Effect of Zhenwu Decoction on electrical remodeling of cardiomyocytes in heart failure via I_(to)/Kv channels / 中国中药杂志

This study aimed to investigate the underlying mechanism of Zhenwu Decoction in the treatment of heart failure by regulating electrical remodeling through the transient outward potassium current(I_(to))/voltage-gated potassium(Kv) channels. Five normal SD rats were intragastrically administered with Zhenwu Decoction granules to prepare drug-containing serum, and another seven normal SD rats received an equal amount of distilled water to prepare blank serum. H9c2 cardiomyocytes underwent conventional passage and were treated with angiotensin Ⅱ(AngⅡ) for 24 h. Subsequently, 2%, 4%, and 8% drug-containing serum, simvastatin(SIM), and BaCl_2 were used to interfere in H9c2 cardiomyocytes for 24 h. The cells were divided into a control group [N, 10% blank serum + 90% high-glucose DMEM(DMEM-H)], a model group(M, AngⅡ + 10% blank serum + 90% DMEM-H), a low-dose Zhenwu Decoction-containing serum group(Z1, AngⅡ + 2% drug-containing serum of Zhenwu Decoction + 8% blank serum + 90% DMEM-H), a medium-dose Zhenwu Decoction-containing serum group(Z2, AngⅡ + 4% drug-containing serum of Zhenwu Decoc-tion + 6% blank serum + 90% DMEM-H), a high-dose Zhenwu Decoction-containing serum group(Z3, AngⅡ + 8% drug-containing serum of Zhenwu Decoction + 2% blank serum + 90% DMEM-H), an inducer group(YD, AngⅡ + SIM + 10% blank serum + 90% DMEM-H), and an inhibitor group(YZ, AngⅡ + BaCl_2 + 10% blank serum + 90% DMEM-H). The content of ANP in cell extracts of each group was detected by ELISA. The relative mRNA expression levels of ANP, Kv1.4, Kv4.2, Kv4.3, DPP6, and KChIP2 were detected by real-time quantitative PCR. The protein expression of Kv1.4, Kv4.2, Kv4.3, DPP6, and KChIP2 was detected by Western blot. I_(to) was detected by the whole cell patch-clamp technique. The results showed that Zhenwu Decoction at low, medium, and high doses could effectively reduce the surface area of cardiomyocytes. Compared with the M group, the Z1, Z2, Z3, and YD groups showed decreased ANP content and mRNA level, increased protein and mRNA expression of Kv4.2, Kv4.3, DPP6, and KChIP2, and decreased protein and mRNA expression of Kv1.4, and the aforementioned changes were the most notable in the Z3 group. Compared with the N group, the Z1, Z2, and Z3 groups showed significantly increased peak current and current density of I_(to). The results indicate that Zhenwu Decoction can regulate myocardial remodeling and electrical remodeling by improving the expression trend of Kv1.4, Kv4.2, Kv4.3, KChIP2, and DPP6 proteins and inducing I_(to) to regulate Kv channels, which may be one of the mechanisms of Zhenwu Decoction in treating heart failure and related arrhythmias.

Potential implications of ketone body metabolism changes and ketogenic therapy in the treatment of heart failure / 中华危重病急救医学

Heart failure (HF) has become a major challenge in the treatment of global cardiovascular diseases. Great progress has been made in the drug treatment of HF, however, rehospitalization rate and mortality of patients with HF are still high. Hence, there is an urgent need to explore new treatment strategy and new underlying pathogenic mechanisms. In recent years, some researchers have suggested that regulation of ketone body metabolism may become a potentially promising therapeutic approach for HF. Some studies showed that the oxidative utilization of fatty acids and glucose was decreased in the failing heart, accompanied by the increase of ketone body oxidative metabolism. The enhancement of ketone body metabolism in HF is a compensatory change during HF. The failing heart preferentially uses ketone body oxidation to provide energy, which helps to improve the body's cardiac function. This review will discuss the potential significance of ketone body metabolism in the treatment of HF from three aspects: normal myocardial ketone body metabolism, the change of ketone body metabolism in HF, the effect of ketogenic therapy on HF and its treatment.

Similarities and differences of myocardial metabolic characteristics between HFpEF and HFrEF mice based on LC-MS/MS metabolomics / 中华心血管病杂志

Objective: To reveal the similarities and differences in myocardial metabolic characteristics between heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) mice using metabolomics. Methods: The experimental mice were divided into 4 groups, including control, HFpEF, sham and HFrEF groups (10 mice in each group). High fat diet and Nω-nitroarginine methyl ester hydrochloride (L-NAME) were applied to construct a"two-hit"HFpEF mouse model. Transverse aortic constriction (TAC) surgery was used to construct the HFrEF mouse model. The differential expression of metabolites in the myocardium of HFpEF and HFrEF mice was detected by untargeted metabolomics (UHPLC-QE-MS). Variable importance in projection>1 and P<0.05 were used as criteria to screen and classify the differentially expressed metabolites between the mice models. KEGG functional enrichment and pathway impact analysis demonstrated significantly altered metabolic pathways in both HFpEF and HFrEF mice. Results: One hundred and nine differentially expressed metabolites were detected in HFpEF mice, and 270 differentially expressed metabolites were detected in HFrEF mice. Compared with the control group, the most significantly changed metabolite in HFpEF mice was glycerophospholipids, while HFrEF mice presented with the largest proportion of carboxylic acids and their derivatives. KEGG enrichment and pathway impact analysis showed that the differentially expressed metabolites in HFpEF mice were mainly enriched in pathways such as biosynthesis of unsaturated fatty acids, ether lipid metabolism, amino sugar and nucleotide sugar metabolism, glycerophospholipid metabolism, arachidonic acid metabolism and arginine and proline metabolism. The differentially expressed metabolites in HFrEF mice were mainly enriched in arginine and proline metabolism, glycine, serine and threonine metabolism, pantothenate and CoA biosynthesis, glycerophospholipid metabolism, nicotinate and nicotinamide metabolism and arachidonic acid metabolism, etc. Conclusions: HFpEF mice have a significantly different myocardial metabolite expression profile compared with HFrEF mice. In addition, biosynthesis of unsaturated fatty acids, arachidonic acid metabolism, glycerophospholipid metabolism and arginine and proline metabolism are significantly altered in both HFpEF and HFrEF mice, suggesting that these metabolic pathways may play an important role in disease progression in both types of heart failure.

Research progress on the expression of the RBM20 gene in dilated cardiomyopathy / 中国当代儿科杂志

Dilated cardiomyopathy (DCM) is a significant contributor to heart failure and can lead to life-threatening cardiovascular events at any stage. RNA-binding motif protein 20 (RBM20) gene mutation is known to be one of the causes of DCM. This mutation exhibits familial aggregation and is associated with arrhythmias, increasing the risk of sudden and early death. This article delves into the characteristics of the RBM20 gene, highlighting its role in regulating alternative splicing of the TTN gene and calcium/calmodulin-dependent protein kinase type II gene. Furthermore, the article provides a summary of treatment options available for DCM caused by RBM20 gene mutations, aiming to enhance clinicians' understanding of the RBM20 gene and provide new ideas for precision medicine treatment.

Effect and mechanism of Jiming Powder on myocardial fibrosis in mice with myocardial infarction / 中国中药杂志

Jiming Powder is a traditional ancient prescription with good therapeutic effect in the treatment of heart failure, but its mechanism lacks further exploration. In this study, a mouse model of coronary artery ligation was used to evaluate the effect and mechanism of Jiming Powder on myocardial fibrosis in mice with myocardial infarction. The study constructed a mouse model of heart failure after myocardial infarction using the method of left anterior descending coronary artery ligation. The efficacy of Jiming Powder was evaluated from multiple angles, including ultrasound imaging, hematoxylin-eosin(HE) staining, Masson staining, Sirius Red staining, and serum myocardial enzyme spectrum detection. Western blot analysis was performed to detect key proteins involved in ventricular remodeling, including transforming growth factor-β1(TGF-β1), α-smooth muscle actin(α-SMA), wingless-type MMTV integration site family member 3a(Wnt3a), β-catenin, matrix metallopeptidase 2(MMP2), matrix metallopeptidase 3(MMP3), TIMP metallopeptidase inhibitor 1(TIMP1), and TIMP metallopeptidase inhibitor 2(TIMP2). The results showed that compared with the model group, the high and low-dose Jiming Powder significantly reduced the left ventricular internal diameter in systole(LVID;s) and diastole(LVID;d), increased the left ventricular ejection fraction(LVEF) and left ventricular fractional shortening(LVFS), effectively improved cardiac function in mice after myocardial infarction, and effectively reduced the levels of myocardial injury markers such as creatine kinase(CK), creatine kinase isoenzyme(CK-MB), and lactic dehydrogenase(LDH), thus protecting ischemic myocardium. HE staining showed that Jiming Powder could attenuate myocardial inflammatory cell infiltration after myocardial infarction. Masson and Sirius Red staining demonstrated that Jiming Powder effectively inhibited myocardial fibrosis, reduced the collagen Ⅰ/Ⅲ ratio in myocardial tissues, and improved collagen remodeling after myocardial infarction. Western blot results showed that Jiming Powder reduced the expression of TGF-β1, α-SMA, Wnt3a, and β-catenin, decreased the levels of MMP2, MMP3, and TIMP2, and increased the level of TIMP1, suggesting its role in inhibiting cardiac fibroblast transformation, reducing extracellular matrix metabolism in myocardial cells, and lowering collagen Ⅰ and α-SMA content, thus exerting an anti-myocardial fibrosis effect after myocardial infarction. This study revealed the role of Jiming Powder in improving ventricular remodeling and treating myocardial infarction, laying the foundation for further research on the pharmacological effect of Jiming Powder.

Mechanism of Jiming Powder in ameliorating heart failure with preserved ejection fraction based on metabolomics / 中国中药杂志

In this study, untargeted metabolomics was conducted using the liquid chromatography-tandem mass spectrometry(LC-MS/MS) technique to analyze the potential biomarkers in the plasma of mice with heart failure with preserved ejection fraction(HFpEF) induced by a high-fat diet(HFD) and nitric oxide synthase inhibitor(Nω-nitro-L-arginine methyl ester hydrochloride, L-NAME) and explore the pharmacological effects and mechanism of Jiming Powder in improving HFpEF. Male C57BL/6N mice aged eight weeks were randomly assigned to a control group, a model group, an empagliflozin(10 mg·kg~(-1)·d~(-1)) group, and high-and low-dose Jiming Powder(14.3 and 7.15 g·kg~(-1)·d~(-1)) groups. Mice in the control group were fed on a low-fat diet, and mice in the model group and groups with drug intervention were fed on a high-fat diet. All mice had free access to water, with water in the model group and Jiming Powder groups being supplemented with L-NAME(0.5 g·L~(-1)). Drugs were administered on the first day of modeling, and 15 weeks later, blood pressure and cardiac function of the mice in each group were measured. Heart tissues were collected for hematoxylin-eosin(HE) staining to observe pathological changes and Masson's staining to observe myocardial collagen deposition. Untargeted metabolomics analysis was performed on the plasma collected from mice in each group, and metabolic pathway analysis was conducted using MetaboAnalyst 5.0. The results showed that the blood pressure was significantly lower and the myocardial concentric hypertrophy and left ventricular diastolic dysfunction were significantly improved in both the high-dose and low-dose Jiming Powder groups as compared with those in the model group. HE and Masson staining showed that both high-dose and low-dose Jiming Powder significantly alleviated myocardial fibrosis. In the metabolomics experiment, 23 potential biomarkers were identified and eight strongly correlated metabolic pathways were enriched, including linoleic acid metabolism, histidine metabolism, alpha-linolenic acid metabolism, glycerophospholipid metabolism, purine metabolism, porphyrin and chlorophyll metabolism, arachidonic acid metabolism, and pyrimidine metabolism. The study confirmed the pharmacological effects of Jiming Powder in lowering blood pressure and ameliorating HFpEF and revealed the mechanism of Jiming Powder using the metabolomics technique, providing experimental evidence for the clinical application of Jiming Powder in treating HFpEF and a new perspective for advancing and developing TCM therapy for HFpEF.

Resection of the atrial appendages and its impact in the natriuretic homeostasis: development and validation of an animal model in an academic medical center

ABSTRACT Background: The left atrial appendage (LAAp) resection is an effective treatment approach to reduce the risk of thromboembolism in patients with atrial fibrillation. Objective: To study was to study the impact of removing atrial appendages in the production of natriuretic peptides (NPs) in conditions of volume overload and to develop an experimental model of LAAp resection. Materials and Methods: In a swine model of ischemic heart failure (HF), serum NP levels were measured before (Basal-1A) and after (Basal-1B) a fluid overload. Animals were grouped as follows: (0) preserved appendages, (1) resected LAAp, and (2) both atrial appendages resected. Levels of NP were measured before (2A) and after a fluid overload (2B). Results: Furin levels were higher in Group 0-2A than in Group 2-2A, and a significant increase was found in Group 0-2B compared to Groups 1-2B and 2-2B. Corin levels increased in Basal-1B versus Basal-1A. Atrial NP (ANP) decreased in Basal-1B compared to Basal-1A. After HF induction, ANP increased in Groups 2-2A and 2-2B. Conclusions: Resection of atrial appendages drastically modifies the natriuretic mechanisms of cardiac homeostasis, especially after a fluid overload challenge. Herein, we describe the face and predictive validation of an animal model of atrial appendage resection useful to investigations in translational medicine.

Beta-Blocker Type Effect on Substrate Oxidation during HIIE in Heart Failure Patients: Pilot Data / Efeito do Tipo Betabloqueador na Oxidação de Substratos durante HIIE em Pacientes com Insuficiência Cardíaca: Dados Piloto

Abstract The effect of third and second-generation type of beta-blocker on substrate oxidation especially during high-intensity exercises are scarce. The objective of the study is to explore differences of beta-blocker regimens (vasodilating vs. non-vasodilating beta-blockers) for substrate oxidation during in high-intensity intermittent exercise (HIIE) in chronic heart failure and reduced ejection fraction (HFrEF). Eighteen CHF males (58.8 ± 9 years), 8 under use of β1 specific beta-blockers+alfa 1-blocker and 10 using β1 non-specific beta-blockers, were randomly assigned to 4 different HIIE, in a cross-over design. The 4 protocols were: 30 seconds (A and B) or 90 seconds (C and D) at 100% peak power output, with passive (A and C) or active recovery (50% of PPO; B and D). Energy expenditure (EE; kcal/min), quantitative carbohydrate (CHO) and lipid oxidation (g/min) and qualitative (%) contribution were calculated. Two-way ANOVA and Bonferroni post-hoc test were used (p-value ≤ 0.05) to compare CHO and lipid oxidation at rest and at 10min. Total exercise time or EE did not show differences for beta-blocker use. The type of beta-blocker use showed impact in CHO (%) and lipid (g/min and %) for rest and 10 min, but absolute contribution of CHO (g/min) was different just at 10min (Interaction p = 0.029). Higher CHO oxidation was found in vasodilating beta-blockers when comparing to non-vasodilating. According to our pilot data, there is an effect of beta-blocker type on substrate oxidation during HIIE, but no influence on EE or exercise total time in HFrEF patients.

Resumo Os dados sobre efeito do tipo de betabloqueador de terceira e segunda geração na oxidação do substrato, especialmente durante exercícios de alta intensidade, são escassos. O objetivo do estudo é explorar as diferenças de tratamentos com betabloqueadores (betabloqueadores vasodilatadores vs. não-vasodilatadores) na oxidação de substratos durante exercícios intermitentes de alta intensidade (HIIE) na insuficiência cardíaca crônica e fração de ejeção do ventrículo esquerdo reduzida (ICFEr). Dezoito pacientes do sexo masculino com ICC (58,8 ± 9 anos), 8 em uso de betabloqueadores β1 específicos + bloqueador α-1 e 10 utilizando betabloqueadores β1 não-específicos, foram aleatoriamente designados para 4 diferentes HIIE, em um desenho cruzado. Os 4 protocolos foram: 30 segundos (A e B) ou 90 segundos (C e D) a 100% da potência de pico de saída (PPO), com recuperação passiva (A e C) ou ativa (50% de PPO; B e D). O gasto energético (GE; kcal/min), a ingestão de carboidratos quantitativos (CHO) e oxidação lipídica (g/min) e qualitativa (%) foram calculados. Anova de dois fatores e teste post-hoc de Bonferroni foram usados (p-valor ≤ 0,05) para comparar a oxidação de CHO e lipídios em repouso e aos 10 minutos. O tempo total de exercício ou GE não mostraram diferenças de acordo com o uso de betabloqueadores. O tipo de betabloqueador mostrou impacto em CHO (%) e lípides (g/min e %) para repouso e aos 10 min, mas a contribuição absoluta de CHO (g/min) foi diferente apenas aos 10 minutos (Interação p = 0,029). Foram encontradas maiores oxidações de CHO com betabloqueadores vasodilatadores quando comparados com os não-vasodilatadores. De acordo com nossos dados piloto, há um efeito do tipo do betabloqueador na oxidação do substrato durante o HIIE, mas nenhuma influência no GE ou no tempo total de exercício nos pacientes com ICFEr.

A practical approach to assess leg muscle oxygenation during ramp-incremental cycle ergometry in heart failure

Heart failure is characterized by the inability of the cardiovascular system to maintain oxygen (O2) delivery (i.e., muscle blood flow in non-hypoxemic patients) to meet O2 demands. The resulting increase in fractional O2 extraction can be non-invasively tracked by deoxygenated hemoglobin concentration (deoxi-Hb) as measured by near-infrared spectroscopy (NIRS). We aimed to establish a simplified approach to extract deoxi-Hb-based indices of impaired muscle O2 delivery during rapidly-incrementing exercise in heart failure. We continuously probed the right vastus lateralis muscle with continuous-wave NIRS during a ramp-incremental cardiopulmonary exercise test in 10 patients (left ventricular ejection fraction <35%) and 10 age-matched healthy males. Deoxi-Hb is reported as % of total response (onset to peak exercise) in relation to work rate. Patients showed lower maximum exercise capacity and O2 uptake-work rate than controls (P<0.05). The deoxi-Hb response profile as a function of work rate was S-shaped in all subjects, i.e., it presented three distinct phases. Increased muscle deoxygenation in patients compared to controls was demonstrated by: i) a steeper mid-exercise deoxi-Hb-work rate slope (2.2±1.3 vs 1.0±0.3% peak/W, respectively; P<0.05), and ii) late-exercise increase in deoxi-Hb, which contrasted with stable or decreasing deoxi-Hb in all controls. Steeper deoxi-Hb-work rate slope was associated with lower peak work rate in patients (r=-0.73; P=0.01). This simplified approach to deoxi-Hb interpretation might prove useful in clinical settings to quantify impairments in O2 delivery by NIRS during ramp-incremental exercise in individual heart failure patients.

Valoración de la composición corporal y su influencia pronóstica en insuficiencia cardiaca crónica. Más allá de la «paradoja de la obesidad¼ / Assessment of body composition and prognosis in chronic heart failure. Beyond the "obesity paradox"

Resumen Objetivo Se desconoce la influencia pronóstica que la composición corporal guarda en la relación inversa de la mortalidad con el sobrepeso y la obesidad en pacientes con insuficiencia cardiaca. Método Se evaluó a 234 pacientes ambulatorios con insuficiencia cardiaca. Se determinaron el índice de masa corporal, el pliegue tricipital, el perímetro muscular braquial y el porcentaje de grasa corporal evaluado mediante impedanciometría bioeléctrica. Se analizó la influencia sobre la mortalidad total de las variables antropométricas citadas. Resultados El seguimiento medio fue 21 ± 10.7 meses. Se observó una relación inversa de la mortalidad total con el índice de masa corporal (hazard ratio = 0.91; intervalo confianza del 95%, 0.87-0.96; p < 0.001), con la masa grasa estimada por el pliegue tricipital (hazard ratio = 0.95; intervalo confianza del 95%, 0.92-0.99; p = 0.013) y por el porcentaje graso obtenido mediante impedanciometría (hazard ratio = 0.96; intervalo confianza del 95%,0.93-0.99; p = 0.007) y con la masa muscular estimada mediante el perímetro muscular braquial (hazard ratio = 0.87; intervalo confianza del 95%, 0.81-0.94; p = 0.001). Solo el perímetro muscular braquial mantuvo su influencia pronóstica en el análisis multivariante que incluyó a las diferentes medidas antropométricas (hazard ratio = 0.88; intervalo confianza del 95%, 0.77-0.99; p = 0.035). Finalmente, se observó una correlación lineal positiva entre los valores del índice de masa corporal con los del pliegue tricipital, porcentaje graso y perímetro muscular braquial. Conclusiones La masa muscular del paciente con insuficiencia cardiaca, estimada mediante el perímetro muscular braquial, se asocia de manera inversa con la mortalidad global. La correlación de sus valores con los del índice de masa corporal explicaría la «paradoja de la obesidad¼ observada.

Abstract Objective It is unknown the influence of body composition in the inverse relationship of mortality with overweight and obesity in heart failure patients. Methods 234 patients with chronic heart failure were evaluated. Body mass index, tricipital skinfold thickness, brachial muscle circumference and body fat percentage determined by bioelectrical impedance analysis were measured. The influence of previous anthropometric variables on total mortality was analyzed. Results Mean follow-up was 21 ± 10.7 months. We observed an inverse relationship of total mortality with body mass index (hazard ratio = 0.91, 95% confidence interval, 0.87-0.96; P<.001), with body fat estimated by the tricipital skinfold thickness (hazard ratio = 0.95, 95% confidence interval, 0.92-0.99; P=.013) and the fat percentage obtained by bioelectrical impedance analysis (hazard ratio = 0.96; 95% confidence interval, 0.93-0.99; P=.007) and with muscle mass estimated by the brachial muscle circumference (hazard ratio = 0.87; 95% confidence interval,0.81-0.94; P=.001). Only brachial muscle circumference maintained its prognostic significance in multivariate analysis that included different anthropometric measurements (hazard ratio = 0.88, 95% confidence interval 0.77-0.99; P=.035). Finally we found a positive linear correlation between the values of body mass index with tricipital skinfold thickness, fat percentage and brachial muscle circumference. Conclusions The muscle mass of patients with heart failure, estimated by the brachial muscle circumference, is associated inversely with overall mortality. The correlation between values of brachial muscle circumference with the body mass index would explain the “obesity paradox” observed.

Biological significance of miR-126 expression in atrial fibrillation and heart failure

We investigated the biological significance of microRNA-126 (miR-126) expression in patients with atrial fibrillation (AF) and/or heart failure (HF) to examine the possible mechanism of miR-126-dependent AF and development of HF. A total of 103 patients were divided into three groups: AF group (18 men and 17 women, mean age: 65.62±12.72 years), HF group (17 men and 15 women, mean age: 63.95±19.71 years), and HF-AF group (20 men and 16 women, mean age: 66.56±14.37 years). Quantitative real-time PCR was used to measure relative miR-126 expression as calculated by the 2−ΔΔCt method. miR-126 was frequently downregulated in the 3 patient groups compared with controls. This reduction was significantly lower in permanent and persistent AF patients than in those with paroxysmal AF (P<0.05, t-test). Moreover, miR-126 expression was markedly lower in the HF-AF group compared with the AF and HF groups. The 3 patient groups had higher N-terminal prohormone brain natriuretic peptide (NT-proBNP) levels, lower left ventricular ejection fraction (LVEF), larger left atrial diameter, and higher cardiothoracic ratio compared with controls. There were significant differences in NT-proBNP levels and LVEF among the AF, HF, and HF-AF groups. Pearson correlation analysis showed that relative miR-126 expression was positively associated with LVEF, logarithm of NT-proBNP, left atrial diameter, cardiothoracic ratio, and age in HF-AF patients. Multiple linear regression analysis showed that miR-126 expression was positively correlated with LVEF, but negatively correlated with the logarithm of NT-pro BNP and the cardiothoracic ratio (all P<0.05). Serum miR-126 levels could serve as a potential candidate biomarker for evaluating the severity of AF and HF. However, to confirm these results, future studies with a larger and diverse patient population are necessary.

Influence of Spironolactone on Matrix Metalloproteinase-2 in Acute Decompensated Heart Failure / Influência da Espironolactona na Metaloproteinase de Matriz 2 na Insuficiência Cadíaca Aguda Descompensada

Background: Matrix metalloproteinases (MMPs) are a family of enzymes important for the resorption of extracellular matrices, control of vascular remodeling and repair. Increased activity of MMP2 has been demonstrated in heart failure, and in acutely decompensated heart failure (ADHF) a decrease in circulating MMPs has been demonstrated along with successful treatment. Objective: Our aim was to test the influence of spironolactone in MMP2 levels. Methods: Secondary analysis of a prospective, interventional study including 100 patients with ADHF. Fifty patients were non-randomly assigned to spironolactone (100 mg/day) plus standard ADHF therapy (spironolactone group) or standard ADHF therapy alone (control group). Results: Spironolactone group patients were younger and had lower creatinine and urea levels (all p < 0.05). Baseline MMP2, NT-pro BNP and weight did not differ between spironolactone and control groups. A trend towards a more pronounced decrease in MMP2 from baseline to day 3 was observed in the spironolactone group (-21 [-50 to 19] vs 1.5 [-26 to 38] ng/mL, p = 0.06). NT-pro BNP and weight also had a greater decrease in the spironolactone group. The proportion of patients with a decrease in MMP2 levels from baseline to day 3 was also likely to be greater in the spironolactone group (50% vs 66.7%), but without statistical significance. Correlations between MMP2, NT-pro BNP and weight variation were not statistically significant. Conclusion: MMP2 levels are increased in ADHF. Patients treated with spironolactone may have a greater reduction in MMP2 levels. .

Fundamento: As metaloproteinases de matriz (MMPs) constituem uma família de enzimas importantes para a reabsorção da matriz extracelular e controle do remodelamento e da reparação vasculares. Demonstrou-se aumento da atividade de MMP2 na insuficiência cardíaca, e, na insuficiência cardíaca agudamente descompensada (ICAD), demonstrou-se uma diminuição nas MMPs circulantes juntamente com o tratamento bem-sucedido. Objetivos: Testar a influência da espironolactona nos níveis de MMP2. Métodos: Análise secundária de estudo prospectivo, intervencionista, incluindo 100 pacientes com ICAD, 50 designados não aleatoriamente para o uso de espironolactona (100 mg/dia) mais terapia padrão para ICAD (grupo espironolactona) e 50 para terapia padrão para ICAD apenas (grupo controle). Resultados: Os pacientes do grupo espironolactona eram mais jovens e tinham níveis mais baixos de creatinina e ureia (todos p < 0,05). Os valores basais de MMP2, NT-pro BNP e peso não diferiram entre os grupos espironolactona e controle. Observou-se tendência para uma redução mais pronunciada na MMP2 do basal para o dia 3 no grupo espironolactona (-21 [-50 a 19] vs 1,5 [-26 a 38] ng/ml, p = 0,06). Os valores de NT-pro BNP e peso também apresentaram maior diminuição no grupo espironolactona. A proporção de pacientes com redução nos níveis de MMP2 do basal para o dia 3 também foi maior no grupo espironolactona (50% vs 66,7%), embora sem significado estatístico. As correlações entre as variações de MMP2, NT-pro BNP e peso não apresentaram significado estatístico. Conclusões: Os níveis de MMP2 acham-se aumentados na ICAD. Pacientes tratados com espironolactona podem apresentar maior redução nos níveis de MMP2. .

Changes in cardiac aldosterone and its synthase in rats with chronic heart failure: an intervention study of long-term treatment with recombinant human brain natriuretic peptide

The physiological mechanisms involved in isoproterenol (ISO)-induced chronic heart failure (CHF) are not fully understood. In this study, we investigated local changes in cardiac aldosterone and its synthase in rats with ISO-induced CHF, and evaluated the effects of treatment with recombinant human brain natriuretic peptide (rhBNP). Sprague-Dawley rats were divided into 4 different groups. Fifty rats received subcutaneous ISO injections to induce CHF and the control group (n=10) received equal volumes of saline. After establishing the rat model, 9 CHF rats received no further treatment, rats in the low-dose group (n=8) received 22.5 μg/kg rhBNP and those in the high-dose group (n=8) received 45 μg/kg rhBNP daily for 1 month. Cardiac function was assessed by echocardiographic and hemodynamic analysis. Collagen volume fraction (CVF) was determined. Plasma and myocardial aldosterone concentrations were determined using radioimmunoassay. Myocardial aldosterone synthase (CYP11B2) was detected by quantitative real-time PCR. Cardiac function was significantly lower in the CHF group than in the control group (P<0.01), whereas CVF, plasma and myocardial aldosterone, and CYP11B2 transcription were significantly higher than in the control group (P<0.05). Low and high doses of rhBNP significantly improved hemodynamics (P<0.01) and cardiac function (P<0.05) and reduced CVF, plasma and myocardial aldosterone, and CYP11B2 transcription (P<0.05). There were no significant differences between the rhBNP dose groups (P>0.05). Elevated cardiac aldosterone and upregulation of aldosterone synthase expression were detected in rats with ISO-induced CHF. Administration of rhBNP improved hemodynamics and ventricular remodeling and reduced myocardial fibrosis, possibly by downregulating CYP11B2 transcription and reducing myocardial aldosterone synthesis.

Increased cardiac endothelin-1 and nitric oxide in adriamycin-induced acute cardiotoxicity: Protective effect of Ginkgo biloba extract.

Cardiotoxicity and congestive heart failure are the major factors that limit the use of anti-neoplastic drug adriamycin (ADR). There is increasing experimental evidence that endothelin-1 (ET-1) and nitric oxide (NO) are vasoactive mediators that regulate cardiac performance. The present study was undertaken to investigate the role of ET-1 and NO in ADR-induced acute cardiotoxicity and to evaluate the protective effect of Ginkgo biloba extract (EGb761) in rats. A single dose of ADR (20 mg/kg i.p.) caused a significant increase in the cardiac enzyme activities of aspartate transaminases (AST), lactate dehydrogenase (LDH) and creatine phosphokinase isoenzyme (CK-MB) in the serum of animals. This was accompanied by significant increase in cardiac malondialdehyde (MDA), total antioxidant capacity (TAC), tumor necrosis factor-alpha (TNF-α), ET-1 and nitrite/nitrate (NOx) levels. On the other hand, reduced glutathione (GSH) was significantly depressed. Histopathological examination of heart tissues showed hyalinization of the myocardium, with interstitial edema and inflammatory exudates. Pre-treatment of the animals with EGb761 (100 mg/kg, orally) 10 days before and 5 days after ADR treatment reversed the cardiac enzyme levels to normal value, decreased cardiac MDA, TAC, TNF-α, ET-1 and NOx, increased GSH and reversed the histopathological damage induced by ADR. In conclusion, the cardioprotective effects of EGb761 on markers of ADR-induced acute cardiotoxicity appeared to have been mediated by the regulation of inflammatory and vasoactive mediators, as well as the inhibition of membrane lipid peroxidation. Thus, EGb761 may find use as promising adjuvant therapy to ameliorate cardiotoxicity of ADR.

The role and significance of microRNA in human cardiovascular disease and forensic science / 法医学杂志

microRNA (miRNA or miR) is a small single stranded non-coding RNA (21-25nt) that regulates gene expression in almost creatures. Currently, plenty of researches on how miRNA affects human cardiovascular disease have been reported. This review highlights recent findings about the role of miRNA in heart tissue and circulation correlated with human cardiovascular disease and explores the application of miRNA in sudden cardiac death in forensic science.

Actualidades farmacológicas en el tratamiento de la insuficienciacardiaca crónica / News in the pharmacological treatment of chronic heart failure

La insuficiencia cardiaca es, actualmente, una de las grandes epidemias del nuevo siglo. Durante las últimas dos décadas se ha incrementado de manera dramática y exponencial, ubicándose como la primera causa de morbimortalidad y hospitalización a nivel mundial hasta en un 159% y ocupando 10% de morbilidad en la población mexicana. Es por esto que en la actualidad se ha modificado drásticamente el rumbo del tratamiento farmacológico, dejando de lado la paliación de las complicaciones propias de la evolución del padecimiento, enfocándose hacia la identificación y ruptura de los eslabones más precisos que conforman la cadena de acontecimientos adaptativos fisiológicos desencadenados por la misma, los cuales, durante los últimos años, se ha demostrado que son causantes directos de la progresión patológica de la enfermedad y la exacerbación de un sistema de retroalimentación positivo que se magnifica a sí mismo. En la presente revisión se contemplan los diferentes mecanismos compensatorios de la insuficiencia cardiaca, como los objetivos directos del tratamiento farmacológico actual, partiendo de los archivos de la Revista Española de Cardiología y la Revista Mexicana de Medicina Interna. Con este nuevo enfoque se pretende aminorar la mortalidad y los índices de hospitalización de manera importante, y al mismo tiempo mejorar la calidad de vida de las personas que la padecen.

Heart failure is currently one of the great epidemics of the century, that during the past two decades has increased dramatically and exponentially, ranking as the leading cause of morbidity and hospitalization worldwide up to 159% and ranking 10% morbidity of the Mexican population. That’s why today has changed dramatically the course of drug treatment, palliation aside from the complications of the disease evolution, toward identifying and breaking most accurate links in the chain of events adaptative physiological triggered by it, which in recent years has proven to be the direct cause of pathological progression of the disease and the exacerbation of a positive feedback system is magnified himself. Thus, in this review referred to the various compensatory mechanisms of heart failure, such as direct targets of current drug treatment, starting from the archives of the Spanish Journal of Cardiology and internal Medicine Mexican Magazine. With this new approach seeks to reduce mortality and hospitalization rates significantly, while improving the quality of life of people who have it.

Gasto energético basal em idosos com insuficiência cardíaca / Resting energy expenditure in elderly patients with heart failure

Na insuficiência cardíaca descompensada há aumento de gasto energético basal e, frequentemente, redução do consumo alimentar, associado também ao envelhecimento. Assim, o objetivo foi verificar o consumo alimentar e o gasto energético basal em idosos com insuficiência cardíaca. Métodos: Estudo transversal com pacientes com insuficiência cardíaca congestiva descompensada, divididos em idosos (> ou igual 60 anos) e não idosos (< 60 anos). O consumo alimentar foi medido pelo método direto de pesagem e o gasto energético basal foi medido pela calorimetria indireta e foi comparado com a fórmula de Harris-Benedict. A relação entre o gasto energético basal medido pela calorimetria indireta e Harris-Benedict foi feita pelo método de Bland-Altman, p<0,05. Resultados: Foram estudados 55 pacientes, 12 idosos, 43 não idodos. A fração de ejeção nos idosos foi 26% (DP=11,45) e nos adultos de 25,2% (DP=11,2%). O gasto energético basal pela calorimetria indireta foi de 1.165 (DP=447)kcal para os idosos e 1.367(DP=532)kcal para os adultos (p=0,236). Por Harris-Benedict, o gasto enerético basal foi de 1.248 (DO=160)kcal para os idosos e de 1.372 (DP=169)kcal para os adultos (p=0,028). O consumo alimentar dos idosos foi de 1.916(DP=643)kcal e dos adultos foi de 1.910(DP=638)kcal. Houve concordância entre o gasto energético basal pela calorimetria indireta e Harris-Benedict (p=0,001;R=0,435). Conclusão: O consumo alimentar e o gasto energético basal dos idosos foram semelhantes aos dos não idosos, Houve concordância e uma correlação positiva entre a calorimetria indireta e a fórmula de Harris-Benedict.

In decompensate heart failure there is an increased resting energy expenditure and often a reduction in food intake, also associated with aging. The objective was to assess food intake and resting energy expenditure in elderly patients with heart failure. Methods: This was a cross-sectional study of patients with decompensate congestive heart failure and were divided into elderly (> ou igual 60 years) and nonelderly (< 60 years). Food intake was measured by the direct method of weighing and resting enegy expenditure was measured by indirect calorimetry and was compared with the Harris-Bendict formula. The relationship between resting energy expenditure measured by indirect calorimetry and Harris-Benedict was made by a Band-Altman, p<0,05. Results: We studied 55 patients, 12 elderly, 43 nonelderly. The ejection fraction in elderly patients was 26% (SD=11,4%) of adults and 25,2%(SD==11,2%). The resting energy expenditure by indirect calorimetry was 1.165(SD=447)kcal for the elderly and 1.372(SD=532)kcal for adults(p=0,236). For the Harris-Benedict resting energy expenditure was 1.248(SD=160)kcal for the elderly and 1.372(SD=169)kcal for adults(p=0,028). The food intake of elderly was 1.916(SD=643)kcal and adults was 1.910(SD=638)kcal. There was agreement between resting energy expenditure by indirect calorimetry and Harris-Benedict (p=0,001,R=0,435). Conclusions: Dietary intake and resting expenditure of the elderly were similar to those of non-elderly. There was agreement and a positive correlation between indirect clorimetry and the Harris-Benedict formula.

Microalbuminúria é um marcador prognóstico independente em pacientes com insuficiência cardíaca crônica / Microalbuminuria is an independent prognostic marker in patients with chronic heart failure / Microalbuminuria es un marcador pronóstico independiente en pacientes con insuficiencia cardíaca crónica

FUNDAMENTO: A microalbuminúria tem sido descrita como um fator de risco para doenças cardiovasculares e renais progressivas. Pouco se sabe sobre seu valor prognóstico em pacientes (pts) com Insuficiência Cardíaca (IC) estabelecida. OBJETIVO: Avaliar o papel da microalbuminúria como um marcador de prognóstico em pacientes com IC crônica recebendo medicação padrão. MÉTODOS: De janeiro de 2008 até setembro de 2009, 92 pacientes com IC crônica foram prospectivamente incluídos. A idade média foi de 63,7 ± 12,2 e 37 (40,7 por cento) eram do sexo masculino. A média de fração de ejeção do ventrículo esquerdo (FEVE) foi de 52,5 ± 17,5 por cento. Pacientes em diálise foram excluídos. A Concentração de Albumina Urinária (CAU) foi determinada em primeira amostra de urina da manhã. O tempo decorrido até o primeiro evento (internação por IC, consulta no departamento de emergência por IC ou morte cardiovascular) foi definido como endpoint. O seguimento médio foi de 11 ± 6,1 meses. RESULTADOS: No momento da inclusão no estudo, 38 (41,3 por cento) pacientes tinham microalbuminúria e nenhum paciente teve albuminúria evidente. Pacientes com microalbuminúria apresentaram menor fração de ejeção ventricular esquerda do que o restante dos indivíduos (47,9 ± 18,5 vs. 54,5 ± 17,7 por cento, p = 0,08). A CAU apresentou-se maior em pacientes com eventos (mediana 59,8 vs. 18 mg/L, p = 0,0005). Sobrevida livre de eventos foi menor nos pacientes com microalbuminúria quando comparados com albuminúria normal (p < 0,0001). As variáveis independentes relacionadas a eventos cardíacos foram CAU (taxa de risco p < 0,0001 = 1,02, 95 por cento CI = 1,01-1,03 por 1-U aumento da CAU), e histórico de infarto do miocárdio (p = 0,025, IC = 3,11, 95 por cento IC = 1,15-8,41). CONCLUSÃO: A microalbuminúria é um marcador prognóstico independente em pacientes com IC crônica. Pacientes com microalbuminúria tinham tendência para FEVE inferior.

BACKGROUND: Microalbuminuria has been described as a risk factor for progressive cardiovascular and renal diseases. Little is known about its prognostic value in patients (pts) with established heart failure (HF). OBJECTIVE: To assess the role of microalbuminuria as a prognostic marker in patients with chronic HF receiving standard medication. METHODS: From January 2008 through September 2009, 92 pts with chronic HF, were prospectively included. Mean age was 63.7±12.2 and 37 (40.7 percent) were male. Mean left ventricular ejection fraction (LVEF) was 52.5±17.5 percent. Pts under dialysis were excluded. Urinary albumin concentration (UAC) was determined in first morning spot sample of urine. Time to first event (HF hospitalization, emergency department visit for HF or cardiovascular death) was defined as endpoint. Mean follow-up was 11±6.1 months. RESULTS: At the time of inclusion in the study, 38 (41.3 percent) pts had microalbuminuria and no patient had overt albuminuria. Pts with microalbuminuria had lower left ventricular ejection fraction than the rest of the individuals (47.9±18.5 vs 54.5±17.7 percent, p=0.08). UAC was higher in patients with events (median 59.8 vs 18 mg/L, p=0.0005). Event-free survival was lower in pts with microalbuminuria as compared with normoalbuminuria (p<0.0001). Independent variables related to cardiac events were UAC (p<0.0001, hazard ratio=1.02, 95 percent CI=1.01 to 1.03 per 1-U increase of UAC), and previous myocardial infarction (p=0.025, HR=3.11, 95 percent CI=1.15 to 8.41). CONCLUSION: Microalbuminuria is an independent prognostic marker in pts with chronic HF. Pts with microalbuminuria had a trend for lower LVEF.

FUNDAMENTO: La microalbuminuria ha sido descripta como un factor de riesgo para enfermedades cardiovasculares y renales progresivas. Poco se sabe sobre su valor pronóstico en pacientes (pts) con Insuficiencia Cardíaca (IC) establecida. OBJETIVOS: Evaluar el papel de la microalbuminuria como un marcador de pronóstico en pacientes con IC crónica recibiendo medicación estándar. MÉTODOS: De enero de 2008 hasta setiembre de 2009, 92 pacientes con IC crónica fueron prospectivamente incluidos. La edad media fue de 63,7 ± 12,2 y 37 (40,7 por ciento) eran del sexo masculino. La media de fracción de eyección del ventrículo izquierdo (FEVI) fue de 52,5 ± 17,5 por ciento. Pacientes en diálisis fueron excluidos. La Concentración de Albúmina Urinaria (CAU) fue determinada en primera muestra de orina de la mañana. El tiempo transcurrido hasta el primer evento (internación por IC, consulta en el departamento de emergencia por IC o muerte cardiovascular) fue definido como endpoint. El seguimiento medio fue de 11 ± 6,1 meses. RESULTADOS: En el momento de la inclusión en el estudio, 38 (41,3 por ciento) pacientes tenían microalbuminuria y ningún paciente tuvo albuminuria evidente. Pacientes con microalbuminuria presentaron menor fracción de eyección ventricular izquierda que el resto de los individuos (47,9 ± 18,5 vs. 54,5 ± 17,7 por ciento, p = 0,08). La CAU presentó mayor en pacientes con eventos (mediana 59,8 vs. 18 mg/L, p = 0,0005). La sobrevida libre de eventos fue menor en los pacientes con microalbuminuria cuando fueron comparados con albuminuria normal (p < 0,0001). Las variables independientes relacionadas a eventos cardíacos fueron CAU (tasa de riesgo p < 0,0001 = 1,02, 95 por ciento CI = 1,01-1,03 por 1-U aumento de la CAU), e historia de infarto de miocardio (p = 0,025, IC = 3,11, 95 por ciento IC = 1,15-8,41). CONCLUSIÓN: La microalbuminuria es un marcador pronóstico independiente en pacientes con IC crónica. Pacientes con microalbuminuria tenían tendencia a FEVI inferior.

Comportamento dos quimiorreflexos central e periférico na insuficiência cardíaca / Behavior of central and peripheral chemoreflexes in heart failure / Comportamiento de los quimiorreflejos central y periférico en la insuficiencia cardíaca

A síndrome da insuficiência cardíaca (IC) pode ser definida como via final de qualquer forma de doença cardíaca. Os reflexos cardiovasculares simpatoinibitórios como o reflexo arterial barorreceptor estão significativamente suprimidos na IC. Pacientes com IC apresentam maior ventilação para determinada carga de trabalho quando comparados a indivíduos normais. Esse fato gera baixa eficiência ventilatória e relaciona-se com maior ventilação relativa à produção de gás carbônico, que é um preditor de mau prognóstico, além de ser um fator limitante ao exercício. Há evidências de que o desequilíbrio autonômico contribua para a patogênese e a progressão da insuficiência cardíaca. Os quimiorreflexos são os principais mecanismos de controle e regulação das respostas ventilatórias às mudanças de concentração do oxigênio e gás carbônico arterial. A ativação do quimiorreflexo causa aumento da atividade simpática, frequência cardíaca, pressão arterial e volume minuto. No entanto, o aumento do volume minuto e da pressão arterial, pelo feedback negativo provocam inibição da resposta simpática à ativação do quimiorreflexo. Apesar das alterações funcionais dos reflexos, seu comportamento em condições normais e patológicas, especialmente sua contribuição para o estado simpatoexcitatório encontrado na IC, não tem sido amplamente estudado. Dessa forma, esta revisão tem por objetivo integrar os conhecimentos a respeito dos quimiorreflexos central e periférico na síndrome da insuficiência cardíaca, bem como esclarecer a influência da terapêutica medicamentosa da insuficiência cardíaca nos quimiorreflexos.

The heart failure (HF) syndrome can be defined as the final pathway of any type of heart disease. The sympatho-inhibitory cardiovascular reflexes, such as the arterial baroreceptor reflex, are significantly decreased in HF. Patients with HF present higher ventilation for a certain workload when compared with normal individuals. This fact generates low ventilatory efficiency and is related to higher ventilation associated with the carbon dioxide production, which is a predictor of bad prognosis, in addition to being a limiting factor for the practice of exercises. There is evidence that the autonomic imbalance contributes to the pathogenesis and the progression of heart failure. The chemoreflexes are the main mechanisms of control and regulation of the ventilatory responses to the changes in concentrations of arterial oxygen and carbon dioxide. The chemoreflex activation causes an increase in the sympathetic activity, heart rate, arterial pressure and minute volume. However, the increase in the minute volume and the arterial pressure, due to negative feedback, cause inhibition of the sympathetic response at the chemoreflex activation. In spite of the functional alterations of the reflexes, their behavior in normal and pathological conditions, especially their contribution to the sympathoexcitatory state observed in HF has not been broadly studied. Therefore, this review aims at integrating the knowledge on central and peripheral chemoreflexes in HF syndrome, as well as clarifying the influence of the heart failure drug therapy on the chemoreflexes.

El síndrome de insuficiencia cardíaca (IC) puede ser definido como vía final de cualquier forma de enfermedad cardíaca. Los reflejos cardiovasculares simpáticoinhibitorios como el reflejo arterial barorreceptor están significativamente suprimidos en la IC. Pacientes con IC presentan mayor ventilación para determinada carga de trabajo cuando son comparados a individuos normales. Ese hecho genera baja eficiencia ventilatoria y se relaciona con mayor ventilación relativa a la producción de gas carbónico, que es un predictor de mal pronóstico, además de ser un factor limitante del ejercicio. Hay evidencias de que el desequilibrio autonómico contribuya a la patogénesis y la progresión de la insuficiencia cardíaca. Los quimiorreflejos son los principales mecanismos de control y regulación de las respuestas ventilatorias a los cambios de concentración del oxígeno y gas carbónico arterial. La activación del quimiorreflejo causa aumento de la actividad simpática, frecuencia cardíaca, presión arterial y volumen minuto. Mientras tanto, el aumento del volumen minuto y de la presión arterial, por el feedback negativo provocan inhibición de la respuesta simpática a la activación del quimiorreflejo. A pesar de las alteraciones funcionales de los reflejos, su comportamiento en condiciones normales y patológicas, especialmente su contribución al estado simpáticoexcitatorio encontrado en la IC, no ha sido ampliamente estudiado. De esa forma, esta revisión tiene por objetivo integrar los conocimientos respecto a los quimiorreflejos central y periférico en el síndrome de insuficiencia cardíaca, así como aclarar la influencia de la terapéutica medicamentosa de la insuficiencia cardíaca en los quimiorreflejos.

Determinaciones de niveles de creatina y lípidos mediante espectroscopia por resonancia magnética en miocardio de pacientes con insuficiencia cardiaca no isquémica / Myocardial lipids and creatine measured by magnetic resonance spectroscopy among patients with heart failure

Background: Heart failure (HF) is characterized, among other features, by the development of alterations in myocardial energy metabolism, involving a decrease in glucose utilization and increased free fatty acid uptake by cardiomyocytes, associated with decreased deposits of high-energy phosphates (creatine phosphate/ creatine transporter). Magnetic resonance (MR) imaging allows a direct and noninvasive assessment of myocardial metabolites. Aim: To measure myocardial creatine and lipids by MR spectroscopy among patients with HF. Material and Methods: Cardiac MR spectroscopy (1.5 Tesla) with Hydrogen antenna and single voxel acquisition was performed in fve patients with non-ischemic heart failure, aged 58 ± 9.7 years, (60 percent males) and 5 healthy volunteers matched for age and sex. We analyzed the signals of creatine (Cr), lipids (L) and water (W) in the interventricular septum, establishing the water/lipid (W/L) and water/creatine (W/Cr) index to normalize the values obtained. Results: Among patients, left ventricular ejection fraction was 32 ± 6.9 percent, 60 percent were in functional capacity II, 60 percent had hypertension and one was diabetic. Spectroscopic curves showed a depletion of total Cr, evidenced by the W/ Cr index, among patients with heart failure, when compared with healthy controls (1.46 ± 1.21 and 5.96 ± 2.25 respectively, p < 0,05). Differences in myocardial lipid content, measured as the W/L index, were not significant (5.06 ± 2.66 and 1.80 ± 1.62 respectively, p = 0.08). Conclusions: Among patients with heart failure of non-ischemic etiology, there is a depletion of creatine levels measured by MR spectroscopy.