A red wine intervention does not modify plasma trimethylamine N-oxide but is associated with broad shifts in the plasma metabolome and gut microbiota composition.

BACKGROUND: Gut microbiota profiles are closely related to cardiovascular diseases through mechanisms that include the reported deleterious effects of metabolites, such as trimethylamine N-oxide (TMAO), which have been studied as diagnostic and therapeutic targets. Moderate red wine (RW) consumption is reportedly cardioprotective, possibly by affecting the gut microbiota. OBJECTIVES: To investigate the effects of RW consumption on the gut microbiota, plasma TMAO, and the plasma metabolome in men with documented coronary artery disease (CAD) using a multiomics assessment in a crossover trial. METHODS: We conducted a randomized, crossover, controlled trial involving 42 men (average age, 60 y) with documented CAD comparing 3-wk RW consumption (250 mL/d, 5 d/wk) with an equal period of alcohol abstention, both preceded by a 2-wk washout period. The gut microbiota was analyzed via 16S rRNA high-throughput sequencing. Plasma TMAO was evaluated by LC-MS/MS. The plasma metabolome of 20 randomly selected participants was evaluated by ultra-high-performance LC-MS/MS. The effect of RW consumption was assessed by individual comparisons using paired tests during the abstention and RW periods. RESULTS: Plasma TMAO did not differ between RW intervention and alcohol abstention, and TMAO concentrations showed low intraindividual concordance over time, with an intraclass correlation coefficient of 0.049 during the control period. After RW consumption, there was significant remodeling of the gut microbiota, with a difference in ß diversity and predominance of Parasutterella, Ruminococcaceae, several Bacteroides species, and Prevotella. Plasma metabolomic analysis revealed significant changes in metabolites after RW consumption, consistent with improved redox homeostasis. CONCLUSIONS: Modulation of the gut microbiota may contribute to the putative cardiovascular benefits of moderate RW consumption. The low intraindividual concordance of TMAO presents challenges regarding its role as a cardiovascular risk biomarker at the individual level. This study was registered at clinical trials.gov as NCT03232099.

Latin American Consensus on management of residual cardiometabolic risk. A consensus paper prepared by the Latin American Academy for the Study of Lipids and Cardiometabolic Risk (ALALIP) endorsed by the Inter-American Society of Cardiology (IASC), the International Atherosclerosis Society (IAS), and the Pan-American College of Endothelium (PACE).

BACKGROUND: Hypertension, hyperglycemia, dyslipidemia, overweight, obesity, and tobacco (smoking, chewing, and vaping), together with a pro-inflammatory and procoagulant state, are the main risk factors related to atherosclerotic cardiovascular disease. OBJECTIVE AND METHODS: A group of experts from the Americas, based on their clinical expertise in cardiology, cardiovascular prevention, and cardiometabolic (CM) diseases, joined together to develop these practical recommendations for the optimal evaluation and treatment of residual CM risk factors in Latin America, using a modified Delphi methodology (details in electronic TSI) to generate a comprehensive CM risk reduction guideline, and through personalized medicine and patient-centered decision, considering the cost-benefit ratio The process was well defined to avoid conflicts of interest that could bias the discussion and recommendations. RESULTS: Residual risk reduction should consider therapeutic options adapted to specific patient needs, based on five treatment objectives: triglyceride-rich lipoproteins, inflammation, impaired glucose metabolism, high blood pressure, and prothrombotic status. Comprehensive control of all CM risk factors should be a priority to deal with this important public health problem and prevent premature deaths. The recommendations in this paper address the evidence-based treatment of CM risk and are intended for clinical application in Latin American countries.

Antecedentes: Un grupo de factores de riesgo cardiometabólicos (hipertensión, hiperglucemia, dislipidemia, sobrepeso, obesidad y tabaco (fumado, masticado, vaporizado), junto con un estado proinflamatorio y procoagulante, son los principales factores de riesgo relacionados con la enfermedad cardiovascular aterosclerótica. Objetivo y métodos: Basándose en su experiencia en cardiología, prevención cardiovascular y enfermedades cardiometabólicas, un grupo de expertos de las Américas se unió para desarrollar estas recomendaciones prácticas para la evaluación y tratamiento óptimos de los factores de riesgo cardiometabólicos residuales en América Latina, utilizando una metodología Delphi modificada con el objetivo de generar una guía integral de pautas para la reducción del riesgo cardiometabólico, mediante la medicina personalizada y la decisión centrada en el paciente teniendo en cuenta la relación costo-beneficio. El proceso fue bien definido para evitar conflictos de intereses que podrían sesgar la discusión y las recomendaciones. Resultados: La reducción del riesgo residual debe considerar opciones terapéuticas adaptadas a las necesidades específicas del paciente, basadas en 5 objetivos de tratamiento: lipoproteínas ricas en triglicéridos inflamación, metabolismo de la glucosa, presión arterial alta y estado protrombótico. El Control integral de todos los factores de riesgo cardiometabólicos debe ser una prioridad para hacer frente a este importante problema de salud pública y prevenir las muertes prematuras. Las recomendaciones de este documento abordan el tratamiento basado en evidencia del riesgo cardiometabólico y están destinadas a la aplicación clínica en los países de América Latina.

The Pathogenesis of COVID-19 Myocardial Injury: An Immunohistochemical Study of Postmortem Biopsies.

Rationale: Myocardial injury associates significantly and independently with mortality in COVID-19 patients. However, the pathogenesis of myocardial injury in COVID-19 remains unclear, and cardiac involvement by SARS-CoV-2 presents a major challenge worldwide. Objective: This histological and immunohistochemical study sought to clarify the pathogenesis and propose a mechanism with pathways involved in COVID-19 myocardial injury. Methods and Results: Postmortem minimally invasive autopsies were performed in six patients who died from COVID-19, and the myocardium samples were compared to a control group (n=11). Histological analysis was performed using hematoxylin-eosin and toluidine blue staining. Immunohistochemical (IHC) staining was performed using monoclonal antibodies against targets: caspase-1, caspase-9, gasdermin-d, ICAM-1, IL-1ß, IL-4, IL-6, CD163, TNF-α, TGF-ß, MMP-9, type 1 and type 3 collagen. The samples were also assessed for apoptotic cells by TUNEL. Histological analysis showed severe pericardiocyte interstitial edema and higher mast cells counts per high-power field in all COVID-19 myocardium samples. The IHC analysis showed increased expression of caspase-1, ICAM-1, IL-1ß, IL-6, MMP-9, TNF-α, and other markers in the hearts of COVID-19 patients. Expression of caspase-9 did not differ from the controls, while gasdermin-d expression was less. The TUNEL assay was positive in all the COVID-19 samples supporting endothelial apoptosis. Conclusions: The pathogenesis of COVID-19 myocardial injury does not seem to relate to primary myocardiocyte involvement but to local inflammation with associated interstitial edema. We found heightened TGF-ß and interstitial collagen expression in COVID-affected hearts, a potential harbinger of chronic myocardial fibrosis. These results suggest a need for continued clinical surveillance of patients for myocardial dysfunction and arrythmias after recovery from the acute phase of COVID-19.

Gaps in beliefs and practice in dyslipidaemia management in Japan, Germany, Colombia and the Philippines: insights from a web-based physician survey.

BACKGROUND: Implementing evidence-based management of dyslipidaemia is a challenge worldwide. OBJECTIVES: To understand physician beliefs and behaviour and identify uncertainties in dyslipidaemia management across four world regions. METHODS: Web-based survey of 1758 physicians in Japan, Germany, Colombia and the Philippines who were selected randomly from existing databases. Key inclusion criteria were 1) for cardiologists and diabetes/endocrinology specialists: ≥50 dyslipidaemia patients examined in the last month; 2) for specialists in neurology/neurosurgery/stroke medicine: ≥50 dyslipidaemia patients and ≥ 20 patients with a history of ischaemic stroke examined in the last month; and 3) for specialists in nephrology and general medicine: based at centres with ≥20 beds and ≥ 50 dyslipidaemia patients examined in the last month. The self-report survey covered dyslipidaemia management, target low-density lipoprotein cholesterol (LDL-C) levels in different patient groups, and statin safety. All physicians gave voluntary consent and all data were anonymised. Analysis was solely descriptive. RESULTS: The survey highlighted key areas of uncertainty in dyslipidaemia management in the four countries. These related to LDL-C targets in different patient groups, the safety of low LDL-C levels, the safety of statins, especially for effects on cognitive, renal and hepatic function and for haemorrhagic stroke risk, and lipid management strategies in patients with chronic kidney disease, including those with concomitant hypertriglyceridaemia. CONCLUSIONS: This survey of physicians in Japan, Germany, Colombia and the Philippines has identified key gaps in knowledge about dyslipidaemia management. These relate to the safety of low LDL-C levels, the safety of statins, and lipid management of chronic kidney disease. The findings from this survey highlight the need for further education to improve the implementation of guideline recommendations for dyslipidaemia management.

Atherosclerosis and inflammation: overview and updates.

The concept that inflammation participates pivotally in the pathogenesis of atherosclerosis and its complications has gained considerable attention, but has not yet entered clinical practice. Experimental work has elucidated molecular and cellular pathways of inflammation that promote atherosclerosis. The recognition of atherogenesis as an active process rather than a cholesterol storage disease or a repository of calcium has highlighted some key inflammatory mechanisms. For example, mononuclear phagocytes contribute to all stages of this disease, illustrating the link between inflammation and atherosclerosis. From a clinical perspective, harnessing inflammation may now help target therapeutics, change guidelines, and enter daily practice. Multiple lines of incontrovertible evidence have proven a causal role for low-density lipoprotein (LDL) cholesterol in atherosclerosis, and we have highly effective tools for lowering LDL, consequently reducing events. Yet, even with intense LDL reduction, events still occur. Inflammation can explain some of this residual risk. An anti-inflammatory intervention has now proven capable of improving outcomes in individuals well treated with LDL-lowering agents. A suite of trials are now pursuing anti-inflammatory therapies in this context. Assessment and treatment of residual inflammatory risk are poised to provide new inroads into preventive cardiology. This brief review aims to explore the potential mechanisms underlying the association of inflammation and atherogenesis, and their clinical consequences.

Selective cathepsin S inhibition attenuates atherosclerosis in apolipoprotein E-deficient mice with chronic renal disease.

Chronic renal disease (CRD) accelerates the development of atherosclerosis. The potent protease cathepsin S cleaves elastin and generates bioactive elastin peptides, thus promoting vascular inflammation and calcification. We hypothesized that selective cathepsin S inhibition attenuates atherogenesis in hypercholesterolemic mice with CRD. CRD was induced by 5/6 nephrectomy in high-fat high-cholesterol fed apolipoprotein E-deficient mice. CRD mice received a diet admixed with 6.6 or 60 mg/kg of the potent and selective cathepsin S inhibitor RO5444101 or a control diet. CRD mice had significantly higher plasma levels of osteopontin, osteocalcin, and osteoprotegerin (204%, 148%, and 55%, respectively; P < 0.05), which were inhibited by RO5444101 (60%, 40%, and 36%, respectively; P < 0.05). Near-infrared fluorescence molecular imaging revealed a significant reduction in cathepsin activity in treated mice. RO5444101 decreased osteogenic activity. Histologic assessment in atherosclerotic plaque demonstrated that RO5444101 reduced immunoreactive cathepsin S (P < 0.05), elastin degradation (P = 0.01), plaque size (P = 0.01), macrophage accumulation (P < 0.01), growth differentiation factor-15 (P = 0.0001), and calcification (alkaline phosphatase activity, P < 0.01; osteocalcin, P < 0.05). Furthermore, cathepsin S inhibitor or siRNA significantly decreased expression of growth differentiation factor-15 and monocyte chemotactic protein-1 in a murine macrophage cell line and human primary macrophages. Systemic inhibition of cathepsin S attenuates the progression of atherosclerotic lesions in 5/6 nephrectomized mice, serving as a potential treatment for atherosclerosis in patients with CRD.

Braunwald tratado de doenças cardiovasculares / Braunwald cardiovascular disease treated

O conteúdo dessa edição também foi melhorado de forma abrangente. Todos os 51 capítulos da 6ª.edição, mantidos para a edição atual, foram completamente revisados e atualizados. Além disso, 36 novos capítulos foram incluídos, cujos tópicos variam de tomada de decisão clínica a manifestações cardiovasculares de distúrbios autonômicos. Cinqüenta e sete novos autores fizeram contribuições. Portanto, a excelência na informação, servindo como fundamento da vitalidade intelectual do texto, foi mantida e fortalecida nesta edição. Referências bibliográficas foram limitadas geralmente às fontes publicadas em 1998, ou depois, para evitar o acréscimo de citações que podem consumir páginas valiosas sem oferecer a utilidade de conteúdo novo. Continuamos a apresentar a compreensão de mecanismos básicos subjacentes a doenças, mas também enfatizamos a avaliação prática e o tratamento de pacientes com esses problemas, bem como fornecemos um compêndio de Diretrizes atuais para a conveniência do leitor. A Parte I abrange as considerações gerais sobre a doença cardiovascular, com capítulos sobre ônus global, economia, tomada de decisão clínica, avaliação da qualidade dos cuidados cardiovasculares, princípios de terapia medicamentosa e cuidado de pacientes terminais com doenças do coração. A Parte II mantém a tradição da edição anterior, enfatizando história e exame físico, eletrocardiografia, teste de esforço e ecocardiografia. Entretanto, reconhecendo a importância crescente de novas técnicas, incluímos novos capítulos como radiologia do coração e grandes vasos, cardiologia nuclear, ressonância magnética, tomografia computadorizada, cateterismo cardíaco, angiografia coronariana e ultra-sonografia intravascular, bem como um capítulo que inclui as mais variadas modalidades de imagem em perspectiva. A insuficiência cardíaca surgiu como um dos problemas mais importantes na cardiologia, como está refletido na Parte III

Braunwald tratado de doenças cardiovasculares / Braunwald cardiovascular disease treated

O conteúdo dessa edição também foi melhorado de forma abrangente. Todos os 51 capítulos da 6ª.edição, mantidos para a edição atual, foram completamente revisados e atualizados. Além disso, 36 novos capítulos foram incluídos, cujos tópicos variam de tomada de decisão clínica a manifestações cardiovasculares de distúrbios autonômicos. Cinqüenta e sete novos autores fizeram contribuições. Portanto, a excelência na informação, servindo como fundamento da vitalidade intelectual do texto, foi mantida e fortalecida nesta edição. Referências bibliográficas foram limitadas geralmente às fontes publicadas em 1998, ou depois, para evitar o acréscimo de citações que podem consumir páginas valiosas sem oferecer a utilidade de conteúdo novo. Continuamos a apresentar a compreensão de mecanismos básicos subjacentes a doenças, mas também enfatizamos a avaliação prática e o tratamento de pacientes com esses problemas, bem como fornecemos um compêndio de Diretrizes atuais para a conveniência do leitor.A Parte I abrange as considerações gerais sobre a doença cardiovascular, com capítulos sobre ônus global, economia, tomada de decisão clínica, avaliação da qualidade dos cuidados cardiovasculares, princípios de terapia medicamentosa e cuidado de pacientes terminais com doenças do coração. A Parte II mantém a tradição da edição anterior, enfatizando história e exame físico, eletrocardiografia, teste de esforço e ecocardiografia. Entretanto, reconhecendo a importância crescente de novas técnicas, incluímos novos capítulos como radiologia do coração e grandes vasos, cardiologia nuclear, ressonância magnética, tomografia computadorizada, cateterismo cardíaco, angiografia coronariana e ultra-sonografia intravascular, bem como um capítulo que inclui as mais variadas modalidades de imagem em perspectiva. A insuficiência cardíaca surgiu como um dos problemas mais importantes na cardiologia, como está refletido na Parte III