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.

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.

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

Terapia celular no tratamento do infarto agudo do miocárdio / Cell therapy in the treatment of acute myocardial infarction

Neste artigo, os autores abordam os conceitos e evidências atualmente disponíveis sobre a terapia celular no tratamento de pacientes pós-infarto agudo do miocárdio. Os tipos celulares potencialmente candidatos ao uso clínico são enfatizados, considerando-se as vias de administração e as perspectivas futuras.

In this article, the authors discuss the concepts and available current evidence about cell therapy in the treatment of patients with acute myocardial infarction. The cell types that are potential candidates for clinical use are detailed as are the administration routes and future perspectives.

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.

Mesenchymal stem cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a canine chronic ischemia model.

BACKGROUND: Bone marrow-derived stem cells are under investigation as a treatment for ischemic heart disease. Mesenchymal stem cells (MSCs) have been used preferentially in the acute ischemia model; data in the chronic ischemia model are lacking. METHODS AND RESULTS: Twelve dogs underwent ameroid constrictor placement. Thirty days later, they received intramyocardial injections of either MSCs (100x10(6) MSCs/10 mL saline) (n=6) or saline only (10 mL) (controls) (n=6). All were euthanized at 60 days. Resting and stress 2D echocardiography was performed at 30 and 60 days after ameroid placement. White blood cell count (WBC), C-reactive protein (CRP), creatine kinase MB (CK-MB), and troponin I levels were measured. Histopathological and immunohistochemical analyses were performed. Mean left ventricular ejection fraction was similar in both groups at baseline but significantly higher in treated dogs at 60 days. WBC and CRP levels were similar over time in both groups. CK-MB and troponin I increased from baseline to 48 hours, eventually returning to baseline. There was a trend toward reduced fibrosis and greater vascular density in the treated group. MSCs colocalized with endothelial and smooth muscle cells but not with myocytes. CONCLUSIONS: In a canine chronic ischemia model, MSCs differentiated into smooth muscle cells and endothelial cells, resulting in increased vascularity and improved cardiac function.

Catheter-based transendocardial delivery of autologous bone-marrow-derived mononuclear cells in patients listed for heart transplantation.

Growing evidence suggests that transplantation of autologous bone-marrow mononuclear cells (ABMMNCs) can improve the perfusion and contractile function of ischemic myocardium. This procedure could potentially benefit transplant candidates awaiting a donor heart. To study the safety and feasibility of ABMMNC injection, we performed a prospective, nonrandomized, open-label study in 5 heart transplant candidates with severe ischemic heart failure. Each patient underwent baseline single-photon emission computed tomography, a ramp treadmill protocol, 2-dimensional echocardiography, 24-hour Holter monitoring, and signal-averaged electrocardiography, which were repeated at 2 and 6 months. Transendocardial delivery of ABMMNCs was done with the aid of electromechanical mapping to identify viable myocardium. Each patient received 15 ABMMNC injections of 0.2 cc each. There were no deaths, significant arrhythmias, or other major complications. The ABMMNC injection reduced the amount of ischemic myocardium (not statistically significant). More important, exercise test results improved significantly. Myocardial volume oxygen consumption increased from 10.6 +/- 3 mL/kg/min (baseline) to 16.3 +/- 7 mL/kg/min (2 months) and 23 +/- 7 mL/kg/min (6 months) (P = 0.0091). In 4 of the 5 cases, this was such an improvement that the patients were no longer eligible for cardiac transplantation. In addition, metabolic equivalents improved from 3.03 +/- 0.66 (baseline) to 4.65 +/- 1.99 (2 months) and 6.5 +/- 2.0 (6 months) (P = 0.0092). In conclusion, ABMMNC injections were performed safely and resulted in improved exercise capacity. This technique may hold promise as an alternative to medical management in patients with severe ischemic heart failure who are ineligible for conventional revascularization.

Síndromes coronarianas agudas: protocolo de avaliaçäo e manejo inicial de pacientes com dor torácica / Acute Curonary Syndromes: rotocol of evaluation and initial manegement for patients with chest pain

A angina instável, o infarto agudo do miocárdio näo-Q e o infarto agudo do miocárdio säo manifestaçöes agudas da doença arterial coronariana que afetam milhöes de pessoas anualmente em todo o mundo. A adoçäo de terapias apropriadas é essencial para o alívio da isquemia miocárdica inicial e para a reduçäo de riscos de eventos futuros. Além desses aspectos, um guia prático voltado ao diagnóstico e ao manejo das síndromes coronarianas agudas nas salas de emergência é apresentado com o objetivo de orientar a conduta terapêutica.

Prevalência dislipidemia em pacientes com doença arterial coronariana / Prevalence of hyperlipedemia in patients with coronarian arterial disease

Este trabalho objetivou verificar a prevalencia de dislipidemias em pacientes com Doenca Arterial Coronariana (DAC) estabelecida, selecionados aleatoriamente em consultorios cardioløgicos. Foi determinada a frequencia de desvios dos valores considerados ideais para a faixa etaria da colesterolemia total-CT, suas fracoes (HDL-C e LDL-C), e trigliceridemia-TG. No conjunto estudado, nenhum dos pacientes apresentou HDL-C em n­veis sericos indicativos de risco negativo para DAC, sendo que 100 por cento dos pacientes apresentaram pelo menos um dos quatro valores lip­dicos alterados. Os resultados confirmam a preponderancia de n­veis lip­dicos alterados como FR no desenvolvimento de DAC.

Insuficiência cardíaca de alto débito causada por fístula renal arteriovenosa: relato de um caso / High-output cardiac failure caused by arteriovenous fistula: a case report

Os autores relatam um caso de insuficiência cardíaca de alto débito, causada por fístula arteriovenosa de origem renal, apresentando sua demonstraçäo angiográfica. Salientam o diagnóstico diferencial entre as patologias que se apresentam sob o quadro sindrômico de insuficiência cardíaca, e destacam o tratamento definitivo da fístula arteriovenosa