Mario Lusini

Mid-term results after extensive vein patch reconstruction and internal mammary grafting of the diffusely diseased left anterior descending coronary artery

OBJECTIVE To analyze the results of extensive reconstruction of the left anterior descending coronary artery (LAD) by an autologous vein patch, with or without endarterectomy (EA), associated with left internal mammary artery grafting onto the patch. METHODS Between January 1994 and April 2001, among 5871 myocardial revascularizations, 83 patients (1.4%), 77 male (93%), with a mean age+/-SD of 64+/-8 years (range 44-84) underwent the above mentioned procedure. Seventy-three of them (88%) were in Canadian Cardiovascular Society (CCS) Class III or IV, and 78 (94%) had a three-vessel disease. Mean preoperative ejection fraction was 58+/-12%. Risk factors included hypertension (63%), family history (51%), hyperlipidemia (41%), smoking (38%), diabetes (19%). Mean number of anastomoses/patient was 3+/-0.6. Mean length of vein patch was 2.8+/-0.9 cm (range 2-6 cm). A total of 16% of the patients underwent associated LAD-EA (mean cardiopulmonary bypass time: 132+/-21 min; mean aortic crossclamp time: 81+/-15 min). RESULTS There was one hospital death (recurrent MI, 1.2%). Seven patients (8%) had a perioperative myocardial infarction, in three cases in the region supplied by the LAD (none after associated LAD-EA). Mean follow-up period was 47+/-20 months (range 5-90) and is 99% complete. There were five late cardiac deaths (6%). A total of 74% survivors have no symptoms, 12% are in CCS Class I-II, and 14% in III-IV. Actuarial freedom from recurrent angina at 3 and 5 years is 77 and 69%, respectively. Follow-up angiograms (49 patients, 60%) revealed a full patent LAD graft in 82% of the cases (GI), versus poor run-off/occluded graft in the remaining 18% (GII). Anginal status was significantly worse in GII patients (P<0.05). CONCLUSIONS Extended reconstruction of the LAD coronary artery increases surgical risk. The procedure however enhances the probability for a complete revascularization in patients with an unfavourable anatomical substrate, with acceptable mid-term results.

A G‐CSF functionalized scaffold for stem cells seeding: a differentiating device for cardiac purposes

Myocardial infarction and its consequences represent one of the most demanding challenges in cell therapy and regenerative medicine. Transfer of skeletal myoblasts into decompensated hearts has been performed through intramyocardial injection. However, the achievements of both cardiomyocyte differentiation and precise integration of the injected cells into the myocardial wall, in order to augment synchronized contractility and avoid potentially life‐threatening alterations in the electrical conduction of the heart, still remain a major target to be pursued. Recently, granulocytes colony‐stimulating factor (G‐CSF) fuelled the interest of researchers for its direct effect on cardiomyocytes, inhibiting both apoptosis and remodelling in the failing heart and protecting from ventricular arrhythmias through the up‐regulation of connexin 43 (Cx43). We propose a tissue engineering approach concerning the fabrication of an electrospun cardiac graft functionalized with G‐CSF, in order to provide the correct signalling sequence to orientate myoblast differentiation and exert important systemic and local effects, positively modulating the infarction microenvironment. Poly‐(l‐lactide) electrospun scaffolds were seeded with C2C12 murine skeletal myoblast for 48 hrs. Biological assays demonstrated the induction of Cx43 expression along with morphostructural changes resulting in cell elongation and appearance of cellular junctions resembling the usual cardiomyocyte arrangement at the ultrastructural level. The possibility of fabricating extracellular matrix‐mimicking scaffolds able to promote myoblast pre‐commitment towards myocardiocyte lineage and mitigate the hazardous environment of the damaged myocardium represents an interesting strategy in cardiac tissue engineering.

Heparin-releasing scaffold for stem cells: a differentiating device for vascular aims

AIMS Current limitations of tissue-engineered vascular grafts include timing for the scaffold preparation, cell type, cell differentiation and growth inside the construct, and thrombogenicity of the final device. To surmount these shortcomings, we developed a heparin-releasing poly-L-lactide (PLLA) scaffold using the electrospinning technique, to guide the differentiation of human mesenchymal stem cells towards the endothelial phenotype and to deliver a useful drug in the management of the postimplantation period. MATERIALS & METHODS The heparin-releasing PLLA scaffold was produced by means of the electrospinning technique in a tubular shape. The scaffold was seeded with human mesenchymal stem cells and cultured for up to 1 week. Cell viability and cytotoxicity assays were performed, and cell differentiation was evaluated by immunofluorescence with confocal microscopy, cytofluorometry and western blotting. Heparin release was assayed by Azure A method and biological effectiveness of the drug was assessed by activated clotting time measurements. RESULTS The scaffold exhibited a morphology favorable to cell attachment. Heparin release showed an initial burst within the first 24 h, followed by a further sustained release profile. After 48 h of culturing, the construct demonstrated adequate engraftment and viability. Increased proliferation compared with the control scaffold in bare PLLA, suggested the induction of a favorable microenvironment. A shift towards CD31 positivity and modifications in cell morphology were observed in the heparin-releasing PLLA scaffold. CONCLUSION By exploiting the biological effects of heparin, we developed an ad hoc differentiating device towards the endothelial phenotype for autologous stem cell seeding and, at the same time, we were able to facilitate and optimize the management of the construct once in clinical settings.

Serum proteomics in patients with diagnosis of abdominal aortic aneurysm

BACKGROUND Molecular mechanisms underlying abdominal aneurysm (AAA) formation and rupture are not well understood. Early detection and repair of AAA may reduce the high mortality rates associated with rupture. Serum proteomics allows the detection of alterations in the expression of proteins, guiding further studies on these target molecules as potential markers. Analysis of proteomic profile of asymptomatic patients with AAA allows the identification of reliable predictors or markers of disease presence or progression. METHODS A proteomics approach based on two-dimensional electrophoresis and mass spectrometry was used to compare serum proteomic profiles of patients with AAA who are candidates for surgical repair compared with healthy controls. We analyzed in parallel the proteomic profile of subjects with cardiac heart failure to discriminate these two pathologies, which show similar pattern of systemic inflammation process. RESULTS We identified in AAA subjects four serum proteins that show altered expression profile and that could be specifically linked to AAA pathology. We discuss the role of our identified proteins with their possible implications in disease outcome. CONCLUSIONS This approach could provide an initial screening tool that may drive the basis for further research in the field of cardiovascular diseases. These results need to be validated in larger studies to find potential markers of AAA presence or progression to use in clinical settings. SUMMARY A proteomics approach was used to compare serum proteomic profiles of patients with abdominal aortic aneurysm who are candidates for surgical repair compared with healthy controls. Four serum proteins showed altered expression profile that could be correlated with the pathology. This approach could provide an initial screening tool that may drive the basis for further research in the field of cardiovascular diseases.

Doxorubicinolone Formation and Efflux: A Salvage Pathway against Epirubicin Accumulation in Human Heart

Secondary alcohol metabolites and reactive oxygen species mediate cardiomyopathy induced by cumulative doses of antitumor anthracyclines, such as doxorubicin and epirubicin. Epirubicin exhibits a defective conversion to both toxic species, thereby inducing cardiotoxicity at doses higher than equiactive to doxorubicin; however, the gain in cardiac tolerability seems to be marginal compared with the magnitude of the metabolic defects of epirubicin. Cardiomyopathy may occur independent of toxic metabolites if a given anthracycline tends to accumulate in the heart; therefore, we characterized whether epirubicin showed an unusual accumulation in human myocardial strips incubated in plasma. Epirubicin exhibited a higher uptake and reached myocardial levels 2 times higher than those of doxorubicin. Epirubicin also showed a unique metabolization to doxorubicinolone, the product of epirubicin deglycosidation and carbonyl reduction. In diffusing from the strips to plasma, doxorubicinolone caused membrane permeation effects that augmented epirubicin elimination. Experiments with purified doxorubicinolone showed that the efflux of 1 mol doxorubicinolone promoted the concomitant elimination of as many as ∼40 mol epirubicin. Doxorubicinolone could also diffuse from plasma back to the strips, causing a permeation effect that promoted epirubicin reuptake; however, this reverse process was slower and less potent. On balance, doxorubicinolone efflux diminished the epirubicin to doxorubicin accumulation ratio to ∼1.5. These results suggest that the cardiac tolerability of epirubicin is limited by its accumulation in the heart and that such accumulation would be even higher in the absence of doxorubicinolone formation and efflux. These results may also serve guidelines for developing noncardiotoxic anthracyclines.

Advanced glycation end products in diabetic patients with optimized glycaemic control and their effects on endothelial reactivity: possible implications in venous graft failure

Diabetic patients exhibit an increased risk of saphenous graft occlusion after coronary bypass. Advanced glycation end products (AGEs) are ubiquitous signalling proteins that are associated with vascular and neurological complication of diabetes. The aim of this study is to verify whether AGE levels may promote endothelial cell alterations responsible for vein graft failure.

Aortic valve replacement in a patient with severe nickel allergy.

Abstract  Nickel allergy can raise clinical problems in patients undergoing cardiac surgery who require sternal closure with stainless steel wire. We describe the case of a 51‐year‐old woman with severe nickel allergy who underwent aortic valve replacement with a nickel‐free ON‐X prosthesis and sternal closure by Fiberwire # 2 suture without complications. Considering its biocompatibility and its mechanical characteristics including optimal strength and knot resistance, this suture might be a viable alternative in patients in which the use of stainless steel wire is contraindicated. (J Card Surg 2011;26:618‐620)

Is subvalvular repair worthwhile in severe ischemic mitral regurgitation? Subanalysis of the Papillary Muscle Approximation trial.

Objective: The symmetry of mitral valve tethering and regional left ventricle wall dysfunction are reported to play a fundamental role in the outcomes and long‐term durability of surgical repair in ischemic mitral regurgitation (IMR). We recently demonstrated in a randomized clinical trial (the Papillary Muscle Approximation trial) the superiority of papillary muscle approximation (PMA) in combination with standard restrictive annuloplasty (RA) in severe IMR over annuloplasty alone in terms of adverse left ventricular remodeling and mitral regurgitation (MR) recurrence. This approach, however, failed to produce a survival advantage and was still plagued by a high incidence of reoperation. We therefore performed a subanalysis of the PMA trial on the basis of preoperative parameters to elucidate the value of subvalvular surgery in certain subcategories of patients with the aim of creating a decisional algorithm on the best operative strategy. Methods: We performed a subanalysis of PMA trial, evaluating 96 patients with severe IMR and eligible for myocardial revascularization randomized to PMA + RA (n = 48) versus RA alone (n = 48) in association with coronary artery bypass grafting. Endpoints included left ventricular remodeling, MR recurrence, overall mortality, reoperation, and a composite cardiac endpoint (cardiac death, stroke, reintervention, hospitalization for heart failure, or New York Heart Association class worsening). Stratification variables were preoperative symmetry of mitral valve tethering and regional wall motion abnormality. Results: PMA improved ventricular remodeling and recurrence of MR in both preoperative symmetric and asymmetric tethering and in case of inferior wall dyskinesia but did not produce an additional benefit in anterolateral wall dysfunction. Conclusions: Preoperative symmetric and asymmetric tethering and isolated inferior wall dyskinesia are an indication for subvalvular apparatus surgery in IMR.

Usefulness of preprocedural levels of advanced glycation end products to predict restenosis in patients with controlled diabetes mellitus undergoing drug-eluting stent implantation for stable angina pectoris (from the prospective ARMYDA-AGEs study)

Diabetes mellitus (DM) remains the main predictor of restenosis rates and cardiovascular events following successful percutaneous coronary intervention (PCI) despite the use of drug-eluting stents (DES). HbA1c <6.0% is considered an index of optimized metabolic control in patients with DM, but several studies are downsizing its role in the clinical management of these patients. Increasing evidence points at the role of advanced glycation end products (AGEs) in restenosis pathogenesis independently on Hb1AC levels. Thus, we investigated the predictive value of preprocedural AGE levels for in-stent restenosis in a population of euglycaemic diabetic patients undergoing PCI with DES implantation. One hundred twenty-five consecutive patients with DM in optimized glycemic control admitted for stable angina pectoris and treated with elective DES implantation at a tertiary hospital were prospectively included. The primary end point of the ARMYDA-AGEs study was to compare rates of angiographic ISR at 6 months after the intervention according to pre-PCI levels of AGEs. Secondary end points were the correlations of AGE levels with occurrence of periprocedural myocardial damage, major adverse cardiac events, and in-stent late loss at 6-month control coronary angiography. AGE levels >17 μM was found to be an independent predictor of ISR at 6 months and stent lumen loss. AGEs failed to predict occurrence of secondary endpoints. In conclusion, elevated AGE levels predict occurrence of in-stent restenosis after DES implantation in patients with DM on optimized glycemic control and might represent a dosable marker of adverse outcome after PCI.

Effect of Preoperative Aspirin Replacement With Enoxaparin in Patients Undergoing Primary Isolated On-Pump Coronary Artery Bypass Grafting

Management of preoperative antiplatelet therapy in coronary artery bypass grafting (CABG) is variable among surgeons: guidelines collide with prejudices because replacement of aspirin with low-molecular-weight heparin is still performed because of a presumed minor bleeding risk. This study aims to analyze postoperative bleedings and complications in patients scheduled for elective primary isolated on-pump CABG, depending on preoperative aspirin treatment or its replacement with enoxaparin. In this cohort study, we propensity score matched 200 patients in whom aspirin was stopped at least 5 days before CABG and replaced with enoxaparin and 200 patients who continued aspirin therapy until the day before surgery. Postoperative bleedings and complications were monitored during hospitalization. Among patients who continued aspirin treatment, mean overall bleeding was 701.0 ± 334.6 ml, whereas in the matched enoxaparin group, it was significantly greater (882.6 ± 64.6 ml, p value <0.001); this was associated with reduced postoperative complications, lower values of postoperative C-reactive protein in aspirin takers, and a presumed protective effect for statins. After propensity score adjustment, aspirin treatment carried a protective effect against major postoperative bleeding (odds ratio 0.312, p = 0.001). In conclusion, postoperative bleeding is reduced in patients who continued aspirin, likely due to a reduction in postoperative inflammation. The practice of empirically discontinuing aspirin and replacing it with enoxaparin before CABG should be abandoned. Patients with coronary artery disease referred to CABG should continue antiplatelet medications until the surgical procedure. Those results might be extended to patients under oral anticoagulant therapy requiring CABG.