Marine n3 polyunsaturated fatty acids enhance resistance to mitochondrial permeability transition in heart failure but do not improve survival.

Mitochondrial dysfunction in heart failure includes greater susceptibility to mitochondrial permeability transition (MPT), which may worsen cardiac function and decrease survival. Treatment with a mixture of the n3 polyunsaturated fatty acids (n3 PUFAs) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) is beneficial in heart failure patients and increases resistance to MPT in animal models. We assessed whether DHA and EPA have similar effects when given individually, and whether they prolong survival in heart failure. Male δ-sarcoglycan null cardiomyopathic hamsters were untreated or given either DHA, EPA, or a 1:1 mixture of DHA + EPA at 2.1% of energy intake. Treatment did not prolong survival: mean survival was 298 ± 15 days in untreated hamsters and 335 ± 17, 328 ± 14, and 311 ± 15 days with DHA, EPA, and DHA + EPA, respectively (n = 27-32/group). A subgroup of cardiomyopathic hamsters treated for 26 wk had impaired left ventricular function and increased cardiomyocyte apoptosis compared with normal hamsters, which was unaffected by n3 PUFA treatment. Evaluation of oxidative phosphorylation in isolated subsarcolemmal and interfibrillar mitochondria with substrates for complex I or II showed no effect of n3 PUFA treatment. On the other hand, interfibrillar mitochondria from cardiomyopathic hamsters were significantly more sensitive to Ca(2+)-induced MPT, which was completely normalized by treatment with DHA and partially corrected by EPA. In conclusion, treatment with DHA or EPA normalizes Ca(2+)-induced MPT in cardiomyopathic hamsters but does not prolong survival or improve cardiac function. This suggest that greater susceptibility to MPT is not a contributor to cardiac pathology and poor survival in heart failure.

Early Change in Area Strain Detected by 3D Speckle Tracking Is Associated With Subsequent Cardiotoxicity in Patients Treated With Low Doses of Anthracyclines.

Objective: To evaluate the prognostic impact of the parameters of myocardial deformation using three-dimensional speckle tracking echocardiography (3DSTE) in patients with breast cancer who underwent chemotherapy with low doses of anthracyclines. Background: Chemotherapy-related cardiotoxicity has an important prognostic impact on cancer survivors. Three-dimensional STE has revealed more consistent data than two-dimensional techniques and may represent a more accurate tool in the evaluation of myocardial function in patients who underwent chemotherapy. Methods: We evaluated patients with breast cancer who were treated with anthracyclines (associated or not with trastuzumab) in five stages: baseline, after cumulative doses of 120 and 240 mg/m2 of doxorubicin, and then, after 6 months and at least 1 year after anthracyclines. Ultrasensitive troponin I (US-TnI) and a standard echocardiography study were performed at each stage. We analyzed left ventricular ejection fraction (LVEF) by Simpson's method, two-dimensional speckle tracking (2DSTE) with longitudinal and radial strain values, and 3DSTE with longitudinal, radial, and circumferential strain as well as twist, torsion, rotation, and three-dimensional global area strain (3DGAS). Cardiotoxicity was defined as a decrease in LVEF by more than 10 percentage points to a value lower than 53%. Results: We evaluated 51 female patients who were aged 50.6 ± 11 years. After the cumulative dose of 240 mg/m2 of doxorubicin, US-TnI was increased (>34 pg/ml) in 21 patients (45%, p > 0.001), LVEF remained unchanged (p = 0.178), while 2DSTE longitudinal strain was decreased (from -17.8% to -17.1%, p < 0.001) and 3DSTE detected changes in longitudinal, radial, circumferential, and area strain. After a lower cumulative dose of doxorubicin (120 mg/m2), 3DGAS (p < 0.001) was the only parameter that was changed. In the follow-up, 7 (13%) patients presented a decrease in LVEF. Three-dimensional GAS early changed to abnormal values was the only variable associated with a subsequent decrease in LVEF (definitive cardiotoxicity). Conclusion: In patients with breast cancer, 3DSTE detected early changes in area strain after very low doses of doxorubicin. The 3DGAS early changed to abnormal values was associated with a subsequent decrease in LVEF, representing a promising technique to predict chemotherapy-induced cardiomyopathy.

Effects of environmental stress following myocardial infarction on behavioral measures and heart failure progression: The influence of isolated and group housing conditions.

BACKGROUND: Heart failure (HF) prognosis is negatively influenced by adverse environmental conditions associated with psychological distress and depression. The underlying mechanisms are not well understood because of insufficient experimental control in prior clinical and epidemiological studies. Using a validated animal model we examined whether distress-producing environmental manipulations (social isolation and crowding) increase HF progression following myocardial infarction (MI). METHODS: MI was induced using coronary artery ligation in 8-week old male Wistar rats (N=52) and results were compared to sham surgery (N=24). Housing conditions were randomly assigned at 5 days post MI or sham surgery (1/cage=isolation, 2/cage=standard reference condition, or 4/cage=crowding) and continued for 17 weeks until the end of observation. The open field test was used to test behavioral responses. Echocardiograms were obtained at weeks 8 and 16, and left ventricular (LV) weight at week 17. RESULTS: Housing conditions increased behavioral markers of distress (p=0.046) with the strongest effects for the isolated (1/cage) (p=0.022). MI did not increase distress-related behaviors compared to sham. MI-surgery resulted in characteristic HF indices (left ventricular ejection fraction (LVEF) at week 16=46 ± 12% vs. 80 ± 7% in sham, p<0.001). Housing condition was not related to LVEF or LV weight (p>0.10). CONCLUSIONS: Adverse environmental conditions, particularly isolated housing, produce increases in some of the behavioral indicators of distress. No effects of housing were found on post-MI progression of HF. The distress-HF associations observed in humans may therefore reflect common underlying factors rather than an independent causal pathway. Stronger environmental challenges may be needed in future animal research examining distress as related HF progression.

High-sugar intake does not exacerbate metabolic abnormalities or cardiac dysfunction in genetic cardiomyopathy.

OBJECTIVE: A high-sugar intake increases heart disease risk in humans. In animals, sugar intake accelerates heart failure development by increased reactive oxygen species (ROS). Glucose-6-phosphate dehydrogenase (G6PD) can fuel ROS production by providing reduced nicotinamide adenine dinucleotide phosphate (NADPH) for superoxide generation by NADPH oxidase. Conversely, G6PD also facilitates ROS scavenging using the glutathione pathway. We hypothesized that a high-sugar intake would increase flux through G6PD to increase myocardial NADPH and ROS and accelerate cardiac dysfunction and death. METHODS: Six-week-old TO-2 hamsters, a non-hypertensive model of genetic cardiomyopathy caused by a δ-sarcoglycan mutation, were fed a long-term diet of high starch or high sugar (57% of energy from sucrose plus fructose). RESULTS: After 24 wk, the δ-sarcoglycan-deficient animals displayed expected decreases in survival and cardiac function associated with cardiomyopathy (ejection fraction: control 68.7 ± 4.5%, TO-2 starch 46.1 ± 3.7%, P < 0.05 for TO-2 starch versus control; TO-2 sugar 58.0 ± 4.2%, NS, versus TO-2 starch or control; median survival: TO-2 starch 278 d, TO-2 sugar 318 d, P = 0.133). Although the high-sugar intake was expected to exacerbate cardiomyopathy, surprisingly, there was no further decrease in ejection fraction or survival with high sugar compared with starch in cardiomyopathic animals. Cardiomyopathic animals had systemic and cardiac metabolic abnormalities (increased serum lipids and glucose and decreased myocardial oxidative enzymes) that were unaffected by diet. The high-sugar intake increased myocardial superoxide, but NADPH and lipid peroxidation were unaffected. CONCLUSION: A sugar-enriched diet did not exacerbate ventricular function, metabolic abnormalities, or survival in heart failure despite an increase in superoxide production.

High intake of saturated fat, but not polyunsaturated fat, improves survival in heart failure despite persistent mitochondrial defects.

AIMS: The impact of a high-fat diet on the failing heart is unclear, and the differences between polyunsaturated fatty acids (PUFA) and saturated fat have not been assessed. Here, we compared a standard low-fat diet to high-fat diets enriched with either saturated fat (palmitate and stearate) or PUFA (linoleic and α-linolenic acids) in hamsters with genetic cardiomyopathy. METHODS AND RESULTS: Male δ-sarcoglycan null Bio TO2 hamsters were fed a standard low-fat diet (12% energy from fat), or high-fat diets (45% fat) comprised of either saturated fat or PUFA. The median survival was increased by the high saturated fat diet (P< 0.01; 278 days with standard diet and 361 days with high saturated fat)), but not with high PUFA (260 days) (n = 30-35/group). Body mass was modestly elevated (∼10%) in both high fat groups. Subgroups evaluated after 24 weeks had similar left ventricular chamber size, function, and mass. Mitochondrial oxidative enzyme activity and the yield of interfibrillar mitochondria (IFM) were decreased to a similar extent in all TO2 groups compared with normal F1B hamsters. Ca(2+)-induced mitochondrial permeability transition pore opening was enhanced in IFM in all TO2 groups compared with F1B hamsters, but to a significantly greater extent in those fed the high PUFA diet compared with the standard or high saturated fat diet. CONCLUSION: These results show that a high intake of saturated fat improves survival in heart failure compared with a high PUFA diet or low-fat diet, despite persistent mitochondrial defects.

Cardioprotection conferred by exercise training is blunted by blockade of the opioid system.

OBJECTIVES: To investigate the effect of opioid receptor blockade on the myocardial protection conferred by chronic exercise and to compare exercise training with different strategies of myocardial protection (opioid infusion and brief periods of ischemia-reperfusion) preceding irreversible left anterior descending coronary ligation. INTRODUCTION: The acute cardioprotective effects of exercise training are at least partly mediated through opioid receptor-dependent mechanisms in ischemia-reperfusion models. METHODS: Male Wistar rats (n = 76) were randomly assigned to 7 groups: (1) control; (2) exercise training; (3) morphine; (4) intermittent ischemia-reperfusion (three alternating periods of left anterior descending coronary occlusion and reperfusion); (5) exercise training+morphine; (6) naloxone (a non-selective opioid receptor blocker) plus morphine; (7) naloxone before each exercise-training session. Myocardial infarction was established in all groups by left anterior descending coronary ligation. Exercise training was performed on a treadmill for 60 minutes, 5 times/week, for 12 weeks, at 60% peak oxygen (peak VO2). Infarct size was histologically evaluated. RESULTS: Exercise training significantly increased exercise capacity and ΔVO2 (VO2 peak - VO2 rest) (p < 0.01 vs. sedentary groups). Compared with control, all treatment groups except morphine plus naloxone and exercise training plus naloxone showed a smaller infarcted area (p < 0.05). No additional decrease in infarct size occurred in the exercise training plus morphine group. No difference in myocardial capillary density (p = 0.88) was observed in any group. CONCLUSIONS: Exercise training, morphine, exercise training plus morphine and ischemia-reperfusion groups had a smaller infarcted area than the control group. The effect of chronic exercise training in decreasing infarct size seems to occur, at least in part, through the opioid receptor stimulus and not by increasing myocardial perfusion.

Cardioprotection conferred by exercise training is blunted by blockade of the opioid system

OBJECTIVES: To investigate the effect of opioid receptor blockade on the myocardial protection conferred by chronic exercise and to compare exercise training with different strategies of myocardial protection (opioid infusion and brief periods of ischemia-reperfusion) preceding irreversible left anterior descending coronary ligation. INTRODUCTION: The acute cardioprotective effects of exercise training are at least partly mediated through opioid receptor-dependent mechanisms in ischemia-reperfusion models. METHODS: Male Wistar rats (n = 76) were randomly assigned to 7 groups: (1) control; (2) exercise training; (3) morphine; (4) intermittent ischemia-reperfusion (three alternating periods of left anterior descending coronary occlusion and reperfusion); (5) exercise training+morphine; (6) naloxone (a non-selective opioid receptor blocker) plus morphine; (7) naloxone before each exercise-training session. Myocardial infarction was established in all groups by left anterior descending coronary ligation. Exercise training was performed on a treadmill for 60 minutes, 5 times/week, for 12 weeks, at 60 percent peak oxygen (peak VO2). Infarct size was histologically evaluated. RESULTS: Exercise training significantly increased exercise capacity and ΔVO2 (VO2 peak - VO2 rest) (p<0.01 vs. sedentary groups). Compared with control, all treatment groups except morphine plus naloxone and exercise training plus naloxone showed a smaller infarcted area (p<0.05). No additional decrease in infarct size occurred in the exercise training plus morphine group. No difference in myocardial capillary density (p = 0.88) was observed in any group. CONCLUSIONS: Exercise training, morphine, exercise training plus morphine and ischemia-reperfusion groups had a smaller infarcted area than the control group. The effect of chronic exercise training in decreasing infarct size seems to occur, at least in part, through the opioid receptor stimulus and not by increasing ...

Validaçäo de questionário para diagnóstico de cefaléia em ambulatório de hospital universitário / Validation of a headache questionnarie in an outpatient clinic of an university hospital

A cefaléia é sintoma de alta prevalência na populaçäo, sendo queixa frequente na prática clínica. Cursa geralmente com exame físico geral e neurológico normais. A triagem de pacientes com cefaléia facilitaria o atendimento em centros médicos näo especializados. No presente estudo utilizou-se um questionário baseado nos critérios da Sociedade Internacional de Cefaléias modificado pelos autores em 204 pacientes de ambulatório do Hospital das Clínicas da FMUSP. Metade destes pacientes foi submetida a conculta clínica. Os resultados do questionário foram entäo comparados com os resultados da consulta clínica (padräo-ouro). As cefaléias encontradas eram primárias (89,6 por cento) na sua maioria. O questionário demonstrou sensibilidade de 90,2 por cento para detecçäo das enxaquecas e especificidade de 57,9 por cento, com coeficiente de comparaçäo (kappa) de 0,47, e valor preditivo positivo (VPP) de 65,7 por cento e um valor preditivo negativo (VPN) de 86,8. A sensibilidade para detecçäo de cefaléia do tipo-tensional foi 60,8 por cento e a especificidade foi 87,1 por cento com kappa de 0,49, e VPP de 77,8 por cento e VPN de 75,9. Concluíram que esse questionário pode ser utilizado como um método de triagem para o diagnóstico de cefaléias, podendo ser aplicado por pessoal nao médico. Futuramente, ele poderá ser utilizado em estudos populacionais.

Angiogenese: uma opcao no tratamento da doenca arterial coronaria / Angiogenesis: option in traitement of arterial coronary disease

Com o intuito de reverter-se o desequilibrio entre oferta e demanda de oxigenio miocardico vem se tentando, ao longo dos anos, promover o aumento do fluxo coronario. Uma alternativa e a estimulacao de um processo fisiologico: a angiogenese; processo complexo, resultante da interacao de varios fatores pelo qual novos vasos sao formados, como extensoes de vasos pre-existentes. Diversos metodos podem ser utilizados para se promover a angiogenese: os cirurgicos, a aplicacao local de fatores angiogenicos e a implantacao de celulas capilares autologas ex vivo. Investigacoes sobre os fatores de crescimento foram iniciados em 1971. Estudos posteriores demonstraram a existencia de varios outros fatores angiogenicos que foram divididos em duas categorias: fatores de crescimento peptidicos e fatores de baixo peso molecular...