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Resting heart rate is an independent predictor of all-cause mortality in the middle aged general population

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  • University Hospital Essen, University of Duisburg-Essen
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Background High resting heart rate (RHR) predicts cardiovascular outcomes in patients with vascular disease and heart failure. We evaluated the prognostic value of RHR in a large contemporary population-based, prospective cohort of individuals without known coronary artery disease. Methods and results Resting heart rate (RHR) was determined in 4091 individuals (mean age 59.2 ± 7.7; 53 % women) from the Heinz Nixdorf RECALL study, of whom, 3348 were free of heart rate lowering medication. During 10.5 years of follow-up (median), 159 (3.9 %) individuals developed a coronary event and 398 (9.7 %) died of any cause. Persons without any event (n = 3603) had similar heart rates as persons with coronary events (69.5 ± 11 versus 69.9 ± 11 bpm, p = 0.51) but lower heart rates than persons who died (72.3 ± 13 bpm, p < 0.0001). In individuals without heart rate lowering medication, an increase in heart rate by 5 bpm was associated with an increased hazard ratio (HR) for all-cause mortality of 13 % in unadjusted analysis and also upon adjustment for traditional cardiovascular risk factors, including coronary artery calcification [full model: HR (95 % CI) 1.13 (1.07–1.20), p < 0.0001], but not for coronary events [HR 1.02 (0.94–1.11), p = 0.60]. In individuals without heart rate lowering medication, the HR (full model) for heart rate ≥70 versus <70 bpm with regard to all-cause mortality and coronary events was 1.68 (1.30–2.18), p < 0.0001, and 1.20 (0.82–1.77), p = 0.35. Analysis of the entire cohort revealed a continuous relationship of heart rate with all-cause mortality [HR for lowest to highest heart rate quartile 1.64 (1.22–2.22), p = 0.001, full model] but not with coronary events [HR 1.04 (0.65–1.66), p = 0.86]. Conclusions In the general population without known coronary artery disease and heart rate lowering medication, elevated RHR is an independent risk marker for all-cause mortality but not for coronary events.
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ORIGINAL PAPER
Resting heart rate is an independent predictor of all-cause
mortality in the middle aged general population
Florian Custodis
1
Ulla Roggenbuck
2
Nils Lehmann
2
Susanne Moebus
2
Ulrich Laufs
1
Amir-Abbas Mahabadi
3
Gerd Heusch
4
Klaus Mann
5
Karl-Heinz Jo
¨ckel
2
Raimund Erbel
3
Michael Bo
¨hm
1
Stefan Mo
¨hlenkamp
3,6
Received: 6 August 2015 / Accepted: 21 December 2015 / Published online: 23 January 2016
ÓSpringer-Verlag Berlin Heidelberg 2016
Abstract
Background High resting heart rate (RHR) predicts car-
diovascular outcomes in patients with vascular disease and
heart failure. We evaluated the prognostic value of RHR in
a large contemporary population-based, prospective cohort
of individuals without known coronary artery disease.
Methods and results Resting heart rate (RHR) was
determined in 4091 individuals (mean age 59.2 ±7.7;
53 % women) from the Heinz Nixdorf RECALL study, of
whom, 3348 were free of heart rate lowering medication.
During 10.5 years of follow-up (median), 159 (3.9 %)
individuals developed a coronary event and 398 (9.7 %)
died of any cause. Persons without any event (n=3603)
had similar heart rates as persons with coronary events
(69.5 ±11 versus 69.9 ±11 bpm, p=0.51) but lower
heart rates than persons who died (72.3 ±13 bpm,
p\0.0001). In individuals without heart rate lowering
medication, an increase in heart rate by 5 bpm was asso-
ciated with an increased hazard ratio (HR) for all-cause
mortality of 13 % in unadjusted analysis and also upon
adjustment for traditional cardiovascular risk factors,
including coronary artery calcification [full model: HR
(95 % CI) 1.13 (1.07–1.20), p\0.0001], but not for
coronary events [HR 1.02 (0.94–1.11), p=0.60]. In indi-
viduals without heart rate lowering medication, the HR
(full model) for heart rate C70 versus\70 bpm with regard
to all-cause mortality and coronary events was 1.68
(1.30–2.18), p\0.0001, and 1.20 (0.82–1.77), p=0.35.
Analysis of the entire cohort revealed a continuous rela-
tionship of heart rate with all-cause mortality [HR for
lowest to highest heart rate quartile 1.64 (1.22–2.22),
p=0.001, full model] but not with coronary events [HR
1.04 (0.65–1.66), p=0.86].
Conclusions In the general population without known
coronary artery disease and heart rate lowering medication,
elevated RHR is an independent risk marker for all-cause
mortality but not for coronary events.
Keywords Resting heart rate Mortality Coronary
events
Abbreviations
CAC Coronary artery calcium
CAD Coronary artery disease
CVD Cardiovascular disease
PAD Peripheral arterial disease
RHR Resting heart rate
On behalf of the Heinz Nixdorf Recall Study Investigators.
&Stefan Mo
¨hlenkamp
stefan.moehlenkamp@bethanienmoers.de
1
Clinic of Internal Medicine III, Cardiology, Angiology and
Intensive Care Medicine, Saarland University Clinic,
Homburg, Saar, Germany
2
Institute for Medical Informatics, Biometry and
Epidemiology, University Clinic Essen, Essen, Germany
3
Clinic of Cardiology, West-German Heart and Vascular
Center Essen, University Clinic Essen, Essen, Germany
4
Institute for Pathophysiology, West-German Heart and
Vascular Center Essen, University Clinic Essen, Essen,
Germany
5
Institute of Clinical Chemistry and Laboratory Medicine,
University Clinic Essen, Essen, Germany
6
Clinic of Cardiology and Intensive Care Medicine, Bethanien
Hospital Moers, Bethanienstrasse 21, 47441 Moers, Germany
123
Clin Res Cardiol (2016) 105:601–612
DOI 10.1007/s00392-015-0956-7
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... A positive association between resting heart rate (RHR) and mortality has been repeatedly demonstrated in the literature. This association has been replicated in diverse study populations, including cohorts with known CVD, and in healthy populations [2][3][4][5][6]. There is general agreement, that in men, this relationship is driven by excess CVD mortality. ...
... Elevated RHR has been repeatedly linked to increased all-cause mortality in multiple studies and in diverse populations [2][3][4][5]. However, the sex-differential pattern of this relationship is incompletely understood. ...
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... 3,4 Epidemiological studies have also found that elevated RHR is an independent predictor of all-cause, non-cardiovascular, and cardiovascular deaths. 5 The effects of an increased RHR are equivalent to those of smoking, hypertension, and dyslipidemia and it is a risk factor for coronary heart disease (CHD). 6 The mechanisms underlying the harmful effects of an elevated RHR are unclear, but several plausible biological mechanisms have been proposed. ...
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... However, the influence of heart rate may be unrepresentative, due to the study conducted in 1 rural site of Henan Province, not at a national level. Other relevant studies only focused on normotensive or hypertensive populations (10)(11)(12)(13)(14), without comparison between them. Besides, the dose-response relations between heart rate and adverse outcomes in different research were inconsistent. ...
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Collateral arteries protect tissue from ischaemia. Heart rate correlates with vascular events in patients with arterial obstructive disease. Here, we tested the effect of heart-rate reduction (HRR) on collateral artery growth. The I(f)-channel inhibitor ivabradine reduced heart rate by 11% in wild-type and 15% in apolipoprotein E (ApoE)(-/-) mice and restored endothelium-dependent relaxation in aortic rings of ApoE(-/-) mice. Microsphere perfusion and angiographies demonstrated that ivabradine did not change hindlimb perfusion in wild-type mice but improved perfusion in ApoE(-/-) mice from 40.5 ± 15.8-60.2 ± 18.5% ligated/unligated hindlimb. Heart rate reduction (13%) with metoprolol failed to improve endothelial function and perfusion. Protein expression of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS, and eNOS activity were increased in collateral tissue following ivabradine treatment of ApoE(-/-) mice. Co-treatment with nitric oxide-inhibitor N (G)-nitro-L-arginine methyl ester abolished the effects of ivabradine on arteriogenesis. Following ivabradine, classical inflammatory cytokine expression was lowered in ApoE(-/-) circulating mononuclear cells and in plasma, but unaltered in collateral-containing hindlimb tissue, where numbers of perivascular macrophages also remained unchanged. However, ivabradine reduced expression of anti-arteriogenic cytokines CXCL10and CXCL11 and of smooth muscle cell markers smoothelin and desmin in ApoE(-/-) hindlimb tissue. Endothelial nitric oxide synthase and inflammatory cytokine expression were unchanged in wild-type mice. Ivabradine did not affect cytokine production in HUVECs and THP1 mononuclear cells and had no effect on the membrane potential of HUVECs in patch-clamp experiments. Ivabradine-induced HRR stimulates adaptive collateral artery growth. Important contributing mechanisms include improved endothelial function, eNOS activity, and modulation of inflammatory cytokine gene expression.
Article
Objective Resting heart rate (RHR) is an established predictor of myocardial infarction (MI) and mortality, but the relationship between variation in RHR over a period of several years and health outcomes is unclear. We evaluated the relationship between long-term variation in RHR and the risks of incident MI and mortality among older adults. Methods 1991 subjects without cardiovascular disease from the Cardiovascular Health Study were included. RHR was taken from resting ECGs at the first five annual study visits. RHR mean, trend and variation were estimated with linear regression. Subjects were followed for incident MI and death until December 2010. HRs for RHR mean, trend and variation are reported for differences of 10 bpm, 2 bpm/year and 2 bpm, respectively. Results 262 subjects had an incident MI event (13%) and 1326 died (67%) during 12 years of median follow-up. In primary analyses adjusted for cardiovascular risk factors, RHR mean (HR 1.12; 95% CI 1.05 to 1.20) and variation (HR 1.08; 95% CI 1.03 to 1.13) were associated with the risk of death while trend was not. None of the RHR variables were significantly associated with the risk of incident MI events; however, CIs were wide and the MI associations with RHR variables were not significantly different from the mortality associations. Adjusting for additional variables did not affect estimates, and there were no significant interactions with sex. Conclusions Variation in RHR over a period of several years represents a potential predictor of long-term mortality among older persons free of cardiovascular disease.
Article
Heart rate was proposed as an emergent cardiovascular (CV) risk factor. Previous studies have shown associations between increased heart rate and CV risk in various populations. We aimed to evaluate the prognostic relevance of heart rate in a large contemporaneous medically optimized cohort of patients with stable chronic CV disease. In a post hoc analysis of the ONTARGET/TRANSCEND trials, we evaluated associations between baseline and average heart rate in trial with CV risk in 31, 531 patients followed for a median of 5 years. The primary outcome, major vascular events (MVE), was a composite of CV death, myocardial infarction (MI), stroke, and congestive heart failure (CHF). Pre-specified secondary outcomes included all-cause death and the individual components of the primary outcome. Associations between heart rate and outcomes were computed with heart rate as a continuous variable, baseline heart rate >70 vs ≤70 bpm, and across heart rate quintiles, adjusting for other markers of risk, beta-blocker and non-dihydropyridine calcium channel blocker use. For each 10 bpm increase in baseline and average heart rate, we observed a significant increase in risk of MVE, CV death, CHF and all-cause death. There was a continuous relationship between MVE and baseline and, more importantly, average in-trial heart rate, with no observed threshold. MVE, CV death, stroke, CHF, and all-cause death increased across heart rate quintiles. There was no association between MI and HR. Results were consistent in clinically relevant subgroups. There were modest but significant improvements in C-statistic and in statistical measures of model calibration for models that included heart rate for MVE, CV death, CHF and all-cause death. This large study examined and quantitated associations between heart rate and CV events in a contemporary medically optimized population with stable CV disease. Resting and, in particular, in-trial average heart rate are independently associated with significant increases in CV events and all-cause death.
Article
Resting heart rate is an easily measured, noninvasive vital sign that is associated with cardiovascular disease events. The pathophysiology of this association is not known. We investigated the relationship between resting heart rate and stiffness of the carotid (a peripheral artery) and the aorta (a central artery) in an asymptomatic multi-ethnic population. Resting heart rate was recorded at baseline in the Multi-Ethnic Study of Atherosclerosis (MESA). Distensibility was used as a measure of arterial elasticity, with a lower distensibility indicating an increase in arterial stiffness. Carotid distensibility was measured in 6484 participants (98% of participants) using B-mode ultrasound, and aortic distensibility was measured in 3512 participants (53% of participants) using cardiac MRI. Heart rate was divided into quintiles and we used progressively adjusted models that included terms for physical activity and atrioventricular nodal blocking agents. Mean resting heart rate of participants (mean age, 62 years; 47% men) was 63 bpm (SD, 9.6 bpm). In unadjusted and fully adjusted models, carotid distensibility and aortic distensibility decreased monotonically with increasing resting heart rate (P for trend <0.001 and 0.009, respectively). The relationship was stronger for carotid versus aortic distensibility. Similar results were seen using the resting heart rate taken at the time of MRI scanning. Our results suggest that a higher resting heart rate is associated with an increased arterial stiffness independent of atrioventricular nodal blocker use and physical activity level, with a stronger association for a peripheral (carotid) compared with a central (aorta) artery.
Article
High heart rate is associated with longevity in many animal species including men.1 It has been shown in various cardiovascular diseases that high resting heart rate is a known marker of cardiovascular outcomes in hypertension,2 atherosclerosis,3 myocardial infarction4 and heart failure.5 ,6 Among the different conditions the threshold from which risk is increased is different. More close correlations at low thresholds (≥70 bpm) to risk have been established in heart failure.5–8 One beat increase of baseline heart rate and five beats increase of resting heart rate is associated with an increase of cardiovascular death and heart failure hospitalisation of 3% and 16%, respectively.6 Therefore, it was tempting to speculate that heart rate reduction reverses risk, in particular in heart failure, where the association of heart rate and risk is very close. Furthermore, the pathophysiology is plausible for heart failure, because the force-frequency relationship is reversed in the failing heart in vitro9 ,10 and in vivo.11 Shortening of diastole reduces oxygen supply to the myocardium. High heart rates are associated with atherosclerosis12 ,13 potentially important in energy starvation of the failing heart.7 ,8 Finally, high heart rates are a reflection of neurohormonal activation and are associated with malignant arrhythmias.14–16 A reduction of events by heart rate reduction only, would qualify heart rate as a target of treatment and risk factor beyond representing just a surrogate or risk marker. Evidence for heart rate being indeed one of the crucial pathophysiological steps in progression of left ventricular dysfunction, has already been scrutinised by β blocker trials in heart failure.17–20 There is evidence that β blockers …
Article
Impaired vascular compliance is associated with cardiovascular mortality. The effects of heart rate on vascular compliance are unclear. Therefore, we characterized effects of heart rate reduction (HRR) by I(f) current inhibition on aortic compliance and underlying molecular mechanisms in apolipoprotein E-deficient (ApoE(-)/(-)) mice. ApoE(-)/(-) mice fed a high-cholesterol diet and wild-type (WT) mice were treated with ivabradine (20 mg/kg/d) or vehicle for 6 weeks. Compliance of the ascending aorta was evaluated by MRI. Ivabradine reduced heart rate by 113 ± 31 bpm (~19%) in WT mice and by 133 ± 6 bpm (~23%) in ApoE(-)/(-) mice. Compared to WT controls, ApoE(-)/(-) mice exhibited reduced distensibility and circumferential strain. HRR by ivabradine increased distensibility and circumferential strain in ApoE(-)/(-) mice but did not affect both parameters in WT mice. Ivabradine reduced aortic protein and mRNA expression of the angiotensin II type 1 (AT1) receptor and reduced rac1-GTPase activity in ApoE(-)/(-) mice. Moreover, membrane translocation of p47(phox) was inhibited. In ApoE(-)/(-) mice, HRR induced anti-inflammatory effects by reduction of aortic mRNA expression of IL-6, TNF-alpha and TGF-beta. HRR by ivabradine improves vascular compliance in ApoE(-)/(-) mice. Contributing mechanisms include downregulation of the AT1 receptor, attenuation of oxidative stress and modulation of inflammatory cytokine expression.
Article
Vascular effects of mental stress are only partially understood. Therefore, we studied effects of chronic stress and heart rate (HR) on endothelial function and cerebral ischemia. 129S6/SvEv mice were randomized to the I(f)-channel inhibitor ivabradine (10 mg/kg per day) or vehicle and underwent a chronic stress protocol for 28 days. Stress increased HR from 514 ± 10 bpm to 570 ± 14 bpm, this was prevented by ivabradine (485 ± 7 bpm). Endothelium-dependent relaxation of aortic rings was impaired in mice exposed to stress. HR reduction restored endothelial function to the level of naive controls. Vascular lipid hydroperoxides were increased to 333% ± 24% and vascular NADPH oxidase activity was upregulated to 223 ± 38% in stressed mice, which was prevented by ivabradine. Stress reduced aortic endothelial nitric oxide synthase mRNA expression to 84% ± 3% and increased AT1 receptor mRNA to 168% ± 18%. Both effects were attenuated by HR reduction. In brain tissue, stress resulted in an upregulation of lipid hydroperoxides to 140% ± 11%, which was attenuated by HR reduction. Ivabradine increased brain capillary density in naive and in stressed mice. Mice exposed to chronic stress before induction of ischemic stroke by transient middle cerebral artery occlusion exhibited increased lesion size (33.7 ± 2.3 mm3 versus 23.9 ± 2.4 mm3). HR reduction led to a marked reduction of the infarct volume to 12.9 ± 3.3 mm3. Chronic stress impairs endothelial function and aggravates ischemic brain injury. HR reduction protects from cerebral ischemia via improvement of endothelial function and reduction of oxidative stress. These results identify heart rate as a mediator of vascular effects induced by chronic stress.