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Genetic insights into resting heart rate and its role in cardiovascular disease.

ABSTRACT: Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.

SUBMITTER: van de Vegte YJ

PROVIDER: S-EPMC10397318 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Genetic insights into resting heart rate and its role in cardiovascular disease.

van de Vegte Yordi J YJ Eppinga Ruben N RN van der Ende M Yldau MY Hagemeijer Yanick P YP Mahendran Yuvaraj Y Salfati Elias E Smith Albert V AV Tan Vanessa Y VY Arking Dan E DE Ntalla Ioanna I Appel Emil V EV Schurmann Claudia C Brody Jennifer A JA Rueedi Rico R Polasek Ozren O Sveinbjornsson Gardar G Lecoeur Cecile C Ladenvall Claes C Zhao Jing Hua JH Isaacs Aaron A Wang Lihua L Luan Jian'an J Hwang Shih-Jen SJ Mononen Nina N Auro Kirsi K Jackson Anne U AU Bielak Lawrence F LF Zeng Linyao L Shah Nabi N Nethander Maria M Campbell Archie A Rankinen Tuomo T Pechlivanis Sonali S Qi Lu L Zhao Wei W Rizzi Federica F Tanaka Toshiko T Robino Antonietta A Cocca Massimiliano M Lange Leslie L Müller-Nurasyid Martina M Roselli Carolina C Zhang Weihua W Kleber Marcus E ME Guo Xiuqing X Lin Henry J HJ Pavani Francesca F Galesloot Tessel E TE Noordam Raymond R Milaneschi Yuri Y Schraut Katharina E KE den Hoed Marcel M Degenhardt Frauke F Trompet Stella S van den Berg Marten E ME Pistis Giorgio G Tham Yih-Chung YC Weiss Stefan S Sim Xueling S XS Li Hengtong L HL van der Most Peter J PJ Nolte Ilja M IM Lyytikäinen Leo-Pekka LP Said M Abdullah MA Witte Daniel R DR Iribarren Carlos C Launer Lenore L Ring Susan M SM de Vries Paul S PS Sever Peter P Linneberg Allan A Bottinger Erwin P EP Padmanabhan Sandosh S Psaty Bruce M BM Sotoodehnia Nona N Kolcic Ivana I Arnar David O DO Gudbjartsson Daniel F DF Holm Hilma H Balkau Beverley B Silva Claudia T CT Newton-Cheh Christopher H CH Nikus Kjell K Salo Perttu P Mohlke Karen L KL Peyser Patricia A PA Schunkert Heribert H Lorentzon Mattias M Lahti Jari J Rao Dabeeru C DC Cornelis Marilyn C MC Faul Jessica D JD Smith Jennifer A JA Stolarz-Skrzypek Katarzyna K Bandinelli Stefania S Concas Maria Pina MP Sinagra Gianfranco G Meitinger Thomas T Waldenberger Melanie M Sinner Moritz F MF Strauch Konstantin K Delgado Graciela E GE Taylor Kent D KD Yao Jie J Foco Luisa L Melander Olle O de Graaf Jacqueline J de Mutsert Renée R de Geus Eco J C EJC Johansson Åsa Å Joshi Peter K PK Lind Lars L Franke Andre A Macfarlane Peter W PW Tarasov Kirill V KV Tan Nicholas N Felix Stephan B SB Tai E-Shyong ES Quek Debra Q DQ Snieder Harold H Ormel Johan J Ingelsson Martin M Lindgren Cecilia C Morris Andrew P AP Raitakari Olli T OT Hansen Torben T Assimes Themistocles T Gudnason Vilmundur V Timpson Nicholas J NJ Morrison Alanna C AC Munroe Patricia B PB Strachan David P DP Grarup Niels N Loos Ruth J F RJF Heckbert Susan R SR Vollenweider Peter P Hayward Caroline C Stefansson Kari K Froguel Philippe P Groop Leif L Wareham Nicholas J NJ van Duijn Cornelia M CM Feitosa Mary F MF O'Donnell Christopher J CJ Kähönen Mika M Perola Markus M Boehnke Michael M Kardia Sharon L R SLR Erdmann Jeanette J Palmer Colin N A CNA Ohlsson Claes C Porteous David J DJ Eriksson Johan G JG Bouchard Claude C Moebus Susanne S Kraft Peter P Weir David R DR Cusi Daniele D Ferrucci Luigi L Ulivi Sheila S Girotto Giorgia G Correa Adolfo A Kääb Stefan S Peters Annette A Chambers John C JC Kooner Jaspal S JS März Winfried W Rotter Jerome I JI Hicks Andrew A AA Smith J Gustav JG Kiemeney Lambertus A L M LALM Mook-Kanamori Dennis O DO Penninx Brenda W J H BWJH Gyllensten Ulf U Wilson James F JF Burgess Stephen S Sundström Johan J Lieb Wolfgang W Jukema J Wouter JW Eijgelsheim Mark M Lakatta Edward L M ELM Cheng Ching-Yu CY Dörr Marcus M Wong Tien-Yin TY Sabanayagam Charumathi C Oldehinkel Albertine J AJ Riese Harriette H Lehtimäki Terho T Verweij Niek N van der Harst Pim P

Nature communications 20230802 1

Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously ident ...[more]

PMID: 37532724

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Project description:ImportanceIncreased resting heart rate is associated with worse outcomes in studies of mostly white populations, but its significance is not well established in African Americans persons whose cardiac comorbidities and structural abnormalities differ.ObjectiveTo study the prognostic utility of heart rate in a community-based African American cohort in the Jackson Heart Study.Design, setting, and participantsA total of 5261 participants in the Jackson Heart Study, a prospective, community-based study in Jackson, Mississippi, were evaluated. Baseline heart rate was assessed by quintiles and as a continuous variable. All participants with baseline heart rate documented by a 12-lead electrocardiogram without pacing or atrial fibrillation noted on their baseline Jackson Heart Study examination were included in the study. Follow-up began September 26, 2000, and was completed December 31, 2011. Data analysis was performed from July to October 2015.Main outcomes and measuresUnadjusted and adjusted associations between heart rate and all-cause mortality and heart failure hospitalization using Cox proportional hazards regression models.ResultsOf the 5261 individuals included in the analysis, 1921 (36.5%) were men; median (25th-75th percentile) age was 55.7 (45.4-64.8) years. Median (25th-75th percentile) baseline heart rate was 63 beats per minute (bpm) (57-71 bpm). The highest heart rate quintile (73-118 bpm) had higher rates of diabetes (398 [37.4%]; P < .001) and hypertension (735 [69.1%]; P < .001), higher body mass index (median [IQR], 32.4 [28.1-38.3]; P < .001), less physical activity (0 hours per week, 561 [52.8%]; P < .001), and lower β-blocker use (73 [6.9%]; P < .001) compared with lower quintiles. Caffeine intake (from 80.7 to 85.5 mg/d; P = .57) and left ventricular ejection fraction (from 62% to 62.3%; P = .01) were similar between groups. As a continuous variable, elevated heart rate was associated with increased mortality and heart failure hospitalizations, with adjusted hazard ratios for every 5-bpm increase of 1.14 (95% CI, 1.10-1.19) and 1.10 (95% CI, 1.05-1.16), respectively. Similar patterns were observed in comparisons between the highest and lowest quintiles.Conclusions and relevanceHigher baseline heart rate was associated with increased mortality and heart failure hospitalizations among African American participants in the Jackson Heart Study. These findings are similar to those seen in white populations, but further study is needed to understand whether African American individuals benefit from interventions targeting heart rate reduction.

Project description:BackgroundData on resting heart rate and risk of all-cause and cardiovascular mortality are inconsistent; the magnitude of associations between resting heart rate and risk of all-cause and cardiovascular mortality varies across studies. We performed a meta-analysis of prospective cohort studies to quantitatively evaluate the associations in the general population.MethodsWe searched PubMed, Embase and MEDLINE from inception to Jan. 1, 2015. We used a random-effects model to combine study-specific relative risks and 95% confidence intervals (CIs). We used restricted cubic spline functions to assess the dose-response relation.ResultsA total of 46 studies were included in the meta-analysis, involving 1 246 203 patients and 78 349 deaths for all-cause mortality, and 848 320 patients and 25 800 deaths for cardiovascular mortality. The relative risk with 10 beats/min increment of resting heart rate was 1.09 (95% CI 1.07-1.12) for all-cause mortality and 1.08 (95% CI 1.06-1.10) for cardiovascular mortality. Compared with the lowest category, patients with a resting heart rate of 60-80 beats/min had a relative risk of 1.12 (95% CI 1.07-1.17) for all-cause mortality and 1.08 (95% CI 0.99-1.17) for cardiovascular mortality, and those with a resting heart rate of greater than 80 beats/min had a relative risk of 1.45 (95% CI 1.34-1.57) for all-cause mortality and 1.33 (95% CI 1.19-1.47) for cardiovascular mortality. Overall, the results did not differ after adjustment for traditional risk factors for cardiovascular disease. Compared with 45 beats/min, the risk of all-cause mortality increased significantly with increasing resting heart rate in a linear relation, but a significantly increased risk of cardiovascular mortality was observed at 90 beats/min. Substantial heterogeneity and publication bias were detected.InterpretationHigher resting heart rate was independently associated with increased risks of all-cause and cardiovascular mortality. This indicates that resting heart rate is a predictor of all-cause and cardiovascular mortality in the general population.

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Genetic insights into resting heart rate and its role in cardiovascular disease.

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Genetic insights into resting heart rate and its role in cardiovascular disease.

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