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J Am Coll Cardiol, 2008; 51:331-332, doi:10.1016/j.jacc.2007.10.013 © 2008 by the American College of Cardiology Foundation |
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* Chair of Cardiology, University of Ferrara, Corso Giovecca 203, Ferrara 44100, Italy (Email: fri{at}unife.it).
In their letter to the Journal, Drs. Messerli and Bangalore suggest that bradycardia induced by negative chronotropic drugs may not necessarily be as beneficial as bradycardia occurring physiologically and support the suggestion with the observation that blood pressure reduction with beta-blockers, which is associated with heart rate reduction, is less beneficial in minimizing cardiovascular outcome in hypertensive patients as compared with other non-heart rate slowing antihypertensive agents.
In contrast with post-MI or HF studies, the beta-blocker atenolol was the chronotropic drug used in most of the hypertension clinical trials reported by Drs. Messerli and Bangalore. By reducing heart rate and myocardial inotropism and increasing left ventricular (LV) ejection time, atenolol (like the majority of beta-blockers) alters the pattern of pulse-wave reflection. The increase in the augmentation index reported after beta-blockers results in increased central systolic blood pressure in hypertensive patients. Thus, beta-blockers could have a deleterious effect on LV-aortic coupling, LV afterload, LV hypertrophy, and, ultimately, the risk of cardiovascular events. The observations could explain the less-than-expected beneficial effect of atenolol on clinical outcome in the CAFÉ (Conduit Artery Function Evaluation) study (2) reported by Drs. Messerli and Bangalore.
However, although the pulse-wave dyssynchrony observed with atenolol may account for the beta-blocker paradox and the increase in central blood pressure observed in hypertensive patients, we should be cautious about attributing the phenomenon to heart rate slowing per se. As previously mentioned, beta-blockers not only affect heart rate, they also reduce blood pressure and alter cardiac contractility, relaxation, systolic ejection time, and pulse-wave reflection.
An interesting point is that for a given reduction in a heart rate, the dyssynchrony between the forward and the reflected pulse wave may not be the same for atenolol as for other beta-blockers. (3).
In addition to the potentially deleterious effect of beta-blockers, as a group, on pulse-wave reflection for reasons unrelated to heart rate reduction, other issues might be considered in assessing the impact of beta-blockers, including, perhaps most importantly, the magnitude of heart rate reduction achieved in the individual trials or individual patients in the meta-analysis by Bangalore et al. (4), which may determine the extent to which any deleterious effects of beta-blockade might be obviated by heart rate slowing.
Therefore, the hypertension paradox observed with beta-blockers (mainly atenolol) cannot be solely explained by pharmacologic heart rate slowing, and findings should not be extrapolated to pharmacologic interventions aiming at pure heart rate reduction. In other words, the way in which one slows the heart rate may be important in determining the outcome of heart rate slowing. We all are aware, however, of the limitations of observational datasets, whether when suggesting benefit of a spontaneously "low" heart rate or possible harm from pharmacologic heart rate reduction with beta-blockers in hypertension. Fortunately, the hypothesis that heart rate lowering is beneficial clinically is being put to test in 2 large-scale outcome randomized clinical trials.
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