Mechanisms behind the high mortality rate in chronic Chagas cardiomyopathy: Unmasking a three-headed monster.

Chagas disease is a neglected tropical disease caused by the parasite Trypanosoma cruzi. Chronic Chagas cardiomyopathy (CCC), the most severe form of target organ involvement in Chagas disease, is characterized by a complex pathophysiology and a unique phenotype that differentiates it from other cardiomyopathies, highlighting its worse prognosis compared to other aetiologies of heart failure. The three pathophysiological mechanisms with the largest impact on this differential mortality include rapidly progressive heart failure, a high incidence of stroke, and a high burden of ventricular arrhythmias. However, despite significant advances in understanding the unique molecular circuits underlying these mechanisms, the new knowledge acquired has not been efficiently translated into specific diagnostic and therapeutic approaches for this unique cardiomyopathy. The lack of dedicated clinical trials and the limited CCC-specific risk stratification tools available are evidence of this reality. This review aims to provide an updated perspective of the evidence and pathophysiological mechanisms associated with the higher mortality observed in CCC compared to other cardiomyopathies and highlight opportunities in the diagnostic and therapeutic approaches of the disease.

Riesgo de eventos embólicos en pacientes con miocardiopatía chagásica y fibrilación auricular a pesar de terapia antitrombótica: ¿es la anticoagulación suficiente? / Risk of Embolic Events in Patients with Chagasic Cardiomyopathy and Atrial Fibrillation Despite Antithrombotic Therapy: Is Anticoagulation Enough?

RESUMEN Introducción: La miocardiopatía chagásica (MC) difiere de otras causas de insuficiencia cardíaca en múltiples aspectos, destacándose el riesgo de embolias sistémicas. Sin embargo, pocos estudios han evaluado el riesgo de eventos embólicos en pacientes anticoagulados con MC en comparación con otras miocardiopatías. Objetivo: Nuestro objetivo fue analizar la incidencia de embolias sistémicas en una cohorte de pacientes anticoagulados con diagnóstico de fibrilación auricular (FA) con y sin MC. Material y métodos: Se realizó un estudio de cohorte retrospectivo en hospital de cuarto nivel en Colombia durante el periodo 2014-2020. Se incluyeron todos los pacientes con diagnóstico de miocardiopatía de cualquier etiología y FA que estuvieran en régimen de anticoagulación. El resultado primario fue la incidencia de eventos embólicos. Se realizó un análisis de supervivencia mediante modelos de riesgos proporcionales de Cox ajustados. Un valor de p <0,05 se consideró significativo. Todas las pruebas estadísticas fueron de dos colas. Resultados: Se evaluaron 149 pacientes anticoagulados con miocardiopatía (mediana de edad: 71 años; mujeres: 30,20%). La incidencia acumulada de eventos embólicos fue significativamente mayor en los pacientes con MC (17,50%) en comparación con aquellos con otras miocardiopatías (4,95%), a pesar de que estos últimos tenían una puntuación CHA2DS2-VASc significativamente mayor (p=0,013). Tras el análisis multivariado, los pacientes con MC tuvieron un riesgo significativamente mayor de eventos embólicos independientemente de la puntuación CHA2DS2-VASc y del tipo de anticoagulante prescrito (HR 5,65; IC 95% 1,46-21,83; p=0,012). Conclusiones: La MC se asoció con un riesgo significativamente mayor de eventos embólicos, a pesar del tratamiento anticoagulante en ambos grupos. Se requiere más investigación para comprender el origen de este riesgo observado y traducir este conocimiento en indicaciones específicas de anticoagulación para pacientes con MC.

ABSTRACT Background: Chagasic cardiomyopathy (CC) differs from other heart failure causes in multiple aspects, highlighting the risk of systemic embolisms. However, few studies have evaluated the risk of embolic events in anticoagulated patients with CC compared with other cardiomyopathies. Objective: We aimed to analyze the incidence of systemic embolisms in a cohort of anticoagulated patients diagnosed with atrial fibrillation (AF) with and without CC. Methods: A retrospective cohort study was carried out at a fourth level hospital in Colombia during the period 2014-2020. All patients diagnosed with cardiomyopathy of any etiology and AF, who were on an anticoagulation regimen were included. The primary outcome was the incidence of embolic events. A survival analysis was performed using adjusted Cox proportional hazard models. A p-value <0.05 was considered significant. All statistical tests were two-tailed. Results: A total of 149 anticoagulated patients with cardiomyopathy were evaluated (median age: 71 years; women: 30.20%). The cumulative incidence of embolic events was significantly higher in patients with CC (17.50%) compared with those presenting other cardiomyopathies (4.95%), despite that the latter had a significantly higher CHA2DS2-VASc score (p=0.013). After multivariate analysis, patients with CC had a significantly higher risk of embolic events regardless of the CHA2DS2-VASc score and the type of anticoagulant prescribed (HR 5.65; 95% CI 1.46-21.83; p=0.012). Conclusions: Chagasic cardiomyopathy was associated with a significantly higher risk of embolic events, despite anticoagulation therapy in both groups. More research is required to understand the origin of the risk observed in order to translate this knowledge into specific indications for anticoagulation in patients with CC.

Prevalence of Neutralizing Antibodies against Adeno-Associated Virus Serotypes 1, 2, and 9 in Non-Injected Latin American Patients with Heart Failure-ANVIAS Study.

Neutralizing antibody (NAb) activity against the viral capsid of adeno-associated viral (AAV) vectors decreases transduction efficiency, thus limiting transgene expression. Several reports have mentioned a variation in NAb prevalence according to age, AAV serotype, and, most importantly, geographic location. There are currently no reports specifically describing the anti-AAV NAb prevalence in Latin America. Here, we describe the prevalence of NAb against different serotypes of AAV vectors (AAV1, AAV2, and AAV9) in Colombian patients with heart failure (HF) (referred to as cases) and healthy individuals (referred to as controls). The levels of NAb were evaluated in serum samples of 60 subjects from each group using an in vitro inhibitory assay. The neutralizing titer was reported as the first dilution inhibiting ≥50% of the transgene signal, and the samples with neutralizing titers at ≥1:50 dilution were considered positive. The prevalence of NAb in the case and control groups were similar (AAV2: 43% and 45%, respectively; AAV1 33.3% in each group; AAV9: 20% and 23.2%, respectively). The presence of NAb for two or more of the serotypes analyzed was observed in 25% of the studied samples, with the largest amount in the positive samples for AAV1 (55-75%) and AAV9 (93%), suggesting serial exposures, cross-reactivity, or coinfection. Moreover, patients in the HF group exhibited more common combined seropositivity for NAb against AAV1 d AAV9 than those in the control group (91.6% vs. 35.7%, respectively; p = 0.003). Finally, exposure to toxins was significantly associated with the presence of NAb in all regression models. These results constitute the first report of the prevalence of NAb against AAV in Latin America, being the first step to implementing therapeutic strategies based on AAV vectors in this population in our region.

Survival after heart transplantation for Chagas cardiomyopathy using a conventional protocol: A 10-year experience in a single center.

BACKGROUND: Heart transplant (HT) remains the most frequently indicated therapy for patients with end-stage heart failure that improves prognosis in Chagas cardiomyopathy (CCM). However, the lack of benznidazole therapy and availability of RT-PCR follow-up in many centers is a major limitation to perform this life-saving intervention, as there are concerns related with the risk of reactivation. We aimed to describe the outcomes of a cohort of patients with CCM who underwent HT using a conventional protocol with mycophenolate mofetil, without benznidazole prophylaxis or RT-PCR follow-up. METHODS: Retrospective cohort study. Between 2008 and 2018, 43 patients with CCM underwent HT. A descriptive analysis to characterize outcomes as rejection, infectious and neoplastic complications and a survival analysis was carried out. RESULTS: Median of follow-up was 4.3 (IR 4.28) years. Survival at 1 month, 1 year, and 5 years was 95%, 85%, and 75%, respectively, infections being the main cause of death (60%). Reactivations occurred in only three patients (7.34%) and were not related to mortality. CONCLUSION: This cohort showed a favorable survival and a low reactivation rate without an impact on mortality. Our results suggest that performing HT in patients with CCM following conventional guidelines and recommendations for other etiologies is a safe approach.