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• W2153584953 abstract "HomeHypertensionVol. 58, No. 5Role of Elevated Heart Rate in the Development of Cardiovascular Disease in Hypertension Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessReview ArticlePDF/EPUBRole of Elevated Heart Rate in the Development of Cardiovascular Disease in Hypertension Paolo Palatini Paolo PalatiniPaolo Palatini From the Department of Clinical and Experimental Medicine, University of Padova, Padua, Italy. Search for more papers by this author Originally published6 Sep 2011https://doi.org/10.1161/HYPERTENSIONAHA.111.173104Hypertension. 2011;58:745–750Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2011: Previous Version 1 IntroductionThat 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 DiabetesNumerous studies have demonstrated that tachycardia is frequently associated with hypertension in both sexes and that this relationship is present at all ages and all BP levels.1,10 This association remains significant even after taking into account several confounding factors, such as body mass index (BMI), age, and metabolic parameters. HR has also emerged as a risk factor for future development of hypertension. The first study to demonstrate a longitudinal relationship between HR and BP dates back to 1945, when an American army doctor11 observed that transient tachycardia detected during routine examination could predict the development of stable hypertension later in life. The predictive power of HR for the development of hypertension has been confirmed in numerous other studies. In a Japanese cohort, normotensive men and women with an HR in the upper quartile had a 60% higher 3-year risk of developing hypertension than persons in the bottom quartile.12 This longitudinal association has been demonstrated not only for baseline HR but also for the change in HR over time. In the HARVEST study, both baseline and follow-up HRs were potent predictors of subsequent development of hypertension needing drug therapy.5 In many cross-sectional analyses, high HR was found to be associated with increased BMI, higher glucose and lipid abnormalities, and was considered as a key component of the metabolic syndrome.10 However, it was unclear whether higher HR in metabolic syndrome was a cause, consequence, or simply an epiphenomenon. The results of 2 recent longitudinal analyses have shown that elevated HR may predispose to the development of obesity and diabetes mellitus.13,14 In the Chicago study, higher resting HR was prospectively associated with diabetes claims in older age, and this association was only due in part to BMI and concurrently measured glucose.15 In the Atherosclerosis Risk in Communities Study (ARIC), higher HR and lower HR variability were both associated with an increased likelihood of developing diabetes over 9 years of follow-up, even when concurrent BMI and physical activity levels were taken into account.16 Thus, measurement of HR can be of help for identifying subjects who are most likely to develop hypertension, obesity, the metabolic syndrome, and diabetes.The longitudinal association between increased HR, obesity, and metabolic abnormalities probably reflects persistent sympathetic stimulation.1,9,13,14 In longitudinal studies, it has been demonstrated that plasma noradrenaline concentrations predict both future BP elevation and weight gain in lean normotensives.17 Previous results from our laboratory showed that a sympathovagal balance in favor of sympathetic activity against a background of reduced HR variability promotes an increase in BMI, BP, and total cholesterol, leading to increased susceptibility to vascular complications early in life.18 Downregulation of adrenoceptor-mediated thermogenic responses may be the mechanism by which longstanding sympathetic overactivity may favor weight gain in subjects with elevated sympathetic tone.19 In a previous study, we demonstrated that both plasma and urinary noradrenaline negatively correlated with HR response to isoproterenol bolus and with systolic BP and energy expenditure responsiveness to isoproterenol infusion.20 The thermogenic effect of sympathetic activity represents a physiological compensatory mechanism against weight gain. This thermogenic effect is exerted through norepinephrine release with stimulation of all 3 β-adrenoceptor subtypes, and an impairment of this mechanism may be important in promoting and maintaining excess body weight.19 The experimental evidence for the linkage between increased sympathetic tone and insulin resistance was provided by numerous studies. Epinephrine infusion induces acute insulin resistance in healthy volunteers, and this can be blocked by propranolol.21 In animals chronically infused with epinephrine, a shift in skeletal muscle fibers was observed, with an increase in rapidly contracting fibers, which is associated with insulin resistance.22 Vasoconstriction produced by α-adrenergic stimulation also induces insulin resistance. This has been observed in studies conducted by Jamerson et al23 on the forearm with infusion of insulin into the brachial artery and determination of glucose utilization. In this model, central sympathetic activation elicited by thigh-cuff inflation was able to decrease glucose utilization in the forearm. This points to a specific role of vasoconstriction induced by sympathetic overactivity in determining insulin resistance, probably diverting capillary blood flow away from nutritional beds.HR as a Determinant of Target Organ DamageIn the International Survey Evaluating Microalbuminuria Routinely by Cardiologists in Patients with Hypertension (I-SEARCH), investigating 21 050 patients with high-risk hypertension, elevated HR was an independent predictor of microalbuminuria.24 In a Japanese study, subjects with a higher HR had higher frequencies of proteinuria, although they were all normotensive, indicating that subjects with elevated HR are likely to have early-stage vascular damage, even if they are normotensive.25 In hypertensive patients assessed with 24-hour ambulatory monitoring, Facila et al26 showed that patients with nocturnal HR ≥65 bpm (41.3%) had a higher prevalence of target organ damage compared with those with HR <65 bpm. HR was also shown to be a main determinant of arterial stiffness. Benetos et al,27 in a 6-year longitudinal study, found that increased HR was one of the most powerful predictors of accelerated progression in pulse-wave velocity. Interestingly, the greatest influence of HR on the acceleration of arterial stiffness was observed in the hypertensive segment of the population. In a recent report, Tomiyama et al28 found that both HR at the baseline examination and changes in HR during the follow-up period were significantly associated with the corresponding changes in pulse-wave velocity during a 5-year follow-up. These relationships held true also after adjustment for a variety of atherogenic risk factors. In keeping with the above data, in a group of young to middle-aged subjects with stage 1 hypertension, Saladini et al29 found that high baseline HR and increase in HR over time were independent determinants of evolution of arterial stiffness.HR as a Cardiovascular Risk Factor in General PopulationsA review of the literature showed that 33 articles had been published on the prognostic significance of elevated HR for cardiovascular and/or all-cause mortality in general populations. All but 1 article reported a significant association between all-cause mortality and fast HR in men or women.1 After adjustment for confounders, 3 other studies failed to reach the level of statistical significance for cardiovascular mortality.1 However, in a more recent analysis of the Chicago Heart Association Project Cohort, a significant relationship between HR and cardiovascular mortality was found for men and women 40 to 59 years of age, independent of other risk factors.30 Likewise, a longer follow-up of the Paris Prospective Study showed an independent association of HR with sudden death and fatal myocardial infarction after adjustment for many confounders.31 In all the other studies performed in subjects free of disease, the association of HR with total and/or cardiovascular mortality remained significant after adjustment for traditional risk factors for atherosclerosis and other possible confounders. It should be pointed out that in some of those studies the predictive power of HR for mortality was higher than that of cholesterol and/or BP.1HR as a Cardiovascular Risk Factor in HypertensionA systematic review of the literature identified 12 articles encompassing 11 studies on the association between HR and mortality in hypertension4,32–42 (see the online Data Supplement, available at http://hyper.ahajournals.org). Details of the 11 studies are shown on Table S1 (please see http://hyper.ahajournals.org). The size of these studies varied from 2293 to 60 343 patients (overall number, 184 157 patients), with duration of follow-ups from 2.5 to 36 years. Mean patient age ranged from 51 to 70.2 years and was >65 years in 5 studies. The percentage of men ranged from 33% to 77% in 10 studies and was 100% in 1 study. One cohort study enrolled subjects with prehypertension and 4 cohort studies recruited subjects with hypertension. The 6 clinical trials were performed in elderly patients with systolic hypertension (n=1), patients with hypertension associated with coronary artery disease (CAD, n=1) or left ventricular hypertrophy (n=1), and patients with high-risk hypertension (n=3). In the individuals with prehypertension from the ARIC study,32 subjects with HR ≥80 bpm had 50% higher all-cause mortality than people with lower resting HR, which was essentially unchanged after controlling for several confounders and other risk factors. In the Framingham Study,4 the relative risk of cardiovascular death adjusted for age and BP was 1.68 among men and 1.70 among women, for an increase in HR of 40 bpm. The relationship of HR with all-cause mortality rate was even stronger, with >100% increase in the adjusted relative risk. In the placebo arm of the Systolic Hypertension in Europe (Syst-Eur) trial,35 patients with HR >79 bpm had a 1.89 times greater risk of all-cause mortality and a 1.60 greater risk of cardiovascular mortality than subjects with HR below that level. In the INternational VErapamil-SR/trandolapril STudy (INVEST) study36 in patients with hypertension and CAD treated with either verapamil or atenolol, a 5-bpm increment in resting HR was associated with a 6% excess risk in adverse outcome (all-cause death, nonfatal myocardial infarction, or nonfatal stroke). The HR-mortality association was not linear for follow-up HR, as a tendency to an upturn in mortality was observed for the low HRs with a nadir at 59 bpm. In the LIFE study in hypertensive patients with ECG left ventricular hypertrophy treated with losartan- or atenolol-based regimens,37 a 10 bpm higher HR was associated with a 25% increased risk of cardiovascular death and a 27% greater risk of all-cause mortality. Persistence or development of a HR ≥84 bpm during the follow-up was associated with an 89% greater risk of cardiovascular death and a 97% increased risk of all-cause mortality. Interestingly, there was a significant interaction between in-trial HR and baseline HR. For a 10 bpm higher in-trial HR, there was a 44% increase in risk of cardiovascular death in patients with a baseline HR ≥84 as opposed to only a 12% increase in risk in patients with a baseline HR <84 bpm. In the Glasgow Blood Pressure Clinic Study,38 hypertensive patients with persistently elevated HR (>80 bpm) had an increased risk of all-cause and cardiovascular mortality. The highest risk of all-cause mortality was associated with a final HR of 81 to 90 bpm, and the lowest risk was associated with a final HR of 61 to 70 bpm. In the ASCOT-BPLA study, baseline HR predicted all-cause, noncardiovascular, and cardiovascular mortality that occurred during the follow-up but not nonfatal cardiovascular events.39 However, follow-up accumulated mean levels of HR were better predictors of cardiovascular events than baseline HR.40 Similar results were obtained in a recent analysis of the VALUE study,41 in hypertensive patients treated with either valsartan- or amlodipine-based therapy. Both baseline and in-trial HRs >79 bpm were powerful predictors of the composite cardiovascular outcome after adjustment for other risk factors. In ONTARGET and TRANSCEND, the risk of cardiovascular death increased by 41% to 58% (depending on the risk-adjusted model used) among the patients with HR ≥70 bpm and by 77% in those with HR >78 bpm.42 In conclusion, across the 10 studies that reported data for all-cause death4,33,34,36–43 and the 9 studies that reported data for cardiovascular mortality,4,33–35,37–42 HR was found to be independently associated with outcome after adjustment for comorbid risk factors as well as for cardiac-slowing drugs. In addition, a significant association between baseline or follow-up HR and CAD was observed in the 8 studies in which this information was available.4,32,33,35,38–42 However, in the study by Benetos et al,33 no HR-mortality association was found among the hypertensive women. The 6 studies that also analyzed follow-up HRs showed that follow-up HR may add prognostic information over and above HR measured at baseline.36–42 This may be due to the fact that HR recorded during follow-up is a more stable trait than baseline HR and thus may be more representative of the overall hemodynamic bulk on the arterial wall over time. At least 2 studies have shown that the increase in cardiovascular risk related to high HR is even higher in hypertensive than in normotensive subjects, suggesting that HR and BP may act synergistically in the development of cardiovascular complications.4,41 Although the above studies have shown that high HR is strongly associated with mortality, a reason for concern is that in some individuals tachycardia may be due to an underlying disease that is not yet clinically manifest, such as incipient cardiac failure or a chronic disorder, especially in elderly people. In that case, an elevated HR is an indicator of poor physical health, and the association between high HR and cardiovascular events might be explained by reverse causality. To account for this, several studies excluded patients who died within the initial years of follow-up and then repeated the survival analyses, showing that the association between high HR and risk of mortality or cardiovascular events remained robust and did not deviate substantially from that observed in the entire cohort.4,41Predictive Value of Ambulatory HRHR measured out of the office with the ambulatory measurement might be more representative of a subject's usual HR. Indeed, a study performed in 839 hypertensive subjects showed that the reproducibility of HR was better for the ambulatory than the office measurement.43 However, only a few studies examined the association between ambulatory HR and total or cardiovascular mortality. Recent results from the Ohasama study have shown that neither daytime nor nighttime HR predicted cardiovascular disease mortality, whereas both predicted noncardiovascular disease mortality.44 In a recent analysis of 6 populations, 24-hour HR predicted total and noncardiovascular mortality but not cardiovascular mortality or any of the fatal combined with nonfatal events.45 The above data are in agreement with previous results obtained in the PAMELA46 and Syst-Eur cohorts35 and indicate that HR measured with ambulatory recording is of little use for stratifying the cardiovascular risk. No conclusive explanation has yet been provided for the lack of association of ambulatory HR with cardiovascular mortality. This might be related to the different nature of HR measured for 24 hours outside the medical environment compared with clinic HR. HR measured in the office may reflect the sympathetic activation associated with the alerting reaction induced by the medical environment. Ambulatory HR is affected by a number of confounders related to the different daily life behaviors, as exemplified by the degree of physical activity habits, which may greatly differ from subject to subject. On such a background, the better relationship of clinic rather than of ambulatory HR with cardiovascular events might thus reflect its greater ability to more specifically reflect an underlying sympathetic overactivity.The β-Blocker ControversyIf HR is an important independent risk factor in hypertension, drugs that decrease BP and HR such as nondihydropyridine calcium antagonists or β-blockers might be beneficial in hypertensive patients with high HR. β-Blockers cause a marked reduction of HR and theoretically should be a first-choice treatment in these patients. However, in intervention trials the efficacy of β-blocking therapy in hypertensive subjects was lower than that predicted on an epidemiological basis.47 It should be pointed out that in some trials a considerable number of patients on β-blockers were withdrawn because of a low HR, which was a sign of effective β-blockade.48 According to a recent meta-analysis of 147 randomized trials of BP-lowering drugs, the reduction in incidence of stroke was smaller with β-blockers (17%) than with other classes of antihypertensive drugs (29%).49 However, in that analysis, 37 trials of β-blockers in patients with history of CAD were excluded, and in those 37 studies, the risk reduction of recurrent CAD events was 29% compared with 15% in trials of other antihypertensive drugs.49 A recent meta-analysis of >34 000 patients with hypertension in 9 large β-blocker trials showed that a lower HR achieved from β-blockade compared with other antihypertensives or placebo was associated with an increase in all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, and heart failure.50 In the ASCOT-BPLA dataset, the authors found no evidence that the superiority of amlodipine-based therapy over atenolol-based therapy for patients with hypertension uncomplicated by CAD was attenuated with higher baseline HR.39 This evidence led many authors to conclude that β-blockers will remain as indicated for heart failure, for after myocardial infarction, and for tachyarrhythmias but no longer for hypertension in the absence of these compelling indications. The disappointing effects of β-blockers in hypertension have been attributed to their unfavorable effects on the lipid profile and insulin sensitivity.51 The higher central BP with β-blocker–based therapy compared with a calcium entry blocker–ACE-inhibitor association, recently found in the CAFE (Conduit Artery Function Evaluation) study, is another possible cause of the unsatisfactory effect of β-blockers in noncardiac patients.52 The effect on central pressure was attributed mainly to a shift of the reflected wave into late systole due to the reduction in ejection duration at lower HRs and to the vasoconstrictor effect of β-blockers on the peripheral circulation that increases pulse-wave reflection. The results of the above study were certainly provocative. On the other hand, in the ASCOT-BPLA study there was a significant association of attained HR at 6 weeks after random assignment with myocardial infarction and fatal coronary outcome.40 This indicates that a low final achieved HR (lower on atenolol) actually had a favorable effect on cardiovascular outcomes, as it did in the INVEST study. It should be noted that the great majority of the patients enrolled in past clinical trials were prescribed atenolol,49 and it is possible that atenolol and not all β-blockers are associated with the untoward effects mentioned above. It is possible that atenolol exerts a beneficial effect on the cardiovascular system due to the HR-lowering action and a detrimental one due to its untoward effects on metabolic variables and central BP. The newer β-blockers such as carvedilol and nebivolol have a more favorable effect on the lipid profile and insulin resistance compared with older β-blockers.53 In contrast with traditional β-blockers, carvedilol was shown to decrease vascular resistance, with little effect on cardiac output.53 In addition, a neutral effect on insulin sensitivity and a decrease in central aortic pressure have been observed with vasodilatory β-blockers.53 β-Blockers might have advantages over other antihypertensive drugs in individuals with elevated HRs and activation of the sympathetic nervous system, as shown by experimental studies in monkeys.54 Unfortunately, in no clinical trial was β-blocker efficacy in preventing coronary events tested as a function of HR. Also, no data are available on long-term cardiovascular morbidity and mortality in hypertension for vasodilatory β-blockers. Controlled clinical trials performed with third-generation β-blockers may shed more light on this controversial issue. If the disappointing effects of β-blockers are mainly due to their negative hemodynamic effects, drugs that reduce HR without altering central hemodynamics should provide better results in patients with high HR. Sharman et al55 showed that the strongest predictor of central systolic BP augmentation is the duration of systolic ejection (accounting for 78% of the variance) rather than HR itself. β-Blockers decrease the HR by causing a disproportionate increase in the duration of systole that might be responsible for the augmentation of central systolic pressure.56 At variance with β-blockers, the selective HR-reducing agent ivabradine reduces HR chiefly by prolonging diastole and does not induce α-adrenergic vasoconstriction.57 These properties will have beneficial effects on the relative timing of reflected pressure waves in the proximal conduit arteries.56 In addition, the greater increase in diastolic time caused by ivabradine facilitates myocardial perfusion.56 Thus, the impact of HR reduction on outcome may depend on the means by which HR is lowered.Normalcy LimitsAs a result of the epidemiological evidence, the 2007 European Society of Hypertension/European Society of Cardiology guidelines suggested including elevated HR when assessing the cardiovascular risk profile of a hypertensive patient or a person with high-normal BP.58 However, the same guidelines still raise some doubts about the clinical utility of measuring resting HR because no precise cutoff can be offered to the practicing physician for increasing the accuracy of risk stratification. The lack of official normal values should not discourage the physician from measuring HR in hypertensive patients. For most cardiovascular risk factors, the relationship between the factor and the level of risk is a continuous one and limits of normality have been identified arbitrarily. In most epidemiological studies, the upper normal limit for resting HR was identified from the lower limit of the top HR quintile, because in this group a remarkable increase in the risk of morbidity and/or mortality was invariably observed. In most studies, this limit was between 80 and 85 bpm, and there is no doubt that a HR ≥80 to 85 bpm implies a noticeable increase in risk. Also, the results of the intervention trials in post–myocardial infarction patients or in subjects with congestive heart failure suggest that the limit of normality of HR should be set at this level.59PerspectivesToday, there is a body of evidence to suggest that tachycardia should no longer be viewed as an innocent clinical feature. Given the high prevalence of fast HR among patients with hypertension, treatment of elevated HR might have a major public health significance in this clinical setting. However, no results of clinical trials specifically designed to investigate the clinical value of cardiac slowing in hypertensive patients without cardiovascular disease are available, and, in the absence of evidence from prospective trials, no specific treatment recommendations can be made. Lifestyle changes including a program of regular aerobic exercise and the reduction of caffeine and alcohol consumption should be recommended to any hypertensive patient with elevated HR. Smoking and stimulating drugs should be avoided. Effective drugs for the treatment of elevated HR, some provided with antihypertensive effects and some with a neutral effect on BP, are available and might be of help. A final answer to whether these conceptual advantages can be translated into clinical benefit can come only from future prospective studies in hypertensive patients with tachycardia.DisclosuresNone.FootnotesCorrespondence to Paolo Palatini, Clinica Medica 4, University of Padova, Via Giustiniani, 2, 35128 Padova, Italy. E-mail [email protected]itReferences1. Palatini P, Benetos A, Grassi G, Julius S, Kjeldsen SE, Mancia G, Narkiewicz K, Parati G, Pessina AC, Ruilope LM, Zanchetti A. 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.CrossrefMedlineGoogle Scholar2. Fox K, Borer JS, Camm J, Danchin N, Ferrari R, Lopez Sendon JL, Steg PG, Tardif JC, Tavazzi L, Tendera M; the Heart Rate Working Group. Resting heart rate in cardiovascular disease. J Am Coll Cardiol. 2007; 50:823–830.CrossrefMedlineGoogle Scholar3. Cook S, Togni M, Schaub MC, Wenaweser P, Hess OM. High heart rate: a cardiovascular risk factor?Eur Heart J. 2006; 27:2387–2393.CrossrefMedlineGoogle Scholar4. Gillman MW, Kannel WB, Belanger A, D'Agostino RB. Influence of heart rate on mortality among persons with hypertension: the Framingham Study. Am Heart J. 1993; 125:1148–1154.CrossrefMedlineGoogle Scholar5. Palatini P, Dorigatti F, Zaetta V, Mormino P, Mazzer A, Bortolazzi A, D'Este D, Pegoraro F, Milani L, Mos L. Heart rate as a predictor of development of sustained hypertension in subjects screened for stage 1 hypertension: the HARVEST Study. J Hypertens. 2006; 24:1873–1880.CrossrefMedlineGoogle Scholar6. Farinaro E, Stranges S, Guglielmucci G, Iermano P, Celentano E, Cajafa A, Trevisan M. Heart rate as a risk factor in hypertensive individuals: the Italian TensioPulse Study. Nutr Metab Cardiovasc Dis. 1999; 9:196–202.MedlineGoogle Scholar7. Morcet J, Safar M, Thomas F, Guize L, Benetos A. Associations between heart rate and other risk factors in a large French population. J Hypertens. 1999; 17:1671–1676.CrossrefMedlineGoogle Scholar8. Giannoglou GD, Chatzizisis YS, Zamboulis C, Parcharidis GE, Mikhailidis DP, Louridas GE. Elevated heart rate and atherosclerosis: an overview of the pathogenetic mechanisms. Int J Cardiol. 2008; 126:302–312.CrossrefMedlineGoogle Scholar9. Custodis F, Shirmer SH, Baumhäkel M, Heusch G, Böhm M, Laufs U. Vascular pathophysiology in response to increased heart rate. J Am Coll Cardiol. 2010; 56:1973–1983.CrossrefMedlineGoogle Scholar10. Palatini P. Heart rate as a cardiovascular risk factor: do women differ from men?Ann Med. 2001; 33:213–221.CrossrefMedlineGoogle Scholar11. Levy RL, White PD, Stroud WD, Hillman CC. Transient tachycardia: prognostic significance alone and in association with transient hypertension. JAMA. 1945; 129:585–588.CrossrefGoogle Scholar12. Inoue T, Iseki K, Iseki C, Kinjo K, Ohya Y, Takishita S. Higher heart rate predicts the risk of developing hypertension in a normotensive screened cohort. Circ J. 2007; 71:1755–1760.CrossrefMedlineGoogle Scholar13. Palatini P, Mos L, Santonastaso M, Zanatta N, Mormino P, Saladini F, Bortolazzi A, Cozzio S, Garavelli G. Resting heart rate as a predictor of body weight gain in the early stage of hypertension. Obesity. 2011; 19:618–623.CrossrefMedlineGoogle Scholar14. Shigetoh Y, Adachi H, Yamagishi S, Enomoto M, Fukami A, Otsuka M, Kumagae S, Furuki K, Nanjo Y, Imaizumi T. Higher heart rate may predispose to obesity and diabetes mellitus: 20-year prospective study in a general popu" @default.
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• W2153584953 title "Role of Elevated Heart Rate in the Development of Cardiovascular Disease in Hypertension" @default.
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