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. 2024 Mar 15;81(5):1132–1144. doi: 10.1161/HYPERTENSIONAHA.123.22504

Identification of Circulating Plasma Proteins as a Mediator of Hypertension-Driven Cardiac Remodeling: A Mediation Mendelian Randomization Study

Yuanlong Hu 1, Lin Lin 2, Lei Zhang 3, Yuan Li 4, Xinhai Cui 3, Mengkai Lu 2, Zhiyuan Zhang 2, Xiuya Guan 2, Muxin Zhang 1, Jiaqi Hao 2, Xiaojie Wang 5, Jiaming Huan 1, Wenqing Yang 2,✉, Chao Li 2,✉, Yunlun Li 1,6,✉
PMCID: PMC11025611  PMID: 38487880

Abstract

BACKGROUND:

This study focused on circulating plasma protein profiles to identify mediators of hypertension-driven myocardial remodeling and heart failure.

METHODS:

A Mendelian randomization design was used to investigate the causal impact of systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure on 82 cardiac magnetic resonance traits and heart failure risk. Mediation analyses were also conducted to identify potential plasma proteins mediating these effects.

RESULTS:

Genetically proxied higher SBP, DBP, and pulse pressure were causally associated with increased left ventricular myocardial mass and alterations in global myocardial wall thickness at end diastole. Elevated SBP and DBP were linked to increased regional myocardial radial strain of the left ventricle (basal anterior, mid, and apical walls), while higher SBP was associated with reduced circumferential strain in specific left ventricular segments (apical, mid-anteroseptal, mid-inferoseptal, and mid-inferolateral walls). Specific plasma proteins mediated the impact of blood pressure on cardiac remodeling, with FGF5 (fibroblast growth factor 5) contributing 2.96% (P=0.024) and 4.15% (P=0.046) to the total effect of SBP and DBP on myocardial wall thickness at end diastole in the apical anterior segment and leptin explaining 15.21% (P=0.042) and 23.24% (P=0.022) of the total effect of SBP and DBP on radial strain in the mid-anteroseptal segment. Additionally, FGF5 was the only mediator, explaining 4.19% (P=0.013) and 4.54% (P=0.032) of the total effect of SBP and DBP on heart failure susceptibility.

CONCLUSIONS:

This mediation Mendelian randomization study provides evidence supporting specific circulating plasma proteins as mediators of hypertension-driven cardiac remodeling and heart failure.

Keywords: blood pressure, blood proteins, heart failure, hypertension, ventricular remodeling

NOVELTY AND RELEVANCE.

What Is New?

Eight plasma proteins were identified as mediators in the causal pathway of hypertension-driven cardiac remodeling through a mediation Mendelian randomization study that integrated genetic, proteomic data, and cardiac magnetic resonance imaging data.

Fibroblast growth factor 5 has been found to mediate the effect of hypertension on both cardiac remodeling and heart failure.

What Is Relevant?

These findings emphasize the role of plasma proteins as mediators in the causal pathway from blood pressure to cardiac remodeling.

Clinical/Pathophysiological Implications?

The identification of these plasma proteins as mediators might facilitate the development of targeted drugs and the repurposing of approved drugs to alleviate the adverse effects of hypertension on cardiac structure and function. Additionally, these plasma proteins hold potential as biomarkers that can indicate the risk of cardiac remodeling or heart failure associated with hypertension.

Hypertensive heart disease (HHD) continues to pose a significant challenge in the management of hypertension. In 2017, the global age-standardized prevalence of HHD increased by 7.4% compared with 1990, reaching a rate of 217.9 cases per 100 000 individuals,1 and it is projected that the HHD mortality burden will increase rapidly in the next decade.2 HHD is characterized by cardiac remodeling, especially left ventricular (LV) remodeling, which ultimately leads to heart failure.3 Echocardiographic LV hypertrophy was prevalent in 36% to 41% of adult or elderly individuals with hypertension.4 The incidence of elevated blood pressure/hypertension in adolescents is on the rise. Cumulative exposure to elevated systolic blood pressure (SBP) and diastolic blood pressure (DBP) may contribute to cardiac damage in adolescents.5 In addition to SBP and DBP, an increase in pulse pressure (PP) as a biomarker of arterial stiffness triggers concentric LV remodeling and hypertrophy.6 Therefore, the prevention of hypertension-driven cardiac remodeling might be clinically significant.

Cardiac remodeling is a physiological adaptation to chronic pressure overload.7 Hypertension induces immune cell infiltration into the myocardium, leading to the secretion of cytokines and growth factors that shape the crucial local inflammatory microenvironment of the heart during the pathological process of cardiac remodeling.8 Besides autocrine or paracrine proteins that act locally, circulating plasma proteins also contribute to mediating the pathological processes of hypertension, myocardial remodeling, and subsequent heart failure.9,10 In a recent Mendelian randomization (MR) study, 6 circulating plasma proteins were identified as influencing blood pressure levels, including N-terminal pro-B-type natriuretic peptide, urokinase-type plasminogen activator, adrenomedullin, IL (interleukin)-16, cellular fibronectin, and insulin-like growth factor–binding protein 3.11 Prolonged exposure to the hemodynamic stresses associated with hypertension contributes to inflammation, immune activation, and myocardial injury, thereby altering the plasma protein profile.12 Previous preclinical and clinical observational studies identify multiple circulating plasma proteins associated with myocardial remodeling in hypertension, including CXCL (C-X-C motif chemokine ligand) 1),13 FGF (fibroblast growth factor) 23),14 IL-6,15,16 LEP (leptin),17 MCP-1 (monocyte chemoattractant protein-1,18 and GDF (growth differentiation factor) 15).19 However, the specific plasma protein responsible for mediating the causal pathway of hypertension-driven cardiac remodeling and heart failure is still unclear.

We presented a hypothesis that hypertension could lead to alterations in the levels of specific plasma proteins, which in turn mediate hypertension-induced cardiac remodeling and heart failure. The reference standard for characterization of cardiac regional structure and function is currently tagged cardiac magnetic resonance (CMR) imaging.20,21 The recently published UK Biobank study provides the latest summary-level genome-wide association study (GWAS) data. The combination of GWAS data for CMR imaging traits22,23 with pQTL (protein quantitative trait locus) data derived from plasma24,25 has presented novel opportunities for investigating the impact of hypertension on cardiac structure and function. In this study, we designed a mediation MR analysis to identify potential plasma proteins that could act as mediators in the relationship between hypertension-driven changes in CMR traits and the development of heart failure.

METHODS

Data Availability

All available data are shown within the article and the Supplemental Material.

Study Design

Mediation MR design is ideal for addressing this hypothesis. To obtain unbiased estimates of causal effects through mediation analysis, it is necessary that there are no unobserved confounding factors that cannot be accounted for in the estimation and that there is no measurement error in the exposure or mediator variables.26,27 MR designs leverage the natural distribution of genetic variation and allow for causal effect estimation in the presence of unobserved confounding and measurement errors in the exposure.28

This study used mediation MR as its design (Figure 1A). Initially, the effects of elevated SBP, DBP, and PP on 82 CMR traits related to cardiac structure and function were assessed. Subsequently, the circulating plasma proteins influenced by elevated systolic and diastolic pressures were identified. Then, the causal effects of those plasma proteins on CMR traits associated with blood pressure were assessed. Finally, the proportions of mediation mediated by the plasma proteins were calculated. The instrumental variables used for MR need to satisfy 3 assumptions. First, the instrumental variables must be robustly associated with plasma proteins, CMR traits, or heart failure. Second, the instrumental variables should not be related to confounding factors. Third, the instrumental variables only affect the outcome through the exposure factor. This article adheres to the Strengthening the Reporting of Observational Studies in Epidemiology using MR guidelines (Table S1).

Figure 1.

Figure 1.

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Overall design and assumptions of the mediation Mendelian randomization analyses. A, Overall design and assumptions. B, Chromosomal location of all circulating plasma protein. CMR indicates cardiac magnetic resonance.

Data Source

This study utilized publicly available summary-level data from GWAS studies (Table S2). The summary-level GWAS data pertaining to SBP, DBP, or PP were acquired from a meta-analysis of 75 studies encompassing 810 865 individuals of European ancestry.29 Additionally, the summary-level GWAS data associated with circulating inflammatory proteins and cardiovascular proteins were retrieved from a meta-analysis of pQTL. A total of 153 circulating plasma proteins were included as exposures or outcomes (Table S3; Figure 1B). This meta-analysis comprised 11 cohorts with a total of 14 824 participants of European ancestry24 and 13 cohorts with a total of 21 758 participants of European ancestry,25 respectively. Within the aforementioned studies, plasma protein levels were assessed using the Olink Target-96 Inflammation immunoassay panel24 and the Olink proximity extension assay cardiovascular I panel,25,30 respectively.

The summary-level GWAS data on 82 traits related to cardiac structure and function were sourced from 31 875 participants of European ancestry in the UK Biobank study.22,23 These traits were derived from the measurement of different anatomic structures based on cardiovascular magnetic resonance imaging through the previously reported heart segmentation and feature extraction pipeline (https://github.com/baiwenjia/ukbb_cardiac),31 including LV, left atrium, right ventricle, right atrium, ascending aorta, and descending aorta. Furthermore, the summary-level GWAS data on heart failure were obtained from a meta-analysis of 977 323 individuals of European ancestry across 26 studies conducted by the Heart Failure Molecular Epidemiology for Therapeutic Targets consortium.32

All the data analyzed in this study are publicly available. The protocol for each GWAS study was approved by the relevant institutional review board, and informed consent was obtained from the participants or their guardians.

Genetic Variant Selection

For SBP, DBP, and PP, we selected independent single-nucleotide polymorphisms (SNPs) that are strongly associated with SBP, DBP, or PP levels at a genome-wide significance level (P<5×10−8). Independent SNPs were identified through linkage disequilibrium clumping, using a threshold of R2<0.001. For plasma proteins, cis-pQTLs for each plasma protein were considered as a candidate instrumental variable. Variants located within 1 Mb of the transcription start site of the gene encoding the target protein (P<5×10−8) were defined as cis-instrumental variables. Furthermore, SNPs with palindrome alleles (A/T allele or G/C allele) were excluded to prevent strand ambiguity errors. The F statistic was computed using a formula outlined in prior research, and SNPs with an F statistic <10 were excluded, consistent with the Staiger-Stock rule.33,34

Enrichment Analysis

Enrichment analysis was performed using clusterProfiler (version 4.7.1.003)35 and ReactomePA (version 1.42.0) R packages36 based on Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway database, and Reactome pathway database. Benjamini-Hochberg false discovery rate correction was used to correct nominal P values, and false discovery rate <0.05 was considered significant. Pairwise similarities of the enriched Gene Ontology terms were calculated using Jaccard similarity index, and hierarchical clustering of the enriched Gene Ontology terms was performed using Wards variance minimization.37

Drug Target Analysis

The druggability of each protein candidate was assessed using the following resources: Therapeutic Target Database (update of July 31, 2023),38 Drug Gene Interaction Database (version 5.0.3),39 DrugBank (version 5.1.11),40 and Open Targets (version 23.12).41 The corresponding receptors for these plasma proteins were also included in the analysis. Ligand receptors were determined by querying the ligand-receptor data sources of CellphoneDB (version 5.0.0)42 and CellChatDB (version 2.0).43 Drug-gene pairs for each repository were reported using both approved and nonapproved drugs. Additionally, in the Open Targets database, the tractability index for the development of small molecules, antibodies, Proteolysis targeting chimeras, and other modalities was reported.

Statistical Analysis

The causal effects of exposure on outcome were estimated using the multiplicative random-effects inverse variance weighted method where >1 instrument was available, while the Wald ratio was utilized when only 1 instrument was present. The 2-step MR approach was used to explore potential mediating effects of plasma proteins, with the product of coefficients method used to assess indirect effects and calculate the mediated proportion by dividing the indirect effect by the total effect. SEs for the indirect effects were derived using the delta method.26,44,45 Both total and mediated effects were significant, and the mediated proportion was in the positive direction.46 The equations of these analyses are given in the Supplemental Text. Multiple testing corrections were performed using the Benjamini-Hochberg method, reporting as false discovery rate.

For sensitivity analysis, the MR-Egger and weighted median were used for reanalysis. The intercept test from MR-Egger regression served as the principal method to identify directional pleiotropy. Heterogeneity was quantified using Cochran Q statistic and I2 value.

All statistical analyses were performed using R (version 4.2.0; R Core Team) and RStudio (version 2023.06.2 Build 561; Posit PBC, Boston, MA) software. The TwoSampleMR (version 0.5.6) R package was used for MR analysis and sensitivity analysis.

RESULTS

Impact of Blood Pressure on CMR Traits

We observed conservative estimates of F statistics ranging from 30 to 751 for the genetic instruments related to the 3 blood pressure traits examined, indicating that our analyses were robust against weak instrument bias. Tables S4 through S6 present the detailed characteristics and estimated F statistics of the genetic variants.

As expected, MR analysis revealed a causal association between genetically proxied higher SBP (β, 0.33 [95% CI, 0.26–0.39]; P=6.76×10−25), DBP (β, 0.18 [95% CI, 0.12–0.25]; P=9.79×10−8), and PP (β, 0.34 [95% CI, 0.27–0.41]; P=3.12×10−20) and increased LV myocardial mass, as depicted in Figure 2A. Furthermore, regional LV remodeling was also assessed. The LV was divided into 16 segments according to the segmentation model proposed by the American Heart Association.47 Figure 2A shows that increased SBP, DBP, and PP affected both the global and each segment of myocardial wall thickness at end diastole according to the American Heart Association segmentation model.

Figure 2.

Figure 2.

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Effect of blood pressure on cardiac magnetic resonance (CMR) traits. A, Structure and function of left ventricle (LV). B, Structure and function of left atrium (LA), right atrium (RA), and right ventricle (RV). AAo indicates ascending aorta; Ao, aorta; DAo, descending aorta; DBP, diastolic blood pressure; Ecc AHA, peak circumferential strain according to the American Heart Association; Ell, longitudinal strain; Err AHA, radial strain according to the American Heart Association; LAEF, left atrium ejection fraction; LASV, left atrium stroke volume; LAV, left atrium volume; LVCO, left ventricular cardiac output; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; LVM, left ventricular mass; LVSV, left ventricular stroke volume; max, maximum; min, minimum; PP, pulse pressure; RAEF, right atrium ejection fraction; RASV, right atrium stroke volume; RAV, right atrium volume; RVEF, right ventricular ejection fraction; RVEDV, right ventricular end-diastolic volume; RVESV, right ventricular end-systolic volume; RVSV, right ventricular stroke volume; SBP, systolic blood pressure; and WT AHA, myocardial wall thickness at end diastole according to the American Heart Association.

Abnormalities in blood pressure also have an impact on global myocardial strain, particularly radial strain (Err). Higher SBP and DBP were associated with increased global Err (per 1 mm Hg higher SBP: β, 0.32 [95% CI, 0.24–0.41], P=9.52×10−14; per 1 mm Hg higher DBP: β, 0.22 [95% CI, 0.13–0.30], P=1.47×10−6). For regional Err of LV, mainly the basal anterior (segment 1), mid (segments 7–12), and apical (segments 13–16) walls had significantly increased Err. In addition, reduced circumferential strain affected by higher SBP was mainly noted at the apical (segments 13–16), mid-anteroseptal (segment 8), mid-inferoseptal (segment 9), and mid-inferolateral (segment 11) walls. In addition to LV, higher SBP, DBP, and PP were associated with reduced right ventricular end-systolic volume, ascending aorta distensibility, and descending aorta distensibility.

The remaining methods yielded results similar to the main results (Tables S7 through S9). Overall, statistical heterogeneity among individual SNP estimates was low to moderate for most CMR traits (Tables S10 through S12). Besides, the MR-Egger intercept test showed no indication of directional pleiotropy (Tables S13 through S15).

Identification of the Hypertension-Induced Plasma Protein

The next question that arises is which plasma proteins are affected by elevated SBP, DBP, and PP. MR analysis identified 41 causal associations between 3 blood pressure characteristics and 31 plasma proteins. Figure 3 demonstrates that elevated SBP and DBP promote an increase in circulating levels of FGF5) and IL-18, while decreasing levels of CCL2 (C-C Motif Chemokine Ligand 2), FLT3LG (Fms-related receptor tyrosine kinase 3 ligand), and LEP. Additionally, elevated SBP promotes an increase in circulating levels of MMP10 (matrix metallopeptidase 10), PD-L1 (Programmed Death Ligand 1) (CD274 [programmed cell death 1 ligand 1]), IL-33, and IL-10, while decreasing levels of CCL8, IL-20RA, CCL13, CXCL16, and GDF15. Elevated DBP promotes an increase in circulating levels of TGFA (transforming growth factor α), OSM (oncostatin M), CCL28, SELE (selectin E), PECAM1 (platelet and endothelial cell adhesion molecule 1), F3 (coagulation factor III), HAVCR1 (hepatitis A virus cellular receptor 1), GH1 (growth hormone 1), and IL-6R (IL-6 receptor subunit alpha), while causing a decrease in ADA (adenosine deaminase), ADM (adrenomedullin), PRL (prolactin), and IL-16 levels. Elevated PP was casually associated with LIFR (leukemia inhibitory factor receptor), TNFRSF11B (TNF Receptor Superfamily Member 11b), IL-1RL1 (Interleukin 1 Receptor Like 1), and decreased CCL13, IL-20RA (Interleukin 20 Receptor Subunit Alpha), CCL8, ADM, and LEP. Importantly, elevated SBP, DBP, or PP can all lead to a decrease in plasma LEP levels.

Figure 3.

Figure 3.

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Effect of blood pressure on the levels of circulating inflammatory proteins and cardiovascular-related proteins. A, Heatmap for the effect of blood pressure on the levels of circulating inflammatory proteins. B, Heatmap for the effect of blood pressure on the levels of circulating cardiovascular-related proteins. C, Forest plot for the effect of systolic blood pressure (SBP) on the levels of circulating plasma proteins. D, Forest plot for the effect of diastolic blood pressure (DBP) on the levels of circulating plasma proteins. E, Forest plot for the effect of pulse pressure (PP) on the levels of circulating plasma proteins. Significance is marked with * for P<0.05. Full names of the proteins can be found in Table S3.

To gain a deeper insight into the biological significance of 31 circulating plasma proteins affected by blood pressure, a functional enrichment analysis was conducted using the Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Reactome databases. Enrichment analysis showed that those plasma proteins were significantly enriched in the JAK-STAT (Janus Kinase-signal transducers and activators of transcription) and the PI3K-AKT (Phosphoinositide 3 kinase- protein kinase B) signaling pathway (Figure 4).

Figure 4.

Figure 4.

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Enrichment analysis for elevated blood pressure–related circulating plasma proteins. A, Gene ontology enrichment analysis. B, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. C, Reactome pathway enrichment analysis. D, Heatmap plot of enriched terms based on the KEGG pathway. E, Tree plot of hierarchical clustering of enriched gene ontology terms. DBP indicates diastolic blood pressure; FDR, false discovery rate; PP, pulse pressure; and SBP, systolic blood pressure. Full names of the proteins can be found in Table S3.

Mediation Effect of Plasma Protein on Hypertension-Driven Cardiac Remodeling

A total of 192 causal associations of plasma proteins with CMR traits were identified (Figure 5A). Utilizing a mediation MR framework, we investigated whether plasma proteins mediate the impact of blood pressure on cardiac remodeling. As depicted in Figure 5, the mediation analysis revealed that FGF5, CCL13, LEP, MMP10, ADA, AGRP (Agouti Related Neuropeptide), F3, and IL-16 mediated the relationship between SBP (Figure 5B) or DBP (Figure 5C) and CMR traits. Specifically, FGF5 contributed 2.96% (P=0.024) and 4.15% (P=0.046) to the total effect of SBP and DBP on the myocardial wall thickness at end diastole in the apical anterior segment (segment 13), respectively. Meanwhile, LEP explained 15.21% (P=0.042) and 23.24% (P=0.022) of the total effect of SBP and DBP on Err in the mid-anteroseptal segment (segment 8) of the myocardial wall, respectively.

Figure 5.

Figure 5.

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Mediation effect of blood pressure on cardiac magnetic resonance (CMR) traits and heart failure via circulating plasma proteins. A, Heatmap for the effect of circulating plasma proteins on blood pressure (BP)–related CMR traits. Significance is marked with * for P<0.05. B, Forest plot for the mediation effect of systolic blood pressure (SBP) on CMR traits via circulating plasma proteins. C, Forest plot for the mediation effect of diastolic blood pressure (DBP) on CMR traits via circulating plasma proteins. D, Forest plot for the mediation effect of 3 BP traits on heart failure via circulating plasma proteins. AAo indicates ascending aorta; DAo, descending aorta; Ecc AHA, peak circumferential strain according to the American Heart Association; Ell, longitudinal strain; Err AHA, radial strain according to the American Heart Association; LA, left atrium; LAEF, left atrium ejection fraction; LAV, left atrium volume; LASV, left atrium stroke volume; LV, left ventricle; LVCO, left ventricular cardiac output; LVEDV, left ventricular end-diastolic volume; LVM, left ventricular myocardial mass; LVSV, left ventricular stroke volume; max, maximum; min, minimum; OR, odds ratio; PP, pulse pressure; RVESV, right ventricular end-systolic volume; RA, right atrium; RASV, right atrium stroke volume; RAV, right atrium volume; RV, right ventricle; RVEDV, right ventricular end-diastolic volume; RVEF, right ventricular ejection fraction; RVSV, right ventricular stroke volume; and WT AHA, myocardial wall thickness at end diastole according to the American Heart Association. Full names of the proteins can be found in Table S3.

Mediation Effect of Plasma Protein on the Risk of Hypertension-Driven Heart Failure

In the progression of hypertension-driven cardiac remodeling, heart failure represents the ultimate outcome and a manifestation of decompensation. Consequently, we further investigated whether 8 plasma proteins (FGF5, CCL13, LEP, MMP10, ADA, AGRP, F3, and IL-16) could mediate the causal relationship between hypertension and heart failure. Higher levels of FGF5 (odds ratio [OR], 1.025 [95% CI, 1.024–1.026]; P<0.001) and ADA (OR, 0.969 [95% CI, 0.943–0.995]; P=0.020) were causally associated with an increased risk of heart failure (Table S16). Each 1 mm Hg rise in SBP was linked to a 31% increase in the risk of heart failure (OR, 1.31 [95% CI, 1.16–1.49]; P=2.59×10−5; Table S16), and similarly, each 1 mm Hg increase in DBP was associated with a 24% rise in the risk of heart failure (OR, 1.24 [95% CI, 1.10–1.41]; P=5.10×10−4; Table S17). Mediation analysis showed that FGF5 was the only mediator, explaining 4.19% (indirect effect OR, 1.012 [95% CI, 1.002–1.021]; P=0.013) and 4.54% (indirect effect OR, 1.010 [95% CI, 1.001–1.019]; P=0.032) of the total effect of SBP and DBP on heart failure susceptibility (Figure 5D). This implies that the odds ratio of heart failure prevalence increased by 1.2% for each 1 mm Hg increase in SBP and 1.0% for each 1 mm Hg increase in DBP, as a result of the mediational mechanism of FGF5.

Drug Target Analysis

Multiple resources were utilized to conduct a drug target analysis. We examined plasma proteins and corresponding receptors (Table S18) to determine whether they serve as targets for approved or in-development small molecules or biologics. The Therapeutic Target Database reports 3 plasma proteins (F3, AGRP, and ADA) and the corresponding receptors of 5 plasma proteins (FGF5, IL-16, AGRP, LEP, and CCL13) as either targets in clinical trials or successful targets (Table S19). The Drug Gene Interaction Database and DrugBank reported a total of 417 drug-target pairs (Tables S20 and S21) involving 4 plasma proteins (F3, MMP10, ADA, and LEP) and the corresponding receptors of 5 plasma proteins (FGF5, IL-16, AGRP, LEP, and CCL13). Open Targets reports a total of 1838 clinical trial information entries for 109 drug-target pairs (Table S22). According to Open Targets reports, 7 plasma proteins (FGF5, MMP10, AGRP, ADA, IL-16, LEP, and CCL13) and the corresponding receptors of 3 plasma proteins (FGF5, AGRP, and CCL13) are deemed tractable for the development of antibodies (Figure S1).

Taken together, these data suggest that FGF5, AGRP, MMP10, F3, and LEP are potential targets for hypertension-driven cardiac remodeling or heart failure according to their directional effects and biological actions. These plasma proteins or their receptors are the object of approved, in-development inhibitors or deemed tractable for the development of novel inhibitors (antibodies) or agonists.

DISCUSSION

To the best of our knowledge, this is the first study to comprehensively assess the causal associations between blood pressure, plasma protein, CMR traits, and heart failure. The findings from our study, which utilized mediation MR analysis, systematically investigated the mediating effects of circulating plasma proteins on the relationship between blood pressure traits and cardiac remodeling. Our results indicate that several proteins, including FGF5, LEP, CCL13, MMP10, ADA, AGRP, F3, and IL-16, play notable roles in mediating the association between hypertension and CMR traits, with particular emphasis on the contributions of LEP and FGF5. FGF5 also mediated the causal association of high SBP or DBP with increased susceptibility to heart failure. These findings offer insights into the potential mechanisms underlying these complex relationships.

Our study demonstrates the landscape of changes in cardiac structure and functional phenotypes as blood pressure increases. Previous observational studies have demonstrated that advanced HHD exhibits reduced radial, circumferential, and longitudinal strain. An increased Err in the LV indicates that the myocardium affected by hypertension is still in a compensatory state.48

Previous studies have identified FGF5as the gene associated with susceptibility to hypertension,49–51 particularly in salt-sensitive49,52 and obese populations.53 Elevated levels of FGF5 have been observed in the peripheral blood of patients with hypertension, and these levels have shown a significant correlation with SBP and DBP.54 Our study further supports the notion that elevated SBP or DBP leads to increased plasma FGF5 levels, consistent with the findings of previous studies. Previous studies have shown that FGF5 induces hypertrophy and proliferation in cardiomyocytes.55–57 This process is believed to be one of the underlying mechanisms contributing to FGF5-driven wall thickening through increased myocardial mass. FGF is released from cardiac myocytes that have experienced wounding due to mechanical loading, which subsequently triggers hypertrophy in neighboring myocyte.55,58 Similar to patients with hypertension, athletes experiencing endurance exercise also undergo physiological cardiac hypertrophy to accommodate cardiac pressure overload. The FGF and FGFR (fibroblast growth factor receptor) signaling systems regulate exercise-induced cardiac hypertrophy.59 However, current research has primarily focused on FGF260 and FGF21,61 neglecting FGF5. Furthermore, large prospective studies are needed to investigate the role of FGF5.

Our analysis also revealed that FGF5 drives global myocardial wall thickening at end diastole and mediates the effects of hypertension on myocardial wall segments 1, 13, and 16. These findings indicate that elevated circulating plasma FGF5 levels are critical for early adaptive cardiac hypertrophy in hypertension. Interestingly, FGF5 was also observed to mediate the relationship between hypertension and heart failure in this study, which are not reported in the previous studies. Providing indirect evidence that sustained high plasma FGF5 levels may promote the development of heart failure in patients with hypertension.

FGF5 plays a role in mediating the relationship between high SBP or DBP and cardiac remodeling as well as heart failure. FGFR1, FGFR2, and FGFR3 serve as receptors for FGF5, with FGFR1 being the predominant isoform in the myocardium. Overexpression of FGFR1 results in cardiac hypertrophy.62 Several FGFR1-targeting kinase inhibitors have been approved for the treatment of malignancies and idiopathic pulmonary fibrosis. Among these inhibitors are nintedanib, regorafenib, sorafenib, ponatinib, and lenvatinib, which exhibit potential as treatments for HHD. Additionally, the development of FGF5 antibodies also presents a new opportunity for treating HHD.

The effect of LEP on cardiac remodeling has been controversial, and excessive or lower LEP levels can lead to cardiac remodeling. There is a view that circulating LEP levels can only be maintained at the right level to maintain cardiometabolic health.63 Multiple population-based studies have documented the impact of LEP on cardiac hypertrophy.64,65 In contrast to those, several recent studies suggested that humans or mice with lower LEP exhibit cardiac hypertrophy,66–70 which this study substantiates. It is noteworthy that lower LEP affects primarily the Err, which is a critical mediator of hypertension-driven increased Err in the mid-anteroseptal segment of LV.

Our findings indicate that in addition to FGF5 and LEP, AGRP, MMP10, and F3 are also potential targets for hypertension-induced cardiac remodeling. Consistent with our results, the Hoorn Study reported a positive association between MMP10 and left atrial remodeling.71 F3, also known as TF (tissue factor), plays a crucial role as an initiator in the coagulation cascade. Hypertension can lead to increased circulating levels of F3, potentially contributing to thrombotic events in patients with hypertension.72 Currently, there is no evidence suggesting an association between F3 and hypertension-driven cardiac remodeling. However, a few studies have indicated a possible correlation between elevated F3 levels and myocardial hypertrophy.73 Similarly, there is no evidence of a correlation between AGRP and hypertension-driven cardiac remodeling. Nonetheless, inhibiting the AGRP receptor MC3/4R (Melanocortin 3/4 Receptor) has been shown to reduce mean arterial pressure in a spontaneous hypertension rat model.74,75

Mediation MR studies offer a practical and efficient approach to comprehending the contribution of risk factors to the development of diseases. By examining the mediators along the causal pathway from the risk factor to the disease, these studies enable the identification of suitable targets for developing therapies that can mitigate the potential consequences of harmful exposures. In the context of hypertension-driven cardiac remodeling and heart failure, mediation analysis has identified 8 plasma proteins with potential as biomarkers of hypertension-driven cardiac remodeling or heart failure. These findings contribute to our understanding of the molecular mechanisms underlying the impact of hypertension on cardiovascular health, providing objective insights for future research and clinical applications in cardiology. By elucidating the roles of these proteins in mediating the relationship between hypertension and cardiac remodeling, the study might offer new insights that could inform the development of targeted drugs aimed at mitigating the adverse effects of hypertension on cardiac structure and function. This has the potential to offer a new direction for the development of more effective treatments for hypertension-induced cardiac remodeling and heart failure.

Genetic variants respond to lifelong changes in blood pressure and plasma proteins. The results of MR analyses could be interpreted as the average effects of blood pressure and plasma proteins over a lifetime, representing the cumulative impact of exposure levels from conception and throughout the course of life.76 Conversely, in prospective observational studies based on individual-level data, assessing the lifetime effects requires measuring blood pressure (exposures), plasma proteins (mediators), and CMR traits/heart failure (outcomes) at separate and consecutive time points, with sufficient follow-up time for repeated measurements. In such scenarios, the timing of measurements becomes crucial for estimating both direct and indirect effects. Exposure to elevated blood pressure can result in cardiac remodeling or heart failure, a gradual process that can persist over several years. Thus, compared with individual-level observational studies, the effect sizes estimated by MR study based on summary-level data tend to be overestimated.77 Consequently, one view is that the results of MR analyses are more likely to indicate causal direction rather than quantify the magnitude of the causal effect.77 Furthermore, despite the emphasis on causation, the findings of this MR study can actually be interpreted as the percentage of outcome variances that can be explained by variances within the gene pool using specific causal models. The linear models used in this study serve as simplified representations of reality. In nature, causal models can exhibit even greater complexity, forming intricate networks in reality.

The study presents several strengths. First, unlike observational studies, MR designs can establish causal relationships between exposure and outcome rather than mere associations. Second, cardiac magnetic resonance imaging offers a more comprehensive assessment of the heart’s structural and functional phenotype, enabling this study to investigate the impact of plasma proteins on local myocardial tissue, a perspective overlooked in previous research. However, our study has limitations. First, due to the unavailability of individual-level GWAS data in the public domain, this study was unable to evaluate the nonlinear quantitative effects of blood pressure and circulating plasma proteins on cardiac structural and functional phenotypes. Second, variations in plasma protein profiles resulting from hypertension show ethnic heterogeneity; nonetheless, this study only included GWAS data from individuals of European descent, thereby constraining the generalizability of the study’s findings to other diverse populations. Third, it is important to note that MR analysis may not fully capture the time-varying nature of blood pressure and plasma proteins, which is recognized as a current methodological challenge for MR studies.78 This limitation highlights the need for future advancements in methodology to effectively account for temporal changes. Lastly, replicating this study through individual-level analyses is limited by the lack of suitable prospective observational data. Addressing this limitation will require future long-term follow-up cohort studies.

In summary, this study identified 8 circulating plasma proteins as mediators of hypertension-driven cardiac remodeling and heart failure. These findings emphasize the importance of elucidating the underlying mechanisms between hypertension and cardiac remodeling. Notably, FGF5 could serve as a potential biomarker and drug target for hypertension-driven cardiac remodeling, providing new insights into the prevention and treatment of hypertension-driven cardiac remodeling.

PERSPECTIVES

Utilizing a mediation MR approach, the present study demonstrates that 8 plasma proteins act as mediators in the causal pathway of hypertension-driven cardiac remodeling. It is noteworthy that FGF5 has been implicated in both hypertension-driven cardiac remodeling and heart failure. These plasma proteins show potential as biomarkers for assessing the risk of cardiac remodeling or heart failure associated with hypertension. Further studies are needed to investigate the evolving dynamics of the mediating effects exerted by the 8 plasma proteins on hypertension-driven cardiac remodeling or heart failure over an extended period. The identification of these plasma proteins as mediators might facilitate the development of targeted drugs and the repurposing of approved drugs to mitigate the adverse effects of hypertension on cardiac structure and function. This highlights promising directions for future research in this field.

ARTICLE INFORMATION

Acknowledgments

This work was made possible by the generous sharing of genome-wide association study summary statistics. The authors thank all the patients who provided the sample that made the data available and all the investigators who provided these data to support this study.

Sources of Funding

This study was supported by the Major Science and Technology Demonstration Project in Shandong Province (No. 2021SFGC0503), State Administration of Traditional Chinese Medicine High-level Chinese Medicine Key Discipline Construction Project (No. zyyzdxk-2023120), and Key Projects of Natural Science Foundation of Shandong Province (No. ZR2020KH034).

Disclosures

None.

Supplemental Material

Supplemental Text

Figure S1

Tables S1–S22

Supplementary Material

hyp-81-1132-s001.pdf (7.1MB, pdf)

Nonstandard Abbreviations and Acronyms

ADA
adenosine deaminase
ADM
adrenomedullin
AGRP
agouti related neuropeptide
CMR
cardiac magnetic resonance
CXCL
C-X-C motif chemokine ligand
DBP
diastolic blood pressure
Err
radial strain
F3
coagulation factor III
FGF
fibroblast growth factor
FGFR
fibroblast growth factor receptor
FLT3LG
Fms-related receptor tyrosine kinase 3 ligand
GDF
growth differentiation factor
GH1
growth hormone 1
GWAS
genome-wide association study
HAVCR1
hepatitis A virus cellular receptor 1
HHD
hypertensive heart disease
IL
interleukin
LEP
leptin
LV
left ventricle
MCP-1
monocyte chemoattractant protein-1
MMP10
matrix metallopeptidase 10
MR
Mendelian randomization
OR
odds ratio
OSM
oncostatin M
PECAM1
platelet and endothelial cell adhesion molecule 1
PP
pulse pressure
pQTL
protein quantitative trait locus
PRL
prolactin
SBP
systolic blood pressure
SELE
selectin E
SNP
single-nucleotide polymorphism
TF
tissue factor
TGFA
transforming growth factor α
*

Y. Hu and L. Lin contributed equally.

For Sources of Funding and Disclosures, see page 1142.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

hyp-81-1132-s001.pdf (7.1MB, pdf)

Data Availability Statement

All available data are shown within the article and the Supplemental Material.

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