Quimioterapia e cardiotoxicidade / Chemotherapy and cardiotoxicity

A evolução do tratamento oncológico resultou no desenvolvimento de fármacos altamente eficazes. No entanto, os efeitos colaterais da terapia antitumoral ainda são frequentes e, muitas vezes, limitantes. Entre os efeitos adversos possíveis, a cardiotoxicidade representa um grupo importante de manifestações, com impacto negativo a curto e longo prazo na evolução desses pacientes. Esses eventos podem ocorrer na ausência de fatores de risco de doença cardiovascular e sua evolução ainda não está totalmente esclarecida. Curiosamente, podem ser desencadeadas tanto por terapias sistêmicas convencionais quanto por novas terapias relacionadas com alvos moleculares específicos. As definições de cardiotoxicidade ainda são diversas e não há um consenso universal. Em linhas gerais, pode ser entendida como qualquer alteração da homeostase do sistema cardiovascular induzida pelo tratamento do câncer. O dano cardíaco pode apresentar-se por vasta gama de condições clínicas, como por exemplo, alterações metabólicas, hipertensão arterial sistêmica, síndromes coronarianas agudas, tromboembolismo arterial e venoso, arritmias, entre outros. Muitos destes eventos têm prognóstico pior que muitas neoplasias. Assim, o conhecimento dos efeitos adversos cardíacos do tratamento antineoplásico é de suma importância, e a avaliação cardiovascular do paciente com câncer é fundamental. O intuito desta revisão é apresentar de forma prática as drogas oncológicas com maior potencial cardiotóxico e discutir de forma resumida seus principais efeitos cardiovasculares. Serão discutidas brevemente as definições, os mecanismos de agressão cardíaca e as manifestações clínicas principais, além da evolução e manejo inicial

The evolution of oncological treatment has resulted in the development of highly effective drugs. However, the side effects of antineoplastic therapy are still frequent, and often limiting. Among the possible adverse effects, cardiotoxicity represents an important group of manifestations, with negative impact on the clinical development of these patients in the short and long terms. These events can occur in the absence of risk factors for cardiovascular disease, and their clinical course is still not fully clarified. Interestingly, they can be triggered by both conventional systemic therapies and by new therapies with specific molecular targets. There are several definitions of cardiotoxicity, and there is no universal consensus. In general terms, it can be understood as any modification of cardiovascular system homeostasis induced by cancer treatment. Cardiac damage can present as a wide range of clinical conditions, such as metabolic changes, systemic arterial hypertension, acute coronary syndromes, arterial and venous thromboembolism, and arrhythmias, among others. Many of these events have a worse prognosis than many neoplasms. Thus, the knowledge of the adverse cardiac effects of antineoplastic treatment is of paramount importance, and the cardiovascular evaluation of the cancer patient is essential. The purpose of this review is to offer a practical presentation of oncological drugs with greater cardiotoxic potential, and to summarize its main cardiovascular effects. The definitions, mechanisms of cardiac aggression, and main clinical manifestations will be briefly discussed, as well as the clinical course and initial management

Previous exercise training increases levels of PPAR-α in long-term post-myocardial infarction in rats, which is correlated with better inflammatory response.

OBJECTIVE: Exercise is a protective factor for cardiovascular morbidity and mortality, with unclear mechanisms. Changing the myocardial metabolism causes harmful consequences for heart function and exercise contributes to metabolic adjustment modulation. Peroxisome proliferator-activated receptors (PPARs) are also myocardium metabolism regulators capable of decreasing the inflammatory response. We hypothesized that PPAR-α is involved in the beneficial effects of previous exercise on myocardial infarction (MI) and cardiac function, changing the expression of metabolic and inflammatory response regulators and reducing myocardial apoptosis, which partially explains the better outcome. METHODS AND RESULTS: Exercised rats engaged in swimming sessions for 60 min/day, 5 days/week, for 8 weeks. Both the exercised rats and sedentary rats were randomized to MI surgery and followed for 1 week (EI1 or SI1) or 4 weeks (EI4 or SI4) of healing or to sham groups. Echocardiography was employed to detect left ventricular function and the infarct size. Additionally, the TUNEL technique was used to assess apoptosis and immunohistochemistry was used to quantitatively analyze the PPAR-α, TNF-α and NF-κB antigens in the infarcted and non-infarcted myocardium. MI-related mortality was higher in SI4 than in EI4 (25% vs 12%), without a difference in MI size. SI4 exhibited a lower shortening fraction than EI4 did (24% vs 35%) and a higher apoptosis/area rate (3.97±0.61 vs 1.90±1.82) in infarcted areas (both p=0.001). Immunohistochemistry also revealed higher TNF-α levels in SI1 than in EI1 (9.59 vs 4.09, p<0.001) in infarcted areas. In non-infarcted areas, EI4 showed higher levels of TNF-α and positive correlations between PPAR-α and NF-κB (r=0.75, p=0.02), in contrast to SI4 (r=0.05, p=0.87). CONCLUSION: Previously exercised animals had better long-term ventricular function post-MI, in addition to lower levels of local inflammatory markers and less myocardial apoptosis, which seemed to be related to the presence of PPAR-α.

Previous exercise training increases levels of PPAR-α in long-term post-myocardial infarction in rats, which is correlated with better inflammatory response

OBJECTIVE: Exercise is a protective factor for cardiovascular morbidity and mortality, with unclear mechanisms. Changing the myocardial metabolism causes harmful consequences for heart function and exercise contributes to metabolic adjustment modulation. Peroxisome proliferator-activated receptors (PPARs) are also myocardium metabolism regulators capable of decreasing the inflammatory response. We hypothesized that PPAR-α is involved in the beneficial effects of previous exercise on myocardial infarction (MI) and cardiac function, changing the expression of metabolic and inflammatory response regulators and reducing myocardial apoptosis, which partially explains the better outcome. METHODS AND RESULTS: Exercised rats engaged in swimming sessions for 60 min/day, 5 days/week, for 8 weeks. Both the exercised rats and sedentary rats were randomized to MI surgery and followed for 1 week (EI1 or SI1) or 4 weeks (EI4 or SI4) of healing or to sham groups. Echocardiography was employed to detect left ventricular function and the infarct size. Additionally, the TUNEL technique was used to assess apoptosis and immunohistochemistry was used to quantitatively analyze the PPAR-α, TNF-α and NF-κB antigens in the infarcted and non-infarcted myocardium. MI-related mortality was higher in SI4 than in EI4 (25% vs 12%), without a difference in MI size. SI4 exhibited a lower shortening fraction than EI4 did (24% vs 35%) and a higher apoptosis/area rate (3.97±0.61 vs 1.90±1.82) in infarcted areas (both p=0.001). Immunohistochemistry also revealed higher TNF-α levels in SI1 than in EI1 (9.59 vs 4.09, p<0.001) in infarcted areas. In non-infarcted areas, EI4 showed higher levels of TNF-α and positive correlations between PPAR-α and NF-κB (r=0.75, p=0.02), in contrast to SI4 (r=0.05, p=0.87). CONCLUSION: Previously exercised animals had better long-term ventricular function post-MI, in addition to lower levels of local inflammatory markers and less myocardial apoptosis, which seemed to be related to the presence of PPAR-α.

O processo inflamatório após a indução de infarto agudo do miocárdio é atenuado por treinamento físico prévio em ratos - análise dos mecanismos de cardioproteção induzida com o exercício / The inflammatory process after induced myocardial infarcts in rats is attenuated by previous exercise: analysis of the mechanisms of cardioprotection induced with the exercise

O exercício é hoje reconhecidamente um fator de proteção para morbidade e mortalidade cardiovascular. Apesar de extensos dados de estudos epidemiológicos e de intervenção, os mecanismos subjacentes cardioprotetores do exercício ainda não estão bem elucidados. Alguns autores acreditam que o treinamento físico induz o desenvolvimento de células miocárdicas mais resistentes a agressões externas e maior vascularização. Além disso, o exercício parece exercer grande influência sobre o sistema imunológico. O entendimento dos mecanismos através dos quais o exercício influencia o desfecho clínico do infarto agudo do miocárdio (IM) pode trazer uma melhor compreensão das diferentes evoluções clínicas de indivíduos aparentemente semelhantes. O estudo de quais moléculas e sistemas estão envolvidas nessa cardioproteção e de como medeiam e integram a resposta miocárdica ao estresse pode influenciar futuras terapias. O objetivo do presente trabalho é testar a hipótese de que a ocorrência de IM em animais previamente treinados é acompanhada de melhor função ventricular pós-IM, maior vascularização, em associação com menor expressão de marcadores inflamatórios e moduladores do metabolismo, e menos apoptose. Materiais e Métodos: Sessões de 60 min/dia, 05 dias/semana, por 08 semanas foram aplicadas no grupo exercício. Após este período os animais exercitados e sedentários foram randomizados para cirurgia de IM através da ligadura da artéria coronária esquerda (EI e SI, respectivamente), ou cirurgia controle (ES e SS, respectivamente), seguido de um período de sedentarismo de 04 semanas. A função ventricular esquerda foi obtida através da ecocardiografia, bem como o tamanho do infarto. A técnica de imunohistoquímica foi utilizada para detecção de PPAR-α, PPAR-γ, TNF-α, NF-kB, e α-actina, e os resultados foram quantificados através de um sistema de análise de imagens automática por detecção de cores. A técnica de TUNEL foi utilizada para marcação de apoptose. Foram estudadas...

Exercise is a well recognized protective factor for cardiovascular morbidity and mortality. In spite of extensive data from epidemiologic studies and intervention, the subjacent cardioprotective mechanisms of exercise are still non clear. Some authors believe that the physical training induces development of more resistant myocardial fibers against external injuries and increased vascularization. Also, exercise seems to influence the modulation of the immune system. The understanding of mechanisms by which the exercise acts in the acute myocardial infarction (MI) progression may bring a better comprehension of different clinical outcome in apparently similar individuals. The knowledge of which molecules and systems are involved in this cardioprotection and how they mediate and integrate the stress myocardial response may help future therapies. The objective of the present work is to test the hypothesis that the occurrence of MI in previously trained animals is associated with a better post MI ventricular function, major vascularization, in association with lower expression of inflammatory markers and of metabolic modulators, and less apoptosis. Material and Methods: Sessions of 60 min/day, 05 days/week, for 08 weeks were applied in the exercised group. After this period, the exercised and sedentary animals were randomized to surgery for myocardial infarction, through the ligature of left coronary artery (EI and SI, respectively), or control surgery (ES and SS, respectively), followed by a 04 week sedentary period. The left ventricular function was obtained by the echocardiography as also the infarct size. Immunohistochemistry was used for detection of PPAR-α, PPAR-γ, TNF-α, NF-kB, ad α-actin, and the results were quantified in an image analysis system by automatic collor detection. TUNEL technique was used for detection of apoptosis. Three regions of the heart were studied: infarcted (I), peri-infarcted (P), and non infarcted myocardium (M)...

Cholestasis in a murine experimental model: lesions include hepatocyte ischemic necrosis.

OBJECTIVE: To establish a murine experimental model of bile duct obstruction that would enable controlled observations of the acute and subacute phases of cholestasis. METHODOLOGY: Adult male isogenic BALB/c mice underwent a bile duct ligation (22 animals) or a sham operation (10 animals). Fifteen days after surgery, or immediately after the animal's death, macroscopic findings were noted and histological study of the liver, biliary tree, and pancreas was performed (hematoxylin-eosin and Masson trichromic staining). RESULTS: Beginning 24 hours after surgery, all animals from the bile duct ligation group presented progressive generalized malaise. All animals presented jaundice in the parietal and visceral peritoneum, turgid and enlarged liver, and accentuated dilatation of gallbladder and common bile duct. Microscopic findings included marked dilatation and proliferation of bile ducts with accentuated collagen deposits, frequent areas of ischemic necrosis, hepatic microabscesses, and purulent cholangitis. Animals from the sham operation group presented no alterations. CONCLUSION: We established a murine experimental model of induced cholestasis, which made it possible to study acute and subacute tissue lesions. Our data suggests that in cholestasis, hepatic functional ischemia plays an important role in inducing hepatic lesions, and it also suggests that the infectious process is an important factor in morbidity and mortality.

Cholestasis in a murine experimental model: lesions include hepatocyte ischemic necrosis

OBJECTIVE: To establish a murine experimental model of bile duct obstruction that would enable controlled observations of the acute and subacute phases of cholestasis. METHODOLOGY: Adult male isogenic BALB/c mice underwent a bile duct ligation (22 animals) or a sham operation (10 animals). Fifteen days after surgery, or immediately after the animal's death, macroscopic findings were noted and histological study of the liver, biliary tree, and pancreas was performed (hematoxylin-eosin and Masson trichromic staining). RESULTS: Beginning 24 hours after surgery, all animals from the bile duct ligation group presented progressive generalized malaise. All animals presented jaundice in the parietal and visceral peritoneum, turgid and enlarged liver, and accentuated dilatation of gallbladder and common bile duct. Microscopic findings included marked dilatation and proliferation of bile ducts with accentuated collagen deposits, frequent areas of ischemic necrosis, hepatic microabscesses, and purulent cholangitis. Animals from the sham operation group presented no alterations. CONCLUSION: We established a murine experimental model of induced cholestasis, which made it possible to study acute and subacute tissue lesions. Our data suggests that in cholestasis, hepatic functional ischemia plays an important role in inducing hepatic lesions, and it also suggests that the infectious process is an important factor in morbidity and mortality