RESUMEN
BACKGROUND: Currently there is no reliable medical treatment for aortic regurgitation (AR). METHODS: Thirty-nine Sprague-Dawley rats underwent creation of AR or sham operation. Treated rats were assigned to early or late institution of sildenafil therapy (100 mg/kg/day) for a total of 10 weeks. Treatment-effects were measured by serial echocardiography, invasive hemodynamic measurements, and tissue analysis. RESULTS: Rats assigned to early treatment developed less remodeling than untreated rats. Thus, left ventricular (LV) dilation was blunted by sildenafil with end-systolic diameter being significantly smaller (6.6 ± 0.4 vs. 7.7 ± 0.4 mm, respectively, p < 0.05). Also, LV wall thickness was significantly decreased in treated rats compared to controls (2.23 ± 0.08 vs. 2.16 ± 0.05 mm, p < 0.01). Fractional shortening was improved by treatment (p < 0.05). Myocardial fibrosis was borderline decreased by treatment (p = 0.09). Akt was increased in treated compared to controls (p < 0.05). CONCLUSION: Sildenafil slightly inhibits LV remodeling and improves fractional shortening in rats with AR when treatment is initiated early.
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Patients with nonobstructive hypertrophic cardiomyopathy (HC) are considered low risk, generally not requiring aggressive intervention. However, nonobstructive and labile-obstructive HC have been traditionally classified together, and it is unknown if these 2 subgroups have distinct risk profiles. We compared cardiovascular outcomes in 293 patients HC (96 nonobstructive, 114 labile-obstructive, and 83 obstructive) referred for exercise echocardiography and magnetic resonance imaging and followed for 3.3 ± 3.6 years. A subgroup (34 nonobstructive, 28 labile-obstructive, 21 obstructive) underwent positron emission tomography. The mean number of sudden cardiac death risk factors was similar among groups (nonobstructive: 1.4 vs labile-obstructive: 1.2 vs obstructive: 1.4 risk factors, p = 0.2). Prevalence of late gadolinium enhancement (LGE) was similar across groups but more non-obstructive patients had late gadolinium enhancement ≥20% of myocardial mass (23 [30%] vs 19 [18%] labile-obstructive and 8 [11%] obstructive, p = 0.01]. Fewer labile-obstructive patients had regional positron emission tomography perfusion abnormalities (12 [46%] vs nonobstructive 30 [81%] and obstructive 17 [85%], p = 0.003]. During follow-up, 60 events were recorded (36 ventricular tachycardia/ventricular fibrillation, including 30 defibrillator discharges, 12 heart failure worsening, and 2 deaths). Nonobstructive patients were at greater risk of VT/VF at follow-up, compared to labile obstructive (hazed ratio 0.18, 95% confidence interval 0.04 to 0.84, p = 0.03) and the risk persisted after adjusting for age, gender, syncope, family history of sudden cardiac death, abnormal blood pressure response, and septum ≥3 cm (p = 0.04). Appropriate defibrillator discharges were more frequent in nonobstructive (8 [18%]) compared to labile-obstructive (0 [0%], p = 0.02) patients. In conclusion, nonobstructive hemodynamics is associated with more pronounced fibrosis and ischemia than labile-obstructive and is an independent predictor of VT/VF in HC.
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Cardiomiopatía Hipertrófica/fisiopatología , Insuficiencia Cardíaca/fisiopatología , Taquicardia Ventricular/etiología , Fibrilación Ventricular/etiología , Obstrucción del Flujo Ventricular Externo/fisiopatología , Adulto , Anciano , Cardiomiopatía Hipertrófica/clasificación , Cardiomiopatía Hipertrófica/complicaciones , Cardiomiopatía Hipertrófica/diagnóstico , Estudios de Cohortes , Progresión de la Enfermedad , Ecocardiografía de Estrés , Femenino , Corazón/diagnóstico por imagen , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/diagnóstico , Humanos , Estimación de Kaplan-Meier , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Imagen de Perfusión Miocárdica , Miocardio/patología , Modelos de Riesgos Proporcionales , Obstrucción del Flujo Ventricular Externo/clasificación , Obstrucción del Flujo Ventricular Externo/diagnóstico , Obstrucción del Flujo Ventricular Externo/etiologíaRESUMEN
The exercise heart rate (HR) profile and its relation to cardiac function and arrhythmias were investigated in patients with hypertrophic cardiomyopathy (HC). Chronotropic response (CR) and heart rate recovery (HRR) were computed during and after treadmill exercise testing in 273 patients with HC and 95 age-matched healthy controls. Patients with HC had higher prevalence of chronotropic incompetence and lower HRR1-5min compared with controls. Exercise capacity, diastolic function (assessed by E/e') and left atrial volume index were associated with HRR1min and CR in HC. Septal myectomy was associated with reduction in chronotropic incompetence but did not affect HRR1min. In conclusion, impaired CR and HRR1min are associated with advanced disease and do not appear to be independent clinical markers indicating high-risk status in HC. Improving CR by titrating doses of negative chronotropic agents, myectomy, and atrial pacing may be useful to increase exercise capacity in patients with HC.
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Cardiomiopatía Hipertrófica/fisiopatología , Electrocardiografía , Ejercicio Físico/fisiología , Frecuencia Cardíaca/fisiología , Ventrículos Cardíacos/fisiopatología , Recuperación de la Función , Función Ventricular Izquierda/fisiología , Cardiomiopatía Hipertrófica/diagnóstico , Ecocardiografía Doppler en Color , Prueba de Esfuerzo/métodos , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Pronóstico , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Beta-blockade is contraindicated in severe aortic regurgitation (AR) due to the fear of prolonging diastole and thus aggravate regurgitation. However, this has never been scientifically proven and positive effects of targeting the sympathetic system in AR has been demonstrated in several studies. METHOD: Thirty-nine Sprague-Dawley rats with AR were randomized to ten weeks of medical treatment with carvedilol or no treatment. Treatment was initiated either early or late after AR induction. The effect of carvedilol was assessed by serial echocardiography and invasive hemodynamic measurements. RESULTS: AR resulted in eccentric hypertrophy and left ventricular (LV) dysfunction. LV remodeling and function as measured by echocardiography was unaffected by treatment. LV dimensions were similar between treated and untreated groups and measures of LV performance (including strain and strain rate) were also unaltered. This result was confirmed by invasive measurements showing maximal and minimal pressure-time development, LV volumes, and LV pressures, to be unaltered by treatment. On the contrary, despite relative bradycardia carvedilol did not reflect any negative impact on the heart. CONCLUSION: Carvedilol did not improve left ventricular remodeling or function in rats with surgically induced AR. Despite relative bradycardia, we did not find carvedilol to negatively impact the heart, either when treatment was initiated early or late in the course of disease.
RESUMEN
RATIONALE: In cardiomyocytes from failing hearts, insufficient mitochondrial Ca(2+) accumulation secondary to cytoplasmic Na(+) overload decreases NAD(P)H/NAD(P)(+) redox potential and increases oxidative stress when workload increases. These effects are abolished by enhancing mitochondrial Ca(2+) with acute treatment with CGP-37157 (CGP), an inhibitor of the mitochondrial Na(+)/Ca(2+) exchanger. OBJECTIVE: Our aim was to determine whether chronic CGP treatment mitigates contractile dysfunction and arrhythmias in an animal model of heart failure (HF) and sudden cardiac death (SCD). METHODS AND RESULTS: Here, we describe a novel guinea pig HF/SCD model using aortic constriction combined with daily ß-adrenergic receptor stimulation (ACi) and show that chronic CGP treatment (ACi plus CGP) attenuates cardiac hypertrophic remodeling, pulmonary edema, and interstitial fibrosis and prevents cardiac dysfunction and SCD. In the ACi group 4 weeks after pressure overload, fractional shortening and the rate of left ventricular pressure development decreased by 36% and 32%, respectively, compared with sham-operated controls; in contrast, cardiac function was completely preserved in the ACi plus CGP group. CGP treatment also significantly reduced the incidence of premature ventricular beats and prevented fatal episodes of ventricular fibrillation, but did not prevent QT prolongation. Without CGP treatment, mortality was 61% in the ACi group <4 weeks of aortic constriction, whereas the death rate in the ACi plus CGP group was not different from sham-operated animals. CONCLUSIONS: The findings demonstrate the critical role played by altered mitochondrial Ca(2+) dynamics in the development of HF and HF-associated SCD; moreover, they reveal a novel strategy for treating SCD and cardiac decompensation in HF.
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Clonazepam/análogos & derivados , Muerte Súbita Cardíaca/prevención & control , Insuficiencia Cardíaca/tratamiento farmacológico , Intercambiador de Sodio-Calcio/antagonistas & inhibidores , Tiazepinas/farmacología , Animales , Antiarrítmicos/farmacología , Calcio/metabolismo , Cardiomegalia/etiología , Clonazepam/farmacología , Modelos Animales de Enfermedad , Electrocardiografía/efectos de los fármacos , Cobayas , Insuficiencia Cardíaca/complicaciones , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Estrés Oxidativo , Receptores Adrenérgicos beta/fisiologíaRESUMEN
Obesity is independently associated with left ventricular (LV) hypertrophy and thus may be an important modifier of the hypertrophic cardiomyopathy (HC) phenotype. We examined if obesity modifies the clinical presentation, LV morphology, outflow hemodynamics, and exercise tolerance in HC. In this cross-sectional study, 88 obese (body mass index [BMI] ≥30 kg/m(2)) and 154 nonobese (BMI <30 kg/m(2)) patients from the Johns Hopkins HC clinic were compared with respect to a variety of clinical and LV echocardiographic measurements. Obese patients (36.4%) were more likely to report exertional dyspnea (p = 0.04) and chest pain (p = 0.002) and had greater prevalence of hypertension (p = 0.008). LV posterior wall thickness (p = 0.01) but not the septal wall (p ≥0.21) was significantly greater in obese patients, resulting in an increased LV mass index (p = 0.003). No significant differences in LV systolic and diastolic functions were observed, but obesity was associated with higher LV stroke volume (p = 0.03), inducible LV outflow tract gradients (p = 0.045), and chance of developing LV outflow tract obstruction during stress (p = 0.035). In multivariate analysis, BMI was associated with increased posterior (but not septal) wall thickness (ß = 0.15, p = 0.02) and LV mass index (ß = 0.18, p = 0.005), particularly in those with hypertension. Obesity was also associated with reduced exercise time and functional capacity, and BMI independently correlated with reduced exercise tolerance. In conclusion, obesity is associated with larger LV mass, worse symptoms, lower exercise tolerance, and labile obstructive hemodynamics in HC. The association with increased outflow tract gradients has particular importance as contribution of obesity to the pressure gradients may influence clinical decisions in labile obstructive HC.
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Cardiomiopatía Hipertrófica/diagnóstico por imagen , Tolerancia al Ejercicio/fisiología , Ventrículos Cardíacos/fisiopatología , Hemodinámica/fisiología , Hipertrofia Ventricular Izquierda/fisiopatología , Obesidad/complicaciones , Índice de Masa Corporal , Cardiomiopatía Hipertrófica/etiología , Cardiomiopatía Hipertrófica/fisiopatología , Estudios Transversales , Ecocardiografía , Femenino , Estudios de Seguimiento , Ventrículos Cardíacos/diagnóstico por imagen , Humanos , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/etiología , Masculino , Persona de Mediana Edad , Obesidad/fisiopatología , Estudios ProspectivosRESUMEN
The development of left ventricular hypertrophy and dysfunction in aortic regurgitation (AR) has only been sparsely studied experimentally. In a new model of chronic AR in rats, we examined activation of molecular pathways involved in myocardial hypertrophy. Chronic AR was produced by damaging one or two valve cusps, resulting in eccentric remodeling and left ventricular dysfunction, with no increase in overall fibrosis. Western blotting showed increased activation of Akt and p38 at 12 weeks and of c-Jun amino-terminal kinase at 2 weeks, decreased activation of extracellular regulated kinase 5 at both 2 and 12 weeks, while activation of calcium/calmodulin-dependent protein kinase II and extracellular regulated kinase 1/2 was unchanged. Expression of calcineurin and ANF was also unchanged. Eccentric hypertrophy and early cardiac dysfunction in experimental AR are associated with a pattern of activation of intracellular pathways different from that seen with pathological hypertrophy in pressure overload, and more similar to that associated with benign physiological hypertrophy.
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Insuficiencia de la Válvula Aórtica/complicaciones , Hipertrofia Ventricular Izquierda/etiología , Miocardio/metabolismo , Transducción de Señal , Disfunción Ventricular Izquierda/etiología , Animales , Insuficiencia de la Válvula Aórtica/diagnóstico por imagen , Insuficiencia de la Válvula Aórtica/metabolismo , Insuficiencia de la Válvula Aórtica/fisiopatología , Factor Natriurético Atrial/metabolismo , Calcineurina/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Enfermedad Crónica , Modelos Animales de Enfermedad , Ecocardiografía Doppler en Color , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/metabolismo , Hipertrofia Ventricular Izquierda/fisiopatología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Masculino , Miocardio/patología , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/fisiopatología , Función Ventricular Izquierda , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
OBJECTIVES: Invasive measurements of intracardiac hemodynamics in animal models have allowed important advances in the understanding of cardiac disease. Currently they are performed either through a carotid arteriotomy or via a thoracotomy and apical insertion. Both of these techniques have disadvantages and are not conducive to repeated measurements. Therefore, the purpose of this study was to develop a new technique for measuring intracardiac hemodynamics. METHODS: In 13 male rats, hemodynamic measurements were performed using a new echocardiographically guided percutaneous apical technique. An intravenous catheter was percutaneously inserted into the left ventricle (LV) in the direction of the LV long axis. Through this catheter, a micromanometer-tipped pressure catheter was inserted, and invasive hemodynamic traces were recorded. After LV recordings, the pressure catheter was advanced into the aorta where pressures were obtained. In 11 rats, measurements were repeated after 1 week (n = 2), 2 weeks (n = 4), 3 weeks (n = 4), or 4 weeks (n = 1). In 3 rats, invasive measurements were performed using a carotid arteriotomy before the percutaneous technique. RESULTS: Among the 13 rats subjected to the procedure, the survival rate was 85%. Of the 11 rats that had the procedure repeated, 3 died (27%). The mean differences ± SD when comparing the two techniques were 10 ± 4 mm Hg for the LV end-systolic pressure and 1 ± 1 mm Hg for the LV end-diastolic pressure. The mean procedure times were 21 ± 3 and 6 ± 1 minutes for the carotid and percutaneous techniques, respectively. CONCLUSIONS: We have successfully developed a percutaneous technique for insertion of LV microtip catheters in rats.
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Cateterismo Cardíaco/métodos , Ecocardiografía/métodos , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/cirugía , Hemodinámica/fisiología , Punciones , Animales , Masculino , Manometría/instrumentación , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: We sought to investigate the relationship between infarct and dyssynchrony post- myocardial infarct (MI), in a porcine model. Mechanical dyssynchrony post-MI is associated with left ventricular (LV) remodeling and increased mortality. METHODS: Cine, gadolinium-contrast, and tagged cardiovascular magnetic resonance (CMR) were performed pre-MI, 9 ± 2 days (early post-MI), and 33 ± 10 days (late post-MI) post-MI in 6 pigs to characterize cardiac morphology, location and extent of MI, and regional mechanics. LV mechanics were assessed by circumferential strain (eC). Electro-anatomic mapping (EAM) was performed within 24 hrs of CMR and prior to sacrifice. RESULTS: Mean infarct size was 21 ± 4% of LV volume with evidence of post-MI remodeling. Global eC significantly decreased post MI (-27 ± 1.6% vs. -18 ± 2.5% (early) and -17 ± 2.7% (late), p < 0.0001) with no significant change in peri-MI and MI segments between early and late time-points. Time to peak strain (TTP) was significantly longer in MI, compared to normal and peri-MI segments, both early (440 ± 40 ms vs. 329 ± 40 ms and 332 ± 36 ms, respectively; p = 0.0002) and late post-MI (442 ± 63 ms vs. 321 ± 40 ms and 355 ± 61 ms, respectively; p = 0.012). The standard deviation of TTP in 16 segments (SD16) significantly increased post-MI: 28 ± 7 ms to 50 ± 10 ms (early, p = 0.012) to 54 ± 19 ms (late, p = 0.004), with no change between early and late post-MI time-points (p = 0.56). TTP was not related to reduction of segmental contractility. EAM revealed late electrical activation and greatly diminished conduction velocity in the infarct (5.7 ± 2.4 cm/s), when compared to peri-infarct (18.7 ± 10.3 cm/s) and remote myocardium (39 ± 20.5 cm/s). CONCLUSIONS: Mechanical dyssynchrony occurs early after MI and is the result of delayed electrical and mechanical activation in the infarct.
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Imagen por Resonancia Cinemagnética , Contracción Miocárdica , Infarto del Miocardio/complicaciones , Disfunción Ventricular Izquierda/diagnóstico , Función Ventricular Izquierda , Remodelación Ventricular , Animales , Fenómenos Biomecánicos , Medios de Contraste , Modelos Animales de Enfermedad , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Miocardio/patología , Porcinos , Factores de Tiempo , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/patología , Disfunción Ventricular Izquierda/fisiopatología , Imagen de Colorante Sensible al VoltajeRESUMEN
Cardiac resynchronization therapy (CRT), in which both ventricles are paced to recoordinate contraction in hearts that are dyssynchronous from conduction delay, is the only heart failure (HF) therapy to date to clinically improve acute and chronic function while also lowering mortality. CRT acutely enhances chamber mechanical efficiency but chronically alters myocyte signaling, including improving ß-adrenergic receptor reserve. We speculated that the latter would identify unique CRT effects that might themselves be effective for HF more generally. HF was induced in dogs by 6 weeks of atrial rapid pacing with (HFdys, left bundle ablated) or without (HFsyn) dyssynchrony. We used dyssynchronous followed by resynchronized tachypacing (each 3 weeks) for CRT. Both HFdys and HFsyn myocytes had similarly depressed rest and ß-adrenergic receptor sarcomere and calcium responses, particularly the ß2-adrenergic response, whereas cells subjected to CRT behaved similarly to those from healthy controls. CRT myocytes exhibited suppressed Gαi signaling linked to increased regulator of G protein (heterotrimeric guanine nucleotide-binding protein) signaling (RGS2, RGS3), yielding Gαs-biased ß2-adrenergic responses. This included increased adenosine cyclic AMP responsiveness and activation of sarcoplasmic reticulum-localized protein kinase A. Human CRT responders also showed up-regulated myocardial RGS2 and RGS3. Inhibition of Gαi (with pertussis toxin, RGS3, or RGS2 transfection), stimulation with a Gαs-biased ß2 agonist (fenoterol), or transient (2-week) exposure to dyssynchrony restored ß-adrenergic receptor responses in HFsyn to the values obtained after CRT. These results identify a key pathway that is triggered by restoring contractile synchrony and that may represent a new therapeutic approach for a broad population of HF patients.
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Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/terapia , Receptores Adrenérgicos beta 2/metabolismo , Transducción de Señal/fisiología , Animales , Terapia de Resincronización Cardíaca , Células Cultivadas , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Perros , Transferencia Resonante de Energía de Fluorescencia , Proteínas de Unión al GTP/metabolismo , Proteínas Activadoras de GTPasa/metabolismo , Proteínas de Unión al GTP Heterotriméricas/metabolismo , Humanos , Técnicas In Vitro , Células Musculares/metabolismo , Miocardio/metabolismo , Proteínas RGS/metabolismoRESUMEN
OBJECTIVES: This study sought to investigate the prevalence and mechanisms underlying right ventricular (RV) dyssynchrony in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) using tissue Doppler echocardiography (TDE). BACKGROUND: An ARVD/C is characterized by fibrofatty replacement of RV myocardium and RV dilation. These pathologic changes may result in electromechanical dyssynchrony. METHODS: Echocardiography, both conventional and TDE, was performed in 52 ARVD/C patients fulfilling Task Force criteria and 25 control subjects. The RV end-diastolic and -systolic areas, right ventricular fractional area change (RVFAC), and left ventricular (LV) volumes and function were assessed. Mechanical synchrony was assessed by measuring differences in time-to-peak systolic velocity (T(SV)) between the RV free wall, ventricular septum, and LV lateral wall. An RV dyssynchrony was defined as the difference in T(SV) between the RV free wall and the ventricular septum, >2 SD above the mean value for control subjects. RESULTS: The mean difference in RV T(SV) was higher in ARVD/C compared with control subjects (55 +/- 34 ms vs. 26 +/- 15 ms, p < 0.001). Significant RV dyssynchrony was not noted in any of the control subjects. Based on a cutoff value of 56 ms, significant RV dyssynchrony was present in 26 ARVD/C patients (50%). Patients with RV dyssynchrony had a larger RV end-diastolic area (22 +/- 5 cm(2) vs. 19 +/- 4 cm(2), p = 0.02), and lower RVFAC (29 +/- 8% vs. 34 +/- 8%, p = 0.03) compared with ARVD/C patients without RV dyssynchrony. No differences in QRS duration, LV volumes, or function were present between the 2 groups. CONCLUSIONS: An RV dyssynchrony may occur in up to 50% of ARVD/C patients, and is associated with RV remodeling. This finding may have therapeutic and prognostic implications in ARVD/C.
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Displasia Ventricular Derecha Arritmogénica/epidemiología , Displasia Ventricular Derecha Arritmogénica/fisiopatología , Disfunción Ventricular Derecha/patología , Disfunción Ventricular Derecha/fisiopatología , Adulto , Displasia Ventricular Derecha Arritmogénica/patología , Ecocardiografía Doppler , Electrocardiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Remodelación VentricularRESUMEN
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.
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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.