The pulse; from adagio to prestissimo; the prognostic importance of heart rate increase and its associations with cardiovascular risk factors

As in nature and music, dynamics are essential for life. However, chronotropic incompetence is an underappreciated condition, and is often overlooked in clinical practice. The reasons for this are numerous, including multiple definitions, confounding effects of aging and medications, and the need for formal exercise testing for definitive diagnosis. The popular definition of maximum pulse rate is the ability to reach 80% of age predicted maximal pulse rate: 220 – age,1 However, the dynamic phrase ‘heart rate reserve’ might be a more precise measure in that resting heart rate is also taken into account.2 Baseline heart rate is by itself a significant prognostic indicator. Resting heart rate above 90 beats/min has been shown to be associated with mortality from coronary heart disease. However, also, a resting heart rate that is currently considered as ‘normal’ in the general population has specifically been associated with the incidence of certain major cardiovascular diseases and death, with the risk starting at lower resting heart rate levels in men compared with women.3 Although most studies support the notion that augmented heart rate is an independent risk factor for cardiovascular mortality and morbidity,4 the link between sudden cardiac death and elevated heart rate is perhaps the most compelling. This is further underlined by The Norwegian Timolol Multicentre Study Group, which documented the effect of the beta-blocker Timolol on mortality and reinfarction after acute myocardial infarction, confirming the prognostic importance of pharmacological reduction of heart rate at rest in this population.5 The association between coronary artery disease (CAD) and sudden death in men has been shown to remain significant even after adjustment of multiple risk factors in a cohort in the Framingham study.6 Several mechanisms might thus be operable for the positive effects of beta-blockers, including reduction of ischaemia in patients with CAD and modulation of beta-receptor density in heart failure. However, the consistently favourable effects of beta-blockade in patients with ischaemic heart disease emphasize the significance of sympathetic blockade with associated augmentation in vagal activity.7 The reduced heart rate has also been shown to be associated both with severity of coronary atherosclerosis in young patients after myocardial infarction and with rate of progression of atherosclerotic disease per se.8 Also in the general population changes in long-term individual resting heart rate may provide additional prognostic information. In the Tromsø Study surveys, among five long-term resting heart rate trajectories defined, increasing and elevated trajectories were associated with an increased risk of myocardial infarction and total death in men.9 The importance of increased baseline heart rate and its potential relationship to adverse cardiovascular events is further underlined in another cohort of the Framingham Heart Study, in which increased heart rates were associated with a prothrombotic state with significant age-adjusted increases in fibrinogen, viscosity, factor VII antigen and impaired fibrinolytic potential.10 Numerous studies have demonstrated the negative prognostic effect of exercise chronotropic incompetence in heart failure11 and CAD.12 In addition, untreated catecholaminergic polymorphic ventricular tachycardia patients with chronotropic incompetence have more ventricular arrhythmias than those without chronotropic incompetence.13 However, the incidence and clinical significance of chronotropic incompetence in apparently healthy subjects is less known. The obvious impact of sympathetic and parasympathetic neural stimulation on heart rate (HR) is clearly demonstrated after heart transplantation (TPX). HR response is one of the most important predictors of exercise capacity in this population without relevant transplant vasculopathy or acute allograft rejection.14 Partial normalization of HR is achieved by approximately 70% of heart TPX patients at 12 months, with significant changes occurring within six months in most subjects. It is suggested that these findings should contribute to reducing the exercise restrictions that apply to the denervated heart.15 The frequently estimated HRmax at a given age by the ‘220 − age’ formula is underlining the importance of age for calculation of maximal pulse. However, several reports indicate that this equation is too simple because of the underestimated measured HRmax in subjects older than 30 years. Based on a combined meta-analysis and a cross-validation in a sample of 514 healthy subjects, Tanaka et al. suggested a new formula, 208 – 0.7·age, yielding a more precise estimate of HRmax over a wide age range.16 The Nord-Trøndelag Health Study (HUNT) investigators found that HRmax was univariately explained by the formula 211 – 0.64·age (standard error of the estimate (SEE), 10.8), without any evidence of interaction with gender, physical activity, VO2max level or body mass index (BMI) groups.17 Consequently they concluded that HRmax predicted by age alone may be practically convenient for various groups, although a standard error of 10.8 beats/min must be taken into account. These results support several studies in demonstrating that the traditional 220 – age formula is inappropriate in predicting HRmax, especially in older subjects. Moreover, the HUNT investigators found that the rate of decline in HRmax with age was not influenced by gender substantially, physical activity status, maximal oxygen uptake, smoking or BMI. In addition, the results from the HUNT study demonstrated that HRmax in healthy, older subjects and women were higher than previously reported. Therefore it was concluded that HRmax predicted by age alone may be practically convenient for various groups. The population in the HUNT study was free from cardiovascular disease, hypertension and cancer and is thereby considered apparently healthy. The proposed regression equation may therefore not be suitable for some patient-groups. Despite various reports of the effect of gender on HRmax, it seems like obesity may have impact on predicting HRmax, making it necessary to modify current equations from 220 – age to the equation 200 – 0.5 × age.18 This is confirmed in a small study in 59 obese adolescents, in which the investigators found that the formula 200 – 0.48 × age, with 12 as a SEE, presented similar results (p = 0.103) as the measured HRmax in the cardiopulmonary exercise test (CPET).19 Physical activity status may also affect HRmax. HRmax can be altered by 3–7% with aerobic training/detraining, indicating that a positive training effect is associated with a decrease in HRmax.20 In contrast to previous studies, Guazzi and co-workers elegantly demonstrated that exercise chronotropic incompetence is common in a study in apparently healthy subjects from the Euro-EX prevention trial. However, the included apparently healthy adults had a broad cardiovascular risk factor profile, which may indicate a small selection bias.21 In the research paper ‘Exercise chronotropic insufficiency phenotypes the level of cardiovascular risk and exercise gas exchange impairment in the general population. An analysis of the Euro-EX prevention trial’ by Laforgia et al. in this issue of the journal, the same research group demonstrates that exercise chronotropic incompetence also phenotypes the progressive level of cardiovascular risk by a tight relationship with major cardiovascular risk factors (MCVRFs) in apparently healthy subjects.22 Chronotropic incompetence was defined as failure to reach 80% of the HR reserve (HRR), defined as (HRmax – HRrest)/age-predicted maximal HR (APMHR) – HRrest, which is a validated criterion for detecting chronotropic incompetence during exercise.2 Moreover, they extend these findings by demonstrating that chronotropic incompetence patients exhibit abnormal exercise gas exchange patterns and echocardiography derived measures. The trial was performed in a large prospective cohort of 702 apparently healthy individuals, including almost 54% females, with at least one MCVRF, namely, hypertension, dyslipidaemia, smoking history, diabetes mellitus, BMI > 25, but no manifest previous cardiovascular disease, who underwent maximal CPET. Compared with non-chronotropic incompetence, the authors showed that chronotropic incompetence subjects were more frequently females with a history of hypertension. Moreover, chronotropic incompetence subjects also exhibited a significantly lower peak VO2 and circulatory power, and an echocardiographic pattern indicative of higher left atrium volume index and left ventricular (LV) mass index. In addition, an inverse stepwise relationship between HRR and number of MCVRFs was observed (one MCVRF: 0.71 ± 0.23; two MCVRFs: 0.68 ± 0.24, three MCVRFs: 0.64 ± 0.20; four MCVRFs: 0.64 ± 0.23; five MCVRFs: 18 ± 0.57; p < 0.01). At multivariate analysis the only variable found predicting chronotropic incompetence was peak VO2 (p < 0.05; odds ratio 0.91; confidence interval 0.85–0.97). In contrast to the findings by the HUNT investigators, the current study demonstrated that chronotropic incompetence subjects were more frequently females with a history of hypertension. On the other hand, the inclusion of hypertension as risk factor underlines that these two populations are not quite similar because the current population studied is recruited from a cardiac risk clinic in contrast to the HUNT population, which comprised healthy adults free from self-reported cardiovascular diseases, pulmonary diseases, cancer, hypertension and physical disability. None of the participants in the HUNT study were on any medication considered to potentially affect HR, including beta-blockers. Another explanation for the finding of chronotropic incompetence in females might be that maximum heart rate relative to age based on studies with a predominance of male patients may be an overestimate for women.23 A difference in mean age (46 years compared with 62 years in the current report) should not affect the findings considerably. On the other hand, level of physical activity and its correlate with exercise capacity was not systematically assessed, which is in contrast to the HUNT report. The authors also correctly underline that chronotropic incompetence in a population of apparently normal subjects has been less investigated, and that its implications in phenotyping the general population in terms of exercise gas exchange analysis have not previously been thoroughly investigated. In the Framingham study chronotropic incompetence was predictive of CAD and total mortality.2 In the present report the investigators employed VO2 as an objective quantification of cardiorespiratory fitness by CPET to define the individuals who exactly perform a maximal test on a metabolic standpoint and provide a set of additional CPET-derived measures demonstrated to have prognostic significance.24 This significantly strengthens the study and should be taken into account in future planned studies on this issue. The authors state that the findings of a high rate of hypertension as the most predominant risk factor; female gender as the most represented; the average age of either chronotropic incompetence and non-chronotropic incompetence populations, are exactly typical of heart failure with preserved ejection fraction (HFpEF). A mean left ventricular ejection fraction (LVEF) of 67% with a mean VO2max of 17 ml/kg per min confirms a reduced functional capacity despite preserved ejection fraction. These features may indicate that exercise chronotropic incompetence would be central in the continuum between early stages of cardiovascular risk and progressive development of HFpEF. This is in accordance with the findings from a secondary analysis of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist study, in which the authors found high resting heart rate as a risk factor for adverse outcomes in patients with HFpEF.25 Moreover, the authors found that chronotropic incompetence patients exhibit peculiar abnormal exercise gas exchange patterns (lower peak VO2 and exercise oscillatory ventilation) and echo-derived measures (higher left atrium size and LV mass) that may well anticipate evolution toward heart failure. The increased LV mass is well compatible with the large proportion of patients who had had hypertension. The hypertrophic myocardium shows fibrosis, alterations in the coronary circulation and cardiomyocyte apoptosis, which may result in heart failure, myocardial ischaemia and arrhythmias. This LV hypertrophy is also consistently associated with increased cardiovascular morbidity and mortality, questioning whether this phenotype is an adaptive response.26 In the current study we do not know the level of physical activity, which might influence both HRR and LV hypertrophy.27 This is supported by the findings of enhanced heart rate variability (HRV) in individuals with metabolic syndrome after a three-week residential programme with intensive volumes of physical activity (15–20 h/week). Participants with moderate intensity training had greater improvements in sympathovagal balance, whereas those with high intensity in resistance training had greater decreases in HR and greater increases in very low frequency. In addition, modality-specific relationships were observed between enhanced HRV and visceral fat loss.28 Higher resting HR and chronotropic incompetence are both associated with more severe heart failure, but correlate poorly with each other. On the other hand, they both provide independent and additive prognostic information in heart failure across the LVEF spectrum.29 This brings us to the most novel findings in the current report: the inverse stepwise relationship between HRR and number of MCVRFs. The risk factors assessed in this otherwise healthy population were hypertension, dyslipidaemia, smoking history, diabetes mellitus and BMI > 25, of which hypertension was the most frequent. Hypertension, dyslipidaemia, smoking history and diabetes mellitus are all associated with endothelial dysfunction and development of CAD. Endothelial dysfunction is associated with systemic abnormal HRR and chronotropic incompetence per se. Moreover, interrelationships between exercise capacity, HRR, chronotropic incompetence and erectile dysfunction have further documented these pathophysiological links and may have important implications for the estimation of cardiovascular risk in erectile dysfunction patients.30 Endothelial dysfunction is the precursor of CAD. However, despite chronotropic incompetence being an independent predictor of mortality, its pathophysiological mechanisms remain unknown. Manifestations might be silent ischaemia with reduced LV function during increased workload with dominant heart failure symptoms. Moreover, a direct effect of significant coronary artery stenosis in patients with chronotropic incompetence has been shown to be associated with ventricular dysfunction in peak exercise and critical right coronary artery lesions.31 Microvascular disease is a precursor of CAD and is also associated with endothelial dysfunction. Moreover, HR recovery and exaggerated blood pressure response have been shown to be associated with microvascular angina, which suggests a link between this entity and autonomic dysregulation.32 A large cohort of patients admitted for chest pain have normal coronary angiogram33 but impaired coronary flow reserve (CFR). Several mechanisms are operative for development of impaired CFR. In patients with hypertension, both microvascular dysfunction and increased LV mass are described sequels.34 LV mass has also been associated with endothelial dysfunction and coronary artery remodelling.35 Diastolic dysfunction as measured by Em/Am ratio during stress dobutamine echocardiography is also related to impaired CFR.36 In addition, another of the MCVRFs, diabetes mellitus, impairs prognosis and longstanding disease influences microvascular physiology.37 In the current study microvascular dysfunction was not assessed directly, but no patient was symptomatic for angina on medical history. In addition, in cases where patients had performed a previous exercise test, no one was diagnosed with electrocardiogram or symptom criteria during exercise test indicating reduced CFR. CAD per se was, on the other hand, not objectively excluded in the current population. However, such objective tests as coronary angiogram or non-invasive diagnostics for ischaemia would imply a large burden on asymptomatic subjects In the current study 30% were on beta blockers and an additional 26% were on Ca++ antagonists, which both might have a not-negligible effect on HRmax. However, the authors also performed a sub-analysis in 395 patients, free of beta-blocker therapy and with a respiratory exchange ratio > 1.05. They found that the prevalence of chronotropic incompetence was similar to that observed in the whole population, confirming the main findings of a large predominance of chronotropic incompetence in otherwise healthy subjects with at least one MCVRF. Prevention of cardiovascular events in a population at cardiovascular risk should be one of the main foci in disease control. The current study provides some potentially intriguing findings indicating that exercise chronotropic incompetence may have a central role in refining the cardiovascular risk. In addition to the confirmation that exercise chronotropic incompetence mediates a poor exercise performance, the authors extend the importance of chronotropic incompetence by showing how exercise chronotropic incompetence phenotypes the level of risk in terms of gas exchange pattern and echo-derived measures. Moreover, chronotropic incompetence may be considered as an early marker in the continuum from cardiovascular risk to the development of HFpEF, thereby creating a ‘phenotype-guided’ approach to the management of patients with HFpEF, based on a stepwise method of making the HFpEF diagnosis, identifying and treating the prominent sources of risk factors before the manifestations of organ dysfunction.38 This includes targeted therapy of known risk factors such as hypertension, obesity, diabetes mellitus and smoking. Moreover, the least recognized important factor for disease progression, inactivity, must be taken into account. Unfortunately this was not evaluated in the current study. Exercise training has now a strong indication both in heart failure and in CAD, and current guidelines for the general population are now recommending at least 150 min of moderate physical activity a week and strength training.39 The authors of the current report have been able to demonstrate the prognostic importance of heart rate increase – from adagio to prestissimo – and its associations with cardiovascular risk factors. The findings underline the importance of dynamics to obtain a harmonic life, and the prognostic significance of modulating the dynamics with lifestyle interventions, including exercise training, that have beneficial effects on BMI, blood pressure, heart rate variability, fatty acid metabolism and serum glucose levels. All of which are fundamental for improved endothelial function and autonomous nerve balance. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author(s) received no financial support for the research, authorship, and/or publication of this article.