Special Considerations for Mechanical Circulatory Support or Device Therapy in Adult Congenital Heart Disease Heart Failure.

Heart failure has become the leading cause of mortality in adult congenital heart disease (ACHD) patients after the fifth decade of life. There is scanty evidence supporting the use of guideline-directed medical therapy in ACHD, especially in systemic right ventricle or single ventricle physiology. In complex patients, diagnosing heart failure and timely referral for advanced therapies are challenging. Mechanical circulatory support has been significantly developed over the past decade and has recently emerged as a feasible therapeutic option for these patients. This review summarizes current evidence of mechanical circulatory support in this population, its potential uses, and challenges.

Ecto-CD38-NADase inhibition modulates cardiac metabolism and protects mice against doxorubicin-induced cardiotoxicity.

AIMS: Doxorubicin (DXR) is a chemotherapeutic agent that causes dose-dependent cardiotoxicity. Recently, it has been proposed that the NADase CD38 may play a role in doxorubicin-induced cardiotoxicity (DIC). CD38 is the main NAD+-catabolizing enzyme in mammalian tissues. Interestingly, in the heart, CD38 is mostly expressed as an ecto-enzyme that can be targeted by specific inhibitory antibodies. The goal of the present study is to characterize the role of CD38 ecto-enzymatic activity in cardiac metabolism and the development of DIC. METHODS AND RESULTS: Using both a transgenic animal model and a non-cytotoxic enzymatic anti-CD38 antibody, we investigated the role of CD38 and its ecto-NADase activity in DIC in pre-clinical models. First, we observed that DIC was prevented in the CD38 catalytically inactive (CD38-CI) transgenic mice. Both left ventricular systolic function and exercise capacity were decreased in wild-type but not in CD38-CI mice treated with DXR. Second, blocking CD38-NADase activity with the specific antibody 68 (Ab68) likewise protected mice against DIC and decreased DXR-related mortality by 50%. A reduction of DXR-induced mitochondrial dysfunction, energy deficiency, and inflammation gene expression were identified as the main mechanisms mediating the protective effects. CONCLUSION: NAD+-preserving strategies by inactivation of CD38 via a genetic or a pharmacological-based approach improve cardiac energetics and reduce cardiac inflammation and dysfunction otherwise seen in an acute DXR cardiotoxicity model.

A nitroalkene derivative of salicylate alleviates diet-induced obesity by activating creatine metabolism and non-shivering thermogenesis.

Obesity-related type II diabetes (diabesity) has increased global morbidity and mortality dramatically. Previously, the ancient drug salicylate demonstrated promise for the treatment of type II diabetes, but its clinical use was precluded due to high dose requirements. In this study, we present a nitroalkene derivative of salicylate, 5-(2-nitroethenyl)salicylic acid (SANA), a molecule with unprecedented beneficial effects in diet-induced obesity (DIO). SANA reduces DIO, liver steatosis and insulin resistance at doses up to 40 times lower than salicylate. Mechanistically, SANA stimulated mitochondrial respiration and increased creatine-dependent energy expenditure in adipose tissue. Indeed, depletion of creatine resulted in the loss of SANA action. Moreover, we found that SANA binds to creatine kinases CKMT1/2, and downregulation CKMT1 interferes with the effect of SANA in vivo. Together, these data demonstrate that SANA is a first-in-class activator of creatine-dependent energy expenditure and thermogenesis in adipose tissue and emerges as a candidate for the treatment of diabesity.

The CD38 glycohydrolase and the NAD sink: implications for pathological conditions.

Nicotinamide adenine dinucleotide (NAD) acts as a cofactor in several oxidation-reduction (redox) reactions and is a substrate for a number of nonredox enzymes. NAD is fundamental to a variety of cellular processes including energy metabolism, cell signaling, and epigenetics. NAD homeostasis appears to be of paramount importance to health span and longevity, and its dysregulation is associated with multiple diseases. NAD metabolism is dynamic and maintained by synthesis and degradation. The enzyme CD38, one of the main NAD-consuming enzymes, is a key component of NAD homeostasis. The majority of CD38 is localized in the plasma membrane with its catalytic domain facing the extracellular environment, likely for the purpose of controlling systemic levels of NAD. Several cell types express CD38, but its expression predominates on endothelial cells and immune cells capable of infiltrating organs and tissues. Here we review potential roles of CD38 in health and disease and postulate ways in which CD38 dysregulation causes changes in NAD homeostasis and contributes to the pathophysiology of multiple conditions. Indeed, in animal models the development of infectious diseases, autoimmune disorders, fibrosis, metabolic diseases, and age-associated diseases including cancer, heart disease, and neurodegeneration are associated with altered CD38 enzymatic activity. Many of these conditions are modified in CD38-deficient mice or by blocking CD38 NADase activity. In diseases in which CD38 appears to play a role, CD38-dependent NAD decline is often a common denominator of pathophysiology. Thus, understanding dysregulation of NAD homeostasis by CD38 may open new avenues for the treatment of human diseases.

Benefits in cardiac function by CD38 suppression: Improvement in NAD+ levels, exercise capacity, heart rate variability and protection against catecholamine-induced ventricular arrhythmias.

CD38 enzymatic activity regulates NAD+ and cADPR levels in mammalian tissues, and therefore has a prominent role in cellular metabolism and calcium homeostasis. Consequently, it is reasonable to hypothesize about its involvement in cardiovascular physiology as well as in heart related pathological conditions. AIM: To investigate the role of CD38 in cardiovascular performance, and its involvement in cardiac electrophysiology and calcium-handling. METHODS AND RESULTS: When submitted to a treadmill exhaustion test, a way of evaluating cardiovascular performance, adult male CD38KO mice showed better exercise capacity. This benefit was also obtained in genetically modified mice with catalytically inactive (CI) CD38 and in WT mice treated with antibody 68 (Ab68) which blocks CD38 activity. Hearts from these 3 groups (CD38KO, CD38CI and Ab68) showed increased NAD+ levels. When CD38KO mice were treated with FK866 which inhibits NAD+ biosynthesis, exercise capacity as well as NAD+ in heart tissue decreased to WT levels. Electrocardiograms of conscious unrestrained CD38KO and CD38CI mice showed lower basal heart rates and higher heart rate variability than WT mice. Although inactivation of CD38 in mice resulted in increased SERCA2a expression in the heart, the frequency of spontaneous calcium release from the sarcoplasmic reticulum under stressful conditions (high extracellular calcium concentration) was lower in CD38KO ventricular myocytes. When mice were challenged with caffeine-epinephrine, CD38KO mice had a lower incidence of bidirectional ventricular tachycardia when compared to WT ones. CONCLUSION: CD38 inhibition improves exercise performance by regulating NAD+ homeostasis. CD38 is involved in cardiovascular function since its genetic ablation decreases basal heart rate, increases heart rate variability and alters calcium handling in a way that protects mice from developing catecholamine induced ventricular arrhythmias.

CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels.

Decreased NAD+ levels have been shown to contribute to metabolic dysfunction during aging. NAD+ decline can be partially prevented by knockout of the enzyme CD38. However, it is not known how CD38 is regulated during aging, and how its ecto-enzymatic activity impacts NAD+ homeostasis. Here we show that an increase in CD38 in white adipose tissue (WAT) and the liver during aging is mediated by accumulation of CD38+ immune cells. Inflammation increases CD38 and decreases NAD+. In addition, senescent cells and their secreted signals promote accumulation of CD38+ cells in WAT, and ablation of senescent cells or their secretory phenotype decreases CD38, partially reversing NAD+ decline. Finally, blocking the ecto-enzymatic activity of CD38 can increase NAD+ through a nicotinamide mononucleotide (NMN)-dependent process. Our findings demonstrate that senescence-induced inflammation promotes accumulation of CD38 in immune cells that, through its ecto-enzymatic activity, decreases levels of NMN and NAD+.

Seguridad de la exclusión quirúrgica del apéndice auricular izquierdo en pacientes con fibrilación auricular sometidos a cirugía valvular mitral / Safety of left atrial appendage exclusion in patients with atrial fibrillation undergoing mitral valve surgery / Segurança da exclusão cirúrgica do apêndice atrial esquerdo em pacientes com fibrilação atrial submetidos a cirurgia valvar mitral

Resumen: Introducción: la fibrilación auricular (FA) es la arritmia sostenida más frecuente en la práctica clínica. Asocia un aumento significativo de morbimortalidad. La prevención de fenómenos embólicos es un pilar del tratamiento, basado en gran medida en la anticoagulación oral (ACO). Hay un porcentaje significativo de pacientes que presentan contraindicaciones para ACO, a los cuales se deben ofrecer tratamientos alternativos. La exclusión quirúrgica del apéndice auricular izquierdo (AAI) determina beneficios en tal sentido y se asocia a una menor tasa de eventos neurológicos. Objetivo: primario, valorar la seguridad de la exclusión quirúrgica del AAI en pacientes con FA sometidos a cirugía valvular mitral; secundario, analizar la incidencia de ataque cerebrovascular (ACV) en dicha población y analizar la sobrevida entre los pacientes con y sin exclusión del AAI. Método: estudio unicéntrico, analítico, observacional, retrospectivo, comparando exclusión o no del AAI en pacientes con FA sometidos a cirugía cardíaca sobre válvula mitral, entre enero de 2012 y diciembre de 2018. Las variables se obtuvieron de la base de datos institucional. El seguimiento fue telefónico y la sobrevida fue derivada de datos oficiales nacionales. Resultados: se incluyeron 69 pacientes (en 45 se realizó exclusión del AAI). Como características con diferencias significativas destacan la edad (69,1±8,2 años sin exclusión del AAI; 63,6±10,3 años con exclusión del AAI, p=0,026) y el porcentaje de ablación quirúrgica de FA en cada grupo (29,2% sin exclusión del AAI; 68,9% con exclusión del AAI, p=0,002). Se obtuvo un seguimiento de 33 pacientes, entre los cuales no hubo diferencias significativas en los parámetros considerados. Se evaluó la sobrevida del total de los pacientes incluidos, sin diferencia a largo plazo. Conclusión: según los datos analizados, la exclusión del AAI es un procedimiento seguro que no agrega complicaciones a la cirugía valvular mitral en pacientes con FA. No fue posible demostrar que la exclusión del AAI reduzca de manera significativa la prevalencia de ACV isquémico a largo plazo, ni modifique la sobrevida.

Summary: Introduction: atrial fibrillation is the most common sustained cardiac arrythmia in clinical practice. It is associated to significant morbimortality. The prevention of embolic episodes is a pillar of atrial fibrillation treatment and is based mainly on anticoagulation. However, there is a significant proportion of patients with contraindications for anticoagulation, to whom alternative treatments must be offered. Surgical exclusion of the left atrial appendage offers benefits in this regard, and is associated to a lower rate of neurological events. Objective: primary endpoint: to evaluate the safety of the surgical exclusion of the left atrial appendage in patients with atrial fibrillation undergoing mitral valve surgery; secondary endpoint: to analyze the incidence of stroke in this population, and to analyze the survival rate in patients with and without left atrial appendage exclusion. Method: a single center, analytic, observational, retrospective study, comparing exclusion and no exclusion of the left atrial appendage in patients with atrial fibrillation undergoing mitral valve surgery between January 2012 and December 2018. The variables were obtained from the institutional database. The follow up was telephonic and survival rates were obtained from a national official database. Results: 69 patients were included (45 underwent surgical left atrial appendage exclusion). Statistically significant features between the groups were age (69.1±8.2 years without left atrial appendage exclusion; 63.6±10.3 years with left atrial appendage exclusion, p=0.026), and the rate of surgical ablation of atrial fibrillation (29.2% without exclusion; 68.9% with exclusion, p=0.002). The follow up was carried out in 33, finding no statistically significant differences between the groups. The survival rate of all patients was analyzed, finding no long term differences. Conclusion: according to the data analyzed, left atrial appendage exclusion is a safe procedure, and adds no further complications to mitral valve surgery in patients with atrial fibrillation. It was not possible to prove that left atrial appendage exclusion significantly reduces the long term prevalence of ischemic stroke or modifies the survival rate.

Resumo: Introdução: a fibrilação atrial é a arritmia sustentada mais frequente na prática clínica. Associa um aumento significativo na morbimortalidade. A prevenção de fenômenos embólicos é um dos pilares do tratamento, amplamente baseado na anticoagulação oral. Existe uma percentagem significativa de pacientes que apresentam contra-indicações, a quem tratamentos alternativos devem ser oferecidos. A exclusão cirúrgica do apêndice atrial esquerdo determina benefícios nesse sentido e está associada a uma menor taxa de eventos neurológicos. Objetivo: primário: avaliar a segurança da exclusão cirúrgica do apêndice atrial esquerdo em pacientes com fibrilação atrial submetidos a cirurgia valvar mitral; secundário: analisar a incidência de ataque cerebrovascular na referida população e análise de sobrevida em pacientes com e sem exclusão de apêndice atrial esquerdo. Método: estudo de centro único, analítico, observacional, retrospectivo que comparou a exclusão ou não de apêndice atrial esquerdo em pacientes com fibrilação atrial submetidos a cirurgia cardíaca na válvula mitral, entre janeiro de 2012 e dezembro de 2018. As variáveis foram obtidas no banco de dados institucional. O acompanhamento foi por telefone e a sobrevivência foi obtida a partir de dados nacionais oficiais. Resultados: 69 pacientes foram incluídos (45 foram excluídos da apêndice atrial esquerdo). Como elementos estatisticamente significativos, destacam-se a idade (69,1 ± 8,2 anos sem exclusão do apêndice atrial esquerdo; 63,6 ± 10,3 anos com exclusão do apêndice atrial esquerdo, p = 0,026) e a taxa de ablação cirúrgica da fibrilação atrial em cada grupo (29,2% sem exclusão; 68,9% com exclusão, p = 0,002). Foi obtido um seguimento de 33 pacientes, entre os quais não houve diferenças significativas nos parâmetros considerados. A sobrevida de todos os pacientes incluídos foi avaliada, sem diferença na sobrevida a longo prazo. Conclusão: de acordo com os dados analisados, a exclusão do apêndice atrial esquerdo é um procedimento seguro que não agrega complicações à cirurgia valvar mitral em pacientes com fibrilação atrial. Não foi possível demonstrar que a exclusão da apêndice atrial esquerdo reduz significativamente a prevalência de ataque vascular cerebral isquêmico a longo prazo, nem modifica a sobrevida.