Heart rate variability, but not heart rate, is associated with handgrip strength and mortality in older Africans at very low cardiovascular risk: A population-based study

Abstract

A high heart rate and a low heart rate variability at rest are established predictors of various forms of functional impairment, morbidity, and mortality [1Böhm M. Reil J.C. Deedwania P. Kim J.B. Borer J.S. Resting heart rate: risk indicator and emerging risk factor in cardiovascular disease.Am. J. Med. 2015; 128: 219-228Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 2Xhyheri B. Manfrini O. Mazzolini M. Pizzi C. Bugiardini R. Heart rate variability today.Prog. Cardiovasc. Dis. 2012; 55: 321-331Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar, 3Thayer J.F. Yamamoto S.S. Brosschot J.F. The relationship of autonomic imbalance, heart rate variability and cardiovascular disease risk factors.Int. J. Cardiol. 2010; 141: 122-131Abstract Full Text Full Text PDF PubMed Scopus (1314) Google Scholar, 4Varadhan R. Chaves P.H.M. Lipsitz L.A. et al.Frailty and impaired cardiac autonomic control: new insights from principal components aggregation of traditional heart rate variability indices.J. Gerontol. Ser. A Biol. Sci. Med. Sci. 2009; 64: 682-687Crossref PubMed Scopus (67) Google Scholar, 5Chaves P.H.M. Varadhan R. Lipsitz L.A. et al.Physiological complexity underlying heart rate dynamics and frailty status in community-dwelling older women.J. Am. Geriatr. Soc. 2008; 56: 1698-1703Crossref PubMed Scopus (64) Google Scholar, 6Fox K. Borer J.S. Camm A.J. et al.Resting heart rate in cardiovascular disease.J. Am. Coll. Cardiol. 2007; 50: 823-830Abstract Full Text Full Text PDF PubMed Scopus (802) Google Scholar]. Two explanations can be given for these associations. On one hand, a high heart rate and a low heart rate variability are thought to reflect dysfunction of the flexible autonomic regulation of the heart rate in particular and of the body's functioning in general that arises during ageing [3Thayer J.F. Yamamoto S.S. Brosschot J.F. The relationship of autonomic imbalance, heart rate variability and cardiovascular disease risk factors.Int. J. Cardiol. 2010; 141: 122-131Abstract Full Text Full Text PDF PubMed Scopus (1314) Google Scholar, 4Varadhan R. Chaves P.H.M. Lipsitz L.A. et al.Frailty and impaired cardiac autonomic control: new insights from principal components aggregation of traditional heart rate variability indices.J. Gerontol. Ser. A Biol. Sci. Med. Sci. 2009; 64: 682-687Crossref PubMed Scopus (67) Google Scholar, 5Chaves P.H.M. Varadhan R. Lipsitz L.A. et al.Physiological complexity underlying heart rate dynamics and frailty status in community-dwelling older women.J. Am. Geriatr. Soc. 2008; 56: 1698-1703Crossref PubMed Scopus (64) Google Scholar]. On the other hand, a high heart rate and a low heart rate variability are brought about by cardiovascular risk factors, such as obesity, hyperlipidaemia, diabetes, hypertension, and physical inactivity [2Xhyheri B. Manfrini O. Mazzolini M. Pizzi C. Bugiardini R. Heart rate variability today.Prog. Cardiovasc. Dis. 2012; 55: 321-331Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar, 3Thayer J.F. Yamamoto S.S. Brosschot J.F. The relationship of autonomic imbalance, heart rate variability and cardiovascular disease risk factors.Int. J. Cardiol. 2010; 141: 122-131Abstract Full Text Full Text PDF PubMed Scopus (1314) Google Scholar, 7Grassi G. Arenare F. Quarti-Trevano F. Seravalle G. Mancia G. Heart rate, sympathetic cardiovascular influences, and the metabolic syndrome.Prog. Cardiovasc. Dis. 2009; 52: 31-37Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 8Valentini M. Parati G. Variables influencing heart rate.Prog. Cardiovasc. Dis. 2009; 52: 11-19Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar, 9Silva de Paula R. Antelmi I. Vincenzi M.A. et al.Influence of age, gender, and serum triglycerides on heart rate in a cohort of asymptomatic individuals without heart disease.Int. J. Cardiol. 2005; 105: 152-158Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar]. Since research on heart rate and heart rate variability has almost exclusively been conducted in western populations with an affluent sedentary lifestyle and high prevalences of these risk factors, it has been difficult to determine whether or not heart rate and heart rate variability are associated with functional impairment, morbidity, and mortality independently of cardiovascular risk factors. To disentangle the effects of ageing and the lifestyle-related cardiovascular risk factors, we investigated the associations of heart rate and heart rate variability with physical function and mortality among older persons in one of the least developed rural regions in Ghana. In this population, contrary to western populations, food is scarce, lifelong manual labour is necessary for subsistence agriculture, and obesity, hyperlipidaemia, diabetes, hypertension, and cardiovascular diseases are rare [10Koopman J.J.E. van Bodegom D. Westendorp R.G.J. Jukema J.W. Scarcity of atrial fibrillation in a traditional African population: a community-based study.BMC Cardiovasc. Disord. 2014; 14: 87Crossref PubMed Scopus (21) Google Scholar, 11Koopman J.J.E. van Bodegom D. Jukema J.W. Westendorp R.G.J. Risk of cardiovascular disease in a traditional African population with a high infectious load: a population-based study.PLoS One. 2012; 7: e46855Crossref PubMed Scopus (46) Google Scholar]. We measured physical function as handgrip strength, which strongly and independently predicts mortality in this population [[12]Koopman J.J.E. van Bodegom D. van Heemst D. Westendorp R.G.J. Handgrip strength, ageing, and mortality in rural Africa.Age Ageing. 2015; 44: 465-470Crossref PubMed Scopus (45) Google Scholar]. Elaborate descriptions of this population have been given elsewhere [10Koopman J.J.E. van Bodegom D. Westendorp R.G.J. Jukema J.W. Scarcity of atrial fibrillation in a traditional African population: a community-based study.BMC Cardiovasc. Disord. 2014; 14: 87Crossref PubMed Scopus (21) Google Scholar, 11Koopman J.J.E. van Bodegom D. Jukema J.W. Westendorp R.G.J. Risk of cardiovascular disease in a traditional African population with a high infectious load: a population-based study.PLoS One. 2012; 7: e46855Crossref PubMed Scopus (46) Google Scholar, 12Koopman J.J.E. van Bodegom D. van Heemst D. Westendorp R.G.J. Handgrip strength, ageing, and mortality in rural Africa.Age Ageing. 2015; 44: 465-470Crossref PubMed Scopus (45) Google Scholar]. Ethical approval was given by the Ghana Health Services and the local chiefs and elders. Because of illiteracy, informed consent was obtained orally in the participant's own language. The study conforms to the ethical guidelines of the Declaration of Helsinki. In 2009 and 2010 we registered demographic characteristics and conducted measurements of cardiovascular risk factors among 924 inhabitants of the Garu-Tempane District aged 50 years and older [10Koopman J.J.E. van Bodegom D. Westendorp R.G.J. Jukema J.W. Scarcity of atrial fibrillation in a traditional African population: a community-based study.BMC Cardiovasc. Disord. 2014; 14: 87Crossref PubMed Scopus (21) Google Scholar, 11Koopman J.J.E. van Bodegom D. Jukema J.W. Westendorp R.G.J. Risk of cardiovascular disease in a traditional African population with a high infectious load: a population-based study.PLoS One. 2012; 7: e46855Crossref PubMed Scopus (46) Google Scholar, 12Koopman J.J.E. van Bodegom D. van Heemst D. Westendorp R.G.J. Handgrip strength, ageing, and mortality in rural Africa.Age Ageing. 2015; 44: 465-470Crossref PubMed Scopus (45) Google Scholar]. To ensure maximal participation, we set up a mobile research station and brought less mobile participants by car. Twelve-lead electrocardiograms (ECGs) were obtained as two sequential recordings of ten seconds in a lying and resting position (Schiller AT-104 PC). Three participants with atrial fibrillation were excluded from the analyses; the recordings of the other participants displayed sinus rhythm. The timing of the QRS complexes was automatically identified and verified manually. Recordings with ectopic complexes were excluded from the analyses, except for twelve participants with an ectopic complex in the last 2 s of the recording, in which cases all complexes from the ectopic complex onward were excluded. We determined heart rate in beats per minute (bpm) and heart rate variability in milliseconds (ms) as the standard deviation of normal RR intervals (SDNN) and as the root mean square of the differences between successive normal RR intervals (RMSSD). Handgrip strength was measured using a Jamar dynamometer (Sammons Preston) while the participant was standing in an upright position with the arms parallel to the body. The highest handgrip strength of both hands was registered [[12]Koopman J.J.E. van Bodegom D. van Heemst D. Westendorp R.G.J. Handgrip strength, ageing, and mortality in rural Africa.Age Ageing. 2015; 44: 465-470Crossref PubMed Scopus (45) Google Scholar]. Follow-up for mortality after the measurements lasted until death, migration out of the research area, loss to follow-up, or our last visit to the research area in 2011. Data on follow-up were available for 814 (99.0%) participants and comprised 1396 person-years and 42 deaths. Table 1 provides the demographic and cardiovascular characteristics of the Ghanaian study population. Of the 924 individuals who participated in the measurements, 822 could be included with data on heart rate, heart rate variability, and handgrip strength.Table 1Characteristics of the Ghanaian study population.Median (interquartile range) or n (%)Individuals, n822Male sex, n (%)421 (51.2)Age, years65 (56–72)Tribe, n (%) Bimoba572 (69.6) Kusasi195 (23.7) Other55 (6.7)Household property value, US$1085 (516–1944)Safe drinking water, n (%)721 (87.7)Body mass index, kg/m218.1 (16.6–19.6)Waist circumference, cm77 (72–81)Capillary glucose, mmol/l3.9 (3.4–4.4)Diastolic blood pressure, mm Hg70 (65–80)Systolic blood pressure, mm Hg120 (110–135)Ankle–arm index1.15 (1.08–1.23)Heart rate, bpm70 (62–78)Heart rate variability, ms SDNN19.6 (13.6–29.3) RMSSD18.0 (11.4–28.4)Heart rate variability was calculated as the standard deviation of normal RR intervals (SDNN) and as the root mean square of the differences between successive normal RR intervals (RMSSD). Bpm: beats per minute. Open table in a new tab Heart rate variability was calculated as the standard deviation of normal RR intervals (SDNN) and as the root mean square of the differences between successive normal RR intervals (RMSSD). Bpm: beats per minute. Fig. 1 shows the distributions of heart rate and heart rate variability over age. As age increased one year, heart rate increased with 0.15 bpm, SDNN decreased with 0.013 ln ms, and RMSSD decreased with 0.016 ln ms (all p < 0.001). Their variances were constant over age. Besides age, heart rate was higher in females, in individuals with a lower BMI, in individuals with a higher glucose level, and in individuals with a higher diastolic blood pressure. Both SDNN and RMSSD were higher in individuals with a higher wealth index and lower in individuals with a higher heart rate (Supplementary Table 1). Handgrip strength was lower in individuals with a higher heart rate and higher in individuals with a higher SDNN or RMSSD (all p < 0.001). After adjustment for age, sex, tribe, and height, heart rate was not associated with handgrip strength, but handgrip strength remained higher in individuals with a higher SDNN (p = 0.009) or RMSSD (p = 0.013). After additional adjustment for other demographic and cardiovascular characteristics, these associations did not change (p < 0.025). The association of heart rate variability with handgrip strength was not different between males and females, individuals younger and older than 65 years, or individuals with and without underweight, defined as a BMI below 18.5 kg/m2 (Supplementary Table 2). Fig. 2 provides adjusted estimates of handgrip strength per tertiles of heart rate and heart rate variability. From the lowest to the highest tertile of heart rate, handgrip strength declined non-significantly with 0.57 kg. From the lowest to the highest tertile of SDNN, handgrip strength increased with 1.00 kg. From the lowest to the highest tertile of RMSSD, handgrip strength increased with 1.12 kg. Heart rate was not associated with mortality. Heart rate variability and mortality were inversely associated with hazard ratios of 0.49 per ln ms increase in SDNN (p = 0.006) and 0.65 per ln ms increase in RMSSD (p = 0.048). After adjustment for age, sex, and tribe, these hazard ratios remained similar and remained significant for SDNN (p = 0.021), but lost significance for RMSSD (p = 0.121). After additional adjustment for other demographic and cardiovascular characteristics, the hazard ratios remained similar (Supplementary Table 3). Our results remained similar after exclusion of twelve participants who had shown ectopic complexes in the last 2 s of the ECG and after exclusion of 28 participants with sinus arrhythmia, defined as the presence of consecutive normal RR intervals differing by more than 120 ms. This study is the first to investigate heart rate and heart rate variability in relation to physical function and mortality in rural Africa. Few studies have described their associations with cardiovascular risk factors in rural African populations, all in accordance with our results [13Kunutsor S. Powles J. Cardiovascular risk in a rural adult West African population: is resting heart rate also relevant?.Eur. J. Prev. Cardiol. 2014; 21: 584-591Crossref PubMed Scopus (3) Google Scholar, 14Osakwe C.E. Jacobs L. Anisiuba B.C. et al.Heart rate variability on antihypertensive drugs in black patients living in sub-Saharan Africa.Blood Press. 2014; 23: 174-180Crossref PubMed Scopus (2) Google Scholar, 15Torsvik M. Häggblom A. Eide G.E. et al.Cardiovascular autonomic function tests in an African population.BMC Endocr. Disord. 2008; 8: 19Crossref PubMed Scopus (5) Google Scholar, 16Longo-Mbenza B. Lukoki Luila E. M'Buyamba-Kabangu J.R. Nutritional status, socio-economic status, heart rate, and blood pressure in African school children and adolescents.Int. J. Cardiol. 2007; 121: 171-177Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar]. We showed that heart rate increased slightly over age and was dependent on cardiovascular risk factors, while heart rate variability decreased over age and was not dependent on cardiovascular risk factors. Heart rate was associated with neither handgrip strength nor mortality, while a lower heart rate variability was associated with lower handgrip strength and a higher risk of mortality independent of age, sex, tribe, and cardiovascular risk factors. In western populations, conflicting results have been reported as to whether and how heart rate changes over age [8Valentini M. Parati G. Variables influencing heart rate.Prog. Cardiovasc. Dis. 2009; 52: 11-19Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar, 9Silva de Paula R. Antelmi I. Vincenzi M.A. et al.Influence of age, gender, and serum triglycerides on heart rate in a cohort of asymptomatic individuals without heart disease.Int. J. Cardiol. 2005; 105: 152-158Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar]. Our findings suggest that heart rate is dependent on lifestyle-related cardiovascular risk factors rather than age and that its association with functional impairment and mortality is predominantly mediated by these risk factors. Cardiovascular risk factors can increase heart rate by inducing haemodynamic alterations, cardiac conduction abnormalities, and sympathetic hyperactivation [3Thayer J.F. Yamamoto S.S. Brosschot J.F. The relationship of autonomic imbalance, heart rate variability and cardiovascular disease risk factors.Int. J. Cardiol. 2010; 141: 122-131Abstract Full Text Full Text PDF PubMed Scopus (1314) Google Scholar, 7Grassi G. Arenare F. Quarti-Trevano F. Seravalle G. Mancia G. Heart rate, sympathetic cardiovascular influences, and the metabolic syndrome.Prog. Cardiovasc. Dis. 2009; 52: 31-37Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar]. By contrast, heart rate variability decreases over age [2Xhyheri B. Manfrini O. Mazzolini M. Pizzi C. Bugiardini R. Heart rate variability today.Prog. Cardiovasc. Dis. 2012; 55: 321-331Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar, 8Valentini M. Parati G. Variables influencing heart rate.Prog. Cardiovasc. Dis. 2009; 52: 11-19Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar, 9Silva de Paula R. Antelmi I. Vincenzi M.A. et al.Influence of age, gender, and serum triglycerides on heart rate in a cohort of asymptomatic individuals without heart disease.Int. J. Cardiol. 2005; 105: 152-158Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar, 17Antelmi I. de Paula R.S. Shinzato A.R. et al.Influence of age, gender, body mass index, and functional capacity on heart rate variability in a cohort of subjects without heart disease.Am. J. Cardiol. 2004; 93: 381-385Abstract Full Text Full Text PDF PubMed Scopus (392) Google Scholar] and has been reported to be unaffected by cardiovascular risk factors in western populations as in rural African populations [17Antelmi I. de Paula R.S. Shinzato A.R. et al.Influence of age, gender, body mass index, and functional capacity on heart rate variability in a cohort of subjects without heart disease.Am. J. Cardiol. 2004; 93: 381-385Abstract Full Text Full Text PDF PubMed Scopus (392) Google Scholar, 18Kluttig A. Kuss O. Greiser K.H. Ignoring lack of association of heart rate variability with cardiovascular disease and risk factors.Int. J. Cardiol. 2010; 145: 375-376Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 19Wang X. Thayer J.F. Treiber F. Snieder H. Ethnic differences and heritability of heart rate variability in African- and European American youth.Am. J. Cardiol. 2005; 96: 1166-1172Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar]. These findings suggest that heart rate variability is associated with functional impairment and mortality through mechanisms independent of cardiovascular risk factors. It is possible that heart rate variability declines during ageing as a result of a deteriorating autonomic regulation of the heart rate that occurs across populations with different lifestyles [3Thayer J.F. Yamamoto S.S. Brosschot J.F. The relationship of autonomic imbalance, heart rate variability and cardiovascular disease risk factors.Int. J. Cardiol. 2010; 141: 122-131Abstract Full Text Full Text PDF PubMed Scopus (1314) Google Scholar, 4Varadhan R. Chaves P.H.M. Lipsitz L.A. et al.Frailty and impaired cardiac autonomic control: new insights from principal components aggregation of traditional heart rate variability indices.J. Gerontol. Ser. A Biol. Sci. Med. Sci. 2009; 64: 682-687Crossref PubMed Scopus (67) Google Scholar, 5Chaves P.H.M. Varadhan R. Lipsitz L.A. et al.Physiological complexity underlying heart rate dynamics and frailty status in community-dwelling older women.J. Am. Geriatr. Soc. 2008; 56: 1698-1703Crossref PubMed Scopus (64) Google Scholar]. Since a high heart rate is a long-established predictor of cardiovascular disease and death, it is regarded as a potential therapeutic target [1Böhm M. Reil J.C. Deedwania P. Kim J.B. Borer J.S. Resting heart rate: risk indicator and emerging risk factor in cardiovascular disease.Am. J. Med. 2015; 128: 219-228Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 6Fox K. Borer J.S. Camm A.J. et al.Resting heart rate in cardiovascular disease.J. Am. Coll. Cardiol. 2007; 50: 823-830Abstract Full Text Full Text PDF PubMed Scopus (802) Google Scholar]. While pharmacological lowering of the heart rate has been found to benefit patients with heart failure, it fails to do so in patients without heart failure [[20]Fox K. Ford I. Steg P.G. et al.Ivabradine in stable coronary artery disease without clinical heart failure.N. Engl. J. Med. 2014; 371: 1091-1099Crossref PubMed Scopus (357) Google Scholar]. Our study reinforces the explanation of others that the heart rate is accelerated not as a cause, but as an effect of cardiovascular disease [1Böhm M. Reil J.C. Deedwania P. Kim J.B. Borer J.S. Resting heart rate: risk indicator and emerging risk factor in cardiovascular disease.Am. J. Med. 2015; 128: 219-228Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 20Fox K. Ford I. Steg P.G. et al.Ivabradine in stable coronary artery disease without clinical heart failure.N. Engl. J. Med. 2014; 371: 1091-1099Crossref PubMed Scopus (357) Google Scholar]. It could be that in the detection and prevention of cardiovascular disease the role of heart rate is overrated, while that of heart rate variability has thus far remained underrated.