Hannu Leinonen

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.

Exclusion of coronary artery disease by exercise thallium-201 tomography in patients with aortic valve stenosis.

In many patients with valvular aortic stenosis (AS), management decisions may be possible without invasive studies if coexistent coronary artery disease (CAD) can be ruled out noninvasively. The use of thallium-201 single-photon emission computed tomography to the exclusion of CAD was studied in 44 patients aged 41 to 78 years with AS. In addition to cardiac catheterization and selective coronary angiography, patients underwent a cardiac ultrasound study and thallium-201 myocardial perfusion imaging at rest and after bicycle ergometer exercise. Two thirds of the patients had critical AS (valve area index less than or equal to 0.5 cm2/m2) but none had left ventricular systolic dysfunction. Twenty-one patients had angiographically significant CAD (greater than or equal to 50% diameter stenosis in greater than or equal to 1 coronary artery), whereas 23 had either a fully normal angiogram (n = 17) or mild (less than 50%) stenoses (n = 6). Each patient with significant CAD had an abnormal thallium-201 tomogram, either a strictly segmental perfusion defect (n = 19), or a patchy nonsegmental abnormality (n = 2); however, 10 of 23 patients free of significant CAD had similar results. Thus, the sensitivity and specificity of an abnormal scintigram were 100 and 57%, respectively. If only segmental perfusion defects typical of CAD had been considered abnormal, then the sensitivity of the test would have been 90% and the specificity 70%. Patients with false abnormal scintigrams had more severe AS and more angiographically nonsignificant CAD than those with true normal findings.(ABSTRACT TRUNCATED AT 250 WORDS)

Double-peaking circadian variation in the occurrence of sustained supraventricular tachyarrhythmias☆

We studied 251 patients less than or equal to 65 years of age admitted for treatment of symptomatic supraventricular tachyarrhythmia to assess whether these arrhythmias begin evenly throughout the day or manifest circadian variation in occurrence. The arrhythmias included 152 episodes of atrial fibrillation, 50 episodes of supraventricular reentry tachycardia, 30 episodes of atrial flutter, and 19 cases of ectopic atrial tachycardia. A total of 209 patients could tell the exact time their symptoms had started. In 38 of them (18%), the arrhythmia had begun between midnight and 6:00 AM, in 63 (30%) between 6:01 AM and noon, in 46 (22%) between noon and 6:00 PM, and in 62 (30%) between 6:01 PM and midnight. This distribution differed significantly from uniform occurrence (chi square 8.7, p less than 0.05). Fifty patients were using beta-adrenoceptor blocking agents when the arrhythmia occurred. Compared with the other 159 patients, they had no morning surge of arrhythmias (20% versus 33.3% of episodes between 6:01 AM and noon), but instead a much higher incidence at night (34% versus 13.2% of episodes between midnight and 6:00 AM) (chi square 14.4, p less than 0.005). We conclude that the frequency of onset of sustained supraventricular tachyarrhythmias varies with the time of day, showing nearly equal peaks in the morning and in the evening and a trough at night. The modifying effect of beta-adrenoceptor blockage suggests that many morning arrhythmias are of adrenergic origin while other, probably vagal arrhythmogenic mechanisms, prevail at night.

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)

Effect of propranolol and pindolol on the up-regulation of lymphocytic beta adrenoceptors during acute submaximal physical exercise. A placebo-controlled double-blind study.

The effect of β-adrenoceptor antagonists, with and without intrinsic sympathomimetic activity, on the regulation of lymphocytic β adrenoceptors during acute physical exercise was studied. Seven healthy volunteers underwent a graded maximal ergometer test after treatment for 7 days with placebo, propranolol (2 x 80 mg/ day), or pindolol (2 x 10 mg/day). Each subject received the three types of drug treatment in a double-blind, randomized fashion, with 3 weeks wash-out periods between the on-drug periods. The mean resting density of lymphocytic β adrenoceptors was 46 ± 5 fmol/mg protein (mean ± SEM) during placebo, 53 ± 5 fmol/mg protein during propranolol, and 29 ± 4 fmol/mg protein during pindolol treatment (p < 0.05, pindolol vs. propranolol). Exercise induced a significant up-regulation of the β-adrenoceptor density during each treatment modality, but the increment was attenuated during propranolol (mean elevation, 16 ± 2 fmol/mg protein, p < 0.05) and pindolol intake (13 ± 4 fmol/mg protein, p < 0.02) as compared with the placebo value (56 ± 13 fmol/mg protein). Moreover, exercise-induced increment of lymphocytic cyclic AMP (cAMP) production was virtually abolished by the two β-adrenoceptor antagonists. In conclusion, administration of β-adrenoceptor antagonists is associated with a subnormal up-regulation of the lymphocytic β-adreno-ceptors and alterations in their functioning during heavy physical effort. This attenuation is not modified by intrinsic sympathomimetic activity of the compound.

Value of routine echocardiography in new-onset atrial fibrillation

We studied 100 patients with new-onset atrial fibrillation to assess the role of echocardiography in their initial cardiac evaluation. Clinical examination with routine laboratory tests and chest radiography was sufficient in establishing or excluding an underlying condition in 96% of the cases. Echocardiography uncovered a heart condition in three of 38 patients (8%) classified as having isolated atrial fibrillation, but this had no effect on short-term treatment. Routine echocardiography adds very little to a careful clinical examination in these patients.

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 ( \(\ddot V{O_2}\max \)).