Aidan Flynn

Differential left ventricular remodelling and longitudinal function distinguishes low flow from normal-flow preserved ejection fraction low-gradient severe aortic stenosis

AIMS There is uncertainty in identifying patients with severe aortic stenosis (AS) with preserved left ventricular (LV) ejection fraction, low flow, and low gradients (LFLG). Prior studies propose that these patients demonstrate significant concentric remodelling and decreased survival, while others suggest that they have features and survival similar to moderate AS. METHODS AND RESULTS We compared the clinical characteristics, echocardiographic features, and overall survival of LFLG AS patients (n = 38) to those with normal-flow, low-gradient (NFLG) severe AS (n = 75) and moderate AS (n = 70). Low-flow, low-gradient patients had the lowest end-diastolic volume index (43 vs. 54 vs. 54 mL/m², P < 0.001), highest relative wall thickness (RWT) (60 vs. 49 vs. 48%, P < 0.001), and lowest septal mitral annular displacement (1.0 vs. 1.5 vs. 1.5 cm, P < 0.001). New York Heart Association (NYHA) class III/IV symptoms were the most frequent in the LFLG group (29 vs. 11 vs. 3%, P < 0.001). Survival at 3 years was significantly lower in LFLG compared with NFLG (P = 0.006) and moderate AS (P = 0.002), but not different between NFLG and moderate AS (P = 0.49). Higher NYHA classification (HR 1.77, 95% CI 1.22-2.57), RWT > 50% (HR 3.28, 95% CI 1.33-8.1), and septal displacement <1.1 cm (HR 3.93, 95% CI 1.96-7.82) but not low flow were independent predictors of survival in Cox proportional hazards analysis. CONCLUSION Preserved ejection fraction, LFLG AS patients exhibit marked concentric remodelling and impaired longitudinal functional-features that predict their poor long-term survival. Normal-flow, low-gradient AS patients have outcomes similar to moderate AS.

UC blood-derived mesenchymal stromal cells: an overview

The UC is a readily available source of blood that may be used for analysis and treatment. Some authors suggest that within the UC blood (UCB) are cells with potential for differentiation down mesenchymal lineages. Isolation and characterization of these cells has been accomplished in some centers. Differentiation of these cells down multiple lineages has been documented. Surface marker expression and gene expression profiling has been performed, and mesenchymal stromal cells (MSC) from BM and adipose tissue have been compared with those derived from UCB. The use of UCB-derived stem cells has been investigated in pre-clinical studies. As this field is rapidly advancing, this review summarizes the current state of our knowledge of MSC derived from UCB.

Mesenchymal Stem Cell Survival in the Infarcted Heart Is Enhanced by Lentivirus Vector-Mediated Heat Shock Protein 27 Expression

Mesenchymal stem cell (MSC) therapy offers the potential to promote recovery after myocardial infarction (MI). However, therapeutic efficacy may be limited by poor survival and retention of transplanted cells. A combination of gene and cell therapy has the capacity to prevent donor cell death and augment the reparative and regenerative effects of cell transfer. The present study investigates the effect of exogenous heat shock protein 27 (Hsp27) expression in MSCs in an in vitro model of ischemia and in an in vivo rat MI model and aims to determine if this could enhance the therapeutic benefit associated with cell delivery. Hsp27 overexpression by lentivirus vector modification resulted in increased MSC survival in vitro and in vivo. Furthermore, decreased apoptosis in the infarcted tissue and improved cardiac function was observed in the Hsp27 group, enhancing the therapeutic effect of MSCs. Together, these data demonstrate that ex vivo genetic modification-specifically Hsp27 overexpression-offers the possibility of enhancing the efficacy of MSC therapy in MI.

Stem cell therapy for cardiac disease

Introduction: Cardiovascular disease is the leading cause of mortality throughout the world. Stem cell therapy offers the potential for significantly reducing the burden of this disease. Areas covered: In this review, we broadly discuss cell therapy for cardiac repair. We describe mammalian cardiac regeneration, and discuss animal models of cardiac disease. The effects of various cell therapies on cardiovascular disease are described. Particular attention is given to adult bone-marrow-derived mesenchymal stem cells. Additional cell populations that have been studied are also described. We provide suggestions of where further advances in the field will be made. We anticipate that the reader will gain a comprehensive knowledge of the context of cell therapy for cardiac disease, will be informed of recent advances, and will have an appreciation of the possible future direction of cellular therapeutics for cardiac disease. Expert opinion: There is a sound rationale behind cell therapy for cardiac repair and animal studies have shown promising results. Early clinical trials have demonstrated that cell therapy is safe, with modest therapeutic efficacy. Carefully designed future trials are required if cell therapy is to progress to mainstream therapy.

In Vivo Noninvasive Characterization of Brown Adipose Tissue Blood Flow by Contrast Ultrasound in Mice

Background—Interventions to increase brown adipose tissue (BAT) volume and activation are being extensively investigated as therapies to decrease the body weight in obese subjects. Noninvasive methods to monitor these therapies in animal models and humans are rare. We investigated whether contrast ultrasound (CU) performed in mice could detect BAT and measure its activation by monitoring BAT blood flow. After validation, CU was used to study the role of uncoupling protein 1 and nitric oxide synthases in the acute regulation of BAT blood flow. Methods and Results—Blood flow of interscapular BAT was assessed in mice (n=64) with CU by measuring the signal intensity of continuously infused contrast microbubbles. Blood flow of BAT estimated by CU was 0.5±0.1 (mean±SEM) dB/s at baseline and increased 15-fold during BAT stimulation by norepinephrine (1 µg·kg−1·min−1). Assessment of BAT blood flow using CU was correlated to that performed with fluorescent microspheres (R2=0.86, P<0.001). To evaluate whether intact BAT activation is required to increase BAT blood flow, CU was performed in uncoupling protein 1–deficient mice with impaired BAT activation. Norepinephrine infusion induced a smaller increase in BAT blood flow in uncoupling protein 1–deficient mice than in wild-type mice. Finally, we investigated whether nitric oxide synthases played a role in acute norepinephrine-induced changes of BAT blood flow. Genetic and pharmacologic inhibition of nitric oxide synthase 3 attenuated the norepinephrine-induced increase in BAT blood flow. Conclusions—These results indicate that CU can detect BAT in mice and estimate BAT blood flow in mice with functional differences in BAT.

Pretreatment of endothelial progenitor cells with osteopontin enhances cell therapy for peripheral vascular disease.

Tissue necrosis resulting from critical limb ischemia (CLI) leads to amputation in a significant number of patients. Autologous cell therapy using angiogenic cells such as endothelial progenitor cells (EPCs) holds promise as a treatment for CLI but a limitation of this treatment is that the underlying disease etiology that resulted in CLI may also contribute to dysfunction of the therapeutic EPCs. This study aimed to elucidate the mechanism of EPC dysfunction using diabetes mellitus as a model and to determine whether correction of this defect in dysfunctional EPCs ex vivo would improve the outcome after cell transplantation in the murine hind limb ischemia model. EPC dysfunction was confirmed in a homogenous population of patients with type 1 diabetes mellitus and a microarray study was preformed to identify dysregulated genes. Notably, the secreted proangiogenic protein osteopontin (OPN) was significantly downregulated in diabetic EPCs. Furthermore, OPN-deficient mice showed impaired recovery following hind limb ischemia, suggesting a critical role for OPN in postnatal neovascularization. EPCs isolated from OPN KO mice showed decreased ability to adhere to endothelial cells as well as impaired angiogenic potential. However, this dysfunction was reversed upon exposure to recombinant OPN, suggesting that OPN may act in an autocrine manner on EPCs. Indeed, exposure of OPN knockout (KO) EPCs to OPN was sufficient to induce the secretion of angiogenic proteins (IL-6, TGF-α, and FGF-α). We also demonstrated that vascular regeneration following hind limb ischemia in OPN KO mice was significantly improved upon injection of EPCs preexposed to OPN. We concluded that OPN acts in an autocrine manner on EPCs to induce the secretion of angiogenic proteins, thereby playing a critical role in EPC-mediated neovascularization. Modification of cells by exposure to OPN may improve the efficacy of autologous EPC transplantation via the enhanced secretion of angiogenic proteins.

Incremental Value of the Preoperative Echocardiogram to Predict Mortality and Major Morbidity in Coronary Artery Bypass Surgery

Background— Although echocardiography is commonly performed before coronary artery bypass surgery, there has yet to be a study examining the incremental prognostic value of a complete echocardiogram. Methods and Results— Patients undergoing isolated coronary artery bypass surgery at 2 hospitals were divided into derivation and validation cohorts. A panel of quantitative echocardiographic parameters was measured. Clinical variables were extracted from the Society of Thoracic Surgeons database. The primary outcome was in-hospital mortality or major morbidity, and the secondary outcome was long-term all-cause mortality. The derivation cohort consisted of 667 patients with a mean age of 67.2±11.1 years and 22.8% females. The following echocardiographic parameters were found to be optimal predictors of mortality or major morbidity: severe diastolic dysfunction, as evidenced by restrictive filling (odds ratio, 2.96; 95% confidence interval, 1.59-5.49), right ventricular dysfunction, as evidenced by fractional area change <35% (odds ratio, 3.03; 95% confidence interval, 1.28-7.20), or myocardial performance index >0.40 (odds ratio, 1.89; 95% confidence interval, 1.13-3.15). These results were confirmed in the validation cohort of 187 patients. When added to the Society of Thoracic Surgeons risk score, the echocardiographic parameters resulted in a net improvement in model discrimination and reclassification with a change in c-statistic from 0.68 to 0.73 and an integrated discrimination improvement of 5.9% (95% confidence interval, 2.8%-8.9%). In the Cox proportional hazards model, right ventricular dysfunction and pulmonary hypertension were independently predictive of mortality over 3.2 years of follow-up. Conclusions— Preoperative echocardiography, in particular right ventricular dysfunction and restrictive left ventricular filling, provides incremental prognostic value in identifying patients at higher risk of mortality or major morbidity after coronary artery bypass surgery.

Contrast-Enhanced Ultrasound: A Novel Noninvasive, Nonionizing Method for the Detection of Brown Adipose Tissue in Humans

BACKGROUND Brown adipose tissue (BAT) consumes glucose when it is activated by cold exposure, allowing its detection in humans by (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) with computed tomography (CT). The investigators recently described a novel noninvasive and nonionizing imaging method to assess BAT in mice using contrast-enhanced ultrasound (CEUS). Here, they report the application of this method in healthy humans. METHODS Thirteen healthy volunteers were recruited. CEUS was performed before and after cold exposure in all subjects using a continuous intravenous infusion of perflutren gas-filled lipid microbubbles and triggered imaging of the supraclavicular space. The first five subjects received microbubbles at a lower infusion rate than the subsequent eight subjects and were analyzed as a separate group. Blood flow was estimated as the product of the plateau (A) and the slope (β) of microbubble replenishment curves. All underwent (18)F-FDG PET/CT after cold exposure. RESULTS An increase in the acoustic signal was noted in the supraclavicular adipose tissue area with increasing triggering intervals in all subjects, demonstrating the presence of blood flow. The area imaged by CEUS colocalized with BAT, as detected by ¹⁸F-FDG PET/CT. In a cohort of eight subjects with an optimized CEUS protocol, CEUS-derived BAT blood flow increased with cold exposure compared with basal BAT blood flow in warm conditions (median Aβ = 3.3 AU/s [interquartile range, 0.5-5.7 AU/s] vs 1.25 AU/s [interquartile range, 0.5-2.6 AU/s]; P = .02). Of these eight subjects, five had greater than twofold increases in blood flow after cold exposure; these responders had higher BAT activity measured by (18)F-FDG PET/CT (median maximal standardized uptake value, 2.25 [interquartile range, 1.53-4.57] vs 0.51 [interquartile range, 0.47-0.73]; P = .02). CONCLUSIONS The present study demonstrates the feasibility of using CEUS as a noninvasive, nonionizing imaging modality in estimating BAT blood flow in young, healthy humans. CEUS may be a useful and scalable tool in the assessment of BAT and BAT-targeted therapies.

A comparison of the efficacy of transplantation of bone marrow-derived mesenchymal stem cells and unrestricted somatic stem cells on outcome after acute myocardial infarction

IntroductionA number of questions remain unanswered in the field of cell therapy for acute myocardial infarction, including what is the optimal cell type, and can therapeutic efficacy be enhanced by conditioning regimens. In this study, we sought to address these questions by directly comparing the effect of bone marrow-derived mesenchymal stem cells and unrestricted somatic stem cells delivered 24 hours post-myocardial infarction and by determining if the therapeutic efficacy of unrestricted somatic stem cells could be enhanced by exposing the cells to guiding factors before cell transplantation.MethodsUnrestricted somatic stem cells were guided by exposure to 50 ng/mL basic fibroblast growth factor, 20 ng/mL hepatocyte growth factor and 20 ng/mL bone morphogenetic protein-2 for 24 hours. Using a Sprague-Dawley rat model of acute myocardial infarction, we transplanted cells by intramyocardial injection 24 hours post-myocardial infarction. Cardiac function was serially measured using echocardiography, and histological analyses of infarct morphology, angiogenesis and apoptosis were obtained. Transcriptomic and proteomic changes were assessed using microarray and real-time quantitative PCR.ResultsWhen assessed 28 days after the myocardial infarction, the delivery of mesenchymal stem cells 24 hours post-myocardial infarction did not improve ejection fraction (P = 0.19), and did not prevent the decline in ejection fraction observed in the absence of cell therapy (P = 0.17). The administration of unrestricted somatic stem cells also did not improve ejection fraction (P = 0.11), but did prevent a further decline in ejection fraction (P = 0.001). Delivery of guided unrestricted somatic stem cells significantly improved ejection fraction (P = 0.03). Guided unrestricted somatic stem cells restored function to a greater extent than mesenchymal stem cells (P = 0.03). The infarct area (P = 0.2), apoptosis (P = 0.07) and angiogenesis (P = 0.09) did not differ between groups. Microarray analysis revealed that, following pre-implantation guiding, the gene groupings of mitosis, signalling and angiogenesis were highly overrepresented, mediators of apoptosis were overrepresented, and cardiomyocyte-associated genes were not differentially expressed.ConclusionsThese results suggest that guided unrestricted somatic stem cells have a moderate capacity to repair cardiac damage and that they are more effective than mesenchymal stem cells in restoring cardiac function after a myocardial infarction. The mechanism of the benefit was not fully elucidated in this study, but these observations may be mediated by favorable dysregulation of angiogenic and apoptotic gene groupings.

Usefulness of right ventricular dysfunction to predict new-onset atrial fibrillation following coronary artery bypass grafting.

Postoperative atrial fibrillation (AF) is a serious yet common complication after coronary artery bypass grafting (CABG) surgery. Risk factors for postoperative AF have been identified, including echocardiographic parameters, and these are relied on to implement preventative strategies that reduce the incidence of AF. There has yet to be a study examining the impact of echocardiographic right-sided cardiac parameters on the prediction of postoperative AF. Thus, a panel of right-sided cardiac parameters was measured in a cohort of patients undergoing isolated CABG surgery, excluding those who did not have echocardiographic assessment within 30 days before surgery and those with any history of AF. The primary outcome was postoperative AF defined as any episode of AF requiring treatment during the index hospitalization. Postoperative AF occurred in 197 of 768 patients (25.6%); these were older and more likely to have hypertension and chronic kidney disease. After adjustment for clinical and echocardiographic variables, left atrial volume index ≥34 ml/m(2) (odds ratio [OR] 1.98, 95% confidence interval [CI] 1.36 to 2.87), abnormal right ventricular myocardial performance index (OR 1.50, 95% CI 1.01 to 2.24), and advancing age (OR 1.05, 95% CI 1.03 to 1.07) were found to be independent predictors of postoperative AF. In conclusion, right ventricular myocardial performance index is a novel predictor of postoperative AF in patients undergoing isolated CABG surgery and appears to be additive to established risk factors such as age and left atrial volume.