Sergio Sciacca

MicroRNA-29 in Aortic Dilation: Implications for Aneurysm Formation

Rationale: Aging represents a major risk factor for coronary artery disease and aortic aneurysm formation. MicroRNAs (miRs) have emerged as key regulators of biological processes, but their role in age-associated vascular pathologies is unknown. Objective: We aim to identify miRs in the vasculature that are regulated by age and play a role in age-induced vascular pathologies. Methods and Results: Expression profiling of aortic tissue of young versus old mice identified several age-associated miRs. Among the significantly regulated miRs, the increased expression of miR-29 family members was associated with a profound downregulation of numerous extracellular matrix (ECM) components in aortas of aged mice, suggesting that this miR family contributes to ECM loss, thereby sensitizing the aorta for aneurysm formation. Indeed, miR-29 expression was significantly induced in 2 experimental models for aortic dilation: angiotensin II-treated aged mice and genetically induced aneurysms in Fibulin-4R/R mice. More importantly, miR-29b levels were profoundly increased in biopsies of human thoracic aneurysms, obtained from patients with either bicuspid (n=79) or tricuspid aortic valves (n=30). Finally, LNA-modified antisense oligonucleotide-mediated silencing of miR-29 induced ECM expression and inhibited angiotensin II-induced dilation of the aorta in mice. Conclusion: In conclusion, miR-29-mediated downregulation of ECM proteins may sensitize the aorta to the formation of aneurysms in advanced age. Inhibition of miR-29 in vivo abrogates aortic dilation in mice, suggesting that miR-29 may represent a novel molecular target to augment matrix synthesis and maintain vascular wall structural integrity.

MicroRNA-29 in aortic dilation: implications for aneurysm formation [Molecular Medicine]

Rationale: Aging represents a major risk factor for coronary artery disease and aortic aneurysm formation. MicroRNAs (miRs) have emerged as key regulators of biological processes, but their role in age-associated vascular pathologies is unknown. Objective: We aim to identify miRs in the vasculature that are regulated by age and play a role in age-induced vascular pathologies. Methods and Results: Expression profiling of aortic tissue of young versus old mice identified several age-associated miRs. Among the significantly regulated miRs, the increased expression of miR-29 family members was associated with a profound downregulation of numerous extracellular matrix (ECM) components in aortas of aged mice, suggesting that this miR family contributes to ECM loss, thereby sensitizing the aorta for aneurysm formation. Indeed, miR-29 expression was significantly induced in 2 experimental models for aortic dilation: angiotensin II-treated aged mice and genetically induced aneurysms in Fibulin-4R/R mice. More importantly, miR-29b levels were profoundly increased in biopsies of human thoracic aneurysms, obtained from patients with either bicuspid (n=79) or tricuspid aortic valves (n=30). Finally, LNA-modified antisense oligonucleotide-mediated silencing of miR-29 induced ECM expression and inhibited angiotensin II-induced dilation of the aorta in mice. Conclusion: In conclusion, miR-29-mediated downregulation of ECM proteins may sensitize the aorta to the formation of aneurysms in advanced age. Inhibition of miR-29 in vivo abrogates aortic dilation in mice, suggesting that miR-29 may represent a novel molecular target to augment matrix synthesis and maintain vascular wall structural integrity.

Primary Graft Failure After Heart Transplantation: The Importance of Donor Pharmacological Management

BACKGROUND Primary graft failure (PGF) remains the strongest determinant of perioperative mortality after heart transplantation (HT). Donor management may play an important role in the incidence of PGF. MATERIALS AND METHODS Multivariate analysis was used to identify PGF determinants after HT. Donor and recipient data were analyzed together with preharvest management information and perioperative results. PGF was defined as the need for mechanical circulatory support immediately post-HT. RESULTS Isolated HT was performed in 54 consecutive patients from January 2006 to June 2009. PGF occurred in 11 (20%) patients. Upon univariate analysis, preoperative mean pulmonary arterial pressure was significantly higher among patients developing PGF (P=.02). The donors for PGF patients had more often been managed with high inotropic support (dopamine>10 microg/kg/min and/or alpha agonists>0.06 microg/kg/min; P=.008). In contrast, death for head trauma was more common among donors for patients who did not develop PGF (P=.02). In-hospital mortality was 13% (7/54); 71% of these deceased patients displayed PGF (5/7). Upon multivariate analysis, preharvest high donor inotropic support was the strongest determinant of PGF (P=.01, odds ratio [OR]=7.5). Donor death due to head trauma showed a protective effect against PGF (P=.03, OR=0.1). CONCLUSION PGF remains a lethal perioperative complication despite modern tools for prompt cardiac mechanical assistance. As a result of the organ shortage, many centers accept marginal hearts assuming that donor hemodynamic management shows a reduced impact on PGF. We suggest a timely evaluation of the hazards for PGF whenever high inotropic support is used, especially among donors dying for causes other than head trauma.

Anti-correlation between longevity gene SirT1 and Notch signaling in ascending aorta biopsies from patients with bicuspid aortic valve disease

About 1–2% of the population present with bicuspid aortic valves (BAV), a defect of the aortic valve resulting in the formation of two leaflets instead of three. This disease leads to an abnormal aorta, altered in strength and size, which in turn is a high risk factor for potentially lethal events such as aortic dissection and aneurysm formation. BAV is inheritable, with a demonstrated association with Notch1, a member of the Notch intercellular signaling pathway that is implicated in various cardiovascular disorders. Sirtuin 1 (SirT1) is a protein deacetylase of the sirtuin family, whose activation appears beneficial for cardiac diseases. A recent study has shown that SirT1 can limit Notch signaling in model systems of vascular growth. If a concomitant dysregulation in Notch and SirT1 signaling pathways can cause the phenotypic form of human BAV is unknown. To address this issue, we analyzed human ascending aorta biopsies from BAV and control patients obtained at the time of cardiac surgery. RNA and proteins were extracted from formalin-fixed and paraffin-embedded specimens, and quantitative real-time PCR and immunoblotting were used to determine the expression of sirtuins and members of the Notch family of proteins. We found a significant increase in SirT1 expression that correlates with a decreased expression of the Notch signaling effectors detected. We put forward the idea that an altered interaction between SirT1 and Notch signaling could participate in BAV pathogenesis and that these molecules could be used as potential clinical markers.

Donor pharmacological hemodynamic support is associated with primary graft failure in human heart transplantation

The aim of this study was to test the impact of donor and recipient characteristics on the development of primary graft failure (PGF) after heart transplantation (HT) by focusing on the donors inotropic support. Heart donors and matched recipients data were prospectively collected. Univariate and multivariate analyses were used to determine independent predictors for PGF and peri-operative mortality. The donors high inotrope requirement was defined as sustained need for dopamine exceeding 10 microg/kg/min and/or alpha agonists exceeding 0.06 microg/kg/min. PGF instead was defined as need for immediate post-HT mechanical circulatory support. Since 2006, we have performed 37 HTs. PGF occurred in six patients (16.2%). Although four patients (66.6%) were weaned off circulatory support, two of them (33.3%) died on mechanical assistance. Total in-hospital mortality was 10.8% (4/37). Upon multivariate analysis, pre-harvesting donor high inotrope dosage was the major determinant for PGF (P=0.03, OR=10.8). Given the organ shortage, many centers accepted marginal hearts assuming the donors pre-harvest hemodynamic managing has a reduced impact on PGF development. As PGF remains the most lethal postoperative complication, the hazards should be carefully considered when using pre-harvesting high inotrope infusion rates.

MicroRNA-30 mediates anti-inflammatory effects of shear stress and KLF2 via repression of angiopoietin 2

MicroRNAs are endogenously expressed small noncoding RNAs that regulate gene expression. Laminar blood flow induces atheroprotective gene expression in endothelial cells (ECs) in part by upregulating the transcription factor KLF2. Here, we identified KLF2- and flow-responsive miRs that affect gene expression in ECs. Bioinformatic assessment of mRNA expression patterns identified the miR-30-5p seed sequence to be highly enriched in mRNAs that are downregulated by KLF2. Indeed, KLF2 overexpression and shear stress stimulation in vitro and in vivo increased the expression of miR-30-5p family members. Furthermore, we identified angiopoietin 2 (Ang2) as a target of miR-30. MiR-30 overexpression reduces Ang2 levels, whereas miR-30 inhibition by LNA-antimiRs induces Ang2 expression. Consistently, miR-30 reduced basal and TNF-α-induced expression of the inflammatory cell–cell adhesion molecules E-selectin, ICAM1 and VCAM1, which was rescued by stimulation with exogenous Ang2. In summary, KLF2 and shear stress increase the expression of the miR-30-5p family which acts in an anti-inflammatory manner in ECs by impairing the expression of Ang2 and inflammatory cell–cell adhesion molecules. The upregulation of miR-30-5p family members may contribute to the atheroprotective effects of shear stress.

Extracorporeal membrane oxygenation for graft failure after heart transplantation: A multidisciplinary approach to maximize weaning rate

Objectives Primary graft failure (PGF) after heart transplantation is a detrimental complication, and carries high morbidity and mortality. The aim of this study was to analyze the results of our multidisciplinary approach in supporting patients affected with PGF after heart transplantation. Methods Out of 114 consecutive patients receiving orthotopic heart transplantation between January 2006 and July 2013, 18 (15.7%) developed PGF requiring veno-arterial extracorporeal membrane oxygenator (VA-ECMO) support. Fourteen patients were male and the mean age was 49 ± 11 years. General principles in treating the patients were based on a low dose of adrenaline (0.05 mic/kg per min) infusion; femoral intra-aortic balloon pump (13 of the 18 patients); low dose of vasoconstrictors; careful fluid balance; daily echocardiographic transesophageal monitoring. Results Mean graft recipient pulmonary vascular resistance was 3.6 ± 3.2 WU. Five patients had absolute contraindication to IABP placement. The mean left ventricle ejection fraction pre-VA-ECMO was 18.4% ± 10.2%. The mean VA-ECMO and IABP support times were 6.7 ± 3.2 and 9.2 ± 7.6 days, respectively. Mean VA-ECMO flow was 4164 ± 679 l/min. The mean left ventricle ejection fraction increased to 43.4% ± 17.7% at the end of support. Weaning and discharge rates in patients treated with VA-ECMO+IABP were 84% and 53%, respectively. Causes of death were primarily end-stage organ failure. Conclusions A multidisciplinary evaluation of ECMO patients done by intensivists, cardiologists, and surgeons may influence weaning and survival rate. Our approach seems to be a safe and reproducible strategy for avoiding left ventricle distension and fluid overload, and for detecting complications that negatively affect outcomes.

Ischemic mitral valve regurgitation in patients with depressed ventricular function: cardiac geometrical and myocardial perfusion evaluation with magnetic resonance imaging

OBJECTIVE To investigate geometrical and functional changes involving the left ventricle (LV) and mitral valve (MV) apparatus in patients with depressed LV ejection fraction (LVEF) and ischemic MV regurgitation (IMVR). METHODS A series of patients with three vessels coronary artery disease (CAD) and depressed LVEF underwent cardiac magnetic resonance imaging to investigate MV/LV geometry and function, and myocardial perfusion/vitality. Geometrical data were indexed by anterior MV leaflet length. Two groups were identified: CAD without IMVR (group CAD), and with IMVR (group IMV). RESULTS Eleven patients were enrolled in the CAD group and 13 in the IMV group. IMVR volume was significantly higher in the IMV group (24.0+/-12.0 vs 4.5+/-5.2; p<0.0001). LVEF% was comparable (IMV 34.6+/-13.0 vs CAD 31.5+/-13.0; p=ns). Indexed MV/LV geometrical variables were comparable in the two groups. Perfusion/vitality study showed inferior myocardial necrosis occurred more often in the IMV group (p=0.01). At Pearson test, MV regurgitation occurrence correlated with inferior myocardial necrosis (r=0.5; p=0.006), non-indexed systolic/diastolic annular inter-commissural diameters (r=0.4; p=0.04) and MV annular areas (r=0.4; p=0.04). Papillary muscles distance (PMD) and LV volumes inversely correlated with LVEF% (r=-0.6; p<0.05 and r=-0.8; p<0.001). At multivariable analysis, no independent determinants for IMVR were identified and LV volumes were the sole determinants for LVEF% (p<0.05). CONCLUSION In patients with depressed LVEF%, IMV cannot be explained by LV geometrical modifications alone. Although PMD, LV volumes, and LVEF% are correlated, they have no direct impact in the development of IMVR. In contrast, inferior myocardial necrosis and increased inter-commissural MV diameters may lead to deformity of MV complex and subsequent IMV.

Can learning to interpret pump messages help lead to an early diagnosis of HeartWare ventricular assist device thrombosis

Left ventricular assist device thrombosis is a detrimental complication that, if not properly diagnosed and treated, can lead to low output syndrome and death. When ongoing thrombus formation is caused by inappropriate anticoagulation, timely identification is possible, and could perhaps be the key to successful treatment.

Can multiple previous treatment-requiring rejections affect biventricular myocardial function in heart transplant recipients? A two-dimensional speckle-tracking study

a Cardiology Unit, Department for the Treatment and Study of Cardiothoracic Diseases and Cardiothoracic Transplantation, IRCCS— ISMETT (IstitutoMediterraneo per i Trapianti e Terapie ad alta Specializzazione), Via Tricomi 5, 90127 Palermo, Italy b Cardiac Surgery and Heart Transplantation Unit, Department for the Treatment and Study of Cardiothoracic Diseases and Cardiothoracic Transplantation, IRCCS— ISMETT (IstitutoMediterraneo per i Trapianti e Terapie ad alta Specializzazione), Via Tricomi 5, 90127 Palermo, Italy c Research Office, IRCCS — ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Via Tricomi 5, 90127 Palermo, Italy d University of Liege Hospital, GIGA Cardiovascular Sciences, Department of Cardiology, Heart Valve Clinic, CHU Sart Tilman, Liege, Belgium