Variations of heart rate variability parameters prior to the onset of ventricular tachyarrhythmia and sinus tachycardia in ICD patients. Results from the heart rate variability analysis with automated ICDs (HAWAI) registry.

The HAWAI registry evaluated the role of heart rate variability in predicting the occurrence of ventricular tachycardia and fibrillation (VT/VF) and sinus tachycardia in patients with an implantable cardioverter-defibrillator (45 patients with 155 RR recordings). A significant decrease of the mean value of all RR intervals (MeanNN) was observed in the period starting 20 and 40 min prior to VT/VF and sinus tachycardia, respectively. The standard deviation of RR intervals (SDNN) and the power at low frequency (LF) were the only parameters with significant changes prior to VT/VF. For sinus tachycardia, the root mean square of successive differences of all successive RR intervals (r-MSSD) and the power at low and high frequency (HF) decreased, whereas SDNN and the power at very low frequency increased. Comparison of RR recordings preceding VT/VF and sinus tachycardia revealed significant differences of the MeanNN, SDNN, r-MSSD, LF and HF. Based on a classification and regression tree analysis, MeanNN, SDNN and r-MSSD showed a sensitivity of 94.4% and a specificity of 50.6% as predictors of VT/VF. Our results suggest that the temporal changes in heart rate before an arrhythmic event can be used to predict the occurrence of VT/VF. These parameters may be used to optimize pacing therapies designed to prevent VT/VF recurrences as well as for improving device-based discriminators for VT/VF and sinus tachycardia.

Oxygen supply and oxidative phosphorylation limitation in rat myocardium in situ.

The 1H-NMR signal of the proximal histidyl-N(delta)H of deoxymyoglobin is detectable in the in situ rat myocardium and can reflect the intracellular PO2. Under basal normoxic conditions, the cellular PO2 is sufficient to saturate myoglobin (Mb). No proximal histidyl signal of Mb is detectable. On ligation of the left anterior descending coronary artery, the Mb signal at 78 parts/million (ppm) appears, along with a peak shoulder assigned to the corresponding signal of Hb. During dopamine infusion up to 80 microg. kg(-1) x min(-1), both the heart rate-pressure product (RPP) and myocardial oxygen consumption (MVO2) increase by about a factor of 2. Coronary flow increases by 84%, and O2 extraction (arteriovenous O2 difference) rises by 31%. Despite the increased respiration and work, no deoxymyoglobin signal is detected, implying that the intracellular O2 level still saturates MbO2, well above the PO2 at 50% saturation of Mb. The phosphocreatine (PCr) level decreases, however, during dopamine stimulation, and the ratio of the change in P(i) over PCr (DeltaP(i)/PCr) increases by 0.19. Infusion of either pyruvate, as the primary substrate, or dichloroacetate, a pyruvate dehydrogenase activator, abolishes the change in DeltaP(i)/PCr. Intracellular O2 supply does not limit MVO2, and the role of ADP in regulating respiration in rat myocardium in vivo remains an open question.

Comparative analysis of NMR and NIRS measurements of intracellular PO2 in human skeletal muscle.

1H NMR has detected both the deoxygenated proximal histidyl NdeltaH signals of myoglobin (deoxyMb) and deoxygenated Hb (deoxyHb) from human gastrocnemius muscle. Exercising the muscle or pressure cuffing the leg to reduce blood flow elicits the appearance of the deoxyMb signal, which increases in intensity as cellular PO2 decreases. The deoxyMb signal is detected with a 45-s time resolution and reaches a steady-state level within 5 min of pressure cuffing. Its desaturation kinetics match those observed in the near-infrared spectroscopy (NIRS) experiments, implying that the NIRS signals are actually monitoring Mb desaturation. That interpretation is consistent with the signal intensity and desaturation of the deoxyHb proximal histidyl NdeltaH signal from the beta-subunit at 73 parts per million. The experimental results establish the feasibility and methodology to observe the deoxyMb and Hb signals in skeletal muscle, help clarify the origin of the NIRS signal, and set a stage for continuing study of O2 regulation in skeletal muscle.

Observing the deoxy myoglobin and hemoglobin signals from rat myocardium in situ.

1H NMR proximal histidyl NdeltaH signals of deoxy hemoglobin (Hb) and myoglobin (Mb) are distinguishable in the rat myocardium in situ. In the normoxic resting state, the blood and tissue pO2 is sufficient to saturate both Mb and Hb. No deoxy Mb or Hb signals are detected. Under 12% inspired O2, the erythrocyte Hb is partially desaturated and yields the alpha and beta proximal histidyl NdeltaH signals of deoxy Hb. The detection of the Hb signals clarifies the debate about the NMR visibility of erythrocyte Hb in vivo and augments the strategy to observe tissue pO2.

[Successful resuscitation of a patient with ventricular fibrillation in Bland-White-Garland syndrome in adulthood. A case report]. / Erfolgreiche Reanimation einer Patientin mit Kammerflimmern beim Bland-White-Garland-Syndrom im Erwachsenenalter. Ein Fallbericht.

The Bland-White-Garland Syndrome represents the anomalous origin of the left coronary artery of pulmonary trunk. Only 10% of the patients reach adulthood. Clinical manifestations of the syndrome are angina, dyspnoe, ECG signs of ischemia, myocardial infarction, and death in childhood. We present the case of a 47 year old woman with Bland-White-Garland Syndrome, who was resuscitated from ventricular fibrillation. The only symptom shown in her personal history was progressive dyspnoea in the last 6 months, though mitral insufficiency was known since childhood. On echocardiographic examination, she showed an anterolateral infarction and a mitral insufficiency II. As operation procedure, the ligation of the left main coronary artery and bypass surgery with a left internal mammarian graft to the left descending branch of the left coronary artery was chosen. The mechanism of onset of ventricular tachycardia in our patient is not known. Three pathophysiological mechanisms may be possible: (1) local ischemia caused by the shunt, (2) a reentry circuit in the border zone of myocardial infarction, (3) electrical instability caused by endocardial fibrosis. As local ischemia and reentry circuit were widely excluded, only endocardial fibrosis could induce further ventricular arrhythmia. We therefore intended to implant an AICD to have the most possible safety for our patient. But this, postoperatively was refused by the patient. In analogy to Coronary Artery Disease, the risk for sudden cardiac death postoperatively may be due to three factors: (1) presence of a reentrant circuit, (2) LV-function below 40%, and (3) presence of endocardial fibrosis. Our patient showed a low risk for sudden cardiac death. On electrophysiological study, no ventricular tachycardia could be induced in our patient, indicating the absence of a reentry circuit. LV function exceeded more than 40%. In Holter ECG, only few ventricular premature beats could be registrated, indicating a low risk for sudden cardiac death in the presence of endocardial fibrosis. In the follow-up of fourteen months, the patient remained free from arrhythmic events.

Role of oxygen in limiting respiration in the in situ myocardium.

1H NMR has now detected the proximal histidyl N delta H myoglobin (Mb) signal from the myocardium in situ. Upon ligation of the left anterior descending coronary artery in the rat myocardium, the deoxy Mb signal appears at 78 ppm During dopamine infusion at up to 80 micrograms/kg/min, the heart rate pressure product (RPP) increases by a factor of 2, the phosphocreatine (PCr) decreases by 17%, and the ratio of the change in inorganic phosphate over PCr (delta Pi/PCr) increases by 0.2. However, no deoxy myoglobin signal is detected. Oxygen availability does not appear to limit oxygen consumption nor oxidative phosphorylation under dopamine enhanced work state in myocardium.

Myoglobin and hemoglobin rotational diffusion in the cell.

The detection of the 1H NMR signal of myoglobin (Mb) in tissue opens an opportunity to examine its cellular diffusion property, which is central to its purported role in facilitating oxygen transport. In perfused myocardium the field-dependent transverse relaxation analysis of the deoxy Mb proximal histidyl NdeltaH indicates that the Mb rotational correlation time in the cell is only approximately 1.4 times longer than it is in solution. Such a mobility is consistent with the theory that Mb facilitates oxygen diffusion from the sarcoplasm to the mitochondria. The microviscosities of the erythrocyte and myocyte environment are different. The hemoglobin (Hb) rotational correlation time is 2.2 longer in the cell than in solution. Because both the overlapping Hb and Mb signals are visible in vivo, a relaxation-based NMR strategy has been developed to discriminate between them.

Metabolic response in Arenicola marina to limiting oxygen as reflected in the 1H-NMR oxymyoglobin signal.

Many intertidal animals can endure prolonged periods of environmental stress and have developed strategies to preserve a functioning energy state in the cell. Recent 1H/31P-NMR techniques have allowed investigators to monitor directly mammalian tissue metabolism in vivo. In particular, the signals of myoglobin (Mb) offer a unique opportunity to explore the intracellular oxygen-partial-pressure [p(O2)] interaction in Arenicola marina, a standard model to study hypoxia tolerance in invertebrates. The present study reveals that the 1H-NMR MbO2 signal at -2.9 ppm is detectable in tissue and reflects directly the oxygenated state. As the p(O2) declines, MbO2 saturation and oxygen consumption decrease. However, phosphotaurocyamine concentration remains unaltered until the MbO2 saturation falls below 33%. The extracellular to intracellular p(O2) gradient appears substantial. The study establishes the 1H-NMR technique as an approach to measure the intracellular p(O2) with an oxygenated state marker and presents the interrelationship between oxygen and the metabolic adaptation during hypoxic stress.

H-NMR signal of Arenicola marina myoglobin in vivo as an index of tissue oxygenation.

Key questions on how intertidal animals adapt to hypoxic stress center on the high energy phosphate response to decreasing oxygenation. With recent 1H/31P-NMR techniques to monitor mammalian tissue metabolism, a novel approach has emerged to observe potentially the intracellular oxygen interaction in invertebrates. The present study indicates that Arenicola marina, a standard model for intertidal animals, exhibits a distinct set of Mb 1H-NMR signals in vivo, corresponding to the two isolated Mb isoforms. Specifically both deoxy-Mb I and deoxy-Mb II exhibit paramagnetically shifted signals at 93.4 ppm and 92.5 ppm at 25 degrees C, respectively, which arise from the proximal histidyl NdeltaH. These signals reflect the cellular oxygenation state and indicate clearly that the phosphotaurocyamine level begins to drop at the onset of anoxia and declines gradually to 50% of control after 3.5 h. 1H Mb spectra indicate protein heterogeneity originating from heme as well as structural disorder.

Critical intracellular O2 in myocardium as determined by 1H nuclear magnetic resonance signal of myoglobin.

The 1H nuclear magnetic resonance (NMR) signal of tissue myoglobin has provided an opportunity to determine the critical O2 level in saline-perfused myocardium at room temperature. Above the intracellular PO2 of 4 mmHg, the myocardium exhibits no sign of hypoxia. At 4 mmHg, the rate pressure product (RPP) decreases, and the lactate formation rate, measured enzymatically, increases. However, O2 consumption and the 31P-NMR signal of phosphocreatine level remain relatively constant until the cellular PO2 reaches 2 mmHg. The ATP signal intensity dips only when cellular O2 reaches 0.8 mmHg, while pH remains unchanged at 7.2. The sequential nature of the cellular response to limiting O2, starting with alterations in the lactate formation rate and RPP, indicates that NADH, rather than ADP, signals tissue hypoxia. Moreover, the study suggests that the O2 gradient from capillary to cell is larger than that from cytosol to mitochondria.

1H NMR approach to observe tissue oxygenation with the signals of myoglobin.

The myoglobin technique measures oxygen tension in myocytes. It relies on a quantitative measurement of the Val E11 and His F8 signals and an accurate value for the [O2]50 for Mb. Even though the Mb oxygen affinity in the cell is in question, the NMR results still reflect the degree of Mb oxygen saturation. Although magnetic resonance has established a variety of strategies to measure tissue oxygenation, the Mb approach is the most direct and will lead to a better understanding of oxygen's role in regulating cellular activity.

Myocardial adaptation during acute hibernation: mechanisms of phosphocreatine recovery.

OBJECTIVES: Acute hibernation, defined as a prolonged period of moderately reduced oxygen supply and stable haemodynamic function, results in metabolic adaptation characterised primarily by an increase in phosphocreatine. The mechanism of this increase in phosphocreatine is unknown, but has been postulated to result from either an increase in adenosine triphosphate (ATP) production or a decrease in ATP utilisation under conditions of constant myocardial oxygen consumption (MVO2). These experiments were performed to test the hypotheses that (1) acute hibernation could be modelled in an isolated perfused rat heart exhibiting metabolic adaptation; and (2) recovery of phosphocreatine could be explained by alterations in relative creatine kinase flux during hibernation. METHODS: Nuclear magnetic resonance techniques were used in an isolated, perfused rat heart model of acute hibernation to determine the changes in metabolites and creatine kinase kinetics. A flow reduction from 12.5 to 5.4 ml.min-1 was employed for two hours, followed by reperfusion. RESULTS: Reduction of flow resulted in a stable 44% reduction in rate-pressure product. Phosphocreatine had a significant decrease of 9% within the first 15 minutes of ischaemia, but recovered to control values by the end of ischaemia. ATP and [ADP], although unchanged in the early phase of ischaemia, were progressively reduced during the later phase of ischaemia. Intracellular pH fell from 6.99(0.04) to 6.92(0.03) after 15 minutes of ischaemia with little recovery. Saturation transfer measurements showed stability of the forward flux in the creatine kinase reaction during ischaemia, but a progressive reduction in the calculated reverse flux. CONCLUSIONS: These data show that acute hibernation can be modelled in an isolated perfused heart, exhibiting recovery of phosphocreatine despite progressive reductions in ATP. Metabolic changes during acute hibernation have a phasic response characterised by an early ischaemic phase and a later adaptive phase. There is a time related change in measured creatine kinase flux, consistent with a differential change in either ATP production via an increase in MB creatine kinase isoenzyme or a shift in the activity of mitochondrial v cytosolic creatine kinase, a reduction in ATP utilisation via increased efficiency of ATP utilisation at the myofibril, or a changing contribution of glycolytically produced ATP.

H-NMR characterization of the human myocardium myoglobin and erythrocyte hemoglobin signals.

The 1H-NMR signal of deoxy Mb provides a unique opportunity to measure tissue oxygenation in vivo. To utilize the technique for human application, however, requires a specific spectral characterization of both human Mb and erythrocyte Hb. We report that the proximal histidyl-NH signal of human deoxy Mb resonates at 80.3 ppm at 25 degrees C and maintains a 3.9 ppm separation with the corresponding Hb A signal throughout the physiological temperature range. In the particular case of the human thenar muscle, the deoxy Mb signal is clearly detectable without any interference from Hb.

Observing the 1H NMR signal of the myoglobin Val-E11 in myocardium: an index of cellular oxygenation.

The 1H NMR signal from oxymyoglobin, a low-concentration diamagnetic protein, is visible in myocardial tissue. The methyl group of the Val-E11 resonates in a clear spectral region at -2.76 ppm and responds to dynamic changes in cellular oxygenation. With CO, the signal shifts to -2.4 ppm. The Val-E11 peak assignment and its response to oxygen and CO agree perfectly with previous myoglobin solution studies. Intracellular oxygen level can now be determined in vivo with the signal intensity ratio of oxymyoglobin/deoxymyoglobin, reflected by the Val-E11 and His-F8 peaks in the 1H NMR spectra. Moreover, protein structure-function relationship in vivo can now be probed.

1H-nuclear magnetic resonance deoxymyoglobin signal as indicator of intracellular oxygenation in myocardium.

We report in this study that the intracellular oxygenation state is measurable with the 1H nuclear magnetic resonance signal of the proximal histidine N delta H proton of deoxymyoglobin. The signal appears in a clear spectral region of the 1H spectrum and is sensitive to various hypoxic and ischemic conditions. In perfused heart, the deoxymyoglobin's response to tissue oxygenation precedes the one reflected in the 31P phosphocreatine or ATP signals, suggesting that oxidative energy metabolism is still sufficient even when the myoglobin is partially saturated with oxygen. Our method offers then a unique way to observe tissue oxygenation and its interaction in localized tissue region in vivo.

Subcellular distribution of malate-aspartate cycle intermediates during normoxia and anoxia in the heart.

The subcellular distribution of adenine nucleotides, phosphocreatine and intermediates of the malate-aspartate cycle was investigated in adult rat heart myocytes under normoxia and anoxia. Cytosolic and mitochondrial concentrations of metabolites were determined by a fractionation method using digitonin. Under normoxia, cytosolic/mitochondrial gradients were found for ATP (c/m = 4), AMP (c/m less than 0.01), citrate (c/m = 0.5), aspartate (c/m = 3), glutamate (c/m = 2), while phosphocreatine and glutamine were confined to the cytosolic space. No gradients were found for malate and 2-oxoglutarate. The results show that the transport of electrons from the cytosol into the mitochondria is supported by the glutamate gradient and by a high glutamate/aspartate ratio inside the mitochondria (Glu/Asp = 15) which is maintained by the energy-dependent Glu-Asp exchange across the mitochondrial membrane. Under anoxia, cytosolic glutamate is transaminated with pyruvate, yielding alanine and 2-oxoglutarate, which is oxidized to succinate inside the mitochondria and leaves the cell. The data indicate that stimulation of transamination is caused by a mass action effect following a decrease in cytosolic 2-oxoglutarate which may be due to succinate-2-oxoglutarate exchange across the mitochondrial membrane. Inhibition of the energy-dependent inward transport of glutamate may support this process.