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Prognostic significance of masked tachycardia in hypertension: evidence from a prospective international registry

Hering, Dagmara; Grassi, Guido

doi: 10.1097/HJH.0000000000001234

aDobney Hypertension Centre, School of Medicine and Pharmacology, Royal Perth Hospital Unit, The University of Western Australia, Perth, Australia

bClinica Medica, Department of Medicine and Surgery, University Milano-Bicocca, Milan

cIRCCS Multimedica, Sesto San Giovanni, Milan, Italy

Correspondence to Dagmara Hering, MD, PhD, Dobney Hypertension Centre, School of Medicine and Pharmacology, Royal Perth Hospital Unit, The University of Western Australia, Level 3 MRF Building, Rear 50 Murray Street, Perth 6000 MDBP: M570, WA, Australia. Tel: +61 8 9224 0316; fax: +61 8 9224 0374; e-mail:

Elevated resting heart rate (HR) is implicated in the development of hypertension, metabolic abnormalities, atherosclerosis and cardiovascular disease. Numerous cohort studies and clinical trials have documented a strong independent association between tachycardia and all-cause cardiovascular morbidity and mortality in the general population [1], patients with prehypertension, patients with hypertension [2], cardiovascular disease [3] and heart failure [4]. The usefulness of HR measurements derived from ECG recordings in predicting cardiac events has been also supported by the Valsartan Antihypertensive Long-term Use Evaluation trial which included 15 193 patients with high-risk hypertension followed over a 5-year period [5]. Patients with the highest HR quintile had a greater risk [hazard ratio 1.53; 95% confidence interval (CI) 1.26–1.85] for the primary endpoint when compared with patients in the lowest HR quintile. Furthermore, the negative impact of elevated HR on patient prognosis was unrelated to blood pressure (BP) control suggesting that even patients with reasonably well controlled hypertension but presence of tachycardia display high risk for cardiac events. Further support for the prognostic value of resting HR comes from a cohort of 528 patients with resistant hypertension [6]. In this study, not only fast (>75 bpm or >70 bpm for night-time HR) but also slow values (<60 bpm or <55 bpm for night-time HR) were predictors of cardiovascular mortality (hazard ratio 2.3; 95% CI, 1.1–5.1) in resistant hypertensive patients at follow-up (median 4.8 years). Moreover, ambulatory HR was found to be a superior risk marker to clinic or ECG HR. Notably, 79% of patients from this cohort were treated with beta-blockers which had an impact on HR-related prognosis. Although fast HR was a significant risk marker in patients using beta-blockers, slow HR was also a predictor in those not using beta-blockers suggesting an overall U-shaped phenomenon between the levels of HR and outcomes in resistant hypertension [6].

In the present issue of the Journal of Hypertension, Palatini et al.[7] provide the first clinical evidence for the important independent predictive role of masked tachycardia for risk stratification in hypertensive patients. This prospective Ambulatory Blood Pressure in Referred Hypertensive Subjects International Database Study included analysis of 24-h ambulatory BP monitoring data in a subset of 7602 patients with untreated hypertension (office BP ≥140 mmHg SBP or ≥90 mmHg DBP) from Italy, Japan and Australia. In-office (palpation over ≥15 s) and out-off-office HR were measured using ambulatory BP monitoring devices. Masked tachycardia defined as normal office (≤85 bpm) and night-time (≥76 bpm) HR increased both the risk of excess major adverse cardiovascular events (hazard ratio 1.40; 95% CI 1.11–1.77) and mortality (hazard ratio 1.62; 95% CI; 1.14–2.29) in patients with hypertension at follow-up (median 5.0 years). In contrast, patients with sustained tachycardia (elevated office and night-time HR values) presented a greater risk for major adverse cardiovascular events (hazard ratio 1.86; 95% CI 1.44–2.40) only but not all-cause-death (hazard ratio 1.35; CI 95% 0.83–2.19), whereas white-coat tachycardia bore no association with any cardiac events or all-cause mortality. The relationship between masked tachycardia and sustained tachycardia in predicting major adverse cardiovascular events remained significant and unchanged after adjustment for age, sex, BMI, serum creatinine, total cholesterol, alcohol intake and 24-h average SBP, but it was attenuated after correction for smoking and presence of diabetes. In this context, it would have been relevant for Authors to adjust the data set for plasma glucose levels which are known to elevate HR [2]. Notably, although 13% (n = 996) of the study cohort received beta-blockers during the follow-up, the prognostic significance of masked tachycardia and sustained tachycardia in future major adverse cardiovascular events was independent of beta-blockers use.

The exact prevalence of masked tachycardia in hypertension has not yet been reported. Nevertheless ∼10% of patients demonstrated normal clinic and out-of-office elevated night-time HR, a strong predictor of adverse cardiovascular outcome [13]. Although the underlying mechanisms linking masked tachycardia to worsening prognosis are not yet entirely understood, numerous previously identified factors in masked hypertension appear to contribute to masked or sustained tachycardia. Accordingly, younger age, smoking or diabetic status, higher ambulatory BP levels and metabolic abnormalities more often characterized patients with masked or sustained tachycardia when compared with normal HR or white-coat tachycardia. Although not indicated in this study, it is possible that increased night-time HR may be associated with less pronounced dipping BP profile, metabolic syndrome, obstructive sleep apnoea or obesity which are associated with sympathetic activation [8,9], likely contribute to adverse outcomes. Indeed, night-time ambulatory HR has been associated with increased muscle sympathetic nerve activity–independent of age, BMI and sex in a sizeable cohort of patients with untreated essential hypertension [10]. Whether sympathetic activation is the underlying mechanism linking masked tachycardia to an unfavourable cardiovascular outcome and mortality merits further investigation.

Unlike previous studies demonstrating the prognostic value of elevated office HR, it is surprising that in the present study white-coat tachycardia alone was not associated with an adverse cardiovascular outcome. The disparity with previous findings may be explained and perhaps limited by the use of an office HR measurement (i.e. pulse palpation, automated BP monitoring device, ECG etc.) in nonstandardized conditions and not combined with out-of-office HR to indeed confirm sustained tachycardia. Therefore, Palatini et al.[7] should be commended on their efforts in performing a combined office and ambulatory HR assessment and studying their relationship to morbidity and mortality in untreated hypertensive patients, the largest study cohort to date. These findings emphasize the need for measuring out-of-office HR in patients with hypertension even with apparently normal or elevated clinic values or in the presence of metabolic abnormalities or behavioural factors (i.e. smoking, obesity etc.).

HR derived from 24-h ambulatory BP monitoring could be viewed as a limitation of this study as opposed to holter ECG which provides beat-to-beat measurements. However, 24-h monitoring is superior to office measurements and the prognostic values of HR and BP levels are well recognized. Ambulatory BP monitoring allows for simultaneous assessment of diurnal BP and HR profile including variability which is integral for the management of hypertension. With the increased availability of ambulatory BP devices and greater understanding of the prognostic significance of night-time HR as demonstrated in the present study, HR is a simple marker which can be easily assessed in the clinical settings to improve awareness of cardiovascular risk as a treatment target. This demonstrates that not only masked hypertension is associated with target organ complications and cardiovascular events [11] but also that masked tachycardia confers high cardiovascular risk and worse prognosis. Therefore, a standardized assessment of HR should be implemented in clinical practice for patient risk stratification. The prevalence of target organ damage (i.e. left ventricular mass index, carotid intima–media thickness, arterial stiffness etc.), obstructive sleep apnoea, diabetes and kidney injury in masked tachycardia is unknown. Whether the attenuation of tachycardia-related end organ damage may indirectly lower HR and improve cardiovascular outcomes needs to be determined.

Considering that a substantial proportion of hypertension-related disease attributable to the global burden of cardiovascular-related mortality comes from Asian regions [12], it would be relevant to determine if ethnicity (white vs Asian populations) influenced the outcomes of the present study. Indeed, only 13.4% of the total study cohort included Asian hypertensive patients [7] which may have impacted masked tachycardia-related major adverse cardiovascular events and all-cause mortality. Indeed, a previous study showed that resting ambulatory HR predicted all-cause mortality in the Japanese general population [13]. In another study, Chinese hypertensive patients with elevated resting HR (≥80 bpm) had the highest risks of stroke and coronary heart disease compared with those with lower BP and HR levels suggesting that the coexistence of hypertension and high HR are valuable predictors of coronary and cerebrovascular events [14].

Despite robust evidence for the prognostic significance of resting HR, its broad clinical applicability in hypertension management is limited by a number of factors. For example, the lack of data defining the exact threshold of abnormal values and randomized clinical trials investigating the efficacy of a therapeutic reduction in HR on outcomes in hypertension [15]. Furthermore, it should be noted that office (but not out-of-office) tachycardia is not a reliable indicator of sympathetic activity and no association has been found between supine resting HR and a direct marker of adrenergic drive, such as muscle sympathetic nerve traffic, in essential hypertension [16]. Finally, a need for long-term properly designed randomized clinical studies targeting elevated HR in hypertension clearly exists, and the hope is to have such studies planned and performed in the very near future.

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Conflicts of interest

There are no conflicts of interest.

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