存活心肌31P-MR波谱的研究

目的 :探讨存活心肌高能磷酸盐变化。方法 :用心脏电影磁共振成像 （Cine MRI）和 2 D- CSI31 P磁共振频谱（MRS）研究 17例急性前壁心肌梗死 6h内成功再灌注患者 6± 2 d后的磷酸肌酸 （PCr）与 ATP的比值 ;其中 16例患者急性前壁心肌梗死后 3 9± 8d再次做 31 P- MRS及心脏 Cine - MRI检查。7位健康自愿者作对照组参加研究。结果 :患者心功能明显恢复心肌阶段 （存活心肌 ） PCr/ ATP比值 ,早期为 1.5 3± 0 .16,晚期为 1.5 7± 0 .10 ,早期与晚期比较 ,早期与正常对照组 （1.5 9± 0 .13 ）比较均 P>0 .0 5。结论 :国人存活心肌状态下心肌 PCr/ ATP比值在正常范围内     

Effects of diltiazem on phosphate metabolism in ischemic and reperfused myocardium using phosphorus31 nuclear magnetic resonance spectroscopy in vivo

Diltiazem may provide a protective effect to ischemic and reperfused myocardium through preservation of high-energy phosphate metabolism. To test this hypothesis, rabbits had a 1.3 cm solenoidal coil placed over the myocardium to be rendered ischemic. Data were acquired with a 22 cm bore nuclear magnetic resonance spectrometer at 2.0 T. Animals were treated with diltiazem (200 micrograms/kg intravenous bolus of drug followed by a 15 micrograms/kg/min continuous intravenous infusion, n = 10) or by an equal volume of saline (n = 6). The left circumflex artery was occluded and reperfused using a reversible snare while electrocardiogram-gated spectra were accumulated. Levels of phosphocreatine were decreased during occlusion in both groups; however, this decrease was attenuated in the diltiazem treated animals compared to control (in relative percent area: 7.8 +/- 1.0 to 2.5 +/- 0.5, p less than 0.01). Levels of phosphocreatine promptly returned to baseline following reperfusion and there was no difference between the two groups. The inorganic phosphate metabolites of high-energy phosphate consumption increased with occlusion, though more so in the control group compared with the diltiazem-treated rabbits (in relative percent area: 72.5 +/- 0.9 to 55.4 +/- 1.3, p less than 0.01). With reperfusion, levels of inorganic phosphates returned toward baseline in both groups; however, the diltiazem group had a more complete recovery relative to control (in relative percent area: 38.8 +/- 2.1 to 47.6 +/- 2.7, p less than 0.05). Levels of adenosine triphosphate decreased in both groups relative to baseline; however, the amount of decrease was similar in the two groups. With reperfusion there was a definite though incomplete recovery of levels of adenosine triphosphate in the diltiazem-treated group (in relative percent area: 10.7 +/- 1.0 at occlusion, 12.3 +/- 0.4 during reperfusion, p less than 0.05), but in the control group levels of adenosine triphosphate remained depressed (in relative percent area: 9.8 +/- 0.6 at occlusion, 9.8 +/- 0.8 during reperfusion, p = NS). During ischemia there was a trend toward attenuation of intracellular acidosis in the diltiazem group; however, this trend did not reach statistical significance. These data indicate that diltiazem provides a protective effect on myocardial high-energy phosphate metabolism during regional ischemia and reperfusion in the intact animal.     

31P magnetic resonance spectroscopy in dilated cardiomyopathy and coronary artery disease. Altered cardiac high-energy phosphate metabolism in heart failure.

BACKGROUND. The purpose of this work was to further define the value of cardiac 31P magnetic resonance (MR) spectroscopy for patients with coronary artery disease and dilated cardiomyopathy. METHODS AND RESULTS. Blood-corrected and T1-corrected 31P MR spectra of anteroseptal myocardium were obtained at rest using image-selected in vivo spectroscopy localization, a selected volume of 85 +/- 12 cm3, and a field strength of 1.5 T. Nineteen volunteers had a creatine phosphate (CP)/ATP ratio of 1.95 +/- 0.45 (mean +/- SD) and a PDE/ATP ratio of 1.06 +/- 0.53; in four patients with left anterior descending coronary artery (LAD) stenosis, six patients with chronic anterior wall infarction, and four patients with chronic posterior wall infarction, CP/ATP and phosphodiester (PDE)/ATP ratios did not differ from those in volunteers. Twenty-five measurements of 19 patients with dilated cardiomyopathy yielded a CP/ATP of 1.78 +/- 0.51 and a PDE/ATP of 0.98 +/- 0.56 (p = NS versus volunteers). When these patients were grouped according to the severity of heart failure, however, CP/ATP was 1.94 +/- 0.43 in mild (p = NS versus volunteers) and 1.44 +/- 0.52 in severe DCM (p < 0.05), respectively. No correlation was found between CP/ATP and left ventricular ejection fraction or fractional shortening, but correlation of CP/ATP with the New York Heart Association (NYHA) class was significant (r = 0.60, p < 0.005). Six patients with dilated cardiomyopathy were studied repeatedly before and after 12 +/- 6 weeks of drug treatment leading to clinical recompensation with improvement of the NYHA status by 0.8 +/- 0.3 classes. Concomitantly, CP/ATP increased from 1.51 +/- 0.32 to 2.15 +/- 0.27 (p < 0.01), whereas PDE/ATP did not change significantly. CONCLUSIONS. Cardiac high-energy phosphate metabolism at rest is normal in LAD stenosis and chronic myocardial infarction in the absence of heart failure. The CP/ATP ratio has low specificity for the diagnosis of dilated cardiomyopathy. However, CP/ATP correlated with the clinical severity of heart failure and may improve during clinical recompensation.     

Study of human liver disease with P-31 magnetic resonance spectroscopy.

Liver metabolism and energetics of 24 patients with liver disease were studied using phosphorus-31 magnetic resonance spectroscopy. Significant abnormalities were detected in the majority of these patients. A striking diversity in metabolic patterns was observed. Patients with acute viral hepatitis had low liver phosphodiesters and high phosphomonoesters, possibly phosphocholine and phosphoethanolamine. In alcoholic hepatitis phosphomonoesters were raised. Intracellular inorganic phosphate and inorganic phosphate/ATP ratios were decreased in primary biliary cirrhosis and in some patients with hepatitis. These spectroscopic results were evaluated in respect of the pattern of liver damage and cellular regeneration. Liver tumours had raised phosphomonoesters and also showed evidence for altered spin-lattice relaxation of the phosphorus nucleus in various metabolites. In iron overload the liver ATP resonances were broadened. The line broadening correlated with the degree of iron overload suggesting the potential use of P-31 magnetic resonance spectroscopy for measuring liver iron.     

Cardiac metabolism during exercise in healthy volunteers measured by 31P magnetic resonance spectroscopy

A technique was devised for individuals to exercise prone in a magnet during magnetic resonance spectroscopy of the heart and phosphorus-31 magnetic resonance spectra of the heart were obtained by the phase modulated rotating frame imaging technique in six healthy volunteers during steady state dynamic quadriceps exercise. During prone exercise heart rate, blood pressure, and total body oxygen consumption were measured at increasing loads and the results were compared with those during Bruce protocol treadmill exercise. During prone exercise with a 5 kg load the heart rate was similar and the systolic and diastolic blood pressures were higher than those during stage 1 of the Bruce protocol. The rate-pressure products were similar but the total body oxygen consumption was lower during prone exercise. There was no difference in the ratio of phosphocreatine to adenosine triphosphate during rest and exercise.Thus during exercise that produced a local cardiac stress equal to or greater than that during stage 1 of the Bruce protocol treadmill exercise, the energy requirements of the normal human myocardium were adequately supplied by oxidative phosphorylation.     

Cardiac metabolism during exercise in healthy volunteers measured by 31P magnetic resonance spectroscopy

A technique was devised for individuals to exercise prone in a magnet during magnetic resonance spectroscopy of the heart and phosphorus-31 magnetic resonance spectra of the heart were obtained by the phase modulated rotating frame imaging technique in six healthy volunteers during steady state dynamic quadriceps exercise. During prone exercise heart rate, blood pressure, and total body oxygen consumption were measured at increasing loads and the results were compared with those during Bruce protocol treadmill exercise. During prone exercise with a 5 kg load the heart rate was similar and the systolic and diastolic blood pressures were higher than those during stage 1 of the Bruce protocol. The rate-pressure products were similar but the total body oxygen consumption was lower during prone exercise. There was no difference in the ratio of phosphocreatine to adenosine triphosphate during rest and exercise.

Thus during exercise that produced a local cardiac stress equal to or greater than that during stage 1 of the Bruce protocol treadmill exercise, the energy requirements of the normal human myocardium were adequately supplied by oxidative phosphorylation.

     

Nuclear magnetic resonance imaging-guided phosphorus-31 spectroscopy of the human heart

Phosphorus-31 nuclear magnetic resonance spectroscopy can determine the status of high energy phosphates in vivo. However, its application to human cardiac studies requires precise spatial localization without significant contamination from other tissues. Using image-selected in-vivo spectroscopy (ISIS), a technique that allows three-dimensional localization of the volume of interest, 12 subjects were studied to determine the feasibility and reproducibility of phosphorus-31 spectroscopy of the human heart. Nuclear magnetic resonance imaging was performed using a commercial 1.5 tesla system to define the volume of interest. Phosphorus-31 spectra were obtained from the septum and anteroapical region of the left ventricle in 10 studies. Relative peak heights and areas were determined for high energy phosphates. The mean phosphocreatine to adenosine triphosphate ratio was 1.33 +/- 0.19 by height analysis and 1.23 +/- 0.27 by area analysis. Duplicate measurements in four subjects showed a reproducibility of less than or equal to 10% in three of the subjects. All spectra showed significant signal contribution from the 2,3 diphosphoglycerate in chamber red cells without evidence of skeletal muscle contamination. These results demonstrate the feasibility of image-guided phosphorus-31 spectroscopy for human cardiac studies and indicate the potential of this technique to study metabolic disturbances in human myocardial disease.     

Simultaneous evaluations of contractility and energy metabolism of stunned myocardium using 31P magnetic resonance spectroscopy

A canine model of postischemic myocardial dysfunction (15 min ischemia, 60 min reperfusion) was used to evaluate the relationship between energy metabolism and myocardial contractile function by on-line measurements of ECG, left ventricular pressure, coronary blood flow and regional segment shortening (%SS) with the continuous acquisition of 31PMR spectra. Two groups emerged from these studies; the first (n = 7) in which regional myocardial %SS remained significantly depressed after 60 min of reperfusion (stunned) and the second (n = 5) in which regional %SS returned to control levels after 60 min of reperfusion (non-stunned). Both groups exhibited rapid, similar decreases in %SS and parallel rapid decreases in the phosphocreatine to inorganic phosphate (PCr/Pi) ratio with the onset of ischemia. The PCr/ATP ratio exceeded control levels in the stunned group immediately upon reperfusion and remained significantly above control after 60 min of reperfusion. Measurements of tissue myocardial creatine kinase (CK) revealed a significant decrease in total tissue CK activity in stunned myocardium compared to control. A significant inverse relationship (r = -0.904, p < 0.003) was found between myocardial tissue CK specific activity and the PCr/ATP ratios. We postulate that the elevated PCr/ATP ratio caused by the impairment of energy transfer to the contractile apparatus constitutes a contractile dysfunction in the postischemic heart.     

Phospholipid profiles of human colon cancer using 31P magnetic resonance spectroscopy

Phospholipids of 16 malignant and 11 non-malignant human colon specimens were analyzed using a chloroform-methanol analytical reagent in conjunction with ³¹P magnetic resonance spectroscopy (MRS) at 202.4 MHz. Sixteen individual generic phospholipids were identified and quantified for statistical intergroup comparisons. Statistically significant elevations in the relative concentrations of lysophosphatidylcholine and phosphatidylcholine plasmalogen were seen in malignant tissues along with significantly depressed levels of sphingomyelin and phosphatidylethanolamine plasmalogen. The malignant and non-malignant tissue groups were further differentiated by the detection of the minor phospholipids, lysophosphatidylcholine plasmalogen, lysophosphatidylethanolamine plasmalogen, lysophosphatidic acid and phosphatidylglycerol exclusively present in the malignant tissues and by significant changes in computed phospholipid metabolic indices that were dominated by choline containing lipids. The ³¹P MRS methods used represent an advancement over previous protocols for identifying and quantifying major and minor tissue phospholipids making this the first direct study of membrane phospholipids in human colon tissues using ³¹P MRS. The phospholipid profiles obtained may provide important information regarding the nature of the malignant cell's membrane system and identify markers which may be used to estimate malignant propensity, aggressiveness of disease and provide prognostic information.

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Résumé Les phospholipides de 16 échantillons de colons humains atteints de tumeurs malignes de 11 sans tumeur maligne ont été analysés en utilisant une méthode analytique avec un réactif chloroforme-métanol en conjonction avec une résonance magnétique spectroscopique (MRS au P31 à 202,4 MHz). 16 phospholipides différents ont été identifiés et quantifiés pour des comparaisons statistiques inter-groupes. Une élèvation statistiquement significative dans les concentrations relatives de l'isophosphatidylcholine et phosphatidylcholine plasmalogène ont été trouvées dans le tissue malin avec des taux significativement diminués de sphingomyéline et de phosphatidylétanolamine plasmalogène. Les groupes de tissus malins et non malins ont été de plus différenciés par la détection des phospholipides mineurs, lysophosphatidylcholine plasmalogène, lyophosphatidylétanolamine plasmalogène, acide lysophasphatidique et phosphatidylglycérol exclusivement présents dans les tissus malins ainsi que par des différences significatives des indices métaboliques computérisés de phospholipides qui étaient dominés par des lipides contenant de la choline. La résonance magnétique par spectroscopie au P31 utilisée représente une avance sur tous les protocoles précedents pour identifier et quantifier les phospholipides tissulaires majeurs et mineurs faisant de cette méthode la première étude directe des phospholipides membranaires du colon humain utilisant la résonance magnétique par spectroscopie au P31. Le profil de phospholipides obtenu peut fournir des informations importantes quant à la nature du système menbranaire des cellules malignes et identifier des marqueurs qui pourraient être utilisés pour estimer le potentiel malin, l'agressivité de la maladie et fournir des informations pronostiques.

     

Evaluation of transient apical ballooning with cardiac magnetic resonance imaging and 31-phosphorous magnetic resonance spectroscopy

Apical ballooning is an increasingly reported transient cardiomyopathy with yet unknown origin. In this study 2 cases of apical ballooning are described in whom we used a combined approach of cardiac magnetic resonance imaging (CMR) and 31-Phosphorous magnetic resonance spectroscopy (31P MRS). Electrocardiogram showed ST abnormalities and cardiac serum markers were mildly elevated, but CAG demonstrated smooth coronary arteries. Cine-CMR revealed severe apical akinesia and significantly decreased ejection fraction. Furthermore we detected reduced myocardial phosphocreatine to beta-ATP (PCr/b-ATP) ratios during the first week of acute disease. After 1 week we observed an improvement of PCr/b-ATP ratios by 68% and 34%, which was associated with an increase in left ventricular function. Our data suggest that 31P MRS might be a valuable tool in the evaluation of apical ballooning, but larger cohorts are needed to improve the understanding of metabolic changes during transient apical ballooning.     

Brain glucose concentrations in poorly controlled diabetes mellitus as measured by high-field magnetic resonance spectroscopy

Hyperglycemia and diabetes alter the function and metabolism of many tissues. The effect on the brain remains poorly defined, but some animal data suggest that chronic hyperglycemia reduces rates of brain glucose transport and/or metabolism. To address this question in human beings, we measured glucose in the occipital cortex of patients with poorly controlled diabetes and healthy volunteers at the same levels of plasma glucose using proton magnetic resonance spectroscopy. Fourteen patients with poorly controlled diabetes (hemoglobin A 1c = 9.8% +/- 1.7%, mean +/- SD) and 14 healthy volunteers similar with respect to age, sex, and body mass index were studied at a plasma glucose of 300 mg/dL. Brain glucose concentrations of patients with poorly controlled diabetes were lower but not statistically different from those of control subjects (4.7 +/- 0.9 vs 5.3 +/- 1.1 micromol/g wet wt; P = .1). Our sample size gave 80% power to detect a difference as small as 1.1 micromol/g wet wt. We conclude that chronic hyperglycemia in diabetes does not alter brain glucose concentrations in human subjects.     

Proton and phosphorus-31 nuclear magnetic resonance spectroscopy of human bile in hepatopancreaticobiliary cancer

OBJECTIVE: Hepatopancreaticobiliary cancers can be difficult to diagnose. Nuclear magnetic resonance (NMR) spectroscopy provides non-invasive information on phospholipid metabolism, and previous studies of liver tissue have highlighted changes in phospholipids in malignancy. We hypothesised that in-vitro NMR spectroscopy of human bile may provide independent diagnostic indices in cancer management through an assessment of the phospholipid content. DESIGN AND METHODS: Bile samples from 24 patients were collected at endoscopic retrograde cholangiopancreatography and from one subject at cholecystectomy. Thirteen patients had cancer: pancreatic carcinoma (eight), cholangiocarcinoma (three) and metastatic liver disease (two). The remaining 12 patients had non-malignant pathology. In-vitro proton (H) and phosphorus-31 (P) NMR spectra were obtained from all samples using an 11.7 Tesla NMR spectroscopy system. RESULTS: Complementary information was obtained from the H and P NMR spectra. Signals were assigned to phosphatidylcholine in both H and P NMR spectra. Phosphatidylcholine levels were significantly reduced in the bile from cancer patients when compared with bile from non-cancer patients (P=0.007). CONCLUSION: These preliminary studies suggest that H and P NMR spectroscopy of bile may be used to detect differences in phospholipid content between cancer and non-cancer patients. This may have implications for the development of novel diagnostic strategies in hepatopancreaticobiliary cancers. Further larger-scale studies are warranted.     

正常人颞叶质子磁共振波谱研究

目的 运用质子磁共振波谱（^1H—MRS）研究年龄对正常人颞叶脑组织代谢物浓度的影响。方法 将80例健康人分为4个不同年龄组并对双侧颞叶进行^1H—MRS检测，对比分析不同年龄组的颞叶N-乙酰基天门冬氨酸（NAA）／肌酸复合物（Cr）和含胆碱化合物（Cho）／Cr比值的变化。结果 随着年龄的增长，在≤50岁年龄段颞叶的NAA／Cr和Cho／Cr比值无明显改变（P〉0．05），但在〉50岁年龄段颞叶的NAA／Cr比值逐渐降低（P〈0．05）、Cho／Cr比值逐渐增高（P〈0．05）。结论 ^1H-MRS是一种可以为正常人颞叶与年龄相关的代谢物浓度改变提供有价值信息的无创技术。     

Measurement of transmural distribution of phosphorus metabolites in the pig heart by 31P magnetic resonance spectroscopy

We used the phase modulated rotating frame imaging technique to measure transmural distribution of phosphorus metabolites in 10 anaesthetised ventilated pigs using a double surface coil placed on the surface of the left ventricle. Anaesthesia was maintained in five animals with halothane, barbiturate and nitrous oxide and in five others with intravenous chloralose. 31Phosphorus spectra were acquired, gated to expiration and systole. From phantom experiments the resolution of the experiment was shown to be approximately 2 mm. The anatomical limits of the myocardium were identified by the appearance of 2,3-diphosphoglycerate peaks from red blood cells. The limits of the epicardium were confirmed by obtaining images after placing a phantom containing fluorophosphate on the surface of the heart. The endocardium was identified by inserting a small balloon catheter through the centre of the coil into the left ventricular cavity, filling it with 0.5 ml of fluorophosphate and pulling it gently against the endocardium. No transmural differences in phosphocreatine to ATP ratio were identified in the normal heart. The animals anaesthetised with chloralose showed a significantly higher phosphocreatine to ATP ratio compared to those anaesthetised with halothane and barbiturate. The chloralose animals tended to have a higher blood pressure and a lower heart rate when compared to the other animals. No transmural differences, however, were identified in either group. When regional ischaemia was produced using a snare to occlude the left coronary artery, phosphocreatine fell and the signal from the inorganic phosphate + 2,3-diphosphoglycerate region increased. The inner wall tended to become more acid compared to the outer wall during ischaemia. These experiments show that the phase modulated rotating frame imaging technique can be used to study the effects of changes in workload, ischaemia, or pharmacological intervention on transmural distribution of metabolites in the heart and thus help elucidate factors responsible for subendocardial vulnerability to stress.     

钙调神经磷酸酶在人类心肌中的表达与分布

目的 了解钙调神经磷酸酶(CaN)在人类健康心肌和衰竭心肌中的表达与分布.方法 以12例行移植手术的终末期衰竭心脏和5例因车祸丧生的"健康供体"心脏为研究对象,分别利用免疫组化和Western blot技术对左、右心室中CaN的表达与分布进行研究.结果 CaN在心脏的心肌细胞、纤维母细胞、心外膜间皮细胞中染色阳性,且Western blot实验在后两种细胞中均检测到单一的58 000带,心肌内血管内皮细胞和平滑肌细胞中CaN染色阴性.与"供体"心肌比较,无论左心室还是右心室,衰竭心肌的CaN蛋白水平差异均无统计学意义(衰竭右心室和供体右心室电泳带强度分别为130.20±8.66和139.87±6.21,P=0.33.衰竭左心室和供体左心室电泳带强度分别为106.45和126.34±12.09),且左右心室肌CaN蛋白水平差异也无统计学意义(衰竭心肌左、右心室电泳带强度分别为96.99±10.67和104.58±13.18,P=0.63.供体心肌左、右心室电泳带强度分别为132.12和120.74).结论 CaN存在于人类心脏多数类型细胞中,包括心肌细胞、纤维母细胞和心外膜间皮细胞.心力衰竭时,CaN蛋白水平没有改变.     

Differentiation of reperfused-viable (stunned) from reperfused-infarcted myocardium at 1 to 3 days postreperfusion by in vivo phosphorus-31 nuclear magnetic resonance spectroscopy

Thrombolytic therapy has increased the need for a technique to assess the viability of recently reperfused myocardium. This study examined the ability of in vivo phosphorus-31 (P-31) nuclear magnetic resonance (NMR) spectroscopy to distinguish reperfused-viable (stunned) from reperfused-infarcted myocardium at 6, 30, and 54 hours following coronary artery occlusion in a canine model. A 15-minute occlusion produced reperfused-viable myocardium in five animals and a 360-minute occlusion produced reperfused-infarcted myocardium in six animals. Postreperfusion risk zone myocardial phosphocreatine (PCr) concentration measured by P-31 NMR spectroscopy was significantly depressed throughout the 3-day study period in infarcted but not in viable myocardium (p less than 0.01 between groups, all time points). The postreperfusion ratio of inorganic phosphate (Pi) to PCr concentration, as determined by NMR spectroscopy, was elevated throughout the study period in infarcted but not in viable reperfused myocardium (p less than 0.01 between groups, all time points). Postreperfusion Pi concentration was elevated at 6 hours but not subsequently in reperfused-infarcted myocardium, and was not elevated in reperfused-viable myocardium. Logistic regression models selected PCr concentration and the Pi/PCr ratio as providing the best discrimination between reperfused-viable and reperfused-infarcted myocardium. The accuracy of P-31 NMR variables selected by logistic regression analysis for determining myocardial viability ranged from 97% to 100%.     

Investigation of fluoroquinolone-induced myalgia using (31)P magnetic resonance spectroscopy and in vitro contracture tests

OBJECTIVE: To investigate muscle function in patients with severe myalgia resulting from fluoroquinolone (FQ) treatment. We used histology, in vitro contracture tests (IVCTs), and (31)P magnetic resonance spectroscopy ((31)P MRS) to explore muscle contraction and metabolism. METHODS: We studied 3 patients with myalgia, hyperalgia tendinopathy, and arthralgia following FQ treatment and 3 normal subjects after taking FQs. Results were compared with those of a control group of 9 subjects free of any muscle disease and not taking FQs. Muscle biopsies were performed on the left biceps, and IVCTs were performed in accordance with the protocol recommended by the European Malignant Hyperthermia Group. (31)P MR spectra of forearm flexor muscles were recorded at 4.7T throughout a rest-exercise-recovery protocol. RESULTS: (31)P MRS showed a significant reduction of pH changes measured at the end of exercise and a faster rate of proton efflux measured during recovery in all patients. IVCTs diagnosed 1 patient as being susceptible to malignant hyperthermia. No specific histologic anomalies were observed in muscle biopsy samples, which showed normal mitochondria. CONCLUSION: The adverse effects recorded in the 3 patients are related to a preexisting muscular anomaly revealed by FQ treatment.     

Gating of the late Na+ channel in normal and failing human myocardium

We previously reported an ultraslow inactivating late Na+ current (INaL) in left ventricular cardiomyocytes (VC) isolated from normal (NVC) and failing (FVC) human hearts. This current could play a role in heart failure-induced repolarization abnormalities. To identify properties of NaCh contributing to INaL, we examined early and late openings in cell-attached patches of HEK293 cells expressing human cardiac NaCh alpha-subunit (alpha-HEK) and in VC of one normal and three failing human hearts. Two types of the late NaCh openings underlay INaL in all three preparations: scattered late (SLO) and bursts (BO). Amplitude analysis revealed that slope conductance for both SLO and BO was the same compared to the main level of early openings (EO) in both VC (21 vs 22.7pS, NVC; 22.7 vs 22.6pS, FVC) and alpha-HEK (23.2 vs 23pS), respectively. Analysis of SLO latencies revealed voltage-independent ultraslow inactivation in all preparations with tendency to be slower in FVC compared to NCV. EO and SLO render one open voltage-independent state (tau approximately 0.4ms) for NVC and FVC. One open (voltage-dependent) and two closed states (one voltage-dependent and another voltage-independent) were found in BO of both specimens. Burst duration tend to be longer in FVC ( approximately 50ms) than in NVC ( approximately 30ms). In FVC we found both modes SLO and BO at membrane potential of -10mV that is attribute for take-off voltages (from -18 to -2mV) for early afterdepolarizations (EAD's) in FVC. In conclusions, we found a novel gating mode SLO that manifest slow (hundreds of ms), voltage-independent inactivation in both NVC and FVC. We were unable to reliably demonstrate any differences in the properties of the late NaCh in failing vs a normal human heart. Accordingly, the late current appears to be generated by a single population of channels in normal and failing human ventricular myocardium. Both SLO and BO could be implicated in EADs in HF.