Victor Dayan

Human umbilical cord perivascular cells exhibit enhanced cardiomyocyte reprogramming and cardiac function after experimental acute myocardial infarction.

We were interested in evaluating the ability of the mesenchymal stromal cell (MSC) population, human umbilical cord perivascular cells (HUCPVCs), to undergo cardiomyocyte reprogramming in an established coculture system with rat embryonic cardiomyocytes. Results were compared with human bone marrow-derived (BM) MSCs. The transcription factors GATA4 and Mef 2c were expressed in HUCPVCs but not BM-MSCs at baseline and, at 7 days, increased 7.6- and 3.5-fold, respectively, compared with BM-MSCs. Although cardiac-specific gene expression increased in both cell types in coculture, upregulation was more significant in HUCPVCs, consistent with Mef 2c-GATA4 synergism. Using a lentivector with eGFP transcribed from the α-myosin heavy chain (α-MHC) promoter, we found that cardiac gene expression was greater in HUCPVCs than BM-MSCs after 14 days coculture (52 ± 17% vs. 29 ± 6%, respectively). A higher frequency of HUCPVCs expressed α-MHC protein compared with BM-MSCs (11.6 ± 0.9% vs. 5.3 ± 0.3%); however, both cell types retained MSC-associated determinants. We also assessed the ability of the MSC types to mediate cardiac regeneration in a NOD/SCID γ mouse model of acute myocardial infarction (AMI). Fourteen days after AMI, cardiac function was significantly better in cell-treated mice compared with control animals and HUCPVCs exhibited greater improvement. Although human cells persisted in the infarct area, the frequency of α-MHC expression was low. Our results indicate that HUCPVCs exhibit a greater degree of cardiomyocyte reprogramming but that differentiation for both cell types is partial. We conclude that HUCPVCs may be preferable to BM-MSCs in the cell therapy of AMI.

Human mesenchymal stromal cells improve scar thickness without enhancing cardiac function in a chronic ischaemic heart failure model

Few data address the role of human mesenchymal stromal cells (MSCs) in the management of chronic ischaemic heart failure. We assessed their effect in immune-deficient animals. MSCs were cultured from bone marrow of human volunteers. Non-obese diabetes severe combined immunodeficiency (NOD/SCID) gamma null mice were randomly assigned to intramyocardial injection of human MSCs or phosphate-buffered saline 4 weeks after induction of acute myocardial infarction (MI). Echocardiography was performed 4 weeks after MI and 1 and 4 weeks after injection. Donor cell chimerism was assessed by DNA for human Alu sequences 2 and 4 weeks after injection. Histological assessment and quantification of neovascularization were determined 4 weeks after treatment. Donor MSCs at frequencies of 0.006 and 0.001% were present 2 and 4 weeks after cell injection, respectively. The infarcted ventricular wall was significantly thicker in the cohort receiving MSCs compared with control mice. There was no difference in fractional shortening, left ventricular dimensions or scar area between the groups. Small vessel density was also similar between the groups. Human MSCs increased the thickness of the infarcted ventricular wall without improving cardiac function in this chronic ischaemic heart failure model. Further studies are required to assess the benefit of MSCs in this setting.

Risk of subsequent aortic dilatation is low in patients with bicuspid aortic valve and normal aortic root diameter at the time of aortic valve replacement

Bicuspid aortic valves (BAVs) are associated with ascending aortic aneurysms. We studied BAV patients before and after aortic valve replacement (AVR) to determine the risk and predictors of aortic root dilatation after surgery. BAV patients (n=60) with an aortic root <or=45 mm who underwent AVR were followed by echocardiography (6.2+/-2 years) and aortic root measured. No statistical difference was found between the preoperative and postoperative diameter of the aortic root as well as association with the variables studied. The use of statins or beta-blockers did not affect the follow-up on the aortic root diameter. Preoperative aortic root diameter between patients who died due to cardiovascular cause in the long-term did not vary when compared with those who survived. Even though the numbers of patients studied is low to make any kind of conclusions, our study permits us to suggest that AVR prevents aortic root dilation in BAV patients whose aortic root diameter at time of surgery was <or=45 mm.

First-degree relatives of bicuspid aortic valve patients with normal aortic dimensions do not carry an increased risk of aortic dilatation

Bicuspid aortic valve (BAV) is the most common congenital cardiac diseasewith an estimated incidence in the North American population of 1–2% [1]. Patients with BAV have a lifetime risk of 22–25% of surgery due to aortic valve disease and/or ascending aorta dilatation [1]. This has encouraged cardiac surgeons to be more aggressive in considering replacement of the ascending aorta at a lower diameter (50 mm) than in tricuspid aortic valve (TAV) patients (55 mm) [2]. Recent studies have questioned this kind of “paradigm” [3,4]. First-degree relatives (FDR) of BAV individuals are at an increased risk of inheriting a BAV (9%), or any congenital cardiac disease (31%) [5]. Recently, Biner et al. have shown that 32% of FDRs of BAV patients have dilated aorta [6]. Based on these data, guidelines recommend as class IC, echocardiographic evaluation of all FDR of patients with BAV in search of aortic dilatation and/or BAV [2]. In Biner et al.s study, BAV patients from whom FDRs were contacted had normal and pathological aorta. We hypothesized that FDRs of BAV patients with normal aortic diameter share a similar risk of aortic dilatation as FDRs of TAV patients. Patients with BAV and TAV who underwent isolated aortic valve replacement and had normal aortic dimensions were identified from the database. FDRs of these patients were contacted by phone to participate in this study. The study complies with the Declaration of Helsinki. Informed consent was obtained and the ethical review board approved the study. Echocardiographic evaluation was done entirely at the echocardiography laboratory of the Department of Cardiology of the University Hospital (Hospital de Clinicas). A single observer supervised by an expert blinded to anthropometric and clinical data of participants performed the measurements. Aortic dimensions (annulus, root, sino-tubular junction, ascending aorta) were obtained during end systole and indexed to body surface area of patients. In order to calculate the sample size needed to find differences between both groups, we used published data obtained from a sample of North American individuals [6]. Based on these data our sample size calculation estimated a total of 20 individuals per group. Continuous data were presented as mean ± standard deviation (SD) and categorical variables as percentage. Continuous variables were compared using independent t test. For comparison of categorical data among the study groups, the Fisher exact test was used. Analysis was performed using the statistical software program SPSS version 18. The significance level was set at p b 0.05. Body surface area was significantly greater in FDR of TAV patients than in BAV patients (p = 0.006). This was mainly due to a higher weight (p = 0.006) (Table 1). All evaluated patients had a normal functioning tricuspid aortic valve. No differences were found at either of the aortic segments between both groups (Fig. 1). There is no evidence regarding the risk of aortopathy in tricuspid FDR of BAV individuals with normal aortic dimensions. The only published report in the matter, documents that aortic root dilation is highly prevalent (32%) in tricuspid FDRs of BAV patients [6]. In this study [6], FDRs were derived from BAV patients in whom 53% had a dilated aorta. Our results show that FDRs of BAV and TAV patients with

Is patient–prosthesis mismatch a predictor of survival or a surrogate marker of co-morbidities in cardiac surgery?☆

BACKGROUND Patient-prosthesis mismatch (PPM) has ignited much debate and no definite conclusions have been drawn on the outcome of these patients. Therefore, additional large studies with long-term follow-up are required to help the cardiologist and surgeon outline the best therapeutic strategy for patients with high risk for PPM. METHODS Patients who underwent aortic valve replacement (AVR) from 2000 to 2013 were identified. Baseline and operative data was extracted and indexed effective orifice area calculated for each patient. The presence of PPM was defined in those patients with an iEOA ≤ 0.85 cm(2)/m(2). Regression analyses were performed to determine the association of PPM with operative mortality, post-operative complications and survival. Predictors for PPM were evaluated based on clinical and operative data. RESULTS From 2023 patients who underwent AVR, PPM was present in 64.6%. These patients had increased age, more coronary artery bypass procedures, increased risk of diabetes, hypertension, higher creatinine values and higher Euroscore. Age, body surface area, prosthesis type and size were found to be predictors of mismatch. Operative mortality (8.1% vs 5.7%, p = 0.05), stroke (3.9% vs 2.4, p = 0.02) and acute kidney injury (47.6% vs 35.1%, p =< 0 .001) were more frequent in patients with PPM and mean 10-year survival was reduced (6.6 years, 95% CI: 6.3-6.8 vs 7.3, 95% CI: 6.9-7.2, p < 0.001). After adjusting for confounders, PPM was not found to be associated to either adverse outcome or survival. CONCLUSIONS Patients with PPM have worse operative mortality, post-operative complications and survival mainly due to the fact that they represent a higher risk population based on age and co-morbidities.

Apical 4-Chamber Longitudinal Strain by Vector Velocity Imaging: A Promising Predictor of Left Ventricular Ejection Fraction in Healthy Individuals

the RAp has collapsed (it is now flat), we recommend applying a semicompressive bandage directly over it. After proximal occlusive compression of the RAp for 3 to 4 hours, we then recommend a semiocclusive compression (of the RAp and proximally) for an additional 24 hours. Due to the risk of external breakage, we recommend hospitalization for the following 24 hours. 3. If the above is ineffective, we recommend treatment with ultrasound-guided injection of thrombin (1 mL, 500 IU). 4. Surgery should be reserved for cases in which this more conservative management strategy has not been effective.

Predictors of aortic events after aortic valve replacement for bicuspid valve stenosis

We would like to congratulate the authors on their study [1]. A controversial area in cardiac surgery is addressed in a very scientific and academic way. The authors use data from stenotic bicuspid aortic valve (BAV) patients operated on from 1995 to 2000 who underwent aortic valve replacement (AVR) without ascending aorta replacement. Inclusion criteria were aortic diameter between 40 and 50 mm. This historic cohort allows the authors to evaluate long-term aortic events (15-year follow-up) and include patients with aortic diameter between 45 and 50 mm, who at that time were not included in the US guidelines for ascending aorta replacement. Adverse aortic events were experienced in 8 of 153 patients (5.3%) with a mean progression rate of 0.5 mm/patient-year. Cox-regression analysis was performed including only two preoperative variables, hypertension and ascending aorta diameter. No statistical predictors of adverse aortic events were identified. It has been previously reported that aortic dilatation in BAV patients is hereditary [2] and related to its configuration (anterior–posterior vs right–left) [3]. Our group has found body surface area (BSA) and family history of BAV and/or aortopathy to be independent predictors for aortic dilatation [4]. Have the authors taken into account these variables (BAV configuration, family history of BAV and/or aortopathy, BSA) in their regression analysis? Pharmacological treatments such as use of statins and beta-blockers have shown to be protective of aneurysmal dilatation [5, 6]. Taking into account the large cohort the authors are analysing, it would be extremely interesting to know if either is protective of adverse aortic events. Finally, we consider this study as contributing significantly to such a debated topic and therefore congratulate the authors for their endeavour.

Human mesenchymal stromal cells do not promote recurrence of soft tissue sarcomas in mouse xenografts after radiation and surgery

BACKGROUND Mesenchymal stromal cells (MSCs) promote wound healing, including after radiotherapy (RT) and surgery. The use of MSCs in regenerative medicine in the context of malignancy, such as to enhance wound healing post-RT/surgery in patients with soft tissue sarcomas (STSs), requires safety validation. The aim of this study was to determine the effects of human MSCs on STS growth in vitro and local recurrence and metastasis in vivo. METHODS Human primary STS and HT-1080 fibrosarcoma lines were transduced to express luciferase/eGFP (enhanced green fluorescent protein). Sarcoma cells were co-cultured or co-injected with bone marrow-derived MSCs for growth studies. Xenograft tumor models were established with STS lines in NOD/SCID/γcnull mice. To emulate a clinical scenario, subcutaneous tumors were treated with RT/surgery prior to MSC injection into the tumor bed. Local and distant tumor recurrence was studied using histology and bioluminescence imaging. RESULTS MSCs did not promote STS proliferation upon co-culture in vitro, which was consistent among MSCs from different donors. Co-injection of MSCs with sarcoma cells in mice exhibited no significant tumor-stimulating effect, compared with control mice injected with sarcoma cells alone. MSC administration after RT/surgery had no effect on local recurrence or metastasis of STS. DISCUSSION These studies are important for the establishment of a safety profile for MSC administration in patients with STS. Our data suggest that MSCs are safe in STS management after standard of care RT/surgery, which can be further investigated in early-phase clinical trials to also determine the efficacy of MSCs in reducing morbidity and to mitigate wound complications in these patients.

On-Pump Beating/Non-Beating CABG in Stable Angina Have Similar Outcomes

Objective On pump beating/non-beating coronary artery bypass grafts (CABG) has been compared in patients with unstable angina and/or severe left ventricular dysfunction. There is scarce evidence regarding the beneficial use of on-pump beating CABG in patients with stable angina and normal left ventricular function. Our aim was to study the postoperative results using both techniques in this group of patients. Methods One thousand one hundred and forty-five patients with stable angina underwent on-pump isolated CABG in Uruguay from 2011 to 2015. Patients were grouped into beating/non-beating CABG. Operative mortality and long-term survival were evaluated as primary outcome. Logistic regression analysis was performed to define the predictive role of aortic cross clamp (AXC) on prolonged inotropic support, ventilator support and intraoperative glycemia. Results Among the included patients, 988 underwent aortic cross clamp. No differences were found in operative mortality, stroke and long-term survival among both groups. Patients without AXC showed higher intraoperative values of glycemia and higher incidence of postoperative prolonged mechanical ventilator support (7.6% vs. 2.4%; P=0.001). The need for prolonged inotropic support was lower in this group of patients (27.4% vs. 49.5%; P<0.001). Conclusion On-pump beating CABG has similar operative mortality and long-term survival compared with conventional AXC. Higher intraoperative glycemia and higher incidence for prolonged mechanical ventilator is associated with on-pump beating CABG. On the contrary, higher incidence for prolonged inotropic support is associated with AXC. Taking these factors into consideration, both techniques are safe and allow the surgeon to choose the most comfortable option.

CABG and Preoperative use of Beta-Blockers in Patients with Stable Angina are Associated with Better Cardiovascular Survival

Objective In contrast to unstable angina, optimal therapy in patients with stable angina is debated. Our aim was to evaluate the outcomes of patients with stable angina scheduled for isolated coronary artery bypass grafts and the effect of preoperative use of beta-blockers. Overall and cardiovascular survivals were our primary outcome. Operative mortality and postoperative complications along with subgroup analysis of diabetic patients were our secondary outcomes. Methods Retrospective evaluation of patients with stable angina scheduled for isolated coronary artery bypass grafts was included. Pre- and postoperative variables were extracted from the institution database. Survival was obtained from the National Registry. Results We included 282 patients with stable angina, with a mean age of 65.6±9.5 years. 26.6% were female and 38.7% had diabetes. Three-vessel disease was present in 76.6% of patients. Previous beta-blocker treatment was evident in 69.9% of patients. 10-year overall survival in the whole population was 60.5% (95% confidence interval [CI]: 50.3-70.7%). Operative mortality during the study period was 3.5%. Patients with preoperative use of beta-blocker therapy had better overall survival (9.0 years, 95%CI: 8.6-9.5) than those without treatment (7.9 years, 95%CI: 7.1-8.8 years; P=0.048). Predictors for overall survival were: hypertension, diabetes, and age. Predictors for cardiovascular survival in diabetic patients were: beta-blocker use, gender, and age. Conclusion Coronary artery bypass grafts surgery in patients with stable angina carries low operative mortality, postoperative complications, and excellent long-term cardiovascular survival. The preoperative use of beta-blockers in diabetic patients is associated with better cardiovascular survival after coronary artery bypass grafts.