Peak oxygen uptake in relation to total heart volume discriminates heart failure patients from healthy volunteers and athletes

Background: An early sign of heart failure (HF) is a decreased cardiac reserve or inability to adequately increase cardiac output during exercise. Under normal circumstances maximal cardiac output is closely related to peak oxygen uptake (VO(2)peak) which has previously been shown to be closely related to total heart volume (THV). Thus, the aim of this study was to derive a VO(2)peak/THV ratio and to test the hypothesis that this ratio can be used to distinguish patients with HF from healthy volunteers and endurance athletes. Thirty-one patients with HF of different etiologies were retrospectively included and 131 control subjects (60 healthy volunteers and 71 athletes) were prospectively enrolled. Peak oxygen uptake was determined by maximal exercise test and THV was determined by cardiovascular magnetic resonance. The VO(2)peak/THV ratio was then derived and tested. Results: Peak oxygen uptake was strongly correlated to THV (r(2) = 0.74, p < 0.001) in the control subjects, but not for the patients (r(2) = 0.0002, p = 0.95). The VO(2)peak/THV ratio differed significantly between control subjects and patients, even in patients with normal ejection fraction and after normalizing for hemoglobin levels (p < 0.001). In a multivariate analysis the VO(2)peak/THV ratio was the only independent predictor of presence of HF (p < 0.001). Conclusions: The VO(2)peak/THV ratio can be used to distinguish patients with clinically diagnosed HF from healthy volunteers and athletes, even in patients with preserved systolic left ventricular function and after normalizing for hemoglobin levels

Regulation of Insulin Secretion in Relation to Nitric Oxide, Carbon Monoxide and Acid alpha-Glucoside Hydrolase Activities

The main stimulus for insulin secretion is elevated blood glucose levels. In this thesis the aim was to study less well-known systems involved in the complex regulation of glucose-stimulated insulin release, emphasizing the role of the lysosomal/vacuolar system and the associated glycogenolytic acid alpha-glucoside hydrolases, but also the HO-CO and NOS-NO systems. We performed studies both in healthy and diabetic animals. We show that the acid alpha-glucoside hydrolases are dependent on Ca2+ and the activities of these enzymes seems to be coupled to Ca2+-glucose-stimulated insulin release. The effect of Ca2+ is probably elicited through activation of the acidic organelles and not on the enzymes themselves. We also show that the acid alpha-glucoside hydrolases are dependent on the NOS-NO-system and the HO-CO system, where NO inhibits and NOS inhibition amplifies the acid alpha-glucoside hydrolase activities, while CO in contrast stimulates the acid alpha-glucoside hydrolases and glucose-stimulated insulin release in parallel. In the diabetic GK rat we found several abnormalities that could, at least in part, explain the impaired response to glucose seen in this diabetic animal model. We show that the GK rat has a dysfunctional lysosomal/vacuolar system in the islets of Langerhans, and this seems to prevent the normal function of the glucose-stimulated acid alpha-glucoside hydrolase signalling pathway and insulin release. The GK islets expressed inducible NOS (iNOS) and displayed a marked iNOS activity when incubated at low and high glucose, and NOS inhibition resulted in an amplification of glucose-stimulated insulin release. The HO-CO system on the other hand was suppressed, HO-2 expressed and CO production being decreased. Interestingly, the GK islets expressed inducible HO (HO-1) in islets isolated "ex vivo". The GK islets displayed a decreased glucose-stimulated CO production when incubated in vitro, in parallel with impaired glucose-stimulated insulin release. In conclusion the results suggest that NO and CO have interacting roles on glucose-stimulated insulin release, and that this regulation is, at least partly, transduced through the activity of the lysosomal/vacuolar system and the associated acid alpha-glucoside hydrolases and cGMP, but also through a direct effect on the cAMP system. NO acts inhibitory and CO stimulatory. In the GK rat we found abnormalities in the lysosomal/vacuolar system, as well as in the HO-CO and NOS-NO systems, and these findings might contribute to the understanding of the impaired insulin response to glucose seen in type 2 diabetes

Clinical experience of a new reference material for exercise capacity in exercise stress testing in Sweden

Summary: Background: In 2014, the Swedish Association of Clinical Physiology recommended the use of a new reference material for exercise capacity in bicycle exercise stress testing, 'the Kalmar material'. Compared to the formerly used reference material, 'the Kristianstad material', an increase in the amount of patients being classified as having decreased exercise capacity was expected, but the extent of this in clinical practice is not known. Methods: Results of exercise capacity from 1449 bicycle exercise tests, in patients aged ≥20 years (656 women, 793 men) performed at two departments of Clinical Physiology before and after change of reference materials, were collected. Maximal workload was related to the predicted values of both reference materials. If made, recommendations for supplemental nuclear myocardial perfusion imaging study by the attending physician were noted. Results: Using the new reference material, 31% of all patients were classified as having a decreased exercise capacity, compared to 17% using the formerly used reference material. The difference between the two reference materials was largest in the older age groups. In one of the departments, an increase in recommendations of supplemental myocardial perfusion studies was seen after introduction of the new reference material, whereas the opposite was seen at the other department. Conclusion: A large amount of patients are being classified as having decreased exercise capacity and very few as having good exercise capacity using the new reference material for exercise capacity

Atrial remodelling is less pronounced in female endurance-trained athletes compared with that in male athletes.

Objectives. Little data exists on atrial adaptation to training in women. Furthermore, data on right atrial (RA) volumes is lacking for both male and female athletes. The objective of this study was therefore to investigate atrial volumes in male and female athletes. Design. A total of 75 athletes (33 women) and 53 controls (21 women) underwent cardiovascular magnetic resonance imaging. Left atrial (LA) and RA volumes were measured by manual delineation. The atrial appendage was included in the volumes, and pulmonary veins were excluded. Results. Atrial volumes were larger in athletes compared with those in controls (males: LA 116 ± 19 ml versus 93 ± 19 ml, RA 166 ± 32 ml versus 133 ± 23 ml, p < 0.0001, females: LA 90 ± 15 ml versus 83 ± 17 ml, p < 0.05, RA 119 ± 24 ml versus 108 ± 18 ml, p = 0.07). When normalized for body surface area, atrial volumes remained larger in athletes. However, when normalized for total heart volume (THV) there were no differences between groups except for LA volumes in females where controls had higher LA/THV compared with those in athletes (p < 0.05). Conclusion. Atrial volumes were significantly larger in athletes. Atrial volumes normalized for THV did not differ between athletes and controls indicating a balanced enlargement. There was only a small difference between female controls and female athletes, suggesting that atrial adjustment to training is more modest in women

Nitric oxide, islet acid glucan-1,4-alpha-glucosidase activity and nutrient-stimulated insulin secretion

The mechanism of nutrient-evoked insulin release is clearly complex. One part of that mechanism is postulated to be the activation of the glycogenolytic enzyme acid glucan-1,4-alpha-glucosidase. As nitric oxide (NO) has been found to be a potent inhibitor of glucose-stimulated insulin secretion, we have now investigated a possible influence of exogenous NO and inhibition of endogenous NO production on islet acid glucan-1,4-alpha-glucosidase activity in relation to insulin release stimulated by glucose and l-arginine. In isolated islets, NO derived from the intracellular NO donor hydroxylamine inhibited the activation of acid glucan-1, 4-alpha-glucosidase and its isoform acid alpha-glucosidase in parallel with inhibition of glucose-stimulated insulin release. In comparison, other lysosomal enzymes were largely unaffected. Similarly, the spontaneous NO donor sodium nitroprusside, as well as NO gas, when added to islet homogenates, suppressed the activities of these acid alpha-glucosidehydrolases and, to a lesser extent, the activities of other lysosomal enzymes. Finally, in the presence of the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester, insulin release from isolated islets stimulated by glucose or l-arginine was markedly potentiated in parallel with an accompanying increase in the activities of acid glucan-1,4-alpha-glucosidase and acid alpha-glucosidase. Other lysosomal enzymes and neutral alpha-glucosidase were not influenced. We propose that an important inhibitory effect of NO on the insulin secretory processes stimulated by glucose and l-arginine is exerted via inactivation of islet acid glucan-1,4-alpha-glucosidase, a putative key enzyme in nutrient-stimulated insulin release

Insulin release transduction mechanism through acid glucan 1,4-alpha-glucosidase activation is Ca2+ regulated

An important signal involved in glucose-stimulated insulin secretion is transduced through the action of a lysosomal acid, glucan 1,4-alpha-glucosidase. We investigated the Ca2+ dependency of this enzyme activity in relation to insulin release. In isolated islets, increased levels of extracellular Ca2+ induced a large increase in acid glucan 1,4-alpha-glucosidase activity accompanied by a similar increase in insulin release at both substimulatory and stimulatory concentrations of glucose. At low glucose the Ca2+ "inflow" blocker nifedipine unexpectedly stimulated enzyme activity without affecting insulin release. However, nifedipine suppressed 45Ca2+ outflow from perifused islets at low glucose and at Ca2+ deficiency when intracellular Ca2+ was mobilized by carbachol. This nifedipine-induced retention of Ca2+ was reflected in increased acid glucan 1,4-alpha-glucosidase activity. Adding different physiological Ca2+ concentrations or nifedipine to islet homogenates did not increase enzyme activity. Neither selective glucan 1,4-alpha-glucosidase inhibition nor the ensuing suppression of glucose-induced insulin release was overcome by a maximal Ca2+ concentration. Hence, Ca(2+)-induced changes in acid glucan 1,4-alpha-glucosidase activity were intimately coupled to similar changes in Ca(2+)-glucose-induced insulin release. Ca2+ did not affect the enzyme itself but presumably activated either glucan 1,4-alpha-glucosidase-containing organelles or closely interconnected messengers