Occurrence of coronary events in the absence of traditional risk factors: Understanding residual risk

Natalie Arnold; Alina Goßling; Jessica Weimann; Benjamin Bay; Tanja Zeller; Marco M. Ferrario; Luigi Palmieri; Philippe Amouyel; Marie Moitry; Jean Ferrières; Hermann Brenner; Abdonas Tamosiunas; Sofia Malyutina; Satu Männistö; Wojciech Drygas; Guido Grassi; Sameline Grimsgaard; Allan Linneberg; Stefan Söderberg; Licia Iacoviello; Susana Sans; Renate Schnabel; Giovanni Veronesi; Barbara Thorand; Hugh Tunstall-Pedoe; Frank Kee; Veikko Salomaa; Kari Kuulasmaa; Stefan Blankenberg; Christoph Waldeyer; Francisco Ojeda; Christina Magnussen; Wolfgang Koenig; MORGAM Investigators

doi:10.1016/j.atherosclerosis.2025.120475

Occurrence of coronary events in the absence of traditional risk factors: Understanding residual risk

Natalie Arnold
, Alina Goßling
, Jessica Weimann
, Benjamin Bay
, Tanja Zeller
, Marco M. Ferrario
, Luigi Palmieri
, Philippe Amouyel
, Marie Moitry
, Jean Ferrières
, Hermann Brenner
, Abdonas Tamosiunas
, Sofia Malyutina
, Satu Männistö
, Wojciech Drygas
, Guido Grassi
, Sameline Grimsgaard
, Allan Linneberg
, Stefan Söderberg
, Licia Iacoviello

Susana Sans, Renate Schnabel, Giovanni Veronesi, Barbara Thorand, Hugh Tunstall-Pedoe, Frank Kee, Veikko Salomaa, Kari Kuulasmaa, Stefan Blankenberg, Christoph Waldeyer, Francisco Ojeda, Christina Magnussen, Wolfgang Koenig (Lead / Corresponding author), MORGAM Investigators

Cardiovascular Research

Research output: Contribution to journal › Article › peer-review

4 Citations (Scopus)

13 Downloads (Pure)

Abstract

Background and aims: The major predictors of future coronary heart disease (CHD) events in individuals without traditional modifiable cardiovascular risk factors (CVRFs) remain unknown. We investigated the association between circulating biomarkers, reflecting residual risk, with incident CHD in a general population, according to the presence of five CVRFs (hypertension, diabetes mellitus, hypercholesterolemia, smoking and obesity) at baseline.

Methods: Overall 212,598 CHD-free individuals from 21 European population-based cohorts were stratified by CVRF burden into three groups, having zero (n = 35,707), one (n = 68,548) or ≥2 (n = 108,343) risk factors at baseline. Five biomarkers (triglycerides (TGs), high-sensitivity C-reactive protein (hsCRP), cystatin C, N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin I) were assessed in a subset with available measurements.

Results: During a median follow-up of 13.97 years, 17,499 participants developed incident CHD with 453 events occurring among individuals without CVRFs. Although increased concentrations of all biomarkers were related to incident CHD, significant risk modulation by CVRFs was seen only for TGs and, to a lesser extent, for hsCRP. The fully-adjusted sub-distribution Hazard Ratios (95 % CI) were for TGs (≥vs < 1.70 mmol/L) 1.66 (1.29–2.15) in those without CVRFs versus 1.35 (1.21–1.49)/1.14 (1.07–1.20) in those with 1 or ≥2 risk factors (p_interaction<0.01) and for hsCRP (≥vs < 2 mg/L) 1.39 (1.02–1.90) versus 1.42 (1.26–1.61) or 1.22 (1.13–1.32), respectively (p_interaction = 0.092).

Conclusion: Even in the absence of CVRFs, elevated triglycerides and hsCRP were significantly associated with an increased risk of CHD. These results highlight the importance of residual risk assessment using those biomarkers in individuals deemed metabolically healthy by conventional standards.

Original language	English
Article number	120475
Number of pages	9
Journal	Atherosclerosis
Volume	409
Early online date	8 Aug 2025
DOIs	https://doi.org/10.1016/j.atherosclerosis.2025.120475
Publication status	Published - Oct 2025

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Cardiovascular risk factors (CVRFs)
Circulating biomarkers
Coronary heart disease
General population
High-sensitivity C-Reactive protein (hsCRP)
Triglycerides

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

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10.1016/j.atherosclerosis.2025.120475Licence: CC BY

Final Published VersionFinal published version, 2.66 MBLicence: CC BY

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Arnold, N., Goßling, A., Weimann, J., Bay, B., Zeller, T., Ferrario, M. M., Palmieri, L., Amouyel, P., Moitry, M., Ferrières, J., Brenner, H., Tamosiunas, A., Malyutina, S., Männistö, S., Drygas, W., Grassi, G., Grimsgaard, S., Linneberg, A., Söderberg, S., ... MORGAM Investigators (2025). Occurrence of coronary events in the absence of traditional risk factors: Understanding residual risk. Atherosclerosis, 409, Article 120475. https://doi.org/10.1016/j.atherosclerosis.2025.120475

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title = "Occurrence of coronary events in the absence of traditional risk factors: Understanding residual risk",

abstract = "Background and aims: The major predictors of future coronary heart disease (CHD) events in individuals without traditional modifiable cardiovascular risk factors (CVRFs) remain unknown. We investigated the association between circulating biomarkers, reflecting residual risk, with incident CHD in a general population, according to the presence of five CVRFs (hypertension, diabetes mellitus, hypercholesterolemia, smoking and obesity) at baseline.Methods: Overall 212,598 CHD-free individuals from 21 European population-based cohorts were stratified by CVRF burden into three groups, having zero (n = 35,707), one (n = 68,548) or ≥2 (n = 108,343) risk factors at baseline. Five biomarkers (triglycerides (TGs), high-sensitivity C-reactive protein (hsCRP), cystatin C, N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin I) were assessed in a subset with available measurements.Results: During a median follow-up of 13.97 years, 17,499 participants developed incident CHD with 453 events occurring among individuals without CVRFs. Although increased concentrations of all biomarkers were related to incident CHD, significant risk modulation by CVRFs was seen only for TGs and, to a lesser extent, for hsCRP. The fully-adjusted sub-distribution Hazard Ratios (95 \% CI) were for TGs (≥vs < 1.70 mmol/L) 1.66 (1.29–2.15) in those without CVRFs versus 1.35 (1.21–1.49)/1.14 (1.07–1.20) in those with 1 or ≥2 risk factors (pinteraction<0.01) and for hsCRP (≥vs < 2 mg/L) 1.39 (1.02–1.90) versus 1.42 (1.26–1.61) or 1.22 (1.13–1.32), respectively (pinteraction = 0.092).Conclusion: Even in the absence of CVRFs, elevated triglycerides and hsCRP were significantly associated with an increased risk of CHD. These results highlight the importance of residual risk assessment using those biomarkers in individuals deemed metabolically healthy by conventional standards.",

keywords = "Cardiovascular risk factors (CVRFs), Circulating biomarkers, Coronary heart disease, General population, High-sensitivity C-Reactive protein (hsCRP), Triglycerides",

author = "Natalie Arnold and Alina Go{\ss}ling and Jessica Weimann and Benjamin Bay and Tanja Zeller and Ferrario, \{Marco M.\} and Luigi Palmieri and Philippe Amouyel and Marie Moitry and Jean Ferri{\`e}res and Hermann Brenner and Abdonas Tamosiunas and Sofia Malyutina and Satu M{\"a}nnist{\"o} and Wojciech Drygas and Guido Grassi and Sameline Grimsgaard and Allan Linneberg and Stefan S{\"o}derberg and Licia Iacoviello and Susana Sans and Renate Schnabel and Giovanni Veronesi and Barbara Thorand and Hugh Tunstall-Pedoe and Frank Kee and Veikko Salomaa and Kari Kuulasmaa and Stefan Blankenberg and Christoph Waldeyer and Francisco Ojeda and Christina Magnussen and Wolfgang Koenig and \{MORGAM Investigators\}",

note = "Copyright: {\textcopyright} 2025 The Authors.",

year = "2025",

month = oct,

doi = "10.1016/j.atherosclerosis.2025.120475",

language = "English",

volume = "409",

journal = "Atherosclerosis",

issn = "0021-9150",

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Arnold, N, Goßling, A, Weimann, J, Bay, B, Zeller, T, Ferrario, MM, Palmieri, L, Amouyel, P, Moitry, M, Ferrières, J, Brenner, H, Tamosiunas, A, Malyutina, S, Männistö, S, Drygas, W, Grassi, G, Grimsgaard, S, Linneberg, A, Söderberg, S, Iacoviello, L, Sans, S, Schnabel, R, Veronesi, G, Thorand, B, Tunstall-Pedoe, H, Kee, F, Salomaa, V, Kuulasmaa, K, Blankenberg, S, Waldeyer, C, Ojeda, F, Magnussen, C, Koenig, W & MORGAM Investigators 2025, 'Occurrence of coronary events in the absence of traditional risk factors: Understanding residual risk', Atherosclerosis, vol. 409, 120475. https://doi.org/10.1016/j.atherosclerosis.2025.120475

TY - JOUR

T1 - Occurrence of coronary events in the absence of traditional risk factors

T2 - Understanding residual risk

AU - Arnold, Natalie

AU - Goßling, Alina

AU - Weimann, Jessica

AU - Bay, Benjamin

AU - Zeller, Tanja

AU - Ferrario, Marco M.

AU - Palmieri, Luigi

AU - Amouyel, Philippe

AU - Moitry, Marie

AU - Ferrières, Jean

AU - Brenner, Hermann

AU - Tamosiunas, Abdonas

AU - Malyutina, Sofia

AU - Männistö, Satu

AU - Drygas, Wojciech

AU - Grassi, Guido

AU - Grimsgaard, Sameline

AU - Linneberg, Allan

AU - Söderberg, Stefan

AU - Iacoviello, Licia

AU - Sans, Susana

AU - Schnabel, Renate

AU - Veronesi, Giovanni

AU - Thorand, Barbara

AU - Tunstall-Pedoe, Hugh

AU - Kee, Frank

AU - Salomaa, Veikko

AU - Kuulasmaa, Kari

AU - Blankenberg, Stefan

AU - Waldeyer, Christoph

AU - Ojeda, Francisco

AU - Magnussen, Christina

AU - Koenig, Wolfgang

AU - MORGAM Investigators

PY - 2025/10

Y1 - 2025/10

N2 - Background and aims: The major predictors of future coronary heart disease (CHD) events in individuals without traditional modifiable cardiovascular risk factors (CVRFs) remain unknown. We investigated the association between circulating biomarkers, reflecting residual risk, with incident CHD in a general population, according to the presence of five CVRFs (hypertension, diabetes mellitus, hypercholesterolemia, smoking and obesity) at baseline.Methods: Overall 212,598 CHD-free individuals from 21 European population-based cohorts were stratified by CVRF burden into three groups, having zero (n = 35,707), one (n = 68,548) or ≥2 (n = 108,343) risk factors at baseline. Five biomarkers (triglycerides (TGs), high-sensitivity C-reactive protein (hsCRP), cystatin C, N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin I) were assessed in a subset with available measurements.Results: During a median follow-up of 13.97 years, 17,499 participants developed incident CHD with 453 events occurring among individuals without CVRFs. Although increased concentrations of all biomarkers were related to incident CHD, significant risk modulation by CVRFs was seen only for TGs and, to a lesser extent, for hsCRP. The fully-adjusted sub-distribution Hazard Ratios (95 % CI) were for TGs (≥vs < 1.70 mmol/L) 1.66 (1.29–2.15) in those without CVRFs versus 1.35 (1.21–1.49)/1.14 (1.07–1.20) in those with 1 or ≥2 risk factors (pinteraction<0.01) and for hsCRP (≥vs < 2 mg/L) 1.39 (1.02–1.90) versus 1.42 (1.26–1.61) or 1.22 (1.13–1.32), respectively (pinteraction = 0.092).Conclusion: Even in the absence of CVRFs, elevated triglycerides and hsCRP were significantly associated with an increased risk of CHD. These results highlight the importance of residual risk assessment using those biomarkers in individuals deemed metabolically healthy by conventional standards.

AB - Background and aims: The major predictors of future coronary heart disease (CHD) events in individuals without traditional modifiable cardiovascular risk factors (CVRFs) remain unknown. We investigated the association between circulating biomarkers, reflecting residual risk, with incident CHD in a general population, according to the presence of five CVRFs (hypertension, diabetes mellitus, hypercholesterolemia, smoking and obesity) at baseline.Methods: Overall 212,598 CHD-free individuals from 21 European population-based cohorts were stratified by CVRF burden into three groups, having zero (n = 35,707), one (n = 68,548) or ≥2 (n = 108,343) risk factors at baseline. Five biomarkers (triglycerides (TGs), high-sensitivity C-reactive protein (hsCRP), cystatin C, N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin I) were assessed in a subset with available measurements.Results: During a median follow-up of 13.97 years, 17,499 participants developed incident CHD with 453 events occurring among individuals without CVRFs. Although increased concentrations of all biomarkers were related to incident CHD, significant risk modulation by CVRFs was seen only for TGs and, to a lesser extent, for hsCRP. The fully-adjusted sub-distribution Hazard Ratios (95 % CI) were for TGs (≥vs < 1.70 mmol/L) 1.66 (1.29–2.15) in those without CVRFs versus 1.35 (1.21–1.49)/1.14 (1.07–1.20) in those with 1 or ≥2 risk factors (pinteraction<0.01) and for hsCRP (≥vs < 2 mg/L) 1.39 (1.02–1.90) versus 1.42 (1.26–1.61) or 1.22 (1.13–1.32), respectively (pinteraction = 0.092).Conclusion: Even in the absence of CVRFs, elevated triglycerides and hsCRP were significantly associated with an increased risk of CHD. These results highlight the importance of residual risk assessment using those biomarkers in individuals deemed metabolically healthy by conventional standards.

KW - Cardiovascular risk factors (CVRFs)

KW - Circulating biomarkers

KW - Coronary heart disease

KW - General population

KW - High-sensitivity C-Reactive protein (hsCRP)

KW - Triglycerides

UR - https://www.scopus.com/pages/publications/105013316195

U2 - 10.1016/j.atherosclerosis.2025.120475

DO - 10.1016/j.atherosclerosis.2025.120475

M3 - Article

C2 - 40829292

AN - SCOPUS:105013316195

SN - 0021-9150

VL - 409

JO - Atherosclerosis

JF - Atherosclerosis

M1 - 120475

ER -

Occurrence of coronary events in the absence of traditional risk factors: Understanding residual risk

Abstract

UN SDGs

Keywords

ASJC Scopus subject areas

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