Connexin43 promotes exocytosis of damaged lysosomes through actin remodelling.

A robust and efficient cellular response to lysosomal membrane damage prevents leakage from the lysosome lumen into the cytoplasm. This response is understood to happen through either lysosomal membrane repair or lysophagy. Here we report exocytosis as a third response mechanism to lysosomal damage, which is further potentiated when membrane repair or lysosomal degradation mechanisms are impaired. We show that Connexin43 (Cx43), a protein canonically associated with gap junctions, is recruited from the plasma membrane to damaged lysosomes, promoting their secretion and accelerating cell recovery. The effects of Cx43 on lysosome exocytosis are mediated by a reorganization of the actin cytoskeleton that increases plasma membrane fluidity and decreases cell stiffness. Furthermore, we demonstrate that Cx43 interacts with the actin nucleator Arp2, the activity of which was shown to be necessary for Cx43-mediated actin rearrangement and lysosomal exocytosis following damage. These results define a novel mechanism of lysosomal quality control whereby Cx43-mediated actin remodelling potentiates the secretion of damaged lysosomes.

Advanced Erosive Gouty Arthropathy of the Knee.

A 57-year-old male, with chronic bilateral knee pain and a history of poorly controlled hyperuricemia leading to gouty attacks, underwent orthopedic assessment. Radiographic and MRI findings confirmed chronic gouty arthropathy with erosive bony defects, the most significant on the right proximal tibia. Total knee arthroplasty (TKA) was performed without any complications, addressing the bony defect with cement and a semi-constrained prosthesis. However, a gouty attack led to prolonged wound discharge and periprosthetic infection postoperatively, prompting revision surgery with debridement, antibiotics, and implant retention (DAIR). Intraoperative cultures revealed methicillin-sensitive Staphylococcus aureus (MSSA). The treatment included vancomycin and rifampicin. Two years post-surgery, the patient walked pain-free with a knee range of motion of 0-90º. This report highlights the complexity of treating gout-related knee osteoarthritis, emphasizing early intervention to mitigate risks of extensive surgical procedures and infections.

Shear thickening fluid (STF) in engineering applications and the potential of cork in STF-based composites.

Shear thickening fluids (STFs) are a unique type of fluids that can quickly transform into a solid-like state when subjected to forces (rate dependent). These fluids are created by dispersing micro and nanoparticles within a medium. When the force is removed, they return to their original liquid state. Shear thickening fluids can absorb a significant amount of impact energy, making them useful for reducing vibrations and serving as a damper. This study provides a comprehensive and brief overview of existing literature on shear thickening fluids, including their properties, classification, and the rheological mechanisms behind the shear thickening behaviour. It also examines the use of these fluids in various applications, such as improving resistance to stabs and spikes, protecting against low- and high-velocity impacts, and as a new medium for energy dissipation in industries such as battery safety, vibration control and adaptive structures. Lastly, this work reviews the promising combination of STFs with cork. Given the sustainability of cork and its energy absorption capacity, cork-STF composites are a promising solution for various impact-absorbing applications. Overall, the paper underscores the versatility and potential of STFs, and advocates for further research and exploration.

Accuracy and efficiency of finite element head models: The role of finite element formulation and material laws.

Traumatic brain injury is a significant problem worldwide. In the United States of America, around 1.7 million cases are documented annually, displaying the need for a deeper understanding of the effects on the human brain. The tests required for this assessment are very complex. Tests on cadavers may raise serious ethical questions, and in vivo crash tests are not viable. In this context, there is a great need to developing finite element head models (FEHM) to study the biomechanics of the tissues when submitted to a certain impact or acceleration/deceleration scenario. An excellent compromise between accuracy and CPU efficiency is always desirable for a FEHM, For this reason, this work focuses on the improvement of an existing head model, including the study of the behavior of the brain using distinct finite element types. The finite element type and formulation is of utmost importance for the general accuracy and efficiency of the models. Several validations were performed, comparing the simulation results against experimental data. The simulations with hexahedral elements, under specific conditions, obtained more accurate results with a lower computational cost. Using hexahedrals, a comparison was also performed using two material characterizations with more than 10 years apart, using the latest finite element head model validation experiment. Overall, the newer material model displays a less stiff response, although its implementation must always depend on the overall purpose of the model it is being applied to.

Eco-Friendly Cork-Polyurethane Biocomposites for Enhanced Impact Performance: Experimental and Numerical Analysis.

Cork composites are byproducts from wine stopper production, resulting from the agglomeration of cork granules with a thermoset resin. The resulting compound is a versatile and durable material with numerous industrial applications. Due to its unique properties, such as low-density, high-strength, excellent energy absorption, and good thermal and acoustic insulators, cork composites find room for application in demanding industries such as automotive, construction, and aerospace. However, agglomerated cork typically has a polyurethane matrix derived from petrochemical sources. This study focuses on developing eco-friendly porous polyurethane biocomposites manufactured with the used cooking oil polyol modified with cork. Since cork and polyurethane foam are typically used for impact shock absorption, the manufactured samples were subjected to impact loading. The assessment of crashworthiness is performed through 100 J impact tests. A finite element numerical model was developed to simulate the compression of these new composites under impact, and the model validation was performed. The highest specific absorbed energy was obtained for petrochemical polyol composites with the 3% addition of natural or modified cork. The research conducted in this study showcased the feasibility of substituting certain petrochemical components used for the synthesis of the polyurethane matrix with ecological waste vegetable oil components.

Scintigraphic and Echocardiographic Study of Patients with Pathogenic or Probably Pathogenic Variants of the TTR Gene without Overt Cardiac Involvement. / Avaliação Cintilográfica e Ecocardiográfica em Portadores de Variantes Patogênicas ou Provavelmente Patogênicas do Gene TTR sem Envolvimento Cardíaco Manifesto.

BACKGROUND: Transthyretin amyloidosis (ATTR) is an infiltrative disease caused by abnormal protein deposition mainly in the heart and peripheral nervous system. When it affects the heart, the disease presents as restrictive cardiomyopathy; when it affects the peripheral and autonomic nervous system, it manifests as polyneuropathy, and is called familial amyloid polyneuropathy (FAP). There are two ATTR subtypes: wild-type ATTR, where there is no mutation, and mutant ATTR (ATTRm), which is characterized by a mutation in the gene encoding the transthyretin protein (TTR). In both subtypes, cardiac involvement is the major marker of poor prognosis. OBJECTIVES: To assess the prevalence of subclinical cardiac involvement in a sample of patients with TTR gene mutation by using pyrophosphate scintigraphy and strain echocardiography; to compare scintigraphy and strain findings; to evaluate the association between neurological manifestations (FAP) and subclinical cardiac involvement; and to analyze whether there is an association between any specific mutation and cardiac involvement. METHODS: This is a cross-sectional study with carriers of the TTR gene mutation, without cardiovascular symptoms or changes in electrocardiographic or conventional echocardiographic parameters. All patients underwent pyrophosphate scintigraphy and strain echocardiography. Subclinical cardiac involvement was defined as a Perugini score ≥ 2, heart-to-contralateral lung (H/CL) ratio ≥ 1.5 at 1 h, H/CL ≥1.3 at 3 h, or global longitudinal strain (GLS) ≤ -17%. Descriptive and analytical analyses were performed and Fisher's exact test and Mann-Whitney test were applied. A value of p < 0.05 was considered significant. RESULTS: The 23 patients evaluated had a median age of 51 years (IQR 37-57 years), 15 (65.2%) were female, 12 (52.2%) were Pardo, nine (39.1%) had systemic arterial hypertension, and nine (39.1%) had a previous diagnosis of FAP. Of the nine patients with FAP, 8 (34.8%) were on tafamidis. The associated mutations were Val142IIe, Val50Met, and IIe127Val. The median GLS in the sample was -19% (-16% to -20%). Of the 23 patients, nine (39.1%; 95% CI = 29-49%) met criteria for cardiac involvement, six (26%) by the GLS-based criteria only. There was no association between having FAP and being an asymptomatic carrier, as assessed by strain echocardiography and pyrophosphate scintigraphy (p = 0.19). The prevalence of systemic arterial hypertension, diabetes mellitus, dyslipidemia, smoking, and reduced GLS did not differ between groups. Septal e' wave velocity was the only variable that significantly differed between individuals with and without reduced GLS, with an area under the ROC curve of 0.80 (95% CI = 0.61-0.98, p = 0.027). The best diagnostic accuracy was achieved with a septal e' velocity ≤ 8.5 cm/s. There was no association between mutation type and preclinical cardiac involvement, nor between tafamidis use and lower degree of cardiac involvement (37.5% versus 40.0%, p = 0.90). CONCLUSION: Subclinical cardiac involvement was common in a sample of TTR mutation carriers without cardiac involvement. Reduced left ventricular GLS was the most frequent finding. There was no association between the presence of amyloid polyneuropathy and subclinical cardiac involvement. Type of mutation was not associated with early cardiac involvement. In this sample, the use of tafamidis 20 mg/day was not associated with a lower prevalence of subclinical cardiac involvement.

FUNDAMENTO: A amiloidose por transtirretina (ATTR) é uma doença infiltrativa causada pela deposição anormal de proteína principalmente no coração e no sistema nervoso periférico. Quando acomete o coração, a doença manifesta-se como uma cardiomiopatia restritiva e, quando afeta o sistema nervoso periférico e autônomo, apresenta-se como uma polineuropatia, podendo ser chamada de Polineuropatia Amiloidótica Familiar (PAF). Existem dois subtipos de ATTR, a ATTR selvagem, em que não há variantes genéticas, e a ATTR hereditária, caracterizada por uma variante no gene que codifica a proteína transtirretina (T\TR). Em ambos os subtipos, o envolvimento cardíaco é o principal marcador prognóstico. OBJETIVOS: Avaliar a prevalência do envolvimento cardíaco subclínico em uma amostra de pacientes com variantes genéticas no gene TTR usando a cintilografia com pirofosfato e o ecocardiograma com strain; comparar os achados cintilográficos e as medidas de strain; avaliar a associação entre PAF e o envolvimento subclínico; e analisar se existe uma associação entre uma variante genética específica e o envolvimento cardíaco. MÉTODOS: Estudo transversal com carreadores de variantes no gene TTR sem sintomas cardiovasculares e sem alterações nos parâmetros da eletrocardiografia ou do ecocardiograma convencional. Todos os pacientes foram submetidos à cintilografia com pirofosfato e à ecocardiografia com análise de strain. O envolvimento cardíaco subclínico, definido como um escore de Perugini ≥ 2, razão Coração (C)/ Hemitórax Contralateral (CL) ≥ 1,5 em uma hora, C/CL ≥ 1,3 na terceira hora, ou um strain longitudinal global (SGL) ≤ −17%. Realizadas análises descritiva e analítica, e aplicados o teste exato de Fisher e o teste de Mann-Whitney. Um valor de p<0,05 foi considerado significativo. RESULTADOS: Os 23 pacientes avaliados apresentavam uma idade mediana de 51 (37-57) anos, 15 (65,2%) eram do sexo feminino, 12 (52,2%) eram pardos, nove (39,1%) apresentavam hipertensão arterial sistêmica, e nove (39,1%) tinham um diagnóstico prévio de PAF. Dos nove pacientes com PAF, oito (34,8%) usavam tafamidis. As variantes genéticas identificadas foram Val142IIe, Val50Met e IIe127Val. O valor mediano do SGL foi −19% (-16% ­ −20%). Dos 23 pacientes, nove (39,1%; 95% CI = 29­49%) preencheram os critérios de envolvimento cardíaco, seis (26%) somente pelo critério do SGL. Não houve associação entre PAF e um carreador assintomático avaliado por ecocardiograma com análise de strain e pela cintilografia com pirofostato (p=0,19). A prevalência de hipertensão arterial sistêmica, diabetes mellitus, dislipidemia, tabagismo e SGL reduzido não foi diferente entre os grupos. A velocidade da onda e' septal foi a única variável que apresentou diferença significativa entre os indivíduos com e sem SGL reduzido, com uma área sob a curva ROC de 0,80 (IC95% = 0,61­0,98, p = 0,027). A melhor acurácia diagnóstica foi alcançada com uma velocidade e' septal ≤ 8,5 cm/s. Não houve associação entre o tipo de variante genética e o envolvimento cardíaco pré-clínico, nem entre o uso de tafamidis e este mesmo envolvimento (37,5% versus 40,0%, p = 0,90). CONCLUSÃO: O envolvimento cardíaco subclínico foi frequente em uma amostra de carreadores da variante genética do gene TTR. Um valor do SGL reduzido foi o achado mais comum. Não houve associação entre a presença de polineuropatia amiloidótica e o envolvimento subclínico. O tipo de variante genética não foi associado com envolvimento cardíaco precoce. Nesta amostra, o uso de tafamidis (20mg/dia) não foi associado com uma menor prevalência de envolvimento cardíaco subclínico.

Echocardiographic factors associated with thromboembolic events in patients with cardiac amyloidosis without atrial fibrillation.

AIMS: Cardiac amyloidosis (CA) is associated with various complications, and one of them are thromboembolic events (TEEs), which can significantly impact patients' quality of life. Predicting and managing the risk of these TEEs in patients without atrial fibrillation (AF) pose significant challenges, as many occur independently of AF presence. Several predictors, particularly echocardiographic ones, have been linked to an increased risk, but there is no consensus on stratification or preventive treatment. The main objective was to determine the prevalence of TEEs in a cohort of CA patients without AF and identify echocardiographic predictors. METHODS: A retrospective, single-center study including confirmed CA patients. A prespecified list of variables was defined, and only patients with at least 70 % of these variables were included. Risk rates were analyzed through binary logistic regression, with a significance level set at p < 0.05. RESULTS: 75 patients were included. Baseline characteristics are depicted in Fig. 1. Fifteen TEEs (20 %) were described, with 80 % being ischemic strokes. While diastolic dysfunction and pulmonary systolic arterial pressure (PSAP) were predictors in univariate analysis, the multivariate backward LR model identified interventricular septum diameter (IVSD) as the sole predictor, OR 1.280 (1.061-1.543), p = 0.010. It is also interesting to mention that analyzing the increase of every 3 mm in SIV, the chance of developing ETES was: OR = 2.095 (1.195-3.671), p = 0.010. CONCLUSIONS: An IVSD evaluated by echocardiography demonstrated good performance capacity as a factor associated with TEEs in this cohort of patients with AC without AF. For every 3 mm increase in IVSD, the risk of developing TEEs doubles.

Assessment of potential transthyretin amyloid cardiomyopathy cases in the Brazilian public health system using a machine learning model.

OBJECTIVES: To identify and describe the profile of potential transthyretin cardiac amyloidosis (ATTR-CM) cases in the Brazilian public health system (SUS), using a predictive machine learning (ML) model. METHODS: This was a retrospective descriptive database study that aimed to estimate the frequency of potential ATTR-CM cases in the Brazilian public health system using a supervised ML model, from January 2015 to December 2021. To build the model, a list of ICD-10 codes and procedures potentially related with ATTR-CM was created based on literature review and validated by experts. RESULTS: From 2015 to 2021, the ML model classified 262 hereditary ATTR-CM (hATTR-CM) and 1,581 wild-type ATTR-CM (wtATTR-CM) potential cases. Overall, the median age of hATTR-CM and wtATTR-CM patients was 66.8 and 59.9 years, respectively. The ICD-10 codes most presented as hATTR-CM and wtATTR-CM were related to heart failure and arrythmias. Regarding the therapeutic itinerary, 13% and 5% of hATTR-CM and wtATTR-CM received treatment with tafamidis meglumine, respectively, while 0% and 29% of hATTR-CM and wtATTR-CM were referred to heart transplant. CONCLUSION: Our findings may be useful to support the development of health guidelines and policies to improve diagnosis, treatment, and to cover unmet medical needs of patients with ATTR-CM in Brazil.

Clinical and genetic profiles of patients with hereditary and wild-type transthyretin amyloidosis: the Transthyretin Cardiac Amyloidosis Registry in the state of São Paulo, Brazil (REACT-SP).

BACKGROUND: Transthyretin amyloidosis (ATTR) is a multisystem disease caused by the deposition of fibrillar protein in organs and tissues. ATTR genotypes and phenotypes are highly heterogeneous. We present data on physical signs and symptoms, cardiac and neurological assessments and genetic profile of patients enrolled in the Transthyretin Cardiac Amyloidosis Registry of the State of São Paulo, Brazil. RESULTS: Six hundred-forty-four patients were enrolled, 505 with the variant form (ATTRv) and 139 with wild-type (ATTRwt). Eleven different mutations were detected, the most common being Val50Met (47.5%) and V142Ile (39.2%). Overall, more than half of the patients presented cardiac involvement, and the difference in this proportion between the ATTRv and ATTRwt groups was significant (43.9 vs. 89.9%; p < 0.001). The prevalence of the neurological phenotype also differed between ATTRv and ATTRwt (56.8 vs. 31.7%; p < 0.001). The mixed phenotype was found in 25.6% of the population, without a significant difference between ATTRv and ATTRwt groups. A group of patients remained asymptomatic (10.4%), with a lower proportion of asymptomatic ATTRwt patients. CONCLUSIONS: This study details the clinical and genetic spectrum of patients with ATTR in São Paulo, Brazil. This preliminary analysis highlights the considerable phenotypic heterogeneity of neurological and cardiac manifestations in patients with variant and wild-type ATTR.

Limitations of apical sparing pattern in cardiac amyloidosis: a multicentre echocardiographic study.

AIMS: Although impaired left ventricular (LV) global longitudinal strain (GLS) with apical sparing is a feature of cardiac amyloidosis (CA), its diagnostic accuracy has varied across studies. We aimed to determine the ability of apical sparing ratio (ASR) and most common echocardiographic parameters to differentiate patients with confirmed CA from those with clinical and/or echocardiographic suspicion of CA but with this diagnosis ruled out. METHODS AND RESULTS: We identified 544 patients with confirmed CA and 200 controls (CTRLs) as defined above (CTRL patients). Measurements from transthoracic echocardiograms were performed using artificial intelligence software (Us2.AI, Singapore) and audited by an experienced echocardiographer. Receiver operating characteristic curve analysis was used to evaluate the diagnostic performance and optimal cut-offs for the differentiation of CA patients from CTRL patients. Additionally, a group of 174 healthy subjects (healthy CTRL) was included to provide insight on how patients and healthy CTRLs differed echocardiographically. LV GLS was more impaired (-13.9 ± 4.6% vs. -15.9 ± 2.7%, P < 0.0005), and ASR was higher (2.4 ± 1.2 vs. 1.7 ± 0.9, P < 0.0005) in the CA group vs. CTRL patients. Relative wall thickness and ASR were the most accurate parameters for differentiating CA from CTRL patients [area under the curve (AUC): 0.77 and 0.74, respectively]. However, even with the optimal cut-off of 1.67, ASR was only 72% sensitive and 66% specific for CA, indicating the presence of apical sparing in 32% of CTRL patients and even in 6% healthy subjects. CONCLUSION: Apical sparing did not prove to be a CA-specific biomarker for accurate identification of CA, when compared with clinically similar CTRLs with no CA.

Do social protection programmes affect the burden of breast and cervical cancer? A systematic review.

Background: Socioeconomic conditions are strongly associated with breast and cervical cancer incidence and mortality patterns; therefore, social protection programmes (SPPs) might impact these cancers. This study aimed to evaluate the effect of SPPs on breast and cervical cancer outcomes and their risk/protective factors. Methods: Five databases were searched for articles that assessed participation in PPS and the incidence, survival, mortality (primary outcomes), screening, staging at diagnosis and risk/protective factors (secondary outcomes) for these cancers. Only peer-reviewed quantitative studies of women receiving SPPs compared to eligible women not receiving benefits were included. Independent reviewers selected articles, assessed eligibility, extracted data, and assessed the risk of bias. A harvest plot represents the included studies and shows the direction of effect, sample size and risk of bias. Findings: Of 17,080 documents retrieved, 43 studies were included in the review. No studies evaluated the primary outcomes. They all examined the relationship between SPPs and screening, as well as risk and protective factors. The harvest plot showed that in lower risk of bias studies, participants of SPPs had lower weight and fertility, were older at sexual debut, and breastfed their infants for longer. Interpretation: No studies have yet assessed the effect of SPPs on breast and cervical cancer incidence, survival, or mortality; nevertheless, the existing evidence suggests positive impacts on risk and protective factors.

The Significance of Cross-Sectional Shape Accuracy and Non-Linear Elasticity on the Numerical Modelling of Cerebral Veins under Tensile Loading.

Traumatic brain injury (TBI) is a serious global health issue, leading to serious disabilities. One type of TBI is acute subdural haematoma (ASDH), which occurs when a bridging vein ruptures. Many numerical models of these structures, mainly based on the finite element method, have been developed. However, most rely on linear elasticity (without validation) and others on simplifications at the geometrical level. An example of the latter is the assumption of a regular cylinder with a constant radius, or the geometry of the vein acquired from medical images. Unfortunately, these do not replicate the real conditions of a mechanical tensile test. In this work, the main goal is to evaluate the influence of the vein's geometry in its mechanical behaviour under tensile loading, simulating the real conditions of experimental tests. The second goal is to implement a hyperelastic model of the bridging veins where it would be possible to observe its non-linear elastic behaviour. The results of the developed finite element models were compared to experimental data available in the literature and other models. It was possible to conclude that the geometry of the vein structure influences the tensile stress-strain curve, which means that flattened specimens should be modelled when validating constitutive models for bridging veins. Additionally, the implementation of hyperelastic material models has been verified, highlighting the potential application of the Marlow and reduced polynomial (of fourth and sixth orders) constitutive models.

A Review of the Metal Additive Manufacturing Processes.

Metal additive manufacturing (AM) is a layer-by-layer process that makes the direct manufacturing of various industrial parts possible. This method facilitates the design and fabrication of complex industrial, advanced, and fine parts that are used in different industry sectors, such as aerospace, medicine, turbines, and jewelry, where the utilization of other fabrication techniques is difficult or impossible. This method is advantageous in terms of dimensional accuracy and fabrication speed. However, the parts fabricated by this method may suffer from faults such as anisotropy, micro-porosity, and defective joints. Metals like titanium, aluminum, stainless steels, superalloys, etc., have been used-in the form of powder or wire-as feed materials in the additive manufacturing of various parts. The main criterion that distinguishes different additive manufacturing processes from each other is the deposition method. With regard to this criterion, AM processes can be divided into four classes: local melting, sintering, sheet forming, and electrochemical methods. Parameters affecting the properties of the additive-manufactured part and the defects associated with an AM process determine the method by which a certain part should be manufactured. This study is a survey of different additive manufacturing processes, their mechanisms, capabilities, shortcomings, and the general properties of the parts manufactured by them.

Avaliação Cintilográfica e Ecocardiográfica em Portadores de Variantes Patogênicas ou Provavelmente Patogênicas do Gene TTR sem Envolvimento Cardíaco Manifesto / Scintigraphic and Echocardiographic Study of Patients with Pathogenic or Probably Pathogenic Variants of the TTR Gene without Overt Cardiac Involvement

Resumo Fundamento: A amiloidose por transtirretina (ATTR) é uma doença infiltrativa causada pela deposição anormal de proteína principalmente no coração e no sistema nervoso periférico. Quando acomete o coração, a doença manifesta-se como uma cardiomiopatia restritiva e, quando afeta o sistema nervoso periférico e autônomo, apresenta-se como uma polineuropatia, podendo ser chamada de Polineuropatia Amiloidótica Familiar (PAF). Existem dois subtipos de ATTR, a ATTR selvagem, em que não há variantes genéticas, e a ATTR hereditária, caracterizada por uma variante no gene que codifica a proteína transtirretina (T/TR). Em ambos os subtipos, o envolvimento cardíaco é o principal marcador prognóstico. Objetivos: Avaliar a prevalência do envolvimento cardíaco subclínico em uma amostra de pacientes com variantes genéticas no gene TTR usando a cintilografia com pirofosfato e o ecocardiograma com strain; comparar os achados cintilográficos e as medidas de strain; avaliar a associação entre PAF e o envolvimento subclínico; e analisar se existe uma associação entre uma variante genética específica e o envolvimento cardíaco. Métodos: Estudo transversal com carreadores de variantes no gene TTR sem sintomas cardiovasculares e sem alterações nos parâmetros da eletrocardiografia ou do ecocardiograma convencional. Todos os pacientes foram submetidos à cintilografia com pirofosfato e à ecocardiografia com análise de strain. O envolvimento cardíaco subclínico, definido como um escore de Perugini ≥ 2, razão Coração (C)/ Hemitórax Contralateral (CL) ≥ 1,5 em uma hora, C/CL ≥ 1,3 na terceira hora, ou um strain longitudinal global (SGL) ≤ −17%. Realizadas análises descritiva e analítica, e aplicados o teste exato de Fisher e o teste de Mann-Whitney. Um valor de p<0,05 foi considerado significativo. Resultados: Os 23 pacientes avaliados apresentavam uma idade mediana de 51 (37-57) anos, 15 (65,2%) eram do sexo feminino, 12 (52,2%) eram pardos, nove (39,1%) apresentavam hipertensão arterial sistêmica, e nove (39,1%) tinham um diagnóstico prévio de PAF. Dos nove pacientes com PAF, oito (34,8%) usavam tafamidis. As variantes genéticas identificadas foram Val142IIe, Val50Met e IIe127Val. O valor mediano do SGL foi −19% (-16% - −20%). Dos 23 pacientes, nove (39,1%; 95% CI = 29-49%) preencheram os critérios de envolvimento cardíaco, seis (26%) somente pelo critério do SGL. Não houve associação entre PAF e um carreador assintomático avaliado por ecocardiograma com análise de strain e pela cintilografia com pirofostato (p=0,19). A prevalência de hipertensão arterial sistêmica, diabetes mellitus, dislipidemia, tabagismo e SGL reduzido não foi diferente entre os grupos. A velocidade da onda e' septal foi a única variável que apresentou diferença significativa entre os indivíduos com e sem SGL reduzido, com uma área sob a curva ROC de 0,80 (IC95% = 0,61-0,98, p = 0,027). A melhor acurácia diagnóstica foi alcançada com uma velocidade e' septal ≤ 8,5 cm/s. Não houve associação entre o tipo de variante genética e o envolvimento cardíaco pré-clínico, nem entre o uso de tafamidis e este mesmo envolvimento (37,5% versus 40,0%, p = 0,90). Conclusão: O envolvimento cardíaco subclínico foi frequente em uma amostra de carreadores da variante genética do gene TTR. Um valor do SGL reduzido foi o achado mais comum. Não houve associação entre a presença de polineuropatia amiloidótica e o envolvimento subclínico. O tipo de variante genética não foi associado com envolvimento cardíaco precoce. Nesta amostra, o uso de tafamidis (20mg/dia) não foi associado com uma menor prevalência de envolvimento cardíaco subclínico.

Abstract Background: Transthyretin amyloidosis (ATTR) is an infiltrative disease caused by abnormal protein deposition mainly in the heart and peripheral nervous system. When it affects the heart, the disease presents as restrictive cardiomyopathy; when it affects the peripheral and autonomic nervous system, it manifests as polyneuropathy, and is called familial amyloid polyneuropathy (FAP). There are two ATTR subtypes: wild-type ATTR, where there is no mutation, and mutant ATTR (ATTRm), which is characterized by a mutation in the gene encoding the transthyretin protein (TTR). In both subtypes, cardiac involvement is the major marker of poor prognosis. Objectives: To assess the prevalence of subclinical cardiac involvement in a sample of patients with TTR gene mutation by using pyrophosphate scintigraphy and strain echocardiography; to compare scintigraphy and strain findings; to evaluate the association between neurological manifestations (FAP) and subclinical cardiac involvement; and to analyze whether there is an association between any specific mutation and cardiac involvement. Methods: This is a cross-sectional study with carriers of the TTR gene mutation, without cardiovascular symptoms or changes in electrocardiographic or conventional echocardiographic parameters. All patients underwent pyrophosphate scintigraphy and strain echocardiography. Subclinical cardiac involvement was defined as a Perugini score ≥ 2, heart-to-contralateral lung (H/CL) ratio ≥ 1.5 at 1 h, H/CL ≥1.3 at 3 h, or global longitudinal strain (GLS) ≤ −17%. Descriptive and analytical analyses were performed and Fisher's exact test and Mann-Whitney test were applied. A value of p < 0.05 was considered significant. Results: The 23 patients evaluated had a median age of 51 years (IQR 37-57 years), 15 (65.2%) were female, 12 (52.2%) were Pardo, nine (39.1%) had systemic arterial hypertension, and nine (39.1%) had a previous diagnosis of FAP. Of the nine patients with FAP, 8 (34.8%) were on tafamidis. The associated mutations were Val142IIe, Val50Met, and IIe127Val. The median GLS in the sample was −19% (−16% to −20%). Of the 23 patients, nine (39.1%; 95% CI = 29-49%) met criteria for cardiac involvement, six (26%) by the GLS-based criteria only. There was no association between having FAP and being an asymptomatic carrier, as assessed by strain echocardiography and pyrophosphate scintigraphy (p = 0.19). The prevalence of systemic arterial hypertension, diabetes mellitus, dyslipidemia, smoking, and reduced GLS did not differ between groups. Septal e' wave velocity was the only variable that significantly differed between individuals with and without reduced GLS, with an area under the ROC curve of 0.80 (95% CI = 0.61-0.98, p = 0.027). The best diagnostic accuracy was achieved with a septal e' velocity ≤ 8.5 cm/s. There was no association between mutation type and preclinical cardiac involvement, nor between tafamidis use and lower degree of cardiac involvement (37.5% versus 40.0%, p = 0.90). Conclusion: Subclinical cardiac involvement was common in a sample of TTR mutation carriers without cardiac involvement. Reduced left ventricular GLS was the most frequent finding. There was no association between the presence of amyloid polyneuropathy and subclinical cardiac involvement. Type of mutation was not associated with early cardiac involvement. In this sample, the use of tafamidis 20 mg/day was not associated with a lower prevalence of subclinical cardiac involvement.

Rare association between giant-cell aortitis and giant-cell aortic valvulitis

ABSTRACT Giant cell arteritis (GCA) is a type of chronic vasculitis that affects medium and large-caliber arteries, frequently related to aortic involvement and, consequently, to aneurysm formation. However, associated valvulitis with giant cells is uncommon. We describe the case of a 50-year-old female patient with aortic aneurysm and valvular insufficiency, whose anatomopathological examination revealed giant-cell aortic valvulitis associated with giant cell aortitis.

Resource utilization and costs related to the management of obstructive hypertrophic cardiomyopathy under the Brazilian supplementary healthcare system´s perspective: results from a modified Delphi panel / Utilização de recursos e custos relacionados ao manejo da cardiomiopatia hipertrófica obstrutiva sob a perspectiva do sistema de saúde suplementar brasileiro: resultados de um painel Delphi modificado

Objective: To generate data on the costs associated with the diagnosis and treatment of obstructive ypertrophic cardiomyopathy (HCM) from the perspective of the private health system in Brazil. Methods: A modified Delphi panel including seven different specialists (three clinical cardiologists with experience in obstructive HCM, two hemodynamicists with experience in septal ablation and two cardiac surgeons with expertise in myectomy), from two Brazilian states (São Paulo and Pernambuco), was conducted between August and November 2022. Two rounds of questions about the use of healthcare resources according to the functional class (NYHA I-IV) and a panel in a virtual platform were conducted to obtain the final consensus. Micro-costing defined costs and unit values were determined based on official price lists. Results: The total diagnosis cost per patient was estimated at BRL 11,486.81. The obstructive HCM management costs analysis showed average annual costs per patient of BRL 17,026.74, BRL 19,401.46, BRL 73,310.07, and BRL 94,885.75 for the functional classes NYHA I, NYHA II, NYHA III, and NYHA IV, respectively. The average costs per patient related to procedures in a year were BRL 12,698.53, BRL 13,462.30, BRL 58,841.67, and BRL 75,595.90 for the functional classes NYHA I, II, III, and IV, respectively. Conclusions: The annual costs of HCM management increased according to the functional class, highlighting the need for safe and effective strategies to improve patient's NYHA functional class while promoting a decrease in the need for invasive therapies.

Objetivo: Gerar dados acerca dos custos associados ao diagnóstico e tratamento da cardiomiopatia hipertrófica (CMH) obstrutiva, sob a perspectiva do sistema de saúde privado no Brasil. Métodos: Um painel Delphi modificado incluindo sete especialistas (três cardiologistas clínicos com experiência em CMH obstrutiva, dois hemodinamicistas com experiência em ablação de septo e dois cirurgiões cardíacos com experiência em miectomia) de dois estados brasileiros (São Paulo e Pernambuco) foi conduzido entre agosto e novembro de 2022. Foram realizadas duas rodadas de perguntas acerca da utilização de recursos de acordo com a classe funcional (NYHA I-IV) e uma reunião virtual para obtenção do consenso final. Os custos foram definidos por meio de microcusteio, e os valores unitários foram definidos com base em listas de preço oficiais. Resultados: O custo total do diagnóstico por paciente foi estimado em R$ 11.486,81. A análise de custos de manejo da CMH obstrutiva mostrou custos médios anuais por paciente de R$ 17.026,74, R$ 19.401,46, R$ 73.310,07 e R$ 94.885,75 para as classes funcionais NYHA I, NYHA II, NYHA III e NYHA IV, respectivamente. Os custos médios por paciente relacionados a procedimentos em um ano foram de R$ 12.698,53, R$ 13.462,30, R$ 58.841,67 e R$ 75.595,90 para as classes NYHA I, II, III e IV, respectivamente. Conclusões: Os custos anuais com o manejo da CMH aumentam de acordo com a classe funcional, destacando a necessidade de estratégias seguras e eficazes capazes de melhorar a classe funcional NYHA do paciente, ao mesmo tempo que promove diminuição da necessidade de terapias invasivas.

Prótesis Starr-Edwards vigente y funcional por más de 40 años / Starr-Edwards prosthesis current and functional for more than 40 years

INTRODUCCIÓN. Las enfermedades valvulares cardíacas han sido un foco de estudio y de evolución continua, pues existen grupos de pacientes seleccionados en quienes el cambio valvular es parte de su terapéutica. En 1960 surgió el modelo de prótesis de válvula en forma de esfera enjaulada de Albert Starr y Lowell Edwards. El diseño fue perfeccionándose y es usado hasta la actualidad ya que muestra resultados clínicos aceptables. OBJETIVO. Describir el caso de un paciente portador, de uno de los primeros prototipos de prótesis valvular cardiaca metálica Starr-Edwards vigente y funcional por más de 40 años. CASO CLÍNICO. Paciente masculino con prótesis Starr-Edwards en posición aórtica, quien hasta la fecha lleva más de 40 años de uso, mantiene la clase funcional II de la New York Heart Association, realizando anticoagulación con Warfarina así como controles estrictos del índice internacional normalizado. DISCUSIÓN. Es primordial la evaluación y seguimiento de portadores de prótesis valvular para analizar anifestaciones clínicas (disnea) y hallazgos en los exámenes de laboratorio o de imagen (ecografía) para el control clínico y hemodinámica del paciente, con la intención de contemplar circunstancias que podrían determinar la nueva intervención valvular. CONCLUSIONES. Las válvulas metálicas, en particular las del tipo de prótesis de Starr-Edwards presentan alto riesgo trombótico por lo que es recomendable mantener anticoagulación plena evitando valores de índice internacional normalizado muy elevados que podrían crear escenarios de eventos hemorrágicos. Varios pacientes portadores de una de las prótesis más antiguas como es el modelo la prótesis Starr-Edwards, pueden llegar a tener una mejor supervivencia y resultados clínicos aceptables.

INTRODUCTION. Cardiac valve diseases have been a focus of study and continuous evolution, since there are selected groups of patients in whom valve replacement is part of their therapy. In 1960, the caged sphere valve prosthesis model of Albert Starr and Lowell Edwards was developed. The design was refined and is still used today because it shows acceptable clinical results. OBJECTIVE. To describe the case of a patient with one of the first prototypes of Starr- Edwards metallic heart valve prosthesis, which has been in use and functional for more than 40 years. CLINICAL CASE. Male patient with Starr-Edwards prosthesis in aortic position, who to date has been used for more than 40 years, maintains functional class II of the New York Heart Association, performing anticoagulation with Warfarin as well as strict controls of the international normalized index. DISCUSSION. The evaluation and follow-up of valve prosthesis carriers is essential to analyze clinical manifestations (dyspnea) and findings in laboratory or imaging tests (ultrasound) for the clinical and hemodynamic control of the patient, with the intention of contemplating circumstances that could determine the new valve intervention. CONCLUSIONS. Metallic valves, particularly those of the Starr-Edwards prosthesis type, present a high thrombotic risk and it is therefore advisable to maintain full anticoagulation, avoiding very high values of the international normalized index that could create scenarios of hemorrhagic events. Several patients carrying one of the older prostheses, such as the Starr-Edwards prosthesis model, may have better survival and acceptable clinical results.

Análise Crítica e Limitações do Diagnóstico de Insuficiência Cardíaca com Fração de Ejeção Preservada (ICFEp) / Critical Analysis and Limitations of the Diagnosis of Heart Failure with Preserved Ejection Fraction (HFpEF)

Resumo Com o aumento da expectativa de vida da população e a maior frequência de fatores de risco como obesidade, hipertensão arterial e diabetes, espera-se um aumento na prevalência de insuficiência cardíaca com fração de ejeção preservada (ICFEp). Entretanto, no momento, o diagnóstico e o tratamento de pacientes com ICFEp permanecem desafiadores. O diagnóstico sindrômico de ICFEp inclui diversas etiologias e doenças com tratamentos específicos, mas que apresentam pontos em comum em relação à apresentação clínica e à avaliação laboratorial no que diz respeito aos biomarcadores como BNP e NT-ProBNP, à avaliação ecocardiográfica do remodelamento cardíaco e às pressões de enchimento diastólico ventricular esquerdo. Extensos ensaios clínicos randomizados envolvendo a terapia nesta síndrome falharam na demonstração de benefícios para o paciente, fazendo-se necessária uma reflexão acerca do diagnóstico, dos mecanismos de morbidade, da taxa de mortalidade e da reversibilidade. Na revisão, serão abordados os conceitos atuais, as controvérsias e, especialmente, os desafios no diagnóstico da ICFEp através de uma análise crítica do escore da European Heart Failure Association.

Abstract With the increase in the population's life expectancy and the higher frequency of risk factors such as obesity, hypertension and diabetes, an increase in the prevalence of heart failure with preserved ejection fraction (HFpEF) is expected. However, to date, the diagnosis and treatment of patients with HFpEF remain challenging. The syndromic diagnosis of HFpEF includes several etiologies and diseases with specific treatments but has points in common regarding the clinical presentation, laboratory evaluation related to biomarkers, such as BNP and NT-ProBNP, and echocardiographic evaluation of cardiac remodeling and left ventricular diastolic filling pressures. Extensive randomized clinical trials involving the treatment of this condition have failed to demonstrate benefits to the patient, making it necessary to reflect on the diagnosis, mechanisms of morbidity, mortality and reversibility in this syndrome. In this review, the current concepts, controversies and challenges, especially regarding diagnosis, will be addressed, critically analyzing the European Heart Failure Association score for the diagnosis of HFpEF.