Hannu Näveri

Blood ketone bodies in congestive heart failure

OBJECTIVES The present study was designed to assess whether blood ketone bodies are elevated in congestive heart failure (CHF) and whether ketonemia is related to the hemodynamic and neurohumoral abnormalities of CHF. BACKGROUND In CHF, consumption of the bodys fat stores may become abnormally high, contributing to the development of cardiac cachexia. Increased mobilization of free fatty acids could, in theory, augment ketogenesis, but whether patients with CHF are prone to ketosis remains unknown. METHODS Forty-five patients with chronic CHF (mean age [+/- SD] 57 +/- 13 years) and 14 control subjects free of CHF (mean age 53 +/- 13 years) underwent invasive and noninvasive cardiac studies and determination of blood ketone bodies (acetoacetate plus beta-hydroxybutyrate), circulating free fatty acids, glucose, lactate, insulin, glucagon, growth hormone, cortisol, norepinephrine, N-terminal proatrial natriuretic peptide, tumor necrosis factor-alpha and interleukin-6 after an overnight fast. RESULTS Patients with CHF had elevated blood ketone bodies (median 267 mumol/liter, range 44 to 952) compared with control subjects (median 150 mumol/liter, range 31 to 299, p < 0.05). In the total study group, blood ketone bodies were related to pulmonary artery wedge pressure (r5 = 0.45, p < 0.001), left ventricular ejection fraction (r3 = -0.37, p < 0.01), right atrial pressure (r3 = 0.36, p < 0.01) and circulating concentrations of free fatty acids (r5 = 0.52, p < 0.001), glucose (r5 = -0.39, p < 0.001), norepinephrine (r3 = 0.45, p < 0.001), growth hormone (r5 = 0.30, p < 0.05) and interleukin-6 (r3 = 0.27, p < 0.05). In multivariate analysis, left ventricular ejection fraction, serum free fatty acids and serum glucose were independent predictors of ketonemia. CONCLUSIONS Blood ketone bodies are elevated in CHF in proportion to the severity of cardiac dysfunction and neurohormonal activation. This may be at least partly attributable to increased free fatty acid mobilization in response to augmented neurohormonal stimulation. Additional studies are needed to identify the detailed mechanisms and clinical implications of CHF ketosis.

Effect of ethanol drinking, hangover, and exercise on adrenergic activity and heart rate variability in patients with a history of alcohol-induced atrial fibrillation

To elucidate the mechanism of alcohol-induced atrial fibrillation (AF) we studied the heart rate variability and parameters of the adrenergic system during alcohol intake, hangover, and exercise in 6 men (mean age 43 years) prone to alcohol-induced AF, together with 6 age-matched controls. The ambulatory (15 hour) electrocardiogram was recorded and blood samples were taken for lymphocytic beta adrenoceptor, plasma catecholamine, and cyclic adenosine monophosphate (cAMP) measurements before and after alcohol intake (blood alcohol 1.5 per thousand), during hangover, and after a standardized bicycle exercise test. The beta-adrenoceptor density in lymphocytes was unchanged in the control group after alcohol intake or during hangover. Each of the AF patients had an increase in beta-adrenoceptor density after ethanol drinking (mean increase 29%, p <0.05). The hangover or exercise beta-receptor values did not differ from those in corresponding controls. Plasma adrenaline concentration tended to decrease and noradrenaline to increase after drinking and during hangover in both groups. Plasma cAMP levels were lower in patients after drinking than in controls (p <0.05). The exercise values of the adrenergic parameters were very similar in AF patients whether or not preceded by alcohol. Analysis of ambulatory electrocardiography showed a very low rate of ectopic beats in both AF patients and controls. Analysis of heart rate variability revealed a tendency toward an increase in sympathetic/parasympathetic component ratio (low-frequency/high-frequency ratio) in AF patients, but not in controls, after ethanol drinking. In conclusion, no signs of arrhythmogenic cardiac disease were detected in patients with AF to explain the tendency toward AF. Increases in beta-adrenoceptor density and low-frequency/high-frequency ratio during ethanol intoxication in patients with AF suggest an exaggerated sympathetic reaction.

The effect of physical training on skeletal muscle in patients with chronic heart failure.

The improvement of exercise capacity in patients with chronic heart failure (CHF) by physical training has been connected with reversal of the abnormalities in muscle fiber distribution and with the reduced activity of the enzymes of oxidative metabolism in skeletal muscle. However, the change in fiber type distribution induced by training is controversial and in previous studies the activities of the rate‐limiting enzymes of the metabolic pathways have not been measured.

Skeletal muscle fiber distribution influences serum high-density lipoprotein cholesterol level

Earlier we have shown a significant positive association between muscle fiber distribution, i.e. percentage of slow-twitch (ST) fibers in the vastus lateralis muscle, and serum high-density lipoprotein cholesterol (HDL-C) level. This association may be due to the fact that ST fibers have a high capacity for oxidative energy metabolism and a high number of surrounding capillaries. These fibers have a high capacity to metabolize fatty acids liberated by lipoprotein lipase (LPL) from triglyceride-rich lipoproteins. This in turn elevates serum HDL-C levels. Thus, a high percentage of ST fibers (ST-%) may be one factor having a beneficial effect on serum HDL-C concentration. A high ST-% may also increase the likelihood that a person will become involved in an endurance type of physical activity, which further increases serum HDL-C concentration by increasing further LPL activity in the capillary bed of skeletal muscle. In this paper we present a hypothetical background of the role that ST fibers may have on serum lipid and lipoprotein profile.

Alteration of regulatory enzyme activities in fast-twitch and slow-twitch muscles and muscle fibres in low-intensity endurance-trained rats.

The effect of progressive, low-intensity endurance training on regulatory enzyme activities in slow-twitch (ST) and fast-twitch (FT) muscle fibres was studied in 32 rats. Of those rats 16 were trained on a treadmill at a running speed of 10m · min−1 5 days a week over an 8-week period. Running time was progressively increased from 15 min to 2 h · day−1. Of the rats 4 trained and 4 sedentary rats were also subjected to acute exhausting exercise. Enzyme activities of phosphofructokinase 1 (PFKI) from glycolysis, α-ketoglutarate dehydrogenase (α-KGDH) from the Krebs cycle and carnitine palmitoyltransferase (CPT I and II) from fatty acid metabolism in soleus, tibialis anterior and gastrocnemius muscles were measured in trained and sedentary rats. Enzyme activities of individual ST and FT fibres were measured from the freeze-dried gastrocnemius muscle of 8 trained and 8 sedentary rats. In the sedentary rats the activity of PFK1 in tibialis anterior and soleus muscles was 141% and 41% of the activity in gastrocnemius muscle, respectively. The activity of α-KGDH in tibialis anterior and soleus muscles was 164% and 278% of the activity in gastrocnemius muscle, respectively. The activity of CPT I in tibialis anterior and gastrocnemius muscles were at the same level, but in soleus muscle the activity was 127% of that in mixed muscle. Endurance training increased enzyme activities of α-KGDH and CPT I significantly (P < 0.05) in gastrocnemius muscle but not in soleus or tibialis anterior muscle. After training both α-KGDH and CPT II activities were elevated significantly (P < 0.05) in the ST fibres of gastrocnemius muscle, whereas in FT fibres only α-KGDH was increased. For PFK1 activity no significant change was observed in ST or FT fibres. After acute exercise, activities of mitochondrial enzymes α-KGDH and CPT I tended to be elevated in all muscles. Thus, low-intensity endurance training induced significant peripheral changes in regulatory enzyme activities in oxidative and fatty acid metabolism in individual ST or FT muscle fibres.

Response of the beta-adrenergic system to maximal dynamic exercise in congestive heart failure secondary to idiopathic dilated cardiomyopathy

In congestive heart failure (CHF), prolonged exposure to high plasma catecholamine levels may reduce the responsiveness of the adrenergic system to physiologic stimuli. In healthy subjects, exercise is known to induce a rapid up-regulation of lymphocytic beta adrenoceptors. Lymphocytic beta-adrenoceptor density, lymphocytic basal and isoproterenol-stimulated cyclic adenosine monophosphate (cAMP) response, plasma catecholamine concentrations and plasma cAMP levels were studied during maximal ergometer exercise in 11 patients with CHF secondary to dilated cardiomyopathy and in 6 healthy control subjects. At rest, there was no difference in the lymphocytic beta-adrenoceptor levels between the patients and control subjects (48 +/- 3 vs 42 +/- 5 fmol/mg protein, respectively). However, the exercise-induced increase in lymphocytic beta adrenoceptors was attenuated in patients when compared with controls (26 +/- 6 fmol/mg protein [56%] vs 75 +/- 16 fmol/mg protein [204%], respectively, p less than 0.02). A subgroup of 4 patients with the lowest exercise capacity (peak oxygen uptake less than 12.5 ml/min/kg) had even more reduced up-regulation compared with the other 7 patients (13 +/- 1 fmol/mg protein [29%] vs 34 +/- 9 fmol/mg protein [71%], p less than 0.05). The lymphocytic cAMP response at rest and during exercise tended to be lower in patients compared with controls, but the differences did not reach statistical significance. The plasma levels of epinephrine and norepinephrine at rest were higher in patients compared with controls, but no difference was found in the exercise values. The plasma levels of cAMP correlated closely with plasma catecholamine levels at rest, but not during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcitonin gene-related peptide is not elevated in rat plasma by heart failure or by neutral endopeptidase inhibition

Some studies have indicated that plasma calcitonin gene-related peptide (CGRP) increases in congestive heart failure (CHF). In vitro, neutral endopeptidase (NEP) cleaves CGRP. We studied CGRP-like immunoreactivity (CGRP-ir) in rat plasma in a coronary artery-ligation model of CHF with and without NEP inhibition. Rats with CHF (n = 6) and sham-operated controls (n = 6) were administered vehicle and, separately, SCH 34826, a NEP inhibitor, subcutaneously 90 mg/kg. Plasma sample was taken 60 minutes later. Seventeen untreated coronary-ligated rats with various degrees of CHF were studied separately. Systolic arterial pressure (SAP) was measured while conscious. All rats were killed by exsanguination, and heart and lungs were removed and weighed. In CHF rats, plasma atrial natriuretic peptide after vehicle (basal ANP) was 7.6-fold, but basal CGRP-ir was similar compared to controls. After SCH 34826, plasma CGRP-ir decreased marginally in CHF rats (57-> 51 ng/l, p = 0.011), and ANP increased 1.8-fold (418-> 730 ng/l, p = 0.001). In controls, these changes by SCH 34826 were small. Basal ANP correlated strongly with relative weight of heart (HE; R = 0.93, p < 0.001) and lungs (LU; R = 0.96, p < 0.001). There was no correlation between basal CGRP-ir, basal plasma renin activity (PRA), HE and LU. In the untreated coronary-ligated rats, plasma CGRP-ir did not correlate with HE, LU, SAP, plasma ANP or PRA, but plasma ANP correlated with HE (R = 0.62, p = 0.011) and LU (R = 0.70, p = 0.002). We conclude that, in rat plasma, CGRP-ir is not elevated either by NEP inhibition, or in post-infarction CHF.

Basal and Exercise Plasma Levels of Atrial Natriuretic Peptide and Noradrenaline in Congestive Heart Failure

Plasma levels of atrial natriuretic peptide (ANP) are elevated in patients with congestive heart failure (CHF) and related to the severity of the disease, judged by functional capacity of the patients [9] and by direct measurements of cardiac preload [8]. Thus, plasma ANP measurements have been suggested to be useful in the evaluation of the degree of cardiac impairment [4, 6, 8]. Plasma noradrenaline (NA) levels have also been shown to increase in proportion to the severity of CHF, and high NA levels are associated with increased mortality [1]. In the present study, plasma ANP and NA levels were measured at rest and during maximal exercise in patients with chronic CHF to see if there is a correlation between ANP, NA, and the severity of heart failure, assessed by maximal oxygen consumption ( \(\ddot V{O_2}\max \)).