Clinical cardiac magnetic resonance spectroscopy--present state and future directions.

MR spectroscopy opens a window to the non-invasive evaluation of various aspects of cardiac metabolism. Experimentally, the method has extensively been used since 1970's. 31P-MR allows the registration of cardiac high-energy phosphate metabolism to non-invasively estimate the energetic state of the heart: ATP, phosphocreatine, inorganic phosphate, monophosphate esters and intracellular pH can all be quantitated. In conjunction with extracellular shift reagents such as [DyTTHA]3- or [TmDOTP]5-, 23Na- and 39K-MR allow the measurement of intra- and extra-cellular cation pools. 1H-MR spectroscopy allows the detection of a large number of metabolites such as, e.g. creatine, lactate, or carnitine. Human cardiac spectrocsopy has so far been confined to the 31P nucleus. Localization techniques (DRESS, ISIS, 3D-CSI etc.) are required to confine the acquired signal to the heart region. Relative quantification is straightforward (phosphocreatine/ATP ratio), absolute quantification (mM) is under development. Cardiac 31P-MR spectroscopy has research application in at least three clinical areas: (1) Coronary artery disease: A biochemical stress test for non-invasive ischemia detection (decrease of phosphocreatine with exercise) and viability assessment via quantification of ATP may become feasible. (2) Heart failure: The phosphocreatine/ATP ratio may provide an independent index for grading of heart failure, allow to monitor the longterm effects of different forms of drug therapy on cardiac energy metabolism in heart failure, and may also hold prognostic information on survival. (3) Valve disease: It is possible that the decrease of phosphocreatine/ATP can be used to guide the timing for the valve replacement. At the present time, no routine clinical applications can be defined for the use of human cardiac spectroscopy in patients with cardiac disease. However, the technique holds great potential for the future as a non-invasive approach to cardiac metabolism, and in coming years routine applications may become reality.

Cardiac high-energy phosphate metabolism in patients with aortic valve disease assessed by 31P-magnetic resonance spectroscopy.

BACKGROUND: The purpose of this work was to determine the clinical and hemodynamic correlates of alterations in cardiac high-energy phosphate metabolism in patients with aortic stenosis and with aortic incompetence. METHODS: Fourteen volunteers, 13 patients with aortic stenosis, and 9 patients with aortic incompetence were included. Patients underwent echocardiography and left and right heart catheterization. 31P-MR spectra from the anterior myocardium were obtained with a 1.5 Tesla clinical MR system. RESULTS: Aortic stenosis and aortic incompetence patients had similar New York Heart Association (NYHA) classes (2.77 +/- 0.12 vs 2.44 +/- 0.18), ejection fractions (normal), left ventricular (LV) end-diastolic pressures, and LV wall thickness. In volunteers, phosphocreatine/adenosine triphosphate (ATP) ratios were 2.02 +/- 0.11. For all patients, phosphocreatine/ATP was significantly reduced (1.64 +/- 0.09; *p = 0.011 vs volunteers). Phosphocreatine/ATP decreased to 1.55 +/- 0.12 (*p = 0.008) in aortic stenosis, while in aortic incompetence, phosphocreatine/ATP only showed a trend for a reduction (1.77 +/- 0.12; p = 0.148). For all patients, phosphocreatine/ATP decreased significantly only with NYHA class III (1.51 +/- 0.09; *p = 0.001), but not with NYHA classes I and II (phosphocreatine/ATP 1.86 +/- 0.18). In aortic stenosis, phosphocreatine/ATP ratios decreased (1.13 +/- 0.03; *p = 0.019) only when LV end-diastolic pressures were > 15 mm Hg or when LV diastolic wall stress was > 20 kdyne cm-2 (1.13 +/- 0.03; *p = 0.024). CONCLUSIONS: For a similar clinical degree of heart failure in human myocardium, volume overload hypertrophy does not, but pressure overload does, induce significant impairment of cardiac high-energy phosphate metabolism. In aortic valve disease, alterations of high-energy phosphate metabolism are related to the degree of heart failure.

Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy.

BACKGROUND: In patients with heart failure due to dilated cardiomyopathy, cardiac energy metabolism is impaired, as indicated by a reduction of the myocardial phosphocreatine-to-ATP ratio, measured noninvasively by 31P-MR spectroscopy. The purpose of this study was to test whether the phosphocreatine-to-ATP ratio also offers prognostic information in terms of mortality prediction as well as how this index compares with well-known mortality predictors such as left ventricular ejection fraction (LVEF) or New York Heart Association (NYHA) class. METHODS AND RESULTS: Thirty-nine patients with dilated cardiomyopathy were followed up for 928+/-85 days (2.5 years). At study entry, LVEF and NYHA class were determined, and the cardiac phosphocreatine-to-ATP ratio was measured by localized 31P-MR spectroscopy of the anterior myocardium. During the study period, total mortality was 26%. Patients were divided into two groups, one with a normal phosphocreatine-to-ATP ratio (>1.60; mean+/-SE, 1.98+/-0.07; n=19; healthy volunteers: 1.94+/-0.11, n=30) and one with a reduced phosphocreatine-to-ATP ratio (<1.60; 1.30+/-0.05; n=20). At re-evaluation (mean, 2.5 years), 8 of 20 patients with reduced phosphocreatine-to-ATP ratios had died, all of cardiovascular causes (total and cardiovascular mortality, 40%). Of the 19 patients with normal phosphocreatine-to-ATP ratios, 2 had died (total mortality, 11%), one of cardiovascular causes (cardiovascular mortality, 5%). Kaplan-Meier analysis showed significantly reduced total (P=.036) and cardiovascular (P=.016) mortality for patients with normal versus patients with low phosphocreatine-to-ATP ratios. A Cox model for multivariate analysis showed that the phosphocreatine-to-ATP ratio and NYHA class offered significant independent prognostic information on cardiovascular mortality. CONCLUSIONS: The myocardial phosphocreatine-to-ATP ratio, measured noninvasively with 31P-MR spectroscopy, is a predictor of both total and cardiovascular mortality in patients with dilated cardiomyopathy.

Influence of cardiac dysfunction on fast sodium current regulation by Forskolin.

There are several reports of an altered beta-adrenergic pathway in heart failure. Since the fast cardiac sodium current (INa+) is also subject to beta-receptor dependent regulation, we investigated its regulation in a model of cardiac dysfunction. Adenylyl cyclase was stimulated directly with forskolin as one step in the beta-adrenergic pathway. Twelve-week-old Wistar rats were infarcted by ligation of the left anterior descending coronary artery. Eight weeks later, the induced hemodynamic changes were evaluated. The left ventricular end-diastolic pressure (LVEDP) was used as a measure of the hemodynamic effects of the myocardial infarction. With the loose patch clamp technique, INa+ was measured in intact papillary muscles at an external sodium concentration of 150 mmol/L. Potential dependent availability was tested with pulses to 0 mV from various conditioning potentials. In animals with minor infarction (n = 7, LVEDP = 7.7 +/- 0.9 mmHg), forskolin (3 mumol/L) increased the maximal available INa+ to 109% +/- 13% of baseline values. This increase was nearly the same in the group with significant infarctions (n = 7, LVEDP = 15.7 +/- 1.6 mmHg) to 113% +/- 6%. Thus, although we previously observed a reduction of the isoproterenol induced increase of INa+ in rats with significant myocardial infarctions, this increase remains the same when adenylyl cyclase is stimulated directly. This is consistent with a direct beta-receptor down-regulation or desensitization.

[The diagnosis and therapy of acquired factor-VIII inhibitors in combination with lupus anticoagulants]. / Diagnose und Therapie eines erworbenen Faktor-VIII-Inhibitors in Kombination mit Lupus-Antikoagulanzien.

HISTORY AND CLINICAL FINDINGS: A 63-year-old woman, known to have a primary factor VIII inhibitor (FFI) in combination with lupus anticoagulants (LA) was hospitalised because of life-threatening bleeding from mouth and neck. INVESTIGATIONS: The activity of coagulation factor VIII was 9% under substitution, while the factor VIII inhibitor titre was 123 U/ml. A lupus anticoagulant test was positive. Antibodies against varicella-zoster virus and Epstein-Barr virus were demonstrated. The right adrenal was found to be enlarged on computed tomography. TREATMENT AND COURSE: Coagulation became normal on administration of porcine factor VIII concentrate. Three cycles of a combination of three protein A immunoadsorptions, cyclophosphamide (twice 1.0 g intravenously), IgG (30 g daily for 5 days) as well as long-term oral cyclophosphamide administration (150 mg daily) during the interval were undertaken to reduce the inhibitor and produce immuno-tolerance. The factor VIII inhibitor titre was stabilised at a low level, but factor VIII activity could not be normalised without substitution. CONCLUSIONS: The simultaneous presence of specific and non-specific inhibitors makes laboratory diagnosis and treatment more difficult. Porcine factor VIII and a combination of immunoadsorption and suppression are important components in the treatment of bleeding episodes and the production of immunotolerance.

Dose-dependent alteration of rat cardiac sodium current by isoproterenol: results from direct measurements on multicellular preparations.

Conflicting results have been reported in literature about the influence of beta-adrenergic stimulation on the fast cardiac sodium current (INa+). To elucidate these mechanisms in multicellular preparations we used the loose-patch-clamp technique to evaluate the effect of the beta-adrenergic agonist isoproterenol 1-1000 nmol/l. Isoproterenol enhanced INa+ at all membrane potentials by elevation of the maximal available INa+ . Only at the high concentration of 1 micromol/l was INa+ slightly depressed after depolarizing conditioning clamps. The most marked increase of the maximal available INa+ was 30+/-9% after application of 100 nmol/l isoproterenol. To learn about the mechanisms in view of sodium channel modulation we combined isoproterenol with the sodium channel blocker lidocaine (47 micromol/l). Under these circumstances the effects of both drugs were completely independent. This investigation shows clearly that low concentrations of isoproterenol increase INa+ in multicellular preparations by a gating-independent mechanism.

[Nonobstructive mesenteric ischemia--a diagnostic problem in internal intensive care]. / Nicht-okklusive Mesenterialischämie--ein diagnostisches Problem der internistischen Intensivmedizin.

Four cases of acute gut ischemia in elderly patients due to non-occlusive disease (NOD) are presented. Bowel necrosis occurred after episodes of hypotension in the course of myocardial infarction, arrhythmias and sepsis. Symptoms and clinical findings were blurred by the underlying extraintestinal disease. Angiography showed coexistent atherosclerosis but no occlusion of the major celiac and mesenteric vessels. At laparotomy (three cases) or autopsy (one case) extensive small and large bowel necroses were detected. Early laparotomy (possibly preceded by laparoscopy) is recommended for patients with suspected acute gut ischemia even if angiography fails to reveal occlusion of the large splanchnic arteries.

Exogenous surfactant application in respiratory failure due to chronic obstructive pulmonary disease.

Recent results of basic research on regulation of surfactant secretion and surfactant physiology not only in the alveolus but also in peripheral small airways allow the conclusion that disorders in surfactant homeostasis may contribute to the pathophysiology of airway obstruction and hyperinflation. We therefore hypothesized that patients with respiratory failure due to obstructive lung disease may benefit from exogenous surfactant. Here we report a case that indicates the clinical situation to be considered for treatment with exogenous surfactant. The benefit for the patient was successful weaning from the ventilator. Improvements in effective compliance, resistance and blood gas parameters were observed following surfactant application.

Dissimilar action of two cyclic adenosine-monophosphate analogues on the sodium current in intact rat papillary muscle.

In intact papillary muscles from rat we have found with the loose-patch-clamp technique an increase of the fast cardiac sodium current (INa+) by isoproterenol (ISO). In this study we have tested two membrane permeable analogues of the intracellular second messenger cyclic adenosine-monophosphate (cAMP) to investigate the intracellular pathway: 8-Br-cAMP (50 microM) and the newer developed Sp-5,6-Dichloro-1-beta-D-ribofuranosylbenzimidazole- 3',5'-cyclic-monophosphorothioate (5,6-DCl-cBiMPS, 20 microM). The availability of INa+ was determined with test pulses to +/- 0 mV every 3.5 seconds after 2.5-second conditioning between -130 mV and -50 mV and a holding potential at the resting potential of the cell under examination, and after wash-in of either compound. The peak currents were fit to a Boltzmann equation, and expressed by the maximal attainable current INa+,max, the mid-point potential V1/2, and a steepness parameter alpha. Values are given by mean +/- SEM. 8-Br-cAMP showed a significant shift of the availability curve in the hyperpolarized direction (V1/2 = -82 +/- 2 mV vs -86 +/- 2 mV, n = 5, P < 0.05) with only minor changes of INa+,max and alpha. In contrast, 5,6-DCl-cBiMPS had no significant effect on V1/2 but increased INa+,max by 8% +/- 2% versus control (n = 5, P < 0.05). In an intact muscle preparation we have found that 5,6-DCl-cBiMPS has a similar effect as that observed with the beta-adrenergic agonist ISO (100 nM), whereas 8-Br-cAMP exhibited a dissimilar action.(ABSTRACT TRUNCATED AT 250 WORDS)

Phosphorylation of focal adhesion vasodilator-stimulated phosphoprotein at Ser157 in intact human platelets correlates with fibrinogen receptor inhibition.

Integrins and other adhesion receptors are essential components for outside-in and inside-out signaling through the cell membrane. The platelet glycoprotein IIb-IIIa (also known as fibrinogen receptor or integrin alpha IIb beta 3) is activated by platelet agonists, inhibited by cyclic-nucleotide-elevating agents, and is involved in the activation of protein tyrosine kinases including the 125-kDa focal adhesion kinase (pp125FAK). However, the molecular details of glycoprotein IIb-IIIa regulation are not well understood. Here we report that in ADP-activated human platelets cAMP- and cGMP-dependent protein-kinase-mediated phosphorylation of the focal adhesion vasodilator-stimulated phosphoprotein (VASP) at Ser157 correlates well with glycoprotein IIb-IIIa inhibition. Human platelets contain similar concentrations of glycoprotein IIb-IIIa complexes (fibrinogen binding sites) and VASP. Using gel-filtered platelets, cAMP-elevating agents [e.g. prostaglandin E1 and the forskolin analog 6-(3-dimethylaminopropionyl)forskolin (NKH 477)] caused VASP Ser157 phosphorylation and inhibited glycoprotein IIb-IIIa activation up to 70-100%. NO-generating, cGMP-elevating agents [e.g. 3-morpholinosydnonimine hydrochloride (SIN1) and sodium nitroprusside] stimulated VASP Ser157 phosphorylation and inhibited glycoprotein IIb-IIIa activation up to a maximal extent of 30-50%. The effects of cAMP- and cGMP-elevating agents on VASP phosphorylation and fibrinogen binding were reversible and could be mimicked by membrane-permeant selective activators of platelet cAMP- or cGMP-dependent protein kinase, respectively. Using threshold concentrations, the nitrovasodilator SIN 1 potentiated the effects of the forskolin analog NKH 477 with respect to inhibition of platelet aggregation, VASP phosphorylation and glycoprotein IIb-IIIa inhibition. It is proposed that the inhibition of glycoprotein IIb-IIIa induced by cyclic nucleotide involves cAMP-and cGMP-dependent protein-kinase-mediated VASP phosphorylation at Ser157.