in laser artery anastomoses, diode laser and Indocyanine Green (ICG) enhanced albumin were applied to medium-size artery anastomoses with three different methods, that is, direct laser vascular anastomoses, direct method enforced with ICG albumin, and laser welding with ICG albumin as 'solder'. Internal mammary artery (IMA) harvested from patients undergoing coronary bypass procedures, in vivo rat abdominal artery, and in vitro swine heart and IMA were chosen as the experimental materials. The results revealed that only 3.15 +/- 0.36 minutes were required for each anastomosis; the bursting pressure and tensile strength were greater in the groups enforced with ICG albumin and laser welding than that with direct laser anastomoses. In the laser soldering group, the thermal damage was limited in the adventitial layer, only at a depth of 200 micrometers . There was also a satisfied result in the in vivo laser welding rat's abdominal adventitial layer, only at a depth of 200 micrometers . There was also a satisfied result in the in vivo laser welding rat's abdominal arteries. However, end-to-side laser welding of IMA soronary artery with ICG albumin needs further investigation about its tensile strength in an in vivo model.© (1998) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

Transmyocardial laser revascularization (TMR) for the treatment of medically unresponsive angina pectoris has been shown to be clinically effective. The mechanism of its action, however, is not quite understood. Over the last five years my collaborators and I have conducted a variety of in vivo and in vitro studies using different animal models, lasers and experimental protocols. The results seem to indicate that the mechanism of action of TMR is related to neovascularization rather than chronically patent channels, as originally proposed.© (1996) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

Radiofrequency catheter ablation of left-sided accessory pathways is technically demanding and usually requires left heart catheterization. The feasibility of creating lesions from within the coronary sinus of sufficient size to ablate accessory pathways in humans using a thermal balloon catheter was studied in 20 dogs. In group 1 (n = 14), 17 thermal inflations were performed in 12 dogs at either 70 degrees, 80 degrees, or 90 degrees C each for 30 or 60 seconds (in 2 dogs two non-thermal control inflations were performed). Animals were sacrificed 6.3 +/- 1.6 days later. In group 2 (n = 6), seven thermal inflations were performed at 90 degrees C each for 180, 300, or 360 seconds. Group 2 animals received antiplatelet and anticoagulant therapy for 1 week and were sacrificed at 13 +/- 10.7 days. In both groups, hemodynamic, angiographic, and electrocardiographic studies were performed at baseline, 1 hour after inflation, and prior to sacrifice. All dogs remained clinically stable throughout the procedure and no complications were attributed to the effect of thermal inflation. Thermal lesions measured 14.4 +/- 4.4 mm in length and extended from the coronary sinus intima to a mean depth of 2.9 +/- 1.2 mm (range 1.4-6.5 mm). Group 2 lesions were significantly deeper than group 1 lesions (P = 0.03). Of the 24 thermal lesions created, atrial necrosis was present in 23 and ventricular necrosis in 11. In all lesions there was some degree of either atrial necrosis, ventricular necrosis, or both. A variable degree of coronary sinus thrombus was present in 18 dogs without clinical sequelae. It is concluded that radiofrequency balloon heating via the coronary sinus can create thermal lesions in the atrioventricular sulcus of dogs that may be of sufficient size to ablate accessory left-sided pathways in humans.

Absorbable sutures have been advocated for tracheal anastomosis to reduce fibrosis and foreign body reaction leading to recurrent stenosis. Fibrin tissue adhesive (FTA) and diode laser welding with indocyanine green-dyed fibrinogen were evaluated in tracheal anastomosis to reduce the number of sutures and to improve healing. In vitro studies demonstrated strong anastomoses with a combination of laser welding and FTA with minimal tissue damage. In a controlled in vivo study, circumferential resections of canine tracheas were repaired with laser welding and FTA augmented with a few stay sutures. These anastomoses had less fibrosis and tissue damage than anastomoses in control animals repaired with sutures alone. This study supports investigation of laser welding and FTA in human beings for tracheal anastomosis and other procedures in which suturing may be difficult.

Objectives. This study was designed to assess the feasibility of using hydrogel-coated balloons to deliver biologically active agents to the blood vessel wall.Background. The tool intramural delivery of therapeutic agents during balloon angioplasty has been proposed as an adjunctive technique for preventing early intracoronary thrombosis and late restenosis.Methods. To assess the efficacy of delivery and depth of penetration in vitro, local delivery of horseradish peroxidase was performed in 40 porcine peripheral arteries, and delivery of fluoresceinated heparin was performed in 20 porcine peripheral arteries and 7 human atheromatous arteries. To determine the persistence of these agents in the vessel wall in vivo, horseradish peroxidase was delivered to 18 porcine peripheral arteries that were harvested at intervals of 45 min to 48 h. Fluoresceinated heparin was delivered to 22 porcine peripheral arteries, 14 with the use of a protective sleeve, harvested at intervals of 30 s to 24 h.Results. In vitro agent delivery was successful in all specimens. The depth of penetration of horseradish peroxidase was directly related to both balloon pressure (p < 0.04) and duration of inflation (p < 0.01). In vivo peroxidase staining was evident at 45 and 90 min but not thereafter. With the use of a protective sleeve, heparin was present in all arteries harvested at 30s, with marked dissipation at 1 and 24 h. Without a sleeve, no fluorescein staining was detected in any artery. With both agents, delivery occurred consistently over broad regions of the vessel wall that were free of architectural disruption.Conclusions. Hydrogel-coated balloons can deliver biologically active agents to the vessel wall without gross tissue disruption and may provide an atraumatic method for the local delivery of therapeutic agents during balloon angioplasty.