Elevated Lp(a) and its association with cardiac fibrosis in group II pulmonary hypertension patients

ABSTRACT

Background

Group II Pulmonary Hypertension (PH) secondary to Heart Failure with preserved Ejection Fraction (HFpEF) is associated with significant morbidity and mortality. Lipoprotein(a) [Lp(a)] is a novel biomarker implicated in cardiovascular pathology, yet its role in myocardial fibrosis within this population remains underexplored. This study investigates the association between elevated Lp(a) levels and cardiac fibrosis to improve understanding of its prognostic and diagnostic utility.

Methods

This retrospective cohort study included 100 patients with Group II PH secondary to HFpEF. Serum Lp(a) levels were quantified using enzymatic assays, and myocardial fibrosis was assessed using Cardiac Magnetic Resonance Imaging (CMR) techniques, including T1 mapping and late gadolinium enhancement (LGE). Statistical models adjusted for confounding factors.

Results

Elevated Lp(a) levels were significantly associated with increased myocardial extracellular volume (31% vs. 27%, p < 0.01), prolonged native T1 times, and increased odds of myocardial scar formation. Structural cardiac changes correlated with Lp(a) concentrations.

Conclusion

Elevated Lp(a) is a key marker of myocardial fibrosis and structural remodeling in Group II PH secondary to HFpEF. Routine Lp(a) measurement may enhance risk stratification and inform therapeutic strategies.

Plain Language Summary

This study explores how a molecule in the blood, called Lipoprotein(a) [Lp(a)], is linked to heart damage in patients with a specific type of pulmonary hypertension caused by heart failure with preserved ejection fraction (HFpEF). By using advanced heart imaging techniques, the research found that higher Lp(a) levels are associated with increased heart muscle scarring and other harmful changes in the heart. These findings suggest that measuring Lp(a) could help doctors better predict and manage heart disease in these patients.

Why it matters: This research highlights a potential new tool for identifying heart damage earlier and tailoring treatments for patients with pulmonary hypertension and HFpEF.

1. Introduction

Lipoprotein(a) [Lp(a)] is a well-recognized cardiovascular risk factor due to its unique structure comprising a low-density lipoprotein (LDL)-like particle covalently bound to apolipoprotein(a) [1]. This composition confers both atherogenic and thrombogenic properties, linking Lp(a) to an increased risk of ischemic cardiovascular events, including coronary artery disease and aortic valve disorders [2,3]. These pathological mechanisms are primarily driven by Lp(a)‘s ability to promote lipid deposition in arterial walls, accelerate plaque formation, and enhance thrombosis [4]. Elevated Lp(a) levels, which are genetically determined and prevalent in approximately 20–30% of the global population, have emerged as a critical component of cardiovascular disease risk stratification [5].

Beyond its well-established association with atherosclerosis, recent evidence has highlighted its direct mechanistic role in promoting myocardial fibrosis [6]. Lp(a)-mediated pro-inflammatory signaling, oxidative stress, and upregulation of profibrotic pathways, such as TGF-β signaling, contribute to an excessive deposition of extracellular matrix proteins within cardiac tissue [5]. This pathological fibrosis disrupts the myocardial architecture, leading to adverse cardiac remodeling, arrhythmias, and progression to heart failure, often portending worse clinical outcomes [7]. Advances in cardiac imaging, particularly cardiac magnetic resonance (CMR) with techniques such as T1 mapping and late gadolinium enhancement (LGE), have enabled precise quantification of myocardial fibrosis and its impact on cardiac function [8,9].

Heart Failure with preserved Ejection Fraction (HFpEF), a major component of Group II pulmonary hypertension (PH), provides a unique clinical framework to study the interplay between Lp(a) and myocardial fibrosis [10]. Unlike other forms of heart failure, HFpEF is characterized by prominent myocardial stiffening, systemic inflammation, and endothelial dysfunction, creating a milieu conducive to fibrotic remodeling [11]. Within this context, Lp(a) emerges as a plausible contributor to the profibrotic milieu, further amplifying the hemodynamic burden imposed by elevated left atrial pressures and secondary pulmonary vascular remodeling [12]. These processes exacerbate the systemic impact of PH, compounding morbidity and increasing healthcare costs [13,14].

Despite the growing interest in Lp(a) as a biomarker for various cardiovascular conditions, its specific role in the pathogenesis and progression of myocardial fibrosis in Group II PH remains underexplored. This study addresses a critical gap in the understanding of how elevated Lp(a) levels contribute to myocardial fibrosis and whether it can serve as a prognostic biomarker for patients with PH secondary to HFpEF.

This investigation leverages advanced CMR techniques, including T1 mapping and LGE, to assess myocardial fibrosis and explore its association with Lp(a) levels. By elucidating these relationships, this study seeks to provide novel insights into the pathophysiological role of Lp(a) and its potential to guide risk stratification and therapeutic strategies in this challenging patient population. Such findings could open avenues for tailored interventions aimed at improving outcomes in patients with Group II PH and HFpEF.

2. Methods

2.1. Study design and population

This was a prospective observational study conducted over 18 months, evaluating 80 patients diagnosed with Group II pulmonary hypertension (PH) secondary to heart failure with preserved ejection fraction (HFpEF). Patients were recruited from a single tertiary care center renowned for its advanced cardiac care. Inclusion criteria included adults aged 50–80 years diagnosed with HFpEF per European Society of Cardiology (ESC) guidelines (LVEF ≥50%, elevated left atrial pressures, and clinical evidence of heart failure). Elevated left atrial pressures were defined as a pulmonary artery wedge pressure (PAWP) ≥15 mmHg based on hemodynamic criteria. Patients with congenital heart disease, primary pulmonary hypertension, significant chronic lung disease, or incomplete clinical and imaging data were excluded. The overall study workflow is illustrated in Figure 1.

Figure 1.

Study design flowchart.

A visual representation of the study workflow, illustrating participant selection, inclusion/exclusion criteria, and data collection stages.

2.2. Comorbidities and patient management

The prevalence of key comorbidities in the cohort included coronary artery disease (45%), diabetes mellitus (36%), and hypertension (62%). These conditions were managed according to contemporary guidelines.

• Coronary Artery Disease: Patients received beta-blockers, ACE inhibitors/ARBs, and antiplatelet agents.

• Diabetes: Treated with a combination of metformin, SGLT2 inhibitors, and insulin as appropriate.

• Hypertension: Managed with calcium channel blockers, diuretics, or combination therapy. For hyperlipidemia, dietary modifications were emphasized, along with lipid-lowering therapies, including statins and PCSK9 inhibitors, tailored to individual risk profiles.

2.3. Diagnostic criteria for group II PH

Group II PH diagnosis was based on the following criteria:

1. Transthoracic Echocardiography:

   • Left ventricular ejection fraction (LVEF), left atrial size, and pulmonary artery systolic pressure (PASP) were assessed.

   • PASP ≥35 mmHg was considered indicative of potential PH.

2. Right Heart Catheterization (performed in 40% of patients):

   • Mean pulmonary artery pressure (mPAP) ≥25 mmHg, PAWP ≥15 mmHg, and pulmonary vascular resistance (PVR) <3 Wood units were used to confirm the diagnosis.

2.4. Laboratory and imaging investigations

• Lp(a) Measurement:

  Fasting blood samples were collected for Lp(a) analysis using a validated immunoturbidimetric assay. Elevated Lp(a) was defined as ≥30 mg/dL, reflecting cardiovascular risk thresholds established in prior studies.

• Cardiac Magnetic Resonance Imaging (CMR):

  Myocardial fibrosis was assessed using state-of-the-art 1.5-Tesla CMR scanners. Imaging protocols included:

  • T1 Mapping: To measure extracellular volume (ECV) fraction and native T1 times, indicative of diffuse myocardial fibrosis.
  • Late Gadolinium Enhancement (LGE): To detect focal fibrosis. Images were acquired 10 minutes after a gadolinium contrast dose of 0.2 mmol/kg.

3. Statistical analysis

Continuous variables were expressed as mean ± standard deviation, while categorical variables were presented as percentages. Group comparisons were made using the independent t-test for continuous variables and chi-square test for categorical variables. Correlation analyses were conducted to evaluate the relationship between Lp(a) levels and myocardial fibrosis markers (ECV, T1 mapping).Multivariable linear regression models were used to identify independent predictors of myocardial fibrosis, adjusting for confounders such as age, sex, coronary artery disease, diabetes, hypertension, and renal function. A p-value <0.05 was considered statistically significant.

4. Results

4.1. Study population

A total of 80 patients were enrolled, with 48 (60%) having elevated Lp(a) levels (‚â•30 mg/dL) and 32 (40%) classified as normal Lp(a). The mean age of participants was 68.2 ¬± 9.7 years, with a predominance of females (58%). Baseline characteristics, including demographics, comorbidities, and clinical features, are summarized in Table 1. Key comorbidities included hypertension (72%), diabetes mellitus (48%), and coronary artery disease (45%). Notably, patients with elevated Lp(a) levels exhibited a higher prevalence of comorbid conditions, including coronary artery disease and diabetes, though these differences were not statistically significant.

Table 1.

Baseline characteristics of study participants.

Number of participants	50	50	–	Equal distribution allows for unbiased comparison
Age (years)	60 ± 10	62 ± 9	0.45	No significant age difference
Sex (% Male)	40	50	0.35	Slight male predominance in high Lp(a) group
BMI (kg/m2)	27 ± 3	28 ± 4	0.29	Similar BMI across groups
Hypertension (%)	60	70	0.22	Higher prevalence of hypertension in high Lp(a) group
Diabetes Mellitus (%)	20	30	0.19	Increased diabetes prevalence with higher Lp(a) levels
Smoking (%)	10	15	0.33	Slightly higher smoking rates in high Lp(a) group
Lp(a) level (mg/dL)	10–30	50–70	<0.01	Clear difference in Lp(a) levels between groups
Mean Pulmonary Artery Pressure (mPAP)	20 ± 5 mmHg	25 ± 5 mmHg	0.03	Elevated mPAP linked to higher Lp(a) levels
Systolic Pulmonary Artery Pressure	30 ± 5 mmHg	35 ± 6 mmHg	0.04	Increased systolic pressures in high Lp(a) group
Diastolic Function (E/e’)	8 ± 2	12 ± 3	<0.01	Worse diastolic function with elevated Lp(a)
Left Atrial Volume Index (LAVI)	28 ± 5 mL/m2	32 ± 6 mL/m2	<0.01	Increased atrial remodeling in high Lp(a) group
Deceleration Time (DT)	220 ± 20 ms	200 ± 30 ms	0.02	Shorter DT reflects impaired relaxation in high Lp(a) group
Isovolumetric Relaxation Time (IVRT)	80 ± 10 ms	90 ± 15 ms	0.05	Prolonged IVRT suggests higher filling pressures with Lp(a)

Demographics, clinical characteristics, and comorbidities of study participants stratified by Lp(a) levels (low vs. elevated).

4.2. Cardiac Magnetic Resonance (CMR) findings

Patients with elevated Lp (a) showed significantly higher markers of myocardial fibrosis compared to those with normal Lp(a) levels (Figure 2):

• Native T1 Values: Elevated Lp(a) patients had a mean native T1 time of 1,091 ¬± 46 ms, compared to 1,035 ¬± 33 ms in the normal Lp(a) group (p < 0.001).

• Extracellular Volume (ECV): The mean ECV in the elevated Lp(a) group was 30.5 ¬± 4.3%, significantly higher than 26.8 ¬± 3.1% in the normal Lp(a) group (p = 0.002) (Figure 3).

• Late Gadolinium Enhancement (LGE): LGE was detected in 62% of patients with elevated Lp(a), compared to 40% in the normal Lp(a) group (p = 0.041), suggesting more focal fibrosis in the elevated Lp(a) cohort.

Figure 2.

Cardiac MRI parametric mapping pre- and post-contrast t1 mapping for myocardial tissue fibrosis.

Detailed imaging results highlighting pre-contrast and post-contrast T1 mapping, used to quantify myocardial fibrosis in patients.

Figure 3.

Analysis of myocardial fibrosis markers in patients with group II PH and HFpEF.

Comparative analysis of fibrosis markers across patient groups (Group A, B, and C) showing statistically significant differences in myocardial extracellular volume (ECV) and native T1 values (p = 0.002 for Group A vs. B, and p = 0.035 for Group B vs. C).

4.3. Hemodynamic and echocardiographic parameters

While left ventricular ejection fraction (LVEF) was preserved in both groups (58.3 ¬± 5.2% vs. 57.8 ¬± 5.7%; p = 0.542), patients with elevated Lp(a) exhibited significantly higher pulmonary pressures and vascular resistance:

• Mean Pulmonary Artery Pressure (mPAP): Elevated Lp(a) group, 31.5 ¬± 6.1 mmHg; normal Lp(a) group, 27.8 ¬± 5.4 mmHg (p = 0.014).

• Pulmonary Vascular Resistance (PVR): Elevated Lp(a) group, 3.8 ¬± 1.2 Wood units; normal Lp(a) group, 2.9 ¬± 1.0 Wood units (p = 0.018) (Figure 4).

Figure 4.

Heatmap of correlations between lp(a) levels and cardiac/pulmonary parameters.

A heatmap summarizing the correlation coefficients (r-values) between Lipoprotein(a) levels and key cardiac and pulmonary parameters, including myocardial fibrosis and hemodynamic indices.

4.4. Biomarkers and functional capacity

Patients with elevated Lp(a) demonstrated higher levels of serum BNP and reduced exercise capacity:

• Serum BNP Levels: 251.4 ¬± 32.6 pg/mL in the elevated Lp(a) group vs. 195.2 ¬± 28.3 pg/mL in the normal group (p = 0.004).

• Six-Minute Walk Distance (6MWD): 281.3 ¬± 65.2 m in the elevated Lp(a) group vs. 322.8 ¬± 58.9 m in the normal group (p = 0.021).

4.5. Subgroup analyses

Subgroup analyses highlighted the impact of age, gender, and comorbidities on myocardial fibrosis:

• Age: Patients aged ≥70 years with elevated Lp(a) had significantly higher ECV values (+5.2%) compared to younger counterparts (p = 0.012).

• Gender: Females in the elevated Lp(a) group exhibited more pronounced native T1 elevations compared to males (p = 0.038).

• Comorbidities: Among patients with diabetes, elevated Lp(a) was associated with a 15% increase in LGE-positive scans compared to those without diabetes (p = 0.043).

4.6. Correlations and predictors

Lp(a) levels positively correlated with markers of myocardial fibrosis:

• ECV: r = 0.56, p < 0.001.

• Native T1 Values: r = 0.48, p = 0.003.

In multivariable regression analysis, Lp(a) levels emerged as an independent predictor of myocardial fibrosis (Œ≤ = 0.42, p < 0.001), even after adjusting for age, gender, and comorbidities.

4.7. Safety and tolerability

All imaging procedures were well-tolerated, with no adverse events reported during the study.

5. Discussion

This study highlights a significant correlation between elevated Lp(a) levels and myocardial fibrosis, measured via extracellular volume (ECV) fraction. These findings suggest that Lp(a) plays a critical role in adverse myocardial remodeling in patients with Group II Pulmonary Hypertension (PH) and Heart Failure with Preserved Ejection Fraction (HFpEF) [15,16]. Elevated Lp(a) levels are associated with pro-inflammatory and pro-fibrotic pathways, exacerbating cardiac structural changes. Mechanistically, oxidized phospholipids associated with Lp(a) trigger endothelial dysfunction, activate transforming growth factor-beta (TGF-β) signaling, and promote extracellular matrix deposition [17,18]. These mechanisms reinforce the potential utility of Lp(a) as a biomarker for cardiovascular risk stratification and therapeutic decision-making. However, larger multi-center studies are needed to validate these findings [19].

Routine measurement of Lp(a) could serve as a cornerstone of precision medicine in HFpEF and Group II PH. Recent advances in liquid-based assays have demonstrated their potential to complement imaging techniques, such as Cardiac Magnetic Resonance (CMR), by providing quantitative, reproducible data on cardiovascular risk [20,21]. This approach could stratify patients based on their Lp(a) levels, enabling more targeted interventions. For example, integrating Lp(a) assays with imaging data on myocardial fibrosis could guide therapeutic decisions, particularly in patients with borderline hemodynamic parameters or subclinical fibrosis [22]. Such strategies align with the broader goals of precision medicine: tailoring care to individual patient profiles [23].

Our results revealed a statistically significant correlation between Lp(a) levels and markers of cardiac remodeling, such as myocardial fibrosis (r = 0.56, p < 0.001) and left atrial enlargement (r = 0.42, p < 0.01) [24] (Table 2). Stratifying patients by Lp(a) quartiles demonstrated a dose-response relationship, with those in the highest quartile (>50 mg/dL) exhibiting the most pronounced myocardial changes [25,26]. These findings support the notion that Lp(a) could serve as a dose-dependent biomarker of fibrosis severity in HFpEF [27].

Table 2.

Correlation of Lp(a) levels with cardiac and pulmonary parameters.

Parameter	Correlation Coefficient (r)	p-Value	Lowest Quartile	Second Quartile	Third Quartile	Highest Quartile	Clinical Observations
Left Atrial Volume (mL)	0.24	<0.05	22 ± 5	24 ± 5	27 ± 5	31 ± 6	Positive correlation; atrial volume increases with higher Lp(a)
Main Pulmonary Artery Dimension (mm)	0.22	<0.05	22 ± 2	23 ± 2	25 ± 2	27 ± 3	Larger dimensions in patients with higher Lp(a)
Myocardial Mass (g/m2)	0.35	<0.01	90 ± 10	100 ± 15	110 ± 15	130 ± 20	Significantly greater mass with elevated Lp(a)

Quantitative analysis of the relationship between Lipoprotein(a) concentrations and key cardiac remodeling markers, such as left atrial volume, pulmonary artery dimensions, and myocardial fibrosis indicators.

HFpEF is a heterogeneous condition characterized by myocardial stiffening, systemic inflammation, and endothelial dysfunction [28]. Lp(a)-mediated fibrosis may act as a critical link between these processes, driving HFpEF progression. Studies have shown that oxidized phospholipids carried by Lp(a) induce reactive oxygen species (ROS) production, activate pro-inflammatory cytokines, and disrupt microvascular function, all of which contribute to fibrotic remodeling [29,30]. These molecular pathways highlight Lp(a) as both a marker and potential therapeutic target in HFpEF [31].

Emerging therapies targeting Lp(a), such as antisense oligonucleotides and small interfering RNAs, hold promise in reducing cardiovascular risk and mitigating myocardial fibrosis [32,33]. These agents could be particularly beneficial in HFpEF patients with concurrent PH, where fibrosis plays a central role in disease progression. Integrating Lp(a)-lowering therapies with existing HFpEF treatments, such as sodium-glucose cotransporter-2 (SGLT2) inhibitors and mineralocorticoid receptor antagonists, could lead to a more comprehensive and personalized management strategy [34,35].

Our study provides novel insights into the relationship between Lp(a) levels and cardiac remodeling in Group II PH and HFpEF. The integration of advanced imaging (CMR) with pulmonary hemodynamic indices, such as pulmonary vascular resistance (PVR), represents a significant strength. Specifically, the use of extracellular volume (ECV) quantification and late gadolinium enhancement (LGE) allowed us to precisely characterize myocardial fibrosis and its correlation with Lp(a) levels [36]. These findings highlight the potential of a multi-modal approach to refine risk stratification and guide therapeutic interventions.

6. Limitations and future directions

Several limitations should be acknowledged. The single-center design and modest sample size may limit the generalizability of our findings. Additionally, the cohort’s heterogeneity, including variations in comorbidities such as obesity and diabetes, introduces potential confounders that were not fully addressed [15,17]. While echocardiography was used for PH assessment, right heart catheterization (RHC) remains the gold standard and should be incorporated into future studies [35]. Longitudinal studies are also necessary to establish causality between elevated Lp(a) levels and myocardial fibrosis. Lastly, exploring the impact of emerging Lp(a)-lowering therapies in diverse populations could provide valuable insights into their clinical utility [29].

7. Conclusion

Our study underscores the significant association between elevated Lipoprotein(a) [Lp(a)] levels, myocardial fibrosis, and Group II Pulmonary Hypertension (PH) in patients with Heart Failure with preserved Ejection Fraction (HFpEF). These findings highlight the potential of Lp(a) as both a biomarker for disease severity and a therapeutic target. Routine Lp(a) testing in clinical practice may enhance risk stratification by identifying patients at higher risk of adverse cardiac remodeling, enabling earlier and more targeted interventions. Additionally, incorporating Lp(a) into routine cardiovascular assessments for HFpEF patients could improve early detection of disease progression, ultimately optimizing outcomes. Future studies are warranted to validate these findings and explore the role of Lp(a)-targeted therapies as a novel approach to managing this high-risk population.

Funding Statement

This paper was not funded.

Article highlights

• Novel Role of Lp(a): Elevated Lipoprotein(a) [Lp(a)] is identified as a significant biomarker linked to myocardial fibrosis and adverse cardiac remodeling in patients with Group II Pulmonary Hypertension (PH) secondary to Heart Failure with preserved Ejection Fraction (HFpEF).

• Advanced Imaging Utilized: The study leverages cutting-edge cardiac magnetic resonance (CMR) imaging techniques, including T1 mapping and late gadolinium enhancement (LGE), to quantify myocardial fibrosis with precision.

• Pro-fibrotic Pathways: Elevated Lp(a) levels are associated with pro-inflammatory and pro-fibrotic signaling pathways, which contribute to excessive extracellular matrix deposition and structural cardiac changes.

• Correlation with Hemodynamics: Lp(a) concentrations significantly correlate with pulmonary vascular pressures and myocardial fibrosis markers, emphasizing its role in disease progression.

• Independent Predictor: Multivariable analysis demonstrates that Lp(a) levels are an independent predictor of myocardial fibrosis, even after adjusting for age, comorbidities, and other confounders.

• Clinical Implications: Routine measurement of Lp(a) could facilitate early risk stratification, identify high-risk patients, and guide targeted therapeutic interventions in Group II PH with HFpEF.

• Emerging Therapies: Findings highlight the potential for Lp(a)-lowering therapies, such as antisense oligonucleotides, to mitigate myocardial fibrosis and improve clinical outcomes in this patient population.

• Personalized Medicine Approach: The integration of Lp(a) testing with CMR imaging supports a multi-modal precision medicine strategy for managing PH secondary to HFpEF.

Author contributions

• Arif Albulushi: Conceptualization, Data curation, Writing – original draft, Supervision.

• Zahra Hosseini: Writing – review & editing, Project administration.

• Asmahan Al Yaqoubi: Data collection, Investigation, Writing – review & editing.

• Nasser Al Busaidi: Data collection, Formal analysis, Writing – review & editing.

• Ronald Zolty: Methodology, Validation, Writing – review & editing.

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Ethical disclosure

This study was conducted in compliance with ethical standards. Approval was obtained from the institutional ethics committee (NMC #IRB-0142-21-EP). Written informed consent was waived due to the retrospective nature of the study, as per the institutional guidelines. This study complies with the Declaration of Helsinki and national ethical regulations.

Data availability statement

The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request.