Cardiovascular Age

Cardiovascular age is a metric that reflects the health and functional status of an individual’s cardiovascular system relative to their chronological age. It provides an intuitive measure of an individual’s overall risk for developing cardiovascular diseases (CVDs), such as heart attack, stroke, and heart failure. When an individual’s estimated cardiovascular age is significantly higher than their actual age, it indicates an accelerated aging of their heart and blood vessels, signifying an elevated risk for future adverse cardiac events.

Biological Basis

The biological underpinnings of cardiovascular age are complex, arising from an intricate interplay of genetic predispositions, environmental factors, and lifestyle choices. Extensive research, particularly through genome-wide association studies (GWAS), has identified numerous genetic loci and single nucleotide polymorphisms (SNPs) that contribute to various cardiovascular traits.^[1]These traits include factors like blood pressure regulation, lipid metabolism, the progression of subclinical atherosclerosis, heart structure and function, and endothelial health, all of which have been shown to be heritable.^[1]By examining these genetic markers in large cohorts, researchers aim to unravel how inherited factors influence the rate at which the cardiovascular system ages and its susceptibility to disease.

Clinical Relevance

Clinically, cardiovascular age serves as a powerful prognostic tool for assessing CVD risk and educating patients. It translates complex risk factor information into a more relatable and impactful metric than traditional risk scores, facilitating clearer communication between healthcare providers and individuals. Identifying those with an “older” cardiovascular age allows for early and targeted interventions, encompassing lifestyle modifications, pharmacological therapies, and enhanced monitoring, to slow or reverse the progression of CVDs.^[2]Studies, such as those conducted within the Framingham Heart Study, have extensively characterized the genetic and clinical correlates of key cardiovascular health indicators, offering valuable insights for the development of personalized prevention and treatment strategies.^[1]

Social Importance

The concept of cardiovascular age holds significant social importance by enhancing public awareness and promoting proactive engagement in cardiovascular health. It empowers individuals to understand that the health of their cardiovascular system can diverge from their chronological age, influenced by their daily habits and genetic makeup. This understanding can serve as a strong motivator for adopting healthier behaviors, inform public health initiatives, and guide policies aimed at reducing the societal burden of cardiovascular disease.

Limitations

Methodological and Statistical Considerations

Studies on cardiovascular age, particularly those utilizing genome-wide association studies (GWAS), face inherent methodological and statistical constraints that influence the interpretation of findings. The moderate sample sizes in some cohorts, such as the Framingham Heart Study, can lead to limited statistical power, especially for detecting genetic effects that explain less than 4% of total phenotypic variation.^[1] Furthermore, the use of 100K Affymetrix GeneChips in earlier studies provided limited genomic coverage, potentially missing true associations with variants not present on the array or within targeted gene regions. ^[2] The extensive multiple testing inherent in GWAS also necessitates stringent significance thresholds, increasing the risk of both false positives and false negatives, and making replication in independent cohorts crucial but often challenging. ^[3] Indeed, a significant portion of previously reported phenotype-genotype associations have not been consistently replicated across studies, highlighting the need for further validation. ^[3]

An additional concern relates to potential cohort biases. For instance, the requirement for participants to survive long enough to provide DNA for genotyping may introduce a survival bias, meaning the genotyped sample could be healthier than the broader population. ^[4] Moreover, the moderate genotyping call rate threshold of 80% used in some analyses, while intended to be inclusive, might contribute to the reporting of less robust associations. ^[1]These factors collectively underscore the exploratory nature of some findings and the necessity for robust replication and deeper genomic exploration to confirm genetic associations with cardiovascular age.^[4]

Phenotype Assessment and Generalizability

The precise characterization of cardiovascular phenotypes and the generalizability of findings represent significant limitations in understanding cardiovascular age. Averaging echocardiographic traits over extended periods, sometimes spanning two decades, assumes a consistent genetic and environmental influence across a wide age range, which may not hold true and could mask age-dependent gene effects.^[1] Such long-term averaging also introduces potential misclassification due to evolving echocardiographic equipment over time. ^[1] While this strategy aims to reduce regression dilution bias, its application across diverse measurement periods and technologies warrants careful consideration. ^[1]

A major generalizability concern stems from the demographic composition of the study cohorts, which are predominantly white individuals of European descent. ^[1]This homogeneity means that the identified genetic associations and the overall understanding of cardiovascular age may not be directly applicable to individuals from other ethnic or racial backgrounds.^[1] The exclusion of non-European ancestry individuals in some analyses further limits the broader applicability of these findings to a diverse global population. ^[5]

Unexplored Genetic and Environmental Interactions

Current research often simplifies the complex interplay between genetics and environment, leading to remaining knowledge gaps in understanding cardiovascular age. Many studies, including those on cardiovascular age, have not undertaken investigations into gene-environment interactions or epistasis, which are crucial for a comprehensive understanding of complex traits.^[1] Genetic variants are known to influence phenotypes in a context-specific manner, with environmental factors potentially modulating their effects; for example, associations of ACE and AGTR2with left ventricular mass have been shown to vary with dietary salt intake.^[1] The omission of these interactions means that the full picture of how genetic predispositions manifest under different environmental conditions remains largely unexplored. ^[1]

While some cardiovascular phenotypes exhibit substantial heritability, the identified genetic variants often explain only a fraction of the total phenotypic variance, pointing to “missing heritability” and the need for further discovery.^[1]The current findings, while valuable, are often considered hypothesis-generating, indicating that much remains unknown about the complete network of genetic and environmental factors contributing to cardiovascular age. Future research incorporating detailed analyses of gene-environment interactions and epistasis will be essential to bridge these knowledge gaps and provide a more nuanced understanding of cardiovascular health and aging.^[4]

Variants

Genetic variations play a crucial role in determining an individual’s predisposition to cardiovascular diseases and influence the rate of cardiovascular aging. Several single nucleotide polymorphisms (SNPs) are associated with genes involved in fundamental cardiac functions, vascular integrity, and metabolic regulation. These variants offer insights into the complex genetic architecture underlying the aging of the cardiovascular system, which is an active area of research in large-scale genomic studies such as the Framingham Heart Study.^[4]

Variants impacting cardiac electrical activity and structural components are critical determinants of cardiovascular health. For instance, SNPsrs7373065 and rs6773331 are located within or near the SCN5A and SCN10A genes. SCN5Aencodes the alpha subunit of the cardiac sodium channel, which is essential for the initiation and propagation of electrical impulses in the heart. Variations inSCN5Acan alter cardiac excitability, predisposing individuals to various arrhythmias, including Brugada syndrome and long QT syndrome, thereby accelerating cardiovascular age through increased risk of sudden cardiac events.^[6] Similarly, the TTNgene encodes Titin, the largest known human protein, which is vital for the structural integrity and passive elasticity of cardiac and skeletal muscle. Variants likers11902709 and rs2042995 in or near TTN or its antisense RNA, TTN-AS1, could affect cardiac muscle function and elasticity, contributing to conditions like dilated cardiomyopathy and influencing the heart’s long-term ability to pump blood efficiently, thus impacting cardiovascular age.^[2] Furthermore, the ELN gene, often found near TMEM270, encodes elastin, a protein that provides elasticity to blood vessels. The rs7795735 variant in this region may influence arterial stiffness, a significant marker of vascular aging and a predictor of cardiovascular events.

Intracellular signaling pathways and cellular regulation are also influenced by genetic variants, with implications for cardiovascular aging. Thers35866366 variant in SIPA1L1 (Signal Induced Proliferation Associated 1 Like 1) is relevant as SIPA1L1is involved in Rho GTPase signaling, which regulates cell migration, adhesion, and cytoskeletal dynamics, processes crucial for vascular remodeling and the progression of atherosclerosis. Similarly,CAMK2D(Calcium/Calmodulin Dependent Protein Kinase II Delta) plays a pivotal role in calcium signaling, which is fundamental to cardiac contractility and the development of hypertrophy and arrhythmias. Thers35430511 variant in CAMK2Dcould modulate calcium handling or downstream signaling, affecting cardiac function and contributing to accelerated cardiovascular aging.^[2] Another important gene is PLCE1 (Phospholipase C Epsilon 1), involved in cell growth, differentiation, and inflammatory responses. The rs61886308 variant in PLCE1might influence vascular smooth muscle cell proliferation and endothelial function, thereby affecting the development of atherosclerosis and hypertension.^[7]

Other variants contribute to cardiovascular age through broader effects on metabolism, tissue development, or immune responses. Thers6901720 variant, located in the RNA5SP214 - VGLL2 region, involves VGLL2(Vestigial Like Family Member 2), a transcriptional co-factor implicated in muscle development. While direct links to adult cardiovascular aging are still being explored, developmental genes can have long-term effects on tissue maintenance and repair. TheAGAP5 gene (ArfGAP With SH3 Domain, Ankyrin Repeat And PH Domain 5), and its pseudogene BMS1P4, with variant rs147790633 , are involved in intracellular trafficking and signaling, potentially influencing lipid metabolism or cellular stress responses, which are key drivers of cardiovascular aging.^[5] Finally, DEFB136 (Defensin Beta 136), located near OR7E161P, is part of the defensin family, which contributes to innate immunity. Given that inflammation is a critical component of atherosclerosis and cardiovascular aging, thers4240678 variant could influence local inflammatory responses within the vasculature, contributing to arterial damage and accelerated biological age. ^[3]

Key Variants

RS ID	Gene	Related Traits
rs35866366	SIPA1L1	cardiovascular age measurement
rs35430511	CAMK2D	cardiovascular age measurement electrocardiography
rs6901720	RNA5SP214 - VGLL2	cardiovascular age measurement
rs7795735	TMEM270 - ELN	aortic measurement cardiovascular age measurement
rs7373065	SCN5A - SCN10A	atrial fibrillation T wave morphology measurement TPE interval measurement cardiovascular age measurement
rs147790633	BMS1P4-AGAP5, AGAP5	cardiovascular age measurement
rs61886308	PLCE1	cardiovascular age measurement
rs6773331	SCN5A	cardiovascular age measurement
rs4240678	OR7E161P - DEFB136	cardiovascular age measurement left ventricular systolic function measurement left ventricular ejection fraction measurement left ventricular function
rs11902709 rs2042995	TTN-AS1, TTN	acute myeloid leukemia cardiovascular age measurement QRS complex

Classification, Definition, and Terminology

Core Indicators of Cardiovascular Health

Cardiovascular age, conceptually, represents the cumulative impact of various physiological traits and risk factors on the cardiovascular system, reflecting its functional and structural integrity relative to chronological age. Key indicators defining cardiovascular health include precise measurements of blood pressure, such as systolic blood pressure (SBP) and diastolic blood pressure (DBP), with hypertension (HTN) defined clinically as SBP > 140 mmHg or DBP > 90 mmHg or being on treatment for high blood pressure.^[2]Body Mass Index (BMI), calculated as kilograms per square meter (kg m⁻²), serves as a fundamental anthropometric measure of body fat, a known determinant of cardiovascular health^[3]. ^[8]Furthermore, comprehensive lipid profiles, encompassing total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides (TG), along with their ratios (e.g., TC/HDL), provide critical insights into metabolic health and atherosclerotic risk^[3]. ^[8]

Beyond these fundamental measures, other significant factors contribute to the overall assessment of cardiovascular health. These include diabetes status, smoking habits (quantified by cigarettes per day), and specific hormonal influences such as menopausal status and hormone replacement therapy (HRT) in women.^[2]Lifestyle factors like alcohol intake are also considered. Echocardiographic dimensions, notably left ventricular (LV) mass and left atrial (LA) size, offer direct structural assessments of the heart, with measurements often categorized using height- and sex-specific reference limits to account for physiological variations.^[1] These diverse parameters are often adjusted for covariates like age and sex to derive normalized residuals for genetic analyses, effectively isolating the underlying biological trait from demographic influences ^[2]. ^[1]

Classification of Cardiovascular Conditions and Subclinical Atherosclerosis

The classification of cardiovascular conditions ranges from major clinical events to subclinical manifestations of atherosclerosis. Major coronary heart disease (CHD) events are categorized to include recognized myocardial infarction, coronary insufficiency, and death attributable to CHD.^[6]Expanding this, major atherosclerotic cardiovascular disease (CVD) events encompass major CHD events alongside atherothrombotic stroke.^[6]Specific cardiac conditions such as Heart Failure (HF) and Atrial Fibrillation (AF) are also distinct classifications of cardiovascular morbidity.^[6]

Subclinical atherosclerosis is classified through various imaging-based measures that quantify the extent of arterial damage before the onset of symptomatic disease. Coronary artery calcification (CAC) and abdominal aortic calcification (AAC) are assessed using multidetector Computed Tomography (MDCT) and indicate the presence and burden of calcified plaque in critical arterial territories.^[2] Carotid intimal medial thickness (IMT), including measurements from the common carotid artery, carotid artery bulb, and internal carotid artery, is another key classification, reflecting arterial wall thickness and early atherosclerotic changes. ^[2]The Ankle-Brachial Index (ABI) serves as a classification for peripheral arterial disease, indicating arterial stenosis or occlusion in the lower extremities.^[2]These classifications, often adjusted for age, sex, and other risk factors, provide a detailed dimensional approach to understanding the progression and severity of cardiovascular pathology.

Operational Definitions and Measurement Methodologies

Operational definitions and standardized measurement methodologies are crucial for consistent assessment of cardiovascular health indicators. Blood pressure is typically measured by trained nurses using a mercury sphygmomanometer following a standardized procedure, with the average of duplicate measures used as the trait value.^[8]For individuals on blood pressure medication, systolic blood pressure is adjusted by adding 15 mmHg and diastolic blood pressure by adding 10 mmHg to estimate unmedicated values^[8]. ^[2]BMI is calculated directly from height and weight measurements (kg m⁻²), while lipid traits like triglycerides (TG) and C-reactive protein (CRP) are often natural log-transformed for association analyses.^[8]

The diagnosis of major cardiovascular events relies on specific clinical criteria. Myocardial infarction is diagnosed by the presence of at least two out of three criteria: new diagnostic Q-waves on ECG, prolonged ischemic chest discomfort, and elevated serum biomarkers of myocardial necrosis.^[6]Heart failure diagnosis requires the presence of at least two major criteria (e.g., paroxysmal nocturnal dyspnea, pulmonary rales, distended jugular veins, enlarging heart size) or one major and two minor criteria.^[6]For subclinical atherosclerosis, CAC and AAC are quantified using a modified Agatston score, where a calcified lesion is defined as an area of at least three connected pixels with CT attenuation >130 Hounsfield Units.^[2] Carotid IMT measurements are performed using carotid ultrasonography with specific transducers (e.g., 7.5 MHz for common carotid artery), following standardized protocols. ^[2]

Key Terminology and Related Concepts in Cardiovascular Assessment

A precise terminology underpins the understanding and study of cardiovascular health. Key terms such as Hypertension (HTN), Body Mass Index (BMI), and various lipid components like Total Cholesterol (TC), High-Density Lipoprotein (HDL), Low-Density Lipoprotein (LDL), and Triglycerides (TG) form the vocabulary for metabolic and physiological risk factors.^[3]Terms related to subclinical atherosclerosis include Coronary Artery Calcification (CAC), Abdominal Aortic Calcification (AAC), Carotid Intimal Medial Thickness (IMT), and Ankle-Brachial Index (ABI), each representing a specific measure of arterial health.^[2] These terms are integral to assessing the structural integrity of the vasculature.

Clinical outcomes are described using terms such as Myocardial Infarction (MI), Heart Failure (HF), Atrial Fibrillation (AF), and Atherothrombotic Stroke, which denote specific disease endpoints.^[6]Related concepts like “treatment-adjusted systolic blood pressure” are used in research to account for the impact of medication on observed values, providing a more accurate reflection of the underlying physiological state.^[2]Standardized vocabularies and “previously published criteria” ensure consistency in diagnosis and measurement across studies, as exemplified by the Framingham Heart Study’s adjudication processes for cardiovascular events.^[6] For genetic analyses, phenotypes are often transformed into “sex-specific residuals” or “ranked normalized deviates” after covariate adjustment, allowing for the isolation of genetic effects on these complex traits ^[2]. ^[1]

Causes of Cardiovascular Age

Cardiovascular age, an indicator reflecting the cumulative impact of various factors on the health and function of the cardiovascular system, is influenced by a complex interplay of genetic predispositions, lifestyle choices, environmental exposures, and broader physiological conditions. Understanding these causes is crucial for developing strategies to maintain cardiovascular health and mitigate the risk of adverse outcomes.

Genetic Predisposition to Cardiovascular Traits

An individual’s cardiovascular age is significantly shaped by their inherited genetic makeup, which can influence susceptibility to various cardiovascular conditions and risk factors. Genome-wide association studies (GWAS) have identified numero For instance, echocardiographic dimensions, brachial artery endothelial function, and,.^[9] Specific genetic variants, such as rs10501920 in CNTN5, have been associated with atrial fibrillation and heart failure, while single nucleotide polymorphisms (SNPs) nearPHACTR1 (rs499818 , rs1512411 , rs507369 ) correlate with major CVD and coronary heart disease.^[6]

Beyond single genetic variants, polygenic risk, involving the cumulative effect of many common variants, plays a substantial role in conditions like dyslipidemia, where common variants at 30 loci contribute to the trait. ^[10]Newly identified loci also influence lipid concentrations and the risk of coronary artery disease^{[7], [10]}. ^[5] Additionally, cis-acting regulatory variants can influence the expression levels of genes, such as the CRPgene affecting C-reactive protein concentration, further contributing to individual differences in cardiovascular health.^[3]

Environmental and Lifestyle Influences

Environmental factors and lifestyle choices exert a profound influence on cardiovascular age by modulating key physiological processes and risk factors. Major contributors to cardiovascular risk include smoking, diabetes, elevated systolic blood pressure, and high total cholesterol levels^[6]. ^[11]Dietary habits also play a critical role, with studies exploring the impact of nutritional interventions, such as antioxidant vitamins and minerals, on cardiovascular disease prevention^[12]. ^[13]

Other significant lifestyle and environmental factors include body mass index (BMI), waist circumference, triglyceride levels, alcohol consumption, and exposure to various agents that can impact cardiovascular function.^[3]Socioeconomic factors and geographic influences, though not explicitly detailed in the provided context, often correlate with access to healthcare, dietary patterns, and exposure to environmental stressors, thereby indirectly affecting cardiovascular health. These modifiable factors highlight the potential for interventions to improve cardiovascular age.

Complex Gene-Environment Interactions

The interplay between an individual’s genetic predisposition and their environment significantly shapes cardiovascular age, often in a context-specific manner. Genetic variants may influence phenotypes differently depending on environmental exposures, mean For example, the associations of genes likeACE and AGTR2with left ventricular mass have been reported to var

Furthermore, genetic effects can be age-dependent, meaning This dynamic interaction suggests that a person’s cardiovascular trajectory is not solely determined at birth but is a continuous process influenced by how their genes respond to accumulated environmental exposures over time. Understanding these complex interactions is crucial for personalized prevention and treatment strategies.

Comorbidities and Age-Related Physiological Changes

Beyond genetic and environmental factors, existing health conditions and the natural process of aging contribute significantly to cardiovascular age. Comorbidities such as diabetes and hypertension are well-established risk factors that accelerate cardiovascular aging by placing chronic stress on the heart and blood vessels.^[6]The presence and management of these conditions, often involving anti-hypertensive or lipid-lowering therapies, directly impact cardiovascular health outcomes^[6]. ^[3]

The physiological changes associated with chronological aging also play a direct role in advancing cardiovascular age, independent of other factors. As individuals age, changes in vascular elasticity, myocardial function, and the accumulation of subclinical atherosclerosis, such as coronary artery and aortic calcification, contribute to a less efficient cardiovascular system.^[14]Research into the mechanisms responsible for aging aims to identify pathways for health promotion in middle-aged and older adults, with the goal of extending healthy cardiovascular function.^[4]

Biological Background

Genetic Influences on Cardiovascular Health

Cardiovascular health is profoundly shaped by an individual’s genetic makeup, with numerous genetic variants contributing to the risk and progression of cardiovascular diseases. Genome-wide association studies (GWAS) are instrumental in identifying specific genetic loci that exert modest yet significant influences on complex cardiovascular traits.^[1]These studies leverage extensive genotype data, such as that from the Framingham Heart Study, to explore the genetic underpinnings of phenotypes like left ventricular remodeling, endothelial function, and exercise performance.^[1]Such research generates hypotheses regarding novel biological pathways that contribute to longevity and healthy aging.^[4]

Genetic mechanisms play a critical role in regulating key cardiovascular risk factors, notably lipid concentrations. Common variants found at approximately 30 loci are known to contribute to polygenic dyslipidemia, influencing levels of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides.^[10]For instance, specific single nucleotide polymorphisms (SNPs) in theHMGCR gene, which encodes HMG-CoA reductase, have been associated with LDL-C levels and affect the alternative splicing of exon 13. ^[15] Furthermore, alleles of the PCSK9gene are convincingly associated with cardiovascular disease risk, highlighting the importance of genetic targets in disease prevention.^[10]

Molecular and Cellular Regulation of Vascular Function

The intricate balance of molecular and cellular pathways is essential for maintaining vascular homeostasis and preventing premature cardiovascular aging. Lipid metabolism is a central process, where critical biomolecules such as LDL-C, HDL-C, and triglycerides are tightly regulated, with their concentrations serving as widely applied predictors for cardiovascular diseases.^[7]Genetic risk profiles, influenced by genes affecting these lipid levels, can explain a significant proportion of their variance, comparable to traditional risk factors like body mass index.^[5]Disruptions in these metabolic processes, often driven by genetic predispositions, can lead to conditions like dyslipidemia which accelerate cardiovascular decline.^[10]

Beyond lipid metabolism, cellular functions like endothelial health and cardiac electrical activity are crucial. Brachial artery endothelial function, a measure of vascular health, is a heritable trait linked to specific genetic loci. ^[1]Endothelial dysfunction is an early indicator of vascular damage, contributing to arterial stiffness and the development of atherosclerosis.^[1]Similarly, cardiac repolarization, the electrical recovery of the heart muscle, is influenced by genetic variants, such as those found in theNOS1AP (CAPON) gene. ^[14]These molecular and cellular mechanisms are interconnected, with their proper functioning vital for overall cardiovascular integrity.

Pathophysiological Processes of Cardiovascular Aging

Cardiovascular aging is characterized by a series of pathophysiological processes that gradually compromise the structure and function of the heart and blood vessels. A primary mechanism is atherosclerosis, a disease characterized by the buildup of plaque in the arteries. Subclinical atherosclerosis can be quantified by measures such as carotid artery intima-media thickness (IMT), abdominal aortic calcification (AAC), and coronary artery calcification (CAC).^[2]These calcific deposits and arterial thickening are significant risk factors for myocardial infarction and stroke, and are strong predictors of vascular morbidity and mortality.^[2]

Another critical pathophysiological process is left ventricular (LV) remodeling, which involves changes in the heart’s size, shape, and function. Echocardiographic dimensions, including LV mass (LVM), LV wall thickness (LVWT), LV diastolic diameter (LVDD), and LV systolic diameter (LVSD), are heritable traits that reflect these changes and are associated with cardiovascular disease outcomes.^[1]These structural alterations can lead to impaired cardiac function and contribute to conditions like congestive heart failure.^[1]Systemic factors such as hypertension and diabetes significantly exacerbate these processes, highlighting the complex interplay between metabolic health and cardiovascular deterioration.^[2]

Systemic Consequences and Biomarkers of Cardiovascular Disease

The impact of cardiovascular aging extends systemically, affecting various organs and manifesting through measurable biomarkers that reflect overall disease burden. Dyslipidemia, characterized by abnormal lipid levels, is a major systemic risk factor that broadly influences cardiovascular health and disease progression.^[10]Similarly, chronic hypertension and diabetes are profound systemic disruptions that accelerate vascular damage, contributing to the development of atherosclerosis and other cardiovascular complications.^[2]Understanding these systemic consequences is crucial for developing targeted interventions to promote healthy aging.

Biomolecules serve as vital indicators of cardiovascular health and disease. For example, brain natriuretic peptide (BNP) and C-reactive protein (CRP) are biomarkers whose concentrations can be influenced by cis-acting regulatory variants in their respective genes.^[3]Elevated levels of these and other biomarkers, alongside lipid profiles, provide insights into the systemic inflammatory state and cardiac strain, which are integral to assessing cardiovascular age and risk.^[3]The ankle-brachial index (ABI) is another systemic measure, reflecting peripheral artery disease and serving as a predictor of future cardiovascular outcomes.^[2]These systemic markers collectively offer a comprehensive view of an individual’s cardiovascular health status and their trajectory of aging.

Pathways and Mechanisms

Lipid Metabolism and Dyslipidemia

Cardiovascular age is significantly influenced by the regulation of lipid metabolism, where imbalances can lead to dyslipidemia and accelerate atherosclerotic processes. Key metabolic pathways involve the synthesis, transport, and catabolism of lipoproteins, which are tightly controlled by various genetic and molecular mechanisms. For instance, common genetic variants in theHMGCRgene, which encodes 3-hydroxy-3-methylglutaryl-CoA reductase—a rate-limiting enzyme in cholesterol biosynthesis—have been shown to affect alternative splicing of exon 13, thereby influencing low-density lipoprotein cholesterol (LDL-C) levels.^[15]This post-transcriptional regulatory mechanism directly impacts the availability and activity of a crucial enzyme, highlighting how gene regulation can fine-tune metabolic flux critical for cardiovascular health.

Beyond synthesis, the catabolism and clearance of lipids are equally vital, involving proteins like sortilin/neurotensin receptor-3 (SORT1). This receptor is implicated in binding and mediating the degradation of lipoprotein lipase, an enzyme essential for hydrolyzing triglycerides in circulating lipoproteins.^[7]Dysregulation in such catabolic pathways can lead to elevated triglyceride levels, a known risk factor for cardiovascular disease.^[7]Furthermore, the microsomal triglyceride transfer protein (MTP), involved in the assembly of lipoproteins, has been investigated for its potential role in human lifespan, although some studies indicate no direct association between its haplotypes and longevity. ^[4]Collectively, these detailed metabolic and regulatory mechanisms underscore the complex interplay determining lipid profiles, which are central to an individual’s cardiovascular age.

Cellular Signaling and Vascular Homeostasis

The maintenance of vascular homeostasis and proper cardiac function, critical determinants of cardiovascular age, relies on intricate cellular signaling pathways and regulatory mechanisms. Receptor activation initiates intracellular signaling cascades that orchestrate cellular responses, such as those involving nitric oxide synthase 1 adaptor protein (NOS1AP). Genetic variants in NOS1AP have been shown to modulate cardiac repolarization, a fundamental electrical process of the heart, indicating its role in maintaining cardiac rhythm and potentially influencing arrhythmogenic risk. ^[2] This exemplifies how specific protein interactions within signaling networks can have profound effects on the heart’s electrical stability.

Furthermore, the vascular system is subject to complex hormonal and paracrine regulation. For instance, angiotensin II can antagonize cGMP signaling in vascular smooth muscle cells, influencing vascular tone and structure.^[1]This pathway crosstalk between the renin-angiotensin system and nitric oxide-cGMP pathway is crucial for blood pressure regulation and endothelial function, with dysregulation contributing to hypertension and arterial stiffness, hallmarks of accelerated cardiovascular aging.^[1]These regulatory interactions at the cellular level, along with their impact on global physiological parameters like blood pressure and endothelial health, collectively contribute to the structural and functional integrity of the cardiovascular system over time.

Metabolic Regulation and Longevity Pathways

Beyond immediate lipid regulation, broader metabolic regulatory mechanisms and pathways linked to longevity significantly impact cardiovascular age by influencing cellular resilience and overall systemic health. TheSIRT3 gene, a human homologue of the silent information regulator Sir2, has been associated with survivorship in the elderly, suggesting its role in mitochondrial function, energy metabolism, and stress response pathways. ^[4]Similarly, reduced insulin/IGF-1 signaling has been linked to human longevity, indicating a conserved pathway that influences metabolic regulation and cellular aging processes.^[4] These pathways often involve intricate feedback loops and post-translational modifications, such as deacetylation by sirtuins, that modulate enzyme activity and transcription factor regulation, thereby affecting metabolic flux and cellular lifespan.

Endocrine systems also exert pervasive control over cardiovascular aging through their influence on metabolic and physiological processes. Thyroid dysfunction, for example, has been associated with total cholesterol levels in older populations, demonstrating a direct link between hormonal balance and lipid profiles.^[16]Endogenous sex hormones are likewise known to affect cardiovascular disease incidence in men, highlighting their regulatory role in maintaining cardiovascular health.^[16]Furthermore, elevated serum uric acid levels, influenced by genetic factors, are associated with various metabolic and cardiovascular conditions, acting as a biomarker and potentially a mediator of cardiovascular risk.^[16]The complex interplay of these endocrine and metabolic pathways represents a hierarchical regulation system whose integrity is vital for healthy cardiovascular aging.

Systemic Biomarkers and Disease Progression

The progression of cardiovascular age is characterized by the dysregulation of various systemic pathways, leading to the accumulation of damage and the manifestation of disease-relevant mechanisms. Inflammatory markers, such as C-reactive protein (CRP), are strongly predictive of incident stroke, coronary heart disease, and all-cause mortality, indicating that chronic low-grade inflammation is a central component of accelerated cardiovascular aging.^[3]These inflammatory cascades involve complex network interactions and can be triggered by diverse stimuli, contributing to endothelial dysfunction and the development of atherosclerosis, a key mechanism of vascular aging.^[2]

Beyond inflammation, other systemic biomarkers provide insights into the emergent properties of cardiovascular aging and potential therapeutic targets. Natriuretic peptides, hepatic function markers, and vitamin levels have all been linked to cardiovascular disease risk and mortality, reflecting the widespread systemic impact of aging on organ function.^[3]For instance, mechanisms of matrix accumulation and glomerulosclerosis observed in hypertension illustrate how chronic stress and dysregulation in one system (renal) can contribute to broader cardiovascular pathology.^[16]The identification of such biomarkers and their underlying pathway dysregulations offers opportunities for early intervention and the development of personalized therapeutic strategies aimed at mitigating the progression of cardiovascular age.

Clinical Relevance

Understanding an individual’s “cardiovascular age” provides crucial insights into their cardiovascular health beyond chronological age, offering a more nuanced perspective on disease risk and progression. This concept integrates various physiological and anatomical markers, alongside genetic predispositions and traditional risk factors, to offer a comprehensive assessment for clinical decision-making.

Prognostic Indicators of Cardiovascular Morbidity and Mortality

Various markers contribute significantly to determining an individual’s cardiovascular age and predicting future adverse events. Subclinical atherosclerosis, evidenced by coronary artery calcification (CAC) and abdominal aortic calcification (AAC), has been identified as a strong predictor of vascular morbidity and mortality.^[17]Similarly, carotid artery intima-media thickness (IMT) serves as a risk factor for myocardial infarction and stroke in older adults.^[18]The ankle-brachial index (ABI) also demonstrates sensitivity and specificity in predicting future cardiovascular outcomes.^[19]

Beyond arterial health, cardiac structural changes, such as left ventricular mass, are significant predictors of stroke risk in elderly cohorts.^[20]Echocardiographic measurements further provide prognostic value, predicting the six- to seven-year incidence of coronary heart disease, stroke, congestive heart failure, and mortality.^[21]These markers collectively contribute to a more accurate estimation of an individual’s cardiovascular risk, highlighting their utility in identifying patients at higher likelihood of developing severe cardiovascular disease or experiencing adverse outcomes.

Advancing Risk Stratification and Personalized Prevention Strategies

The assessment of cardiovascular age enhances conventional risk stratification by integrating advanced markers and genetic insights, moving towards a more personalized medicine approach. Biomarkers, including inflammatory markers like C-reactive protein (CRP), natriuretic peptides, and indicators of hepatic function, have been linked to an increased risk of cardiovascular disease and mortality, withCRPspecifically predicting incident stroke, coronary heart disease, and all-cause mortality.^[3] These biomarkers can help risk-stratify individuals for prognosis and potential intervention, aligning with the goal of “predictive, preemptive, personalized medicine”. ^[3]

Genetic risk profiles, particularly those related to lipid levels, offer an improved prediction of conditions like hypercholesterolemia and coronary heart disease beyond traditional factors such as age, sex, and body mass index.^[5]For instance, a total cholesterol (TC) genetic risk score has been significantly associated with intima media thickness (IMT) and improved the prediction of hypercholesterolemia.^[5]Such genetic insights facilitate the early detection of dyslipidemias and related cardiovascular risks, enabling the implementation of targeted preventive strategies for high-risk groups.^[5]

Diagnostic Utility and Therapeutic Guidance in Cardiovascular Care

The comprehensive evaluation of cardiovascular age extends its clinical utility into diagnostic assessment and guiding therapeutic interventions. The various subclinical atherosclerosis measures and cardiac remodeling indicators serve not only as prognostic tools but also as diagnostic aids, helping to characterize the extent of cardiovascular disease burden in asymptomatic individuals. This diagnostic utility is particularly relevant when considering the impact of traditional cardiovascular risk factors such as high blood pressure, diabetes, obesity, and dyslipidemia, all of which are frequently adjusted for in studies evaluating cardiovascular health markers.^[1]

Furthermore, understanding cardiovascular age can inform treatment selection and monitoring strategies. For example, studies have compared different therapeutic approaches, such as calcium antagonists versus diuretics and beta-blockers, for their effects on cardiovascular morbidity and mortality in hypertension.^[10]The integration of advanced cardiovascular markers into clinical practice allows for more precise monitoring of disease progression and the effectiveness of interventions, ensuring that treatment plans are tailored to an individual’s specific cardiovascular risk profile and disease trajectory.

References

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[4] Lunetta KL et al. “Genetic correlates of longevity and selected age-related phenotypes: a genome-wide association study in the Framingham Study.” BMC Med Genet, 2007.

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[10] Kathiresan S et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, 2008.

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