A comparative study on the effects of mind-wandering, distraction, and fatigue on driving performance and physiological responses

Over the past 15 years there has been major change in the treatment of chronic heart failure (HF), involving both pharmacological and non-pharmacological (device) therapy. This has impacted favourably on outcome but HF still has a poor prognosis. There is need for better implementation of existing therapies as well as consideration of additional treatments. Establishing the aetiology of heart failure is also important, as is detecting co-morbidities such as asthma or renal dysfunction that can influence therapeutic decisions. One of the areas attracting particular interest is the importance of increased heart rate as a risk factor, and specific treatment target, in patients with HF. Elevated resting heart rate is common in HF with systolic dysfunction and is an established marker of risk of morbidity and mortality (1,2). For example, retrospective analysis of one of the major beta-blocker HF trials showed that elevated resting heart rate at baseline was strongly associated with increased 1-year mortality. In this trial, the best prognosis was related independently to being randomized to beta-blocker therapy, a lower baseline heart rate, and a greater heart rate reduction (2). The importance of heart rate as a prognostic marker in HF with systolic dysfunction was also demonstrated in the placebo group of the recent SHIFT study (3). Patients with the highest heart rates [≥ 87 beats per minute (bpm)] were at more than two-fold higher risk for the primary composite endpoint (cardiovascular death or hospital admission for worsening HF) than patients with the lowest heart rates (70–< 72 bpm; hazard ratio 2.34, 95% CI 1.84–2.98, p < 0.0001, Figure 1). Risk of these endpoint events increased by 16% for every 5 bpm increase. Kaplan–Meier cumulative event curves for the primary composite endpoint (cardiovascular death or first hospital admission for worsening heart failure) in the placebo group (n = 3264) of the SHIFT study, according to groups defined by quintiles of heart rate at baseline. The log-rank p value is shown for the difference between the Kaplan–Meier curves (from Bohm, Ref. 3) Increased heart rate in patients with HF is associated with increased oxygen demand, reduced ventricular efficiency and reduced ventricular relaxation. It is also reported to be directly associated with atherogenesis (4). Heart rate reduction decreases energy expenditure, increases blood supply by prolonging diastole and reduces ventricular loading (3). Although a raised heart rate is associated with worsening prognosis in HF it does not necessarily follow that heart rate reduction is clinically beneficial. However, there is increasing evidence that heart rate is indeed a modifiable risk factor. Heart rate reduction, with beta-blockers or other drugs, was associated with reduced mortality in an analysis of major HF trials (5). In addition, a recent meta-analysis showed that the magnitude of heart rate reduction was significantly associated with survival benefit of beta-blockers in chronic HF: for every heart rate reduction of 5 bpm, there was an 18% reduction in risk of death (6). These data suggest that the proven clinical benefits of beta-blockers in HF are, to some extent, associated with heart rate reduction. Beta-blockers reduce heart rate by decreasing sympathetic drive. However, this group of drugs has multiple effects on the cardiovascular system and so the specific benefit of heart rate lowering is uncertain. It is only with recent studies with ivabradine, a pure heart rate lowering drug, that clear evidence has emerged that reduction of heart rate per se improves outcome, i.e., that heart rate is not only a marker of risk but is also a true modifiable risk factor. Ivabradine is a novel heart rate-lowering agent that acts by selective inhibition of the If current (‘funny’ current) in the sino-atrial node (7). The If current controls spontaneous diastolic depolarisation and regulates heart rate. Heart rate reduction is the drug’s only known effect on the cardiovascular system. The SHIFT study (8) was a randomised trial of ivabradine (up to 7.5 mg bd) versus placebo in 6558 patients with symptomatic heart failure, an ejection fraction of 35% or lower, sinus rhythm with resting heart rate of 70 bpm or higher, and a hospital admission for heart failure within the previous year. Patients were on stable background therapy, including a beta-blocker if tolerated. Over a median follow up of 22.9 months, there was an 18% relative risk reduction for the primary composite end-point of cardiovascular death or hospital admission for worsening heart failure (p < 0.0001). The effect was mainly driven by hospital admissions for worsening heart failure, which were reduced by 26% (p < 0.0001), and deaths due to heart failure (relative risk reduction 26%, p = 0.014). Treatment benefit was shown to be related to heart rate reduction and ivabradine therapy was well tolerated. Bradycardia led to drug withdrawal in 1.5% of patients treated with ivabradine, compared with 0.3% of patients treated with placebo. In terms of background therapy, around 10% of patients were not considered suitable for beta-blocker therapy; of those taking beta-blockers, 56% were taking at least 50% of the European Society of Cardiology (ESC) (9) target dose. This is a much higher use of beta-blockade therapy than is found in routine practice, as discussed below. Sub-studies of SHIFT found that heart rate reduction was associated with reversal of cardiac remodelling, additional to that achieved with background ACE inhibitors and beta blockade, as shown by reduction in left ventricular volumes and increase in left ventricular ejection fraction (10). The reduced heart rate was also associated with improved health-related quality of life (11). Current data therefore point to the clinical benefit of reducing heart rate in patients with HF. The question is how best to achieve this. Beta-blockers are central to the pharmacological management of HF with systolic dysfunction and are recommended for all patients, unless contraindicated or not tolerated. Guidelines recommend starting at a low dose and slowly uptitrating to the target dose, or to maximally tolerated dose (9). Despite the guideline recommendations, in clinical practice the use of beta-blockers in HF is still suboptimal, although it has increased in recent years. Data for November 2010 from the UK national HF audit (12) show that 65% of patients with a new diagnosis of HF receive a beta-blocker on discharge from hospital, with these drugs more likely to be prescribed to men and to younger patients (under age 75 years). Many patients do not receive the recommended doses of beta-blocker. A study using the UK General Practice Research Database analysed beta-blocker dose 12 months after initiation of therapy for heart failure and showed that 57% of patients were receiving less than 50% of the recommended target dose. Only 17% of patients were at target dose (13). The study also showed poor persistence with therapy: 29% of patients had discontinued their beta-blocker at 1 year and 56% at 3 years (14). Similar findings on underdosing were reported in the ESC-HF pilot, a survey of patients in 12 European countries. Beta-blockers were prescribed to 87% of outpatients but target dose was achieved in only 21%–37% of patients (depending on the specific drug) (15). The latest data from the French IMPACT RECO registry (IMPACT RECO III) show that, in 2007, 78% of HF outpatients were prescribed a beta-blocker (compared with 65% in 2005) but only 26% were on a target dose and 60% on 50% of target dose (16). Suboptimal use of beta-blockers would be expected to be associated with poor heart rate control and this is borne out by European registry data. Recent HF registries show that more than 50% of patients have heart rates of 70 bpm or higher, and around one-third have heart rates of > 75 bpm. To assess how well heart rate is controlled in our HF patients, at the Royal Brompton hospital in 2011 we carried out an audit of 100 consecutive outpatients in sinus rhythm and with ejection fraction ≤ 40%. The average age of patients was 65 years (range 22–90), 74% were men, 63% had ischaemic heart disease and 20% had diabetes. Of the 100 patients, 20 were intolerant of beta-blocker (e.g., because of wheeze or hypotension) and were not taking the drug; 17 patients were on a “low” dose of beta-blocker (< 50% of target dose) and unable to increase the dose; 15 were on a “moderate” dose of beta-blocker (50%–99% of target dose) and unable to increase the dose; and 22 were on a full dose of beta-blocker (100% or above target dose). The remaining 26 patients were in the process of having their beta-blocker dose uptitrated. Among the 74 patients who had completed beta-blocker uptitration and were at maximally tolerated dose (n = 54) or were intolerant of beta-blockers (n = 20), 53% had a heart rate > 70 bpm and 20% had a heart rate of > 80 bpm. Our audit data are therefore similar to the recent registry data and show that there is opportunity to take further steps to lower patients’ heart rate, even where beta-blocker therapy is pursued aggressively in a specialist clinic. New data indicate that elevated heart rate is an independent risk factor in HF: lowering heart rate improves outcomes and is an important therapeutic target. Beta-blockers remain the first-choice drugs for reducing heart rate. There is no evidence for using ivabradine in preference to beta-blockers. But for patients with HF and reduced systolic function who cannot take beta-blockers or are unable to reach target dosage, there is now good evidence to support the addition of ivabradine for patients in sinus rhythm who have an elevated heart rate. Professor Cowie has received honoraria for lecturing at scientific meetings on the use of ivabradine to reduce heart rate.

That elevated heart rate (HR) is a risk factor for cardiovascular morbidity and mortality in healthy people as well as in patients with cardiac diseases is supported by numerous epidemiological association studies.1–4 Increased HR has been recognized as a negative prognostic factor independent of many other clinical parameters that can influence the HR, including physical activity scores, left ventricular function, or use of β-blockers. Thus, HR appears to satisfy all epidemiological criteria for being considered as a true risk factor, and its predictive value for cardiovascular disease appeared to be as strong as that of most important cardiovascular risk factors. This is particularly true for the results obtained in hypertensive patients. Elevated HR is a common feature among hypertensive individuals.1 Among the young hypertensive subjects participating in the HARVEST study, >15% had a baseline resting HR ≥85 bpm and 27% had a HR ≥80 bpm.5 According to the Tensiopulse study, which evaluated 38 145 patients cared for by 2000 general practitioners all across Italy, >30% of the hypertensive patients had a resting HR ≥80 bpm.6 In a large French population, untreated hypertensive subjects had approximately a 6-bpm faster HR than normotensive individuals.7 Elevated HR is frequently associated with high blood pressure (BP) and metabolic disturbances and increases the risk of new onset hypertension and diabetes.1 Many experimental data obtained both in animals and in human beings support the importance of HR as a true risk factor for atherosclerosis and cardiovascular disease, providing convincing evidence for this pathogenetic mechanism.1–3 The pathogenetic connection between HR and cardiovascular disease has been discussed in several reports1–3,8,9 and is beyond the scope of this review. ### High HR as a Precursor of Hypertension, Obesity, and Diabetes Numerous studies have demonstrated that tachycardia is frequently associated with hypertension in …

Elevated heart rate is also a risk factor after cardiac transplantation: Time to slow down?

Thirty-eight studies have been published to date on the association between elevated heart rate and mortality. After adjustment for other risk factors, only two studies for all-cause mortality and four studies for cardiovascular mortality reported an absence of association between heart rate and mortality in male populations. This relationship has been found to be generally weaker among females. Most of these studies investigated samples of general populations. The four studies performed in hypertensive men found a positive association between heart rate and all-cause mortality (hazard ratios ranging from 1.9 to 2.0) or cardiovascular mortality (hazard ratios ranging from 1.3 to 1.7). In spite of this evidence, elevated heart rate remains a neglected cardiovascular risk factor in both genders. The pathogenetic mechanisms connecting high heart rate, hypertension, atherosclerosis and cardiovascular events have also been explicated in many studies. Elevated heart rate is due to an increased sympathetic and decreased parasympathetic tone. This altered balance of the autonomic nervous system tone could explain the increase in events with the increased heart rate. However, it has also been proved that blood flow changes associated with high heart rate favour both the formation of the atherosclerotic lesion and the occurrence of the cardiovascular event. Reduction of heart rate in hypertensive patients with increased heart rate could be an additional goal of antihypertensive therapy. Several trials retrospectively showed the beneficial effect of cardiac-slowing drugs, such as beta-adrenoceptor antagonists (beta-blockers) and non-dihydropyridine calcium channel antagonists, on mortality, notably in patients with coronary heart disease, but no published data are available in patients with hypertension free of coronary heart disease. Other antihypertensive drugs that have been shown to reduce the heart rate are centrally acting drugs and angiotensin II receptor antagonists, but their bradycardic effect is rather weak. The f-channel antagonist ivabradine is a selective heart rate-lowering agent with no effect on blood pressure. Although it has not been proven in existing trials, it would seem reasonable to recommend antihypertensive agents that decrease the heart rate in hypertensive patients with a heart rate higher than 80-85 beats per minute. Since the fast heart rate per se causes cardiovascular damage, all drugs that lower the heart rate have the potential of further reducing cardiovascular events in patients with elevated heart rate. Unfortunately, lowering of the heart rate is not a clinically recognised goal. Prospective trials investigating whether treatment of high heart rate can prevent cardiovascular events, notably in hypertensive patients, are warranted.

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

Exploring the Association between Heart Rate Control and Patient Outcomes: A Retrospective Medical Record Review of Patients Hospitalized with Systolic Heart Failure

Elevated heart rate is known to induce myocardial ischaemia in patients with coronary artery disease (CAD), and heart rate reduction is a recognized strategy to prevent ischaemic episodes. In addition, clinical evidence shows that slowing the heart rate reduces the symptoms of angina by improving microcirculation and coronary flow. Elevated heart rate is an established risk factor for cardiovascular events in patients with CAD and in those with chronic heart failure (HF). Accordingly, reducing heart rate improves prognosis in patients with HF, as demonstrated in SHIFT. By contrast, data from SIGNIFY indicate that heart rate is not a modifiable risk factor in patients with CAD who do not also have HF. Heart rate is also an important determinant of cardiac arrhythmias; low heart rate can be associated with atrial fibrillation, and high heart rate after exercise can be associated with sudden cardiac death. In this Review, we critically assess these clinical findings, and propose hypotheses for the variable effect of heart rate reduction in cardiovascular disease.

Heart rate (HR) is strongly associated with both peripheral and central blood pressures. This association has implications in hypertension (HTN) prognosis and management. Elevated HR in HTN further elevates the risk of adverse outcomes. Evidence suggests that HR is an independent risk factor for cardiovascular (CV) and total mortality in patients with HTN. With objective to engage physicians and researchers in India to identify and discuss the implications related to HR management in HTN, experts in the HTN management provided consensus recommendations. The key expert recommendations included the following. (i) Heart rate (HR) has inverse relationship with the central aortic pressure, whereby reduction in HR is associated with an increase in central aortic pressure. This counter-balances the benefit of HR reduction with the harmful effects of rising central aortic pressure. (ii) Increase in the resting HR is associated with increased risk of incident HTN. A linear association between the two is observed especially in individuals with HR >80 bpm. (iii) A reduced HR variability further adds to the propensity for the development of HTN, especially in men. (iv) Each 10 beats per minute increase in the resting HR can substantially increase the risk of adverse CV and mortality outcomes. On treatment HR provides a better prognostic guide. (v) Ambulatory HR with day-time and night-time HR evaluation may also suggest different impact on outcomes. (vi) Target HR in patients with HTN remains unclear. Generally, HR<70 bpm on beta blocker (BB) treatment is advised which may be further lowered in patients with comorbidities like heart failure and coronary artery disease. (vii) Adopting healthy lifestyle approaches to keep check on BP and HR is essential. (viii) Use selective beta-1 blocker in symptomatic cases with elevated HR beyond 80-85 mmHg. BBs are expected to benefit by lowering HR by nearly 10 bpm. Preference should be given to newer beta-blockers which reduce HR and both peripheral and central blood pressure to derive comprehensive advantage of this dual action. (ix) It still remains unclear whether reducing HR in HTN without comorbidities alters the CV and mortality outcomes.

Introduction: An elevated heart rate is associated with an increased risk of death or cardiac transplant in children with dilated cardiomyopathy (DCM). Whether heart rate is a clinical marker to address therapy, is poorly investigated in children. Aim: To investigate the relationship between heart rate reduction (HRR) and left ventricular ejection fraction (LVEF) in DCM, treated with carvedilol. Methods: This is a multi center retrospective analysis conducted on all children with DCM (aged <18years) between 2013 and 2020, with LVEF <40% and treated with carvedilol. Carvedilol was up titrated to the maximal tolerated dose or to 1mg/kg/day. Echocardiographic data on left ventricular function and dimension were collected. The relationship between HRR and LVEF, left ventricular end-diastolic (LVEDd) and end-systolic diameter (LVESd) was assessed before and after HRR with carvedilol, using regression analysis. Results: 100 patients were enrolled (M: 51%; age 7 ± 8years). The mean LVEF was 30.2 ± 10% before treatment and 43.7 ± 9.6% after treatment, at the maximum therapeutic dose (p < 0.0001). There was a positive relationship between HRR and increase in LVEF (R 2 = 0.06, p = 0.014). A HRR of >20% correlated with an improvement in LVEF >13%. At 3years follow up, HRR demonstrated a significant reduction of LVESd (R2 = 0.1, p = 0.003) LVEDd (R2 = 0.07, p = 0.008) and LVEF recovery up to 15% (p < 0.0001). No deaths or heart transplant occurred during follow-up. Conclusion: This study demonstrates that HRR is safe and improvement in LVEF is related to the degree of HRR. The magnitude of LVEF improvement was enhanced by a major reduction in HR. It provides evidence that HRR could be used as a clinical marker to treat HF in children.

Heart rate (HR) is of relevant prognostic value not only in the general population and patients with cardiovascular disease, but also in critically ill patients with multiple organ dysfunction syndrome (MODS). An elevated HR in MODS patients is associated with a worse prognosis. Beta-blocker (BB) administration has been shown to reduce mortality in MODS. In most cases, negative inotropic effects prevent administration of BBs in MODS patients. In this trial we investigate, whether the "funny current" (I (f)) channel inhibitor ivabradine is able and apt to reduce pathologically elevated HR in MODS patients. We hypothesize that critically ill patients could derive particular benefit from the specific HR-lowering agent ivabradine. MODI (f)Y is a prospective, single centre, open label, randomized, controlled two arms, phase II-trial to evaluate the potential of ivabradine to reduce an elevated HR in MODS patients. The primary end point is the proportion of patients with a reduction of HR by at least 10 beats per minute (bpm) within 4days. This trial will randomize 70 patients (men and women, aged ≥18years) with newly diagnosed MODS, with an elevated HR (sinus rhythm with HR ≥90bpm) and contraindications to BB therapy. Treatment period will last for 4days. All patients will be followed for 6months. The first patient was randomized on May 21, 2010. The MODI (f)Y trial is the first application of ivabradine as a pure heart rate reducing agent in MODS patients.

Preliminary evidence of parasympathetic influence on basal heart rate in posttraumatic stress disorder

Heart rate: an independent risk factor in cardiovascular disease

Purpose: It is still controversial whether elevated baseline heart rate (HR) is associated with higher mortality in patients with heart failure (HF) with preserved ejection fraction (HFpEF). We compared the prognostic impact of baseline HR between patients with HFpEF and those with HF with reduced ejection fraction (HFrEF). Methods and results: We enrolled consecutive 2,688 patients with symptomatic Stage C/D HF with sinus rhythm from our Chronic Heart Failure Analysis and Registry in the Tohoku District 2 (CHART-2) Study (n=10,219). The prognostic impact of HR increase was compared between HFrEF (LVEF 50%, n=1,803). Cox regression analysis revealed that elevated baseline HR was significantly associated with increased all-cause mortality in both groups (hazard ratio for the highest tertile (HH) 1.77 in HFrEF, P=0.008; HH1.82 in HFpEF, P=0.001) (Figure 1). However, elevated HR was significantly associated with cardiovascular (CV) death in HFpEF (HH 2.17, P=0.012) but not in HFrEF (HH1.49, P=0.14). Furthermore, the impact of elevated HR on HF death was different between HFpEF (HH 3.79, P=0.020) and HFrEF (HH 1.07, P=0.864). This was also the case for CV death in patients without β-blocker therapy in both HFpEF (HH 2.89, P=0.013) and HFrEF (HH 2.07, P=0.131). Furthermore, β-blocker therapy was significantly associated with reduced HF mortality in HFrEF (hazard ratio 0.51, P=0.041) but not in HFpEF (hazard ratio 0.59, P=0.243). ![Figure][1] Figure 1 Conclusions: These results indicate that elevated HR is associated with increased CV death, particularly HF death, in HFpEF compared with HFrEF, whereas its impact on all-cause mortality is comparable between the 2 groups. They also suggest that β-blocker therapy is associated with improved HF mortality in HFrEF but not in HFpEF. [1]: pending:yes

Background and Objectives: An elevated heart rate is an independent risk factor for cardiovascular disease; however, the relationship between heart rate control and the long-term outcomes of patients with heart failure with reduced ejection fraction (HFrEF) remains unclear. This study explored the long-term prognostic importance of heart rate control in patients hospitalized with HFrEF. Materials and Methods: We retrieved the records of patients admitted for decompensated heart failure with a left ventricular ejection fraction (LVEF) of ≤40%, from 1 January 2005 to 31 December 2019. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure (HHF) during follow-up. We analyzed the outcomes using Cox proportional hazard ratios calculated using the patients’ heart rates, as measured at baseline and approximately 3 months later. The mean follow-up duration was 49.0 ± 38.1 months. Results: We identified 5236 eligible patients, and divided them into five groups on the basis of changes in their heart rates. The mean LVEFs of the groups ranged from 29.1% to 30.6%. After adjustment for all covariates, the results demonstrated that lesser heart rate reductions at the 3-month screening period were associated with long-term cardiovascular death, HHF, and all-cause mortality (p for linear trend = 0.033, 0.042, and 0.003, respectively). The restricted cubic spline model revealed a linear relationship between reduction in heart rate and risk of outcomes (p for nonlinearity > 0.2). Conclusions: Greater reductions in heart rate were associated with a lower risk of long-term cardiovascular death, HHF, and all-cause mortality among patients discharged after hospitalization for decompensated HFrEF.

Heart rate is measured in every critically ill patient and high values often reflect the severity of underlying disease. Nevertheless, in clinical practice the pathophysiological implications of an increase in heart rate are often undervalued. The importance of elevated heart rate and its role in determining or contributing to cardiovascular diseases began to be recognized at the end of the 1970s. Nowadays, it is clear that tachycardia represents an independent risk factor for mortality and morbidity in several clinical conditions, including coronary artery disease, myocardial infarction, and congestive heart failure [1–7]. Furthermore, it has also been demonstrated that with respect to other cardiovascular factors, a high heart rate is the best predictor of mortality in different categories of patients [6]. Results of numerous large epidemiological trials confirm that an elevated heart rate not only represents a clinical sign of altered cardiac function but also contributes to cardiac dysfunction. Although the role of an elevated heart rate is well established and has clearly been linked to outcome in cardiology patients, the topic has gained less attention in septic patients. To date only a few small clinical studies have evaluated the relationship between increased heart rate and mortality in patients suffering from septic shock. However, the results of such studies strongly suggest that elevated heart rate is a risk factor for increased mortality, even in septic shock patients [8–10]. A reduction in heart rate could, therefore, improve outcomes for septic shock patients by lowering cardiac workload and improving diastolic coronary perfusion of the septic heart. Recently, the results from a monocenter trial that investigated the hemodynamic effects of reducing heart rate with the β-blocker esmolol in septic shock patients attracted the interest of critical care physicians [10]. The aim of this article is to provide an overview of the pathophysiology of sepsis-induced tachycardia and its implications in the clinical management of affected patients.