RESUMEN
BACKGROUND: Atherosclerotic peripheral artery disease affects 8% to 12% of Americans >65 years of age and is associated with a major decline in functional status, increased myocardial infarction and stroke rates, and increased risk of ischemic amputation. Current treatment strategies for claudication have limitations. PACE (Patients With Intermittent Claudication Injected With ALDH Bright Cells) is a National Heart, Lung, and Blood Institute-sponsored, randomized, double-blind, placebo-controlled, phase 2 exploratory clinical trial designed to assess the safety and efficacy of autologous bone marrow-derived aldehyde dehydrogenase bright (ALDHbr) cells in patients with peripheral artery disease and to explore associated claudication physiological mechanisms. METHODS: All participants, randomized 1:1 to receive ALDHbr cells or placebo, underwent bone marrow aspiration and isolation of ALDHbr cells, followed by 10 injections into the thigh and calf of the index leg. The coprimary end points were change from baseline to 6 months in peak walking time (PWT), collateral count, peak hyperemic popliteal flow, and capillary perfusion measured by magnetic resonance imaging, as well as safety. RESULTS: A total of 82 patients with claudication and infrainguinal peripheral artery disease were randomized at 9 sites, of whom 78 had analyzable data (57 male, 21 female patients; mean age, 66±9 years). The mean±SEM differences in the change over 6 months between study groups for PWT (0.9±0.8 minutes; 95% confidence interval [CI] -0.6 to 2.5; P=0.238), collateral count (0.9±0.6 arteries; 95% CI, -0.2 to 2.1; P=0.116), peak hyperemic popliteal flow (0.0±0.4 mL/s; 95% CI, -0.8 to 0.8; P=0.978), and capillary perfusion (-0.2±0.6%; 95% CI, -1.3 to 0.9; P=0.752) were not significant. In addition, there were no significant differences for the secondary end points, including quality-of-life measures. There were no adverse safety outcomes. Correlative relationships between magnetic resonance imaging measures and PWT were not significant. A post hoc exploratory analysis suggested that ALDHbr cell administration might be associated with an increase in the number of collateral arteries (1.5±0.7; 95% CI, 0.1-2.9; P=0.047) in participants with completely occluded femoral arteries. CONCLUSIONS: ALDHbr cell administration did not improve PWT or magnetic resonance outcomes, and the changes in PWT were not associated with the anatomic or physiological magnetic resonance imaging end points. Future peripheral artery disease cell therapy investigational trial design may be informed by new anatomic and perfusion insights. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01774097.
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Tratamiento Basado en Trasplante de Células y Tejidos , Enfermedad Arterial Periférica/terapia , Anciano , Aldehído Deshidrogenasa/metabolismo , Células de la Médula Ósea/metabolismo , Trasplante de Médula Ósea , Tratamiento Basado en Trasplante de Células y Tejidos/efectos adversos , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Comorbilidad , Ejercicio Físico , Extremidades/irrigación sanguínea , Femenino , Estudios de Seguimiento , Humanos , Claudicación Intermitente/terapia , Masculino , Persona de Mediana Edad , Perfusión , Enfermedad Arterial Periférica/diagnóstico , Enfermedad Arterial Periférica/metabolismo , Calidad de Vida , Factores de Riesgo , Resultado del TratamientoRESUMEN
PURPOSE: Pacemakers and implantable cardioverter defibrillators are widely used and often encountered in urology practices worldwide. Safety and performance during electrosurgery, extracorporeal shock wave lithotripsy, magnetic resonance imaging, positron emission tomography and radiotherapy are not clearly defined. We reviewed the literature on their use and implications in urological practice. MATERIALS AND METHODS: We performed a PubMed® search and all relevant articles were studied to understand the basic functioning of these devices along with the technological advances designed to reduce electromagnetic interference. RESULTS: A modern permanent pacemaker is comprised of a generator and leads connecting to the atrial or ventricular myocardium with sensing and pacing functions. Implantable cardioverter defibrillators respond to episodes of ventricular tachycardia and fibrillation by discharging a defibrillating current. From a device perspective, several protective mechanisms have been developed in the permanent pacemaker/implantable cardioverter defibrillator to reduce the effects of electromagnetic interference. These involve generator material changes, lead modification, and better sensing and pacing algorithms. Magnetic resonance imaging compatible pacemakers have now been developed and are approved for use in Europe. From a urologist's perspective 5 procedures require the close monitoring of permanent pacemaker/implantable cardioverter defibrillator function. 1) For electrosurgery modifications in the device and in the methods of use have been recommended. 2) For extracorporeal shock wave lithotripsy the European Association of Urology provides some guidance with regard to patients with these devices. 3) During positron emission tomography the pulse generator and the lead area should be covered with lead to protect the device. 4) Magnetic resonance imaging is contraindicated but currently trials are under way for a new pacing system for safe use in the magnetic resonance imaging environment. 5) Patients can undergo radiotherapy with standard precautions but those with an abdominal permanent pacemaker/implantable cardioverter defibrillator require careful planning. Finally, implanted devices should have a full evaluation before and after the procedure. CONCLUSIONS: Clear guidelines are essential given the rapid advances in technology to enhance patient safety. Magnetic resonance imaging should be avoided in patients without a magnetic resonance imaging compatible device. However, patients can undergo extracorporeal shock wave lithotripsy, radiotherapy and positron emission tomography as long as the device is not in the path.
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Desfibriladores Implantables , Campos Electromagnéticos , Marcapaso Artificial , Enfermedades Urológicas/diagnóstico , Enfermedades Urológicas/terapia , Electrocirugia , Humanos , Complicaciones Intraoperatorias , Litotricia , Imagen por Resonancia Magnética , Monitoreo Intraoperatorio , Tomografía de Emisión de Positrones , RadioterapiaRESUMEN
Renin-angiotensin (RAS) system activation is associated with an increased risk of sudden death. Previously, we used cardiac-restricted angiotensin-converting enzyme (ACE) overexpression to construct a mouse model of RAS activation. These ACE 8/8 mice die prematurely and abruptly. Here, we have investigated cardiac electrophysiological abnormalities that may contribute to early mortality in this model. In ACE 8/8 mice, surface ECG voltages are reduced. Intracardiac electrograms showed atrial and ventricular potential amplitudes of 11% and 24% compared with matched wild-type (WT) controls. The atrioventricular (AV), atrio-Hisian (AH), and Hisian-ventricular (HV) intervals were prolonged 2.8-, 2.6-, and 3.9-fold, respectively, in ACE 8/8 vs. WT mice. Various degrees of AV nodal block were present only in ACE 8/8 mice. Intracardiac electrophysiology studies demonstrated that WT and heterozygote (HZ) mice were noninducible, whereas 83% of ACE 8/8 mice demonstrated ventricular tachycardia with burst pacing. Atrial connexin 40 (Cx40) and connexin 43 (Cx43) protein levels, ventricular Cx43 protein level, atrial and ventricular Cx40 mRNA abundances, ventricular Cx43 mRNA abundance, and atrial and ventricular cardiac Na(+) channel (Scn5a) mRNA abundances were reduced in ACE 8/8 compared with WT mice. ACE 8/8 mice demonstrated ventricular Cx43 dephosphorylation. Atrial and ventricular L-type Ca(2+) channel, Kv4.2 K(+) channel alpha-subunit, and Cx45 mRNA abundances and the peak ventricular Na(+) current did not differ between the groups. In isolated heart preparations, a connexin blocker, 1-heptanol (0.5 mM), produced an electrophysiological phenotype similar to that seen in ACE 8/8 mice. Therefore, cardiac-specific ACE overexpression resulted in changes in connexins consistent with the phenotype of low-voltage electrical activity, conduction defects, and induced ventricular arrhythmia. These results may help explain the increased risk of arrhythmia in states of RAS activation such as heart failure.
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Conexinas/metabolismo , Bloqueo Cardíaco/fisiopatología , Sistema de Conducción Cardíaco/fisiopatología , Peptidil-Dipeptidasa A/metabolismo , Taquicardia Ventricular/fisiopatología , Animales , Regulación Enzimológica de la Expresión Génica , Ratones , Regulación hacia ArribaRESUMEN
To investigate the local effects of angiotensin II on the heart, we created a mouse model with 100-fold normal cardiac angiotensin-converting enzyme (ACE), but no ACE expression in kidney or vascular endothelium. This was achieved by placing the endogenous ACE gene under the control of the alpha-myosin heavy chain promoter using targeted homologous recombination. These mice, called ACE 8/8, have cardiac angiotensin II levels that are 4.3-fold those of wild-type mice. Despite near normal blood pressure and a normal renal function, ACE 8/8 mice have a high incidence of sudden death. Both histological analysis and in vivo catheterization of the heart showed normal ventricular size and function. In contrast, both the left and right atria were three times normal size. ECG analysis showed atrial fibrillation and cardiac block. In conclusion, increased local production of angiotensin II in the heart is not sufficient to induce ventricular hypertrophy or fibrosis. Instead, it leads to atrial morphological changes, cardiac arrhythmia, and sudden death.
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Angiotensina II/metabolismo , Arritmias Cardíacas/patología , Fibrilación Atrial/patología , Muerte Súbita/patología , Modelos Animales de Enfermedad , Bloqueo Cardíaco/patología , Peptidil-Dipeptidasa A/fisiología , Animales , Presión Sanguínea , Bradiquinina/metabolismo , Femenino , Marcación de Gen , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Cadenas Pesadas de Miosina/genética , Peptidil-Dipeptidasa A/genética , Regiones Promotoras Genéticas , Recombinación Genética , Distribución TisularRESUMEN
Computed tomography is widely used to diagnose acute pancreatitis. Iodinated contrast medium lengthens the duration of pancreatitis and may increase the incidence of local or systemic complications. Total parenteral nutrition including IV lipid emulsion plays an important role in the management of patients with pancreatitis. Induction of pancreatitis by IV lipid emulsion is exceedingly rare. We report a 30-year-old patient with the acquired immunodeficiency syndrome in whom pancreatitis was exacerbated by oral and IV contrast medium and also by IV lipid emulsion in the absence of hypertriglyceridemia. Exclusion of the lipid emulsion resulted in prompt reduction of lipase levels on three separate occasions. This case is the first to implicate IV lipid emulsion in the exacerbation of pancreatitis in a patient with acquired immunodeficiency syndrome and normal baseline triglyceride levels. Thus, this case report suggests that we must exercise caution in the use of contrast medium and IV lipids in the diagnosis and management of acute pancreatitis.
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Síndrome de Inmunodeficiencia Adquirida/complicaciones , Medios de Contraste/efectos adversos , Emulsiones Grasas Intravenosas/efectos adversos , Yohexol/efectos adversos , Pancreatitis/etiología , Enfermedad Aguda , Adulto , Femenino , HumanosRESUMEN
This brief report describes an asymptomatic patient with a myocardial mass. Two-dimensional echocardiography, technetium Tc 99m cardiac nuclear scan, and transesophageal echocardiography were performed to define the mass. The mass, which involved the subvalvar right ventricular free wall, was resected and determined to be a metastatic carcinoid tumor by histologic and immunohistochemical analysis. Further investigation revealed the presence of a midgut carcinoid tumor located within the terminal ileum, which was also resected surgically. The patient recovered well after surgery and adjunctive chemotherapy. To our knowledge, this is the first report of comprehensive nuclear and echocardiographic imaging, supplemented by surgical and pathologic findings, in an asymptomatic patient with isolated myocardial metastasis of an ileal carcinoid tumor.