Despite these differences, all beta blockers seem to be equally efficacious in SIHD.765 767,770,771 Two large long-term follow-up studies investigating the prognostic importance of heart rate showed that all-cause mortality rate progressively increases with higher resting heart rate after adjustment for exercise capacity, age, diabetes mellitus, systolic arterial pressure, BMI, and level of physical activity.772,773 Therefore, it is recommended that beta-blocker dosing be adjusted to limit the heart rate to 55 to 60 beats per minute at rest. In large prospective studies, bisoprolol, carvedilol, and metoprolol, when administered on a background of ACE inhibitors and diuretics with or without digoxin, have been shown to reduce the risk of death and to improve symptoms, clinical status, and quality of life in patients with chronic systolic heart failure. Importantly, these benefits were seen in patients with and without IHD.571,760,761 Studies on multiple polymorphisms in the gene encoding for the beta-adrenergic receptor have variously shown asso- ciations with physiological responses to exercise.774 781 Clin- ical studies with a variety of beta blockers in different patient populations with hypertension have, however, yielded diver- gent results in terms of associations with BP and heart rate,782 785 but it remains to be studied whether this variation is mainly a function of beta-adrenergic receptor genotype and whether genotype influences the clinical outcome of beta- blocker use in patients with SIHD. Beta blockers have been compared with and combined with dihydropyridine calcium channel blockers in controlled clinical trials. 