Challenges in the approach to a patient with aortic stenosis and cardiac amyloidosis with ATTR mutation associated with negative scintigraphy - A case report.

Introduction: Cardiac amyloidosis (CA) poses significant diagnostic and therapeutic challenges. In this case report, we detail a patient with CA due to a rare transthyretin (CA-TTR) mutation, manifesting with negative myocardial scintigraphy and requiring genetic testing for diagnosis. The patient also had severe aortic stenosis (AS), necessitating discussion with a heart team to determine the optimal treatment strategy. Case report: A 70-year-old male with a family history of sudden death was previously diagnosed with third-degree atrioventricular block and treated with a pacemaker. He presented with worsening exertional dyspnoea, and examination revealed a third heart sound, a systolic murmur indicative of AS and bilateral muscular atrophy in the thenar region. Transthoracic echocardiography indicated severe AS and moderate left ventricular dysfunction, with images suggesting infiltrative disease. Pyrophosphate scintigraphy revealed no abnormal cardiac tracer uptake. Cardiac magnetic resonance imaging (MRI) revealed extensive, heterogeneous, subendocardial late gadolinium enhancement in both the atria and ventricles, which was consistent with CA. Genetic testing identified the Phe84Leu mutation in the TTR gene. Following heart team discussions, the patient underwent successful transcatheter aortic valve implantation (TAVI) and remained asymptomatic in follow-up, being monitored at an outpatient clinic specializing in CA and using tafamidis. Discussion: CA-TTR can be an autosomal dominant disease with variable penetrance involving abnormal amyloid protein deposition in tissues and can often be diagnosed noninvasively via myocardial scintigraphy. However, some TTR mutations do not affect scintigraphy results, necessitating genetic testing when clinical suspicion is high, potentially avoiding endomyocardial biopsy. Moreover, AS occurs in up to 16 % of TTR amyloidosis patients, with the conditions mutually exacerbating each other. Recent consensus suggests that TAVI reduces mortality in patients with severe AS and amyloidosis. Conclusions: Various diagnostic algorithms emphasize the use of myocardial scintigraphy for suspected CA-TTR. Genetic testing is crucial when scintigraphy results are negative, but clinical suspicion remains high, potentially circumventing invasive procedures. Compared with medical management alone, TAVI has been shown to improve quality of life and survival in patients with concurrent severe AS and CA.

Impact of the immune profiles of hypertensive patients with and without obesity on COVID-19 severity.

BACKGROUND: Comorbidities such as obesity, hypertension, and diabetes are associated with COVID-19 development and severity, probably due to immune dysregulation; however, the mechanisms underlying these associations are not clear. The immune signatures of hypertensive patients with obesity with COVID-19 may provide new insight into the mechanisms of immune dysregulation and progression to severe disease in these patients. METHODS: Hypertensive patients were selected prospectively from a multicenter registry of adults hospitalized with COVID-19 and stratified according to obesity (BMI ≥ 30 kg/m²). Clinical data including baseline characteristics, complications, treatment, and 46 immune markers were compared between groups. Logistic regression was performed to identify variables associated with the risk of COVID-19 progression in each group. RESULTS: The sample comprised 213 patients (89 with and 124 without obesity). The clinical profiles of patients with and without obesity differed, suggesting potential interactions with COVID-19 severity. Relative to patients without obesity, patients with obesity were younger and fewer had cardiac disease and myocardial injury. Patients with obesity had higher EGF, GCSF, GMCSF, interleukin (IL)-1ra, IL-5, IL-7, IL-8, IL-15, IL-1ß, MCP 1, and VEGF levels, total lymphocyte counts, and CD8+ CD38+ mean fluorescence intensity (MFI), and lower NK-NKG2A MFI and percentage of CD8+ CD38+ T cells. Significant correlations between cytokine and immune cell expression were observed in both groups. Five variables best predicted progression to severe COVID-19 in patients with obesity: diabetes, the EGF, IL-10, and IL-13 levels, and the percentage of CD8+ HLA-DR+ CD38+ cells. Three variables were predictive for patients without obesity: myocardial injury and the percentages of B lymphocytes and HLA-DR+ CD38+ cells. CONCLUSION: Our findings suggest that clinical and immune variables and obesity interact synergistically to increase the COVID-19 progression risk. The immune signatures of hypertensive patients with and without obesity severe COVID-19 highlight differences in immune dysregulation mechanisms, with potential therapeutic applications.

How Cardiac Fibrosis Assessed via T1 Mapping Is Associated with Liver Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease.

(1) Background: Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. Although cardiovascular and NAFLD risk factors overlap, an independent association between these conditions may exist. Hepatic and cardiac fibrosis are important markers of mortality, but the correlation between these markers in patients with NAFLD has not been well studied. Our main objective was to determine the degree of myocardial fibrosis in patients with NAFLD and its correlation with the severity of liver fibrosis. (2) Methods: In this cross-sectional study, patients with NAFLD were allocated to two groups according to the stage of liver fibrosis assessed using MRI: no or mild fibrosis (F0-F1) and significant fibrosis (F2-F4). Framingham risk scores were calculated to evaluate cardiovascular risk factors, and patients underwent multiparametric cardiac and abdominal MRIs. (3) Results: The sample comprised 44 patients (28 with no or mild liver fibrosis and 16 with significant liver fibrosis). The mean age was 57.9 ± 12 years, and 41% were men. Most patients had high cardiac risk factors and carotid disease. Relative to patients with no or mild liver fibrosis, those with significant fibrosis had a higher median calcium score (p = 0.05) and increased myocardial extracellular volume (ECV; p = 0.02). Liver fibrosis correlated with cardiac fibrosis, represented by the ECV (r = 0.49, p < 0.001). The myocardial ECV differentiated patients with and without significant liver fibrosis (AUC = 0.78). (4) Conclusion: This study showed that diffuse myocardial fibrosis is associated with liver fibrosis in patients with NAFLD.

Use of PET/CT to detect myocardial inflammation and the risk of malignant arrhythmia in chronic Chagas disease.

BACKGROUND: Chagas heart disease (CHD) is characterized by progressive myocardial inflammation associated with myocardial fibrosis and segmental abnormalities that may lead to malignant ventricular arrhythmia and sudden cardiac death. This arrhythmia might be related to the persistence of parasitemia or inflammation in the myocardium in late-stage CHD. Positron emission tomography/computed tomography (PET/CT) has been used to detect myocardial inflammation in non-ischemic cardiomyopathies, such as sarcoidosis, and might be useful for risk prediction in patients with CHD. METHODS AND RESULTS: Twenty-four outpatients with chronic CHD were enrolled in this prospective cross-sectional study between May 2019 and March 2022. The patients were divided into two groups: those with sustained ventricular tachycardia and/or aborted sudden cardiac death who required implantable cardioverter-defibrillators, and those with the same stages of CHD and no complex ventricular arrhythmia. Patients underwent 18F-fluorodeoxyglucose (18F-FDG) and 68Ga-DOTATOC PET/CT, and blood samples were collected for qualitative parasite assessment by polymerase chain reaction. Although similar proportions of patients with and without complex ventricular arrhythmia showed 18F-FDG and 68Ga-DOTATOC uptake, 68Ga-DOTATOC corrected SUVmax was higher in patients with complex arrhythmia (3.4 vs 1.7; P = .046), suggesting that inflammation could be associated with the presence of malignant arrhythmia in the late stages of CHD. We also detected Trypanosoma cruzi in both groups, with a nonsignificant trend of increased parasitemia in the group with malignant arrhythmia (66.7% vs 33.3%). CONCLUSION: 18F-FDG and 68Ga-DOTATOC uptake on PET/CT may be useful for the detection of myocardial inflammation in patients with Chagas cardiomyopathy, and 68Ga-DOTATOC uptake may be associated with the presence of malignant arrhythmia, with potential therapeutic implications.

Autonomic denervation, myocardial hypoperfusion and fibrosis may predict ventricular arrhythmia in the early stages of Chagas cardiomyopathy.

BACKGROUND: Sudden cardiac death (SCD) can be the first clinical event of Chagas heart disease (CHD). However, current guidelines contain no clear recommendation for early cardioverter-defibrillator implantation. Using imaging modalities, we evaluated associations among autonomic denervation, myocardial hypoperfusion, fibrosis and ventricular arrhythmia in CHD. METHODS AND RESULTS: Twenty-nine patients with CHD and preserved left ventricular function underwent 123I-metaiodobenzylguanidine (MIBG) scintigraphy, 99mTc-methoxyisobutylisonitrile (MIBI) myocardial perfusion and cardiac magnetic resonance imaging (MRI). They were divided into arrhythmic (≥ 6 ventricular premature complexes/h and/or non-sustained ventricular tachycardia on 24-hour Holter, n = 15) and non-arrhythmic (< 6 ventricular premature complexes/h and no ventricular tachycardia; n = 14) groups. The arrhythmic group had higher denervation scores from MIBG imaging (23.2 ± 18.7 vs 5.6 ± 4.9; P < .01), hypoperfusion scores from MIBI SPECT (4.7 ± 6.8 vs 0.29 ± 0.6: P = .02), innervation/perfusion mismatch scores (18.5 ± 17.5 vs 5.4 ± 4.8; P = .01) and fibrosis by late gadolinium enhancement on MRI (14.3% ± 13.5% vs 4.0% ± 2.9%; P = .04) than the non-arrhythmic group. CONCLUSION: These imaging parameters were associated with ventricular arrhythmia in early CHD and may enable risk stratification and the implementation of primary preventive strategies for SCD.

Acute-phase proteins in cats with obstructive feline lower urinary tract disease.

BACKGROUND: Feline obstructive disease of the lower urinary tract (FLUTD) is a common pathologic condition of cats. It can be related to sterile inflammation, which leads to acute impairment of renal function and the accumulation of electrolytes and acid-base imbalance. Acute-phase proteins (APPs) are biomarkers of tissue damage from inflammation that assist in monitoring treatment and prognosis. OBJECTIVE: Monitoring the inflammatory processes of obstructive feline lower urinary tract disease through the determination of plasma fibrinogen concentrations and serum concentrations of the acute-phase proteins, serum amyloid A (SAA), alpha-1-acid glycoprotein (AGP), and albumin. METHODOLOGY: Twenty-five male cats were included in this study. They were divided into two experimental groups: a control group (CG) and an obstruction group (OG). There were 8 healthy cats in the CG group and 17 cats with obstructive FLUTD in the OG group. APP measurements were conducted using ELISA kits. Samples were collected for APP analyses, serum biochemical assays, urinalyses, and urine protein: creatinine ratio calculations at diagnosis, before urethral clearance (H0), and 12 (H12), 24 (H24), and 48 (H48) hours after urethral clearance from cats in the OG group. Samples were collected once from cats in the CG group cats. RESULTS: At H0, we found positive correlations of SAA, AGP, and fibrinogen with urea and creatinine, and negative correlations of albumin with hematuria, SAA, and potassium. At H48, we found positive correlations between SAA and AGP, AGP and urea, fibrinogen and urea, fibrinogen and creatinine, fibrinogen and AGP, and fibrinogen and SAA. In addition, a negative correlation of albumin with urea and creatinine was observed. CONCLUSIONS: Serum amyloid A, AGP, fibrinogen, and albumin could be used as biomarkers of inflammatory processes in cats with obstructive FLUTD.

The translation initiation factor EIF4E5 from Leishmania: crystal structure and interacting partners.

The mRNA cap-binding protein, eIF4E, mediates the recognition of the mRNA 5' end and, as part of the heterotrimeric eIF4F complex, facilitates the recruitment of the ribosomal subunits to initiate eukaryotic translation. Various regulatory events involving eIF4E and a second eIF4F subunit, eIF4G, are required for proper control of translation initiation. In pathogenic trypanosomatids, six eIF4Es and five eIF4Gs have been described, several forming different eIF4F-like complexes with yet unresolved roles. EIF4E5 is one of the least known of the trypanosomatid eIF4Es and has not been characterized in Leishmania species. Here, we used immunoprecipitation assays, combined with mass-spectrometry, to identify major EIF4E5 interacting proteins in L. infantum. A constitutively expressed, HA-tagged, EIF4E5 co-precipitated mainly with EIF4G1 and binding partners previously described in Trypanosoma brucei, EIF4G1-IP, RBP43 and the 14-3-3 proteins. In contrast, no clear co-precipitation with EIF4G2, also previously reported, was observed. EIF4E5 also co-precipitated with protein kinases, possibly associated with cell-cycle regulation, selected RNA binding proteins and histones. Phosphorylated residues were identified and mapped to the Leishmania-specific C-terminal end. Mutagenesis of the tryptophan residue (W53) postulated to mediate interactions with protein partners or of a neighbouring tryptophan conserved in Leishmania (W45) did not substantially impair the identified interactions. Finally, the crystal structure of Leishmania EIF4E5 evidences remarkable differences in the eIF4G interfacing region, when compared with human eIF4E-1 and with its Trypanosoma orthologue. Mapping of its C-terminal end near the cap-binding site also imply relevant differences in cap-binding function and/or regulation.

Prone Myocardial Perfusion Imaging and Breast Attenuation: A Phantom Study.

BACKGROUND: Soft tissue attenuation artifacts are the most common cause of misinterpretation in myocardial perfusion Imaging (MPI). Few studies assessing the value of prone imaging in women have been published. Breast attenuation artifacts can be present in up to 40% of the MPI studies in women. OBJECTIVES: This study aimed at evaluating the potential impact of prone MPI on breast attenuation, with a critical analysis of activity optimization and breast size influence. METHODS: MPI of an Anthropomorphic Torso Phantom with silicone breast prostheses and equivalent adipose tissue was compared to a standard MPI database. RESULTS: A medical qualitative and semiquantitative analysis demonstrated higher uptake in the LV anterior segments in the prone position for all injected activities. An artificial myocardium lesion was diagnosable in the right segment in all images, which shows that prone positioning would not mask a true lesion and it assists the cardiologist with a more accurate analysis. These results showed that it is possible to optimize the activity to be injected by up to 55.6% when using combined supine-prone images. CONCLUSION: Prone position has a high impact on the interpretation of MPI in female patients since it reduces the breast attenuation artifacts, and optimizes the radiation protection of the patient and all staff involved in the procedure, making it more cost-effective.

The Effects of Photobiomodulation on Inflammatory Infiltrate During Muscle Repair in Advanced-Age Rats.

Photobiomodulation (PBM) enhances muscle repair in aged animals, but its effect on the modulation of the phenotype of immune cells has not yet been determined. Rats (20-month-old) were submitted to cryoinjury of the tibialis anterior muscle and were treated with PBM. After 1, 3, and 7 days, the muscles were submitted to immunohistochemical analysis for the determination of neutrophils and macrophage phenotypes. The muscles treated with PBM exhibited a smaller number of neutrophils after 1 day of treatment and a greater number of both M1 and M2 macrophages after 3 days of treatment. The irradiated tissues exhibited a smaller amount of both macrophage phenotypes after 7 days of treatment. PBM produced temporal alterations in the phenotype of the inflammatory cells during muscle repair process in advanced-age animals, indicating that these mechanisms may contribute to the beneficial effects of this therapy in the treatment of muscle injuries.

Effect of photobiomodulation on connective tissue remodeling and regeneration of skeletal muscle in elderly rats.

The purpose of this study was to evaluate the effects of low-level laser therapy (LLLT) on morphological aspects, IL-6 and IL-1ß expressions, as well as the distribution and organization of collagen in the tibialis anterior (TA) muscle of elderly rats submitted to cryoinjury. Histological photomicrographs were taken of TA muscles stained with HE and picrosirius red. Immunohistochemistry was used for the evaluation of IL-6 and IL-1ß. Male Wistar rats, aged 20 months, were distributed into three groups: (1) control animals not injured or treated with LLLT (n = 5), (2) cryoinjury without LLLT treatment (n = 15), and (3) cryoinjury treated with infrared LLLT (n = 15). LLLT was applied to the TA 2 h after of the injury induction and consisted of daily applications until the sacrifice (1, 3, and 7 days). The following parameters were used: λ = 780 nm, power density 1 W/cm2, output power 40 mW, 10 s per point, 8 points, and 3.2 J of total energy. In the histomorphological analysis, the treated group exhibited a significant decrease in inflammatory infiltrate (p < 0.001) as well as an increase immature fibers and new blood vessels at 7 days compared to the untreated group (p < 0.05). Furthermore, treatment induced a better collagen distribution and organization at 7 days in comparison to the untreated group (p < 0.05). In conclusion, LLLT demonstrated a modulatory effect on the muscle repair process in elderly animals with regard to the collagen remodeling and morphological aspects of muscle tissue.

Women infected with HIV type 1 Brazilian variant, subtype B (B'-GWGR motif) have slower progression to AIDS, compared with patients infected with subtype B (B-GPGR motif).

INTRODUCTION: The Brazilian variant of human immunodeficiency virus (HIV) type 1 (HIV-1) subtype B (serotype B'-GWGR) has a tryptophan replacing a proline in position 328 of the HIV-1 envelope, a feature that may induce a different HIV disease progression. We aimed to evaluate the role of the B subtypes of HIV-1 (serotypes B-GPGR and B'-GWGR) on HIV disease progression. METHODS: A total of 137 HIV-infected individuals who had been admitted to the hospital were tested with an anti-V3 serologic assay, using peptides representing 2 HIV-1 subtype B strains, MN and SF2, and 2 Brazilian variant B'-GWGR strains, BR1 and BR2. RESULTS: Of 137 serum samples tested with the anti-V3 serologic assay, 4 (3%) yielded indeterminate results, 74 (54%; from 25 women and 49 men) were found to be B-GPGR, and 59 (43%; from 20 women and 39 men) were found to be the B'-GWGR variant. In general, a longer interval from the first known positive HIV test result to an AIDS-defining event was observed in the B'-GWGR group than in the B-GPGR group (21 vs. 7 months). The CD4+ T cell counts were higher in the B'-GWGR group (median CD4+ T cell count, 65 vs. 31 cells/mm3; P=.01), and women infected with the B'-GWGR variant were less likely to die than were men infected with the same variant (P=.01). The median viral load in the B'-GWGR group was 3.395 copies/mL, compared with 39.350 copies/mL in the B-GPGR group (P=.01). CONCLUSIONS: Taken together, our results indicate that B'-GWGR-infected women may have more-favorable outcomes than B-GPGR-infected subjects.

Epidemiological and serological aspects in canine toxoplasmosis in animals with nervous symptoms.

The presence of anti-Toxoplasma gondii IgM and IgG antibodies was studied in samples of blood serum taken from eighty dogs with nervous symptoms at the Serviço de Enfermidades Infecciosas dos Animais, Faculdade de Medicina Veterinária e Zootecnia, Unesp, Botucatu, São Paulo, Brazil. The frequency of IgG titers were 16 (13.7%), 64 (13.7%), and 256 (5%), and for IgM titers were 16 (7.5%), 64 (15%), and 256 (8.7%). Positive reactions were more frequent in the older animals, males, from a rural environment, in constant contact with small animals, principally birds and rodents. There was a higher frequency of a positive reaction in dogs fed with kitchen food, especially in those fed with raw ingredients. The most common neurological pictures were alterations in consciousness, in movement, and in the hand-cart test. The percentage of reagents with specific IgM antibodies was high, indicating active infections, but the possibility of co-infection with the distemper virus can not be discarded, and this may be a predisposing factor for toxoplasmosis infection, once the distemper virus has a potent immunosuppressive action.