Alessandro Mazzucco

Polymorphisms in the factor VII gene and the risk of myocardial infarction in patients with coronary artery disease

BACKGROUND High plasma levels of coagulation factor VII have been suggested to be predictors of death due to coronary artery disease. Since polymorphisms in the factor VII gene contribute to variations in factor VII levels, such polymorphisms may be associated with the risk of myocardial infarction, which is precipitated by thrombosis. METHODS We studied a total of 444 patients, 311 of whom had severe, angiographically documented coronary atherosclerosis. Of these 311 patients, 175 had documentation of a previous myocardial infarction. As a control group, 133 patients with normal coronary arteriograms were also included. We measured the levels of activated factor VII and assessed three polymorphisms in the factor VII gene, one involving the promoter (A1 and A2 alleles), one involving the catalytic region (R353Q), and one involving intron 7. RESULTS Each of the polymorphisms influenced factor VII levels. Patients with the A2A2 and QQ genotypes had the lowest levels of activated factor VII (66 percent and 72 percent lower, respectively, than the levels in patients with the wild-type genotypes). The frequencies of the various genotypes in the patients free of coronary artery disease were similar to those in the entire population of patients with coronary artery disease. In the latter group, there were significantly more heterozygotes and homozygotes for the A2 and Q alleles among those who had not had a myocardial infarction than among those who had had an infarction (P=0.008 for the presence of the promoter polymorphism and P=0.01 for the presence of the R353Q polymorphism by chi-square analysis). The adjusted odds ratio for myocardial infarction among the patients with the A1A2 or RQ genotype was 0.47 (95 percent confidence interval, 0.27 to 0.81). CONCLUSIONS Our findings suggest that certain factor VII genotypes have a role in protection against myocardial infarction. This may explain why some patients do not have myocardial infarction despite the presence of severe coronary atherosclerosis.

Fate of the Aortic Root Late After Ross Operation

Background—The Ross operation is an alternative to mechanical aortic valve replacement in the young. Early dilatation of the pulmonary autograft root exposed to the systemic circulation has been reported. To define the prevalence of, risk factors for, and consequences of late autograft dilatation, outcome in all consecutive patients operated since May 1994 was reviewed. Methods and Results—Ninety one patients, 77 males and 14 females, with at least 1 year of follow-up underwent cross-sectional clinical and echocardiographic examination. Age at operation was 27±10 years (range 6 to 49), and the indication was aortic regurgitation in 54 (59%) patients and bicuspid valve was present in 62 (68%). End-points of the study were freedom from autograft dilatation (root diameter >4 cm or 0.21 cm/m2), from (moderate) autograft regurgitation and from reoperation. Follow-up (4.0±1.9, range 1 to 8 years) autograft root diameters were anulus, 29±4 mm (18–39); sinus of Valsalva, 38±7 mm (24–53); sinotubular junction, 37±6 mm (23–54); and ascending aorta, 37±5 mm (27–54). Late autograft dilatation was identified in 31 (34%) patients and regurgitation in 13 (14%), 7 of whom had autograft dilatation. At 7 years, freedom from dilatation was 42±8%, freedom from regurgitation was 75±8%, and freedom from reoperation was 85±10%. Cox proportional hazard analysis identified younger age (P =0.05), preoperative sinus of Valsalva (P =0.02), root replacement technique (P =0.03), and absence of pericardial buttressing (P =0.04) as predictive of autograft dilatation, whereas female sex (P =0.002), follow-up sinus of Valsalva (P =0.003), and sinotubular junction diameter (P =0.02) as predictive of autograft regurgitation. Conclusions—Autograft dilatation is common late after the Ross procedure, particularly in younger patients, in those with preoperative aortic aneurysm, and those having root replacement without support of anulus and sinotubular junction. Bicuspid aortic valve is not a risk factor. Significant autograft valve dysfunction affects a minority of patients, but it is more prevalent in those with autograft dilatation.

Heparin-coated circuits for high-risk patients: a multicenter, prospective, randomized trial

BACKGROUND Heparin-coated circuits (HCCs) in low-risk cardiac patients who have coronary revascularization have a limited impact on postoperative outcome. In this prospective, randomized investigation, we studied high-risk patients who had cardiac operations with or without HCCs. METHODS A total of 886 patients who had cardiac operations with cardiopulmonary bypass and at least one patient-related or procedure-related risk factor were enrolled in a multicenter study. They were randomly allocated to have cardiopulmonary bypass with Duraflo II HCCs (HCC group, n = 442) or conventional circuits (control group, n = 444). Postoperative outcome was investigated with respect to the occurrence of organ dysfunction. RESULTS HCCs are associated with a shorter intensive care unit and postoperative hospital stay and with a lower rate of patients having a severely impaired clinical outcome (stay in intensive care unit for more than 5 days or death) (relative risk 0.66, p = 0.045). Lung dysfunction rate was significantly lower for the patients in HCC group affected by chronic obstructive pulmonary disease or who had mitral procedure (relative risk, respectively, 0.31, p = 0.018 and 0.05, p = 0.02). Renal dysfunction rate was significantly (p = 0.05) lower for diabetics in the HCC group (relative risk 0.28). CONCLUSIONS When HCCs were used postoperative times decreased and they had a protective effect on lung and kidney function in high-risk patients.

Risk of late reoperations in patients with acute type A aortic dissection : impact of a more radical surgical approach

OBJECTIVE To evaluate the incidence and risk factors for reoperations on the pre-isthmic aorta after repair of type A acute aortic dissection. METHODS From January 1979 to December 1996, 178 patients (125 males and 53 females with a mean age of 57 +/- 9 years) underwent emergency surgery for acute type A aortic dissection with an overall operative mortality rate of 21%. One hundred and forty-one patients (100 males and 41 females, aged 58 +/- 12 years), were discharged after successful replacement of the ascending aorta in 136 cases (96%) with extension to the transverse arch in 22 (16.2%) and associated total root or aortic valve replacement in 31 (22.8%) and 6 (4.4%) cases, respectively. Intimal tear resection and direct primary anastomosis of the aorta were performed in 5 patients (4%). Total follow-up was 690 patient-years, mean 5.1 +/- 4.1 years, with an actuarial survival rate at 5,10 and 15 years of 88%, 73% and 42%, respectively. RESULTS Nineteen patients (13%), 13 males and 6 females, aged 50 +/- 10 years, required a total of 22 reoperations with an actuarial freedom from reoperation at 5, 10 and 15 years of 94%, 64% and 35%, respectively. Initial repair consisted of replacement of the ascending aorta in 16 (84%) cases, with total root replacement in 2 (12%) and isolated aortic valve replacement in 1 (6%). Three patients (16%) were treated by intimal tear resection and direct primary anastomosis of the aorta. Mean interval between initial repair and reoperation was 5.2 +/- 3.1 years and indication to re-do surgery were severe aortic regurgitation in 2 (11%), aneurysmal evolution of the false lumen in 4 (21%) or both in 13 (68%). Extensive aortic reconstruction comprising simultaneous graft replacement of the aortic root, ascending aorta and aortic arch was necessary in 13 cases (68%), isolated replacement of the ascending aorta in 3 (16%), aortic valve in 2 (11%) and aortic arch in 1 (5%). There were 1 hospital (5%) and 2 late (11%) deaths at a mean follow-up of 2.5 +/- 2.4 years, with an actuarial survival at 5 years of 88%. Retrospective analysis of our total experience revealed that the introduction of the open distal anastomosis technique since 1990, reduced the incidence of reoperation from 11/46 (24%) to 8/95 (8.4%) (P < 0.05). However, also with this strategy 8/73 (11%) patients surviving replacement limited to the ascending aorta required reoperation versus none of the 22 patients surviving repair extended to the aortic arch. Three out of 5 (60%) patients undergoing intimal tear resection and primary anastomosis of the aorta early in our experience, required reoperation. CONCLUSIONS Management of patients with acute type A aortic dissection may include one or more surgical procedures after the initial emergency repair. Reoperations carry a low operative risk with good long-term survival and their incidence is reduced by routine open distal anastomosis and aggressive replacement of the aortic arch. Intimal tear resection and primary anastomosis of the aorta appear to be associated with increased risk of reoperation.

Reconstruction and functional analysis of altered molecular pathways in human atherosclerotic arteries

BackgroundAtherosclerosis affects aorta, coronary, carotid, and iliac arteries most frequently than any other body vessel. There may be common molecular pathways sustaining this process. Plaque presence and diffusion is revealed by circulating factors that can mediate systemic reaction leading to plaque rupture and thrombosis.ResultsWe used DNA microarrays and meta-analysis to study how the presence of calcified plaque modifies human coronary and carotid gene expression. We identified a series of potential human atherogenic genes that are integrated in functional networks involved in atherosclerosis. Caveolae and JAK/STAT pathways, and S100A9/S100A8 interacting proteins are certainly involved in the development of vascular disease. We found that the system of caveolae is directly connected with genes that respond to hormone receptors, and indirectly with the apoptosis pathway.Cytokines, chemokines and growth factors released in the blood flux were investigated in parallel. High levels of RANTES, IL-1ra, MIP-1alpha, MIP-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-17, PDGF-BB, VEGF and IFN-gamma were found in plasma of atherosclerotic patients and might also be integrated in the molecular networks underlying atherosclerotic modifications of these vessels.ConclusionThe pattern of cytokine and S100A9/S100A8 up-regulation characterizes atherosclerosis as a proinflammatory disorder. Activation of the JAK/STAT pathway is confirmed by the up-regulation of IL-6, STAT1, ISGF3G and IL10RA genes in coronary and carotid plaques. The functional network constructed in our research is an evidence of the central role of STAT protein and the caveolae system to contribute to preserve the plaque. Moreover, Cav-1 is involved in SMC differentiation and dyslipidemia confirming the importance of lipid homeostasis in the atherosclerotic phenotype.

Preservation of the aortic valve in acute type A dissection complicated by aortic regurgitation

BACKGROUND The aim of the present study was to verify the efficacy of preserving the aortic valve in patients with acute type A aortic dissection complicated by significant aortic regurgitation. METHODS From January 1979 to December 1996, 178 patients (125 males; mean age 57 +/- 9 years) underwent emergency surgery for acute type A aortic dissection, with an overall operative mortality rate of 21%. Based on a retrospective analysis of the preoperative angio- or echocardiographic findings, the 141 survivors were divided into 2 groups: Group 1 (G1) included 80 patients (57%) with no or mild aortic regurgitation, and Group 2 (G2) the remaining 61 patients with moderate-to-severe aortic regurgitation. The native aortic valve was preserved by means of a uniform technique consisting of reconstruction of the aortic root and sinotubular junction in 99 patients (70%) [68 in G1 (85%) and 31 in G2 (51%)]. Forty-two patients required aortic valve (8 patients; 6%) or total root replacement (34 patients; 24%). RESULTS At a mean follow-up of 4 +/- 3.6 years (range, 6 months to 19 years), 19 of the 99 patients with a preserved aortic valve developed moderate-to-severe aortic insufficiency [19%; 7/68 in G1 (10%) and 12/31 in G2 (39%)]. Multivariate analysis revealed that moderate-to-severe preoperative aortic valve insufficiency was a significant risk factor for development of postoperative aortic valve regurgitation (p = 0.008). Reoperation was necessary in 7 G1 patients (10%) and in 8 G2 patients (26%), with an actuarial freedom from reoperation at 5 and 10 years of 93% +/- 7% and 80% +/- 9% in G1 patients, and 81% +/- 8% and 40% +/- 15% in G2 patients (p = 0.045). CONCLUSIONS Preservation of the aortic valve and aortic root is recommended in patients with acute type A aortic dissection and absent or mild aortic insufficiency. Patients presenting with moderate-to-severe aortic regurgitation and treated conservatively present an increased risk of recurrent valvular insufficiency.

Adiponectin gene expression and adipocyte diameter: a comparison between epicardial and subcutaneous adipose tissue in men

INTRODUCTION Interest has recently focused on epicardial fat, but little is known about epicardial adipocyte size and its relation with insulin resistance and adipokines. METHODS Biopsies were collected from subcutaneous, epicardial-, and peritoneal fat from 21 males undergoing elective cardiac surgery either for coronary artery bypass grafting (n=11) or for valve replacement (n=10). We assessed epicardial adipocyte size, comparing it with that from subcutaneous fat and peritoneal fat. The adipocyte size was determined by using collagenase digestion of adipose tissue, separation of adipocytes by centrifugation, methylene blue staining of the nuclei, and measurement of the cell diameter. Patients weight, height, body mass index, waist, as well as glucose, insulin, homeostatic model assessment index, adiponectin, and leptin serum levels were determined. Adiponectin mRNA levels were determined by real-time polymerase chain reaction on subcutaneous fat and epicardial fat biopsies. RESULTS Adipocytes in epicardial fat were significantly smaller than those in subcutaneous and peritoneal fat. The adipocyte size in epicardial fat correlated positively with insulin resistance and serum leptin, and correlated negatively with serum and mRNA expression of adiponectin. Adiponectin mRNA expression in epicardial fat was significantly lower than in subcutaneous fat. Adipocyte size in epicardial fat was significantly smaller in valve-replacement patients than in coronary artery bypass graft patients. Adiponectin gene expression was lower in the latter than in the former, although not significantly. CONCLUSIONS Adipocytes in epicardial fat are smaller than those in peritoneal and subcutaneous fat. Adipocyte size, both in epicardial and in subcutaneous fat, is positively related with insulin resistance, shows negative association with local adiponectin gene expression, and is decreased in subjects with coronary artery disease. Adiponectin gene expression is significantly lower in epicardial- than in subcutaneous fat.

Comparative finite element model analysis of ascending aortic flow in bicuspid and tricuspid aortic valve.

In bicuspid aortic valve (BAV) disease, the role of genetic and hemodynamic factors influencing ascending aortic pathology is controversial. To test the effect of BAV geometry on ascending aortic flow, a finite element analysis was undertaken. A surface model of aortic root and ascending aorta was obtained from magnetic resonance images of patients with BAV and tricuspid aortic valve using segmentation facilities of the image processing code Vascular Modeling Toolkit (developed at the Mario Negri Institute). Analytical models of bicuspid (antero-posterior [AP], type 1 and latero-lateral, type 2 commissures) and tricuspid orifices were mathematically defined and turned into a volumetric mesh of linear tetrahedra for computational fluid dynamics simulations. Numerical simulations were performed with the finite element code LifeV. Flow velocity fields were assessed for four levels: aortic annulus, sinus of Valsalva, sinotubular junction, and ascending aorta. Comparison of finite element analysis of bicuspid and tricuspid aortic valve showed different blood flow velocity pattern. Flow in bicuspid configurations showed asymmetrical distribution of velocity field toward the convexity of mid-ascending aorta returning symmetrical in distal ascending aorta. On the contrary, tricuspid flow was symmetrical in each aortic segment. Comparing type 1 BAV with type 2 BAV, more pronounced recirculation zones were noticed in the latter. Finally, we found that in both BAV configurations, maximum wall shear stress is highly localized at the convex portion of the mid-ascending aorta level. Comparison between models showed asymmetrical and higher flow velocity in bicuspid models, in particular in the AP configuration. Asymmetry was more pronounced at the aortic level known to be more exposed to aneurysm formation in bicuspid patients. This supports the hypothesis that hemodynamic factors may contribute to ascending aortic pathology in this subset of patients.

Hancock versus stentless bioprostheses for aortic valve replacement in patients older than 75 years

BACKGROUND Stented aortic bioprostheses are routinely used in elderly patients. The stent, however, is obstructive and implies several hazards. Stentless aortic valves appear to be hemodynamically advantageous. However, their implantation is longer and technically more demanding, and durability is still under investigation. METHODS Between January 1993 and December 1996, 77 patients (28 men) were prospectively randomized to undergo aortic valve replacement using the Hancock valves (group A: 40 patients, 16 men; age, 77+/-3 years; body surface area, 1.7+/-0.17 m2) or a stentless bioprostheses (group B: 37 patients, 12 men; age, 76+/-2 years; body surface area, 1.7+/-0.15 m2; Biocor, 17; Toronto SPV, 20). Preoperative variables were not significantly different between the two groups. Bypass time was 123+/-46 versus 133+/-51 minutes, and aortic cross-clamp time was 83+/-26 versus 95+/-24 minutes for group A and group B, respectively (not significant). Seven patients in group A (17.5%) and 5 in group B (13.5%) had enlargement of the aortic annulus. Valve size normalized to body surface area was 13.7+/-1.5 versus 14.1+/-1.6 mm/m2 for group A and group B, respectively (not significant). Eleven patients in group A (27.5%) and 5 in group B (13.5%) had concomitant myocardial revascularization. RESULTS Overall perioperative mortality was 5% in group A (low cardiac output in 2 patients), and 8% in group B (low cardiac output in 1; major neurologic event in 2). Follow-up is 97% complete (group A, 14.5+/-10 months; group B, 18.5+/-12 months). One patient in group B died at 28 months of myocardial infarction. Actuarial survival at 12 and 24 months is 92% versus 91% and 92% versus 81% for group A and group B, respectively. At 6 months, patients in group A showed a peak transaortic gradient of 25+/-7 versus 20+/-9 mm Hg in group B. Progressive regression of left ventricular mass expressed as a percentage of preoperative value was 10.5% and 19% for group A and group B at 1 year postoperatively (not significant). CONCLUSIONS Stentless valves represent a valuable alternative to conventional prostheses in patients older than 75 years, although no great advantages with their use emerge from this study. Continued evaluation particularly with regard to evidence of left ventricular remodeling and valve degeneration in the long term is warranted.

Paclitaxel-eluting biodegradable synthetic vascular prostheses: a step towards reduction of neointima formation?

Background— Clinical small-caliber vascular prostheses are unsatisfactory. Reasons for failure are early thrombosis and late intimal hyperplasia. We thus prepared biodegradable small-caliber vascular prostheses using electrospun polycaprolactone (PCL) with slow-releasing paclitaxel (PTX), an antiproliferative drug. Methods and Results— PCL solutions containing PTX were used to prepare nonwoven nanofibre-based 2-mm ID prostheses. Mechanical morphological properties and drug loading, distribution, and release were studied in vitro. Infrarenal abdominal aortic replacement was carried out with nondrug-loaded and drug-loaded prostheses in 18 rats and followed for 6 months. Patency, stenosis, tissue reaction, and drug effect on endothelialization, vascular remodeling, and neointima formation were studied in vivo. In vitro prostheses showed controlled morphology mimicking extracellular matrix with mechanical properties similar to those of native vessels. PTX-loaded grafts with suitable mechanical properties and controlled drug-release were obtained by factorial design. In vivo, both groups showed 100% patency, no stenosis, and no aneurysmal dilatation. Endothelial coverage and cell ingrowth were significantly reduced at 3 weeks and delayed at 12 and 24 weeks in PTX grafts, but as envisioned, neointima formation was significantly reduced in these grafts at 12 weeks and delayed at 6 months. Conclusions— Biodegradable, electrospun, nanofibre, polycaprolactone prostheses are promising because in vitro they maintain their mechanical properties (regardless of PTX loading), and in vivo show good patency, reendothelialize, and remodel with autologous cells. PTX loading delays endothelialization and cellular ingrowth. Conversely, it reduces neointima formation until the end point of our study and thus may be an interesting option for small caliber vascular grafts.