Heart rate in the assessment of cardiovascular prognosis






Aldo Pietro MAGGIONI, MD, FESC
ANMCO Research Center
Firenze, ITALY
Letizia RIVA,MD, PhD
Gloria Vassilikì
COUTSOUMBAS, MD
Cardiology Department Maggiore Hospital
Bologna, ITALY

Heart rate in the assessment of cardiovascular prognosis


by L . Riva, G. V. Coutsoumbas ,
and A. P. Maggioni ,
Italy



Observational studies have shown that resting heart rate (HR) is an independent predictor of cardiovascular and all-cause mortality. In patients with heart failure, there are benefits to pharmacologically reducing HR. It seems desirable to maintain HR in the “normal” range, below the traditionally defined tachycardia threshold of 90 or 100 beats per minute (bpm). In coronary patients, including those treated with percutaneous coronary intervention, a HR greater than or equal to 70 bpm increases cardiovascular risk; and in patients affected by heart failure, a HR lower than 60 bpm is associated with fewer cardiovascular events than are higher HRs. Resting HR would be a particularly useful measure to include in risk models because it is extremely easy to apply and has no associated costs. For this reason, and its strong correlation with both in-hospital mortality and mortality in the subsequent follow-up period, HR is already included in a number of risk assessment models for acute coronary syndrome.

Medicographia. 2012;34:414-420 (see French abstract on page 420)



Heart rate (HR) is a major determinant of myocardial oxygen demand, coronary blood flow, and myocardial performance, and affects nearly all stages of cardiovascular disease.

It has been postulated that reducing HR might prolong life, but, until now, this effect has not been demonstrated.1 However, in the past two decades, there has been growing evidence that resting HR might be a marker of risk or even a risk factor for cardiovascular morbidity and mortality. The importance of resting HR as a prognostic factor or as potential therapeutic target is not yet generally accepted. Recent large epidemiological studies have confirmed earlier studies that showed resting HR to be an independent predictor of cardiovascular and all-cause mortality, with a global estimation of 30% to 50% mortality excess for every 20 beats per minute (bpm) increase at rest. Studies have found a continuous increase in risk with HR above 60 bpm. A considerable number of epidemiological studies have reported a strong association between HR and cardiovascular risk, and this association appears to be independent of other major risk factors for atherosclerosis.2 This relationship has been consistent and was observed in healthy populations among men and women, various races, hypertensive subjects, patients with coronary artery disease (CAD), and in those with heart failure. This increasing evidence suggests that HR does not merely predict outcome, but that elevated HR may be a true cardiovascular risk factor.



Figure 1. Pathophysiological mechanisms promoted by increased heart rate.

After reference 10: Malcolm et al. Can J Cardiol. 2008;24(suppl A): 3A-8A. © 2008, Pulsus Group Inc.



In clinical practice, risk models may be useful for patient risk stratification and treatment decisions. Resting HR would be a particularly useful measure to include in risk models because it is extremely easy to apply and has no associated costs.

HR, when adjusted for age, is higher in women than in men (approximately 2-7 bpm)3 and has been reported to decrease with age (around 1 beat/min over 8 years).4 It has a clear circadian rhythm and is substantially higher during waking hours, varying relatively little between 10 AM and 6 PM.5 HR is affected by posture, and is approximately 3 bpm higher in the sitting position than in the supine position.6 Resting HR varies widely, but there does seem to be a pattern of distribution within the population, albeit not a normal distribution: Palatini et al have shown a mixture of two subpopulations, the first with a “normal” mean resting HR and the second with a “high” mean resting HR.7 The segregation value between the subgroups varied between 75 and 85 bpm. The previous epidemiological data suggest that it is desirable to keep HR within the “normal” rather than the “high” range, and more specifically, to maintain resting HR substantially below the tachycardia threshold of 90 or 100 bpm.




Pathophysiological mechanisms linking elevated HR and cardiovascular disease

Increased HR, due to imbalances of the autonomic nervous system with increased sympathetic activity or reduced vagal tone, has an impact on perfusion-contraction matching, which is the dynamic that regulates myocardial blood supply and function. An increase in HR results not only in an increase in myocardial oxygen demands, but also in a potential impairment of oxygen supply resulting from a reduction in collateral perfusion pressure.8 The imbalance may promote ischemia, arrhythmias, and ventricular dysfunction, as well as acute coronary syndromes (ACS), heart failure, and sudden death. With increased HR, the diastolic perfusion time lessens while myocardial oxygen demand increases. Peak coronary flow increases markedly during diastole, subjecting the coronary arteries to enhanced endothelial shear stress and pulsatile wall stress. The stressed endothelium releases growth hormones and vasoconstrictor peptides, while rapid pulsatile changes are associated with increased mechanical damage on the already stressed endothelium. All these factors encourage the development of atherosclerotic lesions (Figure 1).9,10


Figure 2
Figure 2. Independent predictors of 30-day mortality after STEMI in TIMI risk score.

Abbreviations: BP, blood pressure; CI, confidence interval; LBBB, left bundle branch block; MI, myocardial infarction; OR, odds ratio; STEMI, STsegment–elevation
myocardial infarction; TIMI, Thrombolysis In Myocardial Infarction.
After reference 13: Morrow et al. Circulation. 2000;102: 2031-2037. © 2000, American Heart Association, Inc.


Epidemiological association between HR and cardiovascular morbidity/mortality

Observational studies have shown an elevated resting HR to be associated with future development of cardiovascular disease, but all data on the possible importance of HR are retrospective and a demonstration of the benefits of reducing HR pharmacologically is limited to patients with myocardial infarction or heart failure. HR is already included in many models of risk assessment in patients affected by CAD—including those treated with percutaneous coronary intervention (PCI)— or heart failure.

_ Increased HR and CAD
_ HR and angina pectoris
HR reduction is helpful in preventing angina, and there is some evidence that it may improve coronary endothelial function and atherosclerosis. To assess whether a lower HR is also associated with a more favorable prognosis in patients with CAD, an analysis was performed in 24 913 patients with suspected or proven CAD from the Coronary Artery Surgery Study (CASS) registry followed for a median time period of 14.7 years.11 In this study, patients with resting HR between 77 and 82 bpm had a significantly higher risk of total mortality (hazard ratio 1.16), and this association was even stronger in patients with a resting HR ≥83 bpm (hazard ratio 1.32). The association between HR and total mortality held true in all analyzed subgroups. A high resting HR was also an independent predictor of time to first rehospitalization due to angina and congestive heart failure. Interestingly, the multivariable models were adjusted for the use of β-blockers and this confirmed resting HR as an independent predictor of overall and cardiovascular mortality.

_ HR and acute risk stratification in ACS
Considerable variability in mortality risk exists among patients with acute coronary syndromes (ACS). Individual patients reflect a combination of clinical features that influence prognosis, and these factors must be appropriately weighted to produce an accurate assessment of risk.

In the thrombolytic era, a number of studies were performed to define prognosis in ST-segment–elevation myocardial infarction (STEMI), initially developing sophisticated multivariable models not readily applied in routine clinical practice, and later proposing more convenient bedside clinical risk scores. A multivariable analysis from GUSTO-I (Global Utilization of Streptokinase and t-PA for Occluded coronary arteries; a randomized trial of four thrombolytic strategies in 41 021 patients with STEMI) identified a large number of independent clinical predictors correlated with prognosis (30-day mortality), five of which contain most of the prognostic information: age, lower systolic blood pressure, higher Killip class, elevated HR, and anterior infarction.12 Similarly, a subsequent study derived from logistic regression analysis of the In TIME-II database (Intravenous nPA for Treatment of Infarcting Myocardium Early II trial, in which 15 078 patients with STEMI were randomized to two different thrombolytic strategies within 6 hours of symptom onset) identified 10 baseline variables that were independent predictors of 30-day all-cause mortality, accounting for 97% of the predictive capacity of the multivariate model (Figure 2).13 Based on these data, the Thrombolysis In Myocardial Infarction (TIMI) risk score was assessed, calculated from the simple arithmetic sum of point values assigned to each risk factor based on the multivariate-adjusted risk relationship (1 point for odds ratios [ORs] from 1.0 to <2.0; 2 points for ORs >2.0 to 2.5; 3 points for ORs >2.5). This score system was validated for the prediction of 30-day all-cause mortality in an external population of patients treated with fibrinolytics for STEMI, derived from the TIMI 9 A/B trial. In this model, HRs >100 bpm (OR 2.3 [1.9-2.8] at the multivariate analysis) received 2 points, as did Killip classes II-IV and ages 65-74 years.

In order to further simplify the prognostic risk stratification in the acute phase of STEMI, a simple risk index—the TIMI risk index—based only on age and vital signs, was derived from the In TIME-II trial.14 The TIMI risk index was calculated using the equation: (HR x [age/10]2 / systolic blood pressure) and when tested in the real world (153 486 patients with STEMI from the National Registry of Myocardial Infarction [NRMI] 3 and 4) revealed a significant graded relationship with all-cause mortality at 24 hours, hospital discharge, and 30 days. Also, the evaluation of the individual components of the TIMI risk index, using a logistic regression model, showed similar associations with mortality in the In TIME-II trial and in NRMI-2 and -3, further supporting the assertion that these variables are useful alone or in combination for risk stratification in a general population with STEMI. In this analysis, each HR increase of 10 bpm significantly raised the mortality risk, with an OR of 1.3 in In-TIME-II and 1.2 in NRMI (Table I).


Table I
Table I. Odds ratios for mortality and discriminative capacity (C
statistic) for individual components of the TIMI risk index.

Abbreviations: BP, blood pressure; HR, heart rate; NRMI, National Registry of
Myocardial Infarction; OR, odds ratio; InTIME-II, Intravenous nPA for Treatment
of Infarcting Myocardium Early II (trial); TIMI, Thrombolysis In Myocardial Infarction;
U, units.
After reference 14: Wiviott et al. J Am Coll Cardiol. 2004;44:783-789. © 2004,
American College of Cardiology Foundation.



With the increasing adoption of primary PCI as the preferable method for achieving reperfusion, risk scores based on primary PCI trials were developed and validated. The Primary Angioplasty in Myocardial Infarction (PAMI) score, developed from 3252 PCI-treated patients enrolled in the various PAMI trials, is based on only 5 clinical and electrocardiographic characteristics—similarly to the TIMI risk score (age, Killip >1, HR >100 bpm, diabetes mellitus, and anterior STEMI or new left branch bundle block)—which are strictly associated with 30-day and 1-year all-cause mortality.15 With the exception of age, all components of this score had the same statistical weight (2 points) (Table II).


Table II
Table II. Components of PAMI risk score.

Abbreviations: PAMI, Primary Angioplasty in Myocardial Infarction; STEMI,
ST-segment–elevation myocardial infarction.
After reference 15: Addala et al. Am J Cardiol. 2004;93:629-632. © 2004,
Excerpta Medica, Inc.



A new model to determine the risk of 90-day mortality in patients undergoing primary PCI was derived from the analysis of APEX AMI (Assessment of Pexelizumab in Acute Myocardial Infarction trial), which enrolled 5745 patients with STEMI undergoing primary PCI within 6 hours of symptom onset.16 Of the variables assessed at the time of presentation that were independently predictive of 90-day mortality, the 7 most significantly associated with prognosis were incorporated in the final model: older age (hazard ratio 2.03 per increments of 10 years), lower systolic blood pressure (hazard ratio 0.86 per increments of 10 mm Hg), higher Killip class (hazard ratio 4.28 per Killip 3-4), higher HR (hazard ratio 1.45; HR >70 to <110 bpm per increments of 10 bpm), baseline total ST deviations (hazard ratio 1.25 per increments of 10 mm), serum creatinine higher than 90 mol/L (hazard ratio 1.23 per increments of 10 mol/L), and anterior location of myocardial infarction (hazard ratio 1.47). It is remarkable that even though the reperfusion method is different and more effective, many of the most important predictors in STEMI remained the same, and, in particular, elevated HR was confirmed to have an independent inverse correlation with prognosis. A general score applicable to all ACS (ST-elevated or not) was determined by the analysis of the large multinational, observational, Global Registry of Acute Coronary Events (GRACE) (43 810 patients presenting with ACS with or without ST-segment elevation) with two primary end points: all-cause death and the composite outcome measure of death or nonfatal myocardial infarction during admission to hospital or within 6 months from discharge.17 The GRACE risk score includes 8 variables (age, HR, systolic blood pressure, Killip class, initial serum creatinine concentration, elevated initial cardiac markers, cardiac arrest on admission, and ST-segment deviation) containing most (>90%) of the predictive information. This model was externally validated using the GUSTO IIb dataset including 12 142 patients with ACS, confirming its excellent discrimination power. In GRACE, the hazard ratio for death in association with HR was 1.2 (1.16-1.31) per incremental increase of 30 bpm during the period from hospital admission to the 6-month follow-up assessment.

In conclusion, HR measured at presentation has confirmed prognostic value in the ACS setting and is predictive of inhospital mortality and mortality during follow-up.

_ HR and subsequent risk stratification in ACS
HR retains its prognostic value even when measured after the acute phase of ACS. An analysis of the GISSI-Prevenzione study (Gruppo Italiano per lo Studio della Streptochinasi nell’ Infarto miocardico – Prevenzione; including 11 324 patients recruited within 3 months of myocardial infarction and followed up for 4 years) identified major determinants of prognosis.18 Among other determinants, a HR >75 bpm was significantly associated with worse prognosis when compared with lower HRs (relative risk for HR >75 bpm in males, 1.32; in females, 1.52). Lower HR (64 bpm in males and 69 bpm in females) was associated with lower risk.

This study proved the existence of a strong correlation between HR and prognosis in ACS acute phase or in the short term, and showed that this correlation remains strong in the longer term—after years—as well.

_ Increased HR and heart failure
Elevated resting HR is one of the key findings in acute and chronic heart failure. The association of HR with mortality was retrospectively addressed in the subanalyses of CIBIS-II (Cardiac Insufficiency BIsoprolol Study II),19 MERIT-HF (MEtoprolol CR/XL Randomised Intervention Trial in-congestive Heart Failure),20 and the COMET trial (Carvedilol Or Metoprolol European Trial).21 The general trend of these three trials clearly demonstrated that high resting HR contributed to poor survival in patients with advanced systolic heart failure. However, it was unknown whether, or to what extent, the benefit from β-blockers in patients with heart failure is attributable to HR reduction per se or to other beneficial effects, such as protection of the myocardium from the effects of prolonged exposure to high levels of circulating catecholamines or improved β-receptor function.

In the SHIFT trial (Systolic Heart failure treatment with the If inhibitor ivabradine Trial), the effect of pure HR reduction by ivabradine was evaluated in addition to guideline-based treatment on cardiovascular outcomes, symptoms, and quality of life in patients with systolic heart failure (left ventricular ejection fraction ≤35%). Similarly to the β-blocker trials, treatment with ivabradine was associated with an average reduction in HR of nearly 15 bpm from a baseline value of 80 bpm, which was associated with an 18% risk reduction for the primary composite end point: cardiovascular death or hospital admission for worsening heart failure.22 Therefore, SHIFT demonstrated for the first time the beneficial effects of HR reduction alone in patients with systolic heart failure. Previously, in the BEAUTIFUL study (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction), no overall benefit of ivabradine vs placebo was demonstrated in patients with stable coronary heart disease and left ventricular systolic dysfunction;23 however, in the prespecified subgroup with a baseline HR ≥70 bpm, there was a significant reduction in the secondary end point of hospital admission for acute myocardial infarction or unstable angina and coronary revascularization.24

Several existing predictive models for long-term mortality in heart failure include more than 20 variables, some of which are not frequently assessed in clinical practice for heart failure.25,26 The American Heart Association Get With the Guidelines– Heart Failure (GWTG-HF) risk score reliably predicts inhospital mortality of patients with preserved or impaired left ventricular systolic function using 7 clinical factors routinely collected at the time of admission.27 Older age, low systolic blood pressure, elevated HR, low serum sodium, elevated blood urea nitrogen, presence of chronic obstructive pulmonary disease (COPD), and nonblack race predicted an increased risk of death. This model is widely applicable because it includes a relatively small number of variables routinely assessed at the time of patient hospital admission. The application of this risk score could influence the type and quality of care provided to patients hospitalized with heart failure by guiding clinical decision- making. Nevertheless, in the GWTG-HF risk score, age, systolic blood pressure, and blood urea nitrogen contributed most substantially to the overall point score, whereas HR, presence of COPD, serum sodium, and nonblack race contributed relatively few points to the overall score.

_ Increased HR and hypertension
Several studies have demonstrated that individuals with high HR have increased blood pressure readings28 and that this association is stronger in subjects with elevated sympathetic activity.29 This phenomenon may be due to hypertension and tachycardia having a common denominator: increased sympathetic tone. Thus, it is crucial to know whether HR also has independent predictive power for cardiovascular mortality in hypertensive individuals. Much less is known about the association of HR and mortality in hypertensive patients as only three studies have examined this relationship in such a population30,31,32 and only one study in elderly subjects with isolated systolic hypertension.33 In the Framingham Study, it was found that for an increment of 40 bpm there was a 118% and 114% increased age- and systolic BP–adjusted OR in men and women, respectively, for total mortality, and a 68% and 70% increased risk, respectively, for cardiovascular mortality.30 In the Syst-Eur study (Systolic Hypertension in Europe), performed in elderly patients with systolic hypertension, patients with a HR higher than 79 bpm had an 89% greater risk of mortality than those with a HR ≤79 bpm.33

On the other hand, data derived from HARVEST (Hypertension and Ambulatory Recording VEnetia STudy) demonstrated that baseline resting HR and changes in HR in the first few months of follow-up were able to predict the development of sustained hypertension in white, younger subjects evaluated for stage 1 hypertension.34

Even if all data on the possible relevance of HR lowering in hypertensive patients are retrospective, it is reasonable that patient outcome may be improved with drugs that reduce both blood pressure and HR. On the basis of the epidemiological data, for a 10%-12% reduction in HR, a 20%-40% decrease in cardiovascular morbidity–mortality should be expected.35

_ Increased HR and diabetes mellitus
There are few data specifically exploring the relationship between resting HR and cardiovascular outcome in patients with diabetes mellitus. However, the association between HR, glucose, and insulin levels is strong. In addition, diabetes is commonly associated with abnormal function of the autonomic nervous system, the main regulator of resting HR. In the Swiss cohort of the World Health Organization Multinational Study of Vascular Disease in Diabetes, a relationship between resting HR and both all-cause and cardiovascular mortality was reported in patients affected by type 2 diabetes mellitus. Interestingly, a similar relationship was not observed in patients with type 1 diabetes mellitus.36 Recently, the Euro Heart Survey investigators reported that, in diabetic patients, a higher resting HR was associated with an increased risk in all-cause mortality.37 In the ADVANCE study (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation), a higher resting HR was associated with a significantly increased risk in all-cause mortality, cardiovascular death, and major cardiovascular outcomes. The increased risk associated with a higher baseline resting HR was more obvious in patients with previous macrovascular complications. Moreover, the relationship between HR and metabolic derangement has been reinforced by data derived from the Chicago Heart Association Detection Project: in middle-aged patients, the adjusted risk of developing diabetes increased by 10% for each 12-bpm increment in baseline HR in patients older than 65 years.38 It remains unclear whether a higher HR directly mediates increased risk or whether it is a marker for other factors that determine a poor outcome.39

Conclusion

There is consistent evidence that resting HR is able to predict life expectancy and is an independent predictor of morbidity and mortality in healthy subjects. Furthermore, resting HR is a predictor of death in both stable CAD and ACS. Elevated resting HR is also able to independently predict clinical outcomes in patients with heart failure. In spite of the large body of evidence on the evaluation of cardiovascular risk, little attention has been paid to the role of HR in cardiovascular risk assessment in daily practice, even if this is a simple and easily measurable clinical parameter that can be utilized with no additional cost.40

Recent evidence supports the concept that increased resting HR is an independent cardiovascular risk factor. A HR ≥70 bpm increases cardiovascular risk and this measurement should be used to guide therapy in coronary patients. HR is also an important target for the treatment of heart failure. Specifically, patients affected by heart failure with HRs lower than 60 bpm have fewer cardiovascular events than patients with higher HRs. For all these reasons and the strong correlation with both in-hospital and long-term mortality, HR has already been included in many models of ACS risk assessment. _

References

1. Orso F, Baldasseroni S, Maggioni AP. Heart rate in coronary syndromes and heart failure. Prog Cardiovasc Dis. 2009;52:38-45.
2. Palatini P, Julius S. Elevated heart rate: a major risk factor for cardiovascular disease. Clin Exp Hypertens. 2004;26:637-644.
3. Palatini P, Benetos A, Julius S. Impact of increased heart rate on clinical outcomes in hypertension: implications for antihypertensive drug therapy. Drugs. 2006;66:133-144.
4. Bonnemeier H, Wiegand UK, Brandes A, et al. Circadian profile of cardiac autonomic nervousmodulation in healthy subjects: differing effects of aging and gender on heart rate variability. J Cardiovasc Electrophysiol. 2003;14:791-799.
5. Nakagawa M, Iwao T, Ishida S, et al. Circadian rhythm of the signal averaged electrocardiogram and its relation to heart rate variability in healthy subjects. Heart. 1998;79:493-496.
6. Kristal-Boneh E, Harari G, Weinstein Y, et al. Factors affecting differences in supine, sitting, and standing heart rate: the Israeli CORDIS study. Aviat Space Environ Med. 1995;66:775-779.
7. Palatini P, Casiglia E, Pauletto P, et al. Relationship of tachycardia with high blood pressure and metabolic abnormalities: a study with mixture analysis in three populations. Hypertension. 1997;30:1267-1273.
8. Heusch G, Schulz R. The role of heart rate and the benefits of heart rate reduction in acute myocardial ischaemia. Eur Heart J Suppl. 2007;9(suppl F): F8-F14.
9. Kjekshus J, Gullestad L. Heart rate as a therapeutic target in heart failure. Eur Heart J. 1999;1(suppl H):H64-H69.
10. Malcolm AJ, Fitchett DH, Howlett JG, Lonn EM, Tardif JC. Resting heart rate: A modifiable prognostic indicator of cardiovascular risk and outcomes? Can J Cardiol. 2008;24(suppl A):3A-8A.
11. Diaz A, Bourassa MG, Guertin MC, Tardif JC. Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. European Heart Journal. 2005;26:967-974.
12. Lee KL, Woodlief LH, Topol EJ. Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction. Results from an international trial of 41,021 patients. GUSTO-I Investigators. Circulation. 1995;91:1659-1668.
13. Morrow DA, Antman EM, Charlesworth A, et al. TIMI Risk Score for ST-Elevation Myocardial Infarction: A Convenient, Bedside, Clinical Score for Risk Assessment at Presentation An Intravenous nPA for Treatment of Infarcting Myocardium Early II Trial Substudy. Circulation. 2000;102:2031-2037.
14. Wiviott SD, Morrow DA, Frederick PD, et al. Performance of the Thrombolysis In Myocardial Infarction risk index in the National Registry of Myocardial Infarction- 3 and -4. A simple index that predicts mortality in ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2004;44:783-789.
15. Addala S, Grines CL, Dixon SR. Predicting mortality in patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention (PAMI risk score). Am J Cardiol. 2004;93:629-632.
16. Stebbins A, Mehta RH, Armstrong PW, et al. A model for predicting mortality in acute ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention results from the Assessment of Pexelizumab in Acute Myocardial Infarction Trial. Circ Cardiovasc Interv. 2010;3:414-422.
17. Fox KA, Dabbous OH, Goldberg RJ, et al. Prediction of risk of death and myocardial infarction in the six months after presentation with acute coronary syndrome: prospective multinational observational study (GRACE). BMJ. 2006; 333:1091-1096.
18. Marchioli R, Avanzini F, Barzi F, et al. Assessment of absolute risk of death after myocardial infarction by use of multiple-risk-factor assessment equations. GISSIPrevenzione mortality risk chart. Eur Heart J. 2001;22:2085-2103.
19. Lechat P, Hulot JS, Escolano S, et al. Heart rate and cardiac rhythm relationships with bisoprolol benefit in chronic heart failure in CIBIS II trial. Circulation. 2001;103:1428-1433.
20. Gullestad L, Wikstrand J, Deedwania P, et al; MERIT-HF Study Group. What resting heart rate should one aim for when treating patients with heart failure with a beta-blocker? Experiences from the Metoprolol Controlled Release/Extended Release Randomized Intervention Trial in Chronic Heart Failure (MERITHF). J Am Coll Cardiol. 2005;45:252-259.
21. Metra M, Torp-Pedersen C, Swedberg K, et al. Influence of heart rate, blood pressure, and beta-blocker dose on outcome and the difference in outcome between carvedilol and metoprolol tartrate in patients with chronic heart failure: results from the COMET trial. Eur Heart J. 2005;26:2259-2568.
22. Böhm M, Swedberg K, Komajda M, et al. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomized placebo-controlled trial. Lancet. 2010;376:886-894.
23. Fox K, Ford I, Steg PG, et al; BEAUTIFUL Investigators. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:807-816.
24. Fox K, Ford I, Steg PG, et al; BEAUTIFUL Investigators. Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Lancet. 2008;372:817-821.
25. Pocock SJ, Wang D, Pfeffer MA, et al. Predictors of mortality and morbidity in patients with chronic heart failure. Eur Heart J. 2006;27:65-75.
26. Levy WC, Mozaffarian D, Linker DT, et al. The Seattle Heart Failure Model: prediction of survival in heart failure. Circulation. 2006;113:1424-1433.
27. Peterson PN, Rumsfeld JS, Liang L, et al; American Heart Association GetWith the Guidelines-Heart Failure Program. A validated risk score for in-hospital mortality in patients with heart failure from the American Heart Association Get With the Guidelines Program. Circ Cardiovasc Qual Outcomes. 2010;3:25-32.
28. Palatini P, Julius S. Review article: heart rate and the cardiovascular risk. J Hypertens. 1997;15:3-17.
29. Narkiewicz K, Somers VK. Interactive effect of heart rate and muscle sympathetic nerve activity on blood pressure. Circulation. 1999;100:2514-2518.
30. Gillmann MW, Kannel WB, Belanger A, et al. Influence of heart rate on mortality among persons with hypertension: The Framingham Study. Am Heart J. 1993; 125:1148-1154.
31. Thomas F, Bean K, Provost JC, et al. Combined effects of heart rate and pulse pressure on cardiovascular mortality according to age. J Hypertens. 2001;19: 863-869.
32. Thomas F, Rudnichi A, Bacri AM, et al. Cardiovascular mortality in hypertensive men according to presence of associated risk factors. Hypertension. 2001;37: 1256-1261.
33. Palatini P, Thijs L, Staessen JA, et al. Predictive value of clinic and ambulatory heart rate for mortality in elderly subjects with systolic hypertension. Arch Intern Med. 2002;162:2313-2321.
34. Palatini P, Dorigatti F, Zaetta V, et al. Heart rate as a predictor of development of sustained hypertension in subjects screened for stage 1 hypertension: the HARVEST study. J Hypertension. 2006;24:1873-1880.
35. Palatini P, Benetos A, Grassi G, et al; European Society of Hypertension. Identification and management of the hypertensive patient with elevated heart rate: statement of a European Society of Hypertension Consensus Meeting. J Hypertens. 2006;24:603-610.
36. Stettler C, Bearth A, Allemann S, et al. QTc interval and resting heart rate as long-term predictors of mortality in type 1 and type 2 diabetes mellitus: a 23- year follow-up. Diabetologia. 2007;50:186-194.
37. Anselmino M, Ohrvik J, Ryden L. Resting heart rate in patients with stable coronary artery disease and diabetes: a report from the Euro Heart Survey on diabetes and the heart. Eur Heart J. 2010;31:3040-3045.
38. Carnethon MR, Yan L, Greenland P, et al. Resting heart rate in middle age and diabetes development in older age. Diabetes Care. 2008;31:335-339.
39. Hillis GS,Woodward M, Rodgers A, et al. Resting heart rate and the risk of death and cardiovascular complications in patients with type 2 diabetes mellitus. Diabetologia. 2012;55(5):1283-1290.
40. Tardif JC. Heart rate as a treatable cardiovascular risk factor. Br Med Bull. 2009; 90:71-84.


Keywords: cardiovascular disease; cardiovascular prognosis; heart rate; risk factor