Significant Improvement In Ejection Fraction Research Articles

Abstract 165: Chronic Ethanol Consumption Impacts Post-Myocardial Infarction Cardiac Function and Modulates Gene Expression in Cardiac Cell Types through Alteration of Histone 3 Lysine 79 Methylation

The beliefs surrounding the cardiac effects of chronic ethanol (EtOH) consumption in humans are known to be dictated by the frequency of ingestion. Studies have established that moderate consumption (i.e. 1-2 drinks/day) imparts a cardiac benefit to patients by reducing the frequency of adverse cardiovascular events (ACE). EtOH consumption beyond moderate levels (i.e. >2 drinks per day) is associated with a significant increase in ACEs. Despite this knowledge, little is known regarding the functional impact of chronic EtOH consumption on post-myocardial infarct repair or the cellular mechanisms involved in this process. Therefore, we investigated the post-AMI functional consequences of chronic ethanol consumption in mice. Mice received chronic ethanol via the Lieber-DeCarli paradigm and each group of mice received either: 0%, 1% (moderate) or 5% (high) ethanol v/v in an isocaloric fashion for 8 weeks. After 8 weeks, mice then underwent a 60 minute ischemic/reperfusion injury and the subsequent assessment of their cardiac function at 1, 2 and 4 weeks after AMI. As early as two weeks post-AMI, mice fed the 1% EtOH displayed significant improvements in ejection fraction, systolic ventricular volumes and infarct size as compared to control mice. Conversely, mice that consumed the 5% EtOH diet displayed diminished ejection fraction and increased systolic chamber volume and infarct size. To investigate the mechanistic basis behind these changes, isolated murine cardiac fibroblasts (CFBs) were exposed to EtOH using a “chronic” 5 day treatment paradigm in which media ± EtOH was replaced daily. CFB lysates were then harvested and several epigenetic histone marks were assessed via western blotting. Specifically, methylation of histone 3 lysine 79 (H3K79) was significantly increased at the moderate dose (0.1% v/v) and severely diminished at the high dose (0.5% v/v). H3K79 is exclusively methylated by the methyl-transferase Dot1, suggesting that chronic ethanol may have biphasic dose effects on the regulation of genes influenced by H3K79 methylation. This data represents the first indication that chronic EtOH may affect cells of the post-ischemic heart by influencing their gene expression profiles through manipulation of their epigenetic fingerprint.

Simvastatin treatment inhibits hypoxia inducible factor 1-alpha-(HIF-1alpha)-prolyl-4-hydroxylase 3 (PHD-3) and increases angiogenesis after myocardial infarction in streptozotocin-induced diabetic rat

Statins (HMG-CoA reductase inhibitors), are known to improve cardiac function in diabetes-induced cardiovascular disease. We investigated the mechanism by which statins ameliorate cardiac function after myocardial infarction (MI). Simvastatin (S) increased tube formation and migration of HUVEC in vitro. We examined the role of simvastatin on cardiac function in streptozotocin (STZ) induced diabetic rats subjected to MI. Rats were randomly assigned to 1) Control (non-diabetic) Sham (CS); 2) Control (non-diabetic) MI (CMI); 3) Control Statin treated Sham (CSS); 4) Control Statin treated MI (CSMI); 5) Diabetic Sham (DS); 6) Diabetic MI (DMI); 7) Diabetic Statin treated Sham (DSS); 8) Diabetic Statin treated MI (DSMI). Two weeks after STZ/saline injection Simvastatin (1mg/kg.b.wt) was gavaged for 15 days (d). MI was induced 30 d after treatment by permanent LAD ligation. The S treated MI groups exhibited increased arteriolar density (23 ± 0.6 vs. 14.8 ± 0.4 counts/mm(2), DSMI vs. DMI) and reduced fibrosis at 30 d post-MI. VEGF measurement by ELISA after 4d post-MI showed increased expression in DSMI group compared to DMI group. Western blot analysis showed decreased Prolyl-4-Hydroxylase 3 (PHD-3) in DSMI group as compared to DMI group. Echocardiographic analysis 4 weeks after post-MI showed significant improvement in ejection fraction (50.11 ± 1.83 vs. 32.46 ± 2.19%; DSMI vs. DMI) and fractional shortening (26.77 ± 1.12 vs.16.36 ± 1.22%; DSMI vs. DMI) in both statin-treated MI groups regardless of diabetic status. These results suggest that statin therapy mitigates impairment of angiogenesis and myocardial dysfunction following MI in the diabetic rat through PHD3 inhibition.

Effect of coenzyme Q10 supplementation on heart failure: a meta-analysis

Coenzyme Q₁₀ (CoQ₁₀; also called ubiquinone) is an antioxidant that has been postulated to improve functional status in congestive heart failure (CHF). Several randomized controlled trials have examined the effects of CoQ₁₀ on CHF with inconclusive results. The objective of this meta-analysis was to evaluate the impact of CoQ₁₀ supplementation on the ejection fraction (EF) and New York Heart Association (NYHA) functional classification in patients with CHF. A systematic review of the literature was conducted by using databases including MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and manual examination of references from selected studies. Studies included were randomized controlled trials of CoQ₁₀ supplementation that reported the EF or NYHA functional class as a primary outcome. Information on participant characteristics, trial design and duration, treatment, dose, control, EF, and NYHA classification were extracted by using a standardized protocol. Supplementation with CoQ₁₀ resulted in a pooled mean net change of 3.67% (95% CI: 1.60%, 5.74%) in the EF and -0.30 (95% CI: -0.66, 0.06) in the NYHA functional class. Subgroup analyses showed significant improvement in EF for crossover trials, trials with treatment duration ≤12 wk in length, studies published before 1994, and studies with a dose ≤100 mg CoQ₁₀/d and in patients with less severe CHF. These subgroup analyses should be interpreted cautiously because of the small number of studies and patients included in each subgroup. Pooled analyses of available randomized controlled trials suggest that CoQ₁₀ may improve the EF in patients with CHF. Additional well-designed studies that include more diverse populations are needed.

Wharton’s Jelly or Bone Marrow Mesenchymal Stromal Cells Improve Cardiac Function Following Myocardial Infarction for More Than 32 Weeks in a Rat Model: A Preliminary Report

The therapeutic effect of mesenchymal stromal cells (MSCs) following myocardial infarction (MI) is small. This may be due to differences in cellular sources and donor age, route of administration, in vitro cellular manipulations and the short time course of follow up in many animal studies. Here, we compared MSCs from two different sources (adult bone marrow or Wharton's jelly from umbilical cord) for their long-term therapeutic effect following MI in a rat model to evaluate the effect of donor age. MSCs (or control infusions) were given intravenously 24-48 hr after myocardial ischemia (MI) induced by coronary artery ligation. Cardiac function was assessed by ultrasound at time points starting from before MSC infusion through 68 weeks after MI. A significant improvement in ejection fraction was seen in animals that received MSCs in time points 25 to 31 wks after treatment (p < 0.01). These results support previous work that show that MSCs can cause improvement in cardiac function and extend that work by showing that the beneficial effects are durable. To investigate MSCs' cardiac differentiation potential, Wharton's jelly MSCs were co-cultured with fetal or adult bone-derived marrow MSCs. When Wharton's jelly MSCs were co-cultured with fetal MSCs, and not with adult MSCs, myotube structures were observed in two-three days and spontaneous contractions (beating) cells were observed in fiveseven days. The beating structures formed a functional syncytium indicated by coordinated contractions (beating) of independent nodes. Taken together, these results suggest that MSCs given 24-48 hr after MI have a significant and durable beneficial effect more than 25 weeks after MI and that MSC treatment can home to damaged tissue and improve heart function after intravenous infusion 24-48 hrs after MI, and that WJCs may be a useful source for off-the-shelf cellular therapy for MI.

Basic Science of Cardiac Resynchronization Therapy

Electromechanical dyssynchrony can markedly worsen heart failure (HF) morbidity and mortality, independent of traditional risk factors.1–4 Depending on the metric used, current estimates of the prevalence of dyssynchrony vary from 25–30% in patients with HF (based on QRS widening) up to 60%, based on tissue Doppler or MRI measures of dyssynchronous contraction of the left ventricle (LV).5,6 Cardiac resynchronization therapy (CRT) or biventricular pacing has emerged as a promising option to treat patients with HF and dyssynchronous contraction.7–9 The past few decades have seen the rise of pharmacotherapy, primarily through agents that antagonize the effect of excessive concentrations of circulating neurohormones, yet, HF-related morbidity and mortality remain high.3–6 Biventricular stimulation has been demonstrated to improve contractile performance in patients with mechanical dyssynchrony acutely and chronically while also prolonging long-term survival—something not yet achieved by drug therapy.10 Although the clinical and mechanical effectiveness of CRT are well described, 30% of patients do not benefit from CRT and clinical criteria to identify CRT nonresponders remain elusive8,11,12 Currently, the most widely used predictor of reverse remodeling is the presence of marked mechanical dyssynchrony before CRT, as indexed by the width of the QRS.13 Mechanical dyssynchrony seems important, yet imaging-based measures have not predicted response well14 and even improvement in dyssynchrony after initiation of CRT only weakly predicts chronic response.15 Limited understanding of the molecular mechanisms underlying reverse cardiac remodeling induced by CRT has hampered the selection of potential responders. In this review, we focus on the electrophysiological aspects and molecular networks underlying the benefits of CRT. We will review how CRT homogenizes regional differences in stress kinase signaling and electric remodeling and then review its global effect on myocyte function and its …

Evaluation of Multimeric Tyrosine-O-Sulfate as a Cytoprotectant in an in vivo Model of Acute Myocardial Infarction in Pigs

Objectives: Intracoronary administration of glycosaminoglycan analogs, including the complement inhibitor dextran sulfate, attenuates myocardial ischemia/reperfusion injury (I/R injury). However, dextran sulfate has a distinct anticoagulatory effect, possibly limiting its use in specific situations in vivo. We therefore developed multimeric tyrosine sulfate (sTyr-PAA), a novel, minimally anticoagulatory, fully synthetic non-carbohydrate-containing polyacrylamide conjugate, for in vivo testing in an acute closed-chest porcine model of acute myocardial infarction. Methods: Following balloon occlusion of the left anterior descending artery just after the first diagonal branch (60-minute ischemia), sTyr-PAA (approx. 10 mg/kg bodyweight, fraction with strongest complement-inhibitory and minimal anticoagulatory properties, n = 11) or phosphate-buffered saline (controls, n = 9) was administered intracoronarily into ischemic myocardium prior to 120 min of reperfusion. Results: sTyr-PAA significantly reduced infarct size (from 61.0 ± 12.0% of the ischemic area at risk to 39.4 ± 17.0%), plasma creatine kinase, local complement deposition and tissue factor upregulation, without affecting systemic coagulation. Protection was associated with significantly reduced myocardial neutrophil extravasation and translated into a significant improvement of ejection fraction and left ventricular enddiastolic pressure. Conclusions: sTyr-PAA protected significantly against myocardial I/R injury without substantially affecting systemic coagulation. Local intravascular sTyr-PAA administration may prove advantageous in situations where bleeding complications are likely or are to be avoided at all costs.

Atrioventricular Nodal Ablation in Atrial Fibrillation

Background— In the treatment of patients with refractory atrial fibrillation (AF), the safety and efficacy of atrioventricular nodal ablation (AVNA) versus pharmacotherapy alone remains unclear. Additionally, the impact of AVNA in patients with reduced systolic function is of growing interest. Methods and Results— A total of 5 randomized or prospective trials were included for efficacy review (314 patients), 11 studies for effectiveness review (810 patients), and 47 studies for safety review (5632 patients). All-cause mortality was similar between AVNA and medical therapy (3.1% versus 3.3%; relative risk ratio, 1.05; 95% confidence interval [CI], 0.29–3.85). There was no significant difference in exercise duration or ejection fraction (EF) with AVNA relative to pharmacotherapy. In subgroup analysis, patients with baseline systolic dysfunction (116 patients; mean EF, 44%) showed significant relative improvement in EF after AVNA (+4% greater; 95% CI, 3.11–4.89). In pooled observational analysis, AVNA was also associated with significant improvement in EF only in patients with systolic dysfunction (+7.44%; 95% CI, 5.4–9.5). The incidence of procedure-related mortality (0.27%) and malignant arrhythmia (0.57%) was low. At mean follow-up of 26.5 months, the incidence of sudden cardiac death after AVNA was 2.1%. There was significant heterogeneity in quality-of-life scales used; compared with pharmacotherapy, AVNA was associated with significant improvement in several symptoms (palpitations, dyspnea). Conclusions— In the management of refractory AF, AVNA is associated with improvement in symptoms and quality of life, with a low incidence of procedure morbidity. In patients with reduced systolic function, AVNA demonstrates small but significantly improved echocardiographic outcomes relative to medical therapy alone.

Combination Angiotensin Converting Enzyme and Direct Renin Inhibition in Heart Failure following Experimental Myocardial Infarction

Diminishing the activity of the renin-angiotensin system (RAS) plays a pivotal role in the treatment of heart failure. In addition to angiotensin converting enzyme (ACE) inhibitors and angiotensin-receptor blockers, direct renin inhibition has emerged as a potential adjunctive treatment to conventional RAS blockade. We sought to determine the effectiveness of this strategy after myocardial infarction (MI) in the setting of preexisting hypertension, a common premorbid condition in patients with ischemic heart disease. Ten-week-old female heterozygous hypertensive (mRen-2)27 transgenic rats (Ren-2), were randomized to one of five groups (n = 8 per group); sham, MI, MI + aliskiren, MI + lisinopril and MI + combination lisinopril and aliskiren. Cardiac function was assessed by echocardiography and in vivo cardiac catheterization. Untreated MI animals developed heart failure with hypotension, dilation, reduced ejection fraction (EF), and raised left ventricular end-diastolic pressure (LVEDP). Treatment with single agent treatment had only modest effect on cardiac function though combination therapy was associated with significant improvements in EF and LVEDP when compared to untreated MI animals (P < 0.05). Histologic analysis demonstrated increase extracellular matrix deposition and cardiomyocyte hypertrophy in the noninfarct region of all MI groups when compared with sham operated animals (P < 0.05) that was reduced by ACE inhibitor monotherapy and combination treatment but not by aliskiren alone. In a hypertensive rat model that underwent experimental MI, EF, and LVEDP, key functional indices of heart failure, were improved by treatment with combination ACE and direct renin inhibition when compared with either agent used alone.

Outcomes of coronary artery bypass grafting and reduction annuloplasty for functional ischemic mitral regurgitation: A prospective multicenter study (Randomized Evaluation of a Surgical Treatment for Off-Pump Repair of the Mitral Valve)

Functional ischemic mitral regurgitation is a complication of ventricular remodeling; standard therapy is reduction annuloplasty and coronary artery bypass grafting. Unfortunately, outcomes are retrospective and contradictory. We report a multicenter study that documents the outcomes of reduction annuloplasty for functional ischemic mitral regurgitation. Twenty-one centers randomized 75 patients to the coronary artery bypass grafting + reduction annuloplasty subgroup that was the control arm of the Randomized Evaluation of a Surgical Treatment for Off-pump Repair of the Mitral Valve trial. Entry criteria included patients requiring revascularization, patients with severe or symptomatic moderate functional ischemic mitral regurgitation, an ejection fraction 25% or greater, a left ventricular end-diastolic dimension 7.0 cm or less, and more than 30 days since acute myocardial infarction. All echocardiograms were independently scored by a core laboratory. Reduction annuloplasty was achieved by device annuloplasty. Two patients underwent immediate intraoperative conversion to a valve replacement because reduction annuloplasty was unable to correct mitral regurgitation; as-treated results are presented. Thirty-day mortality was 4.1% (3/73). Patients received an average of 2.8 bypass grafts. Mean follow-up was 24.6 months. Mitral regurgitation was reduced from 2.6 ± 0.8 preoperatively to 0.3 ± 0.6 at 2 years. Freedom from death or valve reoperation was 78% ± 5% at 2 years. There was significant improvement in ejection fraction and New York Heart Association class with reduction of left ventricular end-diastolic dimension. Cox regression analyses suggested that increasing age (P = .001; hazard ratio, 1.16 per year; 95% confidence interval, 1.06-1.26) and renal disease (P = .018; hazard ratio, 3.48; 95% confidence interval, 1.25-9.72) were associated with decreased survival. Coronary artery bypass grafting + reduction annuloplasty for functional ischemic mitral regurgitation predictably reduces mitral regurgitation and relieves symptoms. This treatment of moderate to severe mitral regurgitation is associated with improved indices of ventricular function, improved New York Heart Association class, and excellent freedom from recurrent mitral insufficiency. Although long-term prognosis remains guarded, this multicenter study delineates the intermediate-term benefits of such an approach.

49 The Biochemical and Echocardiographic Effects of Anaemia of Prematurity and Red Cell Transfusion on Cardiac Functions in the Vlbw Infants

Aim: We investigated myocardial contractility as measured by Echocardiographic parameters of Tissue Doppler Imaging (TDI), Myocardial Performance Index (MPI), Ejection Fraction (EF) and Biochemical markers in VLBW infants before and after red cell transfusion. Method:Prospective, observational study on VLBW infants of 2 weeks of age. Blood sampling and echocardiogram performed in 12 hours before and between 3 to 7 days after transfusion. Infants with congenital heart lesions were excluded. Data was analysed using paired t-test, Wilcoxon signed rank and Kendall's Tau to compare the differences and to see correlation between pre and post values. Results: 74 pre and post transfusion (Pst) studies were performed on 28 infants. Pre-transfusion (Prt) haematocrit (Hct) ranged between 0.20% and 0.29%. Significant improvement in each biochemical and echocardiographic parameters were seen after transfusion: Table There was also a significant improvement in EF, septal and right ventricular contractility as assessed by TDI and MPI. Conclusion: Assessment of myocardial performance by echocardiography and biochemical markers demonstrate significant improvement following transfusion which is not proportional to the severity of the anaemia.

Usefulness of Cardiac Resynchronization Therapy in Patients With Adriamycin-Induced Cardiomyopathy

Adriamycin is a chemotherapeutic agent that can cause severe cardiotoxicity, which potentially carries a poorer long-term prognosis than other forms of cardiomyopathy. Cardiac resynchronization therapy (CRT) has been shown to improve quality of life, exercise capacity, left ventricular ejection fraction, and survival in selected patients with heart failure. It is unclear if patients with Adriamycin-induced cardiomyopathy (AIC) respond to CRT. We reviewed clinical and echocardiographic data on 18 consecutive patients with AIC who underwent implantation of a CRT device at the Cleveland Clinic from February 2000 to April 2007. Changes in clinical and echocardiographic parameters were compared to 189 consecutive patients with other forms of nonischemic cardiomyopathy (NIC) using similar end points. Patients with AIC demonstrated significant improvements in ejection fraction, left ventricular end-diastolic and end-systolic diameters, mitral regurgitation, and New York Heart Association functional class with CRT. These changes were similar to patients in the NIC cohort. In conclusion, patients with AIC may derive a significant echocardiographic and symptomatic benefit from CRT, which is similar to that seen in other forms of NIC.

Calpain inhibition preserves myocardial structure and function following myocardial infarction.

Cardiac pathology, such as myocardial infarction (MI), activates intracellular proteases that often trigger programmed cell death and contribute to maladaptive changes in myocardial structure and function. To test whether inhibition of calpain, a Ca(2+)-dependent cysteine protease, would prevent these changes, we used a mouse MI model. Calpeptin, an aldehydic inhibitor of calpain, was intravenously administered at 0.5 mg/kg body wt before MI induction and then at the same dose subcutaneously once per day. Both calpeptin-treated (n = 6) and untreated (n = 6) MI mice were used to study changes in myocardial structure and function after 4 days of MI, where end-diastolic volume (EDV) and left ventricular ejection fraction (EF) were measured by echocardiography. Calpain activation and programmed cell death were measured by immunohistochemistry, Western blotting, and TdT-mediated dUTP nick-end labeling (TUNEL). In MI mice, calpeptin treatment resulted in a significant improvement in EF [EF decreased from 67 + or - 2% pre-MI to 30 + or - 4% with MI only vs. 41 + or - 2% with MI + calpeptin] and attenuated the increase in EDV [EDV increased from 42 + or - 2 microl pre-MI to 73 + or - 4 microl with MI only vs. 55 + or - 4 microl with MI + calpeptin]. Furthermore, calpeptin treatment resulted in marked reduction in calpain- and caspase-3-associated changes and TUNEL staining. These studies indicate that calpain contributes to MI-induced alterations in myocardial structure and function and that it could be a potential therapeutic target in treating MI patients.

The BALANCE Study: Clinical Benefit and Long-Term Outcome After Intracoronary Autologous Bone Marrow Cell Transplantation in Patients With Acute Myocardial Infarction

The aim of this study was to investigate the quantitative amount of improvement of ventricular hemodynamic status, geometry, and contractility as well as the long-term clinical outcome of cell-treated patients after acute myocardial infarction (AMI).Animal experiments as well as clinical studies have demonstrated that autologous bone marrow cell (BMC) transplantation might improve ventricular function and prevent remodeling.Sixty-two patients underwent intracoronary autologous BMC transplantation 7 +/- 2 days after AMI. Cells were infused directly into the infarct-related artery. The control group consisted of 62 patients with comparable left ventricular (LV) ejection fraction (EF) and diagnosis. All patients had several examinations (e.g., coronary angiography, right heart catheterization, biplane left ventriculography, electrocardiogram [ECG] at rest and exercise, echocardiography, late potential [LP], heart rate variability [HRV], and 24-h Holter ECG). The therapeutic follow-up was performed 3, 12, and 60 months after BMC therapy.Three months after BMC therapy there was significant improvement of EF and stroke volume index. The infarct size was significantly reduced by 8%. Contraction velocities (lengths/second, volumes/second) increased significantly and the slope of the ventricular function curve (systolic pressure/end-systolic volume) became steeper. There was significant improvement of contractility in the infarct zone, as evidenced by a 31% increase of LV velocity of shortening (VCF), preferably in the border zone of the infarct zone. In contrast, the noninfarcted area showed no difference in VCF before and after BMC therapy. Furthermore, decreases of abnormal HRV, LP, and ectopic beats were documented after BMC therapy. Twelve and 60 months after BMC therapy the parameters of contractility, hemodynamic status, and geometry of the LV were stable. The exercise capacity of treated patients was significantly augmented, and the mortality was significantly reduced in comparison with the control group.BMC therapy leads to significant and longstanding improvements of LV performance as well as quality of life and mortality of patients after AMI. After BMC therapy, no side effects were observed, showing that BMC therapy is safe.

Association of electrostimulation with cell transplantation in ischemic heart disease

Until now, cell therapy has constituted a passive therapeutic approach; the only effects seem to be related to the reduction of the myocardial fibrosis and the limitation of the adverse ventricular remodeling. Cardiac resynchronization therapy is indicated in patients with heart failure to correct conduction disorders associated with chronic systolic and diastolic dysfunction. The association of electrostimulation with cellular cardiomyoplasty could be a way to transform passive cell therapy into "dynamic cellular support." Electrostimulation of ventricles following skeletal myoblast implantation should induce the contraction of the transplanted cells and a higher expression of slow myosin, which is better adapted for chronic ventricular assistance. The purpose of this study is to evaluate myogenic cell transplantation in an ischemic heart model associated with cardiac resynchronization therapy. Twenty two sheep were included. All animals underwent myocardial infarction by ligation of 2 coronary artery branches (distal left anterior descending artery and D2). After 4 weeks, autologous cultured myoblasts were injected in the infarcted areas with or without pacemaker implantation. Atrial synchronized biventricular pacing was performed using epicardial electrodes. Echocardiography was performed at 4 weeks (baseline) and 12 weeks after infarction. Echocardiography showed a significant improvement in ejection fraction and limitation of left ventricular dilatation in cell therapy with cardiac resynchronization therapy as compared with the other groups. Viable cells were identified in the infarcted areas. Differentiation of myoblasts into myotubes and enhanced expression of slow myosin heavy chain was observed in the electrostimulated group. Transplantation of cells with cardiac resynchronization therapy caused an increase in diastolic wall thickening in the infarcted zone relative to cells-only group and cardiac resynchronization therapy-only group. Biventricular pacing seems to induce synchronous contraction of transplanted myoblasts and the host myocardium, thus improving ventricular function. Electrostimulation was related with enhanced expression of slow myosin and the organization of myoblasts in myotubes, which are better adapted at performing cardiac work. Patients with heart failure presenting myocardial infarct scars and indication for cardiac resynchronization therapy might benefit from simultaneous cardiac pacing and cell therapy.

Myocardial oxygenation and functional recovery in infarct rat hearts transplanted with mesenchymal stem cells

Stem cell therapy for myocardial tissue repair is limited by the poor survival of transplanted cells, possibly because of inadequate supply of oxygen and nutrients. The purpose of this study was to assess the oxygenation level and functional recovery after allogenic transplantation of mesenchymal stem cells (MSC) in a rat model of myocardial infarction (MI). Myocardial oxygen tension (Po(2)) was measured by electron paramagnetic resonance oximetry using an implantable oxygen-sensing spin probe (OxySpin). MSCs incubated with OxySpins showed substantial uptake of the probe without affecting its oxygen sensitivity or calibration. The cells internalized with OxySpins were able to differentiate into osteogenic, adipogenic, cardiomyocyte, and endothelial cell lineages. The labeled cells tested positive for CD44 and CD29 markers and negative for the hematopoietic markers CD14 and CD45. For the in vivo studies, MI was induced in rats by permanently ligating the left anterior descending coronary artery. MSCs with OxySpins were transplanted in the infarct region of hearts. A significant increase in Po(2) was observed in the MSC group compared with the untreated MI group (18.1 +/- 2.6 vs. 13.0 +/- 1.8 mmHg, n = 4, P < 0.05) at 4 wk after transplantation. Echocardiography showed a significant improvement in ejection fraction and fraction shortening, which inversely correlated with the magnitude of fibrosis in the treated hearts. The cell-transplanted hearts also showed an increase in vascular endothelial growth factor level and capillary density in the infarct region. The study established our ability to measure and correlate changes in myocardial tissue oxygenation with cardiac function in infarcted rat hearts treated with MSCs.

Improved outcomes of cardiopulmonary resuscitation in rats with myocardial infarction treated with allogenic bone marrow mesenchymal stem cells*

We hypothesized that rats in which myocardial infarction had been treated with mesenchymal stem cells (MSCs) would have better outcomes following the global myocardial ischemia of cardiac arrest and cardiopulmonary resuscitation (CPR) compared with rats in which myocardial infarction had been treated with phosphate buffer solution (PBS). Prospective, randomized controlled study. University-affiliated research institute. Male Sprague-Dawley rats. Myocardial infarction was induced in 18 male Sprague-Dawley rats. Four weeks later, animals were randomized to receive 5 x 10 MSCs labeled with red fluorescent dye gel (PKH26) in PBS or a PBS-alone injection into right femoral vein. Echocardiographically measured myocardial function, including ejection fraction, left ventricular end-diastolic volume, and left ventricular end-systolic volume, was quantitated 2 and 4 weeks after administering MSCs or PBS. Four weeks after MSCs or PBS injection, 6 minutes of ventricular fibrillation (VF) and 6 minutes of CPR were performed before defibrillation. Myocardial function, including cardiac index, left ventricular, dP/dt max (dP/dt max), left ventricular negative dP/dt min (-dP/dt min), and left ventricular diastolic pressure, was measured before inducing VF and hourly following return of spontaneous circulation. Labeled MSCs were observed in 5-mum cryostat sections from each harvested heart. Significant improvements in ejection fraction, left ventricular end-diastolic volume, left ventricular end-systolic volume, cardiac index, dP/dt max, -dP/dt min, and left ventricular diastolic pressure followed injection of MSCs before inducing VF. Following return of spontaneous circulation, myocardial function was significantly better in animals pretreated with MSCs; this was associated with significantly increased duration of postresuscitation survival. Myocardial function before and after CPR and duration of survival after CPR were significantly improved in animals in which myocardial infarction was treated with MSCs. MSCs existing in the myocardium resisted a secondary ischemic event and provided better postresuscitation myocardial function.

Preoperative Intraaortic Balloon Pumping Improves Outcomes for High-Risk Patients in Routine Coronary Artery Bypass Graft Surgery

We evaluated the association between the preoperative use of intraaortic balloon pumping and in-hospital and long-term outcomes in high-risk patients undergoing coronary artery bypass grafting. From 714 total patients undergoing coronary artery bypass grafting during a 4-year period, we compared the clinical, biochemical, and echocardiographic findings up to 1 year after surgery between 111 patients who had a European System for Cardiac Operative Risk Evaluation (EuroSCORE) of 12 or greater and received intraaortic balloon pumping preoperatively (group A) and 130 patients who had a EuroSCORE of 5 or less and received no preoperative intraaortic balloon pumping (group B). Group A patients were significantly older, had significantly more comorbid conditions, and had a significantly lower mean preoperative ejection fraction (all p < 0.001). Intraoperative data were comparable between groups, as were lactate and troponin I levels sampled from the coronary sinus. Lactate, troponin I, creatine kinase, and creatine kinase-MB mass showed comparable leakage at all postoperative times. The incidences of in-hospital mortality, perioperative myocardial damage, and acute myocardial infarction and duration of hospital stay were comparable. High-risk patients showed significant improvements in ejection fraction (p < 0.001) and wall-motion score index (p = 0.06) after surgery, but low-risk patients showed no significant change in these variables. The incidences of death, recurrent angina, myocardial infarction, and repeat coronary procedures did not differ significantly between groups. The preoperative use of intraaortic balloon pumping appears to shift high-risk patients undergoing coronary artery bypass grafting into a lower-risk category and is associated with comparable perioperative troponin leakage and short-term and long-term outcomes similar to low-risk patients not receiving intraaortic balloon pumping.

Inelastic compression increases venous ejection fraction more than elastic bandages in patients with superficial venous reflux

To investigate the influence of compression bandages, manufactured using materials with different elastic properties, on the impaired venous pumping function in patients with venous insufficiency. Ejection volume (EV) and ejection fraction (EF) were measured using strain gauge plethysmography distal from the patella without and with elastic and inelastic compression bandages in a total of 30 patients with major venous reflux in the great saphenous vein. The interface pressure of the bandages was measured simultaneously in the medial gaiter area. Normal values of EV and EF were obtained from 15 healthy controls. Patients with venous insufficiency showed a statistically significant reduction of EV and EF compared to controls. Elastic bandages with an average pressure of 42 mm Hg in the supine position achieved a moderate increase of EV and a significant improvement of EF (p < .01), while inelastic bandages applied with comparable resting pressure (41 mm Hg) raised EV and EF into a normal range (p < .001). The improvement of the ejection fraction correlates well with the pressure differences between standing and lying (Static Stiffness Index) and between muscle systole and diastole during exercise (Pearson r = 0.69 and 0.74 respectively, p < .001). Elastic bandages applied with high stretch in order to achieve standing pressures comparable to those of inelastic bandages (>60 mm Hg) led only to a minor improvement of the venous pumping function. Ejected volume and ejection fraction, which are severely reduced in venous insufficiency, can be increased by compression therapy. Inelastic compression is much more effective than elastic bandages, and is able to normalize venous pumping function. With elastic bandages EV and EF always remain below the normal range even when applied with high stretch producing a resting pressure that is barely tolerable.

Non-Acute Reversible Cardiomyopathy: Clinical Characteristics, Time Course and Etiologic Considerations

Introduction: The time course of recovery of myocardial function in patients (pts) with left ventricular (LV) systolic dysfunction following the initial diagnosis is uncertain. A better understanding of the likelihood of recovery may have implications for the timing of ICD implantation. It is believed that pts ≥70 yrs old and those with a LV end-diastolic diameter (EDD) of ≥65mm are unlikely to demonstrate significant improvement in ejection fraction (EF) with treatment. The aim of this study was to delineate the clinical characteristics and the time course of improvement in pts diagnosed with severe nonischemic cardiomyopathy (EF≤30%) in whom the EF improved to ≥ 50%.

Surgical Ventricular Restoration Versus Cardiac Transplantation: A Comparison of Cost, Outcomes, and Survival

Background Cardiac transplantation is the accepted standard treatment for end-stage heart disease but is donor limited. Surgical ventricular remodeling is an established treatment for patients with ischemic cardiomyopathy. We sought to compare charges, outcomes, and survival in patients undergoing surgical ventricular restoration (SVR) versus cardiac transplantation (CTx). Methods and Results We retrospectively analyzed hospital charges, length of stay (LOS), and survival for 69 SVR and 53 CTx patients at our institution between January 2002 and June 2005. We also compared New York Heart Association (NYHA) status and Kaplan-Meier survival of our SVR patients with CTx patients with ischemic cardiomyopathy from the International Society of Heart & Lung Transplantation (ISHLT) registry. Median total LOS (12 days vs. 17 days, P = .01) and median postoperative LOS (10 days vs. 15 days, P = .02) were shorter for SVR patients than our CTx patients. Median total hospital charges ($45,506 vs. $137,679, P < .0001) and median total drug charges ($2,625 vs. $15,930, P < .0001) were lower for SVR patients. Significant improvements in ejection fraction were seen after both SVR (27% vs. 37%; P < .0001) and CTx (14% vs. 62%, P < .0001). Furthermore, 91% (49/54) of surviving SVR patients, 98% (44/45) of surviving CTx patients, and 91% of ISHLT CTx patients improved to NYHA Class I/II at follow-up. Survival did not differ between groups. Conclusions SVR patients demonstrate cost-effective clinical improvements that lead to good overall survival. SVR is an excellent surgical option for CHF patients who are not transplant candidates, and should be considered for ischemic cardiomyopathy patients who qualify for transplantation. This strategy may help relieve donor shortage and improve allocation of donor organs.