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.

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 q&) 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 (~~1 2 5~~~) .However, the molecular details of glycoprotein IIb-IIIa regulation are not well understood. Here we report that in ADP-activated human platelets CAMP-and cGMPdependent 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 E, 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 inhitition of glycoprotein IIb-IIIa induced by cyclic nucleotide involves CAMPand cGMP-dependent protein-kinase-mediated VASP phosphorylation at Ser157.Adhesion, activation and aggregation of platelets and platelet -vessel-wall interactions are tightly regulated under physiological conditions and often impaired in diseases including congenital hemorrhagic diseases, atherosclerosis, hypertension and diabetes 11, 21. Important components of this vascular cell -cell and cell -matrix interaction are integrins and other adhesion receptors [3 -81. The platelet glycoprotein IIb-IIIa ((xllbp3) is one of the best-studied integrins and represents the functional fibrinogen receptor which is absent or impaired in the hereditary disorder Glanzmann's thrombasthenia [l, 5-81. Activated platelets contain at their sur-

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In an animal preparation of congestive heart failure in the dog, during the development of cardiac failure due to rapid right ventricular pacing we observed significant decreases in cardiac output and arterial pressure and increases in pulmonary arterial and right atrial pressure. We also observed a related increase in right atrial pressure and increases in plasma levels of atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (c-GMP). Ultrastructure changes in the atrial myoendocrine cells indicated extreme stimulation of the secretory apparatus of ANP. The response of hemodynamic, renal, and hormonal variables was investigated after incremental infusions (0.01, 0.03, 0.1, 0.3, and 0.6 ,ug/kg/min) of exogenous ANP. In healthy animals ANP significantly decreased mean arterial pressure, cardiac output, stroke volume, and right atrial pressure without changing heart rate or peripheral vascular resistance. As expected, we found a striking increase in urine flow and urinary excretion of sodium, chloride, magnesium and calcium and a smaller increase in potassium excretion. ANP suppressed renin secretion, and increased renal plasma flow, glomerular filtration rate, and filtration fraction. In dogs with heart failure ANP caused a small reduction in mean arterial pressure. No effect was seen on other hemodynamic variables or plasma renin concentration. The excretory effects on the kidneys were completely absent, and smaller increases in glomerular filtration rate and filtration fraction were observed. We found no difference between healthy dogs and animals with heart failure with respect to the secretion of c-GMP during ANP infusions in relation to the plasma levels of ANP. This suggests an intracellular defect that prevents the mediation of the hormonal signal into biological action in the presence of heart failure.Circulation 77, No. 2, 398-406, 1988 It has been shown3 that ANP is elevated in the presence of heart failure in proportion to the severity of the disease, suggesting that ANP may be important in the pathophysiology of cardiac failure. It has been reported that in patients with severe chronic congestive heart

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In a study of 20 patients with hypercholesterolemia (type IIa) the effects of lovastatin (20-80 mg/day) on various clotting and thrombosis parameters were monitored for 12 months. On 11 occasions various cholesterol fractions and clotting parameters were determined in each patient. In addition, the clotting inhibitors AT III, protein C, protein S, and C1-esterase inhibitor and the fibrinolysis parameters plasminogen and alpha 2-antiplasmin were examined. Platelet function was monitored on the basis of spontaneous and induced (collagen, ADP, epinephrine, ristocetin) aggregation. Lovastatin in the above dosage brought about a 66 mg/dl (from 320 +/- 12.6 to 254 +/- 12.0 mg/dl) reduction in the total cholesterol level and a 56 mg/dl (from 244 +/- 11.4 to 188 +/- 12.1 mg/dl) reduction in LDL cholesterol at the end of the study. Fibrinogen showed a significance decrease during the study period, whereas PT and aPTT remained unaffected. The initial slopes of the ADP-induced platelet aggregation revealed a significant decrease. C-reactive protein and platelet count remained within the normal range, indicating no significant change. Thrombin clotting time, AT III, C1-esterase inhibitor, plasminogen, and alpha 2-antiplasmin were not modified. Protein C and S behaved in a contradictory way, but remained within the normal range. Long-term treatment with lovastatin was associated with a significant reduction of fibrinogen levels and platelet aggregation induced by ADP in type-IIa hypercholesterolemic patients. These alterations, as well as their role in cardiovascular disease, should be the subject of further investigations.

In many pacemaker patients bicycle and treadmill ergometry are not practicable. As an alternative, we performed a 6-minute walk on a 20-m corridor in 97 pacemaker patients, who were asked to walk as far as possible determining their speed by themselves. Results were compared with those of bicycle ergometry in 42 of these patients and with treadmill exercise of a group of 92 other pacemaker patients. In the 6-minute walk, performance and maximal heart rate were slightly lower (49 +/- 18 W; 96 +/- 23 beats/min) than in bicycle (57 +/- 16 W; 110 +/- 26 beats/min) and treadmill ergometry (50 +/- 37 W; 102 +/- 35 beats/min). A good correlation was found between walking and bicycling (r = 0.74) and in subgroups of patients with different pacemaker indications. All patients preferred the walk to bicycle ergometry considering it to be more related to daily physical activity. In conclusion, a 6-minute walk is a simple and physiological exercise test for nearly all pacemaker patients with good correlation to other types of exercise. It seems to be preferable to other tests because of its better acceptance and practicability.