Next Article in Journal
Deoxygenation Trends and Their Multivariate Association with Self-Reported Fatigue in Post-COVID Syndrome
Previous Article in Journal
The Role and Function of Non-Coding RNAs in Cholangiocarcinoma Invasiveness
Previous Article in Special Issue
The Effect of Early Spironolactone Administration on 2-Year Acute Graft Rejection in Cardiac Transplant Patients
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Soluble CD146 in Heart Failure: Pathophysiological Role and Diagnostic Potential

by
Daniela Mocan
1,2,3,4,
Radu Jipa
5,6,*,
Daniel Alexandru Jipa
7,8,
Radu Ioan Lala
1,8,
Maria Puschita
1,
Florin-Claudiu Rasinar
2,3,4,
Diana-Federica Balta
1,6,
Iulia-Silvia Groza
6,7 and
Amelia Uzum
1,6
1
Multidisciplinary Doctoral School, Vasile Goldis Western University of Arad, 310025 Arad, Romania
2
Research Center of the Institute of Cardiovascular Diseases Timisoara, 300310 Timisoara, Romania
3
Department VII, Internal Medicine II, Discipline of Cardiology, University of Medicine and Pharmacy “Victor Babes” Timisoara, E. Murgu Square, Nr. 2, 300041 Timisoara, Romania
4
Institute of Cardiovascular Diseases of Timisoara, 300310 Timisoara, Romania
5
Department of “Life Sciences”, Faculty of Medicine, Vasile Goldis Western University of Arad, Romania 86, Liviu Rebreanu Street, 310048 Arad, Romania
6
Arad County Clinical Emergency Hospital, 310037 Arad, Romania
7
Doctoral School, Victor Babes University of Timisoara, 300041 Timisoara, Romania
8
Victor Babes Clinical Hospital for Infectious Diseases and Pneumology of Timisoara, 300041 Timisoara, Romania
*
Author to whom correspondence should be addressed.
Biomedicines 2025, 13(6), 1370; https://doi.org/10.3390/biomedicines13061370
Submission received: 13 April 2025 / Revised: 22 May 2025 / Accepted: 28 May 2025 / Published: 3 June 2025
(This article belongs to the Special Issue Heart Failure: New Diagnostic and Therapeutic Approaches)

Abstract

:
Heart failure (HF) remains a major global health challenge, driven by multifactorial pathophysiological processes, such as systemic congestion, endothelial dysfunction, and inflammation. While natriuretic peptides are well-established biomarkers for diagnosing and monitoring HF, they do not fully capture the complexity of vascular involvement. CD146, also known as melanoma cell adhesion molecule (MCAM), is a transmembrane glycoprotein primarily expressed on endothelial cells and involved in cell adhesion, vascular permeability, and angiogenesis. Its soluble form (sCD146), released in response to multiple pathophysiological stimuli, including venous and arterial endothelial stretch, oxidative stress, and inflammatory cytokine activation, has emerged as a promising biomarker reflecting both hemodynamic congestion and systemic endothelial stress. This review synthesizes current knowledge on the structure, regulation, and release mechanisms of CD146 and explores its clinical utility in HF. Elevated sCD146 levels have been associated with echocardiographic and radiological indicators of congestion, as well as with adverse outcomes. While promising, its application is limited by variability, lack of standardization, and confounding elevations in non-cardiac conditions, including malignancy.

1. Introduction

Heart failure (HF) remains a leading cause of global morbidity and mortality, characterized by complex pathophysiological mechanisms, including impaired cardiac output, neurohormonal activation, systemic congestion, and endothelial dysfunction [1,2,3]. Despite advances in pharmacological and device-based therapies, HF continues to present substantial diagnostic and therapeutic challenges, particularly due to the heterogeneous nature of the syndrome and its overlapping clinical presentations [4].
One of the most significant contributors to HF progression and symptom burden is hemodynamic congestion. Congestion, resulting from elevated intracardiac filling pressures and impaired fluid redistribution, manifests as pulmonary and peripheral edema, ascites, jugular venous distention, and hepatic congestion [5,6,7,8,9,10]. Its presence is not only associated with acute decompensation but is also a major predictor of rehospitalization and adverse outcomes in both acute and chronic HF [1,2,5]. However, traditional clinical assessment of congestion is often subjective and imprecise, highlighting the critical need for more reliable and dynamic biomarkers [4].
In this context, endothelial dysfunction has emerged as a pivotal link between hemodynamic stress and clinical deterioration in HF [11,12,13,14]. The vascular endothelium plays a central role in maintaining vascular tone, permeability, and immune regulation. Disruption of endothelial homeostasis leads to increased vascular permeability, inflammation, and tissue edema, hallmarks of advanced HF [14,15]. Biomarkers that capture this vascular component could significantly enhance our ability to diagnose, stratify, and monitor patients with HF more effectively [1,16,17].
CD146, also known as the melanoma cell adhesion molecule (MCAM), is a transmembrane glycoprotein predominantly expressed on endothelial cells, where it functions in cell adhesion, angiogenesis, and the regulation of vascular permeability [1,18,19]. Its soluble form (sCD146), released into the bloodstream under conditions of endothelial stress, has garnered attention as a potential biomarker of systemic congestion and endothelial injury in HF [1,20].

2. CD146: Structure, Expression, and Regulation

CD146 was originally identified in 1987 on the surface of melanoma cells. Since then, its physiological relevance has been substantially redefined, with emerging roles in vascular biology, immune modulation, and tissue remodeling. Now considered a critical adhesion molecule of the endothelial junction, CD146 is deeply involved in maintaining vascular integrity, regulating immune cell trafficking, and responding to environmental stressors such as inflammation and mechanical stretch [16,20,21].

2.1. Molecular Structure

Encoded on chromosome 11q23.3 in humans, the CD146 gene spans 16 exons and encodes a 113-kDa transmembrane glycoprotein belonging to the immunoglobulin superfamily, involved in cell adhesion and endothelial signaling [22,23]. The mature CD146 protein comprises an N-terminal signal peptide, a large extracellular domain with five immunoglobulin (Ig)-like domains, eight predicted N-glycosylation sites, a 24-amino-acid hydrophobic transmembrane region, and a short cytoplasmic tail that mediates intracellular signaling. These domains work synergistically to mediate cell–cell adhesion, endothelial cohesion, and downstream signaling cascades involved in cell proliferation, migration, and vascular remodeling [22,24].
The Ig-like domains within the extracellular region of CD146 facilitate both homophilic CD146–CD146 interactions and heterophilic binding with other adhesion molecules, thereby contributing to endothelial cell–cell cohesion and vascular barrier integrity. Glycosylation motifs support proper protein folding, receptor–ligand interactions, and membrane localization, while the cytoplasmic tail engages intracellular signaling cascades that regulate endothelial responses to inflammatory stimuli and vascular injury [24].

2.2. Expression Profile

CD146 is predominantly expressed on vascular endothelial cells, particularly at intercellular junctions in both arteries and veins, where it supports endothelial barrier integrity and regulates permeability [1,16,25]. Beyond the endothelium, CD146 is also expressed in vascular smooth muscle cells, where it contributes to vessel remodeling, and in pericytes, which support microvascular stability [26,27,28]. In addition to its vascular localization, CD146 expression has been detected in a variety of extra-vascular tissues, including mesenchymal stromal cells within the bone marrow, trophoblasts in the placenta, and subsets of immune cells, such as T cells, B cells, and natural killer (NK) cells. This broad expression profile highlights the multifunctional nature of CD146, encompassing roles in vascular biology, immune surveillance, and tissue regeneration [23,29].

2.3. Isoforms of CD146

Three major isoforms of CD146 have been described: the long form (lgCD146), the short form (shCD146), and the sCD146 [23]. The lgCD146 isoform is localized primarily at the intercellular junctions of endothelial cells and is critical for maintaining cell–cell adhesion and the integrity of the endothelial barrier. In contrast, shCD146 is localized apically on endothelial surfaces and is implicated in dynamic processes such as endothelial proliferation, migration, and wound healing [23].
The third isoform, sCD146, is of particular interest in clinical cardiology [1,20,30,31]. sCD146 is generated through proteolytic cleavage of its membrane-bound form, predominantly mediated by matrix metalloproteinases (MMPs), especially MMP-2 and MMP-9. This shedding process is typically induced by pro-inflammatory cytokines or mechanical endothelial stretch, leading to elevated circulating levels of sCD146 in various pathological conditions, including HF, systemic inflammation, and certain malignancies [23,32]. While sCD146 levels in healthy individuals range between 200 and 400 ng/mL, this reference interval is not yet universally standardized and may be influenced by population demographics, assay specificity, and clinical status [23,33].

2.4. Regulation of CD146 Expression and Shedding

CD146 expression and its conversion to a soluble form are regulated by a complex interplay of transcriptional and post-translational mechanisms. Pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and transforming growth factor-beta (TGF-β), are potent inducers of CD146 gene transcription and promote the activation of metalloproteinases that mediate ectodomain shedding [23]. Oxidative stress, primarily mediated by reactive oxygen species (ROS), contributes to the destabilization of endothelial junctions and promotes the proteolytic shedding of CD146, thereby increasing circulating sCD146 levels in conditions characterized by endothelial dysfunction [19].
In the context of HF, elevated intracardiac and venous pressures result in a mechanical stretch of endothelial cells, a powerful stimulus for CD146 shedding [23]. Additional factors such as hypoxia, ischemia–reperfusion injury, and oxidized low-density lipoprotein (oxLDL) may synergistically enhance both transcriptional upregulation and post-translational modifications of CD146. Collectively, these regulatory mechanisms underscore the dynamic sensitivity of CD146 expression to diverse pathological stimuli, reinforcing the utility of circulating sCD146 as a biomarker of vascular stress and systemic congestion, as illustrated in Figure 1 [19,32].

3. Pathophysiological Role of CD146 in Heart Failure: Mechanisms and Vascular Implications

HF is not solely a disorder of impaired myocardial function but also a disease of profound vascular involvement. Central to this vascular dysfunction is the activation and shedding of endothelial markers, among which CD146, particularly its sCD146, has emerged as both a consequence and indicator of systemic congestion and endothelial barrier disruption [16,20,30]. The release of sCD146 is governed by a complex interplay of hemodynamic, inflammatory, oxidative, and hypoxic stimuli that reflect the severity of vascular involvement in HF. Beyond being a passive biomarker, CD146 may also actively contribute to the pathological cascade that perpetuates vascular permeability and congestion [20,21,23].

3.1. Hemodynamic Stress and Endothelial Activation

Elevated central venous and intracardiac pressures are hallmark features of both acute and chronic HF [1,20,21,34]. Hemodynamic overload imposes increased mechanical tension on the vascular endothelium, particularly within the highly compliant venous system. Sustained intravascular pressure disrupts endothelial junctional integrity, leading to heightened vascular permeability and facilitating plasma extravasation into the interstitial space. Clinically, this process manifests as peripheral edema, ascites, or pleural effusion, hallmarks of systemic and pulmonary congestion in advanced HF [1,4].
CD146 is constitutively expressed at the intercellular junctions of endothelial cells, where it contributes to vascular cohesion and barrier integrity. In response to pathological hemodynamic stress, such as venous stretch or elevated arterial afterload, mechanical forces activate matrix metalloproteinases, particularly MMP-2 and MMP-9, which cleave membrane-bound CD146. This proteolytic event releases its extracellular domain into the circulation as sCD146, reflecting endothelial perturbation and vascular stress. This release serves as a quantitative marker of endothelial stress, correlating with the degree of vascular strain and systemic congestion [18,23,25].

3.2. Inflammatory Cytokines and Oxidative Stress

Inflammation plays a pivotal role in both the initiation and perpetuation of HF pathophysiology. Circulating cytokines such as TNF-α, IL-1β, IL-6, and TGF-β not only contribute to myocardial dysfunction but also trigger endothelial activation, enhance CD146 gene expression, and promote its shedding [7,19,25].
Moreover, the oxidative stress environment in HF, marked by an imbalance between reactive oxygen species (ROS) and antioxidant defenses, directly impairs endothelial integrity and further stimulates MMP activity, potentiating sCD146 release. These inflammatory and oxidative stimuli interact synergistically with mechanical stressors to amplify endothelial injury, linking systemic inflammation to the vascular features of HF [16,19,23,27].

3.3. CD146 and Endothelial Dysfunction: Amplifying Congestion

Once released, sCD146 not only reflects endothelial stress but may also contribute to its progression. sCD146 can exert paracrine and autocrine effects, promoting endothelial hyperpermeability, enhancing leukocyte transmigration across the endothelium, and amplifying local inflammatory responses. These actions further compromise vascular integrity and contribute to the progression of inflammatory and cardiovascular disorders [23,32,33]. Specifically, sCD146 interacts with integrins such as αvβ1 on endothelial cells, leading to cytoskeletal remodeling and disruption of tight and adherens junctions. These changes result in endothelial hyperpermeability, facilitating plasma leakage into the interstitial space and contributing directly to tissue congestion.
Moreover, sCD146 enhances leukocyte adhesion and transmigration across the endothelium by upregulating chemokines like IL-8 and increasing the expression of adhesion molecules. This process not only amplifies local inflammatory responses, but also leads to the accumulation of immune cells within the vascular wall and surrounding tissues, further increasing vascular permeability and exacerbating fluid extravasation. These inflammatory and permeability changes compromise vascular integrity, disrupt fluid homeostasis, and contribute to the persistence of both intravascular and extravascular volume overload [23,26,32,33].
Thus, a self-sustaining feedback loop emerges: hemodynamic stress and inflammation promote the shedding of CD146, increasing sCD146 levels, which then worsen endothelial dysfunction, promote vascular leak, and perpetuate systemic and organ congestion. Elevated sCD146 not only marks this pathophysiological state but also actively drives its progression, making it a critical mediator and potential therapeutic target in congestive HF [23,32,33].

4. Clinical Relevance and Diagnostic Studies

In the evolving landscape of HF diagnosis, the search for biomarkers that reflect not only myocardial strain, but also vascular dysfunction and congestion, remains a priority [25]. sCD146, a product of endothelial stress and activation, has emerged as a clinically relevant biomarker that complements traditional cardiac-derived indicators, as depicted in Table 1. Unlike natriuretic peptides, which primarily capture myocardial wall stretch, sCD146 reflects endothelial barrier disruption and systemic venous congestion, dimensions central to the pathophysiology of both acute and chronic HF [1,31,34].

4.1. Diagnostic Value in Acute and Chronic Heart Failure

Several key studies underscore the diagnostic utility of sCD146 in the setting of acute decompensated heart failure (ADHF). One of the most comprehensive was conducted by Gayat et al., involving a multicenter cohort of patients admitted with ADHF. The study demonstrates that sCD146 concentrations were significantly elevated in patients with clinical and radiographic signs of congestion, independent of left-ventricular ejection fraction (LVEF). Notably, sCD146 showed a diagnostic performance comparable to N-terminal proBNP (NT-proBNP), and the combination of both biomarkers provided enhanced sensitivity and specificity in identifying volume overload [20].
These findings were particularly relevant for patients with HF with preserved ejection fraction (HFpEF), a group in which the diagnosis is often complicated by inconclusive natriuretic peptide levels. Because sCD146 is independent of systolic function and more reflective of vascular and endothelial strain, it has been proposed as a valuable adjunct biomarker, especially in those with ambiguous or non-specific presentations [20].

4.2. Associations with Imaging and Hemodynamic Parameters

The credibility of sCD146 as a congestion marker is further supported by its correlation with objective hemodynamic and imaging parameters. In a study by Kuběna et al., elevated sCD146 levels were significantly associated with radiographic signs of pulmonary congestion (e.g., alveolar edema, pleural effusion) in patients with acute coronary syndromes, independent of myocardial injury as assessed by troponin levels. This highlighted the vascular-specific signal of sCD146, distinguishing it from cardiac necrosis markers [31,34,35].
Similarly, Van Aelst et al. observed that sCD146 correlated strongly with echocardiographic markers of systemic congestion, including right atrial enlargement, increased inferior vena cava (IVC) diameter, reduced IVC collapsibility, elevated E/e′ ratio, and increased systolic pulmonary artery pressure (sPAP) [36]. These relationships validate sCD146 as a surrogate marker of right-sided and pulmonary venous congestion, with relevance for bedside clinical evaluation, especially when echocardiographic assessment is limited or inconclusive [36].
Elevated sCD146 levels have been strongly associated with radiographic signs of pulmonary congestion, enlarged right atrial size, inferior vena cava dilation, elevated pulmonary artery pressures, and subclinical congestion, even in patients who appear clinically euvolemic [1,20,34,37]. These correlations confirm the role of sCD146 as a biologically plausible, noninvasive marker of congestion severity that reflects real-time endothelial derangement.

4.3. Complementarity to Established Biomarkers

Rather than serving as a replacement for established biomarkers, such as NT-proBNP or troponins, sCD146 should be viewed as complementary, offering distinct yet synergistic information about vascular congestion and endothelial integrity, as depicted in Figure 2 [20,34,36,38]. When combined with NT-proBNP, sCD146 has been shown to improve diagnostic precision in patients with borderline or ambiguous presentations, particularly those with multiple comorbidities or non-specific dyspnea [20].
This diagram illustrates the role of sCD146 as a biomarker for endothelial dysfunction and systemic congestion in HF. The figure shows how sCD146 is released in response to various pathophysiological triggers, such as venous and arterial stretch, oxidative stress, and inflammatory cytokine activation. It highlights the cascade of events leading to endothelial cell activation, proteolytic shedding of sCD146, and its subsequent elevation in circulation. The figure also emphasizes the clinical relevance of sCD146 in diagnosing and monitoring congestion and endothelial integrity, correlating with traditional biomarkers like NT-proBNP and contributing to diagnostic precision in HF management.

5. CD146 and Traditional Biomarkers in Heart Failure

5.1. Comparative Analysis: CD146 vs. Traditional Biomarkers in Heart Failure

HF is a complex and heterogeneous syndrome characterized by a range of overlapping pathophysiological processes, myocardial stress, systemic congestion, neurohormonal activation, inflammation, and endothelial dysfunction [6,7,35,37,39]. No single biomarker can comprehensively reflect all these components. Therefore, evaluating how sCD146 compares with and complements established HF biomarkers is essential to appreciating its unique and additive value in clinical practice. Table 2 presents a comparative analysis between biomarkers.
Among the traditional biomarkers, natriuretic peptides, namely B-type natriuretic peptide (BNP) and NT-proBNP, remain the cornerstone of HF diagnosis and monitoring. Unlike natriuretic peptides (e.g., NT-proBNP), which are secreted by cardiac myocytes in response to chamber stretch, sCD146 reflects vascular and endothelial components of HF pathology [1,20,40]. This distinction is critical, especially in HFpEF, where myocardial biomarkers may be misleadingly normal, elderly, or obese patients, in whom NT-proBNP levels may be attenuated, post-treatment or residual congestion, where cardiac markers normalize faster than vascular integrity [41]. Cardiac troponins, on the other hand, are highly specific markers of myocardial injury. Their elevation reflects acute or chronic myocardial cell damage and plays a vital role in distinguishing HF with concomitant ischemia or myocardial infarction. Nevertheless, they do not convey information regarding volume status, congestion, or endothelial function [42,43,44].
Emerging biomarkers, including galectin-3, soluble ST2, and MR-proADM, have gained attention for their ability to reflect fibrosis, inflammation, or neurohormonal dysregulation, expanding the biomarker landscape. However, they also face challenges regarding specificity and clinical implementation [1,16,44,45,46,47,48,49].
CD146 is fundamentally different in origin and scope. Unlike NT-proBNP or troponins, which are cardiomyocyte-derived, CD146 is endothelial in origin, reflecting vascular stress, junctional disruption, and permeability alterations. This pathophysiological lens allows sCD146 to offer unique diagnostic and prognostic insights, especially in contexts where endothelial dysfunction plays a central role, such as HF with preserved ejection fraction (HFpEF), systemic congestion, or comorbid inflammatory states [29,31,33,34]. While traditional and emerging biomarkers reflect key components of HF pathophysiology, recent attention has turned to endothelial biomarkers for their potential to enhance short-term prognostic assessment, particularly in acute and hospitalized HF contexts. Among these, syndecan-1, endocan, sCD146, and Vascular Cell Adhesion Molecule 1 (VCAM-1) are gaining prominence for their roles in endothelial injury, inflammation, and congestion. Their ability to capture processes not directly sensed by myocardial or fibrotic markers may provide critical insight into patient trajectories in acute settings [1,20,33]. Syndecan-1, a marker of endothelial glycocalyx degradation, has shown strong associations with adverse outcomes in acute HF. Elevated levels are predictive of 6-month mortality and correlate with systemic inflammation and acute kidney injury [50]. Syndecan-1 may therefore serve as an early warning signal for identifying high-risk patients [51].
Endocan, secreted by activated endothelial cells, rises sharply in patients with cardiogenic shock or severe ADHF. It correlates with disease severity scores (e.g., APACHE II) and natriuretic peptides, and persistent elevation during hospitalization may indicate ongoing endothelitis [52,53]. VCAM-1, associated with cytokine-induced endothelial inflammation, is elevated during acute decompensation and may reflect a systemic inflammatory state. Elevated VCAM-1 levels have been independently associated with adverse long-term outcomes in HF patients [54,55]. Among endothelial biomarkers in acute HF, syndecan-1 appears to be the strongest independent marker of early mortality and multi-organ dysfunction [56]. Endocan and sCD146 provide complementary information—endocan highlighting inflammatory endothelial activation and sCD146 reflecting systemic and pulmonary venous congestion [20,33].

5.2. Diagnostic Utility of Integrated Biomarker Panels in Heart Failure

HF involves diverse and overlapping mechanisms, myocardial stretch, inflammation, fibrosis, congestion, and endothelial dysfunction that no single biomarker can fully capture. Panels combining NT-proBNP, soluble ST2 (sST2), and sCD146 show strong potential to enhance diagnostic accuracy by targeting complementary pathophysiological domains: cardiac strain, fibrotic stress, and vascular congestion [20,34,46]. Empirical studies support the synergistic value of this approach, demonstrating that sCD146 performed comparably to NT-proBNP in diagnosing acute decompensated HF (ADHF). Importantly, combining sCD146 with NT-proBNP significantly improved diagnostic precision, particularly in patients with intermediate (“gray zone”) natriuretic peptide levels [20].
In HFpEF, diagnosis remains particularly challenging. In such cases, adjunct markers can reveal pathophysiological changes not reflected by NT-proBNP. For instance, sCD146 was shown by Juknevičienė et al. to be elevated in HFpEF patients with clinical congestion even when NT-proBNP was inconclusive, highlighting its utility in detecting vascular overload [34].
Similarly, sST2 captures the inflammatory and fibrotic component of HF and is unaffected by confounders such as age, obesity, or renal impairment. Elevated sST2 in these patients is associated with worse outcomes, and clinical studies show that adding sST2 to NT-proBNP improves diagnostic confidence and risk stratification [46]. ST2 is now included in HF guidelines with a Class IIb recommendation for selected diagnostic and prognostic scenarios [46].
Further refinements to diagnostic panels may come from incorporating additional endothelial markers. Syndecan-1, a marker of glycocalyx degradation, is elevated in acute HF and correlates with organ dysfunction and early mortality [55]. Its addition to NT-proBNP or troponin-based models enhances prognostic accuracy. Endocan, secreted during endothelial activation, reflects pulmonary hypertension and vascular congestion [51,56]; VCAM-1 is associated with poor long-term outcomes and reflects systemic endothelial activation [52,54]. Taken together, panels combining cardiac markers (NT-proBNP, troponins), fibrotic/inflammatory markers (sST2, galectin-3), and vascular markers (sCD146, syndecan-1, endocan, VCAM-1) offer a comprehensive framework for precision diagnostics in HF. They are particularly useful in diagnostically complex cases, such as HFpEF, obesity, chronic kidney disease, or atypical presentations—where conventional markers may fall short. Integrating these biomarkers into routine diagnostic pathways may significantly improve early detection, individualized treatment, and outcome prediction in both acute and chronic HF [20,34,45,46].

6. Limitations and Confounding Conditions

Despite its growing recognition as a biomarker of endothelial dysfunction and vascular congestion, sCD146 (sCD146) remains an investigational tool in managing HF. Several important limitations must be acknowledged when considering its application in research or practice, particularly in the absence of large-scale prospective validation studies [57].
One of the most notable challenges lies in the lack of standardization across available assays for sCD146. Differences in analytical methods, sample preparation, and calibration procedures may lead to inconsistent results between laboratories, complicating the establishment of universal reference ranges or diagnostic thresholds. Moreover, the current literature reflects a heterogeneous mix of study populations, assay types, and clinical endpoints, further limiting the generalizability of existing findings [58].
In addition to methodological concerns, biological variability introduces the potential for misinterpretation. sCD146 levels may be influenced by age, sex, renal function, and systemic inflammatory conditions, factors commonly encountered in HF populations. In particular, non-cardiac elevations have been reported in malignancies, autoimmune diseases, and infectious states. CD146 was originally described as a melanoma cell adhesion molecule and is overexpressed in a range of solid tumors, including breast, prostate, and hepatocellular carcinoma. In such contexts, elevated sCD146 may reflect oncological or immunological processes rather than cardiovascular pathology, thus reducing its specificity as a congestion biomarker [37,45].
Furthermore, the pathophysiological mechanisms underlying sCD146 elevation are still incompletely understood. While mechanical stretch, inflammation, and oxidative stress are known triggers of CD146 shedding, the temporal dynamics and interactions between these stimuli remain to be fully clarified. This gap in mechanistic understanding limits the clinical interpretability of sCD146 in borderline or multifactorial cases, particularly in polymorbid patients with overlapping disease processes. sCD146 has demonstrated correlations with markers of congestion and prognosis in observational studies; it has yet to be tested in prospective biomarker-guided interventional trials [16,59,60]. Its role in therapeutic decision making, patient stratification, or treatment response remains speculative at this stage.

sCD146 and Renal Dysfunction

Renal dysfunction is a prevalent and prognostically significant comorbidity in HF (HF), affecting up to 50% of patients, especially those with preserved ejection fraction or advanced disease. Notably, kidney dysfunction not only reflects disease severity but also actively influences vascular biology and biomarker behavior, including that of sCD146 [1,2,61].
While sCD146 is primarily released in response to endothelial stress and venous congestion, emerging evidence indicates that impaired renal function can independently elevate sCD146 levels, even in the absence of overt volume overload. In patients with chronic kidney disease (CKD), a reduced glomerular filtration rate (GFR) may hinder renal clearance of sCD146, leading to its accumulation [1,2,18,62].
Beyond impaired elimination, CKD fosters a pro-inflammatory and pro-oxidative vascular milieu that promotes endothelial dysfunction, upregulates CD146 expression, and enhances its shedding via matrix metalloproteinase (MMP-2 and MMP-9) activation [63]. Uremic toxins, such as indoxyl sulfate, and inflammatory cytokines, like TNF-α and IL-6, have been shown to stimulate CD146 release from endothelial cells [64].
These mechanisms result in chronically elevated sCD146 concentrations in patients with moderate-to-severe CKD, independent of HF congestion status. This presents a critical interpretive challenge: in patients with coexisting HF and renal dysfunction—a common and high-risk phenotype—elevated sCD146 may reflect a combination of hemodynamic congestion, endothelial inflammation, and impaired clearance. Consequently, reliance on unadjusted sCD146 levels could lead to overestimation of volume status or endothelial stress in this subgroup [65,66,67].

7. Therapeutic Prospects of Targeting CD146 in Heart Failure

While sCD146 is primarily studied as a biomarker, emerging research highlights its active contribution to HF pathophysiology, making it a potential therapeutic target. Under inflammatory or hemodynamic stress, membrane-bound CD146 is cleaved by matrix metalloproteinases (MMP-2 and MMP-9), releasing sCD146 into circulation [33,50,68]. This soluble form promotes leukocyte transmigration, vascular permeability, and endothelial activation, exacerbating congestion and multi-organ dysfunction [22,32]. Meanwhile, loss of membrane CD146 destabilizes endothelial junctions, worsening capillary leak and inflammation [24,50].
Several therapeutic strategies have been proposed to counteract this cascade:
  • MMP inhibition aims to preserve junctional CD146 by preventing its proteolytic cleavage. Although broad-spectrum MMP inhibitors have shown limited clinical success in HF due to side effects, selective MMP blockade could reduce endothelial injury with fewer off-target effects [54,68].
  • Neutralization of sCD146 is an alternative approach. The monoclonal antibody M2J-1, developed to specifically bind sCD146 while sparing the membrane-bound form, has shown efficacy in preclinical cancer models, reducing pathological angiogenesis and inflammation without compromising vascular stability [38,69]. This targeted strategy may have relevance in HF, especially in HFpEF, where persistent congestion and endothelial inflammation are key drivers of disease [14,19].
  • Direct blockade of endothelial CD146 has also been explored. In neuroinflammation models, the monoclonal antibody AA98 reduced leukocyte extravasation and tissue injury by disrupting CD146-mediated immune cell adhesion [36,70]. Translating this concept to HF could help modulate chronic inflammatory infiltration in the myocardium and peripheral organs, though careful dosing would be needed to avoid impairing normal immune function.
These mechanisms are particularly promising in HFpEF, which is characterized by microvascular inflammation, endothelial dysfunction, and diastolic stiffening [15,19]. In this phenotype, CD146-targeted therapy could mitigate disease progression by restoring barrier function and reducing cytokine-induced vascular permeability. In HFrEF, while myocyte loss and neurohormonal activation dominate early disease, chronic systemic congestion and immune activation play increasing roles. CD146 inhibition may help alleviate residual organ congestion and vascular injury, improving quality of life and functional status [14,50].
Although no HF therapies currently target CD146 directly, guideline-directed medications, including ARNI, β-blockers, MRAs, and SGLT2 inhibitors, partially overlap [48,71]. For instance, MRAs reduce MMP activity and oxidative stress and SGLT2 inhibitors have been shown to improve endothelial function and lower inflammatory signaling [46,72]. These effects may indirectly modulate CD146 shedding, though the pathway remains largely unaddressed by existing treatments.
Notably, recent pooled analyses from DELIVER and EMPEROR-Preserved trials confirmed the efficacy of SGLT2 inhibitors across a broad ejection fraction range, highlighting the clinical relevance of vascular and metabolic mechanisms in HF therapy [1,2,40,73,74,75,76,77]. Adding CD146-modulating strategies to this armamentarium could address persistent endothelial dysfunction and systemic congestion, which are only partially controlled by current regimens.
In conclusion, CD146 is more than a biomarker, it is a mediator of vascular injury and inflammation in HF. Therapeutic strategies targeting MMP-mediated shedding, neutralizing sCD146, or modulating endothelial CD146 function could offer novel, mechanism-based interventions in both HFpEF and HFrEF. These approaches warrant translational studies to evaluate their additive potential alongside established therapies and their ability to improve clinical outcomes in this complex and heterogeneous syndrome.

8. Conclusions

CD146, particularly in its soluble form (sCD146), has emerged as a compelling biomarker at the intersection of vascular biology and HF pathophysiology. Its expression on endothelial cells and regulated release in response to mechanical, inflammatory, and oxidative stimuli provide a unique window into the endothelial response to systemic congestion, a central yet often underappreciated feature of HF progression [6,16,59].
Unlike traditional biomarkers, such as natriuretic peptides, which predominantly reflect myocardial stretch and intracardiac pressure, sCD146 captures an endothelial and vascular perspective [26,34,77]. This distinction is especially valuable in diagnostically ambiguous cases, such as those with preserved ejection fraction, obesity, renal dysfunction, or residual subclinical congestion, where conventional markers may fall short [1,16,34].
While the current evidence underscores the diagnostic and prognostic promise of sCD146, its use in clinical practice remains limited by biological variability, assay non-standardization, and a lack of prospective interventional data. Nonetheless, its consistent associations with congestion markers, endothelial dysfunction, and adverse outcomes support further investigation and integration into multi-marker strategies for a more nuanced assessment of HF [17].
Moving forward, validation in large-scale cohorts, mechanistic elucidation, and biomarker-guided therapeutic studies are needed to define the clinical role of CD146. If successfully integrated, CD146 could help personalize HF care by refining diagnosis, enhancing prognostication, and guiding decongestive management, ultimately aligning with the goals of precision medicine in cardiovascular disease [1].

Author Contributions

Conceptualization, D.M., R.J., A.U. and R.I.L.; writing—original draft preparation, D.M., R.J., A.U. and R.I.L.; writing—review and editing, D.M.; visualization, D.M., R.J., D.A.J., F.-C.R., I.-S.G., D.-F.B., M.P. and A.U.; supervision, A.U. and M.P. All authors have read and agreed to the published version of the manuscript.

Funding

The APC received no external funding.

Acknowledgments

During the preparation of this manuscript, the author(s) used ChatGPT (OpenAI, GPT-4, https://chat.openai.com/, accessed on 1 March 2025) to assist with language editing and phrasing. The authors have reviewed and edited the AI-generated content and take full responsibility for the final version of the manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
HFHeart failure
NYHANew York Heart Association
RAASRenin–angiotensin–aldosterone system
SNSSympathetic nervous system
ADHAntidiuretic hormone
NOAntidiuretic hormone
ROSReactive oxygen species
CKDChronic kidney disease
lgCD146long form CD146
shCD146short form CD146
sCD146soluble form CD146
MMPMatrix metalloproteinases

References

  1. Mocan, D.; Lala, R.I.; Puschita, M.; Pilat, L.; Darabantiu, D.A.; Pop-Moldovan, A. The Congestion “Pandemic” in Acute Heart Failure Patients. Biomedicines 2024, 12, 951. [Google Scholar] [CrossRef] [PubMed]
  2. Mocan, D.; Jipa, R.; Jipa, D.A.; Lala, R.I.; Rasinar, F.C.; Groza, I.; Sabau, R.; Bratu, D.S.; Balta, D.F.; Cioban, S.T.; et al. Unveiling the Systemic Impact of Congestion in Heart Failure: A Narrative Review of Multisystem Pathophysiology and Clinical Implications. J. Cardiovasc. Dev. Dis. 2025, 12, 124. [Google Scholar] [CrossRef]
  3. Shahim, B.; Kapelios, C.J.; Savarese, G.; Lund, L.H. Global Public Health Burden of Heart Failure: An Updated Review. Card. Fail. Rev. 2023, 9, e11. [Google Scholar] [CrossRef]
  4. Ambrosy, A.P.; Pang, P.S.; Khan, S.; Konstam, M.A.; Fonarow, G.C.; Traver, B.; Maggioni, A.P.; Cook, T.; Swedberg, K.; Burnett, J.C.; et al. Clinical course and predictive value of congestion during hospitalization in patients admitted for worsening signs and symptoms of heart failure with reduced ejection fraction: Findings from the EVEREST trial. Eur. Heart J. 2013, 34, 835–843. [Google Scholar] [CrossRef] [PubMed]
  5. Martens, P.; Mullens, W. How to tackle congestion in acute heart failure. Korean J. Intern. Med. 2018, 33, 462–473. [Google Scholar] [CrossRef]
  6. Mullens, W.; Damman, K.; Harjola, V.; Mebazaa, A.; Rocca, H.B.; Martens, P.; Testani, J.M.; Tang, W.W.; Orso, F.; Rossignol, P.; et al. The use of diuretics in heart failure with congestion—A position statement from the Heart Failure Association of the European Society of Cardiology. Eur. J. Heart Fail. 2019, 21, 137–155. [Google Scholar] [CrossRef] [PubMed]
  7. Dupont, M.; Mullens, W.; Tang, W.H.W. Impact of Systemic Venous Congestion in Heart Failure. Curr. Heart Fail. Rep. 2011, 8, 233–241. [Google Scholar] [CrossRef]
  8. Sammons, R.D.; Gaines, T.A. Glyphosate resistance: State of knowledge. Pest Manag. Sci. 2005, 70, 1367–1377. [Google Scholar] [CrossRef]
  9. Alevroudis, I.; Kotoulas, S.-C.; Tzikas, S.; Vassilikos, V. Congestion in Heart Failure: From the Secret of a Mummy to Today’s Novel Diagnostic and Therapeutic Approaches: A Comprehensive Review. J. Clin. Med. 2023, 13, 12. [Google Scholar] [CrossRef]
  10. Boorsma, E.M.; ter Maaten, J.M.; Damman, K.; Dinh, W.; Gustafsson, F.; Goldsmith, S.; Burkhoff, D.; Zannad, F.; Udelson, J.E.; Voors, A.A. Congestion in heart failure: A contemporary look at physiology, diagnosis and treatment. Nat. Rev. Cardiol. 2020, 17, 641–655. [Google Scholar] [CrossRef]
  11. Colombo, P.C.; Doran, A.C.; Onat, D.; Wong, K.Y.; Ahmad, M.; Sabbah, H.N.; Demmer, R.T. Venous Congestion, Endothelial and Neurohormonal Activation in Acute Decompensated Heart Failure: Cause or Effect? Curr. Heart Fail. Rep. 2015, 12, 215–222. [Google Scholar] [CrossRef] [PubMed]
  12. Pirrotta, F.; Mazza, B.; Gennari, L.; Palazzuoli, A. Pulmonary Congestion Assessment in Heart Failure: Traditional and New Tools. Diagnostics 2021, 11, 1306. [Google Scholar] [CrossRef] [PubMed]
  13. Rosenkranz, S.; Howard, L.S.; Gomberg-Maitland, M.; Hoeper, M.M. Systemic Consequences of Pulmonary Hypertension and Right-Sided Heart Failure. Circulation 2020, 141, 678–693. [Google Scholar] [CrossRef]
  14. Drera, A.; Rodella, L.; Brangi, E.; Riccardi, M.; Vizzardi, E. Endothelial Dysfunction in Heart Failure: What Is Its Role? J. Clin. Med. 2024, 13, 2534. [Google Scholar] [CrossRef]
  15. McMurray, J.J.; Packer, M.; Desai, A.S.; Gong, J.; Lefkowitz, M.P.; Rizkala, A.R.; Rouleau, J.L.; Shi, V.C.; Solomon, S.D.; Swedberg, K.; et al. Committees, Angiotensin-neprilysin inhibition versus enalapril in heart failure. N. Engl. J. Med. 2014, 371, 993–1004. [Google Scholar] [CrossRef]
  16. Núñez, J.; de la Espriella, R.; Rossignol, P.; Voors, A.A.; Mullens, W.; Metra, M.; Chioncel, O.; Januzzi, J.L.; Mueller, C.; Richards, A.M.; et al. Congestion in heart failure: A circulating biomarker-based perspective. A review from the Biomarkers Working Group of the Heart Failure Association, European Society of Cardiology. Eur. J. Heart Fail. 2022, 24, 1751–1766, Erratum in Eur. J. Heart. Fail. 2023, 25, 443. [Google Scholar] [CrossRef] [PubMed]
  17. Al-Sadawi, M.; Saad, M.; Ayyadurai, P.; Shah, N.N.; Bhandari, M.; Vittorio, T.J. Biomarkers in Acute Heart Failure Syndromes: An Update. Curr. Cardiol. Rev. 2022, 18, 35–45. [Google Scholar] [CrossRef]
  18. Zhang, Z.-Y.; Zhai, C.; Yang, X.-Y.; Li, H.-B.; Wu, L.-L.; Li, L. Knockdown of CD146 promotes endothelial-to-mesenchymal transition via Wnt/β-catenin pathway. PLoS ONE 2022, 17, e0273542. [Google Scholar] [CrossRef]
  19. Joshkon, A.; Heim, X.; Dubrou, C.; Bachelier, R.; Traboulsi, W.; Stalin, J.; Fayyad-Kazan, H.; Badran, B.; Foucault-Bertaud, A.; Leroyer, A.S.; et al. Role of CD146 (MCAM) in Physiological and Pathological Angiogenesis—Contribution of New Antibodies for Therapy. Biomedicines 2020, 8, 633. [Google Scholar] [CrossRef]
  20. Gayat, E.; Caillard, A.; Laribi, S.; Mueller, C.; Sadoune, M.; Seronde, M.-F.; Maisel, A.; Bartunek, J.; Vanderheyden, M.; Desutter, J.; et al. Soluble CD146, a new endothelial biomarker of acutely decompensated heart failure. Int. J. Cardiol. 2015, 199, 241–247. [Google Scholar] [CrossRef]
  21. Arrigo, M.; A Truong, Q.; Onat, D.; Szymonifka, J.; Gayat, E.; Tolppanen, H.; Sadoune, M.; Demmer, R.T.; Wong, K.Y.; Launay, J.M.; et al. Soluble CD146 Is a Novel Marker of Systemic Congestion in Heart Failure Patients: An Experimental Mechanistic and Transcardiac Clinical Study. Clin. Chem. 2017, 63, 386–393. [Google Scholar] [CrossRef] [PubMed]
  22. Bardin, N.; Blot-Chabaud, M.; Despoix, N.; Kebir, A.; Harhouri, K.; Arsanto, J.-P.; Espinosa, L.; Perrin, P.; Robert, S.; Vely, F.; et al. CD146 and its Soluble Form Regulate Monocyte Transendothelial Migration. Arterioscler. Thromb. Vasc. Biol. 2009, 29, 746–753. [Google Scholar] [CrossRef] [PubMed]
  23. Leroyer, A.S.; Blin, M.G.; Bachelier, R.; Bardin, N.; Blot-Chabaud, M.; Dignat-George, F. CD146 (Cluster of Differentiation 146). Arterioscler. Thromb. Vasc. Biol. 2019, 39, 1026–1033. [Google Scholar] [CrossRef] [PubMed]
  24. Bardin, N.; Anfosso, F.; Massé, J.-M.; Cramer, E.; Sabatier, F.; Le Bivic, A.; Sampol, J.; Dignat-George, F. Identification of CD146 as a component of the endothelial junction involved in the control of cell-cell cohesion. Blood 2001, 98, 3677–3684. [Google Scholar] [CrossRef]
  25. Piek, A.; Du, W.; de Boer, R.A.; Silljé, H.H.W. Novel heart failure biomarkers: Why do we fail to exploit their potential? Crit. Rev. Clin. Lab. Sci. 2018, 55, 246–263. [Google Scholar] [CrossRef]
  26. Wang, Z.; Xu, Q.; Zhang, N.; Du, X.; Xu, G.; Yan, X. CD146, from a melanoma cell adhesion molecule to a signaling receptor. Signal Transduct. Target. Ther. 2020, 5, 148. [Google Scholar] [CrossRef]
  27. Mussbacher, M.; Schossleitner, K.; Kral-Pointner, J.B.; Salzmann, M.; Schrammel, A.; Schmid, J.A. More than Just a Monolayer: The Multifaceted Role of Endothelial Cells in the Pathophysiology of Atherosclerosis. Curr. Atheroscler. Rep. 2022, 24, 483–492. [Google Scholar] [CrossRef]
  28. Kratzer, A.; Chu, H.W.; Salys, J.; Moumen, Z.; Leberl, M.; Bowler, R.; Cool, C.; Zamora, M.; Taraseviciene-Stewart, L. Endothelial cell adhesion molecule CD146: Implications for its role in the pathogenesis of COPD. J. Pathol. 2013, 230, 388–398. [Google Scholar] [CrossRef]
  29. Espagnolle, N.; Guilloton, F.; Deschaseaux, F.; Gadelorge, M.; Sensébé, L.; Bourin, P. CD146 expression on mesenchymal stem cells is associated with their vascular smooth muscle commitment. J. Cell. Mol. Med. 2013, 18, 104–114. [Google Scholar] [CrossRef]
  30. Simonavičius, J.; Mikalauskas, A.; Rocca, H.-P.B.-L. Soluble CD146-an underreported novel biomarker of congestion: A comment on a review concerning congestion assessment and evaluation in acute heart failure. Heart Fail. Rev. 2021, 26, 731–732. [Google Scholar] [CrossRef]
  31. Kubena, P.; Arrigo, M.; Parenica, J.; Gayat, E.; Sadoune, M.; Ganovska, E.; Pavlusova, M.; Littnerova, S.; Spinar, J.; Mebazaa, A.; et al. Plasma Levels of Soluble CD146 Reflect the Severity of Pulmonary Congestion Better Than Brain Natriuretic Peptide in Acute Coronary Syndrome. Ann. Lab. Med. 2016, 36, 300–305. [Google Scholar] [CrossRef] [PubMed]
  32. Stalin, J.; Harhouri, K.; Hubert, L.; Subrini, C.; Lafitte, D.; Lissitzky, J.-C.; Elganfoud, N.; Robert, S.; Foucault-Bertaud, A.; Kaspi, E.; et al. Soluble Melanoma Cell Adhesion Molecule (sMCAM/sCD146) Promotes Angiogenic Effects on Endothelial Progenitor Cells through Angiomotin. J. Biol. Chem. 2013, 288, 8991–9000. [Google Scholar] [CrossRef]
  33. Moal, V.; Anfosso, F.; Daniel, L.; Brunet, P.; Sampol, J.; George, F.D.; Bardin, N. Soluble CD146, a novel endothelial marker, is increased in physiopathological settings linked to endothelial junctional alteration. Thromb. Haemost. 2003, 90, 915–920. [Google Scholar] [CrossRef] [PubMed]
  34. Juknevičienė, R.; Simonavičius, J.; Mikalauskas, A.; Čerlinskaitė-Bajorė, K.; Arrigo, M.; Juknevičius, V.; Alitoit-Marrote, I.; Kablučko, D.; Bagdonaitė, L.; Vitkus, D.; et al. Soluble CD146 in the detection and grading of intravascular and tissue congestion in patients with acute dyspnoea: Analysis of the prospective observational Lithuanian Echocardiography Study of Dyspnoea in Acute Settings (LEDA) cohort. BMJ Open 2022, 12, e061611. [Google Scholar] [CrossRef] [PubMed]
  35. Dick, S.A.; Epelman, S. Chronic Heart Failure and Inflammation. Circ. Res. 2016, 119, 159–176. [Google Scholar] [CrossRef]
  36. Van Aelst, L.N.; Arrigo, M.; Placido, R.; Akiyama, E.; Girerd, N.; Zannad, F.; Manivet, P.; Rossignol, P.; Badoz, M.; Sadoune, M.; et al. Acutely decompensated heart failure with preserved and reduced ejection fraction present with comparable haemodynamic congestion. Eur. J. Heart Fail. 2017, 20, 738–747. [Google Scholar] [CrossRef]
  37. De la Espriella, R.; Cobo, M.; Santas, E.; Verbrugge, F.H.; Fudim, M.; Girerd, N.; Miñana, G.; Górriz, J.L.; Bayés-Genís, A.; Núñez, J. Assessment of filling pressures and fluid overload in heart failure: An updated perspective. Rev. Esp. Cardiol. (Engl. Ed.) 2023, 76, 47–57. (In Spanish) [Google Scholar] [CrossRef]
  38. Omar, H.R.; Guglin, M. The emerging role of new biomarkers of congestion in heart failure. J. Lab. Precis. Med. 2017, 2, 24. [Google Scholar] [CrossRef]
  39. Farmakis, D.; Parissis, J.; Papingiotis, G.; Filippatos, G. Acute Heart Failure; Oxford University Press (OUP): Oxford, UK, 2018. [Google Scholar]
  40. Castiglione, V.; Aimo, A.; Vergaro, G.; Saccaro, L.; Passino, C.; Emdin, M. Biomarkers for the diagnosis and management of heart failure. Heart Fail. Rev. 2022, 27, 625–643. [Google Scholar] [CrossRef]
  41. Choi, H.-I.; Lee, M.Y.; Kil Oh, B.; Lee, S.J.; Kang, J.G.; Lee, S.H.; Lee, J.-Y.; Kim, B.J.; Kim, B.S.; Kang, J.H.; et al. Effects of Age, Sex, and Obesity on N-Terminal Pro B-Type Natriuretic Peptide Concentrations in the General Population. Circ. J. 2021, 85, 647–654. [Google Scholar] [CrossRef]
  42. Berkmen, Y.M.; Lande, A. Chest roentgenography as a window to the diagnosis of Takayasu’s arteritis. Am. J. Roentgenol. 1975, 125, 842–846. [Google Scholar] [CrossRef] [PubMed]
  43. Peacock, W.F.I.; De Marco, T.; Fonarow, G.C.; Diercks, D.; Wynne, J.; Apple, F.S.; Wu, A.H. Cardiac Troponin and Outcome in Acute Heart Failure. N. Engl. J. Med. 2008, 358, 2117–2126. [Google Scholar] [CrossRef] [PubMed]
  44. Januzzi, J.L.; Filippatos, G.; Nieminen, M.; Gheorghiade, M. Troponin elevation in patients with heart failure: On behalf of the third Universal Definition of Myocardial Infarction Global Task Force: Heart Failure Section. Eur. Heart J. 2012, 33, 2265–2271. [Google Scholar] [CrossRef] [PubMed]
  45. Zaborska, B.; Sikora-Frąc, M.; Smarż, K.; Pilichowska-Paszkiet, E.; Budaj, A.; Sitkiewicz, D.; Sygitowicz, G. The Role of Galectin-3 in Heart Failure—The Diagnostic, Prognostic and Therapeutic Potential—Where Do We Stand? Int. J. Mol. Sci. 2023, 24, 13111. [Google Scholar] [CrossRef] [PubMed]
  46. Riccardi, M.; Myhre, P.L.; Zelniker, T.A.; Metra, M.; Januzzi, J.L.; Inciardi, R.M. Soluble ST2 in Heart Failure: A Clinical Role beyond B-Type Natriuretic Peptide. J. Cardiovasc. Dev. Dis. 2023, 10, 468. [Google Scholar] [CrossRef]
  47. Voors, A.A.; Kremer, D.; Geven, C.; ter Maaten, J.M.; Struck, J.; Bergmann, A.; Pickkers, P.; Metra, M.; Mebazaa, A.; Düngen, H.; et al. Adrenomedullin in heart failure: Pathophysiology and therapeutic application. Eur. J. Heart Fail. 2018, 21, 163–171. [Google Scholar] [CrossRef]
  48. Pandhi, P.; ter Maaten, J.M.; Emmens, J.E.; Struck, J.; Bergmann, A.; Cleland, J.G.; Givertz, M.M.; Metra, M.; O’Connor, C.M.; Teerlink, J.R.; et al. Clinical value of pre-discharge bio-adrenomedullin as a marker of residual congestion and high risk of heart failure hospital readmission. Eur. J. Heart Fail. 2019, 22, 683–691. [Google Scholar] [CrossRef]
  49. Rademaker, M.T.; Cameron, V.A.; Charles, C.J.; Lainchbury, J.G.; Nicholls, M.; Richards, A. Adrenomedullin and heart failure. Regul. Pept. 2003, 112, 51–60. [Google Scholar] [CrossRef]
  50. Johansson, P.I.; Stensballe, J.; Rasmussen, L.S.; Ostrowski, S.R. A High Admission Syndecan-1 Level, A Marker of Endothelial Glycocalyx Degradation, Is Associated With Inflammation, Protein C Depletion, Fibrinolysis, and Increased Mortality in Trauma Patients. Ann. Surg. 2011, 254, 194–200. [Google Scholar] [CrossRef]
  51. Miftode, R.-S.; Costache, I.-I.; Constantinescu, D.; Mitu, O.; Timpau, A.-S.; Hancianu, M.; Leca, D.-A.; Miftode, I.-L.; Jigoranu, R.-A.; Oancea, A.-F.; et al. Syndecan-1: From a Promising Novel Cardiac Biomarker to a Surrogate Early Predictor of Kidney and Liver Injury in Patients with Acute Heart Failure. Life 2023, 13, 898. [Google Scholar] [CrossRef]
  52. Reina-Couto, M.; Silva-Pereira, C.; Pereira-Terra, P.; Quelhas-Santos, J.; Bessa, J.; Serrão, P.; Afonso, J.; Martins, S.; Dias, C.C.; Morato, M.; et al. Endothelitis profile in acute heart failure and cardiogenic shock patients: Endocan as a potential novel biomarker and putative therapeutic target. Front. Physiol. 2022, 13, 965611. [Google Scholar] [CrossRef] [PubMed]
  53. Chen, J.; Jiang, L.; Yu, X.-H.; Hu, M.; Zhang, Y.-K.; Liu, X.; He, P.; Ouyang, X. Endocan: A Key Player of Cardiovascular Disease. Front. Cardiovasc. Med. 2022, 8, 798699. [Google Scholar] [CrossRef]
  54. Patel, R.B.; Colangelo, L.A.; Bielinski, S.J.; Larson, N.B.; Ding, J.; Allen, N.B.; Michos, E.D.; Shah, S.J.; Lloyd-Jones, D.M. Circulating Vascular Cell Adhesion Molecule-1 and Incident Heart Failure: The Multi-Ethnic Study of Atherosclerosis (MESA). J. Am. Heart Assoc. 2020, 9, e019390. [Google Scholar] [CrossRef] [PubMed]
  55. Troncoso, M.F.; Ortiz-Quintero, J.; Garrido-Moreno, V.; Sanhueza-Olivares, F.; Guerrero-Moncayo, A.; Chiong, M.; Castro, P.F.; García, L.; Gabrielli, L.; Corbalán, R.; et al. VCAM-1 as a predictor biomarker in cardiovascular disease. Biochim. Biophys. Acta (BBA)-Mol. Basis Dis. 2021, 1867, 166170. [Google Scholar] [CrossRef]
  56. Tromp, J.; van der Pol, A.; Klip, I.T.; de Boer, R.A.; Jaarsma, T.; van Gilst, W.H.; Voors, A.A.; van Veldhuisen, D.J.; van der Meer, P. Fibrosis Marker Syndecan-1 and Outcome in Patients with Heart Failure with Reduced and Preserved Ejection Fraction. Circ. Heart Fail. 2014, 7, 457–462. [Google Scholar] [CrossRef]
  57. Pellicori, P.; Kallvikbacka-Bennett, A.; Dierckx, R.; Zhang, J.; Putzu, P.; Cuthbert, J.; Boyalla, V.; Shoaib, A.; Clark, A.L.; Cleland, J.G.F. Prognostic significance of ultrasound-assessed jugular vein distensibility in heart failure. Heart 2015, 101, 1149–1158. [Google Scholar] [CrossRef]
  58. El-Kenawy, H.A.; Altuwayhir, A.K.I.; Fatani, D.A.Q.; Barayan, N.A.; Alshahrani, M.S.; Sabbagh, A.A.; Alnemer, M.A.M.; AlAhmad, Z.A.; Albakri, A.A.; Kabrah, L.K.; et al. Overview on Congestive Heart Failure Imaging. Saudi Med. Horiz. J. 2022, 3, 21–28. [Google Scholar] [CrossRef]
  59. Arrigo, M.; Parissis, J.T.; Akiyama, E.; Mebazaa, A. Understanding acute heart failure: Pathophysiology and diagnosis. Eur. Heart J. Suppl. 2016, 18, G11–G18. [Google Scholar] [CrossRef]
  60. Naddaf, N.; Maleki, N.D.; Goldschmidt, M.E.; Kalogeropoulos, A.P. Point of Care Ultrasound (POCUS) in the Management of Heart Failure: A Narrative Review. J. Pers. Med. 2024, 14, 766. [Google Scholar] [CrossRef]
  61. Blankstein, R.; Bakris, G.L. Renal Hemodynamic Changes in Heart Failure. Heart Fail. Clin. 2008, 4, 411–423. [Google Scholar] [CrossRef]
  62. Fan, Y.; Fei, Y.; Zheng, L.; Wang, J.; Xiao, W.; Wen, J.; Xu, Y.; Wang, Y.; He, L.; Guan, J.; et al. Expression of Endothelial Cell Injury Marker Cd146 Correlates with Disease Severity and Predicts the Renal Outcomes in Patients with Diabetic Nephropathy. Cell. Physiol. Biochem. 2018, 48, 63–74. [Google Scholar] [CrossRef] [PubMed]
  63. Six, I.; Flissi, N.; Lenglet, G.; Louvet, L.; Kamel, S.; Gallet, M.; Massy, Z.A.; Liabeuf, S. Uremic Toxins and Vascular Dysfunction. Toxins 2020, 12, 404. [Google Scholar] [CrossRef] [PubMed]
  64. Li, X.; Wen, J.; Dong, Y.; Zhang, Q.; Guan, J.; Liu, F.; Zhou, T.; Li, Z.; Fan, Y.; Wang, N. Wnt5a promotes renal tubular inflammation in diabetic nephropathy by binding to CD146 through noncanonical Wnt signaling. Cell Death Dis. 2021, 12, 92. [Google Scholar] [CrossRef] [PubMed]
  65. Zhang, H.; Zhang, L.; Tian, D.; Bai, Y.; Feng, Y.; Liu, W.; Diao, Z. CD146⁺ Endothelial Cells Facilitate Renal Interstitial Fibrosis Through Endothelial-to-Mesenchymal Transition. Ann. Transplant. 2024, 29, e945917. [Google Scholar] [CrossRef]
  66. Boutin, L.; Figueroa, S.M.; Hadjadj, S.; Amar, M.; Roger, E.; Elganfoud, N.; Blot-Chabaud, M.; Depret, F.; Samuel, J.L.; Azibani, F.; et al. CD146 Deletion Protects against Kidney and Heart Damage after AKI: FR-PO166. J. Am. Soc. Nephrol. 2024, 35. [Google Scholar] [CrossRef]
  67. Boutin, L.; Roger, E.; Gayat, E.; Depret, F.; Blot-Chabaud, M.; Chadjichristos, C.E. The role of CD146 in renal disease: From experimental nephropathy to clinics. J. Mol. Med. 2023, 102, 11–21. [Google Scholar] [CrossRef]
  68. Visse, R.; Nagase, H. Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases. Circ. Res. 2003, 92, 827–839. [Google Scholar] [CrossRef]
  69. Stalin, J.; Nollet, M.; Dignat-George, F.; Bardin, N.; Blot-Chabaud, M. Therapeutic and Diagnostic Antibodies to CD146: Thirty Years of Research on Its Potential for Detection and Treatment of Tumors. Antibodies 2017, 6, 17. [Google Scholar] [CrossRef] [PubMed]
  70. Yan, X.; Lin, Y.; Yang, D.; Shen, Y.; Yuan, M.; Zhang, Z.; Li, P.; Xia, H.; Li, L.; Luo, D.; et al. A novel anti-CD146 monoclonal antibody, AA98, inhibits angiogenesis and tumor growth. Blood 2003, 102, 184–191. [Google Scholar] [CrossRef]
  71. Leopold, J.A. Aldosterone, Mineralocorticoid Receptor Activation, and Cardiovascular Remodeling. Circulation 2011, 124, e466–e468. [Google Scholar] [CrossRef]
  72. Durante, W.; Behnammanesh, G.; Peyton, K.J. Effects of Sodium-Glucose Co-Transporter 2 Inhibitors on Vascular Cell Function and Arterial Remodeling. Int. J. Mol. Sci. 2021, 22, 8786. [Google Scholar] [CrossRef] [PubMed]
  73. Böhm, M.; Butler, J.; Filippatos, G.; Ferreira, J.P.; Pocock, S.J.; Abdin, A.; Mahfoud, F.; Brueckmann, M.; Gollop, N.D.; Iwata, T.; et al. Empagliflozin Improves Outcomes in Patients With Heart Failure and Preserved Ejection Fraction Irrespective of Age. J. Am. Coll. Cardiol. 2022, 80, 1–18. [Google Scholar] [CrossRef] [PubMed]
  74. Lavalle, C.; Mariani, M.V.; Severino, P.; Palombi, M.; Trivigno, S.; D’amato, A.; Silvetti, G.; Pierucci, N.; Di Lullo, L.; Chimenti, C.; et al. Efficacy of Modern Therapies for Heart Failure with Reduced Ejection Fraction in Specific Population Subgroups: A Systematic Review and Network Meta-Analysis. Cardiorenal Med. 2024, 14, 570–580. [Google Scholar] [CrossRef] [PubMed]
  75. Solomon, S.D.; de Boer, R.A.; DeMets, D.; Hernandez, A.F.; Inzucchi, S.E.; Kosiborod, M.N.; Lam, C.S.P.; Martinez, F.; Shah, S.J.; Lindholm, D.; et al. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. Eur. J. Heart Fail. 2021, 23, 1217–1225. [Google Scholar] [CrossRef]
  76. Bayes-Genis, A. The DELIVER Trial: The Beginning of the End of Ejection Fraction Tyranny. Eur. Cardiol. Rev. 2022, 17, e30. [Google Scholar] [CrossRef]
  77. Banach, J.; Grochowska, M.; Gackowska, L.; Buszko, K.; Bujak, R.; Gilewski, W.; Kubiszewska, I.; Wołowiec, Ł.; Michałkiewicz, J.; Sinkiewicz, W. Melanoma Cell Adhesion Molecule as an Emerging Biomarker with Prognostic Significance in Systolic Heart Failure. Biomark. Med. 2016, 10, 733–742. [Google Scholar] [CrossRef]
Figure 1. Pathophysiological cascade leading to sCD146 release in heart failure. Inflammation, venous stretch, and oxidative stress act as upstream triggers that induce CD146 activation. This activation is associated with endothelial dysfunction and matrix metalloproteinase (MMP)-mediated shedding of membrane-bound CD146. The result is increased release of sCD146 into the circulation, serving as a potential biomarker of vascular stress and systemic congestion. There is no copyright issue.
Figure 1. Pathophysiological cascade leading to sCD146 release in heart failure. Inflammation, venous stretch, and oxidative stress act as upstream triggers that induce CD146 activation. This activation is associated with endothelial dysfunction and matrix metalloproteinase (MMP)-mediated shedding of membrane-bound CD146. The result is increased release of sCD146 into the circulation, serving as a potential biomarker of vascular stress and systemic congestion. There is no copyright issue.
Biomedicines 13 01370 g001
Figure 2. sCD146 as a Biomarker in Heart Failure.
Figure 2. sCD146 as a Biomarker in Heart Failure.
Biomedicines 13 01370 g002
Table 1. Clinical Applications of sCD146 in Heart Failure.
Table 1. Clinical Applications of sCD146 in Heart Failure.
ApplicationDetails
Diagnostic UtilityElevated sCD146 levels are associated with systemic and pulmonary congestion, reflecting endothelial dysfunction and vascular strain. It complements traditional biomarkers like NT-proBNP in diagnosing HF.
Prognostic ValueHigh sCD146 levels predict adverse outcomes, including rehospitalization, disease progression, and mortality. It provides independent prognostic information, especially in conjunction with other biomarkers.
Monitoring TherapySerial measurements of sCD146 can be used to monitor treatment response, especially in decongestive therapy. Reductions in sCD146 levels may indicate effective decongestion and improved endothelial function.
Utility in HF with Preserved Ejection Fraction (HFpEF)sCD146 is valuable in diagnosing and monitoring HFpEF, where traditional markers like NT-proBNP may be less reliable.
Identification of Subclinical CongestionPersistent elevation of sCD146 levels may indicate residual congestion even after apparent clinical improvement, identifying patients at risk for relapse.
Abbreviations: sCD146 (soluble CD146), NT-proBNP (N-terminal proBNP), HFpEF (heart failure with preserved ejection fraction).
Table 2. Comparative Analysis: CD146 vs. Traditional Biomarkers in Heart Failure.
Table 2. Comparative Analysis: CD146 vs. Traditional Biomarkers in Heart Failure.
BiomarkerSourcePrimary SignalClinical StrengthsLimitations
NT-proBNPCardiomyocytesMyocardial wall stretchHigh sensitivity for volume overload; prognosisAffected by renal function, obesity
Troponin I/TCardiomyocytesMyocyte necrosisAcute coronary syndrome, myocardial injuryDoes not reflect congestion
Galectin-3FibroblastsFibrosis, inflammationRisk stratificationLow specificity
sST2Immune cells, myocardiumCardiac stress, inflammationPrognosisInfluenced by comorbidities
sCD146Endothelial cellsEndothelial dysfunction, congestionComplements NT-proBNP; reflects vascular strain and central congestionElevated in malignancy, inflammatory diseases; limited outcome data
Syndecan-1Endothelial glycocalyxGlycocalyx degradation, microvascular damageIndependent predictor of early mortality, reflects systemic endothelial injuryElevated in other critical illnesses (e.g., sepsis); lacks cardiac specificity
EndocanActivated endothelial cellsEndothelial inflammation and dysfunctionElevated in cardiogenic shock; correlates with BNP and disease severityPrognostic role in HF still emerging; not specific to HF
VCAM-1Cytokine-activated endotheliumLeukocyte adhesion and inflammationReflects cytokine-driven endothelial inflammation; part of the acute HF inflammatory profilePrognostic power unclear in acute HF; overlap with CRP and other inflammatory markers
Abbreviations: NT-proBNP (N-terminal proBNP), sST2 (Soluble Suppression of Tumorigenicity-2), sCD146 (soluble CD146), HF (heart failure), CRP (C-reactive protein).
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Mocan, D.; Jipa, R.; Jipa, D.A.; Lala, R.I.; Puschita, M.; Rasinar, F.-C.; Balta, D.-F.; Groza, I.-S.; Uzum, A. Soluble CD146 in Heart Failure: Pathophysiological Role and Diagnostic Potential. Biomedicines 2025, 13, 1370. https://doi.org/10.3390/biomedicines13061370

AMA Style

Mocan D, Jipa R, Jipa DA, Lala RI, Puschita M, Rasinar F-C, Balta D-F, Groza I-S, Uzum A. Soluble CD146 in Heart Failure: Pathophysiological Role and Diagnostic Potential. Biomedicines. 2025; 13(6):1370. https://doi.org/10.3390/biomedicines13061370

Chicago/Turabian Style

Mocan, Daniela, Radu Jipa, Daniel Alexandru Jipa, Radu Ioan Lala, Maria Puschita, Florin-Claudiu Rasinar, Diana-Federica Balta, Iulia-Silvia Groza, and Amelia Uzum. 2025. "Soluble CD146 in Heart Failure: Pathophysiological Role and Diagnostic Potential" Biomedicines 13, no. 6: 1370. https://doi.org/10.3390/biomedicines13061370

APA Style

Mocan, D., Jipa, R., Jipa, D. A., Lala, R. I., Puschita, M., Rasinar, F.-C., Balta, D.-F., Groza, I.-S., & Uzum, A. (2025). Soluble CD146 in Heart Failure: Pathophysiological Role and Diagnostic Potential. Biomedicines, 13(6), 1370. https://doi.org/10.3390/biomedicines13061370

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop