Case Report: The Challenge for Diagnosis of Myocarditis and Transplant Rejection After COVID Infection in a Heart-Transplanted Adolescent.

Patients who have undergone organ transplantation are immunosuppressed hosts, leaving them at a higher risk of infections. SARS-COV-2 has been shown to affect heart-transplanted patients. In this case report, we present the case of a 14-year-old heart transplant recipient who developed signs and symptoms of heart failure, along with fatigue, after a COVID-19 infection. An endomyocardial biopsy was performed to diagnose rejection and to evaluate whether this was myocarditis due to SARS-COV-2. The biopsy showed intense acute cellular rejection (3R) and antibody rejection PAMR1 H+ but was negative for the SARS-CoV-2 virus. The patient received organ rejection therapy with high-dose methylprednisolone and human immunoglobulin. After treatment, her heart function recovered, with biopsy investigations showing a lower level of cellular rejection (1R).

Matrix Metalloproteinase 2 and 9 Enzymatic Activities are Selectively Increased in the Myocardium of Chronic Chagas Disease Cardiomyopathy Patients: Role of TIMPs.

Chronic Chagas disease (CCC) is an inflammatory dilated cardiomyopathy with a worse prognosis compared to other cardiomyopathies. We show the expression and activity of Matrix Metalloproteinases (MMP) and of their inhibitors TIMP (tissue inhibitor of metalloproteinases) in myocardial samples of end stage CCC, idiopathic dilated cardiomyopathy (DCM) patients, and from organ donors. Our results showed significantly increased mRNA expression of several MMPs, several TIMPs and EMMPRIN in CCC and DCM samples. MMP-2 and TIMP-2 protein levels were significantly elevated in both sample groups, while MMP-9 protein level was exclusively increased in CCC. MMPs 2 and 9 activities were also exclusively increased in CCC. Results suggest that the balance between proteins that inhibit the MMP-2 and 9 is shifted toward their activation. Inflammation-induced increases in MMP-2 and 9 activity and expression associated with imbalanced TIMP regulation could be related to a more extensive heart remodeling and poorer prognosis in CCC patients.

3D Echocardiography for Rheumatic Heart Disease Analysis: Ready for Prime Time.

Rheumatic heart disease (RHD) remains to be a very important health issue worldwide, mainly in underdeveloped countries. It continues to be a leading cause of morbidity and mortality throughout developing countries. RHD is a delayed non-suppurative immunologically mediated inflammatory response to the throat infection caused by a hemolytic streptococcus from the A group (Streptococcus pyogenes). RHD keeps position 1 as the most common cardiovascular disease in young people aged <25 years considering all the continents. The disease can lead to valvular cardiac lesions as well as to carditis. Rheumatic fever valvular injuries lead most commonly to the fusion and thickening of the edges of the cusps and to the fusion, thickening, and shortening of the chordae and ultimately to calcification of the valves. Valvular commissures can also be deeply compromised, leading to severe stenosis. Atrial and ventricular remodeling is also common following rheumatic infection. Mixed valvular lesions are more common than isolated valvular disorders. Echocardiography is the most relevant imaging technique not only to provide diagnostic information but also to enable prognostic data. Further, it presents a very important role for the correction of complications after surgical repair of rheumatic heart valvulopathies. Three-dimensional (3D) echocardiography provides additional anatomical and morphofunctional information of utmost importance for patients presenting rheumatic valvopathies. Accordingly, three-dimensional echocardiography is ready for routine use in patients with RHD presenting with valvular abnormalities.

STING Signaling Drives Production of Innate Cytokines, Generation of CD8+ T Cells and Enhanced Protection Against Trypanosoma cruzi Infection.

A variety of signaling pathways are involved in the induction of innate cytokines and CD8+ T cells, which are major players in protection against acute Trypanosoma cruzi infection. Previous data have demonstrated that a TBK-1/IRF3-dependent signaling pathway promotes IFN-ß production in response to Trypanosoma cruzi, but the role for STING, a main interactor of these proteins, remained to be addressed. Here, we demonstrated that STING signaling is required for production of IFN-ß, IL-6, and IL-12 in response to Trypanosoma cruzi infection and that STING absence negatively impacts activation of IRF-dependent pathways in response to the parasite. We reported no significant activation of IRF-dependent pathways and cytokine expression in RAW264.7 macrophages in response to heat-killed trypomastigotes. In addition, we showed that STING is essential for T. cruzi DNA-mediated induction of IFN-ß, IL-6, and IL-12 gene expression in RAW264.7 macrophages. We demonstrated that STING-knockout mice have significantly higher parasitemia from days 5 to 8 of infection and higher heart parasitism at day 13 after infection. Although we observed similar heart inflammatory infiltrates at day 13 after infection, IFN-ß, IL-12, CXCL9, IFN-γ, and perforin gene expression were lower in the absence of STING. We also showed an inverse correlation between parasite DNA and the expression of CXCL9, IFN-γ, and perforin genes in the hearts of infected animals at day 13 after infection. Finally, we reported that STING signaling is required for splenic IFN-ß and IL-6 expression early after infection and that STING deficiency results in lower numbers of splenic parasite-specific IFN-γ and IFN-γ/perforin-producing CD8+ T cells, indicating a pivotal role for STING signaling in immunity to Trypanosoma cruzi.

Sequential measurement of Trypanosoma cruzi parasitic load in endomyocardial biopsies for early detection and follow-up of Chagas disease reactivation after heart transplantation.

BACKGROUND: Reactivation of Chagas disease after heart transplantation is characterized by proliferation and dissemination of Trypanosoma cruzi parasites to several organs. Reactivation affecting the allograft can simulate acute cellular rejection, from which it should be distinguished through the analysis of endomyocardial biopsies (EMB). METHODS: We evaluated retrospectively 100 EMB collected in the first year of follow-up from 13 heart-transplanted, chagasic patients who presented reactivation and were successfully treated. Additionally, 37 EMB from 8 patients who did not present reactivation constituted the control group. We reviewed histopathology and performed a real-time PCR-based assay in order to evaluate the T cruzi parasitic load of each EMB. RESULTS: The parasitic load of the EMB at the time of reactivation ranged from 22.80 to 190 000/106 cells (median: 1555). In 6 patients, none of the EMB obtained prior to reactivation amplified T cruzi DNA. On the other hand, 10 EMB from 7 patients, obtained 9-105 days before reactivation (median: 26 days), showed parasitic load ranging from 8.25 to 625/106 cells (median: 167.55). In all patients, the parasitic load increased at the time of reactivation, usually sharply. After initiation of treatment, all patients showed negative PCR or a dramatic reduction of the parasitic load in the following EMB. None of the EMB from the control group amplified T cruzi DNA. CONCLUSIONS: Sequential measurement of T cruzi parasitic load in EMB is useful for monitoring Chagas disease reactivation after heart transplantation. Its increase suggests imminent reactivation and its decrease after treatment indicates favorable evolution for cure of the episode of reactivation.

Thromboembolic findings in patients with heart failure at autopsy.

BACKGROUND: The risk of thromboembolic events is increased in patients with heart failure (HF); however, few studies have reported thromboembolic findings in HF patients who have undergone autopsy. METHODS AND RESULTS: We reviewed 1457 autopsies (January 2000/July 2006) and selected 595 patients with HF. We studied the occurrence of thromboembolic events in patients' autopsy reports. Mean age was 61.8±15.9 years; 376 (63.2%) were men and 219 (36.8%) women; left ventricular ejection fraction was 42.1±18.7%. HF etiologies were coronary artery disease in 235 (39.5%) patients, valvular disease in 121 (20.3%), and Chagas' disease in 81 (13.6%). The main cause of death was progressive HF in 253 (42.5%) patients, infections in 112 (18.8%), myocardial infarction in 86 (14.5%), and pulmonary embolism in 81 (13.6%). Altogether, 233 patients (39.2%) suffered 374 thromboembolic events. A thromboembolic event was considered the direct cause of death in 93 (24.9%) patients and related to death in 158 (42.2%). The most frequent thromboembolism was pulmonary embolism in 135 (36.1%) patients; in 81 events (60%), it was considered the cause of death. When we compared clinical characteristics of patients, sex (OR=1.511, CI 95% 1.066-2.143, P=.021) and Chagas disease (OR=2.362, CI 95% 1.424-3.918, P=.001) were independently associated with the occurrence of thromboembolisms. CONCLUSIONS: Thromboembolic events are frequent in patients with heart failure revealed at autopsy, and are frequently associated with the death process. Our findings warrant a high degree of suspicion for these occurrences, especially during the care of more susceptible populations, such as women and Chagas patients.