In a two-part meta-analysis of 23 population-based studies, an observational analysis first found that compared with never smoking, current smoking was associated with lower systolic and diastolic blood pressure and a lower risk of hypertension, but it was also tied to a higher resting heart rate[1]. However, a Mendelian-randomization analysis showed that when a genetic variant was used as a surrogate for heavy smoking, this was strongly associated with a higher resting heart rate, without a significant impact on blood pressure.

Specifically, smoking 20 cigarettes a day was associated having a 7-beats-per-minute (bpm) higher resting heart.

"These findings suggest that part of the cardiovascular risk of smoking may operate through increasing [the] resting heart rate," Dr Allan Linneberg (University of Copenhagen, Denmark) and colleagues report. Their meta-analysis, based on data from the Causal Analysis Research in Tobacco and Alcohol (CARTA) consortium, was published in the December 2015 issue of Circulation: Cardiovascular Genetics.

"At a population level, Mendelian analyses can be used to establish if an observational association is likely to be causal, since genetic variants are free of confounding factors that may distort observational analyses," they note.

"There have been a few other studies on the topic, but not as large and conclusive as this one," Linneberg told heartwire from Medscape. The findings "fit well with the fact that resting-heart-rate–lowering interventions—both pharmacological and nonpharmacological (eg, physical activity)—tend to lower [the] risk of heart disease." It was surprising that smoking does not seem to have significant effects on blood pressure, he added, because this has been the general belief among scientists.

The findings suggest that heavy smokers who decrease their smoking by 20 cigarettes a day may lower their resting heart rate by 7 bpm, consistent with a large body pointing to cardiovascular benefits with reduced heart rate.

Observational Study, Then Genetic Analysis, for 23 Trials

The mechanism to explain why smoking is a major risk factor for cardiovascular disease is unclear, Linneberg and colleagues write. Observational epidemiological studies have shown that compared with nonsmokers, smokers have lower blood pressure and risk of hypertension, but these studies may have been hampered by confounding, they add.

However, according to the group, Mendelian randomization analyses that use genetic markers to test for causal associations can eliminate this confounding. Previous studies have shown that, among smokers, a single nucleotide polymorphism (SNP), rs16969968, in the CHRNA5-CHRNA3-CHRNB4 nicotinic-receptor subunit gene cluster on chromosome 15 is strongly associated with heavy smoking. Another SNP, rs1051730, represents the same genetic signal, so the two can be used interchangeably.

Linneberg and colleagues aimed to investigate the association between smoking and both blood pressure and heart rate by first performing an observational analysis and then a Mendelian randomization analysis, where rs16969968/rs1051730 was used as a surrogate for heavy smoking.

They analyzed data from 23 European population-based studies with 141,317 participants: 62,666 never-smokers, 40,669 former smokers, and 37,982 current smokers.

First, the observational analysis showed that compared with nonsmokers, smokers were more likely to have lower systolic blood and diastolic blood pressure and a lower risk of hypertension, but also a higher resting heart rate. Moreover, among current smokers, an increase of one cigarette/day was associated with a 0.08-mm-Hg and 0.05-mm-Hg increase in systolic and diastolic blood pressure, respectively, and a 0.21-bpm increase in resting heart rate.

However, the second genetics analysis showed that among current smokers, each rs16969968/rs1051730 allele was strongly associated with a higher resting heart rate (0.36 bpm/allele), but this was not strongly associated with blood pressure or hypertension.

"The clinical implications of smoking-induced higher resting heart rate are not clear," Linneberg and colleagues write. "However, considering the well-documented detrimental effects of smoking on risk of cardiovascular disease and our finding that this might not involve a strong direct effect on blood pressure, it may be speculated that more attention should be paid to resting heart rate as a marker of cardiovascular health and risk prediction."

Several studies have shown that the resting heart rate predicts cardiovascular events, independent of blood pressure, and other studies have shown that heart-rate–lowering drugs improve long-term survival of patients with MI, they note.


  1. Linneberg A, Jacobsen RK, Skaaby T, et al. Effect of smoking on blood pressure and resting heart rate: A Mendelian randomization meta-analysis in the CARTA consortium. Circ Cardiovasc Genet 2015; 8:832-841. Abstract


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