RESUMEN
BACKGROUND: The nitroxyl (HNO) donor, Angeli's salt, exerts positive inotropic, lusitropic, and vasodilator effects in vivo that are cAMP independent. Its clinical usefulness is limited by chemical instability and cogeneration of nitrite which itself has vascular effects. Here, we report on effects of a novel, stable, pure HNO donor (CXL-1020) in isolated myoctyes and intact hearts in experimental models and in patients with heart failure (HF). METHODS AND RESULTS: CXL-1020 converts solely to HNO and inactive CXL-1051 with a t1/2 of 2 minutes. In adult mouse ventricular myocytes, it dose dependently increased sarcomere shortening by 75% to 210% (50-500 µmol/L), with a ≈30% rise in the peak Ca(2+) transient only at higher doses. Neither inhibition of protein kinase A nor soluble guanylate cyclase altered this contractile response. Unlike isoproterenol, CXL-1020 was equally effective in myocytes from normal or failing hearts. In anesthetized dogs with coronary microembolization-induced HF, CXL-1020 reduced left ventricular end-diastolic pressure and myocardial oxygen consumption while increasing ejection fraction from 27% to 40% and maximal ventricular power index by 42% (both P<0.05). In conscious dogs with tachypacing-induced HF, CXL-1020 increased contractility assessed by end-systolic elastance and provided venoarterial dilation. Heart rate was minimally altered. In patients with systolic HF, CXL-1020 reduced both left and right heart filling pressures and systemic vascular resistance, while increasing cardiac and stroke volume index. Heart rate was unchanged, and arterial pressure declined modestly. CONCLUSIONS: These data show the functional efficacy of a novel pure HNO donor to enhance myocardial function and present first-in-man evidence for its potential usefulness in HF. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01096043, NCT01092325.
Asunto(s)
Insuficiencia Cardíaca/tratamiento farmacológico , Óxidos de Nitrógeno/administración & dosificación , Volumen Sistólico/efectos de los fármacos , Función Ventricular Izquierda/fisiología , Animales , Antioxidantes/administración & dosificación , Perros , Relación Dosis-Respuesta a Droga , Femenino , Radicales Libres , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Ratones , Contracción Miocárdica/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Resultado del TratamientoRESUMEN
BACKGROUND: Cardiac resynchronization therapy (CRT) is widely applied in patients with heart failure and dyssynchronous contraction (DHF), but the electrophysiological consequences of CRT in heart failure remain largely unexplored. METHODS AND RESULTS: Adult dogs underwent left bundle-branch ablation and either right atrial pacing (190 to 200 bpm) for 6 weeks (DHF) or 3 weeks of right atrial pacing followed by 3 weeks of resynchronization by biventricular pacing at the same pacing rate (CRT). Isolated left ventricular anterior and lateral myocytes from nonfailing (control), DHF, and CRT dogs were studied with the whole-cell patch clamp. Quantitative polymerase chain reaction and Western blots were performed to measure steady state mRNA and protein levels. DHF significantly reduced the inward rectifier K(+) current (I(K1)), delayed rectifier K(+) current (I(K)), and transient outward K(+) current (I(to)) in both anterior and lateral cells. CRT partially restored the DHF-induced reduction of I(K1) and I(K) but not I(to), consistent with trends in the changes in steady state K(+) channel mRNA and protein levels. DHF reduced the peak inward Ca(2+) current (I(Ca)) density and slowed I(Ca) decay in lateral compared with anterior cells, whereas CRT restored peak I(Ca) amplitude but did not hasten decay in lateral cells. Calcium transient amplitudes were depressed and the decay was slowed in DHF, especially in lateral myocytes. CRT hastened the decay in both regions and increased the calcium transient amplitude in lateral but not anterior cells. No difference was found in Ca(V)1.2 (alpha1C) mRNA or protein expression, but reduced Ca(V)beta2 mRNA was found in DHF cells. DHF reduced phospholamban, ryanodine receptor, and sarcoplasmic reticulum Ca(2+) ATPase and increased Na(+)-Ca(2+) exchanger mRNA and protein. CRT did not restore the DHF-induced molecular remodeling, except for sarcoplasmic reticulum Ca(2+) ATPase. Action potential durations were significantly prolonged in DHF, especially in lateral cells, and CRT abbreviated action potential duration in lateral but not anterior cells. Early afterdepolarizations were more frequent in DHF than in control cells and were reduced with CRT. CONCLUSIONS: CRT partially restores DHF-induced ion channel remodeling and abnormal Ca(2+) homeostasis and attenuates the regional heterogeneity of action potential duration. The electrophysiological changes induced by CRT may suppress ventricular arrhythmias, contribute to the survival benefit of this therapy, and improve the mechanical performance of the heart.
Asunto(s)
Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/terapia , Miocitos Cardíacos/fisiología , Marcapaso Artificial , Potenciales de Acción/fisiología , Animales , Bloqueo de Rama/diagnóstico , Bloqueo de Rama/fisiopatología , Bloqueo de Rama/terapia , Calcio/metabolismo , Canales de Calcio/genética , Canales de Calcio/metabolismo , Circulación Coronaria , Perros , Ecocardiografía , Electrocardiografía , Insuficiencia Cardíaca/diagnóstico por imagen , Homeostasis/fisiología , Proteínas de Interacción con los Canales Kv/genética , Proteínas de Interacción con los Canales Kv/metabolismo , Masculino , Técnicas de Placa-Clamp , Canales de Potasio de Rectificación Interna/genética , Canales de Potasio de Rectificación Interna/metabolismo , ARN Mensajero/metabolismo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/genética , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Canales de Potasio Shal/genética , Canales de Potasio Shal/metabolismoRESUMEN
BACKGROUND: Cardiac resynchronization therapy (CRT) is the first clinical heart failure treatment that improves chamber systolic function in both the short-term and long-term yet also reduces mortality. The mechanical impact of CRT is immediate and well documented, yet its long-term influences on myocyte function and adrenergic modulation that may contribute to its sustained benefits are largely unknown. METHODS AND RESULTS: We used a canine model of dyssynchronous heart failure (DHF; left bundle ablation, atrial tachypacing for 6 weeks) and CRT (DHF for 3 weeks, biventricular tachypacing for subsequent 3 weeks), contrasting both to nonfailing controls. CRT restored contractile synchrony and improved systolic function compared with DHF. Myocyte sarcomere shortening and calcium transients were markedly depressed at rest and after isoproterenol stimulation in DHF (both anterior and lateral walls), and CRT substantially improved both. In addition, beta(1) and beta(2) stimulation was enhanced, coupled to increased beta(1) receptor abundance but no change in binding affinity. CRT also augmented adenylate cyclase activity over DHF. Inhibitory G-protein (Galpha(i)) suppression of beta-adrenergic stimulation was greater in DHF and reversed by CRT. Galpha(i) expression itself was unaltered; however, expression of negative regulators of Galpha(i) signaling (particularly RGS3) rose uniquely with CRT over DHF and controls. CRT blunted elevated myocardial catecholamines in DHF, restoring levels toward control. CONCLUSIONS: CRT improves rest and beta-adrenergic-stimulated myocyte function and calcium handling, upregulating beta(1) receptors and adenylate cyclase activity and suppressing G(i)-coupled signaling associated with novel RGS upregulation. The result is greater rest and sympathetic reserve despite reduced myocardial neurostimulation as components underlying its net benefit.
Asunto(s)
Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/terapia , Marcapaso Artificial , Receptores Adrenérgicos beta 1/fisiología , Receptores Adrenérgicos beta 2/fisiología , Adenilil Ciclasas/metabolismo , Animales , Catecolaminas/metabolismo , Colforsina/farmacología , Perros , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismo , Insuficiencia Cardíaca/metabolismo , Contracción Miocárdica/fisiología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/fisiología , Proteínas RGS/fisiología , Ensayo de Unión Radioligante , Sarcómeros/fisiología , Transducción de Señal/fisiologíaRESUMEN
BACKGROUND: Cardiac dyssynchrony in the failing heart worsens global function and efficiency and generates regional loading disparities that may exacerbate stress-response molecular signaling and worsen cell survival. We hypothesized that cardiac resynchronization (CRT) from biventricular stimulation reverses such molecular abnormalities at the regional and global levels. METHODS AND RESULTS: Adult dogs (n=27) underwent left bundle-branch radiofrequency ablation, prolonging the QRS by 100%. Dogs were first subjected to 3 weeks of atrial tachypacing (200 bpm) to induce dyssynchronous heart failure (DHF) and then randomized to either 3 weeks of additional atrial tachypacing (DHF) or biventricular tachypacing (CRT). At 6 weeks, ejection fraction improved in CRT (2.8+/-1.8%) compared with DHF (-4.4+/-2.7; P=0.02 versus CRT) dogs, although both groups remained in failure with similarly elevated diastolic pressures and reduced dP/dtmax. In DHF, mitogen-activated kinase p38 and calcium-calmodulin-dependent kinase were disproportionally expressed/activated (50% to 150%), and tumor necrosis factor-alpha increased in the late-contracting (higher-stress) lateral versus septal wall. These disparities were absent with CRT. Apoptosis assessed by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling staining, caspase-3 activity, and nuclear poly ADP-ribose polymerase cleavage was less in CRT than DHF hearts and was accompanied by increased Akt phosphorylation/activity. Bcl-2 and BAD protein diminished with DHF but were restored by CRT, accompanied by marked BAD phosphorylation, enhanced BAD-14-3-3 interaction, and reduced phosphatase PP1alpha, consistent with antiapoptotic effects. Other Akt-coupled modulators of apoptosis (FOXO-3alpha and GSK3beta) were more phosphorylated in DHF than CRT and thus less involved. CONCLUSIONS: CRT reverses regional and global molecular remodeling, generating more homogeneous activation of stress kinases and reducing apoptosis. Such changes are important benefits from CRT that likely improve cardiac performance and outcome.
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Apoptosis , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Estimulación Cardíaca Artificial/métodos , Insuficiencia Cardíaca/terapia , Procesamiento Proteico-Postraduccional , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Proteínas 14-3-3/metabolismo , Animales , Bloqueo de Rama/complicaciones , Perros , Activación Enzimática , Factores de Transcripción Forkhead/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Insuficiencia Cardíaca/enzimología , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/patología , Fosforilación , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Distribución Aleatoria , Volumen Sistólico , Taquicardia Atrial Ectópica/complicaciones , Taquicardia Atrial Ectópica/enzimología , Taquicardia Atrial Ectópica/patología , Taquicardia Atrial Ectópica/terapia , Taquicardia Ventricular/complicaciones , Taquicardia Ventricular/enzimología , Taquicardia Ventricular/patología , Taquicardia Ventricular/terapia , Factor de Necrosis Tumoral alfa/biosíntesis , Proteína Letal Asociada a bcl/metabolismoRESUMEN
OBJECTIVES: We compared mechanical dyssynchrony and the impact of cardiac resynchronization therapy (CRT) in failing hearts with a pure right (RBBB) versus left bundle branch block (LBBB). BACKGROUND: Cardiac resynchronization therapy is effective for treating failing hearts with conduction delay and discoordinate contraction. Most data pertain to LBBB delays. With RBBB, the lateral wall contracts early so that biventricular (BiV) pre-excitation may not be needed. Furthermore, the magnitude of dyssynchrony and impact of CRT in pure RBBB versus LBBB remains largely unknown. METHODS: Dogs with tachypacing-induced heart failure combined with right or left bundle branch radiofrequency ablation were studied. Basal dyssynchrony and effects of single and BiV CRT on left ventricular (LV) function were assessed by pressure-volume catheter and tagged magnetic resonance imaging, respectively. RESULTS: Left bundle branch block and RBBB induced similar QRS widening, and LV function (ejection fraction, maximum time derivative of LV pressure [dP/dt(max)]) was similarly depressed in failing hearts with both conduction delays. Despite this, mechanical dyssynchrony was less in RBBB (circumferential uniformity ratio estimate [CURE] index: 0.80 +/- 0.03 vs. 0.58 +/- 0.09 for LBBB, p < 0.04; CURE 0-->1 is dyssynchronous-->synchronous). Cardiac resynchronization therapy had correspondingly less effect on hearts with RBBB than those with LBBB (i.e., 5.5 +/- 1.1% vs. 29.5 +/- 5.0% increase in dP/dt(max), p < 0.005), despite similar baselines. Furthermore, right ventricular-only pacing enhanced function and synchrony in RBBB as well or better than did BiV, whereas LV-only pacing worsened function. CONCLUSIONS: Less mechanical dyssynchrony is induced by RBBB than LBBB in failing hearts, and the corresponding impact of CRT on the former is reduced. Right ventricular-only pacing may be equally efficacious as BiV CRT in hearts with pure right bundle branch conduction delay.
Asunto(s)
Bloqueo de Rama/fisiopatología , Bloqueo de Rama/terapia , Estimulación Cardíaca Artificial , Disfunción Ventricular/fisiopatología , Animales , Perros , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia MagnéticaRESUMEN
BACKGROUND: The efficacy of cardiac resynchronization therapy (CRT) depends on placement of the left ventricular lead within the late-activated territory. The geographic extent and 3-dimensional distribution of left ventricular (LV) locations yielding optimal CRT remain unknown. METHODS AND RESULTS: Normal or tachypacing-induced failing canine hearts made dyssynchronous by right ventricular free wall pacing or chronic left bundle-branch ablation were acutely instrumented with a nonconstraining epicardial elastic sock containing 128 electrodes interfaced with a computer-controlled stimulation/recording system. Biventricular CRT was performed using a fixed right ventricular site and randomly selected LV sites covering the entire free wall. For each LV site, global cardiac function (conductance catheter) and mechanical synchrony (magnetic resonance imaging tagging) were determined to yield 3-dimensional maps reflecting CRT impact. Optimal CRT was achieved from LV lateral wall sites, slightly more anterior than posterior and more apical than basal. LV sites yielding > or = 70% of the maximal dP/dtmax increase covered approximately 43% of the LV free wall. This distribution and size were similar in both normal and failing hearts. The region was similar for various systolic and diastolic parameters and correlated with 3-dimensional maps based on mechanical synchrony from magnetic resonance imaging strain analysis. CONCLUSIONS: In hearts with delayed lateral contraction, optimized CRT is achieved over a fairly broad area of LV lateral wall in both nonfailing and failing hearts, with modest anterior or posterior deviation still capable of providing effective CRT. Sites selected to achieve the most mechanical synchrony are generally similar to those that most improve global function, confirming a key assumption underlying the use of wall motion analysis to optimize CRT.
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Estimulación Cardíaca Artificial/métodos , Animales , Perros , Electrocardiografía , Imagenología Tridimensional , Imagen por Resonancia Magnética , Análisis de RegresiónRESUMEN
The purpose of this study was to establish reference ranges for magnetic resonance imaging (MRI) measurements of the adult right ventricle stratified by gender. Cardiovascular MRI is increasingly used for evaluating the right ventricle in congenital and acquired heart disease, but gender-specific normative values are currently unavailable. Study participants included 500 subjects free of clinical cardiovascular disease who were participants in the Multi-Ethnic Study of Atherosclerosis (MESA). All subjects underwent MRI according to a standard protocol. The endocardial margins of the right ventricle were manually contoured on short-axis images, and right ventricular (RV) volumes were calculated using a summation-of-disks method. RV dimensions were measured on 4-chamber gradient-echo images and in the short-axis plane. Except for the ejection fraction, all unadjusted RV parameters were significantly greater in men than in women (p <0.001). In the entire study population, RV volumes and linear dimensions each correlated significantly with height (r = 0.38 to 0.64, p = 0.001 for all) and body surface area (r = 0.41 to 0.64, p = 0.001 for all). Gender differences persisted after adjustment for subject height. After adjustment for body surface area, volumetric variables remained significantly greater (p = 0.001) in men than in women. Even after adjusting for body surface area and height, Chinese participants had significantly lower RV volumes compared with Caucasians. In conclusion, gender-specific normal values for the adult right ventricle by MRI are presented. Cardiovascular MRI measures of RV volumes and linear dimensions differ significantly according to gender and body size. These values will be useful to differentiate RV health from diseases that result in abnormal RV structure and function.
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Ventrículos Cardíacos/anatomía & histología , Imagen por Resonancia Magnética , Adulto , Anciano , Anciano de 80 o más Años , Estatura , Superficie Corporal , Femenino , Humanos , Masculino , Persona de Mediana Edad , Grupos Raciales , Valores de Referencia , Caracteres Sexuales , Volumen SistólicoRESUMEN
The first known descriptions regarding the basic aspects of circulation was probably in 500 B.C., by the Greek thinker Alcmaeon of Croton who observed arteries and veins to be dissimilar in animal dissection, and this was followed by the description of the human heart as a three chambered organ by Aristotle in 350 B.C. Herophilus of Chalcedon, a Greek anatomist, confirmed the findings of dissimilarity between arteries and veins in human cadaver dissections in 300 B.C., and determines that arteries were thicker than veins and contained blood. The advancement by far in the learning of human circulation was made possible first by significant contribution of Galen followed by observations of Ibn al-Nafis, Servetus, Colombo, Cesalpino, Vesalius and Fabricius. In 17th century William Harvey, an English physician, made important advancements into the understanding of this important area of medicine, advancements that continued with the observations of Malpighi.
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Circulación Sanguínea , Fisiología/historia , Historia del Siglo XVI , Historia del Siglo XVII , Historia Antigua , HumanosRESUMEN
Vascular malformations of the mediastinum including mediastinal lymphangioma are exceedingly rare in adults. A resected case of mediastinal cystic lymphangioma (cystic hygroma) that presented with acute onset of retrosternal chest pain is reported in a 45-year-old man. Cystic hygromas are benign cysts frequently discovered incidentally on chest radiograph. Although computed tomography scan provides helpful information about the size, density, and site of the cysts, it cannot establish a precise diagnosis concerning its nature. Complete removal of the cyst is the treatment of choice and allows precise diagnosis on histologic examination. However, surgical excision is sometimes difficult, owing to the size and extension of the cysts, infiltrating mediastinal planes, enveloping great vessels, and displacing mediastinal organs without invasion. The difficulty of completely eradicating certain cysts explains cases of insidious progression with compressive recurrence. The subject is succinctly reviewed.
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Dolor en el Pecho/etiología , Linfangioma Quístico , Neoplasias del Mediastino , Estudios de Seguimiento , Humanos , Linfangioma Quístico/complicaciones , Linfangioma Quístico/diagnóstico por imagen , Linfangioma Quístico/patología , Linfangioma Quístico/cirugía , Masculino , Neoplasias del Mediastino/complicaciones , Neoplasias del Mediastino/diagnóstico por imagen , Neoplasias del Mediastino/patología , Neoplasias del Mediastino/cirugía , Mediastino/patología , Persona de Mediana Edad , Radiografía Torácica , Síndrome , Factores de Tiempo , Tomografía Computarizada por Rayos XRESUMEN
Left ventricular free wall rupture is an uncommon complication after a myocardial infarction that is associated with a high mortality rate from pericardial tamponade, especially in the elderly. Early recognition and management of this clinical entity affects the outcome; therefore, a high index of suspicion is imperative. We present a case of an 80-year-old man admitted with myocardial infarction, who had subsequent findings of left ventricular free wall rupture complicated by pericardial tamponade. Emergent surgical repair led to successful recovery. A brief overview of the clinical presentation, diagnosis, and management of this challenging and potentially fatal complication is presented.
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Rotura Cardíaca Posinfarto/cirugía , Ventrículos Cardíacos/patología , Infarto del Miocardio/complicaciones , Rotura/etiología , Factores de Edad , Anciano , Anciano de 80 o más Años , Ventrículos Cardíacos/cirugía , Humanos , MasculinoRESUMEN
Essential thrombocythemia is a clonal disorder of the myeloid stem cell that causes pathologic expansion of the megakaryocytic elements in the bone marrow, with a persistent increase in the platelet count. The disease is associated with an elevated risk of thrombosis, hemorrhage, and vasomotor symptoms. The presenting features of essential thrombocythemia can range from being asymptomatic to thrombohemorrhagic complications including acute myocardial infarction. Acute ST-segment elevation myocardial infarction due to left main trunk and ostial left anterior descending coronary artery lesions was diagnosed in a young 31-year-old man. Platelet count was markedly increased and essential thrombocythemia was also diagnosed. Because of left main disease, primary coronary intervention was not feasible and an emergent coronary artery bypass grafting was performed along with pharmacologic management of essential thrombocythemia. The early postoperative period was complicated by acute pulmonary embolism. Hydroxyurea and anagrelide were administered postoperatively, resulting in the decrease of platelet count. A succinct review of myocardial infarction in patients with essential thrombocythemia is presented, and therapeutic strategies in such patients are discussed.
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Electrocardiografía , Infarto del Miocardio/etiología , Trombocitemia Esencial/complicaciones , Adulto , Angiografía Coronaria , Trombosis Coronaria/diagnóstico por imagen , Trombosis Coronaria/etiología , Humanos , Masculino , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/cirugía , Trombocitemia Esencial/terapiaRESUMEN
Torsade de pointes is a polymorphic form of ventricular tachycardia associated with prolongation of the QT interval, which may be either congenital or acquired. Etiologies for the acquired forms include drug effects, hypokalemia, hypomagnesemia, hypocalcemia, starvation, sick sinus syndrome, and atrioventricular block. We present a 76-year-old man with acute on chronic renal failure, hypocalcemia, on ciprofloxacin, and a prolonged QT interval with torsade de pointes triggered by hemodialysis. The QT prolongation was corrected by treating the hypocalcemia. Hypocalcemia and ciprofloxacin are known to independently cause prolonged QT interval and torsade de pointes; our case illustrates that dialysis can trigger torsade on a background of this risk factor combination.