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Despite currently available treatments, risk of death and hospitalizations in patients with heart failure with reduced ejection fraction (HFrEF) remains high. The pathophysiology of HFrEF includes neurohormonal activation characterized by stimulation of deleterious pathways (i.e., sympathetic nervous and renin-angiotensin-aldosterone systems) and suppression of pro-tective pathways such as nitric oxide-dependent pathways. Inhibition or stimulation of some, but not all, of these pathways is insufficient. In HFrEF, there is reduced nitric oxide, soluble guanylate cyclase, and cGMP activity, leading to deleterious effects in the myocardial, vascu-lar, and renal systems. Vericiguat is able to stimulate the activity of this protective pathway. The VICTORIA study demonstrated that the addition of vericiguat to optimal medical treatment in patients with HFrEF and recent decompensation significantly reduced the incidence of the primary endpoint, a composite of cardiovascular death or HF hospitalization, with a number needed to treat of 24 patients and excellent tolerability.

Advanced heart failure; Inotropes; Palliative care Insuficiencia cardiaca avanzada; Inotropos; Cuidados paliativos Insuficiència cardíaca avançada; Inòtrops; Cures pal·liatives Aim Patients with advanced heart failure (AHF) who are not candidates to advanced therapies have poor prognosis. Some trials have shown that intermittent levosimendan can reduce HF hospitalizations in AHF in the short term. In this real-life registry, we describe the patterns of use, safety and factors related to the response to intermittent levosimendan infusions in AHF patients not candidates to advanced therapies. Methods and results Multicentre retrospective study of patients diagnosed with advanced heart failure, not HT or LVAD candidates. Patients needed to be on the optimal medical therapy according to their treating physician. Patients with de novo heart failure or who underwent any procedure that could improve prognosis were not included in the registry. Four hundred three patients were included; 77.9% needed at least one admission the year before levosimendan was first administered because of heart failure. Death rate at 1 year was 26.8% and median survival was 24.7 [95% CI: 20.4–26.9] months, and 43.7% of patients fulfilled the criteria for being considered a responder lo levosimendan (no death, heart failure admission or unplanned HF visit at 1 year after first levosimendan administration). Compared with the year before there was a significant reduction in HF admissions (38.7% vs. 77.9%; P < 0.0001), unplanned HF visits (22.7% vs. 43.7%; P < 0.0001) or the combined event including deaths (56.3% vs. 81.4%; P < 0.0001) during the year after. We created a score that helps predicting the responder status at 1 year after levosimendan, resulting in a score summatory of five variables: TEER (+2), treatment with beta-blockers (+1.5), Haemoglobin >12 g/dL (+1.5), amiodarone use (−1.5) HF visit 1 year before levosimendan (−1.5) and heart rate >70 b.p.m. (−2). Patients with a score less than −1 had a very low probability of response (21.5% free of death or HF event at 1 year) meanwhile those with a score over 1.5 had the better chance of response (68.4% free of death or HF event at 1 year). LEVO-D score performed well in the ROC analysis. Conclusion In this large real-life series of AHF patients treated with levosimendan as destination therapy, we show a significant decrease of heart failure events during the year after the first administration. The simple LEVO-D Score could be of help when deciding about futile therapy in this population.

Background: Patients hospitalized for acute heart failure experience poor health status, including a high burden of symptoms and physical limitations, and poor quality of life. SGLT2 (sodium-glucose cotransporter 2) inhibitors improve health status in chronic heart failure, but their effect on these outcomes in acute heart failure is not well characterized. We investigated the effects of the SGLT2 inhibitor empagliflozin on symptoms, physical limitations, and quality of life, using the Kansas City Cardiomyopathy Questionnaire (KCCQ) in the EMPULSE trial (Empagliflozin in Patients Hospitalized With Acute Heart Failure Who Have Been Stabilized). Methods: Patients hospitalized for acute heart failure were randomized to empagliflozin 10 mg daily or placebo for 90 days. The KCCQ was assessed at randomization and 15, 30, and 90 days. The effects of empagliflozin on the primary end point of clinical benefit (hierarchical composite of all-cause death, heart failure events, and a 5-point or greater difference in KCCQ Total Symptom Score [TSS] change from baseline to 90 days) were examined post hoc across the tertiles of baseline KCCQ-TSS. In prespecified analyses, changes (randomization to day 90) in KCCQ domains, including TSS, physical limitations, quality of life, clinical summary, and overall summary scores were evaluated using a repeated measures model. Results: In total, 530 patients were randomized (265 each arm). Baseline KCCQ-TSS was low overall (mean [SD], 40.8 [24.0] points). Empagliflozin-treated patients experienced greater clinical benefit across the range of KCCQ-TSS, with no treatment effect heterogeneity (win ratio [95% CIs] from lowest to highest tertile: 1.49 [1.01–2.20], 1.37 [0.94–1.99], and 1.48 [1.00–2.20], respectively; P for interaction=0.94). Beneficial effects of empagliflozin on health status were observed as early as 15 days and persisted through 90 days, at which point empagliflozin-treated patients experienced a greater improvement in KCCQ TSS, physical limitations, quality of life, clinical summary, and overall summary (placebo-adjusted mean differences [95% CI]: 4.45 [95% CI, 0.32–8.59], P =0.03; 4.80 [95% CI, 0.00–9.61], P =0.05; 4.66 [95% CI, 0.32–9.01], P =0.04; 4.85 [95% CI, 0.77–8.92], P =0.02; and 4.40 points [95% CI, 0.33–8.48], P =0.03, respectively). Conclusions: Initiation of empagliflozin in patients hospitalized for acute heart failure produced clinical benefit regardless of the degree of symptomatic impairment at baseline, and improved symptoms, physical limitations, and quality of life, with benefits seen as early as 15 days and maintained through 90 days. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT0415775.

Orientador: Stephen Hyslop Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas Resumo: As peçonhas do gênero bothrops causam hipotensão, no entanto as alterações cardíacas e hemodinâmicas, associadas com este fenômeno não têm sido bem investigadas. Neste estudo, analisamos as alterações cardiovasculares causadas pela peçonha de Bothrops alternatus (urutu) em cães e, avaliamos a cardiotoxicidade desta peçonha em átrio direito isolado de rato. Em cães anestesiados com isoflurano, a peçonha (0,3 mg/kg, i.iv.) causou hipotensão imediata atingindo o ápice aos 5 minutos, seguida por uma lenta recuperação para níveis não significativamente diferentes do basal após 2h. Não foi observada recuperação no grupo tratado com a dose de 1,0 mg/kg. A hipotensão foi acompanhada por uma queda abrupta do débito cardíaco, dos trabalhos tanto do ventrículo direito quanto do esquerdo, bem como do volume e índice sistólico, os quais permaneceram reduzidos até o final do experimento. Não ocorreu alteração significativa na freqüência cardíaca, no ECG, nos valores pressóricos pulmonares, nos níveis dos gases sanguíneos (pO2, pCO2, HCO3, SBCe e SBEc), e nem nos parâmetros metabólicos (pH, lactato, glicose e creatinoquinase), porém, foi observado um aumento significativo nos níveis de lactato desidrogenase logo no início do envenenamento. Nenhuma alteração histológica no tecido cardíaco foi observada, no entanto, observou-se microaneurismas e alguma descamação epitelial nos túbulos renais. Houve uma diminuição rápida da peçonha circulante, após a administração i.v., que ainda foi detectada aos 240 minutos. A peçonha de B. alternatus (0,5; 1,0 e 2,0 mg/ml) não alterou a frequência atrial, mas reduziu significativamente a força contrátil (redução máxima de ~76%) e aumentou acentuadamente a liberação de creatinoquinase (CK) e creatinoqunase - MB (CK-MB). A análise histopatológica mostrou extensa mionecrose dos cardiomiócitos. A peçonha dialisada (1,0 mg/ml, membrana de 2000 Da) contra NaCl 0,9 % (24h a 4 °C) não alterou a redução progressiva na força contrátil, enquanto que o aquecimento (100 °C, 20 min) aboliu esta redução; A liberação de CK e CK-MB não foi alterada pela diálise e pelo aquecimento. A atropina, o atenolol e propranol, a cimetidina ou a indometacina não alteraram a força contrátil atrial, no entanto o L-NAME - inibidor da NOS, atenuou a redução na contratilidade, sugerindo um possível envolvimento do NO na resposta induzida pela peçonha. Estes resultados mostram que em cães, a peçonha de B. alternatus produziu acentuadas alterações cardiovasculares, envolvendo uma ação cardíaca direta, com poucas alterações metabólicas. A peçonha é também tóxica para átrio isolado de rato, provavelmente em função dos efeitos proteolíticos e/ou de PLA2. Abstract: Bothrops snake venoms cause hypotension, but the hemodynamic and cardiac alterations associated with this phenomenon have not been extensively investigated. In this study, we examined the cardiovascular changes caused by Bothrops alternatus (urutu) venom in anesthetized dogs and examined the cardiotoxicity of the venom in rat isolated rat atria. In isofluorane-anesthetized dogs, venom (0.3 mg/kg, i.v.) caused immediate hypotension that was maximal within 5 min followed by a slow recovery to levels not significantly different from pre-venom values after 2 h; no recovery was seen with a venom dose of 1 mg/kg. The hypotension was accompanied by an abrupt decrease in cardiac output, left and right ventricular systolic work, and systolic indices and volume that persisted without recovery until the end of the experiment. There were no significant changes in heart rate, ECG, pulmonary hemodynamics, blood gas levels (pO2, pCO2, HCO3, SBCe and SBEc) and metabolic parameters (blood pH, lactate, glucose and creatine kinase); however, a slight, significant increase in lactate dehydrogenase was seen soon after venom. There were no histological alterations in cardiac tissue, but microaneurysms and epithelial desquamation were seen in renal tubules. Circulating venom decreased rapidly after i.v. administration, but was still detectable after 240 min. Venom (0.5, 1.0 and 2.0 mg/ml) did not affect the beating rate of rat isolated right atria but significantly reduced the contractile force (maximal reduction of ~76%) and markedly increased the release of creatine kinase (CK) and CK-MB. Histological analysis revealed extensive myonecrosis. Venom dialysis (1.0 mg/ml; membrane nominal MW cut-off = 2000 Da) against 0.9% NaCl (24 h, 4°C) did not affect the decrease in contractile force whereas heating (100°C, 20 min) abolished the venom-induced reduction; CK and CK-MB release was also unaltered by dialysis but attenuated by heating. The decrease in atrial contractility was unaffected by atropine, atenolol, propranolol, cimetidine or indomethacin, but was attenuated by L-NAME, an inhibitor of nitric oxide synthase, indicating a possible role for nitric oxide in the venom-induced response. These results show that in dogs B. alternatus produces marked cardiovascular alterations involving a direct cardiac action, with little role for metabolic changes. The venom is also toxic to rat atria, probably as a result of venom proteolytic and/or phospholipase A2 activity. Doutorado Farmacologia Doutor em Farmacologia

Orientador: Stephen Hyslop Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas Resumo: O envenenamento por serpentes do gênero Bothrops resulta em alterações sistêmicas que incluem coagulopatia, hemorragia sistêmica, choque hipovolêmico e insuficiência renal aguda. Neste estudo investigamos a ação de da peçonha de B. jararacussu e suas frações cromatográficas sobre alguns parâmetros cardiovasculares (pressão arterial, freqüências cardíaca e respiratória, e eletrocardiograma) em ratos anestesiados com uretana. Ratos Wistar (300-400 g) foram canulados na arteria carótida esquerda para monitoramento contínuo da pressão arterial sistêmica e na veia femoral para administração das peçonhas e frações cromatográficas. A freqüência cardíaca e o ECG foram monitorados por um eletrocardiógrafo. No final do experimento, coração, rins, fígado e pulmão foram processados para avaliação histológica. Os ratos foram monitorados durante 120 min. Para análise histológica, foram coletados amostras de coração, pulmão, rim e fígado. A peçonha (0.25, 0.5 and 0.75 mg/kg, i.v.) casou queda acentuada da pressão arterial nos até os 5 minutos após administração das peçonhas, tendo recuperação para valores de níveis basais nas doses menores, e a dose maior não houve recuperação. As doses menores não causaram alterações nas freqüências cardíacas e respiratórias, porem a dose maior causou queda irreversivel destes parâmetros. Alterações transitórias vistas no ECG foram extra sístole, taquicardia ventricular e alteração na amplitude do complexo QRS. Ratos injetados com a menor dose sobreviveram durante os 120 minutos monitorados no experimento, já os injetados com a maior dose morreram com aproximadamente 15 minutos após a administração da peçonha. A gel filtração resultou em 5 picos (PI-PV), sendo que a administração dos 2 primeiros picos mostraram alterações semelhantes a peçonha bruta. O fracionamento do pico I por troca iônica, não resultou em alterações cardiovasculares,pois provavelmente eles agem em sinergismo. Similarmente, a Bothropstoxina isolada do pico III não causou alterações. Analise histológica mostraram alterações em órgãos, principalmente em pulmões. Adicionalmente,foi visualizado mionecrose, edema e infiltrado inflamatório no coração, perda da arquitetura tecidual no fígado, e microaneurismas capilares, presença de proteína na luz tubular, e infiltrado inflamatório nos rins. Os picos I, II e III mostraram alterações similares a peçonha bruta. Estes resultados mostram que as peçonhas botrópicas produzem alterações cardiovasculares importantes, alem de alterações morfológicas em diversos órgãos. A predominância de hemorragia e presença de atividade hemorrágica nos picos I, II e III indicam a presença de diversas proteínas hemorrágicas nesta peçonha. Abstract: Envenoming by Bothrops snakes results in systemic alterations that include coagulopathy, internal hemorrhage, hypovolemic shock and acute renal failure. In this work, we investigated the action of Bothrops jararacussu snake venom and its chromatographic fractions on arterial blood pressure, heart and respiratory rates, and electrocardiogram in urethane-anesthetized male Wistar rats. The rats were cannulated for blood pressure measurements (carotid artery) and the injection of venom or fraction (femoral vein). The heart rate and electrocardiogram (ECG) were measured with an ECG recorder. At the end of the experiments, samples of heart, liver, lung and kidney were processed for histological analysis. Venom (0.25, 0.5 and 0.75 mg/kg, i.v.) caused immediate hypotension that lasted for 5 min followed by a gradual recovery to pre-venom levels with the two lowest doses, whereas there was no recovery with the highest dose. The two lowest doses did not significantly affect the heart rate or respiratory rate, but these parameters were depressed with the highest dose. Transient changes in the ECG seen during the first 5 min included ventricular extrasystoles, ventricular tachycardia and alterations in the QRS complex amplitude. Rats injected with the two lowest doses survived for 120 min post-venom, whereas with the highest dose the survival time was 15 min at the most. Gel filtration (Sephacryl 75) of venom resulted in five peaks (PI - PIV), the first two of which produced cardiovascular alterations similar to those of the venom. Fractionation of PI resulted in two major peaks, neither of which produced significant cardiovascular alterations, perhaps because they normally act in synergy. Similarly, a PLA2 (bothropstoxin) isolated from peak PIII did not alter the parameters investigated. Histological analysis revealed hemorrhage in the organs examined, particularly the lungs. In addition, there were focal lesions in hepatic and renal tissue, as well as renal epithelial desquamation, glomerular microaneurysms, an increase in the capsular space and the presence of protein-like material in the lumen of proximal and distal tubules. Peaks PI, PII and PIII produced histological alterations similar to those of the venom. These results show that B. jararacussu venom causes important cardiovascular changes in anesthetized rats, in addition to morphological alterations in a variety of organs. The predominance of hemorrhage and the presence of hemorrhagic activity in peaks PI - PIII indicate the presence of a variety of hemorrhagic proteins in this venom. Mestrado Farmacologia Mestre em Farmacologia

Orientador: Profa Dra Eunice André Dissertação (mestrado) - Universidade Federal do Paraná, Setor de Ciências Biológicas, Programa de Pós-Graduação em Farmacologia. Defesa : Curitiba, 16/04/2021 Inclui referências: p. 61-73 Resumo: As estatinas são as principais classes de fármacos para a prevenção primária e secundária de doenças cardiovasculares. Baseado nisso é de extrema importância o conhecimento dos efeitos adversos relacionados ao uso desse fármaco. Tosse seca tem sido relatada em pacientes que recebem terapia com estatinas; no entanto, o mecanismo deste efeito adverso é desconhecido. O objetivo deste estudo foi analisar o papel do óxido nítrico (NO), do receptor B2 de bradicinina e TRPV1 nas alterações das vias aéreas induzidas pela sinvastatina em ratos. Usando métodos para detectar alterações na resistência das vias aéreas e extravasamento plasmático, nós demonstramos que a sinvastatina (20 mg/kg, intravenoso, i.v.) causou extravasamento plasmático na traqueia (79,8 ± 14,8 ug/g) e brônquios (73,3 ± 8,8 ug/g) de ratos, comparado aos veículos (34,2 ± 3,6 ug/g e 29,3 ± 5,3 ug/g de tecido, respectivamente). L-NAME (30 mg/kg, intraperitoneal), o inibidor de óxido nítrico sintase, HOE 140 (10 nmol/50ul, intratraqueal), o antagonista do receptor de bradicinina B2 e capsazepina (100 nmol/50 ul, intratraqueal) o antagonista de TRPV1, atenuaram o extravasamento plasmático induzido por sinvastatina na traqueia e brônquios de ratos. Sinvastatina (5, 10 e 20 mg/kg, i.v.) não causou broncoconstrição per se, mas exacerbou a resposta broncoconstritora á bradicinina (30 nmol/kg, i.v.) o agonista B2 (0,7 ± 0,1 ml/H20) ou capsaicina (30 nmol/kg, i.v.), agonista do TRPV1 (0,8 ± 0,1 ml/H20), comparado com o veículo (0,1 ± 0,04 ml/H20 e 0,04 ± 0,01 ml/H20, respectivamente). A broncoconstrição provocada por bradicinina (100 nmol/kg, i.v.) em ratos não tratados com sinvastatina, foi inibida pelo L-NAME. A exacerbação da broncoconstrição induzida por bradicinina ou capsaicina em ratos tratados com sinvastatina também foi inibida por L-NAME, HOE 140 ou capsazepina. Esses achados sugerem uma possível relação entre NO, bradicinina B2 e TRPV1 e os efeitos da sinvastatina nas vias aéreas de ratos e poderia explicar, em parte, porque alguns pacientes relatam tosse seca após o tratamento com estatinas. Abstract: Statins are the main classes of drugs for the primary and secondary prevention of cardiovascular diseases. Based on this, it is extremely important to know the adverse effects related to the use of this drug. Dry cough has been reported in patients receiving statin therapy; however, the mechanism of this adverse effect is unknown. The objective of this study was to analyse the role of nitric oxide (NO), bradykinin B2 receptor, and TRPV1 in airways alterations induced by simvastatin in rats. Using methods to detect alterations in airway resistance and plasma extravasation, we demonstrated that simvastatin (20 mg/kg, intravenous, i.v.) caused plasma extravasation in the trachea (79.8 ± 14.8 ?g/g/tissue) and bronchi (73.3 ± 8.8 ug/g/tissue) of rats, compared to the vehicle (34.2 ± 3.6 ug/g and 29.3 ± 5.3 ug/g of tissue, respectively). L-NAME (30 mg/kg, intraperitoneal), an NO synthase inhibitor, HOE 140 (10 nmol/50ul, intratracheal), a bradykinin B2 antagonist, and capsazepine (100 nmol/50?l, intratracheal), a TRPV1 antagonist, attenuated simvastatin-induced plasma extravasation in the trachea and bronchi of rats. Simvastatin (5, 10 and 20 mg/kg) did not cause bronchoconstriction per se, but exacerbated the bronchoconstrictive response to bradykinin (30 nmol/kg, i.v.) a B2 agonist (0.7 ± 0.1 ml/H2O) or capsaicin (30 nmol/kg, i.v.), a TRPV1 agonist (0.8 ± 0.1 ml/H2O), compared to the vehicle (0.1 ± 0.04 ml/H2O and 0.04 ± 0.01 ml/H2O, respectively). The bronchoconstriction elicited by bradykinin (100 nmol/kg, i.v.) in simvastatin nontreated rats was inhibited by L-NAME. The exacerbation of bronchoconstriction induced by bradykinin or capsaicin in simvastatin-treated rats was also inhibited by LNAME, HOE 140, or capsazepine. These findings suggest a possible relationship between NO, bradykinin B2, and TRPV1 and the effects of simvastatin in rat airways and could explain, in part, why some patients report dry cough after treatment with statins.

[eng] Atrial fibrillation (AF) is the most common arrhythmia affecting 1 of every 20 persons older than 65 years and 9% of the octogenarians, and extensive research efforts have been undertaken to identify molecular, electrophysiological, and clinical mechanisms that contribute to the induction and maintenance of this arrhythmia. In spite of this, treatment of this arrhythmia remains deficient or inefficient, with frequent re-incidence of the arrhythmia after treatment because knowledge of the complex pathophysiology of the disease remains incomplete. However, dysfunctional calcium handling is gaining strength as a key contributor to the induction of cardiac arrhythmia. In the literature is described those pathological changes in adenosine A2A receptor (A2AR) expression and activation promote arrhythmogenic calcium release from the sarcoplasmic reticulum (SR) in atrial myocytes from patients with AF. Accordingly, this proposal aims to test the general working hypothesis postulating that adenosine receptors constitute a new source of therapeutical targets and biomarkers for prevention, risk-stratification, and treatment of atrial fibrillation. In the present work we analysed the A2AR expression and mRNA content from AF patients to determine its AF phenotype. Moreover, we analysed the impact of AF in peripheral tissues. Thus, A2AR expression was measured in peripheral blood mononuclear cells (PBMCs) from AF patients, finding its enhanced expression. In addition, ADA and adenosine plasma content was also altered in AF patients. Concomitantly, these results suggest a huge imbalance in adenosinergic signalling that is not hitting just cardiac tissue but also peripherical ones. Secondly, we aimed to develop new tools to use in the AF research. In our case were the HL-1 cells for in vitro assays and pigs for animal modelling. We compared the results on adenosine 1 receptor (A1R) and A2AR expression and heterodimerization of the induced AF phenotype in the two models with AF human patients. Interestingly, we found the same alterations (enhanced expression and reduced heterodimer levels) in all of them. These results point to a usefulness of these two models in the AF research. Moreover, this was the first time that heterodimer A1R-A2AR was detected in a protein:protein interaction assay. Nevertheless, further research is needed to understand the role and the impact of this imbalance during AF events. Also, we have found the same alterations in calcium handling related proteins in pig and humans with AF. We found a reduction in calsequestrin CSQ and PLB expression in both models, which probably contributes to a loss of calcium buffering in AF. In the last chapter, we aimed to develop new pharmacological approaches y precluding A2AR activation or enhancing A1R activity, which will probably restore the normal beating in the heart during the arrythmia. We successfully blocked A2AR activity by the SCH442416 full antagonist. Also, we enhanced A1R activity with CPA agonist and T62 PAM. In addition, we measured the impact on the heterodimerization in a heterologous system by transfected A1R-A2AR HEK cells. Our results shown that T-62 and SCH442416 does not affect heterodimer formation, being potentially useful in the AF treatment. Finally, we developed the same drugs from the optopharmacological point of view, in order to avoid side-off target effects. We have successfully developed the four light-sensitive compounds, which mimic the effect of the classical drugs under light conditions. This opens a new field to treat AF and other diseases. In conclusion, the present work has deepened into the AF understanding and treatment. We have revealed new insights related with AF through the ADA and Adenosine alterations found in plasma. Also, we have revealed new impacts of AF in surrounding cells that offer a new course to study or prevent and detect AF. We have additionally provided evidence for the use of relevant tools to research about AF in in vitro and animal models by using HL-1 cells and pigs. That will facilitate the future analysis of AF causes, effects, and treatment. In addition, novel findings of AF impacts have been found in the three systems through the heterodimeric A1-A2AR reduced formation and the alterations in CSQ, PLB and A1R expression. Finally, we showed new potential approaches to pharmacologically tackle this disease by antagonizing A2AR or potentiate A1R activity. In addition, we have demonstrated that the emerging field of optopharmacology could give us the chance to go further the classical pharmacology and possibly be useful for the development of light- dependent treatments in the near future.

Treballs Finals de Grau de Farmàcia, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, 2020. Tutor/a: Palomer Tarridas, Francesc Xavier, [eng] Acute myocardial infarction (AMI) is defined as myocardial cell death caused by prolonged myocardial ischemia. Although advances in both acute and secondary prevention treatment in recent years have improved the prognosis of the disease, it continues to have a great impact on society, as 14% of individuals with AMI will die because of it in the following year. First, this project seeks to contextualize, through epidemiological studies, the relevance of type 1 AMI worldwide, as well as the acute treatment of the disease. Finally, it delves into the pathophysiology involved and focuses on prevention. Accumulation of low density lipoproteins (LDL) in the arterial wall is one of the major risk factors for developing atherosclerosis, the main trigger for type 1 AMI. Statins are currently established as the reference treatment for AMI prevention, both in monotherapy and in combination with other lipid-lowering drugs. Combined therapies have shown to induce major reductions in cardiovascular risk, but research must be continued to improve outcomes. Statins have traditionally been used together with cholesterol absorption inhibitors, bile acid sequestrants and fibrates. A new lipid-lowering drug family, monoclonal antibodies inhibiting PCSK9 proteins, has been developed recently, showing promising results for the disease prevention, awaiting further safety and efficiency studies., [cat] L’infart agut de miocardi (AMI) es defineix com la mort del miocardi causada per una isquèmia prolongada. Tot i que els avenços en el tractament tant agut com de prevenció secundària dels últims anys han millorat la prognosi de la malaltia, aquesta segueix tenint un gran impacte en la societat, ja que el 14% dels individus que pateixin un AMI en moriran com a conseqüència abans d'un any. En primer lloc, aquest treball busca contextualitzar, mitjançant estudis epidemiològics, la rellevància global de l’AMI tipus 1 així com el tractament agut de la malaltia. Finalment, aprofundeix en la fisiopatologia involucrada per després centrar-se en la prevenció. L’acumulació de lipoproteïnes de baixa densitat en la paret arterial és un dels principals factors de risc per a desenvolupar aterosclerosi, el desencadenant principal de l’AMI tipus 1. Actualment les estatines estan establertes com el tractament de referència per a la prevenció de l’AMI, tant en monoteràpia com en teràpia combinada amb altres fàrmacs hipolipemiants. Les teràpies combinades han demostrat induir majors reduccions del risc d’esdeveniments cardiovasculars, però s’ha de continuar la recerca per a millorar els resultats. Tradicionalment les estatines s'han utilitzat conjuntament amb inhibidors de l’absorció del colesterol, segrestadors d’àcids biliars i fibrats. Recentment s'ha desenvolupat una nova família d’hipolipemiants, els anticossos monoclonals inhibidors de la PCSK9, els quals mostren resultats prometedors en la prevenció de la malaltia, a l’espera de nous estudis de seguretat i eficiència.

Inotropes aim at increasing cardiac output by enhancing cardiac contractility. They constitute the third pharmacological pillar in the treatment of patients with decompensated heart failure, the other two being diuretics and vasodilators. Three classes of parenterally administered inotropes are currently indicated for decompensated heart failure, (i) the beta adrenergic agonists, including dopamine and dobutamine and also the catecholamines epinephrine and norepinephrine, (ii) the phosphodiesterase III inhibitor milrinone and (iii) the calcium sensitizer levosimendan. These three families of drugs share some pharmacologic traits, but differ profoundly in many of their pleiotropic effects. Identifying the patients in need of inotropic support and selecting the proper inotrope in each case remain challenging. The present consensus, derived by a panel meeting of experts from 21 countries, aims at addressing this very issue in the setting of both acute and advanced heart failure., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: Women are underrepresented in sacubitril/valsartan (SV) clinical trials. The aim of this study was to assess sex-specific differences in efficacy, tolerability, and safety of SV in real-world heart failure with reduced ejection fraction (HFrEF) patients. Methods: A prospective registry in 10 centers including all patients who started SV during the last 6 months was analyzed in this study. Results: A total of 427 patients were included, 126 (29.5%) were women. There were no substantial differences in HFrEF treatment before SV initiation, although fewer women than men carried an implantable cardioverter defibrillator (57 [45.2%] vs. 173 [58.1%], p = 0.02). SV starting dose was 24/26 mg b.i.d. in 206 patients (48.2%), 49/51 mg b.i.d. in 184 (43.1%), and 97/103 mg b.i.d. in 34 (8.2%), without relevant differences associated to sex. There were no losses during a mean follow-up of 7.0 ± 0.1 months. The proportion of patients who discontinued the drug (16 [12.7%] women vs. 33 [11.0%] men, p = 0.66) or presented SV-related adverse effects (31 [24.6%] women vs. 79 [26.5%] men, p = 0.72) was also similar in both sexes. However, female sex was an independent predictor of functional class improvement in the multivariate analysis (odds ratio 2.33, 95% confidence interval: 1.24–4.38, p = 0.04). Conclusions: SV in women with HFrEF has a similar tolerability as in men. Females seem to have a more frequent functional class improvement than males.

El clopidogrel es un profármaco cuyo metabolito activo ha demostrado su eficacia como antiagregante en la prevención de eventos cardiovasculares mayores secundarios a síndrome coronario agudo, enfermedad arterial periférica y cerebrovascular. Para la obtención del metabolito activo, clopidogrel se metaboliza a nivel hepático principalmente por la enzima CYP2C19, y su absorción depende en parte de la glicoproteina-P, cuya expresión está codificada por el gen ABCB1. La presencia de los polimorfismos CYP2C19*2, *3, *17 y ABCB1 C3435T en pacientes con síndrome coronario agudo sometidos a una intervención coronaria percutánea, ha sido asociada a una respuesta antiagregante variable en el tratamiento con clopidogrel. En pacientes con enfermedad arterial periférica o enfermedad cerebrovascular, en los que clopidogrel ha demostrado también su eficacia, la evidencia científica es menor. - Objetivo: Estudiar la influencia de los polimorfismos CYP2C19*2, *3, *17 y ABCB1 3435C>T sobre la respuesta a clopidogrel en pacientes con enfermedad arterial periférica y en pacientes con enfermedad cerebrovascular. - Metodología: Se realizaron 2 estudios: uno con pacientes con enfermedad arterial periférica de miembros inferiores sometidos a una angioplastia transluminal percutánea, y otro con pacientes diagnosticados de ictus o accidente isquémico transitorio. En ambos, los pacientes fueron tratados con clopidogrel desde la cirugía y desde el diagnóstico respectivamente. Se genotipó la presencia de los polimorfismos CYP2C19*2, *3, *17 y ABCB1 C3435T en los pacientes reclutados y se estudió su asociación con la eficacia del clopidogrel. Como variables respuesta (eficacia), en pacientes con enfermedad arterial periférica sometidos a angioplastia transluminal percutánea se estudió la ocurrencia de eventos isquémicos en el miembro intervenido durante el tratamiento con clopidogrel en 12 meses de seguimiento, y en los pacientes con ictus o accidente isquémico transitorio se estudió como evento primario la ocurrencia de infarto agudo de miocardio, ictus o muerte cardiovascular desde el diagnóstico, durante el tiempo de tratamiento con clopidogrel, hasta el 31 de julio de 2017. - Resultados: En pacientes con enfermedad arterial periférica y angioplastia transluminal percutánea tratados con clopidogrel, la presencia del polimorfismo CYP2C19*2 se asoció de manera independiente (OR=4.89; IC 95%=1.32-12.83; p=0.018) y combinado con el genotipo ABCB1 3435TT (OR=4.66; IC 95%=1.37-15.84; p=0.014), con un aumento del riesgo de sufrir un evento isquémico en el miembro intervenido. Además, en estos pacientes, se asoció la presencia de estos polimorfismos con la mala evolución de la clasificación de Fontaine, ondas pletismográficas y distancia de claudicación. En pacientes con ictus o accidente isquémico transitorio tratados con clopidogrel, la presencia del CYP2C19*2 mostró una asociación estadísticamente significativa con el aumento del riesgo de la combinada de ictus o accidente isquémico transitorio, infarto agudo de miocardio y muerte cardiovascular (evento primario) (OR=5.07; IC95%=1.2-21.45; p=0.023). Por otro lado, en estos pacientes, se asoció la presencia del CYP2C19*17 con la protección frente la aparición del evento primario (OR=0.19; IC95%=0.03-1.09; p=0.037). - Conclusiones: Los polimorfismos CYP2C19*2 y ABCB1 3435C>T pueden ser marcadores genéticos de la aparición de eventos isquémicos en pacientes andaluces con enfermedad arterial periférica y sometidos a angioplastia transluminal percutánea tratados con clopidogrel. El polimorfismo CYP2C19*2 puede ser un marcador de la aparición de eventos cardiovasculares mayores en pacientes con ictus o accidente isquémico transitorio tratados con clopidogrel, mientras, el CYP2C19*17 puede ser indicador de la prevención frente la aparición de estos eventos entre estos pacientes., Tesis Univ. Granada. Programa Oficial de Doctorado en Farmacia

Background: Cardiovascular disease (CVD) is a group of disorders of the heart and blood vessels, such as coronary heart disease (CHD), cerebrovascular disease, and peripheral artery disease. CVD is the leading threat to global health, whether measured by mortality, morbidity, or economic cost. Long-term administration of aspirin, statins, beta-blockers, and angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers improves survival in patients with stablished coronary heart disease. Nevertheless, adherence to prescribed medication is poor for long-term drug treatment. Objective: We aim to assess the relationship between adherences to the four pharmacological groups recommended for secondary prevention and the clinical outcomes of cardiovascular morbidity and mortality in patients with established CHD according to the level of adherence to these drugs in a population of incident cases of acute coronary syndrome (ACS). Methods: Population-based cohort study of patients with a first episode of ACS during 2006-2015 in the Information System for Research in Primary Care (SIDIAP) database. We will estimate adherence to these drugs. The primary endpoint is a composite of all-cause mortality, ACS, and ischaemic stroke. Bivariate analyses will be performed estimating odds ratios for categorical variables and mean differences for continuous variables. Hazard ratios for adherences will be calculated for outcome events using Cox proportional hazard regression models, and proportionality of hazards assumption will be tested. Results: We expect to estimate adherence to all four study treatments, the incidence of MACE, and to analyze if this incidence is associated with the level of drug adherence. Conclusions: We expect to find that adherent patients have a lower risk of the primary endpoints compared with nonadherent patients. Trial Registration: This study protocol was classified as EPA-OD by the AEMPS (IJG-EST-2017-01-2017-01, 07/04/2017) and registered in the EU PAS register (EUPAS19017, 09/05/2017). [JMIR Res Protoc 2018;7(3):e73]

Insuficiència cardíaca; Medicaments; Tractament Insuficiencia cardíaca; Medicamentos; Tratamiento Heart failure; Medications; Treatment Aquest article explica les pautes que se segueixen actualment per tractar la insuficiència cardíaca, quins medicaments hi ha disponibles, com funcionen, com s’administren i quins són els principals efectes adversos. Este artículo explica las pautas que se siguen actualmente para tratar la insuficiencia cardíaca, qué medicamentos hay disponibles, cómo funcionan, cómo se administran y cuáles son los principales efectos adversos. This article explains the guidelines that are currently being followed to treat heart failure, what medications are available, how they work, how they are administered, and what are the main adverse effects.

Insuficiència cardíaca; Medicaments; Tractament Insuficiencia cardíaca; Medicamentos; Tratamiento Heart failure; Medications; Treatment Aquest article explica les pautes que se segueixen actualment per tractar la insuficiència cardíaca, quins medicaments hi ha disponibles, com funcionen, com s’administren i quins són els principals efectes adversos. Este artículo explica las pautas que se siguen actualmente para tratar la insuficiencia cardíaca, qué medicamentos hay disponibles, cómo funcionan, cómo se administran y cuáles son los principales efectos adversos. This article explains the guidelines that are currently being followed to treat heart failure, what medications are available, how they work, how they are administered, and what are the main adverse effects.

Submitted by Boris Flegr (boris@uerj.br) on 2021-01-06T20:53:47Z No. of bitstreams: 1 TESE_FINAL_PUBLICADA_Ronald_de_Albuquerque_Lima.pdf: 1735241 bytes, checksum: a23d0cc648d754486e832a38427599c3 (MD5) Made available in DSpace on 2021-01-06T20:53:47Z (GMT). No. of bitstreams: 1 TESE_FINAL_PUBLICADA_Ronald_de_Albuquerque_Lima.pdf: 1735241 bytes, checksum: a23d0cc648d754486e832a38427599c3 (MD5) Previous issue date: 2014-05-29 This work aimed at evaluating the systemic and microcirculatory effects, as well as changes in renal gene expression elicited by noradrenalin, sodium nitroprusside and levosimendan associated to volume resuscitation in the treatment of hemorrhagic shock. The dorsal chamber model was used in this study. Animals were subjected to hemorrhagic shock and after that, were randomly distributed between four groups. Groups were: CTRL, received only lactated ringer's solution; NPS received lactated ringer's solution with sodium nitroprusside; NA received lactated ringer's solution with noradrenaline and LEV received lactated ringer's with levosimendan. Systemic and microcirculatory parameters were evaluated ( as percent change compared to baseline). Furthermore, renal genic expression of eNOS, HIF-1a and caspase-3 were also evaluated. NPS group presented a sustained recovery of arteriolar diameter ( 89± 12 %) and FCD (125 ±114 %) at the end of the treatment. There was a red blood cell velocity recovery in CTRL and NPS groups. There was no difference regarding adhered or rolling leukocytes at the end of the treatment. eNOS and caspase-3 renal genic expression between groups showed no differences, however, there was a significant difference in renal genic expression of HIF-1α in NA group (0,65 ± 0,08, AU) compared to CTRL (0,44 ± 0,06, AU) e LEV (0,45 ± 0,06, AU). All groups had a higher expression of ICAM (0,65 ± 0,12; 0,7 ± 0,12; 0,069 ± 0,06; 0,65 ± 0,12, AU) compared to the SHAM group (0,50 ± 0,05, AU). Ringer's lactate solution associated or not to noradrenaline or levosimendan were not enough to recover and sustain microvascular parameters. Treatment with sodium nitroprusside presented the best results, with sustained arteriolar diameter, FCD and RBCV recoveries. Este trabalho teve como objetivo avaliar os efeitos sistêmicos, microcirculatórios assim como mudanças na expressão gênica renal, causados pela ação da noradrenalina, nitropussiato de sódio e levosimendan no tratamento do choque hemorrágico. Nesse estudo foi utilizado o modelo da câmara dorsal.Os animais foram sujeitos a choque hemorrágico e após, foram aleatoriamente divididos em quatro grupos. Os grupos foram: CTRL, recebeu apenas ringer lactato; NPS recebeu ringer lactato com nitroprussiato de sódio; NA recebeu ringer lactato com noradrenalina e LEV, recebeu ringer lactato com levosimendan. Foram avaliados parâmetros sistêmicos, assim como parâmetros microcirculatórios (comparados como percentual em relação ao momento basal). Além disso, foi avaliada a expressão gênica renal de eNOS, HIF-1α, ICAM e caspase-3. O grupo NPS apresentou uma recuperação sustentada do diâmetro arteriolar ( 89± 12 %) e DCF (125 ±114 %) ao final do tratamento. Houve recuperação da velocidade de hemácias nos grupos CTRL e NPS. Não houve diferença em relação ao número de leucócitos aderidos e/ou rolantes ao final do tratamento. A expressão gênica renal de eNOS e caspase-3 entre os grupos não apontou diferenças, entretanto houve diferença significativa na expressão renal de HIF- 1α no grupo NA (0,65 ± 0,08, UA) em relação ao grupo CTRL (0,44 ± 0,06, UA) e LEV (0,45 ± 0,06, UA). Todos os grupos tiveram uma maior expressão de ICAM (0,65 ± 0,12; 0,7 ± 0,12; 0,069 ± 0,06; 0,65 ± 0,12, UA) em relação ao grupo SHAM (0,50 ± 0,05, UA). Ringer lactato puro ou associado com noradrenalina ou levosimendan não foram suficientes para recuperar e sustentar os parâmetros microvasculares. O tratamento com nitroprussiato de sódio foi o que apresentou os melhores resultados, com recuperação dos diâmetros arteriolar, da DCF e velocidade de hemácias.

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al., Rationale: Recently it has been shown that long-term intensive exercise practice is able to induce myocardial fibrosis in an animal model. Angiotensin II is a profibrotic hormone that could be involved in the cardiac remodeling resulting from endurance exercise. Objective: This study examined the antifibrotic effect of losartan, an angiotensin II type 1 receptor antagonist, in an animal model of heart fibrosis induced by long-term intense exercise. Methods and Results: Male Wistar rats were randomly distributed into 4 experimental groups: Exercise, Exercise plus losartan, Sedentary and Sedentary plus losartan. Exercise groups were conditioned to run vigorously for 16 weeks. Losartan was orally administered daily before each training session (50 mg/kg/day). Time-matched sedentary rats served as controls. After euthanasia, heart hypertrophy was evaluated by histological studies; ventricular collagen deposition was quantified by histological and biochemical studies; and messenger RNA and protein expression of transforming growth factor-β1, fibronectin-1, matrix metalloproteinase-2, tissue inhibitor of metalloproteinase-1, procollagen-I and procollagen-III was evaluated in all 4 cardiac chambers. Daily intensive exercise caused hypertrophy in the left ventricular heart wall and originated collagen deposition in the right ventricle. Additionally long-term intensive exercise induced a significant increase in messenger RNA expression and protein synthesis of the major fibrotic markers in both atria and in the right ventricle. Losartan treatment was able to reduce all increases in messenger RNA expression and protein levels caused by exercise, although it could not completely reverse the heart hypertrophy. Conclusions: Losartan treatment prevents the heart fibrosis induced by endurance exercise in training animals. © 2013 Gay-Jordi et al., This work was supported by grants from the Sociedad Española de Cardiología, Fondo de Investigaciones Sanitarias from Instituto de Salud Carlos III (PI050210 and PS09/02362), and Rio Hortega (CM06/00189 and CM08/00201) from the Spanish Health Ministry, Universitats i Recerca (2005SGR00497).

Insuficiència cardíaca; Medicaments; Recomanacions Heart failure; Medications; Recommendations Insuficiencia cardíaca; Medicamentos; Recomendaciones Document on es donen una sèrie de recomanacions relacionades amb la medicació per tractar la insuficiència cardíaca, així com les complicacions que poden sorgir.

Orientador: Stephen Hyslop Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas Resumo: Serpentes do gênero Bothrops são a principal causa de acidentes ofídicos no Brasil. Acidentes envolvendo a Bothrops jararacussu (jararacuçu) resultam em envenenamento moderado e grave, devido principalmente à grande quantidade de peçonha injetada por esta espécie. Entre os efeitos observados, o quadro de hipotensão e de choque são fatores importantes a serem considerados. Neste trabalho, avaliamos as alterações cardíacas causadas pela peçonha de B. jararacussu em átrio direito isolado de rato. A incubação das preparações com peçonha (0,025, 0,050, 0,1 e 0,2 mg/ml) resultou em uma marcada contratura atrial em altas concentrações que levou a uma redução progressiva da força contrátil e a freqüência atrial, especialmente na maior concentração utilizada (0,2 mg/ml). A maior concentração da peçonha também causou uma marcada liberação de CK-BM e desorganização das fibras musculares atriais. A peçonha aquecida (100°C, 20 min) aboliu esta atividade enquanto a diálise não alterou significativamente essas respostas. O fracionamento da peçonha de B. jararacussu em cromatografia por gel filtração e troca iônica nos forneceu a fração (III3) que reproduziu todas as alterações funcionais e morfológicas vistas com a peçonha bruta. SDS-PAGE da fração III3, na presença e ausência de ditiotreitol e ß-mecaptoetanol revelaram uma massa molecular de ~28 KDa e 14 KDa, respectivamente, semelhantes às bothropstoxinas, as principais PLA2 miotóxicas desta peçonha. Os antivenenos comerciais utilizados (botrópico e botrópico/crotálico) se mostraram eficientes em neutralizar os efeitos produzidos pela peçonha bruta tanto na força e freqüência atriais como na liberação de CK-MB e nas alterações histológicas. A pré-incubação com antagonistas farmacológicos (bloqueadores de receptores adrenérgicos, histaminérgicos, muscarínicos, e inibidores da ciclooxigenase e óxido nítrico sintase) não afetou significativamente as alterações induzidas pela peçonha. Estes resultados indicam que as alterações induzidas pela peçonha de B. jararacussu estão envolvidas diretamente com o dano a fibra muscular atrial mediada provavelmente através da atividade das PLA2 miotóxicas. Abstract: The genus Bothrops is the principal cause of snakebite in Brazil. Bites by Bothrops jararacussu (jararacuçu) result in moderate to severe envenoming partly because of the large amount of venom injected by this species. Hypotension and circulatory shock are important systemic manifestations associated with bites by this species. In this work, we examined the cardiac alterations caused by B. jararacussu venom in rat isolated right atria. Incubation of atria with venom (0.025, 0.050, 0.1 and 0.2 mg/ml) resulted in marked muscle contracture at high concentrations that led to a progressive decrease in contractile force and beating rate, especially at the highest concentration (0.2 mg/ml). The highest venom concentrations also caused a marked release of CK-MB and disorganization of atrial muscle fibers. Heating the venom (100ºC, 20 min) abolished this activity whereas dialysis did not significantly alter the responses. Fractionation of B. jararacussu venom by gel filtration and ion exchange chromatographies yielded a peak (III-3) that reproduced all of the morphological and functional changes seen with the venom. SDS-PAGE of the peak III-3 protein in the absence and presence - mercaptoethanol revealed a molecular mass of ~28 KDa and 14 KDa, respectively, similar to bothropstoxins, the main myotoxic PLA2 of this venom. Bothropic and bothropic/crotalic antivenoms prevented the venom (0.2 mg/ml)-induced decrease in contractile force and atrial rate, as well as the tissue damage (CK-MB release and histological alterations). Pre-incubation with adrenergic, histaminergic and muscarinic receptor antagonists, or with cyclooxygenase and nitric oxide synthase inhibitors, did not significantly affect the venom-induced changes. These results indicate that the B. jararacussu venom-induced alterations probably involve direct to atrial muscle fibers mediated by venom myotoxic PLA2. Mestrado Mestre em Farmacologia

Mehta et al. do not show any significant difference between early and delayed intervention in patients with acute coronary syndrome. In their study, 9.9% of patients in the...

Orientador: Heitor Moreno Junior Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas Resumo: Avaliou-se o comportamento da pressão arterial (PA) e da freqüência cardíaca (FC) durante a interrupção do ato de fumar, por meio dos sistemas Finapres (batlbat) e MAPA (Monitorização Ambulatorial da Pressão Arterial), em fumantes de grau moderado, após sete dias de tratamento com bupropiona, isolada ou associada à nicotina de liberação transdérmica....Observação: O resumo, na íntegra, poderá ser visualizado no texto completo da tese digital Abstract: The purpose of this study was to evaluate the changes in arterial blood pressure (BP) and heart rate (HR) during smoking abstinence, as measured by Finapres (beatlbeat) and ABPM (Ambulatory Blood Pressure Monitoring) devices, in moderate smokers after 7 days of treatment with bupropion alone, or bupropion combined with transdermal nicotine....Note: The complete abstract is available with the full electronic digital thesis or dissertations Mestrado Farmacologia Mestre em Farmacologia

Les alteracions en el metabolisme dels àcids grassos estan implicades tant en l'aparició de la hipertròfia cardíaca com de la resistència a la insulina, encara que els mecanismes responsables són poc coneguts. Per aquesta raó, l'objectiu general d'aquesta tesi doctoral ha estat aprofundir en el coneixement dels mecanismes responsables de l'aparició d'aquestes dues patologies, així com els efectes de diferents fàrmacs sobre la hipertròfia cardíaca i la resistència a la insulina. Per a la consecució d'aquest objectiu general s'han realitzat una sèrie d'estudis amb els següents objectius específics: I. Determinar els efectes que produeix l'activació de NF-kappaB durant la hipertròfia cardíaca sobre l'expressió dels gens implicats en el metabolisme dels àcids grassos i l'efecte produit pels inhibidors d'aquest factor de transcripció.II. Avaluar si l'activador de PPAR-beta/delta, L-165041, és capaç de revertir la hipertròfia cardíaca en cardiomiòcits neonatals, i en cas que així sigui, determinar el mecanisme responsable.III. Examinar nous mecanismes potencials a través dels quals l'activació de NF-kappaB afecta l'acció dels PPARs en un model de rates amb constricció de la aorta abdominal que desenvolupen hipertròfia cardíaca i determinar l'efecte del tractament amb estatines en aquest model.IV. Estudiar l'efecte de les estatines sobre l'activitat de PPAR-beta/delta en cèl·lules H9c2 estimulades amb LPS i la possible participació del cofactor PGC-1 en aquest procés. V. Determinar si el tractament amb inhibidors de NF-kappaB afecta a la via Akt-GSK3-beta implicada en l'aparició de la hipertròfia cardíaca.VI. Examinar els efectes de l'HTB sobre la hipertròfia induïda per fenilefrina en cardiomiòcits neonatals i del triflusal en un model de rates amb constricció de la aorta abdominal.VII. Estudiar com el tractament amb troglitazona afecta a l'expressió de l'Akt i a l'activitat d'AMPK al múscul esquelètic i la seva implicació en els efectes d'aquest fàrmac sobre el metabolisme dels àcids grassos i la glucosa. Els resultats obtinguts semblen indicar que l'activació del factor NF-kappaB durant la hipertròfia cardíaca redueix l'activitat de PPAR-beta/delta tant in vivo com in vitro, a través d'un mecanisme que implica la interacció entre la subunitat p65 de NF-kappa-B i PPARbeta/delta. D'altra banda l'activació de PPARbeta/delta amb un agonista selectiu inhibeix la hipertròfia cardíaca induïda per fenilefrina en cardiomiòcits neonatals. Aquest tractament també inhibeix l'activació de NF-kappaB induïda per LPS a través d'un mecanisme que implica la interacció física entre aquest subtipus de PPAR i la subunitat p65 de NF-kappaB. Pel que fa al tractament amb atorvastatina, podem concloure que la reducció de l'oxidació dels àcids grassos observada durant la hipertròfia cardíaca, sembla ser el resultat de la reducció tant dels nivells de PPAR-alfa com de PPAR-beta/delta i de la interacció dels dos subtipus de PPAR i p65. Aquests canvis es reverteixen després del tractament amb atorvastatina. A més, l'activació de NF-kappaB induïda per LPS redueix l'expressió de la PGC-1. Aquest fet disminueix la interacció d'aquest coactivador i PPAR-beta/delta provocant un descens en l'expressió dels gens implicats en l'oxidació dels àcids grassos. Aquests canvis es reverteixen en presència d'inhibidors de NF-kappaB com l'atorvastatina i el partenolide. Finalment, l'atorvastatina inhibeix l'activació de la via Akt/GSK3-beta per estímuls hipertròfics, a través d'un mecanisme que implica la supressió de l'activitat NF-kappaB.Finalment, el triflusal, i el seu metabòlit actiu HTB, eviten la hipertròfia cardíaca tant in vitro com in vivo a través de la inhibició de NF-kappaB. En els resultats de resistència a la insulina, sembla que el tractament amb troglitazona incrementa l'expressió de la proteïna Akt en múscul esquelètic, a través de la reducció dels nivells intracel·lulars de ceramides., Cardiac hypertrophy is a response of the heart to a wide range of extrinsic stimuli, such as arterial hypertension, valvular heart disease, myocardial infarction, and cardiomyopathy. Although this process is initially compensatory for an increase workload, its prolongation frequently results in congestive heart failure, arrhythmia, and sudden death. Among the signal transduction pathways involved in the hypertrophic growth of the myocardium, the nuclear factor (NF)-kappaB signaling pathway plays a pivotal role, since it has been shown that NF-kappaB inhibition blocks or attenuates the hypertrophic response of cultured cardiac myocytes. In addition, cardiac hypertrophy is associated with an increase in glucose utilization and a decrease in fatty acid oxidation, which is characteristic of fetal heart. Defects in mitochondrial fatty acid oxidation enzymes cause childhood hypertrophic cardiomyopathy, and perturbation of fatty acid oxidation in animal models causes cardiac hypertrophy, demonstrating that substrate utilization is important in the pathogenesis of hypertrophy.In this work we demonstrate that activation of PPARbeta/delta by the specific ligand L-165041, atorvastatin and triflusal inhibits cardiac hypertrophy.On the other hand, insulin resistance is a common metabolic abnormality associated with obesity, hypertension and type 2 diabetes mellitus. Skeletal muscle accounts for the majority of insulin-stimulated glucose utilization and is, therefore, the major site of insulin resistance. During the development of insulin resistance in skeletal muscle an impairment of glucose utilization and insulin sensitivity has been related to the presence of increased availability of certain lipid-derived second messengers, such as ceramides, which can attenuate several insulin signaling pathways leading to insulin resistance. Thiazolidinediones (ciglitazone, pioglitazone, rosiglitazone and troglitazone) are oral antidiabetic agents that improve insulin sensitivity and glucose homeostasis in type 2 diabetic patients as well as in various animal models of diabetes and obesity. The findings obtained implicate ceramide as an important intermediate in the regulation of Akt after troglitazone treatment and suggest that prior thiazolidinedione treatment may preserve or delay the onset of insulin resistance by increasing Akt in skeletal muscle.

Objetivos: A pesar de las mejoras en los resultados y en la técnica de los procedimientos de revascularización percutánea coronaria, existen pocos estudios que validen los resultados clínicos de la aplicación de los nuevos diseños de stents, las características de la lesión y los fármacos empleados.En nuestro estudio, los objetivos principales son los siguientes:1. Evaluar los resultados del stent estudiado (NIR). Confirmar la influencia de los factores de riesgo coronario sobre la evolución de los pacientes tratados con stent, determinar la influencia de las características propias de la lesión y de las variables del procedimiento. 2. Determinar la influencia de los diferentes fármacos empleados en los pacientes a los que se ha implantado un stent coronario. Hipótesis:1- Procedimiento El stent empleado representa el prototipo de los stents de segunda generación y debe ofrecer ventajas respecto a los stents de primera generación (Palmaz), por lo que se le supone una elevada tasa de éxito angiográfico (definida como adecuada implantación del stent con una estenosis residual < 30% por estimación visual); una elevada tasa de éxito clínico de implantación (definido como consecución de éxito angiográfico junto a la ausencia de complicaciones mayores durante la hospitalización); una tasa reducida de MACE (MACE fue definida como muerte, IM o revascularización coronaria por ACTP o Pontaje quirúrgico) y una tasa reducida de restenosis angiográfica (definida como la presencia en el segmento previamente tratado de una estenosis > 50% en cualquier coronariografía durante el seguimiento). Las mejoras en el diseño del stent estudiado (paradigma de los llamados de segunda generación) permitirán reducir la curva de aprendizaje y en casos seleccionados la implantación sin predilatación previa.2- Influencia de fármacos Los pacientes con enfermedad coronaria, que precisan la implantación de un stent, son sometidos a distintos tratamientos farmacológicos: Durante la intervención, durante el primer mes y de forma crónica. Nuestra segunda hipótesis es que los tratamientos farmacológicos se indican por situaciones clínicas y factores de riesgo, y que estos tratamientos ejercen alguna influencia positiva en la evolución de los pacientes. Pacientes y métodos Entre agosto de 1997 y octubre de 1998, fueron incluidos en este estudio 1.004 pacientes (cada centro incluyó a un máximo de 25 pacientes con un total de 1.136 lesiones tratadas). El diseño del estudio fue prospectivo multicéntrico con un total de 50 centros participantes de España y Portugal. El anagrama del estudio fue ESPORT NIR (ESPaña y PORtugal registro NIR stent ). Todos los pacintes fueron sometidos a seguimiento clinico durante siete meses.Del total de 1004 pacientes incluidos se seleccionó una muestra aleatoria de 210 enfermos consecutivos (239 lesiones) para una reevaluación angiográfica a los 6 meses de la ACTP. Además, se realizó una angiografía durante el periodo de seguimiento (a los 6 meses o antes) a cualquier paciente incluido en el estudio con recurrencia de la isquemia. En estos pacientes se realizó cuantificación de la estenosis residual mediante evaluación angiográfica automática cuantitativa con el sistema MEDIS 4,0 CMS, en un laboratorio central y por técnicos expertos no participantes en los procedimientos de ACTP. Las películas de angiografía debían seguir un riguroso protocolo, que incluyó la recogida del segmento distal del catéter utilizado. Resultados La edad media de los pacientes fue de 60 años y el 82% eran varones. La indicación de la angioplastia fue angina inestable en el 61% de los casos. El éxito angiográfico fue del 99% y el éxito clínico del procedimiento del 98%. La restenosis angiográfica fue del 16% (IC del 95%, 11,7-21,2). La tasa acumulada de eventos mayores al séptimo mes de seguimiento fue del 8,7%: un 0,9% de fallecimientos, un 1,2% de infartos de miocardio y un 6,6% de revascularizaciones sobre el vaso tratado. Conclusiones1. Stent NIR en el tratamiento de lesiones coronarias1.1. El tratamiento de lesiones coronarias significativas con el stent estudiado muestra:1.1.1. Elevado éxito angiográfico (99,6%; definido como adecuada implantación con una estenosis residual < 30% por estimación visual) 1.1.2. Elevado éxito clínico de implantación (98,7%; definido como consecución de éxito angiográfico junto a la ausencia de complicaciones mayores durante la hospitalización).1.2. Tras siete meses de seguimiento desde la implantación del stent coronario:1.2.1. La incidencia de acontecimientos cardiacos mayores (MACE) es baja (8,7%; definidos como muerte, IM o revascularización coronaria por angioplástia o pontaje quirúrgico). 1.2.2. La tasa de restenosis angiográfica de las lesiones tratadas es baja (16,32 %; definida como la presencia, en el segmento previamente tratado, de una estenosis > 50% en cualquier coronariografía durante el seguimiento). Son predictores independientes de reestenosis la diabetes y la longitud de los stents1.3. Influencia de la técnica de implantación y del seguimiento1.3.1. La experiencia en stents del centro de intervención no da lugar a diferencias en las tasas de éxito angiográfico o clínico de implantación o en la incidencia de MACE o reestenosis.1.3.2. Los pacientes con seguimiento angiográfico tienen un exceso de revascularización en comparación a los que siguen un control clínico.1.3.3. En casos seleccionados, la utilización de stent sin predilatación no da lugar a diferencias en el éxito angiográfico, clínico, MACE o restenosis, 2. Influencia de fármacos en la angioplastia con stent2.1. Fármacos indicados por protocolo:2.1.1. El tratamiento con ticlopidina reduce el riesgo de MACE al primer mes.2.1.2. El tratamiento con AAS reduce el riesgo de MACE al primer mes en los pacientes diabéticos. El tratamiento mantenido se asocia a una reducción del riesgo de MACE para toda la población estudiada. 2.2. Fármacos electivos:2.2.1. La administración de abciximab es más frecuente en pacientes con antecedentes de infarto agudo y se asocia a una mayor incidencia de MACE aguda.2.2.2. Se adminitra IECA a una población de más edad, HTA, IM previo, angioplastia previa e insuficiencia ventricular izquierda. Sin embargo, no aparece un incremento de MACE en ninguno de los subgrupos estudiados.2.2.3. Se administran betabloqueantes a una población de mayor indencia de IM previo, HTA y lesiones más graves. A pesar de ello, el grupo tratado no muestra mayor incidencia de MACE que la población que no precisó este tratamiento. 2.2.4. Se trata con calcioantagonistas una población con mayor incidencia de diabetes, IM previo y angina. Sin embargo, el grupo tratado no muestra un incremento MACE. 2.2.5. Se administran estatinas a una población con más dislipemia y diabetes. Los pacientes tratados muestran una incidencia de angina superior, aunque no un mayor riesgo de MACE o de restenosis angiográfica.2.2.6. Se trata con nitritos a una población de pacientes con mayor incidencia de HTA, diabetes y angina. Solo aparece un aumento en la incidencia de MACE en los pacientes tratados con dislipemia. La tasa de restenosis es mayor en los pacientes diabéticos tratados con nitritos.

Insuficiència cardíaca; Medicaments; Tractament Insuficiencia cardíaca; Medicamentos; Tratamiento Heart failure; Medications; Treatment Aquest article explica les pautes que se segueixen actualment per tractar la insuficiència cardíaca, quins medicaments hi ha disponibles, com funcionen, com s’administren i quins són els principals efectes adversos. Este artículo explica las pautas que se siguen actualmente para tratar la insuficiencia cardíaca, qué medicamentos hay disponibles, cómo funcionan, cómo se administran y cuáles son los principales efectos adversos. This article explains the guidelines that are currently being followed to treat heart failure, what medications are available, how they work, how they are administered, and what are the main adverse effects.

Insuficiència cardíaca; Medicaments; Tractament Insuficiencia cardíaca; Medicamentos; Tratamiento Heart failure; Medications; Treatment Aquest article explica les pautes que se segueixen actualment per tractar la insuficiència cardíaca, quins medicaments hi ha disponibles, com funcionen, com s’administren i quins són els principals efectes adversos. Este artículo explica las pautas que se siguen actualmente para tratar la insuficiencia cardíaca, qué medicamentos hay disponibles, cómo funcionan, cómo se administran y cuáles son los principales efectos adversos. This article explains the guidelines that are currently being followed to treat heart failure, what medications are available, how they work, how they are administered, and what are the main adverse effects.

Insuficiència cardíaca; Medicaments; Recomanacions Heart failure; Medications; Recommendations Insuficiencia cardíaca; Medicamentos; Recomendaciones Document on es donen una sèrie de recomanacions relacionades amb la medicació per tractar la insuficiència cardíaca, així com les complicacions que poden sorgir.

Insuficiència cardíaca; Medicaments; Recomanacions Heart failure; Medications; Recommendations Insuficiencia cardíaca; Medicamentos; Recomendaciones Document on es donen una sèrie de recomanacions relacionades amb la medicació per tractar la insuficiència cardíaca, així com les complicacions que poden sorgir.