Henrik Mosén

Relation between cardiac dimensions and peak oxygen uptake

BackgroundLong term endurance training is known to increase peak oxygen uptake () and induce morphological changes of the heart such as increased left ventricular mass (LVM). However, the relationship between and the total heart volume (THV), considering both the left and right ventricular dimensions in both males and females, is not completely described. Therefore, the aim of this study was to test the hypothesis that THV is an independent predictor of and to determine if the left and right ventricles enlarge in the same order of magnitude in males and females with a presumed wide range of THV.Methods and ResultsThe study population consisted of 131 subjects of whom 71 were athletes (30 female) and 60 healthy controls (20 female). All subjects underwent cardiovascular MR and maximal incremental exercise test. Total heart volume, LVM and left- and right ventricular end-diastolic volumes (LVEDV, RVEDV) were calculated from short-axis images. was significantly correlated to THV, LVM, LVEDV and RVEDV in both males and females. Multivariable analysis showed that THV was a strong, independent predictor of (R2 = 0.74, p < 0.001). As LVEDV increased, RVEDV increased in the same order of magnitude in both males and females (R2 = 0.87, p < 0.001).ConclusionTotal heart volume is a strong, independent predictor of maximal work capacity for both males and females. Long term endurance training is associated with a physiologically enlarged heart with a balance between the left and right ventricular dimensions in both genders.

Cardiac output and cardiac index measured with cardiovascular magnetic resonance in healthy subjects, elite athletes and patients with congestive heart failure

BackgroundCardiovascular Magnetic Resonance (CMR) enables non-invasive quantification of cardiac output (CO) and thereby cardiac index (CI, CO indexed to body surface area). The aim of this study was to establish if CI decreases with age and compare the values to CI for athletes and for patients with congestive heart failure (CHF).MethodsCI was measured in 144 healthy volunteers (39 ± 16 years, range 21–81 years, 68 females), in 60 athletes (29 ± 6 years, 30 females) and in 157 CHF patients with ejection fraction (EF) below 40% (60 ± 13 years, 33 females). CI was calculated using aortic flow by velocity-encoded CMR and is presented as mean ± SD. Flow was validated in vitro using a flow phantom and in 25 subjects with aorta and pulmonary flow measurements.ResultsThere was a slight decrease of CI with age in healthy subjects (8 ml/min/m2 per year, r2 = 0.07, p = 0.001). CI in males (3.2 ± 0.5 l/min/m2) and females (3.1 ± 0.4 l/min/m2) did not differ (p = 0.64). The mean ± SD of CI in healthy subjects in the age range of 20–29 was 3.3 ± 0.4 l/min/m2, in 30–39 years 3.3 ± 0.5 l/min/m2, in 40–49 years 3.1 ± 0.5 l/min/m2, 50–59 years 3.0 ± 0.4 l/min/m2 and >60 years 3.0 ± 0.4 l/min/m2. There was no difference in CI between athletes and age-controlled healthy subjects but HR was lower and indexed SV higher in athletes. CI in CHF patients (2.3 ± 0.6 l/min/m2) was lower compared to the healthy population (p < 0.001). There was a weak correlation between CI and EF in CHF patients (r2 = 0.07, p < 0.001) but CI did not differ between patients with NYHA-classes I-II compared to III-IV (n = 97, p = 0.16) or patients with or without hospitalization in the previous year (n = 100, p = 0.72). In vitro phantom validation showed low bias (−0.8 ± 19.8 ml/s) and in vivo validation in 25 subjects also showed low bias (0.26 ± 0.61 l/min, QP/QS 1.04 ± 0.09) between pulmonary and aortic flow.ConclusionsCI decreases in healthy subjects with age but does not differ between males and females. We found no difference in CI between athletes and healthy subjects at rest but CI was lower in patients with congestive heart failure. The presented values can be used as reference values for flow velocity mapping CMR.

Dysfunction of the Islet Lysosomal System Conveys Impairment of Glucose-Induced Insulin Release in the Diabetic GK Rat*

Accumulated evidence links an important signal involved in glucose-stimulated insulin release to the activation of the islet lysosomal glycogenolytic enzyme acid glucan-1,4-alpha-glucosidase. We have analyzed the function of the lysosomal system/lysosomal enzyme activities in pancreatic islets of young (6-8 weeks), spontaneously diabetic, GK (Goto-Kakizaki) rats and Wistar control rats in relation to glucose-induced insulin release. The insulin secretory response to glucose was markedly impaired in the GK rat, but was restored by the adenylate cyclase activator forskolin. Islet activities of classical lysosomal enzymes, e.g.. acid phosphatase, N-acetyl-beta-D-glucosaminidase, beta-glucuronidase, and cathepsin D, were reduced by 20-35% in the GK rat compared with those in Wistar controls. In contrast, the activities of the lysosomal alpha-glucosidehydrolases, i.e.. acid glucan-1,4-alpha-glucosidase and acid alpha-glucosidase, were increased by 40-50%. Neutral alpha-glucosidase (endoplasmic reticulum) was unaffected. Comparative analysis of liver tissue showed that lysosomal enzyme activities were of the same magnitude in GK and Wistar rats. Notably, in Wistar rats, the activities of acid glucan-1,4-alpha-glucosidase and acid alpha-glucosidase were approximately 15-fold higher in islets than in liver. Other lysosomal enzymes did not display such a difference. Normalization of glycemia in GK rats by phlorizin administered for 9 days did not influence either the lysosomal alpha-glucosidehydrolase activities or other lysosomal enzyme activities in GK islets. Finally, the pseudotetrasaccharide acarbose, which accumulates in the lysosomal system, inhibited acid glucan-1,4-alpha-glucosidase activity in parallel with its inhibitory action on glucose-induced insulin release in intact Wistar islets, whereas no effect was recorded for either parameter in intact GK islets. In contrast, acarbose inhibited the enzyme activity equally in islet homogenates from both GK and Wistar rats, showing that the catalytic activity of the enzyme itself in disrupted cells was unaffected. We propose that dysfunction of the islet lysosomal/vacuolar system is an important defect impairing the transduction mechanisms for glucose-induced insulin release in the GK rat.

Interaction of the islet nitric oxide system with L‐arginine‐induced secretion of insulin and glucagon in mice

1 Several recent in vitro studies have suggested that production of nitric oxide (NO) from the islet NO system may have an important regulatory influence on the secretion of insulin and glucagon. In the present paper we have investigated, mainly with an in vivo approach, the influence and specificity of the NO synthase (NOS) blocker NG‐nitro‐L‐arginine methyl ester (L‐NAME) on L‐arginine‐induced secretion of insulin and glucagon. 2 In freely fed mice, L‐NAME pretreatment (1.2 mmol kg−1) influenced the dynamics of insulin and glucagon release following an equimolar dose of L‐arginine, the specific substrate for NOS activity, in that the NOS inhibitor enhanced the insulin response but suppressed the glucagon responses. This was reflected in a large decrease in the plasma glucose levels of the L‐NAME pretreated animals. 3 L‐NAME pretreatment did not influence the insulin and glucagon secretory responses to the L‐arginine‐enantiomer D‐arginine, which cannot serve as a substrate for NOS activity. 4 Replacing L‐NAME pretreatment by pretreatment with D‐arginine or L‐arginine itself, which both carry the same cationic charge and are devoid of NOS inhibitory properties, did not mimic the effects of L‐NAME on L‐arginine‐induced hormone release. 5 Fasting the animals for 24 h totally abolished the L‐NAME‐induced potentiation of L‐arginine stimulated insulin release suggesting that the sensitivity of the β‐cell secretory machinery to NO‐production is greatly changed in the fasting state. However, the L‐NAME‐induced suppression of L‐arginine stimulated glucagon release was unaffected by starvation. 6 In isolated islets from freely fed mice, L‐arginine (5 mM) stimulated insulin release was greatly enhanced and glucagon release markedly suppressed by the presence of the NOS inhibitor L‐NAME in the incubation medium. These effects were abolished in isolated islets taken from 24 h fasted mice. 7 Our present results, which showed that the NOS inhibitor L‐NAME markedly enhances insulin release but suppresses glucagon release induced by L‐arginine in the intact animal, give strong support to our previous hypothesis that the islet NO system is a negative modulator of insulin secretion and a positive modulator of glucagon secretion. Additionally, we observed that the importance of the β‐cell NO‐production for secretory mechanisms, as evaluated by the effect of L‐NAME on L‐arginine‐induced insulin release, was greatly changed after starvation, an effect less prominent with regard to glucagon release.

Impaired glucose-stimulated insulin secretion in the GK rat is associated with abnormalities in islet nitric oxide production.

We investigated implications of nitric oxide (NO) derived from islet neuronal constitutive NO synthase (ncNOS) and inducible NOS (iNOS) on insulin secretory mechanisms in the mildly diabetic GK rat. Islets from GK rats and Wistar controls were analysed for ncNOS and iNOS by HPLC, immunoblotting and immunocytochemistry in relation to insulin secretion stimulated by glucose or l-arginine in vitro and in vivo. No obvious difference in ncNOS fluorescence in GK vs control islets was seen but freshly isolated GK islets displayed a marked iNOS expression and activity. After incubation at low glucose GK islets showed an abnormal increase in both iNOS and ncNOS activities. At high glucose the impaired glucose-stimulated insulin release was associated with an increased iNOS expression and activity and NOS inhibition dose-dependently amplified insulin secretion in both GK and control islets. This effect by NOS inhibition was also evident in depolarized islets at low glucose, where forskolin had a further amplifying effect in GK but not in control islets. NOS inhibition increased basal insulin release in perfused GK pancreata and amplified insulin release after glucose stimulation in both GK and control pancreata, almost abrogating the nadir separating first and second phase in controls. A defective insulin response to l-arginine was seen in GK rats in vitro and in vivo, being partially restored by NOS inhibition. The results suggest that increased islet NOS activities might contribute to the defective insulin response to glucose and l-arginine in the GK rat. Excessive iNOS expression and activity might be deleterious for the beta-cells over time.

Imidazoline‐induced amplification of glucose‐ and carbachol‐stimulated insulin release includes a marked suppression of islet nitric oxide generation in the mouse

Aim:  The role of islet nitric oxide (NO) production in insulin‐releasing mechanisms is unclear. We examined whether the beneficial effects of the imidazoline derivative RX 871024 (RX) on β‐cell function might be related to perturbations of islet NO production.

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

Abstract 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.

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

BackgroundAn 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 (VO2peak) which has previously been shown to be closely related to total heart volume (THV). Thus, the aim of this study was to derive a VO2peak/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 VO2peak/THV ratio was then derived and tested.ResultsPeak oxygen uptake was strongly correlated to THV (r2 = 0.74, p < 0.001) in the control subjects, but not for the patients (r2 = 0.0002, p = 0.95). The VO2peak/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 VO2peak/THV ratio was the only independent predictor of presence of HF (p < 0.001).ConclusionsThe VO2peak/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.

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

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.

Physiological variation in left atrial transverse orientation does not influence orthogonal P-wave morphology

It has previously been demonstrated that orthogonal P‐wave morphology in healthy athletes does not depend on atrial size, but the possible impact of left atrial orientation on P‐wave morphology remains unknown. In this study, we investigated if left atrial transverse orientation affects P‐wave morphology in different populations.