Title:Association of resting heart rate with cardiovascular function: a cross-sectional study in 522 Finnish subjects

Transcription

1 Author's response to reviews Title:Association of resting heart rate with cardiovascular function: a cross-sectional study in 522 Finnish subjects Authors: Jenni K Koskela (jenni.k.koskela@uta.fi) Anna Tahvanainen (anna.tahvanainen@uta.fi) Antti Haring (antti.haring@uta.fi) Antti J Tikkakoski (antti.tikkakoski@uta.fi) Erkki Ilveskoski (erkki.ilveskoski@sydankeskus.fi) Jani Viitala (jani.viitala@uta.fi) Miia H Leskinen (miia.leskinen@uta.fi) Terho Lehtimäki (terho.lehtimaki@uta.fi) Mika AP Kähönen (mika.kahonen@uta.fi) Tiit Kööbi (tiit.koobi@pshp.fi) Onni Niemelä (onni.niemela@epshp.fi) Jukka T Mustonen (jukka.mustonen@uta.fi) Ilkka H Pörsti (ilkka.porsti@uta.fi) Version:2Date:2 November 2013 Author's response to reviews: see over

2 The 1 st of November, 2013, Tampere, Finland Dear Editor Professor Aletta Schutte, Thank you for the insightful comments and critique on our manuscript Association of resting heart rate with cardiovascular function: a cross-sectional study in 522 Finnish subjects. We have responded to all of the concerns raised, and we have revised our manuscript according to the reviewers comments. Our specific point-by-point responses to the comments of the reviewers are given below. The changes in the manuscript have been highlighted using blue font. We believe that our manuscript has greatly benefited from the review process. We sincerely hope that the manuscript would now be deemed suitable for publication in BMC Cardiovascular Disorders. With kindest regards on behalf of the research team, Jenni Koskela, MD School of Medicine Department of Internal Medicine Lääkärinkatu 1 (Arvo-Building) FIN University of Tampere FINLAND. Tel: Fax: jenni.k.koskela@uta.fi

3 Referee 1: Ruan Gruger We thank the reviewer for these important comments, and our detailed responses are given below. Our corrections have been printed using blue font. Reviewer s report The manuscript entitled: Association of resting heart rate with cardiovascular function: a cross-sectional study in 522 Finnish subjects aimed to describe the relationship between increasing heart rate (HR) and haemodynamic measures along with differences in supine and 60 degree head-tilt. This manuscript is theoretically based and does not elucidate definite mechanisms at work for sympathetic changes in HR, however did describe the basic trends observed in different categories of HR from lower to higher pulse rates. The study sample is quite young, non-diseased and had normal to mild cardiovascular profiles. In some way this study lacks the benefit of having a group of patients with Tachycardia, which could explain a more extreme benefit of lowering HR clinically. Overall the results were clear and the methods were addressed and explained in detail. Major Compulsory Revisions: 1) In the methods section, the authors described that smokers who stopped a year prior to the study were regarded as non-smokers. Is there any scientific basis for this decision? How long did those patient smoke before they stopped? It is possible that a person who smoked for 10 years and then stopped has stiffer blood vessels opposed to a person that smoked 2 years and then stopped? This is just to clarify any future questions. Response: This is a very relevant question. In the very first version of the manuscript, the classification that the reviewer is referring to was used in the statistical analyses. Importantly, in all later analyses (including the statistics of the present manuscript) smoking was expressed in pack years, and this was also presented in the Results of the original manuscript (Table 1). The incorrect statement that was left in the earlier version of the Methods section has now been removed and the amount of smoking has now been correctly expressed in pack years in the Study Population section of the Methods (page 7, paragraph 1). 2) The only part in the discussion that is unclear is the lack of the explanation on why aortic pulse pressure (also a measure of stiffness) is lower in the high HR (tertile 3) group? This is inconsistent with the PWV that is higher in the HR group. If the authors could provide a brief reasoning for this trend observed then it removes potential confusion. One reason could be that central stiffness is not yet observed in a young and apparently healthy cohort as described in this cohort. Response: It is true that aortic pulse pressure was lower in the highest heart rate tertile when compared with the lowest heart rate tertile, in spite of the finding that pulse wave velocity was higher in the tertile with the highest heart rate. We think that the explanations for the lower pulse pressure in the highest heart rate tertile, in spite of higher pulse wave velocity, are the following: 1) Higher heart rate was associated with lower augmentation index, i.e. lower summation of the reflected pressure wave to the systolic volume wave caused by left ventricular ejection, and this

4 naturally reduces pulse pressure. 2) Pulse pressure is not only determined by arterial stiffness but also by stroke volume (Dart and Kingwell 2001). We found that although pulse wave velocity was directly correlated (r=0.23, p<0.001) with heart rate, stroke index was inversely correlated (r=-0.31, p<0.001) with heart rate. Taken together, lower aortic pulse pressure in the highest heart rate group is probably a consequence of the reduced augmentation index and lower stroke volume in that group (Figure 2B in the manuscript). These matters have now beed added to the Discussion section (page 18, paragraph 2). Reference Dart, AM and Kingwell, BA (2001). Pulse pressure - a review of mechanisms and clinical relevance. J Am Coll Cardiol 37(4): Minor Essential Revisions: 3) In the Background section in paragraph 3, second sentence, remove the word importantly. Also in the same paragraph in the third sentence remove the words Of note. Response: The suggested words have been removed. 4) In the Methods section the author did not mention how data on physical activity was collected. Was it questionnaire or a device? Response: We thank the reviewer for noticing that information concerning the evaluation of physical activity was insufficient. Physical activity was documented by interview and objective registration of physical activity frequency by some device was not performed. This information has bee added to the Methods Study Population section (page 7, paragraph 1). Final remarks: 5) It is recommended that the paper must be checked for language errors and for basic words that are missing, making sentences hard to interpret. Response: The spelling of the manuscript has been checked and errors have been corrected to our best ability. One paragraph in the Discussion has been totally rewritten (page 16, last paragraph; page 17, first paragraph). Level of interest: An article whose findings are important to those with closely related research interests Quality of written English: Needs some language corrections before being published Statistical review: No, the manuscript does not need to be seen by a statistician.

5 Referee 2: Praveen Veerabhadrappa We sincerely thank the reviewer for the constrictive criticism and valuable comments. Our detailed responses are given below. Our corrections have been printed using blue font. Reviewer s report: In this manuscript- Association of resting heart rate with cardiovascular function: a cross-sectional study in 522 Finnish subjects, the authors studied the association of resting HR with cardiovascular function and examined whether the hemodynamics remained similar during head-up tilt. They concluded that supine and upright hemodynamic profile associated with higher resting HR was characterized by higher cardiac output, lower systemic vascular resistance and was associated with reduced central wave reflection. This study has merit, but a few aspects have to be addressed. 1) Was nitroglycerin used during Pulse wave velocity to assess endothelial independent hemodynamic effects? Response: In the present set of experiments nitroglycerin was not used during the measurements. Thus, this approach cannot be used for the evaluation of endothelial independent effects that might influence the regulation of heart rate (i.e. acute vasodilatation via exogenous nitric oxide). We have previously shown the acute cardiovascular effects of nitroglycerin using the present protocol (Tahvanainen et al. 2012), and the nitroglycerin response has also been compared to that induced by salbutamol and by intravenous L-arginine (Tahvanainen et al. 2009; Tahvanainen et al. 2012). 2) It might benefit if the authors can state the reproducibility of the PWV for this study, in the methodology. Response: We are grateful for this valuable remark. We have shown the good reproducibility of pulse wave velocity (PWV) measurements using whole body impedance cardiography (ICG WB ) in a study comprising 32 subjects (Tahvanainen et al. 2012). This reference has been added to the text of the Methods section (page 9, paragraph 1). In the present study, two separate supine measurements of PWV were actually performed during a period of 15 minutes, as the whole-body impedance cardiography (ICG WB ) recording was continued for 5 min in supine position after the passive head-up tilt. Now we have compared the mean PWV values before and after the head-up tilt: the average difference (mean ± SD) between these PWV measurements was ± m/s, and the repeatability of PWV measurement was thus very good (repeatability index R 98%; Bland-Altman repeatability index 0.8) (British-Standards-Institution 1979). This information has been included in the Methods (page 9, paragraph 1). In addition, we also tested the reproducibility in a third subgroup (n=342) of the DYNAMIC study. In this group of subjects two separate supine PWV recordings were performed on the same day with at least one hour between the measurements using the ICG WB method. The mean difference in PWV (Mean±SD) between the two measurements was ± m/s and repeatability was also good (repeatability index R 95%; Bland-Altman repeatability index 0.9).

6 References British-Standards-Institution (1979). Precicion of test methods 1: Guide for the determination and reproducability for a standard test method (BS 5497). British Standards Institution, London. Tahvanainen, A, Leskinen, M, Koskela, J, Ilveskoski, E, Alanko, J, Kahonen, M, Koobi, T, Lehtimaki, L, Moilanen, E, Mustonen, J and Porsti, I (2009). Non-invasive measurement of the haemodynamic effects of inhaled salbutamol, intravenous L-arginine and sublingual nitroglycerin. Br J Clin Pharmacol 68(1): Tahvanainen, AM, Tikkakoski, AJ, Leskinen, MH, Nordhausen, K, Kahonen, M, Koobi, T, Mustonen, JT and Porsti, IH (2012). Supine and upright haemodynamic effects of sublingual nitroglycerin and inhaled salbutamol: a double-blind, placebo-controlled, randomized study. J Hypertens 30(2): ) Was there gender differences for all the outcome variables in the whole study group and gender differences among the resting HR tertiles? Response: This is a very relevant question. As presented in the Results section, the distribution of female and male subjects was not similar in the heart rate tertile groups (please see section Study Population, paragraph 1, sentences 2 and 3, and Table 1). Thus, the logical question emerges whether there are sex-related differences in the other hemodynamic variables. Importantly, it should be noticed that the most significant confounding factors, including sex, were included in the adjusted statistical analyses. Furthermore, the main focus in the present study was on the relations between resting heart rate and other hemodynamic variables, in both supine and upright positions, and not in the sex-related differences in hemodynamics. Nevertheless, we completely agree with the reviewer that this makes an interesting topic for research. In response to the above question, we checked the main results separately for men and women, and the findings did not significantly change. As an example, we attach a figure below (see next page), where the male and female subjects are divided to tertiles according to resting heart rate, and also the differences in cardiac index between the tertiles are shown (all values as mean and 95% confidence intervals). In both men and women, the clear differences in heart rate and cardiac index that were present in the supine position also persisted in the upright position. It should also be noted that if all results would be presented first for all subjects and then for men and women separately, the total number of figures would increase three-fold. 4) Since, physical fitness greatly influences HR, and long-term increase in physical activity/exercise reduces resting HR; was fitness assessed? If so, was it accounted for, during the statistical analyses? Response: Physical activity was documented by interview and objective evaluation of fitness was not performed. We have added this information to the Methods (Study Population section, page 7, paragraph 1). Physical exercise frequency was expressed as bouts of physical activity per week that lasted for at least 30 min each time and caused sweating or shortness of breath (given in the Methods section). The statistics concerning the self-reported weekly amount of physical exercise

7 (mean and CI) were as follows: 3.4 in tertile 1 (CI 3.1 to 3.7), 3.0 in tertile 2 (CI 2.7 to 3.3), and 3.1 in tertile 3(CI 2.7 to 3.5) (given on page 11, first paragraph of Results). As the differences between the tertiles were not statistically significant (p=0.143), they were not included in the statistical adjustments. 5) In the conclusion section, the authors state- thus, possible causes for the less favorable prognosis associated with higher resting HR. It would benefit if it is changed to thus, factors associated with less favorable prognosis of high resting HR are... Response: The concluding sentence has been changed as follows: Thus, possible factors associating higher resting HR with less favourable prognosis in the population studies are higher cardiac workload, elevated BP, and increased arterial stiffness.

8 6) Hemodynamics is also spelt as haemodynamics. Please be consistent. Response: The spelling of the manuscript has been checked and languge errors corrected to our best ability. 7) It might benefit if the length of the discussion is shortened. Response: The length of the Discussion section has been shortened without reducing the factual contents. 8) It might benefit if the references can be (re)checked Response: The references have been rechecked and some new references have been added in response to the reviewers comments.