RESUMO
Recent studies have revealed that familial hypertrophic cardiomyopathy (FHC) is caused by missence mutations in myosin heavy chain or other sarcomeric proteins. To investigate the functional impact of FHC mutations in myosin heavy chain, mutants of Dictyostelium discoideum myosin II equivalent to human FHC mutations were generated by site-directed mutagenesis, and their motor function was characterized at the molecular level. These mutants, i.e., R397Q, F506C, G575R, A699R, K703Q, and K703W are respectively equivalent to R403Q, F513C, G584R, G716R, R719Q, and R719W FHC mutants. We measured the force generated by these myosin mutants as well as the sliding velocity and the actin-activated ATPase activity. These measurements showed that the A699R, K703Q, and K703W myosins exhibited unexpectedly weak affinity with actin and the lowest level of force, though their ATPase activity remained rather high. F506C mutant which has been reported to have benign prognosis exhibited the least impairment of the motile and enzymatic activities. The motor functions of R397Q and G575R myosins were classified as intermediate. These results suggest that the force level of mutant myosin molecule may be one of the key factors for pathogenesis which affect the prognosis of human FHC.
Assuntos
Cardiomiopatia Hipertrófica/genética , Dictyostelium/genética , Regulação da Expressão Gênica , Mutagênese Sítio-Dirigida , Miosinas/genética , Miosinas/fisiologia , Actinas/metabolismo , Actinas/fisiologia , Adenosina Trifosfatases/metabolismo , Sequência de Aminoácidos , Animais , Eletroforese em Gel de Poliacrilamida , Vetores Genéticos , Humanos , Dados de Sequência Molecular , Estrutura Molecular , Miosinas/isolamento & purificação , Proteínas Recombinantes/metabolismo , Recombinação Genética , Transformação GenéticaRESUMO
We measured forces generated by myosin molecules and a single actin filament using an optical trap system. The force per unit length of actin filament did not differ significantly between cardiac myosin isoforms. V1 and V3. This indicates that the ability to generate force is equal between V1 and V3, despite their difference in the unloaded sliding velocity past actin.
Assuntos
Actinas/fisiologia , Coração/fisiologia , Miosinas/fisiologia , Animais , Metabolismo Energético , Contração Miocárdica , Ratos , Ratos WistarRESUMO
The difference in kinetic properties between two myosin isozymes (V1 and V3) in rat ventricular myocardium was studied by determining the steady-state force-velocity (P-V) relations in the ATP-dependent movement of V1 and V3-coated polystyrene beads on actin cables of giant algal cells mounted on a centrifuge microscope. The maximum unloaded velocity of bead movement was larger for V1 than for V3. The velocity of bead movement decreased with increasing external load applied by the centrifuge microscope, and eventually reached zero when the load was equal to the maximum isometric force (P0) generated by the myosin heads. The maximum isometric force P0 was less than 10 pN, and did not differ significantly between V1 and V3. The P-V curves consisted of a hyperbolic part in the low force range and a non-hyperbolic part in the high force range. The critical force above which the curve deviated from the hyperbola was much smaller for V1 than for V3. An analysis using a model with an extremely small number of myosin heads involved in the bead movement suggested a marked difference in kinetic properties between V1 and V3.
Assuntos
Miocárdio/enzimologia , Miosinas/química , Actinas , Animais , Eucariotos , Hipotireoidismo/induzido quimicamente , Hipotireoidismo/enzimologia , Cinética , Modelos Biológicos , Poliestirenos , Ratos , Ratos WistarRESUMO
BACKGROUND: Diminished myocardial vasodilatation (MVD) in hypercholesterolemics without overt coronary stenosis has been reported. However, whether the diminished MVD of angiographically normal coronary arteries in hypercholesterolemics can be reversed after lipid-lowering therapy is not known. METHODS AND RESULTS: A total of 27 hypercholesterolemics and 16 age-matched controls were studied. All patients had >1 normal coronary artery, and those segments that were perfused by anatomically normal coronary arteries were studied. Myocardial blood flow (MBF) was measured during dipyridamole loading and at baseline using positron emission tomography and 13N-ammonia, after which MVD was calculated before and after lipid-lowering therapy. Total cholesterol was significantly higher in hypercholesterolemics (263+/-33.8) than in controls (195+/-16.6), and it normalized after lipid-lowering therapy (197+/-19.9). Baseline MBF (ml. min-1. 100 g-1) was comparable among hypercholesterolemics (both before and after therapy) and controls. MBF during dipyridamole loading was significantly lower in hypercholesterolemics before therapy (189+/-75.4) than in controls (299+/-162, P<0.01). However, MBF during dipyridamole loading significantly increased after therapy (226+/-84.7; P<0.01). MVD significantly improved after therapy in hypercholesterolemics (2.77+/-1.35 after treatment [P<0.05] versus 2. 02+/-0.68 before treatment [P<0.01]), but it remained significantly higher in controls (3.69+/-1.13, P<0.01). There was a significant relationship between the percent change of total cholesterol and the percent change of MVD before and after lipid-lowering therapy (r=-0. 61, P<0.05). CONCLUSIONS: Diminished MVD of anatomically normal coronary arteries in hypercholesterolemics can be reversed after lipid-lowering therapy.
Assuntos
Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/fisiopatologia , Vasos Coronários/fisiopatologia , Hipercolesterolemia/complicações , Hipercolesterolemia/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Vasodilatação/fisiologia , Idoso , Circulação Coronária/efeitos dos fármacos , Circulação Coronária/fisiologia , Diabetes Mellitus/fisiopatologia , Dipiridamol/farmacologia , Eletrocardiografia , Feminino , Hemodinâmica/fisiologia , Humanos , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Vasodilatadores/farmacologiaRESUMO
To clarify if coronary flow reserve (CFR) is related to insulin resistance or hyperglycemia in normotensive NIDDM, myocardial blood flow (MBF) at baseline and during dipyridamole loading were measured with 13N-ammonia positron-emission tomography. CFR was significantly reduced in NIDDM patients compared with age-matched control subjects. CFR in patients with well-controlled NIDDM was significantly higher than in those with poorly controlled NIDDM, whereas insulin resistance was comparable between the two groups. CFR in NIDDM patients was not related to the degree of insulin resistance. CFR correlated significantly with average fasting glucose concentration and average HbA1c, but not with insulin resistance, age, lipid parameters, or blood pressure. In conclusion, control of blood glucose concentration rather than insulin resistance is most likely related to the reduced CFR in NIDDM.
Assuntos
Vasos Coronários/fisiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Hiperglicemia/fisiopatologia , Resistência à Insulina/fisiologia , Adulto , Idoso , Glicemia/análise , Pressão Sanguínea/fisiologia , Diabetes Mellitus Tipo 2/sangue , Dipiridamol/farmacologia , Eletrocardiografia , Feminino , Hemoglobinas Glicadas/análise , Hemodinâmica , Humanos , Hiperglicemia/sangue , Insulina/sangue , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Fluxo Sanguíneo Regional/fisiologia , Tomografia Computadorizada de EmissãoRESUMO
The relation between left ventricular diastolic abnormalities and myocardial blood flow during ischemia was studied in eight open chest dogs with critical stenoses of the proximal left anterior descending and circumflex coronary arteries. The heart was paced at 1.7 times the heart rate at rest for 3 min. In dogs with coronary stenoses, left ventricular end-diastolic pressure increased from 8 +/- 1 to 14 +/- 2 mm Hg during pacing tachycardia (p less than 0.01) and 16 +/- 3 mm Hg (p less than 0.01) after pacing, with increased end-diastolic and end-systolic segment lengths in the ischemic regions. Left ventricular diastolic pressure-segment length relations for ischemic regions shifted upward during and after pacing tachycardia in dogs with coronary stenoses, indicating decreased regional diastolic distensibility. In dogs without coronary stenoses, the left ventricular diastolic pressure-segment length relation was unaltered. Pacing tachycardia without coronary stenoses induced an increase in anterograde coronary blood flow (assessed by flow meter) in both the left anterior descending and circumflex coronary arteries, and a decrease in regional vascular resistance. In dogs with coronary stenoses, regional vascular resistance before pacing was decreased by 18%; myocardial blood flow (assessed by microspheres) was unchanged in both the left anterior descending and circumflex coronary artery territories. During pacing tachycardia with coronary stenoses, regional coronary vascular resistance did not decrease further; subendocardial myocardial blood flow distal to the left anterior descending coronary artery stenosis decreased (from 1.03 +/- 0.07 to 0.67 +/- 0.12 ml/min per g, p less than 0.01), as did subendocardial to subepicardial blood flow ratio (from 1.04 +/- 0.09 to 0.42 +/- 0.08, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Estimulação Cardíaca Artificial , Circulação Coronária/fisiologia , Doença das Coronárias/fisiopatologia , Função Ventricular Esquerda/fisiologia , Animais , Doença das Coronárias/etiologia , Diástole/fisiologia , Cães , Hemodinâmica/fisiologia , Taquicardia/fisiopatologia , Resistência Vascular/fisiologiaRESUMO
OBJECTIVES: We analyzed myocardial flow reserve (MFR) in patients with non-insulin-dependent (type II) diabetes mellitus (NIDDM) without symptoms and signs of ischemia. BACKGROUND: Diminished MFR in diabetes has been suggested. However, it remains controversial whether MFR is related to glycemic control, mode of therapy or gender in NIDDM. METHODS: Myocardial blood flow (MBF) was measured at baseline and during dipyridamole loading in 25 asymptomatic, normotensive, normocholesterolemic patients with NIDDM and 12 age-matched control subjects by means of positron emission tomography and nitrogen-13 ammonia, after which MFR was calculated. RESULTS: Baseline MBF in patients with NIDDM ([mean +/- SD] 74.0 +/- 24.0 ml/min per 100 g body weight) was comparable to that in control subjects (73.0 +/- 17.0 ml/min per 100 g). However, MBF during dipyridamole loading was significantly lower in patients with NIDDM (184 +/- 99.0 ml/min per 100 g, p < 0.01) than in control subjects (262 +/- 120 ml/min per 100 g), as was MFR (NIDDM: 2.77 +/- 0.85; control subjects: 3.8 +/- 1.0, p < 0.01). A significantly decreased MFR was seen in men (2.35 +/- 0.84) compared with women with NIDDM (3.18 +/- 0.79, p < 0.05); however, no significant differences were found in terms of age, hemoglobin a1c and baseline MBF. MFR was comparable between the diet (2.78 +/- 0.80) and medication therapy groups (2.76 +/- 0.77) and was inversely correlated with average hemoglobin A1c for 5 years (r = -0.55, p < 0.01) and fasting plasma glucose concentration (r = -0.57, p < 0.01) but not age or lipid fractions. CONCLUSIONS: Glycemic control and gender, rather than mode of therapy, is related to MFR in NIDDM.
Assuntos
Circulação Coronária , Diabetes Mellitus Tipo 2/fisiopatologia , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Cardiovasculares , Fatores SexuaisRESUMO
OBJECTIVES: This study sought to investigate the specific role of hypertriglyceridemia in the myocardial hyperemic stress with dipyridamole/rest flow ratio (MDR). BACKGROUND: Reduced MDR has been reported in hypercholesterolemic patients without evidence of ischemia. However, the specific role of hypertriglyceridemia in MDR has not been studied. METHODS: Fifteen nondiabetic normocholesterolemic hypertriglyceridemic patients and 13 age-matched control subjects were studied. Myocardial blood flow (MBF) during dipyridamole administration and baseline MBF in hypertriglyceridemic patients and control subjects were measured using positron emission tomography and nitrogen-13 ammonia, after which the MDR was calculated. RESULTS: Baseline MBF (ml/min per 100 g heart weight) in hypertriglyceridemic patients (mean +/- SD 73.6 +/- 24.1) did not differ significantly from that in control subjects (81.6 +/- 37.2). MBF during dipyridamole loading in hypertriglyceridemic patients (198 +/- 106) was significantly reduced compared with that in control subjects (313 +/- 176, p < 0.05), as was the MDR (2.71 +/- 1.07 vs. 3.73 +/- 1.14, respectively, p < 0.05). Spearman rank-order correlation analysis showed a significant relation between plasma triglyceride concentration and MDR (r = -0.466, asymptotic SE 0.157, p = 0.0125); however, no such significant relation was seen between total plasma cholesterol concentration and MDR (r = -0.369, asymptotic SE 0.130, p = 0.059). CONCLUSIONS: Impaired myocardial vasodilation was suggested in hypertriglyceridemic patients without symptoms and signs of ischemia.
Assuntos
Circulação Coronária , Coração/fisiopatologia , Hiperemia/fisiopatologia , Hipertrigliceridemia/fisiopatologia , Adulto , Dipiridamol , Eletrocardiografia , Teste de Esforço , Feminino , Testes de Função Cardíaca , Hemodinâmica , Humanos , Hipertrigliceridemia/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada de Emissão , Vasodilatação , VasodilatadoresRESUMO
OBJECTIVES: We measured end-tidal CO2 pressure (PETCO2) during exercise and investigated the relationship between PETCO2 and exercise capacity, ventilatory parameters and cardiac output to determine the mechanism(s) of changes in this parameter. BACKGROUND: It is unclear whether PETCO2 is abnormal at rest and during exercise in cardiac patients. METHODS: Cardiac patients (n = 112) and normal individuals (n = 29) performed exercise tests with breath-by-breath gas analysis, and measurement of cardiac output and arterial blood gases. RESULTS: PETCO2 was lower in patients than in normal subjects at rest and decreased as the New York Heart Association class increased, whereas the partial pressure of arterial CO2 did not differ among groups. Although PETCO2 increased during exercise in patients, it remained lower than in normal subjects. PETCO2 in relation to cardiac output was similar in patients and normal subjects. PETCO2 at the respiratory compensation point was positively correlated with the O2 uptake (r = 0.583, p < 0.0001) and the cardiac index at peak exercise (r = 0.582, p < 0.0001), and was negatively correlated with the ratio of physiological dead space to the tidal volume. The sensitivity and specificity of PETCO2 to predict an inadequate cardiac output were 76.6% and 75%, respectively, when PETCO2 at respiratory compensation point and a cardiac index at peak exercise that were less than the respective control mean-2 SD values were considered to be abnormal. CONCLUSIONS: PETCO2 was below normal in cardiac patients at rest and during exercise. PETCO2 was correlated with exercise capacity and cardiac output during exercise, and the sensitivity and specificity of PETCO2 regarding decreased cardiac output were good. PETCO2 may be a new ventilatory abnormality marker that reflects impaired cardiac output response to exercise in cardiac patients diagnosed with heart failure.
Assuntos
Dióxido de Carbono/sangue , Débito Cardíaco , Exercício Físico/fisiologia , Insuficiência Cardíaca/fisiopatologia , Limiar Anaeróbio/fisiologia , Gasometria , Teste de Esforço , Feminino , Insuficiência Cardíaca/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Índice de Gravidade de Doença , Volume de Ventilação Pulmonar/fisiologiaRESUMO
The end-systolic pressure-volume relation has been postulated as a load-independent measure of cardiac contractility, but has been difficult to measure because of technical problems associated with the serial measurement of intracardiac volume over a physiologic range of ventricular loading conditions. Utilizing a multielectrode impedance catheter to assess continuous, on-line left ventricular relative volume during transient inferior vena cava occlusion, a method is described for determining the end-systolic pressure-volume relation and for assessing changes in this relation secondary to inotropic modulation. In particular, using this method, the relative inotropic properties were determined of four drugs: dobutamine, milrinone, epinephrine and an experimental cardiotonic agent (Ro 13-6438, Posicor). Left ventricular micromanometer pressure and impedance catheter volume were measured continuously in 10 open chest, anesthetized dogs and 14 pigs. Arterial pressure was altered over a range of 20 to 60 mm Hg by brief inferior vena cava constriction. A linear end-systolic pressure-volume relation was observed in pressure-volume diagrams constructed from on-line pressure and impedance catheter recordings. Administration of dobutamine, milrinone and epinephrine resulted in a leftward shift and an increase in the slope of the end-systolic pressure-volume relation as compared with baseline; Posicor did not alter the slope over a range of doses, despite an increase in the cardiac output secondary to arterial vasodilation. Volume changes as measured by the impedance method closely paralleled simultaneous changes in the ultrasonic crystal-determined segment length, and the impedance end-systolic pressure-volume relation slope was reproducible with repeated load-altering maneuvers.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Cardiotônicos/farmacologia , Dobutamina/farmacologia , Epinefrina/farmacologia , Contração Miocárdica/efeitos dos fármacos , Piridonas/farmacologia , Quinazolinas/farmacologia , Volume Sistólico/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Cardiografia de Impedância , Constrição , Cães , Avaliação Pré-Clínica de Medicamentos , Frequência Cardíaca/efeitos dos fármacos , Milrinona , Suínos , Veia Cava InferiorRESUMO
Fungal endocarditis caused by Candida species is associated with high morbidity and mortality. A combination of surgical resection and antifungal drug therapy is the golden standard for treatment. We reported a case of fungal endocarditis due to Candida lusitaniae found at onset of lower limb acute aortic occlusion cured by emergency operation. This case suggests that Candida endocariditis can be managed medically with antifungal drug therapy in life time.
Assuntos
Doenças da Aorta/cirurgia , Arteriopatias Oclusivas/cirurgia , Candidíase/cirurgia , Endocardite/cirurgia , Doença Aguda , Antifúngicos/uso terapêutico , Doenças da Aorta/diagnóstico , Arteriopatias Oclusivas/diagnóstico , Candidíase/tratamento farmacológico , Terapia Combinada , Endocardite/tratamento farmacológico , Fluconazol/uso terapêutico , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: The clinical use of skeletal muscle cardiomyoplasty is limited because of its inadequate haemodynamic benefits. To facilitate experimental and clinical efforts to improve the efficacy of this technique, a mathematical model was proposed and its validity was tested in acute experiments. METHODS: The model was based on the assumption that the skeletal muscle wrapped around the heart behaves as a time varying elastance that is connected in series with another time varying elastance representing the native heart. From this model two predictions were made: (1) Skeletal muscle augments the contractility of the heart by increasing the slope (Ees) of the end systolic pressure-volume relation; (2) time varying elastance of the skeletal muscle chamber (Es(t)) can be estimated from that of the assisted heart. These predictions were examined in experiments. In nine anaesthetised, open chest dogs, preconditioned latissimus dorsi muscle was transposed to wrap the heart. Left ventricular pressure (catheter tipped micromanometer), and volume (conductance catheter) were measured while reducing the preload by vena caval occlusion to evaluate Ees with 1:2 (stimulation:heart beat ratio) stimulation of the skeletal muscle. RESULTS: With the stimulation of latissimus muscle, the end systolic pressure-volume relation was linear and Ees increased from 8.6(SEM 2.4) to 11.9(SEM 3.4) mm Hg.ml-1. Estimated Es(t) reflected the stimulation pattern and could account for the mechanism of the cardiac assistance. CONCLUSIONS: Skeletal muscle cardiomyoplasty improved the haemodynamic variable (Ees) as predicted by a mathematical model.
Assuntos
Circulação Assistida/métodos , Insuficiência Cardíaca/fisiopatologia , Coração/fisiopatologia , Modelos Cardiovasculares , Músculos/transplante , Animais , Cães , Insuficiência Cardíaca/cirurgia , Hemodinâmica , Matemática , Contração Miocárdica/fisiologiaRESUMO
UNLABELLED: Familial hypercholesterolemia (FH) presents the highest risk for coronary artery disease (CAD) among patients with hyperlipidemia. Therefore, early detection of coronary arterial atherosclerosis is important for the treatment of FH patients. The aim of this study was to detect early coronary arterial abnormalities that may relate to future atherosclerosis in asymptomatic FH patients by measuring coronary flow reserve (CFR) using PET and 13N-ammonia. METHODS: Twenty-five patients with FH (14 men, 11 women) without a history of myocardial ischemia and 14 control subjects (9 men, 5 women) were studied. Total serum cholesterol (mmole/liter) was 5.33 +/- 0.66 in control subjects and 7.90 +/- 0.77 in FH patients (p < 0.01 versus control subjects). RESULTS: Myocardial blood flow (MBF) at rest and during dipyridamole loading was measured using PET, and CFR was calculated. MBF (ml/min/100 g weight heart) at rest in the FH group (79.0 +/- 20.0) was comparable to that in control subjects (70.0 +/- 17.0). However, MBF during dipyridamole loading was significantly lower in FH patients (163.0 +/- 67.0) than in control subjects (286.0 +/- 120.0, p < 0.01). CFR in FH patients (2.09 +/- 0.62) was also significantly lower than that in control subjects (4.13 +/- 1.38, p < 0.01). CFR showed a gender-specific variance in FH patients (1.85 +/- 0.40 in men versus 2.55 +/- 0.74 in women p < 0.05) but not in control subjects. Significant inverse correlations between CFR and the total plasma cholesterol level as well as plasma LDL cholesterol were observed. CONCLUSION: The CFR was reduced in patients with FH. This abnormality was more prominent in men than in women patients. Noninvasive assessment of CFR by 13N-ammonia PET was useful to detect early abnormalities of the coronary arteries in asymptomatic patients with FH.
Assuntos
Circulação Coronária , Hiperlipoproteinemia Tipo II/fisiopatologia , Tomografia Computadorizada de Emissão , Amônia , Colesterol/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/etiologia , Dipiridamol , Feminino , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/complicações , Masculino , Pessoa de Meia-Idade , Radioisótopos de Nitrogênio , VasodilatadoresRESUMO
UNLABELLED: Abnormal heart and skeletal muscle glucose metabolism in diabetes or essential hypertension has been demonstrated. However, the role of hypertension in heart and skeletal muscle glucose utilization in diabetes has not been clarified yet. METHODS: We compared heart and skeletal muscle glucose utilization using PET and the whole-body glucose disposal rate (GDR) during insulin clamping in 9 patients with noninsulin-dependent diabetes mellitus (NIDDM) and essential hypertension and 11 patients with NIDDM without hypertension to examine the effect of hypertension on heart and skeletal muscle glucose utilization. Results also were compared with those for 8 asymptomatic healthy control participants. RESULTS: Skeletal muscle glucose utilization rate was comparable between hypertensive NIDDM patients (61.2 +/- 55.5 micromol x min(-1) x kg(-1)) and normotensive NIDDM patients (50.9 +/- 25.2 micromol x min(-1) x kg(-1)) but was significantly reduced in both groups compared with control subjects (94.2 +/- 57.3 micromol x min(-1) x kg(-1)), as was the GDR (25.2 +/- 11.3 and 24.0 +/- 7.5 micromol x min(-1) x kg(-1)), respectively, for patients compared with 38.5 +/- 11.5 micromol x min(-1) x kg(-1) for control participants). However, the myocardial glucose utilization (MGU) rate was significantly reduced in NIDDM patients without hypertension (389 +/- 185 micromol x min(-1) x kg(-1)) than in those with hypertension (616 +/- 86.4 micromol x min(-1) x kg(-1), p < 0.01). Multivariate stepwise regression analysis has shown that MGU was significantly correlated with systolic blood pressure and plasma free fatty acid concentration. CONCLUSION: Whole-body insulin resistance was observed in NIDDM patients independent of hypertension. The MGU rate may have different properties to oppose insulin resistance than glucose utilization of skeletal muscle in hypertensive patients with NIDDM.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Angiopatias Diabéticas/metabolismo , Glucose/metabolismo , Hipertensão/metabolismo , Resistência à Insulina , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , Tomografia Computadorizada de Emissão , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Angiopatias Diabéticas/diagnóstico por imagem , Ácidos Graxos não Esterificados/sangue , Feminino , Radioisótopos de Flúor , Fluordesoxiglucose F18 , Técnica Clamp de Glucose , Coração/diagnóstico por imagem , Humanos , Hipertensão/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Compostos RadiofarmacêuticosRESUMO
UNLABELLED: Abnormal heart and skeletal muscle 18F-fluorodeoxyglucose (FDG) uptake in patients with insulin resistance has been demonstrated. Although the existence of whole-body insulin resistance has been reported in hypertriglyceridemics, its specific role in heart and skeletal muscle FDG uptake in hypertriglyceridemics has not been clarified. METHODS: We compared heart and skeletal muscle FDG uptake using PET and the whole-body glucose disposal rate (GDR) during insulin clamping in 17 hypertriglyceridemics and 12 age-matched control subjects to increase our knowledge of whole-body insulin resistance and its relationship to heart and skeletal muscle FDG uptake in hypertriglyceridemics. RESULTS: GDR was significantly reduced in hypertriglyceridemics compared with control subjects (4.50 +/- 1.37 mg/min/kg versus 10.0 +/- 2.97 mg/min/kg, P = 0.00001), as were the skeletal muscle FDG Ki = (k1 x k3)/(k2 + k3) (SFKi: 0.007 +/- 0.003 mL/min/g versus 0.018 +/- 0.01 mL/min/g, P = 0.0001) and skeletal muscle FDG uptake ([SMFU] 0.725 +/- 0.282 mg/min/100 g versus 1.86 +/- 1.06 mg/min/100 g, P = 0.00023). However, myocardial FDG Ki (MFKi) tended to be reduced in hypertriglyceridemics compared with that in control subjects (0.062 +/- 0.017 mL/min/g versus 0.068 +/- 0.015 mL/min/g), but the difference was statistically insignificant (P = 0.3532). Moreover, myocardial FDG uptake (MFU) in hypertriglyceridemics (6.47 +/- 1.72 mg/min/100 g) tended to be reduced compared with that in control subjects (6.97 +/- 1.73 mg/min/100 g), but the difference was statistically insignificant (P = 0.4485). GDR was significantly correlated with SFKi (r = 0.69, P = 0.0022), SMFU (r = 0.612, P = 0.009), MFKi (r = 0.57, P = 0.0174) and MFU (r = 0.505, P = 0.0385) in hypertriglyceridemics. CONCLUSION: Both heart and skeletal muscle glucose utilization were related to insulin resistance in hypertriglyceridemics. However, the less severe reduction in MFU (compared with SMFU) suggests that myocardium may have a mechanism to oppose insulin resistance in hypertriglyceridemics.
Assuntos
Coração/diagnóstico por imagem , Hipertrigliceridemia/diagnóstico por imagem , Resistência à Insulina , Insulina/fisiologia , Músculo Esquelético/diagnóstico por imagem , Tomografia Computadorizada de Emissão , Estudos de Casos e Controles , Feminino , Radioisótopos de Flúor , Fluordesoxiglucose F18 , Glucose/metabolismo , Técnica Clamp de Glucose , Humanos , Hipertrigliceridemia/metabolismo , Masculino , Pessoa de Meia-Idade , Compostos RadiofarmacêuticosRESUMO
Patients with chronic heart failure performed exercise tests to evaluate the relation of kinetics of oxygen uptake to cardiac output and arteriovenous oxygen difference at the onset of exercise. The kinetics of oxygen uptake are primarily determined by cardiac output; these kinetics are useful in evaluating exercise intolerance and cardiac output response during exercise.
Assuntos
Débito Cardíaco/fisiologia , Exercício Físico/fisiologia , Insuficiência Cardíaca/fisiopatologia , Consumo de Oxigênio/fisiologia , Oxigênio/sangue , Adulto , Artérias/química , Doença Crônica , Teste de Esforço , Feminino , Insuficiência Cardíaca/sangue , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Veias/químicaRESUMO
Changes in parameters of left ventricular (LV) diastolic filling flow obtained with Doppler echocardiography during the lower body positive and negative pressure method were analyzed in 15 patients (12 with coronary artery disease and 3 with dilated cardiomyopathy). Lower body pressure was altered at 5 steps (+20, +10, 0, -20 and -40 mm Hg vs atmospheric pressure). Pulmonary capillary wedge pressure measured with a balloon-tipped catheter was changed proportionally with lower body pressure during the procedures (p less than 0.01). Mean systemic arterial pressure was changed slightly during lower body positive pressure and negative pressure of -40 mm Hg. Heart rate was almost unchanged except at lower body pressure of -40 mm Hg. The peak velocity of LV early diastolic filling flow was changed with pulmonary capillary wedge pressure in an almost parallel fashion during the procedures (p less than 0.01). The peak velocity of LV late diastolic filling flow showed smaller changes than that of early diastolic filling flow. Changes in pulmonary capillary wedge pressure correlated positively with changes in the peak velocity of LV early diastolic filling flow (r = 0.759, p less than 0.01), but not with changes in the peak velocity of LV late diastolic filling flow (r = 0.039, not significant) during lower body negative pressure of -20 mm Hg. These data suggest that left atrial pressure is one of the important determinants of LV early diastolic filling flow in this acute clinical setting and that LV late diastolic filling flow is less sensitive to changes in left atrial pressure than LV early diastolic filling flow.
Assuntos
Circulação Coronária , Descompressão , Ecocardiografia Doppler , Coração/fisiologia , Pressão Negativa da Região Corporal Inferior , Adulto , Idoso , Velocidade do Fluxo Sanguíneo , Diástole , Ventrículos do Coração , Hemodinâmica , Humanos , Masculino , Pessoa de Meia-Idade , Pressão Propulsora PulmonarRESUMO
To elucidate the mechanism of the Ca(2+)-sensitizing action of pimobendan, cardiac thin filaments were reconstituted from actin and tropomyosin-troponin complex and made to slide on a myosin layer. Although filaments showed Brownian movement with a low Ca2+ concentration, they slid at a constant velocity above a certain level of Ca2+ concentration, showing that the sliding was regulated by Ca2+ within a narrow pCa range. Acidosis, addition of inorganic phosphate, and phosphorylation of troponin I increased the threshold Ca2+ concentration. Addition of pimobendan reversed these desensitization effects. These results clearly demonstrated that pimobendan directly increases the Ca2+ sensitivity of thin filament.
Assuntos
Cálcio/metabolismo , Cardiotônicos/farmacologia , Miosinas/efeitos dos fármacos , Piridazinas/farmacologia , Animais , Masculino , Ratos , Ratos WistarRESUMO
BACKGROUND: Nitric oxide (NO) plays an important role in renal hemodynamics and function. Although production of NO in the glomeruli has been found to be increased in animal models of glomerulonephritis, it remains unclear whether its endogenous production is enhanced in patients with chronic glomerulonephritis (CGN). SUBJECTS AND METHODS: We measured NO output in exhaled air as an indicator of its local production in the lungs and plasma and urinary nitrite plus nitrate (NO2-/NO3-) levels as indicators of its production in the whole body in 21 patients with CGN in 31 healthy controls. RESULTS: The patients exhaled higher concentrations of NO (29.5 +/- 1.4 vs. 18.7 +/- 1.0 parts per billion (ppb), mean +/- SEM, p < 0.0001) and exhaled NO output was also higher than in controls (166.6 +/- 6.8 vs. 95.5 +/- 5.6 nl/min/m2, p < 0.0001). Plasma NO2-/NO3- concentrations were also significantly greater in the patients than in the controls (81.6 +/- 7.2 vs. 41.1 +/- 4.3 micromol/l, p < 0.001). In patients with CGN, exhaled NO output correlated negatively with creatinine clearance (r = -0.62, p < 0.05). Oral administration of prednisolone (60 mg/day) for two weeks did not significantly affect the exhaled NO output in the patients (160 +/- 7 vs. 200 +/- 30 nl/min/m2, p = NS) despite a decrease in urinary protein excretion (12.0 +/- 2.9 vs. 1.4 +/- 0.6 g/day, p < 0.01). CONCLUSION: These findings suggested that endogenous NO production is increased in patients with CGN. Increased endogenous NO production may play some pathophysiological role in these patients.
Assuntos
Sequestradores de Radicais Livres/análise , Glomerulonefrite/metabolismo , Óxido Nítrico/análise , Respiração , Administração Oral , Análise de Variância , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Estudos de Casos e Controles , Doença Crônica , Creatinina/sangue , Feminino , Sequestradores de Radicais Livres/metabolismo , Glomerulonefrite/sangue , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/urina , Humanos , Glomérulos Renais/metabolismo , Pulmão/metabolismo , Masculino , Pessoa de Meia-Idade , Nitratos/sangue , Nitratos/urina , Óxido Nítrico/biossíntese , Nitritos/sangue , Nitritos/urina , Prednisolona/administração & dosagem , Prednisolona/uso terapêutico , Proteinúria/tratamento farmacológico , Proteinúria/urina , EspirometriaRESUMO
Familial hypertrophic cardiomyopathy (FHC) is caused by missence mutations in beta-myosin heavy chain or other various sarcomeric proteins. To elucidate the functional impact of FHC mutations in myosin heavy chain, we generated Dictyostelium discoideum myosin II mutants equivalent to human FHC mutations by site-directed mutagenesis, and characterized their molecular-basis motor function. The current mutants, i.e. R397Q, F506C, G575R, A699R, K703Q and K703W are equivalent to R403Q, F513C, G584R, G716R, R719Q and R719W FHC mutants respectively. We measured the molecular-basis force and the sliding velocity generated by these myosin mutants. The measurement revealed that the A699R, K703Q and K703W myosins exhibited the lowest level of force with their preserved actin-activated MgATPase activity. F506C mutant showed the least impairment of the motile and enzymatic activities. The motor function of R397Q and G575R myosins were classified as intermediate. These results suggest that ELC binding domain might be important for force production.