Pulsatile flow and atherogenesis: results from in vivo studies.

Compliance mismatch between prosthetic vascular replacement (possibly stented) and native artery is considered to be an important factor in implant failure due, e.g., to vascular remodeling, tissutal growth or intimal hyperplasia (IH). From an in vivo study involving altered vascular mechanics (and, consequently, compliance mismatch), carried out using the Moncada model of atherosclerosis development and smooth muscle cell (SMC) proliferation, the hemodynamic assessment was followed by means of real-time multigated ultrasound profilometry, of collared carotid artery using two different models: non-constrictive and constrictive plastic collars, wrapped around the vessel. The experiments provided the real-time measurement of velocity profiles in vivo and the subsequent estimation of wall shear stresses, locally responsible for the altered hemodynamics. Endothelium modifications were correlated with local hemodynamic alterations by using statistical regression analysis of the development of intimal hyperplasia and the mechanical stimulus applied to the endothelium by means of the two different manipulation models. Different correlations were found between wall shear rate and IH in the two models, showing the importance of the vascular pulsatility in determining SMC proliferation. This result could be useful in minimizing the negative consequences of clinical interventions such as graft and/or stent implantation.

Uso de anfotericina B en mezcla lipídica: ¿previene la toxicidad de la droga en pacientes críticos? / Use of amphotericin B as lipid emulsion: does it prevent drug toxicity in critical patients?

Background: Amphotericin B is efficacious for the treatment of systemic candidiasis, however it has potentially serious toxic effects. Administration as lipid emulsions has been advocated to decrease its toxicity. Aim: To compare the safety and tolerance of amphotericin B administered as lipid emulsion or dissolved in dextrose in water. Patients and methods: Forty five patients with confirmed or highly suspected systemic candidiasis were studied. Between January 1996 and June 1997 amphotericin B was administered in dextrose in water to 17 patients (group 1). Between July 1997 and December 1998, the drug was delivered in lipid emulsions (Intralipid, group 2). Clinical and laboratory parameters (serum creatinine, urea nitrogen and potassium), were assessed daily. Results: Both treatment groups were clinically comparable and had the same survival. Accumulative amphotericin B dose administered was 343.2 ñ 197 and 414.6 ñ 518 mg respectively. Hypokalemia was more frequent in group 2 (52 and 25 percent respectively, p < 0.05). There were no differences in the outcome of renal function or other adverse reactions. Conclusions: Administration of amphotericin B as lipid emulsions did not reduce its toxicity in critical patients

Non-atherosclerotic saccular aneurysmal degeneration of a saphenous-vein graft inserted for repair of a popliteal aneurysm.

The Authors describe a case of a saccular aneurysm formation in a femoropopliteal autologous saphenous vein graft, inserted 12 years before. The patient was initially treated for a popliteal aneurysm. The graft revealed no microscopic signs of atherosclerosis. In spite of the widespread use of the autologous saphenous vein as arterial substitute, this complication is extremely rare.

Inflammatory aneurysm of the abdominal aorta. A prospective clinical study.

OBJECTIVE: This study was undertaken to investigate a consecutive series of abdominal aortic aneurysm studied with histology to highlight the etiology, the incidence, the value of preoperative studies and intraoperative findings. EXPERIMENTAL DESIGN: Prospective study. SETTING: University hospital. PATIENTS: Between 1992 and 1994, 102 patients underwent elective surgical repair of an abdominal aortic aneurysm. The patients were prospectively divided as having an inflammatory aneurysm (IA) or an atherosclerotic aneurysm (AA) on the basis of preoperative and intraoperative findings. Further histological evaluation assigned the patients to one of the two groups. RESULTS: The incidence of IA was 15%. Overall, symptoms, CT scan studies, aneurysmal wall thickness, white glistening perianeurysmal fibrosis, bleeding from the aneurysmal wall and adhesion to the duodenum diagnosed 11 (73%) cases of IA. Histology showed that a granulomatous reaction against some components of the atherosclerotic plaques resulting in an auto-allergic response to this component could initiate the inflammatory process thus resulting in a progressive adventitial and peri-adventitial fibrosis with inflammation, lymphadenitis and lymphatic dilatation. CONCLUSIONS: Preoperative and intraoperative findings underestimate the incidence of IA. Aortic resection can prevent the progression of the inflammatory process and the complications usually observed when the exposure to the allergen determines an involvement of the periaortic structures.

Maternally inherited cardiomyopathy: clinical and molecular characterization of a large kindred harboring the A4300G point mutation in mitochondrial deoxyribonucleic acid.

OBJECTIVES: The purpose of this study was to describe the clinical and molecular features of a large family with maternally inherited cardiomyopathy (MICM). BACKGROUND: Recently, several mitochondrial deoxyribonucleic acid (mtDNA) point mutations have been associated with MICM. However, the distinctive clinical and morphologic features of MICM are not fully appreciated. This is partially due to the small size of the reported pedigrees, often lacking detailed clinical and laboratory information. METHODS: Clinical and genetic analysis of the family was carried out. RESULTS: Echocardiography showed mostly symmetrical hypertrophic cardiomyopathy in 10 family members. The illness had an unfavorable course. Progressive heart failure occurred in three subjects, who eventually died; one individual underwent heart transplantation. Electrocardiographic or echocardiographic signs of cardiac hypertrophy in the absence of significant clinical complaints were observed in five subjects. Neurologic examination was normal. The mutation was detected in blood from all available subjects. Abundance of mutated molecules ranged between 13% and 100% of total mtDNA genomes. The severity of the disease could not be foreseen by the proportion of mutation in blood. CONCLUSIONS: This report contributes a better description of the clinical aspects of MICM and provides important clues to distinguish it from hypertrophic cardiomyopathy. We suggest that mtDNA mutations, particularly in the transfer ribonucleic acid for isoleucin, should be systematically searched in patients with MICM. The identification of an underlying maternally inherited mitochondrial DNA defect in familial cases of cardiomyopathy may considerably influence the management and genetic counseling of affected patients.

Cross-sectional imaging in a case of adventitial cystic disease of the popliteal artery.

Adventitial cystic disease of the popliteal artery is an unusual condition of uncertain etiology, in which a mucin-containing cyst forms in the wall of the artery and produces lower extremity claudication, typically in young and middle-aged men. A diagnosis of adventitial cystic disease of the popliteal artery was made preoperatively in a 47-year-old man by means of several imaging modalities, including angiography, magnetic resonance imaging, and ultrasound. The pathological findings confirmed the suggested diagnosis.

Rupture of Dacron aorto-femoral graft. Case report.

A 74-year-old patient was admitted to our department in a serious general condition due to massive bleeding. He had been treated 10 years previously in another hospital with an aorto-bifemoral bypass for obstructive disease using a knitted-Dacron graft. A large pulsating mass was present in the right iliac fossa as well as enormous pulsating enlargement of the scrotum. Echo color-Doppler investigation detected dilation up to 5 cm in diameter of the right branch of the graft and a large perigraft hematoma communicating with a similar mass in the scrotum. The patient was submitted to emergency surgery and a large rupture of the graft was found. The dilated segment was resected and replaced by a new 8 mm Dacron graft. Postoperative course was uneventful.

ET(A)/ET(B) receptor antagonist bosentan inhibits neointimal development in collared carotid arteries of rabbits.

The contribution of endothelin to the genesis of neointimal development in collared rabbit carotid arteries, a widely accepted model of atherosclerosis, was investigated. Three sets of rabbits were studied. In the first group, a non-occlusive, biologically inert silastic collar was positioned around the right carotid artery of the rabbit. In another group, the application of the collar was accompanied by endothelial denudation via a Fogarty arterial balloon catheter, while the third group of animals underwent only endothelial denudation. After two weeks, intimal hyperplasia of a similar degree was observed in all groups. The administration of the nonselective ET(A)/ET(B) receptor antagonist Bosentan, significantly reduced both the neointimal area and the intima/media area ratio in all groups. However, the beneficial effects of Bosentan were less pronounced in balloon injured vessels than in collared ones. The results of the present study indicate that i) endothelin has a key role in the development of intimal hyperplasia following arterial collaring, ii) the contribution of endothelin to intimal hyperplasia is greater in collared arteries that in balloon injured ones, and iii) the nonselective ET(A)/ET(B) receptor antagonists are potential tools for the prevention of intimal hyperplasia.

Causes of late failure after heart transplantation: a ten-year survey.

BACKGROUND: Little is known about the causes of death of heart transplant recipients who survive long-term. METHODS: The pathologic and clinical records of 97 patients who underwent heart transplantation in Italy from 1985 to 1995 and died (85 of 97) or underwent retransplantation (12 of 97) at least 2 years after transplantation were surveyed. Graft failures were classified as late (occurring between 2 and 5 years after transplantation) and belated (more than 5 years). RESULTS: Graft vasculopathy was the single most common cause of death (40.0%) and the only cause of late retransplantation. Tumors ranked second (23.5% of deaths), but the expected non-Hodgkin's lymphomas and Kaposi's sarcoma were accompanied by a high number of lung cancers (especially metastasizing adenocarcinomas). They were followed by the emergence or recurrence of pretransplantation diseases (9.4%), fatal infections (exclusively bacterial) (4.7%), the development of transmissible diseases (viral hepatitis and acquired immunodeficiency syndrome, 4.7%), and late acute rejection (2.3%). The distribution of failures differed in the late and belated periods: death and organ loss proportions for graft vasculopathy, respectively, fell and rose from the late to the belated period; some types of malignancy and fatal acute rejection were never observed in the belated period, whereas the emergence of pretransplantation diseases prevailed in the belated period. Graft vasculopathy was more frequent and tumors were less frequent among patients undergoing transplantation for ischemic heart disease. CONCLUSIONS: The reasons why heart transplant recipients die or undergo retransplantation, respectively, in the late and belated periods slightly differ from one another and are widely different than in short-term survivors.

Felodipine protects human atrial muscle from hypoxia-reoxygenation dysfunction: a force-frequency relationship study in an in vitro model of stunning.

AIMS: We aimed at investigating contractile changes after hypoxia-reoxygenation and dobutamine challenge in superfused human atrial pectinate muscle to see whether high versus low stimulation rate during hypoxia might account for outcome differences compatible with the definition of an in vitro model of myocardial stunning and whether pretreatment with the dihydropyridine Ca2+ entry blocker felodipine might afford protection. METHODS: Human right atrial trabeculae obtained from adult patients were superfused in an organ bath with oxygenated (O2 content 16 ml/l) and modified (NaHCO3 25.7 mmol/l) Tyrode's solution at 37 degrees C. Dobutamine (1 nmol/l to 10 micromol/l) was superfused in 10 oxygenated preparations to select the optimal drug concentration to be used in another 22 which were randomized. Group (A) consisted of time-related controls (Tyrodes's solution for 225 min at cycle length (CL) 1600 ms and no dobutamine). There were two test groups, respectively: (B) low (1600 ms CL) and (C) high (400 ms CL) stimulation rate. After 60 min of stabilization, in groups B and C, hypoxic superfusion (O2 content 5 ml/l) lasted 60 min, then reoxygenation (60 min) and dobutamine challenge (1 micromol/l, 15 min) were performed. Analysis of variance for repeated measures with the Greenhouse-Geisser correction, and a repeated measures model with structured covariance (preparation mass, length, width and time-varying time to peak tension) matrices were used whereby grouping (G), time (T) and G x T interaction were weighted. Force-frequency relationship and post-pausal potentiation were studied after each phase. Electrophysiology, histomorphometry and electron microscopy were carried out (n=6). Felodipine (0.1 micromol/l, n=5) pretreatment (15 min before hypoxia) was given in parallel experiments. RESULTS: Time-related controls showed approximately 10% per hour decrease of developed tension and the Paradise test provided approximately 80% of control values. In test groups (as compared to baseline values) contractility was decreased approximately 65% after hypoxia-reoxygenation and it increased approximately 25% after dobutamine (G, 0.0065

bFGF release is dependent on flow conditions in experimental vein grafts.

OBJECTIVES: Basic Fibroblastic Growth Factor (bFGF) is a powerful mitogen for smooth muscle cells and has been implicated in the genesis of Myointimal hyperplasia. The aim of this study was to determine the release of bFGF by veins in different haemodynamic conditions. DESIGN AND SETTING: Laboratory animal study. MATERIALS: In 39 Lewis rats, a 1 cm long segment of inferior vena cava was inserted at the level of the abdominal aorta. The segments of inferior vena cava were obtained from syngenic Lewis rats. Arterial Vein Grafts (AVG) were harvested after 4 weeks (AVG 4) and 12 weeks (AVG 12). In 16 animals the arterial vein grafts were explanted 4 weeks after the initial operation and reimplanted (Reimplanted Vein Grafts: RVG) in syngenic Lewis rats as venous-venous bypass grafts at the level of the left iliac vein and harvested after 2 weeks (RVG 2) and 8 weeks (AVG 8). OUTCOME MEASURES: The tissue was studied in organ culture in a serum-free system for (1) release of bFGF (immunoassay) and (2) mitogenic activity of the conditioned media. Scanning electron and light microscopy studies were also performed. RESULTS: bFGF release by veins increased significantly (p < 0.01) when veins were inserted in the arterial circulation, and decreased significantly (p < 0.01) when grafts were reimplanted in the venous system. bFGF release (ng/cm2): [Formula: see text] CONCLUSION: Vein inserted in the arterial circulation release a higher quantity of bFGF. This could explain in part, the formation of myointimal hyperplasia in arterial vein graft.

Does cyclosporin A have any effect on accelerated atherosclerosis in absence of graft rejection? Pathologic and morphometric evaluation in an experimental model.

BACKGROUND: The effects of cyclosporin A on accelerated atherosclerosis were studied in an experimental model of aortic isotransplantation. METHODS: Seventy-six Lewis rats were studied. Forty-one abdominal aortic isografts were performed and divided into five groups: 2-day isografts and 15- and 100-day isografts with and without cyclosporin treatment. The remaining rats were divided into seven groups: 15- and 100-day sham-operated, with and without cyclosporin administration; 15- and 100-day animals with cyclosporin treatment only; and normal controls. Cyclosporin was injected subcutaneously in doses of 10 mg/kg daily for the first 15 days and afterward every other day. Longitudinal sections of the proximal anastomosis and cross sections of the midgraft region were measured with a semiautomatic image-analyzer. RESULTS: Histologic analysis showed that accelerated atherosclerosis was not observed either in NT2 rats or in nontransplanted animals. In the 15-day isografts, accelerated atherosclerosis was present in the perianastomotic tract of the recipient aorta in nine of nine NT15 rats, whereas it was found only in three of nine T15 animals (p < 0.02). Histomorphometric analysis showed that accelerated atherosclerosis was less pronounced in the T100 isografts than in the NT100 ones, this difference being significant at the recipient anastomotic side only (p < 0.0005). CONCLUSIONS: The present results support the hypothesis that cyclosporin, at immunosuppressant and nontoxic doses, can delay the onset and progression of accelerated atherosclerosis and that its effects are more significant at the recipient side of the anastomosis where accelerated atherosclerosis begins to develop.

Aneurysms of the infrapopliteal arteries.

Atherosclerotic aneurysms involving only infrapopliteal arteries are extremely rare. The present report describes a patient with two completely separate aneurysmal dilatations involving the tibioperoneal trunk and the anterior tibial artery. To our knowledge, this condition has not been previously described. An international bibliographic review was also made, collecting four patients affected by atherosclerotic infrapopliteal aneurysms. Clinical presentation, radiographic findings, and surgical management are discussed.

A novel mtDNA point mutation in maternally inherited cardiomyopathy.

A novel mtDNA mutation at position nt. 4300 in the tRNAIle gene is associated with hypertrophic cardiomyopathy inherited as a maternal trait. Interestingly, this mutation seems to cause a pure heart disease as opposed to most other mtDNA mutations, which are associated with multisystemic disorders. Hypertrophic cardiomyopathies are genetically heterogeneous, and mtDNA defects should be considered in the differential diagnosis, especially when there is evidence of maternal inheritance.

The pattern of desmin filaments in myocardial disarray.

"Myofiber disarray" defines a nonparallel arrangement of cardiac myocytes. The presence of a sufficient quantity of myocardial fibers showing this change is considered to be a specific histological feature of hypertrophic cardiomyopathy (HCM). However, small zones of myofiber disarray are found in both cardiac hypertrophy and other pathological conditions. Recently, we demonstrated an altered pattern of desmin intermediate filaments in disarrayed myofibers from specimens of HCM. To test the hypothesis that desmin alterations might be specific for cardiomyopathy, we performed an immunohistochemical study on myocardial surgical samples from 11 patients with HCM and from 12 patients with tetralogy of Fallot (toF) on 14 endomyocardial biopsy specimens (EMBs) from transplant recipients with myofiber disarray surrounding areas of scarring (previous biopsy site) and on specimens of four autoptic hearts with severe acquired left ventricular hypertrophy. Disarrayed myofibers from all specimens of HCM showed the following abnormalities in the pattern of desmin intermediate filament distribution: (1) decrease or loss of labeling of intercalated discs and Z bands, (2) longitudinal arrangement of desmin intermediate filaments, and (3) intense, granular staining of several myocytes. This spectrum of desmin alterations was never observed in disarrayed myofibers in specimens of toF or acquired myocardial hypertrophy or in EMBs. Altered distribution of desmin intermediate filaments seems to be specific to myofiber disarray in HCM and it may play a role in the altered myocyte arrangement in HCM.

Functional significance of myocellular hypertrophy in dilated cardiomyopathy: histomorphometric analysis on 40 endomyocardial biopsies.

Dilated cardiomyopathy is characterized by an increase in myocardial mass. In order to study the functional significance of myocellular hypertrophy in dilated cardiomyopathy, 40 left ventricular endomyocardial biopsies were investigated, by comparing morphometrical data with functional indexes. The extent of myofibril volume fraction was directly associated with a better functional condition, as measured by ejection fraction (p < 0.01) and cardiac index (p < 0.05). Patients with oversize nuclei (nuclear area being > or = 70 microns 2) had a worse functional status (p < 0.05), as determined by ejection fraction and cardiac index. Finally, the extent of interstitial fibrosis was directly correlated to mean right atrial pressure (p < 0.01), right ventricular end-diastolic pressure (p < 0.02) and mean pulmonary artery pressure (p < 0.02). In conclusion, a worse functional status correlates with a reduced myofibril volume fraction and an oversize nuclear area, as in hypertrophic cells undergoing regressive changes.

Histomorphometric features predict 1-year outcome of patients with idiopathic dilated cardiomyopathy considered to be at low priority for cardiac transplantation.

Cardiac transplantation for patients with idiopathic dilated cardiomyopathy (IDC) and poor left ventricular function usually is postponed until symptoms have become intolerable. However, the short-term prognosis of this subset of patients has been defined poorly. Accordingly, the 1-year outcome was investigated in 30 patients with IDC with an ejection fraction < or = 25% who showed a stabilized clinical condition at assessment for transplantation and were therefore considered at low priority for surgery. During follow-up, 10 patients (group A) showed a poor outcome: 2 died suddenly, and 8 had hemodynamic failure (4 of whom underwent transplantation and 4 of whom died from heart failure while on the waiting list). The remaining 20 patients (group B) had a benign outcome. At assessment for cardiac transplantation, clinical and electrocardiographic features, left ventricular dimension, and ejection fraction were similar between the two groups. However, group A patients had higher left ventricular end-diastolic pressure (p < 0.03) and lower cardiac index (p < 0.02) and stroke volume index (p < 0.03) with respect to group B patients. In addition, the former had a lower myofibril volume fraction (p < 0.001) and a higher nuclear area (p < 0.001) compared with the latter. Multivariate analysis selected myofibril volume fraction (p < 0.001) and nuclear area (p < 0.005) as the only independent predictors of a poor 1-year outcome. The combination of myofibril volume fraction < or = 89% and nuclear area > 50 microns 2 was found in all group A patients (sensitivity 100%) but in only 2 group B patients (specificity 90%). It is concluded that in patients with IDC considered at low priority for cardiac transplantation: (1) the 1-year freedom from a cardiac event is lower than that currently expected with surgery; (2) histomorphometric features, that is, the concurrency of low myofibril volume fraction and increased nuclear area, predict short-term outcome; and (3) endomyocardial biopsy at assessment for cardiac transplantation might improve the rationalization of the timing of the procedure.

[Inflammatory aneurysm of the abdominal aorta: anatomo-clinical study on 16 cases and pathogenetic hypothesis]. / Aneurismi infiammatori dell'aorta addominale: studio anatomo-clinico su 16 casi e ipotesi patogenetiche.

BACKGROUND: Inflammatory aneurysms of the abdominal aorta constitute an anatomoclinical entity characterised by prominent thickening and fibrosis of the aneurysmal wall, extending to the adjoining structures. Etiology, pathogenesis and relation with atherosclerosis still remain controversial. METHODS: Sixteen consecutive patients undergoing surgery for inflammatory aneurysm of the abdominal aorta between March 1987 and December 1990 were studied (Group I); as a control, a series of 16 consecutive patients operated on in the same period for atherosclerotic aneurysm of the abdominal aorta was selected (Group II). As far as clinical history and symptoms are concerned, the comparison between the two groups revealed significant differences only for hydronephrosis (exclusively present in Group I, p < 0.05) and abdominal pain (more frequent in Group I, p < 0.01). The microscopic study of the aneurysmal wall was performed by scoring its histological features (atherosclerotic lesions, medial and adventitial fibrosis, inflammatory infiltrates and lymphatic stasis) from 1+ to 3+. RESULTS: As regards the microscopical features, atherosclerotic lesions were present in all the examined cases, whereas periadventitial fibrosis appeared in all the aneurysms of Group I and in none of Group II; the comparison between the two groups revealed further significant differences for extensive intimal calcification (exclusively present in Group II, p < 0.05), fibrous replacement of the tunica media (more thorough in Group I, p < 0.02), and the extent of inflammatory infiltrates (more prominent in Group I, p < 0.05). CONCLUSIONS: From the scarcity of pathognomonic features in both case-history and clinical presentation, the constant coexistence of prominent atherosclerotic lesions, and the progressive trend of the pathologic features, inflammatory aneurysms may be inferred to be a variant of atherosclerotic ones, characterised by a particular prominence of inflammation and fibrosis. The frequent occurrence of dilation of both periaortic lymphatic vessels and lymph node sinuses, even in "incipient" aneurysms, supports the hypothesis that it may be the lymphatic stasis which determines periaortic fibrosis. Finally, atherosclerotic components passing into periaortic fibrosis and eliciting granulomatous reaction were observed in two Group I cases featuring prominent "inflammatory" symptoms; such a finding favours the hypothesis that an immune reaction against some components of the atherosclerotic plaque may lead to the pronounced inflammatory response that is peculiar of inflammatory aneurysms.