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PURPOSE: Our aim was to evaluate the acute success and complication rates of the transradial and transulnar access for iliac artery stenting using sheathless guiding systems. METHODS: Clinical and angiographic data from 156 consecutive patients with symptomatic iliac artery stenosis who were treated with transradial or transulnar access were evaluated. All patients underwent Duplex ultrasound before and after the intervention. The primary endpoints were the procedural success rate, major adverse events, and access site complication rates. The secondary endpoints were the angiographic result of the iliac artery intervention, fluoroscopy time, X-ray dose, procedure length, crossover rate to another puncture site and hospitalization duration. The impact of the learning curve was also investigated, along with right or left radial access. RESULTS: The indication for the intervention was intermittent claudication in 109 patients (69.9%), critical limb ischemia in 44 (28.2%) subjects and acute limb ischemia in three individuals (1.9%). Technical success was achieved in 155 patients (99.4%), with a crossover rate of 3.8%. Radial and ulnar artery access was used in 151 (96.8%) and 7 (4.5%) patients, respectively. The Ankle-brachial index increased from 0.69 [0.65-0.72] to 0.91 [0.88-0.95] as a result of the procedures (P < 0.001). The cumulative incidence of major adverse events was 3.8% at the 2-month follow-up (0% in patients with intermittent claudication and 13.8% in patients with critical limb ischemia). Radial artery access site complications were encountered in eight patients (5.1%). We documented decreased X-ray doses (1742.0 [783.9-2701] vs. 1435 [991.1-1879] vs. 692.8 [275.3-1110] Gy cm-2 P < 0.05) over time; however, the fluoroscopy time, procedure time, and contrast consumption were not significantly different. Left hand access was not associated with significantly better results than right radial artery access. CONCLUSIONS: Iliac artery stenting can be safely and effectively performed using radial or ulnar artery access and sheathless guiding catheters, with acceptable complication rates and high levels of technical success. The physician learning curve plays an important role in decreasing the X-ray dose. © 2016 The Authors. Catheterization and Cardiovascular Interventions Published by Wiley Periodicals, Inc.
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Angiografía/instrumentación , Angioplastia de Balón/instrumentación , Cateterismo Periférico/instrumentación , Arteria Ilíaca , Claudicación Intermitente/terapia , Diseño de Equipo , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Humanos , Claudicación Intermitente/diagnóstico , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Arteria Radial , Estudios Retrospectivos , Arteria Cubital , Ultrasonografía Doppler DúplexRESUMEN
BACKGROUND AND PURPOSE: Omecamtiv mecarbil (OM) is a novel cardiac myosin activator drug for inotropic support in systolic heart failure. Here we have assessed the concentration-dependent mechanical effects of OM in permeabilized cardiomyocyte-sized preparations and single skeletal muscle fibres of Wistar-Kyoto rats under isometric conditions. EXPERIMENTAL APPROACHES: Ca2+ -dependent active force production (Factive ), its Ca2+ sensitivity (pCa50 ), the kinetic characteristics of Ca2+ -regulated activation and relaxation, and Ca2+ -independent passive force (Fpassive ) were monitored in Triton X-100-skinned preparations with and without OM (3nM-10 µM). KEY RESULTS: In permeabilized cardiomyocytes, OM increased the Ca2+ sensitivity of force production (ΔpCa50 : 0.11 or 0.34 at 0.1 or 1 µM respectively). The concentration-response relationship of the Ca2+ sensitization was bell-shaped, with maximal effects at 0.3-1 µM OM (EC50 : 0.08 ± 0.01 µM). The kinetics of force development and relaxation slowed progressively with increasing OM concentration. Moreover, OM increased Fpassive in the cardiomyocytes with an apparent EC50 value of 0.26 ± 0.11 µM. OM-evoked effects in the diaphragm muscle fibres with intrinsically slow kinetics were largely similar to those in cardiomyocytes, while they were less apparent in muscle fibres with fast kinetics. CONCLUSIONS AND IMPLICATIONS: OM acted as a Ca2+ -sensitizing agent with a downstream mechanism of action in both cardiomyocytes and diaphragm muscle fibres. The mechanism of action of OM is connected to slowed activation-relaxation kinetics and at higher OM concentrations increased Fpassive production.
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AIMS: Myeloperoxidase (MPO) catalyses the formation of a wide variety of oxidants, including hypochlorous acid (HOCl), and contributes to cardiovascular disease progression. We hypothesized that during its action MPO evokes substantial vasomotor responses. METHODS: Following exposure to MPO (1.92 mU mL(-1)) in the presence of increasing concentrations of hydrogen peroxide (H2O2), changes in arteriolar diameter of isolated gracilis skeletal muscle arterioles (SMAs) and coronary arterioles (CAs) and in the isometric force in basilar arteries (BAs) of the rat were monitored. RESULTS: Myeloperoxidase increased vascular tone to different degrees in CAs, SMAs and BAs. The mechanism of increased vasoconstriction was studied in detail in SMAs. MPO-evoked vasoconstrictions were prevented by the MPO inhibitor 4-aminobenzhydrazide (50 µM), by endothelium removal in the SMAs. Surprisingly, the HOCl scavenger L-methionine (100 µM), the thromboxane A2 (TXA2) antagonist SQ-29548 (1 µM) or the non-specific cyclooxygenase (COX) antagonist indomethacin (1 µM) converted the MPO-evoked vasoconstrictions to pronounced vasodilations in SMAs, not seen in the presence of H2O2. In contrast to noradrenaline-induced vasoconstrictions, the MPO-evoked vasoconstrictions were not accompanied by significant increases in arteriolar [Ca(2+)] levels in SMAs. CONCLUSION: These data showed that H2O2 -derived HOCl to be a potent vasoconstrictor upon MPO application. HOCl activated the COX pathway, causing the synthesis and release of a TXA2-like substance to increase the Ca(2+) sensitivity of the contractile apparatus in vascular smooth muscle cells and thereby to augment H2 O2 -evoked vasoconstrictions. Nevertheless, inhibition of the HOCl-COX-TXA2 pathway unmasked the effects of additional MPO-derived radicals with a marked vasodilatory potential in SMAs.
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Arteriolas/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Peroxidasa/farmacología , Vasoconstricción/efectos de los fármacos , Animales , Arteriolas/fisiología , Arteria Basilar/efectos de los fármacos , Arteria Basilar/fisiología , Vasos Coronarios/efectos de los fármacos , Peróxido de Hidrógeno/farmacología , Masculino , Contracción Muscular/efectos de los fármacos , Músculo Esquelético/irrigación sanguínea , Músculo Liso Vascular/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
BACKGROUND: The intravenous inodilator levosimendan was developed for the treatment of patients with acutely decompensated heart failure. In the last decade scientific and clinical interest has arisen for its repetitive or intermittent use in patients with advanced chronic, but not necessarily acutely decompensated, heart failure. Recent studies have suggested long-lasting favourable effects of levosimendan when administered repetitively, in terms of haemodynamic parameters, neurohormonal and inflammatory markers, and clinical outcomes. The existing data, however, requires further exploration to allow for definitive conclusions on the safety and clinical efficacy of repetitive use of levosimendan. METHODS AND RESULTS: A panel of 30 experts from 15 countries convened to review and discuss the existing data, and agreed on the patient groups that can be considered to potentially benefit from intermittent treatment with levosimendan. The panel gave recommendations regarding patient dosing and monitoring, derived from the available evidence and from clinical experience. CONCLUSIONS: The current data suggest that in selected patients and support out-of-hospital care, intermittent/repetitive levosimendan can be used in advanced heart failure to maintain patient stability. Further studies are needed to focus on morbidity and mortality outcomes, dosing intervals, and patient monitoring. Recommendations for the design of further clinical studies are made.
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Insuficiencia Cardíaca/tratamiento farmacológico , Hidrazonas/administración & dosificación , Piridazinas/administración & dosificación , Vasodilatadores/administración & dosificación , Enfermedad Crónica , Humanos , Guías de Práctica Clínica como Asunto , Índice de Severidad de la Enfermedad , SimendánRESUMEN
BACKGROUND AND PURPOSE: The transient receptor potential vanilloid 1 (TRPV1) plays a role in the activation of sensory neurons by various painful stimuli and is a therapeutic target. However, functional TRPV1 that affect microvascular diameter are also expressed in peripheral arteries and we attempted to characterize this receptor. EXPERIMENTAL APPROACH: Sensory TRPV1 activation was measured in rats by use of an eye wiping assay. Arteriolar TRPV1-mediated smooth muscle specific responses (arteriolar diameter, changes in intracellular Ca(2+)) were determined in isolated, pressurized skeletal muscle arterioles obtained from the rat and wild-type or TRPV1(-/-) mice and in canine isolated smooth muscle cells. The vascular pharmacology of the TRPV1 agonists (potency, efficacy, kinetics of action and receptor desensitization) was determined in rat isolated skeletal muscle arteries. KEY RESULTS: Capsaicin evoked a constrictor response in isolated arteries similar to that mediated by noradrenaline, this was absent in arteries from TRPV1 knockout mice and competitively inhibited by TRPV1 antagonist AMG9810. Capsaicin increased intracellular Ca(2+) in the arteriolar wall and in isolated smooth muscle cells. The TRPV1 agonists evoked similar vascular constrictions (MSK-195 and JYL-79) or were without effect (resiniferatoxin and JYL-273), although all increased the number of responses (sensory activation) in the eye wiping assay. Maximal doses of all agonists induced complete desensitization (tachyphylaxis) of arteriolar TRPV1 (with the exception of capsaicin). Responses to the partial agonist JYL-1511 suggested 10% TRPV1 activation is sufficient to evoke vascular tachyphylaxis without sensory activation. CONCLUSIONS AND IMPLICATIONS: Arteriolar TRPV1 have different pharmacological properties from those located on sensory neurons in the rat.
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Arteriolas/fisiología , Canales Catiónicos TRPV/agonistas , Canales Catiónicos TRPV/fisiología , Vasoconstrictores/farmacología , Acrilamidas/farmacología , Animales , Arteriolas/efectos de los fármacos , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Células CHO , Calcio/fisiología , Capsaicina/farmacología , Vasos Coronarios/citología , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/fisiología , Cricetinae , Cricetulus , Perros , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Esquelético/irrigación sanguínea , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/fisiología , Ratas , Ratas Wistar , Células Receptoras Sensoriales/fisiología , Relación Estructura-Actividad , Canales Catiónicos TRPV/antagonistas & inhibidores , Canales Catiónicos TRPV/deficiencia , Vasoconstricción/efectos de los fármacos , Vasoconstrictores/químicaRESUMEN
During heart failure, alterations occur in contractile protein expression and phosphorylation, which may influence the effects of Ca2+ -sensitizers. To quantify the magnitude of these effects, isometric force was studied in mechanically isolated Triton-skinned myocytes from end-stage failing and non-failing donor hearts under control conditions (pH 7.2; no added inorganic phosphate (Pi)) and under mimicked ischemic conditions (pH 6.5; 10 mM Pi). Two different Ca2+ -sensitizers were used: EMD 53998 (10 microM), which exerts its influence through the actin-myosin interaction, and OR-1896 (10 microM) (the active metabolite of levosimendan), which affects the Ca2+ -sensory function of the thin filaments. The maximal force (Po) measured at saturating Ca2+ concentration and the resting force (Prest) determined in the virtual absence of Ca2+ (pCa 9) did not differ between the failing and non-failing myocytes, but the Ca2+ concentration required to induce the half-maximal force under control conditions was significantly lower in the failing than in the non-failing myocytes (DeltapCa50=0.15). This difference in Ca2+ -sensitivity, however, was abolished during mimicked ischemia. EMD 53998 increased Po and Prest by approximately 15% of Po and greatly enhanced the Ca2+ -sensitivity (DeltapCa50 > 0.25) of force production. OR-1896 did not affect Po and Prest, and provoked a small, but significant Ca2+ -sensitization (DeltapCa50 approximately 0.1). All of these effects were comparable in the donor and failing myocytes, but, in contrast with OR-1896, EMD 53998 considerably diminished the difference in the Ca2+ -sensitivities between the failing and non-failing myocytes. The action of Ca2+ -sensitizers under mimicked ischemic conditions was impaired to a similar degree in the donor and the failing myocytes. Our results indicate that the Ca2+ -activation of the myofibrillar system is altered in end-stage human heart failure. This modulates the effects of Ca2+ -sensitizers both under control and under mimicked ischemic conditions.
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Acetamidas/farmacología , Calcio/metabolismo , Insuficiencia Cardíaca/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Piridazinas/farmacología , Quinolinas/farmacología , Tiadiazinas/farmacología , Adulto , Anciano , Permeabilidad de la Membrana Celular/efectos de los fármacos , Femenino , Humanos , Técnicas In Vitro , Masculino , Persona de Mediana Edad , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Donantes de TejidosRESUMEN
The effects of the Ca2+-sensitiser levosimendan alone or in combination with beta-adrenergic stimulation on the contractile function were studied in various guinea pig cardiac preparations. Echocardiography in narcotised animals indicated that a maximal dose of levosimendan (50 microg x kg(-1)) increased the left ventricular posterior wall movement velocity during systoles and diastoles by 25 +/- 3% (mean +/- S.E.M.) and 17 +/- 2%, respectively. In Langendorff hearts, a saturating concentration of levosimendan (0.3 micromol x l(-1) for 5 min) increased +dP/dt(max) and dP/dt(max) by 28 +/- 3% and 14 +/- 2%, respectively. Further, the Ca2+-sensitising potential of levosimendan in Triton-skinned cardiomyocytes (EC50: 5 +/- 3 nmol x l(-1)) was illustrated by a maximal increase in the isometric force production by 51 +/- 5% (at pCa 6.2). However, following stimulation by isoproterenol, when the level of troponin I phosphorylation was elevated, no significant additional increase in the contractile parameters could be demonstrated upon levosimendan administration. Moreover, the levosimendan-induced increase in force production in isolated skinned myocytes could be prevented by incubation with the catalytic subunit of protein kinase A (100 U x ml(-1) for 40 min). These data indicate that thin filament-targeted Ca2+-sensitisation by levosimendan is modulated by phosphorylation of the contractile filaments, an effect that should be considered during combination therapy with levosimendan.
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Hidrazonas/farmacología , Isoproterenol/farmacología , Contracción Miocárdica/efectos de los fármacos , Contracción Miocárdica/fisiología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/fisiología , Piridazinas/farmacología , Agonistas Adrenérgicos beta/farmacología , Animales , Calcio/metabolismo , Cardiotónicos/farmacología , Células Cultivadas , Técnicas de Cultivo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Cobayas , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/efectos de los fármacos , Contracción Isométrica/efectos de los fármacos , Contracción Isométrica/fisiología , Receptores Adrenérgicos beta/metabolismo , Simendán , Ultrasonografía , Función VentricularRESUMEN
Role of beta-blockers in the treatment of chronic heart failure has been changed over a 25-year period from contraindication to an established indication. To date, controlled clinical trials performed in more than 13,000 patients with chronic heart failure have consistently shown that the long term administration of beta-blockers is associated with significant improvement in left ventricular function, clinical symptoms, and survival. This favorable clinical trial experiences support a recommendation that beta-blockers should be used in all heart failure patients with stable symptoms due to left ventricular systolic dysfunction unless contraindicated. Ongoing beta-blocker studies address further new topics, such as treatment of elderly patients and direct comparison of different agents. Although, the use of beta-blockers for heart failure tends to increase, implementation of the experiences from the clinical trials to the everyday practice still remains a challenge.
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Antagonistas Adrenérgicos beta/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Antagonistas Adrenérgicos beta/administración & dosificación , Antagonistas Adrenérgicos beta/efectos adversos , Antagonistas Adrenérgicos beta/economía , Bisoprolol/uso terapéutico , Carbazoles/uso terapéutico , Carvedilol , Enfermedad Crónica , Ensayos Clínicos Controlados como Asunto , Progresión de la Enfermedad , Esquema de Medicación , Insuficiencia Cardíaca/economía , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/fisiopatología , Humanos , Metoprolol/uso terapéutico , Contracción Miocárdica/efectos de los fármacos , Selección de Paciente , Propanolaminas/uso terapéutico , Tasa de Supervivencia , Disfunción Ventricular Izquierda/tratamiento farmacológico , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
We studied the effect of experimental hypercholesterolaemia/atherosclerosis on changes in coronary flow and cardiac function, induced by protein kinase C and ATP-sensitive K(+) (K(ATP)) channel modulators in isolated Langendorff-perfused rabbit hearts. Both phorbol 12-myristate-13-acetate (PMA) and phorbol 12,13-dibutyrate (PDB, 0.1 microM each), activators of protein kinase C, decreased, whereas staurosporine, (0.1 microM), a protein kinase C inhibitor, increased coronary flow and left ventricular dP/dt, an index of ventricular contractility. Glyburide (5-50 microM), a K(ATP) channel inhibitor, blocked the effect of staurosporine. The phorbol esters were without effect in the presence of pinacidil (5 microM), a K(ATP) channel activator. Neither the protein kinase C modulators nor glyburide produced any effect on coronary flow and left ventricular contractility, when the hearts were prepared from animals either maintained on a cholesterol (1.5%)-enriched diet or treated with lovastatin (5 mg/kg/day per os). Treatment with farnesol (1 mg/kg twice a day for 7 days intravenously) restored the reactivity of hearts from either hypercholesterolaemic or lovastatin-treated animals to protein kinase C modulators. We conclude that non-cholesterol mevalonate products are necessary for the functional integrity of the protein kinase C-K(ATP) channel pathway in the rabbit heart.
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Circulación Coronaria/fisiología , Hipercolesterolemia/fisiopatología , Canales de Potasio/fisiología , Proteína Quinasa C/metabolismo , Adenosina Trifosfato/fisiología , Animales , Circulación Coronaria/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/fisiopatología , Técnicas In Vitro , Masculino , Forbol 12,13-Dibutirato/farmacología , Proteína Quinasa C/antagonistas & inhibidores , Conejos , Estaurosporina/farmacología , Acetato de Tetradecanoilforbol/farmacologíaRESUMEN
Detection of left ventricular contractile reserve by means of dobutamine stress echocardiography is a well known technique. The aim of the present study was to detect velocity changes during the administration of dobutamine, to establish if Doppler myocardial imaging is a suitable method for determining left ventricular contractile reserve, and to determine if the technique provides more information than traditional stress echocardiography. Twenty-five patients (all males; mean age, 53.4 years) were examined for a clinical diagnosis of idiopathic dilated cardiomyopathy with a poor left ventricular systolic function (ejection fraction less than 30%). Doses of 5-10 and 20 mg/kg/min dobutamine were administered and elevated at 4-minute intervals. Ejection fraction was calculated using the Simpson rule. The peak systolic and the early and late diastolic velocities were measured in the basal segment of the septum and the inferior wall at baseline and at full dose of dobutamine. Results indicated that peak systolic velocity increased significantly, both in the septum (0.11±0.03 vs. 0.20±0.05 m/sec; p=0.001) and in the inferior wall (0.10±0.05 vs. 0.17±0.06 m/sec; p=0.03). Late diastolic velocities also increased significantly, both in the septum (0.17±0.05 vs. 0.22±0.07 m/sec; p=0.01) and in the inferior wall (0.18±0.08 vs.0.21±0.02 m/sec; p=0.01). There was a significant linear correlation between the relative increases in basal ejection fraction value and in peak systolic velocity upon dobutamine stimulation. Patients were divided into responders and nonresponders based on responses in either ejection fraction (25% relative increase) or peak systolic velocity (5 cm/s increase). This study concludes that 1) Doppler myocardial imaging is an adequate and simple technique to examine left ventricular contractile reserve; and 2) measurement of peak systolic velocity during dobutamine stimulation seems to be a simple and good indicator of left ventricular contractile reserve. (c)2001 CHF, Inc.
RESUMEN
Dilated cardiomyopathy and end-stage heart failure result in characteristic functional, biochemical and molecular alterations. Multiple defects in cardiac excitation-contraction coupling have been suggested to underlie disturbed myocardial function and progressive remodeling. Ca2+ uptake and release by the sarcoplasmic reticulum (SR) have been shown to be altered in various animal models and human conditions. This review will focus on SR Ca2+ ATPase and its regulatory protein, phospholamban, as potential therapeutic targets. We summarize structural and genetic approaches, which have helped to elucidate the physiological role of phospholamban as a principal regulator of cardiac contractility and beta-adrenergic stimulation in the heart. These findings are extended to the clinical arena, indicating a phospholamban/SR Ca2+ ATPase mismatch in human heart failure. Evidence is then provided, using genetically engineered mouse models, that SR dysfunction may play a key role in the onset and progression of heart failure. Phospholamban deficiency may prevent such left ventricular dysfunction and its progression to heart failure in some of the animal models with dilated cardiomyopathy. Based on these findings, we discuss the question of whether and how interfering with the phospholamban/SR Ca2+ ATPase interaction may be a promising therapeutic approach for heart failure.
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Proteínas de Unión al Calcio/fisiología , ATPasas Transportadoras de Calcio/metabolismo , Cardiomiopatía Dilatada/fisiopatología , Contracción Miocárdica/fisiología , Retículo Sarcoplasmático/fisiología , Animales , Proteínas de Unión al Calcio/genética , Cardiomiopatía Dilatada/genética , Cardiomiopatía Dilatada/metabolismo , Humanos , Ratones , Ratones Noqueados , Contracción Miocárdica/genética , Retículo Sarcoplasmático/enzimología , ATPasas Transportadoras de Calcio del Retículo SarcoplásmicoRESUMEN
The objective of this study was to compare the changes in the values of allergen-specific serum IgE levels and zymosan-induced whole blood chemiluminescence (CL) in 41 patients who had exclusively only ragweed allergy in the season of acute symptoms of disease in July, August and September. All patients had allergic rhinitis or rhinoconjunctivitis. Each patient was investigated as a self-control. The ragweed-specific IgE levels were measured by enzyme immunoassay (EIA). The luminol amplified zymosan-induced CL of whole human blood was detected. The allergen-specific serum IgE levels showed slight, but not significant, gradually increasing elevations during the whole season. On the other hand, significant increases were found in the values of the basal but especially in the zymosan-stimulated CL of peripheral blood phagocytes during the acute phase of allergy. Both the basal and the zymosan-induced CL reflected significantly the activated state of the immune system. These observations clearly show that there are well detectable signs of the systemic activation of the immune system in allergic rhinoconjunctivitis beside the local alterations. In addition, the measurements of the basal and zymosan-induced CL of peripheral phagocytes could clearly reflect the clinical state of disease in vitro.
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Alérgenos/inmunología , Conjuntivitis Alérgica/inmunología , Inmunoglobulina E/sangre , Mediciones Luminiscentes , Fagocitos/fisiología , Polen/inmunología , Rinitis Alérgica Estacional/inmunología , Adulto , Especificidad de Anticuerpos , Conjuntivitis Alérgica/sangre , Femenino , Humanos , Inmunoglobulina E/inmunología , Masculino , Neutrófilos/efectos de los fármacos , Neutrófilos/fisiología , Fagocitos/efectos de los fármacos , Rinitis Alérgica Estacional/sangre , Estaciones del Año , Factores de Tiempo , Zimosan/farmacologíaRESUMEN
The widely accepted theories for the decreased function in the stunned myocardium relate to Ca2+ desensitization and free radical-mediated tissue damage of the myofilaments. The aim of the present study was to examine whether the depressed contractile function and Ca2+ responsiveness of the stunned myocardium may be restored by a new Ca2+ sensitizer (levosimendan), which has been shown to improve the Ca2+ response of the myofilaments. The effects of levosimendan on the left ventricular function and the in vivo protein phosphorylation were examined in both the non-ischemic and the stunned myocardium. Myocardial stunning was induced in Langendorff-perfused guinea pig hearts by suspending the circulation for 8 min, followed by a 20-min reperfusion period. Perfusion of post-ischemic guinea pig hearts with levosimendan (0.03-0.48 microM, 6 min) was associated with dose- and time-dependent increases in both dP/dtmax (contractility) and dP/dtmin (speed of relaxation). When the effectiveness of levosimendan was compared in non-ischemic and post-ischemic hearts, no significant differences were noted in the relative stimulatory effects on contractility and relaxation, at any given time point (time-response curve) or concentration (dose-response curve). Perfusion of the guinea pig hearts with a high (0.3 microM) levosimendan concentration did not reveal any qualitative or quantitative difference in the phosphodiesterase inhibitory potential of the compound (elevation of tissue cyclic AMP levels and characteristics of protein phosphorylation) between the non-ischemic and the post-ischemic myocardium. However, when isoproterenol was administered to induce maximal in vivo phosphorylation of cardiac phosphoproteins, an attenuation of the 32P-incorporation into troponin I was noted in the post-ischemic hearts. The decrease in isoproterenol-induced 32P-incorporation into troponin I was associated with similar alterations in the tissue level of this protein. We conclude that the Ca2+ sensitizer levosimendan exerts dose- and time-dependent positive inotropic and lusitropic effects on the post-ischemic myocardium, lending support to the hypothesis tha Ca2+ desensitization of the myofibrils is involved in myocardial stunning.
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Cardiotónicos/farmacología , Hidrazonas/farmacología , Isquemia Miocárdica/tratamiento farmacológico , Proteínas/metabolismo , Piridazinas/farmacología , Función Ventricular Izquierda/efectos de los fármacos , Animales , AMP Cíclico/análisis , Cobayas , Masculino , Isquemia Miocárdica/fisiopatología , Aturdimiento Miocárdico/tratamiento farmacológico , Miocardio/metabolismo , Fosforilación , SimendánRESUMEN
Left ventricular aneurysm had detected at the 55-year-old woman after extensive anterior myocardial infarction in association with progressive ventricular dilatation and symptoms of heart failure. Coronary angiogram revealed a serious lesion in the proximal segment of the left anterior descending coronary branch with a poor run off tract. 18FDG-PET and 99mTc-MIBI-SPECT investigation were performed in order to differentiate the scarred regions from the viable myocardial segments. Taking into consideration the results an aneurysm resection was performed without revascularisation procedure. After the surgery not only the ejection fraction and the left ventricular dilatation had improved but the tissue perfusion in the segments surrounding the resected aneurysm had also showed a significant increase at the follow up MIBI-SPECT imaging.
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Aneurisma Cardíaco/cirugía , Disfunción Ventricular Izquierda/cirugía , Angiografía Coronaria , Circulación Coronaria , Dilatación Patológica , Femenino , Humanos , Persona de Mediana Edad , Reperfusión MiocárdicaRESUMEN
The aim of the present study was to determine the effects of beta -adrenergic stimulation in wild-type and phospholamban-deficient mouse hearts with altered thyroid conditions. Hypothyroidism was associated with significant decreases in heart/body weight ratio in wild-type and phospholamban-deficient mice, whereas hyperthyroidism was associated with significant increases in heart/body weight ratio in both groups. Hypothyroid hearts of wild-type and phospholamban-deficient mice exhibited similar increases in beta -myosin heavy chain protein levels and decreases in alpha -myosin heavy chain protein levels. In hyperthyroidism, there were increases in the alpha -myosin heavy chain protein levels and these were similar in wild-type and phospholamban-deficient hearts. There were no detectable levels of beta -myosin heavy chain protein in the hyperthyroid hearts. The relative tissue level of phospholamban in wild-type hearts was increased (133%, P<0.01) in hypothyroidism, and decreased (69%, P<0.01) in hyperthyroidism, when compared to euthyroid controls (100%). Similar increases and decreases in SR Ca(2+)-ATPase protein levels were observed between phospholamban-deficient and wild-type hearts in hyperthyroidism and hypothyroidism, respectively. The basal contractile state of wild-type and phospholamban-deficient hearts was significantly depressed in hypothyroidism. On the other hand, the basal contractile state of wild-type and phospholamban-deficient hearts was significantly increased in hyperthyroidism. During beta -agonist stimulation of wild-type hearts, the responses in the rates of contraction and relaxation were highest in the hypothyroid group, followed by the euthyroid, and lastly by the hyperthyroid groups. There was a close linear correlation between the magnitude of the contractile parameter responses and the phospholamban/SERCA2 ratios in these hearts. However, the phospholamban-deficient hypothyroid, euthyroid, and hyperthyroid hearts did not exhibit any responses to isoproterenol, indicating that the alterations in the thyroid states of these hearts do not influence the effects of isoproterenol on cardiac function. These findings suggest that phospholamban is an important regulator of the heart's responses to beta -adrenergic stimulation under various thyroid states.
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Proteínas de Unión al Calcio/fisiología , Corazón/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Hipertiroidismo/fisiopatología , Hipotiroidismo/fisiopatología , Isoproterenol/farmacología , Cadenas Pesadas de Miosina/genética , Glándula Tiroides/fisiología , Animales , Presión Sanguínea/efectos de los fármacos , Proteínas de Unión al Calcio/deficiencia , Proteínas de Unión al Calcio/genética , Circulación Coronaria/efectos de los fármacos , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/fisiología , Corazón/fisiología , Corazón/fisiopatología , Masculino , Ratones , Ratones Noqueados , Contracción Miocárdica/efectos de los fármacos , Miocardio/metabolismo , Isoformas de Proteínas/genética , Hormonas Tiroideas/fisiologíaRESUMEN
Alterations in the expression levels of the sarcoplasmic reticulum (SR) Ca2+-ATPase and its regulator, phospholamban, have been implicated in the effects of thyroxine hormone on cardiac function. To determine the role of phospholamban in these effects, hypothyroidism and hyperthyroidism were induced in phospholamban-deficient mice and their isogenic wild types. Hypothyroidism resulted in significant decreases of left ventricular contractility, which could be moderately stimulated by increases in preload or afterload, in both phospholamban-deficient and wild-type mice. However, the basal contractile parameters in hypothyroid phospholamban-deficient hearts were at least as high as those exhibited by hyperthyroid wild-type hearts. In hyperthyroidism, there was no further enhancement of the hyperdynamic contractile parameters in phospholamban-deficient hearts, although the wild-type hearts exhibited significantly increased contractile function compared with their respective euthyroid groups. Furthermore, increases in preload or afterload did not enhance contractility in either phospholamban-deficient or wild-type hyperthyroid hearts. Examination of the relative tissue levels of cardiac SR Ca2+-ATPase revealed increases in hyperthyroidism and decreases in hypothyroidism compared with euthyroidism, and these changes were similar between phospholamban-deficient and wild-type hearts. An opposite trend was observed for phospholamban expression levels in the wild-type group, which were depressed in hyperthyroid hearts but increased in hypothyroid hearts. These findings indicate that (1) thyroid hormones induce similar changes in the cardiac SR Ca2+-ATPase levels in either the presence or absence of phospholamban, (2) the thyroxine-induced increases in SR Ca2+-ATPase levels are not associated with any further stimulation of the hyperdynamic cardiac function in phospholamban-deficient mice, and (3) the decreased contractile parameters in hypothyroid phospholamban-deficient hearts associated with decreases in SR Ca2+-ATPase levels and myosin heavy chain isoform switches are at least as high as those of the stimulated hyperthyroid wild-type hearts. Thus, alterations in the phospholamban level or its activity may be a critical determinant of the contractile responses to altered thyroid states in the mammalian heart.
Asunto(s)
Proteínas de Unión al Calcio/deficiencia , Miocardio/química , Hormonas Tiroideas/farmacología , Animales , ATPasas Transportadoras de Calcio/farmacología , Femenino , Hipotiroidismo/metabolismo , Masculino , Ratones , Contracción Miocárdica/efectos de los fármacos , Función Ventricular/fisiologíaRESUMEN
Phospholamban is a low molecular weight phosphoprotein in cardiac sarcoplasmic reticulum. The regulatory role of phospholamban in vivo has recently been elucidated by targeting the gene of this protein in embryonic stem cells and generating phospholamban-deficient mice. The phospholamban knockout hearts exhibited significantly enhanced contractile parameters and attenuated responses to beta-agonists. The hyperdynamic cardiac function of the phospholamban knockout mice was not accompanied by any cytoarchitectural abnormalities or alterations in the expression levels of the cardiac sarcoplasmic reticulum Ca(2+)-ATPase, calsequestrin, Na(+)-Ca2+ exchanger, or the contractile proteins. Furthermore, the attenuation of the cardiac responses to beta-agonists was not due to alterations in the phosphorylation levels of the other key cardiac phosphoproteins in the phospholamban knockout hearts. However, ablation of phospholamban was associated with down-regulation of the ryanodine receptor, which suggests that a cross-talk between cardiac sarcoplasmic reticulum Ca2+ uptake and Ca2+ release occurred in an attempt to maintain Ca2+ homeostasis in these hyperdynamic phospholamban knockout hearts.
Asunto(s)
Proteínas de Unión al Calcio/fisiología , Corazón/fisiología , Contracción Miocárdica/fisiología , Agonistas Adrenérgicos beta/farmacología , Animales , Proteínas de Unión al Calcio/deficiencia , Proteínas de Unión al Calcio/genética , ATPasas Transportadoras de Calcio/genética , Calsecuestrina/genética , Proteínas Contráctiles/genética , Regulación de la Expresión Génica , Ratones , Ratones Noqueados , Contracción Miocárdica/efectos de los fármacos , Miocardio/ultraestructura , Fosforilación , ARN Mensajero/genética , Retículo Sarcoplasmático/fisiología , Retículo Sarcoplasmático/ultraestructura , Intercambiador de Sodio-Calcio/genética , Transcripción GenéticaAsunto(s)
Calcio/metabolismo , Cardiotónicos/farmacología , AMP Cíclico/metabolismo , Corazón/fisiología , Isoproterenol/farmacología , Proteínas Musculares/metabolismo , Función Ventricular Izquierda/efectos de los fármacos , Animales , Cobayas , Corazón/efectos de los fármacos , Hidrazonas/farmacología , Miocardio/metabolismo , Fosforilación , Piridazinas/farmacología , Quinolinas/farmacología , Simendán , Tiadiazinas/farmacología , Función Ventricular Izquierda/fisiologíaRESUMEN
Left ventricular wall rupture after myocardial infarction is a mechanical complication that may result in a pseudoaneurysm. Between January 1994 and October 1996, false or pseudoaneurysms were detected in 6 (0.0026%) of 2,600 consecutive patients (4 women, 2 men; mean age 59.4 years) undergoing cardiac catheterization at University Medical School, Debrecen, Hungary. All patients had a history of cardiovascular disease, with diagnosis of pseudoaneurysm confirmed by echocardiography. The average time from the occurrence of acute infarction to diagnosis was 37.0 days (range 3-80 days). All patients were in New York Heart Association functional class IV congestive heart failure; in four patients cardiogenic shock was present. Five patients underwent coronary angiography, which demonstrated multivessel disease and occlusion of the infarct-related artery (TIMIO) without adequate collateral circulation (grade 0-1). Five patients had surgical repair of the false aneurysm, and, in three patients, concomitant coronary bypass grafting was performed. The 2-year mortality rate for all patients was 50%. Early diagnosis of false aneurysm is facilitated by echocardiography, and coronary angiography is required before surgery. Early surgical correction with coronary revascularization is advised.
Asunto(s)
Aneurisma Falso/etiología , Ventrículos Cardíacos , Infarto del Miocardio/complicaciones , Anciano , Aneurisma Falso/diagnóstico , Aneurisma Falso/cirugía , Resultado Fatal , Femenino , Ventrículos Cardíacos/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Radiografía , Rotura EspontáneaRESUMEN
Coronary angiography revealed three-vessel disease in a 56-year-old male with two previous myocardial infarctions. Coronary bypass surgery was initially ruled out by cardiac surgeon because of the poor left ventricular function (EF: 23%), despite moderate viability signs during conventional isotope techniques. Positron emission tomography with 18FDG indicated a large periinfarction area of hibernating myocardium. Accordingly, coronary bypass grafting was performed. Postoperatively, the symptoms disappeared, the left ventricular wall motion abnormalities (with the exception of the scarred region demonstrated by PET) improved, and the global left ventricular function increased significantly. This case and the role of cardiac PET study for prediction of the result of revascularization are discussed.