Heart rate as marker of cardiovascular risk

1) Background

The first study reporting an association between elevated heart rate values and cardiovascular disease dates back to more than 60 years, with the evidence that subjects with a resting tachycardia state were more prone to developing hypertension (1).

Since, more than 40 epidemiological studies, including the Framingham study, have provided evidence that heart rate is independently associated with cardiovascular and all-cause mortality (2-5).

The association between heart rate and cardiovascular events :

• is present at all ages and even in subjects older than 70 years (2),
• takes place in patients with and without cardiovascular complications (2, 4 ,6-8),
• appears to be independent of other risk factors for the atherosclerotic disease and
• is consistent as the association between other
  "classic" risk factors and cardiovascular disease

Despite this evidence, a number of unaddressed questions (schematically listed in Table 1) prevent inclusion of heart rate in the assessment of total cardiovascular risk.
This paper will provide information of the heart rate as marker of cardiovascular risk, also in the light of a recently published Consensus Document of the European Society of Hypertension (9).

2) Tachycardia as an Independent Cardiovascular Risk Factor

In several studies, the heart rate displays a positive relationship with blood pressure values, body weight, triglycerides, insulin and glucose metabolism, raising the possibility that the ability of this haemodynamic variable to predict cardiovascular events is somewhat aspecific and at least in part dependent on other well known cardiovascular risk factors.

However, in the follow-up of two recent surveys, an association between heart rate sudden death and acute coronary events has been reported, and it remained significant even after adjustment for age, body mass index, smoking, blood pressure, lipid profile, diabetes and history of cardiovascular disease (10-11).

Interestingly, in these studies the predictive power of heart rate for fatal cardiovascular and non-cardiovascular events was :

• often greater than that of hypertension and/or hypercholesterolemia (12) and
• manifest not only in ischaemic heart disease, but also in heart failure, hypertension and diabetes (12).

Two still unanswered questions related to the prognostic significance of elevated heart rate values deserve to be highlighted.

The first one refers to the lack of information on the cut-off normality values for heart rate and on the definition of a resting tachycardic state. Extrapolation of data obtained in different studies allows to provisionally identify some figures, i.e. heart rate normality values between 60 and 80 beats/minute and tachycardia as values greater than 100 beats/minute (9).

The second question refers to the threshold heart rate values from which the risk starts to increase. Again extrapolation of data from the very few studies addressing the problem seems to indicate values below 64 beats/minute (9), although no conclusive information can be drawn from the available (and often conflicting) study’s results.

3) Pathogenetic mechanisms

Several hypotheses have been advanced for explaining the relationship between an elevated heart rate and cardiovascular risk. Two of them have been confirmed by experimental and clinical studies. The first one refers to the evidence that :

• the heart rate represents an integrated index of autonomic cardiovascular function and elevated heart rate values are markers of an adrenergic overdrive, which exerts - particularly in an ischaemic, failing or hypertrophyc heart - pro-arrhythmogenic effects, thereby predisposing to fatal arrhythmias and sudden death (13).
• the second pathogenetic hypothesis, not mutually exclusive of the first one, says that an elevated heart rate 1) increases shear stress, 2) impairs arterial compliance and 3) favours the development of atherosclerotic vascular lesions.

4) Which heart rate values better reflect risk?

Although the high variability of heart rate values in the single subject during day and night allows to hypothesise that a 24-hour heart rate would provide a better prognostic estimation of risk than traditional measurements (“office heart rate”), very few studies have so far systematically compared the prognostic value of clinic vs. “out-of-office” heart rate, providing often conflicting results.

In the already mentioned Systolic Hypertension in Europe (Syst-Eur) Trial Investigators study (6), no relative superiority of one approach over the other was detected. This finding has been confirmed by the recent Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study, whose results, however, document the marginal relevance of office, home or 24-hour heart rate values in predicting cardiovascular morbidity and mortality in a general population.

5) Therapeutic Implications

The evidence discussed so far imply that lowering heart rate by therapeutic interventions should have a favourable prognostic relevance. However, all the information on the clinical impact of a pharmacologically-induced heart rate reduction is retrospective.
Furthermore, and more importantly, the benefits in terms of prognosis of reducing heart rate by drugs are limited to myocardial infarction and heart failure, i.e. two conditions in which administration of beta-blockers has been shown to reduce mortality (9, 12).

In contrast, no study has so far addressed this issue in hypertension and thus no evidence is available on the benefits of the heart rate reduction in this condition. In making practical recommendations, however, the already mentioned Consensus Document issued by the European Society of Hypertension suggests that, despite the lack of conclusive data, “heart rate reduction by antihypertensive agents may have beneficial effects” (9). This suggestion, as already mentioned, becomes a strong recommendation in the post-myocardial phases and in heart failure patients.

6) Heart rate and cardiovascular risk : unanswered questions

• Are data on prognostic importance of heart rate consistent?
• Does evidence pertain only to hypertensive or to the general population?
• Is it really an independent risk factor?
• Are all cardiovascular event types involved?
• Do data hold for both genders / all ages / all ethnic groups / all comorbidities etc?
• Can the contribution of heart rate to risk be quantified? Is it linear?
• How should heart rate be measured
• Is there evidence of benefit independently related to heart rate reduction?

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.