Elevated Heart Rate in Cardiovascular Diseases: A Target for Treatment?

doi:10.1016/j.pcad.2009.05.005

Progress in Cardiovascular Diseases

Volume 52, Issue 1, July–August 2009, Pages 46-60

https://doi.org/10.1016/j.pcad.2009.05.005 Get rights and content

Abstract

Heart rate is a major determinant of myocardial oxygen consumption and of cardiac work, and thus reduction of heart rate may represent an important strategy for the treatment of patients with a wide range of cardiac disorders. In addition, several experimental lines of research point to high heart rate as an important risk factor for atherosclerosis and, thus, pharmacologic heart rate reduction could prevent or retard the development of atherosclerotic plaques and increase survival. Today, in patients with acute or chronic coronary syndromes or with congestive heart failure, reducing heart rate is a generally accepted treatment modality. Up to now, no human study has been performed to demonstrate the efficacy and the risk-benefit ratio of cardiac slowing in patients without cardiac disorders. However, recent retrospective analyses of the INternational VErapamil-SR/trandolapril STudy and the Paris Prospective Study 1 provided promising results. Treatment of high heart rate in healthy subjects appears to be premature, but in clinical conditions such as hypertension or diabetes, the reduction of elevated heart rate appears a desirable additional goal of therapy.

Section snippets

Elevated heart rate as an independent risk factor for cardiovascular disease

The relation between heart rate and atherosclerotic lesions can be explained by numerous direct mechanisms (Fig 1). A relationship between spontaneous heart rate and coronary artery lesions in monkeys was found by Kaplan et al.11, 12 Bassiouny et al¹³ also found a correlation between a stress index (rate-pressure product) and the thickness of major atherosclerotic lesions in the infrarenal aorta and iliac arteries of cynomolgus monkeys. An association between heart rate and carotid stenosis has

Effect of heart rate reduction in animal studies

If heart rate is a major determinant of myocardial oxygen consumption and of cardiac work, it follows that reduction of heart rate may represent an important strategy for the treatment of patients with a wide range of cardiac disorders. In addition, several experimental lines of research point to high heart rate as an important risk factor for atherosclerosis, and thus, pharmacologic heart rate reduction could prevent or retard the development of atherosclerotic plaques and increase survival

Lifestyle modifications

An unfavorable lifestyle is accompanied by higher heart rate values. Sedentary habits, smoking, excessive alcohol consumption, and coffee use increase the sympathetic activity with consequent effects on resting heart rate.3, 4, 5, 6, 7 It follows that improvement of an unhealthy lifestyle should be effective in subjects with high heart rate, particularly in patients with hypertension. Besides reducing the consumption of tobacco, alcohol, and caffeinated beverages, effort should be put in

Future perspectives in noncardiac patients

There is no doubt today that a high heart rate is associated with a poorer outcome and that tachycardia should be looked upon as a major risk factor for cardiovascular morbidity and mortality. Treatment of high heart rate in healthy subjects taking no therapy appears to be premature, however; but in clinical conditions such as hypertension or diabetes, the reduction of elevated heart rate appears a desirable additional goal of therapy. In these 2 conditions, heart rate proved to be a powerful

Methodological issues

Although resting heart rate is an easily measurable cardiovascular parameter, it is subject to high variability due to the effects of physical, psychological, and environmental factors.3, 4, 135 Methodological issues have often been neglected by the investigators even when heart rate was one of the major variables to measure.¹³⁶ Studies focusing on heart rate should take into account all possible causes of variability, and according to the Consensus Panel of the European Society of Hypertension,

Conclusions

In patients with acute or chronic coronary syndromes and in patients with congestive heart failure, treatment strategies resulting in heart rate reduction improved prognosis, whereas those accompanied by an increase in heart rate exhibited detrimental effects on survival. Thus, reducing heart rate is a generally accepted treatment modality in these clinical conditions. To date, no human study has been performed to demonstrate the efficacy and the risk-benefit ratio of cardiac slowing in

Statement of Conflict of Interest

All authors declare that there are no conflicts of interest.

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Impact of dronedarone on patients with atrial fibrillation and diabetes: A sub-analysis of the ATHENA and EURIDIS/ADONIS studies
2022, Journal of Diabetes and its Complications
Citation Excerpt :
The higher heart rate in patients with diabetes reflects severity of underlying disease, including autonomic dysfunction, the latter of which may be preferentially impacted after exposure to dronedarone with broad AAD effects. However, the correlation of a lower heart rate observed in this analysis with less risk of adverse outcomes is consistent with multiple observations in patients with various types of heart disease.38 As heart rate often reflects disease severity and coexistent disease presence, patients with diabetes and ACS are at a higher risk of CV events because of pro-atherosclerotic, pro-inflammatory, and pro-thrombotic states associated with diabetes,39,40 and interestingly, data in this analysis demonstrated a consistent trend with a lower risk for ACS and stroke in the dronedarone treatment group, similar to previously reported main findings in the ATHENA study.13
This post hoc analysis evaluated efficacy and safety of dronedarone in atrial fibrillation (AF) and atrial flutter (AFL) patients with/without diabetes.
Patients were categorized according to baseline diabetes status. Time-to-event analyses were performed using Kaplan-Meier method. Hazard-ratios were assessed using Cox models.
945/4628 (dronedarone = 482; placebo = 463) patients in ATHENA and 215/1237 (dronedarone = 148; placebo = 67) patients in EURIDIS/ADONIS studies had diabetes. In ATHENA, there were higher rates of CV hospitalization/death in patients with diabetes (39.5%) than without diabetes (34.7%). Incidence of first CV hospitalization/death was lower in patients with diabetes treated with dronedarone (35.1%) than placebo (44.1%), and time to this event was longer in those treated with dronedarone than placebo (log-rank p = 0.005). Median AF/AFL recurrence time was longer in patients treated with dronedarone than placebo in patients with diabetes (ATHENA: 722 vs 527 days, log-rank p = 0.004; EURIDIS/ADONIS: 100 vs 23 days, log-rank p = 0.15) or without diabetes (ATHENA: 741 vs 492 days, log-rank p < 0.0001; EURIDIS/ADONIS: 120 vs 59 days, log-rank p = 0.0002). Occurrence of any treatment-related adverse events with dronedarone was similar for patients with/without diabetes and was comparable to placebo.
Dronedarone reduced incidence of CV hospitalization/death, AF/AFL recurrence and increased time to these events in AF/AFL patients with/without diabetes.
Not applicable, as it was a post hoc analysis. This article is based on previously conducted studies (ATHENA: NCT00174785, EURIDIS: NCT00259428, and ADONIS: NCT00259376).
Moderate heart rate reduction promotes cardiac regeneration through stimulation of the metabolic pattern switch
2022, Cell Reports
Citation Excerpt :
Together, others and our data consistently show that PPP is involved in neonatal heart regeneration and may be an effective therapeutic target for heart injury. A lower heart rate is beneficial in multiple cardiovascular diseases (Bohm et al., 2010, 2015; Palatini, 2009). Clinically, a higher heart rate has been identified as an independent risk factor for cardiovascular diseases, while HRR has a beneficial effect on the prognosis of heart diseases (Bhatt et al., 2017; Psotka and Teerlink, 2016).
As a biological pump, the heart needs to consume a substantial amount of energy to maintain sustained beating. Myocardial energy metabolism was recently reported to be related to the loss of proliferative capacity in cardiomyocytes (CMs). However, the intrinsic relationship between beating rate and proliferation in CMs and whether energy metabolism can regulate this relationship remains unclear. In this study, we find that moderate heart rate reduction (HRR) induces CM proliferation under physiological conditions and promotes cardiac regenerative repair after myocardial injury. Mechanistically, moderate HRR induces G1/S transition and increases the expression of glycolytic enzymes in CMs. Furthermore, moderate HRR induces a metabolic pattern switch, activating glucose metabolism and increasing the relative proportion of ATP production by the glycolytic pathway for biosynthesis of substrates needed for proliferative CMs. These results highlight the potential therapeutic role of HRR in not only acute myocardial protection but also long-term CM restoration.
Increased heart rate with sleep disordered breathing in hypertrophic cardiomyopathy
2021, International Journal of Cardiology
Current guidelines recommend medications with rate control properties for symptomatic patients with hypertrophic cardiomyopathy (HCM) based on the rationale that lowering heart rate (HR) improves their symptoms. Whether sleep disordered breathing (SDB) is associated with increased HR in HCM patients is not known.
We diagnosed uncontrolled SDB (oxygen desaturation index ≥5) in consecutive echocardiographically confirmed HCM patients seen at Mayo Clinic, Rochester, and analyzed their HR as recorded by a 24-h Holter monitor. We compared mean, minimum, maximum HR between those with vs without SDB. In a pilot subanalysis of HCM patients with SDB who also underwent subsequent diagnostic polysomnography (PSG), we analyzed RR interval changes coinciding with obstructive sleep apnea and hypopnea episodes.
Of the 230 HCM patients included in this study (age 54 ± 16 years; 138 male; LVOT pressure gradient at rest 45 ± 39 mmHg), 115 (50%) patients had SDB. HCM patients with SDB were recorded to have higher mean HR (71 vs. 67 bpm; p = .002, adjusted p = .001), and this difference was most pronounced during night hours of 10 PM to 5 AM (61 vs. 67 bpm; p < .001). In the pilot analysis of the available PSG data, the release of obstructive sleep apneas and hypopneas coincided with fluctuation of HR.
SDB is independently associated with higher mean HR in patients with HCM, and this difference is most significant during sleep. Treatment of SDB, which is readily available, should be tested as a complementary modality to the currently recommended pharmacotherapy aimed at lowering HR in patients with symptomatic HCM.
Direct evidence of bradycardic effect of omega-3 fatty acids acting on nucleus ambiguus
2020, Neuroscience Letters
Docosahexaenoic acid (DHA) an omega-3 polyunsaturated fatty acid, is an agonist of FFA1 receptor. DHA administration reduces the heart rate via unclear mechanisms. We examined the effect of DHA on neurons of nucleus ambiguus that provide the parasympathetic control of heart rate. DHA produced a dose-dependent increase in cytosolic Ca²⁺ concentration in cardiac-projecting nucleus ambiguus neurons; the effect was prevented by GW1100, a FFA1 receptor antagonist. DHA depolarized cultured nucleus ambiguus neurons via FFA1 activation. Bilateral microinjection of DHA into nucleus ambiguus produced bradycardia in conscious rats. Our results indicate that DHA decreases heart rate by activation of FFA1 receptor on cardiac-projecting nucleus ambiguus neurons.
Risk Factor Variability and Cardiovascular Outcome: JACC Review Topic of the Week
2019, Journal of the American College of Cardiology
Citation Excerpt :
These provocative data notwithstanding, we should remember that although various studies document that BP variability varies from one antihypertensive drug to the other, there has been no study documenting that reduction of such variability per se (independent of BP reduction) improved outcomes. Similar to BP, resting heart rate has been identified as a risk factor for CVD (34,35). However, unlike variability of other cardiovascular risk factors, increased heart rate variability (HRV) is not associated with an increased risk.
Until recently, intraindividual visit-to-visit variability of cardiovascular risk factors has been dismissed as random fluctuation. This simplistic concept was challenged by demonstrating that visit-to-visit blood pressure variability, independent of average blood pressure, was a powerful risk factor for stroke. Subsequently, variability of other cardiovascular risk factors such as cholesterol, glycemia, and body weight was documented to increase risk independent of their absolute values. Variability of these risk factors has been demonstrated to be a powerful predictor for all-cause and cardiovascular mortality, stroke, coronary artery disease, heart failure, end-stage renal disease, and dementia. With the notable exception of heart rate, cardiovascular risk factors must now be defined by 2 components: the magnitude and duration of sustained risk factor elevation and, equally important, the variability of the same risk factor over time.
Bradycardia is associated with future cardiovascular diseases and death in men from the general population
2014, Atherosclerosis
Citation Excerpt :
Significant associations between higher resting heart rates and future cardiovascular disease (CVD) events or mortality have been reported in a general population cohort [1–4], in the clinical setting for patients with hypertension, diabetes, or CVD [5–9], and in patients undergoing hemodialysis [10–12].
Although a higher heart rate is known to be a risk factor for cardiovascular disease (CVD) events, there have been no reports concerning bradycardia. Whether lower and higher resting pulse rates (RPRs) are associated with cardiovascular risk was investigated in subjects from a community-based, prospective cohort study.
After subjects with atrial fibrillation, subjects with a history of CVD, and subjects receiving antihypertensive treatment were excluded, 17,766 subjects (5958 men), aged 40–79 (mean 61.5) years, were analyzed. The RPR at baseline was categorized into four groups (RPR<60, 60–69.5, 70–79.5, ≥80 beats per minute (bpm)) using the average value of two consecutive measurements. The endpoint was set as the composite outcome of myocardial infarction, stroke, or sudden death.
During a mean follow-up of 5.6 years, there were 213 events in men and 186 events in women. In Cox regression models, increased risks of CVD were found in the men group with RPR<60 bpm, as well as the group with RPR≥80 bpm, compared with the reference group with RPR 60–69.5 bpm (hazard ratio [HR] = 1.73, p = 0.005 and HR = 2.01, p < 0.001). These increased risks were found even when adjusted for age and other CVD risk factors (HR = 1.55, p = 0.026 with RPR<60 bpm and HR = 1.72, p = 0.009 with RPR≥80 bpm). In women, there were no significant associations between RPR and CVD risk.
Bradycardia, as well as a higher pulse rate, may be an independent risk factor for future cardiovascular events in apparently healthy men.

View all citing articles on Scopus

: Statement of Conflict of Interest: see page 57.

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Elevated Heart Rate in Cardiovascular Diseases: A Target for Treatment?

Abstract

Section snippets

Elevated heart rate as an independent risk factor for cardiovascular disease

Effect of heart rate reduction in animal studies

Lifestyle modifications

Future perspectives in noncardiac patients

Methodological issues

Conclusions

Statement of Conflict of Interest

J Am Coll Cardiol

J Vasc Surg

Int J Cardiol

J Am Coll Cardiol

Am Heart J

Am Heart J

J Am Coll Cardiol

Am J Cardiol

Am J Cardiol

Lancet

Am Heart J

Lancet

Lancet

Am Heart J

Lancet

J Am Coll Cardiol

Am J Cardiol

J Am Coll Cardiol

Am Heart J

Rest heart rate and life expectancy

J Am Coll Cardiol

Universal biological scaling and mortality

Proc Natl Acad Sci U S A

Association of tachycardia with morbidity and mortality: pathophysiological considerations

J Hum Hypertens

Review article: heart rate and the cardiovascular risk

J Hypertens

High heart rate: a cardiovascular risk factor?

Eur Heart J

The role of heart rate in the development of cardiovascular disease

Clin Res Cardiol

Epinephrine-induced insulin resistance in man

J Clin Invest

Slow to fast alterations in skeletal muscle fibers caused by clenbuterol, a beta-2-receptor agonist

Am J Physiol

Reflex sympathetic activation induces acute insulin resistance in the human forearm

Hypertension

The influence of heart rate on coronary artery atherosclerosis

J Cardiovasc Pharmacol

Inhibition of coronary atherosclerosis by propranolol in behaviorally predisposed monkeys fed an atherogenic diet

Circulation

Morbidity, mortality, and antihypertensive treatment effects by extent of atherosclerosis in older adults with isolated systolic hypertension

Stroke

Heart rate as a cardiovascular risk factor

Eur Heart J

Intimal alterations in rat aorta induced by stressful stimuli

Lab Invest

Exercise haemodynamics in the normotensive and the hypertensive subject

Clin Sci

Association between 24-hour ambulatory heart rate and arterial stiffness

J Hum Hypertens

Association between high heart rate and high arterial rigidity in normotensive and hypertensive subjects

J Hypertens

Determinants of accelerated progression of arterial stiffness in normotensive and treated hypertensive subjects over a 6-year period

Circulation

Heart rate-dependence of arterial distensibility in vivo

J Hypertens

Heart-rate–proportional oxygen consumption for constant cardiac work in dog heart

Jpn J Physiol

Coronary vasoconstriction during myocardial ischemia induced by rises in metabolic demand in patients with coronary artery disease

Circulation

Heart rate dynamics as a marker of vulnerability to atrial fibrillation

J Cardiovasc Electrophysiol

Left ventricular muscle mass and elevated heart rate are associated with coronary plaque disruption

Circulation

High heart rate: a risk factor for cardiovascular death in elderly men

Arch Intern Med

Heart-rate profile during exercise as a predictor of sudden death

N Engl J Med

Observations on the relation of heart rate, life span, weight and mineralization in the digoxin-treated A/J mouse