Giorgio M. Aru

Induction of oxidative stress by homocyst(e)ine impairs endothelial function

Previous studies have demonstrated a relationship between hyperhomocysteinemia and endothelial dysfunction, reduced bioavailability of nitric oxide, elastinolysis and, vascular muscle cell proliferation. In vivo decreased nitric oxide production is associated with increased matrix metalloproteinase (MMP) activity and formation of nitrotyrosine. To test the hypothesis that homocysteine neutralizes vascular endothelial nitric oxide, activates metalloproteinase, causes elastinolysis and vascular hypertrophy, we isolated aortas from normotensive Wistar rats and cultured them in medium containing homocysteine, and calf serum for 14 days. Homocysteine‐mediated impairment of endothelial‐dependent vasodilatation was reversed by co‐incubation of homocysteine with nicotinamide (an inhibitor of peroxinitrite and nitrotyrosine), suggesting a role of homocysteine in redox‐mediating endothelial dysfunction and nitrotyrosine formation. The Western blot analysis, using anti‐nitrotyrosine antibody, on aortic tissue homogeneates demonstrated decreased nitrotyrosine in hyperhomocysteinemic vessels treated with nicotinamide. Zymographic analysis revealed increased elastinolytic gelatinase A and B (MMP‐2, ‐9) in homocysteine treated vessels and the treatment with nicotinamide decreases the homocysteine‐induced MMP activation. Morphometric analyses revealed significant medial hypertrophic thickening (1.4 ± 0.2‐fold of control, P = 0.03) and elastin disruption in homocysteine‐treated vessels as compared to control. To determine whether homocysteine causes endothelial cell injury, cross‐sections of aortas were analyzed for caspase activity by incubating with Ac‐YVAD‐AMC (substrate for apoptotic enzyme, caspase). The endothelium of homocysteine treated vessels, and endothelial cells treated with homocysteine, showed marked labeling for caspase. The length‐tension relationship of homocysteine treated aortas was shifted to the left as compared to untreated aortas, indicating reduced vascular elastic compliance in homocysteine‐treated vessels. Co‐incubation of homocysteine and inhibitors of MMP, tissue inhibitor of metalloproteinase‐4 (TIMP‐4), and caspase, YVAD‐CHO, improved vascular function. The results suggest that alteration in vascular elastin/collagen ratio and activation of MMP‐2 are associated with decreased NO production in hyperhomocysteinemia. J. Cell. Biochem. 82:491–500, 2001.

Early induction of matrix metalloproteinase-9 transduces signaling in human heart end stage failure

Extracellular matrix (ECM) turnover is regulated by matrix metalloproteinases (MMPs) and plays an important role in cardiac remodeling. Previous studies from our lab demonstrated an increase in gelatinolytic‐MMP‐2 and ‐9 activities in endocardial tissue from ischemic cardiomyopathic (ICM) and idiopathic dilated cardiomyopathic (DCM) hearts. The signaling mechanism responsible for the left ventricular (LV) remodeling, however, is unclear. Administration of cardiac specific inhibitor of metalloproteinase (CIMP) prevented the activation of MMP‐2 and ‐9 in ailing to failing myocardium. Activation of MMP‐2 and ‐9 leads to induction of proteinase activated receptor‐1 (PAR‐1). We hypothesize that the early induction of MMP‐9 is a key regulator for modulating intracellular signaling through activation of PAR and various downstream events which are implicated in development of cardiac fibrosis in an extracellular receptor mediated kinase‐1 (ERK‐1) and focal adhesion kinase (FAK) dependent manner. To test this hypothesis, explanted human heart tissues from ICM and DCM patients were obtained at the time of orthotopic cardiac transplants. Quantitative analysis of MMP‐2 and ‐9 gelatinolytic activities was made by real‐time quantitative zymography. Gel phosphorylation staining for PAR‐1 showed a significant increase in ICM hearts. Western blot and RT‐PCR analysis and in‐situ labeling, showed significant increased expression of PAR‐1, ERK‐1and FAK in ICM and DCM. These observations suggest that the enhanced expression and potentially increased activity of LV myocardial MMP‐9 triggers the signal cascade instigating cardiac remodeling. This early mechanism for the initiation of LV remodeling appears to have a role in end‐stage human heart failure.

The Predictive Value of Left Atrial Size for Incident Ischemic Stroke and All-Cause Mortality in African Americans. The Atherosclerosis Risk in Communities (ARIC) Study

Background and Purpose— The association between left atrial (LA) size, ischemic stroke, and death has not been well established in African Americans despite their disproportionately higher rates of stroke and cardiovascular mortality compared to non-Hispanic whites. Methods— For the analysis, participants in the Jackson cohort of the Atherosclerosis Risk in Communities Study were followed from the date of the echocardiogram in cycle three to the date of the first ischemic stroke event (or death) or to December 31, 2004 if no ischemic stroke event (or death) was detected. Results— There were 1886 participants in the study population (mean age 58.9 years, 65% women). Participants in the top quintile of LA diameter indexed to height (LA diameter/height; 2.57 to 3.55 cm/m) were more likely women, hypertensive, diabetic, and obese compared to those not in the top quintile. Over a median follow-up of 9.8 years for ischemic stroke and 9.9 years for all-cause mortality, there were 106 strokes and 242 deaths. In a multivariable model adjusting for traditional clinical risk factors, the top quintile of LA diameter/height was significantly related to ischemic stroke (HR 1.7; 95% CI: 1.1, 2.7) and all-cause mortality (HR 2.0; 95% CI: 1.5, 2.7). After further adjustment for left ventricular (LV) hypertrophy and low LV ejection fraction, the top quintile remained significantly related to all-cause mortality (HR 1.8; 95% CI: 1.3, 2.5). Conclusions— In this population-based cohort of African Americans, LA size was a predictor of all-cause mortality after adjusting for traditional cardiovascular risk factors, LV hypertrophy, and low LV ejection fraction.

Regurgitant Flow of Mitral Valve Prostheses: An Intraoperative Transesophageal Echocardiographic Study

To assess the regurgitant characteristics of mitral biologic and mechanical prostheses immediately after implantation, intraoperative transesophageal echocardiography was performed in 27 patients, aged 32 to 69 years, undergoing open-heart surgery for rheumatic heart disease (n = 19), mitral valve prolapse (n = 3), malfunctioning prostheses (n = 3), or periprosthetic leaks (n = 2). The prostheses included 13 biologic (Carpentier-Edwards) and 14 mechanical valves (five Starr-Edwards, five Medtronic-Hall, and four Bjork-Shiley). Physiologic transvalvular regurgitant flow was detected in both biologic and mechanical prostheses. The spatial extent of the regurgitant jets was usually greater in the mechanical than in the biologic valves, and systolic jets, characteristic of each type of valve, were visualized consistently. Trivial periprosthetic jets (PPJs) were observed in many implanted valves (14/27). The median maximal jet area was 0.46 cm2 (range 0.1 to 1.5 cm2). Cardiopulmonary bypass was reinstituted in two patients. In one patient a PPJ was judged extensive enough (area 3.6 cm2) to warrant surgical revision of the implant, but no dehiscence was found. In the other patient a turbulent PPJ (area 5.5 cm2) was associated with a 0.5 cm dehiscence at the surgical inspection. In conclusion, (1) all mitral prostheses exhibit physiologic transvalvular regurgitation, (2) trivial mitral PPJ is a common finding in newly implanted mitral valves and does not require the revision of the implant, and (3) further experience based on larger series of patients is required to determine the maximal acceptable size of a mitral PPJ detected by intraoperative transesophageal echocardiography.

Origin of the left pulmonary artery from the aorta: embryologic considerations

We observed a case of anomalous origin of the left pulmonary artery from the aorta in which the media of the abnormal vessel and the main pulmonary artery were fused, but without communication. This is the fifth isolated case of repair without the use of cardiopulmonary bypass reported in the literature. This pathology should be included in the aortic arch anomalies as a partial or complete failure of development of the left sixth arch.

Intrathoracic Vacuum-Assisted Management of Persistent and Infected Pleural Spaces

PURPOSE This study was designed to assess the use of the intrathoracic vacuum-assisted management of persistent and infected pleural spaces. DESCRIPTION Five patients with a persistent and infected pleural space after pulmonary resection underwent intrathoracic vacuum-assisted management to reduce the duration and frequency of dressing changes and to accelerate the formation of granulation tissue and the obliteration of the pleural space. Three patients also underwent a pleural space filling procedure. EVALUATION Resolution of the infection or complete obliteration of the pleural space, or both, was in all patients achieved using fewer dressing changes than with traditional methods. No major complications related to the vacuum-assisted management were reported. CONCLUSIONS The use of intrathoracic vacuum-assisted management of a persistent and infected pleural space after lung resection may reduce the duration and frequency of dressing changes necessary to allow spontaneous chest closure or a space filling procedure. Its use may decrease patient discomfort and contribute to a faster resolution of the infectious process.

Cardiac Papillary Fibroelastoma Presents as an Acute Embolic Stroke in a 35-year-old African American Male

This is an interesting case of a young patient suffering an acute embolic stroke in the middle cerebral artery distribution, who was later found to have a papillary fibroelastoma on the mitral valve. The mass was first recognized by transesophageal echocardiography and eventually resected surgically. The retrieved specimen had classic histologic findings of a papillary fibroelastoma. A thrombus was noted on the tip of the specimen, supporting the theory that these masses are risks for strokes secondary to damage along the endothelial lining predisposing to subsequent fibrin deposition and mural thrombus formation.

Selective use of chest tubes in thoracotomies for congenital cardiovascular procedures.

BACKGROUND Advantages and complications have been reported from the use of chest tubes (CT). To reduce the incidence of complications we have employed a selective use of CT in thoracotomy for congenital cardiovascular procedure; ie, in absence of air leaks and fluid to be drained, no CT was inserted. METHODS The lung was reexpanded and air evacuated during the chest closure. Early and 6 hours chest roentgenograms were performed on every patient. This study retrospectively reviews the results of this selective approach in 546 patients operated on between 1980 and 1998 mainly for patent ductus arteriosum ligation, pulmonary artery band, aortic coarctation, Blalock-Taussig shunt. Four hundred and eighteen patients did not receive a CT at the initial surgery (group I), and 128 patients received a CT either before or at surgery (group II). RESULTS 40 patients in group I developed an air or fluid collection large enough to require a CT. Only one patient had complication, from an undetected hemothorax. Nine patients in group II required another CT, and one patient developed a pneumothorax upon pulling out the CT. No death in either group was related to the use or lack of use of the CT. A total of 378 CTs and collecting chambers were saved. CONCLUSIONS A selective approach to the use of CT in thoracotomies for cardiovascular procedures can be employed with minimal complications, more comfort for the patient, and cost savings.

Cardiac allograft rejection correlates with increased expressions of Toll-like receptors 2 and 4 and allograft inflammatory factor 1.

BACKGROUND Evidence suggests that injury-induced activation of the recipients innate immune response determines the outcome of allograft transplantation. The mechanism responsible for the induction of such innate immune response is not clear yet. We hypothesized that in cardiac transplantation settings, the initial myocardial ischemia and postischemia graft reperfusion may release allograft inflammatory factor (AIF) 1, causing Toll-like receptor (TLR)-mediated activation of macrophages and dendritic cells, leading to the production of cytokines and the activation of adaptive alloimmunity. Therefore, our goal was to validate the presence of these biomarkers in the peripheral blood and biopsy specimens of patients presenting allograft rejection. METHODS We studied 90 peripheral blood and 30 endomyocardial biopsy specimens from patients who had undergone cardiac transplantation. Specimens were tested by quantitative reverse-transcription polymerase chain reaction to determine TLR-2 and -4 and AIF-1 expression levels, correlating with clinical rejection grades. The group differences for mRNA transcript levels between the rejection grades were determined by 1-way analysis of variance. The level of significance was set at P < .05 for comparison between the groups. RESULTS The mean ± SEM level of TLR-2 mRNA expression was increased 1.7-fold in monocytes (P < .05) and 4.2-fold in biopsy samples from groups with grade 3A compared with grade 1A or grade 0 rejection (P < .0001). AIF-1 expression was increased 2.4-fold in monocytes (P < .05) and 4.2-fold in biopsy samples comparing grade 3A versus 1A rejections. The TLR-4 mRNA expression was also increased in the group with 3A rejections; however, the difference was only significant in biopsy specimens (P < .0001). CONCLUSIONS Our data demonstrated that expression profiles of AIF-1 and TLR-2 correlated with biopsy-proven allograft rejection in both peripheral blood and local tissue, suggesting their potential as diagnostic biomarkers for early detection of allograft rejection.

Electrostimulation for Intractable Delayed Emptying of Intrathoracic Stomach After Esophagectomy

PURPOSE The use of the denervated intrathoracic stomach as esophageal substitute can rarely lead to severe delayed gastric emptying. We describe the use of electrostimulation for this condition. DESCRIPTION Gastric electrical stimulation (GES) is used to treat medically refractory gastroparesis and uses a battery powered neurostimulator connected to the gastric antrum with two electrodes. We implant the electrodes through a right thoracotomy and tunnel them to the right subcostal area where the pacemaker is placed. EVALUATION Medically refractory gastroparesis developed in 2 male patients, aged 52 and 60 years, who underwent Ivor-Lewis esophagectomies for esophageal adenocarcinoma and were dependant on jejunostomy feedings. These patients initially had endoscopic placement of temporary stimulating electrodes with significant improvement in symptoms and radionucleotide gastric emptying. The patients subsequently underwent implantation of a permanent GES device. Relief of symptoms was persistent with no nausea or vomiting and a decrease of total symptom score (maximum 20) from 12.5 and 16 to 6 and 9, respectively. CONCLUSIONS Patients with intractable delayed gastric emptying after esophagogastrectomy may benefit from a GES device implanted through a thoracotomy.