Karl-Erik Karlberg

Peak skeletal muscle perfusion is maintained in patients with chronic heart failure when only a small muscle mass is exercised

OBJECTIVES The issue to be resolved was whether peripheral leg blood flow in patients with chronic heart failure (CHF) is reduced by low local flow capacity or as a function of the amount of muscle mass activated during exercise. METHODS AND RESULTS In ten CHF patients (ejection fraction 26 (9)%), and 12 healthy controls central and peripheral circulatory responses were assessed during dynamic one- and two-legged knee extensor work. The patients reached a peak perfusion of 234 (16) ml 100 g-1 min-1 in the one-legged mode, which was similar to the controls (244 (11) ml 100 g-1 min-1). At peak two-legged work muscle perfusion was reduced in the patients by 24% (P < 0.05). In contrast the controls maintained their peak muscle perfusion. The mass of the quadriceps femoris muscle and peak leg blood flow correlated closely for both groups at peak one-legged work (r = 0.85, P < 0.001). Peak oxygen uptake in the active limb during one-legged exercise was similar for patients and controls (0.52 (0.06) vs. 0.63 (0.06) l min-1), but it was 38% lower (P < 0.05) in patients than controls during exhaustive two-legged exercise. Arterial systemic oxygen delivery (cardiac output x arterial oxygen content), at peak exercise was highly correlated with peak one- and two-legged workload for both groups, explaining 70% of the difference in peak workload attained (P < 0.001). At peak two-legged exercise non-exercising tissues of the body in the male CHF patients with the largest limb muscle mass, received a blood flow of only 1.2 (0.7) 1 min-1. Mean arterial blood pressure at peak work in both test conditions was significantly lower for the patients than the controls. A higher sympathetic nerve activity in the patients, as evaluated by arterial noradrenaline concentration (NA) and leg NA spillover, contributed to maintain the perfusion pressure. CONCLUSIONS Patients with moderate CHF can reach a peak skeletal muscle perfusion and a leg oxygen uptake comparable to that of healthy individuals when a sufficiently small muscle mass is activated. Exercise involving a larger muscle mass, for the patients in this study about 4 kg, markedly reduces peak leg blood flow, perfusion and oxygen uptake as well as blood flow to non-exercising organs and tissues.

Dose-Dependent Effect of Intravenous Nitroglycerin on Platelet Aggregation, and Correlation with Plasma Glyceryl Dinitrate Concentration in Healthy Men

Nitroglycerin has been reported to reduce mortality in patients with acute myocardial infarction. This beneficial effect has been attributed to vasodilation, but it was speculated that part of this effect may be due to altered platelet function. The influence of intravenous nitroglycerin on platelet aggregation was assessed. Eight healthy subjects (aged 22 to 48 years) were studied using filtragometry at baseline, and 3 different nitroglycerin doses. Compared with baseline, aggregation time (which indexes platelet aggregation) increased dose-dependently by 91 +/- 68% (p less than 0.001) at the maximal dose of nitroglycerin (1.1 +/- 0.3 micrograms/kg/min). Plasma concentration-effect relations were observed between nitroglycerin as well as the glyceryl dinitrate metabolites and platelet aggregation (r = 0.6 [p less than 0.002] and r = 0.8 [p less than 0.0001], respectively). It is concluded that increasing doses of intravenous nitroglycerin profoundly and dose-dependently inhibit platelet aggregation. This inhibitory effect correlates with glyceryl dinitrate formation.

Skeletal muscle strength and endurance in chronic congestive heart failure secondary to idiopathic dilated cardiomyopathy.

Abstract Long-term heart failure may affect both skeletal muscle strength and endurance as a result of fiber atrophy, decreased percentage of oxidative muscle fibers, lowered oxidative enzyme capacity and a reduced number of capillaries per fiber found in patients with chronic congestive heart failure (CHF).1–4 Isometric strength of the musculus quadriceps femoris in patients with CHF has been shown to be markedly lower,5,6 but also unaltered,7 in comparison with healthy subjects. In addition, patients with CHF have a lower muscular endurance in the forearm, as well as postural muscles, than in healthy subjects.5,7,8 Although Minotti et al7 showed a greater force reduction after an anaerobic, short-lasting bout of knee extensions in patients with CHF, it remains to be shown that patients respond in the same way after a challenge that activates the metabolism to a higher degree. The aim of the present study was to investigate whether muscular strength and endurance are lower in patients with CHF, and if so, to determine the degree and manner in which functional capacity is altered. Specifically, this study examined the force velocity relation of musculus quadriceps femoris during single isometric, concentric and eccentric, as well as repeated, muscular contractions. Furthermore, the muscle cross-sectional area was measured to study specific tension and possible atrophy of the muscles of patients with CHF in relation to healthy subjects.

Heparin and low molecular weight heparin but not hirudin stimulate platelet aggregation in whole blood from acetylsalicylic acid treated healthy volunteers

The platelet aggregatory effect of heparin was investigated with whole blood aggregometry in blood from healthy volunteers with collagen as activator. Tests were performed before and 3 hours after 0.5 g acetylsalicylic acid given perorally. Three protocols were tested. In the first experiment and before acetylsalicylic acid low doses (2.5 and 5 IU/ml) of heparin and low molecular weight heparin (LMW-heparin) did not affect aggregation while higher doses (25 and 250 IU/ml) had an antiaggregatory effect (p less than 0.0001). After acetylsalicylic acid, and with the same amount of collagen as before acetylsalicylic acid, aggregation decreased by 82 +/- 4%. Both heparin and LMW-heparin increased the aggregation (p less than 0.05). In the second experiment the collagen dose was titrated to give a similar light to moderate degree of aggregation before as compared to after acetylsalicylic acid. Low doses of heparin (p less than 0.01) but not hirudin increased the aggregation to the same degree before and after acetylsalicylic acid. In the third experiment the RGDS peptide (ARG-GLY-ASP-SER), a blocker of GPIIb/IIIa platelet receptor dose dependently inhibited platelet aggregation by 93 +/- 17%. With added RGDS peptide heparin still increased aggregation (p less than 0.001). In conclusion, with whole blood aggregometry both heparin and LMW-heparin but not the specific thrombin inhibitor hirudin stimulated platelet aggregation before and after acetylsalicylic acid ingestion. The heparin aggregatory effect was not inhibited by the RGDS peptide implying platelet activation via non specific mechanisms. These heparin effects could be of clinical importance for the treatment of arterial thromboembolic disease.

Intravenous nitroglycerin reduces ischaemia in unstable angina pectoris: a double‐blind placebo‐controlled study

Karlberg K‐E, Saldeen T, Wallin R, Henriksson P, Nyquist O, Sylvén C (Huddinge Hospital, Huddinge; University of Uppsala, Uppsala; and Södertälje; Sweden). Intravenous nitroglycerin reduces ischaemia in unstable angina pectoris: a double‐blind placebo‐controlled study. J Intern Med 1998; 243: 25–31

Heparin enhances platelet aggregation irrespective of anticoagulation with citrate or with hirudin

The effects of anticoagulation with citrate or hirudin on heparin effects on platelet aggregation was studied with whole blood aggregometry on blood from healthy volunteers. Platelet aggregation was initiated by collagen. The heparin effect was also studied with filtragometry where hirudin was used as the anticoagulant. In citrated blood, a mean collagen dose of 0.42 +/- 0.04 micrograms/ml resulted in an impedance change of 1.1 +/- 0.3 Ohm. Preincubation with heparin doses of 0.5, 2.5 and 5 IU/ml enhanced the impedance induced by the same dose of collagen by 2.9 +/- 1.4, 11.4 +/- 1.6 and 9.9 +/- 2.3 times, respectively (p less than 0.0001, ANOVA). In hirudinized blood a similar degree of change in impedance (1.5 +/- 0.2 Ohm) was achieved at significantly lower concentration of collagen (0.08 +/- 0.006 micrograms/ml, p less than 0.0001). Preincubation with heparin in doses of 0.5, 2.5 and 5 IU/ml increased impedance by 1.5 +/- 0.5, 3.9 +/- 1.6 and 1.3 +/- 0.5 times, respectively (p less than 0.0001, ANOVA). The dose-related increments were smaller in hirudinized blood as compared to citrated blood (p less than 0.04). With filtragometry, heparin dose-dependently shortened the aggregation time (p less than 0.0007). Compared to hirudin alone as anticoagulant, heparin in an equipotent dose in these experiments shortened aggregation time (p less than 0.05). In conclusion, heparin enhanced platelet aggregation both in calcium-chelated blood and in blood anticoagulated with hirudin. Heparin also dose-dependently increased platelet aggregation in filtragometry. Thus the heparin potentiating effect on platelet aggregation seems to be independent of extracellular ionized calcium and be operative at physiological calcium concentrations.

Effects of nitroglycerin on platelet aggregation beyond the effects of acetylsalicylic acid in healthy subjects

Abstract Acetylsalicylic acid (ASA) is widely used in the treatment of acute myocardial infarction. In the Second International Study of Infarct Survival, the reduction in mortality by ASA alone was of the same magnitude as by streptokinase therapy. This beneficial effect was attributed to platelet antiaggregation. 1 Intravenous nitroglycerin also reduces mortality in acute myocardial infarction. 2 This beneficial effect has been attributed to vasodilation, but nitroglycerin administered in clinically used doses may also reduce platelet aggregation. 3 This study was designed to investigate the possibility that the antiaggregatory effects of ASA and nitroglycerin may be additive, because the platelet antiaggregatory effect of ASA, which is based on suppression of thromboxane synthesis, 4 differs from that of nitroglycerin, which is based on increased synthesis of cyclic guanosine monophosphate. 5

Enhanced platelet function in acute myocardial infarction is attenuated by streptokinase treatment

Abstract. The aim of this study was to determine whether platelets are activated and aggregation is increased in myocardial infarction treated with streptokinase. Twelve consecutive patients were studied. Before streptokinase infusion (1.5 times 106 IU i.v. over a period of 1 h), 7 ± 4 h after the onset of symptoms, fibrinogen, leucocyte and platelet functions were enhanced compared to reference values. Plasma fibrinogen was 3.1 ± 0.6 g l‐1 (P < 0.03), leucocyte count was 14.3 ± 3.3 times 103 l‐1 (P < 0.0005), elastase was 39 ± 8 μg l‐1 (P < 0.0002), β‐thromboglobulin was 68 ± 71 μg l‐1 (P < 0.0001) and filtragometer platelet aggregation time was 137 ± 40 s (P < 0.0001). After streptokinase the leucocyte count, elastase and β‐thromboglobulin levels increased further, by about 40% (P < 0.02), 130% (P < 0.02) and 140% (P < 0.005), respectively. Fibrinogen was almost eliminated. Despite signs of increased activation, platelet aggregation was decreased as indicated by both filtragometer aggregation time, which increased by about 480% (P < 0.003), and whole‐blood aggregometry, in which electrical impedance decreased by about 65% (P < 0.01).

Streptokinase, but not tissue plasminogen activator, attenuates platelet aggregation in patients with acute myocardial infarction.

Abstract. Objectives. To investigate if tissue plasminogen activator (tPA) and streptokinase given during acute myocardial infarction (AMI) have different effects on platelet aggregation which could contribute to the higher reocclusion rate observed after tPA.

Platelet Aggregation in Vitro and Ex Vivo in Normal Pregnancy, Pregnancy-Induced Hypertension, and Preeclampsia

Objective: To compare women with preeclampsia, pregnancy-induced hypertension (PIH), and norrnotensive pregnant women with regard to different coagulation variables including filtragometry, reflecting the in vivo situation more closely than conventional in vitro methods.Methods: Blood was sampled for analyses of platelet count, antithrombin III (AT III) concentration, activated partial thromboplastin (APT) time, and prothrombin time in 15 patients with preeclampsia, 11 with PIH, and 13 normotensive pregnant women in the third trimester. We also applied whole blood aggregometry in vitro by the addition of 1 μg of collagen to 1 mL of diluted blood and filtragometry measuring spontaneous platelet aggregation ex vivo by estimating the time to develop a pressure gradient of 10 mm Hg over a filter occluded by platelet aggregates. The Kruskal—Wallis nonparametric test was used for statistical analyses.Results: APT time and prothrombin time did not differ among the three groups. Platelet count was normal except f...