Vascular Endothelial Function

Vascular endothelial function refers to the health and performance of the endothelium, a single layer of cells lining the inside of blood vessels throughout the body. These cells play a critical role in maintaining cardiovascular health by regulating various physiological processes. The proper functioning of the endothelium is essential for blood vessel dilation and constriction, blood clotting, inflammation, and the formation of new blood vessels.

The biological basis of vascular endothelial function lies in the endothelium’s ability to produce and release various substances that influence the underlying vascular smooth muscle cells and circulating blood components. A key aspect is its role in vasodilation, primarily through the release of nitric oxide (NO), a powerful vasodilator. Healthy endothelial cells produce sufficient NO, ensuring appropriate blood flow and maintaining vascular tone. Conversely, impaired endothelial function, often termed endothelial dysfunction, is characterized by a reduced ability to produce or respond to vasodilators, leading to vasoconstriction and other detrimental changes.

Clinically, endothelial dysfunction is recognized as a fundamental component in the development and progression of atherosclerosis and a precursor to overt cardiovascular diseases (CVD), including heart attacks and strokes.^[1] Traits related to brachial artery (BA) endothelial function, such as flow-mediated dilation (FMD), are studied as intermediate phenotypes, offering insights into the pathway from traditional risk factors to clinical CVD. ^[1] Research indicates that these traits, including FMD, are heritable, with estimates for FMD being approximately 19%. ^[1] Understanding these heritable components is crucial for identifying individuals at higher risk.

The social importance of vascular endothelial function stems from the widespread impact of cardiovascular diseases globally. By serving as an early indicator of vascular damage, assessing endothelial function can aid in identifying individuals at risk before the onset of more severe symptoms. This allows for earlier interventions and lifestyle modifications, potentially reducing the burden of CVD on public health systems. Genetic studies, such as genome-wide association studies (GWAS), are being utilized to uncover specific genetic variants that influence endothelial function, providing a deeper understanding of the genetic underpinnings of complex diseases like CVD.^[1]This knowledge can lead to personalized prevention strategies and the development of targeted therapies to improve cardiovascular outcomes.

Limitations

Methodological and Statistical Power Constraints

The investigation was conducted on a “moderate-sized community-based sample” from the Framingham Heart Study, which inherently limited the statistical power to detect subtle genetic effects. ^[2]Specifically, the study could only achieve over 90% power for detecting single nucleotide polymorphisms (SNPs) that explained 4% or more of the total phenotypic variation, even at a stringent alpha level of 10^-8.^[2]This restricted power contributed to the “lack of genome-wide significance for any association observed” despite extensive multiple statistical testing, suggesting that numerous weaker, yet biologically significant, genetic influences on vascular endothelial function might have been missed.^[2]

Furthermore, the utilization of the Affymetrix 100K GeneChip provided only “partial coverage of genetic variation” within specific candidate genes, which means it “may be insufficient to exclude real associations” that exist in regions not covered by the array ^[3]. ^[2] The choice of a “liberal 80% genotyping call rate threshold,” while aiming for inclusivity, could also introduce a higher potential for error. ^[2] Consequently, some of the moderately strong associations identified in this exploratory analysis “may represent false-positive results” and are appropriately viewed as “hypotheses that warrant further testing” rather than definitive genetic discoveries ^[2]. ^[4]

Generalizability and Phenotype Specificity

The study’s reliance on a “community-based sample” from the Framingham Heart Study, while beneficial for its well-characterized nature, inherently limits the generalizability of the findings to broader and more diverse populations ^[3]. ^[2] Genetic variants can affect phenotypes in a “context-specific manner,” implying that associations observed within this specific cohort might not directly apply to individuals of different ancestral backgrounds or those living in distinct environmental conditions. ^[2]Therefore, external replication in ethnically varied cohorts is essential to confirm the universal applicability of these genetic insights into vascular endothelial function.

Regarding phenotype characterization, while many traits related to brachial artery function, such as baseline flow velocity and vessel diameter, exhibited moderate heritability (32% and 25%, respectively), hyperemic flow demonstrated particularly low heritability at 6%. ^[2] This lower heritable component for certain vascular responses can make it considerably more challenging to identify robust genetic associations, potentially obscuring genetic influences that contribute to these specific aspects of endothelial function.

Unexplored Environmental Interactions and Replication Demands

A significant limitation of this study is the absence of an investigation into gene-environment interactions. ^[2] The genetic influence on phenotypes, including various aspects of vascular function, can be critically “modulated by environmental influences”. ^[2] Prior research, for instance, has demonstrated that associations involving genes like ACE and AGTR2 can vary based on dietary salt intake. ^[2] By not exploring these complex interactions, the study may have overlooked crucial insights into how genetic predispositions and environmental factors jointly determine vascular endothelial health.

Ultimately, the associations identified in this genome-wide association study are “hypothesis-generating” and necessitate “replication in other cohorts” for their definitive validation ^[5]. ^[2] Given the exploratory nature of these analyses and the inherent limitations in SNP coverage, the identified genetic loci are considered potential candidates that require further corroboration. ^[2]Moreover, additional “functional” studies are indispensable to fully understand the biological mechanisms through which these genetic variants impact vascular endothelial function, thereby addressing existing knowledge gaps.^[5]

Variants

Genetic variations play a crucial role in influencing an individual’s predisposition to various health outcomes, including the intricate regulation of vascular endothelial function. These variants can affect gene expression, protein function, or cellular pathways that are critical for maintaining healthy blood vessels, potentially contributing to conditions such as atherosclerosis, hypertension, and impaired blood flow. Identifying specific single nucleotide polymorphisms (SNPs) and their associated genes provides insight into the molecular mechanisms underlying vascular health.^[5]

Several variants are located within or near genes with established roles in cellular signaling and metabolic processes vital for vascular integrity. For instance, *rs2402591 * is associated with _PTPRZ1_ (Protein Tyrosine Phosphatase, Receptor Type, Z1), a gene encoding a receptor-type protein tyrosine phosphatase that influences cell growth, differentiation, and migration, all processes relevant to endothelial cell behavior and vascular remodeling. Similarly, *rs11767547 * in _TFR2_(Transferrin Receptor 2) highlights the impact of iron metabolism on vascular health, as_TFR2_plays a role in regulating hepcidin, a key iron hormone, and iron dysregulation can lead to oxidative stress in endothelial cells. The*rs220963 * variant near _EPHA7_ (Ephrin Receptor A7), a receptor tyrosine kinase, is pertinent because Eph/ephrin signaling regulates endothelial cell migration and angiogenesis, processes fundamental to vascular development and repair. Moreover, *rs76772770 * in _PIK3R3_ (Phosphoinositide-3-Kinase Regulatory Subunit 3), a regulatory subunit of the critical PI3K enzyme, underscores the pathway’s importance for endothelial cell survival, nitric oxide production, and overall vascular function, with variants potentially modulating these effects and influencing metabolic risk factors. ^[6]

Other variants are located within non-coding RNA genes or regions that regulate gene expression, which are increasingly recognized for their roles in endothelial biology. The *rs10914886 * variant within the _C1orf94_ - _MIR552_ region is particularly noteworthy, as _MIR552_ is a microRNA that can modulate gene expression pathways involved in inflammation and endothelial function. Alterations in _MIR552_ activity due to this variant could impact the delicate balance of endothelial cell proliferation and survival. Furthermore, the *rs639405 * variant associated with _PITX1-AS1_, an antisense RNA, suggests regulatory influences on _PITX1_, a transcription factor, potentially affecting broader developmental pathways with indirect consequences for vascular health. Similarly, *rs7236698 * linked to the _ZNF516-DT_ - _LINC00683_ region and *rs61931005 * associated with _TBX5-AS1_ - _RN7SKP216_ implicate long non-coding RNAs (lncRNAs) and other non-coding elements. These lncRNAs can regulate nearby gene expression, chromatin structure, and cellular processes within vascular cells, making variants in these regions potential contributors to endothelial dysfunction or protection. ^[5]

Finally, some variants reside in less characterized regions or pseudogenes, highlighting the complexity of genetic influences. The *rs1499339 * variant within the _RPL7AP28_ - _ELL2P2_ region involves ribosomal protein and elongation factor pseudogenes, which, while not encoding functional proteins themselves, can sometimes impact the expression of their functional counterparts or other genes through regulatory mechanisms. Similarly, *rs12871441 * in the _RNU6-67P_ - _SLITRK1_ region associates a small nuclear RNA pseudogene with _SLITRK1_, a transmembrane protein primarily recognized for its neuronal roles. While its direct involvement in vascular endothelium is less understood, genes with neuronal functions can sometimes have broader systemic effects, including influence on neurovascular coupling or inflammatory responses relevant to vascular health. The specific functional consequences of these variants, whether direct or through linkage to other functional elements, contribute to the polygenic architecture of vascular endothelial function and related traits.^[6]

Key Variants

RS ID	Gene	Related Traits
rs2402591	PTPRZ1	vascular endothelial function measurement
rs1499339	RPL7AP28 - ELL2P2	vascular endothelial function measurement
rs11767547	TFR2	vascular endothelial function measurement
rs220963	EPHA7 - MTCYBP36	vascular endothelial function measurement
rs10914886	C1orf94 - MIR552	vascular endothelial function measurement
rs7236698	ZNF516-DT - LINC00683	vascular endothelial function measurement
rs76772770	PIK3R3, P3R3URF-PIK3R3	vascular endothelial function measurement
rs639405	PITX1-AS1	vascular endothelial function measurement
rs61931005	TBX5-AS1 - RN7SKP216	electrocardiography body mass index vascular endothelial function measurement
rs12871441	RNU6-67P - SLITRK1	vascular endothelial function measurement

Classification, Definition, and Terminology

Defining Vascular Endothelial Function and Dysfunction

Vascular endothelial function pertains to the healthy physiological state and optimal performance of the endothelium, the innermost lining of blood vessels, which is critical for maintaining overall cardiovascular health. Endothelial dysfunction, conversely, describes an impairment in the endothelium’s capacity to regulate crucial vascular processes, including vasodilation, inflammation, and blood clotting. This dysfunction is recognized as a fundamental early event in the development of atherosclerosis and acts as a significant precursor to overt cardiovascular disease (CVD), encompassing conditions such as stroke and heart failure.^[2]The term “endothelial dysfunction” therefore represents a range of functional impairments indicating an elevated risk for developing severe cardiovascular pathologies.

Measurement and Operational Definitions

The primary diagnostic approach for assessing vascular endothelial function, particularly in scientific and clinical investigations, is through brachial artery flow-mediated dilation (FMD). This non-invasive ultrasound technique quantifies the endothelium-dependent widening of the brachial artery in response to transiently increased blood flow, which elevates shear stress on the vessel wall. Operationally, FMD is precisely defined as the percentage change in the brachial artery’s diameter from its baseline measurement to its maximal dilation one minute after induced reactive hyperemia, calculated as 100 * [hyperemic diameter at 1 minute - baseline diameter] / baseline diameter.^[2] This measurement typically employs a specialized Toshiba SSH-140A ultrasound system with a 7.5 MHz linear array transducer and dedicated software, such as Brachial Analyzer version 3.2.3, with reported coefficients of variation for baseline and hyperemic diameters being 0.5% and 0.7% respectively. ^[2]

Clinical and Research Classification

Endothelial dysfunction, as quantified by brachial artery FMD, is critically classified as an intermediate phenotype within the complex pathway linking traditional cardiovascular risk factors to the manifestation of overt cardiovascular disease.^[2]This classification underscores its value in identifying individuals who, despite having an intermediate pre-test probability of CVD, are at an increased likelihood of experiencing future clinical events, similar to the predictive power of exercise treadmill stress testing.^[2] In research, FMD values are frequently adjusted for a comprehensive set of covariates, including age, sex, and established risk factors, to accurately determine their clinical and genetic associations. ^[2]The demonstrated heritability of FMD further solidifies its role as a quantifiable trait in genetic studies aimed at uncovering specific genetic loci linked to the development and progression of cardiovascular diseases.^[2]

Biological Background

The endothelium, a single layer of cells lining the inner surface of blood vessels, plays a critical role in maintaining vascular health and regulating various physiological processes throughout the body. Its proper function, often assessed through metrics like brachial artery flow-mediated dilation (FMD), is essential for preventing cardiovascular diseases (CVD). Flow-mediated dilation measures the ability of blood vessels to widen in response to increased blood flow, reflecting the endothelium’s capacity to release vasodilatory substances.^[1]Endothelial dysfunction, characterized by an impaired ability of the endothelium to perform these regulatory functions, is recognized as a fundamental component of atherosclerosis and a significant precursor to overt CVD, including high blood pressure, stroke, and heart failure.^[1]

The Endothelium: Sentinel of Vascular Homeostasis

The endothelium acts as a dynamic interface between circulating blood and the vessel wall, maintaining vascular homeostasis through a balance of vasodilators and vasoconstrictors, as well as anti-thrombotic and pro-thrombotic factors. A key function involves the regulation of vascular tone, controlling blood vessel diameter and thus blood flow and pressure. ^[1]Proper endothelial function ensures the smooth passage of blood, prevents the adhesion of inflammatory cells, and inhibits the formation of clots. When this intricate balance is disrupted, for example, through impaired vasodilation, it signals the onset of endothelial dysfunction, serving as an early indicator of heightened cardiovascular risk.^[1]

Molecular Signaling and Regulation of Vascular Tone

At the molecular level, vascular endothelial function is primarily mediated by signaling pathways involving nitric oxide (NO), a potent vasodilator. The enzymeendothelial nitric oxide synthase (eNOS) in endothelial cells produces NO, which then diffuses into adjacent vascular smooth muscle cells, activating guanylate cyclase and leading to the production of cyclic guanosine monophosphate (cGMP).^[2]This cGMP signaling pathway promotes smooth muscle relaxation and, consequently, vasodilation.^[7] Conversely, the enzyme phosphodiesterase 5 (PDE5) degrades cGMP in smooth muscle cells, thereby facilitating the contracted state of blood vessels.^[8]Angiotensin II, a key component of the renin-angiotensin system, can antagonize cGMP signaling by increasingPDE5Aexpression in vascular smooth muscle cells, which also plays a role in the growth-promoting effects of Angiotensin II.^[7]Additionally, the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel is expressed in human endothelia and its activity influences chloride transport and mechanical properties of smooth muscle cells, highlighting its potential role in vascular regulation.^[9]

Genetic and Epigenetic Modulators of Endothelial Function

Endothelial function is a complex, heritable trait influenced by genetic factors. ^[10] Variations within genes encoding key regulatory molecules can impact vascular health. For instance, common genetic variations at the endothelial nitric oxide synthase locus have been linked to differences in brachial artery vasodilator function. ^[2] Similarly, polymorphisms in genes belonging to the renin-angiotensin system are associated with endothelium-dependent vasodilation in normotensive individuals. ^[11]Genetic factors also extend to metabolic pathways; common single nucleotide polymorphisms (SNPs) inHMGCR, a gene involved in cholesterol synthesis, affect the alternative splicing of exon 13 and are associated with LDL-cholesterol levels, which indirectly impacts endothelial health. ^[12] Furthermore, the ABO histo-blood group antigen has been found to be associated with circulating levels of soluble intercellular adhesion molecule-1 (ICAM-1) and influences plasma von Willebrand factor levels, both of which are critical factors in vascular integrity and function. ^[13]

Pathophysiological Consequences of Endothelial Dysfunction

The breakdown of proper endothelial function initiates a cascade of pathophysiological processes that contribute significantly to cardiovascular disease progression. Endothelial dysfunction is an early and fundamental event in the development of atherosclerosis, where compromised endothelium allows for increased leukocyte adhesion and inflammatory cell infiltration.^[14] Soluble adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), are crucial in this inflammatory process; their elevated plasma concentrations serve as risk markers for atherosclerosis and subsequent cardiovascular events.^[15] ICAM-1expression, for example, can be upregulated by thrombin in monocytes, further contributing to vascular inflammation and injury.^[16]This sustained inflammatory state and impaired vascular regulation ultimately contribute to increased arterial stiffness, reduced organ perfusion, and the heightened risk of serious clinical outcomes such as myocardial infarction and stroke.^[1]

Pathways and Mechanisms

Vasodilatory Signaling and Cyclic Nucleotide Regulation

Vascular endothelial function relies critically on precise signaling pathways governing vasodilation, primarily through the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) cascade. Endothelial nitric oxide synthase (NOS3), a key enzyme, produces NO, which then activates soluble guanylate cyclase in underlying vascular smooth muscle cells, leading to increased cGMP levels and subsequent relaxation and vasodilation.^[2] The efficiency of this pathway is finely tuned by regulatory mechanisms, including genetic variation at the NOS3 locus, which has been associated with brachial artery vasodilator function. ^[2] This highlights how genetic factors can modulate the initiation of intracellular signaling cascades that are fundamental to vascular tone.

Dysregulation within this system, often stemming from intracellular signaling cascades, can significantly impair endothelial function. For instance, Angiotensin II, a potent vasoconstrictor, can increase the expression of phosphodiesterase 5A (PDE5A) in vascular smooth muscle cells.^[7] This elevation in PDE5A activity leads to accelerated cGMP degradation, thereby antagonizing the vasodilatory effects of NO and representing a critical feedback loop in vascular tone regulation. ^[7]Such pathway dysregulation is a central disease-relevant mechanism contributing to conditions like hypertension and cardiovascular disease by altering the balance between vasodilation and vasoconstriction.

Inflammatory Responses and Cell Adhesion

Endothelial cells actively participate in immune surveillance and inflammatory processes through the regulation of cell adhesion molecules and chemokine secretion. Signaling pathways triggered by various stimuli can lead to the transcriptional upregulation of adhesion molecules like intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on the endothelial surface. ^[17]These molecules facilitate the recruitment of circulating leukocytes to sites of inflammation, a process crucial in the initiation and progression of atherosclerosis.^[17] Common genetic variants, such as polymorphisms in the ICAM-1gene cluster on chromosome 19 or the Gly241Arg polymorphism, can influence circulating levels of s_ICAM-1_, thereby modulating inflammatory responses and disease susceptibility.^[18]

Further contributing to inflammatory mechanisms, the chemokine monocyte chemoattractant protein-1 (CCL2), also known as MCP-1, plays a significant role in attracting monocytes to the endothelium. ^[19] Polymorphisms within the CCL2 gene are associated with serum CCL2levels and an increased risk of myocardial infarction, highlighting the direct link between chemokine signaling and cardiovascular pathology.^[19]Moreover, mechanisms involving 5-lipoxygenase activating protein (FLAP), implicated in the synthesis of inflammatory leukotrienes, have been shown to confer risk of myocardial infarction and stroke, underscoring the broad systems-level integration of inflammatory pathways with vascular health.^[20] This intricate network of interactions demonstrates how gene regulation and protein expression are hierarchically regulated to mediate complex inflammatory responses in the vasculature.

Vascular Remodeling and Growth Factor Modulation

The dynamic nature of vascular endothelial function also involves intricate pathways that control vascular remodeling, cell migration, and angiogenesis. The renin-angiotensin system, for example, exerts significant control over endothelium-dependent vasodilation, with genetic polymorphisms in its components influencing vascular responses.^[11] Beyond vasoregulation, this system can impact growth factor pathways that lead to cellular changes. Furthermore, the SLIT2gene, encoding a secreted protein with leucine-rich repeats and epidermal growth factor-like motifs, has been identified to play a novel role in vascular function by contributing to migratory mechanisms in vascular smooth muscle cells.^[2] This highlights hierarchical regulation where extracellular cues guide cellular behavior and structural integrity of the vasculature.

Another important modulator is the neuregulin-2 isoform, which, through its N-terminal region, has been observed to possess inhibitory activity on angiogenesis. ^[21]Such regulatory mechanisms involving growth factor-like proteins demonstrate complex pathway crosstalk that can either promote or inhibit the formation of new blood vessels, a process critical for tissue repair but also implicated in disease states like tumor growth. Dysregulation in these pathways, often stemming from altered receptor activation or intracellular signaling cascades, can lead to aberrant vascular remodeling and contribute to cardiovascular disease progression.

Metabolic Pathways and Lipid Homeostasis

Endothelial health is intrinsically linked to underlying metabolic pathways that regulate lipid processing and energy metabolism. The mevalonate pathway, central to cholesterol biosynthesis, is a critical metabolic route, and its regulation directly influences lipid homeostasis. ^[22] A key enzyme in this pathway is 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), which can be regulated through various mechanisms including alternative splicing. ^[12]Common single nucleotide polymorphisms inHMGCR have been associated with LDL-cholesterol levels and have been shown to affect the alternative splicing of exon 13, illustrating how genetic variation can impact metabolic flux control and biosynthesis. ^[12]

The dysregulation of lipid metabolism, particularly elevated LDL-cholesterol, is a well-established disease-relevant mechanism contributing to endothelial dysfunction and atherosclerosis. These metabolic pathways are not isolated but interact with cellular signaling to influence endothelial phenotype. Alterations in lipid profiles can affect membrane composition and receptor function, thereby impacting the response of endothelial cells to various stimuli and their overall functional integrity through complex regulatory mechanisms and pathway crosstalk.

Ion Channel Activity and Cellular Integrity

Maintaining endothelial cellular integrity and responsiveness involves sophisticated regulatory mechanisms governing ion channel activity and protein dynamics. The cystic fibrosis transmembrane conductance regulator (CFTR), typically known as a chloride channel, is expressed in human endothelia and exhibits chloride channel activity. ^[9] Disruption of CFTRchloride channel activity can alter the mechanical properties and cAMP-dependent chloride transport of aortic smooth muscle cells, suggesting its role in vascular tone and cellular homeostasis.^[23] This indicates that ion transport systems are vital components of the cellular signaling cascades that dictate vascular function.

Furthermore, post-translational regulation and the dynamics of protein expression are crucial for endothelial function. Heat shock protein A8 (HSPA8), a constitutively expressed chaperone protein, and phosphodiesterase 4B (PDE4B), involved in cAMP signaling, represent additional regulatory mechanisms influencing cellular dynamics and potentially vascular integrity. ^[2]These components highlight how both direct ion flux and broader cellular stress responses and signaling enzyme activities integrate to maintain healthy endothelial function, with their dysregulation having implications for emergent properties such as changes in left ventricular mass or left atrial size.

Clinical Relevance of Vascular Endothelial Function

Vascular endothelial function, typically assessed through brachial artery flow-mediated dilation (FMD), is a crucial physiological indicator with significant implications for patient care. It represents an intermediate phenotype in the progression from conventional cardiovascular risk factors to overt cardiovascular disease (CVD).^[1]Understanding its role provides valuable insights for risk stratification, disease monitoring, and personalized therapeutic strategies.

Prognostic Indicator and Cardiovascular Risk Stratification

Endothelial dysfunction is a fundamental component of atherosclerosis and acts as a significant precursor to overt cardiovascular disease events, including stroke and heart failure.^[1]The assessment of brachial artery FMD offers additive prognostic value beyond established indices, such as the ankle-brachial pressure index, for predicting cardiovascular risk in patients with peripheral arterial disease.^[24]Furthermore, research indicates that markers associated with endothelial activation, such as soluble intercellular adhesion molecule-1 (sICAM-1), are potential risk factors for acute coronary syndromes, predict the progression of peripheral atherosclerosis, and are linked to subsequent overall cardiovascular risk.^[15] This collective evidence underscores the utility of endothelial function assessment in identifying high-risk individuals and guiding early prevention strategies.

Association with Atherosclerosis and Related Conditions

Endothelial dysfunction plays a central role in the pathogenesis of atherosclerosis and is closely associated with numerous related comorbidities. Studies have linked impaired endothelial function to conditions such as high blood pressure, and it is considered a key factor contributing to the development of clinical CVD, including stroke and heart failure.^[1]Its association extends to common cardiovascular risk factors, including age, sex, smoking status, hypertension, diabetes, and dyslipidemia, which are frequently adjusted for in clinical assessments of endothelial function.^[1]Moreover, inflammatory biomarkers like sICAM-1, reflecting endothelial activation, are independently linked to an increased risk of cardiovascular disease and mortality.^[5] Genetic predispositions also influence endothelial function; for instance, common genetic variations at the endothelial nitric oxide synthase (NOS3) locus and polymorphisms within the renin-angiotensin system have been shown to relate to brachial artery vasodilator function^[25]. ^[11]

Clinical Utility in Diagnosis and Personalized Medicine

The evaluation of vascular endothelial function offers a valuable tool for diagnostic assessment and monitoring strategies within personalized medicine frameworks. Brachial artery FMD serves as a direct, non-invasive method for assessing endothelial dysfunction, making it accessible for clinical application.^[1] By acting as an intermediate phenotype, it allows for the early detection of subclinical vascular damage, long before the manifestation of overt CVD. ^[1]The integration of such biomarkers, which provide insights into disease pathogenesis and risk, aligns with the goals of “predictive, preemptive, personalized medicine,” facilitating tailored interventions based on an individual’s unique risk profile.^[5]Monitoring parameters such as baseline brachial artery diameter, flow velocity, and FMD percentage can help track disease progression and assess the effectiveness of therapeutic interventions.

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