RESUMEN
BACKGROUND: Vasovagal syncope (VVS) is a common problem associated with a poor quality of life, which improves when syncope frequency is reduced. Effective pharmacological therapies for VVS are lacking. Metoprolol is a ß-adrenergic receptor antagonist that is ineffective in younger patients, but may benefit older (≥40 years) VVS patients. Given the limited therapeutic options, a placebo-controlled clinical trial of metoprolol for the prevention of VVS in older patients is needed. STRUCTURE OF STUDY: The POST5 is a multicenter, international, randomized, placebo-controlled study of metoprolol in the prevention of VVS in patients ≥40 years old. The primary endpoint is the time to first recurrence of syncope. Patients will be randomized 1:1 to receive metoprolol 25 to 100 mg BID or matching placebo, and followed up for 1 year. Secondary end points include syncope frequency, presyncope, quality of life, and cost analysis. Primary analysis will be intention to treat, with a secondary on-treatment analysis. POWER CALCULATIONS: A sample size of 222, split equally between the groups achieves 85% power to detect a hazard rate of 0.3561 when the event rates are 50% and 30% in the placebo and metoprolol arms. Allowing for 10% dropout, we propose to enroll 248 patients. IMPLICATIONS: This study will be the first adequately powered trial to determine whether metoprolol is effective in preventing VVS in patients ≥40 years. If effective, metoprolol may become the first line pharmacological therapy for these patients.
Asunto(s)
Envejecimiento , Metoprolol/administración & dosificación , Calidad de Vida , Síncope Vasovagal/prevención & control , Administración Oral , Antagonistas Adrenérgicos beta/administración & dosificación , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Recurrencia , Síncope Vasovagal/fisiopatología , Síncope Vasovagal/psicología , Factores de Tiempo , Resultado del TratamientoRESUMEN
RATIONALE: Phospholamban (PLN) is an inhibitor of cardiac sarco(endo)plasmic reticulum Ca²âº ATPase. PLN knockout (PLN-KO) enhances sarcoplasmic reticulum Ca²âº load and Ca²âº leak. Conversely, PLN-KO accelerates Ca²âº sequestration and aborts arrhythmogenic spontaneous Ca²âº waves (SCWs). An important question is whether these seemingly paradoxical effects of PLN-KO exacerbate or protect against Ca²âº-triggered arrhythmias. OBJECTIVE: We investigate the impact of PLN-KO on SCWs, triggered activities, and stress-induced ventricular tachyarrhythmias (VTs) in a mouse model of cardiac ryanodine-receptor (RyR2)-linked catecholaminergic polymorphic VT. METHODS AND RESULTS: We generated a PLN-deficient, RyR2-mutant mouse model (PLN-/-/RyR2-R4496C+/-) by crossbreeding PLN-KO mice with catecholaminergic polymorphic VT-associated RyR2-R4496C mutant mice. Ca²âº imaging and patch-clamp recording revealed cell-wide propagating SCWs and triggered activities in RyR2-R4496C+/- ventricular myocytes during sarcoplasmic reticulum Ca²âº overload. PLN-KO fragmented these cell-wide SCWs into mini-waves and Ca²âº sparks and suppressed the triggered activities evoked by sarcoplasmic reticulum Ca²âº overload. Importantly, these effects of PLN-KO were reverted by partially inhibiting sarco(endo)plasmic reticulum Ca²âº ATPase with 2,5-di-tert-butylhydroquinone. However, Bay K, caffeine, or Li⺠failed to convert mini-waves to cell-wide SCWs in PLN-/-/RyR2-R4496C+/- ventricular myocytes. Furthermore, ECG analysis showed that PLN-KO mice are not susceptible to stress-induced VTs. On the contrary, PLN-KO protected RyR2-R4496C mutant mice from stress-induced VTs. CONCLUSIONS: Our results demonstrate that despite severe sarcoplasmic reticulum Ca²âº leak, PLN-KO suppresses triggered activities and stress-induced VTs in a mouse model of catecholaminergic polymorphic VT. These data suggest that breaking up cell-wide propagating SCWs by enhancing Ca²âº sequestration represents an effective approach for suppressing Ca²âº-triggered arrhythmias.
Asunto(s)
Señalización del Calcio/fisiología , Proteínas de Unión al Calcio/deficiencia , Taquicardia Ventricular/prevención & control , Ácido 3-piridinacarboxílico, 1,4-dihidro-2,6-dimetil-5-nitro-4-(2-(trifluorometil)fenil)-, Éster Metílico/farmacología , Animales , Cafeína/farmacología , Señalización del Calcio/efectos de los fármacos , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/fisiología , ATPasas Transportadoras de Calcio/antagonistas & inhibidores , Células Cultivadas/efectos de los fármacos , Células Cultivadas/fisiología , Modelos Animales de Enfermedad , Electrocardiografía , Hidroquinonas/farmacología , Isoproterenol/farmacología , Cloruro de Litio/farmacología , Ratones , Ratones Noqueados , Mutación Missense , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/enzimología , Miocitos Cardíacos/fisiología , Técnicas de Placa-Clamp , Canal Liberador de Calcio Receptor de Rianodina/deficiencia , Canal Liberador de Calcio Receptor de Rianodina/genética , Canal Liberador de Calcio Receptor de Rianodina/fisiología , Retículo Sarcoplasmático/enzimología , Retículo Sarcoplasmático/fisiología , Taquicardia Ventricular/diagnóstico por imagen , Taquicardia Ventricular/fisiopatología , UltrasonografíaRESUMEN
Heart failure is associated with a low-grade and chronic cardiac inflammation that impairs function; however, the mechanisms by which this sterile inflammation occurs in structural heart disease remain poorly defined. Cardiac-specific heterozygous overexpression of the calcineurin transgene (CNTg) in mice results in cardiac hypertrophy, inflammation, apoptosis and ventricular dilatation. We hypothesized that activation of the Nlrp3 inflammasome, an intracellular danger-sensing pathway required for processing the pro-inflammatory cytokine interleukin-1ß (IL-1ß), may contribute to myocardial dysfunction and disease progression. Here we report that Nlrp3 mRNA was increased in CNTg mice compared with wild-type. Consistent with inflammasome activation, CNTg animals had increased conversion of pro-caspase-1 to cleaved and activated forms, as well as markedly increased serum IL-1ß. Blockade of IL-1ß signalling via chronic IL-1 receptor antagonist therapy reduced cardiac inflammation and myocyte pathology in CNTg mice, resulting in improved systolic performance. Furthermore, genetic ablation of Nlrp3 in CNTg mice reduced pro-inflammatory cytokine maturation and cardiac inflammation, as well as improving systolic performance. These findings indicate that activation of the Nlrp3 inflammasome in CNTg mice promotes myocardial inflammation and systolic dysfunction through the production of pro-inflammatory IL-1ß. Blockade of IL-1ß signalling with the IL-1 receptor antagonist reverses these phenotypes and offers a possible therapeutic approach in the management of heart failure.
Asunto(s)
Cardiomiopatías/inmunología , Proteínas Portadoras/metabolismo , Insuficiencia Cardíaca/inmunología , Inflamasomas/metabolismo , Mediadores de Inflamación/metabolismo , Interleucina-1beta/metabolismo , Miocarditis/inmunología , Miocardio/inmunología , Animales , Calcineurina/genética , Calcineurina/metabolismo , Cardiomiopatías/tratamiento farmacológico , Cardiomiopatías/genética , Cardiomiopatías/patología , Cardiomiopatías/fisiopatología , Proteínas Portadoras/genética , Caspasa 1/metabolismo , Modelos Animales de Enfermedad , Activación Enzimática , Precursores Enzimáticos , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/prevención & control , Inflamasomas/deficiencia , Inflamasomas/genética , Mediadores de Inflamación/sangre , Proteína Antagonista del Receptor de Interleucina 1/farmacología , Interleucina-1beta/sangre , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Miocarditis/genética , Miocarditis/patología , Miocarditis/fisiopatología , Miocarditis/prevención & control , Miocardio/patología , Células 3T3 NIH , Proteína con Dominio Pirina 3 de la Familia NLR , Receptores de Interleucina-1/antagonistas & inhibidores , Receptores de Interleucina-1/metabolismo , Recuperación de la Función , Transducción de Señal , Sístole , Factores de Tiempo , Función Ventricular IzquierdaRESUMEN
BACKGROUND: Our objective was to examine patients who initiate renal replacement therapy (RRT) at 10 representative Canadian centers, characterize their initiation as inpatient or outpatient and describe their initial type of dialysis access, duration of pre-dialysis care and clinical status at the time of dialysis initiation. We also examined the impact of an optimal dialysis start (i.e. initiated as an outpatient with an arteriovenous fistula, arteriovenous graft or peritoneal dialysis catheter) on subsequent health outcomes. METHODS: Charts of consecutive incident RRT patients were identified from 1 July to 31 December 2006. Information was collected until 6 months after the initiation or until death, transplant or transfer. RESULTS: Three hundred and thirty-nine incident RRT patients were studied: 39.6% initiated as an inpatient; 54% started hemodialysis (HD) with a central venous catheter; 15.3% had <1 month predialysis care, while 64.6% had >1 year. Optimal starts occurred in 39.5% of patients. For HD patients, optimal starts occurred in 19.8%. Suboptimal starts were noted in patients referred <12 months prior to end-stage renal disease (44%) and in patients referred earlier (56%). The composite end point of death, transfusion or subsequent hospitalization was significantly reduced with an optimal start [hazard ratio 0.47 (95% confidence interval 0.32-0.68), P = 0.0001]. CONCLUSIONS: Suboptimal initiation of dialysis is common in patients referred early or late. The benefits of early referral are lost if dialysis is initiated suboptimally. There is a need to identify factors that lead to suboptimal initiation despite early referral.
Asunto(s)
Hospitalización/estadística & datos numéricos , Fallo Renal Crónico/terapia , Nefrología , Derivación y Consulta , Diálisis Renal/estadística & datos numéricos , Terapia de Reemplazo Renal , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Fallo Renal Crónico/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Estudios Retrospectivos , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
BACKGROUND: Benefit from cardiac resynchronization therapy (CRT) is likely influenced by the location of the left ventricular (LV) lead. PURPOSE: To evaluate the association of LV lead position with outcome after CRT. METHODS: Two-hundred and fifty patients with LV dysfunction, New York Heart Association (NYHA) class III (68%) or IV (32%) symptoms, and QRS durations > or =120 ms were followed for a median of 30 months post-CRT. LV lead position was categorized as anterior (n = 20, 8%), lateral (n = 128, 51%), or posterior (n = 102; 41%) using postero-anterior and lateral postoperative chest radiographs. RESULTS: Median age was 69 years and most (68%) had ischemic LV dysfunction. Clinical response, defined by a > or =1 NYHA class reduction, was lower in patients with an anterior (30%) versus lateral (76%) or posterior (73%) lead position (p = 0.001). An anterior versus nonanterior position was independently associated with a two to three-fold higher risk for nonresponse to CRT, cardiovascular death, death from worsening heart failure or cardiac transplantation, and death from any cause. Repositioning of the LV lead from an anterior to a nonanterior position in seven patients who had not clinically responded to CRT after > or =6 months resulted in clinical improvement in all cases. CONCLUSIONS: An anterior versus nonanterior LV lead position is independently associated with an increased likelihood of nonresponse to CRT and a higher risk of serious outcomes. Repositioning of an anteriorly placed LV lead to a nonanterior position should be considered in CRT nonresponders.
Asunto(s)
Estimulación Cardíaca Artificial/métodos , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/terapia , Anciano , Progresión de la Enfermedad , Electrodos Implantados , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Radiografía , Estadísticas no Paramétricas , Disfunción Ventricular Izquierda/mortalidad , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
Spontaneous Ca(2+) release from intracellular stores is important for various physiological and pathological processes. In cardiac muscle cells, spontaneous store overload-induced Ca(2+) release (SOICR) can result in Ca(2+) waves, a major cause of ventricular tachyarrhythmias (VTs) and sudden death. The molecular mechanism underlying SOICR has been a mystery for decades. Here we show that a point mutation, E4872A, in the helix bundle crossing region (the proposed gate) of the cardiac ryanodine receptor (RyR2) completely abolishes luminal, but not cytosolic, Ca(2+) activation of RyR2. The introduction of metal-binding histidines at this site converts RyR2 into a luminal Ni(2+)-gated channel. Mouse hearts harboring a heterozygous RyR2 mutation at this site (E4872Q) are resistant to SOICR and are completely protected against Ca(2+)-triggered VTs. These data show that the RyR2 gate directly senses luminal (store) Ca(2+), explaining the regulation of RyR2 by luminal Ca(2+), the initiation of Ca(2+) waves and Ca(2+)-triggered arrhythmias. This newly identified store-sensing gate structure is conserved in all RyR and inositol 1,4,5-trisphosphate receptor isoforms.
Asunto(s)
Arritmias Cardíacas/etiología , Arritmias Cardíacas/metabolismo , Calcio/metabolismo , Miocitos Cardíacos/metabolismo , Canal Liberador de Calcio Receptor de Rianodina/genética , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Animales , Cafeína , Cartilla de ADN/genética , Ecocardiografía , Técnicas de Sustitución del Gen , Células HEK293 , Humanos , Immunoblotting , Membrana Dobles de Lípidos/metabolismo , Ratones , Microscopía Confocal , Mutagénesis Sitio-Dirigida , Técnicas de Placa-Clamp , Mutación Puntual/genéticaRESUMEN
Transgenic overexpression of calcineurin (CN/Tg) in mouse cardiac myocytes results in hypertrophy followed by dilation, dysfunction, and sudden death. Nitric oxide (NO) produced via inducible NO synthase (iNOS) has been implicated in cardiac injury. Since calcineurin regulates iNOS expression, and since phenotypes of mice overexpressing iNOS are similar to CN/Tg, we hypothesized that iNOS is pathogenically involved in cardiac phenotypes of CN/Tg mice. CN/Tg mice had increased serum and cardiac iNOS levels. When CN/Tg-iNOS(-/-) and CN/Tg mice were compared, some phenotypes were similar: extent of hypertrophy and fibrosis. However, CN/Tg-iNOS(-/-) mice had improved systolic performance (P < 0.001) and less heart block (P < 0.0001); larger sodium current density and lower serum TNF-alpha levels (P < 0.03); and less apoptosis (P < 0.01) resulting in improved survival (P < 0.0003). To define tissue origins of iNOS production, chimeric lines were generated. Bone marrow (BM) from wild-type or iNOS(-/-) mice was transplanted into CN/Tg mice. iNOS deficiency restricted to BM-derived cells was not protective. Calcineurin activates the local production of NO by iNOS in cardiac myocytes, which significantly contributes to sudden death, heart block, left ventricular dilation, and impaired systolic performance in this murine model of cardiac hypertrophy induced by the overexpression of calcineurin.
Asunto(s)
Calcineurina/genética , Calcineurina/fisiología , Cardiomegalia/genética , Cardiomegalia/patología , Muerte Celular/fisiología , Miocitos Cardíacos/enzimología , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/fisiología , Animales , Apoptosis/genética , Apoptosis/fisiología , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatología , Cardiomiopatía Dilatada/genética , Cardiomiopatía Dilatada/patología , Muerte Súbita , Ecocardiografía , Ensayo de Inmunoadsorción Enzimática , Bloqueo Cardíaco/genética , Bloqueo Cardíaco/fisiopatología , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Ratones , Ratones Noqueados , Ratones Transgénicos , Miocitos Cardíacos/fisiología , Óxido Nítrico/metabolismo , Canales de Sodio/fisiología , Análisis de Supervivencia , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Control db/+ and diabetic db/db mice at 6 and 12 wk of age were subjected to echocardiography to determine whether contractile function was reduced in vivo and restored in transgenic db/db-human glucose transporter 4 (hGLUT4) mice (12 wk old) in which cardiac metabolism has been normalized. Systolic function was unchanged in 6-wk-old db/db mice, but fractional shortening and velocity of circumferential fiber shortening were reduced in 12-wk-old db/db mice (43.8 +/- 2.1% and 8.3 +/- 0.5 circs/s, respectively) relative to db/+ control mice (59.5 +/- 2.3% and 11.8 +/- 0.4 circs/s, respectively). Doppler flow measurements were unchanged in 6-wk-old db/db mice. The ratio of E and A transmitral flows was reduced from 3.56 +/- 0.29 in db/+ mice to 2.40 +/- 0.20 in 12-wk-old db/db mice, indicating diastolic dysfunction. Thus a diabetic cardiomyopathy with systolic and diastolic dysfunction was evident in 12-wk-old diabetic db/db mice. Cardiac function was normalized in transgenic db/db-hGLUT4 mice, indicating that altered cardiac metabolism can produce contractile dysfunction in diabetic db/db hearts.
Asunto(s)
Cardiomiopatías/diagnóstico por imagen , Diabetes Mellitus Tipo 2/diagnóstico por imagen , Diástole/fisiología , Proteínas de Transporte de Monosacáridos/genética , Proteínas Musculares , Sístole/fisiología , Animales , Cardiomiopatías/etiología , Diabetes Mellitus Tipo 2/complicaciones , Ecocardiografía/normas , Ecocardiografía/estadística & datos numéricos , Transportador de Glucosa de Tipo 4 , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Variaciones Dependientes del Observador , Reproducibilidad de los ResultadosRESUMEN
Hearts from insulin-resistant type 2 diabetic db/db mice exhibit features of a diabetic cardiomyopathy with altered metabolism of exogenous substrates and reduced contractile performance. Therefore, the effect of chronic oral administration of 2-(2-(4-phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid (COOH), a novel ligand for peroxisome proliferator-activated receptor-gamma that produces insulin sensitization, to db/db mice (30 mg/kg for 6 wk) on cardiac function was assessed. COOH treatment reduced blood glucose from 27 mM in untreated db/db mice to a normal level of 10 mM. Insulin-stimulated glucose uptake was enhanced in cardiomyocytes from COOH-treated db/db hearts. Working perfused hearts from COOH-treated db/db mice demonstrated metabolic changes with enhanced glucose oxidation and decreased palmitate oxidation. However, COOH treatment did not improve contractile performance assessed with ex vivo perfused hearts and in vivo by echocardiography. The reduced outward K+ currents in diabetic cardiomyocytes were still attenuated after COOH. Metabolic changes in COOH-treated db/db hearts are most likely indirect, secondary to changes in supply of exogenous substrates in vivo and insulin sensitization.