Joint effect of blood pressure and C-reactive protein and the risk of sudden cardiac death : a prospective cohort study

This is a self-archived version of an original article. This version may differ from the original in pagination and typographic details. Author(s): Title: Year: Version: Copyright: Rights: Rights url: Please cite the original version: CC BY-NC-ND 4.0 https://creativecommons.org/licenses/by-nc-nd/4.0/ Joint effect of blood pressure and C-reactive protein and the risk of sudden cardiac death : a prospective cohort study © 2020 Elsevier Accepted version (Final draft) Kurl, Sudhir; Jae, Sae Y.; Voutilainen, Ari; Mäkikallio, Timo; Laukkanen, Jari A. Kurl, S., Jae, S. Y., Voutilainen, A., Mäkikallio, T., & Laukkanen, J. A. (2021). Joint effect of blood pressure and C-reactive protein and the risk of sudden cardiac death : a prospective cohort study. International Journal of Cardiology, 326, 184-188. https://doi.org/10.1016/j.ijcard.2020.10.071 2021 Journal Pre-proof Joint effect of blood pressure and C-reactive protein and the risk of sudden cardiac death: A prospective cohort study Sudhir Kurl, Sae Y. Jae, Ari Voutilainen, Timo Mäkikallio, Jari A. Laukkanen PII: S0167-5273(20)34062-6 DOI: https://doi.org/10.1016/j.ijcard.2020.10.071 Reference: IJCA 29043 To appear in: International Journal of Cardiology Received date: 23 May 2020 Revised date: 26 September 2020 Accepted date: 23 October 2020 Please cite this article as: S. Kurl, S.Y. Jae, A. Voutilainen, et al., Joint effect of blood pressure and C-reactive protein and the risk of sudden cardiac death: A prospective cohort study, International Journal of Cardiology (2020), https://doi.org/10.1016/ j.ijcard.2020.10.071 This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier. Joint Effect of Blood Pressure and C-Reactive Protein and the Risk of Sudden Cardiac Death: A Prospective Cohort Study Sudhir Kurla,b, Sae Y Jaec, Ari Voutilainena, Timo Mäkikalliod, Jari A. Laukkanen a,e,f aInstitute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio. Finland. bDepartment of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio. Finland. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. cDepartment of Sport Science, University of Seoul, Seoul, Republic of Korea; Graduate School of Urban Public Health, University of Seoul, Seoul, Republic of Korea. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. dDivision of Cardiology, Department of Internal Medicine, Oulu University Hospital, Oulu, Finland. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. eCentral Finland Healt Care District, Department of Medicine Jyväskylä, Finland. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. fFaculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland Correspondence: Sudhir Kurl, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, P.O. Box 1627, 70211 KUOPIO, Finland, Tel +358-40-3552966, Fax 358-17-162936. e-mail: [email protected]i Abstract Background: Both blood pressure and C-reactive protein (CRP) are each independently related to mortality risk. However, the combined effect of systolic blood pressure (SBP) and CRP on sudden cardiac death (SCD) risk has not been studied. Patients and Methods: We studied the joint impact of SBP and CRP and the risk of SCD in the Kuopio Ischemic Heart Disease prospective cohort study of 1953 men aged 42-61 years with no history of ischemic heart disease. Baseline investigations were conducted between Journal Pre-proof Journal Pre-proof March 1984 and December 1989. SBP and CRP were measured. SBP was divided based on median values to low and high (median cutoffs 132mm Hg) and CRP as low and high (median cut-off 1.30 mg/L). Hazard ratios (HRs) with confidence intervals (CIs) were calculated after multivariate adjustment. Results: Subjects were followed-up for 23.2 years, and 137 SCDs occurred. In this study, elevated SBP (>132mmHg) combined with elevated (CRP >1.30mg/L) were associated with SCD risk. Adjustment for age, examination year, alcohol consumption, BMI, energy expenditure during exercise, total cholesterol, HDL-cholesterol, type 2 diabetes, smoking, antihypertension medication and aspirin use, the risk of SCD remained statistically significant (HR, 2,73, 95% CI, 1.62-4.60, p <.001). Further adjustment for socio-economic status, years of education and history of cardiovascular disease in a family the results were only slightly changed (HR, 2.65, 95% CI, 1.57-4.49, p <.001). Conclusions: In our male cohort study, the joint effect of high SBP together with increased CRP levels is a risk predictor of SCD compared with low SBP and CRP. Keywords C-reactive protein; Men; Sudden cardiac death; Systolic blood pressure Introduction Sudden cardiac death (SCD) may occur momentarily after the onset of the symptoms without typical warning signs, thus leaving very limited time for any type of medical intervention (1). Due to the wide-scale public health implications, prevention remains to be the most viable approach to reduce the risk of SCD in the general population (2). Although the occurrence of Journal Pre-proof Journal Pre-proof SCD is relatively low in the common population, the absolute numbers are high among asymptomatic subjects. Hypertension is an established risk factor for various cardiovascular diseases including SCD. Similarly, C-reactive protein (CRP), a marker of inflammatory process, and has also been associated with various cardiovascular events (3-6). Among subjects with elevated blood pressure, increased CRP have been observed. Furthermore, it is known that inflammation plays a role in the development of hypertension (6-11). Increased CRP levels are linked to reduced nitric oxide production in endothelial cells (9-10) which may result in excess production of endothelin and vasoconstriction (12-13). It has been assumed that hypertension may be in part associated with inflammatory diseases. Consistently, long-term hypertension may further lead to harmful left ventricular hypertrophy (LVH), a known risk predictor for SCD (14). Therefore, this study was designed to determine if elevated blood pressure together with CRP is a risk predictor for SCD in the Finnish male population without diagnosed coronary heart disease (CHD). Study Population The Kuopio Ischemic Heart Disease (KIHD) risk factor study, is prospective cohort study designed to study atherosclerotic cardiac events in men from Finland. The subjects included 42-61 years of age living in the city of Kuopio and its surrounding communities. Baseline investigations were performed between March 01, 1984, and December 31, 1989. In all 2682 men were included in the overall study. Our analysis included 1953 men with complete data on SCD, covariates and no history of CHD. The study was approved by the Research Ethics Committee of the University of Eastern Finland. Each participant gave a written informed consent to participate in the study. Journal Pre-proof Journal Pre-proof Assessment of risk markers and biochemical measurements The standard blood pressure definition was used for blood pressure measurements. Blood pressure was assessed at 5, 10, and 15 minutes after 15 minutes of supine rest; one standing blood pressure measurement was taken after being for rest for 1 minute; 10 minutes of seated rest with BP measured at minutes 5 and 10 (15). The mean of these values was used as mean blood pressure. A professional nurse measured blood pressure using a sphygmomanometer (Hawksley, United Kingdom) in a resting seated position in a quiet room from 8:00 to 10:00 a.m (15). Hypertension at rest was either hypertension confirmed by the current use of antihypertensive medication and/or SBP >140 mm Hg and/or DBP >90 mm Hg. At baseline various examinations including physical examinations, collection of blood samples and the collection of self-administered questionnaires was done. Body mass index (BMI) was calculated after measuring height and body weight of the subjects. Blood samples were taken according to the protocol in the mornings between 8 and 10 a.m. after an overnight fast. Subjects were also asked to abstain from alcohol consumption for 3 days and smoking for 12 hours before blood collection. Collected serum samples were frozen at −80 °C before analyses of lipids and biochemical analytes. Serum CRP was analyzed using an immunometric assay (Immulite High Sensitivity C-Reactive Protein Assay; DPC, Los Angeles, CA, USA). Fasting plasma glucose (FPG) was measured using the standard glucose dehydrogenase method (Merck, Darmstadt, Germany). Assessments of alcohol consumption, smoking, history of various health conditions, education, and socioeconomic status; subjects were asked to complete health and lifestyle questionnaires (15-18). Physical energy expenditure of various physical activities were assessed using the validated KIHD physical Journal Pre-proof Journal Pre-proof activity questionnaire. Left ventricular hypertrophy (Sokolow-Lyon index) was recorded from the electrocardiogram (ECG) at rest. Classification of Sudden Cardiac Death All the information on fatal cardiac events used for classifying were interviews, hospital documents, death certificates, autopsy reports and medico-legal reports and interviews (18). Deaths that occurred till the end of 2017 were included after checking health and hospital documents including death certificates. SCD was classified as death that occurred either within 1 hour after the onset of symptoms or within 24 hours after sudden onset of a change in symptoms when autopsy report revealed a non-cardiac cause of sudden death. Sudden out-of-hospital deaths were also defined based on all information at disposal including interviews (18). Non-cardiac comorbidities, deaths due to aortic aneurysm rupture, pulmonary embolism, cardiac rupture or tamponade, and cancer deaths were all excluded. The final conclusions were made using available clinical data such as symptoms, investigative and ECG findings, cardiac biomarkers, autopsy findings, use of medications and defibrillator use and data available with the paramedic staff. Complete information was further cross-checked by two physicians (18). For classification purposes independent events committee were-blinded to the data available. Statistical analysis We examined SBP and CRP and the other risk factors for SCD by covariate analysis and the risk of SCD with Cox proportional hazard modeling. To study the joint associations of SBP and CRP, with SCD risk, the median values of SBP and CRP were divided into four categories of low/high. Low SBP (<132mm Hg) and low CRP (<1.30mg/L) were used as a reference. We used three sets of covariates: Model (1) consisted of age and examination year; Journal Pre-proof Journal Pre-proof Model (2) consisted of Model 1 together with type 2 diabetes, BMI, alcohol consumption, energy expenditure, total cholesterol, serum HDL cholesterol, smoking, antihypertensive medication and aspirin use; and Model (3) consisted of Model 1and 2 together with socioeconomic status, education, and history of cardiovascular diseases in the family. Furthermore, in another model we analyzed if CRP was less than 10 mg/L in another model. Relative risk estimates (HRs, hazard ratios) were adjusted for risk factors and estimated as antilogarithms of coefficients from multivariable models. All tests for statistical significance were defined as p-values of <.05 and were 2-sided. The Kaplan-Meier method was used to assess the cumulative survival for SCD. Statistical analysis was performed by using IBM, SPSS Statistics, version 25.0 for Windows (IBM Armonk, New York). Results Baseline characteristics Over an average follow-up of 23.2 years, 137 SCD cases were documented. The baseline characteristics of subjects in the groups are presented in Table 1. The mean age of men was 52 years, while SBP was 134mmHg (median 132 mmHg). Mean serum CRP levels were 2.2 mg/L (median 1.3 mg/L) respectively. In model 3, after further adjustment SBP and CRP levels, significant risk markers for SCD were age (p=.008), alcohol consumption (p=.002), smoking (p=.006) and alcohol consumption (p<.001), and socioeconomic status (p=.010). Among men with high SBP combined with high CRP (>132mmHg and >CRP of >1.30mg/L) had high BMI, consumed more alcohol, had higher total cholesterol, had more cases of type 2 diabetes, used more of antihypertensive but had lower education status as compared to other groups. Journal Pre-proof Journal Pre-proof Systolic blood pressure, C-reactive protein, and sudden cardiac death Elevated SBP combined with elevated CRP levels was related the risk of SCD. In an age and examination year adjusted model, when we compared high SBP combined with high CRP ( >132 mmHg and >1.30 mg/L) with combined low levels of SBP combined with CPR (<132mmHg, <1.30 mg/L reference group) 4.0-fold risk (95% CI 2.44-6.53, p<.001) was observed. Further adjustment for alcohol consumption, BMI, energy expenditure during exercise, serum total cholesterol, serum HDL-cholesterol, type 2 diabetes, smoking, antihypertension medication and aspirin use, the risk of SCD remained statistically significant (HR, 2,73, 95% CI, 1.62-4.60, p <.001) (Table 2). Progressive adjustment (Model 3) for socio-economic status, years of education and history of cardiovascular disease in a family the results were only slightly changed (HR, 2.65, 95% CI, 1.57-4.49, p <.001). The KaplanMeier cumulative survival curves for SCD according to the groups of SBP and CRP levels are shown in Figure 1. The risk of SCD was also significantly increased in the group of low SBP (<132mmHg) combined with high CRP >1.30 mg/L, was (HR 1.73, 95% CI, 1.20-2.48, p=.003). However, the respective risk was not increased in men with high SBP (>132mg Hg) combined with low CRP of (<1.30mg/L) (HR 1.30, 95% CI, 0.89-1.91, p=.17). Increase in systolic blood pressure, C-reactive protein and sudden cardiac death We investigated the role of increased SBP when CRP was less than 10 mg/L at baseline. Subjects were divided into groups depending on their SBP. In the SCD risk analyses, men with a mean SBP of 121 mmHg (range 121-132 mmHg) together with mean CRP of 1.52 mg/L (range 0.10-9.97 mg/L) was the reference group. Among men with mean SBP of 147 mmHg (range 132-203 mmHg) and mean CRP of 1.72mg/L range (1.0-2.98 mg/L) the HR for SCD was 2.12-fold (95% CI, 1.26-3.56, p=.005) higher as compared to the reference group after adjustment for all used risk factors including anti-hypertensive medication, Journal Pre-proof Journal Pre-proof 22. Siegel, D, Cheitlin, MD, Black, DM, Seeley, D, Hearst, N, Hulley, SB. Risk of ventricular arrhythmias in hypertensive men with left ventricular hypertrophy. Am J Cardiol. 1990; 65: 742–747 23. Biagetti, MO. Quinteiro, RA. Gender differences in electrical remodeling and susceptibility to ventricular arrhythmias in rabbits with left ventricular hypertrophy. Heart Rhythm. 2006; 3: 832–839 24. Laukkanen JA, Lavie CJ, Khan H, Kurl S, Kunutsor SK. Cardiorespiratory fitness and the risk of serious ventricular arrhythmias: A prospective cohort study. Mayo Clin Proc. 2019;94: 833-841 25. Laukkanen JA, Jennings JR, Kauhanen J, Mäkikallio TH, Ronkainen K, Kurl S. Relation of systemic blood pressure to sudden cardiac death. Am J Cardiol. 2012; 110:378-82 26. Antony, I, Nitenberg, A, Foult, JM, Aptecar, E. Coronary vasodilator reserve in untreated and treated hypertensive patients with and without left ventricular hypertrophy. J Am Coll Cardiol. 1993; 22: 514–520. 27. Sesso HD, Wang L, Buring JE, Ridker PM, Gaziano JM. Comparison of interleukin-6 and C-reactive protein for the risk of developing hypertension in women. Hypertension. 2007; 49:304-10 28. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997; 336: 973–979. 29.Jiménez-Pavón D, Brellenthin AG, Lee DC, Sui X, Blair SN, Lavie CJ. Role of Muscular Strength on the Risk of Sudden Cardiac Death in Men. Mayo Clin Proc. 2019; 94:2589-2591. Journal Pre-proof Journal Pre-proof 30. Kurl S, Laaksonen DE, Jae SY, et al. Metabolic syndrome and the risk of sudden cardiac death in middle-aged men. Int J Cardiol. 2016; 203:792-799. Table 1. Baseline characteristics of middle-aged men with no history of ischemic heart disease. Values indicate mean ± SD unless otherwise informed. Variable All subjects SBP 132 mmHg CRP <1.30 mg l-1 SBP 132 mmHg CRP ≥1.30 mg/L SBP >132 mmHg CRP <1.30 mg/L SBP >132 mmHg CRP ≥1.30 mg/L P-value Between groups n 1953 545 427 431 550 SCD (n) 137 21 19 29 68 Age 52 ± 5.3 52 ± 5.5 52 ± 5.5 53 ± 5.2 53 ± 5.0 <.001 Year of examination 1987 ± 1.7 1987 ± 1.6 1987 ± 1.6 1986 ± 1.7 1986 ± 1.7 .007 Years of education 9.0 ± 3.6 9.6 ± 3.9 8.9 ± 3.6 8.9 ± 3.6 8.6 ± 3.3 <.001 Socioeconomic status 12 ± 5.1 11 ± 5.2 12 ± 5.2 11 ± 5.1 12 ± 4.9 <.001 BMI 27 ± 3.5 25 ± 2.7 27 ± 3.4 27 ± 3.0 28 ± 3.9 <.001 Alcohol consumption (g week-1) 74 ± 118 62 ± 102 73 ± 105 61 ± 122 98 ± 135 <.001 LTPA (kcal day-1) 138 ± 169 144 ± 166 119 ± 145 149 ± 160 138 ± 192 .051 Serum total cholesterol (mmol l-1) 5.9 ± 1.0 5.8 ± 1.0 5.8 ± 1.1 5.8 ± 1.0 6.0 ± 1.0 .002 HDL-cholesterol (mmol l-1) 1.3 ± 0.3 1.3 ± 0.3 1.3 ± 0.3 1.3 ± 0.3 1.3 ± 0.3 <.001 Diabetes (% of yes: FPG >6.9 mmol l-1 or medication) 4.7 1.7 4.4 4.6 7.8 <.001 Smoker (% of yes: smoked less than a month ago) 30 24 42 19 34 <.001 Uses drugs for hypertension (% of yes) 14 6.6 11 15 24 <.001 Uses acetylsalicylic acid (% of yes) 5.8 5.0 5.9 4.6 7.6 .162 CVD in family (% of yes) 80 78 78 81 84 .103 Left ventricular hypertrophy (% of yes) 0.9 0.4 0 1.1 1.8 .033 Journal Pre-proof Journal Pre-proof Abbreviations. SBP: Systolic blood pressure. CRP: Serum high-sensitive C-reactive protein. SCD: Sudden cardiac death. BMI: Body mass index. LTPA: Leisure-time physical activity. HDL: High-density lipoprotein. FPG: Fasting plasma glucose. CVD: Cardiovascular disease including hypertension. Notes. The p-values are for the analysis of variance or Kruskal-Wallis test. Family refers to mother, father, and siblings. Table 2. Hazard ratios for Sudden Cardiac Death among Men with Systolic blood pressure combined with C-reactive protein SBP combined with CRP Hazards Ratio 95% Confidence interval P-value SBP <132mm hg and CRP <1.30 mg/L 1,02 0,54 1,93 ,94 SBP <132mm hg and CRP ≥1.30 mg/L 1,46 0,82 2,60 ,19 SBP >132mm hg and CRP <1.30 mg/L 2,73 1,62 4,59 <.001 Age, (years) 1,06 1,02 1,10 ,003 Year of examination 0,91 0,81 1,02 ,113 Body mass index (kg/m2) 1,05 1,00 1,10 ,050 Alcohol consumption grams/week 1,00 1,00 1,00 ,001 Energy expenditure (kcal/day) 1,00 0,99 1,00 ,453 Serum total cholesterol, (mmol/l) 1,15 0,98 1,34 ,074 Serum HDLcholesterol, (mmol/l) 0,76 0,40 1,42 ,390 Type 2 diabetes mellitus 1,68 0,90 3,14 ,101 Cigarette smokers (pack-years) 1,75 1,21 2,54 ,003 Use of anti-hypertensive medication 1,36 0,89 2,08 ,154 Use of acetylsalicylic acid 0,81 0,35 1,84 ,611 Abbreviations. SBP: Systolic blood pressure. CRP: Serum high-sensitive C-reactive protein. SCD: Sudden cardiac death. BMI: Body mass index. LTPA: Leisure-time physical activity. HDL: High-density lipoprotein.. CVD: Cardiovascular disease including hypertension. Figure 1. The Kaplan-Meier cumulative survival curves for sudden cardiac death according to median of systolic blood pressure and C-reactive protein levels. Journal Pre-proof Journal Pre-proof SBP was categorized as low and high (median cutoff 132mm Hg) and CRP as low and high (median cut-off of 1.30 mg/L). Hightlights:  Little is known about the combined effect of blood pressure and C-reactive protein on acute sudden cardiac death risk.  This study shows that the combined effect of high systolic blood pressure and CRP is associated increased risk of future sudden cardiac death compared with low SBP and low CRP levels.  The combined effect of high systolic blood pressure and CRP is associated increased risk of future sudden cardiac events and both the factors may help while starting the therapy. Journal Pre-proof Journal Pre-proof Figure 1