Cardiovascular Research 45 (2000) 177–184
Department of Clinical and Experimental Cardiology, Academic Medical Center, Meibergdreef 9, P.O. Box 22700, 1105 AZ Amsterdam, The Netherlands
Jose and Collison published a study on the normal range and the determinants of intrinsic heart rate in man in Cardiovascular Research in 1970 [Jose AD, Collison D. The normal range and determinants of the intrinsic heart rate in man. Cardiovasc Res 1970; 4: 160–167)]. The intrinsic heart rate is the heart rate under complete pharmacological blockade. They showed that (i) the resting heart rate is lower than the intrinsic heart rate and that (ii) the intrinsic heart rate declines with age. They also established that the variability in intrinsic heart rate between individuals of the same age is of the same order as the effect of ageing at the population level. This update discusses the relevance of these data with emphasis on sinus node function and autonomic balance. The paper of Jose and Collison was cited more than 200 times. The frequency of citation started to increase more than 10 years after publication. 2000 Elsevier Science B.V. All rights reserved.
Keywords: Aging; Autonomic nervous system; Gender; Heart rate (variability); Sinus node
In 1970 Jose and Collison published a study on the normal range and the determinants of the intrinsic heart rate in man in Cardiovascular Research. . They did not only study ‘intrinsic heart rate’, which they defined as the heart rate under the simultaneous presence of the non- selective b-adrenoceptor antagonist propranolol (0.2 mg / kg) and the muscarinic receptor blocker atropine (0.04 mg / kg), they also established the inverse relation between age and intrinsic heart rate. Furthermore they made separate analyses in females and males. Therefore the paper included – apart from the measurement of the intrinsic heart rate itself – additional important pieces of information for later studies on areas varying from sinus node dysfunction, autonomic balance, heart rate variability, gender and aging (see preceding historical note ). The authors could have made their paper even more attractive by choosing another title. Fig. 1 taken from the original paper  shows the relation between age and intrinsic heart rate in normal males and females. Both in males and females the intrinsic heart rate decreases, on the average, from 107 beats/min at 20 years to 90 beats/min at 50 years. At the same time Fig. 1 shows that the intrinsic heart rate has 95% confidence limits of 615%. This implies that the variability between individuals of the same age is of the same order as the decrease of the mean intrinsic heart rate of the whole population over about 55 years. In other words, the intrinsic heart rate of an individual of 20 years may actually be lower than that of another individual of 50 years. Obviously, this sets limits to the significance of the aging induced decrease in heart rate.
The interest of the authors in the pharmacological concept of intrinsic heart rate had been raised by previous work of Jose published in 1966  and of Jose and Taylor published in 1969 . In those studies it had already been established that heart rate becomes fixed under the com- bined presence of atropine and propranolol, which is considered to cause complete autonomic blockade. How- ever, propranolol only partially interferes with the activity of the sympathetic limb of the autonomic nervous system, because it blocks b-adrenoceptors but not a-adrenoceptors. Furthermore, there is a classic, small, but convincing literature which claims that vagal chronotropic effects include – apart from the well known negative components mediated by acetylcholine – also positive, i.e. acceleratory, components (see section on autonomic balance). The previous studies [3,4] were directed to normal individuals as well as to patients with heart failure. Thus, Jose and Taylor  showed that the intrinsic heart rate is different in normal individuals and in NYHA class I, class II and class III / IV patients. In normal patients (mean age 25 years) the intrinsic heart rate was 107 beats / min (compar- able to the data in Fig. 1 taken from the paper published by Cardiovascular Research in 1970 ). In class III / IV patients the intrinsic heart rate was 79 beats / min in a subgroup of patients with nonvalvular heart disease and 75 beats / min in a subgroup of patients with aortic stenosis. The mean age of those patients was 50 years. The significance of the paper of Jose and Collison  is that the difference in intrinsic heart rate between normal individuals and patients with heart failure can partially be explained by the difference in age. The lower intrinsic heart rate in patients with heart failure thus may in part result from the underlying pathology. A lower intrinsic heart rate has also been demonstrated in dogs with heart failure (127 beats / min) compared with normal dogs (175 beats / min) . A lower intrinsic heart rate in patients with heart failure may point to impaired sinus node function. A prolongation of cycle length in the isolated right atrium of rabbits with heart failure has indeed been demonstrated . Moreover, the effect of the combined administration of propranolol and atropine, i.e. the difference between heart rate at rest and intrinsic heart rate, is different in normal individuals and in heart failure both in patients  and in dogs .
The data of Jose and Collison  have been confirmed by Alboni and colleagues  and extended to younger age by Marcus and colleagues .
Intrinsic heart rate can be assessed by three ways: (i) in vivo by pharmacological tools, (ii) in vivo by surgical interventions, (iii) in vitro after isolation of the whole heart (Langendorff perfusion) or the right atrium. Finally, car- diac transplantation is of interest, because those patients have two sinus nodes, one innervated (in a rim of remaining tissue of the explanted heart) and one denervated (the implanted-donor-heart).
2. Intrinsic heart rate and sinus node
The human heart beats about 100 000 times a day resulting in 2 billion heartbeats during a lifetime. Normally each cardiac activation originates from the sinus node which was discovered by Martin Flack and Arthur Keith in 1906 in the mole’s heart [9–11]. The relevance of this new anatomic structure was appreciated with little debate, because electrophysiological techniques, needed to verify the pacemaker hypothesis, were available at about the same time as the anatomical discovery of the sinus node [12–14]. The myogenic-neurogenic controversy with re- spect to cardiac automaticity started to be definitely settled in 1921 by Eyster and Meek .
2.1. Differences in heart rate between species
Specific metabolic rate, that is metabolic rate relative to body size, decreases in larger mammals [16,17]. Therefore cardiac output relative to body size also decreases in larger animals. Thus, it is a little surprising that all mammals have the same relative heart mass: about 0.6% of body mass . Stroke volume, one of the two components of cardiac output, increases also linearly with body weight [16,17]. The decrease in relative cardiac output is solely brought about by the other component of cardiac output: heart rate. Fig. 2 (upper panel) shows the relation between body weight and cycle length according to the formula [17,19]:
BCL = 0.249 X BW0.25 (1)
with basic cycle length (BCL) in seconds and body weight (BW) in kilograms. Cycle length is thus longer (or heart rate lower) in larger species. Fig. 2 (upper panel) further shows that longevity (life span) also relates to body weight according to the formula :
Life span = 11.8 X BW0.20 (2)
as far as mammals in captivity without the effects of predation or critical food supply are concerned. Interest- ingly, by dividing formula (2) by formula (1) we obtain the formula for the total number of heartbeats:
Total heartbeats =1.5 billion X BW exp-0.05 (3)…”
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