Xenotransplantation of human unrestricted somatic stem cells in a pig model of acute myocardial infarction.

BACKGROUND: Stem cell therapy may help restore cardiac function after acute myocardial infarction (AMI), but the optimal therapeutic cell type has not been identified. METHODS: We examined the effects of CD34-/CD45- human unrestricted somatic stem cells (USSCs) in pigs (n = 30) with an AMI created by a 90-min occlusion of the left anterior descending coronary artery. Pigs were randomly assigned to receive either USSCs (302 ± 23 × 10(6) cells) or phosphate-buffered saline via 15 NOGA-guided transendocardial injections 10 days after AMI. Cyclosporine A (10 mg/kg orally, twice a day) was started in all pigs 3 days before control or cell treatment. Cardiac function was assessed by echocardiography before injection and at 4 and 8 weeks after treatment. Serum titers for pig IgG antibodies against USSCs were also measured at these time points and before AMI. RESULTS: Compared with control pigs, USSC-treated pigs showed no significant differences in any of the functional parameters examined. USSC-treated pigs showed variable increases in anti-USSC IgG antibody titers in the blood and chronic inflammatory infiltrates at the cell injection sites. Immunohistochemical studies of the injection sites using human anti-mitochondrial antibodies failed to detect implanted USSCs. CONCLUSIONS: We conclude that human USSCs did not improve cardiac function in a pig model of AMI. Cell transplantation in a xenogeneic setting may obscure the benefits of stem cell therapy.

Restoration of microcirculatory patency after myocardial infarction: results of current coronary interventional strategies and techniques.

We sought to evaluate the restoration of microcirculatory patency after primary percutaneous coronary intervention (PCI) in an unselected cohort of patients at a tertiary center.We retrospectively evaluated distributions of the Thrombolysis in Myocardial Infarction (TIMI) myocardial perfusion grade (TMPG) and the myocardial blush grade (MBG) in all primary PCI procedures performed at our institution during 2008. We defined optimal microvascular perfusion as simultaneous TMPG 3 and MBG 3 at procedure's end.Ninety-nine patients (mean age, 61.5 ± 12.7 yr; 64 men) underwent primary PCI. Microvascular perfusion was optimal in 69 patients (69.7%) and was associated with lower peaks of enzymes than those occurring in patients with suboptimal perfusion. When optimal microvascular perfusion was achieved, early spontaneous recanalization was more frequently observed, as expressed by a higher frequency of TIMI-3 flow (34.8% vs 10%; P=0.006), TMPG 3 (26% vs 3.3%; P=0.004), and MBG 3 (24.6% vs 3.3%; P=0.004) on the initial angiogram before primary PCI. A higher frequency of MBG 3 (50% vs 20%; P=0.005) was seen after initial recanalization in patients with optimal microvascular perfusion. Multiple regression analysis showed that MBG after initial recanalization and the use of drug-eluting stents were associated with optimal perfusion.Despite successful recanalization of the culprit coronary artery, optimal microvascular perfusion was achieved in less than 75% of the patients. Restoration of the microvasculature was associated with smaller infarcts. Procedure-related variables associated with suboptimal perfusion were unlikely to be causative.

Randomized, double-blind pilot study of transendocardial injection of autologous aldehyde dehydrogenase-bright stem cells in patients with ischemic heart failure.

BACKGROUND: The optimal type of stem cell for use in patients with ischemic heart disease has not been determined. A primitive population of bone marrow-derived hematopoietic cells has been isolated by the presence of the enzyme aldehyde dehydrogenase and comprises a multilineage mix of stem and progenitor cells. Aldehyde dehydrogenase-bright (ALDH(br)) cells have shown promise in promoting angiogenesis and providing perfusion benefits in preclinical ischemia studies. We hypothesize that ALDH(br) cells may be beneficial in treating ischemic heart disease and thus conducted the first randomized, controlled, double-blind study to assess the safety of the transendocardial injection of autologous ALDH(br) cells isolated from the bone marrow in patients with advanced ischemic heart failure. METHODS: Aldehyde dehydrogenase-bright cells were isolated from patients' bone marrow on the basis of the expression of a functional (aldehyde dehydrogenase) marker. We enrolled 20 patients (treatment, n = 10; control, n = 10). Safety (primary end point) and efficacy (secondary end point) were assessed at 6 months. RESULTS: No major adverse cardiovascular or cerebrovascular events occurred in ALDH(br)-treated patients in the periprocedural period (up to 1 month); electromechanical mapping-related ventricular tachycardia (n = 2) and fibrillation (n = 1) occurred in control patients. Aldehyde dehydrogenase-bright-treated patients showed a significant decrease in left ventricular end-systolic volume at 6 months (P = .04) and a trend toward improved maximal oxygen consumption. The single photon emission computed tomography delta analysis showed a trend toward significant improvement in reversibility in cell-treated patients (P = .053). CONCLUSIONS: We provide preliminary evidence that treatment with the novel cell population, ALDH(br) cells, is safe and may provide perfusion and functional benefits in patients with chronic myocardial ischemia.

Imaging long-term fate of intramyocardially implanted mesenchymal stem cells in a porcine myocardial infarction model.

The long-term fate of stem cells after intramyocardial delivery is unknown. We used noninvasive, repetitive PET/CT imaging with [(18)F]FEAU to monitor the long-term (up to 5 months) spatial-temporal dynamics of MSCs retrovirally transduced with the sr39HSV1-tk gene (sr39HSV1-tk-MSC) and implanted intramyocardially in pigs with induced acute myocardial infarction. Repetitive [(18)F]FEAU PET/CT revealed a biphasic pattern of sr39HSV1-tk-MSC dynamics; cell proliferation peaked at 33-35 days after injection, in periinfarct regions and the major cardiac lymphatic vessels and lymph nodes. The sr39HSV1-tk-MSC-associated [(18)F]FEAU signals gradually decreased thereafter. Cardiac lymphography studies using PG-Gd-NIRF813 contrast for MRI and near-infrared fluorescence imaging showed rapid clearance of the contrast from the site of intramyocardial injection through the subepicardial lymphatic network into the lymphatic vessels and periaortic lymph nodes. Immunohistochemical analysis of cardiac tissue obtained at 35 and 150 days demonstrated several types of sr39HSV1-tk expressing cells, including fibro-myoblasts, lymphovascular cells, and microvascular and arterial endothelium. In summary, this study demonstrated the feasibility and sensitivity of [(18)F]FEAU PET/CT imaging for long-term, in-vivo monitoring (up to 5 months) of the fate of intramyocardially injected sr39HSV1-tk-MSC cells. Intramyocardially transplanted MSCs appear to integrate into the lymphatic endothelium and may help improve myocardial lymphatic system function after MI.

A dosing study of bone marrow mononuclear cells for transendocardial injection in a pig model of chronic ischemic heart disease.

We studied the effect of the dose of bone marrow mononuclear cells, delivered via transendocardial injection, upon capillary density and fibrosis in pigs with chronic ischemic heart disease.Pigs (n = 16) that had undergone ameroid constrictor placement (left circumflex coronary artery) to induce chronic ischemia were divided equally into 4 groups on the basis of bone marrow mononuclear cell dose: control (saline injection) and 50, 100, or 200 × 10(6) bone marrow mononuclear cells. Thirty days after ameroid placement, each pig received 13 transendocardial NOGA-guided injections. An implantable loop recorder monitored possible arrhythmias caused by cell transplantation. Thirty days later, the pigs were killed, and their hearts were evaluated histopathologically for fibrosis and capillary density; the number of cells per segment was correlated with fibrosis and capillary density. No adverse events, arrhythmias, or cardiac inflammatory reactions were associated with cell therapy. Less fibrosis was seen in pigs that received 100 × 10(6) cells than in control pigs. A trend toward higher capillary density was seen with higher cell concentrations. Segments injected with more than 20 × 10(6) million cells had the highest capillary density and the least amount of fibrosis (P < 0.05 vs controls).In conclusion, transendocardial injections (up to 200 × 10(6) bone marrow mononuclear cells) were safe. Analyses of individual injected segments suggest potential benefit from higher cell concentrations per segment.

A randomized study of transendocardial injection of autologous bone marrow mononuclear cells and cell function analysis in ischemic heart failure (FOCUS-HF).

BACKGROUND: Autologous bone marrow mononuclear cell (ABMMNC) therapy has shown promise in patients with heart failure (HF). Cell function analysis may be important in interpreting trial results. METHODS: In this prospective study, we evaluated the safety and efficacy of the transendocardial delivery of ABMMNCs in no-option patients with chronic HF. Efficacy was assessed by maximal myocardial oxygen consumption, single photon emission computed tomography, 2-dimensional echocardiography, and quality-of-life assessment (Minnesota Living with Heart Failure and Short Form 36). We also characterized patients' bone marrow cells by flow cytometry, colony-forming unit, and proliferative assays. RESULTS: Cell-treated (n = 20) and control patients (n = 10) were similar at baseline. The procedure was safe; adverse events were similar in both groups. Canadian Cardiovascular Society angina score improved significantly (P = .001) in cell-treated patients, but function was not affected. Quality-of-life scores improved significantly at 6 months (P = .009 Minnesota Living with Heart Failure and P = .002 physical component of Short Form 36) over baseline in cell-treated but not control patients. Single photon emission computed tomography data suggested a trend toward improved perfusion in cell-treated patients. The proportion of fixed defects significantly increased in control (P = .02) but not in treated patients (P = .16). Function of patients' bone marrow mononuclear cells was severely impaired. Stratifying cell results by age showed that younger patients (≤60 years) had significantly more mesenchymal progenitor cells (colony-forming unit fibroblasts) than patients >60 years (20.16 ± 14.6 vs 10.92 ± 7.8, P = .04). Furthermore, cell-treated younger patients had significantly improved maximal myocardial oxygen consumption (15 ± 5.8, 18.6 ± 2.7, and 17 ± 3.7 mL/kg per minute at baseline, 3 months, and 6 months, respectively) compared with similarly aged control patients (14.3 ± 2.5, 13.7 ± 3.7, and 14.6 ± 4.7 mL/kg per minute, P = .04). CONCLUSIONS: ABMMNC therapy is safe and improves symptoms, quality of life, and possibly perfusion in patients with chronic HF.

Cryoplasty for peripheral artery disease in an unselected patient population in a tertiary center.

Endovascular treatment of peripheral artery occlusive disease has suboptimal long-term patency rates. The addition of cryoplasty to balloon angioplasty, which involves the application of cold thermal energy to atherosclerotic plaque, might improve outcomes and decrease the need for reintervention. At a single tertiary center, we retrospectively analyzed data from the angiograms and medical records of unselected patients who underwent cryoplasty for peripheral artery disease from January 2004 through November 2006. We calculated rates of freedom from amputation, freedom from intervention, and freedom from death and examined the data using the Kaplan-Meier method. Paired t tests were used to compare the ankle-brachial indices before and after cryoplasty. The study population comprised 99 patients who received treatment for 132 atherosclerotic lesions, including 62 lesions in the superficial femoral artery, 28 in the popliteal artery, and 25 in arteries below the knee; 71 patients completed follow-up (64 ± 57 wk). Short-term periprocedural success was achieved in 98.5% of the interventions. Dissections occurred in 12.2% of patients treated successfully without bail-out stenting or additional balloon inflations. At 6 months, more than 88% of the patients were alive and had not had an amputation. However, reintervention was required for 42% of patients. Mean ankle-brachial indices improved significantly after treatment (P < 0.0001). Our results show that cryoplasty for treatment of peripheral artery disease is safe and has a high rate of periprocedural success. However, long-term efficacy is compromised because of the frequent need for reintervention.

Comparative healing response after sirolimus- and paclitaxel-eluting stent implantation in a pig model of restenosis.

OBJECTIVE: We compared local vessel healing and inflammatory responses associated with nonoverlapping sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES). BACKGROUND: Sirolimus and paclitaxel may have different effects on vascular healing. In the present study, we analyzed the local histologic effects of drug-eluting stents (DES). METHODS: We placed 43 stents (22 PES and 21 SES) in 16 Yucatan minipigs. Stents were randomly assigned and placed in the left anterior descending, circumflex, or right coronary arteries (one stent per artery), covering a region previously injured by balloon angioplasty. RESULTS: Histopathologic analysis showed that the distribution of injury scores was similar between the two stent groups, reflecting the homogeneity of coronary injury secondary to balloon overstretch. Electron microscopy showed complete endothelialization in most cases. Incomplete endothelialization was present in 12.5% of PES and almost 20% of SES at 30 days. In the PES group, moderate to severe inflammation was found in eight arteries, whereas only one vessel had moderate inflammation in the SES group. Severe inflammation was observed significantly more often in the PES than in the sirolimus group (P = 0.006). With the PES group, stent struts overlying side branches had a significantly higher frequency of poor endothelialization scores than did stent struts that did not overlay side branches (P = 0.006). CONCLUSIONS: In this preclinical study in a pig model of in-stent restenosis, implantation of nonoverlapping DES was associated with local inflammatory reactions and decreased endothelial repair. Impaired endothelialization was visualized in the struts overlying side branches.

Histopathological study of healing after allogenic mesenchymal stem cell delivery in myocardial infarction in dogs.

In this histological study, we assessed the role of mesenchymal stem cells (MSCs) in the healing process that takes place during the subacute phase of myocardial infarction in dogs. Seven days after occlusion of the left anterior descending coronary artery, adult mongrel dogs received 100 x 10(6) 4'-6-diamidino-2-phenylindole (DAPI)-labeled allogenic bone marrow-derived MSCs by the transendocardial (TE, n=6) and intracoronary (IC, n=4) routes; control dogs (n=6) received no infusion. The dogs were euthanized at 21 days after occlusion. Hearts were excised and sliced from apex to base into four transverse sections, which were divided into nine segments. Paraffin sections from each segment were stained with hematoxylin and eosin, trichrome, picrosirius red, and antibodies against several extracellular matrix components. Frozen sections were immunostained for host cardiac phenotypical markers and analyzed by epifluorescence and deconvolution fluorescence microscopy (DFM). We found less unresolved necrotic myocardium and more extracellular matrix deposition in MSC-treated dogs than in controls 2 weeks after cell delivery. By DFM, no DAPI+ MSC nuclei were observed within native cardiac cells. MSCs delivered during the subacute phase of acute myocardial infarction positively affect healing, apparently by mechanisms other than differentiation into mature native cardiac cells.

Validation of QwikStar Catheter for left ventricular electromechanical mapping with NOGA XP system.

Left ventricular electromechanical mapping (LVEM) is a method for mapping the left ventricular cavity in 3 dimensions by use of a catheter that samples points on the endocardial surface. These points provide data on unipolar voltage and linear local shortening, which can then be used to evaluate myocardial ischemia and viability. The new QwikStar multi-electrode catheter, which acquires data from multiple points simultaneously, potentially improves map quality and decreases mapping time in comparison with the single-point NogaStar catheter. Our study sought to validate the QwikStar catheter's LVEM capabilities in a porcine model of chronic ischemia.Eight pigs underwent ameroid placement over the proximal left circumflex artery, to induce chronic ischemia. In 60 days, LVEM was performed on each animal with the NogaStar and QwikStar catheters. Unipolar voltage and linear local shortening results were displayed in 9-segment polar maps. The unipolar voltage data from both maps were then correlated by means of linear regression.There were no adverse events during LVEM. Mapping time was similar for both groups (QwikStar, 44.6 +/- 25.62 min; NogaStar, 65.75 +/- 25.33 min; P = 0.13). Results of mean unipolar voltage maps acquired with the 2 catheters showed a moderate correlation (r =0.59, P <0.001). Selecting segments with more than 6 point samples increased the Pearson coefficient to 0.69 (P <0.001).Our findings show that the QwikStar catheter enables the reproducible performance of LVEM by sampling fewer points, which shortens procedure time, decreases manipulation of the left ventricular cavity, and might increase procedural safety.

[Diabetic and nondiabetic patients respond differently to transendocardial injection of bone marrow mononuclear cells: findings from prospective clinical trials in "no-option" patients]. / El efecto de la inyección transendocárdica de células mononucleadas de médula ósea es diferente en pacientes diabéticos y en no diabéticos: hallazgos derivados de estudios clínicos prospectivos en pacientes "sin opción".

Whether stem cell treatment has the same effect in diabetics and nondiabetics is unknown. To compare outcomes in these two groups, we analyzed data from 26 consecutive patients with chronic ischemic cardiomyopathy who were taking part in two clinical trials. Revascularization was not an option for these patients and they were treated with bone marrow mononuclear cells (BMMNCs). Patients underwent NOGA electromechanical mapping to identify viable myocardium (i.e., with a unipolar voltage > or = 6.9 mV), after which they received a mean of 28.5+/-4.7 x 10(6) BMMNCs. Patients were followed up at 6 months. In nondiabetics, there was a significant decrease in endsystolic volume between baseline and 6-month follow-up. In addition, New York Heart Association (NYHA) functional class decreased significantly (P=.04) from 3.0 (1.75-3.0) to 1.0 (1.0-2.0), the Canadian Cardiovascular Society angina score (CCSAS) improved significantly (P=.04) from 3.0 (2.0-4.0) to 1.0 (1.0-1.5), and oxygen uptake increased significantly (P=.04) from 16.4 (13.1-21.5) to 24.5 (17.3-29.2) ml/kg/min. These changes were not observed in diabetic patients. This is the first clinical study to show that BMMNC injection could have a smaller effect in diabetics.

El efecto de la inyección transendocárdica de células mononucleadas de médula ósea es diferente en pacientes diabéticos y en no diabéticos: hallazgos derivados de estudios clínicos prospectivos en pacientes «sin opción» / Diabetic and Nondiabetic Patients Respond Differently to Transendocardial Injection of Bone Marrow Mononuclear Cells: Findings From Prospective Clinical Trials in “No-Option” Patients

Se desconoce si la administración de células madre tieneel mismo efecto en pacientes diabéticos y en no diabéticos. Para ello se estudió a 26 pacientes consecutivos, incluidos en dos estudios, tratados con células mononucleadas de médula ósea (CMNMO), con miocardiopatía isquémica crónica y sin opción a revascularización. Se les realizó un mapeo electromecánico con NOGA para identificar miocardio viable (voltaje unipolar ≥ 6,9 mV)y se les inyectó una media de 28,5 ± 4,7 millones deCMNMO. Se realizó un seguimiento a los 6 meses. Enlos pacientes no diabéticos, se observó una reducciónsignificativa del volumen telesistólico a los 6 meses encomparación con el basal, una disminución significativade la clase NYHA (de 3 [1,75-3] a 1 [1-2]; p = 0,04), de la puntuación de angina de la clasificación canadiense (de 3 [2-4] a 1 [1-1,5]; p = 0,04) y un aumento del consumo de oxígeno (de 16,4 [13,1-21,5] a 24,5 [17,3-29,2] ml/kg/min; p = 0,04). Estas diferencias no se observaron en los pacientes diabéticos. Éste es el primer estudio clínico que observa que la inyección de CMNMO podría tener un menor efecto en los diabéticos

Whether stem cell treatment has the same effect indiabetics and nondiabetics is unknown. To compareoutcomes in these two groups, we analyzed data from 26consecutive patients with chronic ischemic cardiomyopathywho were taking part in two clinical trials. Revascularization was not an option for these patients and they were treated with bone marrow mononuclear cells (BMMNCs). Patients underwent NOGA electromechanical mapping to identify viable myocardium (i.e., with a unipolar voltage . 6.9 mV), after which they received a mean of 28.5}4.7~106 BMMNCs. Patients were followed up at 6 months. In nondiabetics, there was a significant decrease in endsystolic volume between baseline and 6-month follow-up. In addition, New York Heart Association (NYHA) functional class decreased significantly (P=.04) from 3.0 (1.75-3.0) to 1.0 (1.0-2.0), the Canadian Cardiovascular Society angina score (CCSAS) improved significantly (P=.04) from 3.0 (2.0-4.0) to 1.0 (1.0-1.5), and oxygen uptake increased significantly (P=.04) from 16.4 (13.1-21.5) to 24.5 (17.3- 29.2) ml/kg/min. These changes were not observed in diabetic patients. This is the first clinical study to show that BMMNC injection could have a smaller effect in diabetics

Histopathological validation of electromechanical mapping in assessing myocardial viability in a porcine model of chronic ischemia.

BACKGROUND AND OBJECTIVE: Left ventricular electromechanical mapping (EMM) determines myocardial viability on the basis of endocardial electrograms. The aim of the present study was to validate EMM in differentiating infarcted myocardium from viable myocardium by histopathological analysis. METHODS: Sixty days after implanting an ameroid constrictor over the left circumflex artery to create chronic ischemia in 19 pigs, EMM was performed to construct unipolar voltage (UPV), bipolar voltage (BPV) and linear local shortening (LLS) maps. Noninfarcted and infarcted myocardium were identified by histopathology. Threshold determinations comparing noninfarcted tissue with scarred tissue were made by measuring the area under the receiver operating characteristic curves. RESULTS: From the 19 hearts, 149 myocardial segments were divided into noninfarcted myocardium (n=128) and transmural infarct (n=21). UPV, BPV and LLS values (4.7+/-1.2 mV, 2.8+/-2.5 mV and 10.0+/-5.1%, respectively) of infarcted segments were significantly lower than those in noninfarcted myocardium (10.9+/-3.4 mV, 4.5+/-2.4 mV and 15.7+/-9.5%, respectively; P<0.01 for each comparison). The threshold values of UPV, BPV and LLS differentiating noninfarcted from infarcted myocardium were 6.2 mV (98% sensitivity, 95% specificity, 97% accuracy), 2.8 mV (80% sensitivity, 72% specificity, 79% accuracy) and 12.3% (68% sensitivity, 67% specificity, 68% accuracy), respectively. The relative dispersion of voltage was lower for UPV versus BPV. CONCLUSION: UPV can accurately differentiate infarcted from noninfarcted tissue in the chronic ischemic heart of pigs; however, BPV and LLS results were less accurate.

Comparison of intracoronary and transendocardial delivery of allogeneic mesenchymal cells in a canine model of acute myocardial infarction.

This study assessed safety of transendocardial (TE) electromechanical-guided delivery of bone marrow mesenchymal stem cells (MSCs) after acute myocardial infarction (AMI) and compared intracoronary (IC) delivery with TE delivery. In a canine acute myocardial ischemia model, 100 x 10(6) MSCs were delivered 7 days after AMI via IC and TE routes. Functional assessment was performed by 2D echocardiogram, and detailed histopathologic analyses were performed to assess the impact of cell therapy in vascular density and fibrosis. Patterns of cell distribution in both delivery methods were also compared. There was a statistically significant reduction in the amount of myocardial ischemia in the TE group (P=0.007). Left ventricular ejection fraction (LVEF) increased 13% (mean) in the TE group (21-day follow-up) and was significantly better than that of the controls (P=0.01), but did not improve in the IC-delivery group. Dissimilar patterns of cell distribution were noted between the IC and TE groups. This study suggests that MSC treatment is probably safe and effective after AMI. In the comparison of TE and IC delivery, the TE group showed higher cell retention (clusters even in the injury center of the infarct) with an increased vascularity and greater functional improvement than did the IC group (no clusters; cells at the border of the infarct). The higher local cell density in the TE group may be important for therapeutic effectiveness.

Assessing intermediate coronary lesions: angiographic prediction of lesion severity on intravascular ultrasound.

BACKGROUND: Intravascular ultrasound (IVUS) can detect atherosclerotic compromise in coronary segments where conventional angiography cannot. However, IVUS is more invasive, expensive and laborious than angiography. We compared the detection of stenosis by IVUS and angiography and identified angiographic predictors of severe luminal stenosis on IVUS in patients with angiographically-intermediate coronary lesions. METHODS: Fifty-six patients with myocardial ischemia and intermediate stenosis by quantitative coronary angiography (QCA) underwent IVUS assessment of the culprit artery. The results from IVUS and QCA were compared using the two-tailed unpaired t-test. Multiple regression analysis was performed to identify QCA parameters that could predict the presence of severe stenosis on IVUS, defined as a minimum luminal area (MLA) < or = 4 mm2. RESULTS: A total of 63 stenotic coronary lesions were classified as intermediate by QCA; 68% of these were found to be severe on IVUS. There was a weak correlation between IVUS and QCA with respect to percentage of stenosis, minimum luminal diameter, reference segment diameter and length of atherosclerotic compromise. In contrast, there was a significant difference in the assessment of reference segment luminal diameter, which was 2.83 +/- 0.56 mm by angiography versus 3.45 +/- 0.69 mm by IVUS (p < 0.0001). The only angiographic predictor of the presence of severe coronary stenosis on IVUS was a distal reference segment diameter < or = 2.42 mm. CONCLUSIONS: In patients with angiographically-intermediate lesions, the frequency of severe stenosis detected by IVUS was high, indicating that angiography underestimated the severity of stenosis. Distal reference segment diameter was the only predictor of a small MLA and could be used to stratify these lesions into groups with higher and lower risk of severe stenosis.

Terapia celular no tratamento da insuficiência cardíaca isquêmica / Cellular therapy in the treatment of ischemic heart failure

Neste artigo, os autores discutem o estado da arte da terapia celular no tratamento da insuficiencia cardiaca isquêmica. São apresentados os principais tipos celulares e suas particularidades no tratamento dessa doença.

In this article the authors discuss the state of the art on cell therapy for ischemic heart failure. The principal cell types and their specific characteristics for the treatment of this pathology are presented.

Regeneração cardíaca. Coração: um órgão pós-mitótico? / Cardiac regeneration: the heart: a postmitotic organ?

A apresentação de evidências de divisão celular e da existência de atividade reparativa intrínseca ao tecido miocárdico gerou uma mudança de paradigma na aceitação do coração como um órgão de população celular dinâmica, a qual atinge um estado de homeostasia a partir de um equilíbrio entre morte e replicação celular. Neste contexto, a terapia celular tenta dar respostas a questões básicas como: contexto clínico ideal para tratamento, tipo celular de escolha, dose e frequencia de tratamento e via de escolha para administração de células...

Evidence of myocardial tissue cell division and repair activities has generated a change of paradigm in accepting the heart as a dynamic cell organ reaching a state of homeostasis as of a point of equilibrium between cell death and replication. Against such scenario, cell therapy tries to find answers to basic issues such as: ideal clinical setting for treatment, cell type choice, dose and frequency for treatment, and choice cell administration.

First experience with remote left ventricular mapping and transendocardial cell injection with a novel integrated magnetic navigation-guided electromechanical mapping system.

AIMS: The purpose of this preclinical feasibility study was to evaluate a novel integrated platform in which magnetic navigation is used to remotely guide electromechanical mapping of the left ventricle (LV) and transendocardial cell injections. Using an integrated remote system would greatly facilitate intramyocardial delivery of stem cells for treating ischaemic heart disease. METHODS AND RESULTS: We used the computer-controlled Stereotaxis magnetic navigation system to guide the NOGA electromechanical mapping system in mapping viable myocardium in the LV of seven pigs. We then tested the feasibility of this system to perform transendocardial injections in three of the pigs and to deliver mesenchymal precursor cells (MPCs) to targeted myocardial segments in four of the pigs. The success or failure of each injection was determined by myocardial contrast staining in the first group and by histopathologic analysis in the last group. The mean time (+/-SD) spent mapping the LV for each pig was 49.3+/-10.6 min. The success rate for transendocardial injections was 94.4%, as indicated by myocardial contrast staining. There was a 95.8% success rate for targeted injections of MPCs, and 4',6-diamidino-2-phenylindole-labeled MPCs were detected in all but one segment of one pig. No epicardial haemorrhage or injury was observed, although there was some venous drainage. CONCLUSIONS: The integrated Stereotaxis/NOGA system has excellent remote navigability inside the LV cavity while sparing the operator from radiation exposure. This system also allows transendocardial cell injections to be performed with a high success rate. Further studies are needed to define the safety profile of this system for clinical use.

Differential local effect of sirolimus eluting stent and paclitaxel eluting stent in a porcine restenosis model

Introdução: Os stents farmacológicos liberadores de sirolimus (SES) e de paclitaxel (PES) reduzem de maneira significativa os índices de reestenose se comparados aos stents de metal. Há muita controvérsia com relação aos possíveis efeitos indesejáveis do SES e do PES, como, por exemplo, a trombosesubaguda intra-stent. Este estudo teve como objetivo comparar o efeito arterial local do SES e do PES. Métodos: A dilatação coronariana foi induzida em 16 suínos pela insuflação de um balão superdimensionado na proporção 1.2:1.0 em 43 artérias. Foram olocados aleatoriamente 21 SES e 22 PES na descendente anterior esquerda e na circunflexa esquerda no local da lesão anterior por balão. Os animais foramenviados para necropsia 30 dias após o procedimento. Vinte artérias foram enviadas para análise pelo métodoWestern Blot (16 segmentos com stent + 4 controles normais). Vinte e sete segmentos com stent foram submetidos à análise histológica e à microscopia eletrônica (ME) a baixo vácuo. Resultados: Não foram observadas diferenças com referência às características morfométricas entre os dois grupos. A espessura neointimal se mostrou semelhante nos segmentos com stent SES e PES (0,23±0,05mm vs 0,21±0,08mm, respectivamente – p=0,08). A cicatrização arterial localavaliada pelo método WB demonstrou níveis significantemente mais altos do fator Von Willebrand e CD 31 em SESvs PES (p=0,005 e 0,03, respectivamente). PES demonstrou,ainda, inflamação local mais intensa, expressa pelos níveis mais altos de PDGF (p=0,0007). Este resultado foi corroborado pelos achados de reação inflamatória local mais intensa pela ME, expressa por dados inflamatórios mais elevados no grupo PES. Conclusão: PES demonstrou maior grau de inflamação e menor expressão de CD31 e do fator VonWillebrand, sugerindo, portanto, cicatrização endotelial comprometidaapós a colocação do stent se comparado ao SES.

Background: Sirolimus eluting stents (SES) and Paclitaxel eluting stents (PES) significantly reduce restenosis rates as compared with bare metal stents. There is much controversyregarding possible untoward effects of SES and PES such as subacute stent thrombosis. The present study aimed tocompare the local arterial effect of SES versus PES. Methods: In 16 pigs coronary overstretch was induced by inflating an oversized angioplasty balloon at 1.2:1.0 ratio in 43 arteries. Twenty one SES and 22 PES were randomly deployed in LAD and LCx in the site of previous balloon injury. Animals were sent to necropsy 30 days after the procedure. Twenty arteries were sent to Western Blot (WB) analysis (16 stented segments plus 4 normal controls). Twenty seven stented segments were submitted to histologyanalysis and low vacuum electron microscopy (EM). Results: There were no differences regarding arterial morphometric characteristics between the two groups. Neo intimal thicknesswere similar in SES and PES stented segments (0.23±0.05mm vs 0.21±0.08mm, respectively – p=0.08). Local arterial healing assessed by WB showed significantly higher local levels of Von Willebrand factor and CD 31 in SES vs PES (p values of 0.005 and 0.03, respectively). Also, PES showed higher local inflammation as expressed byhigher PDGF levels (p= 0.0007). This result was corroborated by the EM findings of higher local inflammatory reaction, expressed by higher inflammation scores in the PES group.Conclusion: PES showed higher inflammation and lower expression of CD31 and Von Willebrand factor, suggesting an impaired endothelial healing after stenting when comparedwith SES.