Resection of the atrial appendages and its impact in the natriuretic homeostasis: development and validation of an animal model in an academic medical center

ABSTRACT Background: The left atrial appendage (LAAp) resection is an effective treatment approach to reduce the risk of thromboembolism in patients with atrial fibrillation. Objective: To study was to study the impact of removing atrial appendages in the production of natriuretic peptides (NPs) in conditions of volume overload and to develop an experimental model of LAAp resection. Materials and Methods: In a swine model of ischemic heart failure (HF), serum NP levels were measured before (Basal-1A) and after (Basal-1B) a fluid overload. Animals were grouped as follows: (0) preserved appendages, (1) resected LAAp, and (2) both atrial appendages resected. Levels of NP were measured before (2A) and after a fluid overload (2B). Results: Furin levels were higher in Group 0-2A than in Group 2-2A, and a significant increase was found in Group 0-2B compared to Groups 1-2B and 2-2B. Corin levels increased in Basal-1B versus Basal-1A. Atrial NP (ANP) decreased in Basal-1B compared to Basal-1A. After HF induction, ANP increased in Groups 2-2A and 2-2B. Conclusions: Resection of atrial appendages drastically modifies the natriuretic mechanisms of cardiac homeostasis, especially after a fluid overload challenge. Herein, we describe the face and predictive validation of an animal model of atrial appendage resection useful to investigations in translational medicine.

Peptídeos natriuréticos / Natriuretic peptides

Os peptídeos natriuréticos são biomarcadores liberados pelo coração e endotélio vascular, que têm importante função na regulação da homeostase. Participam da fisiologia renal e cardíaca, bem como possuem papel fisiopatológico na insuficiência cardíaca, na hipertensão e na doença renal. Dentre os peptídeos natriuréticos atrial (ANP) e o peptídeo natriurético cerebral (BNP). Atualmente, diversas pesquisas demonstram sua importancia na avaliação de dispneia como sintoma de insuficiência cardíaca, seja ela por disfunção ventricular sistólica ou diastólica. O principal sinal para a liberação do ANP é a distensão das paredes dos átrios cardíacos. A ativação do BNP é regulada em resposta a aumentos de pressão nos átrios e ventrículos cardíacos. A concentração do BNP na corrente sanguínea pode ser influênciada por diversos fatores, como doenças cardíacas, idade insuficiência renal e sepse. Estudos iniciais com BNP na avaliação de dispneia demonstraram que sua dosagem consistia em importante preditor de insuficiência cardíaca quando comparado à dispneia de outras causas, com ponto de corte de 100 pg/ml; valores acima de 400 pg/ml têm alto valor predictivo positivo...

Natriuretic peptides are biomarkers released by the heart and vascular endothelium, with an important role in homeostasis regulation. They participate in the physiology of the kidneys and the heart and play a pathophysiological role in heart failure, hypertension and kidney disease. Among the natriuretic peptides, the most important are the atrial natriuretic peptide (ANP) and the brain natriuretic peptide (BNP). Currently, several studies have shown its importance in assessing dyspnea as a symptom of heart failure, due to systolic or diastolic ventricular dysfunction. The main sign for ANP release is the distension of atrial walls. BNP activation is regulated in response to pressure increases in the atria and ventricles. BNP blood concentration may be influenced by different factors, such as heart diseases, age, renal failure and sepsis. Early studies with BNP in the assessment of dyspnea have shown that its dosage was an important heart failure predictor when compared to dyspnea due to other causes, with a cutoff of 100 pg/ml; values higher than 400 pg/ml have a high positive predictive value for the diagnosis of dyspnea of cardiac origin. BNP may be used as a diagnostic and prognostic tool in heart failure. Its blood concentration is directly related to the New York Heart Association functional class and higher values are associated with poor survival, independent of the severity of left ventricular ejection fraction. The treatment of heart failure guided by BNP levels may improve the morbidity and mortality of chronic heart failure.

The broad homeostatic role of natriuretic peptides / O amplo papel homeostático dos peptídeos natriuréticos

A brief non-inclusive review on natriuretic peptides (NP), their receptors, and their main functional properties is presented. The three main NP, atrial (ANP), brain (BNP) and C-type (CNP) are considered. Guanylyl cyclase receptors modulate all the known systemic effects of NP. Clearance receptors determine the metabolic disposal of NP and in this manner regulate their plasma levels and/or local tissue concentrations. Structure-function properties, and homeostatic properties of NP receptors are presented. ANP, which plays a major role in pressure-volume homeostasis, is discussed in relationship to its effects on renal hemodynamic and excretory functions, inhibition of the renin-angiotensin-aldosterone system, vasorelaxant, and third-spacing action. For BNP special attention is directed to its role as a negative modulator of ventricular remodeling, in view of its anti-hypertrophic, anti-fibrotic and anti-inflammatory effects in the heart. The major effect of CNP in promoting vertebral and longitudinal bone growth is briefly addressed. Finally, emphasis is placed on the recent discovery that ANP affects fat metabolism in humans due to its powerful lipolytic action.

Este trabalho apresenta uma breve revisão parcial sobre os peptídeos natriuréticos (NP), seus receptores e suas principais propriedades funcionais. Serão discutidos os três principais NP: atrial (ANP), cerebral (BNP) e tipo-C (CNP). Os receptores guanilil-ciclase modulam todos os efeitos sistêmicos conhecidos dos NP. Receptores de clareamento determinam o catabolismo dos NP e, desta maneira, regulam seus níveis plasmáticos e/ou sua concentração tecidual. As propriedades do tipo estrutura-função e homeostáticas dos receptores de NP são apresentadas. O ANP, que tem um importante papel na homeostase pressão-volume, é discutido em relação aos seus efeitos sobre a hemodinâmica renal e funções de excreção, inibição do sistema renina-angiotensina-aldosterona, vaso-relaxamento e ação no terceiro espaço. Quanto ao BNP, especial atenção é focada no seu papel como um modulador negativo da remodelação ventricular, em vista de seus efeitos anti-hipertróficos, anti-fibróticos e anti-inflamatórios no coração. O principal efeito do CNP em promover crescimento ósseo vertebral e longitudinal é discutido brevemente. Finalmente, enfatiza-se a recente descoberta de que o ANP afeta o metabolismo de gorduras em humanos, devido à sua poderosa ação lipolítica.