Increased time varying heart rate and cardiovascular risk in hypertension – Benefit of selective I_(f) channel inhibitor?

Five decades ago, the status of hypertension as a risk factor for cardiovascular disease was a matter of debate. After further studies and the introduction of antihypertensive medications, few doubt the important role of hypertension in increasing cardiovascular risk. Today a growing body of evidence emphasizes the relationship between heart rate, hypertension and cardiovascular disease, and the measurement of heart rate is becoming an important component of cardiovascular risk assessment. The strongest evidence for a relationship between heart rate and cardiovascular morbidity and mortality is in white, middle-aged men, since most studies have been done in this subgroup. A similar relationship has been described in women, but the association is weaker than in men. The association between heart rate and hypertension has been well documented in cross-sectional studies that have observed a constellation of elevated heart rate, cardiac output and increased plasma catecholamines, the so-called “hyperkinetic state” in persons with borderline hypertension. There is evidence that this hyperkinetic state precedes the development of sustained hypertension and can be used as a prognostic index.

While the evidence that heart rate predicts hypertension and cardiovascular disease is strong, to date most of the data supporting this relationship have come from epidemiologic observations or cross-sectional studies with single measurements of heart rate at the beginning of the study (1–10). Two papers from large randomized clinical trials in hypertension with repeated measurements of heart rate that came online ahead of print on December 12, 2011 add substantial evidence to the heart-rate story in hypertension (11,12).

The relationship of in-treatment heart rate over time based on annual electrocardiograms (ECGs) to incident heart failure was evaluated in 9024 hypertensive patients without heart failure at baseline who were treated with losartan- or atenolol-based regimens in the losartan intervention for endpoint reduction in hypertension (LIFE) study (11). During 4.7  ±  1.1 years mean follow-up, heart failure developed in 285 patients (3.2%). In multivariate Cox analyses that adjusted for randomized treatment, baseline risk factors for heart failure, baseline and in-treatment blood pressure, QRS duration and ECG left ventricular hypertrophy, higher in-treatment heart rate predicted 45% higher adjusted risk of new heart failure for every 10 beats per minute (bpm) higher heart rate (95% confidence interval (CI) 34–57%) or 159% higher risk of heart failure in patients with persistence or development of a heart rate > 84 bpm (95% CI 88–257%). With adjustment for the same covariates, baseline heart rate as a continuous variable was a significantly less powerful predictor of new heart failure (hazard ratio 1.15 per 10 bpm, 95% CI 1.03–1.28) and a baseline heart rate > 84 bpm did not predict new heart failure (hazard ratio 1.00, 95% CI 0.63–1.58). Thus, higher in-treatment heart rate on serial ECGs predicts greater risk of incident heart failure during antihypertensive treatment, independent of covariates, in hypertensive patients with ECG left ventricular hypertrophy. These interesting data add to previous observations from LIFE that higher in-treatment heart rate over time is associated with increased risk of cardiovascular and all-cause mortality and incident atrial fibrillation in patients with hypertension and left ventricular hypertrophy (13,14).

The predictive value of heart rate in patients with high risk hypertension was further evaluated in a pre-planned secondary analysis of data from the Valsartan antihypertensive long-term use evaluation (VALUE) Trial (12). Participants were 15 193 hypertensive patients randomized in the trial and followed for 5 years (14). Heart rate was assessed from ECG recordings obtained annually throughout the study. The primary endpoint was time to cardiac events. After adjustment for confounders, the hazard ratio of the composite cardiac primary endpoint for a 10 bpm increase from baseline heart rate was 1.16 (95% CI, 1.12–1.20). Compared with the lowest heart rate quintile, the adjusted hazard ratio in the highest quintile was 1.73 (1.46–2.04). Compared to the pooled lower quintiles of baseline heart rate the annual incidence of primary endpoint in the top baseline quintile was higher in each of the five study years (all p < 0.05). The adjusted hazard ratio for primary endpoint in the highest in-trial heart rate quintile versus the lowest quintile was 1.53 (1.26–1.85). The incidence of primary endpoints in the highest in-trial heart rate group compared with the pooled four lower quintiles was 53% greater in patients with well controlled blood pressure (BP) (P < 0.001) and 34% greater in those with uncontrolled BP (p = 0.002). These data provide evidence that increased heart rate is a long term predictor of cardiovascular events in patients with high risk hypertension and that this effect is not modified by good blood pressure control.

It is not yet known whether therapeutic reduction of heart rate can improve cardiovascular prognosis. The randomized, double-blind placebo-controlled morBidity-mortality EvAlUaTion of the I- inhibitor ivabradine in patients with coronary artery disease and left-ventricULar dysfunction (BEAUTIFUL) trial showed that reducing heart rate with the selective I_(f) channel inhibitor, ivabradine, did not reduce hospitalization for new or worsening heart failure in patients with stable coronary disease and left ventricular dysfunction at higher risk due to a baseline heart rate ≥ 70 bpm (15). However, in the randomized, placebo-controlled systolic heart failure treatment with the I_F inhibitor ivabradine (SHIFT) trial, ivabradine significantly reduced the composite endpoint of cardiovascular death and hospitalization for worsening heart failure in patients with chronic heart failure at baseline (16,17). In light of the recent finding of the prognostic importance of increased time varying heart rate in high risk hypertensive people (13,14), and the benefit of ivabradine in heart failure patients (16,17), a randomized, controlled trial of this compound in hypertensive people with controlled blood pressure and residual heart rate elevation is warranted and could make consensus on this issue (18) more conclusive.

Conflict of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.