RESUMEN
BACKGROUND: The transmural distribution of apamin-sensitive small conductance Ca(2+)-activated K(+) (SK) current (IKAS) in failing human ventricles remains unclear. METHODS AND RESULTS: We optically mapped left ventricular wedge preparations from 12 failing native hearts and 2 rejected cardiac allografts explanted during transplant surgery. We determined transmural action potential duration (APD) before and after 100 nmol/L apamin administration in all wedges and after sequential administration of apamin, chromanol, and E4031 in 4 wedges. Apamin prolonged APD from 363 ms (95% confidence interval [CI], 341-385) to 409 (95% CI, 385-434; P<0.001) in all hearts, and reduced the transmural conduction velocity from 36 cm/s (95% CI, 30-42) to 32 cm/s (95% CI, 27-37; P=0.001) in 12 native failing hearts at 1000 ms pacing cycle length (PCL). The percent APD prolongation is negatively correlated with baseline APD and positively correlated with PCL. Only 1 wedge had M-cell islands. The percentages of APD prolongation in the last 4 hearts at 2000 ms PCL after apamin, chromanol, and E4031 were 9.1% (95% CI, 3.9-14.2), 17.3% (95% CI, 3.1-31.5), and 35.9% (95% CI, 15.7-56.1), respectively. Immunohistochemical staining of subtype 2 of SK protein showed increased expression in intercalated discs of myocytes. CONCLUSIONS: SK current is important in the transmural repolarization in failing human ventricles. The magnitude of IKAS is positively correlated with the PCL, but negatively correlated with APD when PCL is fixed. There is abundant subtype 2 of SK protein in the intercalated discs of myocytes.
Asunto(s)
Insuficiencia Cardíaca/metabolismo , Ventrículos Cardíacos/metabolismo , Potasio/metabolismo , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/metabolismo , Disfunción Ventricular Izquierda/metabolismo , Potenciales de Acción , Adulto , Anciano , Estimulación Cardíaca Artificial , Femenino , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/fisiopatología , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/fisiopatología , Humanos , Técnicas In Vitro , Masculino , Persona de Mediana Edad , Perfusión , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/antagonistas & inhibidores , Volumen Sistólico , Factores de Tiempo , Disfunción Ventricular Izquierda/diagnóstico , Disfunción Ventricular Izquierda/fisiopatología , Función Ventricular Izquierda , Remodelación VentricularRESUMEN
Spinal cord stimulation with implantable devices has been used worldwide for decades to treat regional pain conditions and cardiac angina refractory to conventional therapies. Preclinical studies with spinal cord stimulation in experimental animal models of heart disease have described interesting effects on cardiac and autonomic nervous system physiology. In canine and porcine animals with failing hearts, spinal cord stimulation reverses left ventricular dilation and improves cardiac function, while suppressing the prevalence of cardiac arrhythmias. In this paper, we present further canine studies that determined the optimal site and intensity of spinal cord stimulation that produced the most robust and beneficial clinical response in heart failure animals. We then explore and discuss the clinically relevant aspects and potential impediments that may be encountered in translating spinal cord stimulation to human patients with advanced cardiac disease.
Asunto(s)
Arritmias Cardíacas/fisiopatología , Sistema Nervioso Autónomo/fisiopatología , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/terapia , Estimulación de la Médula Espinal/métodos , Animales , Modelos Animales de Enfermedad , HumanosRESUMEN
BACKGROUND: Ischemia suppresses action potentials (APs) by elevating interstitial K(+) and activating KATP channels and alters cytosolic Ca(2+) transients (CaTs) via metabolic inhibition. OBJECTIVE: To test the hypothesis that AP and CaT respond to ischemia with different spatiotemporal courses and patterns. METHODS: Thirty-four transmural wedges were isolated from canine left ventricular free walls, perfused arterially, and stained with voltage- and Ca(2+)-sensitive dyes. Twenty-eight wedges underwent 15 minutes of arterial occlusion during pacing at a cycle length (PCL) of 300 ms (n = 19) or 600 ms (n = 9). Six other wedges had a sequential reduction of perfusion flow from full to 50%, 25%, and 10% at 300 ms PCL. AP and CaT were recorded on the cut-exposed transmural surfaces with an optical mapping system. RESULTS: Although ischemia suppressed APs, it enhanced CaT to 150% ± 10% (more in the endocardium than in the epicardium) and induced CaT alternans during the first 2 minutes of arterial occlusion and then suppressed CaT (PCL = 300 ms). Enhancement of CaT (to 159% ± 23%) also occurred during low flow (25%) perfusion (PCL = 300 ms). Faster suppression of AP occurred with subepicardial preference as compared to that of CaT. After 15 minutes of arterial occlusion, AP and CaT remained in only small regions during 300 ms PCL but were preserved in most regions during 600 ms PCL. CONCLUSIONS: Early ischemia induced a surge and alternans in CaT and caused its dissociation from AP both in time course of suppression and in spatial distribution. These results suggested that there were different cellular regulatory mechanisms of AP and of CaT in responding to ischemia from arterial occlusion.
Asunto(s)
Potenciales de Acción/fisiología , Calcio/metabolismo , Endocardio/metabolismo , Ventrículos Cardíacos/metabolismo , Isquemia Miocárdica/metabolismo , Animales , Canales de Calcio/metabolismo , Perros , MasculinoRESUMEN
BACKGROUND: We previously reported that IKAS are heterogeneously upregulated in failing rabbit ventricles and play an important role in arrhythmogenesis. This study goal is to test the hypothesis that subtype 2 of the small-conductance Ca(2+) activated K(+) (SK2) channel and apamin-sensitive K(+) currents (IKAS) are upregulated in failing human ventricles. METHODS AND RESULTS: We studied 12 native hearts from transplant recipients (heart failure [HF] group) and 11 ventricular core biopsies from patients with aortic stenosis and normal systolic function (non-HF group). IKAS and action potential were recorded with patch-clamp techniques, and SK2 protein expression was studied by Western blotting. When measured at 1 µmol/L Ca(2+) concentration, IKAS was 4.22 (median) (25th and 75th percentiles, 2.86 and 6.96) pA/pF for the HF group (n=11) and 0.98 (0.54 and 1.72) pA/pF for the non-HF group (n=8, P=0.008). IKAS was lower in the midmyocardial cells than in the epicardial and the endocardial cells. The Ca(2+) dependency of IKAS in HF myocytes was shifted leftward compared to non-HF myocytes (Kd 314 versus 605 nmol/L). Apamin (100 nmol/L) increased the action potential durations by 1.77% (-0.9% and 7.3%) in non-HF myocytes and by 11.8% (5.7% and 13.9%) in HF myocytes (P=0.02). SK2 protein expression was 3-fold higher in HF than in non-HF. CONCLUSIONS: There is heterogeneous upregulation of IKAS densities in failing human ventricles. The midmyocardial layer shows lower IKAS densities than epicardial and endocardial layers of cells. Increase in both Ca(2+) sensitivity and SK2 protein expression contributes to the IKAS upregulation.
Asunto(s)
Apamina/farmacología , Insuficiencia Cardíaca/metabolismo , Ventrículos Cardíacos/metabolismo , Miocardio/metabolismo , Potasio/metabolismo , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/efectos de los fármacos , Potenciales de Acción , Adulto , Anciano , Biopsia , Western Blotting , Calcio/metabolismo , Estudios de Casos y Controles , Femenino , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/cirugía , Trasplante de Corazón , Ventrículos Cardíacos/fisiopatología , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Técnicas de Placa-Clamp , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/metabolismo , Volumen Sistólico , Factores de Tiempo , Regulación hacia Arriba , Función Ventricular IzquierdaRESUMEN
Ventricular arrhythmia (VA) is a significant factor in the clinical management of patients with congestive heart failure (CHF). Understanding the implications of VA in ventricular assist device-supported CHF patients is critical to appropriate clinical decision making in this special population. This article details research findings on this topic, and attempts to link them to practical patient management strategies.
Asunto(s)
Corazón Auxiliar/efectos adversos , Taquicardia Ventricular/etiología , Taquicardia Ventricular/prevención & control , Disfunción Ventricular Derecha/etiología , Disfunción Ventricular Derecha/prevención & control , Fibrilación Ventricular/etiología , Fibrilación Ventricular/prevención & control , HumanosRESUMEN
Atrial fibrillation (AF) is a common cardiac arrhythmia that is associated with severe consequences, including symptoms, haemodynamic instability, increased cardiovascular mortality and stroke. While other arrhythmias such as torsades de pointes and sinus bradycardia are more typically thought of as drug induced, AF may also be precipitated by drug therapy, although ascribing causality to drug-associated AF is more difficult than with other drug-induced arrhythmias. Drug-induced AF is more likely to occur in patients with risk factors and co-morbidities that commonly co-exist with AF, such as advanced age, alcohol consumption, family history of AF, hypertension, thyroid dysfunction, sleep apnoea and heart disease. New-onset AF has been associated with cardiovascular drugs such as adenosine, dobutamine and milrinone. In addition, medications such as corticosteroids, ondansetron and antineoplastic agents such as paclitaxel, mitoxantrone and doxorubicin have been reported to induce AF. Whether bisphosphonate drugs are associated with new-onset AF remains controversial and requires further study. The potential contribution of specific drug therapy should be considered when patients present with new-onset AF.
Asunto(s)
Arritmias Cardíacas/inducido químicamente , Fibrilación Atrial/inducido químicamente , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Factores de RiesgoRESUMEN
Heart failure is the final common pathway in many forms of heart disease, and is associated with excessive morbidity and mortality. Pathophysiologic alterations in the interaction between the heart and the autonomic nervous system in advanced heart failure have been noted for decades. Over the last decade, great advances have been made in the medical and surgical treatment of heart failure - and some of these modalities target the neuro-cardiac axis. Despite these advances, many patients progress to end-stage heart failure and death. Recently, device-based therapy targeting the neuro-cardiac axis with various forms of neuromodulatory stimuli has been shown to improve heart function in experimental heart failure models. These include spinal cord stimulation, vagal nerve stimulation, and baroreflex modulation. Human trials are now underway to evaluate the safety and efficacy of these device-based neuromodulatory modalities in the heart failure population.
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Barorreflejo , Terapia por Estimulación Eléctrica/métodos , Insuficiencia Cardíaca/terapia , Estimulación de la Médula Espinal/métodos , Estimulación del Nervio Vago/métodos , Sistema Nervioso Autónomo/fisiopatología , Corazón/inervación , Corazón/fisiopatología , Humanos , SimpatectomíaRESUMEN
BACKGROUND: We hypothesize that left-sided low-level vagus nerve stimulation (LL-VNS) can suppress sympathetic outflow and reduce atrial tachyarrhythmias in ambulatory dogs. METHODS AND RESULTS: We implanted a neurostimulator in 12 dogs to stimulate the left cervical vagus nerve and a radiotransmitter for continuous recording of left stellate ganglion nerve activity, vagal nerve activities, and ECGs. Group 1 dogs (N=6) underwent 1 week of continuous LL-VNS. Group 2 dogs (N=6) underwent intermittent rapid atrial pacing followed by active or sham LL-VNS on alternate weeks. Integrated stellate ganglion nerve activity was significantly reduced during LL-VNS (7.8 mV/s; 95% confidence interval [CI] 6.94 to 8.66 versus 9.4 mV/s [95% CI, 8.5 to 10.3] at baseline; P=0.033) in group 1. The reduction was most apparent at 8 am, along with a significantly reduced heart rate (P=0.008). Left-sided low-level vagus nerve stimulation did not change vagal nerve activity. The density of tyrosine hydroxylase-positive nerves in the left stellate ganglion 1 week after cessation of LL-VNS were 99 684 µm(2)/mm(2) (95% CI, 28 850 to 170 517) in LL-VNS dogs and 186 561 µm(2)/mm(2) (95% CI, 154 956 to 218 166; P=0.008) in normal dogs. In group 2, the frequencies of paroxysmal atrial fibrillation and tachycardia during active LL-VNS were 1.4/d (95% CI, 0.5 to 5.1) and 8.0/d (95% CI, 5.3 to 12.0), respectively, significantly lower than during sham stimulation (9.2/d [95% CI, 5.3 to 13.1]; P=0.001 and 22.0/d [95% CI, 19.1 to 25.5], P<0.001, respectively). CONCLUSIONS: Left-sided low-level vagus nerve stimulation suppresses stellate ganglion nerve activities and reduces the incidences of paroxysmal atrial tachyarrhythmias in ambulatory dogs. Significant neural remodeling of the left stellate ganglion is evident 1 week after cessation of continuous LL-VNS.
Asunto(s)
Terapia por Estimulación Eléctrica/métodos , Ganglio Estrellado/fisiología , Taquicardia Atrial Ectópica/fisiopatología , Taquicardia Atrial Ectópica/terapia , Nervio Vago/fisiología , Animales , Modelos Animales de Enfermedad , Perros , Corazón/inervación , Corazón/fisiología , Locomoción , Masculino , Marcapaso Artificial , Sistema Nervioso Simpático/fisiologíaRESUMEN
RATIONALE: Fibrillation/defibrillation episodes in failing ventricles may be followed by action potential duration (APD) shortening and recurrent spontaneous ventricular fibrillation (SVF). OBJECTIVE: We hypothesized that activation of apamin-sensitive small-conductance Ca(2+)-activated K(+) (SK) channels is responsible for the postshock APD shortening in failing ventricles. METHODS AND RESULTS: A rabbit model of tachycardia-induced heart failure was used. Simultaneous optical mapping of intracellular Ca(2+) and membrane potential (V(m)) was performed in failing and nonfailing ventricles. Three failing ventricles developed SVF (SVF group); 9 did not (no-SVF group). None of the 10 nonfailing ventricles developed SVF. Increased pacing rate and duration augmented the magnitude of APD shortening. Apamin (1 µmol/L) eliminated recurrent SVF and increased postshock APD(80) in the SVF group from 126±5 to 153±4 ms (P<0.05) and from 147±2 to 162±3 ms (P<0.05) in the no-SVF group but did not change APD(80) in nonfailing group. Whole cell patch-clamp studies at 36°C showed that the apamin-sensitive K(+) current (I(KAS)) density was significantly larger in the failing than in the normal ventricular epicardial myocytes, and epicardial I(KAS) density was significantly higher than midmyocardial and endocardial myocytes. Steady-state Ca(2+) response of I(KAS) was leftward-shifted in the failing cells compared with the normal control cells, indicating increased Ca(2+) sensitivity of I(KAS) in failing ventricles. The K(d) was 232±5 nmol/L for failing myocytes and 553±78 nmol/L for normal myocytes (P=0.002). CONCLUSIONS: Heart failure heterogeneously increases the sensitivity of I(KAS) to intracellular Ca(2+), leading to upregulation of I(KAS), postshock APD shortening, and recurrent SVF.
Asunto(s)
Insuficiencia Cardíaca/metabolismo , Ventrículos Cardíacos/metabolismo , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/biosíntesis , Fibrilación Ventricular/metabolismo , Animales , Apamina/uso terapéutico , Señalización del Calcio/fisiología , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/prevención & control , Ventrículos Cardíacos/patología , Conejos , Prevención Secundaria , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/fisiología , Fibrilación Ventricular/tratamiento farmacológico , Fibrilación Ventricular/prevención & controlRESUMEN
BACKGROUND: Spinal cord stimulation (SCS) reduces the incidence of ventricular tachyarrhythmias in experimental models. This study investigated the effects of long-term SCS on ventricular function in a postinfarction canine heart failure model. METHODS AND RESULTS: In stage 1, dogs underwent implantable cardioverter-defibrillator implantation and embolization of the left anterior descending artery followed by right ventricular pacing (240 ppm) for 3 weeks to produce heart failure. In stage 2, 28 surviving animals were assigned to the SCS (delivered at the T4/T5 spinal region for 2 hours 3 times a day), medicine (MED; carvedilol therapy at 12.5 mg PO BID), or control (CTRL; no therapy) group for the initial phase 1 study. In a subsequent phase 2 study, 32 stage 1 survivors were equally randomized to the SCS, MEDS (carvedilol plus ramipril 2.5 mg PO QD), SCS plus MEDS (concurrent therapy), or CTRL group. Animals were monitored for 5 weeks (phase 1) or 10 weeks (phase 2). In stage 3, all phase 1 animals underwent circumflex artery balloon occlusion for 1 hour. In the SCS group, left ventricular ejection fraction was 65+/-5% at baseline, 17+/-3% at the end of stage 1, and 47+/-7% at the end of stage 2. In the MED group, left ventricular ejection fraction was 61+/-4% at baseline, 18+/-3% at the end of stage 1, and 34+/-4% at the end of stage 2. In the CTRL group, left ventricular ejection fraction was 64+/-5% at baseline, 19+/-5% at the end of stage 1, and 28+/-3% at the end of stage 2. Left ventricular ejection fraction was significantly improved in the SCS compared with the MED and CTRL groups (P<0.001 for both). The mean number of spontaneous nonsustained ventricular tachyarrhythmias during stage 2 and the occurrence of ischemic ventricular tachyarrhythmias during stage 3 also were significantly decreased in the SCS (27+/-17 and 27%, respectively; P<0.03) and MED (58+/-42 and 33%; P<0.05) versus CTRL (88+/-52 and 76%) group. After 10 weeks in the phase 2 studies, the greatest recovery in ejection fraction was noted in the SCS (52+/-5%) and SCS+MEDS (46+/-4%) groups compared with the MEDS (38+/-2%) and CTRL (31+/-4%) groups. CONCLUSIONS: SCS significantly improved cardiac contractile function and decreased ventricular arrhythmias in canine heart failure.
Asunto(s)
Estimulación Cardíaca Artificial/métodos , Modelos Animales de Enfermedad , Insuficiencia Cardíaca/terapia , Infarto del Miocardio/terapia , Taquicardia Ventricular/terapia , Función Ventricular/fisiología , Animales , Desfibriladores Implantables , Perros , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/fisiopatología , Masculino , Infarto del Miocardio/complicaciones , Infarto del Miocardio/fisiopatología , Médula Espinal/fisiología , Taquicardia Ventricular/etiología , Taquicardia Ventricular/fisiopatologíaAsunto(s)
Arritmias Cardíacas/inducido químicamente , Arritmias Cardíacas/diagnóstico , Distrofia Miotónica , Bloqueadores de los Canales de Sodio/efectos adversos , Adulto , Arritmias Cardíacas/complicaciones , Humanos , Masculino , Distrofia Miotónica/clasificación , Distrofia Miotónica/complicaciones , Distrofia Miotónica/tratamiento farmacológico , Canales de Sodio/fisiologíaRESUMEN
BACKGROUND: Although radiofrequency catheter ablation (RFCA) has been used to treat patients with Brugada syndrome (BS), it is difficult to eliminate polymorphic ventricular tachycardias (VTs) completely. OBJECTIVE: The purpose of this study was to determine the efficacy of RFCA in eliminating recurrent VTs in an experimental model of BS. METHODS: We optically mapped electrical activity on the epicardial (n = 9) or transmural (n = 8) surface in 17 arterially perfused canine right ventricle preparations. Using pinacidil (5 microM) and pilsicainide (5 microM), we induced a model of BS that showed spontaneous VT. We then applied RFCA to the earliest activation site of premature ventricular complexes (PVCs) in the epicardium (EPI) or endocardium (ENDO) of the RV. RESULTS: After induction of BS, the transmural electrocardiogram (ECG) showed BS-type ECG in association with prominent heterogeneity of action potential duration (APDs) within the EPI (APD: maximum 272 +/- 39 ms, minimum 200 +/- 39 ms, P < .01), but not within the ENDO. PVCs originated in the EPI region having short APDs and triggered functional reentry causing VT. Multiple epicardial foci of PVCs existed in each tissue (3.7 +/- 1.9 foci/tissue). RFCA at the earliest activation site of PVCs in the EPI disconnected the short and long APD regions and eliminated all PVCs and VTs, although APD heterogeneity still existed. All successful RFCA lesions were confined to the EPI. RFCA in the ENDO failed to eliminate VT or PVCs. CONCLUSION: These experimental observations suggest that RFCA applied to the EPI may be more effective than applied to the ENDO in eliminating VT in patients with BS.
Asunto(s)
Síndrome de Brugada/complicaciones , Ablación por Catéter/métodos , Sistema de Conducción Cardíaco/cirugía , Frecuencia Cardíaca/fisiología , Pericardio/cirugía , Taquicardia Ventricular/cirugía , Animales , Síndrome de Brugada/fisiopatología , Modelos Animales de Enfermedad , Perros , Técnicas Electrofisiológicas Cardíacas/métodos , Sistema de Conducción Cardíaco/fisiopatología , Masculino , Pericardio/inervación , Taquicardia Ventricular/etiología , Taquicardia Ventricular/fisiopatología , Resultado del TratamientoRESUMEN
The high-affinity choline transporter (CHT1) system is an attractive target for the development of positron emission tomography (PET) biomarkers to probe brain, cardiac, and cancer diseases. An efficient and convenient synthesis of new radiolabeled CHT1 inhibitors [(11)C]hemicholinium-3 and [(18)F]hemicholinium-3 by solid-phase extraction (SPE) technique using a cation-exchange CM Sep-Pak cartridge has been well developed. The preliminary evaluation of both tracers through biodistribution studies in 9L-glioma rats has been performed, and the uptakes in the heart and tumor were observed, while very low brain uptake was seen.
Asunto(s)
Proteínas de Transporte de Catión/antagonistas & inhibidores , Hemicolinio 3/síntesis química , Hemicolinio 3/farmacocinética , Radiofármacos/síntesis química , Animales , Encéfalo/metabolismo , Radioisótopos de Carbono , Radioisótopos de Flúor , Glioma/diagnóstico , Glioma/metabolismo , Miocardio/metabolismo , Tomografía de Emisión de Positrones/métodos , Unión Proteica , Radiofármacos/farmacocinética , RatasRESUMEN
[(11)C]Hemicholinium-15 ([(11)C]HC-15) and [(18)F]hemicholinium-15 ([(18)F]HC-15) have been synthesized as new potential PET tracers for the heart high-affinity choline uptake (HACU) system. [(11)C]HC-15 was prepared by N-[(11)C]methylation of the appropriate precursor, 4-methyl-2-phenyl-morpholin-2-ol, using [(11)C]CH(3)OTf in 55-70% radiochemical yield decay corrected to end of bombardment (EOB) and 2-3Ci/mumol specific activity at end of synthesis (EOS). [(18)F]HC-15 was prepared by N-[(18)F]fluoromethylation of the precursor using [(18)F]FCH(2)OTf in 20-30% radiochemical yield decay corrected to EOB and >1.0Ci/mumol specific activity at EOS. The biodistribution of both compounds was determined in rats at 20min post-intravenous injection, and the results show the heart region uptakes 1.32+/-0.75%ID/g in R-ventricle for [(11)C]HC-15 and 1.28+/-0.81%ID/g in L-ventricle for [(18)F]HC-15, respectively. The dynamic PET imaging studies of [(11)C]HC-15 in rats were acquired 60min post-intravenous injection of the tracer using the IndyPET-II scanner. For the blocking experiments, the rats were intravenously pretreated with 3.0mg/kg of unlabeled HC-15 prior to [(11)C]HC-15 injection. [(11)C]HC-15 rat heart PET studies show rapid heart uptake to give clear heart images. The rat heart PET blocking studies found no significant blocking effect. The dynamic PET studies in normal and ablated dogs were performed using Siemens PET scanner with [(13)N]NH(3), [(11)C]HC-15, and [(18)F]HC-15. PET studies in dogs of both [(11)C]HC-15 and [(18)F]HC-15 also show significant heart uptake and give images of the heart. However, there is no significant change in [(11)C]HC-15 L-ventricle uptake following radiofrequency ablation in the dog. These results suggest that the localization of HC-15 tracers in the heart is mediated by non-specific processes, and the visualization of HC-15 tracers on the heart is related to non-specific binding of HACU.
Asunto(s)
Radioisótopos de Carbono , Colina/metabolismo , Radioisótopos de Flúor , Corazón/fisiología , Hemicolinio 3 , Tomografía de Emisión de Positrones , Radiofármacos , Animales , Radioisótopos de Carbono/farmacocinética , Perros , Femenino , Radioisótopos de Flúor/farmacocinética , Corazón/efectos de los fármacos , Hemicolinio 3/síntesis química , Hemicolinio 3/farmacocinética , Ensayo de Unión Radioligante , Radiofármacos/síntesis química , Radiofármacos/farmacocinética , Ratas , Ratas Endogámicas F344 , Ratas Sprague-Dawley , Distribución TisularAsunto(s)
Muerte Súbita Cardíaca/etiología , Muerte Súbita Cardíaca/prevención & control , Fibrilación Ventricular/complicaciones , Fibrilación Ventricular/fisiopatología , Angina Inestable/fisiopatología , Arritmias Cardíacas/complicaciones , Arritmias Cardíacas/fisiopatología , Muerte Súbita Cardíaca/patología , Electrocardiografía , Humanos , Canales Iónicos/genética , Canales Iónicos/fisiopatología , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/fisiopatología , Mutación/genética , Infarto del Miocardio/patología , Factores de Riesgo , Taquicardia Ventricular/complicaciones , Taquicardia Ventricular/fisiopatología , Disfunción Ventricular Izquierda/complicaciones , Disfunción Ventricular Izquierda/fisiopatología , Fibrilación Ventricular/genéticaRESUMEN
A new AChE tracer N-[(11)C]methyl-3-[[(dimethylamino)carbonyl]oxy]-2-(2',2'-diphenylpropionoxymethyl)pyridinium ([(11)C]MDDP, [(11)C]1) has been synthesized in 40-65% radiochemical yield. Initial PET dynamic studies of [(11)C]MDDP in rat heart showed rapid heart uptake and blood pool clearance to give high-quality heart images. Blocking studies of [(11)C]MDDP with pretreatment drug neostigmine in rats found only minor reductions in rat heart [(11)C]MDDP retention. The results suggest that [(11)C]MDDP delineates the heart very clearly, and the uptakes of [(11)C]MDDP in rat heart might be related to non-specific binding.
Asunto(s)
Acetilcolinesterasa/metabolismo , Miocardio/enzimología , Compuestos de Piridinio/química , Compuestos de Piridinio/síntesis química , Acetilcolinesterasa/sangre , Animales , Encéfalo/enzimología , Butirilcolinesterasa/sangre , Butirilcolinesterasa/metabolismo , Tomografía de Emisión de Positrones , RatasRESUMEN
A series of 11C-labeled analogs of the acetylcholinesterase (AChE) inhibitor pyridostigmine have been synthesized for evaluation as new potential positron emission tomography (PET) imaging agents for heart AChE. The appropriate precursors for radiolabeling were slightly modified from commercial reagents. The new tracers [11C]pyridostigmine (1), [11C]para-pyridostigmine (2) and [11C]ortho-pyridostigmine (3) were prepared by N-[11C]methylation of the precursors using [11C]methyl triflate. Pure target compounds were isolated by a solid-phase extraction (SPE) purification procedure with 60-85% radiochemical yields (decay corrected to end of bombardment), and a synthesis time of 10-15 min. The initial PET dynamic studies of compounds (1-3) in rat heart showed rapid heart uptake and blood pool clearance to give high quality heart images. These results suggest the new tracers delineate the heart very clearly and could be potential heart AChE imaging agents.
Asunto(s)
Acetilcolinesterasa/metabolismo , Corazón/diagnóstico por imagen , Miocardio/metabolismo , Tomografía de Emisión de Positrones/métodos , Bromuro de Piridostigmina/farmacocinética , Animales , Radioisótopos de Carbono/farmacocinética , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/farmacocinética , Estudios de Factibilidad , Femenino , Humanos , Masculino , Tasa de Depuración Metabólica , Especificidad de Órganos , Radiofármacos/síntesis química , Radiofármacos/farmacocinética , Ratas , Ratas Sprague-Dawley , Distribución TisularRESUMEN
OBJECTIVES: We used optical mapping to characterize the reentrant circuit of ventricular tachycardia (VT) during acute myocardial infarction (MI) in isolated canine left ventricular preparations. BACKGROUND: The nature of the reentrant circuit that underlies VT during acute MI is not well understood. METHODS: Using optical mapping in isolated canine left ventricular preparations, we characterized the reentrant circuit of monomorphic VT (mean cycle length 245.3 +/- 15.6 ms, n = 7) induced by programmed stimulation during acute MI. RESULTS: Optical mapping during VT revealed a functional reentrant circuit consisting of four components: (1) a protected isthmus located between the infarction area and the functional line of block; (2) an entrance site located at one end of the isthmus; (3) an exit site located at the other end of the isthmus; and (4) an outer loop consisting of nonischemic normal tissue, connecting the exit and entrance sites. Rate-dependent slow conduction within the border zone was associated with significant changes (n = 6) in action potential amplitude (99.1 +/- 0.4 vs 71.4 +/- 0.6 mV, P < .01), maximal diastolic potential (-80.6 +/- 0.2 vs -65.4 +/- 0.6 mV, P < .05), action potential duration at 90% repolarization (APD(90); 188.4 +/- 1.0 vs 164.3 +/- 3.1 ms, P < .05), and dV/dt (302.4 +/- 7.9 vs 168.5 +/- 3.6 V/s, P < .05). Compared to preparations with no inducible VT (n = 7), formation of a functional line of block was the key mechanism for initiation of functional reentry in preparations with VT. When comparing preparations with sustained and nonsustained VT, preservation of slow conduction over the isthmus was the key component for maintenance of sustained VT. CONCLUSIONS: The reentrant circuit of monomorphic VT in the setting of acute MI involved both the infarction border zone and nonischemic normal tissue. The underlying mechanism is related to the presence of rate-dependent slow conduction and the development of a functional line of block in the border zone.