David operation: single center 10-year experience.

AIM: Aortic valve-sparing operation has been progressively widely performed for the treatment of aortic root aneurysm. Nowadays, this procedure has been proposed even in presence of a bicuspid aortic valve, severe aortic regurgitation or in primary aortic dissection repair. We present our ten-year experience focusing on mid-term echocardiographic follow-up. METHODS: Between June 2002 and February 2012, 139 patients (mean age of 61±12 years) underwent aortic valve-sparing operation with valve reimplantation. Twenty-seven patients (19%) had bicuspid aortic valve; in eighteen cases (13%) cusp motion or anatomical abnormalities concurred in determining aortic regurgitation and needed an adjunct cusp repair. A Gelweave Valsalva™ graft was implanted in all the patients. RESULTS: The mortality pre-discharge was 0.7% (1 patient). The cumulative 1-year, 5-years and 8-years survival rates were 99%, 93% and 87% respectively. Postoperative aortic regurgitation more than mild degree (>2+/4+) was the only significant risk factors for redo aortic valve surgery Freedom from reoperation due to aortic valve regurgitation was 96% at 1 year, 90% at 5 years and 86% at 8 years. When comparing freedom from reoperation in patients with bicuspid vs tricuspid aortic valve, no differences were found (P=0.31) and the rate of aortic valve reoperation was significantly higher (P<0.001) in patients who received leaflet's repair. CONCLUSION: The durability of valve reimplantation was found to be excellent in patients with tricuspid aortic valve and normal or nearly normal cusps. Cusp prolapse and complication after cusp repair turned out to be the main causes for early failure.

Clinical histopathology and ultrastructural analysis of myocardium following microwave energy ablation.

OBJECTIVE: Due to weaknesses of conventional modes for treating atrial fibrillation (AF), surgical energy ablation methods and tools to cure AF have been under rapid development. One of these methods, microwave energy, is beginning to be applied clinically. The purpose of this study was to examine histology and ultrastructure of lesions produced by microwave energy in the myocardium. METHODS: Fifteen consecutive patients underwent surgical microwave energy ablation (Microwave Ablation System with FLEX 4 probe, AFx Inc., Fremont, CA) concomitant to a valve procedure. Epicardial ablation was carried out on the beating normothermic heart prior to performing the valve procedure. Two tissue specimens (1cm(2)) were obtained from each patient; one from the lesion site (right appendage) and the other from an adjacent, non-ablated site, which was used as control. Tissue samples were fixed and stained as appropriate for histological and ultrastructural analysis. RESULTS: All ablated samples revealed observable microscopic alteration, including loss of nuclei, foci of coagulative necrosis or induced irregular bands of contraction. Ultrastructurally, ablated cells demonstrated architectural disarray, loss of contractile filaments, mitochondrial swelling and focal interruption of plasma membrane. CONCLUSIONS: Histologic appearance of lesions created by epicardial microwave energy ablation was consistent over tissue samples, although acute findings demonstrated differences from cryoablation. In most of the cases, lesions were transmural, as was demonstrated by loss of cellular viability throughout the depth of tissue specimens.

Microwave ablation of atrial fibrillation in conjunction with treatment of early postoperative massive left atrial thrombosis.

Left atrial thrombosis is a rare complication of both atrial fibrillation and mitral valve surgery. A patient with a massive atrial thrombosis associated with symptoms of severe heart failure is presented. Restoration of rhythmical ventricular contraction and, ultimately, atrial contractility is of great benefit for providing relief from symptoms and for preventing thrombus recurrence. We present an approach to surgically treat atrial fibrillation using a new microwave energy source in a patient with left atrial thrombosis who requires a mitral valve prosthesis replacement.

Left atrial epicardial ablation associated to a Bentall procedure.

Aortic coarctation is quite a common congenital disease and very often associated with other cardiac malformations. A 21-year-old patient presented to our observation with aortic coarctation, aortic valve regurgitation on a dilated aortic root and chronic atrial fibrillation. We performed a two-step operation: the aortic coarctation was treated first and 1 month later a Bentall procedure associated to an epicardial ablation was performed. Since most of the ablation was performed before aortic cross clamping, the ischemic time was only slightly increased. At 3 months follow-up the patient is still on normal sinus rhythm.

How to determine the correct placement of the retrograde cardioplegia catheter.

Besides the surgeon's experience, there is no objective method to detect whether the retrograde cannula is inserted correctly before injecting the cardioplegia and measuring the coronary sinus pressure after the aorta cross-clamp. Repositioning of the retrograde cannula once extracorporeally is not always an easy maneuver and may include the risk of venous air suction. Manual detection of the cannula's position may jeopardize the stability of an ischemic heart (Ann Thorac Surg 50(6) (1990) 882; J Cardiothorac Vasc Anesth 5(6) (1991) 646; Ann Thorac Surg 52(4) (1991) 879). Determining the retrograde cannula position avoiding unnecessary prolongation of the ischemia would allow a better protection of the heart. To our knowledge such a method has not yet been published.

Normalized diastolic properties after left ventricular assist result from reverse remodeling of chamber geometry.

BACKGROUND: Normalization of diastolic properties after left ventricular (LV) assist may result from a change in myocardial material properties, chamber size, or both. This study tested the hypothesis that reported normalization of LV diastolic properties is primarily due to remodeling of chamber geometry. METHODS AND RESULTS: Hearts were obtained at transplantation from 8 patients with dilated cardiomyopathy (DCM), 6 patients with DCM plus 33+/-5 days of LV assist, and 3 patients with no evidence of heart failure. LV assist normalized passive pressure-volume curves. Chamber dimensions decreased without a change in the ratio of radius to wall thickness. Midwall stress-stretch relations predicted from pressure-volume and dimension data were not different for DCM and LV assist hearts. Passive stress-stretch relations were measured in endocardial trabeculae and were not different for DCM and LV assist hearts. Myocyte size and collagen area fraction were unchanged at this brief duration of support. CONCLUSIONS: These findings are all consistent with the hypothesis that early normalization of diastolic properties after LV assist device support results from remodeling of chamber geometry, not from changes in tissue stiffness. These data emphasize the importance of geometry to ventricular mechanics and demonstrate that reduction of heart size does not necessarily produce a reduction in wall stress.

A comparison of consecutive off-pump versus conventional coronary artery bypass.

BACKGROUND: Coronary revascularization on the beating heart is an attractive alternative to conventional coronary artery bypass grafts (CCABG), but remains controversial. Our study compares the outcomes of consecutive patients undergoing off-pump CABG (OPCABG) with a group of similar patients undergoing consecutive CCABG. METHODS: A retrospective analysis of 268 patients who underwent elective CABG between July 1998 and July 1999 at St. Michael's Medical Center yielded 134 consecutive patients who underwent OPCABG and 134 consecutive patients who had CCABG. Patients' medical charts were reviewed for age, preoperative risk factors, operative findings, postoperative complications, and length of stay (LOS). RESULTS: The two cohorts were well matched, with similar ages (66.4 +/- 11.2 for OPCABG vs. 65.8 +/- 10 for CCABG, p = 0.66) and preoperative ejection fractions (EF) (44 +/- 13 vs. 44 +/- 12, p = 0.85). There were no hospital mortalities, and there were five conversions to cardiopulmonary bypass. The OPCABG group had a significantly shorter ICU and postoperative LOS. CONCLUSIONS: Our data suggests that a fair number of patients are potential candidates for OPCABG, the only contraindications being technical limitations or the surgeon's comfort level. Six- to twelve-month follow-up indicates that OPCABG can be performed safely with a decrease in LOS, and should be part of the surgeon's armamentarium.

Comparison of right and left ventricular responses to left ventricular assist device support in patients with severe heart failure: a primary role of mechanical unloading underlying reverse remodeling.

BACKGROUND: Left ventricular assist devices (LVAD) reverse ventricular, myocardial, and systemic abnormalities characteristic of severe heart failure (reverse remodeling). The relative contributions of hemodynamic unloading and normalized biochemical milieu to reverse remodeling are unknown. METHODS AND RESULTS: Structural and functional characteristics were measured from 53 hearts of patients undergoing transplantation without LVAD support (medical support) and 33 hearts from patients receiving a median of 46 days of LVAD support (range, 8 to 360 days). Compared with medical support alone, patients receiving LVAD support for >/=30 days had higher central venous pressures (11+/-6 versus 8+/-5 mm Hg, P=0.04), lower pulmonary artery diastolic pressures (14+/-9 versus 21+/-9 mm Hg, P=0.01), and higher cardiac outputs (5.1+/-1.6 versus 3.7+/-1.0 L/min, P<0.001). In LVAD versus transplantation hearts, V(30) (ex vivo volume yielding ventricular pressure of 30 mm Hg) was decreased in the left ventricle (LV) (179+/-75 versus 261+/-118 mL, P=0.005) but not in the right ventricle (RV) (140+/-59 versus 148+/-52 mL, P=NS). LV myocyte diameter decreased more significantly after LVAD support (17%, P=0.05) than in the RV (11%, P=NS). Compared with transplantation, LVAD support increased normalized SERCA2a content in the LV (0.51+/-0.26 versus 1.04+/-0.34, P<0.001) but not in the RV (0.48+/-34 versus 0.67+/-0.55, P=NS). Finally, LVAD support improved force-frequency relations of isolated superfused LV trabeculae (P=0.01) but not RV trabeculae. CONCLUSIONS: Reduction of hemodynamic load is a primary factor underlying several important features of reverse remodeling. These findings do not preclude a possible primary role of neurohormonal factors underlying other facets of reverse remodeling during LVAD support.

Time course of reverse remodeling of the left ventricle during support with a left ventricular assist device.

BACKGROUND: Support with a left ventricular assist device leads to normalization of left ventricular chamber geometry, regression of myocyte hypertrophy, alterations in left ventricular collagen content, and normalized expression of genes involved with excitation-contraction coupling in patients with heart failure. The objective of this study was to investigate the time course of these processes. METHODS: Passive left ventricular pressure-volume relationships were obtained from explanted hearts of 19 patients with heart failure undergoing transplantation without left ventricular assist device support, 25 patients with heart failure supported before transplantation (duration of support ranging between 8 and 155 days), and 5 normal human hearts not suitable for transplantation. Left ventricular size was indexed by the volume at which left ventricular pressure reached 30 mm Hg. Left ventricular tissue samples were probed for sarcoplasmic endoreticular calcium adenosine triphosphatase 2a expression and processed for analysis of myocyte diameter and relative myocardial collagen content. RESULTS: The volume at which left ventricular pressure reached 30 mm Hg was not significantly different between hearts without and with assist device support for less than 40 days. However, the volume at which left ventricular pressure reached 30 mm Hg in patients with assist devices supported for more than 40 days was significantly smaller than that of the hearts without assist devices but was larger than that of normal hearts. A similar pattern was observed for myocyte diameter. Sarcoplasmic endoreticular calcium adenosine triphosphatase 2a expression increased to normal levels by about 20 days of support with an assist device. Relative collagen content was significantly increased in hearts supported for more than 40 days. CONCLUSION: Maximum structural reverse remodeling by left ventricular assist devices is complete by about 40 days. Molecular reverse remodeling of sarcoplasmic endoreticular calcium adenosine triphosphatase 2a expression is quicker, being complete by about 20 days.

Chronic unloading by left ventricular assist device reverses contractile dysfunction and alters gene expression in end-stage heart failure.

BACKGROUND: Left ventricular (LV) assist devices (LVADs) can improve contractile strength and normalize characteristics of the Ca(2+) transient in myocytes isolated from failing human hearts. The purpose of the present study was to determine whether LVAD support also improves contractile strength at different frequencies of contraction (the force-frequency relationship [FFR]) of intact myocardium and alters the expression of genes encoding for proteins involved in Ca(2+) handling. METHODS AND RESULTS: The isometric FFRs of LV trabeculae isolated from 15 patients with end-stage heart failure were compared with those of 7 LVAD-supported patients and demonstrated improved contractile force at 1-Hz stimulation, with reversal of a negative FFR after LVAD implantation. In 20 failing hearts, Northern blot analysis for sarcoplasmic endoreticular Ca(2+)-ATPase subtype 2a (SERCA2a), the ryanodine receptor, and the sarcolemmal Na(+)-Ca(2+) exchanger was performed on LV tissue obtained before and after LVAD implantation. These paired data demonstrated an upregulation of all 3 genes after LVAD support. In tissue obtained from subsets of these patients, Western blot analysis was performed, and oxalate-supported Ca(2+) uptake by isolated sarcoplasmic reticular membranes was determined. Despite higher mRNA for all genes after LVAD support, only SERCA2a protein was increased. Functional significance of increased SERCA2a was confirmed by augmented Ca(2+) uptake by sarcoplasmic reticular membranes isolated from LVAD-supported hearts. CONCLUSIONS: LVAD support can improve contractile strength of intact myocardium and reverse the negative FFR associated with end-stage heart failure. The expression of genes encoding for proteins involved in Ca(2+) cycling is upregulated (reverse molecular remodeling), but only the protein content of SERCA2a is increased.

Left ventricular assist device-induced reverse ventricular remodeling.

Left ventricular assist devices provide chronic pressure and volume unloading of the dilated left ventricle in patients with end-stage heart failure. This is associated with reverse structural remodeling (normalization of the passive pressure-volume relationship), reverse molecular remodeling (increased expression of several genes involved in calcium metabolism that are down-regulated in heart failure), improved baseline contractility, and improved contractile response to increased heart rate and to beta-agonist stimulation. These findings indicate the profound degree of recovery of myocardial properties in hearts previously considered to have invincible end-stage heart failure.

Inducible nitric oxide synthase expression in smooth muscle cells and macrophages of human transplant coronary artery disease.

BACKGROUND: The inducible isoform of the nitric oxide synthase (iNOS) produces large amounts of nitric oxide in response to cytokine stimulation. Previous investigations have demonstrated iNOS expression in the setting of acute and chronic rejection in experimental cardiac transplant models. The goal of this study was to investigate whether iNOS is upregulated in human transplant coronary artery disease (TCAD), a major cause of late mortality after cardiac transplantation. METHODS AND RESULTS: We studied 15 patients with TCAD and 10 with normal coronary arteries. In situ hybridization and immunohistochemistry were used in tissue sections to localize iNOS mRNA and protein, respectively. The presence of peroxynitrite was indirectly assessed by immunostaining with an anti-nitrotyrosine antibody. Normal coronary arteries had no evidence of iNOS expression. In contrast, 30 of 36 coronary artery segments with TCAD (83%) were immunostained by the iNOS antibody. The presence of iNOS mRNA was demonstrated in these vessels by in situ hybridization. Specific cell markers identified iNOS-positive cells as neointimal macrophages and smooth muscle cells. Nitrotyrosine immunoreactivity colocalized with iNOS expression in arteries with TCAD, distributed in macrophages and smooth muscle cells. CONCLUSIONS: iNOS mRNA and protein are expressed in human arteries with TCAD, where they are associated with extensive nitration of protein tyrosines. These findings indicate that the high-output nitric oxide pathway and possibly the oxidant peroxynitrite might be involved in the process leading to the development of TCAD.

Evaluation of the antiinflammatory activity of a dual cyclooxygenase-2 selective/5-lipoxygenase inhibitor, RWJ 63556, in a canine model of inflammation.

Sterile perforated polyethylene spheres (wiffle golf balls) were implanted s.c. in beagle dogs. A local inflammatory reaction was elicited within the spheres by injecting carrageenan. Changes in leukocyte count, prostaglandin E2, thromboxane B2 and leukotriene B4 levels were monitored in fluid samples collected over a 24-hr period. Blood samples were also collected at various time points and analyzed for prostaglandin E2 and leukotriene B4 production after ex vivo calcium ionophore treatment. Effects of standard antiinflammatory agents (aspirin, indomethacin, dexamethasone, tenidap and zileuton) and newer cyclooxygenase-2 (COX-2) selective agents (nimesulide, nabumetone and SC-58125) were determined after oral administration. Ex vivo inhibition of cyclooxygenase product synthesis (prostaglandin E2, thromboxane B2) in whole blood was used as an indicator of activity for the constitutive COX-1 isoform, although inhibition of the synthesis of these mediators in the chamber exudate during an inflammatory process is believed to represent COX-2 inhibition. Treatment effects on leukotriene B4 production were also determined both ex vivo in whole blood and in the fluid. All of the compounds tested, except aspirin, inhibited leukocyte infiltration into the fluid exudate. Inhibitors that exert their effects on both isozymes of cyclooxygenase attenuate production of cyclooxygenase metabolites in both the inflammatory exudate and in peripheral blood ex vivo, although COX-2 selective inhibitors only demonstrated activity in the exudate. A 5-lipoxygenase inhibitor (zileuton), a corticosteroid (dexamethasone) and a dual COX-2 selective/5-lipoxygenase inhibitor (RWJ 63556) had similar profiles in that they all inhibited cell infiltration and eicosanoid production in the fluid and also attenuated leukotriene B4 production in both the fluid and blood.

N-(5-substituted) thiophene-2-alkylsulfonamides as potent inhibitors of 5-lipoxygenase.

Compound 4k N-[5-(4-fluoro)phenoxythien-2-yl]methanesulfonamide is representative of a new class of potent inhibitors of 5-lipoxygenase (5-LO). These versatile compounds exhibit dose-dependent inhibition of 5-LO with IC50s ranging from 20-100 nM in the rat basophilic leukemia (RBL-1) cell homogenate assay and submicromolar IC50s in both the RBL-1 and human peripheral blood leukocyte (PBL) whole cell assays. Compound 4k also showed significant anti-inflammatory activity in the adjuvant arthritic rat at an oral dose of 3 mg/kg.

Cytokine-modulating activity of tepoxalin, a new potential antirheumatic.

Tepoxalin is a new dual cyclooxygenase/5-lipoxygenase anti-inflammatory compound currently under clinical investigation. It has been shown to possess anti-inflammatory activity in a variety of animal models and more recently to inhibit IL-2 induced signal transduction. The current study was conducted to evaluate the cytokine modulating activity of tepoxalin and the role of iron in these effects. In human peripheral blood mononuclear cells (PBMC) stimulated with OKT3/PMA, tepoxalin inhibited lymphocyte proliferation with an IC50 of 6 microM. Additionally, it inhibited the production of LTB4 (IC50 = 0.5 microM) and the cytokines IL-2, IL-6 and TNF alpha (IC50 = 10-12 microM). Cytotoxicity was not demonstrated at these concentrations. Add-back experiments with either cytokines (IL-2 or IL-6), LTB4 or conditioned media failed to restore the proliferative response in the presence of tepoxalin. However, the concurrent addition of iron (in the form of ferrous or ferric chloride and other iron salts) reversed the inhibition of proliferation caused by tepoxalin. Tepoxalin also inhibits the activation of NF kappa B, a transcription factor which acts on several cytokine genes. Tepoxalin's effect on NF kappa B is also reversed by the addition of iron salts. These data suggest that the action of tepoxalin to inhibit proliferation in PBMC may be at least in part due to its ability to reduce the amount of available iron resulting in decreased activation of NF kappa B and subsequent inhibition of cytokine production.

Tepoxalin, a novel immunosuppressive agent with a different mechanism of action from cyclosporin A.

Tepoxalin, a compound previously identified as a dual cyclooxygenase/lipoxygenase (CO/LO) inhibitor, is a potent inhibitor of T cell proliferation. Comparing the suppressive effects of tepoxalin and cyclosporin A (CsA) on OKT3-, PMA-, IL-2-, and PMA+ionomycin-induced T cell proliferations revealed marked differences in the mechanism of action between the two compounds. Whereas CsA was most effective in suppressing OKT3-stimulated proliferation, tepoxalin was more potent in inhibiting PMA-, PMA+ionomycin-, and IL-2-induced proliferation. Quantitative PCR (QPCR) assays used to detect cytokine messages showed that tepoxalin blocked IL-2 mRNA transcription in PMA- and PMA+ionomycin-, but not OKT3-stimulated T cells whereas CsA was most potent in inhibiting OKT3-induced IL-2 mRNA induction in these cells. Both tepoxalin and CsA did not inhibit the expression of IL-2R; however, only tepoxalin, but not CsA, inhibited the proliferation of IL-2-dependent blasts and the transcription of IFN-gamma, an IL-2-dependent target gene. Moreover, addition of exogenous IL-2 restored OKT3-induced proliferation to CsA- but not tepoxalin-treated cells. These data suggest that tepoxalin, but not CsA, suppressed T cell proliferation by inhibiting IL-2-induced signal transduction. Consistent with these findings, tepoxalin, unlike CsA, which was most potent when added at the initiation of OKT3 stimulation, was equally active, regardless of whether it was added at the beginning or 48 h after culture initiation. The difference in mechanism of action between tepoxalin and CsA was confirmed further by the synergistic suppressive effects on T cell proliferation upon co-administration of the two compounds.