Respiratory muscle training improves diaphragm citrate synthase activity and hemodynamic function in rats with heart failure

Abstract INTRODUCTION: Enhanced respiratory muscle strength in patients with heart failure positively alters the clinical trajectory of heart failure. In an experimental model, respiratory muscle training in rats with heart failure has been shown to improve cardiopulmonary function through mechanisms yet to be entirely elucidated. OBJECTIVE: The present report aimed to evaluate the respiratory muscle training effects in diaphragm citrate synthase activity and hemodynamic function in rats with heart failure. METHODS: Wistar rats were divided into four experimental groups: sedentary sham (Sed-Sham, n=8), trained sham (RMT-Sham, n=8), sedentary heart failure (Sed-HF, n=7) and trained heart failure (RMT-HF, n=7). The animals were submitted to a RMT protocol performed 30 minutes a day, 5 days/week, for 6 weeks. RESULTS: In rats with heart failure, respiratory muscle training decreased pulmonary congestion and right ventricular hypertrophy. Deleterious alterations in left ventricular pressures, as well as left ventricular contractility and relaxation, were assuaged by respiratory muscle training in heart failure rats. Citrate synthase activity, which was significantly reduced in heart failure rats, was preserved by respiratory muscle training. Additionally, a negative correlation was found between citrate synthase and left ventricular end diastolic pressure and positive correlation was found between citrate synthase and left ventricular systolic pressure. CONCLUSION: Respiratory muscle training produces beneficial adaptations in the diaphragmatic musculature, which is linked to improvements in left ventricular hemodynamics and blood pressure in heart failure rats. The RMT-induced improvements in cardiac architecture and the oxidative capacity of the diaphragm may improve the clinical trajectory of patients with heart failure.

Focal adhesion kinase signaling in cardiac hypertrophy and failure

Focal adhesion kinase (FAK) is a broadly expressed tyrosine kinase implicated in cellular functions such as migration, growth and survival. Emerging data support a role for FAK in cardiac development, reactive hypertrophy and failure. Data reviewed here indicate that FAK plays a critical role at the cellular level in the responses of cardiomyocytes and cardiac fibroblasts to biomechanical stress and to hypertrophic agonists such as angiotensin II and endothelin. The signaling mechanisms regulated by FAK are discussed to provide insight into its role in the pathophysiology of cardiac hypertrophy and failure.

Polimorfismo genético, terapia farmacológica e função cardíaca seqüencial em pacientes com insuficiência cardíaca / Genetic polymorphism, medical therapy and sequential cardiac function in patients with heart failure

FUNDAMENTO: Variantes funcionais do gene da enzima conversora da angiotensina (ECA) podem estar associados com a resposta à terapia em portadores de insuficiência cardíaca (IC). OBJETIVO: Testar a hipótese de diferenças na avaliação ecocardiográfica seqüencial da fração de ejeção do ventrículo esquerdo de pacientes com IC em tratamento farmacológico, inclusive com inibidores da ECA, em relação ao polimorfismo de inserção (I) e deleção (D) do gene da ECA. MÉTODOS: Estudamos 168 pacientes (média de idade 43,3±10,1 anos), 128 (76,2 por cento) dos quais homens, com IC e ecocardiogramas seqüenciais. O polimorfismo I/D foi determinado por reação em cadeia da polimerase. A fração de ejeção do ventrículo esquerdo (FEVE) foi analisada comparativamente aos genótipos. Mais de 90 por cento dos pacientes estavam tomando inibidores da ECA. RESULTADOS: Houve um aumento significantemente maior na FEVE média em pacientes com o alelo D, em comparação com pacientes com genótipo II (p = 0,01) após um seguimento médio de 38,9 meses. O alelo D foi associado com aumento de 8,8 por cento na FEVE média no mesmo período. Além disso, observou-se uma tendência para um efeito do "número de cópias" do alelo D sobre o aumento da FEVE média com o tempo: uma diferença de 3,5 por cento na variação da FEVE entre os pacientes com genótipos II e ID (p = 0,03) e de 5 por cento entre os pacientes com genótipos II e DD (p = 0,02). CONCLUSÃO: O polimorfismo de deleção do gene da ECA pode estar associado com a resposta ao tratamento farmacológico com inibidores da ECA em portadores de IC. Outros estudos controlados poderão contribuir para uma melhor compreensão das influências genéticas sobre a resposta à terapia.

BACKGROUND: Functional variants of angiotensin-converting enzyme (ACE) gene may be associated with response to therapy in patients with heart failure (HF). OBJECTIVE: To test the hypothesis of differences in sequential echocardiographic evaluations of left ventricular ejection fraction in patients with HF on medical therapy, including ACE inhibitors in relation to insertion (I) / deletion (D) polymorphism of the ACE gene. METHODS: We studied 168 patients (mean age 43.3±10.1 years), 128 (76.2 percent) men, with HF and sequential echocardiograms. The I/D polymorphism was determined by polymerase chain reaction. Left ventricular ejection fraction (LVEF) was analyzed comparatively to genotypes. More than 90 percent of patients were on ACE inhibitors. RESULTS: There was a significantly greater increase in mean LVEF in patients with the D allele compared to patients with the II genotype (p=0.01) after a mean follow-up of 38.9 months. The D allele was associated with an increase of 8.8 percent in mean LVEF over the same period. Furthermore, there was a tendency toward a D allele "copy number" effect on the increase of mean LVEF over time: a 3.5 percent difference in LVEF variation between patients with the II and the ID genotypes (p = 0.03) and a 5 percent difference between patients with the II and DD genotypes (p=0.02). CONCLUSION: ACE gene deletion polymorphism may be operative in response to medical treatment that included ACE inhibitors in patients with HF. Further controlled studies may contribute to better understanding of genetic influences on response to therapy.

Superóxido dismutasa ligada al endotelio es un sensible marcador de estrés oxidativo y disfunción endotelial en la insuficiencia cardíaca / Endothelial linked superoxide dismutase is a sensitive marker of oxidative stress and endothelial dysfunction in patients with congestive heart failure

Introducción: En pacientes con insuficiencia cardíaca (IC) existe activación neurohumoral que contribuye a la progresión clínica de la enfermedad y se ha asociado a aumento del estrés oxidativo (EO) y deterioro de la capacidad funcional. Pacientes con IC avanzada tienen niveles aumentados de malodihaldehido, un marcador de EO, pero niveles normales de enzimas antioxidantes. En la pared vascular, la enzima superóxido dismutasa ligada a endotelio (SODec) representa un importante sistema enzimático antioxidante que contribuye a la inactivación de especies reactivas del oxígeno (ROS) y a la modulación del tono vascular. Objetivo: Estudiar el rol de SODec como marcador de EO en IC y su correlación con la función endotelial. Métodos: Estudiamos 20 pacientes con IC moderada (Clase II-III) con fracción de eyección de ventrículo izquierdo (FEVI) < 40 por ciento. Se determinaron los niveles plasmáticos de MDA por sustancias reactivas del ácido tiobarbitúrico y los sistemas de defensa antioxidantes eritrocitarios SOD y catalasa (CAT) por espectofotometría. La enzima ecSOD se liberó de la superficie endotelial mediante la administración de heparina en bolo (5000 U) en la arteria braquial determinando su actividad en sangre venosa. La función endotelial se determinó mediante ecografía de arteria braquial para determinar la vasodilatación dependiente de endotelio. Se utilizó un grupo control de personas sanas pareadas por edad y sexo. Los resultados se expresan como promedio ± DES y en el análisis estadístico se utilizó t-Student y correlación lineal de Pearson. Resultados: Edad promedio de 59 ± 16 años, 17 hombres (85 por ciento). Nueve con etiología isquémica (45 por ciento). La FEVI fue de 33 ± 5 por ciento, el test de caminata de 6 minutos de 412 ± 90 m. Los niveles plasmáticos de MDA y de SOD y CAT eritrocitarios fueronsimilares en pacientes con IC y en grupo control. En los pacientes con IC encontramos una disminución significativa de la actividad de SODec (p< 0.001)...

CaMKIIdelta overexpression in hypertrophy and heart failure: cellular consequences for excitation-contraction coupling

Ca/calmodulin-dependent protein kinase IIdelta (CaMKIIdelta) is the predominant isoform in the heart. During excitation-contraction coupling (ECC) CaMKII phosphorylates several Ca-handling proteins including ryanodine receptors (RyR), phospholamban, and L-type Ca channels. CaMKII expression and activity have been shown to correlate positively with impaired ejection fraction in the myocardium of patients with heart failure and CaMKII has been proposed to be a possible compensatory mechanism to keep hearts from complete failure. However, in addition to these acute effects on ECC, CaMKII was shown to be involved in hypertrophic signaling, termed excitation-transcription coupling (ETC). Thus, animal models have shown that overexpression of nuclear isoform CaMKIIdeltaB can induce myocyte hypertrophy. Recent study from our laboratory has suggested that transgenic overexpression of the cytosolic isoform CaMKIIdeltaC in mice causes severe heart failure with altered intracellular Ca handling and protein expression leading to reduced sarcoplasmic reticulum (SR) Ca content. Interestingly, the frequency of diastolic spontaneous SR Ca release events (or opening of RyR) was greatly enhanced, demonstrating increased diastolic SR Ca leak. This was attributed to increased CaMKII-dependent RyR phosphorylation, resulting in increased and prolonged openings of RyR since Ca spark frequency could be reduced back to normal levels by CaMKII inhibition. This review focuses on acute and chronic effects of CaMKII in ECC and ETC. In summary, CaMKII overexpression can lead to heart failure and CaMKII-dependent RyR hyperphosphorylation seems to be a novel and important mechanism in ECC due to SR Ca leak which may be important in the pathogenesis of heart failure.