Umberto Paradossi

Endothelial nitric oxide synthase gene polymorphisms and risk of coronary artery disease

BACKGROUND Endothelial nitric oxide synthase (eNOS) could be a candidate gene for coronary artery disease (CAD). This study investigated the relationship of the eNOS Glu(298)-->Asp and T(786)-->C polymorphisms with the presence and severity of CAD in the Italian population. METHODS We enrolled 415 unrelated individuals who underwent coronary angiography. The severity of CAD was expressed by means of the Duke score. The eNOS Glu(298)-->Asp and T(786)-->C variants were analyzed by PCR. RESULTS There was significant linkage disequilibrium between the two eNOS polymorphisms (P <0.0001). Both variants were significantly associated with the occurrence and severity of CAD (P = 0.01 and 0.004 for Glu(298)-->Asp and T(786)-->C, respectively). The risk of CAD was increased among individuals homozygous for the C allele of the T(786)-->C polymorphism compared with individuals homozygous for the T allele (odds ratio = 2.5; P <0.01) and was independent of the other common risk factors (P = 0.04). Moreover, individuals with both the Asp/Asp genotype of the Glu(298)-->Asp polymorphism and at least one C allele of the T(786)-->C variant in the promoter region of the eNOS gene had an increased risk of CAD (odds ratio = 4.0; P <0.001) and a significantly higher mean Duke score (26.2 +/- 2.9 vs 45.2 +/- 3.7; P = 0.002) compared with individuals with the TT genotype and the Glu allele. CONCLUSIONS The present study provides evidence that the Glu(298)-->Asp and T(786)-->C polymorphisms of the eNOS gene are associated with the presence and severity of angiographically defined CAD in the Italian population and that those individuals carrying both eNOS variants simultaneously might have a higher risk of developing CAD.

Evidence for association of a common variant of the endothelial nitric oxide synthase gene (Glu298→Asp polymorphism) to the presence, extent, and severity of coronary artery disease

Background: Genetic variants of endothelial nitric oxide synthase (eNOS) could influence individual susceptibility to coronary artery disease. Objective: To assess whether Glu298→Asp polymorphism of the eNOS gene is associated with the occurrence and severity of angiographically defined coronary artery disease in the Italian population. Methods: Polymerase chain reaction/restriction fragment length polymorphism analysis was done to detect the Glu298→Asp variant of the eNOS gene in 201 patients with coronary artery disease and 114 controls. The severity of coronary artery disease was expressed by the number of affected vessels and by the Duke scoring system. Results: The frequencies of the eNOS Glu/Glu, Glu/Asp, and Asp/Asp genotypes in the coronary artery disease group were significantly different from those of controls (45.3%, 38.8%, and 15.9% v 42.1%, 51.8%, and 6.1%, respectively; χ2 = 8.589, p = 0.0136). In comparison with subjects who had a Glu298 allele in the eNOS gene, the risk of coronary artery disease was increased among Asp/Asp carriers (odds ratio 2.9, 95% confidence interval 1.2 to 6.8, p = 0.01) and was independent of the other common risk factors (p = 0.04). There was a significant association between the eNOS Glu298→Asp variant and both the number of stenosed vessels (mean (SEM), 2.3 (0.1) for Asp/Asp v 1.9 (0.1) and 1.8 (0.1) for Glu/Glu and Glu/Asp, respectively; p = 0.01) and the Duke score (56.1 (3.1) for Asp/Asp v 46.7 (2.0) and 46.1 (1.9) for Glu/Glu and Glu/Asp, respectively; p = 0.02). Conclusions: Glu298→Asp polymorphism of the eNOS gene appears to be associated with the presence, extent, and severity of angiographically assessed coronary artery disease.

Endothelial Function and Carotid Intima-Media Thickness in Young Healthy Subjects Among Endothelial Nitric Oxide Synthase Glu298→Asp and T−786→C Polymorphisms

Background and Purpose— To assess the role of the endothelial nitric oxide synthase (eNOS) gene variants as risk factors for early atherosclerosis, we sought to investigate whether two polymorphisms located in the exon 7 (Glu298→Asp) and in the promoter region (T−786→C) of the eNOS gene were associated with functional changes in the endothelium and carotid intima-media thickness (IMT). Methods— Endothelium-dependent flow-mediated brachial artery dilation (FMD), endothelium-independent dilation response to glyceryl trinitrate (GTN), and carotid IMT were assessed by high-resolution ultrasound in 118 healthy young nonsmoker subjects (30.1±0.5 years) genotyped for the eNOS Glu298→Asp and T−786→C polymorphisms. Results— Carotid IMT was inversely related to FMD by univariate analysis (r= −0.28, P= 0.002) and after adjustment for possible confounders in all the subjects (P< 0.01). Asp homozygotes had a significantly lower FMD than Glu carriers (Glu/Glu: 15.0%±1.0%, Glu/Asp: 13.3%±0.7%, Asp/Asp: 9.6%±1.6%; P= 0.005), whereas FMD was unaffected by the T−786→C variant. Neither the Glu298→Asp nor the T−786→C polymorphisms influenced the GTN-mediated dilation. With respect to Glu carriers, Asp/Asp genotype displayed a significantly greater carotid IMT (Glu/Glu: 0.37±0.01 mm, Glu/Asp: 0.35±0.01 mm, Asp/Asp: 0.45±0.03 mm; P= 0.0002) and significant correlations between carotid IMT and FMD (r= −0.48, P= 0.04) and between carotid IMT and resting brachial artery diameter (r= 0.70, P= 0.001). No difference in IMT was found across the T−786→C genotypes. By multivariate regression analysis, Asp/Asp genotype was the only significant and independent predictor of flow-mediated brachial artery dilation (FMD) (P=0.04) and carotid intima-media thickness (IMT) (P=0.006). Conclusions— The eNOS Glu298→Asp polymorphism may be related to early atherogenesis.

Clinical utility of genetic tests for inherited hypertrophic and dilated cardiomyopathies.

Genetic testing has become an increasingly important part of medical practice for heritable form of cardiomyopathies. Hypertrophic cardiomyopathy and about 50% of idiopathic dilatative cardiomyopathy are familial diseases, with an autosomal dominant pattern of inheritance.Some genotype-phenotype correlations can provide important information to target DNA analyses in specific genes. Genetic testing may clarify diagnosis and help the optimal treatment strategies for more malignant phenotypes. In addition, genetic screening of first-degree relatives can help early identification and diagnosis of individuals at greatest risk for developing cardiomyopathy, allowing to focus clinical resources on high-risk family members.This paper provides a concise overview of the genetic etiology as well as the clinical utilities and limitations of genetic testing for the heritable cardiomyopathies.

ET-1 Lys198Asn and ETA Receptor H323H Polymorphisms in Heart Failure

Background: The endothelin (ET) system plays a central role in the control of myocardial function and its pathophysiology. The aim of the present study was to explore whether genetic variations of ET-1 (G/T substitution that predicts an Lys/Asn change at codon 198) and its receptor ETA (T/C in exon 6, H323H) could predispose carriers to heart failure (HF). Methods: Genotyping at these two loci was done in 122 patients with HF [echocardiographic left ventricular ejection fraction (LVEF) ≤40%] and 216 age-matched subjects without HF. Causes of HF included ischemic (n = 96) and idiopathic cardiomyopathies (n = 26). Results: The ET-1 Lys198Asn was significantly associated with the occurrence of HF (p = 0.005). The risk of HF was independently increased among Asn/Asn in comparison to Lys carriers (OR = 3.2, p = 0.03). Moreover, homozygous carriers of both ET-1 and ETA variants showed a marked increase in the risk of HF (adjusted OR = 8.6, p = 0.005), displayed significantly lower LVEF (p = 0.002) and higher left ventricular end-diastolic (p = 0.03) and end-systolic diameters (p = 0.04; for Asn/Asn and TT vs. Lys and C carriers of the ET-1 and ETA polymorphisms, respectively). Furthermore, the extent of coronary artery disease (r = –0.62, p < 0.0001) and the Asn/Asn and TT double genotype (r = –0.30, p = 0.0001) were the only significant and independent predictors of LVEF by multivariate analysis. Conclusions: The ET-1 Lys198Asn and ETA receptor H323H polymorphisms seem to act synergistically to increase the risk of HF.

Mitral valve repair for degenerative disease: is pericardial posterior annuloplasty a durable option?

OBJECTIVE Biological and prosthetic rings are available for supporting mitral valve repair (MVR). Contrasting data are reported on the durability of pericardial ring annuloplasty. This retrospective study was undertaken to assess the durability of MVR for degenerative regurgitation with posterior annuloplasty performed with glutaraldehyde-treated autologous pericardium. METHODS From August 1995 through December 2000, 133 patients underwent mitral repair for degenerative regurgitation (86 men, age 62.9+/-11.5 years). Thirty patients (22.6%) underwent combined coronary artery bypass graft and fourteen (10.5%) underwent tricuspid annuloplasty. Associated aortic disease, previous cardiac surgery and endocarditis were considered exclusion criteria. RESULTS Seventy-seven patients (57.9%) received a Carpentier-Edwards ring and 56 received (42.1%) an autologous pericardium ring. Thirty-day mortality was 3.8%. Mean follow-up, 98.3% complete, was of 35.6+/-18.7 months. Five-year freedom from reoperation and recurrence of mitral regurgitation> or =3+/4+ was significantly higher in the prosthetic ring group (90.1% - CL90%: 81.9-98.3%) compared with the pericardial ring group (62.6% - CL90%: 43.1-82.1%; P=0.027). Prosthetic ring implantation (P=0.004; RR=0.11) and preoperative New York Heart Association (NYHA) class< or =II (P=0.011; RR=0.16) were independently related to a lower risk of reoperation and recurrence of mitral regurgitation> or =3+/4+, by multivariate analysis. Five-year overall survival was 91.4% (CL90%: 87.9.7-95%). A higher preoperative left ventricular end-diastolic diameter (P=0.006; RR=1.17) and the severity of associated coronary artery disease (P=0.021; RR=2.00) were independent predictive factors for poor survival by multivariate analysis. CONCLUSIONS Posterior pericardial annuloplasty can jeopardize reproducibility and durability of MVR for degenerative regurgitation.

Aortic valve disease with severe ventricular dysfunction: Stentless valve for better recovery

BACKGROUND Stentless bioprostheses and homografts show better hemodynamic profiles compared with conventional stented bioprostheses and mechanical valves. Few data are available on stentless aortic valve implantation for patients with severe left ventricular dysfunction. The aim of this retrospective study was to assess the potential benefits of stentless aortic valve implantation for patients undergoing isolated aortic valve replacement with left ventricular ejection fraction < or = 35%. METHODS From November 1988 through March 2000, 53 patients (45 men and 8 women, aged 64.2 +/- 15.2 years) with a LVEF < or = 35% (mean EF, 28.7 +/- 5.4%) underwent isolated, primary aortic valve replacement for chronic aortic valve disease. Twenty patients received stentless aortic valves and 33 patients received conventional stented bioprostheses and mechanical valves. Predictive factors for LVEF recovery at echocardiographic follow-up (36.2 +/- 32.1 months) were analyzed by simple and multiple regression analysis. RESULTS There were no significant differences between groups in early and late mortality. Stentless aortic valve implantation required a longer aortic cross-clamp time (p = 0.037). The stentless aortic valve group showed a better LVEF recovery (p = 0.016). Stentless aortic valves had a larger indexed effective orifice area compared with conventional stented bioprostheses and mechanical valves (p < 0.0001). A smaller indexed effective orifice area (p = 0.0008), chronic obstructive pulmonary disease (p = 0.015), and implantation of a conventional stented bioprosthesis or mechanical valve (p = 0.016) were related to reduced LVEF recovery by univariate analysis. A larger indexed effective orifice area (p = 0.024) was an independent predictive factor for a better LVEF recovery by multivariate analysis. CONCLUSIONS Stentless aortic valve implantation for patients with severe left ventricular dysfunction, even if technically more demanding, is a safe procedure that warrants a larger indexed effective orifice area leading to an enhanced LVEF recovery.

Multimodality imaging in preoperative assessment of left atrial appendage transcatheter occlusion with the Amplatzer Cardiac Plug

AIMS Percutaneous left atrial appendage occlusion (LAAO) with the Amplatzer Cardiac Plug (ACP) emerged as a valid alternative in patients with a formal contraindication to oral anticoagulant therapy. Transoesophageal echocardiography (TEE), cardiac computed tomography angiography (CCTA), intracardiac echocardiography (ICE), and conventional cardiac angiography (CCA) are used to evaluate LAA diameters. The aim of our study was to compare pre- and intraprocedural imaging techniques in determining the correct selection of the device size, with a retrospective evaluation of the results obtained at post-procedural CCTA follow-up. METHODS AND RESULTS Between September 2009 and July 2013, 66 consecutive patients underwent to LAAO with the ACP at our institution. Preoperative LAA evaluation was realized with TEE, CCTA, ICE, and CCA. Fifty-eight (58) patients underwent to post-procedural CCTA to confirm the LAA complete exclusion, the number and extent of the residual leaks, and the positioning of the device. LAA diameters measured by CCTA correlate with the diameters obtained with CCA and ICE, but they are sized slightly larger than the others. TEE has a lower correlation with every other imaging method and a likely tendency to underestimate. The distribution of the leaks and the positioning of the device in post-procedural CCTA show no substantial differences between the devices used greater or equal to the one selected with CCTA in terms of LAA exclusion. CONCLUSION The sizing of the device decided using CCTA in the phase of maximum LAA expansion reduces the risk of high-flow leaks and device malposition due to undersizing.

The prognostic impact of objective nutritional indices in elderly patients with ST-elevation myocardial infarction undergoing primary coronary intervention.

BACKGROUND The prognostic impact of nutritional status in ST-elevation myocardial infarction (STEMI) patients is poorly understood. METHODS We used the controlling nutritional status (CONUT) score and the prognostic nutritional index (PNI) score on outcomes of 945 patients with acute STEMI undergoing primary percutaneous coronary intervention with stent. RESULTS During a median follow-up of 2years (1-3.3years, interquartile range), 56 patients (5.9%) died for all-cause of death. In the dead group, the CONUT and PNI scores were more severe than in the alive group. Elderly patients (≥71years) had nutritional indices more serious than patients <71years. In the whole population of the study, both CONUT and PNI correlated with clinical markers of poor prognosis such as brain natriuretic peptide (BNP), creatinine and liver enzymes. Kaplan-Meier curves revealed that the patients with severe CONUT but not patients with severe PNI index had the highest event rate for all-cause death, with a log-rank of p<0.001. The Cox proportional hazard analyses showed that, contrary to PNI score, the CONUT score was associated with increased risk of all-cause death for both unadjusted model and age- and sex-adjusted model, while in a full-adjusted model the best predictors were age and BNP. CONCLUSIONS In STEMI patients, the nutritional status evaluated by the CONUT score, in addition to other comorbidities, can affect the prognosis in elderly patients. These results suggest a personalized nutritional treatment as well as an accurate assessment of the appropriateness of lipid-lowering treatment after coronary revascularization.

Left atrial appendage occlusion in high-risk patients with non-valvular atrial fibrillation

Objective Percutaneous left atrial appendage (LAA) occlusion has been developed as a viable option for stroke and thromboembolism prevention in patients with non-valvular atrial fibrillation (NVAF) and at high risk for cerebral cardioembolic events. Data on device implantation and long-term follow-up from large cohorts are limited. Methods 110 consecutive patients with NVAF and contraindications to oral anticoagulants (OACs) underwent LAA occlusion procedures and achieved a longer than 1 year follow-up. All patients were enrolled in a prospective registry. Procedures were performed using the Amplatzer Cardiac Plug or Amulet guided by fluoroscopy and intracardiac echocardiography. Results Mean age of the population was 77±6 years old; 68 were men. Atrial fibrillation was paroxysmal in 20%, persistent in 15.5% and permanent in 64.5% of cases, respectively. Mean CHA2DS2-VASc and HAS-BLED scores were 4.3±1.3 and 3.4±1, respectively. Technical success (successful deployment and implantation of device) was achieved in 100% of procedures. Procedural success (technical success without major procedure-related complications) was achieved in 96.4%, with a 3.6% rate of major procedural complications (three cases of pericardial tamponade requiring drainage and one case of major bleeding). Mean follow-up was 30±12 months (264 patient-years). Annual rates for ischaemic stroke and for other thromboembolic events were respectively 2.2% and 0%, and annual rate for major bleeding was 1.1%. Conclusions Our data suggest LAA occlusion in high-risk patients with NVAF not suitable for OACs is feasible and associated with low complication rates as well as low rates of stroke and major bleeding at long-term follow-up.