Abstract
Background: The relationship between basal heart rate (HR) and the occurrence of myocardial ischemia, sudden death, cardiovascular mortality have been described. Therefore, further studies are warranted to evaluate the behaviour of heart rate in different scenarios. We sought to determine whether ambulatory heart rate is associated with the presence of target organ damage (TOD) in hypertensive patients. Patients and Methods: Crossectional study of essential hypertensive patients in whom a twenty-four hour ambulatory blood pressure monitoring (ABPM) was performed. The relationship between TOD and 24 hour ambulatory heart rate (HR) was analyzed. Results: Five hundred and sixty-six patients with arterial hypertension were included (55.8% male, mean age 59.9 ± 14.2 years). 15% were smokers, 62.2% had dyslipidemia, 18.4% diabetes mellitus. Heart rate values were higher during activity as compared to the resting period (72.8 vs 63.3 bpm, p < 0.001). Heart rate, in both periods, was not associated with the presence of TOD. Nevertheless, the patients with nocturnal HR ?65 bpm have high risk and a high prevalence of TOD. This relationship was also present in multivariate analysis (HR 2.41; CI 95% 1.41–4.11; p=0.001). Conclusion: An elevated nocturnal HR, ?65 bpm, obtained with ABPM registry, is associated with the presence of TOD in hypertensive patients. ABPM is a powerful tool for hypertensive patients not only to monitor BP control but also to obtain information on HR which may provide additional information about current and future cardiovascular risk.
Introduction
The relationship between basal heart rate (HR) and the occurrence of myocardial ischemia, sudden death, cardiovascular mortality, as well as all-cause mortality has been described. The relationship was observed not only in patients with previous cardiovascular disease (Citation1–3) but also in population-based studies (Citation4–6). The association remains after adjustment for other cardiovascular risk factors. Moreover, a beneficial effect of HR reduction has been observed in patients with ischemic heart disease and heart failure (Citation1–5). These observations have driven attempts to define a threshold of elevated HR that can be associated with a worse prognosis and to develop clinical trials investigating the potential impact of HR on cardiovascular morbidity and mortality.
Proper assessment of HR is subjected to bias (Citation6). Twenty-four-hour ambulatory heart rate, however, could minimize the bias and offer additional information about the HR circadian pattern and the reduction of HR during the sleep period, since it has been identified as a strong predictor for events in patients with increased cardiovascular risk (Citation7,Citation8). We sought to determine whether 24-h ambulatory HR is associated with the presence of hypertension-induced target organ damage (TOD).
Patients and methods
Study data were collected cross-sectionally from the CARDIORISC project (SEH.LELHA). The details and some analysis of the project have been previously published (Citation9). The protocol was accepted by the Ethics Committee from Hospital Provincial of Castellon and all the subjects gave informed consent. Patients included were recruited from three health centers (two general practitioners and one specialized cardiology clinic) pertaining to the whole project. Data were collected between April 2006 and November 2008. Inclusion criteria were as follows: patients with previous diagnosis of hypertension or subjects referred for hypertension, aged more than 18 years old, with or without previous cardiovascular disease. The patients with atrial fibrillation or significant rhythm disorders were excluded.
Twenty-four-hour ambulatory blood pressure monitoring (ABPM) was performed in all patients with an oscillometric device SPACELABS 90207 (SpaceLabs Medical Inc., Redmond, WA, USA). The cuff was matched to the perimeter of the arm and measurements of blood pressure (BP) and heart rate (HR) were done every 20 min during activity and every 30 min at rest. All patients gave informed written consent prior to inclusion. Prior to ABPM, BP was measured according to standardized protocols (Citation10) using a validated digital sphygmomanometer (Omron M6) (Citation11). After a 5-min rest period, every 2 min a total of three BP measurements were taken. The mean BP of the last two measurements was considered the clinical BP.
Clinical characteristics and results of examination were collected in an online questionnaire. This questionnaire included: history of hypertension, age, sex, height and weight, cardiovascular risk factors, history of cardiovascular disease and TOD. Blood tests were performed and the results added to the questionnaire including total cholesterol, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol and triglycerides, basal glucose levels, uric acid and serum creatinine.
Definitions
Controlled or normal BP values was considered when office BP < 140/90 mmHg and ambulatory BP if the daytime value was < 135/85 mmHg, night-time value < 120/70 mmHg and 24-h value < 130/80 mmHg (Citation12). Nocturnal dipping was defined for systolic BP (SBP) as a ratio of night-time/daytime means 0.90–0.80; extreme dipping <0.80; non-dipping 0.9–1.0 and riser >1.0.
TOD – yes or no – was defined by the presence of at least one of the following conditions: presence of microalbuminuria (average urinary albumin excretion of 30–300 mg daily or albumin/creatinine ratio >22 mg/g in men and >31 mg/g in women), proteinuria (proteinuria as urinary protein excretion >300 mg daily), left ventricular hypertrophy (LVH; left ventricular mass index calculated from an M-mode echocardiogram > 125 g/m2 in men or > 110 g/m2 in women) or the presence of electrocardiographic criteria, Sokoloff index ≥38 mm or Cornell product ≥2440 mm×ms), or increased intima-media thickness (IMT; ≥0.9 mm or the presence of plaque, assessed as mean IMT and as maximum IMT in the right and left common carotid artery, carotid bulb and internal carotid artery). Renal disease was diagnosed when glomerular filtration rate (by MDRD – Modification of Diet in Renal Disease – equation) was <60 ml/min/m2 or when proteinuria was present.
Statistical analysis
Qualitative variables are presented with their frequency distribution. Quantitative variables are presented as mean±standard deviation (SD) and range. The differences between qualitative variables were assessed with the χ2 test or Fisher exact test and the quantitative independent variable was analyzed with the t-test. In all cases, distribution of the variable was compared with theoretical models and the assumption of homogeneity of variance was tested. The null hypothesis was rejected in all tests with a type I or alpha error <0.05. Receiver operating curve (ROC) was constructed to establish a cut-off point of the nocturnal HR for a more specific and sensitive prediction of TOD.
Binary logistic regression models (multivariate analysis) were performed using the presence of TOD as a dependent variable, considering significant p-value <0.10 on univariate analysis. The variables were introduced with a step-wise “Forward: Conditional” method. Statistical analysis was performed using the SPSS version 11.0 software (Chicago, IL, USA).
Results
Baseline characteristics
Five-hundred and sixty-six patients were included. The specific characteristics of the population are described in . Indications for doing ABPM are summarized in . Fifty-six percent of patients did not have BP control of SBP and diastolic BP (DBP), neither during activity nor at rest, despite taking more than one antihypertensive drug (mean 1.24 ± 1.2). Sixty-five percent of patients had an abnormal circadian pattern (Riser, Non Dipper and Extreme-Dipper).
Table I. Baseline characteristics.
Figure 1. Reasons to perform 24-h ambulatory blood pressure monitoring (ABPM). EFT, efficacy of anti-hypertensive treatment; WCH, suspected white coat hypertension; SCP, study of circadian profile assessment; HRP, high-risk patient; HBV, high BP variability; RHT, refractory hypertension.
Parameters associated with the presence of TOD
A total of 69 patients had evidence of TOD (). Among the patients with TOD, there were more males and a higher mean age, prevalence of diabetes, smoking, dyslipidemia and family history of cardiovascular disease compared with those without TOD. There were no differences between groups in waist circumference, body mass index (BMI), serum creatinine levels, glomerular filtration rate and hemoglobin levels. Likewise, there was no association between the presence of organ damage and BP values or abnormal circadian pattern; although there was a non-significant trend towards worse BP control (BP values were slightly elevated). Differences in number and kind of antihypertensive drugs were also minimal, with an increased use of inhibitors of renin–angiotensin system (angiotensin-converting enzyme inhibitor or angiotensin-receptor antagonist) and diuretics in the group of patients with TOD.
Table II. Differential characteristics based on the presence of target organ damage (TOD).
Twenty-four-hour ambulatory heart rate
Heart rate values were higher during activity (72.8 vs 63.3 beats/min, p<0.001), compared with resting period. Heart rate was not associated with the presence of TOD in a univariate analysis whichever the period considered, diurnal or nocturnal. However, when the population was grouped in deciles according to the nocturnal HR values, an increment in the prevalence of TOD was observed above decile 6 at rest, which corresponded to HR of ≥65 beats/min. Patients with TOD had a higher percentage of HR ≥65 beats/ min at rest on ABPM, with no differences during activity or in the global registry of HR. Likewise, in the ROC curve the cut-off point of the nocturnal HR for a more specific (0.79 value) and sensitive (0.89 value) prediction of TOD was also ≥65 beats/min (). Then, this HR value of 65 beats/min was used subsequently to dichotomize the variable.
Figure 2. Receiver operating characteristic curve (ROC) for the presence of target organ damage (TOD). Threshold nocturnal heart rate (HR). AUC, area under curve.
Compared with subjects with HR <65 beats/min, those patients with HR at rest ≥65 beats/min had a larger waist circumference (99.7 vs 95.6 cm, p= 0.031), higher BMI (29.9 vs 28.8 kg/cm2, p=0.015), higher SBP (130.1 vs 125.6 mmHg, p<0.001) higher DBP (77.4 vs 73.3 mmHg, p<0.001), a higher percentage of female patients, (50.0% vs 40.0%, p=0.012), lower use of beta-blocking drugs (12.9% vs 20.9% p=0.018), higher cardiovascular risk (45.2% vs 37.2%, p=0.004) and higher prevalence of TOD (17.2% vs 9.1%, p=0.003) ().
Table III. Differential characteristics based on the presence of heart rate (HR) at rest >65 beats/min.
Twenty-four-hour ambulatory heart rate and TOD
In the multivariate analysis, all variables associated with the presence of TOD with a p-value <0.10 in the bivariate analysis were included. Independent factors associated with TOD were diabetes, dyslipidemia and HR at nocturnal period ≥65 beats/min, whereas the female sex had a protective effect (). It is worthy to mention that the kind of antihypertensive drug used was not related with TOD, despite the fact that patients on beta-blockers had lower HR during the 24-h (65.3 vs 71.7, p<0.001), activity (66.6 vs 74.1, p<0.001) and nocturnal (60.9 vs 63.8, p=0.008) compared with subjects without beta-blockers.
Table IV. Factors associated with the presence of target organ damage (TOD) in a logistic regression analysis.
Discussion
In the present study, nocturnal HR was associated with the presence of TOD in hypertensive patients independently of other classic CV risk factors. Whether or not the high presence of TOD in patients with resting HR ≥65 beats/min is a cause or a consequence of TOD is not possible to elucidate with a cross-sectional study. These findings, however, are in favor of the prognostic value of HR and emphasize the importance of an optimal control of the circadian changes of hemodynamic variables, sleep problems (sleep apnea syndrome, etc.) and 24-h therapeutic effect of drugs (beta-blockers, etc.), that could justify by themselves the lack of response in HR and worse prognosis.
Resting HR is directly associated with ischemic episodes, sudden death, cardiovascular mortality and all-cause mortality, not only in patients with history of cardiovascular disease but also in the general population. There are many studies that have established a relationship between an elevated HR and an increase in cardiovascular and all-cause mortality, after adjustment for other cardiovascular risk factors. On the other hand, reduction of HR in patients with ischemic heart disease and heart failure was associated with beneficial prognosis (Citation1–3). Elevated HR may not only be a marker of prognosis, but could also have a deleterious effect through several other mechanisms, which would have an atherogenic effect; and in patients with cardiovascular risk factors, such as hypertension, it could increase that risk (Citation13).
The relationship between elevated HR and cardiovascular mortality has been known for long time. Dyer et al. (Citation14) in 1980 showed the importance of HR as a risk factor. Afterwards, different studies have shown a significant relationship between patients without a history of cardiovascular disease and basal HR, high BP and adjusted rate of fatal and non-fatal ischemic events. That risk increases above 60 beats/min, and multiplies by five when basal HR is higher than 90 beats/min, independently of age, sex and weight. Furthermore, some studies have shown that an increase in HR provides a higher cardiovascular risk in hypertensive than in normotensive patients, and could also predict a future development of high BP (Citation4,Citation15–25). In the present study, HR value ≥65 beats/min (resting period) was observed as associated to higher cardiovascular risk in hypertensive patients compared with those with the lowest HR.
Most of the studies that identified HR elevation as a predictor of worse prognosis used a clinical measurement of HR at rest. This assessment has a low reproducibility and presents some bias and error of measurement, with a possible false increase related to a medical environment. Measuring the 24-h ambulatory HR, such as in the present study, could avoid those limitations and add some data about circadian changes of the hemodynamic variables, which have been related with the cardiovascular prognosis. In the present study, HR value above 65 beats/min at night was linked to higher cardiovascular risk in hypertensive patients.
Previous studies have suggested that ambulatory HR, during activity and resting periods, could predict cardiovascular and non-cardiovascular mortality (Citation7,Citation26). However, no study to date has suggested a relationship between ambulatory HR and the presence of TOD in hypertensive patients. Besides HR, other factors were associated with the presence of TOD, such as dyslipidemia, diabetes and smoking. Age was not identified as a risk factor, probably because of a low range of it in our sample.
Finally, it is worth commenting on whether the highest HRs are the cause or the consequence of the underlying organ damage. Evidences about the potential causal role have been delineated above. However, the possibility that the high HR was the consequence of the underlying organ damage cannot been excluded. Organ damage, as demonstrated by LVH, renal damage or carotid wall-thickness, is a marker of more generalized vascular damage and consequently of baroreflex dysfunction, which can contribute to the persistent high HR during the resting period.
Limitations of our study are: (i) inherent limitations to any observational and cross-sectional study; (ii) ABPM is not an elective technique for measuring HR; (iii) the presence of TOD was not actively searched for (no additional techniques were performed).
In summary, elevated nocturnal HR (≥65 beats/ min), obtained with ABPM registry, is associated with the presence of TOD in hypertensive patients. ABPM is a powerful tool for hypertensive patients not only to monitor BP control but also to provide information on HR, which may provide additional information about current and future cardiovascular risk in patients. Physicians should pay more attention to the HR and the method of measuring it, as it could provide additional information about current and future cardiovascular risk in patients.
Acknowledgments
The study was funded by an unrestrictive grant from Lacer Spain, S.A. and it was endorsed by the Spanish Society of Hypertension (SEH.LELHA).
Declaration of interest: The authors report no conflicts.
Lacer Spain and the SEHLELHA had no role in the study design, analysis or interpretation of data, writing the report, or the decision to submit the article for publication.
Related Research Data
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