Role of elevated heart rate in the development of cardiovascular disease in hypertension

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1 ONLINE SUPPLEMENT Role of elevated heart rate in the development of cardiovascular disease in By Palatini P Department of Clinical and Experimental Medicine University of Padova, Padua, Italy Running title: Resting heart rate in Word count: 5927 Correspondence to: Professor Paolo Palatini, M.D., Clinica Medica 4 - University of Padova via Giustiniani, Padova (Italy) Phone: Fax:

2 Search strategy and selection of articles An electronic bibliographic search was conducted in PubMed taking into account articles published from 1966 to the present. The keywords for the searches were: heart rate, risk, mortality,. Variants for all keywords were used to increase the number of studies returned by the search. The references in the identified or related articles were then manually reviewed in the search for other relevant citations. Only studies in which cardiovascular mortality or total mortality was available as outcome measure were included. Articles were rejected if they were as follows: gave insufficient data, used other outcomes, were duplicate articles, studies were performed in non hypertensive subjects, in general populations, in patients with diabetes, acute myocardial infarction, or heart failure. Relevant articles were then checked in full to confirm eligibility and extract data. The search was performed in May 2011 and yielded 516 articles. Of these, 366 were excluded on initial screen of title and abstract. The remaining 150 articles were retrieved for detailed analysis and a further 140, including 32 review papers, were excluded because of ineligibility or overlapping subject cohorts from a previous publication. A further 2 studies in the form of abstract were identified from a manual review of references, giving a total of 12 publications, including 6 randomized clinical trials and 5 cohort studies. For the ASCOT study, the data were drawn from a full article (1) and from a reply letter (2). 1. Poulter NR, Dobson JE, Sever PS, Dahlöf B, Wedel H, Campbell NR; ASCOT Investigators. Baseline heart rate, antihypertensive treatment, and prevention of cardiovascular outcomes in ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial). J Am Coll Cardiol. 2009;54: Poulter NR, Dobson JE, Sever PS, Dahlöf B, Wedel H, Campbell NR. Elevated heart rate in :A target for treatment? Reply. J Am Coll Cardiol. 2010;55 :

3 Table S1. Resting heart rate and adverse outcome in one pre-hypertensive and ten hypertensive populations. Author Baseline FU HR Patient Age Male sex Treatment FU Outcome Increased Clinical (Study) HR (bpm) (bpm) number (years) (%) length variables risk for setting (years) high HR* King 13.1% M: 49 No 10.1 Total Mort Pre- (ARIC) R: CHD Gillman M: M: No 36 Total Mort (Framingham) Benetos M: ma= Total Mort (French study) fe=52 Thomas 20%> Middle Total Mort (French study) age and elderly n.av. Palatini M: No 4 Total Mort Isolated 3

4 (Syst-Eur) systolic Kolloch 75.7 At: M: (At vs 2.7 Total Mort (INVEST) Ver: 72.8 ver) or non-fatal with CHD MI, or nonfatal stroke Paul M: Total Mort # (Glasgow # Clinic) # Okin 20% 84 At: M: (At vs 4.8 Total Mort (LIFE) Los: -0.5 los) with LVH Poulter 73.8 At: M: (At vs 5.5 Total Mort (ASCOT) Amlo:-1.3 amlo) CHD with 3 CV risk factors Julius M: (Val vs 4.2 Total Mort High risk** (VALUE) amlo) Comp EP 4

5 Rambihar (Tel vs 5.0 Total Mort High risk (ONTARGET/ ram vs patients $ TRANSCEND) combination) Comp EP & M indicates mean; R, range; FU, follow-up; CHD, coronary heart disease; CV, cardiovascular;, not available; Mort., mortality; MI, myocardial infarction; LVH, left ventricular hypertrophy; At, atenolol; Ver, verapamil; Amlo, amlodipine; Val, valsartan; *for fully adjusted models; only in women; only in men; for follow-up heart rate; change from baseline; for both baseline and follow-up heart rates; #for subjects with high heart rate at baseline and follow-up visits; **age>50 years and presence of cardiovascular risk factors or disease according to an algorithm based on age and sex; a composite of sudden cardiac death, fatal myocardial infarction, death during or after percutaneous coronary intervention or coronary artery bypass graft, death due to heart failure, and death associated with recent myocardial infarction on autopsy, heart failure requiring hospital management, non-fatal myocardial infarction, or emergency procedures to prevent myocardial infarction. & a composite of cardiovascular death, myocardial infarction, stroke, and congestive heart failure. $ in 70%. 5

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